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Sample records for antiangiogenic therapy implications

  1. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

    Nielsen, D.L.; Andersson, M.; Andersen, Jon Alexander Lykkegaard

    2010-01-01

    and optimal use of these agents for the treatment of breast cancer. Currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Small molecular inhibitors of VEGF...... tyrosine kinase activity, such as sorafenib, appear promising. While, the role of sunitinib and inhibitors of mammalian target of rapamycin (mTOR) in breast cancer has to be defined. Several unanswered questions remain, such as choice of drug(s), optimal duration of therapy and patient selection criteria......ABSTRACT: Angiogenesis is an important component of cancer growth, invasion and metastasis. Therefore, inhibition of angiogenesis is an attractive strategy for treatment of cancer. We describe existing clinical trials of antiangiogenic agents and the challenges facing the clinical development...

  2. Reappraising antiangiogenic therapy for breast cancer.

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    Kerbel, Robert S

    2011-10-01

    Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used with various conventional chemotherapy regimens, or have failed altogether, e.g. the small molecule oral tyrosine kinase inhibitor (TKI) sunitinib. No phase III trial has yet demonstrated an overall survival benefit and the progression free survival (PFS) benefits, when attained with bevacizumab are short, with perhaps one exception. Together, these results call for a reappraisal of using antiangiogenic drugs for breast cancer and possible strategies to improve their efficacy. Among the reasons to help explain the limited benefits observed thus far include the possibility that angiogenesis may not be a major driver of breast cancer growth, compared to some other types of cancer; that acquired resistance may develop rapidly to VEGF-pathway targeting antiangiogenic drugs, in part due to angiogenic growth factor redundancy; that optimal chemotherapy regimens have not been used in conjunction with an antiangiogenic drug; and that antiangiogenic drugs may secondarily aggravate biologic aggressiveness of the tumors, thereby reducing their overall efficacy after inducing an initial benefit. Several possible strategies are discussed for improving the efficacy of antiangiogenic drugs, including combination with different chemotherapy regimens, e.g. long term and less toxic metronomic chemotherapy protocols; validation of predictive biomarkers to individualize patient therapy; development of improved preclinical therapy models, e.g. involving advanced metastatic breast cancer, and combination with other types of anti-cancer agents especially biologies such as trastuzumab for Her2-positive breast cancer. Reasons for the current concern regarding use of antiangiogenic drug treatments for early stage cancers, including breast cancer, are also discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

    Nielsen, D.L.; Andersson, M.; Andersen, Jon Alexander Lykkegaard

    2010-01-01

    and optimal use of these agents for the treatment of breast cancer. Currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Small molecular inhibitors of VEGF...... tyrosine kinase activity, such as sorafenib, appear promising. While, the role of sunitinib and inhibitors of mammalian target of rapamycin (mTOR) in breast cancer has to be defined. Several unanswered questions remain, such as choice of drug(s), optimal duration of therapy and patient selection criteria...

  4. New perspectives in glioblastoma antiangiogenic therapy

    Directory of Open Access Journals (Sweden)

    Alisa Madalina Popescu

    2015-12-01

    Full Text Available Glioblastoma (GB is highly vascularised tumour, known to exhibit enhanced infiltrative potential. One of the characteristics of glioblastoma is microvascular proliferation surrounding necrotic areas, as a response to a hypoxic environment, which in turn increases the expression of angiogenic factors and their signalling pathways (RAS/RAF/ERK/MAPK pathway, PI3K/Akt signalling pathway and WTN signalling cascade. Currently, a small number of anti-angiogenic drugs, extending glioblastoma patients survival, are available for clinical use. Most medications are ineffective in clinical therapy of glioblastoma due to acquired malignant cells or intrinsic resistance, angiogenic receptors cross-activation and redundant intracellular signalling, or the inability of the drug to cross the blood-brain barrier and to reach its target in vivo . Researchers have also observed that GB tumours are different in many aspects, even when they derive from the same tissue, which is the reason for personalised therapy. An understanding of the molecular mechanisms regulating glioblastoma angiogenesis and invasion may be important in the future development of curative therapeutic approaches for the treatment of this devastating disease.

  5. NMR with Combined Antiangiogenic and Radiation Therapies - Breast Cancer

    National Research Council Canada - National Science Library

    Brown, Stephen

    2000-01-01

    The original goal of the present study was to determine optimal strategies for combining radiation and antiangiogenic therapies in spontaneous murine tumors and to evaluate the potential of Nuclear Magnetic Resonance (NMR...

  6. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

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    Mauricio P. Pinto

    2016-09-01

    Full Text Available Tumor angiogenesis is widely recognized as one of the “hallmarks of cancer”. Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1 upregulation of compensatory/alternative pathways for angiogenesis; (2 vasculogenic mimicry; and (3 vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses.

  7. Antiangiogenic therapies in urogenital malignancies: Fiction or fact?

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    Haidl, Friederike; Pfister, David; Heidenreich, Axel; Heidegger, Isabel

    2017-01-01

    The use of antiangiogenic agents in cancer therapy has become an attractive target in oncological research. However, concerning the uro-oncological field, current guidelines only recommend the use of antiangiogenic agents in metastatic renal cell cancer. Yet in recent years, several approaches for sequential treatment with angiogenesis inhibitors in other urogenital malignancies apart from renal cell cancer are ongoing. Thus, the present review article aims to provide an overview about clinical studies with antiangiogenic agents in prostate-, bladder-, testicular-, as well as penile cancer patients. For this, a literature search was conducted using Medline; moreover we performed a systematic review of data presented at this year's important urooncological meetings. Preliminary data revealed that there are several promising studies ongoing in prostate-, bladder-, testicular-, as well as penile cancer; however, larger studies should be conducted to optimize the use of antiangiogenic agents in clinical practice.

  8. Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies

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    Pircher, Andreas; Jöhrer, Karin; Kocher, Florian; Steiner, Normann; Graziadei, Ivo; Heidegger, Isabel; Pichler, Renate; Leonhartsberger, Nicolai; Kremser, Christian; Kern, Johann; Untergasser, Gerold; Gunsilius, Eberhard; Hilbe, Wolfgang

    2016-01-01

    Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development. PMID:26956051

  9. Novel concepts of antiangiogenic therapies in metastatic renal cell cancer.

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    Pichler, Renate; Heidegger, Isabel

    2017-01-01

    The era of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway has become a mainstay in the treatment of metastatic renal cell carcinoma (mRCC), showing primary responses in 65-70% of patients. Nevertheless, most of those patients progress to angiogenesis inhibitors over time due to different modes of resistance (adaptive and intrinsic). Both in vitro and in vivo analyses provided evidence that PD-L1 upregulation in hypoxia conditions is dependent on hypoxia-inducible factor (HIF)-2alpha and is associated with an overexpression of VEGF. Thus, additional blockade of PD-L1 along with inhibition of angiogenesis pathways seems to represent a novel and innovative treatment concept in mRCC. In this short review, we provide an overview on ongoing phase III trials combining antiangiogenic therapies with checkpoint inhibitors in the first-line setting. Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action. In addition, response and resistance hypotheses and biomarkers to antiangiogenic therapy in clinical practice are critically discussed.

  10. Progress on Antiangiogenic Therapy for Patients with Malignant Glioma

    Directory of Open Access Journals (Sweden)

    Manmeet S. Ahluwalia

    2010-01-01

    Full Text Available Glioblastoma (GBM is the most common primary brain tumor occurring in America. Despite recent advances in therapeutics, the prognosis for patients with newly diagnosed GBM remains dismal. As these tumors characteristically show evidence of angiogenesis (neovascularization there has been great interest in developing anti-angiogenic therapeutic strategies for the treatment of patients with this disease and some anti-angiogenic agents have now been used for the treatment of patients with malignant glioma tumors. Although the results of these clinical trials are promising in that they indicate an initial therapeutic response, the anti-angiogenic therapies tested to date have not changed the overall survival of patients with malignant glioma tumors. This is due, in large part, to the development of resistance to these therapies. Ongoing research into key features of the neovasculature in malignant glioma tumors, as well as the general angiogenesis process, is suggesting additional molecules that may be targeted and an improved response when both the neovasculature and the tumor cells are targeted. Prevention of the development of resistance may require the development of anti-angiogenic strategies that induce apoptosis or cell death of the neovasculature, as well as an improved understanding of the potential roles of circulating endothelial progenitor cells and vascular co-option by tumor cells, in the development of resistance.

  11. Biomarkers in Tumor Angiogenesis and Anti-Angiogenic Therapy

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    Pircher, Andreas; Hilbe, Wolfgang; Heidegger, Isabel; Drevs, Joachim; Tichelli, André; Medinger, Michael

    2011-01-01

    Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies. PMID:22072937

  12. Perforated Gastric Ulcer Associated with Anti-Angiogenic Therapy

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    Diogo Libânio

    2017-08-01

    Full Text Available Anti-angiogenic therapy with bevacizumab, an inhibitor of vascular endothelial growth factor, is commonly used in metastatic colorectal cancer and is rarely associated with gastrointestinal perforation, perforation being more frequent in the primary tumor site or at the anastomotic level. We present the case of a 64-year-old male with stage IV rectal adenocarcinoma who was on palliative chemotherapy with FOLFOX and bevacizumab. After the 4th chemotherapy cycle, our patient started fever and epigastric pain. He was hemodynamically stable, and signs of peritoneal irritation were absent. There were no alterations in the abdominal X-ray, and C-reactive protein was markedly elevated. A CT scan revealed a de novo thickness in the gastric antrum. Upper digestive endoscopy showed an ulcerated 40-mm lesion in the angulus, with a 20-mm orifice communicating with an exsudative cavity revested by the omentum. A conservative approach was decided including fasting, broad-spectrum intravenous antibiotics, and proton-pump inhibitors. Subsequent gastroduodenal series showed no contrast extravasation, allowing the resumption of oral nutrition. Esophagogastroduodenoscopy after 8 weeks showed perforation closure. Biopsies did not show neoplastic cells or Heliobacter pylori infection. Although the success in the conservative management of perforation allowing the maintenance of palliative chemotherapy (without bevacizumab, the patient died after 4 months due to liver failure. The reported case shows an uncommon endoscopic finding due to a rare complication of anti-angiogenic therapy. Additionally, it reminds clinicians that a history of gastroduodenal ulcers should be actively sought before starting anti-angiogenic treatment and that suspicion for perforation should be high in these cases.

  13. Anti-angiogenic therapy and radioimmunotherapy in colon cancer xenografts

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    Kinuya, Seigo; Yokoyama, Kunihiko; Michigishi, Takatoshi; Tonami, Norihisa [Dept. of Nuclear Medicine, Kanazawa Univ. (Japan); Kawashima, Atsuhiro [Dept. of Pathology (I), Kanazawa Univ. School of Medicine, Kanazawa, Ishikawa (Japan); Kudo, Miho; Kasahara, Yoshihito [Dept. of Pediatrics, Kanazawa University School of Medicine, Kanazawa, Ishikawa (Japan); Watanabe, Naoto [Dept. of Radiology, Toyama Medical and Pharmaceutical University, Toyama (Japan); Shuke, Noriyuki [Dept. of Radiology, Asahikawa Medical College, Asahikawa (Japan); Bunko, Hisashi [Medical Informatics, Kanazawa University Hospital, Kanazawa (Japan)

    2001-09-01

    Angiogenesis is critical to the growth and metastatic process of malignant tumors. An endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), displays anti-angiogenic and anti-tumorigenic effects. The purpose of this investigation was to determine whether exogenously administered 2-ME would enhance the efficacy of radioimmunotherapy (RIT). Experimental RIT with 4.63 MBq of {sup 131}I-A7, an IgG1 anti-colorectal monoclonal antibody, was conducted in mice xenografted with LS180 human colon cancer cells. 2-ME suspended in 0.5% carboxymethylcellulose was administered daily at a dose of 75 mg/kg per day. 2-ME administration suppressed tumor growth and improved the efficacy of RIT in comparison to RIT alone. Tumor volumes on day 13, expressed as a ratio relative to the initial volume, were 12.7{+-}2.95 in the nontreated control, 4.73{+-}0.89 with 2-ME, 3.05{+-}0.37 with RIT and 0.97{+-}0.20 with RIT+2-ME. Immunohistochemistry of tumor sections stained with an antibody against factor VIII demonstrated a decrease in microvessel number within tumors treated with 2-ME (7.9{+-}0.8/200 x field) as compared with that in control tumors (29.9{+-}2.5). Cell proliferation assay at increasing concentrations of 2-ME showed direct cytotoxicity of 2-ME in vitro at 5 {mu}M and greater. In conclusion, 2-ME enhanced the efficacy of RIT with {sup 131}I-A7 via inhibition of angiogenesis within the xenografts. The direct cytotoxicity of 2-ME appears to have contributed to this improvement. Anti-angiogenic therapy may prolong the dormancy of microscopic metastases while RIT may exterminate this population of cells. Therefore, the combined treatment may improve the therapeutic outcome of patients with disseminated cancer. (orig.)

  14. Tumor Oxygen Dynamics as a Prognostic Indicator of Effective Antiangiogenic Therapy

    National Research Council Canada - National Science Library

    Zhao, Dawen

    2003-01-01

    ...: so called angiogenesis. One major goal of this project is to fully understand and precisely assess the dynamic changes in blood perfusion and oxygenation, both during normal growth and following anti-angiogenic therapy...

  15. Tumor Oxygen Dynamics as a Prognostic Indicator of Effective Antiangiogenic Therapy

    National Research Council Canada - National Science Library

    Zhao, Dawen

    2002-01-01

    ...: so called angiogenesis. One major goal of this project is to fully understand and precisely assess the dynamic changes in blood perfusion and oxygenation, both during normal growth and following anti-angiogenic therapy...

  16. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Laura Pisarsky

    2016-05-01

    Full Text Available Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.

  17. Do not say ever never more: the ins and outs of antiangiogenic therapies.

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    Quesada, Ana R; Medina, Miguel Ángel; Muñoz-Chápuli, Ramón; Ponce, Ángel Luis G

    2010-01-01

    Angiogenesis has been described as one of the hallmarks of cancer, playing an essential role in tumor growth, invasion, and metastasis. Antiangiogenic therapy was initially perceived as a "magic bullet" that could eventually be used for the treatment of any type of cancer. For this reason inhibition of angiogenesis has become a major challenge in the development of new anticancer agents, with a countless number of antiangiogenic strategies being tested in preclinical and clinical trials. The initial pessimism about the usefulness of the antiangiogenic therapeutic approach for cancer, derived from the poor results obtained in clinical trials, turned into euphoria after the approvals of the anti-VEGF monoclonal antibody bevacizumab and the multitargeted tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib. Nowadays the clinical development of antiangiogenic therapies seems to be unstoppable, not only for cancer, but also for an increasing number of non-neoplasic angiogenesis-related diseases. Nevertheless, careful analysis of the clinical results reveals that therapy with angiogenesis inhibitors often does not prolong survival of cancer patients for more than months. This fact, combined with the high prices of the new antiangiogenic therapies have made a number of oncologists to doubt if they offer "good value". Moreover, recent experimental findings suggest that some antiangiogenic drugs could promote tumor invasiveness and metastasis. The success in the discovery and pharmacological development of future generations of angiogenesis inhibitors will benefit from further advances in the understanding of the mechanisms involved in human angiogenesis.

  18. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

    OpenAIRE

    Pisarsky Laura; Bill Ruben; Fagiani Ernesta; Dimeloe Sarah; Goosen Ryan William; Hagmann Jorg; Hess Christoph; Christofori Gerhard

    2016-01-01

    Summary Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and?sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward...

  19. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality.

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    McIntyre, Alan; Harris, Adrian L

    2015-04-01

    Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6-8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table 1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  20. Antiangiogenic Metargidin Peptide (AMEP) Gene Therapy in Disseminated Melanoma

    DEFF Research Database (Denmark)

    Spanggaard, Iben; Gehl, Julie

    2015-01-01

    Gene delivery by electroporation is an efficient method for transfecting genes into various tissues including tumors. Here we present the treatment protocol used in a phase 1 study on gene electrotransfer of plasmid DNA encoding an antiangiogenic peptide into cutaneous melanoma....

  1. The role of tumor microenvironment in resistance to anti-angiogenic therapy

    Science.gov (United States)

    Ma, Shaolin; Pradeep, Sunila; Hu, Wei; Zhang, Dikai; Coleman, Robert; Sood, Anil

    2018-01-01

    Anti-angiogenic therapy has been demonstrated to increase progression-free survival in patients with many different solid cancers. Unfortunately, the benefit in overall survival is modest and the rapid emergence of drug resistance is a significant clinical problem. Over the last decade, several mechanisms have been identified to decipher the emergence of resistance. There is a multitude of changes within the tumor microenvironment (TME) in response to anti-angiogenic therapy that offers new therapeutic opportunities. In this review, we compile results from contemporary studies related to adaptive changes in the TME in the development of resistance to anti-angiogenic therapy. These include preclinical models of emerging resistance, dynamic changes in hypoxia signaling and stromal cells during treatment, and novel strategies to overcome resistance by targeting the TME. PMID:29560266

  2. Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer.

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    Yoojoo Lim

    Full Text Available Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear.Tumor attenuation as measured by Hounsfield units (HU in contrast-enhanced computed tomography (CT and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80 treated with regorafenib in a prospective study.141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%-20.7%. Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson's r = 0.37, p = 0.002. Among 53 patients with lung metastases, 17 (32.1% developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50 and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13.Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies.

  3. Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer

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    Yoon, Jeong Hee; Lee, Jeong Min; Lee, Jung Min; Paeng, Jin Chul; Won, Jae-Kyung; Kang, Gyeong Hoon; Jeong, Seung-Yong; Park, Kyu Joo; Lee, Kyung-Hun; Kim, Jee Hyun; Kim, Tae-You

    2015-01-01

    Background Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear. Methods Tumor attenuation as measured by Hounsfield units (HU) in contrast-enhanced computed tomography (CT) and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80) treated with regorafenib in a prospective study. Results 141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%–20.7%). Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson’s r = 0.37, p = 0.002). Among 53 patients with lung metastases, 17 (32.1%) developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD) according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50) and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13). Conclusion Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies. PMID:26671465

  4. Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy.

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    Zhang, Li; Takara, Kazuhiro; Yamakawa, Daishi; Kidoya, Hiroyasu; Takakura, Nobuyuki

    2016-01-01

    Antiangiogenic agents transiently normalize tumor vessel structure and improve vessel function, thereby providing a window of opportunity for enhancing the efficacy of chemotherapy or radiotherapy. Currently, there are no reliable predictors or markers reflecting this vessel normalization window during antiangiogenic therapy. Apelin, the expression of which is regulated by hypoxia, and which has well-described roles in tumor progression, is an easily measured secreted protein. Here, we show that apelin can be used as a marker for the vessel normalization window during antiangiogenic therapy. Mice bearing s.c. tumors resulting from inoculation of the colon adenocarcinoma cell line HT29 were treated with a single injection of bevacizumab, a mAb neutralizing vascular endothelial growth factor. Tumor growth, vessel density, pericyte coverage, tumor hypoxia, and small molecule delivery were determined at four different times after treatment with bevacizumab (days 1, 3, 5, and 8). Tumor growth and vessel density were significantly reduced after bevacizumab treatment, which also significantly increased tumor vessel maturity, and improved tumor hypoxia and small molecule delivery between days 3 and 5. These effects abated by day 8, suggesting that a time window for vessel normalization was opened between days 3 and 5 during bevacizumab treatment in this model. Apelin mRNA expression and plasma apelin levels decreased transiently at day 5 post-treatment, coinciding with vessel normalization. Thus, apelin is a potential indicator of the vessel normalization window during antiangiogenic therapy. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  5. Blood-Based Biomarkers for the Optimization of Anti-Angiogenic Therapies

    Directory of Open Access Journals (Sweden)

    Cristina Rabascio

    2010-05-01

    Full Text Available The dependence of tumor growth and metastasis on blood vessels makes tumor angiogenesis a rational target for therapy. Strategies have been pursued to inhibit neovascularization and to destroy existing tumor vessels, or both. These include direct targeting of endothelial cells, and indirect targeting by inhibiting the release of proangiogenic growth factors by cancer or stromal cells. Many patients benefit from antiangiogenic therapies; thus, development of noninvasive biomarkers of disease response and relapse is a crucial objective to aid in their management. A number of non-invasive tools are described with their potential benefits and limitations. We review currently available candidate biomarkers of anti-angiogenic agent effect. Including these markers into clinical trials may provide insight into appropriate dosing for desired biological effects, appropriate timing of additional therapy, and prediction of individual response. This has important consequences for the clinical use of angiogenesis inhibitors and for drug discovery, not only for optimizing the treatment of cancer, but possibly also for developing therapeutic approaches for various other diseases.

  6. NI-23BRAIN BREAST METASTASES RESPOND TO ANTI-ANGIOGENIC THERAPY BY MODES OF VASCULAR NORMALIZATION

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    Emblem, Kyrre; Pinho, Marco; Chandra, Vyshak; Gerstner, Elizabeth; Stufflebeam, Steve; Sorenson, Greg; Harris, Gordon; Freedman, Rachel; Sohl, Jessica; Younger, Jerry; Krop, Ian; Winer, Eric; Lin, Nancy

    2014-01-01

    INTRODUCTION: As systemic therapy improves, brain metastases are increasingly common in patients with breast cancer. Unfortunately, effective therapy with durable control has remained elusive [1]. Combining bevacizumab and cyototoxic chemotherapy is an appealing approach as the anti-angiogenic effect of bevicizumab may improve delivery of cytotoxic drugs to brain tumors. METHODS: We conducted a Phase II study of patients with parenchymal brain metastasis treated with bevacizumab and carboplatin [2]. Patients could have any hormone receptor status or any number of prior therapies. Patients with HER2+ breast cancer also received trastuzamab. Correlative perfusion MRI scans to look at tumor perfusion, blood volume, vessel calibers and relative oxygen saturation (ΔSO2) levels were performed at baseline, day 1, and after 2 months of therapy [3, 4]. For consistency, the largest contrast-enhancing lesion in each patient visible on all three MR visits was selected for analysis. RESULTS: Thirty-eight patients were enrolled in the study of which 32 had, paired evaluable imaging datasets. Compared to baseline, 12/32 patients were identified as responders by a durable increase in ΔSO2 levels at day 1 and at 2 months above a 5% measurement error threshold. The remaining patients were identified by stable (15/32) or reduced (5/32) ΔSO2 levels. Patients responding to therapy showed increased tumor perfusion (Mann-Whitney; P10 µm) were seen across all patients. CONCLUSIONS: Similar to primary brain tumors [2, 3], perfusion MRI demonstrates that anti-angiogenic therapy can induce vascular normalization in a subset of patients with metastatic breast cancer to the brain. Our data indicate that the vascular response may also be associated with improved survival. [1] Lin NU, Lancet Oncol 2013 [2] Sorensen AG, Cancer Res 2012 [3] Emblem KE, Nat Med 2013

  7. Change in Pattern of Relapse After Antiangiogenic Therapy in High-Grade Glioma

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    Narayana, Ashwatha, E-mail: ashwatha.narayana@nyumc.org [Department of Radiation Oncology, New York University Langone Medical Center, New York, NY (United States); Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Kunnakkat, Saroj D. [Department of Radiation Oncology, New York University Langone Medical Center, New York, NY (United States); Medabalmi, Praveen [Department of Biostatistics, New York University Langone Medical Center, New York, NY (United States); Golfinos, John; Parker, Erik [Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Knopp, Edmond [Department of Radiology, New York University Langone Medical Center, New York, NY (United States); Zagzag, David [Department of Pathology, New York University Langone Medical Center, New York, NY (United States); Eagan, Patricia [Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Atlantic Health System, Overlook Hospital, Summit, NJ (United States); Gruber, Deborah [Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Gruber, Michael L. [Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Atlantic Health System, Overlook Hospital, Summit, NJ (United States)

    2012-01-01

    Purpose: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. Methods and Materials: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. Results: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R{sup 2} = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). Conclusion: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials.

  8. Modeling tumor-associated edema in gliomas during anti-angiogenic therapy and its impact on imageable tumor

    Directory of Open Access Journals (Sweden)

    Andrea eHawkins-Daarud

    2013-04-01

    Full Text Available Glioblastoma, the most aggressive form of primary brain tumor is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd and T2-weighted magnetic resonance imaging (MRI. Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically-driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor-cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR for tumors with lower proliferation rates.

  9. Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab

    Science.gov (United States)

    Mitsuhashi, Atsushi; Goto, Hisatsugu; Saijo, Atsuro; Trung, Van The; Aono, Yoshinori; Ogino, Hirokazu; Kuramoto, Takuya; Tabata, Sho; Uehara, Hisanori; Izumi, Keisuke; Yoshida, Mitsuteru; Kobayashi, Hiroaki; Takahashi, Hidefusa; Gotoh, Masashi; Kakiuchi, Soji; Hanibuchi, Masaki; Yano, Seiji; Yokomise, Hiroyasu; Sakiyama, Shoji; Nishioka, Yasuhiko

    2015-01-01

    Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy. PMID:26635184

  10. Progression of retinal pigment epithelial atrophy in antiangiogenic therapy of neovascular age-related macular degeneration.

    Science.gov (United States)

    Schütze, Christopher; Wedl, Manuela; Baumann, Bernhard; Pircher, Michael; Hitzenberger, Christoph K; Schmidt-Erfurth, Ursula

    2015-06-01

    To monitor retinal pigment epithelial (RPE) atrophy progression during antiangiogenic therapy of neovascular age-related macular degeneration (AMD) over 2 years using polarization-sensitive optical coherence tomography (OCT). Prospective interventional case series. setting: Clinical practice. Thirty patients (31 eyes) with treatment-naïve neovascular AMD. Standard intravitreal therapy (0.5 mg ranibizumab) was administered monthly during the first year and pro re nata (PRN; as-needed) during the second year. Spectral-domain (SD) OCT and polarization-sensitive OCT (selectively imaging the RPE) examinations were performed at baseline and at 1, 3, 6, 12, and 24 months using a standardized protocol. RPE-related changes were evaluated using a semi-automated polarization-sensitive OCT segmentation algorithm and correlated with SD OCT and fundus autofluorescence (FAF) findings. RPE response, geographic atrophy (GA) progression. Atrophic RPE changes included RPE thinning, RPE porosity, focal RPE atrophy, and development of GA. Early RPE loss (ie, RPE porosity, focal atrophy) increased progressively during initial monthly treatment and remained stable during subsequent PRN-based therapy. GA developed in 61% of eyes at month 24. Mean GA area increased from 0.77 mm(2) at 12 months to 1.10 mm(2) (standard deviation = 1.09 mm(2)) at 24 months. Reactive accumulation of RPE-related material at the lesion borders increased until month 3 and subsequently decreased. Progressive RPE atrophy and GA developed in the majority of eyes. RPE migration signifies certain RPE plasticity. Polarization-sensitive OCT specifically images RPE-related changes in neovascular AMD, contrary to conventional imaging methods. Polarization-sensitive OCT allows for precisely monitoring the sequence of RPE-related morphologic changes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Giuseppe Privitera

    2009-01-01

    Full Text Available Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that antiangiogenic therapy should have a role in the management of this disease.

  12. Optical Coherence Tomography and the Development of Antiangiogenic Therapies in Neovascular Age-Related Macular Degeneration

    Science.gov (United States)

    Rosenfeld, Philip J.

    2016-01-01

    Purpose To explain the pivotal role optical coherence tomography (OCT) imaging had in the development of antiangiogenic therapies for the treatment of neovascular age-related macular degeneration (nvAMD). Methods A historical literature review was combined with personal perspectives from the introduction of OCT imaging and the early clinical use of vascular endothelial growth factor (VEGF) inhibitors. Results At the time that OCT emerged, the gold standard for imaging of nvAMD was fluorescein angiography (FA), a time-consuming, dye-based, invasive technique that provided en face images of the retina and was used to characterize leakage, perfusion status, and the types of macular neovascularization (MNV). In comparison, OCT imaging was a fast, safe, noninvasive technique that complemented FA imaging by providing cross-sectional images of the macula. OCT was able to visualize and quantify the macular fluid that was associated with the presence of excess VEGF, which was identified by intraretinal fluid, subretinal fluid, and fluid under the retinal pigment epithelium (RPE). Clinicians quickly appreciated the benefits of OCT imaging for following macular fluid after anti-VEGF therapy. By observing the qualitative and quantitative changes in macular fluid depicted by OCT imaging, clinicians were empowered to compare anti-VEGF drugs and move from fixed-dosing regimens to patient-specific dosing strategies requiring fewer injections. Conclusions Optical coherence tomography imaging was adopted as a VEGF-meter, a method to detect excess VEGF, and evolved to become the gold standard imaging strategy for diagnosing nvAMD, assessing treatment responses to anti-VEGF drugs, deciding when to re-treat, and evaluating disease progression. PMID:27409464

  13. Vasculatures in Tumors Growing From Preirradiated Tissues: Formed by Vasculogenesis and Resistant to Radiation and Antiangiogenic Therapy

    International Nuclear Information System (INIS)

    Chen, Fang-Hsin; Chiang, Chi-Shiun; Wang, Chun-Chieh; Fu, Sheng-Yung; Tsai, Chien-Sheng; Jung, Shih-Ming; Wen, Chih-Jen; Lee, Chung-Chi; Hong, Ji-Hong

    2011-01-01

    Purpose: To investigate vasculatures and microenvironment in tumors growing from preirradiated tissues (pre-IR tumors) and study the vascular responses of pre-IR tumors to radiation and antiangiogenic therapy. Methods and Materials: Transgenic adenocarcinoma of the mouse prostate C1 tumors were implanted into unirradiated or preirradiated tissues and examined for vascularity, hypoxia, and tumor-associated macrophage (TAM) infiltrates by immunohistochemistry. The origin of tumor endothelial cells was studied by green fluorescent protein-tagged bone marrow (GFP-BM) transplantation. The response of tumor endothelial cells to radiation and antiangiogenic agent was evaluated by apoptotic assay. Results: The pre-IR tumors had obvious tumor bed effects (TBE), with slower growth rate, lower microvascular density (MVD), and more necrotic and hypoxic fraction compared with control tumors. The vessels were dilated, tightly adhered with pericytes, and incorporated with transplanted GFP-BM cells. In addition, hypoxic regions became aggregated with TAM. As pre-IR tumors developed, the TBE was overcome at the tumor edge where the MVD increased, TAM did not aggregate, and the GFP-BM cells did not incorporate into the vessels. The vessels at tumor edge were more sensitive to the following ionizing radiation and antiangiogenic agent than those in the central low MVD regions. Conclusions: This study demonstrates that vasculatures in regions with TBE are mainly formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Tumor bed effects could be overcome at the edge of larger tumors, but where vasculatures are formed by angiogenesis and sensitive to both treatments. Vasculatures formed by vasculogenesis should be the crucial target for the treatment of recurrent tumors after radiotherapy.

  14. The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Ding X

    2016-03-01

    Full Text Available Xiaojie Ding,1,2,* Lijuan Qiu,1,2,* Lijuan Zhang,3 Juemin Xi,1,2 Duo Li,1,2 Xinwei Huang,1,2 Yujiao Zhao,1,2 Xiaodang Wang,1,2 Qiangming Sun1,2 1Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 2Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, 3Department of Pathology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Provincial Tumor Hospital, Kunming, People’s Republic of China*These authors contributed equally to this workBackground: Semaphorin 4D (Sema4D belongs to the class IV semaphorins, and accumulating evidence has indicated that its elevated level may be one strategy by which tumors evade current antiangiogenic therapies. The biological roles of Sema4D in colorectal cancer (CRC, however, remain largely undefined. This study was designed to investigate the effects of Sema4D on tumor angiogenesis and growth in CRC, especially in different vascular endothelial growth factor (VEGF backgrounds.Methods: The expression of Sema4D in human CRC was evaluated by immunohistochemical analysis of tumors and their matching normal control tissues. The expression level of Sema4D and VEGF was investigated in different CRC cell lines. To evaluate the contributions of Sema4D to tumor-induced angiogenesis, two CRC cell lines with opposite VEGF backgrounds were infected with lentiviruses expressing Sema4D or Sema4D short hairpin RNA, followed by in vitro migration and in vivo tumor angiogenic assays.Results: Immunohistochemical analysis of human CRC revealed high levels of Sema4D in a cell surface pattern. In all, 84.85% of CRC samples analyzed exhibited moderate to strong Sema4D expression. The positive ratios of Sema4D staining for well, moderately, and poorly differentiated cancers were 71.43%, 96.67%, and 77.27%, respectively. Sema4D is highly expressed in five different CRC cell lines, while VEGF

  15. Dynamic contrast-enhanced micro-CT on mice with mammary carcinoma for the assessment of antiangiogenic therapy response

    Energy Technology Data Exchange (ETDEWEB)

    Eisa, Fabian [University of Erlangen-Nuremberg, Institute of Medical Physics, Erlangen (Germany); University of Erlangen-Nuremberg, Graduate School in Advanced Optical Technologies (SAOT), Erlangen (Germany); Brauweiler, Robert; Hupfer, Martin; Nowak, Tristan; Kalender, Willi A. [University of Erlangen-Nuremberg, Institute of Medical Physics, Erlangen (Germany); Lotz, Laura; Hoffmann, Inge; Dittrich, Ralf; Beckmann, Matthias W. [University of Erlangen-Nuremberg, OB/GYN, University Hospital Erlangen, Erlangen (Germany); Wachter, David [University Hospital Erlangen, Institute of Pathology, Erlangen (Germany); Jost, Gregor; Pietsch, Hubertus [Bayer Pharma AG, Berlin (Germany)

    2012-04-15

    To evaluate the potential of in vivo dynamic contrast-enhanced micro-computed tomography (DCE micro-CT) for the assessment of antiangiogenic drug therapy response of mice with mammary carcinoma. 20 female mice with implanted MCF7 tumours were split into control group and therapy group treated with a known effective antiangiogenic drug. All mice underwent DCE micro-CT for the 3D analysis of functional parameters (relative blood volume [rBV], vascular permeability [K], area under the time-enhancement curve [AUC]) and morphology. All parameters were determined for total, peripheral and central tumour volumes of interest (VOIs). Immunohistochemistry was performed to characterise tumour vascularisation. 3D dose distributions were determined. The mean AUCs were significantly lower in therapy with P values of 0.012, 0.007 and 0.023 for total, peripheral and central tumour VOIs. K and rBV showed significant differences for the peripheral (P{sub per}{sup K} = 0.032, P{sub per}{sup rBV} = 0.029), but not for the total and central tumour VOIs (P{sub total}{sup K} = 0.108, P{sub central}{sup K} = 0.246, P{sub total}{sup rBV} = 0.093, P{sub central}{sup rBV} = 0.136). Mean tumour volume was significantly smaller in therapy (P{sub in} {sub vivo} = 0.001, P{sub ex} {sub vivo} = 0.005). Histology revealed greater vascularisation in the controls and central tumour necrosis. Doses ranged from 150 to 300 mGy. This study indicates the great potential of DCE micro-CT for early in vivo assessment of antiangiogenic drug therapy response. (orig.)

  16. Quantification of serial changes in cerebral blood volume and metabolism in patients with recurrent glioblastoma undergoing antiangiogenic therapy

    Energy Technology Data Exchange (ETDEWEB)

    Stadlbauer, Andreas, E-mail: andi@nmr.at [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria); Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen (Germany); Department of Radiology and Nuclear Medicine, Medical University Vienna, Währinger Gürtel 18-20, A-1097 Vienna (Austria); Pichler, Petra [First Department of Internal Medicine, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Poelten (Austria); Karl, Marianne [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria); Brandner, Sebastian [Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen (Germany); Lerch, Claudia [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria); Renner, Bertold [Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Erlangen (Germany); Heinz, Gertraud [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria)

    2015-06-15

    Highlights: • Antiangiogenic therapy can lead to a decreased in CBV in normal brain tissue. • Responding and pseudoresponding lesions to AAT showed a similar CBV decrease. • Cho and NAA allowed for a distinction of responding and pseudoresponding lesions. • Cr ratios are not suited for evaluation of antiangiogenic therapy response. • Responders to AAT may have an increased risk for remote progression of the GBM. - Abstract: Objectives: To evaluate the usefulness of quantitative advanced magnetic resonance imaging (MRI) methods for assessment of antiangiogenic therapy (AAT) response in recurrent glioblastoma multiforme (GBM). Methods: Eighteen patients with recurrent GBM received bevacizumab and 18 patients served as control group. Baseline MRI and two follow-up examinations were acquired every 3–5 months using dynamic susceptibility-weighted contrast (DSC) perfusion MRI and {sup 1}H-MR spectroscopic imaging ({sup 1}H-MRSI). Maps of absolute cerebral blood volume (aCBV) were coregistered with choline (Cho) and N-acetyl-aspartate (NAA) concentrations and compared to usually used relative parameters as well as controls. Results: Perfusion significantly decreased in responding and pseudoresponding GBMs but also in normal appearing brain after AAT onset. Cho and NAA concentrations were superior to Cr-ratios in lesion differentiation and showed a clear gap between responding and pseudoresponding lesions. Responders to AAT exceptionally frequently (6 out of 8 patients) showed remote GBM progression. Conclusions: Quantification of CBV reveals changes in normal brain perfusion due to AAT, which were not described so far. DSC perfusion MRI seems not to be suitable for differentiation between response and pseudoresponse to AAT. However, absolute quantification of brain metabolites may allow for distinction due to a clear gap at 6–9 months after therapy onset.

  17. Early response assessment in patients with multiple myeloma during anti-angiogenic therapy using arterial spin labelling: first clinical results

    Energy Technology Data Exchange (ETDEWEB)

    Fenchel, Michael [Eberhard-Karls University, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany); Eberhard-Karls University, Department of Diagnostic and Interventional Neuroradiology, Tuebingen (Germany); Konaktchieva, Marina [Eberhard-Karls University, Department of Internal Medicine, Gastroenterology, Tuebingen (Germany); Weisel, Katja; Kraus, Sabina [Eberhard-Karls University, Department of Internal Medicine, Hematology, Tuebingen (Germany); Brodoefel, Harald; Claussen, Claus D.; Horger, Marius [Eberhard-Karls University, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany)

    2010-12-15

    To determine if arterial-spin-labelling (ASL) MRI can reliably detect early response to anti-angiogenic therapy in patients with multiple myeloma by comparison with clinical/haematological response. Nineteen consecutive patients (10 men; mean age 63.5 {+-} 9.1 years) were included in the present study. Inclusion criteria were diagnosis of stage III multiple myeloma and clinical indication for therapeutical administration of bortezomib or lenalidomide. We performed MRI on 3.0T MR in the baseline setting, 3 weeks after onset of therapy and after 8 weeks. Clinical responses were determined on the basis of international uniform response criteria in correlation with haematological parameters and medium-term patient outcome. MRI studies were performed after approval by the local institutional review board. Fifteen patients responded to anti-myeloma therapy; 4/19 patients were non-responders to therapy. Mean tumour perfusion assessed by ASL-MRI in a reference lesion was 220.7 {+-} 132.5 ml min{sup -1} 100 g{sup -1} at baseline, and decreased to 125.7 {+-} 86.3 (134.5 {+-} 150.9) ml min{sup -1} 100 g{sup -1} 3 (8) weeks after onset of therapy (P < 0.02). The mean decrease in paraproteinaemia at week 3 (8) was 52.3 {+-} 47.7% (58.2 {+-} 58.7%), whereas {beta}2-microglobulinaemia decreased by 20.3 {+-} 53.1% (23.3 {+-} 57.0%). Correlation of ASL perfusion with outcome was significant (P = 0.0037). ASL tumour perfusion measurements are a valuable surrogate parameter for early assessment of response to novel anti-angiogenic therapy. (orig.)

  18. Exploring the role of anti-angiogenic therapies in prostate cancer: results from the phase 3 trial of sunitinib

    Directory of Open Access Journals (Sweden)

    Himisha Beltran

    2014-08-01

    Full Text Available Prostate cancer is a leading cause of cancer death in men. Despite recent advances in our understanding and treatment of advanced disease, no systemic therapy is curative and new therapies are needed. Targeting angiogenesis is an attractive therapeutic strategy, as angiogenic pathways are upregulated in prostate tumors similar to other malignancies due to imbalance of pro- and anti-angiogenic factors secreted by tumor, endothelial and stromal cells and increased neovasculature. [1] Vascular endothelial growth factor (VEGF is the most well-characterized pro-angiogenenic factor, with several small molecule inhibitors (sunitinib, sorafenib, pazopanib, axitinib, others, antibodies (bevacizumab and other drugs that target the VEGF pathway approved and/or in development for the treatment of a wide range of tumor types.

  19. Assessing antiangiogenic therapy response by DCE-MRI: development of a physiology driven multi-compartment model using population pharmacometrics.

    Directory of Open Access Journals (Sweden)

    Andreas Steingoetter

    Full Text Available Dynamic contrast enhanced (DCE- MRI is commonly applied for the monitoring of antiangiogenic therapy in oncology. Established pharmacokinetic (PK analysis methods of DCE-MRI data do not sufficiently reflect the complex anatomical and physiological constituents of the analyzed tissue. Hence, accepted endpoints such as Ktrans reflect an unknown multitude of local and global physiological effects often rendering an understanding of specific local drug effects impossible. In this work a novel multi-compartment PK model is presented, which for the first time allows the separation of local and systemic physiological effects. DCE-MRI data sets from multiple, simultaneously acquired tissues, i.e. spinal muscle, liver and tumor tissue, of hepatocellular carcinoma (HCC bearing rats were applied for model development. The full Markov chain Monte Carlo (MCMC Bayesian analysis method was applied for model parameter estimation and model selection was based on histological and anatomical considerations and numerical criteria. A population PK model (MTL3 model consisting of 3 measured and 6 latent (unobserved compartments was selected based on Bayesian chain plots, conditional weighted residuals, objective function values, standard errors of model parameters and the deviance information criterion. Covariate model building, which was based on the histology of tumor tissue, demonstrated that the MTL3 model was able to identify and separate tumor specific, i.e. local, and systemic, i.e. global, effects in the DCE-MRI data. The findings confirm the feasibility to develop physiology driven multi-compartment PK models from DCE-MRI data. The presented MTL3 model allowed the separation of a local, tumor specific therapy effect and thus has the potential for identification and specification of effectors of vascular and tissue physiology in antiangiogenic therapy monitoring.

  20. ADC histograms predict response to anti-angiogenic therapy in patients with recurrent high-grade glioma

    Energy Technology Data Exchange (ETDEWEB)

    Nowosielski, Martha; Tinkhauser, Gerd; Stockhammer, Guenther [Innsbruck Medical University, Department of Neurology, Innsbruck (Austria); Recheis, Wolfgang; Schocke, Michael; Gotwald, Thaddaeus [Innsbruck Medical University, Department of Radiology, Innsbruck (Austria); Goebel, Georg [Innsbruck Medical University, Department of Medical Statistics, Informatics and Health Economics, Innsbruck (Austria); Gueler, Oezguer [Innsbruck Medical University, 4D Visualization Laboratory, University Clinic of Oto-, Rhino- and Laryngology, Innsbruck (Austria); Kostron, Herwig [Innsbruck Medical University, Department of Neurosurgery, Innsbruck (Austria); Hutterer, Markus [Innsbruck Medical University, Department of Neurology, Innsbruck (Austria); Paracelsus Medical University Salzburg-Christian Doppler Hospital, Department of Neurology, Salzburg (Austria)

    2011-04-15

    The purpose of this study is to evaluate apparent diffusion coefficient (ADC) maps to distinguish anti-vascular and anti-tumor effects in the course of anti-angiogenic treatment of recurrent high-grade gliomas (rHGG) as compared to standard magnetic resonance imaging (MRI). This retrospective study analyzed ADC maps from diffusion-weighted MRI in 14 rHGG patients during bevacizumab/irinotecan (B/I) therapy. Applying image segmentation, volumes of contrast-enhanced lesions in T1 sequences and of hyperintense T2 lesions (hT2) were calculated. hT2 were defined as regions of interest (ROI) and registered to corresponding ADC maps (hT2-ADC). Histograms were calculated from hT2-ADC ROIs. Thereafter, histogram asymmetry termed ''skewness'' was calculated and compared to progression-free survival (PFS) as defined by the Response Assessment Neuro-Oncology (RANO) Working Group criteria. At 8-12 weeks follow-up, seven (50%) patients showed a partial response, three (21.4%) patients were stable, and four (28.6%) patients progressed according to RANO criteria. hT2-ADC histograms demonstrated statistically significant changes in skewness in relation to PFS at 6 months. Patients with increasing skewness (n = 11) following B/I therapy had significantly shorter PFS than did patients with decreasing or stable skewness values (n = 3, median percentage change in skewness 54% versus -3%, p = 0.04). In rHGG patients, the change in ADC histogram skewness may be predictive for treatment response early in the course of anti-angiogenic therapy and more sensitive than treatment assessment based solely on RANO criteria. (orig.)

  1. Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

    DEFF Research Database (Denmark)

    Siemann, D W; Chaplin, D J; Horsman, M R

    2017-01-01

    Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting a...

  2. Immunological, anti-angiogenic and clinical effects of intratumoral interleukin 12 electrogene therapy combined with metronomic cyclophosphamide in dogs with spontaneous cancer: A pilot study.

    Science.gov (United States)

    Cicchelero, Laetitia; Denies, Sofie; Vanderperren, Katrien; Stock, Emmelie; Van Brantegem, Leen; de Rooster, Hilde; Sanders, Niek N

    2017-08-01

    The immunological, anti-angiogenic and clinical effects of metronomic cyclophosphamide and 3 consecutive intratumoral interleukin (IL)-12 gene therapy (electrogene therapy (EGT)) treatments were evaluated in 6 dogs with spontaneous cancer. In all dogs, a decrease in peripheral leukocytes 2 days after IL-12 EGT coincided with erythema and swelling of the tumor. In the tumor, a transient increase in IL-12 levels was measured, whereas a continuous increase in interferon γ (IFNγ) and thrombospondin 1 (TSP-1) were determined in contrast to a continuous decrease in vascular endothelial growth factor (VEGF). In the serum, a transient increase in IL-12 and IL-10 levels were noted in contrast to a transient decrease in VEGF and TSP-1. The treatment resulted in a significant anti-angiogenic effect. Although all primary tumors continued to progress in time, this progression was slower than before treatment according to the contrast-enhanced ultrasound data. Besides the encouraging immunostimulatory and anti-angiogenic effects observed in all dogs we also noticed in 4 out of 6 dogs clinically relevant improvements in quality of life and weight. These results hold great promise for combinatorial strategies of IL-12 EGT and metronomic chemotherapy with conventional antitumor (immuno)therapies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Effect of antiangiogenic therapy on luciferase activity in a cytomegalovirus- or HSP70-promoter-transfected M21 tumor model

    Science.gov (United States)

    Hundt, Walter; Schink, Christian; Steinbach, Silke; O'Connell-Rodwell, Caitlin E.; Kiessling, Andreas; Librizzi, Damiano; Burbelko, Mykhaylo; Guccione, Samira

    2012-06-01

    We investigated the effect of targeted gene therapy on heat shock protein 70 expression (Hsp70) and protein production (HSP70) in a melanoma tumor model (M21; M21-L). M21 and M21-L cells transfected with a plasmid containing the Hsp70 (Hspa1b) or the cytomegalovirus (CMV) promoter and the luciferase reporter gene were injected into mice; the resulting tumors grew to a size of 650 mm3. Mice (five per group) were intravenously treated with an Arg-Gly-Asp peptide-nanoparticle/Raf-1 kinase inhibitor protein complex [RGD-NP/RAF(-)] or with a nanoparticle control. Bioluminescence imaging (IVIS®, Xenogen, USA) was performed at 12, 24, 48, and 72 h after the treatment cycle. Western blot analysis of HSP70 protein was performed to monitor protein expression. The size of the treated M21 tumors remained fairly constant (647.8+/-103.4 mm2 at the beginning versus 704.8+/-94.4 mm3 at the end of the experiment). The size of the M21-L tumors increased, similar to the untreated control tumors. Bioluminescent imaging demonstrated that when transcription was controlled by the CMV promoter, luciferase activity decreased to 17.9%+/-4.3% of baseline values in the treated M21 tumors. When transcription was controlled by the Hsp70 promoter, the highest luciferase activity (4.5+/-0.7-fold increase over base-line values) was seen 24 h after injection in the M21 tumors; however, no luciferase activity was seen in the M21-L tumors. In accordance with bioluminescent imaging, western blot analysis showed a peak in HSP70 production at 24 h after the injection of the RGD-NP/RAF(-) complex in the M21 tumors; however, no HSP70 protein induction was seen in the M21-L tumors. Thus, targeted antiangiogenic therapy can induce Hsp70 expression and HSP70 protein in melanoma tumors.

  4. Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.

    Science.gov (United States)

    Faes, Seraina; Uldry, Emilie; Planche, Anne; Santoro, Tania; Pythoud, Catherine; Demartines, Nicolas; Dormond, Olivier

    2016-12-27

    Anti-angiogenic treatments targeting the vascular endothelial growth factor or its receptors have shown clinical benefits. However, impact on long-term survival remains limited. Solid tumors display an acidic microenvironment that profoundly influences their biology. Consequences of acidity on endothelial cells and anti-angiogenic therapies remain poorly characterized and hence are the focus of this study. We found that exposing endothelial cells to acidic extracellular pH resulted in reduced cell proliferation and migration. Also, whereas VEGF increased endothelial cell proliferation and survival at pH 7.4, it had no effect at pH 6.4. Furthermore, in acidic conditions, stimulation of endothelial cells with VEGF did not result in activation of downstream signaling pathways such as AKT. At a molecular level, acidity significantly decreased the expression of VEGFR-2 by endothelial cells. Consequently, anti-angiogenic therapies that target VEGFR-2 such as sunitinib and sorafenib failed to block endothelial cell proliferation in acidic conditions. In vivo, neutralizing tumor acidity with sodium bicarbonate increased the percentage of endothelial cells expressing VEGFR-2 in tumor xenografts. Furthermore, combining sodium bicarbonate with sunitinib provided stronger anti-cancer activity than either treatment alone. Histological analysis showed that sunitinib had a stronger anti-angiogenic effect when combined with sodium bicarbonate. Overall, our results show that endothelial cells prosper independently of VEGF in acidic conditions partly as a consequence of decreased VEGFR-2 expression. They further suggest that strategies aiming to raise intratumoral pH can improve the efficacy of anti-VEGF treatments.

  5. Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway.

    LENUS (Irish Health Repository)

    Korpanty, Grzegorz

    2010-01-01

    Lung cancer (LC) is a leading cause of death worldwide. Recent advances in chemotherapeutic agents have not yielded any significant improvement in the prognosis of patients with LC. The five-year survival rate for all combined disease stages remains about 15%. For this reason, new therapies such as those that inhibit tumor angiogenesis or block activity of growth factor receptors are of special interest in this group of patients. In this review we will summarize the most recent clinical data on biologic therapies that inhibit tumor angiogenesis in LC, focusing on those that are most clinically relevant.

  6. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy

    Science.gov (United States)

    Tamburrino, Anna; Piro, Geny; Carbone, Carmine; Tortora, Giampaolo; Melisi, Davide

    2013-01-01

    Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients’ survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype. PMID:23641216

  7. Platelet-Derived Growth Factor (PDGF/PDGF Receptors (PDGFR Axis as Target for Antitumor and Antiangiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Anca Maria Cimpean

    2010-03-01

    significance of PDGF/PDGFR expression in normal conditions and tumors, focusing on this axis as a potential target for antitumor and antiangiogenic therapy.

  8. An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models.

    Science.gov (United States)

    Fagiani, Ernesta; Bill, Ruben; Pisarsky, Laura; Ivanek, Robert; Rüegg, Curzio; Christofori, Gerhard

    2015-07-01

    Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response. Toward these goals, we have employed several mouse models of tumor angiogenesis to identify cell populations circulating in their blood that correlated with the extent of tumor angiogenesis and therapy response. Flow cytometry analyses of different combinations of cell surface markers that define subsets of bone marrow-derived cells were performed on peripheral blood mononuclear cells from tumor-bearing and healthy mice. We identified one cell population, CD45(dim)VEGFR1(-)CD31(low), that was increased in levels during active tumor angiogenesis in a variety of transgenic and syngeneic transplantation mouse models of cancer. Treatment with various anti-angiogenic drugs did not affect CD45(dim)VEGFR1(-)CD31(low) cells in healthy mice, whereas in tumor-bearing mice, a consistent reduction in their levels was observed. Gene expression profiling of CD45(dim)VEGFR1(-)CD31(low) cells characterized these cells as an immature B cell population. These immature B cells were then directly validated as surrogate marker for tumor angiogenesis and of pharmacologic responses to anti-angiogenic therapies in various mouse models of cancer.

  9. An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice.

    Science.gov (United States)

    Runge, Anja; Hu, Junhao; Wieland, Matthias; Bergeest, Jan-Philip; Mogler, Carolin; Neumann, André; Géraud, Cyrill; Arnold, Bernd; Rohr, Karl; Komljenovic, Dorde; Schirmacher, Peter; Goerdt, Sergij; Augustin, Hellmut G

    2014-08-01

    The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. ©2014 American Association for Cancer Research.

  10. Immuno-Expression of Endoglin and Smooth Muscle Actin in the Vessels of Brain Metastases. Is There a Rational for Anti-Angiogenic Therapy?

    Directory of Open Access Journals (Sweden)

    Valeria Barresi

    2014-04-01

    Full Text Available Despite ongoing clinical trials, the efficacy of anti-angiogenic drugs for the treatment of brain metastases (BM is still questionable. The lower response rate to anti-angiogenic therapy in the presence of BM than in metastatic disease involving other sites suggests that BM may be insensitive to these drugs, although the biological reasons underlining this phenomenon are still to be clarified. With the aim of assessing whether the targets of anti-angiogenic therapies are actually present in BM, in the present study, we analyzed the microvessel density (MVD, a measure of neo-angiogenesis, and the vascular phenotype (mature vs. immature in the tumor tissue of a series of BM derived from different primary tumors. By using immunohistochemistry against endoglin, a specific marker for newly formed vessels, we found that neo-angiogenesis widely varies in BM depending on the site of the primary tumor, as well as on its histotype. According to our results, BM from lung cancer displayed the highest MVD counts, while those from renal carcinoma had the lowest. Then, among BM from lung cancer, those from large cell and adenocarcinoma histotypes had significantly higher MVD counts than those originating from squamous cell carcinoma (p = 0.0043; p = 0.0063. Of note, MVD counts were inversely correlated with the maturation index of the endoglin-stained vessels, reflected by the coverage of smooth muscle actin (SMA positive pericytes (r = −0.693; p < 0.0001. Accordingly, all the endoglin-positive vessels in BM from pulmonary squamous cell carcinoma and renal carcinoma, displayed a mature phenotype, while vessels with an immature phenotype were found in highly vascularized BM from pulmonary large cell and adenocarcinoma. The low MVD and mature phenotype observed in BM from some primary tumors may account for their low sensitivity to anti-angiogenic therapies. Although our findings need to be validated in correlative studies with a clinical response, this should

  11. Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai.

    Science.gov (United States)

    Pantziarka, Pan; Hutchinson, Lisa; André, Nicolas; Benzekry, Sébastien; Bertolini, Francesco; Bhattacharjee, Atanu; Chiplunkar, Shubhada; Duda, Dan G; Gota, Vikram; Gupta, Sudeep; Joshi, Amit; Kannan, Sadhana; Kerbel, Robert; Kieran, Mark; Palazzo, Antonella; Parikh, Aparna; Pasquier, Eddy; Patil, Vijay; Prabhash, Kumar; Shaked, Yuval; Sholler, Giselle Saulnier; Sterba, Jaroslav; Waxman, David J; Banavali, Shripad

    2016-01-01

    The 5 th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6 th - 8 th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

  12. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Gregory J. Baker

    2014-07-01

    Full Text Available As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM, and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.

  13. Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles

    Directory of Open Access Journals (Sweden)

    Cui Y

    2016-11-01

    NPC xenograft model, favoring its potential clinical translation. Keywords: magnetic resonance imaging, ultrasmall superparamagnetic iron oxide, integrin αvβ3, antiangiogenic therapy, Endostar, nasopharyngeal carcinoma

  14. Multiparametric Monitoring of Early Response to Antiangiogenic Therapy: A Sequential Perfusion CT and PET/CT Study in a Rabbit VX2 Tumor Model

    Directory of Open Access Journals (Sweden)

    Jung Im Kim

    2014-01-01

    Full Text Available Objectives. To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Methods. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group or saline infusion (control group. Perfusion CT was analyzed to calculate blood flow (BF, blood volume (BV, and permeability surface area product (PS; FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG, entropy, and homogeneity. The flow-metabolic ratio (FMR was also calculated and immunohistochemical analysis of microvessel density (MVD was performed. Results. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. Conclusions. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism.

  15. Multiparametric monitoring of early response to antiangiogenic therapy: a sequential perfusion CT and PET/CT study in a rabbit VX2 tumor model.

    Science.gov (United States)

    Kim, Jung Im; Lee, Hyun-Ju; Kim, Young Jae; Kim, Kwang Gi; Lee, Kyung Won; Lee, Jae Ho; Lee, Hak Jong; Lee, Won Woo

    2014-01-01

    To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group) or saline infusion (control group). Perfusion CT was analyzed to calculate blood flow (BF), blood volume (BV), and permeability surface area product (PS); FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG), entropy, and homogeneity. The flow-metabolic ratio (FMR) was also calculated and immunohistochemical analysis of microvessel density (MVD) was performed. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism.

  16. Rapamycin/DiR loaded lipid-polyaniline nanoparticles for dual-modal imaging guided enhanced photothermal and antiangiogenic combination therapy.

    Science.gov (United States)

    Wang, Jinping; Guo, Fang; Yu, Meng; Liu, Li; Tan, Fengping; Yan, Ran; Li, Nan

    2016-09-10

    Imaging-guided photothermal therapy (PTT) has promising application for treating tumors. Nevertheless, so far imaging-guided photothermal drug-delivery systems have been developed with limited success for tumor chemo-photothermal therapy. In this study, as the proof-of-concept, a stimuli-responsive tumor-targeting rapamycin/DiR loaded lipid-polyaniline nanoparticle (RDLPNP) for dual-modal imaging-guided enhanced PTT efficacy is reported for the first time. In this system, polyaniline (PANI) with π-π electronic conjugated system and effective photothermal efficiency is chosen as the appropriate model receptor of fluorescence resonance energy transfer (FRET), and loaded cyanine probe (e.g., 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide, DiR) acts as the donor of near-infrared fluorescence (NIRF). In addition, rapamycin (RAPA), which is used as the antiangiogenesis chemotherapeutic drug, can cutdown the tumor vessels and delay tumor growth obviously. After intravenous treatment of RDLPNPs into Hela tumor bearing mice, fluorescent (from DiR) and enhanced photoacoustic (from DLPNPs) signals were found in tumor site over time, which reached to peak at the 6h time point. After irradiating with an NIR laser, a good anti-tumor effect was observed owing to the enhanced photothermal and antiangiogenic effect of RDLPNPs. These results show that the multifunctional nanoparticle can be used as a promising imaging-guided photothermal drug delivery nanoplatform for cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Perfusion CT allows prediction of therapy response in non-small cell lung cancer treated with conventional and anti-angiogenic chemotherapy.

    Science.gov (United States)

    Tacelli, Nunzia; Santangelo, Teresa; Scherpereel, Arnaud; Duhamel, Alain; Deken, Valérie; Klotz, Ernst; Cortot, Alexis; Lafitte, Jean-Jacques; Wallyn, Frédéric; Remy, Jacques; Remy-Jardin, Martine

    2013-08-01

    To determine whether CT can depict early perfusion changes in lung cancer treated by anti-angiogenic drugs, allowing prediction of response. Patients with non-small cell lung cancer, treated by conventional chemotherapy with (Group 1; n = 17) or without (Group 2; n = 23) anti-vascular endothelial growth factor (anti-VEGF) drug (bevacizumab) underwent CT perfusion before (TIME 0) and after 1 (TIME 1), 3 (TIME 2) and 6 (TIME 3) cycles of chemotherapy. The CT parameters evaluated included: (1) total tumour vascular volume (TVV) and total tumour extravascular flow (TEF); (2) RECIST (Response Evaluation Criteria in Solid Tumours) measurements. Tumour response was also assessed on the basis of the clinicians' overall evaluation. In Group 1, significant reduction in perfusion was identified between baseline and: (1) TIME 1 (TVV, P = 0.0395; TEF, P = 0.015); (2) TIME 2 (TVV, P = 0.0043; TEF, P Perfusion CT demonstrates early changes in lung cancer vascularity under anti-angiogenic chemotherapy that may help predict therapeutic response. • Perfusion CT has the potential of providing in vivo information about tumour vasculature. • CT depicts early and specific perfusion changes in NSCLC under anti-angiogenic drugs. • Specific therapeutic effects of anti-angiogenic drugs can be detected before tumour shrinkage. • Early perfusion changes can help predict therapeutic response to anti-angiogenic treatment. • Perfusion CT could be a non-invasive tool to monitor anti-angiogenic treatment.

  18. Early biomarkers from dynamic contrast-enhanced magnetic resonance imaging to predict the response to antiangiogenic therapy in high-grade gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Piludu, Francesca; Vidiri, Antonello [Regina Elena National Cancer Institute, Radiology and Diagnostic Imaging Department, Rome (Italy); Marzi, Simona [Regina Elena National Cancer Institute, Medical Physics Laboratory, Rome (Italy); Pace, Andrea; Villani, Veronica [Regina Elena National Cancer Institute, Neurology Division, Rome (Italy); Fabi, Alessandra [Regina Elena National Cancer Institute, Oncology Department, Rome (Italy); Carapella, Carmine Maria [Regina Elena National Cancer Institute, Oncologic Surgery Department, Rome (Italy); Terrenato, Irene [Regina Elena National Cancer Institute, Biostatistics-Scientific Direction, Rome (Italy); Antenucci, Anna [Regina Elena National Cancer Institute, Clinical Pathology, Rome (Italy)

    2015-12-15

    The aim of this study is to investigate whether early changes in tumor volume and perfusion measurements derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may predict response to antiangiogenic therapy in recurrent high-grade gliomas. Twenty-seven patients who received bevacizumab every 3 weeks were enrolled in the study. For each patient, three MRI scans were performed: at baseline, after the first dose, and after the fourth dose of bevacizumab. The entire tumor volume (V{sub tot}), as well as contrast-enhanced and noncontrast-enhanced tumor subvolumes (V{sub CE-T1} and V{sub NON-CE-T1}, respectively) were outlined using post-contrast T1-weighted images as a guide for the tumor location. Histogram analysis of normalized IAUGC (nIAUGC) and transfer constant K{sup trans} maps were performed. Each patient was classified as a responder patient if he/she had a partial response or a stable disease or as a nonresponder patient if he/she had progressive disease. Responding patients showed a larger reduction in V{sub NON-CE-T1} after a single dose, compared to nonresponding patients. Tumor subvolumes with increased values of nIAUGC and K{sup trans}, after a single dose, significantly differed between responders and nonresponders. The radiological response was found to be significantly associated to the clinical outcome. After a single dose, V{sub tot} was predictive of overall survival (OS), while V{sub CE-T1} showed a tendency of correlation with OS. Tumor subvolumes with increased nIAUGC and K{sup trans} showed the potential for improving the diagnostic accuracy of DCE. Early assessments of the entire tumor volume, including necrotic areas, may provide complementary information of tumor behavior in response to anti-VEGF therapies and is worth further investigation. (orig.)

  19. Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

    Directory of Open Access Journals (Sweden)

    Shujing Shi

    Full Text Available INTRODUCTION: Cytokine-induced killer cells (CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh-endostatin and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells

  20. Circulating anti-retinal antibodies in response to anti-angiogenic therapy in exudative age-related macular degeneration.

    Science.gov (United States)

    Kubicka-Trząska, Agnieszka; Wilańska, Joanna; Romanowska-Dixon, Bożena; Sanak, Marek

    2014-12-01

    To determine changes in anti-retinal antibodies (ARAs) during anti-VEGF therapy in patients with exudative age-related macular degeneration (AMD) and to assess the correlations between ARAs and disease activity. The study comprised 98 patients treated with intravitreal bevacizumab. The ophthalmic examination included best corrected visual acuity (BCVA), slit lamp biomicroscopy, fundoscopy, fluorescein angiography (FA), and optical coherence tomography (OCT). Serum ARAs levels were assessed by indirect immunofluorescence (IIF) on normal monkey retina substrate. These studies were repeated at 4 week intervals within 8 months of a follow-up. The sera of 50 sex- and age-matched healthy subjects were used as controls. At baseline examination, 94 (95.5%) of the 98 patients were positive for ARAs. The ARAs titres were significantly higher (p = 0.0000) than in controls. A positive correlation was found between titres of ARAs and the diameter of choroidal neovascularization (CNV) as measured by FA (p = 0.0000), and central retinal thickness (CRT) assessed by OCT (p = 0.0000). A positive correlation was also found between the diameter of CNV, CRT and the complexity of circulating ARAs. Following treatment all patients demonstrated significant decrease in ARAs levels as well as improvement of BCVA, reduction of subretinal fluid on OCT and decreased leakage on FA. Changes in serum ARAs levels occurred in parallel with clinical outcomes of anti-VEGF therapy. Treatment reduced serum levels of ARAs, with the greatest reduction occurring during the 'loading' phase. This study demonstrated that ARAs may act as a serum biomarker of the efficacy of anti-VEGF therapy. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  1. Monitoring early response to anti-angiogenic therapy: diffusion-weighted magnetic resonance imaging and volume measurements in colon carcinoma xenografts.

    Directory of Open Access Journals (Sweden)

    Moritz Jörg Schneider

    Full Text Available OBJECTIVES: To evaluate the use of diffusion-weighted MRI (DW-MRI and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model. MATERIALS AND METHODS: 23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29 were examined before and after 6 days of treatment with regorafenib (n = 12 or placebo (n = 11 in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10-800 s/mm2 was used. The apparent diffusion coefficient (ADC was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC analysis individually and combined using Fisher's linear discriminant analysis (FLDA. RESULTS: All ADCs and volumes are stated as median±standard deviation. Tumor ADC increased significantly in the therapy group (0.76±0.09×10(-3 mm2/s to 0.90±0.12×10(-3 mm2/s; p<0.001, with significantly higher changes of tumor ADC than in the control group (0.10±0.11×10(-3 mm2/s vs. 0.03±0.09×10(-3 mm2/s; p = 0.027. Tumor volume increased significantly in both groups (therapy: 347.8±449.1 to 405.3±823.6 mm3; p = 0.034; control: 219.7±79.5 to 443.7±141.5 mm3; p<0.001, however, the therapy group showed significantly reduced tumor growth (33.30±47.30% vs. 96.43±31.66%; p<0.001. Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%; and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%. CONCLUSIONS: Regorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and

  2. Exploiting Surface Plasmon Resonance (SPR Technology for the Identification of Fibroblast Growth Factor-2 (FGF2 Antagonists Endowed with Antiangiogenic Activity

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    Marco Presta

    2009-08-01

    Full Text Available Angiogenesis, the process of new blood vessel formation, is implicated in various physiological/pathological conditions, including embryonic development, inflammation and tumor growth. Fibroblast growth factor-2 (FGF2 is a heparin-binding angiogenic growth factor involved in various physiopathological processes, including tumor neovascularization. Accordingly, FGF2 is considered a target for antiangiogenic therapies. Thus, numerous natural/synthetic compounds have been tested for their capacity to bind and sequester FGF2 in the extracellular environment preventing its interaction with cellular receptors. We have exploited surface plasmon resonance (SPR technique in search for antiangiogenic FGF2 binders/antagonists. In this review we will summarize our experience in SPR-based angiogenesis research, with the aim to validate SPR as a first line screening for the identification of antiangiogenic compounds.

