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Sample records for underlying cancer induction

  1. OVULATION INDUCTION AGENTS AND OVARIAN CANCER

    Directory of Open Access Journals (Sweden)

    Barbara Požlep

    2001-10-01

    Full Text Available Background. Ovarian cancer is the most frequentcause of death among gynecologic malignancies. Epidemiologicaldata show that environmental, hormonal and geneticfactors are etiologically significant. Beside the already knownrisk factors, ovulation induction agents have been reported asrisk factors in literature since 1986. Over the last two decades,ovulation induction agents have been widely used in variousassisted reproduction techniques (ART. This study focusedon the question whether in patients receiving ovulation inductionagents the risk for developing pathologic processes onthe ovaries was higher than in those not receiving them, andwhether they were related to the dose and type of ovulationinduction agent.Methods. In a prospective study 380 subjects were enrolled.The study group consisted of 280 women who had undergonean ART procedure three or more times. The control group consistedof 120 infertile women, never included in an ART procedure.All the enrolled subjects underwent the same examinations:a detailed gynecological history was taken, pelvic examinationand vaginal ultrasound were performed, and a bloodsample for tumour marker CA 125 determination was taken.Statistical analysis was done using Chi-square test, t test andlogistic regression.Results. Ultrasound examination revealed pathology on thegenital tract in 136 women in the study group and in 60 womenin the control group. Differences in the incidence of ovarian,tubal and uterine pathology were not statistically significant.The analysis of the medical records showed that the incidenceof ovarian pathology was significantly higher in thestudy than in the control group (p < 0.05. We found no correlationbetween the incidence of ovarian pathology and typeor dose of ovulation induction agent. Increased CA 125 levelswere found in 12 women. In none of the women neither malignantnor borderline malignant disease was found.Conclusions. Although the analysis of the data from medicalhistory showed

  2. Senescence induction; a possible cancer therapy

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    Kondoh Hiroshi

    2009-01-01

    Full Text Available Abstract Cellular immortalization is a crucial step during the development of human cancer. Primary mammalian cells reach replicative exhaustion after several passages in vitro, a process called replicative senescence. During such a state of permanent growth arrest, senescent cells are refractory to physiological proliferation stimuli: they have altered cell morphology and gene expression patterns, although they remain viable with preserved metabolic activity. Interestingly, senescent cells have also been detected in vivo in human tumors, particularly in benign lesions. Senescence is a mechanism that limits cellular lifespan and constitutes a barrier against cellular immortalization. During immortalization, cells acquire genetic alterations that override senescence. Tumor suppressor genes and oncogenes are closely involved in senescence, as their knockdown and ectopic expression confer immortality and senescence induction, respectively. By using high throughput genetic screening to search for genes involved in senescence, several candidate oncogenes and putative tumor suppressor genes have been recently isolated, including subtypes of micro-RNAs. These findings offer new perspectives in the modulation of senescence and open new approaches for cancer therapy.

  3. Beta Human Chorionic Gonadotropin - Induction of Apoptosis in Breast Cancer

    Science.gov (United States)

    2006-01-01

    AD_________________ Award Number: DAMD17-00-1-0682 TITLE: Beta Human Chorionic Gonadotropin ...Beta Human Chorionic Gonadotropin – Induction of Apoptosis in Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER DAMD17-00-1-0682 5c...is increased in breast cancer cells after treatment with hCG 9 REPORTABLE OUTCOMES: 1. Human Chorionic Gonadotropin (hCG) induction of

  4. Cancer under graviditeten

    DEFF Research Database (Denmark)

    Pedersen, Berit Woetmann; Storgaard, Lone; Clausen, Mette Borg

    2015-01-01

    Cancer in pregnancy occurs in about one in 1,000 pregnancies. Recent reports have shown that most treatment regimes in second and third trimester are safe for the mother and the child. This has led to a paradigm shift in treating pregnant women with cancer. The management of the pregnant woman...

  5. Radiation induction of cancer of the skin

    International Nuclear Information System (INIS)

    Fry, R.J.M.; Storer, J.B.; Burns, F.J.