  3. Assessment of response to anti-angiogenic targeted therapy in pulmonary metastatic renal cell carcinoma: R2* value as a predictive biomarker

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    Wu, Guangyu; Liu, Guiqin; Suo, Shiteng; Liu, Xiaosheng; Xu, Jianrong [Shanghai Jiao Tong University, Department of Radiology, Renji Hospital, School of Medicine, Shanghai (China); Kong, Wen; Zhang, Jin [Shanghai Jiao Tong University, Department of Urinary Surgery, Renji Hospital, School of Medicine, Shanghai (China); Qu, Jianxun [GE Healthcare, Shanghai (China)

    2017-09-15

    To evaluate the utility of MR R2*-mapping and the optimal time-point for assessing the response of pulmonary metastatic renal cell carcinoma (mRCC) to anti-angiogenic targeted therapy (aATT). The exploration-sample group and the validation-sample group consisted of 22 and 16 patients. The parameters of MR R2*-mapping, including the R2* value at each time-point (R2*{sub base}, R2*{sub 1cyc} and R2*{sub 2cyc}) and change between different time-points (R2*{sub (1cyc-base)/base}, R2*{sub (2cyc-base)/base} and R2*{sub (2cyc-1cyc)/1cyc}), were evaluated with a receiver-operating-characteristic analysis, and a cut-off value derived from the clinical outcome was applied to the Kaplan-Meier method to assess the value of R2* mapping and Response-Evaluation-Criteria in Solid Tumours (RECIST) during treatment evaluation. The inter-, intra-observer agreements and inter-scan consistency were excellent (p > 0.80). For the exploration-sample group, the areas under the curve for the parameters of MR R2* mapping were 0.55, 0.60, 0.83, 0.64, 0.88 and 0.83 for R2*{sub base}, R2*{sub 1cyc}, R2*{sub 2cyc}, R2*{sub (1cyc-base)/base}, R2*{sub (2cyc-base)/base} and R2*{sub (2cyc-1cyc)/1cyc.} For the validation-sample, R2*{sub (2cyc-base)/base} better predicted progression-free survival (p = 0.03) than RECIST and other R2* mapping parameters with a lower p value. Assessing aATT outcome based on changes in the R2* value between baseline and second treatment is more accurate than assessment at other time-points and assessment based on the RECIST. (orig.)

  4. Perfusion CT allows prediction of therapy response in non-small cell lung cancer treated with conventional and anti-angiogenic chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Tacelli, Nunzia; Santangelo, Teresa; Remy, Jacques [University of Lille Nord de France, Department of Thoracic Imaging, Hospital Calmette (EA 2694), Lille (France); University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); Scherpereel, Arnaud; Cortot, Alexis; Wallyn, Frederic [University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); University of Lille Nord de France, Department of Pulmonary and Thoracic Oncology, Lille (France); Duhamel, Alain; Deken, Valerie [University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); University of Lille Nord de France, Department of Medical Statistics, Lille (France); Klotz, Ernst [Siemens Healthcare, Computed Tomography Division, Forchheim (Germany); Lafitte, Jean-Jacques [University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); University of Lille Nord de France, Department of Pulmonary and Thoracic Oncology, Lille (France); Pasteur Institute of Lille, INSERM unit 1019, CIIL, Lille (France); Remy-Jardin, Martine [University of Lille Nord de France, Department of Thoracic Imaging, Hospital Calmette (EA 2694), Lille (France); University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); Hospital Calmette, Department of Thoracic Imaging, Lille cedex (France)

    2013-08-15

    To determine whether CT can depict early perfusion changes in lung cancer treated by anti-angiogenic drugs, allowing prediction of response. Patients with non-small cell lung cancer, treated by conventional chemotherapy with (Group 1; n = 17) or without (Group 2; n = 23) anti-vascular endothelial growth factor (anti-VEGF) drug (bevacizumab) underwent CT perfusion before (TIME 0) and after 1 (TIME 1), 3 (TIME 2) and 6 (TIME 3) cycles of chemotherapy. The CT parameters evaluated included: (1) total tumour vascular volume (TVV) and total tumour extravascular flow (TEF); (2) RECIST (Response Evaluation Criteria in Solid Tumours) measurements. Tumour response was also assessed on the basis of the clinicians' overall evaluation. In Group 1, significant reduction in perfusion was identified between baseline and: (1) TIME 1 (TVV, P = 0.0395; TEF, P = 0.015); (2) TIME 2 (TVV, P = 0.0043; TEF, P < 0.0001); (3) TIME 3 (TVV, P = 0.0034; TEF, P = 0.0005) without any significant change in Group 2. In Group 1: (1) the reduction in TVV at TIME 1 was significantly higher in responders versus non-responders at TIME 2 according to RECIST (P = 0.0128) and overall clinicians' evaluation (P = 0.0079); (2) all responders at TIME 2 had a concurrent decrease in TVV and TEF at TIME 1. Perfusion CT demonstrates early changes in lung cancer vascularity under anti-angiogenic chemotherapy that may help predict therapeutic response. (orig.)

  5. Anti-angiogenic treatment of gastrointestinal malignancies.

    Science.gov (United States)

    Salmon, J Stuart; Lockhart, A Craig; Berlin, Jordan

    2005-01-01

    The scientific rationale to block angiogenesis as a treatment strategy for human cancer has been developed over the last 30 years, but is only now entering the clinical arena. Preclinical studies have demonstrated the importance of the vascular endothelial growth factor (VEGF) pathways in both physiologic and pathologic angiogenesis, and have led to the development of approaches to block its role in tumor angiogenesis. Bevacizumab is an antibody to VEGF and has been shown to prolong survival when given with chemotherapy in the treatment of metastatic colorectal cancer (CRC). Although this is the first anti-angiogenic treatment to be approved for the treatment of human epithelial malignancy, a number of other approaches currently are in development. Soluble chimeric receptors to sequester serum VEGF and monoclonal antibodies against VEGF receptors have both shown considerable promise in the laboratory and are being brought into clinical investigation. A number of small-molecule tyrosine kinase inhibitors that have activity against VEGF receptors also are in clinical trials. Although these novel treatments are being pioneered in CRC, anti-angiogenic approaches also are being tested in the treatment of other gastrointestinal malignancies. Anti-VEGF therapy has shown promise in such traditionally resistant tumors as pancreatic cancer and hepatocellular carcinoma. This review will examine the preclinical foundation and then focus on the clinical studies of anti-VEGF therapy in gastrointestinal cancers.

  6. Statistical Controversies in Clinical Research: Limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events. A meta-analysis.

    Science.gov (United States)

    Trone, J C; Ollier, E; Chapelle, C; Bertoletti, L; Cucherat, M; Mismetti, P; Magné, N; Laporte, S

    2018-02-05

    Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. We searched Medline, Cochrane, ClinicalTrials.gov databases, and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (OR) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of odds ratio (ROR), by dividing the OR values obtained in open-label trials by those obtained in DB trials. The literature-based meta-analysis included 166 trials (72,024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 (95% CI 2.12-2.73; P events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials. © The Author 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  7. Hipertensión arterial como factor predictivo en pacientes con cáncer renal tratados con antiangiogénicos Hypertension as predictive factor in renal cell cancer treated with antiangiogenic therapy

    Directory of Open Access Journals (Sweden)

    Luciana Gennari

    2011-06-01

    Full Text Available El conocimiento de las diversas vías de oncogénesis ha llevado al desarrollo en los últimos cinco años de nuevas terapias para el tratamiento del cáncer renal avanzado, las que poseen como blanco al factor derivado del endotelio vascular (VEGF y sus receptores (antiangiogénicos y al blanco mamífero de la rapamicina (mTOR. Los antiangiogénicos constituyen un grupo de moléculas activas con un espectro de toxicidad peculiar que comprende el desarrollo de hipertensión arterial, disfunción tiroidea y síndrome de mano-pie. La identificación de factores predictivos clínicos y moleculares lograría identificar aquellos pacientes que se beneficiarían con dicho tratamiento, evitando exposición y toxicidad innecesaria al resto. La aparición de hipertensión arterial se ha correlacionado con respuesta al tratamiento y eficacia clínica. En nuestra serie retrospectiva, los pacientes tratados con antiangiogénicos que desarrollaron hipertensión arterial tuvieron aumento de la tasa de respuestas e intervalo libre de enfermedad en comparación con aquellos que, tratados de la misma manera, no manifestaron hipertensión. La hipertensión arterial debería considerarse como un factor predictor clínico en su tratamiento. Dichos hallazgos deberían ser corroborados en forma prospectiva y con un mayor número de pacientes.Knowledge of several pathways of oncogenesis has led to the development of novel therapies in the treatment of advanced kidney cancer in the last five years. These have targeted the vascular endothelium-derived factor (VEGF (angiogenesis and mammalian target of rapamycin (mTOR. Antiangiogenics are a group of active molecules with a peculiar spectrum of toxicity including the development of hypertension, thyroid dysfunction and hand-foot syndrome. The identification of molecular and clinical predictors would allow to identify those patients who would benefit from such treatment and saveguarding the rest from toxic exposure. The

  8. Comparison of anti-angiogenic properties of pristine carbon nanoparticles

    DEFF Research Database (Denmark)

    Wierzbicki, Mateusz; Sawosz, Ewa; Grodzik, Marta

    2013-01-01

    nanoparticles decreased the expression of vascular endothelial growth factor receptor. These results provide new insights into the biological activity of carbon nanomaterials and emphasise the potential use of multi-wall nanotubes and diamond nanoparticles in anti-angiogenic tumour therapy.......Angiogenesis is vital for tumour formation, development and metastasis. Recent reports show that carbon nanomaterials inhibit various angiogenic signalling pathways and, therefore, can be potentially used in anti-angiogenic therapy. In the present study, we compared the effect of different carbon...... nanomaterials on blood vessel development. Diamond nanoparticles, graphite nanoparticles, graphene nanosheets, multi-wall nanotubes and C60 fullerenes were evaluated for their angiogenic activities using the in ovo chick embryo chorioallantoic membrane model. Diamond nanoparticles and multi-wall nanotubes...

  9. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    2010-09-01

    Full Text Available Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD.Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology.Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic

  10. Antiangiogenic effects of marine sponge derived compounds on cancer.

    Science.gov (United States)

    Senthilkumar, Kalimuthu; Venkatesan, Jayachandran; Manivasagan, Panchanathan; Kim, Se-Kwon

    2013-11-01

    The term "angiogenic switch" refers to a time-restricted event during tumor progression where the balance between pro- and anti-angiogenic factors, resulting in the transition from dormant avascularized hyperplasia to outgrowing vascularized tumor and eventually to malignant tumor progression. Targeting angiogenesis and its mechanistic pathways are critical target for cancer therapy. Recently, marine derived compounds, plays major role in cancer research. Several sponge derived compounds such as alkaloids, terpenes, macrocylic lactone and polyketide are leading drugs in the treatment of different types of diseases including cancer. Those marine sponge compounds inhibit cancer cell proliferation and tumor angiogenesis. Hence, this review sheds light on angiogenic regulators and marine sponge derived antiangiogenic compounds for cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery.

    Directory of Open Access Journals (Sweden)

    Jean-Philip Truman

    2010-08-01

    Full Text Available While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either "normalize" dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery, is provided in the present study.Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase, regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C(16-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. In vivo, MCA/129 fibrosarcoma tumors were implanted in asmase(+/+ mice or asmase(-/- littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in asmase(-/- mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect.These studies show that angiogenic factors fail to suppress apoptosis if ceramide remains elevated while anti-angiogenic therapies fail without ceramide

  12. Growing tumor vessels: more than one way to skin a cat - implications for angiogenesis targeted cancer therapies.

    Science.gov (United States)

    Leite de Oliveira, Rodrigo; Hamm, Alexander; Mazzone, Massimiliano

    2011-04-01

    The establishment of a functional, integrated vascular system is instrumental for tissue growth and homeostasis. Without blood vessels no adequate nutrition and oxygen would be provided to cells, nor could the undesired waste products be efficiently removed. Blood vessels constitute therefore one of the largest and most complex body network whose assembly depends on the precise balance of growth factors acting in a complementary and coordinated manner with cells of several identities. However, the vessels that are crucial for life can also foster death, given their involvement in cancer progression towards malignancy and metastasis. Targeting tumor vasculature has thus arisen as an appealing anti-cancer therapeutic approach. Since the milestone achievements that vascular endothelial growth factor (VEGF) blockade suppressed angiogenesis and tumor growth in mice and prolonged the survival of cancer patients when administered in combination with chemotherapy, the clinical development of anti-VEGF(R) drugs has accelerated remarkably. FDA has approved the use of bevacizumab - a humanized monoclonal antibody against VEGF - in colorectal, lung and metastatic breast cancers in combination with standard chemotherapy. Additional broad-spectrum VEGF receptor tyrosine kinase inhibitors, such as sunitinib and sorafenib, are used in monotherapy for metastatic renal carcinoma, while sunitinib is also approved for imatinib resistant gastrointestinal stromal tumors and sorafenib for advanced stage hepatocellular carcinoma. Nevertheless, the survival benefit offered by VEGF(R) blockers, either as single agents or in combination with chemotherapy, is calculated merely in the order of months. Posterior studies in preclinical models have reported that despite reducing primary tumor growth, the inhibition of VEGF increased tumor invasiveness and metastasis. The clinical implications of these findings urge the need to reconcile these conflicting results. Anti-angiogenic therapy

  13. Postmenopausal hormone replacement therapy--clinical implications

    DEFF Research Database (Denmark)

    Ravn, S H; Rosenberg, J; Bostofte, E

    1994-01-01

    The menopause is defined as cessation of menstruation, ending the fertile period. The hormonal changes are a decrease in progesterone level, followed by a marked decrease in estrogen production. Symptoms associated with these hormonal changes may advocate for hormonal replacement therapy. This re......The menopause is defined as cessation of menstruation, ending the fertile period. The hormonal changes are a decrease in progesterone level, followed by a marked decrease in estrogen production. Symptoms associated with these hormonal changes may advocate for hormonal replacement therapy....... This review is based on the English-language literature on the effect of estrogen therapy and estrogen plus progestin therapy on postmenopausal women. The advantages of hormone replacement therapy are regulation of dysfunctional uterine bleeding, relief of hot flushes, and prevention of atrophic changes...... in the urogenital tract. Women at risk of osteoporosis will benefit from hormone replacement therapy. The treatment should start as soon after menopause as possible and it is possible that it should be maintained for life. The treatment may be supplemented with extra calcium intake, vitamin D, and maybe calcitonin...

  14. Postmenopausal hormone replacement therapy--clinical implications

    DEFF Research Database (Denmark)

    Ravn, S H; Rosenberg, J; Bostofte, E

    1994-01-01

    in the urogenital tract. Women at risk of osteoporosis will benefit from hormone replacement therapy. The treatment should start as soon after menopause as possible and it is possible that it should be maintained for life. The treatment may be supplemented with extra calcium intake, vitamin D, and maybe calcitonin......The menopause is defined as cessation of menstruation, ending the fertile period. The hormonal changes are a decrease in progesterone level, followed by a marked decrease in estrogen production. Symptoms associated with these hormonal changes may advocate for hormonal replacement therapy......, but the contribution of progestins for about 10 days every month excludes this risk. Breast cancer in relation to estrogen-progestogen therapy has been given much concern, and the problem is still not fully solved. If there is a risk, it is small, and only after prolonged use of estrogen (15-20 years). The decision...

  15. Staff rotation: implications for occupational therapy.

    Science.gov (United States)

    Taylor, A; Andriuk, M L; Langlois, P; Provost, E

    1995-10-01

    Occupational therapy departments of tertiary care hospitals can provide staff with opportunities to gain diverse clinical experience if they rotate through the various services such as surgery, medicine, geriatrics, plastic surgery and orthopaedics. The system of rotation offers both advantages and disadvantages for the staff and the institution. The Royal Victoria Hospital in Montreal, a large university teaching hospital, had traditionally offered staff the opportunity to rotate. Changes in staffing and their needs however, resulted in rotation becoming an important issue within the department. This article presents the pros and the cons of rotation and non-rotation systems as identified by therapists and administrators across Canada. Staff rotation was found to have an effect on job satisfaction and a therapist's career orientation. Given these findings, administrators may want to reconsider the role of the generalist and specialist in their facilities.

  16. Results of combined antiangiogenic activity on corneal neovascularization. Experimental and morphological study

    Directory of Open Access Journals (Sweden)

    V. R. Mamikpnyan

    2014-01-01

    Full Text Available Results of comparative experimental and morphological study of activity on corneal neovascularization in rabbit’s eye of photodynamic therapy with Photosense and antiangiogenic therapy with Avastin (bevacizumab alone, and in its combination are represented. The treatment was performed in regimens: 1 photodynamic therapy with Photosense (single intravenous injection in dose of 0.3 mg/kg 72 h prior to laser irradiation, power density of irradiation 500 mW/cm2, wavelength 675 nm; 2 drug antiangiogenic therapy with Avastin (single subconjuctival introduction at dose of 1.25 mg; 3 photodynamic therapy with Photosense (in described regimen in combination with subconjuctival introduction of Avastin at dose of 1.25 mg immediately prior to irradiation. Combined photodynamic therapy with antiangiogenic therapy allows to obtain almost complete occlusion in all regions of corneal neovascular bed with shorter time interval comparing with those for monoregimens. In case of blood flow retention in great vessels courses of combined modality treatment may be repeated. The absence of side-effects on surrounding tissues and the recovery of optical characteristics of cornea may allow to use this upcoming method in clinical practice. 

  17. Angiogenic and anti-angiogenic factor gene transcript level quantitation by quantitative real time PCR in patients with hepatocellular carcinoma.

    Science.gov (United States)

    Sharma, Bal Krishan; Srinivasan, Radhika; Kapil, Shweta; Singla, Bhupesh; Chawla, Yogesh Kumar; Chakraborti, Anuradha; Saini, Nitin; Duseja, Ajay; Das, Ashim; Kalra, Naveen; Dhiman, Radha Krishan

    2013-10-01

    Tumor angiogenesis, a major requirement for tumor growth and metastasis, is regulated by pro- and anti-angiogenic factors. The aim of this study was to quantify the expression of angiogenic (VEGF, HIF-1α, Angiopiotein-2) and anti-angiogenic (endostatin, angiostatin and Thrombospondin-1) factors and to discern their clinical relevance. A total 90 patients (67 HCC, 9 cirrhosis and 14 chronic hepatitis) were enrolled in the study. Tissue transcript levels of angiogenic (VEGF, HIF-1α, Ang-2) and anti-angiogenic (endostatin, angiostatin and TSP-1) factors were analyzed by quantitative real time-polymerase chain reaction (qRT-PCR) in the tissue samples. The tissue transcript levels of VEGF, HIF-1α and endostatin were found to be significantly higher in HCC in comparison to cirrhosis and chronic hepatitis. Although Ang-2, angiostatin and TSP-1 tissue transcript levels were higher in HCC group than the others groups but the difference was not statistically significant. In univariate analysis both VEGF and HIF-1α were found to be associated with poor survival of HCC patients. Multivariate analysis by the cox proportional hazard model revealed only VEGF as an independent factor predicting poor survival of the HCC patients. Angiogenic and anti-angiogenic factors are all highly expressed in HCC patients. Upregulation of tissue anti-angiogenic factors indicates the urgency for the alternative of anti-angiogenic therapies.

  18. Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery.

    Directory of Open Access Journals (Sweden)

    Jean-Philip Truman

    Full Text Available BACKGROUND: While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either “normalize” dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery, is provided in the present study. METHODOLOGY/PRINCIPAL FINDINGS: Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase, regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C16-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. In vivo, MCA/129 fibrosarcoma tumors were implanted in asmase+/+ mice or asmase−/− littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in asmase−/− mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect. CONCLUSIONS/SIGNIFICANCE: These studies show that angiogenic factors fail to suppress apoptosis if

  19. Clinical implications of angiogenesis in cancers

    Directory of Open Access Journals (Sweden)

    Roberta WC Pang

    2006-06-01

    Full Text Available Roberta WC Pang1, Ronnie TP Poon2 Departments of 1Medicine and 2Surgery, The University of Hong Kong, Pokfulam, Hong Kong, ChinaAbstract: Angiogenesis plays an important role in the growth and progression of cancer. The regulation of tumor angiogenesis depends on a net balance of angiogenic factors and antiangiogenic factors, which are secreted by both tumor cells and host-infiltrating cells. Numerous studies have indicated that assessment of angiogenic activity by either microvessel density or expression of angiogenic factors in cancer can provide prognostic information independent of conventional clinicopathological factors such as tumor staging. Some studies also suggested that assessment of tumor angiogenesis may predict cancer response to chemotherapy or radiotherapy. However, the most important clinical implication of tumor angiogenesis is the development of a novel strategy of anticancer therapy targeting tumor vessels instead of cancer cells. Antiangiogenic therapy aims to inhibit the growth of tumor, and current evidence suggests that it works best in combination with conventional cytotoxic chemotherapy. Recently, a monoclonal antibody against vascular endothelial growth factor, which is one of the most potent angiogenic factors, has been approved for clinical use in colorectal cancer patients after a clinical trial confirmed that combining the antibody with standard chemotherapy regimen could prolong patient survival. The clinical implications of angiogenesis in cancer are reviewed in this article.Keywords: angiogenesis, antiangiogenic therapy, cancer, prognosis

  20. The anti-proliferative and anti-angiogenic effect of the methanol extract from brittle star.

    Science.gov (United States)

    Baharara, Javad; Amini, Elaheh; Mousavi, Marzieh

    2015-04-01

    Anti-angiogenic therapy is a crucial step in cancer treatment. The discovery of new anti-angiogenic compounds from marine organisms has become an attractive concept in anti-cancer therapy. Because little data correlated to the pro- and anti-angiogenic efficacies of Ophiuroidea, which include brittle star, the current study was designed to explore the anti-angiogenic potential of brittle star methanol extract in vitro and in vivo. The anti-proliferative effect of brittle star extract on A2780cp cells was examined by MTT assays, and transcriptional expression of VEGF and b-FGF was evaluated by RT-PCR. In an in vivo model, 40 fertilized Ross eggs were divided into control and three experimental groups. The experimental groups were incubated with brittle star extract at concentrations of 25, 50 and 100 µg/ml, and photographed by photo-stereomicroscopy. Ultimately, numbers and lengths of vessels were measured by Image J software. Data were analyzed with SPSS software (pstar extract exerted a dose- and time-dependent anti-proliferative effect on A2780cp cancer cells. In addition, VEGF and b-FGF expression decreased with brittle star methanol extract treatment. Macroscopic evaluations revealed significant changes in the second and third experimental group compared to controls (pstar methanol extract in vitro and in vivo confer novel insight into the application of natural marine products in angiogenesis-related pathologies.

  1. Implications of the Bystander and Abscopal Effects of Radiation Therapy.

    Science.gov (United States)

    Verma, Vivek; Lin, Steven H

    2016-10-01

    Siva and colleagues have demonstrated that localized thoracic radiation resulted in DNA damage at out-of-field sites. Although these interesting findings require validation, we discuss the important clinical implications of these data, especially in the era of immune therapies. Clin Cancer Res; 22(19); 4763-5. ©2016 AACRSee related article by Siva et al., p. 4817. ©2016 American Association for Cancer Research.

  2. Retroviral integration profiles: their determinants and implications for gene therapy

    Directory of Open Access Journals (Sweden)

    Kwang-il Lim

    2012-04-01

    Full Text Available Retroviruses have often been used for gene therapy because oftheir capacity for the long-term expression of transgenes via stableintegration into the host genome. However, retroviral integrationcan also result in the transformation of normal cells into cancercells, as demonstrated by the incidence of leukemia in a recentretroviral gene therapy trial in Europe. This unfortunate outcomehas led to the rapid initiation of studies examining variousbiological and pathological aspects of retroviral integration. Thisreview summarizes recent findings from these studies, includingthe global integration patterns of various types of retroviruses,viral and cellular determinants of integration, implications ofintegration for gene therapy and retrovirus-mediated infectiousdiseases, and strategies to shift integration to safe host genomicloci. A more comprehensive and mechanistic understanding ofretroviral integration processes will eventually make it possible togenerate safer retroviral vector platforms in the near future. [BMBreports 2012; 45(4: 207-212

  3. Antiangiogenic VEGF Isoform in Inflammatory Myopathies

    Directory of Open Access Journals (Sweden)

    Nila Volpi

    2013-01-01

    Full Text Available Objective. To investigate expression of vascular endothelial growth factor (VEGF antiangiogenic isoform A-165b on human muscle in idiopathic inflammatory myopathies (IIM and to compare distribution of angiogenic/antiangiogenic VEGFs, as isoforms shifts are described in other autoimmune disorders. Subjects and Methods. We analyzed VEGF-A165b and VEGF-A by western blot and immunohistochemistry on skeletal muscle biopsies from 21 patients affected with IIM (polymyositis, dermatomyositis, and inclusion body myositis and 6 control muscle samples. TGF-β, a prominent VEGF inductor, was analogously evaluated. Intergroup differences of western blot bands density were statistically examined. Endomysial vascularization, inflammatory score, and muscle regeneration, as pathological parameters of IIM, were quantitatively determined and their levels were confronted with VEGF expression. Results. VEGF-A165b was significantly upregulated in IIM, as well as TGF-β. VEGF-A was diffusely expressed on unaffected myofibers, whereas regenerating/atrophic myofibres strongly reacted for both VEGF-A isoforms. Most inflammatory cells and endomysial vessels expressed both isoforms. VEGF-A165b levels were in positive correlation to inflammatory score, endomysial vascularization, and TGF-β. Conclusions. Our findings indicate skeletal muscle expression of antiangiogenic VEGF-A165b and preferential upregulation in IIM, suggesting that modulation of VEGF-A isoforms may occur in myositides.

  4. Penduliflaworosin, a Diterpenoid from Croton crassifolius, Exerts Anti-Angiogenic Effect via VEGF Receptor-2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yeyin Liang

    2017-01-01

    Full Text Available Anti-angiogenesis targeting vascular endothelial growth factor receptor-2 (VEGFR-2 has been considered as an important strategy for cancer therapy. Penduliflaworosin is a diterpenoid isolated from the plant Croton crassifolius. Our previous study showed that this diterpenoid possesses strong anti-angiogenic activity by inhibiting vessel formation in zebrafish. This study was conducted to further investigate the anti-angiogenic activity and mechanism of penduliflaworosin. Results revealed that penduliflaworosin significantly inhibited VEGF-induced angiogenesis processes including proliferation, invasion, migration, and tube formation of human umbilical vein endothelial cells (HUVECs. Moreover, it notably inhibited VEGF-induced sprout formation of aortic rings and blocked VEGF-induced vessel formation in mice. Western blotting studies showed that penduliflaworosin inhibited phosphorylation of the VEGF receptor-2 and its downstream signaling mediators in HUVECs, suggesting that the anti-angiogenic activity was due to an interference with the VEGF/VEGF receptor-2 pathway. In addition, molecular docking simulation indicated that penduliflaworosin could form hydrogen bonds within the ATP-binding region of the VEGF receptor-2 kinase unit. Finally, cytotoxicity assay showed that penduliflaworosin possessed little toxicity toward both cancer and normal cells. Taken together, our findings demonstrate that penduliflaworosin exerts its anti-angiogenic effect via the VEGF receptor-2 signaling pathway. The anti-angiogenic property and low cytotoxicity of penduliflaworosin suggest that it may be useful in cancer treatments.

  5. Antiangiogenic drugs and advanced proliferative diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Jefferson Augusto Santana Ribeiro

    2011-04-01

    Full Text Available Advanced diabetic retinopathy with tractional retinal detachment or persistent vitreous hemorrhage often requires surgical treatment with pars plana vitrectomy. Despite advances in vitrectomy, surgery for complications of diabetic retinopathy can be a challenge and may be impaired by intense fibrovascular proliferation. Antiangiogenic drugs have been used for the treatment of diabetic retinopathy because of their inhibitory action on vascular endothelial growth factor. In this review, we discuss aspects related to the adjuvant use of these drugs in vitrectomy for complications of diabetic retinopathy. Bevacizumab shows beneficial effects regarding the surgical technique facilitation, but its long-term benefit still needs to be studied.

  6. Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer

    International Nuclear Information System (INIS)

    Retsky, Michael W; Hrushesky, William JM; Gukas, Isaac D

    2009-01-01

    Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing. The therapy must be initiated at least one day prior to surgical removal of the primary tumor and kept at a Down syndrome level perhaps indefinitely. That means the drug must have virtually no toxicity and not interfere meaningfully with wound healing. This specifically excludes drugs that significantly inhibit the VEGF pathway since that is important for wound healing and because these agents have some toxicity. Endostatin is apparently non-toxic and does not significantly interfere with wound healing since Down syndrome patients have no abnormal wound healing problems. We propose a therapy for early stage breast cancer consisting of Endostatin at or above Down syndrome levels starting at least one day before surgery and continuing at that level. This should prevent micrometastatic angiogenesis resulting from surgery or at any time later. Adjuvant chemotherapy or hormone therapy should not be necessary. This can be continued indefinitely since there is no acquired resistance that

  7. Antiangiogenic agents and the skin: cutaneous adverse effects of sorafenib, sunitinib, and bevacizumab.

    Science.gov (United States)

    Ara, M; Pastushenko, E

    2014-12-01

    As new antiangiogenic therapies have been introduced and added to the therapeutic arsenal against various types of cancer, previously unknown adverse effects have been detected. These effects negatively impact patients' quality of life and can even make it necessary to suspend treatment. Adverse skin reactions occur in 90% of patients treated with angiogenesis inhibitors. In some cases, a correlation has been observed between the severity of reactions and treatment efficacy and tumor response. It is therefore extremely important that dermatologists be able to recognize and manage these reactions. Moreover, in order to avoid the unjustified withdrawal of potentially life-extending treatments, dermatologists must be able to differentiate between non-life-threatening reactions and life-threatening reactions that necessitate the suspension of treatment. In this review article, we analyze the main cutaneous adverse effects of the most common antiangiogenic agents. Copyright © 2013 Elsevier España, S.L.U. y AEDV. All rights reserved.

  8. Novel production method of innovative antiangiogenic and antitumor small peptides inEscherichia coli.

    Science.gov (United States)

    Setrerrahmane, Sarra; Yu, Jian; Hao, Jingchao; Zheng, Heng; Xu, Hanmei

    2017-01-01

    Developing innovative drugs with potent efficacy, specificity, and high safety remains an ongoing task in antitumor therapy development. In the last few years, peptide drugs have become attractive agents in cancer therapy. HM-3, mainly with antiangiogenic effect, and AP25, with an additional antiproliferative effect, are two peptides designed in our laboratory targeting α v β 3 and α 5 β 1 integrins, respectively. The low molecular weight of the two peptides renders their recombinant expression very difficult, and the complicated structure of AP25 makes its chemical synthesis restricted, which presents a big challenge for its development. Bifunctional peptides designed by the ligation of HM-3 and AP25, using linkers with different flexibility, were prepared using recombinant DNA technology in Escherichia coli . The fusion peptides were expressed in a modified auto-induction medium based on a mixture of glucose, glycerol, and lactose as carbon substrates and NH 4 + as nitrogen source without any amino acid or other elements. Subsequently, the antiangiogenic, antiproliferative, and cell adhesion assays were conducted to evaluate the bioactivity of the two fusion peptides. The peptides were successfully expressed in a soluble form without any induction, which allows the culture to reach higher cell density before protein expression occurs. Human umbilical vein endothelial cell migration assay and chick embryo chorioallantoic membrane assay showed, at low doses, a significantly increased antiangiogenic effect (>75%) of the purified products compared with the single molecules. Meanwhile, MTT assay confirmed their enhanced antitumor activity against gastric cancer cell line MGC-803; however, no significant effect was observed on hepatoma HepG2 cells and no cytotoxicity on normal human lens epithelial cell SRA01/04 and human epithelial esophageal cells. Bifunctional molecules with antiangiogenic and antiproliferative effects were obtained by using this technique

  9. The Implications of Cancer Stem Cells for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Wenjing Jiang

    2012-12-01

    Full Text Available Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs, a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implications and challenges for cancer treatment.

  10. The Dystrophin Complex: Structure, Function, and Implications for Therapy.

    Science.gov (United States)

    Gao, Quan Q; McNally, Elizabeth M

    2015-07-01

    The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, trigger instability of the plasma membrane, and myofiber loss. Mutations in dystrophin have been extensively cataloged, providing remarkable structure-function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches. © 2015 American Physiological Society.

  11. Antiangiogenic ruthenium(ii) benzimidazole complexes, structure-based activation of distinct signaling pathways.

    Science.gov (United States)

    Lai, Haoqiang; Zhao, Zhennan; Li, Linlin; Zheng, Wenjie; Chen, Tianfeng

    2015-03-01

    Antiangiogenic therapy is considered to be a promising strategy for the treatment of cancers. VEGF and its receptors are important angiogenic factors involved in tumor growth. In the present study, the new ruthenium(ii) complexes containing 2,6-bis(benzimidazolyl)pyridine have been identified as potent antiangiogenic agents in vitro and in vivo, through activation of distinct antiangiogenic signaling pathways. Specifically, [Ru(bbp)(p-mpip)Cl]ClO4 (complex , bbp = 2,6-bis(benzimidazolyl)pyridine; p-mpip = 2-(4-methylphenyl)imidazo[4,5-f]-1,10-phenanthroline) exhibited the highest antiangiogenic activity, as evidenced by significant suppression of neovessel formation in chick chorioallantoic membranes and blockage of the angiogenesis in a matrigel plugs assay, which are significantly higher than those of the most accepted anti-metastasis ruthenium-based drug NAMI-A. Generally, these kinds of complexes induced the G0/G1cell cycle by inhibiting the formation of a Cyclin D1/CDK4 complex and CDK2 activation, through up regulation of the expression levels of p15(INK4B), p21(Cip1) and p27(Kip1). Moreover, the complexes also triggered intracellular DNA damage, and thus activated the phosphorylation of ATM, ATR, CHK1, Histone and p53. The suppression of Akt and ERK1/2 pathways reinforced the cell cycle perturbation effects of the complexes. Interestingly, complex displayed strong inhibition on the activation of VEGF and VEGFR-2 phosphorylation, which blocked the transmission of the mitogenic signal through Akt and ERK1/2 pathways, and thus enhanced cell cycle arrest. In contrast, we found that the most accepted anti-metastasis ruthenium based drug NAMI-A exerted lower antiangiogenic activity via activation of the DNA damage-mediated pathway, but showed no effects on VEGF and VEGFR-2 phosphorylation. Taken together, this study clearly demonstrates the distinct antiangiogenic mechanisms of metal complexes, and these kinds of complexes can be further developed as anti

  12. Mitochondrial ROS and cancer drug resistance: Implications for therapy.

    Science.gov (United States)

    Okon, Imoh S; Zou, Ming-Hui

    2015-10-01

    Under physiological conditions, a well-coordinated and balanced redox system exists to ensure that reactive oxygen species (ROS) are appropriately utilized to accomplish specific functions, such as signaling and protein regulation. The influence of ROS within malignant cells, whether for good or bad may depend on several factors, such as tumor and tissue type, disease stage, treatment strategy, as well as duration, specificity and levels of ROS. What then are the known roles of ROS in cancer? Firstly, ROS significantly impacts cancer phenotypes. Secondly, the oxidative ROS property responsible for killing cancer cells, also impact secondary signaling networks. Thirdly, a strong correlation exist between ROS and genetic instability which may promote mutations. Finally, emerging observations suggest a role for mitochondrial ROS in cancer drug resistance, with implications for therapy. The mitochondria is a key regulator of metabolic-redox (meta-redox) alterations within cancer cells. Like a double-edged sword, mitochondrial ROS perturbations in cancer therapy may be beneficial or detrimental. However, harnessing ROS-specific cancer-targeting benefits remain a major challenge. Published by Elsevier Ltd.

  13. Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer.

    Science.gov (United States)

    Pompas-Veganzones, N; Sandonis, V; Perez-Lanzac, Alberto; Beltran, M; Beardo, P; Juárez, A; Vazquez, F; Cozar, J M; Alvarez-Ossorio, J L; Sanchez-Carbayo, Marta

    2016-10-01

    Myopodin is a cytoskeleton protein that shuttles to the nucleus depending on the cellular differentiation and stress. It has shown tumor suppressor functions. Myopodin methylation status was useful for staging bladder and colon tumors and predicting clinical outcome. To our knowledge, myopodin has not been tested in kidney cancer to date. The purpose of this study was to evaluate whether myopodin methylation status could be clinically useful in renal cancer (1) as a prognostic biomarker and 2) as a predictive factor of response to antiangiogenic therapy in patients with metastatic disease. Methylation-specific polymerase chain reactions (MS-PCR) were used to evaluate myopodin methylation in 88 kidney tumors. These belonged to patients with localized disease and no evidence of disease during follow-up (n = 25) (group 1), and 63 patients under antiangiogenic therapy (sunitinib, sorafenib, pazopanib, and temsirolimus), from which group 2 had non-metastatic disease at diagnosis (n = 32), and group 3 showed metastatic disease at diagnosis (n = 31). Univariate and multivariate Cox analyses were utilized to assess outcome and response to antiangiogenic agents taking progression, disease-specific survival, and overall survival as clinical endpoints. Myopodin was methylated in 50 out of the 88 kidney tumors (56.8 %). Among the 88 cases analyzed, 10 of them recurred (11.4 %), 51 progressed (57.9 %), and 40 died of disease (45.4 %). Myopodin methylation status correlated to MSKCC Risk score (p = 0.050) and the presence of distant metastasis (p = 0.039). Taking all patients, an unmethylated myopodin identified patients with shorter progression-free survival, disease-specific survival, and overall survival. Using also in univariate and multivariate models, an unmethylated myopodin predicted response to antiangiogenic therapy (groups 2 and 3) using progression-free survival, disease-specific, and overall survival as clinical endpoints. Myopodin was revealed

  14. In vitro and in vivo anti-angiogenic activities of Panduratin A.

    Directory of Open Access Journals (Sweden)

    Siew-Li Lai

    Full Text Available Targeting angiogenesis has emerged as an attractive and promising strategy in anti-cancer therapeutic development. The present study investigates the anti-angiogenic potential of Panduratin A (PA, a natural chalcone isolated from Boesenbergia rotunda by using both in vitro and in vivo assays.PA exerted selective cytotoxicity on human umbilical vein endothelial cells (HUVECs with IC(50 value of 6.91 ± 0.85 µM when compared to human normal fibroblast and normal liver epithelial cells. Assessment of the growth kinetics by cell impedance-based Real-Time Cell Analyzer showed that PA induced both cytotoxic and cytostatic effects on HUVECs, depending on the concentration used. Results also showed that PA suppressed VEGF-induced survival and proliferation of HUVECs. Furthermore, endothelial cell migration, invasion, and morphogenesis or tube formation demonstrated significant time- and dose-dependent inhibition by PA. PA also suppressed matrix metalloproteinase-2 (MMP-2 secretion and attenuated its activation to intermediate and active MMP-2. In addition, PA suppressed F-actin stress fiber formation to prevent migration of the endothelial cells. More importantly, anti-angiogenic potential of PA was also evidenced in two in vivo models. PA inhibited neo-vessels formation in murine Matrigel plugs, and angiogenesis in zebrafish embryos.Taken together, our study demonstrated the distinctive anti-angiogenic properties of PA, both in vitro and in vivo. This report thus reveals another biological activity of PA in addition to its reported anti-inflammatory and anti-cancer activities, suggestive of PA's potential for development as an anti-angiogenic agent for cancer therapy.

  15. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM)

    Science.gov (United States)

    Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L.; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

    2016-01-01

    Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment. PMID:27706074

  16. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM).

    Science.gov (United States)

    Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

    2016-10-01

    Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

  17. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ in Multiple Myeloma (MM

    Directory of Open Access Journals (Sweden)

    Daniele Tibullo

    2016-10-01

    Full Text Available Multiple myeloma (MM is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC in the bone marrow (BM leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

  18. Antiangiogenic Agent Might Upgrade tumor Cell Sensitivity to Ionizing Radiation

    International Nuclear Information System (INIS)

    Badr, N.M.S.A.

    2013-01-01

    The understanding of the fundamental role of angiogenesis and metastasis in cancer growth has led to tremendous interest in research regarding its regulatory mechanisms and clinical implications in the management of cancer. The present study was conducted to evaluate the influence of the angiogenic regulators modification on the tumor growth and the cell sensitivity to ionizing radiation targeting the improvement of cancer therapeutic protocols. Accordingly, the antiangiogenic activity of apigenin and selenium was tested in vitro via MTT assay. The action of Apigenin and or Selenium was examined in vivo by using a model of solid tumor carcinoma (EAC). The growth rate of solid tumor in all experimental groups was measured by Caliper. The irradiated mice were exposed to 6.5 Gy of gamma rays. Apigenin 50 mg/kg body weight and selenium 5 μg per mice were daily administrated for 14 consecutive days after tumor volume reached 1mm 3 . The angiogenic activators TNF-α (key cytokine) in spleen, serum MMP 2 and MMP 9, liver and tumor NO, the lipid peroxidation (LPx) and angiogenic inhibitor TIMP-1 in spleen as well as, antioxidant markers (CAT, SOD, GPX) in tumor and liver tissue and DNA fragmentation in splenocytes were estimated to monitor efficacy of Apigenin and selenium in cancer treatment strategy. All parameters were determined as a time course on days 16 and 22 after tumor volume reached 1mm 3 . The using of MTT assay on EAC cells shows inhibition in EAC cell proliferation after the incubation with apigenin and /or selenium. The administration of apigenin and /or selenium to mice bearing tumor and to irradiated mice bearing tumor reduce significantly the TNF-α expression, MMP 2,9 , NO , LPx level and increased the antioxidant enzymes (GPx , SOD and CAT) activities. The DNA fragmentation and the antiangiogenic factors TIMP-1 were significantly increased when compared with their values in mice bearing tumor or in irradiated mice bearing tumor. From the results

  19. Novel production method of innovative antiangiogenic and antitumor small peptides in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Setrerrahmane S

    2017-11-01

    Full Text Available Sarra Setrerrahmane,1 Jian Yu,1 Jingchao Hao,1,2 Heng Zheng,3 Hanmei Xu1,3 1The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, Jiangsu, 2College of Pharmacy & the Provincial Key Laboratory of Natural Drug and Pharmacology, Kunming, Yunnan, 3State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China Background: Developing innovative drugs with potent efficacy, specificity, and high safety remains an ongoing task in antitumor therapy development. In the last few years, peptide drugs have become attractive agents in cancer therapy. HM-3, mainly with antiangiogenic effect, and AP25, with an additional antiproliferative effect, are two peptides designed in our laboratory targeting αvβ3 and α5β1 integrins, respectively. The low molecular weight of the two peptides renders their recombinant expression very difficult, and the complicated structure of AP25 makes its chemical synthesis restricted, which presents a big challenge for its development.Methods: Bifunctional peptides designed by the ligation of HM-3 and AP25, using linkers with different flexibility, were prepared using recombinant DNA technology in Escherichia coli. The fusion peptides were expressed in a modified auto-induction medium based on a mixture of glucose, glycerol, and lactose as carbon substrates and NH4+ as nitrogen source without any amino acid or other elements. Subsequently, the antiangiogenic, antiproliferative, and cell adhesion assays were conducted to evaluate the bioactivity of the two fusion peptides.Results: The peptides were successfully expressed in a soluble form without any induction, which allows the culture to reach higher cell density before protein expression occurs. Human umbilical vein endothelial cell migration assay and chick embryo chorioallantoic membrane assay showed, at low doses, a significantly

  20. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Byeong Mo Kim

    2015-11-01

    Full Text Available Ionizing radiation (IR, such as X-rays and gamma (γ-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.

  1. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

    Science.gov (United States)

    Kim, Byeong Mo; Hong, Yunkyung; Lee, Seunghoon; Liu, Pengda; Lim, Ji Hong; Lee, Yong Heon; Lee, Tae Ho; Chang, Kyu Tae; Hong, Yonggeun

    2015-01-01

    Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR. PMID:26569225

  2. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

    International Nuclear Information System (INIS)

    Beal, Kathryn; Abrey, Lauren E; Gutin, Philip H

    2011-01-01

    Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy

  3. The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy

    Science.gov (United States)

    2017-07-01

    kit (Rankin et al., 2012). Tumor sections will be stained and quantified for CD31, an endothelial cell marker . The number of CD31 positive vessels...AWARD NUMBER: W81XWH-15-1-0097 TITLE: The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy PRINCIPAL...SUBTITLE 5a. CONTRACT NUMBER 0097W81XW 0097The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy

  4. Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

    Science.gov (United States)

    Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Molinolo, Alfredo A.; Hodge, James W.

    2014-01-01

    This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771

  5. Sexual dysfunction in hypertensive patients: implications for therapy ...

    African Journals Online (AJOL)

    Sexual dysfunction associated with hypertension or antihypertensive therapies may impact the ability of patients to stay on therapy and lead to deterioration in patients\\' quality of life. Therefore, it is important for practitioners to become familiar with the wide variation in sexual side effects produced by antihypertensive agents ...

  6. Behavior Therapy versus Psychoanalysis: Therapeutic and Social Implications.

    Science.gov (United States)

    Wolpe, Joseph

    1981-01-01

    That psychoanalytic theory has not been displaced by the behavioral theory of neurosis is remarkable in view of the persuasive evidence that exists for the efficacy of behavior therapy. One reason for this seems to be the persistence of widespread misperceptions of behavior therapy. (Author)

  7. Antiangiogenic Effects of VH02, a Novel Urea Derivative: In Vitro and in Vivo Studies

    Directory of Open Access Journals (Sweden)

    Suwadee Phowichit

    2016-09-01

    Full Text Available Vascular endothelial growth factor receptor 2 (VEGFR2 is a vital target for therapeutic intervention in cancer. We have recently described a computer-based drug design for a small molecule VEGFR2 inhibitor named VH02 (1-((1-(1H-indazol-6-yl-1H-1,2,3-triazol-4-ylmethyl-3-(3-chloromethylphenylurea. This study aimed to further explore the anti-angiogenic activity of VH02 both in vitro and in vivo. The in vitro assays include cell viability, capillary-like tube formation, MMP activity, and western blot analyses of signaling through VEGFR2 while the in vivo anti-angiogenic response were performed to evaluate the effect on vascularization in Matrigel plug applied in C57BL/6L mice. VH02 reduced angiogenesis behavior of EA.hy926 including cell viability, migration, adhesion, capillary-like tube formation, and MMP-2 activity induced by VEGF. Furthermore, VH02 regulated angiogenesis by directly inhibiting VEGFR2 on Tyr1175 signaling pathway leading to the inhibition of Akt-mediated cell survival and migration. Disruption of phosphorylation at VEGFR2-Tyr1175 by VH02 abolished FAK-Tyr397 signaling but not phosphorylation of p38 MAPK. This suggests that blockade of FAK by VH02 apparently associated with reduction of endothelial cell motility. Actin cytoskeleton rearrangement was diminished by VH02 in human endothelial cells. The anti-angiogenic effect of VH02 was confirmed in the in vivo model, revealing the reduction of vascular density in Matrigel plug after VH02 treatment. Additionally, the pericyte-like cells surrounding blood vessels in the plugs were significantly reduced as well as vascular density and p-Akt intensity. Our findings indicate that VH02 successfully inhibits VEGF-induced angiogenesis both in vitro and in vivo models. The compound could be further developed as an antiangiogenesis agent for cancer therapy.

  8. Implications of CI therapy for Visual Deficit Training

    Directory of Open Access Journals (Sweden)

    Edward eTaub

    2014-10-01

    Full Text Available We address here the question of whether the techniques of CI therapy, a family of treatments that has been employed in the rehabilitation of movement and language after brain damage might apply to the rehabilitation of such visual deficits as unilateral spatial neglect and visual field deficits. CI therapy has been used successfully for the upper and lower extremities after chronic stroke, cerebral palsy (CP, multiple sclerosis (MS, other CNS degenerative conditions, resection of motor areas of the brain, focal hand dystonia, and aphasia. Treatments making use of similar methods have proven efficacious for amblyopia.The CI therapy approach consists of four major components: intensive training, training by shaping, a transfer package to facilitate the transfer of gains from the treatment setting to everyday activities, and strong discouragement of compensatory strategies.CI therapy is said to be effective because it overcomes learned nonuse, a learned inhibition of movement that follows injury to the CNS. In addition, CI therapy produces substantial increases in the grey matter of motor areas on both sides of the brain. We propose here that these mechanisms are examples of more general processes: learned nonuse being considered parallel to sensory nonuse following damage to sensory areas of the brain, with both having in common diminished neural connections (DNC in the nervous system as an underlying mechanism. CI therapy would achieve its therapeutic effect by strengthening the diminished neural connections. Use-dependent cortical reorganization is considered to be an example of the more general neuroplastic mechanism of brain structure repurposing (BSR. If the mechanisms involved in these broader categories are involved in each of the deficits being considered, then it may be the principles underlying efficacious treatment in each case may be similar. The lessons learned during CI therapy research might then prove useful for the treatment of

  9. Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality.

    Science.gov (United States)

    Lord, Simon; Funes, Juan M; Harris, Adrian L; Quintela-Fandino, Miguel

    2016-01-01

    Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs.

  10. Breast Cancer Biology: Clinical Implications for Breast Radiation Therapy.

    Science.gov (United States)

    Horton, Janet K; Jagsi, Reshma; Woodward, Wendy A; Ho, Alice

    2018-01-01

    Historically, prognosis and treatment decision making for breast cancer patients have been dictated by the anatomic extent of tumor spread. However, in recent years, "breast cancer" has proven to be a collection of unique phenotypes with distinct prognoses, patterns of failure, and treatment responses. Recent advances in biologically based assays and targeted therapies designed to exploit these unique phenotypes have profoundly altered systemic therapy practice patterns and treatment outcomes. Data associating locoregional outcomes with tumor biology are emerging. However, the likelihood of obtaining level I evidence for fundamental radiation therapy questions within each of the specific subtypes in the immediate future is low. As such, this review aims to summarize the existing data and provide practical context for the incorporation of breast tumor biology into clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Novel insights into mesothelioma biology and implications for therapy.

    Science.gov (United States)

    Yap, Timothy A; Aerts, Joachim G; Popat, Sanjay; Fennell, Dean A

    2017-07-25

    Malignant mesothelioma is a universally lethal cancer that is increasing in incidence worldwide. There is a dearth of effective therapies, with only one treatment (pemetrexed and cisplatin combination chemotherapy) approved in the past 13 years. However, the past 5 years have witnessed an exponential growth in our understanding of mesothelioma pathobiology, which is set to revolutionize therapeutic strategies. From a genomic standpoint, mesothelioma is characterized by a preponderance of tumour suppressor alterations, for which novel therapies are currently in development. Other promising antitumour agents include inhibitors against angiogenesis, mesothelin and immune checkpoints, which are at various phases of clinical trial testing.

  12. Improvements in progression-free and overall survival due to the use of anti-angiogenic agents in gynecologic cancers.

    Science.gov (United States)

    Schmid, Bernd C; Oehler, Martin K

    2015-01-01

    In ovarian cancer (OC), the best established anti-angiogenic drug, bevacizumab, has demonstrated only modest prolonged progression free survival (PFS) and no increased overall survival (OS). The unanswered question is in which clinical situation bevacizumab might benefit ovarian cancer patients most. The cost-benefit analysis in the primary treatment was found not to be favorable but the use in the recurrent OC setting might be more compelling. Multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKI) such as cediranib and pazopanib have shown some therapeutic benefits with improvements of PFS and OS in patients with platinum-sensitive as well as resistant OC, in whom there is a major need for novel therapies. Very promising is also the observed improvement of PFS in recurrent OC in patients when combining cediranib with the PARP inhibitor olaparib without giving additional chemotherapy. The anti-angiogenic agent trebananib has achieved similar results like TKI, but has a favorable toxicity profile which does not overlap with those of VEGF inhibitors. In cervical cancer the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent or metastatic chemotherapy-naive disease results in a significant increase in OS. Considering the lack of therapeutic options in this difficult clinical setting, the inclusion of bevacizumab most likely will become a new standard for recurrent cervical cancer. In uterine sarcomas as very aggressive malignancies with a substantial need for better therapies the observed improved PFS with sorafenib warrants further investigation. No data showing a convincing improvement of survival in endometrial cancer have been presented yet. In view of the limited PFS and OS benefit observed with anti-angiogenics in gynecologic oncology, increased morbidity due to side effects of this treatment resulting in loss of quality of life and also substantial costs have to be taken into consideration. Thorough case selection

  13. Apoptosis and cancer stem cells : Implications for apoptosis targeted therapy

    NARCIS (Netherlands)

    Kruyt, Frank A. E.; Schuringa, Jan Jacob

    2010-01-01

    Evidence is accumulating showing that cancer stem cells or tumor-initiating cells are key drivers of tumor formation and progression. Successful therapy must therefore eliminate these cells, which is hampered by their high resistance to commonly used treatment modalities. Thus far, only a limited

  14. Hypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells.

    LENUS (Irish Health Repository)

    Wang, Jiang Huai

    2012-02-03

    BACKGROUND: Hypoxia in solid tumors potentially stimulates angiogenesis by promoting vascular endothelial growth factor (VEGF) production and upregulating VEGF receptor expression. However, it is unknown whether hypoxia can modulate the effect of anti-angiogenic treatment on tumor-derived endothelium. METHODS: Human tumor-derived endothelial cells (HTDEC) were freshly isolated from surgically removed human colorectal tumors by collagenase\\/DNase digestion and Percol gradient sedimentation. Cell proliferation was assessed by measuring BrdU incorporation, and capillary tube formation was measured using Matrigel. Cell apoptosis was assessed by flow cytometry and ELISA, and Bcl-2 expression was detected by Western blot analysis. RESULTS: Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-gamma-induced apoptosis with significant reductions in both cell proliferation and capillary tube formation, when compared with normal human macrovascular and microvascular EC. Following exposure of HTDEC to hypoxia (5% CO2 plus 2% O2), IFN-gamma-induced cell apoptosis, and antiangiogenic activity (i.e. an inhibition in cell proliferation and capillary tube formation) in HTDEC were markedly attenuated. This finding correlated with hypoxia-induced upregulation of Bcl-2 expression in HTDEC. CONCLUSIONS: These results indicate that hypoxia can protect HTDEC against IFN-gamma-mediated cell death and antiangiogenic activity, and suggest that improvement of tumor oxygenation may potentiate the efficacy of anti-cancer therapies specifically targeting the inhibition of tumor angiogenesis.

  15. The cell based therapy and the policy implications in India.

    Science.gov (United States)

    Mukhopadhyay, Bratati; Basak, Saroj K; Ganguly, Nirmal K

    2011-01-01

    The recent scientific development using stem or other differentiated cells has generated great hopes for treatment of various diseases. Major thrust has been given to formulate country specific laws and regulations considering international guidelines to conduct research and clinical applications of "Cell Based Therapy" (CBT) all over the world. Attempts have made in this review to discuss the current policies that are practiced by various countries in the areas related to CBT with special emphasis on CBT related research and development in India. The two major funding agencies of Government of India e.g. Department of Biotechnology (DBT) and Indian Council of Medical Research (ICMR), have jointly formulated the "Guidelines for Stem Cell Research and Therapy" in 2007 which requires update and revision. Based on the review of the current world scenario of CBT research and development, suggestions have been made for the development of a new CBT policy that will help in progress of research and patient treatment in India.

  16. Schema Therapy for Emotional Dysregulation: Theoretical Implication and Clinical Applications

    Science.gov (United States)

    Dadomo, Harold; Grecucci, Alessandro; Giardini, Irene; Ugolini, Erika; Carmelita, Alessandro; Panzeri, Marta

    2016-01-01

    The term emotional dysregulation refers to an impaired ability to regulate unwanted emotional states. Scientific evidence supports the idea that emotional dysregulation underlies several psychological disorders as, for example: personality disorders, bipolar disorder type II, interpersonal trauma, anxiety disorders, mood disorders and post-traumatic stress disorder. Emotional dysregulation may derive from early interpersonal traumas in childhood. These early traumatic events create a persistent sensitization of the central nervous system in relation to early life stressing events. For this reason, some authors suggest a common endophenotypical origin across psychopathologies. In the last 20 years, cognitive behavioral therapy has increasingly adopted an interactive-ontogenetic view to explain the development of disorders associated to emotional dysregulation. Unfortunately, standard Cognitive Behavior Therapy (CBT) methods are not useful in treating emotional dysregulation. A CBT-derived new approach called Schema Therapy (ST), that integrates theory and techniques from psychodynamic and emotion focused therapy, holds the promise to fill this gap in cognitive literature. In this model, psychopathology is viewed as the interaction between the innate temperament of the child and the early experiences of deprivation or frustration of the subject’s basic needs. This deprivation may lead to develop early maladaptive schemas (EMS), and maladaptive Modes. In the present paper we point out that EMSs and Modes are associated with either dysregulated emotions or with dysregulatory strategies that produce and maintain problematic emotional responses. Thanks to a special focus on the therapeutic relationship and emotion focused-experiential techniques, this approach successfully treats severe emotional dysregulation. In this paper, we make several comparisons between the main ideas of ST and the science of emotion regulation, and we present how to conceptualize pathological

  17. Targeted therapy of brain metastases: latest evidence and clinical implications.

    Science.gov (United States)

    Di Lorenzo, Rodica; Ahluwalia, Manmeet S

    2017-12-01

    Brain metastases (BM) occur in 20-40% of patients with cancer and 60-75% of patients with BM become symptomatic. Due to an aging population and advances in the treatment of primary cancers, patients are living longer and are more likely to experience complications from BM. The diagnosis of BM drastically worsens long-term survival rates, with multiple metastases being a poor prognostic factor. Until recently, the mainstay of treatment consisted of stereotactic radiosurgery (SRS), surgical resection, whole brain radiation therapy (WBRT), or a combination of these modalities. Systemic chemotherapy has been felt largely ineffective in the treatment of BM due to the presence of the blood-brain barrier (BBB), which includes efflux pumps on brain capillaries. Over the past decade however, researchers have identified therapeutic agents that are able to cross the BBB. These findings could make a multimodality treatment approach possible, consisting of surgery, radiation, immunotherapy, and targeted therapy, which could lead to better disease control in this patient population and prolong survival. In this review, we discuss present evidence on available targeted therapies and their role in the treatment of BM from primary tumors with the highest prevalence of central nervous system (CNS) involvement, specifically non-small cell lung cancer (NSCLC), breast cancer melanoma, and renal cell carcinoma.

  18. Evaluation of high frequency ultrasound methods and contrast agents for characterising tumor response to anti-angiogenic treatment

    Energy Technology Data Exchange (ETDEWEB)

    Rix, Anne, E-mail: arix@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Lederle, Wiltrud, E-mail: wlederle@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Siepmann, Monica, E-mail: monica.siepmann@rub.de [Department of Medical Engineering, Universitätstraße 150, 44780 Bochum, Ruhr-University Bochum, Bochum (Germany); Fokong, Stanley, E-mail: sfokong@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Behrendt, Florian F., E-mail: fbehrendt@ukaachen.de [Department of Nuclear Medicine, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Bzyl, Jessica, E-mail: jbzyl@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Grouls, Christoph, E-mail: cgrouls@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Kiessling, Fabian, E-mail: fkiessling@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Palmowski, Moritz, E-mail: mpalmowski@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Department of Nuclear Medicine, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany)

    2012-10-15

    Purpose: To compare non-enhanced and contrast-enhanced high-frequency 3D Doppler ultrasound with contrast-enhanced 2D and 3D B-mode imaging for assessing tumor vascularity during antiangiogenic treatment using soft-shell and hard-shell microbubbles. Materials and methods: Antiangiogenic therapy effects (SU11248) on vascularity of subcutaneous epidermoid-carcinoma xenografts (A431) in female CD1 nude mice were investigated longitudinally using non-enhanced and contrast-enhanced 3D Doppler at 25 MHz. Additionally, contrast-enhanced 2D and 3D B-mode scans were performed by injecting hard-shell (poly-butyl-cyanoacrylate-based) and soft-shell (phospholipid-based) microbubbles. Suitability of both contrast agents for high frequency imaging and the sensitivity of the different ultrasound methods to assess early antiangiogenic therapy effects were investigated. Ultrasound data were validated by immunohistology. Results: Hard-shell microbubbles induced higher signal intensity changes in tumors than soft-shell microbubbles in 2D B-mode measurements (424 ± 7 vs. 169 ± 8 A.U.; p < 0.01). In 3D measurements, signals of soft-shell microbubbles were hardly above the background (5.48 ± 4.57 vs. 3.86 ± 2.92 A.U.), while signals from hard-shell microbubbles were sufficiently high (30.5 ± 8.06 A.U). Using hard-shell microbubbles 2D and 3D B-mode imaging depicted a significant decrease in tumor vascularity during antiangiogenic therapy from day 1 on. Using soft-shell microbubbles significant therapy effects were observed at day 4 after therapy in 2D B-mode imaging but could not be detected in the 3D mode. With non-enhanced and contrast-enhanced Doppler imaging significant differences between treated and untreated tumors were found from day 2 on. Conclusion: Hard-shell microbubble-enhanced 2D and 3D B-mode ultrasound achieved highest sensitivity for assessing therapy effects on tumor vascularisation and were superior to B-mode ultrasound with soft-shell microbubbles and to Doppler

  19. Osteoporosis and osteopenia: implications for periodontal and implant therapy.

    Science.gov (United States)

    Otomo-Corgel, Joan

    2012-06-01

    How does low bone mineral density alter treatment decisions? Osteoporosis and osteopenia are major health care issues that may impact on periodontal and implant therapy. Because of the prevalence of osteoporosis, understanding its etiology and the current treatment regimens for patients with low bone mineral density is essential for dental professionals. Millions of patients are now taking medications for the treatment of osteoporosis, and periodontists should be aware of the many medication options that are prescribed. The most frequently prescribed drugs are the bisphosphonates. It is important to be aware that bisphosphonates are not all the same, and patient responses to treatment may vary depending on which bisphosphonates they are taking. Due to recent concerns about bisphosphonate-induced osteonecrosis of the jaw, this paper provides guidance to help the clinician regarding decision-making about preventive and interventional dental treatment when their patient has been prescribed a bisphosphonate. An understanding of current bisphosphonates, their uses, their structural differences and their intended actions helps to improve clinical decision-making. Current knowledge regarding the effects of osteoporosis/osteopenia on periodontal diseases and alveolar bone loss is inconclusive. It is certainly clear that bisphosphonates are not indicated as an adjunctive treatment as part of periodontal therapy because of the risk of osteonecrosis. Regarding implant placement, there are no convincing data that dental implant placement is contraindicated in the osteoporotic patient. However, patients should understand the small risk of compromised bone healing following implant placement if the patient has been taking bisphosphonates. Due to the risks of osteonecrosis, dental clinicians should work closely with their medical colleagues prior to the physician prescribing oral bisphosphonates. Ideally, optimal periodontal and dental health should be established before the

  20. Restoring Wisconsin Art Therapy Association in Art Therapy History: Implications for Professional Definition and Inclusivity

    Science.gov (United States)

    Potash, Jordan; Burnie, Michele; Pearson, Rosemary; Ramirez, Wayne

    2016-01-01

    The Wisconsin Art Therapy Association (WATA), formally established in 1969, was the first incorporated organization of art therapists in the United States. Under the leadership of Wayne Ramirez, WATA lobbied the national association for an inclusive definition of art therapy that aimed to foster respect for psychiatric, educational, and community…

  1. Bacteriophage Interactions with Marine Pathogenic Vibrios: Implications for Phage Therapy

    Science.gov (United States)

    Castillo, Daniel

    2018-01-01

    A global distribution in marine, brackish, and freshwater ecosystems, in combination with high abundances and biomass, make vibrios key players in aquatic environments, as well as important pathogens for humans and marine animals. Incidents of Vibrio-associated diseases (vibriosis) in marine aquaculture are being increasingly reported on a global scale, due to the fast growth of the industry over the past few decades years. The administration of antibiotics has been the most commonly applied therapy used to control vibriosis outbreaks, giving rise to concerns about development and spreading of antibiotic-resistant bacteria in the environment. Hence, the idea of using lytic bacteriophages as therapeutic agents against bacterial diseases has been revived during the last years. Bacteriophage therapy constitutes a promising alternative not only for treatment, but also for prevention of vibriosis in aquaculture. However, several scientific and technological challenges still need further investigation before reliable, reproducible treatments with commercial potential are available for the aquaculture industry. The potential and the challenges of phage-based alternatives to antibiotic treatment of vibriosis are addressed in this review. PMID:29495270

  2. Bacteriophage Interactions with Marine Pathogenic Vibrios: Implications for Phage Therapy

    Directory of Open Access Journals (Sweden)

    Panos G. Kalatzis

    2018-02-01

    Full Text Available A global distribution in marine, brackish, and freshwater ecosystems, in combination with high abundances and biomass, make vibrios key players in aquatic environments, as well as important pathogens for humans and marine animals. Incidents of Vibrio-associated diseases (vibriosis in marine aquaculture are being increasingly reported on a global scale, due to the fast growth of the industry over the past few decades years. The administration of antibiotics has been the most commonly applied therapy used to control vibriosis outbreaks, giving rise to concerns about development and spreading of antibiotic-resistant bacteria in the environment. Hence, the idea of using lytic bacteriophages as therapeutic agents against bacterial diseases has been revived during the last years. Bacteriophage therapy constitutes a promising alternative not only for treatment, but also for prevention of vibriosis in aquaculture. However, several scientific and technological challenges still need further investigation before reliable, reproducible treatments with commercial potential are available for the aquaculture industry. The potential and the challenges of phage-based alternatives to antibiotic treatment of vibriosis are addressed in this review.

  3. Gastric emptying rate in the elderly: implications for drug therapy

    International Nuclear Information System (INIS)

    Evans, M.A.; Triggs, E.J.; Cheung, M.; Broe, G.A.; Creasey, H.

    1981-01-01

    The effect of the aging process on gastric emptying was studied in 11 elderly subjects (mean age, 77) and in 7 young healthy volunteers (mean age, 26). Gastric emptying rates were assessed by a modified sequential scinti-scanning technique after administration of the nonabsorbable chelated radiopharmaceutical 99mTc-DTPA. The rate of emptying, expressed as half-time (T 1/2e) in minutes, was significantly longer (p less than 0.001) in the elderly subjects (mean apparent T 1/2e . 123.23 min) compared to the young healthy volunteers (mean apparent T 1/2e . 49.69 min). Clinical implications of these findings are discussed, particularly with respect to the rate and extent of drug absorption in elderly persons

  4. Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids.

    Science.gov (United States)

    Ambrożak, Agnieszka; Steinebach, Christian; Gardner, Erin R; Beedie, Shaunna L; Schnakenburg, Gregor; Figg, William D; Gütschow, Michael

    2016-12-06

    The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an ex vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen-bond networking, as revealed by comparative X-ray crystallographic analyses. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Potential implications of cell therapy for osteogenesis imperfecta

    Science.gov (United States)

    Niyibizi, Christopher; Li, Feng

    2009-01-01

    Osteogenesis imperfecta (OI) is a brittle-bone disease whose hallmark is bone fragility. Since the disease is genetic, there is currently no available cure. Several pharmacological agents have been tried with not much success, except the recent use of bisphosphonates. Stem cells have been suggested as an alternative OI treatment, but many hurdles remain before this technology can be applied for treating patients with OI. This review summarizes what is known at present regarding the application of stem cells to treat OI using animal models, clinical trials using mesenchymal stem cells to treat patients with OI and the knowledge gained from the clinical trials. Application of gene therapy in combination with stem cells is also discussed. The hurdles to be overcome to bring stem cells close to the clinic and future perspectives are discussed. PMID:20490372

  6. Genetic basis of type 2 diabetes mellitus: implications for therapy

    DEFF Research Database (Denmark)

    Wolford, Johanna K; de Courten, Barbora

    2004-01-01

    Type 2 diabetes mellitus represents a multifactorial, heterogeneous group of disorders, which result from defects in insulin secretion, insulin action, or both. The prevalence of type 2 diabetes has increased dramatically worldwide over the past several decades, a trend that has been heavily...... in the management of type 2 diabetes include lifestyle intervention through diet modification and exercise, and oral or injected hypoglycemic agents; however, not all individuals with type 2 diabetes respond in the same way to these treatments. Because of variability in the clinical course of the disease...... and in the responsiveness to pharmacologic therapies, identification and characterization of the genetic variants underlying type 2 diabetes susceptibility will be important in the development of individualized treatment. Findings from linkage analyses, candidate gene studies, and animal models will be valuable...

  7. Shoulder Impingement Syndromes: Implications on Physical Therapy Examination and Intervention

    Science.gov (United States)

    2005-01-01

    A painful shoulder presents challenges in examination, diagnosis and intervention for the physical therapist because of the complexity of the structures involved. A common cause of shoulder pain is shoulder impingement syndrome. This was first described as a condition in which the soft tissues of the subacromial space were chronically entrapped and compressed between the humeral head and the subacromial arch. This definition does not account for the myriad potential causes of shoulder impingement conditions, as forms of impingement other than subacromial soft tissue compression may explain different symptomatic shoulder injuries. This paper describes shoulder impingement syndromes that have been hypothesized, identified and analyzed in the literature. Physical Therapy examination and intervention for these syndromes are also discussed. PMID:25792938

  8. Novel peptide-specific quantitative structure-activity relationship (QSAR) analysis applied to collagen IV peptides with antiangiogenic activity.

    Science.gov (United States)

    Rivera, Corban G; Rosca, Elena V; Pandey, Niranjan B; Koskimaki, Jacob E; Bader, Joel S; Popel, Aleksander S

    2011-10-13

    Angiogenesis is the growth of new blood vessels from existing vasculature. Excessive vascularization is associated with a number of diseases including cancer. Antiangiogenic therapies have the potential to stunt cancer progression. Peptides derived from type IV collagen are potent inhibitors of angiogenesis. We wanted to gain a better understanding of collagen IV structure-activity relationships using a ligand-based approach. We developed novel peptide-specific QSAR models to study the activity of the peptides in endothelial cell proliferation, migration, and adhesion inhibition assays. We found that the models produced quantitatively accurate predictions of activity and provided insight into collagen IV derived peptide structure-activity relationships.

  9. BRAFV600E: implications for carcinogenesis and molecular therapy.

    LENUS (Irish Health Repository)

    Cantwell-Dorris, Emma R

    2012-02-01

    The mitogen-activated protein kinase (MAPK)\\/extracellular signal-regulated kinase (ERK) pathway is frequently mutated in human cancer. This pathway consists of a small GTP protein of the RAS family that is activated in response to extracellular signaling to recruit a member of the RAF kinase family to the cell membrane. Active RAF signals through MAP\\/ERK kinase to activate ERK and its downstream effectors to regulate a wide range of biological activities including cell differentiation, proliferation, senescence, and survival. Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers. The BRAF pathway has become a target of interest for molecular therapy, with promising results emerging from clinical trials. Here, the role of the most common BRAF mutation BRAF(V600E) in human carcinogenesis is investigated through a review of the literature, with specific focus on its role in melanoma, colorectal, and thyroid cancers and its potential as a therapeutic target.

  10. Autophagy in breast cancer and its implications for therapy

    Science.gov (United States)

    Jain, Kirti; Paranandi, Krishna S; Sridharan, Savitha; Basu, Alakananda

    2013-01-01

    Autophagy is an evolutionarily conserved process of cellular self-digestion that serves as a mechanism to clear damaged organelles and recycle nutrients. Since autophagy can promote cell survival as well as cell death, it has been linked to different human pathologies, including cancer. Although mono-allelic deletion of autophagy-related gene BECN1 in breast tumors originally indicated a tumor suppressive role for autophagy in breast cancer, the intense research during the last decade suggests a role for autophagy in tumor progression. It is now recognized that tumor cells often utilize autophagy to survive various stresses, such as oncogene-induced transformation, hypoxia, endoplasmic reticulum (ER) stress and extracellular matrix detachment. Induction of autophagy by tumor cells may also contribute to tumor dormancy and resistance to anticancer therapies, thus making autophagy inhibitors promising drug candidates for breast cancer treatment. The scientific endeavors continue to define a precise role for autophagy in breast cancer. In this article, we review the current literature on the role of autophagy during the development and progression of breast cancer, and discuss the potential of autophagy modulators for breast cancer treatment. PMID:23841025

  11. Health economics of insomnia therapy: implications for policy.

    Science.gov (United States)

    Botteman, Marc

    2009-09-01

    Chronic primary insomnia is a major public health problem causing significant burden for those affected. Rising health care costs may cause increased financial pressures on governments and private payers, forcing stricter cost-control measures and, as a result, insomnia, often considered a lifestyle condition, may not receive the proper attention it deserves. In order to highlight the benefits that can be achieved through successful treatment of insomnia, there is a need for further comparative studies of existing and emerging treatments, cost burden of illness and cost-effectiveness analyses. Health economic assessment of insomnia and its treatments is an emerging area. The development of comprehensive assessment of insomnia treatments, however, has been hindered by complexities and gaps in the available data. Health economic models of insomnia, such as the one detailed here, should enable researchers to better address the effects of different treatments on clinical and economic measures for insomnia and related comorbidities. It is apparent that research into the cost-effectiveness of therapies for insomnia is in its infancy and further work is needed.

  12. Cognitive behavior therapy with Internet addicts: treatment outcomes and implications.

    Science.gov (United States)

    Young, Kimberly S

    2007-10-01

    Research over the last decade has identified Internet addiction as a new and often unrecognized clinical disorder that impact a user's ability to control online use to the extent that it can cause relational, occupational, and social problems. While much of the literature explores the psychological and social factors underlying Internet addiction, little if any empirical evidence exists that examines specific treatment outcomes to deal with this new client population. Researchers have suggested using cognitive behavioral therapy (CBT) as the treatment of choice for Internet addiction, and addiction recovery in general has utilized CBT as part of treatment planning. To investigate the efficacy of using CBT with Internet addicts, this study investigated 114 clients who suffered from Internet addiction and received CBT at the Center for Online Addiction. This study employed a survey research design, and outcome variables such as client motivation, online time management, improved social relationships, improved sexual functioning, engagement in offline activities, and ability to abstain from problematic applications were evaluated on the 3rd, 8th, and 12th sessions and over a 6-month follow-up. Results suggested that Caucasian, middle-aged males with at least a 4-year degree were most likely to suffer from some form of Internet addiction. Preliminary analyses indicated that most clients were able to manage their presenting complaints by the eighth session, and symptom management was sustained upon a 6-month follow-up. As the field of Internet addiction continues to grow, such outcome data will be useful in treatment planning with evidenced-based protocols unique to this emergent client population.

  13. Multigenic lentiviral vectors for combined and tissue-specific expression of miRNA- and protein-based antiangiogenic factors

    Directory of Open Access Journals (Sweden)

    Anne Louise Askou

    Full Text Available Lentivirus-based gene delivery vectors carrying multiple gene cassettes are powerful tools in gene transfer studies and gene therapy, allowing coexpression of multiple therapeutic factors and, if desired, fluorescent reporters. Current strategies to express transgenes and microRNA (miRNA clusters from a single vector have certain limitations that affect transgene expression levels and/or vector titers. In this study, we describe a novel vector design that facilitates combined expression of therapeutic RNA- and protein-based antiangiogenic factors as well as a fluorescent reporter from back-to-back RNApolII-driven expression cassettes. This configuration allows effective production of intron-embedded miRNAs that are released upon transduction of target cells. Exploiting such multigenic lentiviral vectors, we demonstrate robust miRNA-directed downregulation of vascular endothelial growth factor (VEGF expression, leading to reduced angiogenesis, and parallel impairment of angiogenic pathways by codelivering the gene encoding pigment epithelium-derived factor (PEDF. Notably, subretinal injections of lentiviral vectors reveal efficient retinal pigment epithelium-specific gene expression driven by the VMD2 promoter, verifying that multigenic lentiviral vectors can be produced with high titers sufficient for in vivo applications. Altogether, our results suggest the potential applicability of combined miRNA- and protein-encoding lentiviral vectors in antiangiogenic gene therapy, including new combination therapies for amelioration of age-related macular degeneration.

  14. Alpha-V Integrin Targeted PET Imagining of Breast Cancer Angiogenesis and Lose-Dose Metronomic Anti-Angiogenic Chemotherapy Efficacy

    Science.gov (United States)

    2005-08-01

    reabsorption of the dimeric RGD peptide and its Bodkin DJ, Cheresh DA (2000). Targeted antiangiogenic therapy Molecular Imaging * Vol. 3, No. 2, April...room lit for 12 hours each day and maintained at 27°C for 1 hour postinjection by cervical dislocation under ketamine/ 2 days prior to injection. Teklad...presence of various concentrations of RGD peptide cervical dislocation under ketaimine-xylazine anesthesia, and (0.1 nmol/L-5 pnmol/L) at room

  15. Sprouting strategies and dead ends in anti-angiogenic targeting of NETs.

    Science.gov (United States)

    Carrasco, Patricia; Zuazo-Gaztelu, Iratxe; Casanovas, Oriol

    2017-07-01

    Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that arise from cells of the neuroendocrine system. NETs are characterized by being highly vascularized tumors that produce large amounts of proangiogenic factors. Due to their complexity and heterogeneity, progress in the development of successful therapeutic approaches has been limited. For instance, standard chemotherapy-based therapies have proven to be poorly selective for tumor cells and toxic for normal tissues. Considering the urge to develop an efficient therapy to treat NET patients, vascular targeting has been proposed as a new approach to block tumor growth. This review provides an update of the mechanisms regulating different components of vessels and their contribution to tumor progression in order to develop new therapeutic drugs. Following the description of classical anti-angiogenic therapies that target VEGF pathway, new angiogenic targets such as PDGFs, EGFs, FGFs and semaphorins are further explored. Based on recent research in the field, the combination of therapies that target multiple and different components of vessel formation would be the best approach to specifically target NETs and inhibit tumor growth. © 2017 The authors.

  16. VEGFR2 heterogeneity and response to anti-angiogenic low dose metronomic cyclophosphamide treatment

    Directory of Open Access Journals (Sweden)

    Skowronski Karolina

    2010-12-01

    stabilization of colorectal microvessels, but no such change in melanoma vessels. Conclusions Overall, our study suggests that while heterogeneous expression of VEGFR2 is a feature of human tumors, it may not affect response to low dose metronomic cyclophosphamide treatment and possibly other anti-angiogenic approaches. It remains to be seen whether this heterogeneity is partly responsible for the variable clinical success seen to date with targeted anti-VEGFR2 therapy.

  17. VEGFR2 heterogeneity and response to anti-angiogenic low dose metronomic cyclophosphamide treatment

    International Nuclear Information System (INIS)

    Patten, Steven G; Adamcic, Una; Lacombe, Kristen; Minhas, Kanwal; Skowronski, Karolina; Coomber, Brenda L

    2010-01-01

    such change in melanoma vessels. Overall, our study suggests that while heterogeneous expression of VEGFR2 is a feature of human tumors, it may not affect response to low dose metronomic cyclophosphamide treatment and possibly other anti-angiogenic approaches. It remains to be seen whether this heterogeneity is partly responsible for the variable clinical success seen to date with targeted anti-VEGFR2 therapy

  18. Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia.

    Science.gov (United States)

    Nayeri, Unzila A; Buhimschi, Irina A; Laky, Christine A; Cross, Sarah N; Duzyj, Christina M; Ramma, Wenda; Sibai, Baha M; Funai, Edmund F; Ahmed, Asif; Buhimschi, Catalin S

    2014-06-01

    Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

  19. Investigation into health science students' awareness of occupational therapy: implications for interprofessional education.

    Science.gov (United States)

    Alotaibi, Naser; Shayea, Abdulaziz; Nadar, Mohammed; Abu Tariah, Hashem

    2015-01-01

    To investigate the level of awareness of the occupational therapy profession among final-year health sciences students at Kuwait University. This study utilized a survey targeting final-year students in the Health Sciences Center at Kuwait University schools of medicine, pharmacy, dentistry, and allied health sciences. The survey addressed awareness of occupational therapy, its scope of practice, work environments, and preference for learning more about the profession. Of the 244 surveys distributed, 132 were returned, for a 54% response rate. The proportion of those who knew about occupational therapy ranged from 94% (radiologic science) to a low of 17% (medicine). Most respondents learned about occupational therapy from colleagues (77.1%), rather than from their academic programs (28.1%). RESULTS indicated that about one fifth of students (21.4%) were unsure about the role of occupational therapists as members of the health care team. Preferences for learning more about the profession were consistent with interprofessional opportunities, such as observing an occupational therapy session (64.5%) and attending a workshop (63.6%) or presentation (59.8%). Although most respondents had some awareness of occupational therapy, specifics about its scope of practice and relevance to the health care team were lacking. Preferences for learning more about occupational therapy were consistent with the current trend for interprofessional education in health care. Implications for interprofessional education are presented.

  20. Anti-angiogenic and anti-inflammatory properties of kahweol, a coffee diterpene.

    Directory of Open Access Journals (Sweden)

    Casimiro Cárdenas

    Full Text Available BACKGROUND: Epidemiological studies have shown that unfiltered coffee consumption is associated with a low incidence of cancer. This study aims to identify the effects of kahweol, an antioxidant diterpene contained in unfiltered coffee, on angiogenesis and key inflammatory molecules. METHODOLOGY/PRINCIPAL FINDINGS: The experimental procedures included in vivo angiogenesis assays (both the chicken and quail choriallantoic membrane assay and the angiogenesis assay with fluorescent zebrafish, the ex vivo mouse aortic ring assay and the in vitro analysis of the effects of treatment of human endothelial cells with kahweol in cell growth, cell viability, cell migration and zymographic assays, as well as the tube formation assay on Matrigel. Additionally, two inflammation markers were determined, namely, the expression levels of cyclooxygenase 2 and the levels of secreted monocyte chemoattractant protein-1. We show for the first time that kahweol is an anti-angiogenic compound with inhibitory effects in two in vivo and one ex vivo angiogenesis models, with effects on specific steps of the angiogenic process: endothelial cell proliferation, migration, invasion and tube formation on Matrigel. We also demonstrate the inhibitory effect of kahweol on the endothelial cell potential to remodel extracellular matrix by targeting two key molecules involved in the process, MMP-2 and uPA. Finally, the anti-inflammatory potential of this compound is demonstrated by its inhibition of both COX-2 expression and MCP-1 secretion in endothelial cells. CONCLUSION/SIGNIFICANCE: Taken together, our data indicate that, indeed, kahweol behaves as an anti-inflammatory and anti-angiogenic compound with potential use in antitumoral therapies. These data may contribute to the explanation of the reported antitumoral effects of kahweol, including the recent epidemiological meta-analysis showing that drinking coffee could decrease the risk of certain cancers.

  1. Heterogeneity of tumor vasculature and antiangiogenic intervention: insights from MR angiography and DCE-MRI.

    Directory of Open Access Journals (Sweden)

    Wenlian Zhu

    Full Text Available Solid tumor vasculature is highly heterogeneous, which presents challenges to antiangiogenic intervention as well as the evaluation of its therapeutic efficacy. The aim of this study is to evaluate the spatial tumor vascular changes due to bevacizumab/paclitaxel therapy using a combination approach of MR angiography and DCE-MRI method.Tumor vasculature of MCF-7 breast tumor mouse xenografts was studied by a combination of MR angiography and DCE-MRI with albumin-Gd-DTPA. Tumor macroscopic vasculature was extracted from the early enhanced images. Tumor microvascular parameters were obtained from the pharmacokinetic modeling of the DCE-MRI data. A spatial analysis of the microvascular parameters based on the macroscopic vasculature was used to evaluate the changes of the heterogeneous vasculature induced by a 12 day bevacizumab/paclitaxel treatment in mice bearing MCF-7 breast tumor.Macroscopic vessels that feed the tumors were not affected by the bevacizumab/paclitaxel combination therapy. A higher portion of the tumors was within close proximity of these macroscopic vessels after the treatment, concomitant with tumor growth retardation. There was a significant decrease in microvascular permeability and vascular volume in the tumor regions near these vessels.Bevacizumab/paclitaxel combination therapy did not block the blood supply to the MCF-7 breast tumor. Such finding is consistent with the modest survival benefits of adding bevacizumab to current treatment regimens for some types of cancers.

  2. Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.

    Science.gov (United States)

    Yang, Guang-Wei; Jiang, Jin-Song; Lu, Wei-Qin

    2015-10-12

    Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.

  3. Anti-angiogenic activity and phytochemical screening of fruit fractions from Vitex agnus castus.

    Science.gov (United States)

    Certo, Giovanna; Costa, Rosaria; D'Angelo, Valeria; Russo, Marina; Albergamo, Ambrogina; Dugo, Giacomo; Germanò, Maria Paola

    2017-12-01

    Although the antitumour activity of Vitex agnus castus fruits has been already addressed, no work has yet assessed their anti-angiogenic potential. To this purpose, several extractive fractions of such fruits were tested on zebrafish embrios by EAP assay, so that only the bioactive fractions could be subsequently tested on the chick chorioallantoic membrane by CAM assay. Bioactive fractions were also phytochemically screened to identify those bioactive compounds responsible for anti-angiogenic activity. A marked inhibition of vessel formation was detected only in zebrafish embryos treated with chloroform or ethyl acetate fractions. Considering CAM assay, chloroform fraction induced a strong reduction of microvasculature and haemoglobin content; while lower anti-angiogenic effects of the ethyl acetate fraction were determined. Phytochemical analyses confirmed the presence of several bioactive anti-angiogenic compounds. Overall, obtained preliminary results highlighted a potential anti-angiogenic activity of V. agnus castus fruits.

  4. A novel delivery vector for targeted delivery of the antiangiogenic drug paclitaxel to angiogenic blood vessels: TLTYTWS-conjugated PEG–PLA nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Fei, E-mail: tanfeivip@126.com; Mo, Xiao-hui, E-mail: 675382206@qq.com [Shanghai Skin Disease Hospital (China); Zhao, Jian, E-mail: 22459402@qq.com [Karolinska University Hospital Solna, Department of Oncology-Pathology, Karolinska Institutet, CCK (Sweden); Liang, Hui, E-mail: nanotan@126.com [People' s Hospital of Longhua New District Shenzhen, Department of urology (China); Chen, Zhong-jian, E-mail: pfjk927627702@126.com; Wang, Xiu-li, E-mail: tanfeit@126.com [Shanghai Skin Disease Hospital (China)

    2017-02-15

    Antiangiogenesis has been widely accepted as an attractive strategy to combat tumor growth, invasion, and metastasis. An actively targeting nanoparticle-based drug delivery system (nano-DDS) would provide an alternative method to achieve antiangiogenic antitumor therapy. In the present study, our group fabricated novel nano-DDS, TLTYTWS (TS) peptide-modified poly(ethylene glycol)–poly(lactic acid) (PEG–PLA) nanoparticles (TS-NPs) encapsulating a drug with antiangiogenic potential, paclitaxel (Ptx) (TS-Ptx-NPs). The nanoparticles were uniformly spherical and had a unimodal particle size distribution and slightly negative zeta potential. TS-NPs accumulated significantly in human umbilical vein endothelial cells (HUVECs) via energy-dependent and caveolae- and lipid raft-mediated endocytosis and improved the antiproliferative, antimigratory, and antitube-forming abilities of paclitaxel in vitro. Following intravenous administration, TS-Ptx-NPs presented favorable pharmacokinetic profiles. Melanoma distribution assays confirmed that TS-NPs achieved higher accumulation and penetration at melanoma sites. These results collectively indicated that TLTYTWS-decorated nanoparticles can be considered to be a promising nano-DDS for chemotherapies targeting tumor angiogenesis and have great potential to improve the efficacy of antiangiogenic therapy in melanoma tumor-bearing nude mice.

  5. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies

    DEFF Research Database (Denmark)

    Horsman, Michael Robert; Siemann, D.W.

    2006-01-01

    A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types of vascu...... on the tumor response to more conventional therapies. This review aims to discuss the pathophysiologic changes induced by VTAs and the implications of these effects on the potential use of VTAs in combined modality therapy....... successful in the clinic they will need to be combined with more conventional therapies. However, by affecting the tumor vascular supply, these VTAs should induce pathophysiologic changes in variables, such as blood flow, pH, and oxygenation. Such changes could have negative or positive influences......A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types...

  6. Therapy of Experimental Nerve Sheath Tumors Using Oncolytic Viruses

    National Research Council Canada - National Science Library

    Rabkin, Samuel D

    2005-01-01

    .... To examine the combination of anti-angiogenic and oncolytic virus therapy, recombinant G47 deta vectors expressing anti- angiogenic factors dominant-negative fibroblast growth factor receptor (dnFGFR...

  7. Survey of handwriting instruction practices of elementary teachers and educational programs: implications for occupational therapy.

    Science.gov (United States)

    Donica, Denise K; Larson, Michelle H; Zinn, Abbey A

    2012-01-01

    ABSTRACT The purpose of this study was to investigate perceptions of elementary school teachers on training in handwriting instruction received during their education, as well as their current classroom practices. The quantity and quality of training in handwriting instruction provided by baccalaureate degree-granting teacher education programs in North Carolina was also examined. An online survey was administered to each population identified to inquire about handwriting instruction practices. Results from 505 teachers and 16 professors indicated that while handwriting instruction content is valued by both teachers and professors, varied levels of training were provided to the teachers. Implications for occupational therapy practice are discussed including strategies for school-based therapists.

  8. Music therapy for prisoners: pilot randomised controlled trial and implications for evaluating psychosocial interventions.

    Science.gov (United States)

    Gold, Christian; Assmus, Jörg; Hjørnevik, Kjetil; Qvale, Liv Gunnhild; Brown, Fiona Kirkwood; Hansen, Anita Lill; Waage, Leif; Stige, Brynjulf

    2014-12-01

    Mental health problems are common among prison inmates. Music therapy has been shown to reduce mental health problems. It may also be beneficial in the rehabilitation of prisoners, but rigorous outcome research is lacking. We compared group music therapy with standard care for prisoners in a pilot randomised controlled trial that started with the establishment of music therapy services in a prison near Bergen in 2008. In all, 113 prisoners agreed to participate. Anxiety (STAI-State [State-Trait Anxiety Inventory], STAI-Trait), depression (HADS-D [Hospital Anxiety and Depression Scale]), and social relationships (Quality of Life Enjoyment and Satisfaction Questionnaire [Q-LES-Q]) were assessed at baseline; every 2 weeks in the experimental group; after 1, 3, and 6 months in the control group; and at release. No restrictions were placed on the frequency, duration, or contents of music therapy. Duration of stay in the institution was short (62% stayed less than 1 month). Only a minority reached clinical cutoffs for anxiety and depression at baseline. Between-group analyses of effects were not possible. Music therapy was well accepted and attractive among the prisoners. Post hoc analysis of within-group changes suggested a reduction of state anxiety after 2 weeks of music therapy (d = 0.33, p = .025). Short sentences and low baseline levels of psychological disturbance impeded the examination of effects in this study. Recommendations for planning future studies are given, concerning the careful choice of participants, interventions and settings, comparison condition and design aspects, choice of outcomes, and integration of research approaches. Thus, the present study has important implications for future studies evaluating interventions for improving prisoners' mental health. ISRCTN22518605. © The Author(s) 2013.

  9. Dawn of ocular gene therapy: implications for molecular diagnosis in retinal disease

    Science.gov (United States)

    Jacques, ZANEVELD; Feng, WANG; Xia, WANG; Rui, CHEN

    2013-01-01

    Personalized medicine aims to utilize genomic information about patients to tailor treatment. Gene replacement therapy for rare genetic disorders is perhaps the most extreme form of personalized medicine, in that the patients’ genome wholly determines their treatment regimen. Gene therapy for retinal disorders is poised to become a clinical reality. The eye is an optimal site for gene therapy due to the relative ease of precise vector delivery, immune system isolation, and availability for monitoring of any potential damage or side effects. Due to these advantages, clinical trials for gene therapy of retinal diseases are currently underway. A necessary precursor to such gene therapies is accurate molecular diagnosis of the mutation(s) underlying disease. In this review, we discuss the application of Next Generation Sequencing (NGS) to obtain such a diagnosis and identify disease causing genes, using retinal disorders as a case study. After reviewing ocular gene therapy, we discuss the application of NGS to the identification of novel Mendelian disease genes. We then compare current, array based mutation detection methods against next NGS-based methods in three retinal diseases: Leber’s Congenital Amaurosis, Retinitis Pigmentosa, and Stargardt’s disease. We conclude that next-generation sequencing based diagnosis offers several advantages over array based methods, including a higher rate of successful diagnosis and the ability to more deeply and efficiently assay a broad spectrum of mutations. However, the relative difficulty of interpreting sequence results and the development of standardized, reliable bioinformatic tools remain outstanding concerns. In this review, recent advances NGS based molecular diagnoses are discussed, as well as their implications for the development of personalized medicine. PMID:23393028

  10. A systems analysis of psychobiology and behavior therapy. Implications for behavioral medicine.

    Science.gov (United States)

    Schwartz, G E

    1981-01-01

    This article examines some basic principles of systems theory and applies them to the integration of psychobiology and behavior therapy in the evolution of behavioral medicine. Using the concepts of whole/part relationships, level and emergent property, and self-regulation and disregulation, it is proposed that all behavioral therapies involve psychobiological processes, and therefore, indirectly impinge on physical health. It is argued that the distinction between behavior and biology is one of level, and, therefore, behavioral therapies are ultimately biobehavioral therapies having biobehavioral consequences. It is proposed that contrary to traditional reductionistic logic, modern advances in biology are providing strong justification for the importance of including psychological methods in treating diseases manifested at the biological level. Various clinical examples are used to demonstrate how systems theory can be applied to differential diagnosis and treatment, computing cost/benefit ratios of different treatments, and conducting comprehensive clinical research and evaluation. Assessing the interaction of biological, psychological, and social treatment modalities becomes the hallmark of responsible patient care. Implications of the systems conception of behavioral medicine for collaboration among health care providers, the training of future clinicians in different disciplines, and policy decisions regarding the larger social consequences of health care are considered.

  11. Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor.

    Science.gov (United States)

    Kumar, Sushil; Mokhtari, Reza Bayat; Sheikh, Reihaneh; Wu, Bing; Zhang, Libo; Xu, Ping; Man, Shan; Oliveira, Indhira Dias; Yeger, Herman; Kerbel, Robert S; Baruchel, Sylvain

    2011-09-01

    Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models. In vitro dose-response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial pro genitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity. In vitro, topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug-drug interaction. Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors. ©2011 AACR.

  12. Synthesis and Antiangiogenic Activity of N-Alkylated Levamisole Derivatives

    DEFF Research Database (Denmark)

    Hansen, Anders N.; Bendiksen, Christine D.; Sylvest, Lene

    2012-01-01

    less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-Levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical...... profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard...... to inhibition of angiogenesis. N-Methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co...

  13. Dual-Energy CT in Patients Treated with Anti-Angiogenic Agents for Non-Small Cell Lung Cancer: New Method of Monitoring Tumor Response?

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yoo Na; Lee, Ho Yun; Lee, Kyung Soo; Chung, Myung Jin; Ahn, Myung Ju; Park, Keun Chil; Kim, Tae Sung; Yi, Chin A [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Seo, Joon Beom [Dept. of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2012-11-15

    To evaluate tumor responses in patients treated with anti-angiogenic agents for non-small cell lung cancer (NSCLC) by assessing intratumoral changes using a dual-energy CT (DECT) (based on Choi's criteria) and to compare it to traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Ten NSCLC patients treated with bevacizumab underwent DECT. Tumor responses to anti-angiogenic therapy were assessed and compared with the baseline CT results using both RECIST (size changes only) and Choi's criteria (reflecting net tumor enhancement). Kappa statistics was used to evaluate agreements between tumor responses assessed by RECIST and Choi's criteria. The weighted {kappa} value for the comparison of tumor responses between the RECIST and Choi's criteria was 0.72. Of 31 target lesions (21 solid nodules, 8 lymph nodes, and two ground-glass opacity nodules [GGNs]), five lesions (16%) showed discordant responses between RECIST and Choi's criteria. Iodine-enhanced images allowed for a distinction between tumor enhancement and hemorrhagic response (detected in 14% [4 of 29, excluding GGNs] of target lesions on virtual nonenhanced images). DECT may serve as a useful tool for response evaluation after anti-angiogenic treatment in NSCLC patients by providing information on the net enhancement of target lesions without obtaining non-enhanced images.

  14. Anti-angiogenic activity of the methanol extract and its fractions of Ulmus davidiana var. japonica.

    Science.gov (United States)

    Jung, Hyun-Joo; Jeon, Hye-Jin; Lim, Eun-Ju; Ahn, Eun-Kyoung; Song, Yun Seon; Lee, Sanghyun; Shin, Kuk Hyun; Lim, Chang-Jin; Park, Eun-Hee

    2007-06-13

    This study aimed to elucidate anti-angiogenic activity of Ulmus davidiana var. japonica that has been widely used in folk medicine. The methanol extract (UDE) of Ulmus davidiana var. japonica concentration-dependently displayed a strong inhibition in the chick chorioallantoic membrane (CAM) angiogenesis. The n-butanol fraction of UDE and subsequent 30% MeOH subfraction were identified to be most responsible for the anti-angiogenic activity.

  15. Cognitive behaviour therapy and inflammation: A systematic review of its relationship and the potential implications for the treatment of depression.

    Science.gov (United States)

    Lopresti, Adrian L

    2017-06-01

    There is growing evidence confirming increased inflammation in a subset of adults with depression. The impact of this relationship has mostly been considered in biologically based interventions; however, it also has potential implications for psychological therapies. Cognitive behaviour therapy is the most commonly used psychological intervention for the treatment of depression with theories around its efficacy primarily based on psychological mechanisms. However, cognitive behaviour therapy may have an effect on, and its efficacy influenced by, physiological processes associated with depression. Accordingly, the purpose of this systematic review was to examine the relationship between cognitive behaviour therapy and inflammation. Studies examining the anti-inflammatory effects of cognitive behaviour therapy in people with depression and other medical conditions (e.g. cancer, diabetes and heart disease) were examined. In addition, the relationship between change in inflammatory markers and change in depressive symptoms following cognitive behaviour therapy, and the influence of pre-treatment inflammation on cognitive behaviour therapy treatment response were reviewed. A total of 23 studies investigating the anti-inflammatory effects of cognitive behaviour therapy were identified. In 14 of these studies, at least one reduction in an inflammatory marker was reported, increases were identified in three studies and no change was found in six studies. Three studies examined the relationship between change in inflammation and change in depressive symptoms following cognitive behaviour therapy. In two of these studies, change in depressive symptoms was associated with a change in at least one inflammatory marker. Finally, three studies examined the influence of pre-treatment inflammation on treatment outcome from cognitive behaviour therapy, and all indicated a poorer treatment response in people with higher premorbid inflammation. Preliminary evidence suggests

  16. Disparity implications of the Medicare medication therapy management eligibility criteria: a literature review.

    Science.gov (United States)

    Munshi, Kiraat D; Shih, Ya-Chen T; Brown, Lawrence M; Dagogo-Jack, Samuel; Wan, Jim Y; Wang, Junling

    2013-04-01

    The emphasis on eliminating racial and ethnic disparities in healthcare has received national attention, with various policy initiatives addressing this problem and proposing solutions. However, in the current economic era requiring tight monetary constraints, emphasis is increasingly being placed on economic efficiency, which often conflicts with the equality doctrine upon which many policies have been framed. The authors' review aims to highlight the disparity implications of one such policy provision - the predominantly utilization-based eligibility criteria for medication therapy management services under Medicare Part D - by identifying studies that have documented racial and ethnic disparities in health status and the use of and spending on prescription medications. Future design and evaluation of various regulations and legislations employing utilization-based eligibility criteria must use caution in order to strike an equity-efficiency balance.

  17. [Implications of antiretroviral therapy in oral medicine--a review of literature].

    Science.gov (United States)

    Jordan, Rainer A

    2007-01-01

    The success of antiretroviral therapy leads to a chronification of HIV-infection resulting in a decline of lethality. The lifelong intake of antiinfectives, though, may result in drug side effects with clinical dental implications. Despite fundamental cellular alterations, including prolonged hemorrhage following surgical interventions, antiretrovirals of all classes, of protease inhibitors, (non-nucleoside) reverse transcriptase inhibitors and of fusion inhibitors may promote oral manifestions like oral ulcera, dysgeusia, salivary gland disorders, papilloma, (peri)oral paresthesia or aphtous stomatitis. Due to inhibitory effects especially of protease inhibitors of cy tochrome P450-isoenzyme CYP3A4 therapeutical interactions with psychotropics/sedatives, antifungal agents, corticoids and intiinfectives, particularly metronidazole, may raise. The application and prescription of systemically metabolized adjuvant drugs as well as the monitoring of the possible progression of HIV infection is a key task in the oral health care of HIV-seropositive patients calling for a close medical coordination of therapeutical interventions.

  18. An examination of human factors in external beam radiation therapy: Findings and implications

    International Nuclear Information System (INIS)

    Henriksen, K.; Kaye, R.D.; Jones, R.E. Jr.; Morisseau, D.S.; Persensky, J.J.

    1994-01-01

    To better understand the contributing factors to human error in external beam radiation therapy, the US Nuclear Regulatory Commission has undertaken a series of human factors evaluations. A team of human factors specialists, assisted by a panel of radiation oncologists, medical physicists, and radiation technologists, conducted visits to 24 radiation oncology departments at community hospitals, university centers, and free-standing clinics. A function and task analysis was initially performed to guide subsequent evaluations in the areas of human-system interfaces, procedures, training and qualifications, and organizational policies and practices. Representative findings and implications for improvement are discussed within the context of a dynamic model which holds that misadministration likely results from the unanticipated interaction of several necessary but singly insufficient conditions

  19. Iron therapy in heart failure patients without anaemia: possible implications for chronic kidney disease patients.

    Science.gov (United States)

    Malyszko, Jolanta; Anker, Stefan D

    2017-12-01

    Iron deficiency anaemia is a global health problem that manifests as fatigue and poor physical endurance. Anaemia can be caused by dietary iron deficiency, blood loss or a combination of poor iron absorption and ineffective iron mobilization in patients with chronic disease. Nephrologists caring for patients with impaired renal function understand that iron treatment is necessary to provide adequate iron for erythropoiesis during the treatment of overt anaemia. However, a less well-understood health problem is iron deficiency, which creates symptoms that overlap with those of anaemia and often occurs in concert with chronic disease. Recently, several randomized controlled clinical trials have been conducted to investigate the effects of treatment with intravenous iron in heart failure patients with iron deficiency who may or may not also have anaemia. Given that heart and kidney disease are often comorbid, these clinical trials may have implications for the way nephrologists view their patients with iron deficiency. In this article, we review several clinical studies of intravenous iron therapy for patients with iron deficiency and heart failure and discuss possible implications for the treatment of patients with kidney disease.

  20. Influence of shoulder pain on muscle function: implications for the assessment and therapy of shoulder disorders.

    Science.gov (United States)

    Struyf, Filip; Lluch, Enrique; Falla, Deborah; Meeus, Mira; Noten, Suzie; Nijs, Jo

    2015-02-01

    Shoulder pain is often a challenging clinical phenomenon because of the potential mismatch between pathology and the perception of pain. Current evidence clearly emphasizes an incomplete understanding of the nature of shoulder pain. Indeed, the effective diagnosis and treatment of shoulder pain should not only rely upon a detailed knowledge of the peripheral pathologies that may be present in the shoulder, but also on current knowledge of pain neurophysiology. To assess and treat shoulder pain, a comprehensive understanding of the way in which pain is processed is essential. This review reflects modern pain neurophysiology to the shoulder and aims to answer the following questions: why does my shoulder hurt? What is the impact of shoulder pain on muscle function? What are the implications for the clinical examination of the shoulder? And finally, what are the clinical implications for therapy? Despite the increasing amount of research in this area, an in-depth understanding of the bidirectional nociception-motor interaction is still far from being achieved. Many questions remain, especially related to the treatment of nociception-motor interactions.

  1. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma.

    Science.gov (United States)

    Best, Timothy; Li, Dalin; Skol, Andrew D; Kirchhoff, Tomas; Jackson, Sarah A; Yasui, Yutaka; Bhatia, Smita; Strong, Louise C; Domchek, Susan M; Nathanson, Katherine L; Olopade, Olufunmilayo I; Huang, R Stephanie; Mack, Thomas M; Conti, David V; Offit, Kenneth; Cozen, Wendy; Robison, Leslie L; Onel, Kenan

    2011-07-24

    Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy-induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.

  2. Dual functionality of interleukin-1 family cytokines: implications for anti-interleukin-1 therapy.

    Science.gov (United States)

    Luheshi, N M; Rothwell, N J; Brough, D

    2009-08-01

    Dysregulated inflammation contributes to disease pathogenesis in both the periphery and the brain. Cytokines are coordinators of inflammation and were originally defined as secreted mediators, released from expressing cells to activate plasma membrane receptors on responsive cells. However, a group of cytokines is now recognized as having dual functionality. In addition to their extracellular effects, these cytokines act inside the nuclei of cytokine-expressing or cytokine-responsive cells. Interleukin-1 (IL-1) family cytokines are key pro-inflammatory mediators, and blockade of the IL-1 system in inflammatory diseases is an attractive therapeutic goal. All current therapies target IL-1 extracellular actions. Here we review evidence that suggests IL-1 family members have dual functionality. Several IL-1 family members have been detected inside the nuclei of IL-1-expressing or IL-1-responsive cells, and intranuclear IL-1 is reported to regulate gene transcription and mRNA splicing. However, further work is required to determine the impact of IL-1 intranuclear actions on disease pathogenesis. The intranuclear actions of IL-1 family members represent a new and potentially important area of IL-1 biology and may have implications for the future development of anti-IL-1 therapies.

  3. Prognostic Implications of Prostate Specific Antigen in Patients Following Fast Neutron Beam Therapy at Fermilab

    Energy Technology Data Exchange (ETDEWEB)

    Gagnon, James D. [Fermilab; Hatcher, Madeline A. [Fermilab; Gagnon, Patrick J. [Fermilab; Lennox, Arlene J. [Fermilab; Tanner, Andrew S. [Fermilab; Shafer, Jeffrey P. [Fermilab; Smoron, Geoffrey L. [Fermilab

    1996-01-01

    Preliminary results regarding prognostic implications of PSA in prostate cancer patients treated with the neutron beam at Fermilab have been published by Saroja et. al. (1) Seventy patients were included, in three groups. Group I included patients whose PSA decreased to the reference range of 0-4 ng/mL following therapy and stayed there. Group II included patients whose PSA dropped below 4 ng/mL and then increased. Group III included patients whose PSA remained elevated. This presentation updates that paper, now looking at 186 patients who had pretreatment PSA values available. The most significant result from analyzing Fermilab data appears to be the effect of neutron irradiation on local control, irrespective in some cases of subsequent changes in PSA value. The determination of local control is clinical rather than pathological, and only time and re-biopsy studies will allow us to know the efficacy of neutron therapy in locally controlling prostate cancer, independent of eventual outcome and PSA values. Fermilab data to date are very promising (2).

  4. 3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Lagerloef, Jakob H.; Kindblom, Jon; Bernhardt, Peter [Department of Radiation Physics, Goeteborg University, Goeteborg 41345 (Sweden); Department of Oncology, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden); Department of Radiation Physics, Goeteborg University, Goeteborg, Sweden and Department of Nuclear Medicine, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden)

    2011-08-15

    Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2

  5. Insulin pump therapy in childhood diabetes-cost implications for Primary Care Trusts.

    Science.gov (United States)

    Feltbower, R G; Campbell, F M; Bodansky, H J; Stephenson, C R; McKinney, P A

    2006-01-01

    Primary Care Trusts (PCTs) are now responsible for the planning and delivery of health-care services throughout England and Wales. As the 25 PCTs throughout Yorkshire are representative of the national distribution in terms of population structure and socio-economic status, we aimed to address the paucity of information describing the burden of childhood diabetes in primary care and to evaluate the cost implications of insulin pump therapy on individual PCTs. We extracted information from a population-based register in Yorkshire, including 1952 patients diagnosed under the age of 15 years from 1990 to 2003. Each patient's postcode was linked to an individual PCT. Incidence rates (per 100 000 patient years) were derived and assessed for evidence of heterogeneity across PCTs and within Strategic Health Authorities (SHAs). Incidence rates were lower in West Yorkshire (19.1, 95% CI 18.0-20.2) than North-east Yorkshire (20.3, 18.9-21.6), although this difference was not significant (P = 0.20). No significant evidence of heterogeneity in incidence rates was observed across PCTs (P = 0.46). Ninety per cent of all PCTs would expect four to seven newly diagnosed children per year, corresponding to a single general practitioner (GP) referring an individual for diagnosis once every 15 years on average. Assuming 1% of current patients under the age of 15 years with diabetes were to move onto insulin pump therapy, this would impose an additional cost of pound400-1300 per year for each PCT. The average cost was 15% lower for PCTs in West Yorkshire than North and East Yorkshire. The additional resources required to pay for insulin pump therapy for a small proportion of the diabetes population would be minimal given the potential benefits to these patients of improved control and anticipated reduction in long-term morbidity.

  6. Use of Physical Therapy Following Total Knee Replacement Surgery: Implications of Orthopedic Surgeons' Ownership of Physical Therapy Services.

    Science.gov (United States)

    Mitchell, Jean M; Reschovsky, James D; Reicherter, Elizabeth Anne

    2016-10-01

    To examine whether the course of physical therapy treatments received by patients who undergo total knee replacement (TKR) surgery differs depending on whether the orthopedic surgeon has a financial stake in physical therapy services. Sample of Medicare beneficiaries who underwent TKR surgery during the years 2007-2009. We used regression analysis to evaluate the effect of physician self-referral on the following outcomes: (1) time from discharge to first physical therapy visit; (2) episode length; (3) number of physical therapy visits per episode; (4) number of physical therapy service units per episode; and (5) number of physical therapy services per episode expressed in relative value units. TKR patients who underwent physical therapy treatment at a physician-owned clinic received on average twice as many physical therapy visits (8.3 more) than patients whose TKR surgery was performed by a orthopedic surgeon who did not self-refer physical therapy services (p physical therapy service units during an episode compared with patients treated by nonself-referring providers (p physical therapy services rendered to the patient look virtually identical to episodes where the TKR surgery was performed by a surgeon nonowner. Physical therapists not involved with physician-owned clinics saw patients for fewer visits, but the composition of physical therapy services rendered during each visit included more individualized therapeutic exercises. © Health Research and Educational Trust.

  7. A review of cognitive impairments in children with intellectual disabilities: Implications for cognitive behaviour therapy.

    Science.gov (United States)

    Hronis, Anastasia; Roberts, Lynette; Kneebone, Ian I

    2017-06-01

    Nearly half of children with intellectual disability (ID) have comorbid affective disorders. These problems are chronic if left untreated and can significantly impact upon future vocational, educational, and social opportunities. Despite this, there is a paucity of research into effective treatments for this population. Notably, one of the most supported of psychological therapies, cognitive behaviour therapy (CBT), remains largely uninvestigated in children with ID. The current review considers the neuropsychological profile of children and adolescents with mild to moderate ID, with a view to informing how CBT might best be adapted for children and adolescents with ID. Narrative review of literature considering the neuropsychological profiles of children and adolescents with ID, with specific focus upon attention, memory, learning, executive functioning, and communication. Studies were identified through SCOPUS, PsycINFO, and PubMed databases, using combinations of the key words 'intellectual disability', 'learning disability', 'neuropsychology', 'attention', 'learning', 'memory', 'executive function', 'language', and 'reading'. Children with ID have significant deficits in attention, learning, memory, executive functions, and language. These deficits are likely to have a negative impact upon engagement in CBT. Suggestions for adapting therapy to accommodate these wide ranging deficits are proposed. There are multiple cognitive factors which need to be considered when modifying CBT for children who have ID. Furthermore, research is required to test whether CBT so modified is effective in this population. Clinical implications Effective ways of providing cognitive behavioural therapy (CBT) to children with intellectual disability (ID) is unclear. This study provides a framework of potential adaptations for clinical practice As rates of mental illness for children with intellectual disability are high, and rates of treatment provision low, it is hoped that the

  8. Antiangiogenic activity of 2-deoxy-D-glucose.

    Directory of Open Access Journals (Sweden)

    Jaime R Merchan

    2010-10-01

    Full Text Available During tumor angiogenesis, endothelial cells (ECs are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG on in vitro and in vivo angiogenesis were investigated.In cell culture, 2-DG inhibited EC growth, induced cytotoxicity, blocked migration, and inhibited actively forming but not established endothelial capillaries. Surprisingly, 2-DG was a better inhibitor of these EC properties than two more efficacious glycolytic inhibitors, 2-fluorodeoxy-D-glucose and oxamate. As an alternative to a glycolytic inhibitory mechanism, we considered 2-DG's ability to interfere with endothelial N-linked glycosylation. 2-DG's effects were reversed by mannose, an N-linked glycosylation precursor, and at relevant concentrations 2-DG also inhibited synthesis of the lipid linked oligosaccharide (LLO N-glycosylation donor in a mannose-reversible manner. Inhibition of LLO synthesis activated the unfolded protein response (UPR, which resulted in induction of GADD153/CHOP and EC apoptosis (TUNEL assay. Thus, 2-DG's effects on ECs appeared primarily due to inhibition of LLOs synthesis, not glycolysis. 2-DG was then evaluated in two mouse models, inhibiting angiogenesis in both the matrigel plug assay and the LH(BETAT(AG transgenic retinoblastoma model.In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies.

  9. Anti-angiogenic activity of a new andrographolide derivative in zebrafish and HUVECs.

    Science.gov (United States)

    Li, Jingjing; Peng, Yuran; Li, Shang; Sun, Yicheng; Chan, Judy Yuet-Wa; Cui, Guozhen; Wang, Decai; Zhou, Guo-Chun; Lee, Simon Ming-Yuen

    2016-10-15

    Andrographolide is among the most promising anti-tumor and anti-angiogenic components in Andrographis paniculata but its poor bioavailability and limited efficacy pose difficulties for its therapeutic development. Therefore, improving its pharmaceutical features and potency, by modifying its chemical structure, is desirable. In the present study, a new andrographolide derivative (AGP-40) was synthesized and characterized for its anti-angiogenic properties. Human umbilical vein endothelial cells (HUVECs) and zebrafish models were used to identify the anti-angiogenic activity of AGP-40. AGP-40 significantly suppressed the formation of blood vessels in zebrafish and inhibited proliferation, migration and tube formation in vitro. The anti-angiogenic effects of AGP-40 are at least partially mediated via the PI3K/Akt and MEK/Erk(1/2) signaling pathways. Furthermore, AGP-40 exhibited stronger anti-proliferative effects than andrographolide against A549, HepG2, Hela cancer cell lines. This study is the first to demonstrate the promising anti-angiogenic activity of the new andrographolide derivative AGP-40. Our results indicate that AGP-40 could serve as a potential therapeutic agent for the treatment and prevention of diseases associated with excessive angiogenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy.

    Science.gov (United States)

    Maldonado, Lauren Y; Arsene, Diana; Mato, José M; Lu, Shelly C

    2018-01-01

    Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes - MAT1A, MAT2A, and MAT2B - with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes' role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S-adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein-protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development

  11. A systematic review on the neural effects of music on emotion regulation: implications for music therapy practice.

    Science.gov (United States)

    Moore, Kimberly Sena

    2013-01-01

    Emotion regulation (ER) is an internal process through which a person maintains a comfortable state of arousal by modulating one or more aspects of emotion. The neural correlates underlying ER suggest an interplay between cognitive control areas and areas involved in emotional reactivity. Although some studies have suggested that music may be a useful tool in ER, few studies have examined the links between music perception/production and the neural mechanisms that underlie ER and resulting implications for clinical music therapy treatment. Objectives of this systematic review were to explore and synthesize what is known about how music and music experiences impact neural structures implicated in ER, and to consider clinical implications of these findings for structuring music stimuli to facilitate ER. A comprehensive electronic database search resulted in 50 studies that met predetermined inclusion and exclusion criteria. Pertinent data related to the objective were extracted and study outcomes were analyzed and compared for trends and common findings. Results indicated there are certain music characteristics and experiences that produce desired and undesired neural activation patterns implicated in ER. Desired activation patterns occurred when listening to preferred and familiar music, when singing, and (in musicians) when improvising; undesired activation patterns arose when introducing complexity, dissonance, and unexpected musical events. Furthermore, the connection between music-influenced changes in attention and its link to ER was explored. Implications for music therapy practice are discussed and preliminary guidelines for how to use music to facilitate ER are shared.

  12. Community mental health provider modifications to cognitive therapy: implications for sustainability.

    Science.gov (United States)

    Wiltsey Stirman, Shannon; Calloway, Amber; Toder, Katherine; Miller, Christopher J; Devito, Andrea K; Meisel, Samuel N; Xhezo, Regina; Evans, Arthur C; Beck, Aaron T; Crits-Christoph, Paul

    2013-10-01

    This study identified modifications to an evidence-based psychosocial treatment (cognitive therapy) within a community mental health system after clinicians had received intensive training and consultation. A coding system, consisting of four types of contextual modifications, 12 types of content-related modifications, seven levels at which modifications can occur, and a code for changes to training or evaluation processes, was applied to data from interviews with 27 clinicians who treat adult consumers within a mental health system. Nine of 12 content modifications were endorsed, and four (tailoring, integration into other therapeutic approaches, loosening structure, and drift) accounted for 65% of all modifications identified. Contextual modifications were rarely endorsed by clinicians in this sample. Modifications typically occurred at the client or clinician level. Clinicians in community mental health settings made several modifications to an evidence-based practice (EBP), often in an effort to improve the fit of the intervention to the client's needs or to the clinician's therapeutic style. These findings have implications for implementation and sustainability of EBPs in community settings, client-level outcomes, and training and consultation.

  13. Toxicity of targeted therapy: Implications for response and impact of genetic polymorphisms.

    Science.gov (United States)

    Liu, Sariah; Kurzrock, Razelle

    2014-08-01

    Targeted therapies have unique toxicity profiles. Common adverse events include rash, diarrhea, hypertension, hypothyroidism, proteinuria, depigmentation, and hepatotoxicity. Some of these toxicities are caused by on-target, mechanism-associated effects, which can be stratified as to whether or not the targets are relevant to response. Other toxicities are off-target and may be caused by the class of agent, e.g. antibody vs small molecule tyrosine kinase inhibitor, or by immune reactions or toxic metabolites. Both on- and off-target toxicities may be due to higher drug concentrations or altered end-organ sensitivity, which in turn can be a consequence of genetic polymorphisms controlling metabolism or tissue responsiveness. On-target toxicities are important to identify as some correlate with response and, hence, amelioration of these side effects is preferable to dose reduction or stopping drug. Toxicities secondary to relevant target impact may be recognized when distinct types of agents, such as antibodies and small molecule kinase inhibitors, with the same target have a similar side effect. For example, both bevacizumab and vascular endothelial growth factor receptor (VEGFR) kinase inhibitors cause hypertension; both epidermal growth factor receptor (EGFR) antibodies and kinase inhibitors cause rash; and these toxicities correlate with response. Herein we review common targeted agent-related toxicities, relevant genetic polymorphisms, and implications for response and patient management. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Metacognition in Speech and Language Therapy for Children with Social (Pragmatic) Communication Disorders: Implications for a Theory of Therapy

    Science.gov (United States)

    Gaile, Jacqueline; Adams, Catherine

    2018-01-01

    Background: Metacognition is a significant component of complex interventions for children who have developmental language disorders. Research into how metacognition operates in the content or process of developmental language therapy delivery is limited. Identification and description of proposed active therapy components, such as metacognition,…

  15. A Comparison of Osteopathic, Pharmacy, Physical Therapy, Physician Assistant and Occupational Therapy Students' Personality Styles: Implications for Education and Practice.

    Science.gov (United States)

    Hardigan, Patrick C.; Cohen, Stanley R.

    This study compared personality traits of students in five health professions. The Myers-Briggs Type Indicator was completed by 1,508 osteopathic students, 654 pharmacy students, 165 physical therapy students, 211 physician assistant students, and 70 occupational therapy students. Comparing the extrovert/introvert dimension revealed that pharmacy…

  16. Implications of technology in music therapy practice and research for music therapy education: a review of literature.

    Science.gov (United States)

    Crowe, Barbara J; Rio, Robin

    2004-01-01

    This article reviews the use of technology in music therapy practice and research for the purpose of providing music therapy educators and clinicians with specific and accurate accounts of the types and benefits of technology being used in various settings. Additionally, this knowledge will help universities comply with National Association of Schools of Music requirements and help to standardize the education and training of music therapists in this rapidly changing area. Information was gathered through a literature review of music therapy and related professional journals and a wide variety of books and personal communications. More data were gathered in a survey requesting information on current use of technology in education and practice. This solicitation was sent to all American Music Therapy Association approved universities and clinical training directors. Technology applications in music therapy are organized according to the following categories: (a) adapted musical instruments, (b) recording technology, (c) electric/electronic musical instruments, (d) computer applications, (e) medical technology, (f) assistive technology for the disabled, and (g) technology-based music/sound healing practices. The literature reviewed covers 177 books and articles from a span of almost 40 years. Recommendations are made for incorporating technology into music therapy course work and for review and revision of AMTA competencies. The need for an all-encompassing clinical survey of the use of technology in current music therapy practice is also identified.

  17. Implications of the 2015 World Health Organization isoniazid preventive therapy recommendations on tuberculosis prevention efforts in Namibia.

    Science.gov (United States)

    Oloo, Stella Anne

    2016-07-01

    The World Health Organization recently released guidelines recommending 36-month use of isoniazid preventive therapy in adults and adolescents living with HIV in resource-limited settings. Namibia continues to grapple with one of the highest incidences of tuberculosis (TB) worldwide. Implementation of these guidelines requires considerations of TB epidemiology, health infrastructure, programmatic priorities and patient adherence. This article explores the challenges Namibia currently faces in its fight against TB and the implications of the new guidelines on Namibian TB prevention efforts.

  18. Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Terence C. Tang

    2010-03-01

    Full Text Available Hepatocellular carcinoma (HCC is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG, which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX, UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.

  19. Metacognition in speech and language therapy for children with social (pragmatic) communication disorders: implications for a theory of therapy.

    Science.gov (United States)

    Gaile, Jacqueline; Adams, Catherine

    2018-01-01

    Metacognition is a significant component of complex interventions for children who have developmental language disorders. Research into how metacognition operates in the content or process of developmental language therapy delivery is limited. Identification and description of proposed active therapy components, such as metacognition, may contribute to our understanding of how to deliver complex communication interventions in an optimal manner. To analyse aspects of metacognition during therapy derived from a manualized speech and language intervention (the Social Communication Intervention Programme-SCIP) as delivered to children who have social (pragmatic) communication disorder (SPCD) and to examine the dynamic process of delivering therapy. A purposive sample of eight filmed therapy sessions was selected from the video data corpus of intervention-arm participants within a randomized controlled trial. The child-therapist interactions during therapy sessions from five children (aged between 5;11 and 10;3) in the SCIP trial were transcribed. Filmed sessions represented a variety of communication profiles and SCIP therapy content. Starting from existing theory on metacognition, cycles of iterative analysis were performed using a mixed inductive-deductive qualitative analysis. A preliminary list of metacognitive content embedded in the intervention was developed into a metacognitive coding framework (MCF). A thematic analysis of the identified metacognitive content of the intervention was then carried out across the whole sample. Thematic analysis revealed the presence of metacognition in the content and delivery of SCIP intervention. Four main themes of metacognitive person, task and strategy knowledge, and monitoring/control were identified. Metacognition was a feature of how children's ability to monitor language, pragmatic and social interaction skills, in themselves and other people, was developed. Task design and delivery methods were found to play a

  20. Biologic targets identified from dynamic 18FDG-PET and implications for image-guided therapy

    International Nuclear Information System (INIS)

    Rusten, Espen; Malinen, Eirik; Roedal, Jan; Bruland, Oeyvind S.

    2013-01-01

    Purpose: The outcome of biologic image-guided radiotherapy depends on the definition of the biologic target. The purpose of the current work was to extract hyper perfused and hypermetabolic regions from dynamic positron emission tomography (D-PET) images, to dose escalate either region and to discuss implications of such image guided strategies. Methods: Eleven patients with soft tissue sarcomas were investigated with D-PET. The images were analyzed using a two-compartment model producing parametric maps of perfusion and metabolic rate. The two image series were segmented and exported to a treatment planning system, and biological target volumes BTV per and BTV met (perfusion and metabolism, respectively) were generated. Dice's similarity coefficient was used to compare the two biologic targets. Intensity-modulated radiation therapy (IMRT) plans were generated for a dose painting by contours regime, where planning target volume (PTV) was planned to 60 Gy and BTV to 70 Gy. Thus, two separate plans were created for each patient with dose escalation of either BTV per or BTV met . Results: BTV per was somewhat smaller than BTV met (209 ±170 cm 3 against 243 ±143 cm 3 , respectively; population-based mean and s.d.). Dice's coefficient depended on the applied margin, and was 0.72 ±0.10 for a margin of 10 mm. Boosting BTV per resulted in mean dose of 69 ±1.0 Gy to this region, while BTV met received 67 ±3.2 Gy. Boosting BTV met gave smaller dose differences between the respective non-boost DVHs (such as D 98 ). Conclusions: Dose escalation of one of the BTVs results in a partial dose escalation of the other BTV as well. If tumor aggressiveness is equally pronounced in hyper perfused and hypermetabolic regions, this should be taken into account in the treatment planning

  1. Adoption of the 2015 World Health Organization guidelines on antiretroviral therapy: Programmatic implications for India.

    Science.gov (United States)

    Rewari, Bharat Bhushan; Agarwal, Reshu; Shastri, Suresh; Nagaraja, Sharath Burugina; Rathore, Abhilakh Singh

    2017-04-01

    The therapeutic and preventive benefits of early initiation of antiretroviral therapy (ART) for HIV are now well established. Reflecting new research evidence, in 2015 the World Health Organization (WHO) recommended initiation of ART for all people living with HIV (PLHIV), irrespective of their clinical staging and CD4 cell count. The National AIDS Control Programme (NACP) in India is currently following the 2010 WHO ART guidelines for adults and the 2013 guidelines for pregnant women and children. This desk study assessed the number of people living with HIV who will additionally be eligible for ART on adoption of the 2015 WHO recommendations on ART. Data routinely recorded for all PLHIV registered under the NACP up to 31 December 2015 were analysed. Of the 250 865 individuals recorded in pre-ART care, an estimated 135 593 would be eligible under the WHO 2013 guidelines. A further 100 221 would be eligible under the WHO 2015 guidelines. Initiating treatment for all PLHIV in pre-ART care would raise the number on ART from 0.92 million to 1.17 million. In addition, nearly 0.07 million newly registered PLHIV will become eligible every year if the WHO 2015 guidelines are adopted, of which 0.028 million would be attributable to implementation of the WHO 2013 guidelines alone. In addition to drugs, there will be a need for additional CD4 tests and tests of viral load, as the numbers on ART will increase significantly. The outlay should be seen in the context of potential health-care savings due to early initiation of ART, in terms of the effect on disease progression, complications, deaths and new infections. While desirable, adoption of the new guidance will have significant programmatic and resource implications for India. The programme needs to plan and strengthen the service-delivery mechanism, with emphasis on newer and innovative approaches before implementation of these guidelines.

  2. Complementary therapy use by patients and parents of children with asthma and the implications for NHS care: a qualitative study

    Directory of Open Access Journals (Sweden)

    Sharp Debbie

    2006-06-01

    Full Text Available Abstract Background Patients are increasingly using complementary therapies, often for chronic conditions. Asthma is the most common chronic condition in the UK. Previous research indicates that some asthma patients experience gaps in their NHS care. However, little attention has been given to how and why patients and parents of children with asthma use complementary therapies and the implications for NHS care. Methods Qualitative study, comprising 50 semi-structured interviews with a purposeful sample of 22 adults and 28 children with asthma (plus a parent, recruited from a range of NHS and non-NHS settings in Bristol, England. Data analysis was thematic, drawing on the principles of constant comparison. Results A range of complementary therapies were being used for asthma, most commonly Buteyko breathing and homeopathy. Most use took place outside of the NHS, comprising either self-treatment or consultation with private complementary therapists. Complementary therapies were usually used alongside not instead of conventional asthma treatment. A spectrum of complementary therapy users emerged, including "committed", "pragmatic" and "last resort" users. Motivating factors for complementary therapy use included concerns about conventional NHS care ("push factors" and attractive aspects of complementary therapies ("pull factors". While participants were often uncertain whether therapies had directly helped their asthma, breathing techniques such as the Buteyko Method were most notably reported to enhance symptom control and enable reduction in medication. Across the range of therapies, the process of seeking and using complementary therapies seemed to help patients in two broad ways: it empowered them to take greater personal control over their condition rather than feel dependant on medication, and enabled exploration of a broader range of possible causes of their asthma than commonly discussed within NHS settings. Conclusion Complementary therapy

  3. Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences.

    NARCIS (Netherlands)

    Broxterman, H.J.; Lankelma, J.; Hoekman, K.

    2003-01-01

    Intrinsic resistance to anticancer drugs, or resistance developed during chemotherapy, remains a major obstacle to successful treatment. This is the case both for resistance to cytotoxic agents, directed at malignant cells, and for resistance to anti-angiogenic agents, directed at non-malignant

  4. Synthesis and biological evaluations of cytotoxic and antiangiogenic triterpenoids-jacaranone conjugates

    DEFF Research Database (Denmark)

    Sun, Hua; Yue, Partick Y. K.; Wang, Shao Rong

    2016-01-01

    showed that these conjugates are more potent in both cytotoxic and antiangiogenic assays than their corresponding parent molecules, and are also selectively more active against melanoma cells B16 and metastatic B16BL6 than the two other cancer cell lines (A549 and MCF-7) tested. The predicted...

  5. Biological evaluation of tubulysin A: A potential anticancer and antiangiogenic natural product

    NARCIS (Netherlands)

    Kaur, Gurmeet; Hollingshead, Melinda; Holbeck, Susan; Schauer-Vukašinović, Vesna; Camalier, Richard F.; Dömling, Alexander; Agarwal, Seema

    2006-01-01

    Tubulysin A (tubA) is a natural product isolated from a strain of myxobacteria that has been shown to depolymerize microtubules and induce mitotic arrest. The potential of tubA as an anticancer and antiangiogenic agent is explored in the present study. tubA shows potent antiproliferative activity in

  6. Multi-parametric assessment of the anti-angiogenic effects of liposomal glucocorticoids

    NARCIS (Netherlands)

    Kluza, Ewelina; Heisen, Marieke; Schmid, Sophie; van der Schaft, Daisy W. J.; Schiffelers, Raymond M.; Storm, Gert; ter Haar Romeny, Bart M.; Strijkers, Gustav J.; Nicolay, Klaas

    2011-01-01

    Inflammation plays a prominent role in tumor growth. Anti-inflammatory drugs have therefore been proposed as anti-cancer therapeutics. In this study, we determined the anti-angiogenic activity of a single dose of liposomal prednisolone phosphate (PLP-L), by monitoring tumor vascular function and

  7. Growth of MCF-7 breast cancer cells and efficacy of anti-angiogenic agents in a hydroxyethyl chitosan/glycidyl methacrylate hydrogel.

    Science.gov (United States)

    Wang, Hejing; Qian, Junmin; Zhang, Yaping; Xu, Weijun; Xiao, Juxiang; Suo, Aili

    2017-01-01

    Breast cancer negatively affects women's health worldwide. The tumour microenvironment plays a critical role in tumour initiation, proliferation, and metastasis. Cancer cells are traditionally grown in two-dimensional (2D) cultures as monolayers on a flat solid surface lacking cell-cell and cell-matrix interactions. These experimental conditions deviate from the clinical situation. Improved experimental systems that can mimic the in vivo situation are required to discover new therapies, particularly for anti-angiogenic agents that mainly target intercellular factors and play an essential role in treating some cancers. Chitosan can be modified to construct three-dimensional (3D) tumour models. Here, we report an in vitro 3D tumour model using a hydroxyethyl chitosan/glycidyl methacrylate (HECS-GMA) hydrogel produced by a series of chitosan modifications. Parameters relating to cell morphology, viability, proliferation, and migration were analysed using breast cancer MCF-7 cells. In a xenograft model, secretion of angiogenesis-related growth factors and the anti-angiogenic efficacy of Endostar and Bevacizumab in cells grown in HECS-GMA hydrogels were assessed by immunohistochemistry. Hydroxyethyl chitosan/glycidyl methacrylate hydrogels had a highly porous microstructure, mechanical properties, swelling ratio, and morphology consistent with a 3D tumour model. Compared with a 2D monolayer culture, breast cancer MCF-7 cells residing in the HECS-GMA hydrogels grew as tumour-like clusters in a 3D formation. In a xenograft model, MCF-7 cells cultured in the HECS-GMA hydrogels had increased secretion of angiogenesis-related growth factors. Recombinant human endostatin (Endostar), but not Bevacizumab (Avastin), was an effective anti-angiogenic agent in HECS-GMA hydrogels. The HECS-GMA hydrogel provided a 3D tumour model that mimicked the in vivo cancer microenvironment and supported the growth of MCF7 cells better than traditional tissue culture plates. The HECS

  8. Implications of prognostic variables in the assessment of autoimmunity in hepatitis C patients receiving interferon therapy

    OpenAIRE

    Arooj, Mahwish; Malik, Arif; Basit, Abdul; Husain Qazi, Mahmood; Asif, Muhammad; Sarwar Jamal, Mohammad; Mostafa Mahmoud, Maged; Choudhry, Hani; Natesan Pushparaj, Peter; Rasool, Mahmood

    2016-01-01

    Systematic administration of interferon-alpha (INF-alpha) is considered as the backbone of HCV therapy since 1991. Interferon (IFN) therapy can cause vasculitis, glomerulonephritis, cryoglobulinemia and certain other autoimmune diseases such as sialoadentitis, lichen planus and thyroiditis. Related to the factors of interferons, extensively studied gland is thyroid gland. A strong association was observed between thyroid disease and HCV patient when they were exposed to IFN therapy. Vitamin D...

  9. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin lymphoma

    Science.gov (United States)

    Best, Timothy; Li, Dalin; Skol, Andrew D; Kirchhoff, Tomas; Jackson, Sarah A; Yasui, Yutaka; Bhatia, Smita; Strong, Louise C; Domchek, Susan M; Nathanson, Katherine L; Olopade, Olufunmilayo I; Huang, R Stephanie; Mack, Thomas M; Conti, David V; Offit, Kenneth; Cozen, Wendy; Robison, Leslie L; Onel, Kenan

    2011-01-01

    Survivors of pediatric Hodgkin lymphoma (HL) are at significant risk for radiation therapy (RT)-induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in HL survivors treated with RT as children but not as adults. The variants comprise a risk locus associated with decreased basal PRDM1 expression and impaired induction of PRDM1 by radiation exposure. These data suggest a novel gene-exposure interaction that may implicate PRDM1 in the etiology of RT-induced SMNs. PMID:21785431

  10. Fast and slow thinking in distressing delusions: A review of the literature and implications for targeted therapy.

    Science.gov (United States)

    Ward, Thomas; Garety, Philippa A

    2017-09-16

    The recent literature on reasoning biases in psychosis and delusions is reviewed. The state-of-the-art knowledge from systematic reviews and meta-analyses on the evidence for jumping to conclusions is briefly summarised, before a fuller discussion of the more recent empirical literature on belief flexibility as applied to delusions. The methodology and evidence in relation to studies of belief flexibility and the Bias Against Disconfirmatory Evidence (BADE) across the delusional continuum will be critically appraised, and implications drawn for improving cognitive therapy. It will be proposed that dual process models of reasoning, which Kahneman (Kahneman, 2011) popularised as 'fast and slow thinking', provide a useful theoretical framework for integrating further research and informing clinical practice. The emergence of therapies which specifically target fast and slow thinking in people with distressing delusions will be described. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  11. A qualitative study of intimate partner violence universal screening by family therapy interns: implications for practice, research, training, and supervision.