    1985-01-01

    The induction of epidermal tumors was studied using exposures to 25 kV x-rays with or without subsequent exposures to 12-0-tetradeconyl phorbol-13 acetate (TPA) or ultraviolet radiation (uvr) 280-400 nm. Fractionation regimens and total exposure up to 4000R produced no squamous cell carcinomas. When these regimes were followed by TPA an incidence of about 80% was obtained, and incidence of 60% when uvr exposures followed the x-irradiation. A dose-dependent increase in fibrosarcomas was found when x-irradiation was followed by 24 weeks of topical treatment with TPA. These results support the contention that uvr can enhance the expression of cells initiated by x-rays. The experimental evidence is compared with the data from the tinea capitis patients treated with x-rays. In C3HF/He male mice exposed to 50, 100, 150 and 200 rads 137 Cs gamma rays the induction rate for fibrosarcomas was 2.9 x 10 -4 per cGy/per mouse. This result compares with 2.5 x 10 -6 transformations per surviving cell per cGy with 10T1/2 cells that are fibroblasts derived from C3H mice. 16 refs., 1 fig., 1 tab

  6. Induction of apoptosis by eugenol in human breast cancer cells

    International Nuclear Information System (INIS)

    Vidhya, N.; Niranjali Devaraj, S.

    2011-01-01

    In the present study, potential anticancer effect of eugenol on inhibition of cell proliferation and induction of apoptosis in human MCF-7 breast cancer cells was investigated. Induction of cell death by eugenol was evaluated following MTT assay and monitoring lactate dehydrogenase released into the culture medium for cell viability and cytotoxicity, giemsa staining for morphological alterations, fluorescence microscopy analysis of cells using ethidium bromide and acridine orange and quantitation of DNA fragments for induction of apoptosis. Effect of eugenol on intracellular redox status of the human breast cancer cells was assessed by determining the level of glutathione and lipid peroxidation products (TBARS). Eugenol treatment inhibited the growth and proliferation of human MCF-7 breast cancer cells through induction of cell death, which was dose and time dependent. Microscopic examination of eugenol treated cells showed cell shrinkage, membrane blebbing and apoptotic body formation. Further, eugenol treatment also depleted the level of intracellular glutathione and increased the level of lipid peroxidation. The dose dependent increase in the percentage of apoptotic cells and DNA fragments suggested that apoptosis was involved in eugenol induced cell death and apoptosis might have played a role in the chemopreventive action of eugenol. (author)

  7. Neural mechanisms underlying the induction and relief of perceptual curiosity

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    Marieke eJepma

    2012-02-01

    Full Text Available Curiosity is one of the most basic biological drives in both animals and humans, and has been identified as a key motive for learning and discovery. Despite the importance of curiosity and related behaviors, the topic has been largely neglected in human neuroscience; hence little is known about the neurobiological mechanisms underlying curiosity. We used functional magnetic resonance imaging (fMRI to investigate what happens in our brain during the induction and subsequent relief of perceptual curiosity. Our core findings were that (i the induction of perceptual curiosity, through the presentation of ambiguous visual input, activated the anterior insula and anterior cingulate cortex, brain regions sensitive to conflict and arousal; (ii the relief of perceptual curiosity, through visual disambiguation, activated regions of the striatum that have been related to reward processing; and (iii the relief of perceptual curiosity was associated with hippocampal activation and enhanced incidental memory. These findings provide the first demonstration of the neural basis of human perceptual curiosity. Our results provide neurobiological support for a classic psychological theory of curiosity, which holds that curiosity is an aversive condition of increased arousal whose termination is rewarding and facilitates memory.

  8. Cancer-selective induction of apotosis by leczyme

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    Takeo eTatsuta

    2014-06-01

    Full Text Available Sialic acid-binding lectin (SBL is a multifunctional protein that is isolated from oocytes of Rana catesbeiana. It has both lectin and ribonuclease (enzyme properties, and therefore is called leczyme. We examined the antitumor effects of SBL and discovered that SBL has potential as a new type of anticancer drug. SBL causes a cancer-selective induction of apoptosis by multiple signaling pathways whereby RNA is its target. It is suggested that the mitochondrial pathway and endoplasmic reticulum stress-mediated pathway participate in SBL-induced signaling. The synergistic antitumor effects with other molecules, such as tumor necrosis factor-related apoptosis ligand (TRAIL and interferon γ (IFN-γ, have been reported. In this study, we summarize the effects of SBL and focus on its cancer-selective apoptotic properties. In addition, we present a possible explanation its cancer specificity.