    Science.gov (United States)

    Todahl, Jeffrey L; Linville, Deanna; Chou, Liang-Ying; Maher-Cosenza, Patricia

    2008-01-01

    Although a few family therapy researchers and clinicians have urged universal screening for intimate partner violence (IPV), how screening is implemented-and, in particular, client and therapist response to screening-is vaguely defined and largely untested. This qualitative study examined the dilemmas experienced by couples and family therapy interns when implementing universal screening for IPV in an outpatient clinic setting. Twenty-two graduate students in a COAMFTE-accredited program were interviewed using qualitative research methods grounded in phenomenology. Three domains, 7 main themes, and 26 subthemes were identified. The three domains that emerged in this study include (a) therapist practice of universal screening, (b) client response to universal screening, and (c) therapist response to universal screening. Implications for practice, research, training, and supervision are discussed.

  12. Occupational Therapy Contributions in Early Intervention: Implications for Personnel Preparation and Interprofessional Practice

    Science.gov (United States)

    Muhlenhaupt, Mary; Pizur-Barnekow, Kris; Schefkind, Sandra; Chandler, Barbara; Harvison, Neil

    2015-01-01

    Occupational therapy provides a unique contribution in early intervention programs for families and their children from birth to 3 years old who are at risk for, or who have, identified disabilities. This article describes occupational therapy's distinct value and presents the profession's perspective on services to enhance families' caregiving…

  13. Orthotopic animal model of pseudomyxoma peritonei: An in vivo model to test anti-angiogenic drug effects.

    Science.gov (United States)

    Dohan, Anthony; Lousquy, Ruben; Eveno, Clarisse; Goere, Diane; Broqueres-You, Dong; Kaci, Rachid; Lehmann-Che, Jacqueline; Launay, Jean-Marie; Soyer, Philippe; Bonnin, Philippe; Pocard, Marc

    2014-07-01

    Pseudomyxoma peritonei (PMP) is an uncommon peritoneal mucinous carcinomatosis confined to the peritoneal cavity. The rarity of PMP in humans makes evaluation of the disease biological features and new therapeutic strategies difficult. Accordingly, there is a need for animal models of PMP. Human PMP tissue was i.p. grafted and grown into nude mice, then constituted into reliable and reproducible orthotopic models. Histological and immunostaining analysis was performed. Bevacizumab was injected twice a week either during tumor growth or after cytoreductive surgery. In vivo imaging of tumor angiogenesis was performed using barium sulfate or isolectin microangiography and Doppler ultrasonography of the superior mesenteric artery. Tumor angiogenesis was confirmed by the presence of tortuous vascular networks with high levels of expression of CD31, vascular endothelial cadherin, and desmin. Doppler ultrasonography of the superior mesenteric artery revealed a twofold increase in blood flow velocity compared with tumor-free mice (P preclinical studies, the efficacy of new therapeutic strategies and anti-angiogenic therapies. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. The state of gene therapy research in Africa, its significance and implications for the future.

    Science.gov (United States)

    Arbuthnot, P; Maepa, M B; Ely, A; Pepper, M S

    2017-09-01

    Gene therapy has made impressive recent progress and has potential for treating a wide range of diseases, many of which are important to Africa. However, as a result of lack of direct public funding and skilled personnel, direct research on gene therapy in Africa is currently limited and resources to support the endeavor are modest. A strength of the technology is that it is based on principles of rational design, and the tools of gene therapy are now highly versatile. For example gene silencing and gene editing may be used to disable viral genes for therapeutic purposes. Gene therapy may thus lead to cure from infections with HIV-1, hepatitis B virus and Ebola virus, which are of significant public health importance in Africa. Although enthusiasm for gene therapy is justified, significant challenges to implementing the technology remain. These include ensuring efficient delivery of therapeutic nucleic acids to target cells, limiting unintended effects, cost and complexity of treatment regimens. In addition, implementation of effective legislation that will govern gene therapy research will be a challenge. Nevertheless, it is an exciting prospect that gene therapy should soon reach the mainstream of medical management. Participation of African researchers in the exciting developments is currently limited, but their involvement is important to address health problems, develop capacity and enhance economic progress of the continent.

  15. Shark cartilage extracts as antiangiogenic agents: smart drinks or bitter pills?

    Science.gov (United States)

    Gingras, D; Renaud, A; Mousseau, N; Béliveau, R

    2000-01-01

    The use of crude cartilage for the treatment of human cancers remains a subject of controversy. In this brief commentary, we reviewed the current knowledge on the anticancer properties of cartilage. We then presented the properties of AE-941, a novel standardized water-soluble extract derived from shark cartilage that represents less than 5% of the crude cartilage. It is a multifunctional antiangiogenic product that contains several biologically active molecules. EA-941 is one of the few antiangiogenic drugs that is under phase III clinical investigation. It is currently evaluated in Europe and North America for the treatment of refractory renal cell carcinoma and in North America for metastatic non small cell lung cancer.

  16. The paradoxical pro- and antiangiogenic actions of resveratrol: therapeutic applications in cancer and diabetes.

    Science.gov (United States)

    Kamaleddin, Mohammad Amin

    2016-12-01

    Resveratrol, a polyphenol found in grapes, peanuts, and red wine, plays different roles in diseases such as cancer and diabetes. Existing information indicates that resveratrol provides cardioprotection, as evidenced by superior postischemic ventricular recovery, reduced myocardial infarct size, and decreased number of apoptotic cardiomyocytes associated with resveratrol treatment in animal models. Cardiovascular benefits are experienced in humans with routine but not acute consumption of red wine. In this concise review, the paradoxical pro- and antiangiogenic effects of resveratrol are described, and different roles for resveratrol in the formation of new blood vessels are explained through different mechanisms. It is hypothesized that the effects of resveratrol on different cell types are not only dependent on its concentration but also on the physical and chemical conditions surrounding cells. The findings discussed herein shed light on potential therapeutic proapoptotic and antiangiogenic applications of low-dose resveratrol treatment in the prevention and treatment of different diseases. © 2016 New York Academy of Sciences.

  17. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

    Directory of Open Access Journals (Sweden)

    R.-D. Hofheinz

    2016-01-01

    Full Text Available Background. In metastatic colorectal cancer (mCRC, continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS and progression-free survival (PFS. Secondary endpoints were the impact of continuing antiangiogenic drugs (i in subgroups, (ii in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors, and (iii on remission rates and prevention of progression. Results. Eight studies (3,668 patients were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75 and OS (HR 0.83; 95%-CI, 0.76–0.89. PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58. Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

  18. Anti-angiogenic effect of curcumin, curcumin ethylenediamine derivative and curcumin ethylenediamine manganese complex

    OpenAIRE

    SUNTORNSUK, Leena; Koizumi, Keiichi; Saitoh, Yurika; Nakamura, ElianeShizuka; KAMMASUD, Naparat; VAJARAGUPTA, Opa; Saiki, Ikuo

    2004-01-01

    We investigated the anti-angiogenic effect of curcumin, curcumin ethylenediamine derivative (curcumin ED) and curcumin ethylenediamine manganese complex (curcumin EDMn) through the inhibition of the formation of tube-like structures by human umbilical vascular endothelial cells (HUVEC). Curcumin, curcumin ED, curcumin EDMn did not show cytotoxicity to HUVEC at concentrations equal and lower than 10 μM. At the concentration of 10 μM,curcumin, curcumin ED and curcumin EDMn inhibited the tube fo...

  19. Integration of International Service Learning in Developing Countries within Occupational Therapy Education: Process and Implications.

    Science.gov (United States)

    Cipriani, Joseph

    2017-01-01

    International service learning (ISL) is included in an increasing number of courses at post-secondary levels of education, including programs which educate future occupational therapy practitioners. There is a limited amount of literature and research concerning best practices for course-based occupational therapy education featuring ISL experiences, in particular within developing countries. The purpose of this paper is to (a) to review key literature on ISL, (b) explicate key elements which can help design course-based ISL experiences; and (c) suggest areas for further research and development of course-based ISL. The seven elements of focus that provide a base to guide occupational therapy educators who create ISL courses with an immersion component in a country with a developing economy are discussed, as well as future challenges and possibilities when providing occupational therapy services to a global society.

  20. Viral Response to Specifically Targeted Antiviral Therapy for Hepatitis C and the Implications for Treatment Success

    Directory of Open Access Journals (Sweden)

    Curtis L Cooper

    2010-01-01

    Full Text Available Currently, hepatitis C virus (HCV antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.

  1. Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance.

    Science.gov (United States)

    Naito, Hisamichi; Wakabayashi, Taku; Kidoya, Hiroyasu; Muramatsu, Fumitaka; Takara, Kazuhiro; Eino, Daisuke; Yamane, Keitaro; Iba, Tomohiro; Takakura, Nobuyuki

    2016-06-01

    Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor-like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor-like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance. Cancer Res; 76(11); 3200-10. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Luan, Xin; Gao, Yun-Ge; Guan, Ying-Yun; Xu, Jian-Rong; Lu, Qin [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Zhao, Mei [Department of Pharmacy, Shanghai Institute of Health Sciences and Health School Attached to SJTU-SM, 279 Zhouzhu Road, Shanghai 201318 (China); Liu, Ya-Rong; Liu, Hai-Jun [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Fang, Chao, E-mail: fangchao100@hotmail.com [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Chen, Hong-Zhuan, E-mail: hongzhuan_chen@hotmail.com [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China)

    2014-11-15

    Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases. - Highlights: • Platycodin D inhibits HUVEC proliferation, motility, migration and tube formation. • Platycodin D inhibits the angiogenesis in chick embryo chorioallantoic membrane. • Platycodin D suppresses the angiogenesis and growth of HCT-15 xenograft in mice. • Platycodin D inhibits the phosphorylation of VEGFR2 and downstream kinases in HUVEC.

  3. Synthesis and antiangiogenic activity study of new hop chalcone Xanthohumol analogues.

    Science.gov (United States)

    Nuti, Elisa; Bassani, Barbara; Camodeca, Caterina; Rosalia, Lea; Cantelmo, AnnaRita; Gallo, Cristina; Baci, Denisa; Bruno, Antonino; Orlandini, Elisabetta; Nencetti, Susanna; Noonan, Douglas M; Albini, Adriana; Rossello, Armando

    2017-09-29

    Angiogenesis induction is a hallmark of cancer. Antiangiogenic properties of Xanthohumol (XN), a naturally occurring prenylated chalcone from hops, have been widely reported. Here we describe the synthesis and study the antiangiogenic activity in vitro of a series of XN derivatives, where different substituents on the B-ring of the chalcone scaffold were inserted. The new XN derivatives inhibited human umbilical-vein endothelial cell (HUVEC) proliferation, adhesion, migration, invasion and their ability to form capillary-like structures in vitro at 10 μM concentration. The preliminary results indicate that the phenolic OH group in R, present in natural XN, is not necessary for having antiangiogenic activity. In fact, the most effective compound from this series, 13, was characterized by a para-methoxy group in R and a fluorine atom in R 2 on B-ring. This study paves the way for future development of synthetic analogues of XN to be used as cancer angiopreventive and chemopreventive agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Fluctuations in the emotional intelligence of therapy students during clinical placements: Implication for educators, supervisors, and students.

    Science.gov (United States)

    Gribble, Nigel; Ladyshewsky, Richard K; Parsons, Richard

    2017-01-01

    This study investigated the changes in emotional intelligence (EI) of occupational therapy, physiotherapy, and speech pathology students (therapy students). Clinical placements have multiple benefits including the development of interprofessional skills, enhancing practice skills and interpersonal skills. Higher EI competencies have been shown to have a positive impact on patient outcomes, teamwork skills, dealing with stress, and patient satisfaction. Data for this study were collected at two time points: before third-year therapy students commenced extended clinical placements (T1 with 261 students) and approximately 7 months later after students had completed one or more clinical placements (T2 with 109 students). EI was measured using the Emotional Quotient Inventory 2.0 (EQ-i 2.0 ). Only one EI score, assertiveness, demonstrated a significant decline. No EI score showed a significant increase. A third or more of the students showed increases of five points or more in self-actualisation, emotional expression, independence, reality testing and optimism. However, of concern were the five EI scores where therapy students' EI scores decreased by more than five points: assertiveness (where 38% of students declined), problem solving (37%), impulse control (35%), self-actualisation (35%), and stress tolerance (33%). With EI scores declining for some students during clinical placements, there are implications for clinical supervisors and interprofessional facilitators as clinical performance may decline concurrently. There is a range of potential reasons that clinical placements could negatively influence the EI competencies of a therapy student, including poor clinical supervision, conflict between a student, and supervisor and failing a clinical placement. The research suggests that interprofessional facilitators and university educators might consider students undertaking EI tests before clinical placements.

  5. Perceptions of speech and language therapy amongst UK school and college students: implications for recruitment.

    Science.gov (United States)

    Greenwood, Nan; Wright, Jannet A; Bithell, Christine

    2006-01-01

    Communication disorders affect both sexes and people from all ethnic groups, but members of minority ethnic groups and males in the UK are underrepresented in the speech and language therapy profession. Research in the area of recruitment is limited, but a possible explanation is poor awareness and understanding of speech and language therapy as a profession. To investigate factors influencing attitudes to a career in speech and language therapy amongst UK school and college students focusing on the similarities and differences between males and females, and between minority ethnic and white students. A total of 651 male and female school and college students from a range of ethnic groups and all close to selecting degree courses completed a questionnaire designed to examine the attitudes and awareness of speech and language therapy. Eleven semi-structured follow-up interviews were conducted to help understand the questionnaire findings. Quantitative and qualitative analyses examined differences in attitudes and the awareness of speech and language therapy amongst these groups. Overall, one-third of participants said they knew nothing about speech and language therapy, and males were significantly less familiar with it. Less than half the participants were aware that speech and language therapy is a degree course, and minority ethnic participants were significantly less likely to know this. Compared with males, females were almost five times as likely to say they would consider a career in speech and language therapy. Participants with relatives in health-related jobs were significantly more likely to consider speech and language therapy than those without such relatives. Compared with white participants, minority ethnic participants said they placed greater importance on studying for a degree, a profession and a scientific career, and were more influenced by a career's prestige and a high salary. In order to increase the ethnic and gender diversity of speech and

  6. A therapist’s perspective of a financial planning course: Implications for financial therapy education and trainings

    Directory of Open Access Journals (Sweden)

    Megan Ann McCoy

    2013-08-01

    Full Text Available This paper presents the autoethnography of a doctoral Marriage and Family Therapy (MFT student studying finances in a graduate course. A dataset in the form of field notes was created through recording observations and reflective journaling during the 15 week financial planning course. This data set included observations and insights on various skills and knowledge that would be helpful for conducting financial therapy, the professional and personal growth of a therapist integrating finances into her clinical work, and evaluations regarding how financial courses can be beneficial for therapists and planners who are interested in the interaction between relational and financial issues. Based on the first author’s experiences, reflections and conversations with the second author, four themes were developed. The themes were: (a Seeing the Unnoticed: Challenging Implicit Assumptions, (b Critically Examining My Own Money Scripts, (c What can Therapists Learn From the Financial Discipline, and (d What Financial Planners can Learn from the Clinical Disciplines. Implications for the burgeoning field of financial therapy are discussed, with special attention given to cross-discipline education and training.

  7. Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies.

    Science.gov (United States)

    Vonder Haar, Cole; Peterson, Todd C; Martens, Kris M; Hoane, Michael R

    2016-06-01

    With the numerous failures of pharmaceuticals to treat traumatic brain injury in humans, more researchers have become interested in combination therapies. This is largely due to the multimodal nature of damage from injury, which causes excitotoxicity, oxidative stress, edema, neuroinflammation and cell death. Polydrug treatments have the potential to target multiple aspects of the secondary injury cascade, while many previous therapies focused on one particular aspect. Of specific note are vitamins, minerals and nutrients that can be utilized to supplement other therapies. Many of these have low toxicity, are already FDA approved and have minimal interactions with other drugs, making them attractive targets for therapeutics. Over the past 20 years, interest in supplementation and supraphysiologic dosing of nutrients for brain injury has increased and indeed many vitamins and nutrients now have a considerable body of the literature backing their use. Here, we review several of the prominent therapies in the category of nutraceutical treatment for brain injury in experimental models, including vitamins (B2, B3, B6, B9, C, D, E), herbs and traditional medicines (ginseng, Gingko biloba), flavonoids, and other nutrients (magnesium, zinc, carnitine, omega-3 fatty acids). While there is still much work to be done, several of these have strong potential for clinical therapies, particularly with regard to polydrug regimens. This article is part of a Special Issue entitled SI:Brain injury and recovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Vitamins and Nutrients as Primary Treatments in Experimental Brain Injury: Clinical Implications for Nutraceutical Therapies

    Science.gov (United States)

    Haar, Cole Vonder; Peterson, Todd C.; Martens, Kris M.; Hoane, Michael R.

    2016-01-01

    With the numerous failures of pharmaceuticals to treat traumatic brain injury in humans, more researchers have become interested in combination therapies. This is largely due to the multimodal nature of damage from injury, which causes excitotoxicity, oxidative stress, edema, neuroinflammation and cell death. Polydrug treatments have the potential to target multiple aspects of the secondary injury cascade, while many previous therapies focused on one particular aspect. Of specific note are vitamins, minerals and nutrients that can be utilized to supplement other therapies. Many of these have low toxicity, are already FDA approved and have minimal interactions with other drugs, making them attractive targets for therapeutics. Over the past 20 years, interest in supplementation and supraphysiologic dosing of nutrients for brain injury has increased and indeed many vitamins and nutrients now have a considerable body of literature backing their use. Here, we review several of the prominent therapies in the category of nutraceutical treatment for brain injury in experimental models, including vitamins (B2, B3, B6, B9, C, D, E), herbs and traditional medicines (ginseng, gingko biloba), flavonoids, and other nutrients (magnesium, zinc, carnitine, omega-3 fatty acids). While there is still much work to be done, several of these have strong potential for clinical therapies, particularly with regard to polydrug regimens. PMID:26723564

  9. The assessment of personality disorders : Implications for cognitive and behavior therapy

    NARCIS (Netherlands)

    VanVelzen, CJM; Emmelkamp, PMG

    This article reviews the comorbidity of personality disorders (PDs) and Axis I disorders and discusses implications for assessment and treatment. Pros and cons of various assessment methods are discussed. The co-occurrence of PDs with Axis I disorders is considerable; roughly half of patients with

  10. Potential implications of adjuvant endocrine therapy for the oral health of postmenopausal women with breast cancer

    Science.gov (United States)

    Taichman, L. Susan; Havens, Aaron M.

    2012-01-01

    Current adjuvant treatment modalities for breast cancer that express the estrogen receptor or progesterone receptor include adjuvant anti-estrogen therapies, and tamoxifen and aromatase inhibitors. Bone, including the jaw, is an endocrine-sensitive organ, as are other oral structures. This review examines the potential links between adjuvant anti-estrogen treatments in postmenopausal women with hormone receptor positive breast cancer and oral health. A search of PubMed, EMBASE, CENTRAL, and the Web of Knowledge was conducted using combinations of key terms “breast,” “cancer,” “neoplasm,” “Tamoxifen,” “Aromatase Inhibitor,” “chemotherapy,” “hormone therapy,” “alveolar bone loss,” “postmenopausal bone loss,” “estrogen,” “SERM,” “hormone replacement therapy,” and “quality of life.” We selected articles published in peer-reviewed journals in the English. The authors found no studies reporting on periodontal diseases, alveolar bone loss, oral health, or oral health-related quality of life in association with anti-estrogen breast cancer treatments in postmenopausal women. Periodontal diseases, alveolar bone density, tooth loss, and conditions of the soft tissues of the mouth have all been associated with menopausal status supporting the hypothesis that the soft tissues and bone of the oral cavity could be negatively affected by anti-estrogen therapy. As a conclusion, the impact of adjuvant endocrine breast cancer therapy on the oral health of postmenopausal women is undefined. The structures of the oral cavity are influenced by estrogen; therefore, anti-estrogen therapies may carry the risk of oral toxicities. Oral health care for breast cancer patients is an important but understudied aspect of cancer survivorship. PMID:22986813

  11. Cognitive behavioral therapy for adolescent depression: implications for Asian immigrants in the United States of America.

    Science.gov (United States)

    Sandil, Riddhi

    2006-06-01

    Many interventions are available for treating adolescent depression. This paper attempts to present a summary of cognitive behavioral therapies/techniques that might be useful for treating depression in Asian immigrant adolescents. Articles were selected by conducting a literature search on Psyc-Info. Prevalence, symptoms and measures of adolescent depression are discussed. Summary of popular therapies like PASCET, CWD-A, Beck's CBT are provided. A rationale for the use of these with Asian immigrants is hypothesized. There is no empirical evidence for the efficacy of CBT with this population. A need to validate the use of CBT with this population is asserted.

  12. HLA dependent immune escape mechanisms in B-cell lymphomas : Implications for immune checkpoint inhibitor therapy?

    NARCIS (Netherlands)

    Nijland, Marcel; Veenstra, Rianne N.; Visser, Lydia; Xu, Chuanhui; Kushekhar, Kushi; van Imhoff, Gustaaf W.; Kluin, Philip M.; van den Berg, Anke; Diepstra, Arjan

    2017-01-01

    Antigen presentation by tumor cells in the context of Human Leukocyte Antigen (HLA) is generally considered to be a prerequisite for effective immune checkpoint inhibitor therapy. We evaluated cell surface HLA class I, HLA class II and cytoplasmic HLA-DM staining by immunohistochemistry (IHC) in 389

  13. Cognitive Behaviour Therapies and Their Implications for Applied Educational Psychology Practice

    Science.gov (United States)

    Rait, Shami; Monsen, Jeremy J.; Squires, Garry

    2010-01-01

    This paper critically considers the growing interest in the use of Cognitive Behaviour Therapies to support children and young people presenting with a wide range of social-emotional difficulties. This focus has emerged since the prevalence of such difficulties in children and young people has increased over the past four decades, and the…

  14. Perceptions of Speech and Language Therapy Amongst UK School and College Students: Implications for Recruitment

    Science.gov (United States)

    Greenwood, Nan; Wright, Jannet A.; Bithell, Christine

    2006-01-01

    Background: Communication disorders affect both sexes and people from all ethnic groups, but members of minority ethnic groups and males in the UK are underrepresented in the speech and language therapy profession. Research in the area of recruitment is limited, but a possible explanation is poor awareness and understanding of speech and language…

  15. Effects of Drawing on Alpha Activity: A Quantitative EEG Study with Implications for Art Therapy

    Science.gov (United States)

    Belkofer, Christopher M.; Van Hecke, Amy Vaughan; Konopka, Lukasz M.

    2014-01-01

    Little empirical evidence exists as to how materials used in art therapy affect the brain and its neurobiological functioning. This pre/post within-groups study utilized the quantitative electroencephalogram (qEEG) to measure residual effects in the brain after 20 minutes of drawing. EEG recordings were conducted before and after participants (N =…

  16. Androgen Induces Adaptation to Oxidative Stress in Prostate Cancer: Implications for Treatment with Radiation Therapy

    Directory of Open Access Journals (Sweden)

    Jehonathan H. Pinthus

    2007-01-01

    Full Text Available Radiation therapy is a standard treatment for prostate cancer (PC. The postulated mechanism of action for radiation therapy is the generation of reactive oxygen species (ROS. Adjuvant androgen deprivation (AD therapy has been shown to confer a survival advantage over radiation alone in high-risk localized PC. However, the mechanism of this interaction is unclear. We hypothesize that androgens modify the radioresponsiveness of PC through the regulation of cellular oxidative homeostasis. Using androgen receptor (AR+ 22rv1 and AR− PC3 human PC cell lines, we demonstrated that testosterone increased basal reactive oxygen species (bROS levels, resulting in dose-dependent activation of phospho-p38 and pAKT, increased expression of clusterin, catalase, manganese superoxide dismutase. Similar data were obtained in three human PC xenografts; WISH-PC14, WISH-PC23, CWR22, growing in testosterone-supplemented or castrated SCID mice. These effects were reversible through AD or through incubation with a reducing agent. Moreover, testosterone increased the activity of catalase, superoxide dismutases, glutathione reductase. Consequently, AD significantly facilitated the response of AR+ cells to oxidative stress challenge. Thus, testosterone induces a preset cellular adaptation to radiation through the generation of elevated bROS, which is modified by AD. These findings provide a rational for combined hormonal and radiation therapy for localized PC.

  17. Hepatitis B reactivation during or after direct acting antiviral therapy - implication for susceptible individuals.

    Science.gov (United States)

    Holmes, Jacinta A; Yu, Ming-Lung; Chung, Raymond T

    2017-06-01

    The FDA issued a warning following 24 cases of HBV reactivation during DAA therapy for HCV, including individuals with inactive, occult and past HBV infection. Clinical presentations ranged from asymptomatic fluctuations in HBV DNA to fulminant hepatic failure, liver transplantation and death. The mechanism is unknown. Areas covered: HCV/HBV coinfection is common, particularly in regions endemic for HBV. HCV and HBV utilize host factors to support replication; both viruses evade/impair host immunity. Clinical presentations of HBV reactivation during DAAs are summarized. Other causes of HBV reactivation are revisited and recent data regarding HBV reactivation are presented. Expert opinion: HBV reactivation during DAAs for HCV occurs, with life-threatening consequences in some individuals. The risk of HBV reactivation is observed in all HBV stages. The rapid removal of HCV likely alters and liberates host-viral ± viral-viral interactions that lead to increased HBV replication. As immune reconstitution occurs with HCV removal, host recognition of HBV DNA likely ensues followed by vigorous host immune responses leading to liver injury (HBV flare). These cases highlight the importance of HBV testing prior to initiating DAA therapy, the need for close monitoring of HBV during therapy and timely administration of anti-HBV therapy to prevent serious sequelae.

  18. Signaling pathways regulating Homer1a expression : implications for antidepressant therapy

    NARCIS (Netherlands)

    Serchov, Tsvetan; Heumann, Rolf; van Calker, Dietrich; Biber, Knut

    Homer1a is upregulated by several different antidepressant measures, including non-pharmacological treatments, like sleep deprivation (SD) and electroconvulsive therapy (ECT) and antidepressant drugs, such as imipramine, fluoxetine and ketamine. Homer1a induction might thus be a crucial joint

  19. Colorectal cancer stem cells : regulation of the phenotype and implications for therapy resistance

    OpenAIRE

    Emmink, B.L.

    2014-01-01

    In this thesis different aspects of cancer stem cells in colorectal cancer are discribed. We focus on the therapy resistance of cancer stem cells and the effect that reactive oxygen species and hypoxia have on the cancer stem cell phenotype. For this purpose a novel culture method to propagate cancer stem cells form resected tumor specimens was used.

  20. Utilizing the Arts for Healing from a Native American Perspective: Implications for Creative Arts Therapies.

    Science.gov (United States)

    Dufrene, Phoebe

    This report on how Native American healing methods can be utilized in Western creative art therapy emphasizes that for Native Americans, art is an element of life--not a separate aesthetic ideal. Furthermore, American Indian philosophy does not separate healing from art or religion; the belief is that traditional healing, which uses shamanic…

  1. Micro-RNAs as Potential Predictors of Response to Breast Cancer Systemic Therapy: Future Clinical Implications

    Science.gov (United States)

    Campos-Parra, Alma D.; Cuamani Mitznahuatl, Gerardo; Pedroza-Torres, Abraham; Vázquez Romo, Rafael; Porras Reyes, Fany Iris; López-Urrutia, Eduardo; Pérez-Plasencia, Carlos

    2017-01-01

    Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance of the tumors to the systemic therapy (chemotherapy, endocrine, and targeted therapies) that patients receive. In the era of personalized treatment, several studies have focused on the search for biomarkers capable of predicting the response to this therapy; microRNAs (miRNAs) stand out among these markers due to their broad spectrum or potential clinical applications. miRNAs are conserved small non-coding RNAs that act as negative regulators of gene expression playing an important role in several cellular processes, such as cell proliferation, autophagy, genomic stability, and apoptosis. We reviewed recent data that describe the role of miRNAs as potential predictors of response to systemic treatments in BC. Furthermore, upon analyzing the collected published information, we noticed that the overexpression of miR-155, miR-222, miR-125b, and miR-21 predicts the resistance to the most common systemic treatments; nonetheless, the function of these particular miRNAs must be carefully studied and further analyses are still necessary to increase knowledge about their role and future potential clinical uses in BC. PMID:28574440

  2. Axitinib Has Antiangiogenic and Antitumorigenic Activity in Myxoid Liposarcoma

    Directory of Open Access Journals (Sweden)

    Lauren T. Kerr

    2016-01-01

    Full Text Available Myxoid liposarcoma is a rare form of soft-tissue sarcoma. Although most patients initially respond well to treatment, approximately 21% relapse, highlighting the need for alternative treatments. To identify novel treatment regimens and gain a better understanding of myxoid liposarcoma tumor biology, we screened various candidate and approved targeted therapeutics and chemotherapeutics against myxoid liposarcoma cell lines. Therapeutics that target angiogenesis showed antitumor activity. The small molecule inhibitor axitinib, which targets angiogenesis by inhibiting the VEGFR and PDGFR families and c-Kit, inhibited cell cycle progression and induced apoptosis in vitro, as well as having significant antitumor activity against MLS 1765 myxoid liposarcoma xenografts in mice. Axitinib also displayed synergistic antitumor activity in vitro when combined with the potassium channel ionophore salinomycin or the BH3 mimetic ABT-737. Another angiogenesis-targeting therapeutic, 4EGI-1, which targets the oncoprotein eIF4E, significantly decreased angiogenic ligand expression by myxoid liposarcoma cells and reduced tumor cell growth. To verify this oncogenic addiction to angiogenic pathways, we utilized VEGFR-derived ligand traps and found that autocrine VEGFR signaling was crucial to myxoid liposarcoma cell survival. Overall, these findings suggest that autocrine angiogenic signaling through the VEGFR family is critical to myxoid liposarcoma cell survival and that further study of axitinib as a potential anticancer therapy is warranted.

  3. Implications and considerations of thermal effects when applying irreversible electroporation tissue ablation therapy.

    Science.gov (United States)

    Davalos, Rafael V; Bhonsle, Suyashree; Neal, Robert E

    2015-07-01

    Irreversible electroporation (IRE) describes a cellular response to electric field exposure, resulting in the formation of nanoscale defects that can lead to cell death. While this behavior occurs independently of thermally-induced processes, therapeutic ablation of targeted tissues with IRE uses a series of brief electric pulses, whose parameters result in secondary Joule heating of the tissue. Where contemporary clinical pulse protocols use aggressive energy regimes, additional evidence is supplementing original studies that assert care must be taken in clinical ablation protocols to ensure the cumulative thermal effects do not induce damage that will alter outcomes for therapies using the IRE non-thermal cell death process for tissue ablation. In this letter, we seek to clarify the nomenclature regarding IRE as a non-thermal ablation technique, as well as identify existing literature that uses experimental, clinical, and numerical results to discretely address and evaluate the thermal considerations relevant when applying IRE in clinical scenarios, including several approaches for reducing these effects. Existing evidence in the literature describes cell response to electric fields, suggesting cell death from IRE is a unique process, independent from traditional thermal damage. Numerical simulations, as well as preclinical and clinical findings demonstrate the ability to deliver therapeutic IRE ablation without occurrence of morbidity associated with thermal therapies. Clinical IRE therapy generates thermal effects, which may moderate the non-thermal aspects of IRE ablation. Appropriate protocol development, utilization, and pulse delivery devices may be implemented to restrain these effects and maintain IRE as the vastly predominant tissue death modality, reducing therapy-mitigating thermal damage. Clinical applications of IRE should consider thermal effects and employ protocols to ensure safe and effective therapy delivery. © 2015 The Authors. The Prostate

  4. Investigation of Antiangiogenic Tumor Therapy Potential of Microencapsulated HEK293 VEGF165b Producing Cells

    Directory of Open Access Journals (Sweden)

    Fatemeh Afkhami

    2010-01-01

    encapsulated and non-encapsulated cells was similar. The effect of VEGF165b harvested from encapsulated cells on Human Umbilical Vein Endothelial cells (HUVECs proliferation were also examined.The same inhibitory effects on HUVECs proliferation was seen when the cells were incubated with a mixture of VEGF165b and a 2-fold VEGF165b or with VEGF165b and 2-fold excess VEGF165b released from encapsulated cells. Subcutaneous injection of microencapsulated VEGF165b producing cells in tumor site of nude mice resulted in the reduction of the number of vessels around the tumors.

  5. Tumor Oxygen Dynamics as a Prognostic Indicator of Effective Antiangiogenic Therapy

    National Research Council Canada - National Science Library

    Zhao, Dawen

    2002-01-01

    ...) MR, our results showed that significantly better oxygenation was found in the well differentiated and slower growing H and HI tumors, compared with anaplastic or metastatic, faster growing ATl and MAT-Lu tumors...

  6. Anti-angiogenic therapy in pediatric brain tumors : An effective strategy?

    NARCIS (Netherlands)

    Sie, Mariska; den Dunnen, Wilfred F. A.; Hoving, Eelco W.; de Bont, Eveline S. J. M.

    Brain tumors are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic options including neurosurgery, chemotherapy and radiation. As angiogenesis is highly crucial in brain tumor growth and progression, numerous clinical trials evaluating diverse

  7. Integrating Molecular Imaging Approaches to Monitor Prostate Targeted Suicide and Anti-angiogenic Gene Therapy

    Science.gov (United States)

    2005-02-01

    Bruno , M. D., Korfhagen, T. R., Liu, C., Morrisey, E. E., and Whitsett, J. A. (2000). GATA-6 activates transcription of surfactant protein A. J. Biol...the tail vein (for in- travenous administration), peritoneum, prostate, or forepaw. Before imaging, mice were anesthetized with ketamine–xy- lazine...DOTAP:cholesterol DNA complexes [Iyer et al., 2002]. In- travenous delivery of transferin-targeted DNA-PEI poly- plexes results in specific fluc gene

  8. Irradiation-induced angiosarcoma and anti-angiogenic therapy: A therapeutic hope?

    Energy Technology Data Exchange (ETDEWEB)

    Azzariti, Amalia, E-mail: a.azzariti@oncologico.bari.it [Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Porcelli, Letizia [Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Mangia, Anita; Saponaro, Concetta [Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Quatrale, Anna E. [Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Popescu, Ondina S. [Department of Pathology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Strippoli, Sabino [Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Simone, Gianni [Department of Pathology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Paradiso, Angelo [Experimental Medical Oncology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Guida, Michele [Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy)

    2014-02-15

    Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin. They can be sporadic or caused by therapeutic radiation, hence secondary breast angiosarcomas are an important subgroup of patients. Assessing the molecular biology of angiosarcomas and identify specific targets for treatment is challenging. There is currently great interest in the role of angiogenesis and of angiogenic factors associated with tumor pathogenesis and as targets for treatment of angiosarcomas. A primary cell line derived from a skin fragment of a irradiation-induced angiosarcoma patient was obtained and utilized to evaluate cell biomarkers CD31, CD34, HIF-1alpha and VEGFRs expression by immunocytochemistry and immunofluorescence, drugs cytotoxicity by cell counting and VEGF release by ELISA immunoassay. In addition to previous biomarkers, FVIII and VEGF were also evaluated on tumor specimens by immunohistochemistry to further confirm the diagnosis. We targeted the VEGF–VEGFR-2 axis of tumor angiogenesis with two different class of vascular targeted drugs; caprelsa, the VEGFR-2/EGFR/RET inhibitor and bevacizumab the anti-VEGF monoclonal antibody. We found the same biomarkers expression either in tumor specimens and in the cell line derived from tumor. In vitro experiments demonstrated that angiogenesis plays a pivotal role in the progression of this tumor as cells displayed high level of VEGFR-2, HIF-1 alpha strongly accumulated into the nucleus and the pro-angiogenic factor VEGF was released by cells in culture medium. The evaluation of caprelsa and bevacizumab cytotoxicity demonstrated that both drugs were effective in inhibiting tumor proliferation. Due to these results, we started to treat the patient with pazopanib, which was the unique tyrosine kinase inhibitor available in Italy through a compassionate supply program, obtaining a long lasting partial response. Our data suggest that the study of the primary cell line could help physicians in choosing a therapeutic approach for patient that almost in vitro shows chances of success and that the anti-angiogenetic agents are a reliable therapeutic opportunity for angiosarcomas patients. - Highlights: • Characterization of a new AS cell line for VEGFR-2, HIF-1 alpha and VEGF. • Caprelsa and bevacizumab inhibit AS cells proliferation. • Anti-angiogenetic agents as a reliable therapeutic opportunity for AS patients.

  9. Viewing and engaging in an art therapy exhibit by people living with mental illness: implications for empathy and social change.

    Science.gov (United States)

    Potash, J S; Ho, R T H; Chick, J K Y; Au Yeung, F S W

    2013-08-01

    To determine how healthcare professionals, family members and community members responded to an art exhibit created by people living with mental illness. Phenomenological study with qualitative analysis. Forty-six participants with various relationships with people living with mental illness attended an art therapy exhibit and art making workshop. Surveys, response art, reflective writing and discussion groups were used in this qualitative research study. Responses were categorized into four cluster themes: empathic, self-oriented, other-oriented and world-oriented. Each response category has strengths and weaknesses, indicating implications for increasing awareness and understanding of the artists and mental illness. They also inform educational interventions that can be utilized when using art exhibits for the purpose of confronting bias and stigma towards people living with mental illness. Copyright © 2013 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  10. Antitumour and antiangiogenic activities of [Pt(O,O′‐acac)(γ‐acac)(DMS)] in a xenograft model of human renal cell carcinoma

    Science.gov (United States)

    Vetrugno, C; Biagioni, F; Calabriso, N; Calierno, M T; Fornai, F; De Pascali, S A; Marsigliante, S; Fanizzi, F P

    2016-01-01

    Background and Purpose It is thought that the mechanism of action of anticancer chemotherapeutic agents is mainly due to a direct inhibition of tumour cell proliferation. In tumour specimens, the endothelial cell proliferation rate increases, suggesting that the therapeutic effects of anticancer agents could also be attributed to inhibition of tumour angiogenesis. Hence, we investigated the potential effects of [Pt(O,O′‐acac)(γ‐acac)(DMS)] ([Pt(DMS)]), a new platinum drug for non‐genomic targets, on human renal carcinoma and compared them with those of the well‐established anticancer drug, cisplatin. Experimental Approach Tumour growth, tumour cell proliferation and microvessel density were investigated in a xenograft model of renal cell carcinoma, developed by injecting Caki‐1 cells into BALB/c nude mice. The antiangiogenic potential of compounds was also investigated using HUVECs. Key Results Treatment of the Caki‐1 cells with cisplatin or [Pt(DMS)] resulted in a dose‐dependent inhibition of cell survival, but the cytotoxicity of [Pt(DMS)] was approximately fivefold greater than that of cisplatin. [Pt(DMS)] was much more effective than cisplatin at inhibiting tumour growth, proliferation and angiogenesis in vivo, as well as migration, tube formation and MMP1, MMP2 and MMP9 secretion of endothelial cells in vitro. Whereas, cisplatin exerted a greater cytotoxic effect on HUVECs, but did not affect tube formation or the migration of endothelial cells. In addition, treatment of the xenograft mice with [Pt(DMS)] decreased VEGF, MMP1 and MMP2 expressions in tumours. Conclusions and Implications The antiangiogenic and antitumour activities of [Pt(DMS)] provide a solid starting point for its validation as a suitable candidate for further pharmacological testing. PMID:27351124

  11. Factors Influencing Texas Physical Therapy Students' Membership in the American Physical Therapy Association and the Texas Physical Therapy Association: Implications for Academicians, Clinicians, and Professional Associations.

    Science.gov (United States)

    Hughes, Lynne C; Book, Ashley; Lewis, Harriet

    2016-01-01

    To determine the factors impacting the decisions of student physical therapists (PTs) and physical therapist assistants (PTAs) to join and maintain membership in the American Physical Therapy Association and the Texas Physical Therapy Association, in light of a membership initiative of Reach 100 that was adopted in Texas. Survey, descriptive. An online membership survey invitation was distributed to Texas PT and PTA students. A total of 479 students responded to the survey. A majority of participants (67%) reported being members, while 33% reported being non-members. The primary reason students (74%) reported for being a member was that they were encouraged by their academic program. Students who are not members (87%) cited the high cost of national dues. A majority of participants (n=379, 83%) rated faculty promotion of membership as somewhat high to high. In contrast, only 26% rated the promotion of membership by their clinical education sites as somewhat high to high. Professional growth and development was cited as the main reason to maintain membership. Although students are being encouraged to join, a third of the respondents still do not belong. It is imperative that clinical mentors model and support membership activities. Association leadership may use this information to develop strategic plans to be inclusive of the student and new professional.

  12. Prospects and implications of using chromatin insulators in gene therapy and transgenesis.

    Science.gov (United States)

    Recillas-Targa, Félix; Valadez-Graham, Viviana; Farrell, Catherine M

    2004-07-01

    Gene therapy has emerged from the idea of inserting a wild-type copy of a gene in order to restore the proper expression and function of a damaged gene. Initial efforts have focused on finding the proper vector and delivery method to introduce a corrected gene to the affected tissue or cell type. Even though these first attempts are clearly promising, several problems remain unsolved. A major problem is the influence of chromatin structure on transgene expression. To overcome chromatin-dependent repressive transgenic states, researchers have begun to use chromatin regulatory elements to drive transgene expression. Insulators or chromatin boundaries are able to protect a transgene against chromatin position effects at their genomic integration sites, and they are able to maintain transgene expression for long periods of time. Therefore, these elements may be very useful tools in gene therapy applications for ensuring high-level and stable expression of transgenes. Copyright 2004 Wiley Periodicals, Inc.

  13. Enzyme targeting strategies for prevention and treatment of cancer: Implications for cancer therapy.

    Science.gov (United States)

    Baig, Mohammad Hassan; Adil, Mohd; Khan, Rosina; Dhadi, Surendar; Ahmad, Khurshid; Rabbani, Gulam; Bashir, Tufail; Imran, Mohammad Azhar; Husain, Fohad Mabood; Lee, Eun Ju; Kamal, Mohammad Amjad; Choi, Inho

    2017-12-14

    Extensive growth of cancer in humans is a major cause of death. Numerous studies are being conducted to improve the early diagnosis, prevention, and treatment of cancer. Recent technological advancements in medical science and research indicate molecular target therapy holds much promise in cancer treatment. In the past, therapeutic and diagnostic targeting of non-glycolytic and glycolytic enzymes in cancer have been successful, and discoveries of biomarker enzymes in cancer hold promise for therapeutic treatments. In this review, we discuss the roles of several cancer-associated enzymes that could potentially act as therapeutic targets, and place special focus on non-glycolytic and glycolytic enzymes. This review indicates that the targeting of metabolic signaling offers a promising means of developing novel anti-cancer therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Implications of silver nanoparticle induced cell apoptosis for in vitro gene therapy

    International Nuclear Information System (INIS)

    Gopinath, P; Ghosh, Siddhartha Sankar; Gogoi, Sonit Kumar; Chattopadhyay, Arun

    2008-01-01

    The impact of manufactured nanomaterials on human health and the environment is a major concern for commercial use of nanotechnology based products. A judicious choice of selective usage, lower nanomaterial concentration and use in combination with conventional therapeutic materials may provide the best solution. For example, silver nanoparticles (Ag NPs) are known to be bactericidal and also cytotoxic to mammalian cells. Herein, we investigate the molecular mechanism of Ag NP mediated cytotoxicity in both cancer and non-cancer cells and find that optimum particle concentration leads to programmed cell death in vitro. Also, the benefit of the cytotoxic effects of Ag NPs was tested for therapeutic use in conjunction with conventional gene therapy. The synergistic effect of Ag NPs on the uracil phosphoribosyltransferase expression system sensitized the cells more towards treatment with the drug 5-fluorouracil. Induction of the apoptotic pathway makes Ag NPs a representative of a new chemosensitization strategy for future application in gene therapy

  15. Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy.

    Science.gov (United States)

    McCutcheon, Keir; Manga, Pravin

    Surgical repair or replacement of the mitral valve is currently the only recommended therapy for severe primary mitral regurgitation. The chronic elevation of wall stress caused by the resulting volume overload leads to structural remodelling of the muscular, vascular and extracellular matrix components of the myocardium. These changes are initially compensatory but in the long term have detrimental effects, which ultimately result in heart failure. Understanding the changes that occur in the myocardium due to volume overload at the molecular and cellular level may lead to medical interventions, which potentially could delay or prevent the adverse left ventricular remodelling associated with primary mitral regurgitation. The pathophysiological changes involved in left ventricular remodelling in response to chronic primary mitral regurgitation and the evidence for potential medical therapy, in particular beta-adrenergic blockers, are the focus of this review.

  16. Understanding positional cues in salamander limb regeneration: implications for optimizing cell-based regenerative therapies

    Directory of Open Access Journals (Sweden)

    Catherine D. McCusker

    2014-06-01

    Full Text Available Regenerative medicine has reached the point where we are performing clinical trials with stem-cell-derived cell populations in an effort to treat numerous human pathologies. However, many of these efforts have been challenged by the inability of the engrafted populations to properly integrate into the host environment to make a functional biological unit. It is apparent that we must understand the basic biology of tissue integration in order to apply these principles to the development of regenerative therapies in humans. Studying tissue integration in model organisms, where the process of integration between the newly regenerated tissues and the ‘old’ existing structures can be observed and manipulated, can provide valuable insights. Embryonic and adult cells have a memory of their original position, and this positional information can modify surrounding tissues and drive the formation of new structures. In this Review, we discuss the positional interactions that control the ability of grafted cells to integrate into existing tissues during the process of salamander limb regeneration, and discuss how these insights could explain the integration defects observed in current cell-based regenerative therapies. Additionally, we describe potential molecular tools that can be used to manipulate the positional information in grafted cell populations, and to promote the communication of positional cues in the host environment to facilitate the integration of engrafted cells. Lastly, we explain how studying positional information in current cell-based therapies and in regenerating limbs could provide key insights to improve the integration of cell-based regenerative therapies in the future.

  17. Discordancy in BRAF mutations among primary and metastatic melanoma lesions: clinical implications for targeted therapy.

    Science.gov (United States)

    Bradish, Joshua R; Richey, Justin D; Post, Kristin M; Meehan, Kari; Sen, Joyashree D; Malek, Amanda J; Katona, Terrence M; Warren, Simon; Logan, Theodore F; Fecher, Leslie A; Cheng, Liang

    2015-04-01

    Systemic targeted molecular therapy, in the form of a selective BRAF inhibitor with or without a MEK inhibitor, is a standard treatment for patients with BRAF V600 mutation-positive melanoma with unresectable stage III and IV disease. Patients with BRAF mutation-negative primary tumors may manifest BRAF mutation-positive metastatic disease. It is unclear whether all metastatic lesions carry the same BRAF mutation status found in the primary tumor and if discordancy exists, in what frequency it occurs. Primary and matched metastatic lesions in 25 melanoma patients were tested for the BRAF V600E/Ec, V600K, V600D, and V600R mutations using a BRAF RGQ PCR kit (Qiagen). Four patients (16%) had discrepancies between their primary and metastatic melanoma BRAF status. Of these patients, 2 (8%) had BRAF mutation-positive primary melanomas with BRAF mutation-negative metastatic lesions and 2 (8%) patient had BRAF mutation-negative melanoma with a BRAF mutation-positive metastatic lesion. In summary, discordancy of BRAF mutation status is not an infrequent finding between primary and metastatic melanoma. It may be prudent in previously negative patients to determine BRAF mutation status of new metastatic tumors for proper allocation of BRAF inhibitor therapy. Discordant BRAF status may have a role in the varying patterns of response and inevitable resistance seen with BRAF inhibitor therapies.

  18. Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

    Directory of Open Access Journals (Sweden)

    Rogerio M. Castilho

    2017-07-01

    Full Text Available Head and neck squamous carcinoma (HNSCC is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs, a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.

  19. New perspectives on the theory of justice: implications for physical therapy ethics and clinical practice.

    Science.gov (United States)

    Edwards, Ian; Delany, Clare M; Townsend, Anne F; Swisher, Laura Lee

    2011-11-01

    Recent revisions of physical therapy codes of ethics have included a new emphasis concerning health inequities and social injustice. This emphasis reflects the growing evidence regarding the importance of social determinants of health, epidemiological trends for health service delivery, and the enhanced participation of physical therapists in shaping health care reform in a number of international contexts. This perspective article suggests that there is a "disconnect" between the societal obligations and aspirations expressed in the revised codes and the individualist ethical frameworks that predominantly underpin them. Primary health care is an approach to health care arising from an understanding of the nexus between health and social disadvantage that considers the health needs of patients as expressive of the health needs of the communities of which they are members. It is proposed that re-thinking ethical frameworks expressed in codes of ethics can both inform and underpin practical strategies for working in primary health care. This perspective article provides a new focus on the ethical principle of justice: the ethical principle that arguably remains the least consensually understood and developed in the ethics literature of physical therapy. A relatively recent theory of justice known as the "capability approach to justice" is discussed, along with its potential to assist physical therapy practitioners to further develop moral agency in order to address situations of health inequity and social injustice in clinical practice.

  20. Imaging anti-angiogenic treatment response with DCE-VCT, DCE-MRI and DWI in an animal model of breast cancer bone metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Baeuerle, Tobias [Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: t.baeuerle@dkfz-heidelberg.de; Bartling, Soenke [Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: s.bartling@dkfz-heidelberg.de; Berger, Martin [Unit of Chemotherapy and Toxicology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: m.berger@dkfz-heidelberg.de; Schmitt-Graeff, Annette [Institute of Pathology, University of Freiburg, Postfach 214, 79002 Freiburg (Germany)], E-mail: annette.schmitt-graeff@uniklinik-freiburg.de; Hilbig, Heidegard [Institute of Anatomy, University of Leipzig, Liebigstrasse 13, 04103 Leipzig (Germany)], E-mail: Heidegard.Hilbig@medizin.uni-leipzig.de; Kauczor, Hans-Ulrich [Department of Diagnostic and Interventional Radiology, Radiologische Klinik, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg (Germany)], E-mail: hans-ulrich.kauczor@med.uni-heidelberg.de; Delorme, Stefan [Department of Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: s.delorme@dkfz-heidelberg.de; Kiessling, Fabian [Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Department of Experimental Molecular Imaging, RWTH Aachen, Pauwelsstrasse 20, 52074 Aachen (Germany)], E-mail: fkiessling@ukaachen.de

    2010-02-15

    As current classification systems for the assessment of treatment response in bone metastasis do not meet the needs of oncologists, new imaging biomarkers are desirable. Therefore, the diagnostic impact of dynamic contrast enhanced (DCE)-volumetric computed tomography (VCT) (descriptive analysis), DCE-MRI (two-compartment model) and diffusion weighted imaging (DWI) for monitoring anti-angiogenic therapy effects of the VEGF antibody bevacizumab in breast cancer bone metastases in rats was studied. Nude rats (n = 8 animals treated with bevacizumab and n = 9 untreated control rats) with site-specific osteolytic bone metastasis of the hind leg were imaged with a 1.5 T clinical MRI-scanner in an animal coil as well as in a volumetric CT-scanner at days 30, 40, 50 and 60 after inoculation of MDA-MB-231 human breast cancer cells. From these data, osteolytic lesion size (OLS), peak enhancement (PE), area under the curve (AUC), amplitude (A), exchange rate constant (k{sub ep}) and apparent diffusion coefficient (ADC) were determined in bone metastases. Prior to changes in OLS (p {<=} 0.05 at days 50 and 60) there was already a significant decrease in PE, AUC and A (p {<=} 0.05 at days 40-60) in treated animals compared to controls. However, for k{sub ep} and ADC there were no significant differences between the groups at any time point (p > 0.05 at days 40-60). In conclusion, anti-angiogenic treatment response in osteolytic breast cancer bone metastases can be assessed early with surrogate markers of vascularization, while DWI appears to be insensitive.

  1. Evaluation of antiangiogenic and antiproliferative potential of the organic extract of green algae chlorella pyrenoidosa

    Science.gov (United States)

    Kyadari, Mahender; Fatma, Tasneem; Azad, Rajvardhan; Velpandian, Thirumurthy

    2013-01-01

    Objective: algae isolates obtained from fresh and marine resources could be one of the richest sources of novel bioactive secondary metabolites expected to have pharmaceutical significance for new drug development. This study was conducted to evaluate the antiangiogenic and antiproliferative activity of Chlorella pyrenoidosa in experimental models of angiogenesis and by MTT assay. Materials and Methods: lyophilized extract of C. pyrenoidosa was extracted using dichloromethane/methanol (2:1), concentrated and vacuum evaporated to obtain the dried extract. The crude extract was evaluated in the vascular endothelial growth factor (VEGF)-induced angiogenesis in in ovo chick chorioallantoic membrane assay (CAM) at various concentrations (n = 8) using thalidomide and normal saline as positive and untreated control groups, respectively. The crude extract was also subjected to the antiangiogenic activity in the silver nitrate/potassium nitrate cautery model of corneal neovascularization (CN) in rats where topical bevacizumab was used as a positive control. The vasculature was photographed and blood vessel density was quantified using Aphelion imaging software. The extract was also evaluated for its anti proliferative activity by microculture tetrazolium test (MTT) assay using HeLa cancer cell line (ATCC). Results: VEGF increased the blood vessel density by 220% as compared to normal and thalidomide treatment decreased it to 67.2% in in ovo assay. In the in-vivo CN model, the mean neovascular density in the control group, the C. pyrenoidosa extract and bevacizumab group were found to be 100%, 59.02%, and 32.20%, respectively. The Chlorella pyrenoidosa extract negatively affected the viability of HeLa cells. An IC50 value of the extract was 570 μg/ml, respectively. Conclusion: a significant antiangiogenic activity was observed against VEGF-induced neovascularization and antiproliferative activity by MTT assay. In this study, it could be attributed that the activity may be

  2. Evaluation of antiangiogenic and antiproliferative potential of the organic extract of green algae Chlorella pyrenoidosa.

    Science.gov (United States)

    Kyadari, Mahender; Fatma, Tasneem; Azad, Rajvardhan; Velpandian, Thirumurthy

    2013-01-01

    algae isolates obtained from fresh and marine resources could be one of the richest sources of novel bioactive secondary metabolites expected to have pharmaceutical significance for new drug development. This study was conducted to evaluate the antiangiogenic and antiproliferative activity of Chlorella pyrenoidosa in experimental models of angiogenesis and by MTT assay. lyophilized extract of C. pyrenoidosa was extracted using dichloromethane/methanol (2:1), concentrated and vacuum evaporated to obtain the dried extract. The crude extract was evaluated in the vascular endothelial growth factor (VEGF)-induced angiogenesis in in ovo chick chorioallantoic membrane assay (CAM) at various concentrations (n = 8) using thalidomide and normal saline as positive and untreated control groups, respectively. The crude extract was also subjected to the antiangiogenic activity in the silver nitrate/potassium nitrate cautery model of corneal neovascularization (CN) in rats where topical bevacizumab was used as a positive control. The vasculature was photographed and blood vessel density was quantified using Aphelion imaging software. The extract was also evaluated for its anti proliferative activity by microculture tetrazolium test (MTT) assay using HeLa cancer cell line (ATCC). VEGF increased the blood vessel density by 220% as compared to normal and thalidomide treatment decreased it to 67.2% in in ovo assay. In the in-vivo CN model, the mean neovascular density in the control group, the C. pyrenoidosa extract and bevacizumab group were found to be 100%, 59.02%, and 32.20%, respectively. The Chlorella pyrenoidosa extract negatively affected the viability of HeLa cells. An IC50 value of the extract was 570 μg/ml, respectively. a significant antiangiogenic activity was observed against VEGF-induced neovascularization and antiproliferative activity by MTT assay. In this study, it could be attributed that the activity may be due to the presence of secondary metabolites in the C

  3. Impact of radiation therapy on the oncolytic adenovirus dl520: Implications on the treatment of glioblastoma

    International Nuclear Information System (INIS)

    Bieler, Alexa; Mantwill, Klaus; Holzmueller, Regina; Juerchott, Karsten; Kaszubiak, Alexander; Staerk, Sybille; Glockzin, Gabriel; Lage, Hermann; Grosu, Anca-Ligia; Gansbacher, Bernd; Holm, Per Sonne

    2008-01-01

    Background and purpose: Viral oncolytic therapy is emerging as a new form of anticancer therapy and has shown promising preclinical results, especially in combination with radio- and chemotherapy. We recently reported that nuclear localization of the human transcription factor YB-1 in multidrug-resistant cells facilitates E1-independent adenoviral replication. The aim of this study was to evaluate the combined treatment of the conditionally-replicating adenovirus dl520 and radiotherapy in glioma cell lines in vitro and in human tumor xenografts. Furthermore, the dependency of YB-1 on dl520 replication was verified by shRNA directed down regulation of YB-1. Methods and material: Localization of YB-1 was determined by immunostaining. Glioma cell lines LN-18, U373 and U87 were infected with dl520. Induction of cytopathic effect (CPE), viral replication, viral yield and viral release were determined after viral infection, radiation therapy and the combination of both treatment modalities. The capacity of treatments alone or combined to induce tumor growth inhibition of subcutaneous U373 tumors was tested also in nude mice. Results: Quantitative real-time PCR demonstrated that the shRNA-mediated down regulation of YB-1 is leading to a dramatic decrease in adenoviral replication of dl520. Immunostaining analysis showed that the YB-1 protein was predominantly located in the cytoplasm in the perinuclear space and less abundant in the nucleus. After irradiation we found an increase of nuclear YB-1. The addition of radiotherapy increased the oncolytic effect of dl520 with enhanced viral replication, viral yield and viral release. The oncolytic activity of dl520 plus radiation inhibited the growth of subcutaneous U373 tumors in a xenograft mouse model. Conclusions: Radiation mediated increase of nuclear YB-1 in glioma cells enhanced the oncolytic potential of adenovirus dl520

  4. New Anti-angiogenic Leading Structure Discovered in the Fruit of Cimicifuga yunnanensis

    Science.gov (United States)

    Nian, Yin; Yang, Jing; Liu, Tong-Yang; Luo, Ying; Zhang, Ji-Hong; Qiu, Ming-Hua

    2015-03-01

    Cimyunnins A-C (1-3), characterized with an unusual fused cyclopentenone ring G, together with cimyunnin D (4), possessing a highly rearranged γ-lactone ring F, were characterized from the fruit of Cimicifuga yunnanensis. Their structures were elucidated by spectroscopic analysis, X-ray diffraction, and density functional theory calculations. In addition, cimyunnin A exhibited comparable anti-angiogenic activities to those of sunitinib, a clinically-used first-line angiogenesis inhibitor, in the in vitro and ex vivo studies.

  5. Rectal cancer and inflammatory bowel disease: natural history and implications for radiation therapy

    International Nuclear Information System (INIS)

    Green, Sheryl; Stock, Richard; Greenstein, Adrian

    1995-01-01

    PURPOSES/OBJECTIVE: There exists little information concerning the natural history of rectal cancer in patients with inflammatory bowel disease. In addition, the tolerance of pelvic irradiation in these patients is unknown. We analyzed the largest series of patients with inflammatory bowel disease and rectal cancer in order to determine the natural history of the disease as well as the effect and tolerance of pelvic irradiation. MATERIAL AND METHODS: A retrospective analysis of 47 patients with inflammatory bowel disease and rectal cancer treated over a 34 year period (1960-1994) was performed. Thirty five patients had Ulcerative Colitis and 12 patients had Crohn's Disease. There were 31 male patients and 16 female patients. The stage (AJC) distribution was as follows: stage 0 in 5 patients, stage I in 13 patients, stage II in 7 patients, stage III in 13 patients and stage IV in 9 patients. Surgical resection was performed in 44 patients. In 2 of these patients, preoperative pelvic irradiation was given followed by surgery. Twenty of these patients underwent post-operative adjuvant therapy (12 were treated with chemotherapy and pelvic irradiation and 8 with chemotherapy alone). Three patients were found to have unresectable disease and were treated with chemotherapy alone (2 patients) or chemotherapy and radiation therapy (1 patient). Radiation complications were graded using the RTOG acute and late effects scoring criteria. Follow up ranged from 4 to 250 months (median - 24 months). RESULTS: The 5 year actuarial results revealed an overall survival (OS) of 42%, a disease free survival (DFS) of 43%, a pelvic control rate (PC) of 67% and a freedom from distant failure (FFDF) of 47%. DFS decreased with increasing T stage with a 5 year rate of 86% for patients with Tis - T2 disease compared to 10% for patients with T3-T4 disease (p ) were noted in 3 patients (20%) receiving radiation therapy and these included two cases of grade 3 skin reactions and one case of grade

  6. Calf muscle venous thrombosis: a review of the clinical implications and therapy.

    Science.gov (United States)

    Henry, Jon C; Satiani, Bhagwan

    2014-01-01

    Calf muscle veins have been demonstrated to be one of the most frequent areas that develop deep venous thrombosis (DVT), both as an isolated finding and in combination with proximal DVT. Calf muscle venous thrombosis (CMVT) has been shown to be more frequently associated with localized calf tenderness, and when left untreated, a proportion tend to propagate proximally and may lead to pulmonary embolism. Imaging with duplex venous scanning is fairly sensitive in the diagnosis of CMVT. Treatment recommendations for CMVT are variable with some studies showing clear clinical benefit of anticoagulation therapy and others showing no benefit. © The Author(s) 2014.

  7. Music-evoked emotions: principles, brain correlates, and implications for therapy.

    Science.gov (United States)

    Koelsch, Stefan

    2015-03-01

    This paper describes principles underlying the evocation of emotion with music: evaluation, resonance, memory, expectancy/tension, imagination, understanding, and social functions. Each of these principles includes several subprinciples, and the framework on music-evoked emotions emerging from these principles and subprinciples is supposed to provide a starting point for a systematic, coherent, and comprehensive theory on music-evoked emotions that considers both reception and production of music, as well as the relevance of emotion-evoking principles for music therapy. © 2015 New York Academy of Sciences.

  8. Radiolabelled RGD peptides for imaging and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Gaertner, F.C.; Schwaiger, M.; Beer, A.J. [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Kessler, H. [Technische Universitaet Muenchen, Institute for Advanced Study and Center of Integrated Protein Science, Department of Chemistry, Garching (Germany); King Abdulaziz University, Chemistry Department, Faculty of Science, Jeddah (Saudi Arabia); Wester, H.-J. [Institute for Pharmaceutical Radiochemistry, Garching (Germany)

    2012-02-15

    Imaging of angiogenesis has become increasingly important with the rising use of targeted antiangiogenic therapies like bevacizumab (Avastin). Non-invasive assessment of angiogenic activity is in this respect interesting, e.g. for response assessment of such targeted antiangiogenic therapies. One promising approach of angiogenesis imaging is imaging of specific molecular markers of the angiogenic cascade like the integrin {alpha}{sub v}{beta}{sub 3}. For molecular imaging of integrin expression, the use of radiolabelled peptides is still the only approach that has been successfully translated into the clinic. In this review we will summarize the current data on imaging of {alpha}{sub v}{beta}{sub 3} expression using radiolabelled RGD peptides with a focus on tracers already in clinical use. A perspective will be presented on the future clinical use of radiolabelled RGD peptides including an outlook on potential applications for radionuclide therapy. (orig.)

  9. Computer-aided combined movement examination of the lumbar spine and manual therapy implications: Case report.

    Science.gov (United States)

    Monie, A P; Barrett, C J; Price, R I; Lind, C R P; Singer, K P

    2016-02-01

    Combined movement examination (CME) of the lumbar spine has been recommended for clinical examination as it confers information about mechanical pain patterns. However, little quantitative study has been undertaken to validate its use in manual therapy practice. This study used computer aided CME to develop a normal reference range, and to guide provisional diagnosis and management. Two cases were assessed, before and after manual therapy using CME, a pain Visual Analogue Scale, the Roland Morris Low Back Pain and Disability Questionnaire and the Short Form (SF-12) Health Survey. Diagnosis and management were guided by comparing each CME pattern with the age and gender matched reference range. Self-reports data and CME total change scores were markedly improved for both cases, particularly for the most painful and restricted CME directions. This report describes how computer-aided CME and a normal reference range may be used objectively to inform a diagnosis and as an outcome measure in cases of mechanical LBP. Future investigations of cases with specific lumbar pathologies are required to validate this concept. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors

    Directory of Open Access Journals (Sweden)

    Katerina T. Xenaki

    2017-10-01

    Full Text Available The use of antibody-based therapeutics has proven very promising for clinical applications in cancer patients, with multiple examples of antibodies and antibody–drug conjugates successfully applied for the treatment of solid tumors and lymphomas. Given reported recurrence rates, improvements are clearly still necessary. A major factor limiting the efficacy of antibody-targeted cancer therapies may be the incomplete penetration of the antibody or antibody–drug conjugate into the tumor. Incomplete tumor penetration also affects the outcome of molecular imaging, when using such targeting agents. From the injection site until they arrive inside the tumor, targeting molecules are faced with several barriers that impact intratumoral distribution. The primary means of antibody transport inside tumors is based on diffusion. The diffusive penetration inside the tumor is influenced by both antibody properties, such as size and binding affinity, as well as tumor properties, such as microenvironment, vascularization, and targeted antigen availability. Engineering smaller antibody fragments has shown to improve the rate of tumor uptake and intratumoral distribution. However, it is often accompanied by more rapid clearance from the body and in several cases also by inherent destabilization and reduction of the binding affinity of the antibody. In this perspective, we discuss different cancer targeting approaches based on antibodies or their fragments. We carefully consider how their size and binding properties influence their intratumoral uptake and distribution, and how this may affect cancer imaging and therapy of solid tumors.

  11. Implications of Therapy-Induced Selective Autophagy on Tumor Metabolism and Survival

    Directory of Open Access Journals (Sweden)

    Luke R. K. Hughson

    2012-01-01

    Full Text Available Accumulating evidence indicates that therapies designed to trigger apoptosis in tumor cells cause mitochondrial depolarization, nuclear damage, and the accumulation of misfolded protein aggregates, resulting in the activation of selective forms of autophagy. These selective forms of autophagy, including mitophagy, nucleophagy, and ubiquitin-mediated autophagy, counteract apoptotic signals by removing damaged cellular structures and by reprogramming cellular energy metabolism to cope with therapeutic stress. As a result, the efficacies of numerous current cancer therapies may be improved by combining them with adjuvant treatments that exploit or disrupt key metabolic processes induced by selective forms of autophagy. Targeting these metabolic irregularities represents a promising approach to improve clinical responsiveness to cancer treatments given the inherently elevated metabolic demands of many tumor types. To what extent anticancer treatments promote selective forms of autophagy and the degree to which they influence metabolism are currently under intense scrutiny. Understanding how the activation of selective forms of autophagy influences cellular metabolism and survival provides an opportunity to target metabolic irregularities induced by these pathways as a means of augmenting current approaches for treating cancer.

  12. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism

    DEFF Research Database (Denmark)

    Yang, Yunlong; Zhang, Yin; Iwamoto, Hideki

    2016-01-01

    The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes...... for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers....

  13. Molecular targeted therapy in modern oncology: Imaging assessment of treatment response and toxicities

    Energy Technology Data Exchange (ETDEWEB)

    Krajewski, Katherine M.; Braschi-Amirfarzan, Marta; DiPiro, Pamela J.; Jagannathan, Jyothi P.; Shinagare, Atul B. [Dept. of of Imaging, Dana Farber Cancer Institute, Boston (United States)

    2017-01-15

    Oncology is a rapidly evolving field with a shift toward personalized cancer treatment. The use of therapies targeted to the molecular features of individual tumors and the tumor microenvironment has become much more common. In this review, anti-angiogenic and other molecular targeted therapies are discussed, with a focus on typical and atypical response patterns and imaging manifestations of drug toxicities.

  14. Interactions between metabolic, reward and cognitive processes in appetite control: Implications for novel weight management therapies

    Science.gov (United States)

    Higgs, Suzanne; Spetter, Maartje S; Thomas, Jason M; Rotshtein, Pia; Lee, Michelle; Hallschmid, Manfred; Dourish, Colin T

    2017-01-01

    Traditional models of appetite control have emphasised the role of parallel homeostatic and hedonic systems, but more recently the distinction between independent homeostatic and hedonic systems has been abandoned in favour of a framework that emphasises the cross talk between the neurochemical substrates of the two systems. In addition, evidence has emerged more recently, that higher level cognitive functions such as learning, memory and attention play an important role in everyday appetite control and that homeostatic signals also play a role in cognition. Here, we review this evidence and present a comprehensive model of the control of appetite that integrates cognitive, homeostatic and reward mechanisms. We discuss the implications of this model for understanding the factors that may contribute to disordered patterns of eating and suggest opportunities for developing more effective treatment approaches for eating disorders and weight management. PMID:29072515

  15. Rectal cancer and inflammatory bowel disease: natural history and implications for radiation therapy

    International Nuclear Information System (INIS)

    Green, Sheryl; Stock, Richard G.; Greenstein, Adrian J.

    1999-01-01

    Purpose: There exists little information concerning the natural history of rectal cancer in patients with inflammatory bowel disease (IBD). In addition, the tolerance of pelvic irradiation in these patients is unknown. We analyzed the largest series of patients with IBD and rectal cancer in order to determine the natural history of the disease as well as the effect and tolerance of pelvic irradiation. Methods and Materials: A retrospective analysis of 47 patients with IBD and rectal cancer treated over a 34-year period (1960-1994) was performed. Thirty-five patients had ulcerative colitis and 12 patients had Crohn's disease. There were 31 male patients and 16 female patients. The stage (AJC) distribution was as follows: stage 0 in 5 patients, stage I in 13 patients, stage II in 7 patients, stage III in 13 patients, and stage IV in 9 patients. Surgical resection was performed in 44 patients. In two of these patients, preoperative pelvic irradiation was given followed by surgery. Twenty of these patients underwent postoperative adjuvant therapy (12 were treated with chemotherapy and pelvic irradiation and 8 with chemotherapy alone). Three patients were found to have unresectable disease and were treated with chemotherapy alone (2 patients) or chemotherapy and radiation therapy (RT) (1 patient). Radiation complications were graded using the RTOG acute and late effects scoring criteria. Follow-up ranged from 4 to 250 months (median 24 months). Results: The 5-year actuarial results revealed an overall survival (OS) of 42%, a disease-free survival (DFS) of 43%, a pelvic control rate (PC) of 67% and a freedom from distant failure (FFDF) of 47%. DFS decreased with increasing T stage with a 5-year rate of 86% for patients with Tis-T2 disease compared to 10% for patients with T3-T4 disease (p ) were noted in three patients (20%) receiving pelvic irradiation ± chemotherapy and these included two cases of grade 3 skin reactions and one case of grade 4 gastrointestinal

  16. Molecular signatures of maturing dendritic cells: implications for testing the quality of dendritic cell therapies

    Directory of Open Access Journals (Sweden)

    Wang Ena

    2010-01-01

    Full Text Available Abstract Background Dendritic cells (DCs are often produced by granulocyte-macrophage colony-stimulating factor (GM-CSF and interleukin-4 (IL-4 stimulation of monocytes. To improve the effectiveness of DC adoptive immune cancer therapy, many different agents have been used to mature DCs. We analyzed the kinetics of DC maturation by lipopolysaccharide (LPS and interferon-γ (IFN-γ induction in order to characterize the usefulness of mature DCs (mDCs for immune therapy and to identify biomarkers for assessing the quality of mDCs. Methods Peripheral blood mononuclear cells were collected from 6 healthy subjects by apheresis, monocytes were isolated by elutriation, and immature DCs (iDCs were produced by 3 days of culture with GM-CSF and IL-4. The iDCs were sampled after 4, 8 and 24 hours in culture with LPS and IFN-γ and were then assessed by flow cytometry, ELISA, and global gene and microRNA (miRNA expression analysis. Results After 24 hours of LPS and IFN-γ stimulation, DC surface expression of CD80, CD83, CD86, and HLA Class II antigens were up-regulated. Th1 attractant genes such as CXCL9, CXCL10, CXCL11 and CCL5 were up-regulated during maturation but not Treg attractants such as CCL22 and CXCL12. The expression of classical mDC biomarker genes CD83, CCR7, CCL5, CCL8, SOD2, MT2A, OASL, GBP1 and HES4 were up-regulated throughout maturation while MTIB, MTIE, MTIG, MTIH, GADD45A and LAMP3 were only up-regulated late in maturation. The expression of miR-155 was up-regulated 8-fold in mDCs. Conclusion DCs, matured with LPS and IFN-γ, were characterized by increased levels of Th1 attractants as opposed to Treg attractants and may be particularly effective for adoptive immune cancer therapy.

  17. Bioelectrical impedance analysis in clinical practice: implications for hepatitis C therapy BIA and hepatitis C

    Directory of Open Access Journals (Sweden)

    Kahraman Alisan

    2010-08-01

    Full Text Available Abstract Background Body composition analysis using phase angle (PA, determined by bioelectrical impedance analysis (BIA, reflects tissue electrical properties and has prognostic value in liver cirrhosis. Objective of this prospective study was to investigate clinical use and prognostic value of BIA-derived phase angle and alterations in body composition for hepatitis C infection (HCV following antiviral therapy. Methods 37 consecutive patients with HCV infection were enrolled, BIA was performed, and PA was calculated from each pair of measurements. 22 HCV genotype 3 patients treated for 24 weeks and 15 genotype 1 patients treated for 48 weeks, were examined before and after antiviral treatment and compared to 10 untreated HCV patients at 0, 24, and 48 weeks. Basic laboratory data were correlated to body composition alterations. Results Significant reduction in body fat (BF: 24.2 ± 6.7 kg vs. 19.9 ± 6.6 kg, genotype1; 15.4 ± 10.9 kg vs. 13.2 ± 12.1 kg, genotype 3 and body cell mass (BCM: 27.3 ± 6.8 kg vs. 24.3 ± 7.2 kg, genotype1; 27.7 ± 8.8 kg vs. 24.6 ± 7.6 kg, genotype 3 was found following treatment. PA in genotype 3 patients was significantly lowered after antiviral treatment compared to initial measurements (5.9 ± 0.7° vs. 5.4 ± 0.8°. Total body water (TBW was significantly decreased in treated patients with genotype 1 (41.4 ± 7.9 l vs. 40.8 ± 9.5 l. PA reduction was accompanied by flu-like syndromes, whereas TBW decline was more frequently associated with fatigue and cephalgia. Discussion BIA offers a sophisticated analysis of body composition including BF, BCM, and TBW for HCV patients following antiviral regimens. PA reduction was associated with increased adverse effects of the antiviral therapy allowing a more dynamic therapy application.

  18. Body temperature change during anesthesia for electroconvulsive therapy: implications for quality incentives in anesthesiology.

    Science.gov (United States)

    Modell, Jerome H; Gravenstein, Nikolaus; Morey, Timothy E

    2008-11-01

    The American Society of Anesthesiologists has announced that perioperative normothermia is a "Quality Incentive in Anesthesiology." We examined whether we could meet this quality incentive in a simple population: patients undergoing anesthesia for electroconvulsive therapy (ECT). We compared infrared-measured ear temperature before anesthesia to temperature upon delivery of patients to the postanesthesia care unit (PACU) after 101 consecutive brief anesthetics to facilitate ECT. For 35 procedures, the patients had an infrared ear thermometer temperature of measures were substandard. Also, current methods of measuring temperature may be inadequate to ascertain if patients are hypothermic after surgery. As the avoidance of hypothermia is a meritorious goal, anesthesia departments need to ensure that their temperature monitoring equipment is adequate to ensure accurate measurement of postanesthetic temperature if this variable is to be used as a quality incentive.

  19. Inflammatory bowel disease. Current concepts of pathogenesis and implications for therapy.

    Science.gov (United States)

    Fiocchi, C

    2002-09-01

    . Cytokines, chemokines and other soluble factors dominate immunological studies aimed at understanding how different anti-inflammatory and pro-inflammatory mediators are improperly regulated and how immune imbalance can be restored. The extent to which T-cells live or die is also a key determinant of chronicity. In addition to classical immune cells, epithelial, endothelial, mesenchymal and nerve cells are slowly gaining more importance in IBD pathogenesis, as they contribute to the ultimate fate of tissue damage. Medical and surgical therapies are vastly better now that they were only a couple of decades ago, but they are still far from satisfactory. Steroid and aminosalicylates are still the most common drugs after 60 years of use, and it is time to renovate our therapeutic approach to a more effective one. The value of biologicals has been highlighted by the recent success of anti-TNF therapy. Timing of therapy must also change. The concept of the step-by-step approach is slowly fading away, and the idea of an ''all-out'' approach with multiple concomitant drugs early in the disease is gaining credibility. New reports on early aggressive therapies, and the demonstration that early and late experimental IBD are caused by different mechanisms are changing the way we think about managing IBD. Both ulcerative colitis and Crohn's disease will continue to challenge the medical establishment for year to come, but the possibility that IBD can be conquered is more realistic now that never before.

  20. Sexual contact between psychologists and their former therapy patients: psychoanalytic perspectives and professional implications.

    Science.gov (United States)

    Shavit, Natalie; Bucky, Steven

    2004-09-01

    Data was analyzed from the semi-structured interviews of 6 heterosexual male psychoanalytic psychotherapists who by self-report had not engaged in a post-termination sexual involvement. The focus of each interview was to elicit the participants' views about sexual contact between psychotherapists and their former therapy patients, as well as their related attitudes towards Standard 4.07 of the APA Ethics Code (1992). The results suggested great disparity of opinion regarding what might constitute acceptable, ethical behavior in this domain. Nonetheless, all the clinicians agreed that the potential for harm resulting from post-termination sexual involvements was great, They all shared the beliefs that transference did not resolve with termination, that professional responsibilities continued after treatment ended, and that power differentials between therapist and patient lingered, perhaps in perpetuity. However, it was determined to be premature to replace the current Standard 4.07 with an absolute prohibition against sexual involvements between therapists and their former patients.

  1. Modulation of Apoptotic Pathways by Human Papillomaviruses (HPV: Mechanisms and Implications for Therapy

    Directory of Open Access Journals (Sweden)

    Chung-Hsiang Yuan

    2012-12-01

    Full Text Available The ability of the host to trigger apoptosis in infected cells is perhaps the most powerful tool by which viruses can be cleared from the host organism. To avoid elimination by this mechanism, human papillomaviruses (HPV have developed several mechanisms that enable the cells they infect to elude both extrinsic and intrinsic apoptosis. In this manuscript, we review the current literature regarding how HPV-infected cells avoid apoptosis and the molecular mechanisms involved in these events. In particular, we will discuss the modifications in intrinsic and extrinsic apoptotic pathways caused by proteins encoded by HPV early genes. Many of the current efforts regarding anti-cancer drug development are focused on directing tumor cells to undergo apoptosis. However, the ability of HPV-infected cells to resist apoptotic signals renders such therapies ineffective. Possible mechanisms for overcoming the resistance of HPV-infected tumor cells to anticancer drugs will be discussed.

  2. Immunoendocrine Interactions during HIV-TB Coinfection: Implications for the Design of New Adjuvant Therapies

    Directory of Open Access Journals (Sweden)

    Guadalupe Veronica Suarez

    2015-01-01

    Full Text Available Worldwide, around 14 million individuals are coinfected with both tuberculosis (TB and human immunodeficiency virus (HIV. In coinfected individuals, both pathogens weaken immunological system synergistically through mechanisms that are not fully understood. During both HIV and TB infections, there is a chronic state of inflammation associated to dramatic changes in immune cytokine and endocrine hormone levels. Despite this, the relevance of immunoendocrine interaction on both the orchestration of an effective immune response against both pathogens and the control of the chronic inflammation induced during HIV, TB, or both infections is still controversial. The present study reviews immunoendocrine interactions occurring during HIV and TB infections. We also expose our own findings on immunoendocrine cross talk in HIV-TB coinfection. Finally, we evaluate the use of adrenal hormones and their derivatives in immune-therapy and discuss the use of some of these compounds like the adjuvant for the prevention and treatment of TB in HIV patients.

  3. Dietary patterns in patients with advanced cancer: implications for anorexia-cachexia therapy.

    Science.gov (United States)

    Hutton, Joanne L; Martin, Lisa; Field, Catherine J; Wismer, Wendy V; Bruera, Eduardo D; Watanabe, Sharon M; Baracos, Vickie E

    2006-11-01

    Severe malnutrition and wasting are considered hallmarks of advanced malignant disease, and clinical research into anorexia-cachexia therapy and nutritional support for cancer patients is ongoing. However, information on typical dietary intakes and food choices for this population is notably lacking; proposed therapies for anorexia and wasting are not framed within the context of current intake. The objective of the study was to characterize the food intake patterns of patients with advanced cancer. Patients with advanced cancer (n = 151) recruited from a regional cancer center and palliative-care program completed a 3-d dietary record a mean (+/-SD) 8 +/- 7 mo before death. Food items were categorized according to macronutrient content and dietary use and subsequently entered into cluster analysis. Wide variations in intakes of energy (range: 4-53 kcal . kg body wt(-1) . d(-1); x +/- SD: 25.1 +/- 10.0 kcal . kg body wt(-1) . d(-1)) and protein (range: 0.2-2.7 g . kg body wt(-1) . d(-1); x +/- SD: 1.0 +/- 0.4 g . kg body wt(-1) . d(-1)) were observed. Even the subjects with the highest intakes had a recent history of weight loss, which suggests that the diets of those persons were consistently inadequate for weight maintenance. Cluster analysis found 3 dietary patterns that differed in food choice and caloric intake. Low intakes and a high risk of weight loss were associated with decreased frequency of eating and dietary profiles with little variety and unusually high proportions of liquids. These data provide a glimpse into dietary habits toward the end of life. Unique dietary patterns were found in this nutritionally vulnerable patient population.

  4. Cervical arterial dissection: An overview and implications for manipulative therapy practice.

    Science.gov (United States)

    Thomas, Lucy C

    2016-02-01

    Cervical arterial dissection (CAD) is a common cause of stroke in young people under 55 years. It can occur spontaneously or subsequent to minor trauma or infection. The incidence is difficult to determine accurately as not all CAD progress to stroke. CAD is the most catastrophic adverse event associated with cervical manipulative therapy but it is rare. Early features of CAD can mimic a painful musculoskeletal presentation and a patient may present for treatment of neck pain and headache with a dissection in progress. Whether the manipulative technique is responsible for dissection or whether the diagnosis of CAD has been missed is unclear. Identification of individuals at risk, or early recognition of CAD could help expedite medical intervention and avoid inappropriate treatment. The aims of this masterclass are to outline current research into the pathophysiology, aetiology and clinical presentation of CAD, to place the risk in context in a manipulative therapy setting and to discuss its possible clinical recognition. For those patients presenting with recent onset, moderate to severe unusual headache or neck pain, clinicians should perform a careful history, in particular questioning about recent exposure to head/neck trauma or neck strain. Cardiovascular factors may not be particularly useful indicators of risk of dissection. Clinicians should also be alert to reports of transient neurological dysfunction such as visual disturbance and balance deficits, arm paraesthesia and speech deficits, as these may be subtle. If clinicians suspect arterial dissection is in progress patients should be urgently referred for medical evaluation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. An ex vivo model for anti-angiogenic drug testing on intact microvascular networks.

    Directory of Open Access Journals (Sweden)

    Mohammad S Azimi

    Full Text Available New models of angiogenesis that mimic the complexity of real microvascular networks are needed. Recently, our laboratory demonstrated that cultured rat mesentery tissues contain viable microvascular networks and could be used to probe pericyte-endothelial cell interactions. The objective of this study was to demonstrate the efficacy of the rat mesentery culture model for anti-angiogenic drug testing by time-lapse quantification of network growth. Mesenteric windows were harvested from adult rats, secured in place with an insert, and cultured for 3 days according to 3 experimental groups: 1 10% serum (angiogenesis control, 2 10% serum + sunitinib (SU11248, and 3 10% serum + bevacizumab. Labeling with FITC conjugated BSI-lectin on Day 0 and 3 identified endothelial cells along blood and lymphatic microvascular networks. Comparison between day 0 (before and 3 (after in networks stimulated by 10% serum demonstrated a dramatic increase in vascular density and capillary sprouting. Growing networks contained proliferating endothelial cells and NG2+ vascular pericytes. Media supplementation with sunitinib (SU11248 or bevacizumab both inhibited the network angiogenic responses. The comparison of the same networks before and after treatment enabled the identification of tissue specific responses. Our results establish, for the first time, the ability to evaluate an anti-angiogenic drug based on time-lapse imaging on an intact microvascular network in an ex vivo scenario.

  6. Age-Related Macular Degeneration: Clinical Findings following Treatment with Antiangiogenic Drugs

    Directory of Open Access Journals (Sweden)

    Ricardo Casaroli-Marano

    2014-01-01

    Full Text Available Purpose. To survey the management of patients with neovascular age-related macular degeneration (nvAMD in Spain. Methods. An observational retrospective multicenter study was conducted. The variables analyzed were sociodemographic characteristics, foveal and macular thickness, visual acuity (VA, type of treatment, number of injections, and the initial administration of a loading dose of an antiangiogenic drug. Results. 208 patients were followed up during 23.4 months in average. During the first and second years, patients received a mean of 4.5±1.8 and 1.6±2.1 injections of antiangiogenic drugs, and 5.4±2.8 and 3.6±2.2 follow-up visits were performed, respectively. The highest improvement in VA was observed at 3 months of follow-up, followed by a decrease in the response that stabilized above baseline values until the end of the study. Patients who received an initial loading dose presented greater VA gains than those without. Conclusions. Our results suggest the need for a more standardized approach in the management and diagnosis of nvAMD receiving VEGF inhibitors. To achieve the visual outcomes reported in pivotal trials, an early diagnosis, proactive approach (more treating than follow-up visits, and a close monitoring might be the key to successfully manage nvAMD.

  7. Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety

    Directory of Open Access Journals (Sweden)

    Welker MW

    2013-10-01

    Full Text Available Martin-Walter Welker, Joerg TrojanMedizinische Klinik 1, Universitätsklinikum Frankfurt, GermanyAbstract: Hepatocellular carcinoma (HCC is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety.Keywords: HCC, sorafenib, antiangiogenesis, TACE, MET

  8. In vitro and in vivo anti-angiogenic activity of girinimbine isolated from Murraya koenigii

    Directory of Open Access Journals (Sweden)

    Iman V

    2015-03-01

    Full Text Available Venoos Iman,1 Hamed Karimian,1 Syam Mohan,2 Yahya Hasan Hobani,2 Mohamed Ibrahim Noordin,1 Mohd Rais Mustafa,3 Suzita Mohd Noor41Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 2Medical Research Center, University of Jazan, Jazan, Saudi Arabia; 3Department of Pharmacology, Centre for Natural Products and Drug Discovery (CENAR, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 4Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, MalaysiaAbstract: Girinimbine is a carbazole alkaloid isolated from the stem bark and root of Murraya koenigii. Here we report that girinimbine is an inhibitor of angiogenic activity both in vitro and in vivo. MTT results showed that girinimbine inhibited proliferation of human umbilical vein endothelial cells, while results from endothelial cell invasion, migration, tube formation, and wound healing assays demonstrated significant time- and dose-dependent inhibition by girinimbine. A proteome profiler array done on girinimbine-treated human umbilical vein endothelial cells showed that girinimbine had mediated regulation of pro-angiogenic and anti-angiogenic proteins. The anti-angiogenic potential of girinimbine was also evidenced in vivo in the zebrafish embryo model wherein girinimbine inhibited neo vessel formation in zebrafish embryos following 24 hours of exposure. Together, these results showed that girinimbine could effectively suppress angiogenesis, suggestive of its therapeutic potential as a novel angiogenesis inhibitor. Keywords: angiogenesis, inhibitor, carbazole alkaloid, zebrafish

  9. The evaluation of anti-angiogenic treatment effects for implanted rabbit VX2 breast tumors using functional multi-slice spiral computed tomography (f-MSCT)

    Energy Technology Data Exchange (ETDEWEB)

    Lei Zhen, E-mail: leizhen2004@163.com [Department of Anatomy, Chinese Medical University, No. 92, Beiermalu Road, Heping District, Shenyang, 110001 (China) and Department of Radiology, The First Hospital of Liaoning Medical College, No. 2, Wuduan, Renmin Street, Jinzhou, 121001 (China); Ma Heji, E-mail: maheji9831@sina.com [Department of Radiology, The First Hospital of Liaoning Medical College, No. 2, Wuduan, Renmin Street, Jinzhou, 121001 (China); Xu Na, E-mail: xuna821230@sohu.com [Department of Radiology, The First Hospital of Liaoning Medical College, No. 2, Wuduan, Renmin Street, Jinzhou, 121001 (China); Xi Huanjiu, E-mail: xihuanjiu2004@yahoo.cn [Anthropology Institute, Liaoning Medical College, No. 40, Sanduan, Songpo Rd, Jinzhou, 121001 (China)

    2011-05-15

    Objective: Investigate the benefit of functional multi-slice spiral computed tomography (f-MSCT) perfusion imaging in the non-invasive assessment of targeted anti-angiogenesis therapy on an implanted rabbit VX2 breast tumor model. Method: 69 female pure New Zealand white rabbits were randomly assigned to one of the 4 groups and received treatment accordingly: control (saline), Endostar, neoadjuvant chemotherapy (Cyclophosphamide, Epirubicin and 5-Fluorouracil, CEF), combination therapy (Endostar and CEF). After 2 weeks of treatment, f-MSCT perfusion scannings were performed for all rabbits and information about blood flow (BF), blood volume (BV), mean transit time (MTT) and surface permeability (SP) was collected. After perfusion imaging, tumor tissues were sampled for immunohistochemistry and the Western blot test of VEGF protein expression. Results: (1) The VEGF expression level, measured by immunohistochemistry and Western blot, decreased by treatment group (control > Endostar > CEF > combination therapy). The same was true for the mean BF, BV, MTT and PS, which decreased from the control group to the combination therapy group gradually. The mean MTT level increased in reverse order from the control to the combination therapy group. The difference between any 2 groups on these measures was statistically significant (P < 0.05). (2) There was moderate positive correlation between VEGF expression and BE, BV, or PS level (P < 0.05) and a negative correlation between VEGF expression and MTT level for all 4 groups (P < 0.05). Conclusion: Therefore, f-MSCT can be used as a non-invasive approach to evaluate the effect of anti-angiogenic therapy for implanted rabbit VX2 breast tumors.

  10. The evaluation of anti-angiogenic treatment effects for implanted rabbit VX2 breast tumors using functional multi-slice spiral computed tomography (f-MSCT)

    International Nuclear Information System (INIS)

    Lei Zhen; Ma Heji; Xu Na; Xi Huanjiu

    2011-01-01

    Objective: Investigate the benefit of functional multi-slice spiral computed tomography (f-MSCT) perfusion imaging in the non-invasive assessment of targeted anti-angiogenesis therapy on an implanted rabbit VX2 breast tumor model. Method: 69 female pure New Zealand white rabbits were randomly assigned to one of the 4 groups and received treatment accordingly: control (saline), Endostar, neoadjuvant chemotherapy (Cyclophosphamide, Epirubicin and 5-Fluorouracil, CEF), combination therapy (Endostar and CEF). After 2 weeks of treatment, f-MSCT perfusion scannings were performed for all rabbits and information about blood flow (BF), blood volume (BV), mean transit time (MTT) and surface permeability (SP) was collected. After perfusion imaging, tumor tissues were sampled for immunohistochemistry and the Western blot test of VEGF protein expression. Results: (1) The VEGF expression level, measured by immunohistochemistry and Western blot, decreased by treatment group (control > Endostar > CEF > combination therapy). The same was true for the mean BF, BV, MTT and PS, which decreased from the control group to the combination therapy group gradually. The mean MTT level increased in reverse order from the control to the combination therapy group. The difference between any 2 groups on these measures was statistically significant (P < 0.05). (2) There was moderate positive correlation between VEGF expression and BE, BV, or PS level (P < 0.05) and a negative correlation between VEGF expression and MTT level for all 4 groups (P < 0.05). Conclusion: Therefore, f-MSCT can be used as a non-invasive approach to evaluate the effect of anti-angiogenic therapy for implanted rabbit VX2 breast tumors.

  11. Advances in the molecular genetics of gliomas - implications for classification and therapy.

    Science.gov (United States)

    Reifenberger, Guido; Wirsching, Hans-Georg; Knobbe-Thomsen, Christiane B; Weller, Michael

    2017-07-01

    Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.

  12. A ternary-complex of a suicide gene, a RAGE-binding peptide, and polyethylenimine as a gene delivery system with anti-tumor and anti-angiogenic dual effects in glioblastoma.

    Science.gov (United States)

    Choi, Eunji; Oh, Jungju; Lee, Dahee; Lee, Jaewon; Tan, Xiaonan; Kim, Minkyung; Kim, Gyeungyun; Piao, Chunxian; Lee, Minhyung

    2018-04-13

    The receptor for advanced glycation end-products (RAGE) is involved in tumor angiogenesis. Inhibition of RAGE might be an effective anti-angiogenic therapy for cancer. In this study, a cationic RAGE-binding peptide (RBP) was produced as an antagonist of RAGE, and a ternary-complex consisting of RBP, polyethylenimine (2 kDa, PEI2k), and a suicide gene (pHSVtk) was developed as a gene delivery system with dual functions: the anti-tumor effect of pHSVtk and anti-angiogenic effect of RBP. As an antagonist of RAGE, RBP decreased the secretion of vascular-endothelial growth factor (VEGF) in activated macrophages and reduced the tube-formation of endothelial cells in vitro. In in vitro transfection assays, the RBP/PEI2k/plasmid DNA (pDNA) ternary-complex had higher transfection efficiency than the PEI2k/pDNA binary-complex. In an intracranial glioblastoma animal model, the RBP/PEI2k/pHSVtk ternary-complex reduced α-smooth muscle actin expression, suggesting that the complex has an anti-angiogenic effect. In addition, the ternary-complex had higher pHSVtk delivery efficiency than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes in an animal model. As a result, the ternary-complex induced apoptosis and reduced tumor volume more effectively than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes. In conclusion, due to its dual anti-tumor and anti-angiogenesis effects, the RBP/PEI2k/pHSVtk ternary-complex might be an efficient gene delivery system for the treatment of glioblastoma. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. Tissue As A Medium For Laser Light Transport-Implications For Photoradiation Therapy

    Science.gov (United States)

    Preuss, L. E.; Bolin, F. P.; Cain, B. W.

    1982-12-01

    An important medical laser application is in the emerging field of photoradiation therapy (PRT). PRT is the process in which malignant tissue is destroyed by administration of light to a specific photosensitized site. Filtered arcs, incandescents and dye lasers have been used as sources of activating light. We have carried out light experiments in tissue to study such PRT light distributions. The results of this research have shown that a number of important optical phenomena occurring within illuminated tissue must be accounted for in order to make good predictions of tumor light dosage. Among these are; tissue type, interface effects and anomalies due to composition. These effects substantially influence light levels in PRT and, thus, the therapeutic effect. The uniqueness of tissue as a medium for light transport presents special problems for optics research and instrumentation. Successful solutions necessarily will involve collaboration between the life sciences and optic specialists. Attempts at treatment of human disease using non-ionizing radiation have a history archaeologically traceable to archaic societies (in which the sun's photons were used and often worshipped).1 Western medicine in the past, has used visible light beneficially, albeit empirically, on a few ailments. However, in this century, a significant development in the understanding and in the therapeutic use of this electromagnetic radiation in the UV, visible and IR has occurred, based on scientific study. This utilization of radiation in the visible and ultraviolet can be by two distinct processes. One is through the direct action of the photons which serve as the sole treatment agent. In this case the photon interacts with the cell, or its components, in a single step, to produce a desired effect. An example is the successful use of blue light for treatment of bilirubinemia in newborns. The second process is a biological effect produced through the combination of electromagnetic radiation

  14. Proton therapy of prostate cancer by anterior-oblique beams: implications of setup and anatomy variations

    Science.gov (United States)

    Moteabbed, M.; Trofimov, A.; Sharp, G. C.; Wang, Y.; Zietman, A. L.; Efstathiou, J. A.; Lu, H.-M.

    2017-03-01

    Proton therapy of prostate by anterior beams could offer an attractive option for treating patients with hip prosthesis and limiting the high-dose exposure to the rectum. We investigated the impact of setup and anatomy variations on the anterior-oblique (AO) proton plan dose, and strategies to manage these effects via range verification and adaptive delivery. Ten patients treated by bilateral (BL) passive-scattering proton therapy (79.2 Gy in 44 fractions) who underwent weekly verification CT scans were selected. Plans with AO beams were additionally created. To isolate the effect of daily variations, initial AO plans did not include range uncertainty margins. The use of fixed planning margins and adaptive range adjustments to manage these effects was investigated. For each case, the planned dose was recalculated on weekly CTs, and accumulated on the simulation CT using deformable registration to approximate the delivered dose. Planned and accumulated doses were compared for each scenario to quantify dose deviations induced by variations. The possibility of estimating the necessary range adjustments before each treatment was explored by simulating the procedure of a diode-based in vivo range verification technique, which would potentially be used clinically. The average planned rectum, penile bulb and femoral heads mean doses were smaller for initial AO compared to BL plans (by 8.3, 16.1 and 25.9 Gy, respectively). After considering interfractional variations in AO plans, the target coverage was substantially reduced. The maximum reduction of V 79.2/D 95/D mean/EUD for AO (without distal margins) (25.3%/10.7/1.6/4.9 Gy, respectively) was considerably larger than BL plans. The loss of coverage was mainly related to changes in water equivalent path length of the prostate after fiducial-based setup, caused by discrepancies in patient anterior surface and bony-anatomy alignment. Target coverage was recovered partially when using fixed planning margins, and fully when

  15. Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions

    DEFF Research Database (Denmark)

    Zibert, John Robert; Wallbrecht, Katrin; Schön, Margarete

    2011-01-01

    with epidermal expression of human TGF-ß1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM...... in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.......-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein-coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue...

  16. Multijoint arm stiffness during movements following stroke: implications for robot therapy.

    Science.gov (United States)

    Piovesan, D; Casadio, M; Mussa-Ivaldi, F A; Morasso, P G

    2011-01-01

    Impaired arm movements in stroke appear as a set of stereotypical kinematic patterns, characterized by abnormal joint coupling, which have a direct consequence on arm mechanics and can be quantified by the net arm stiffness at the hand. The current available measures of arm stiffness during functional tasks have limited clinical use, since they require several repetitions of the same test movement in many directions. Such procedure is difficult to obtain in stroke survivors who have lower fatigue threshold and increased variability compared to unimpaired individuals. The present study proposes a novel, fast quantitative measure of arm stiffness during movements by means of a Time-Frequency technique and the use of a reassigned spectrogram, applied on a trial-by-trial basis with a single perturbation. We tested the technique feasibility during robot mediated therapy, where a robot helped stroke survivors to regain arm mobility by providing assistive forces during a hitting task to 13 targets covering the entire reachable workspace. The endpoint stiffness of the paretic arm was estimated at the end of each hitting movements by suddenly switching of the assistive forces and observing the ensuing recoil movements. In addition, we considered how assistive forces influence stiffness. This method will provide therapists with improved tools to target the treatment to the individual's specific impairment and to verify the effects of the proposed exercises. © 2011 IEEE

  17. Clinicians' perspectives on cognitive therapy in community mental health settings: implications for training and implementation.

    Science.gov (United States)

    Stirman, Shannon Wiltsey; Gutiérrez-Colina, Ana; Toder, Katherine; Esposito, Gregory; Barg, Frances; Castro, Frank; Beck, Aaron T; Crits-Christoph, Paul

    2013-07-01

    Policymakers are investing significant resources in large-scale training and implementation programs for evidence-based psychological treatments (EBPTs) in public mental health systems. However, relatively little research has been conducted to understand factors that may influence the success of efforts to implement EBPTs for adult consumers of mental health services. In a formative investigation during the development of a program to implement cognitive therapy (CT) in a community mental health system, we surveyed and interviewed clinicians and clinical administrators to identify potential influences on CT implementation within their agencies. Four primary themes were identified. Two related to attitudes towards CT: (1) ability to address client needs and issues that are perceived as most central to their presenting problems, and (2) reluctance to fully implement CT. Two themes were relevant to context: (1) agency-level barriers, specifically workload and productivity concerns and reactions to change, and (2) agency-level facilitators, specifically, treatment planning requirements and openness to training. These findings provide information that can be used to develop strategies to facilitate the implementation of CT interventions for clients being treated in public-sector settings.

  18. Temporal Progression of Retinal Progenitor Cell Identity: Implications in Cell Replacement Therapies

    Directory of Open Access Journals (Sweden)

    Awais Javed

    2017-12-01

    Full Text Available Retinal degenerative diseases, which lead to the death of rod and cone photoreceptor cells, are the leading cause of inherited vision loss worldwide. Induced pluripotent or embryonic stem cells (iPSCs/ESCs have been proposed as a possible source of new photoreceptors to restore vision in these conditions. The proof of concept studies carried out in mouse models of retinal degeneration over the past decade have highlighted several limitations for cell replacement in the retina, such as the low efficiency of cone photoreceptor production from stem cell cultures and the poor integration of grafted cells in the host retina. Current protocols to generate photoreceptors from stem cells are largely based on the use of extracellular factors. Although these factors are essential to induce the retinal progenitor cell (RPC fate from iPSCs/ESCs, developmental studies have shown that RPCs alter fate output as a function of time (i.e., their temporal identity to generate the seven major classes of retinal cell types, rather than spatial position. Surprisingly, current stem cell differentiation protocols largely ignore the intrinsic temporal identity of dividing RPCs, which we argue likely explains the low efficiency of cone production in such cultures. In this article, we briefly review the mechanisms regulating temporal identity in RPCs and discuss how they could be exploited to improve cone photoreceptor production for cell replacement therapies.

  19. Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy

    Directory of Open Access Journals (Sweden)

    Luis B Tovar-y-Romo

    2014-02-01

    Full Text Available Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF, glial-derived neurotrophic factor (GDNF, ciliary neurotrophic factor (CNTF and insulin-like growth factor 1 (IGF-1. Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this review we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.

  20. Perceptions of Gender and Femininity Based on Language: Implications for Transgender Communication Therapy.

    Science.gov (United States)

    Hancock, Adrienne B; Stutts, Holly Wilder; Bass, Annie

    2015-09-01

    Recent research presents a picture of diminishing gender differences in language. Two experiments examined whether language use can predict perceptions of gender and femininity; one included male and female speakers telling a personal narrative, the other also included male-to-female transgender speakers and analyzed an oral picture description. In each experiment, raters read transcribed samples before judging the gender and rating the femininity of the speaker. Only number of T-units, words per T-unit, dependent clauses per T-unit, and personal pronouns per T-unit emerged as different between gender groups. As none of the variables were strongly correlated with perceptual judgments, regression analysis was used to determine how combinations of linguistic variables predict female/feminine ratings. Results from these two studies demonstrate that gender-related differences in language use for these two contexts are limited, and that any relationship of language to perceptions of gender and femininity is complex and multivariate. This information calls into question the utility of training key language features in transgender communication therapy.

  1. Anaplastic Lymphoma Kinase Rearrangement in Digestive Tract Cancer: Implication for Targeted Therapy in Chinese Population.

    Directory of Open Access Journals (Sweden)

    Jianming Ying

    Full Text Available Anaplastic lymphoma kinase (ALK rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.Tissue microarray (TMA was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH, real-time polymerase chain reaction (qRT-PCR, target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.Among the tested cases, 2 (0.44% CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4-ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1. One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.

  2. HDACis (class I), cancer stem cell, and phytochemicals: Cancer therapy and prevention implications.

    Science.gov (United States)

    Bayat, Sahar; Shekari Khaniani, Mahmoud; Choupani, Jalal; Alivand, Mohammad Reza; Mansoori Derakhshan, Sima

    2018-01-01

    Epigenetics is independent of the sequence events that physically affect the condensing of chromatin and genes expression. The unique epigenetic memories of various cells trigger exclusive gene expression profiling. According to different studies, the aberrant epigenetic signatures and impaired gene expression profiles are master occurrences in cancer cells in which oncogene and tumor suppressor genes are affected. Owing to the facts that epigenetic modifications are performed earlier than expression and are reversible, the epigenetic reprogramming of cancer cells could be applied potentially for their prevention, control, and therapy. The disruption of the acetylation signature, as a master epigenetic change in cancers, is related to the expression and the activity of HDACs. In this context, class I HDACs play a significant role in the regulation of cell proliferation and cancer. More recently, cancer stem cell (CSC) has been introduced as a minority population of tumor that is responsible for invasiveness, drug resistance, and relapse of cancers. It is now believed that controlling CSC via epigenetic reprogramming such as targeting HDACs could be helpful in regulating the acetylation pattern of chromatin. Recently, a number of reports have introduced some phytochemicals as HDAC inhibitors. The use of phytochemicals with the HDAC inhibition property could be potentially efficient in overcoming the mentioned problems of CSCs. This review presents a perspective concerning HDAC-targeted phytochemicals to control CSC in tumors. Hopefully, this new route would have more advantages in therapeutic applications and prevention against cancer. Copyright © 2017. Published by Elsevier Masson SAS.

  3. Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms.

    Science.gov (United States)

    Frost, James D; Le, John T; Lee, Chong L; Ballester-Rosado, Carlos; Hrachovy, Richard A; Swann, John W

    2015-10-01

    Abnormal high frequency oscillations (HFOs) in EEG recordings are thought to be reflections of mechanisms responsible for focal seizure generation in the temporal lobe and neocortex. HFOs have also been recorded in patients and animal models of infantile spasms. If HFOs are important contributors to infantile spasms then anticonvulsant drugs that suppress these seizures should decrease the occurrence of HFOs. In experiments reported here, we used long-term video/EEG recordings with digital sampling rates capable of capturing HFOs. We tested the effectiveness of vigabatrin (VGB) in the TTX animal model of infantile spasms. VGB was found to be quite effective in suppressing spasms. In 3 of 5 animals, spasms ceased after a daily two week treatment. In the other 2 rats, spasm frequency dramatically decreased but gradually increased following treatment cessation. In all animals, hypsarrhythmia was abolished by the last treatment day. As VGB suppressed the frequency of spasms, there was a decrease in the intensity of the behavioral spasms and the duration of the ictal EEG event. Analysis showed that there was a burst of high frequency activity at ictal onset, followed by a later burst of HFOs. VGB was found to selectively suppress the late HFOs of ictal complexes. VGB also suppressed abnormal HFOs recorded during the interictal periods. Thus VGB was found to be effective in suppressing both the generation of spasms and hypsarrhythmia in the TTX model. Vigabatrin also appears to preferentially suppress the generation of abnormal HFOs, thus implicating neocortical HFOs in the infantile spasms disease state. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients

    Directory of Open Access Journals (Sweden)

    Jaenicke Fritz

    2010-04-01

    Full Text Available Abstract Background Angiogenesis appears to play an important role in ovarian cancer. Vascular endothelial growth factor (VEGF has recently been implicated as a therapeutic target in ovarian cancer. The tissue inhibitor of metalloproteinase 1 (TIMP-1 is involved in tissue invasion and angiogenesis. The application of serum TIMP-1 and VEGF to monitor primary therapy and predict clinical outcome of patients with ovarian cancer is unclear. Methods Patients with epithelial ovarian cancer who presented for primary surgery were included in this study. A total of 148 serum samples from 37 patients were analyzed. Samples were prospectively collected at 4 predefined time points: 1. before radical debulking surgery, 2. after surgery and before platinum/taxane based chemotherapy, 3. during chemotherapy, 4. after chemotherapy. Serum VEGF-165 and TIMP-1 as well as CA-125 were quantified by ELISA or ECLIA and correlation with response and long-term clinical outcome was analyzed. Results Serum levels of all markers changed substantially during first-line therapy. High CA-125 (p = 0.002, TIMP-1 (p = 0.007 and VEGF-165 (p = 0.02 after chemotherapy were associated with reduced overall survival. In addition, elevated CA-125 (p Conclusions TIMP-1 and VEGF serum levels changed significantly during first-line therapy of ovarian cancer patients and predicted prognosis. These findings support the role of angiogenesis in ovarian cancer progression and the use of antiangiogenic therapy.

  5. Proton beam deflection in MRI fields: Implications for MRI-guided proton therapy.

    Science.gov (United States)

    Oborn, B M; Dowdell, S; Metcalfe, P E; Crozier, S; Mohan, R; Keall, P J

    2015-05-01

    This paper investigates, via magnetic modeling and Monte Carlo simulation, the ability to deliver proton beams to the treatment zone inside a split-bore MRI-guided proton therapy system. Field maps from a split-bore 1 T MRI-Linac system are used as input to geant4 Monte Carlo simulations which model the trajectory of proton beams during their paths to the isocenter of the treatment area. Both inline (along the MRI bore) and perpendicular (through the split-bore gap) orientations are simulated. Monoenergetic parallel and diverging beams of energy 90, 195, and 300 MeV starting from 1.5 and 5 m above isocenter are modeled. A phase space file detailing a 2D calibration pattern is used to set the particle starting positions, and their spatial location as they cross isocenter is recorded. No beam scattering, collimation, or modulation of the proton beams is modeled. In the inline orientation, the radial symmetry of the solenoidal style fringe field acts to rotate the protons around the beam's central axis. For protons starting at 1.5 m from isocenter, this rotation is 19° (90 MeV) and 9.8° (300 MeV). A minor focusing toward the beam's central axis is also seen, but only significant, i.e., 2 mm shift at 150 mm off-axis, for 90 MeV protons. For the perpendicular orientation, the main MRI field and near fringe field act as the strongest to deflect the protons in a consistent direction. When starting from 1.5 m above isocenter shifts of 135 mm (90 MeV) and 65 mm (300 MeV) were observed. Further to this, off-axis protons are slightly deflected toward or away from the central axis in the direction perpendicular to the main deflection direction. This leads to a distortion of the phase space pattern, not just a shift. This distortion increases from zero at the central axis to 10 mm (90 MeV) and 5 mm (300 MeV) for a proton 150 mm off-axis. In both orientations, there is a small but subtle difference in the deflection and distortion pattern between protons fired parallel to the

  6. Cinnamon ameliorates experimental allergic encephalomyelitis in mice via regulatory T cells: implications for multiple sclerosis therapy.

    Science.gov (United States)

    Mondal, Susanta; Pahan, Kalipada

    2015-01-01

    Upregulation and/or maintenance of regulatory T cells (Tregs) during an autoimmune insult may have therapeutic efficacy in autoimmune diseases. Although several immunomodulatory drugs and molecules are available, most present significant side effects over long-term use. Cinnamon is a commonly used natural spice and flavoring material used for centuries throughout the world. Here, we have explored a novel use of cinnamon powder in protecting Tregs and treating the disease process of experimental allergic encephalomyelitis (EAE), an animal model of MS. Oral feeding of cinnamon (Cinnamonum verum) powder suppresses clinical symptoms of relapsing-remitting EAE in female PLP-TCR transgenic mice and adoptive transfer mouse model. Cinnamon also inhibited clinical symptoms of chronic EAE in male C57/BL6 mice. Dose-dependent study shows that cinnamon powder at a dose of 50 mg/kg body wt/d or higher significantly suppresses clinical symptoms of EAE in mice. Accordingly, oral administration of cinnamon also inhibited perivascular cuffing, maintained the integrity of blood-brain barrier and blood-spinal cord barrier, suppressed inflammation, normalized the expression of myelin genes, and blocked demyelination in the central nervous system of EAE mice. Interestingly, cinnamon treatment upregulated Tregs via reduction of nitric oxide production. Furthermore, we demonstrate that blocking of Tregs by neutralizing antibodies against CD25 abrogates cinnamon-mediated protection of EAE. Taken together, our results suggest that oral administration of cinnamon powder may be beneficial in MS patients and that no other existing anti-MS therapies could be so economical and trouble-free as this approach.

  7. Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies.

    Science.gov (United States)

    Mottok, Anja; Steidl, Christian

    2018-03-02

    Hodgkin lymphoma is considered a prime example of treatment success with cure rates exceeding 80% using modern combined modality therapies. However, especially in adolescents and young adults, treatment-related toxicity and long-term morbidity still represent persistent challenges. Moreover, outcomes in patients with relapsed or refractory disease remain unfavorable in the era of high-dose chemotherapy and stem cell transplantation. Hence, there is a high demand for novel and innovative alternative treatment approaches. In recent years many new therapeutic agents have emerged from preclinical and clinical studies that target molecular hallmarks of Hodgkin lymphoma, including the aberrant phenotype of the tumor cells, deregulated oncogenic pathways and immune escape. The antibody drug conjugate BV and immune checkpoint inhibitors have already shown great success in patients with relapsed/refractory disease, leading to FDA approval and new trials testing these agents in various clinical settings. Fundamentally important for the success of these and other novel agents continues to be the expanding knowledge and understanding of Hodgkin lymphoma biology and disease progression, as well as the development of robust tools for biomarker-driven risk stratification and therapeutic decision making. We anticipate that the availability and clinical implementation of novel molecular assays will be instrumental in an era of rapid shifts in the treatment landscape of this disease. Here, we review the current knowledge of Hodgkin lymphoma pathobiology, highlighting the related development of novel treatment strategies and prognostic models that hold the promise to continually challenge and change the current standard of care in classical Hodgkin lymphoma. Copyright © 2018 American Society of Hematology.

  8. Sleep architecture, insulin resistance and the nasal cycle: Implications for positive airway pressure therapy

    Directory of Open Access Journals (Sweden)

    Catherine A.P. Crofts

    2018-03-01

    Full Text Available Background: The global pandemic of metabolic disease is worsening. The metabolic theory of obesity proposes that hormonal changes, especially hyperinsulinaemia, precede metabolic disease development. Although quality sleep is recognised as a key factor for good health, less is known about disrupted sleep as a risk factor for hyperinsulinaemia.   Aim: To explore the relationship between sleep, especially sleep architecture and the nasal cycle, on insulin secretion in obstructive sleep apnoea (OSA with comorbid metabolic disease. This review includes a discussion of the potential role of Rest-Activity-Cycler positive airway pressure (RACer-PAP, a novel non-pharmacological OSA treatment strategy.   Methods: A narrative review of all the relevant papers known to the authors was conducted. This review also included results from a polysomnographic sleep clinic pilot study (n = 3 comparing sleep efficiency of RACer-PAP to nasal continuous positive airways pressure (n-CPAP in OSA patients.   Results: Metabolic disease is strongly associated with disturbed sleep. Sleep architecture influences cerebral hormonal secretion, lateral shifts in the autonomic nervous system and nasal airflow dominance. Disturbed sleep shortens short-wave sleep periods, decreasing insulin sensitivity and glucose tolerance. Improvements to metabolic function during n-CPAP treatment are inconsistent. If RACer-PAP demonstrates superior effects on sleep architecture and autonomic function, it may offer advantages in OSA patients with comorbid metabolic disease.   Conclusion: Improving sleep architecture by maintaining the nasal cycle proposes a novel non-pharmacological treatment paradigm for treating OSA with comorbid metabolic disease. Research is required to demonstrate if RACer-PAP therapy influences whole night sleep architecture, sympathovagal balance and markers of metabolic disease.

  9. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy

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    Neoptolemos John P

    2011-04-01

    Full Text Available Abstract Background Nrf2 is a key transcriptional regulator of a battery of genes that facilitate phase II/III drug metabolism and defence against oxidative stress. Nrf2 is largely regulated by Keap1, which directs Nrf2 for proteasomal degradation. The Nrf2/Keap1 system is dysregulated in lung, head and neck, and breast cancers and this affects cellular proliferation and response to therapy. Here, we have investigated the integrity of the Nrf2/Keap1 system in pancreatic cancer. Results Keap1, Nrf2 and the Nrf2 target genes AKR1c1 and GCLC were detected in a panel of five pancreatic cancer cell lines. Mutation analysis of NRF2 exon 2 and KEAP1 exons 2-6 in these cell lines identified no mutations in NRF2 and only synonomous mutations in KEAP1. RNAi depletion of Nrf2 caused a decrease in the proliferation of Suit-2, MiaPaca-2 and FAMPAC cells and enhanced sensitivity to gemcitabine (Suit-2, 5-flurouracil (FAMPAC, cisplatin (Suit-2 and FAMPAC and gamma radiation (Suit-2. The expression of Nrf2 and Keap1 was also analysed in pancreatic ductal adenocarcinomas (n = 66 and 57, respectively and matching normal benign epithelium (n = 21 cases. Whilst no significant correlation was seen between the expression levels of Keap1 and Nrf2 in the tumors, interestingly, Nrf2 staining was significantly greater in the cytoplasm of tumors compared to benign ducts (P Conclusions Expression of Nrf2 is up-regulated in pancreatic cancer cell lines and ductal adenocarcinomas. This may reflect a greater intrinsic capacity of these cells to respond to stress signals and resist chemotherapeutic interventions. Nrf2 also appears to support proliferation in certain pancreatic adenocarinomas. Therefore, strategies to pharmacologically manipulate the levels and/or activity of Nrf2 may have the potential to reduce pancreatic tumor growth, and increase sensitivity to therapeutics.

  10. Local Failure in Resected N1 Lung Cancer: Implications for Adjuvant Therapy

    International Nuclear Information System (INIS)

    Higgins, Kristin A.; Chino, Junzo P.; Berry, Mark; Ready, Neal; Boyd, Jessamy; Yoo, David S.; Kelsey, Chris R.

    2012-01-01

    Purpose: To evaluate actuarial rates of local failure in patients with pathologic N1 non–small-cell lung cancer and to identify clinical and pathologic factors associated with an increased risk of local failure after resection. Methods and Materials: All patients who underwent surgery for non–small-cell lung cancer with pathologically confirmed N1 disease at Duke University Medical Center from 1995–2008 were identified. Patients receiving any preoperative therapy or postoperative radiotherapy or with positive surgical margins were excluded. Local failure was defined as disease recurrence within the ipsilateral hilum, mediastinum, or bronchial stump/staple line. Actuarial rates of local failure were calculated with the Kaplan-Meier method. A Cox multivariate analysis was used to identify factors independently associated with a higher risk of local recurrence. Results: Among 1,559 patients who underwent surgery during the time interval, 198 met the inclusion criteria. Of these patients, 50 (25%) received adjuvant chemotherapy. Actuarial (5-year) rates of local failure, distant failure, and overall survival were 40%, 55%, and 33%, respectively. On multivariate analysis, factors associated with an increased risk of local failure included a video-assisted thoracoscopic surgery approach (hazard ratio [HR], 2.5; p = 0.01), visceral pleural invasion (HR, 2.1; p = 0.04), and increasing number of positive N1 lymph nodes (HR, 1.3 per involved lymph node; p = 0.02). Chemotherapy was associated with a trend toward decreased risk of local failure that was not statistically significant (HR, 0.61; p = 0.2). Conclusions: Actuarial rates of local failure in pN1 disease are high. Further investigation of conformal postoperative radiotherapy may be warranted.

  11. The use of music on Barney & Friends: implications for music therapy practice and research.

    Science.gov (United States)

    McGuire , K M

    2001-01-01

    movement and props/costumes was also prevalent, and may have contributed to high interobserver reliability of tempo. Implications for music therapists and teachers working with young children and music researchers examining various epistemological questions of music learning and behavior are discussed.

  12. Extracorporeal blood oxygenation and ozonation: clinical and biological implications of ozone therapy.

    Science.gov (United States)

    Di Paolo, N; Gaggiotti, E; Galli, F

    2005-01-01

    Some lines of evidence have suggested that the challenge to antioxidants and biomolecules provoked by pro-oxidants such as ozone may be used to generate a controlled stress response of possible therapeutic relevance in some immune dysfunctions and chronic, degenerative conditions. Immune and endothelial cells have been proposed to be elective targets of the positive molecular effects of ozone and its derived species formed during blood ozonation. On the bases of these underlying principles and against often prejudicial scepticism and concerns about its toxicity, ozone has been used in autohemotherapy (AHT) for four decades with encouraging results. However, clinical application and validation of AHT have been so far largely insufficient. Latterly, a new and more effective therapeutic approach to ozone therapy has been established, namely extracorporeal blood oxygenation and ozonation (EBOO). This technique, first tested in vitro and then in vivo in sheep and humans (more than 1200 treatments performed in 82 patients), is performed with a high-efficiency apparatus that makes it possible to treat with a mixture of oxygen-ozone (0.5-1 microg/ml oxygen) in 1 h of extracorporeal circulation up to 4800 ml of heparinized blood without technical or clinical problems, whereas only 250 ml of blood can be treated with ozone by AHT. The EBOO technique can be easily adapted for use in hemodialysis also. The standard therapeutic cycle lasts for 7 weeks in which 14 treatment sessions of 1 h are performed. After a session of EBOO, the interaction of ozone with blood components results in 4-5-fold increased levels of thiobarbituric acid reactants and a proportional decrease in plasma protein thiols without any appreciable erythrocyte haemolysis. On the basis of preliminary in vitro evidence, these simple laboratory parameters may represent a useful complement in the routine monitoring of biological compliance to the treatment. The clinical experience gained so far confirms the

  13. Bladder Cancer Patterns of Pelvic Failure: Implications for Adjuvant Radiation Therapy

    International Nuclear Information System (INIS)

    Baumann, Brian C.; Guzzo, Thomas J.; He Jiwei; Vaughn, David J.; Keefe, Stephen M.; Vapiwala, Neha; Deville, Curtiland; Bekelman, Justin E.; Tucker, Kai; Hwang, Wei-Ting; Malkowicz, S. Bruce; Christodouleas, John P.

    2013-01-01

    Purpose: Local-regional failures (LFs) after cystectomy with or without chemotherapy are common in locally advanced disease. Adjuvant radiation therapy (RT) could reduce LFs, but toxicity has discouraged its use. Modern RT techniques with improved normal tissue sparing have rekindled interest but require knowledge of pelvic failure patterns to design treatment volumes. Methods and Materials: Five-year LF rates after radical cystectomy plus pelvic node dissection with or without chemotherapy were determined for 8 pelvic sites among 442 urothelial bladder carcinoma patients. The impact of pathologic stage, margin status, nodal involvement, and extent of node dissection on failure patterns was assessed using competing risk analysis. We calculated the percentage of patients whose sites of LF would have been completely encompassed within various hypothetical clinical target volumes (CTVs) for postoperative radiation. Results: Compared with stage ≤pT2, stage ≥pT3 patients had higher 5-year LF rates in virtually all pelvic sites. Among stage ≥pT3 patients, margin status significantly altered the failure pattern whereas extent of node dissection and nodal positivity did not. In stage ≥pT3 patients with negative margins, failure occurred predominantly in the iliac/obturator nodes and uncommonly in the cystectomy bed and/or presacral nodes. Of these patients in whom failure subsequently occurred, 76% would have had all LF sites encompassed within CTVs covering only the iliac/obturator nodes. In stage ≥pT3 with positive margins, cystectomy bed and/or presacral nodal failures increased significantly. Only 57% of such patients had all LF sites within CTVs limited to the iliac/obturator nodes, but including the cystectomy bed and presacral nodes in the CTV when margins were positive increased the percentage of LFs encompassed to 91%. Conclusions: Patterns of failure within the pelvis are summarized to facilitate design of adjuvant RT protocols. These data suggest that

  14. Synthesis and anti-angiogenic effect of conjugates between serum albumin and non-steroidal anti-inflammatory drugs

    DEFF Research Database (Denmark)

    Kjaer, B; Struve, C; Friis, T

    2010-01-01

    of investigating the anti-angiogenic efficiency of NSAID-HSA conjugates in vitro, three NSAIDs, aspirin, ibuprofen, and naproxen were conjugated to HSA using different concentrations of their N-hydroxysuccinimide esters. Conjugation ratios from 10 to 50 were achieved and the conjugates retained a growth inhibitory...

  15. Anti-angiogenic potential of an ethanol extract of Annona atemoya seeds in vitro and in vivo.

    Science.gov (United States)

    Yi, Jin-Mu; Park, Jong-Shik; Lee, Jun; Hong, Jin Tae; Bang, Ok-Sun; Kim, No Soo

    2014-09-23

    Angiogenesis, which is initiated by certain tumor micro-environmental conditions and diverse protein factors, plays a pivotal role during tumor development and metastasis. Therefore, many efforts have been made to develop effective anti-angiogenic agents as anticancer therapeutics. In the current study, we investigated the anti-angiogenic potential of an ethanol extract of Annona atemoya seeds (EEAA) in vitro and in vivo. The anti-angiogenic potential of EEAA was evaluated using various in vitro/in vivo models, including cell proliferation, migration, and tube formation by human umbilical vascular endothelial cells (HUVECs); a Matrigel plug assay; and tumor-induced angiogenesis. The expression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) was investigated using reverse transcription-polymerase chain reaction, immunoassays, and western blotting. EEAA was able to significantly inhibit the angiogenic properties of HUVECs in vitro as well as angiogenic factor-induced blood vessel formation in vivo. EEAA down-regulated the expression of VEGF and HIF-1alpha/2alpha at the mRNA and protein levels, respectively, in cancer cells under hypoxic conditions. EEAA shows a strong anti-angiogenic potential in both in vitro and in vivo systems, and we suggest that EEAA may be a valuable herbal source for anticancer drug development.

  16. Bisphosphonate-related osteonecrosis of jaw (BRONJ: an anti-angiogenic side-effect?

    Directory of Open Access Journals (Sweden)

    Petcu Eugen B

    2012-07-01

    Full Text Available Abstract Bisphosphonates are recommended in the treatment of osteoporosis and some cancers, in which case they prevent the appearance of bone metastasis. The patients taking bisphosphonates are at increased risk of developing bisphosphonate-related osteonecrosis of jaw (BRONJ which is characterised by the presence of an un-healing wound after dental surgery. BRONJ might represent an anti-angiogenic side effect. However, the real number of patients with BRONJ might be higher than currently recorded. Considering the differential diagnosis which includes various primary and secondary cancers, a correct histopathological diagnosis is very important. The morphological criteria for diagnosis of BRONJ are highlighted in this material. Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1813972972323288

  17. Aminopeptidase N inhibition could be involved in the anti-angiogenic effect of dobesilates

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    Farsa Oldřich

    2015-01-01

    Full Text Available Calcium, magnesium and zinc 2,5-dihydroxybenzenesulfonates (dobesilates were synthesized by sulfonation of hydroquinone with sulfuric acid under mild conditions. To form the salts, neutralization with calcium carbonate followed by cation exchange by means of magnesium or zinc sulfates was performed. The dobesilates were characterized by standard spectral methods and by AAS for metal content and then tested for inhibitory activity against aminopeptidase N. Calcium and magnesium 2,5-dihydroxybenzene sulfonates exhibited rather weak inhibitory activity to aminopeptidase N as demonstrated by IC50 values of 978.0 and 832.1 mmol l-1 respectively while zinc 2,5-dihydroxybenzene sulfonate reached the more significant inhibitory activity characterized by IC50 77.4 mmol l-1. The inhibitory activity results suggest that the inhibition of aminopeptidase N could play a role in the anti-angiogenic activity of 2,5-dihydroxybenzenesulfonates.

  18. Antiangiogenic properties of cafestol, a coffee diterpene, in human umbilical vein endothelial cells

    International Nuclear Information System (INIS)

    Wang, Shuaiyu; Yoon, Yeo Cho; Sung, Mi-Jeong; Hur, Haeng-Jeon; Park, Jae-Ho

    2012-01-01

    Highlights: ► Cafestol inhibits tube formation and migration of VEGF-stimulated HUVEC. ► Cafestol inhibits phosphorylation of FAK and Akt. ► Cafestol decreases NO production. -- Abstract: As angiogenesis plays important roles in tumor growth and metastasis, searching for antiangiogenic compounds is a promising tactic for treating cancers. Cafestol, a diterpene found mainly in unfiltered coffee, provides benefit through varied biological activity, including antitumorigenic, antioxidative, and anti-inflammatory effects. This study aimed to investigate the effects of cafestol on angiogenesis and to uncover the associated mechanism. We show that cafestol inhibits angiogenesis of human umbilical vascular endothelial cells. This inhibition affects the following specific steps of the angiogenic process: proliferation, migration, and tube formation. The inhibitory effects of cafestol are accompanied by decreasing phosphorylation of FAK and Akt and by a decrease in nitric oxide production. Overall, cafestol inhibits angiogenesis by affecting the angiogenic signaling pathway.

  19. A biomimetic collagen derived peptide exhibits anti-angiogenic activity in triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Elena V Rosca

    Full Text Available We investigated the application of a mimetic 20 amino acid peptide derived from type IV collagen for treatment of breast cancer. We showed that the peptide induced a decrease of proliferation, adhesion, and migration of endothelial and tumor cells in vitro. We also observed an inhibition of triple negative MDA-MB-231 xenograft growth by 75% relative to control when administered intraperitoneally for 27 days at 10 mg/kg. We monitored in vivo the changes in vascular properties throughout the treatment using MRI and found that the vascular volume and permeability surface area product decreased significantly. The treatment also resulted in an increase of caspase-3 activity and in a reduction of microvascular density. The multiple mode of action of this peptide, i.e., anti-angiogenic, and anti-tumorigenic, makes it a viable candidate as a therapeutic agent as a monotherapy or in combination with other compounds.

  20. Evaluation, partial characterization and purification of acetylcholine esterase enzyme and antiangiogenic activity from marine sponges

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    Maushmi Shailesh Kumar

    2014-11-01

    Full Text Available Objective: To test three marine sponges Halichondria glabrata Keller, 1891; Spirastrella pachyspira (S. pachyspira Levi, 1958 and Cliona lobata Hancock, 1849 for the presence of the acetylcholinesterase (AChE in both young and developed samples from western coastal area of India. S. pachyspira methanolic extract was selected for anti/pro angiogenic activity. Methods: They were evaluated for AChE activity using Ellman’s assay based on production of yellow colored 5-thio-2-nitrobenzoate. Purification of the enzyme was planned using ammonium sulphate precipitation and characterization by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Chorioallantoic membrane (ChAM assay model was used for angiogenic/ antiangiogenic testing. Results: All the three sponges showed good specific enzyme activity and S. pachyspira contained maximum specific enzyme activity. Sixty percent of ammonium sulphate precipitation of crude protein sample gave single band at 66 kDa corresponding to the true AChE. ChAM assay was performed at 62.5, 125.0 and 250.0 µg/mL. Dosage beyond 250 µg/mL extract showed toxic response with anti angiogenic activity at all the concentrations. Conclusions: AChE activity was detected in all samples. Extract showed good anti-angiogenic response at 62.5 µg/mL. Extract was highly toxic affecting microvasculature of ChAM as well as normal growth and development of the embryo at 500 µg/mL. With further characterization of bioactive compounds from the extract of S. pachyspira, the compounds can be developed for anti tumor activity.

  1. Blocking a vicious cycle nNOS/peroxynitrite/AMPK by S-nitrosoglutathione: implication for stroke therapy.

    Science.gov (United States)

    Khan, Mushfiquddin; Dhammu, Tajinder S; Matsuda, Fumiyo; Singh, Avtar K; Singh, Inderjit

    2015-07-15

    Stroke immediately sets into motion sustained excitotoxicity and calcium dysregulation, causing aberrant activity in neuronal nitric oxide synthase (nNOS) and an imbalance in the levels of nitric oxide (NO). Drugs targeting nNOS-originated toxicity may therefore reduce stroke-induced damage. Recently, we observed that a redox-modulating agent of the NO metabolome, S-nitrosoglutathione (GSNO), confers neurovascular protection by reducing the levels of peroxynitrite, a product of aberrant NOS activity. We therefore investigated whether GSNO-mediated neuroprotection and improved neurological functions depend on blocking nNOS/peroxynitrite-associated injurious mechanisms using a rat model of cerebral ischemia reperfusion (IR). IR increased the activity of nNOS, the levels of neuronal peroxynitrite and phosphorylation at Ser(1412) of nNOS. GSNO treatment of IR animals decreased IR-activated nNOS activity and neuronal peroxynitrite levels by reducing nNOS phosphorylation at Ser(1412). The Ser(1412) phosphorylation is associated with increased nNOS activity. Supporting the notion that nNOS activity and peroxynitrite are deleterious following IR, inhibition of nNOS by its inhibitor 7-nitroindazole or reducing peroxynitrite by its scavenger FeTPPS decreased IR injury. GSNO also decreased the activation of AMP Kinase (AMPK) and its upstream kinase LKB1, both of which were activated in IR brain. AMPK has been implicated in nNOS activation via Ser(1412) phosphorylation. To determine whether AMPK activation is deleterious in the acute phase of IR, we treated animals after IR with AICAR (an AMPK activator) and compound c (an AMPK inhibitor). While AICAR potentiated, compound c reduced the IR injury. Taken together, these results indicate an injurious nNOS/peroxynitrite/AMPK cycle following stroke, and GSNO treatment of IR inhibits this vicious cycle, resulting in neuroprotection and improved neurological function. GSNO is a natural component of the human body, and its exogenous

  2. Dimethyl sulfoxide-caused changes in pro- and anti-angiogenic factor levels could contribute to an anti-angiogenic response in HeLa cells.

    Science.gov (United States)

    Şimşek, Ece; Aydemir, Esra Arslan; İmir, Nilüfer; Koçak, Orhan; Kuruoğlu, Aykut; Fışkın, Kayahan

    2015-10-01

    Dimethyl sulfoxide (DMSO) is widely used in biological research as a general solvent. While it has been previously demonstrated that DMSO possesses a wide range of pharmacological effects, there is no published work regarding the effects of DMSO on pro-angiogenic factor levels. This study was designed to investigate the possible effects of DMSO on the levels of three pro-angiogenic factors released from HeLa cells in vitro. Cells were treated with two different and previously determined concentrations of DMSO. The cytotoxic effects of DMSO concentrations on HeLa cells were determined via MTT. Survival rates of DMSO-treated cells were determined by Invitrogen live/dead viability/cytotoxicity kit and trypan blue exclusion assay. Changes in the pro-angiogenic levels in media were evaluated by Cayman's Substance P Enzyme Immunoassay ELISA kit. Vascular endothelial growth factor ELISA kit and interferon gamma ELISA kit for substance P, VEGF and IFNγ respectively. Changes in substance P levels were corrected by standard western blotting. Changes in VEGF and IFNγ levels were corrected both by western blot and real time PCR. Treatment with 1.4 μM DMSO caused a time-dependent inhibition of cell proliferation at 24, 48 and 72 h. 1.4 μM DMSO caused a significant reduction in VEGF levels at 72 h of incubation and sharp increases in IFNγ levels at both 48 and 72 h of incubation. According to real time PCR analyses, DMSO (1.4 μM) exhibited an inhibitory effect on VEGF but acted as an augmenter of IFNγ release on HeLa cells in vitro. This is the first report showing that the general solvent DMSO suppressed HeLa cell proliferation, decreased the levels of two pro-angiogenic factors (substance P and VEGF) and increased the release of an anti-angiogenic factor IFNγ in vitro. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Endostatin improves radioresponse and blocks tumor revascularization after radiation therapy for A431 xenografts in mice

    International Nuclear Information System (INIS)

    Itasaka, Satoshi; Komaki, Ritsuko; Herbst, Roy S.; Shibuya, Keiko; Shintani, Tomoaki D.D.S.; Hunter, Nancy R. M.S.; Onn, Amir; Bucana, Corazon D.; Milas, Luka; Ang, K. Kian; O'Reilly, Michael S.