  9. The effect of temperature on photosynthetic induction under fluctuating light in Chrysanthemum morifolium

    DEFF Research Database (Denmark)

    Öztürk, Isik; Ottosen, Carl-Otto; Ritz, Christian

    2013-01-01

    for photosynthetic induction. Gas exchange measurements were used to investigate the rate of induction and the opening of stomata. It was determined that induction equilibrium for C. morifolium at varying temperatures under dynamic light conditions was reached within 15 to 45 minutes except at saturating light...... intensity. For the same photon irradiance, the momentary state of induction equilibrated was higher approximately at 30° C and it decreased as temperature increased. The interaction effect of irradiance and temperature on induction equilibrium was not significant. The rate of photosynthetic induction...

  10. ATM induction insufficiency in a radiosensitive breast-cancer patient

    International Nuclear Information System (INIS)

    Clarke, R.A.; Fang, Z.H.; Marr, P.J.; Kearsley, J.H.; Papadatos, G.; Lee, C.S.; University of Sydney, Camperdown, NSW

    2002-01-01

    ATM induction insufficiency in a radiosensitive breast-cancer patient The ataxia telangiectasia (A-T) gene (ATM) is a dominant breast cancer gene with tumour suppressor activity. ATM also regulates cellular sensitivity to ionising radiation (IR) presumably through its role as a facilitator of DNA repair. In normal cells and tissues the ATM protein is rapidly induced by IR to threshold/maximum levels. The kinase function of the ATM protein is also rapidly activated in response to IR. The fact that women carriers of ATM mutations can have an increased risk of developing breast cancer and that many sporadic breast tumours have reduced levels of the ATM protein broadens the scope of ATM's tumour suppressor within the breast. This report describes the downregulation of ATM protein levels in a radiosensitive breast cancer patient. Postinduction ATM levels were up to tenfold lower in the patient's fresh tissues compared to normal controls. These results might indicate a much broader role for ATM anomalies in breast cancer aetiology. Copyright (2002) Blackwell Science Pty Ltd

  11. Radiation oxidative stress in cancer induction and prevention

    International Nuclear Information System (INIS)

    Meher, Prabodha Kumar; Mishra, Kaushala Prasad

    2017-01-01

    Exposure of cells to ionizing radiation causes generation of intracellular reactive oxygen species (ROS) which are implicated in the mechanism of carcinogenesis. Molecular steps involved in the transformation of normal cells to cancer cells have been enigmatic but generally believed to arise from aberration in cellular redox homeostasis. In normal cell function, a delicate balance is maintained between ROS generated in the metabolic process and level of endogenous antioxidant defense. ROS are known to regulate various cellular functions, such as cell division, signal transduction, and apoptosis. Cells experience oxidative stress when excess production of ROS occurs inside a cell upon exposure to external stress or agents. This redox imbalance affects the cellular functions due to DNA strand breaks, chromosomal aberrations, gene mutations, alteration in signal transduction, and inhibition of apoptosis leading to induction of cancer and other diseases. Radiation-induced ROS are involved in initiation and promotion of carcinogenesis. Therefore, detoxification of ROS by exogenous antioxidants including dietary polyphenols offers an important strategy for cancer prevention. Recent research results have shown that resistance of cancer stem cells to therapies is linked to low level of ROS. Interestingly, in vitro and in vivo experiments have reported that radiotherapy- and chemotherapy-induced ROS in cytosol sensitize the tumor cells to death, resulting in tumor growth retardation. This review is an attempt to delineate mechanisms of ROS in carcinogenesis and prevention by dietary compounds. Natural polyphenols and dietary antioxidants hold potential to prevent cancer. Interventions in ROS-mediated signal alteration, apoptosis activation, and modulation of epigenetic processes may offer effective cancer prevention strategy. (author)

  12. Radiogenic cancer induction associated with spinal radiography: a quantitative analysis

    International Nuclear Information System (INIS)

    Fickel, T.E.