    2007-01-01

    Purpose: Clinical trials of antiangiogenic agents used alone for advanced malignancy have been disappointing but preclinical studies suggest that the addition of radiation therapy could improve antitumor efficacy. To test the hypothesis that antiangiogenic therapy combined with radiation therapy can overcome the limitations of antiangiogenic monotherapy, we studied the effects of endostatin combined with radiation on the growth and vascularization of A431 human epidermoid carcinomas growing intramuscularly in the legs of mice. Methods and Materials: Mice with established A431 human epidermoid leg tumors were treated with radiation, endostatin, both radiation and endostatin, or vehicle control. The experiment was repeated and mice from each group were killed at 2, 7, and 10 days after irradiation so that tumor tissue could be obtained to further analyze the kinetics of the antitumor, antivascular, and antiangiogenic response to therapy. Results: Endostatin enhanced the antitumor effects of radiation, and prolonged disease-free survival was observed in the combined treatment group. Endothelial cell proliferation was increased in tumors after irradiation but was blocked by the concurrent administration of endostatin, and the combination of endostatin with radiation enhanced endothelial cell apoptosis within 48 h after irradiation. Expression of vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-2 were increased in tumors after irradiation, and this increase was blocked by concurrent administration of endostatin. Conclusion: These data indicate that endostatin can block tumor revascularization after radiation therapy and thereby augment radioresponse

  4. Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule.

    Directory of Open Access Journals (Sweden)

    Katiuscia Pagano

    Full Text Available Fibroblast growth factors (FGFs are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs, and heparan sulphate proteoglycans (HSPGs is required for FGF2 pro-angiogenic activity. Here by using a combination of techniques including Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance and cell-based binding assays we clarify the molecular mechanism of inhibition of an angiostatic small molecule, sm27, mimicking the endogenous inhibitor of angiogenesis, thrombospondin-1. NMR and MD data demonstrate that sm27 engages the heparin-binding site of FGF2 and induces long-range dynamics perturbations along FGF2/FGFR1 interface regions. The functional consequence of the inhibitor binding is an impaired FGF2 interaction with both its receptors, as demonstrated by SPR and cell-based binding assays. We propose that sm27 antiangiogenic activity is based on a twofold-direct and allosteric-mechanism, inhibiting FGF2 binding to both its receptors.

  5. The anti-angiogenic effect of dexamethasone in a murine hepatocellular carcinoma model by augmentation of gluconeogenesis pathway in malignant cells.

    Science.gov (United States)

    Shang, Fei; Liu, Mingming; Li, Bingwei; Zhang, Xiaoyan; Sheng, Youming; Liu, Shuying; Han, Jianqun; Li, Hongwei; Xiu, Ruijuan

    2016-05-01

    Angiogenesis is a long-term complex process involving various protein factors in hepatocellular carcinoma (HCC). Dexamethasone (Dex), considered as a synthetic glucocorticoid drug in clinical therapy, has been reported to have the therapeutic efficacy against liver cancer by intervention of abnormal glycolysis. In this study, we investigated the anti-angiogenic effect of Dex in murine liver cancer and attempted to demonstrate the potential mechanism. The malignant cells H22 were treated with Dex. Western blotting was used to explore the expression of PEPCK and G6Pase which were the two key enzymes that regulated gluconeogenesis. The supernatants from cultured H22 treated by Dex were collected and co-cultured with HUVECs. In vitro, migration assay, transwell assay and tube formation assay were performed to assess for migration, proliferation and tube formation abilities of HUVECs, respectively. In situ murine hepatoma model with green fluorescent protein markers (HepG2-GFP) was constructed to determine angiogenesis after treatment by Dex. PEPCK and G6Pase were almost deficient in H22 compared with normal liver cells NCTC-1469 (P gluconeogenesis could be restored significantly (P gluconeogenesis pathway.

  6. Phytochemical screening, antioxidant, anti-inflammatory and antiangiogenic activities of Lophira procera A. Chev. (Ochnaceae medicinal plant from Gabon

    Directory of Open Access Journals (Sweden)

    Rick-Leonid Ngoua-Meye-Misso

    2018-03-01

    Full Text Available The objective of this study was to perform phytochemical screening, to determine the content of phenolic compound, to evaluate antioxidant, anti-inflammatory and antiangiogenic activities of ethanol, water-ethanol and water extracts of Lophira procera. Antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH and phosphomolybdenum assay, anti-inflammatory activity by proteins denaturation inhibition and membranes stabilization test and antiangiogenic activity by chicken chorioallantoic membrane (CAM method. The results showed that this plant is rich in saponins, polyphenols, tannins, total flavonoids, proanthocyanidins and coumarins. Extracts presented a strong antioxidant activity (IC50 values of 5.452 ± 0.119 μg/mL and 6.346 ± 0.544 μg/mL and respective AAI of 9.173 ± 0.203 and 7.919 ± 0.711. Excellent anti-inflammatory activity was also observed (IC50 = 16.952 ± 1.897 and IC50 = 23.172 ± 0.066 μg/mL for inhibition of protein denaturation and membrane stabilization respectively. Finally, extracts manifested a very good anti-angiogenic activity (with inhibitions ranging from 57.142 ± 0.124% to 100%. These biological activities are certainly due to high content of phenolic compound. This is the first study to report the phytochemical screening, the content of phenolic compound, the antioxidant, anti-inflammatory and antiangiogenic activities of extract derived from Lophira procera. The use of this plant in traditional medicine against ulcers, breast cancer, kidney and dental pain is therefore justified and its potential as a candidate for bioactive therapeutic molecule.

  7. Anti-angiogenic effect of triptolide in rheumatoid arthritis by targeting angiogenic cascade.

    Directory of Open Access Journals (Sweden)

    Xiangying Kong

    Full Text Available Rheumatoid arthritis (RA is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogenesis has been proposed as a novel therapeutic strategy for RA. Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, has been extensively used in treatment of RA patients. It also acts as a small molecule inhibitor of tumor angiogenesis in several cancer types. However, it is unclear whether triptolide possesses an anti-angiogenic effect in RA. To address this problem, we constructed collagen-induced arthritis (CIA model using DA rats by the injection of bovine type II collagen. Then, CIA rats were treated with triptolide (11-45 µg/kg/day starting on the day 1 after first immunization. The arthritis scores (P<0.05 and the arthritis incidence (P<0.05 of inflamed joints were both significantly decreased in triptolide-treated CIA rats compared to vehicle CIA rats. More interestingly, doses of 11~45 µg/kg triptolide could markedly reduce the capillaries, small, medium and large vessel density in synovial membrane tissues of inflamed joints (all P<0.05. Moreover, triptolide inhibited matrigel-induced cell adhesion of HFLS-RA and HUVEC. It also disrupted tube formation of HUVEC on matrigel and suppressed the VEGF-induced chemotactic migration of HFLS-RA and HUVEC, respectively. Furthermore, triptolide significantly reduced the expression of angiogenic activators including TNF-α, IL-17, VEGF, VEGFR, Ang-1, Ang-2 and Tie2, as well as suppressed the IL1-β-induced phosphorylated of ERK, p38 and JNK at protein levels. In conclusion, our data suggest for the first time that triptolide may possess anti-angiogenic effect in RA both in vivo and in vitro assay systems by downregulating the

  8. Do anti-angiogenic VEGF (VEGFxxxb isoforms exist? A cautionary tale.

    Directory of Open Access Journals (Sweden)

    Sheila Harris

    Full Text Available Splicing of the human vascular endothelial growth factor-A (VEGF-A gene has been reported to generate angiogenic (VEGFxxx and anti-angiogenic (VEGFxxxb isoforms. Corresponding VEGFxxxb isoforms have also been reported in rat and mouse. We examined VEGFxxxb expression in mouse fibrosarcoma cell lines expressing all or individual VEGF isoforms (VEGF120, 164 or 188, grown in vitro and in vivo, and compared results with those from normal mouse and human tissues. Importantly, genetic construction of VEGF164 and VEGF188 expressing fibrosarcomas, in which exon 7 is fused to the conventional exon 8, precludes VEGFxxxb splicing from occurring. Thus, these two fibrosarcoma cell lines provided endogenous negative controls. Using RT-PCR we show that primers designed to simultaneously amplify VEGFxxx and VEGFxxxb isoforms amplified only VEGFxxx variants in both species. Moreover, only VEGFxxx species were generated when mouse podocytes were treated with TGFβ-1, a reported activator of VEGFxxxb splice selection in human podocytes. A VEGF164/120 heteroduplex species was identified as a PCR artefact, specifically in mouse. VEGFxxxb isoform-specific PCR did amplify putative VEGFxxxb species in mouse and human tissues, but unexpectedly also in VEGF188 and VEGF164 fibrosarcoma cells and tumours, where splicing to produce true VEGFxxxb isoforms cannot occur. Moreover, these products were only consistently generated using reverse primers spanning more than 5 bases across the 8b/7 or 8b/5 splice junctions. Primer annealing to VEGFxxx transcripts and amplification of exon 8b primer 'tails' explained the artefactual generation of VEGFxxxb products, since the same products were generated when the PCR reactions were performed with cDNA from VEGF164/VEGF188 'knock-in' vectors used in the generation of single VEGF isoform-expressing transgenic mice from which the fibrosarcoma lines were developed. Collectively, our results highlight important pitfalls in data

  9. Antiangiogenic effects of AA-PMe on HUVECs in vitro and zebrafish in vivo

    Directory of Open Access Journals (Sweden)

    Jing Y

    2018-04-01

    Full Text Available Yue Jing,1,2,* Gang Wang,1,* Qi Xiao,1 Yachun Zhou,1 Yingjie Wei,3 Zhunan Gong1 1Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China; 2Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China; 3Key Laboratory of Oral Drug Delivery System of Chinese Materia Medica of State Administration of Traditional Chinese Medicine, Jiangsu Branch of China Academy of Chinese Medical Science, Nanjing, China *These authors contributed equally to this work Abstract: Angiogenesis plays a vital role in many physiological and pathological processes and several diseases are connected with its dysregulation. Asiatic acid (AA has demonstrated anticancer properties and we suspect this might be attributable to an effect on angiogenesis. A modified derivative of AA, N-(2α,3β,23-acetoxyurs-12-en-28-oyl-L-proline methyl ester (AA-PMe, has improved efficacy over its parent compound, but its effect on blood vessel development remains unclear. Methods: In this study, we investigated the antiangiogenic activity of AA and AA-PMe in zebrafish embryos and human umbilical vein endothelial cells (HUVECs. First of all, we treated HUVECs with increasing concentrations of AA-PMe or AA, with or without vascular endothelial growth factor (VEGF present, and assessed cell viability, tube formation, and cell migration and invasion. Quantitative real-time polymerase chain reaction and Western blot analysis were later used to determine the role of vascular endothelial growth factor receptor 2 (VEGFR2-mediated signaling in AA-PMe inhibition of angiogenesis. We extended these studies to follow angiogenesis using Tg(fli:EGFP transgenic zebrafish embryos. For these experiments, embryos were treated with varying concentrations of AA-PMe or AA from 24 to 72 hours postfertilization prior to morphological observation, angiogenesis assessment, and endogenous alkaline

  10. Antiangiogenic effects of AA-PMe on HUVECs in vitro and zebrafish in vivo.

    Science.gov (United States)

    Jing, Yue; Wang, Gang; Xiao, Qi; Zhou, Yachun; Wei, Yingjie; Gong, Zhunan

    2018-01-01

    Angiogenesis plays a vital role in many physiological and pathological processes and several diseases are connected with its dysregulation. Asiatic acid (AA) has demonstrated anticancer properties and we suspect this might be attributable to an effect on angio-genesis. A modified derivative of AA, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-L-proline methyl ester (AA-PMe), has improved efficacy over its parent compound, but its effect on blood vessel development remains unclear. In this study, we investigated the antiangiogenic activity of AA and AA-PMe in zebrafish embryos and human umbilical vein endothelial cells (HUVECs). First of all, we treated HUVECs with increasing concentrations of AA-PMe or AA, with or without vascular endothelial growth factor (VEGF) present, and assessed cell viability, tube formation, and cell migration and invasion. Quantitative real-time polymerase chain reaction and Western blot analysis were later used to determine the role of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated signaling in AA-PMe inhibition of angiogenesis. We extended these studies to follow angiogenesis using Tg(fli:EGFP) transgenic zebrafish embryos. For these experiments, embryos were treated with varying concentrations of AA-PMe or AA from 24 to 72 hours postfertilization prior to morphological observation, angiogenesis assessment, and endogenous alkaline phosphatase assay. VEGFR2 expression in whole embryos following AA-PMe treatment was also determined. We found AA-PMe decreased cell viability and inhibited migration and tube formation in a dose-dependent manner in HUVECs. Similarly, AA-PMe disrupted the formation of intersegmental vessels, the dorsal aorta, and the posterior cardinal vein in zebrafish embryos. Both in vitro and in vivo AA-PMe surpassed AA in its ability to block angiogenesis by suppressing VEGF-induced phosphorylation of VEGFR2 and disrupting downstream extracellular regulated protein kinase and AKT signaling. For the first time

  11. Dual energy CT allows for improved characterization of response to antiangiogenic treatment in patients with metastatic renal cell cancer

    Energy Technology Data Exchange (ETDEWEB)

    Hellbach, K.; Sterzik, A.; Sommer, W.; Karpitschka, M.; Hummel, N.; Ingrisch, M.; Graser, A. [Ludwig-Maximilians-University Hospital Munich, Department of Clinical Radiology, Muenchen (Germany); Casuscelli, J.; Staehler, Michael [Ludwig-Maximilians-University Hospital Munich, Department of Urology, Muenchen (Germany); Schlemmer, M. [Krankenhaus Barmherzige Brueder Muenchen, Department of Palliative Care, Muenchen (Germany)

    2017-06-15

    To evaluate the potential role of dual energy CT (DECT) to visualize antiangiogenic treatment effects in patients with metastatic renal cell cancer (mRCC) while treated with tyrosine-kinase inhibitors (TKI). 26 patients with mRCC underwent baseline and follow-up single-phase abdominal contrast enhanced DECT scans. Scans were performed immediately before and 10 weeks after start of treatment with TKI. Virtual non-enhanced (VNE) and colour coded iodine images were generated. 44 metastases were measured at the two time points. Hounsfield unit (HU) values for VNE and iodine density (ID) as well as iodine content (IC) in mg/ml of tissue were derived. These values were compared to the venous phase DECT density (CTD) of the lesions. Values before and after treatment were compared using a paired Student's t test. Between baseline and follow up, mean CTD and DECT-derived ID both showed a significant reduction (p < 0.005). The relative reduction measured in percent was significantly greater for ID than for CTD (49.8 ± 36,3 % vs. 29.5 ± 20.8 %, p < 0.005). IC was also significantly reduced under antiangiogenic treatment (p < 0.0001). Dual energy CT-based quantification of iodine content of mRCC metastases allows for significantly more sensitive and reproducible detection of antiangiogenic treatment effects. (orig.)

  12. VEGF Spliced Variants: Possible Role of Anti-Angiogenesis Therapy

    Directory of Open Access Journals (Sweden)

    Caroline Hilmi

    2012-01-01

    Full Text Available Angiogenesis has been targeted in retinopathies, psoriasis, and a variety of cancers (colon, breast, lung, and kidney. Among these tumour types, clear cell renal cell carcinomas (RCCs are the most vascularized tumours due to mutations of the von Hippel Lindau gene resulting in HIF-1 alpha stabilisation and overexpression of Vascular Endothelial Growth Factor (VEGF. Surgical nephrectomy remains the most efficient curative treatment for patients with noninvasive disease, while VEGF targeting has resulted in varying degrees of success for treating metastatic disease. VEGF pre-mRNA undergoes alternative splicing generating pro-angiogenic isoforms. However, the recent identification of novel splice variants of VEGF with anti-angiogenic properties has provided some insight for the lack of current treatment efficacy. Here we discuss an explanation for the relapse to anti-angiogenesis treatment as being due to either an initial or acquired resistance to the therapy. We also discuss targeting angiogenesis via SR (serine/arginine-rich proteins implicated in VEGF splicing.

  13. Toward an integrative understanding of narrative and emotion processes in Emotion-focused therapy of depression: implications for theory, research and practice.

    Science.gov (United States)

    Angus, Lynne

    2012-01-01

    This paper addresses the fundamental contributions of client narrative disclosure in psychotherapy and its importance for the elaboration of new emotional meanings and self understanding in the context of Emotion-focused therapy (EFT) of depression. An overview of the multi-methodological steps undertaken to empirically investigate the contributions of client story telling, emotional differentiation and meaning-making processes (Narrative Processes Coding System; Angus et al., 1999) in EFT treatments of depression is provided, followed by a summary of key research findings that informed the development of a narrative-informed approach to Emotion-focused therapy of depression (Angus & Greenberg, 2011). Finally, the clinical practice and training implications of adopting a research-informed approach to working with narrative and emotion processes in EFT are described, and future research directions discussed.

  14. Viola tricolor Induces Apoptosis in Cancer Cells and Exhibits Antiangiogenic Activity on Chicken Chorioallantoic Membrane

    Directory of Open Access Journals (Sweden)

    Hamid Reza Sadeghnia

    2014-01-01

    Full Text Available In the present study, the cytotoxic and apoptogenic properties of hydroalcoholic extract and ethyl acetate (EtOAc, n-butanol, and water fractions (0–800 μg/mL of Viola tricolor were investigated in Neuro2a mouse neuroblastoma and MCF-7 human breast cancer cells. In addition, antiangiogenic effect of EtOAc fraction was evaluated on chicken chorioallantoic membrane (CAM. The quality of EtOAc fraction was also characterized using high performance liquid chromatography (HPLC fingerprint. Cytotoxicity assay revealed that EtOAc fraction was the most potent among all fractions with maximal effect on MCF-7 and minimal toxicity against normal murine fibroblast L929 cells. Apoptosis induction by EtOAc fraction was confirmed by increased sub-G1 peak of propidium iodide (PI stained cells. This fraction triggered the apoptotic pathway by increased Bax/Bcl-2 ratio and cleaved caspase-3 level. Moreover, treatment with EtOAc fraction significantly decreased the diameter of vessels on CAM, while the number of newly formed blood vessels was not suppressed significantly. Analysis of quality of EtOAc fraction using HPLC fingerprint showed six major peaks with different retention times. The results of the present study suggest that V. tricolor has potential anticancer property by inducing apoptosis and inhibiting angiogenesis.

  15. Assessment of the anti-angiogenic, anti-inflammatory and antinociceptive properties of ethyl vanillin.

    Science.gov (United States)

    Jung, Hyun-Joo; Song, Yun Seon; Kim, Kyunghoon; Lim, Chang-Jin; Park, Eun-Hee

    2010-02-01

    The present work aimed to assess novel pharmacological properties of ethyl vanillin (EVA) which is used as a flavoring agent for cakes, dessert, confectionary, etc. EVA exhibited an inhibitory activity in the chorioallantoic membrane angiogenesis. Anti-inflammatory activity of EVA was convinced using the two in vivo models, such as vascular permeability and air pouch models in mice. Antinociceptive activity of EVA was assessed using acetic acid-induced writhing model in mice. EVA suppressed production of nitric oxide and induction of inducible nitric oxide synthase in the lipopolysaccharide (LPS)-activated RAW264.7 macrophage cells. However, EVA could not suppress induction of cyclooxygenase-2 in the LPS-activated macrophages. EVA diminished reactive oxygen species level in the LPS-activated macrophages. EVA also suppressed enhanced matrix metalloproteinase-9 gelatinolytic activity in the LPSactivated RAW264.7 macrophage cells. EVA at the used concentrations couldn't diminish viability of the macrophage cells. Taken together, the anti-angiogenic, anti-inflammatory and anti-nociceptive properties of EVA are based on its suppressive effect on the production of nitric oxide possibly via decreasing the reactive oxygen species level.

  16. [Comparison of anti-angiogenic effect in vitro between ranibizumab and bevacizumab].

    Science.gov (United States)

    Souto, Alexandre Cupello; Maricato, Juliana Terzi; Denapoli, Priscila Martins Andrade; Sallum, Juliana Maria Ferraz; Han, Sang Won

    2011-01-01

    To evaluate the comparative in-vitro antiangiogenic effect of Bevacizumab and Ranibizumab. Endothelial venous umbilical cells culture (ECV304) cultivated in F12 media with addition of 10% Fetal Bovine Serum, were plaqued and treated with clinically relevant concentrations of Bevacizumab and Ranibizumab just after the scratch done in the middle of the culture (scratch methodology). Measurements of the linear size of the area free of cell proliferation were done 24, 48 and 72 hours after the scratch day point. All the experiments were done in triplicate and statistical analysis were done with T-student test. Inhibitory effect was observed just at the concentrations of 0.5 and 0.7 mg/ml in both drugs. At 0.7 mg/ml, Ranibizumab demonstrated a more potent proliferative inhibitory effect than Bevacizumab. At the same concentration, Ranibizumab was three times more potent than Ranibizumab. Inhibitory effect was observed just in the first 24 hours for both drugs. Ranibizumab demonstrates an increased effect when compared to Bevacizumab and this is related more to the different molar rate of each drug than related to a real better proliferative inhibitory effect.

  17. Antiangiogenic activity of 11,11'-dideoxyverticillin, a natural product isolated from the fungus Shiraia bambusicola

    International Nuclear Information System (INIS)

    Chen Yi; Zhang Yixiang; Li Meihong; Zhao Weimin; Shi Yuhua; Miao Zehong; Zhang Xiongwen; Lin Liping; Ding Jian

    2005-01-01

    The fungus Shiraia bambusicola yields the phytochemical 11,11'-dideoxyverticillin, which has been shown to possess potent anticancer activity both in vitro and in vivo. In this study, we reveal that 11,11'-dideoxyverticillin has anti-angiogenic activities and explore the potential mechanisms for this effect. Treatment with 11,11'-dideoxyverticillin inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) with IC 50 values of 0.17 ± 0.05 μM for VEGF-stimulated cells and 0.39 ± 0.08 μM for serum-stimulated cells. 11,11'-Dideoxyverticillin also antagonized the antiapoptotic effects of VEGF on serum-deprived HUVECs, inhibited VEGF-induced HUVEC migration in vitro, and blocked serum-induced HUVEC tube formation. Moreover, 11,11'-dideoxyverticillin completely blocked VEGF-induced microvessel sprouting from Matrigel-embedded rat aortic rings and vessel growth in Matrigel plugs in mice. In addition, 11,11'-dideoxyverticillin decreased VEGF secretion by MDA-MB-468 breast cancer cells, and significantly suppressed VEGF-induced tyrosine phosphorylation of Flt-1 and KDR/Flk-1. This inhibition of receptor phosphorylation was correlated with a marked decrease in VEGF-triggered pERK activation and a dramatic increase in pP38 MAPK, but no apparent change in pAkt. Together, these findings strongly suggest that 11,11'-dideoxyverticillin is a structurally novel angiogenesis inhibitor

  18. Controlled delivery of antiangiogenic drug to human eye tissue using a MEMS device

    KAUST Repository

    Pirmoradi, Fatemeh Nazly

    2013-01-01

    We demonstrate an implantable MEMS drug delivery device to conduct controlled and on-demand, ex vivo drug transport to human eye tissue. Remotely operated drug delivery to human post-mortem eyes was performed via a MEMS device. The developed curved packaging cover conforms to the eyeball thereby preventing the eye tissue from contacting the actuating membrane. By pulsed operation of the device, using an externally applied magnetic field, the drug released from the device accumulates in a cavity adjacent to the tissue. As such, docetaxel (DTX), an antiangiogenic drug, diffuses through the eye tissue, from sclera and choroid to retina. DTX uptake by sclera and choroid were measured to be 1.93±0.66 and 7.24±0.37 μg/g tissue, respectively, after two hours in pulsed operation mode (10s on/off cycles) at 23°C. During this period, a total amount of 192 ng DTX diffused into the exposed tissue. This MEMS device shows great potential for the treatment of ocular posterior segment diseases such as diabetic retinopathy by introducing a novel way of drug administration to the eye. © 2013 IEEE.

  19. Anti-Oxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Resveratrol in Ocular Diseases.

    Science.gov (United States)

    Lançon, Allan; Frazzi, Raffaele; Latruffe, Norbert

    2016-03-02

    Resveratrol (3,4',5 trihydroxy-trans-stilbene) is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD) is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

  20. Anti-Oxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Resveratrol in Ocular Diseases

    Directory of Open Access Journals (Sweden)

    Allan Lançon

    2016-03-01

    Full Text Available Resveratrol (3,4′,5 trihydroxy-trans-stilbene is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

  1. Simulated Prism Therapy in Virtual Reality produces larger after-effects than standard prism exposure in normal healthy subject - Implications for Neglect Therapy

    DEFF Research Database (Denmark)

    Wilms, Inge Linda

    2018-01-01

    BACKGROUND: Virtual reality is an important area of exploration within computer-based cognitive rehabilitation of visual neglect. Virtual reality will allow for closer monitoring of patient behaviour during prism adaptation therapy and perhaps change the way we induce prismatic after......-effects. OBJECTIVE: This study compares the effect of two different prism simulation conditions in virtual reality to a standard exposure to prism goggles after one session of Prism Adaptation Therapy in healthy subjects. METHOD: 20 healthy subjects were subjected to one session of prism adaptation therapy under...... three prism conditions: 2 different types of simulated prism techniques in virtual reality and a control session using a set of prism goggles. RESULTS: The study shows that the simulated prism conditions in virtual reality with HTC Vive produced prismatic after-effects larger in size than the after...

  2. The revival of Phage Therapy to fight Antimicrobial Resistance – Part I: What are the legal implications?

    DEFF Research Database (Denmark)

    Minssen, Timo

    2014-01-01

    antibiotics, it might offer the best – or only available – therapy for patients in whom drug treatments have failed. Since the danger is imminent and there is reason to believe that phage therapies will often (arguably not always) be most efficiently developed in Private Public Partnerships (PPPs), this might...

  3. Is anti-platelet therapy interruption a real clinical issue? Its implications in dentistry and particularly in periodontics

    Directory of Open Access Journals (Sweden)

    Kumar A

    2009-01-01

    Full Text Available The use of anti-platelet therapy has reduced the mortality and morbidity of cardiovascular disease remarkably. A considerable number of patients presenting before a dentist or periodontist give a history of anti-platelet therapy. A clinical dilemma whether to discontinue the anti-platelet therapy or continue the same always confronts the practitioner. Diverse opinions exist regarding the management of such patients. While one group of researchers advise continuation of anti-platelet therapy rather than invite remote, but possible, thromboembolic events, another group encourages discontinuation for variable periods. This study aims at reviewing the current rationale of anti-platelet therapy and the various options available to a clinician, with regard to the management of a patient under anti-platelet therapy. Current recommendations and consensus favour no discontinuation of anti-platelet therapy. This recommendation, however, comes with a rider to use caution and consider other mitigating factors as well. With a large number of patients giving a history of anti-platelet therapy, the topic is of interest and helps a clinician to arrive at a decision.

  4. Sleep Restriction Therapy for Insomnia is Associated with Reduced Objective Total Sleep Time, Increased Daytime Somnolence, and Objectively Impaired Vigilance: Implications for the Clinical Management of Insomnia Disorder

    Science.gov (United States)

    Kyle, Simon D.; Miller, Christopher B.; Rogers, Zoe; Siriwardena, A. Niroshan; MacMahon, Kenneth M.; Espie, Colin A.

    2014-01-01

    Study Objectives: To investigate whether sleep restriction therapy (SRT) is associated with reduced objective total sleep time (TST), increased daytime somnolence, and impaired vigilance. Design: Within-subject, noncontrolled treatment investigation. Setting: Sleep research laboratory. Participants: Sixteen patients [10 female, mean age = 47.1 (10.8) y] with well-defined psychophysiological insomnia (PI), reporting TST ≤ 6 h. Interventions: Patients were treated with single-component SRT over a 4-w protocol, sleeping in the laboratory for 2 nights prior to treatment initiation and for 3 nights (SRT night 1, 8, 22) during the acute interventional phase. The psychomotor vigilance task (PVT) was completed at seven defined time points [day 0 (baseline), day 1,7,8,21,22 (acute treatment) and day 84 (3 mo)]. The Epworth Sleepiness Scale (ESS) was completed at baseline, w 1-4, and 3 mo. Measurement and results: Subjective sleep outcomes and global insomnia severity significantly improved before and after SRT. There was, however, a robust decrease in PSG-defined TST during acute implementation of SRT, by an average of 91 min on night 1, 78 min on night 8, and 69 min on night 22, relative to baseline (P sleep restriction therapy is associated with reduced objective total sleep time, increased daytime sleepiness, and objective performance impairment. Our data have important implications for implementation guidelines around the safe and effective delivery of cognitive behavioral therapy for insomnia. Citation: Kyle SD; Miller CB; Rogers Z; Siriwardena AN; MacMahon KM; Espie CA. Sleep restriction therapy for insomnia is associated with reduced objective total sleep time, increased daytime somnolence, and objectively impaired vigilance: implications for the clinical management of insomnia disorder. SLEEP 2014;37(2):229-237. PMID:24497651

  5. Simulated Prism Therapy in Virtual Reality produces larger after-effects than standard prism exposure in normal healthy subject - Implications for Neglect Therapy

    DEFF Research Database (Denmark)

    Wilms, Inge Linda

    2018-01-01

    -effects. OBJECTIVE: This study compares the effect of two different prism simulation conditions in virtual reality to a standard exposure to prism goggles after one session of Prism Adaptation Therapy in healthy subjects. METHOD: 20 healthy subjects were subjected to one session of prism adaptation therapy under...... three prism conditions: 2 different types of simulated prism techniques in virtual reality and a control session using a set of prism goggles. RESULTS: The study shows that the simulated prism conditions in virtual reality with HTC Vive produced prismatic after-effects larger in size than the after...

  6. Early Assessment of Colorectal Cancer Patients with Liver Metastases Treated with Antiangiogenic Drugs: The Role of Intravoxel Incoherent Motion in Diffusion-Weighted Imaging.

    Directory of Open Access Journals (Sweden)

    Vincenza Granata

    Full Text Available To assess the feasibility and effectiveness of quantitative intravoxel incoherent motion (IVIM of Diffusion-weighted imaging (DWI in the assessment of liver metastases treated with targeted chemotherapy agents.12 patients with unresectable liver metastases from colorectal cancer were enrolled and received neoadjuvant FOLFIRI (5-fluorouracil, leucovorin, irinotecan plus bevacizumab therapy. DWI was performed for 36 metastases at baseline and after 14 days from starting the treatment. In addition to the basic IVIM metrics, the product between pseudo-diffusivity and perfusion fraction was considered as a descriptor roughly analogous to the flow. Median diffusion parameters of Region of Interest (ROI were used as representative values for each lesion. Normalized parameters in comparison with the median value of spleen were also collected. The percentual change of the diffusion parameters was calculated. The response to chemotherapy was evaluated according the Response Evaluation Criteria in Solid Tumors (RECIST as calculated on whole-body CT scan obtained three months after treatment. Mann Whitney test and Receiver operating characteristic (ROC analysis were performed.24 lesions were categorized as responding and 12 as not responding. There was no statistically significant difference among absolute and normalized diffusion parameters between the pretreatment and the post-treatment findings. Instead, the perfusion fraction (fp values showed a statistical difference between responder and non-responder lesions: sensitivity and specificity of fp variation was 62% and 93%, respectively.IVIM parameters represent a valuable tool in the evaluation of the anti-angiogenic therapy in patients with liver metastases from colorectal cancer. A percentage change of fp represents the most effective DWI marker in the assessment of tumor response.

  7. Salivary gland damage in radioiodine therapy. Dosimetry results and their implications; Speicheldruesenschaedigung bei Radioiodtherapien. Dosimetrieergebnisse und deren Implikationen

    Energy Technology Data Exchange (ETDEWEB)

    Freudenberg, L.S.; Stahl, A.; Bockisch, A.; Jentzen, W. [Universitaetsklinikum Essen (Germany). Klinik fuer Nuklearmedizin

    2010-12-15

    Radioiodine therapy plays a key role in the management of patients with differentiated thyroid cancer. However, radioiodine is concentrated not only in the target tissues but also by other tissue expressing sodium/iodine symporters - in particular the submandibular and parotid salivary glands. As a consequence, high-activity radioiodine therapy may be associated with unwanted radiogenic salivary gland damages. As a consequence, the most frequently observed adverse short- and long-term side effects of radioiodine therapy include sialoadenitis and some degree of xerostomia, both with a potentially negative impact on quality of life. In this review, we highlight the function and importance of salivary glands and discuss the current results of dosimetry studies of the salivary glands in patients, who undergo radioiodine therapy. Based on the dosimetry findings, the commonly applied radioprotective procedure to diminish damage to the salivary glands are discussed critically. (orig.)

  8. The Adoption of New Adjuvant Radiation Therapy Modalities Among Medicare Beneficiaries With Breast Cancer: Clinical Correlates and Cost Implications

    International Nuclear Information System (INIS)

    Roberts, Kenneth B.; Soulos, Pamela R.; Herrin, Jeph; Yu, James B.; Long, Jessica B.; Dostaler, Edward

    2013-01-01

    Purpose: New radiation therapy modalities have broadened treatment options for older women with breast cancer, but it is unclear how clinical factors, geographic region, and physician preference affect the choice of radiation therapy modality. Methods and Materials: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify women diagnosed with stage I-III breast cancer from 1998 to 2007 who underwent breast-conserving surgery. We assessed the temporal trends in, and costs of, the adoption of intensity modulated radiation therapy (IMRT) and brachytherapy. Using hierarchical logistic regression, we evaluated the relationship between the use of these new modalities and patient and regional characteristics. Results: Of 35,060 patients, 69.9% received conventional external beam radiation therapy (EBRT). Although overall radiation therapy use remained constant, the use of IMRT increased from 0.0% to 12.6% from 1998 to 2007, and brachytherapy increased from 0.7% to 9.0%. The statistical variation in brachytherapy use attributable to the radiation oncologist and geographic region was 41.4% and 9.5%, respectively (for IMRT: 23.8% and 22.1%, respectively). Women undergoing treatment at a free-standing radiation facility were significantly more likely to receive IMRT than were women treated at a hospital-based facility (odds ratio for IMRT vs EBRT: 3.89 [95% confidence interval, 2.78-5.45]). No such association was seen for brachytherapy. The median radiation therapy cost per treated patient increased from $5389 in 2001 to $8539 in 2007. Conclusions: IMRT and brachytherapy use increased substantially from 1998 to 2007; overall, radiation therapy costs increased by more than 50%. Radiation oncologists played an important role in treatment choice for both types of radiation therapy, whereas geographic region played a bigger role in the use of IMRT than brachytherapy

  9. System engineering approach to planning anticancer therapies

    CERN Document Server

    Świerniak, Andrzej; Smieja, Jaroslaw; Puszynski, Krzysztof; Psiuk-Maksymowicz, Krzysztof

    2016-01-01

    This book focuses on the analysis of cancer dynamics and the mathematically based synthesis of anticancer therapy. It summarizes the current state-of-the-art in this field and clarifies common misconceptions about mathematical modeling in cancer. Additionally, it encourages closer cooperation between engineers, physicians and mathematicians by showing the clear benefits of this without stating unrealistic goals. Development of therapy protocols is realized from an engineering point of view, such as the search for a solution to a specific control-optimization problem. Since in the case of cancer patients, consecutive measurements providing information about the current state of the disease are not available, the control laws are derived for an open loop structure. Different forms of therapy are incorporated into the models, from chemotherapy and antiangiogenic therapy to immunotherapy and gene therapy, but the class of models introduced is broad enough to incorporate other forms of therapy as well. The book be...

  10. Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells.

    Science.gov (United States)

    Winter, Ursula; Mena, Hebe A; Negrotto, Soledad; Arana, Eloisa; Pascual-Pasto, Guillem; Laurent, Viviana; Suñol, Mariona; Chantada, Guillermo L; Carcaboso, Angel M; Schaiquevich, Paula

    2016-01-01

    Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure) or metronomic (7-day continuous exposure) treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50) was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks) and metronomic (5 days a week for 2 weeks) topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3-23) was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p0.05). In mice, continuous topotecan lead to significantly lower tumor volumes compared to conventional treatment after 14 days of treatment (pretinoblastoma and endothelial cells to both chemotherapy agents with lower IC50 values compared to short-term treatment. These findings were validated in an in vivo model. None of the dosing modalities induced multidrug resistance mechanisms while apoptosis was the mechanism of cell death after both treatment

  11. HL-217, a new topical anti-angiogenic agent, inhibits retinal vascular leakage and pathogenic subretinal neovascularization in Vldlr−/− mice

    International Nuclear Information System (INIS)

    Kim, Junghyun; Kim, Chan-Sik; Jo, Kyuhyung; Cho, Yun-Seok; Kim, Hyun-Gyu; Lee, Geun-Hyeog; Lee, Yun Mi; Sohn, Eunjin; Kim, Jin Sook

    2015-01-01

    Highlights: • HL-217 is a new synthetic topical anti-angiogenic agent. • HL-217 attenuated subretinal neovascularization in Vldlr −/− mice. • HL-217 blocked the binding of PDGF-BB to PDGFRβ. - Abstract: HL-217 is a new synthetic angiogenesis inhibitor. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. In this study, we examined the mechanism of action and efficacy of topical application of HL-217 on subretinal neovascularization in very low-density lipoprotein receptor knockout (Vldlr −/− ) mice. In three-week-old male Vldlr −/− mice, HL-217 (1.5 or 3 mg/ml) was administered twice per day for 4 weeks by topical eye drop instillation. Neovascular areas were then measured. We used a protein array to evaluate the expression levels of angiogenic factors. The inhibitory effect of HL-217 on the PDGF-BB/PDGFRβ interaction was evaluated in vitro. The neovascular area in the Vldlr −/− mice was significantly reduced by HL-217. Additionally, HL-217 decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, HL-217 dose-dependently inhibited the PDGF-BB/PDGFRβ interaction (IC 50 = 38.9 ± 0.7 μM). These results suggest that HL-217 is a potent inhibitor of PDGF-BB. HL-217, when applied topically, is an effective inhibitor of subretinal neovascularization due to its ability to inhibit the pro-angiogenic effects of PDGF-BB

  12. HL-217, a new topical anti-angiogenic agent, inhibits retinal vascular leakage and pathogenic subretinal neovascularization in Vldlr{sup −/−} mice

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Junghyun; Kim, Chan-Sik; Jo, Kyuhyung [Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon (Korea, Republic of); Cho, Yun-Seok; Kim, Hyun-Gyu; Lee, Geun-Hyeog [Research and Development Center, Hanlim Pharm. Co. Ltd., 1656-10, Seocho-dong, Seocho-gu, Seoul (Korea, Republic of); Lee, Yun Mi; Sohn, Eunjin [Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon (Korea, Republic of); Kim, Jin Sook, E-mail: jskim@kiom.re.kr [Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon (Korea, Republic of)

    2015-01-02

    Highlights: • HL-217 is a new synthetic topical anti-angiogenic agent. • HL-217 attenuated subretinal neovascularization in Vldlr{sup −/−} mice. • HL-217 blocked the binding of PDGF-BB to PDGFRβ. - Abstract: HL-217 is a new synthetic angiogenesis inhibitor. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. In this study, we examined the mechanism of action and efficacy of topical application of HL-217 on subretinal neovascularization in very low-density lipoprotein receptor knockout (Vldlr{sup −/−}) mice. In three-week-old male Vldlr{sup −/−} mice, HL-217 (1.5 or 3 mg/ml) was administered twice per day for 4 weeks by topical eye drop instillation. Neovascular areas were then measured. We used a protein array to evaluate the expression levels of angiogenic factors. The inhibitory effect of HL-217 on the PDGF-BB/PDGFRβ interaction was evaluated in vitro. The neovascular area in the Vldlr{sup −/−} mice was significantly reduced by HL-217. Additionally, HL-217 decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, HL-217 dose-dependently inhibited the PDGF-BB/PDGFRβ interaction (IC{sub 50} = 38.9 ± 0.7 μM). These results suggest that HL-217 is a potent inhibitor of PDGF-BB. HL-217, when applied topically, is an effective inhibitor of subretinal neovascularization due to its ability to inhibit the pro-angiogenic effects of PDGF-BB.

  13. Asymptomatic carotid artery stenosis treated with medical therapy alone: temporal trends and implications for risk assessment and the design of future studies.

    Science.gov (United States)

    Hadar, Nira; Raman, Gowri; Moorthy, Denish; O'Donnell, Thomas F; Thaler, David E; Feldmann, Edward; Lau, Joseph; Kitsios, Georgios D; Dahabreh, Issa J

    2014-01-01

    The rate of adverse clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone can be used to guide clinical decision-making and to inform future research. We aimed to investigate temporal changes in the incidence rate of clinical outcomes among patients with asymptomatic carotid stenosis receiving medical therapy alone and to explore the implications of these changes for the design of future comparative studies. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, US Food and Drug Administration documents, and reference lists of included studies (last search: December 31, 2012). We selected prospective cohort studies of medical therapy for asymptomatic carotid artery stenosis and we extracted information on study characteristics, risk of bias, and outcomes. We performed meta-analyses to estimate summary incidence rates, meta-regressions to assess trends over time, and simulations to explore sample size requirements for the design of future studies comparing new treatments against medical therapy. The main outcomes of interest were ipsilateral stroke, any stroke, cardiovascular death, death, and myocardial infarction. We identified 41 studies of medical therapy for patients with asymptomatic carotid stenosis (last recruitment year: 1978-2009). The summary incidence rate of ipsilateral carotid territory stroke (25 studies) was 1.7 per 100 person-years. This incidence rate was significantly lower in recent studies (last recruitment year from 2000 onwards) as compared to studies that ended recruitment earlier (1.0 vs. 2.3 events per 100 person-years; p rates of any territory stroke (17 studies), cardiovascular death (6 studies), death (13 studies), and myocardial infarction (5 studies) were 2.7, 4.1, 4.6, and 1.8 per 100 person-years, respectively. Simulations showed that future studies would need to enroll large numbers of patients with a relatively high incidence rate under medical therapy, and evaluate

  14. Antioxidant and Antiangiogenic Properties, and Gas Chromatographic-Time of Flight Analysis of Sonchus arvensis Leaves Extracts

    International Nuclear Information System (INIS)

    Itam, A.; Shah, A. M.; Majid, A.; Ismail, Z.

    2015-01-01

    Sonchus arvensis L. (Asteraceae) is one of the medicinal herbs used in traditional medicines, in which the leaf extract was used as a diuretic, lithotriptic and antiurolithiasis agent. The leaves of S. arvensis reported contain several compounds, including a variety of flavonoids, terpenoids and sterol, even this plant also contain silica and potassium. Flavonoids are secondary metabolite compound which have ability as antioxidant. In this study, the aims are to determine of antioxidants and antiangiogenic properties, and phytoconstituents quantitative of aqueous and methanol extracts of S. arvensis leaves. The antioxidant properties were studied using 1,1-Diphenyl-2-picrylhydrazyl (DPPH) free radical, xanthine oxidase and beta-carotene-linoleate models system. Furthermore, the antiangiogenic property was evaluated using ex vivo rat aorta ring assay. Quantitative determination of extracts phytoconstituents were carried out by using Gas Chromatographic-Time of Flight (GC-TOF) mass spectrophotometric methods. The results showed that the aqueous and methanol extracts have ability as antioxidant which is antioxidant activities of aqueous extracts on DPPH radical and inhibition of xanthine oxidase activity are higher than that of methanol extracts. Meanwhile antioxidant activity using beta-carotene-linoleate model system of S. arvensis aqueous extract is lower than that of methanol extracts. Nevertheless, the differences of these antioxidant activities are not significant. Antiangiogenic property of aqueous extract is also higher than that of methanol extract which is measured at 100 meu g mL/sup -1/ of extracts. This indicates that there is correlation between antioxidant activity and antiangigenic property, exhibiting that this plant possesses the potential to prevent or cure the diseases that related to angiogenesis such as cancer. (author)

  15. Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its antiproliferative and antiangiogenic activity in vitro

    Science.gov (United States)

    Dasgupta, P; Mukherjee, R

    2000-01-01

    The therapeutic potential of the somatostatin analogue RC-160 having antiproliferative activity, is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid were conjugated to the N-terminal residue of RC-160. The lipophilized derivatives of RC-160 were synthesized, purified by reverse phase HPLC and characterized by ES-mass spectroscopy. The antiproliferative activity of lipophilized derivatives of RC-160 on the growth of MIA-PaCa2 (human pancreatic carcinoma), DU145 (human prostate carcinoma), ECV304 (human umbilical chord endothelioma), as well as their antiangiogenic activity was evaluated in vitro. The relative stability of myristoyl-RC-160 towards degradation by proteases and serum was also determined. Myristoyl-RC-160 exhibited significantly higher antiproliferative efficacy than RC-160, on the above cell lines (P<0.01). Receptor binding assays, demonstrated that the affinity of RC-160 towards somatostatin receptors remains unaltered by myristoylation. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (P<0.01). Myristoyl-RC-160 exhibited significantly greater antiproliferative activity on ECV304, than RC-160 (P<0.01). Myristoyl RC-160 could also inhibit capillary tube formation more efficiently than RC-160 in a dose dependent manner, suggesting that it possessed enhanced antiangiogenic activity in vitro (P<0.001). Lipophilization of RC-160 with long chain fatty acids like myristic acid endows it with improved antiproliferative and antiangiogenic activity, stability and therapeutic index. PMID:10694208

  16. Apigenin-induced nitric oxide production involves calcium-activated potassium channels and is responsible for antiangiogenic effects.

    Science.gov (United States)

    Erdogan, A; Most, A K; Wienecke, B; Fehsecke, A; Leckband, C; Voss, R; Grebe, M T; Tillmanns, H; Schaefer, C A; Kuhlmann, C R W

    2007-08-01

    The dietary flavonoid apigenin (Api) has been demonstrated to exert multiple beneficial effects upon the vascular endothelium. The aim of this study was to examine whether Ca(2+)-activated K(+) channels (K(Ca)) are involved in endothelial nitric oxide (NO) production and antiangiogenic effects. Endothelial NO generation was monitored using a cyclic guanosine monophosphate radioimmunoassay. K(Ca) activity and changes of the intracellular Ca(2+) concentration [Ca(2+)](i) were analyzed using the fluorescent dyes bis-barbituric acid oxonol, potassium-binding benzofuran isophthalate, and fluo-3. The endothelial angiogenic parameters measured were cell proliferation, [(3)H]-thymidine incorporation, and cell migration (scratch assay). Akt phosphorylation was examined using immunohistochemistry. Api caused a concentration-dependent increase in cyclic guanosine monophosphate levels, with a maximum effect at a concentration of 1 mum. Api-induced hyperpolarization was blocked by the small and large conductance K(Ca) inhibitors apamin and iberiotoxin, respectively. Furthermore, apamin and iberiotoxin blocked the late, long-lasting plateau phase of the Api-induced biphasic increase of [Ca(2+)](i). Inhibition of Ca(2+) signaling and the K(Ca) blockade both blocked NO production. Prevention of all three (NO, Ca(2+), and K(Ca) signaling) reversed the antiangiogenic effects of Api under both basal and basic fibroblast growth factor-induced culture conditions. Basic fibroblast growth factor-induced Akt phosphorylation was also reduced by Api. Based on our experimental results we propose the following signaling cascade for the effects of Api on endothelial cell signaling. Api activates small and large conductance K(Ca), leading to a hyperpolarization that is followed by a Ca(2+) influx. The increase of [Ca(2+)](i) is responsible for an increased NO production that mediates the antiangiogenic effects of Api via Akt dephosphorylation.

  17. Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach

    Directory of Open Access Journals (Sweden)

    Chiara Bianca Maria Platania

    2015-10-01

    Full Text Available Anti-angiogenic agents are biological drugs used for treatment of retinal neovascular degenerative diseases. In this study, we aimed at in-silico analysis of interaction of vascular endothelial growth factor A (VEGFA, the main mediator of angiogenesis, with binding domains of anti-angiogenic agents used for treatment of retinal diseases, such as ranibizumab, bevacizumab and aflibercept. The analysis of anti-VEGF/VEGFA complexes was carried out by means of protein-protein docking and molecular dynamics (MD coupled to molecular mechanics-Poisson Boltzmann Surface Area (MM-PBSA calculation. Molecular dynamics simulation was further analyzed by protein contact networks. Rough energetic evaluation with protein-protein docking scores revealed that aflibercept/VEGFA complex was characterized by electrostatic stabilization, whereas ranibizumab and bevacizumab complexes were stabilized by Van der Waals (VdW energy term; these results were confirmed by MM-PBSA. Comparison of MM-PBSA predicted energy terms with experimental binding parameters reported in literature indicated that the high association rate (Kon of aflibercept to VEGFA was consistent with high stabilizing electrostatic energy. On the other hand, the relatively low experimental dissociation rate (Koff of ranibizumab may be attributed to lower conformational fluctuations of the ranibizumab/VEGFA complex, higher number of contacts and hydrogen bonds in comparison to bevacizumab and aflibercept. Thus, the anti-angiogenic agents have been found to be considerably different both in terms of molecular interactions and stabilizing energy. Characterization of such features can improve the design of novel biological drugs potentially useful in clinical practice.

  18. Client-centred therapy, post-traumatic stress disorder and post-traumatic growth: theoretical perspectives and practical implications.

    Science.gov (United States)

    Joseph, Stephen

    2004-03-01

    In practice it is not unusual for client-centred therapists to work with people who have experienced traumatic events. However, client-centred therapy is not usually considered within texts on traumatic stress and questions have been raised over the appropriateness of client-centred therapy with trauma survivors. The present study shows how, although he was writing well before the introduction of the term 'post-traumatic stress disorder', Carl Rogers provided a theory of therapy and personality that contains an account of threat-related psychological processes largely consistent with contemporary trauma theory. Rogers' theory provides the conceptual underpinnings to the client-centred and experiential ways of working with traumatized people. Furthermore, Rogers' theory provides an understanding of post-traumatic growth processes, and encourages therapists to adopt a more positive psychological perspective to their understanding of how people adjust to traumatic events.

  19. Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy.

    Science.gov (United States)

    Strassl, Robert; Rutter, Karoline; Stättermayer, Albert Friedrich; Beinhardt, Sandra; Kammer, Michael; Hofer, Harald; Ferenci, Peter; Popow-Kraupp, Theresia

    2015-01-01

    Monitoring of chronic Hepatitis C (CHC) treatment relies on HCV RNA quantification by means of real-time PCR methods. Assay specific analytical sensitivities may impact therapy management. Comparative analysis between three commercial assays (Roche COBAS AmpliPrep/COBAS TaqMan Version 1 (CAP/CTM Ver. 1), Version 2 (CAP/CTM Ver. 2) and the Abbott RealTime HCV (ART) assay) was performed on 247 available samples taken at key decision time points during antiviral therapy of 105 genotype 1 patients (triple therapy: n = 70; dual therapy: n = 35). Overall concordance of HCV RNA measurements was high between the two Roche systems (89%; n = 220/247) but lower between the Roche assays and the ART (CAP/CTM Ver. 1 vs ART: 77.3%; n = 191/247 and CAP/CTM v.2 vs ART: 80.1%; n = 198/247). Most discrepancies were noted in week 4/8 samples with residual viremia (HCV RNA by CAP/CTM Ver. 1 (therapy (24 weeks). Only 1 patient experienced virologic breakthrough. If tested by ART, only 6/13 patients (46.2%) would have been eligible for shortened treatment. Consequently, RGT guidelines were adapted and shortening of therapy was allowed if residual viremia was detected by ART at week 4/8. An abbreviated course of treatment can safely be applied in patients with residual viremia (

  20. Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy.

    Directory of Open Access Journals (Sweden)

    Robert Strassl

    Full Text Available Monitoring of chronic Hepatitis C (CHC treatment relies on HCV RNA quantification by means of real-time PCR methods. Assay specific analytical sensitivities may impact therapy management.Comparative analysis between three commercial assays (Roche COBAS AmpliPrep/COBAS TaqMan Version 1 (CAP/CTM Ver. 1, Version 2 (CAP/CTM Ver. 2 and the Abbott RealTime HCV (ART assay was performed on 247 available samples taken at key decision time points during antiviral therapy of 105 genotype 1 patients (triple therapy: n = 70; dual therapy: n = 35.Overall concordance of HCV RNA measurements was high between the two Roche systems (89%; n = 220/247 but lower between the Roche assays and the ART (CAP/CTM Ver. 1 vs ART: 77.3%; n = 191/247 and CAP/CTM v.2 vs ART: 80.1%; n = 198/247. Most discrepancies were noted in week 4/8 samples with residual viremia (therapy (24 weeks. Only 1 patient experienced virologic breakthrough. If tested by ART, only 6/13 patients (46.2% would have been eligible for shortened treatment. Consequently, RGT guidelines were adapted and shortening of therapy was allowed if residual viremia was detected by ART at week 4/8.An abbreviated course of treatment can safely be applied in patients with residual viremia (

  1. Enhanced Efficacy of High Dose Oral Vancomycin Therapy in Clostridium difficile Diarrhea for Hospitalized Adults Not Responsive to Conventional Oral Vancomycin Therapy: Antibiotic Stewardship Implications

    Directory of Open Access Journals (Sweden)

    Burke A. Cunha

    2018-04-01

    Full Text Available Current therapy of Clostridium difficile diarrhea (CDD is problematic. Optimal treatment for CDD remains oral vancomycin, but there is little data on oral vancomycin dosing regimens. The objective of this C. difficile diarrhea study was to compare the efficacy of “high dose” vancomycin, 500 mg (PO q6h, as sole treatment and in those who after 72 h failed to respond to conventional doses of oral vancomycin, 125–250 mg (PO q6h. Hospitalized adults with CDD were evaluated by various oral vancomycin regimens, i.e., a conventional dose group (125–250 mg (PO q6h, a “high dose escalation” dose group (250 mg → 500 mg (PO q6h, and a “high dose” group (500 mg (PO q6h. Oral vancomycin treatment groups were compared by time to improvement, i.e., decrease in >50% of watery stools/day and duration of therapy. The high dose escalation and high dose oral vancomycin groups showed the most rapid resolution of diarrhea. There was marked decrease in stools/day after “high dose” vancomycin escalation from conventional dosing, i.e., 250 mg (PO q6h → 500 mg (PO q6h. This study demonstrated that “high dose” escalation or initial high dose oral vancomycin, i.e., 500 mg (PO q6h was the most efficacious regimen for CDD.

  2. In vitro anti-angiogenic properties of LGD1069, a selective retinoid X-receptor agonist through down-regulating Runx2 expression on Human endothelial cells

    International Nuclear Information System (INIS)

    Fu, Jianjiang; Wang, Wei; Liu, Yu-Hui; Lu, Hong; Luo, Yongming

    2011-01-01

    LGD1069 (Targretin ® ) is a selective retinoid X receptor (RXR) ligand, which is used in patients for cutaneous T-cell lymphoma. Our published study reported that LGD1069 inhibited tumor-induced angiogenesis in non-small cell lung cancer. In present study, we found that LGD1069 suppressed the proliferation, adhesion, invasion and migration of endothelial cells directly, and affected the expression of vegf and some matrix genes. Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. MTT assay and Sulforhodamine B assay were used for cell viability assay; the tube formation assay was used to investigate the effect of LGD1069 on angiogenesis in vitro. In vitro adhesion, migration and invasion of HUVEC cells were analyzed by Matrigel adhesion, migration and invasion assay. Gene expressions were measured by RT-PCR and Western blot analysis. Our data showed here that LGD1069 inhibited the activation of TGF-β/Smad pathway significantly. Furthermore, it was demonstrated that expression of Runx2 was suppressed pronouncedly during incubation with LGD1069. Runx2 is a DNA-binding transcription factor which plays a master role in tumor-induced angiogenesis and cancer cells metastasis by interaction with the TGF-β/Smad pathway of transcriptional modulators. Our results suggested that LGD1069 may impair angiogenic and metastatic potential induced by tumor cells through suppressing expression of Runx2 directly on human endothelial cells, which may point out new pathway through which LGD1069 display anti-angiogenic properties, and provide new molecular evidence to support LGD1069 as a potent anti-metastatic agent in cancer therapy

  3. Dynamic Contrast Enhanced MRI Assessing the Antiangiogenic Effect of Silencing HIF-1α with Targeted Multifunctional ECO/siRNA Nanoparticles.

    Science.gov (United States)

    Malamas, Anthony S; Jin, Erlei; Gujrati, Maneesh; Lu, Zheng-Rong

    2016-07-05

    Stabilization of hypoxia inducible factor 1α (HIF-1α), a biomarker of hypoxia, in hypoxic tumors mediates a variety of downstream genes promoting tumor angiogenesis and cancer cell survival as well as invasion, and compromising therapeutic outcome. In this study, dynamic contrast enhanced MRI (DCE-MRI) with a biodegradable macromolecular MRI contrast agent was used to noninvasively assess the antiangiogenic effect of RGD-targeted multifunctional lipid ECO/siHIF-1α nanoparticles in a mouse HT29 colon cancer model. The RGD-targeted ECO/siHIF-1α nanoparticles resulted in over 50% reduction in tumor size after intravenous injection at a dose of 2.0 mg of siRNA/kg every 3 days for 3 weeks compared to a saline control. DCE-MRI revealed significant decline in vascularity and over a 70% reduction in the tumor blood flow, permeability-surface area product, and plasma volume fraction vascular parameters in the tumor treated with the targeted ECO/siHIF-1α nanoparticles. The treatment with targeted ECO/siRNA nanoparticles resulted in significant silencing of HIF-1α expression at the protein level, which also significantly suppressed the expression of VEGF, Glut-1, HKII, PDK-1, LDHA, and CAIX, which are all important players in tumor angiogenesis, glycolytic metabolism, and pH regulation. By possessing the ability to elicit a multifaceted effect on tumor biology, silencing HIF-1α with RGD-targeted ECO/siHIF-1α nanoparticles has great promise as a single therapy or in combination with traditional chemotherapy or radiation strategies to improve cancer treatment.

  4. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ran-yi, E-mail: liuranyi@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhou, Ling [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhang, Yan-ling [School of Biotechnology, Southern Medical University, Guangzhou 510515 (China); Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Li, Li-xia [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010 (China); Fu, Xiang; Wu, Jiang-xue [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Huang, Wenlin, E-mail: hwenl@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Guangdong Provincial Key Laboratory of Tumor-Targeted Drug, Doublle Bioproducts Inc., Guangzhou 510663 (China)

    2013-12-13

    Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

  5. Perspectives on Cognitive Therapy Training within Community Mental Health Settings: Implications for Clinician Satisfaction and Skill Development.

    Science.gov (United States)

    Wiltsey Stirman, Shannon; Miller, Christopher J; Toder, Katherine; Calloway, Amber; Beck, Aaron T; Evans, Arthur C; Crits-Christoph, Paul

    2012-01-01

    Despite the mounting evidence of the benefits of cognitive therapy for depression and suicidal behaviors over usual care, like other evidence-based psychosocial treatments (EBTs), it has not been widely adopted in clinical practice. Studies have shown that training followed by intensive consultation is needed to prepare providers to an appropriate level of competency in complex, multisession treatment packages such as cognitive therapy. Given the critical role of training in EBT implementation, more information on factors associated with the success and challenges of training programs is needed. To identify potential reasons for variation in training outcomes across ten agencies in a large, urban community mental health system, we explored program evaluation data and examined provider, consultant, and training program administrator perspectives through follow-up interviews. Perceptions of cognitive therapy, contextual factors, and reactions to feedback on audio recordings emerged as broad categories of themes identified from interviews. These factors may interact and impact clinician efforts to learn cognitive therapy and deliver it skillfully in their practice. The findings highlight experiences and stakeholder perspectives that may contribute to more or less successful training outcomes.

  6. Maintenance treatment after induction therapy in non-small cell lung cancer: latest evidence and clinical implications

    Science.gov (United States)

    Gentzler, Ryan D.

    2014-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the industrialized world. Despite significant progress in early stage disease, survival rates for advanced disease remain low. Maintenance therapy is a treatment strategy that has been investigated extensively in NSCLC. Therapies that have been studied in this setting in randomized trials to date include chemotherapy and molecularly targeted agents. Following the development of multiple new agents that show activity in NSCLC and have a tolerable side-effect profile, there has been increasing interest in utilizing them to maintain response to initial therapy after treatment with platinum-based doublets. Two effective strategies have evolved: continuation and switch maintenance. Despite improvements in progression-free survival and often overall survival on multiple clinical trials, there remains considerable controversy around this treatment paradigm. Here, we briefly outline the evolution of this treatment strategy and examine the available data, including recently updated data from the PARAMOUNT, AVAPERL, and PointBreak maintenance trials. Ultimately, the decision to use maintenance chemotherapy requires a nuanced discussion between the patient and physician that adequately assesses benefits of prolonged therapy and impact in terms of toxicity, quality of life, and financial cost. PMID:24381656

  7. Perspectives on Cognitive Therapy Training within Community Mental Health Settings: Implications for Clinician Satisfaction and Skill Development

    Directory of Open Access Journals (Sweden)

    Shannon Wiltsey Stirman

    2012-01-01

    Full Text Available Despite the mounting evidence of the benefits of cognitive therapy for depression and suicidal behaviors over usual care, like other evidence-based psychosocial treatments (EBTs, it has not been widely adopted in clinical practice. Studies have shown that training followed by intensive consultation is needed to prepare providers to an appropriate level of competency in complex, multisession treatment packages such as cognitive therapy. Given the critical role of training in EBT implementation, more information on factors associated with the success and challenges of training programs is needed. To identify potential reasons for variation in training outcomes across ten agencies in a large, urban community mental health system, we explored program evaluation data and examined provider, consultant, and training program administrator perspectives through follow-up interviews. Perceptions of cognitive therapy, contextual factors, and reactions to feedback on audio recordings emerged as broad categories of themes identified from interviews. These factors may interact and impact clinician efforts to learn cognitive therapy and deliver it skillfully in their practice. The findings highlight experiences and stakeholder perspectives that may contribute to more or less successful training outcomes.

  8. Experiences of mobility for people living with rheumatoid arthritis who are receiving biologic drug therapy: implications for podiatry services.

    Science.gov (United States)

    Sanders, Lucy; Donovan-Hall, Margaret; Borthwick, Alan; Bowen, Catherine J

    2017-01-01

    Despite significant advancements in new treatment modalities for rheumatoid arthritis with biological therapies, foot complications remain a disabling and common feature of the disease . In this study the aim was to explore and describe the personal experiences of people with rheumatoid arthritis in receipt of biologic treatments in a bid to understand the impact of this form of medication on their mobility. An interpretative phenomenological analysis (IPA) was undertaken to explore in depth the individual experience of rheumatoid disease through personal accounts of the patient journey spanning both 'before' and 'after' the instigation of biologic therapy. A purposive sampling strategy was adopted and in-depth semi structured interviews used to facilitate rich, detailed interview data exploring the lived experiences of individuals undertaking biological therapy and the changes to mobility experienced as a result. Thematic analysis was employed with an IPA framework to identify key meanings, and report patterns within the data. Five people with rheumatoid arthritis participated in the study. The mean disease duration was 20.2 years (range: 6 -32) and all were being treated with biologic therapies. Four key themes emerged from the data: 1) Life before biologic treatment, depicted in accounts as a negative experience characterised by painful and disabling symptoms and feelings of hopelessness. 2) Life with biologic treatment, often experienced as a life changing transition, restoring function and mobility and offering renewed hope. 3) Sense of self, in which the impact of rheumatoid disease and the subsequent changes arising from biologic therapy reveal a profound impact on feelings of personal identity both pre and post biologic therapy; an effect of footwear on self-image emerges as a dominant sub theme; 4) Unmet footcare needs were evident in the patient narrative, where the unrelenting if diminished impact of foot pain on mobility was viewed in the context of

  9. Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Ursula Winter

    Full Text Available Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure or metronomic (7-day continuous exposure treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50 was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks and metronomic (5 days a week for 2 weeks topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3-23 was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p0.05. In mice, continuous topotecan lead to significantly lower tumor volumes compared to conventional treatment after 14 days of treatment (p<0.05. Continuous exposure to melphalan or topotecan increased the chemosensitivity of retinoblastoma and endothelial cells to both chemotherapy agents with lower IC50 values compared to short-term treatment. These findings were validated in an in vivo model. None of the dosing modalities induced

  10. Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations

    Directory of Open Access Journals (Sweden)

    Ludovica Ciuffreda

    2009-08-01

    Full Text Available The Raf/MEK/ERK pathway is an importantmediator of tumor cell proliferation and angiogenesis. Here, weinvestigated the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells. PD0325901 effects were determined in a panel of melanoma cell lines with different genetic aberrations. PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type melanoma cell lines, with IC50 in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G1-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (cyclin D1, c-Myc, and p27KIP1 and apoptosis (Bcl-2 and survivin regulators were modulated by PD0325901 at the protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally, PD0325901 inhibited the production of the proangiogenic factors vascular endothelial growth factor and interleukin 8 at a transcriptional level. In conclusion, PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing malignant melanoma.

  11. Butyrate-induced proapoptotic and antiangiogenic pathways in EAT cells require activation of CAD and downregulation of VEGF

    International Nuclear Information System (INIS)

    Belakavadi, Madesh; Prabhakar, B.T.; Salimath, Bharathi P.

    2005-01-01

    Butyrate, a short-chain fatty acid produced in the colon, induces cell cycle arrest, differentiation, and apoptosis in transformed cell lines. In this report, we study the effects of butyrate (BuA) on the growth of Ehrlich ascites tumor (EAT) cells in vivo. BuA, when injected intraperitoneally (i.p) into mice, inhibited proliferation of EAT cells. Further, induction of apoptosis in EAT cells was monitored by nuclear condensation, annexin-V staining, DNA fragmentation, and translocation of caspase-activated DNase into nucleus upon BuA-treatment. Ac-DEVD-CHO, a caspase-3 inhibitor, completely inhibited BuA-induced apoptosis, indicating that activation of caspase-3 mediates the apoptotic pathway in EAT cells. The proapoptotic effect of BuA also reflects on the antiangiogenic pathway in EAT cells. The antiangiogenic effect of BuA in vivo was demonstrated by the downregulation of the secretion of VEGF in EAT cells. CD31 immunohistochemical staining of peritoneum sections clearly indicated a potential angioinhibitory effect of BuA in EAT cells. These results suggest that BuA, besides regulating other fundamental cellular processes, is able to modulate the expression/secretion of the key angiogenic growth factor VEGF in EAT cells

  12. Evaluation of anti-HIF and anti-angiogenic properties of honokiol for the treatment of ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Divya Teja Vavilala

    Full Text Available Pathological activation of the hypoxia-inducible-factor (HIF pathway leading to expression of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF, is the fundamental cause of neovascularization in ocular ischemic diseases and cancers. We have shown that pure honokiol inhibits the HIF pathway and hypoxia-mediated expression of pro-angiogenic genes in a number of cancer and retinal pigment epithelial (RPE cell lines. The crude extracts, containing honokiol, from Magnolia plants have been used for thousands of years in the traditional oriental medicine for a number of health benefits. We have recently demonstrated that daily intraperitoneal injection of honokiol starting at postnatal day (P 12 in an oxygen induced retinopathy mouse model significantly reduced retinal neovascularization at P17. Here, we evaluate the mechanism of HIF inhibition by honokiol in RPE cells. Using chromatin immunoprecipitation experiments, we demonstrate that honokiol inhibits binding of HIF to hypoxia-response elements present on VEGF promoter. We further show using a number of in vitro angiogenesis assays that, in addition to anti-HIF effect, honokiol manifests potent anti-angiogenic effect on human retinal micro vascular endothelial cells. Our results suggest that honokiol possesses potent anti-HIF and anti-angiogenic properties. These properties of honokiol make it an ideal therapeutic agent for the treatment of ocular neovascular diseases and solid tumors.

  13. Chemical characterisation and the anti-inflammatory, anti-angiogenic and antibacterial properties of date fruit (Phoenix dactylifera L.).

    Science.gov (United States)

    Taleb, Hajer; Maddocks, Sarah E; Morris, R Keith; Kanekanian, Ara D

    2016-12-24

    Date fruit, Phoenix dactylifera L. has traditionally been used as a medicine in many cultures for the treatment of a range of ailments such as stomach and intestinal disorders, fever, oedema, bronchitis and wound healing. The present review aims to summarise the traditional use and application of P. dactylifera date fruit in different ethnomedical systems, additionally the botany and phytochemistry are identified. Critical evaluation of in vitro and in vitro studies examining date fruit in relation to anti-inflammatory, anti-angiogenic and antimicrobial activities are outlined. The ethnomedical use of P. dactylifera in the treatment of inflammatory disease has been previously identified and reported. Furthermore, date fruit and date fruit co-products such as date syrup are rich sources of polyphenols, anthocyanins, sterols and carotenoids. In vitro studies have demonstrated that date fruit exhibits antibacterial, anti-inflammatory and anti-angiogenic activity. The recent interest in the identification of the numerous health benefits of dates using in vitro and in vivo studies have confirmed that date fruit and date syrup have beneficial health effects that can be attributed to the presence of natural bioactive compounds. Date fruit and date syrup have therapeutic properties, which have the potential to be beneficial to health. However, more investigations are needed to quantify and validate these effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. EGFR, HER2 and HER3 expression in primary colorectal carcinomas and corresponding metastases: Implications for targeted radionuclide therapy.

    Science.gov (United States)

    Wei, Q; Shui, Y; Zheng, S; Wester, K; Nordgren, H; Nygren, P; Glimelius, B; Carlsson, J

    2011-01-01

    Members of the epidermal growth factor receptor, EGFR, family are interesting as targets for radionuclide therapy using targeting agents labeled with α- or β-emitting radionuclides, especially when EGFR-positive colorectal carcinomas, CRC, are resistant to EGFR inhibiting agents like cetuximab and various tyrosine kinase inhibitors. The expression of EGFR, HER2 and HER3 was therefore analyzed in CRC samples from primary tumors, corresponding lymph node metastases and, in a few cases, liver metastases. The expression of HER2 and EGFR was scored from immunohistochemical preparations using the HercepTest criteria 0, 1+, 2+ or 3+ for cellular membrane staining while HER3 expression was scored as no, weak or strong cytoplasm staining. Material from 60 patients was analyzed. The number of EGFR 2+ or 3+ positive primary tumors was 16 out of 56 (29%) and for lymph node metastases 8 out of 56 (14%) whereas only one out of nine (11%) liver metastases were positive. Thus, there was lower EGFR positivity in the metastases. Only one among 53 patients was strongly HER2 positive and this in both the primary tumor and the metastasis. Eight out of 49 primary tumors (16%) were strongly HER3 positive and the corresponding numbers for lymph node metastases were 9 out of 49 (18%) and for liver metastases 2 out of 9 (22%). The observed number of strongly EGFR positive cases was somewhat low but EGFR might be, for the cases with high EGFR expression in metastases, a target for radionuclide therapy. HER2 seems not to be of such interest due to rare expression, neither HER3 due to mainly expression in the cytoplasm. The requirements for successful EGFR targeted radionuclide therapy are discussed, as well as patient inclusion criteria related to radionuclide therapy.

  15. Differential impact of transplantation on peripheral and tissue-associated viral reservoirs: Implications for HIV gene therapy.

    Science.gov (United States)

    Peterson, Christopher W; Wang, Jianbin; Deleage, Claire; Reddy, Sowmya; Kaur, Jasbir; Polacino, Patricia; Reik, Andreas; Huang, Meei-Li; Jerome, Keith R; Hu, Shiu-Lok; Holmes, Michael C; Estes, Jacob D; Kiem, Hans-Peter

    2018-04-01

    Autologous transplantation and engraftment of HIV-resistant cells in sufficient numbers should recapitulate the functional cure of the Berlin Patient, with applicability to a greater number of infected individuals and with a superior safety profile. A robust preclinical model of suppressed HIV infection is critical in order to test such gene therapy-based cure strategies, both alone and in combination with other cure strategies. Here, we present a nonhuman primate (NHP) model of latent infection using simian/human immunodeficiency virus (SHIV) and combination antiretroviral therapy (cART) in pigtail macaques. We demonstrate that transplantation of CCR5 gene-edited hematopoietic stem/progenitor cells (HSPCs) persist in infected and suppressed animals, and that protected cells expand through virus-dependent positive selection. CCR5 gene-edited cells are readily detectable in tissues, namely those closely associated with viral reservoirs such as lymph nodes and gastrointestinal tract. Following autologous transplantation, tissue-associated SHIV DNA and RNA levels in suppressed animals are significantly reduced (p ≤ 0.05), relative to suppressed, untransplanted control animals. In contrast, the size of the peripheral reservoir, measured by QVOA, is variably impacted by transplantation. Our studies demonstrate that CCR5 gene editing is equally feasible in infected and uninfected animals, that edited cells persist, traffic to, and engraft in tissue reservoirs, and that this approach significantly reduces secondary lymphoid tissue viral reservoir size. Our robust NHP model of HIV gene therapy and viral persistence can be immediately applied to the investigation of combinatorial approaches that incorporate anti-HIV gene therapy, immune modulators, therapeutic vaccination, and latency reversing agents.

  16. Experiences of mobility for people living with rheumatoid arthritis who are receiving biologic drug therapy: implications for podiatry services

    OpenAIRE

    Sanders, Lucy; Donovan-Hall, Margaret; Borthwick, Alan; Bowen, Catherine J.

    2017-01-01

    Background Despite significant advancements in new treatment modalities for rheumatoid arthritis with biological therapies, foot complications remain a disabling and common feature of the disease. In this study the aim was to explore and describe the personal experiences of people with rheumatoid arthritis in receipt of biologic treatments in a bid to understand the impact of this form of medication on their mobility. Methods An interpretative phenomenological analysis (IPA) was undertaken to...

  17. Continuity in the provider of home-based physical therapy services and its implications for outcomes of patients.

    Science.gov (United States)

    Russell, David; Rosati, Robert J; Andreopoulos, Evie

    2012-02-01

    A growing body of research suggests that greater continuity of health care is positively associated with improved outcomes of patients. However, few studies have examined this issue in the context of physical therapy. The purpose of this study was to evaluate whether the level of continuity in the provider (provider continuity) of physical therapy services was related to outcomes in a population of patients receiving home health care. This was a retrospective observational study. Clinical and administrative records were retrieved for a population of adult patients receiving physical therapy services from a large, urban, not-for-profit certified home health care agency in 2009. Descriptive and multivariable analyses were used to examine how the level of provider continuity, calculated by use of a formula that models dispersion in contact between the patient and the providers of physical therapy services, varied across characteristics and outcomes of patients. Logistic regression analyses indicated that patients with lower levels of provider continuity had significantly higher odds of hospitalization (odds ratio [OR]=2.06, 95% confidence interval [CI]=1.90-2.23) and lower odds of improvements in the number of activity limitations (OR=0.85, 95% CI=0.80-0.92) and in the severity of activity limitations (OR=0.85, 95% CI=0.78-0.93) between the beginning and the end of the home health care episode. Baseline clinical characteristics associated with continuity of care suggest some level of indication bias. Outcome measures for activities of daily living were limited to patients who were not hospitalized during their home health stay. These findings build upon research suggesting that continuity in the patient-provider relationship is an important determinant of outcomes of patients.

  18. T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy

    DEFF Research Database (Denmark)

    Andersen, Rikke; Westergaard, Marie Christine Wulff; Kjeldsen, Julie Westerlin

    2018-01-01

    . Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8+ TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality......-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. Cancer Immunol Res; 1-14. ©2018 AACR....

  19. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance.

    Science.gov (United States)

    Bekele, Raie T; Venkatraman, Ganesh; Liu, Rong-Zong; Tang, Xiaoyun; Mi, Si; Benesch, Matthew G K; Mackey, John R; Godbout, Roseline; Curtis, Jonathan M; McMullen, Todd P W; Brindley, David N

    2016-02-17

    Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer.

  20. A critique of the representation of human suffering in the cognitive behavioural therapy literature with implications for mental health nursing practice.

    Science.gov (United States)

    Grant, A

    2011-02-01

    This paper is informed by interpretivist understandings and practices, and the author's own conversion to interpretivist writing practice. The aim of the paper is to critique the ways in which suffering people are represented in the mainstream cognitive behavioural therapy (CBT) literature with a view to identifying some implications for mental health nursing practice. It will begin by identifying key assumptions governing the textual portrayal of human experience, and will argue that the language used to describe human suffering is a potential site for struggles over meaning and more adequate representation. However, reductionist portrayals of individuals and their problems have largely gone unchallenged in much of the CBT literature since its early development in the 1970s. This is arguably because of the socialization of new members of the CBT community into established cultural and textual practices. A comparison of reductionist CBT writing with more fleshed out, more fully human possibilities will further clarify that forms of representation are never neutral, given the danger of reductionist representations facilitating reductionist interventions. The paper will end with the following emerging implications for mental health nursing practice: the therapeutic power of self-narratives, narrative research and the recovery movement, and the promising possibilities for autoethnographic research for mental health nurses and for day to day interactions between nurses and service users. © 2010 Blackwell Publishing.

  1. Spectral domain optical coherence tomographic analysis of healthy retina in branch retinal vein occlusion and its response to antiangiogenic therapy.

    Science.gov (United States)

    Salcedo-Villanueva, Guillermo; Harasawa, Mariana; Velez-Montoya, Raul; Mathias, Marc T; Siringo, Frank S; Olson, Jeffrey L; Oliver, Scott C; Mandava, Naresh; Quiroz-Mercado, Hugo

    2015-04-01

    To propose a model that measures the effect of intravitreal bevacizumab (IVB) on relatively healthy retina. The purpose is to analyze the remote effect of a branch retinal vein occlusion in the healthy retina, to determine the response it may have to IVB, and to determine if IVB has an atrophic effect on the healthy retina. Retrospective, longitudinal comparative analysis of patients with branch retinal vein occlusion treated with IVB. Eyes were divided into experimental (branch retinal vein occlusion eye) and control (contralateral eye) groups. Each eye was analyzed for thickness and area. Thickness measurements were performed for total retinal thickness, inner retina thickness, and outer retina thickness. Area was measured for photoreceptors, choroid, and total retina. Eighteen eyes of 9 patients. For thickness analysis, 1,050 scans were studied, and 126 measurements were performed on 42 scans for area analysis. No difference was observed for thickness, except for inner retina thickness. No difference was observed for area. No difference was observed when analyzing a cumulative exposure to IVB. There is no evidence to suggest an atrophic effect caused by IVB when analyzing thickness or area in this experiment. This model could be used to analyze the long-term safety of IVB in larger studies.

  2. Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling

    Directory of Open Access Journals (Sweden)

    Elizabeth Allen

    2016-05-01

    Full Text Available Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.

  3. Contextual factors of the ICF as a tool for analysis of the implications of physical disability for a group of patients under Occupational Therapy care

    Directory of Open Access Journals (Sweden)

    Rosé Colom Toldrá

    2014-09-01

    Full Text Available This article analyzes the implications of the acquisition of physical disability on everyday life situations of persons under occupational therapy care using the International Classification of Functioning, Disability and Health – ICF, with emphasis on contextual factors. The study included 11 adults and elderly with physical impairments resulting from neurological disorders who were under Occupational Therapy care at the Center for Teaching and Research at the University of Sao Paulo from 2009 to 2010. It’s an exploratory qualitative research conducted through documentary study and semi-structured interview for the administration of the ICF components. Changes in body functions are diverse, both mental and related to movement, and when coupled with contextual factors may result in different levels and types of disabilities, preventing participation in life situations. The analysis of contextual factors helps to identify and relate personal and environmental aspects and their dynamic interaction reflects processes that may cause disability, establishing the ICF as a valuable guide for research and development of rehabilitation practices that consider the different aspects of the reality of a person’s life.

  4. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  5. [Management of side effects of targeted therapies in renal cancer: stomatological side effects (mucositis, epistaxis)].

    Science.gov (United States)

    Agbo-Godeau, Scarlette; Nicolas-Virelizier, Emmanuelle; Scotté, Florian

    2011-01-01

    The advent of targeted therapies in the treatment of renal cancer has shown different types of lesions of the oral cavity, which appear to be specific to the drug classes used (mTOR inhibitors, anti-angiogenic agents and conventional cytotoxic drugs). Before starting treatment with targeted therapy, it is essential to have an oral and a dental examination. The treatment of mucositis induced by targeted therapies is based on bicarbonate-based mouthwash, with the optional addition of an antifungal or a local antiseptic. It is possible to use topical or systemic analgesics for the pain. Dietary advice for patients is also useful. Most cases of epistaxis caused by anti-angiogenics stop spontaneously and require no medical intervention. Regular application of an emollient can be used to prevent the formation of scabs. Copyright © 2011 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  6. Dose reduction of scattered photons from concrete walls lined with lead: Implications for improvement in design of megavoltage radiation therapy facility mazes.

    Science.gov (United States)

    Al-Affan, I A M; Hugtenburg, R P; Bari, D S; Al-Saleh, W M; Piliero, M; Evans, S; Al-Hasan, M; Al-Zughul, B; Al-Kharouf, S; Ghaith, A

    2015-02-01

    This study explores the possibility of using lead to cover part of the radiation therapy facility maze walls in order to absorb low energy photons and reduce the total dose at the maze entrance of radiation therapy rooms. Experiments and Monte Carlo simulations were utilized to establish the possibility of using high-Z materials to cover the concrete walls of the maze in order to reduce the dose of the scattered photons at the maze entrance. The dose of the backscattered photons from a concrete wall was measured for various scattering angles. The dose was also calculated by the FLUKA and EGSnrc Monte Carlo codes. The FLUKA code was also used to simulate an existing radiotherapy room to study the effect of multiple scattering when adding lead to cover the concrete walls of the maze. Monoenergetic photons were used to represent the main components of the x ray spectrum up to 10 MV. It was observed that when the concrete wall was covered with just 2 mm of lead, the measured dose rate at all backscattering angles was reduced by 20% for photons of energy comparable to Co-60 emissions and 70% for Cs-137 emissions. The simulations with FLUKA and EGS showed that the reduction in the dose was potentially even higher when lead was added. One explanation for the reduction is the increased absorption of backscattered photons due to the photoelectric interaction in lead. The results also showed that adding 2 mm lead to the concrete walls and floor of the maze reduced the dose at the maze entrance by up to 90%. This novel proposal of covering part or the entire maze walls with a few millimeters of lead would have a direct implication for the design of radiation therapy facilities and would assist in upgrading the design of some mazes, especially those in facilities with limited space where the maze length cannot be extended to sufficiently reduce the dose. © 2015 American Association of Physicists in Medicine.

  7. AAV Vector-Mediated Gene Delivery to Substantia Nigra Dopamine Neurons: Implications for Gene Therapy and Disease Models

    Directory of Open Access Journals (Sweden)

    Katrina Albert

    2017-02-01

    Full Text Available Gene delivery using adeno-associated virus (AAV vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson′s disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson′s disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson′s disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson′s disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV-a-synuclein (a-syn to target substantia nigra dopamine neurons to produce an α-syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP, which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in

  8. Dosimetric Implications of an Injection of Hyaluronic Acid for Preserving the Rectal Wall in Prostate Stereotactic Body Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Chapet, Olivier, E-mail: olivier.chapet@chu-lyon.fr [Department of Radiation Oncology, Centre Hospitalier Lyon Sud, Pierre Benite (France); Udrescu, Corina [Department of Radiation Oncology, Centre Hospitalier Lyon Sud, Pierre Benite (France); Department of Medical Physics, Centre Hospitalier Lyon Sud, Pierre Benite (France); Tanguy, Ronan [Department of Radiation Oncology, Centre Hospitalier Lyon Sud, Pierre Benite (France); Ruffion, Alain [Department of Urology, Centre Hospitalier Lyon Sud, Pierre Benite (France); Fenoglietto, Pascal [Department of Radiation Oncology, Centre Val d' Aurelle, Montpellier (France); Sotton, Marie-Pierre [Department of Medical Physics, Centre Hospitalier Lyon Sud, Pierre Benite (France); Devonec, Marian [Department of Urology, Centre Hospitalier Lyon Sud, Pierre Benite (France); Colombel, Marc [Department of Urology, Hopital Edouard Herriot, Lyon (France); Jalade, Patrice [Department of Medical Physics, Centre Hospitalier Lyon Sud, Pierre Benite (France); Azria, David [Department of Radiation Oncology, Centre Val d' Aurelle, Montpellier (France)

    2014-02-01

    Purpose: This study assessed the contribution of ahyaluronic acid (HA) injection between the rectum and the prostate to reducing the dose to the rectal wall in stereotactic body radiation therapy (SBRT). Methods and Materials: As part of a phase 2 study of hypofractionated radiation therapy (62 Gy in 20 fractions), the patients received a transperineal injection of 10 cc HA between the rectum and the prostate. A dosimetric computed tomographic (CT) scan was systematically performed before (CT1) and after (CT2) the injection. Two 9-beam intensity modulated radiation therapy-SBRT plans were optimized for the first 10 patients on both CTs according to 2 dosage levels: 5 × 6.5 Gy (PlanA) and 5 × 8.5 Gy (PlanB). Rectal wall parameters were compared with a dose–volume histogram, and the prostate–rectum separation was measured at 7 levels of the prostate on the center line of the organ. Results: For both plans, the average volume of the rectal wall receiving the 90% isodose line (V90%) was reduced up to 90% after injection. There was no significant difference (P=.32) between doses received by the rectal wall on CT1 and CT2 at the base of the prostate. This variation became significant from the median plane to the apex of the prostate (P=.002). No significant differences were found between PlanA without HA and PlanB with HA for each level of the prostate (P=.77, at the isocenter of the prostate). Conclusions: HA injection significantly reduced the dose to the rectal wall and allowed a dose escalation from 6.5 Gy to 8.5 Gy without increasing the dose to the rectum. A phase 2 study is under way in our department to assess the rate of acute and late rectal toxicities when SBRT (5 × 8.5 Gy) is combined with an injection of HA.

  9. Dosimetric Implications of an Injection of Hyaluronic Acid for Preserving the Rectal Wall in Prostate Stereotactic Body Radiation Therapy

    International Nuclear Information System (INIS)

    Chapet, Olivier; Udrescu, Corina; Tanguy, Ronan; Ruffion, Alain; Fenoglietto, Pascal; Sotton, Marie-Pierre; Devonec, Marian; Colombel, Marc; Jalade, Patrice; Azria, David

    2014-01-01

    Purpose: This study assessed the contribution of ahyaluronic acid (HA) injection between the rectum and the prostate to reducing the dose to the rectal wall in stereotactic body radiation therapy (SBRT). Methods and Materials: As part of a phase 2 study of hypofractionated radiation therapy (62 Gy in 20 fractions), the patients received a transperineal injection of 10 cc HA between the rectum and the prostate. A dosimetric computed tomographic (CT) scan was systematically performed before (CT1) and after (CT2) the injection. Two 9-beam intensity modulated radiation therapy-SBRT plans were optimized for the first 10 patients on both CTs according to 2 dosage levels: 5 × 6.5 Gy (PlanA) and 5 × 8.5 Gy (PlanB). Rectal wall parameters were compared with a dose–volume histogram, and the prostate–rectum separation was measured at 7 levels of the prostate on the center line of the organ. Results: For both plans, the average volume of the rectal wall receiving the 90% isodose line (V90%) was reduced up to 90% after injection. There was no significant difference (P=.32) between doses received by the rectal wall on CT1 and CT2 at the base of the prostate. This variation became significant from the median plane to the apex of the prostate (P=.002). No significant differences were found between PlanA without HA and PlanB with HA for each level of the prostate (P=.77, at the isocenter of the prostate). Conclusions: HA injection significantly reduced the dose to the rectal wall and allowed a dose escalation from 6.5 Gy to 8.5 Gy without increasing the dose to the rectum. A phase 2 study is under way in our department to assess the rate of acute and late rectal toxicities when SBRT (5 × 8.5 Gy) is combined with an injection of HA

  10. Cellular Response to Exponentially Increasing and Decreasing Dose Rates: Implications for Treatment Planning in Targeted Radionuclide Therapy.

    Science.gov (United States)

    Solanki, Jay H; Tritt, Thomas; Pasternack, Jordan B; Kim, Julia J; Leung, Calvin N; Domogauer, Jason D; Colangelo, Nicholas W; Narra, Venkat R; Howell, Roger W

    2017-08-01

    The treatment of cancer using targeted radionuclide therapy is of interest to nuclear medicine and radiation oncology because of its potential for killing tumor cells while minimizing dose-limiting toxicities to normal tissue. The ionizing radiations emitted by radiopharmaceuticals deliver radiation absorbed doses over protracted periods of time with continuously varying dose rates. As targeted radionuclide therapy becomes a more prominent part of cancer therapy, accurate models for estimating the biologically effective dose (BED) or equieffective dose (EQD2 α/β ) will become essential for treatment planning. This study examines the radiobiological impact of the dose rate increase half-time during the uptake phase of the radiopharmaceutical. MDA-MB-231 human breast cancer cells and V79 Chinese hamster lung fibroblasts were irradiated chronically with 662 keV γ rays delivered with time-varying dose rates that are clinically relevant. The temporal dose-rate patterns were: 1. acute, 2. exponential decrease with a half-time of 64 h (T d = 64 h), 3. initial exponential increase to a maximum (half time T i = 2, 8 or 24 h) followed by exponential decrease (T d = 64 h). Cell survival assays were conducted and surviving fractions were determined. There was a marked reduction in biological effect when T i was increased. Cell survival data were tested against existing dose-response models to assess their capacity to predict response. Currently accepted models that are used in radiation oncology overestimated BED and EQD2 α/β at low-dose rates and underestimated them at high-dose rates. This appears to be caused by an adaptive response arising as a consequence of the initial low-dose-rate phase of exposure. An adaptive response function was derived that yields more accurate BED and EQD2 α/β values over the spectrum of dose rates and absorbed doses delivered. Our experimental data demonstrate a marked increase in cell survival when the dose-rate-increase half-time is

  11. Endoglin as a target of antitumor therapy 

    Directory of Open Access Journals (Sweden)

    Magdalena Jarosz

    2013-02-01

    Full Text Available Blood vascular supply significantly affects progression of tumor growth. Inhibition of endothelial cell proliferation by antiangiogenic drugs should lead to growth arrest of both primary tumors and metastases. During the course of lengthy therapy, endothelial cells may, however, become refractory to the action of antiangiogenic agents. Novel approaches to anticancer treatment should explore the issue of drug resistance shown by endothelial cells. One possible therapeutic solution might be tumor immunotherapy directed against antigens expressed on the surface of endothelial cells which co-form tumor blood vasculature. Such therapy is supposed to break immune tolerance to own antigens and to eliminate tumor blood vessel endothelial cells by activating cytotoxic T lymphocytes. This kind of response can be obtained against endoglin (CD105. Endoglin is overexpressed in proliferating endothelial cells which line tumor blood vessels. Presence of endoglin in solid tumor blood vessels has prognostic value in cancer treatment. CD105 is also expressed by certain cancer cells (prostate, melanoma and Ewing sarcoma. It appears that therapeutic strategies directed against endoglin allow several mechanisms of resistance to antiangiogenic drugs to be omitted. The therapeutic approach that we propose, i.e. a tumor blood vessel-destroying strategy combined with immunotherapy, may become an effective therapeutic tool. 

  12. Randomized phase II trial of urethral sparing intensity modulated radiation therapy in low-risk prostate cancer: implications for focal therapy

    Directory of Open Access Journals (Sweden)

    Vainshtein Jeffrey

    2012-06-01

    Full Text Available Abstract Background Low-risk prostate cancer (PCa patients have excellent outcomes, with treatment modality often selected by perceived effects on quality of life. Acute urinary symptoms are common during external beam radiotherapy (EBRT, while chronic symptoms have been linked to urethral dose. Since most low-risk PCa occurs in the peripheral zone (PZ, we hypothesized that EBRT using urethral sparing intensity modulated radiation therapy (US-IMRT could improve urinary health-related quality of life (HRQOL while maintaining high rates of PCa control. Methods Patients with National Comprehensive Cancer Network (NCCN defined low-risk PCa with no visible lesion within 5 mm of the prostatic urethra on MRI were randomized to US-IMRT or standard (S- IMRT. Prescription dose was 75.6 Gy in 41 fractions to the PZ + 3–5 mm for US-IMRT and to the prostate + 3 mm for S-IMRT. For US-IMRT, mean proximal and distal urethral doses were limited to 65 Gy and 74 Gy, respectively. HRQOL was assessed using the Expanded Prostate Cancer Index (EPIC Quality of Life questionnaire. The primary endpoint was change in urinary HRQOL at 3 months. Results From June 2004 to November 2006, 16 patients were randomized, after which a futility analysis concluded that continued accrual was unlikely to demonstrate a difference in the primary endpoint. Mean change in EPIC urinary HRQOL at 3 months was −0.5 ± 11.2 in the US-IMRT arm and +3.9 ± 15.3 in the S-IMRT arm (p = 0.52. Median PSA nadir was higher in the US-IMRT arm (1.46 vs. 0.78, p = 0.05. At 4.7 years median follow-up, three US-IMRT and no S-IMRT patients experienced PSA failure (p = 0.06; HR 8.8, 95% CI 0.9–86. Two out of 3 patients with PSA failure had biopsy-proven local failure, both located contralateral to the original site of disease. Conclusions Compared with S-IMRT, US-IMRT failed to improve urinary HRQOL and resulted in higher PSA nadir and inferior biochemical

  13. Mathematical modeling of the implications of dominant tolerance for tumor biology and the response to combination therapy

    International Nuclear Information System (INIS)

    Leon, Kalet; Garcia, Karina; Lage, Agustin

    2008-01-01

    The existence of regulatory T lymphocytes (Tregs) that can control effector lymphocytes within the context of autoimmune, infectious and tumoral diseases is definitely accepted in current immunological research. Tregs confirm the theory of dominant tolerance, which holds that the choice of antigen rejection or tolerance in the immune system is the result of a dynamic equilibrium between populations of effector and regulatory T lymphocytes. The present paper summarizes the result of a recent theoretical study using mathematical modeling to analyze the dynamic interplay between T lymphocyte populations in the absence or presence of tumors and in response to different therapeutic treatments. The resulting model, developed at the Center of Molecular Immunology, which received an award from the Cuban Academy of Sciences in 2002, includes tumor cells and can simulate the effect of antitumoral mono- or combination therapies, by taking into account the way in which certain dynamic properties of tumors can, under specific circumstances, lead to the spontaneous expansion of Tregs populations. One of the advantages of the model is the prediction of several new strategies for the differential treatment of tumors, depending upon their ability of inducing the expansion of regulatory T cells. This is the first model available for the study of the impact of Tregs on the growth of malignant tumors, with results supported by international publications. Additionally, the model predicts the practical effects of several combination therapies, including vaccines, the excision of the tumor and depletion of lymphocyte populations. (Author)

  14. A review of mind/body therapies in the treatment of musculoskeletal disorders with implications for the elderly.

    Science.gov (United States)

    Luskin, F M; Newell, K A; Griffith, M; Holmes, M; Telles, S; DiNucci, E; Marvasti, F F; Hill, M; Pelletier, K R; Haskell, W L

    2000-03-01

    A comprehensive, but not systematic, review of the research on complementary and alternative treatments, specifically mind/body techniques, on musculoskeletal disease was conducted at Stanford University. The goals of the review were to establish a comprehensive literature review and provide a rationale for future research carrying the theme of "successful aging." Computerized searches were conducted using MEDLINE, PsychInfo, Stanford Library, Dissertation Abstracts, Lexus-Nexus, the Internet as well as interviews conducted with practitioners and the elderly. Mind/body practices evaluated were: social support, cognitive-behavioral therapy, meditation, the placebo effect, imagery, visualization, spiritual/energy healing, music therapy, hypnosis, yoga, tai chi, and qigong. Studies published after 1990 were the priority, but when more recent literature was scarce, other controlled studies were included. Mind/body techniques were found to be efficacious primarily as complementary treatments for musculoskeletal disease and related disorders. Studies provided evidence for treatment efficacy but most apparent was the need for further controlled research. Reviewers found a dearth of randomized controlled research conducted in the US. There is a lack of studies with which to determine appropriate dosage and understand the mechanisms by which many of the practices work. Anecdotal evidence, some controlled research, clinical observation, as well as the cost effectiveness and lack of side effects of the mind/body treatments make further investigation a high priority.

  15. Model-based, semiquantitative and time intensity curve shape analysis of dynamic contrast-enhanced MRI: a comparison in patients undergoing antiangiogenic treatment for recurrent glioma

    NARCIS (Netherlands)

    Lavini, Cristina; Verhoeff, Joost J. C.; Majoie, Charles B.; Stalpers, Lukas J. A.; Richel, Dick J.; Maas, Mario

    2011-01-01

    To compare time intensity curve (TIC)-shape analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data with model-based analysis and semiquantitative analysis in patients with high-grade glioma treated with the antiangiogenic drug bevacizumab. Fifteen patients had a pretreatment

  16. Synergistic effect of anti-angiogenic herbal composition (Meta-X) in combination with radiotherapy on the inhibition of tumor growth

    International Nuclear Information System (INIS)

    Han, Young Soo; Song, Jie Young; Yoon, Yeon Sook; Kim, Joon Sik; Park, Byung Young; Lee, Hee Suk; Kim, Min Yung

    2004-01-01

    Anti-angiogenic composition called Meta-X was made from herbal medicines that are currently used oral drugs for other indications. We examined biochemical properties of Meta-X, and synergistic effect of Meta-X combined with irradiation on the inhibition of tumor growth

  17. Time until initiation of tumor growth is an effective measure of the anti-angiogenic effect of TNP-470 on human glioblastoma in nude mice

    DEFF Research Database (Denmark)

    Kragh, M; Spang-Thomsen, M; Kristjansen, P E

    1999-01-01

    We examined the effect of the anti-angiogenic compound TNP-470 on early tumor growth characteristics following subcutaneous implantation of 1 mm3 tissue blocks of human glioblastoma U87, in nude mice. The mice received daily injections with TNP-470, 7 mg/kg, from one day before until either 3, 7...

  18. Differential expression of anti-angiogenic factors and guidance genes in the developing macula.

    Science.gov (United States)

    Kozulin, Peter; Natoli, Riccardo; O'Brien, Keely M Bumsted; Madigan, Michele C; Provis, Jan M

    2009-01-01

    The primate retina contains a specialized, cone-rich macula, which mediates high acuity and color vision. The spatial resolution provided by the neural retina at the macula is optimized by stereotyped retinal blood vessel and ganglion cell axon patterning, which radiate away from the macula and reduce shadowing of macular photoreceptors. However, the genes that mediate these specializations, and the reasons for the vulnerability of the macula to degenerative disease, remain obscure. The aim of this study was to identify novel genes that may influence retinal vascular patterning and definition of the foveal avascular area. We used RNA from human fetal retinas at 19-20 weeks of gestation (WG; n=4) to measure differential gene expression in the macula, a region nasal to disc (nasal) and in the surrounding retina (surround) by hybridization to 12 GeneChip microarrays (HG-U133 Plus 2.0). The raw data was subjected to quality control assessment and preprocessing, using GC-RMA. We then used ANOVA analysis (Partek) Genomic Suite 6.3) and clustering (DAVID website) to identify the most highly represented genes clustered according to "biological process." The neural retina is fully differentiated at the macula at 19-20 WG, while neuronal progenitor cells are present throughout the rest of the retina. We therefore excluded genes associated with the cell cycle, and markers of differentiated neurons, from further analyses. Significantly regulated genes (pmacula versus surround" and "macula versus nasal." KEGG pathway clustering of the filtered gene lists identified 25 axon guidance-related genes that are differentially regulated in the macula. Furthermore, we found significant upregulation of three anti-angiogenic factors in the macula: pigment epithelium derived factor (PEDF), natriuretic peptide precurusor B (NPPB), and collagen type IValpha2. Differential expression of several members of the ephrin and semaphorin axon guidance gene families, PEDF, and NPPB was verified by

  19. Incorporating Cancer Stem Cells in Radiation Therapy Treatment Response Modeling and the Implication in Glioblastoma Multiforme Treatment Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Victoria Y.; Nguyen, Dan; Pajonk, Frank; Kupelian, Patrick; Kaprealian, Tania; Selch, Michael; Low, Daniel A.; Sheng, Ke, E-mail: ksheng@mednet.ucla.edu

    2015-03-15

    Purpose: To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model. Methods and Materials: The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non–small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated. Results: Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations. Conclusion: The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from

  20. Physician Decisions to Defer Antiretroviral Therapy in Key Populations: Implications for Reducing Human Immunodeficiency Virus Incidence and Mortality in Malaysia.

    Science.gov (United States)

    Ferro, Enrico G; Culbert, Gabriel J; Wickersham, Jeffrey A; Marcus, Ruthanne; Steffen, Alana D; Pauls, Heather A; Westergaard, Ryan P; Lee, Christopher K; Kamarulzaman, Adeeba; Altice, Frederick L

    2017-01-01

    Antiretroviral therapy (ART) is recommended for all people living with human immunodeficiency virus (HIV), yet physician attitudes and prescribing behaviors toward members of key risk populations may limit ART access and undermine treatment as prevention strategies. Physicians in Malaysia (N = 214) who prescribe antiretroviral therapy (ART) responded in an Internet-based survey to hypothetical clinical scenarios of HIV patients, varying by key risk population and CD4 + T-cell count, on whether they would initiate or defer ART compared with a control patient with sexually acquired HIV. The proportion of physicians who would defer ART in patients with advanced HIV (CD4 = 17 cells/μL) was significantly higher ( P social support (26.6%), compared with a control patient (4.2%). People who inject drugs with advanced HIV (CD4 = 17 cells/μL) were 19-fold (adjusted odds ratio [AOR] = 18.9; 95% confidence interval [CI], 9.8-36.5) more likely to have ART deferred compared with the control. This effect was partially mitigated for PWID receiving methadone (AOR = 2.9; 95% CI, 1.5-5.7). At the highest CD4 + T-cell count (CD4 = 470 cells/μL), sex workers (AOR = 0.55; 95% CI, .44-.70) and patients with an HIV-uninfected sexual partner (AOR = 0.43; 95% CI, .34-.57) were significantly less likely to have ART deferred. Physicians who prescribe antiretroviral therapy in Malaysia may defer ART in some key populations including PWID and released prisoners, regardless of CD4 + T-cell count, which may help to explain very low rates of ART coverage among PWID in Malaysia. Reducing HIV incidence and mortality in Malaysia, where HIV is concentrated in PWID and other key populations, requires clinician-level interventions and monitoring physician adherence to international evidence-based treatment guidelines. © The Author 2017. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

  1. Epigenetic modulation of cancer-germline antigen gene expression in tumorigenic human mesenchymal stem cells: implications for cancer therapy

    DEFF Research Database (Denmark)

    Gjerstorff, Morten; Burns, Jorge S; Nielsen, Ole

    2009-01-01

    Cancer-germline antigens are promising targets for cancer immunotherapy, but whether such therapies will also eliminate the primary tumor stem cell population remains undetermined. We previously showed that long-term cultures of telomerized adult human bone marrow mesenchymal stem cells can...... spontaneously evolve into tumor-initiating, mesenchymal stem cells (hMSC-TERT20), which have characteristics of clinical sarcoma cells. In this study, we used the hMSC-TERT20 tumor stem cell model to investigate the potential of cancer-germline antigens to serve as tumor stem cell targets. We found...... of cancer-germline antigens in hMSC-TERT20 cells, while their expression levels in primary human mesenchymal stem cells remained unaffected. The expression pattern of cancer-germline antigens in tumorigenic mesenchymal stem cells and sarcomas, plus their susceptibility to enhancement by epigenetic...

  2. Cognitive behaviour therapy response and dropout rate across purging and nonpurging bulimia nervosa and binge eating disorder: DSM-5 implications

    Science.gov (United States)

    2013-01-01

    Background With the imminent publication of the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), there has been a growing interest in the study of the boundaries across the three bulimic spectrum syndromes [bulimia nervosa-purging type (BN-P), bulimia nervosa-non purging type (BN-NP) and binge eating disorder (BED)]. Therefore, the aims of this study were to determine differences in treatment response and dropout rates following Cognitive Behavioural Therapy (CBT) across the three bulimic-spectrum syndromes. Method The sample comprised of 454 females (87 BED, 327 BN-P and 40 BN-NP) diagnosed according to DSM-IV-TR criteria who were treated with 22 weekly outpatient sessions of group CBT therapy. Patients were assessed before and after treatment using a food and binging/purging diary and some clinical questionnaires in the field of ED. “Full remission” was defined as total absence of binging and purging (laxatives and/or vomiting) behaviors and psychological improvement for at least 4 (consecutive). Results Full remission rate was found to be significantly higher in BED (69.5%) than in both BN-P (p < 0.005) and BN-NP (p < 0.001), which presented no significant differences between them (30.9% and 35.5%). The rate of dropout from group CBT was also higher in BED (33.7%) than in BN-P (p < 0.001) and BN-NP (p < 0.05), which were similar (15.4% and 12.8%, respectively). Conclusions Results suggest that purging and non-purging BN have similar treatment response and dropping out rates, whereas BED appears as a separate diagnosis with better outcome for those who complete treatment. The results support the proposed new DSM-5 classification PMID:24200085

  3. Gut microbiota and hepatitis-B-virus-induced chronic liver disease: implications for faecal microbiota transplantation therapy.

    Science.gov (United States)

    Kang, Y; Cai, Y

    2017-08-01

    Hepatitis B is one of the most common infectious diseases globally. It has been estimated that there are 350 million chronic hepatitis B virus (HBV) carriers worldwide. The liver is connected to the small intestine by the bile duct, which carries bile formed in the liver to the intestine. Nearly all of the blood that leaves the stomach and intestines must pass through the liver. Human intestines contain a wide diversity of microbes, collectively termed the 'gut microbiota'. Gut microbiota play a significant role in host metabolic processes and host immune modulation, and influence host development and physiology (organ development). Altered gut microbiota is a common complication in liver disease. Changes in intestinal microbiota seem to play an important role in induction and promotion of HBV-induced chronic liver disease progression, and specific species among the intestinal commensal bacteria may play either a pathogenic or a protective role in the development of HBV-induced chronic liver disease. Thus, the gut microbiome may represent fertile targets for prevention or management of HBV-induced chronic liver disease. Faecal microbiota transplantation (FMT) may be a useful therapy for HBV-related disease in the future. However, the data available in this field remain limited, and relevant scientific work has only just commenced. New technologies have enabled systematic studies of gut microbiota, and provided more realistic information about its composition and pathological variance. This review summarizes the cutting edge of research into the relationship between gut microbiota and HBV-induced chronic liver disease, and the future prospects of FMT therapy. Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  4. Treatment mechanism in the MRC preschool autism communication trial: implications for study design and parent-focussed therapy for children.

    Science.gov (United States)

    Pickles, Andrew; Harris, Victoria; Green, Jonathan; Aldred, Catherine; McConachie, Helen; Slonims, Vicky; Le Couteur, Ann; Hudry, Kristelle; Charman, Tony

    2015-02-01

    The PACT randomised-controlled trial evaluated a parent-mediated communication-focused treatment for children with autism, intended to reduce symptom severity as measured by a modified Autism Diagnostic Observation Schedule-Generic (ADOS-G) algorithm score. The therapy targeted parental behaviour, with no direct interaction between therapist and child. While nonsignificant group differences were found on ADOS-G score, significant group differences were found for both parent and child intermediate outcomes. This study aimed to better understand the mechanism by which the PACT treatment influenced changes in child behaviour though the targeted parent behaviour. Mediation analysis was used to assess the direct and indirect effects of treatment via parent behaviour on child behaviour and via child behaviour on ADOS-G score. Alternative mediation was explored to study whether the treatment effect acted as hypothesised or via another plausible pathway. Mediation models typically assume no unobserved confounding between mediator and outcome and no measurement error in the mediator. We show how to better exploit the information often available within a trial to begin to address these issues, examining scope for instrumental variable and measurement error models. Estimates of mediation changed substantially when account was taken of the confounder effects of the baseline value of the mediator and of measurement error. Our best estimates that accounted for both suggested that the treatment effect on the ADOS-G score was very substantially mediated by parent synchrony and child initiations. The results highlighted the value of repeated measurement of mediators during trials. The theoretical model underlying the PACT treatment was supported. However, the substantial fall-off in treatment effect highlighted both the need for additional data and for additional target behaviours for therapy. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for

  5. Canine Mesenchymal Stem Cell Potential and the Importance of Dog Breed: Implication for Cell-Based Therapies.

    Science.gov (United States)

    Bertolo, Alessandro; Steffen, Frank; Malonzo-Marty, Cherry; Stoyanov, Jivko

    2015-01-01

    The study of canine bone marrow-derived mesenchymal stem cells (MSCs) has a prominent position in veterinary cell-based applications. Yet the plethora of breeds, their different life spans, and interbreed variations provide unclearness on what can be achieved specifically by such therapies. In this study, we compared a set of morphological, physiological, and genetic markers of MSCs derived from large dog breeds, namely, Border collie, German shepherd, Labrador, Malinois, Golden retriever, and Hovawart. We compared colony-forming units (CFUs) assay, population doubling time (PDT), senescence-associated β-galactosidase (SA-β-gal) activity, telomere length, and gene expression of MSCs, as well as the ability of cells to differentiate to osteogenic, adipogenic, and chondrogenic phenotypes. The influence of the culture media α-MEM, low-glucose DMEM, and high-glucose DMEM, used in cell isolation and expansion, was investigated in the presence and absence of basic fibroblast growth factor (bFGF). Initial cell yield was not affected by culturing medium, but MSCs expanded best in α-MEM supplemented with bFGF. After isolation, the number of MSCs was similar among breeds--as shown by equivalent CFUs--except in the Hovawart samples, which had fivefold less CFU. Telomere lengths were similar among breeds. MSCs divided actively only for 4 weeks in culture (PDT = ∼50 h/division), except Border collie cells divided for a longer time than cells from other groups. The percentage of senescent cells increased linearly in all breeds with time, with a faster rate in German shepherd, Labrador, and Golden retriever. Border collie cells underwent efficient osteogenic differentiation, Hovawart cells performed the best in chondrogenic differentiation, and Labrador cells in both, while German shepherd cells had the lower differentiation potential. MSCs from all breeds preserved the same adipogenic differentiation potential. In conclusion, despite variations, isolated MSCs can be

  6. The personal, societal, and economic burden of schizophrenia in the People's Republic of China: implications for antipsychotic therapy.

    Science.gov (United States)

    Montgomery, William; Liu, Li; Stensland, Michael D; Xue, Hai Bo; Treuer, Tamas; Ascher-Svanum, Haya

    2013-01-01

    This article describes the personal, societal, and economic burden attributable to schizophrenia in the People's Republic of China and highlights the potential for effective outpatient treatment to reduce this burden given recent changes in the Chinese health care system. The importance of effective antipsychotic therapy in reducing the burden of schizophrenia is also examined. Published research on the burden, disability, management, and economic costs of schizophrenia in the People's Republic of China was examined in the context of the larger body of global research. Research written in English or Chinese and published before June 2012 was identified using PubMed, CNKI, and Wanfang Med database searches. The contribution of effective antipsychotic therapy in reducing the risk for relapse and hospitalization and improving patients' functioning is described. Schizophrenia imposes a substantial burden on Chinese society, with indirect costs accounting for the majority of the total cost. Functional impairment is high, leading to lost wages and work impairment. In the People's Republic of China, schizophrenia is the most common diagnosis among hospitalized psychiatric patients. Ongoing changes in the Chinese health care system may reduce some barriers to effective relapse prevention in schizophrenia and potentially reduce hospitalizations. The use of antipsychotics for acute episodes and maintenance treatment has been shown to decrease symptom severity and reduce the risk for relapse and hospitalization. However, discontinuing antipsychotic medication appears common and is a strong predictor of relapse. Cost-effectiveness research in the People's Republic of China is needed to examine the potential gains from improved outpatient antipsychotic treatment. Schizophrenia is a very costly mental illness in terms of personal, economic, and societal burden, both in the People's Republic of China and globally. When treated effectively, patients tend to persist longer with

  7. Cognitive behaviour therapy response and dropout rate across purging and nonpurging bulimia nervosa and binge eating disorder: DSM-5 implications.

    Science.gov (United States)

    Agüera, Zaida; Riesco, Nadine; Jiménez-Murcia, Susana; Islam, Mohammed Anisul; Granero, Roser; Vicente, Enrique; Peñas-Lledó, Eva; Arcelus, Jon; Sánchez, Isabel; Menchon, Jose Manuel; Fernández-Aranda, Fernando

    2013-11-07

    With the imminent publication of the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), there has been a growing interest in the study of the boundaries across the three bulimic spectrum syndromes [bulimia nervosa-purging type (BN-P), bulimia nervosa-non purging type (BN-NP) and binge eating disorder (BED)]. Therefore, the aims of this study were to determine differences in treatment response and dropout rates following Cognitive Behavioural Therapy (CBT) across the three bulimic-spectrum syndromes. The sample comprised of 454 females (87 BED, 327 BN-P and 40 BN-NP) diagnosed according to DSM-IV-TR criteria who were treated with 22 weekly outpatient sessions of group CBT therapy. Patients were assessed before and after treatment using a food and binging/purging diary and some clinical questionnaires in the field of ED. "Full remission" was defined as total absence of binging and purging (laxatives and/or vomiting) behaviors and psychological improvement for at least 4 (consecutive). Full remission rate was found to be significantly higher in BED (69.5%) than in both BN-P (p < 0.005) and BN-NP (p < 0.001), which presented no significant differences between them (30.9% and 35.5%). The rate of dropout from group CBT was also higher in BED (33.7%) than in BN-P (p < 0.001) and BN-NP (p < 0.05), which were similar (15.4% and 12.8%, respectively). Results suggest that purging and non-purging BN have similar treatment response and dropping out rates, whereas BED appears as a separate diagnosis with better outcome for those who complete treatment. The results support the proposed new DSM-5 classification.

  8. The effect of post-mastectomy radiation therapy on breast implants: Unveiling biomaterial alterations with potential implications on capsular contracture

    Energy Technology Data Exchange (ETDEWEB)

    Ribuffo, Diego; Lo Torto, Federico [Department of Plastic Surgery, “Sapienza” University of Rome, Viale del Policlinico 155, 00166 Rome (Italy); Giannitelli, Sara M. [Tissue Engineering Unit, Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, 00128 Rome (Italy); Urbini, Marco; Tortora, Luca [Surface Analysis Laboratory, Department of Mathematics and Physics, University “Roma Tre”, Via della Vasca Navale 84, 00146 Rome (Italy); INFN — National Institute of Nuclear Physics, Section of Roma Tre, Via della Vasca Navale 84, 00146 Rome (Italy); Mozetic, Pamela; Trombetta, Marcella [Tissue Engineering Unit, Department of Engineering, Università Campus Bio-Medico di Roma, Via Álvaro del Portillo 21, 00128 Rome (Italy); Basoli, Francesco; Licoccia, Silvia [Department of Chemical Science and Technologies, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00173 Rome (Italy); Tombolini, Vincenzo [Department of Radiation Oncology, “Sapienza” University of Rome, Viale del Policlinico 155, 00166 Rome (Italy); Spencer-Lorillard Foundation, Viale Regina Elena 291, 00161 Rome (Italy); Cassese, Raffaele [Department of Radiation Oncology, “Sapienza” University of Rome, Viale del Policlinico 155, 00166 Rome (Italy); Scuderi, Nicolò [Department of Plastic Surgery, “Sapienza” University of Rome, Viale del Policlinico 155, 00166 Rome (Italy); and others

    2015-12-01

    Post-mastectomy breast reconstruction with expanders and implants is recognized as an integral part of breast cancer treatment. Its main complication is represented by capsular contracture, which leads to poor expansion, breast deformation, and pain, often requiring additional surgery. In such a scenario, the debate continues as to whether the second stage of breast reconstruction should be performed before or after post-mastectomy radiation therapy, in light of potential alterations induced by irradiation to silicone biomaterial. This work provides a novel, multi-technique approach to unveil the role of radiotherapy in biomaterial alterations, with potential involvement in capsular contracture. Following irradiation, implant shells underwent mechanical, chemical, and microstructural evaluation by means of tensile testing, Attenuated Total Reflectance Fourier Transform InfraRed spectroscopy (ATR/FTIR), Scanning Electron Microscopy (SEM), high resolution stylus profilometry, and Time of Flight Secondary Ion Mass Spectrometry (ToF-SIMS). Our findings are consistent with radiation-induced modifications of silicone that, although not detectable at the microscale, can be evidenced by more sophisticated nanoscale surface analyses. In light of these results, biomaterial irradiation cannot be ruled out as one of the possible co-factors underlying capsular contracture. - Highlights: • The debate continues whether to perform breast reconstruction before or after PMRT. • Radiation therapy may alter implant material, concurring to capsular contracture. • In this work, irradiated implants were investigated by a multi-technique approach. • Radiation-induced alterations could be evidenced by ATR/FTIR and ToF-SIMS. • Reported alteration might represent a co-factor underlying capsular contracture.

  9. ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy.

    Directory of Open Access Journals (Sweden)

    Clara I Aceves-Luquero

    Full Text Available Resistance to Imatinib Mesylate (IM is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described. In the present report we aim to study the role of several MAPK in IM resistance not associate to BCR/ABL mutations. Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM (K562, Lama 84 as well as primary material from resistant and responder patient without BCR/ABL mutations. Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype. However, Erk2, but not Erk1, is critical for the acquired resistance to IM. In fact, Bcr/Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein. Finally, we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM. In summary our data support the use of therapeutic approaches based on Erk2 inhibition, which could be added to the therapeutic armamentarium to fight CML, especially when IM resistance develops secondary to Erk2 activation.

  10. Dorsal medial prefrontal cortex (MPFC) circuitry in rodent models of cocaine use: implications for drug addiction therapies.

    Science.gov (United States)

    Jasinska, Agnes J; Chen, Billy T; Bonci, Antonello; Stein, Elliot A

    2015-03-01

    Although the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these pre-clinical models of cocaine self-administration and human neuro-imaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  11. Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract

    Directory of Open Access Journals (Sweden)

    Nasim Dana

    2016-01-01

    Full Text Available Objective(s: Herbal medicines are promising cancer preventive candidates. It has been shown that Punica granatum L. could inhibit angiogenesis and tumor invasion. In this study, we investigated whether the anti-angiogenic effect of pomegranate peel extract (PPE is partly attributable to Peroxisome proliferator-activated receptors (PPARs activation in the Human Umbilical Vein Endothelial Cells (HUVECs. Materials and Methods: Ethanol extract from PPE was prepared. HUVECs were treated in four groups (with PPE (10 μg/ml alone, PPE with or without PPARγ (T0070907 and α (GW6471 antagonists, and control group. The possible effect of PPARs on angiogenic regulation was checked by Matrigel assay. The mRNA expression levels of vascular endothelial growth factor (VEGF was detected by Quantitative reverse transcription-polymerase chain reaction (QRT-PCR.  Results: PPE significantly inhibited both tube formation (size, length, and junction of tubes and VEGF mRNA expression (P

  12. Correlation of antiangiogenic, antioxidant and cytotoxic activities of some Sudanese medicinal plants with phenolic and flavonoid contents.

    Science.gov (United States)

    Hassan, Loiy Elsir A; Ahamed, Mohamed B Khadeer; Majid, Aman S Abdul; Baharetha, Hussein M; Muslim, Nahdzatul S; Nassar, Zeyad D; Majid, Amin M S Abdul

    2014-10-20

    Consumption of medicinal plants to overcome diseases is traditionally belongs to the characteristics of most cultures on this earth. Sudan has been a host and cradle to various ancient civilizations and developed a vast knowledge on traditional medicinal plants. The present study was undertaken to evaluate the antioxidant, antiangiogenic and cytotoxic activities of six Sudanese medicinal plants which have been traditionally used to treat neoplasia. Further the biological activities were correlated with phytochemical contents of the plant extracts. Different parts of the plants were subjected to sequential extraction method. Cytotoxicity of the extracts was determined by dimethylthiazol-2-yl)- 2,5diphenyl tetrazolium bromide (MTT) assay on 2 human cancer (colon and breast) and normal (endothelial and colon fibroblast) cells. Anti-angiogenic potential was tested using ex vivo rat aortic ring assay. DPPH (1,1-diphenyl-2-picrylhydrazyl) assay was conducted to screen the antioxidant capabilities of the extracts. Finally, total phenolic and flavonoid contents were estimated in the extracts using colorimetric assays. The results indicated that out of 6 plants tested, 4 plants (Nicotiana glauca, Tephrosia apollinea, Combretum hartmannianum and Tamarix nilotica) exhibited remarkable anti-angiogenic activity by inhibiting the sprouting of microvessels more than 60%. However, the most potent antiangiogenic effect was recorded by ethanol extract of T. apollinea (94.62%). In addition, the plants exhibited significant antiproliferative effects against human breast (MCF-7) and colon (HCT 116) cancer cells while being non-cytotoxic to the tested normal cells. The IC50 values determined for C. hartmannianum, N. gluaca and T. apollinea against MCF-7 cells were 8.48, 10.78 and 29.36 μg/ml, respectively. Whereas, the IC50 values estimated for N. gluaca, T. apollinea and C. hartmannianum against HCT 116 cells were 5.4, 20.2 and 27.2 μg/ml, respectively. These results were more or

  13. Anti-malarial prescribing practices in Sudan eight years after introduction of artemisinin-based combination therapies and implications for development of drug resistance.

    Science.gov (United States)

    Elmannan, Abeer Abuzeid Atta; Elmardi, Khalid Abdelmutalab; Idris, Yassir Ali; Spector, Jonathan M; Ali, Nahid Abdelgadir; Malik, Elfatih Mohamed

    2015-03-26

    The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) as first-line treatment for uncomplicated malaria. Sudan revised its malaria treatment policy accordingly in 2004. However, eight years after ACTs were introduced in Sudan the patterns of ACT prescribing practices among health care providers remain unclear. We systematically analyzed use of ACTs in a large number of primary health facilities and we discuss the public health implications of our findings. This cross-sectional study was based on WHO's guidance for investigating drug use in health facilities. Data were collected from 40 randomly selected primary health centers in five localities in Gezira State, Sudan. The primary outcome of the study was the proportion of patients who were adequately managed according to Sudan's recommended malaria treatment guidelines. Twelve drug-use indicators were used to assess key ACT prescribing practices. One thousand and two hundred patients diagnosed with uncomplicated malaria were recruited into the study. ACT was prescribed for 88.6%patients and artemether injections were (incorrectly) prescribed in 9.5% of cases. Only 40.9% of patients in the study were correctly diagnosed and 26.9% were adequately managed according to the nationally recommended treatment guidelines. Incorrect prescribing activities included failure to use generic medicine names (88.2%), incorrect dosage (27.7%), and unexplained antibiotic co-prescription (24.2%). Dispensing practices were also poor, with labeling practices inadequate (97.1%) and insufficient information given to patients about their prescribed treatment (50.5%). Irrational malaria treatment practices are common in Sudan. This has important public health implications since failure to adhere to nationally recommended guidelines could play a role in the future development of drug resistance. As such, identifying ways to improve the anti-malarial prescribing practices of heath workers in Sudan may

  14. Prognostic implications of baseline anaemia and changes in haemoglobin concentrations with amphotericin B therapy for cryptococcal meningitis.

    Science.gov (United States)

    Tugume, L; Morawski, B M; Abassi, M; Bahr, N C; Kiggundu, R; Nabeta, H W; Hullsiek, K H; Taseera, K; Musubire, A K; Schutz, C; Muzoora, C; Williams, D A; Rolfes, M A; Meintjes, G; Rhein, J; Meya, D B; Boulware, D R

    2017-01-01

    Anaemia represents a common toxicity with amphotericin B-based induction therapy in HIV-infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin-related anaemia on survival. We used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post-diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2- and 10-week mortality risk. We also estimated 10-week mortality risk among participants with nadir haemoglobin < 8.5 g/dL during amphotericin induction and who survived ≥ 2 weeks post-enrolment. The median haemoglobin concentration at meningitis diagnosis was 11.5 g/dL [interquartile range (IQR) 9.7-13 g/dL; n = 311] with a mean decline of 4.2 g/dL [95% confidence interval (CI) -4.6 to -3.8; P < 0.001; n = 148] from diagnosis to nadir value among participants with baseline haemoglobin ≥ 8.5 g/dL. The median haemoglobin concentration was 8.1 g/dL (IQR 6.5-9.5 g/dL) at 2 weeks, increasing to 9.4 g/dL (IQR 8.2-10.9 g/dL) by 4 weeks and continuing to increase to 12 weeks. Among participants with haemoglobin < 8.5 g/dL at diagnosis, mortality risk was elevated at 2 weeks [hazard ratio (HR) 2.7; 95% CI 1.5-4.9; P < 0.01] and 10 weeks (HR 1.8; 95% CI 1.1-2.2; P = 0.03), relative to those with haemoglobin ≥ 8.5 g/dL. New-onset anaemia occurring with amphotericin therapy did not have a statistically significant association with 10-week mortality (HR 2.0; 95% CI 0.5-9.1; P = 0.4). Amphotericin induced significant haemoglobin declines, which were mostly transient and did not impact 10-week mortality. Individuals with moderate to life-threatening anaemia at baseline had a higher mortality risk at 2 and 10 weeks post-enrolment. © 2016 British HIV Association.

  15. Increased serum adipokines implicate chronic inflammation in the pathogenesis of overactive bladder syndrome refractory to antimuscarinic therapy.

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    Hsin-Tzu Liu

    Full Text Available OBJECTIVES: Recent studies have shown that chronic inflammation is involved in overactive bladder (OAB syndrome. OAB could be a subtype of neurogenic inflammation. This pilot study investigated serum adipokine levels in patients with OAB refractory to antimuscarinic therapy. METHODS: Thirty consecutive patients with OAB-dry (n = 16 or OAB-wet (n = 14 refractory to previous antimuscarinic treatment were prospectively enrolled in this study, a group of 26 normal subjects without lower urinary tract symptoms served as controls. Concentrations of serum C-reactive protein (CRP, nerve growth factor (NGF, and adipokines including interleukins ([IL], IL-1β, IL-6, IL-8, tumor necrosis factor (TNF-α, monocyte chemotactic protein (MCP-1, insulin, and leptin were quantified using a bead-based human serum adipokine panel B kit. Data were analyzed using the LX 200 platform. Patients were further classified as having dry or wet OAB and having medical diseases or not. The serum CRP, NGF, and adipokine levels were compared between OAB patients and the controls, and between OAB subgroups. RESULTS: The serum concentrations of CRP, NGF, IL-1β, IL-6, IL-8, and TNF-α in OAB-dry and OAB-wet patients were significantly higher than among the controls. There was no significant difference in adipokine levels between OAB-dry and OAB-wet, or between OAB patients with and without medical diseases. Serum CRP and NGF levels were significantly higher only in OAB-wet or OAB patients with medical diseases than among controls. The MCP-1 levels, on the other hand, were significantly higher in OAB-dry or OAB patients with disease, than the controls. CONCLUSIONS: Both OAB-dry and OAB-wet patients showed increased serum CRP, NGF, and adipokine levels compared with the controls, suggesting chronic inflammation of the bladder involving both peripheral and central mechanisms in all OAB patients refractory to antimuscarinic therapy. The increased serum adipokine levels were

  16. Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry

    Science.gov (United States)

    Baechler, Sébastien; Hobbs, Robert F.; Prideaux, Andrew R.; Wahl, Richard L.; Sgouros, George

    2010-01-01

    In dosimetry-based treatment planning protocols, patients with rapid clearance of the radiopharmaceutical require a larger amount of initial activity than those with slow clearance to match the absorbed dose to the critical organ. As a result, the dose-rate to the critical organ is higher in patients with rapid clearance and may cause unexpected toxicity compared to patients with slow clearance. In order to account for the biological impact of different dose-rates, radiobiological modeling is beginning to be applied to the analysis of radionuclide therapy patient data. To date, the formalism used for these analyses is based on kinetics derived from activity in a single organ, the target. This does not include the influence of other source organs to the dose and dose-rate to the target organ. As a result, only self-dose irradiation in the target organ contributes to the dose-rate. In this work, the biological effective dose (BED) formalism has been extended to include the effect of multiple source organ contributions to the net dose-rate in a target organ. The generalized BED derivation has been based on the Medical Internal Radionuclide Dose Committee (MIRD) schema assuming multiple source organs following exponential effective clearance of the radionuclide. A BED-based approach to determine the largest safe dose to critical organs has also been developed. The extended BED formalism is applied to red marrow dosimetry, as well as kidney dosimetry considering the cortex and the medulla separately, since both those organs are commonly dose limiting in radionuclide therapy. The analysis shows that because the red marrow is an early responding tissue (high α/β), it is less susceptible to unexpected toxicity arising from rapid clearance of high levels of administered activity in the marrow or in the remainder of the body. In kidney dosimetry, the study demonstrates a complex interplay between clearance of activity in the cortex and the medulla, as well as the initial

  17. Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry

    International Nuclear Information System (INIS)

    Baechler, Sebastien; Hobbs, Robert F.; Prideaux, Andrew R.; Wahl, Richard L.; Sgouros, George

    2008-01-01

    In dosimetry-based treatment planning protocols, patients with rapid clearance of the radiopharmaceutical require a larger amount of initial activity than those with slow clearance to match the absorbed dose to the critical organ. As a result, the dose-rate to the critical organ is higher in patients with rapid clearance and may cause unexpected toxicity compared to patients with slow clearance. In order to account for the biological impact of different dose-rates, radiobiological modeling is beginning to be applied to the analysis of radionuclide therapy patient data. To date, the formalism used for these analyses is based on kinetics derived from activity in a single organ, the target. This does not include the influence of other source organs to the dose and dose-rate to the target organ. As a result, only self-dose irradiation in the target organ contributes to the dose-rate. In this work, the biological effective dose (BED) formalism has been extended to include the effect of multiple source organ contributions to the net dose-rate in a target organ. The generalized BED derivation has been based on the Medical Internal Radionuclide Dose Committee (MIRD) schema assuming multiple source organs following exponential effective clearance of the radionuclide. A BED-based approach to determine the largest safe dose to critical organs has also been developed. The extended BED formalism is applied to red marrow dosimetry, as well as kidney dosimetry considering the cortex and the medulla separately, since both those organs are commonly dose limiting in radionuclide therapy. The analysis shows that because the red marrow is an early responding tissue (high α/β), it is less susceptible to unexpected toxicity arising from rapid clearance of high levels of administered activity in the marrow or in the remainder of the body. In kidney dosimetry, the study demonstrates a complex interplay between clearance of activity in the cortex and the medulla, as well as the initial

  18. Low-level laser therapy regulates microglial function through Src-mediated signaling pathways: implications for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Song Sheng

    2012-09-01

    Full Text Available Abstract Background Activated microglial cells are an important pathological component in brains of patients with neurodegenerative diseases. The purpose of this study was to investigate the effect of He-Ne (632.8 nm, 64.6 mW/cm2 low-level laser therapy (LLLT, a non-damaging physical therapy, on activated microglia, and the subsequent signaling events of LLLT-induced neuroprotective effects and phagocytic responses. Methods To model microglial activation, we treated the microglial BV2 cells with lipopolysaccharide (LPS. For the LLLT-induced neuroprotective study, neuronal cells with activated microglial cells in a Transwell™ cell-culture system were used. For the phagocytosis study, fluorescence-labeled microspheres were added into the treated microglial cells to confirm the role of LLLT. Results Our results showed that LLLT (20 J/cm2 could attenuate toll-like receptor (TLR-mediated proinflammatory responses in microglia, characterized by down-regulation of proinflammatory cytokine expression and nitric oxide (NO production. LLLT-triggered TLR signaling inhibition was achieved by activating tyrosine kinases Src and Syk, which led to MyD88 tyrosine phosphorylation, thus impairing MyD88-dependent proinflammatory signaling cascade. In addition, we found that Src activation could enhance Rac1 activity and F-actin accumulation that typify microglial phagocytic activity. We also found that Src/PI3K/Akt inhibitors prevented LLLT-stimulated Akt (Ser473 and Thr308 phosphorylation and blocked Rac1 activity and actin-based microglial phagocytosis, indicating the activation of Src/PI3K/Akt/Rac1 signaling pathway. Conclusions The present study underlines the importance of Src in suppressing inflammation and enhancing microglial phagocytic function in activated microglia during LLLT stimulation. We have identified a new and important neuroprotective signaling pathway that consists of regulation of microglial phagocytosis and inflammation under LLLT

  19. Clinical features of brain metastases in breast cancer: an implication for hippocampal-sparing whole-brain radiation therapy

    Directory of Open Access Journals (Sweden)

    Wu S

    2016-12-01

    Full Text Available San-Gang Wu,1,* Jia-Yuan Sun,2,* Qin Tong,3 Feng-Yan Li,2 Zhen-Yu He2 1Department of Radiation Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, 2Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 3Department of Radiation Oncology, The First Affiliated Hospital of University of South China, Hengyang, People’s Republic of China *These authors contributed equally to this work Objective: The objectives of this study were to describe the distribution of brain metastases (BM in breast cancer patients and investigate the risk factors for perihippocampal metastases (PHM. Patients and methods: Retrospective analysis of the clinicopathological characteristics and patterns of BM was performed. Associations between clinicopathological characteristics and PHM (the hippocampus plus 5 mm margin were evaluated using logistic regression analyses. Results: A total of 1,356 brain metastatic lesions were identified in 192 patients. Patients with 1–3 BM, 4–9 BM, and ≥10 BM accounted for 63.0%, 18.8%, and 18.2%, respectively. There were only 7 (3.6% patients with hippocampal metastases (HM and 14 (7.3% patients with PHM. On logistic regression, the number of BM was an independent risk factor for PHM. Patients with ≥10 BM had a significantly higher risk of PHM compared with those with <10 BM. Breast cancer subtype (BCS was not associated with PHM. The number of BM was significantly correlated with various BCSs. Patients with hormone receptor (HR+/human epidermal growth factor receptor 2 (HER2+, HR-/HER2+, and HR-/HER2- subtypes had a higher probability of ≥10 BM, relative to patients with an HR+/HER2- subtype. Conclusion: Our study suggests that a low incidence of PHM may be acceptable to perform hippocampal-sparing whole-brain radiation therapy for breast cancer patients

  20. The personal, societal, and economic burden of schizophrenia in the People's Republic of China: implications for antipsychotic therapy

    Directory of Open Access Journals (Sweden)

    Montgomery W

    2013-08-01

    Full Text Available William Montgomery,1 Li Liu,2 Michael D Stensland,5 Hai Bo Xue,2 Tamas Treuer,4 Haya Ascher-Svanum31Eli Lilly and Company, Sydney, NSW, Australia; 2Lilly Suzhou Pharmaceutical Company, Ltd, Shanghai, People's Republic of China; 3Eli Lilly and Company, Global Health Outcomes, Indianapolis, IN, USA; 4Eli Lilly and Company, Budapest, Hungary; 5Agile Outcomes Research, Inc, Rochester, MN, USABackground: This article describes the personal, societal, and economic burden attributable to schizophrenia in the People's Republic of China and highlights the potential for effective outpatient treatment to reduce this burden given recent changes in the Chinese health care system. The importance of effective antipsychotic therapy in reducing the burden of schizophrenia is also examined.Methods: Published research on the burden, disability, management, and economic costs of schizophrenia in the People's Republic of China was examined in the context of the larger body of global research. Research written in English or Chinese and published before June 2012 was identified using PubMed, CNKI, and Wanfang Med database searches. The contribution of effective antipsychotic therapy in reducing the risk for relapse and hospitalization and improving patients' functioning is described.Results: Schizophrenia imposes a substantial burden on Chinese society, with indirect costs accounting for the majority of the total cost. Functional impairment is high, leading to lost wages and work impairment. In the People's Republic of China, schizophrenia is the most common diagnosis among hospitalized psychiatric patients. Ongoing changes in the Chinese health care system may reduce some barriers to effective relapse prevention in schizophrenia and potentially reduce hospitalizations. The use of antipsychotics for acute episodes and maintenance treatment has been shown to decrease symptom severity and reduce the risk for relapse and hospitalization. However, discontinuing

  1. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design

    Directory of Open Access Journals (Sweden)

    Pearl Gregory J

    2011-09-01

    Full Text Available Abstract Background Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI. One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP, which is usually combined with mortality for AMP-free survival (AFS. Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control of 48 patients treated with site of service obtained bone marrow cells (BMAC as well as a systematic review of the literature. Methods Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood. Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss. Results Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6% and those with tissue loss (46.7%, irrespective of treatment group, was significant (p = 0.0029. In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337. The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067. Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain. Conclusions BMAC shows promise in improving AMP

  2. Response of eyes with age-related macular degeneration to anti-VEGF drugs and implications for therapy planning

    Directory of Open Access Journals (Sweden)

    Miyamoto N

    2017-04-01

    Full Text Available Noriko Miyamoto,1,2 Michiko Mandai,1,3 Hiroshi Kojima,1,2 Takanori Kameda,1,2 Masataka Shimozono,1,2 Akihiro Nishida,1,2 Yasuo Kurimoto1,2 1Department of Ophthalmology, Kobe City Medical Center General Hospital, 2Department of Ophthalmology, Institute of Biomedical Research and Innovation, 3Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan Purpose: To evaluate the response to and dependence on aflibercept or ranibizumab in patients with age-related macular degeneration (AMD.Methods: We retrospectively reviewed AMD patients who received induction therapy with aflibercept or ranibizumab for the following parameters: whether complete resolution of the retinal fluid (“good response” was achieved and whether recurrence was observed within 3 months (“dependent” after the induction treatment. With aflibercept treatment, treatment-naïve eyes with a good response/non-dependence were recommended a pro re nata regimen, and other eyes were recommended a proactive bimonthly regimen, followed by monitoring of visual acuity (VA for 12 months. The measured values of the groups were compared using one-way analysis of variance with Tukey’s test to evaluate the difference between baseline and postinjection VA.Results: Among the treatment-naïve eyes, 76% had a good response to aflibercept and 37% of these were aflibercept-dependent, while 58% had a good response to ranibizumab but 51% of these were ranibizumab-dependent. Among the eyes that converted from ranibizumab treatment, 92% of the good responders to ranibizumab with dependence and 76% of the poor responders on ranibizumab had a good response to aflibercept. With aflibercept treatment, the mean VA of treatment-naïve patients was significantly better than the baseline VA over 12 months (P<0.001, and the VA of the converted group improved significantly with proactive treatment and the improvement was continuously maintained from 6 to 12 months

  3. Time-of-flight PET/CT using low-activity protocols: potential implications for cancer therapy monitoring

    International Nuclear Information System (INIS)

    Murray, Iain; Hasan, Syed; Quraishi, Shuaib; Avril, Norbert; Kalemis, Antonis; Glennon, Joe; Beyer, Thomas

    2010-01-01

    Accurate quantification of tumour tracer uptake is essential for therapy monitoring by sequential PET imaging. In this study we investigated to what extent a reduction in administered activity, synonymous with an overall reduction in repeated patient exposure, compromised the accuracy of quantitative measures using time-of-flight PET/CT. We evaluated the effect of reducing the emission count statistics, using a 64-channel GEMINI TF PET/CT system. Experiments were performed with the NEMA IEC body phantom at target-to-background ratios of 4:1 and 10:1. Emission data for 10 s, 30 s, 1 min, 2 min, 5 min and 30 min were acquired. Volumes of interest fitted to the CT outline of the spheres were used to calculate recovery coefficients for each target-to-background ratio and for different reconstruction algorithms. Whole-body time-of-flight PET/CT was performed in 20 patients 62±4 min after injection of 350±40 MBq (range 269-411 MBq) 18 F-FDG. From the acquired 2 min per bed position list mode data, simulated 1-min, 30-s and 15-s PET acquisitions were created. PET images were reconstructed using the TOF-OSEM algorithm and analysed for differences in SUV measurements resulting from the use of lower administered activity as simulated by reduced count statistics. In the phantom studies, overall we identified no significant quantitation bias over a wide range of acquired counts. With acquisition times as short as 10 s, lesions as small as 1 cm in diameter could still be identified. In the patient studies, visual analysis showed that emission scans as short as 15 s per bed position sufficiently identified tumour lesions for quantification. As the acquisition time per bed position decreased, the differences in SUV quantification of tumour lesions increased relative to the 2-min reference protocol. However, SUVs remained within the limits of reproducibility required for therapy monitoring. Measurements of SUVmean within the region of interest were less prone to noise than

  4. Comparison of Mutation Profiles in the Duchenne Muscular Dystrophy Gene among Populations: Implications for Potential Molecular Therapies

    Science.gov (United States)

    López-Hernández, Luz Berenice; Gómez-Díaz, Benjamín; Luna-Angulo, Alexandra Berenice; Anaya-Segura, Mónica; Bunyan, David John; Zúñiga-Guzman, Carolina; Escobar-Cedillo, Rosa Elena; Roque-Ramírez, Bladimir; Ruano-Calderón, Luis Angel; Rangel-Villalobos, Héctor; López-Hernández, Julia Angélica; Estrada-Mena, Francisco Javier; García, Silvia; Coral-Vázquez, Ramón Mauricio

    2015-01-01

    Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD), a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162) with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001). To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations. PMID:25761239

  5. Comparison of Mutation Profiles in the Duchenne Muscular Dystrophy Gene among Populations: Implications for Potential Molecular Therapies

    Directory of Open Access Journals (Sweden)

    Luz Berenice López-Hernández

    2015-03-01

    Full Text Available Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD, a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162 with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001. To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations.

  6. The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: Implications in targeted cancer therapies

    Science.gov (United States)

    Yang, Ke; Wang, Xin; Zhang, Hongmei; Wang, Zhongliang; Nan, Guoxin; Li, Yasha; Zhang, Fugui; Mohammed, Maryam K.; Haydon, Rex C.; Luu, Hue H.; Bi, Yang; He, Tong-Chuan

    2015-01-01

    The canonical WNT/β-catenin signaling pathway governs a myriad of biological processes underlying development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the canonical pathway is the activation of β-catenin mediated transcriptional activity. Canonical WNTs control the β-catenin dynamics as the cytoplasmic level of β-catenin is tightly regulated via phosphorylation by the ‘destruction complex’, consisting of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), the scaffold protein AXIN, and the tumor suppressor adenomatous polyposis coli (APC). Aberrant regulation of this signaling cascade is associated with varieties of human diseases, especially cancers. Over the past decade, significant progress has been made in understanding the mechanisms of canonical WNT signaling. In this review, we focus on the current understanding of WNT signaling at the extracellular, cytoplasmic membrane, and intracellular/nuclear levels, including the emerging knowledge of crosstalk with other pathways. Recent progresses in developing novel WNT pathway-targeted therapies will also be reviewed. Thus, this review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/β-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway. PMID:26618721

  7. Similar changes in cognitions following cognitive-behavioral therapy or escitalopram for major depressive disorder: Implications for mechanisms of change.

    Science.gov (United States)

    Farabaugh, Amy; Fisher, Lauren; Nyer, Maren; Holt, Daphne; Cohen, Mariana; Baer, Lee; Shapero, Benjamin G; Huz, Ilana; Cardoos, Amber; Fava, Maurizio; Alpert, Jonathan E

    2015-05-01

    Psychosocial treatments and medications both have been shown to be effective in treating major depressive disorder. We hypothesized that cognitive-behavioral therapy (CBT) would outperform medication on measures of cognitive change. We randomized depressed individuals to 12 weeks of CBT (n = 15) or escitalopram (n = 11). In an intent-to-treat analysis (n = 26), we conducted a repeated measures analysis of variance to examine changes in depressive symptoms (ie, 17-item Hamilton Depression Rating Scale, Beck Depression Inventory), anhedonia (ie, Snaith-Hamilton Pleasure Scale), cognitive measures (ie, Dysfunctional Attitudes Scale, Automatic Thoughts Questionnaire, Perceived Stress Scale), and quality of life (ie, Quality of Life Enjoyment and Satisfaction Questionnaire) at 4 time points: baseline, week 4, week 8, and week 12. Treatment for both groups started at baseline, and patients received either 12 weeks of individual CBT or 12 weeks of escitalopram with flexible dosing (10 to 20 mg). Collapsing the escitalopram and CBT groups, there were statistically significant pre-post changes on all outcome measures. However, there were no statistically significant differences between treatment groups on any of the outcome measures, including cognitive measures across time points. Our results suggest that both CBT and escitalopram have similar effects across a variety of domains and that, in contrast to our a priori hypothesis, CBT and escitalopram were associated with comparable changes on cognitive measures.

  8. α2 adrenergic receptor dysregulation in depressive disorders: implications for the neurobiology of depression and antidepressant therapy

    Science.gov (United States)

    Cottingham, Christopher; Wang, Qin

    2012-01-01

    Dysfunction in noradrenergic neurotransmission has long been theorized to occur in depressive disorders. The α2 adrenergic receptor (AR) family, as a group of key players in regulating the noradrenergic system, has been investigated for involvement in the neurobiology of depression and mechanisms of antidepressant therapies. However, a clear picture of the α2ARs in depressive disorders has not been established due to the existence of apparently conflicting findings in the literature. In this article, we report that a careful accounting of methodological differences within the literature can resolve the present lack of consensus on involvement of α2ARs in depression. In particular, the pharmacological properties of the radioligand (e.g. agonist versus antagonist) utilized for determining receptor density are crucial in determining study outcome. Upregulation of α2AR density detected by radiolabeled agonists but not by antagonists in patients with depressive disorders suggests a selective increase in the density of high-affinity conformational state α2ARs, which is indicative of enhanced G protein coupling to the receptor. Importantly, this high-affinity state α2AR upregulation can be normalized with antidepressant treatments. Thus, depressive disorders appear to be associated with increased α2AR sensitivity and responsiveness, which may represent a physiological basis for the putative noradrenergic dysfunction in depressive disorders. In addition, we review changes in some key α2AR accessory proteins in depressive disorders and discuss their potential contribution to α2AR dysfunction. PMID:22910678

  9. A review of mind-body therapies in the treatment of cardiovascular disease. Part 1: Implications for the elderly.

    Science.gov (United States)

    Luskin, F M; Newell, K A; Griffith, M; Holmes, M; Telles, S; Marvasti, F F; Pelletier, K R; Haskell, W L

    1998-05-01

    A review of research on complementary and alternative treatments, specifically mind-body techniques, was conducted at Stanford University. The goals of the review were to establish a comprehensive literature review and to provide a rationale for future research concerning successful aging. Computerized searches were conducted using MEDLINE, PsychInfo, Stanford Library, Dissertation Abstracts, Lexus-Nexus, the Internet, and interviews conducted with practitioners. All studies since 1990 that examined mind-body treatments of cardiovascular disorders in the elderly were included. Mind-body practices evaluated were social support, cognitive-behavioral treatment, meditation, the placebo effect, hope, faith, imagery, spiritual healing, music therapy, hypnosis, yoga, t'ai chi, qigong and aikido. Studies conducted after 1990 were a priority, but when more recent literature was scarce, other studies using randomized, controlled trials were included. Mind-body techniques were found to be efficacious primarily as complementary and sometimes as stand-alone alternative treatments for cardiovascular disease-related conditions. Studies provided evidence for treatment efficacy, but the need for further controlled research was evident. Reviewers found only a handful of randomized, controlled research studies conducted in the United States. As a result, there is a lack of replicated studies with which to determine appropriate treatment dosage and the mechanisms by which many of the practices work. Compelling anecdotal evidence, the presence of some controlled research, overall cost effectiveness, and the lack of side effects resulting from mind-body treatments make further investigation a high priority.

  10. Scaffold-based rhBMP-2 therapy in a rat alveolar defect model: implications for human gingivoperiosteoplasty.

    Science.gov (United States)

    Nguyen, Phuong D; Lin, Clarence D; Allori, Alexander C; Schachar, Jeffrey S; Ricci, John L; Saadeh, Pierre B; Warren, Stephen M

    2009-12-01

    Primary alveolar cleft repair has a 41 to 73 percent success rate. Patients with persistent alveolar defects require secondary bone grafting. The authors investigated scaffold-based therapies designed to augment the success of alveolar repair. Critical-size, 7 x 4 x 3-mm alveolar defects were created surgically in 60 Sprague-Dawley rats. Four scaffold treatment arms were tested: absorbable collagen sponge, absorbable collagen sponge plus recombinant human bone morphogenetic protein-2 (rhBMP-2), hydroxyapatite-tricalcium phosphate, hydroxyapatite-tricalcium phosphate plus rhBMP-2, and no scaffold. New bone formation was assessed radiomorphometrically and histomorphometrically at 4, 8, and 12 weeks. Radiomorphometrically, untreated animals formed 43 +/- 6 percent, 53 +/- 8 percent, and 48 +/- 3 percent new bone at 4, 8, and 12 weeks, respectively. Animals treated with absorbable collagen sponge formed 50 +/- 6 percent, 79 +/- 9 percent, and 69 +/- 7 percent new bone, respectively. Absorbable collagen sponge plus rhBMP-2-treated animals formed 49 +/- 2 percent, 71 +/- 6 percent, and 66 +/- 7 percent new bone, respectively. Hydroxyapatite-tricalcium phosphate treatment stimulated 69 +/- 12 percent, 86 +/- 3 percent (p scaffold. Radiomorphometrically, absorbable collagen sponge and hydroxyapatite-tricalcium phosphate scaffolds induced more bone formation than untreated controls. The rhBMP-2 added a small but significant histomorphometric osteogenic advantage to the hydroxyapatite-tricalcium phosphate scaffold.

  11. New Insights into p53 Signaling and Cancer Cell Response to DNA Damage: Implications for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Razmik Mirzayans

    2012-01-01

    Full Text Available Activation of the p53 signaling pathway by DNA-damaging agents was originally proposed to result either in cell cycle checkpoint activation to promote survival or in apoptotic cell death. This model provided the impetus for numerous studies focusing on the development of p53-based cancer therapies. According to recent evidence, however, most p53 wild-type human cell types respond to ionizing radiation by undergoing stress-induced premature senescence (SIPS and not apoptosis. SIPS is a sustained growth-arrested state in which cells remain viable and secrete factors that may promote cancer growth and progression. The p21WAF1 (hereafter p21 protein has emerged as a key player in the p53 pathway. In addition to its well-studied role in cell cycle checkpoints, p21 regulates p53 and its upstream kinase (ATM, controls gene expression, suppresses apoptosis, and induces SIPS. Herein, we review these and related findings with human solid tumor-derived cell lines, report new data demonstrating dynamic behaviors of p53 and p21 in the DNA damage response, and examine the gain-of-function properties of cancer-associated p53 mutations. We point out obstacles in cancer-therapeutic strategies that are aimed at reactivating the wild-type p53 function and highlight some alternative approaches that target the apoptotic threshold in cancer cells with differing p53 status.

  12. Generation of iPSCs from genetically corrected Brca2 hypomorphic cells: implications in cell reprogramming and stem cell therapy.

    Science.gov (United States)

    Navarro, S; Moleiro, V; Molina-Estevez, F J; Lozano, M L; Chinchon, R; Almarza, E; Quintana-Bustamante, O; Mostoslavsky, G; Maetzig, T; Galla, M; Heinz, N; Schiedlmeier, B; Torres, Y; Modlich, U; Samper, E; Río, P; Segovia, J C; Raya, A; Güenechea, G; Izpisua-Belmonte, J C; Bueren, J A

    2014-02-01

    Fanconi anemia (FA) is a complex genetic disease associated with a defective DNA repair pathway known as the FA pathway. In contrast to many other FA proteins, BRCA2 participates downstream in this pathway and has a critical role in homology-directed recombination (HDR). In our current studies, we have observed an extremely low reprogramming efficiency in cells with a hypomorphic mutation in Brca2 (Brca2(Δ) (27/) (Δ27)), that was associated with increased apoptosis and defective generation of nuclear RAD51 foci during the reprogramming process. Gene complementation facilitated the generation of Brca2(Δ) (27/) (Δ27) induced pluripotent stem cells (iPSCs) with a disease-free FA phenotype. Karyotype analyses and comparative genome hybridization arrays of complemented Brca2(Δ) (27/) (Δ27) iPSCs showed, however, the presence of different genetic alterations in these cells, most of which were not evident in their parental Brca2(Δ) (27/) (Δ27) mouse embryonic fibroblasts. Gene-corrected Brca2(Δ) (27/) (Δ27) iPSCs could be differentiated in vitro toward the hematopoietic lineage, although with a more limited efficacy than WT iPSCs or mouse embryonic stem cells, and did not engraft in irradiated Brca2(Δ) (27/) (Δ27) recipients. Our results are consistent with previous studies proposing that HDR is critical for cell reprogramming and demonstrate that reprogramming defects characteristic of Brca2 mutant cells can be efficiently overcome by gene complementation. Finally, based on analysis of the phenotype, genetic stability, and hematopoietic differentiation potential of gene-corrected Brca2(Δ) (27/) (Δ) (27) iPSCs, achievements and limitations in the application of current reprogramming approaches in hematopoietic stem cell therapy are also discussed. © AlphaMed Press.

  13. Nonthermal Ablation by Using Intravascular Oxygen Radical Generation with WST11: Dynamic Tissue Effects and Implications for Focal Therapy.

    Science.gov (United States)

    Kimm, Simon Y; Tarin, Tatum V; Monette, Sébastien; Srimathveeravalli, Govindarajan; Gerber, Daniel; Durack, Jeremy C; Solomon, Stephen B; Scardino, Peter T; Scherz, Avigdor; Coleman, Jonathan

    2016-10-01

    Purpose To examine the hypothesis that vascular-targeted photodynamic therapy (VTP) with WST11 and clinically relevant parameters can be used to ablate target tissues in a non-tumor-bearing large-animal model while selectively sparing blood vessels and collagen. Materials and Methods By using an institutional animal care and use committee-approved protocol, 68 ablations were performed in the kidneys (cortex and medulla) and livers of 27 adult pigs. Posttreatment evaluation was conducted with contrast material-enhanced computed tomography in the live animals at 24 hours. Immunohistochemistry was evaluated and histologic examination with hematoxylin-eosin staining was performed at 4 hours, 24 hours, and 7 days. Intravenous infusion of WST11 (4 mg per kilogram of body weight) was followed by using near-infrared illumination (753 nm for 20 minutes) through optical fibers prepositioned in target tissues by using a fixed template. Treated areas were scanned, measured, and statistically analyzed by using the Student t test and two-way analysis of variance. Results Focal WST11 VTP treatment in the liver and kidney by using a single optical fiber resulted in well-demarcated cylindrical zones of nonthermal necrosis concentrically oriented around the light-emitting diffuser, with no intervening viable parenchymal cells. The radius of ablated tissue increased from approximately 5 mm at 150 mW to approximately 7 mm at 415 mW (P the peripheral ablation zone, blood vessels at least 40 μm in diameter were selectively preserved and remained functional at 7 days. Ablated tissues exhibited progressive fibrosis and chronic inflammatory cell infiltrates. No histologic changes consistent with thermal injury were observed in blood vessels or collagen. The renal hilum and collecting system did not show treatment effect, despite treatment proximity. Conclusion WST11 VTP induces nonthermal tissue ablation in target tissue while preserving critical organ structures and bystander blood

  14. Radiosensitivity Differences Between Liver Metastases Based on Primary Histology Suggest Implications for Clinical Outcomes After Stereotactic Body Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Kamran A.; Caudell, Jimmy J. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); El-Haddad, Ghassan [Department of Interventional Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Berglund, Anders E.; Welsh, Eric A. [Department of Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Yue, Binglin [Department of Biostastistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Hoffe, Sarah E.; Naghavi, Arash O.; Abuodeh, Yazan A.; Frakes, Jessica M. [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Eschrich, Steven A. [Department of Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States); Torres-Roca, Javier F., E-mail: Javier.torresroca@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida (United States)

    2016-08-01

    Purpose/Objectives: Evidence from the management of oligometastases with stereotactic body radiation therapy (SBRT) reveals differences in outcomes based on primary histology. We have previously identified a multigene expression index for tumor radiosensitivity (RSI) with validation in multiple independent cohorts. In this study, we assessed RSI in liver metastases and assessed our clinical outcomes after SBRT based on primary histology. Methods and Materials: Patients were identified from our prospective, observational protocol. The previously tested RSI 10 gene assay was run on samples and calculated using the published algorithm. An independent cohort of 33 patients with 38 liver metastases treated with SBRT was used for clinical correlation. Results: A total of 372 unique metastatic liver lesions were identified for inclusion from our prospective, institutional metadata pool. The most common primary histologies for liver metastases were colorectal adenocarcinoma (n=314, 84.4%), breast adenocarcinoma (n=12, 3.2%), and pancreas neuroendocrine (n=11, 3%). There were significant differences in RSI of liver metastases based on histology. The median RSIs for liver metastases in descending order of radioresistance were gastrointestinal stromal tumor (0.57), melanoma (0.53), colorectal neuroendocrine (0.46), pancreas neuroendocrine (0.44), colorectal adenocarcinoma (0.43), breast adenocarcinoma (0.35), lung adenocarcinoma (0.31), pancreas adenocarcinoma (0.27), anal squamous cell cancer (0.22), and small intestine neuroendocrine (0.21) (P<.0001). The 12-month and 24-month Kaplan-Meier rates of local control (LC) for colorectal lesions from the independent clinical cohort were 79% and 59%, compared with 100% for noncolorectal lesions (P=.019), respectively. Conclusions: In this analysis, we found significant differences based on primary histology. This study suggests that primary histology may be an important factor to consider in SBRT radiation dose selection.

  15. The tumour sink effect on the biodistribution of 68Ga-DOTA-octreotate: implications for peptide receptor radionuclide therapy

    International Nuclear Information System (INIS)

    Beauregard, Jean-Mathieu; Hofman, Michael S.; Kong, Grace; Hicks, Rodney J.

    2012-01-01

    Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of 68 Ga-DOTA-octreotate. Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on 68 Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Our results suggest that tumour sequestration of 68 Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. (orig.)

  16. Determination of the inferior border of the thecal sac using magnetic resonance imaging: implications on radiation therapy treatment planning

    International Nuclear Information System (INIS)

    Scharf, Carole B.; Paulino, Arnold C.; Goldberg, Kenneth N.

    1998-01-01

    Purpose: To determine whether the traditional teaching of placing the caudal border of the spinal field at the S2-S3 interspace in children receiving craniospinal irradiation (CSI) is appropriate. Methods and Materials: Twenty-three children had magnetic resonance imaging (MRI) of the spine with gadolinium prior to craniospinal irradiation at one institution. Thecal sac termination using MRI was determined by drawing a perpendicular line from the point of convergence of dural margins to the corresponding vertebral body. Results: Location of thecal sac termination varied from mid-S1 to low S3 vertebral body, with the most frequent site at the upper S2 vertebral level. Only 2 of 23 (8.7%) children had thecal sac terminations below the S2-S3 interspace. For the nine patients with neuraxis disease, none had thecal sac terminations below the S2-S3 interspace. In seven of the nine patients who had neuraxis seeding at initial presentation, MRI of the spine after CSI was performed and showed that thecal sac termination was lower after radiation therapy in two children, higher in one, and the same in four. Conclusions: In 2 of 23 children (8.7%), placement of the inferior border at the bottom of the S2 vertebral body would have missed the entire thecal sac. Treatment to the entire neuraxis with adequate coverage of distal spinal theca can be achieved by using MRI. Individualized spinal fields using the MRI may help minimize radiation scatter to the gonads while adequately covering the target volume

  17. Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes.

    Science.gov (United States)

    Needell, James C; Dinarello, Charles A; Ir, Diana; Robertson, Charles E; Ryan, Sarah M; Kroehl, Miranda E; Frank, Daniel N; Zipris, Danny

    2017-01-01

    Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.

  18. Insulin-like Growth Factor-Dependent Proliferation and Survival of Triple-Negative Breast Cancer Cells: Implications for Therapy

    Directory of Open Access Journals (Sweden)

    Zoë Davison

    2011-06-01

    Full Text Available Triple-negative breast cancers have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The prevailing view is that targeting the insulin-like growth factor (IGF signal transduction pathway will not be beneficial for triple-negative breast cancers because their growth is not IGF-responsive. The present study investigates the importance of IGFs in the proliferation and survival of triple-negative breast cancer cells. Estrogen and progesterone receptors, HER2, type I IGF, and insulin receptors were measured by Western transfer analysis. The effects of IGF-1 on proliferation were assessed by DNA quantitation and on cell survival by poly (ADP-ribose polymerase cleavage. The effect of IGF-1 on phosphorylation of the IGF receptors, Akt and mitogen-activated protein kinase, was measured by Western transfer analysis. Seven cell lines were identified as models of triple-negative breast cancer and shown to express IGF receptors at levels similar to those present in estrogen-responsive cell lines known to respond to IGFs. IGF-1 increased the proliferation and cell survival of all triple-negative cell lines. Proliferation was attenuated after reduction of type I IGF receptor expression. Cells that express higher levels of receptor were more sensitive to subnanomolar IGF-1 concentrations, but the magnitude of the effects was not correlated simply with the absolute amount or phosphorylation of the IGF receptors, Akt or mitogen-activated protein kinase. These results show that IGFs stimulate cell proliferation and promote cell survival in triple-negative breast cancer cells and warrant investigation of the IGF signal transduction pathway as a therapeutic target for the treatment of triple-negative breast cancer.

  19. Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy.

    Directory of Open Access Journals (Sweden)

    Mei Hong Tan

    . This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood.

  20. Elongated styloid processes and calcified stylohyoid ligaments in a patient with neck pain: implications for manual therapy practice.

    Science.gov (United States)

    Green, Bart N; Browske, Lcdr Kristin M; Rosenthal, Capt Michael D

    2014-06-01

    The purpose of this paper is to present a case of a patient with neck pain, tinnitus, and headache in the setting of bilateral elongated styloid processes (ESP) and calcified stylohyoid ligaments (CSL), how knowledge of this anatomical variation and symptomatic presentation affected the rehabilitation management plan for this patient, and to discuss the potential relevance of ESPs and CSLs to carotid artery dissection. A 29-year-old male military helicopter mechanic presented for chiropractic care for chronic pain in the right side of his neck and upper back, tinnitus, and dizziness with a past history of right side parietal headaches and tonsillitis. Conventional radiographs showed C6 and C7 spinous process fractures, degenerative disc disease at C6/7, and an elongated right styloid process with associated calcification of the left stylohyoid ligament. Volumetric computerized tomography demonstrated calcification of the stylohyoid ligaments bilaterally. Given the proximity of the calcified stylohyoid apparatus to the carotid arteries, spinal manipulation techniques were modified to minimize rotation of the neck. Rehabilitation also included soft tissue mobilization and stretching, corrective postural exercises, and acupuncture. An otolaryngologist felt that the symptoms were not consistent with Eagle syndrome and the tinnitus was associated with symmetric high frequency hearing loss, likely due to occupational noise exposure. Initially, the patient's symptoms improved but plateaued by the fifth visit. Neck pain in the presence of ESPs and CSLs can be associated with Eagle syndrome, which can include ipsilateral head and neck pain, odynophagia, dysphagia, and cerebrovascular symptoms. This case, initially thought to be Eagle syndrome, highlights proper diagnostic workup for this condition and presents potential contraindications to consider with regard to cervical spine manipulation in such patients. Manual therapy precautions pertaining to cervical spine

  1. Peripheral blood microRNA and VEGFA mRNA changes following electroconvulsive therapy: implications for psychotic depression.

    Science.gov (United States)

    Kolshus, E; Ryan, K M; Blackshields, G; Smyth, P; Sheils, O; McLoughlin, D M

    2017-12-01

    MicroRNAs are short, non-coding molecules that regulate gene expression. Here, we investigate the role of microRNAs in depression and electroconvulsive therapy (ECT). We performed three studies: a deep sequencing discovery-phase study of miRNA changes in whole blood following ECT (n = 16), followed by a validation study in a separate cohort of patients pre-/post-ECT (n = 37) and matched healthy controls (n = 34). Changes in an experimentally validated gene target (VEGFA) were then analysed in patients pre-/post-ECT (n = 97) and in matched healthy controls (n = 53). In the discovery-phase study, we found no statistically significant differences in miRNA expression from baseline to end of treatment in the group as a whole, but post hoc analysis indicated a difference in patients with psychotic depression (n = 3). In a follow-up validation study, patients with psychotic depression (n = 7) had elevated baseline levels of miR-126-3p (t = 3.015, P = 0.006) and miR-106a-5p (t = 2.598, P = 0.025) compared to healthy controls. Following ECT, these differences disappeared. Baseline VEGFA levels were significantly higher in depressed patients compared to healthy controls (F(1,144) = 27.688, P = <0.001). Following ECT, there was a significant change in VEGFA levels in the psychotic group only (t = 2.915, P = 0.010). Molecular differences (miRNA and VEGFA) may exist between psychotic and non-psychotic depression treated with ECT. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Cancer therapy associated bone loss: Implications for hip fractures in mid-life women with breast cancer

    Science.gov (United States)

    Edwards, Beatrice J.; Raisch, Dennis W.; Shankaran, Veena; McKoy, June M.; Gradishar, William; Bunta, Andrew D.; Samaras, Athena T.; Boyle, Simone N.; West, Dennis P.; Guise, Theresa A.

    2010-01-01

    Purpose Aromatase inhibitors (AIs) have been recently associated with hip fractures. We present a case series of breast cancer survivors and a systematic review of bone health care in breast cancer. Experimental Design We completed clinical assessments and bone density testing (BMD) of hip fractures from January 2005–December 2008. Pre-fracture and 12-month functional status was obtained. Systematic review included case reports and review of MEDLINE, PubMed, EMBASE, and Food and Drug Administration Adverse Event Reporting System (FDA AERS) from January 1998–December 2008 (search terms: breast cancer, bone loss, osteopenia, osteoporosis, malignancy, cancer treatment, menopause, adriamycin, cytoxan, tamoxifen, and AIs). Results Median age was 53.5 years; five women had osteopenia, one osteoporosis. Five cases were ER (+), and received surgery, XRT chemotherapy, and anastrozole. Functional decline was noted at 12 months, with difficulty in performing heavy housekeeping, climbing stairs and shopping. The FDA AERS database included 228 cases of fractures associated with breast cancer therapy; 77/228 (29.4%) were hip or femur fractures. Among mid-life women under the age of 64 years there were 78 fractures; 15/228 (19%) were hip and femur fractures. AIs were the most common drug class associated with fractures (n=149, 65%). Conclusions CTIBL results in hip fractures among mid-life women with breast cancer. Hip fractures occur at younger ages and higher BMD than expected for patients in this age group without breast cancer. Hip fractures result in considerable functional decline. Greater awareness of this adverse drug effect is needed. PMID:21288927

  3. The tumour sink effect on the biodistribution of {sup 68}Ga-DOTA-octreotate: implications for peptide receptor radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Beauregard, Jean-Mathieu [Peter MacCallum Cancer Centre and University of Melbourne, Centre for Cancer Imaging, Melbourne (Australia); Centre hospitalier universitaire de Quebec and Laval University, Molecular Imaging Research Group, Medical Imaging Department, Quebec City, QC (Canada); Hofman, Michael S.; Kong, Grace; Hicks, Rodney J. [Peter MacCallum Cancer Centre and University of Melbourne, Centre for Cancer Imaging, Melbourne (Australia)

    2012-01-15

    Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of {sup 68}Ga-DOTA-octreotate. Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on {sup 68}Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Our results suggest that tumour sequestration of {sup 68}Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. (orig.)

  4. Characterization of ovarian clear cell carcinoma using target drug-based molecular biomarkers: implications for personalized cancer therapy.

    Science.gov (United States)

    Li, Mengjiao; Li, Haoran; Liu, Fei; Bi, Rui; Tu, Xiaoyu; Chen, Lihua; Ye, Shuang; Cheng, Xi

    2017-02-10

    results were observed in HGSC patients. Ovarian CCC showed a markedly different expression map of drug-based molecular biomarkers from HGSC, which suggested a new personalized target therapy in this rare subtype.

  5. New insights into the pathogenesis of cystic fibrosis: pivotal role of glutathione system dysfunction and implications for therapy.

    Science.gov (United States)

    Hudson, Valerie M

    2004-01-01

    findings in this area. Exogenous augmentation of GSH in the lung epithelial lining fluid is possible, and therapeutic approaches include administration of aerosolized buffered GSH, intravenous GSH, and oral GSH. However, it is important to remember that the pathophysiology of cystic fibrosis is multifactorial, and rectification of GSH system dysfunction in patients with cystic fibrosis will not eliminate all harmful effects of the disease. The promising results of two clinical trials of aerosolized buffered GSH in cystic fibrosis patients have been published or accepted for publication at the time of this writing. GSH depletion in lung epithelial lining fluid has also been noted in other respiratory diseases such as COPD, idiopathic pulmonary fibrosis, and adult respiratory distress syndrome, and therapies to augment GSH may also be contemplated in these diseases.

  6. Time-Resolved Intrafraction Target Translations and Rotations During Stereotactic Liver Radiation Therapy: Implications for Marker-based Localization Accuracy

    Energy Technology Data Exchange (ETDEWEB)

    Bertholet, Jenny, E-mail: jennbe@rm.dk [Department of Oncology, Aarhus University Hospital, Aarhus C (Denmark); Worm, Esben S. [Department of Medical Physics, Aarhus University Hospital, Aarhus C (Denmark); Fledelius, Walther; Høyer, Morten; Poulsen, Per R. [Department of Oncology, Aarhus University Hospital, Aarhus C (Denmark)

    2016-06-01

    Purpose: Image guided liver stereotactic body radiation therapy (SBRT) often relies on implanted fiducial markers. The target localization accuracy decreases with increased marker-target distance. This may occur partly because of liver rotations. The aim of this study was to examine time-resolved translations and rotations of liver marker constellations and investigate if time-resolved intrafraction rotational corrections can improve localization accuracy in liver SBRT. Methods and Materials: Twenty-nine patients with 3 implanted markers received SBRT in 3 to 6 fractions. The time-resolved trajectory of each marker was estimated from the projections of 1 to 3 daily cone beam computed tomography scans and used to calculate the translation and rotation of the marker constellation. In all cone beam computed tomography projections, the time-resolved position of each marker was predicted from the position of another surrogate marker by assuming that the marker underwent either (1) the same translation as the surrogate marker; or (2) the same translation as the surrogate marker corrected by the rotation of the marker constellation. The localization accuracy was quantified as the root-mean-square error (RMSE) between the estimated and the actual marker position. For comparison, the RMSE was also calculated when the marker's position was estimated as its mean position for all the projections. Results: The mean translational and rotational range (2nd-98th percentile) was 2.0 mm/3.9° (right-left), 9.2 mm/2.9° (superior-inferior), 4.0 mm/4.0° (anterior-posterior), and 10.5 mm (3-dimensional). Rotational corrections decreased the mean 3-dimensional RMSE from 0.86 mm to 0.54 mm (P<.001) and halved the RMSE increase per millimeter increase in marker distance. Conclusions: Intrafraction rotations during liver SBRT reduce the accuracy of marker-guided target localization. Rotational correction can improve the localization accuracy with a factor of approximately 2

  7. [Genetic basis of head and neck cancers and gene therapy].

    Science.gov (United States)

    Özel, Halil Erdem; Özkırış, Mahmut; Gencer, Zeliha Kapusuz; Saydam, Levent

    2013-01-01

    Surgery and combinations of traditional treatments are not successful enough particularly for advanced stage head and neck cancer. The major disadvantages of chemotherapy and radiation therapy are the lack of specificity for the target tissue and toxicity to the patient. As a result, gene therapy may offer a more specific approach. The aim of gene therapy is to present therapeutic genes into cancer cells which selectively eliminate malignant cells with no systemic toxicity to the patient. This article reviews the genetic basis of head and neck cancers and important concepts in cancer gene therapy: (i) inhibition of oncogenes; (ii) tumor suppressor gene replacement; (iii) regulation of immune response against malignant cells; (iv) genetic prodrug activation; and (v) antiangiogenic gene therapy. Currently, gene therapy is not sufficient to replace the traditional treatments of head and neck cancers, however there is no doubt that it will have an important role in the near future.

  8. Intra-arterial drug and light delivery for photodynamic therapy using Visudyne®: implication for atherosclerotic plaque treatment

    Directory of Open Access Journals (Sweden)

    Manish Jain

    2016-09-01

    Full Text Available Photodynamic therapy (PDT, which is based on the activation of photosensitizers with light, can be used to reduce plaque burden. We hypothesized that intra-arterial photosensitizer administration and photo-activation will lead to high and rapid accumulation within the plaque with reduced systemic adverse effects. Thus this intra-arterial PDT would be expected to have less side effects and due to the short time involved would be compatible with percutaneous coronary interventions. Aim: We characterized the dose-dependent uptake and efficacy of intra-arterial PDT using Liposomal Verteporfin (Visudyne®, efficient for cancer-PDT but not tested before for PDT of atherosclerosis. Methods and Results: Visudyne® (100, 200 and 500 ng/ml was perfused for 5-30 minutes in atherosclerotic aorta isolated from ApoE-/- mice. The fluorescence Intensity (FI after 15 minutes of Visudyne® perfusion increased with doses of 100 (FI-5.5 ± 1.8, 200 (FI-31.9 ± 1.9 or 500 ng/ml (FI-42.9 ± 1.2. Visudyne® (500 ng/ml uptake also increased with the administration time from 5 minutes (FI-9.8 ± 2.5 to 10 minutes (FI-23.3 ± 3.0 and 15 minutes (FI-42.9 ± 3.4 before reaching saturation at 30 minutes (FI-39.3 ± 2.4 contact. Intra-arterial PDT (Fluence: 100 and 200 J/cm2, irradiance-334 mW/cm2 applied immediately after Visudyne® perfusion (500 ng/ml for 15 minutes using a cylindrical light diffuser coupled to a diode laser (690 nm, led to an increase of ROS (Dihydroethidium (FI-6.9 ± 1.8, 25.3 ± 5.5, 43.4 ± 13.9 and apoptotic cells (TUNEL (2.5 ± 1.6 %, 41.3 ± 15.3 %, 58.9 ± 6 %, mainly plaque macrophages (immunostaining (0.3 ± 0.2 %, 37.6 ± 6.4 %, 45.3 ± 5.4 % at light doses of 0, 100 or 200 J/cm2 respectively. Limited apoptosis was observed in the medial wall (0.5 ± 0.2 %, 8.5 ± 4.7 %, 15.3 ± 12.7 %. Finally, Visudyne®-PDT was found to be associated with reduced vessel functionality (Myogram. Conclusion: We demonstrated that sufficient accumulation of

  9. Intra-Arterial Drug and Light Delivery for Photodynamic Therapy Using Visudyne®: Implication for Atherosclerotic Plaque Treatment.

    Science.gov (United States)

    Jain, Manish; Zellweger, Matthieu; Frobert, Aurélien; Valentin, Jérémy; van den Bergh, Hubert; Wagnières, Georges; Cook, Stéphane; Giraud, Marie-Noelle

    2016-01-01

    Photodynamic therapy (PDT), which is based on the activation of photosensitizers with light, can be used to reduce plaque burden. We hypothesized that intra-arterial photosensitizer administration and photo-activation will lead to high and rapid accumulation within the plaque with reduced systemic adverse effects. Thus, this "intra-arterial" PDT would be expected to have less side effects and due to the short time involved would be compatible with percutaneous coronary interventions. We characterized the dose-dependent uptake and efficacy of intra-arterial PDT using Liposomal Verteporfin (Visudyne®), efficient for cancer-PDT but not tested before for PDT of atherosclerosis. Visudyne® (100, 200, and 500 ng/ml) was perfused for 5-30 min in atherosclerotic aorta isolated from ApoE(-/-) mice. The fluorescence Intensity (FI) after 15 min of Visudyne® perfusion increased with doses of 100 (FI-5.5 ± 1.8), 200 (FI-31.9 ± 1.9) or 500 ng/ml (FI-42.9 ± 1.2). Visudyne® (500 ng/ml) uptake also increased with the administration time from 5 min (FI-9.8 ± 2.5) to 10 min (FI-23.3 ± 3.0) and 15 min (FI-42.9 ± 3.4) before reaching saturation at 30 min (FI-39.3 ± 2.4) contact. Intra-arterial PDT (Fluence: 100 and 200 J/cm(2), irradiance-334 mW/cm(2)) was applied immediately after Visudyne® perfusion (500 ng/ml for 15 min) using a cylindrical light diffuser coupled to a diode laser (690 nm). PDT led to an increase of ROS (Dihydroethidium; FI-6.9 ± 1.8, 25.3 ± 5.5, 43.4 ± 13.9) and apoptotic cells (TUNEL; 2.5 ± 1.6, 41.3 ± 15.3, 58.9 ± 6%), mainly plaque macrophages (immunostaining; 0.3 ± 0.2, 37.6 ± 6.4, 45.3 ± 5.4%) respectively without laser irradiation, or at 100 and 200 J/cm(2). Limited apoptosis was observed in the medial wall (0.5 ± 0.2, 8.5 ± 4.7, 15.3 ± 12.7%). Finally, Visudyne®-PDT was found to be associated with reduced vessel functionality (Myogram). We demonstrated that sufficient accumulation of Visudyne® within plaque could be achieved in short

  10. The potential of targeted antiangiogenesis therapies in the treatment of esophageal cancer

    Directory of Open Access Journals (Sweden)

    Xu WW

    2015-04-01

    Full Text Available Wen Wen Xu,1,2 Bin Li,1,2,3 Annie L M Cheung1,2,31Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, 2The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI, 3Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of ChinaAbstract: Esophageal cancer is one of the most lethal cancers worldwide and its incidence is increasing at an alarming rate. Despite advances in surgical techniques and combined multimodality therapy, the survival rate of esophageal cancer remains poor. Clearly, the time is ripe for introducing novel strategies such as targeted therapies to improve treatment outcome. The significance of angiogenesis and angiogenic factors in the progression and aggressiveness of esophageal cancer is well documented. However, although increasing numbers of antiangiogenic agents designed to inhibit angiogenesis through multiple mechanisms have been developed in the past few decades, and some of them have shown promising results in preclinical and clinical studies, there is as yet no antiangiogenic agent approved for esophageal cancer. This review provides a summary of angiogenesis and vasculogenesis, the molecular mechanisms that regulate these processes, and the strategies for targeting angiogenesis in tumors. We will also present the rationale and challenges of antiangiogenic therapy, and the antiangiogenic agents that have been tested in preclinical studies or clinical trials for esophageal cancer. With further research bringing a deeper understanding of the molecular mechanisms involved in angiogenesis, and as new angiogenesis-targeting agents continue to evolve, there are reasons to be optimistic that targeting angiogenesis may bring new opportunities to cure this highly lethal disease.Keywords: esophageal cancer, angiogenesis, vascular endothelial growth factor, targeted therapies

  11. Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor.

    Science.gov (United States)

    Maekawa, R; Maki, H; Yoshida, H; Hojo, K; Tanaka, H; Wada, T; Uchida, N; Takeda, Y; Kasai, H; Okamoto, H; Tsuzuki, H; Kambayashi, Y; Watanabe, F; Kawada, K; Toda, K; Ohtani, M; Sugita, K; Yoshioka, T

    1999-03-15

    The antiangiogenic activity and antitumor efficacy of a newly developed matrix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, but not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMPs tested. Daily oral administration of 200 mg/kg BPHA, but not (-)BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth, and liver metastasis. The growth inhibition activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio-endothelioma model, respectively. BPHA also showed 42% inhibition of the liver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential.

  12. Mechanistic Insights into the Anti-angiogenic Activity of Trypanosoma cruzi Protein 21 and its Potential Impact on the Onset of Chagasic Cardiomyopathy.

    Science.gov (United States)

    Teixeira, Samuel Cota; Lopes, Daiana Silva; Gimenes, Sarah Natalie Cirilo; Teixeira, Thaise Lara; da Silva, Marcelo Santos; Brígido, Rebecca Tavares E Silva; da Luz, Felipe Andrés Cordero; da Silva, Aline Alves; Silva, Makswell Almeida; Florentino, Pilar Veras; Tavares, Paula Cristina Brígido; Dos Santos, Marlus Alves; Ávila, Veridiana de Melo Rodrigues; Silva, Marcelo José Barbosa; Elias, Maria Carolina; Mortara, Renato Arruda; da Silva, Claudio Vieira

    2017-03-21

    Chronic chagasic cardiomyopathy (CCC) is arguably the most important form of the Chagas Disease, caused by the intracellular protozoan Trypanosoma cruzi; it is estimated that 10-30% of chronic patients develop this clinical manifestation. The most common and severe form of CCC can be related to ventricular abnormalities, such as heart failure, arrhythmias, heart blocks, thromboembolic events and sudden death. Therefore, in this study, we proposed to evaluate the anti-angiogenic activity of a recombinant protein from T. cruzi named P21 (rP21) and the potential impact of the native protein on CCC. Our data suggest that the anti-angiogenic activity of rP21 depends on the protein's direct interaction with the CXCR4 receptor. This capacity is likely related to the modulation of the expression of actin and angiogenesis-associated genes. Thus, our results indicate that T. cruzi P21 is an attractive target for the development of innovative therapeutic agents against CCC.

  13. Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity.

    Science.gov (United States)

    Palmer, Kirsten R; Kaitu'u-Lino, Tu'uhevaha J; Hastie, Roxanne; Hannan, Natalie J; Ye, Louie; Binder, Natalie; Cannon, Ping; Tuohey, Laura; Johns, Terrance G; Shub, Alexis; Tong, Stephen

    2015-12-01

    In preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT-1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a-specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a. © 2015 American Heart Association, Inc.

  14. Sp1 inhibition-mediated upregulation of VEGF 165 b induced by rh-endostatin enhances antiangiogenic and anticancer effect of rh-endostatin in A549.

    Science.gov (United States)

    Li, Zhen-yu; Zhu, Fang; Hu, Jian-li; Peng, Gang; Chen, Jing; Zhang, Sheng; Chen, Xu; Zhang, Rui-guang; Chen, Ling-juan; Liu, Pian; Luo, Ming; Sun, Zhi-hua; Ren, Jing-hua; Huang, Li-li; Wu, Gang

    2011-08-01

    Recombinant human endostatin (rh-endostatin), a potential antiangiogenic agent, is used in non-small cell lung carcinoma treatment and represses vascular endothelial cell growth factor (VEGF) levels in tumor cell. However, precise affection of rh-endostatin on the proangiogenic VEGF isoforms (VEGF(165)) or antiangiogenic VEGF isoforms (VEGF(165)b) is not clear. We therefore tested the hypothesis that rh-endostatin could alter expression of these isoforms to regulate tumor growth. A549 cells were exposed to rh-endostatin, and the expression of VEGF(165) and VEGF(165)b was detected. The role of SP1 as a regulator of isoform expression was investigated. We then examined the anticancer and antiangiogenic efficacy of rh-endostatin in combination with exogenous VEGF(165)b against A549 cells, EA.HY 926 cells and xenograft model of human lung cancer. rh-Endostatin reduced VEGF(165) and induced VEGF(165)b as well as inhibited SP1 in A549 cells. SP1 inhibitor (betulinic acid) also developed those changes. VEGF(165)b-rh-endostatin combination was highly synergistic and inhibited growth, survival, and migration of A549 cells, VEGF-mediated VEGFR2 phosphorylation in EA.HY 926 cells, and tumor growth in xenograft model of human lung cancer. rh-Endostatin downregulates proangiogenic vascular endothelial growth factor A (VEGFA) isoform and upregulates antiangiogenic VEGFA isoform, possibly through inhibition of SP1. Furthermore, VEGF(165)b sensitizes A549 to rh-endostatin treatment and enhances the anticancer effect of rh-endostatin.

  15. Zinc-chelation contributes to the anti-angiogenic effect of ellagic acid on inhibiting MMP-2 activity, cell migration and tube formation.

    Directory of Open Access Journals (Sweden)

    Sheng-Teng Huang

    Full Text Available BACKGROUND: Ellagic acid (EA, a dietary polyphenolic compound, has been demonstrated to exert anti-angiogenic effect but the detailed mechanism is not yet fully understood. The aim of this study was to investigate whether the zinc chelating activity of EA contributed to its anti-angiogenic effect. METHODS AND PRINCIPAL FINDINGS: The matrix metalloproteinases-2 (MMP-2 activity, a zinc-required reaction, was directly inhibited by EA as examined by gelatin zymography, which was reversed dose-dependently by adding zinc chloride. In addition, EA was demonstrated to inhibit the secretion of MMP-2 from human umbilical vein endothelial cells (HUVECs as analyzed by Western blot method, which was also reversed by the addition of zinc chloride. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK, known to down-regulate the MMP-2 activity, was induced by EA at both the mRNA and protein levels which was correlated well with the inhibition of MMP-2 activity. Interestingly, zinc chloride could also abolish the increase of EA-induced RECK expression. The anti-angiogenic effect of EA was further confirmed to inhibit matrix-induced tube formation of endothelial cells. The migration of endothelial cells as analyzed by transwell filter assay was suppressed markedly by EA dose-dependently as well. Zinc chloride could reverse these two effects of EA also in a dose-dependent manner. Since magnesium chloride or calcium chloride could not reverse the inhibitory effect of EA, zinc was found to be involved in tube formation and migration of vascular endothelial cells. CONCLUSIONS/SIGNIFICANCE: Together these results demonstrated that the zinc chelation of EA is involved in its anti-angiogenic effects by inhibiting MMP-2 activity, tube formation and cell migration of vascular endothelial cells. The role of zinc was confirmed to be important in the process of angiogenesis.

  16. Mechanistic Insights into the Anti-angiogenic Activity of Trypanosoma cruzi Protein 21 and its Potential Impact on the Onset of Chagasic Cardiomyopathy

    OpenAIRE

    Samuel Cota Teixeira; Daiana Silva Lopes; Sarah Natalie Cirilo Gimenes; Thaise Lara Teixeira; Marcelo Santos da Silva; Rebecca Tavares e Silva Brígido; Felipe Andrés Cordero da Luz; Aline Alves da Silva; Makswell Almeida Silva; Pilar Veras Florentino; Paula Cristina Brígido Tavares; Marlus Alves dos Santos; Veridiana de Melo Rodrigues Ávila; Marcelo José Barbosa Silva; Maria Carolina Elias

    2017-01-01

    Chronic chagasic cardiomyopathy (CCC) is arguably the most important form of the Chagas Disease, caused by the intracellular protozoan Trypanosoma cruzi; it is estimated that 10?30% of chronic patients develop this clinical manifestation. The most common and severe form of CCC can be related to ventricular abnormalities, such as heart failure, arrhythmias, heart blocks, thromboembolic events and sudden death. Therefore, in this study, we proposed to evaluate the anti-angiogenic activity of a ...

  17. Mechanisms of action and resistance to anti-angiogenic small-molecule tyrosine kinase inhibitors in preclinical breast cancer and pancreatic neuroendocrine tumor mouse models

    OpenAIRE

    Bill, Ruben

    2015-01-01

    „Cancer“ – this one term is used to name a large spectrum of different syndromes, ranging from the relatively indolent chronic lymphocytic leukemia to highly lethal cancer types such as glioblastoma multiforme with a median survival of about 15 months even when treated with upfront treatment schedules. Based on the notion that tumors critically rely on their own blood supply, targeting the tumor blood vasculature by anti-angiogenic therapeutics has been implemented as an important treatment m...

  18. Anti-angiogenic effect of Nelumbo nucifera leaf extracts in human umbilical vein endothelial cells with antioxidant potential.

    Directory of Open Access Journals (Sweden)

    Jong Suk Lee

    Full Text Available Nelumbo nucifera Gaertn (Nymphaeaceae has long been used as a traditional herb in Chinese, Japanese, Indian, and Korean medicinal practices since prehistoric times and flourishes today as the primary form of medicine. This study reports for the first time the potent ability of N. nucifera leaf extracts to inhibit vascular endothelial growth factor (VEGF-induced angiogenesis in vitro and in vivo, as well as their antioxidant efficacy in various scavenging models and an analysis of their chemical composition. In vivo anti-angiogenic activity was evaluated in a chick chorioallantoic membrane (CAM model using fertilized chicken eggs, in human umbilical vein endothelial cells (HUVECs by using cell viability, cell proliferation and tube formation assays, and by determining intracellular reactive oxygen species (ROS in vitro. The antioxidant efficacy of N. nucifera leaf extracts was determined in various scavenging models, including total phenolic and flavonoid content. The chemical composition of N. nucifera leaf extracts was determined by GC-MS analysis, which revealed the presence of different phytochemicals. The IC50 values for the DPPH radical scavenging activities of water and methanol extracts were found to be 1699.47 and 514.36 μg ml(-1, and their total phenolic and flavonoid contents were 85.01 ± 2.32 and 147.63 ± 2.23 mg GAE g dry mass(-1 and 35.38 ± 1.32 and 41.86 ± 1.07 mg QA g dry mass(-1, respectively. N. nucifera leaf extracts (10-100 μg ml(-1 exhibited significant dose-dependent inhibition of VEGF-induced angiogenesis, as well as VEGF-induced proliferation and tube formation in HUVECs. In this study, N. nucifera leaf extracts displayed potent antioxidant and inhibitory effects on VEGF-induced angiogenesis. N. nucifera exerted an inhibitory effect on VEGF-induced proliferation and tube formation, as well as CAM angiogenesis in vivo. Moreover, N. nucifera leaf extracts significantly blocked VEGF-induced ROS production in HUVECs

  19. Anti-angiogenic effect of Nelumbo nucifera leaf extracts in human umbilical vein endothelial cells with antioxidant potential.

    Science.gov (United States)

    Lee, Jong Suk; Shukla, Shruti; Kim, Jung-Ae; Kim, Myunghee

    2015-01-01

    Nelumbo nucifera Gaertn (Nymphaeaceae) has long been used as a traditional herb in Chinese, Japanese, Indian, and Korean medicinal practices since prehistoric times and flourishes today as the primary form of medicine. This study reports for the first time the potent ability of N. nucifera leaf extracts to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo, as well as their antioxidant efficacy in various scavenging models and an analysis of their chemical composition. In vivo anti-angiogenic activity was evaluated in a chick chorioallantoic membrane (CAM) model using fertilized chicken eggs, in human umbilical vein endothelial cells (HUVECs) by using cell viability, cell proliferation and tube formation assays, and by determining intracellular reactive oxygen species (ROS) in vitro. The antioxidant efficacy of N. nucifera leaf extracts was determined in various scavenging models, including total phenolic and flavonoid content. The chemical composition of N. nucifera leaf extracts was determined by GC-MS analysis, which revealed the presence of different phytochemicals. The IC50 values for the DPPH radical scavenging activities of water and methanol extracts were found to be 1699.47 and 514.36 μg ml(-1), and their total phenolic and flavonoid contents were 85.01 ± 2.32 and 147.63 ± 2.23 mg GAE g dry mass(-1) and 35.38 ± 1.32 and 41.86 ± 1.07 mg QA g dry mass(-1), respectively. N. nucifera leaf extracts (10-100 μg ml(-1)) exhibited significant dose-dependent inhibition of VEGF-induced angiogenesis, as well as VEGF-induced proliferation and tube formation in HUVECs. In this study, N. nucifera leaf extracts displayed potent antioxidant and inhibitory effects on VEGF-induced angiogenesis. N. nucifera exerted an inhibitory effect on VEGF-induced proliferation and tube formation, as well as CAM angiogenesis in vivo. Moreover, N. nucifera leaf extracts significantly blocked VEGF-induced ROS production in HUVECs, confirming

  20. Molecular Interaction and Computational Analytical Studies of Pinocembrin for its Antiangiogenic Potential Targeting VEGFR-2: A Persuader of Metastasis.

    Science.gov (United States)

    Sharma, Neha; Sharma, Mala; Shakeel, Eram; Jamal, Qazi M Sajid; Kamal, Mohammad A; Sayeed, Usman; Khan, Mohammad K A; Siddiqui, Mohammad H; Arif, Jamal M; Akhtar, Salman

    2018-04-16

    Designing a novel antagonist against VEGFR-2 is being applied currently to inhibit cancer growth and metastasis. Because of the unexpected side effects incurred by the contemporary anticancer medications, the focus has been laid towards identifying natural compounds that might carry the potential to inhibit tumor progression. VEGR-2 remains an important target for anticancer drug development as it is the master regulator of vascular growth. The study focuses on virtual screening of compounds from plants of Asteraceae family that bears antiangiogenic potential and thus, inhibiting VEGFR-2 using a computational approach. Structures of phytochemicals were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, VEGFR-2 was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling were carried out on the phytochemicals of the Asteraceae family and the filtered compounds were further promoted for molecular docking and MD simulation analysis. The study extends towards the SOM analysis of Pinocembrin to predict the possible toxic and non-toxic in vivo metabolites via in silico tools (Xenosite Web and PASS online server) Results: The docking results revealed promising inhibitory potential of Pinocembrin against VEGFR-2 with binding energy of -8.50 kcal/mole as compared to its known inhibitors Sorafenib and YLT192 having binding energy of -6.49 kcal/mole and -8.02 kcal/mol respectively. Further, molecular dynamics (MD) simulations for 10ns were conducted for optimization, flexibility prediction, and determination of folded VEGFR-2 stability. The Hsp90-Pinocembrin complex was found to be quite stable with RMSD value of 0.2nm. Pinocembrin was found to be metabolically stable undergoing phase I metabolism with non-toxic metabolites compared to the standard drug Sorafenib and YLT192. Obtained results propose Pinocembrin as a multi-targeted novel lead compound that bears

  1. Measuring turnover of SIV DNA in resting CD4+ T cells using pyrosequencing: implications for the timing of HIV eradication therapies.

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    Jeanette C Reece

    Full Text Available Resting CD4+ T cells are a reservoir of latent HIV-1. Understanding the turnover of HIV DNA in these cells has implications for the development of eradication strategies. Most studies of viral latency focus on viral persistence under antiretroviral therapy (ART. We studied the turnover of SIV DNA resting CD4+ T cells during active infection in a cohort of 20 SIV-infected pigtail macaques. We compared SIV sequences at two Mane-A1*084:01-restricted CTL epitopes using serial plasma RNA and resting CD4+ T cell DNA samples by pyrosequencing, and used a mathematical modeling approach to estimate SIV DNA turnover. We found SIV DNA turnover in resting CD4+ T cells was slow in animals with low chronic viral loads, consistent with the long persistence of latency seen under ART. However, in animals with high levels of chronic viral replication, turnover was high. SIV DNA half-life within resting CD4 cells correleated with viral load (p = 0.0052 at the Gag KP9 CTL epitope. At a second CTL epitope in Tat (KVA10 there was a trend towards an association of SIV DNA half-life in resting CD4 cells and viral load (p = 0.0971. Further, we found that the turnover of resting CD4+ T cell SIV DNA was higher for escape during early infection than for escape later in infection (p = 0.0084. Our results suggest viral DNA within resting CD4 T cells is more labile and may be more susceptible to reactivation/eradication treatments when there are higher levels of virus replication and during early/acute infection.

  2. Determining true HER2 gene status in breast cancers with polysomy by using alternative chromosome 17 reference genes: implications for anti-HER2 targeted therapy.

    Science.gov (United States)

    Tse, Chun Hing; Hwang, Harry C; Goldstein, Lynn C; Kandalaft, Patricia L; Wiley, Jesse C; Kussick, Steven J; Gown, Allen M

    2011-11-01

    The ratio of human epidermal growth factor receptor 2 (HER2) to CEP17 by fluorescent in situ hybridization (FISH) with the centromeric probe CEP17 is used to determine HER2 gene status in breast cancer. Increases in CEP17 copy number have been interpreted as representing polysomy 17. However, pangenomic studies have demonstrated that polysomy 17 is rare. This study tests the hypothesis that the use of alternative chromosome 17 reference genes might more accurately assess true HER2 gene status. In all, 171 patients with breast cancer who had HER2 FISH that had increased mean CEP17 copy numbers (> 2.6) were selected for additional chromosome 17 studies that used probes for Smith-Magenis syndrome (SMS), retinoic acid receptor alpha (RARA), and tumor protein p53 (TP53) genes. A eusomic copy number exhibited in one or more of these loci was used to calculate a revised HER2-to-chromosome-17 ratio by using the eusomic gene locus as the reference. Of 132 cases classified as nonamplified on the basis of their HER2:CEP17 ratios, 58 (43.9%) were scored as amplified by using alternative chromosome 17 reference gene probes, and 13 (92.9%) of 14 cases scored as equivocal were reclassified as amplified. Among the cases with mean HER2 copy number of 4 to 6, 41 (47.7%) of 86 had their HER2 gene status upgraded from nonamplified to amplified, and four (4.7%) of 86 were upgraded from equivocal to amplified. Our results support the findings of recent pangenomic studies that true polysomy 17 is uncommon. Additional FISH studies that use probes to the SMS, RARA, and TP53 genes are an effective way to determine the true HER2 amplification status in patients with polysomy 17 and they have important potential implications for guiding HER2-targeted therapy in breast cancer.

  3. SU-E-T-375: Passive Scattering to Pencil-Beam-Scanning Comparison for Medulloblastoma Proton Therapy: LET Distributions and Radiobiological Implications

    Energy Technology Data Exchange (ETDEWEB)

    Giantsoudi, D; MacDonald, S; Paganetti, H [Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)

    2014-06-01

    Purpose: To compare the linear energy transfer (LET) distributions between passive scattering and pencil beam scanning proton radiation therapy techniques for medulloblastoma patients and study the potential radiobiological implications. Methods: A group of medulloblastoma patients, previously treated with passive scattering (PS) proton craniospinal irradiation followed by prosterior fossa or involved field boost, were selected from the patient database of our institution. Using the beam geometry and planning computed tomography (CT) image sets of the original treatment plans, pencil beam scanning (PBS) treatment plans were generated for the cranial treatment for each patient, with average beam spot size of 8mm (sigma in air at isocenter). 3-dimensional dose and LET distributions were calculated by Monte Carlo methods (TOPAS) both for the original passive scattering and new pencil beam scanning treatment plans. LET volume histograms were calculated for the target and OARs and compared for the two delivery methods. Variable RBE weighted dose distributions and volume histograms were also calculated using a variable dose and LET-based model. Results: Better dose conformity was achieved with PBS planning compared to PS, leading to increased dose coverage for the boost target area and decreased average dose to the structures adjacent to it and critical structures outside the whole brain treatment field. LET values for the target were lower for PBS plans. Elevated LET values for OARs close to the boosted target areas were noticed, due to end of range of proton beams falling inside these structures, resulting in higher RBE weighted dose for these structures compared to the clinical RBE value of 1.1. Conclusion: Transitioning from passive scattering to pencil beam scanning proton radiation treatment can be dosimetrically beneficial for medulloblastoma patients. LET–guided treatment planning could contribute to better decision making for these cases, especially for

  4. Combination of thalidomide and cisplatin in an head and neck squamous cell carcinomas model results in an enhanced antiangiogenic activity in vitro and in vivo.

    Science.gov (United States)

    Vasvari, Gergely P; Dyckhoff, Gerhard; Kashfi, Farzaneh; Lemke, Britt; Lohr, Jennifer; Helmke, Burkhard M; Schirrmacher, Volker; Plinkert, Peter K; Beckhove, Philipp; Herold-Mende, Christel C

    2007-10-15

    Thalidomide is an immunomodulatory, antiangiogenic drug. Although there is evidence that it might be more effective in combination with chemotherapy the exact mechanism of action is unclear. Therefore, we investigated its effect in combination with metronomically applied cisplatin in a xenotransplant mouse model characteristic for advanced head and neck squamous cell carcinomas, its possible synergistic action in vitro, and which tumor-derived factors might be targeted by thalidomide. Although thalidomide alone was ineffective, a combined treatment with low-dose cisplatin inhibited significant tumor growth, proliferation and angiogenesis in vivo as well as migration and tube formation of endothelial cells in vitro. Noteworthy, the latter effect was enhanced after coapplication of cisplatin in nontoxic doses. An inhibitory effect on tumor cell migration was also observed suggesting a direct antitumor effect. Although thalidomide alone did not influence cell proliferation, it augmented antiproliferative response after cisplatin application emphasizing the idea of a potentiated effect when both drugs are combined. Furthermore, we could show that antiangiogenic effects of thalidomide are related to tumor-cell derived factors including vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and Il-8 some known and with, granulocyte colony stimulating growth factor and granulocyte macrophage colony stimulating growth factor, some new target molecules of thalidomide. Altogether, our findings reveal new insights into thalidomide-mediated antitumor and antiangiogenic effects and its interaction with cytostatic drugs. (c) 2007 Wiley-Liss, Inc.

  5. Radiological evaluation of response to treatment: Application to metastatic renal cancers receiving anti-angiogenic treatment

    International Nuclear Information System (INIS)

    Ammari, S.; Hernigou, A.; Grataloup, C.; Thiam, R.; Cuenod, C.A.; Siauve, N.; Fournier, L.S.; Oudard, S.; Medioni, J.

    2014-01-01

    Targeted therapies have considerably improved the prognosis of patients with metastatic renal cancer (mRCC) but there are no reliable response assessment criteria reflecting the clinical benefits, because there is no regression in size, or it is delayed. Such criteria would help early identification of non-responders, who would then benefit from a change of treatment, and would avoid their being subjected to unnecessary side effects related to the treatment. We will review the imaging techniques currently available for evaluating tumour response in mRCC patients, including the response evaluation criteria in solid tumours (RECIST), the Choi criteria, the modified Choi criteria, and the CT size and attenuation criteria (SACT). We will also discuss functional imaging techniques, which are based on the physiological characteristics of the tumours, such as perfusion CT, magnetic resonance imaging or ultrasound (DCE-CT, DCE-MRI, DCE-US), diffusion MRI, BOLD MRI and new positron emission tomography (PET) tracers. It is not possible at present to propose a unanimously acknowledged criterion for evaluating tumour response to targeted therapy. However, there is a real need for this according to oncologists and the pharmaceutical industry, and radiologists need to be involved in reflecting on the subject. (authors)

  6. Electroconvulsive therapy modulates plasma pigment epithelium-derived factor in depression: a proteomics study.

    Science.gov (United States)

    Ryan, K M; Glaviano, A; O'Donovan, S M; Kolshus, E; Dunne, R; Kavanagh, A; Jelovac, A; Noone, M; Tucker, G M; Dunn, M J; McLoughlin, D M

    2017-03-28

    Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increa