    1988-01-01

    Computations of organ-specific radiation absorption by lung, breast, thyroid, active bone marrow and uterine tissues are used to rank sectional and full spine radiographic procedures according to their potentials for cancer induction. Assuming that the dose-effect relationship of radiation damage is linear and lacks a threshold effect, the prospective and retrospective carcinogenicities of commonly ordered spinal series are estimated. Cervical radiography is demonstrated to pose the least hazard to the patient, while full spine and lumbar (five views) procedures have the greatest. Organs most at risk as a result of spinal radiography are lung (thoracic and full spine), colon (lumbar and full spine), breast (thoracic and full spine), and prostate (full spine and lumbar)

  13. Doubly-Fed Induction Generator Control Under Voltage Sags

    DEFF Research Database (Denmark)

    Teodorescu, Remus; Blaabjerg, Frede; Lima, K.

    2008-01-01

    This paper proposes a new control technique to improve the fault-ride through capability of doubly fed induction generators (DFIG). In such generators the appearance of severe voltage sags at the coupling point make rise to high over currents at the rotor/stator windings, something that makes nec...

  14. Polyploidy induction in Phlox paniculata L. under in vitro conditions

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    Pavel Matiska

    2010-01-01

    Full Text Available The objective of this work was to find an effective method of polyploidy induction using chemomutagens, colchicine and oryzalin, in diploid cultivar of Phlox paniculata ‘Fujiyama’ (syn. Mt. Fuji, Fuji. Ploidy level was determined by the flow cytometry method (FCM. Two methods of treating the explants (in vitro regenerated shoots were tested; chemomutagen infiltration from nutrient media (“the infiltration method” and dipping of the explants in a chemical mutagen solution (“the dip method”. The highest values of tetraploid (5%, mixoploid (1.67% frequency and polyploidization efficiency (1.25 were found in explants treated with 0.2% colchicine for 24 h in the dip method. Concentrations of 10 µM oryzalin and 0.2% colchicine for 14 d were the most effective for obtaining tetraploids in the infiltration method. The results will be exploited to other P. paniculata cultivars for breeding of this species.

  15. Methoxyphenyl chalcone sensitizes aggressive epithelial cancer to cisplatin through apoptosis induction and cancer stem cell eradication.

    Science.gov (United States)

    Su, Yu-Kai; Huang, Wen-Chien; Lee, Wei-Hwa; Bamodu, Oluwaseun Adebayo; Zucha, Muhammad Ary; Astuti, Indwiani; Suwito, Heri; Yeh, Chi-Tai; Lin, Chien-Min

    2017-05-01

    Current standard chemotherapy for late stage ovarian cancer is found unsuccessful due to relapse after completing the regimens. After completing platinum-based chemotherapy, 70% of patients develop relapse and resistance. Recent evidence proves ovarian cancer stem cells as the source of resistance. Therefore, treatment strategy to target both cancer stem cells and normal stem cells is essential. In this study, we developed a novel chalcone derivative as novel drug candidate for ovarian cancer treatment. We found that methoxyphenyl chalcone was effective to eliminate ovarian cancer cells when given either as monotherapy or in combination with cisplatin. We found that cell viability of ovarian cancer cells was decreased through apoptosis induction. Dephosphorylation of Bcl2-associated agonist of cell death protein was increased after methoxyphenyl chalcone treatment that led to activation of caspases. Interestingly, this drug also worked as a G2/M checkpoint modulator with alternative ways of DNA damage signal-evoking potential that might work to increase response after cisplatin treatment. In addition, methoxyphenyl chalcone was able to suppress autophagic flux and stemness regulator in ovarian spheroids that decreased their survival. Therefore, combination of methoxyphenyl chalcone and cisplatin showed synergistic effects. Taken together, we believe that our novel compound is a promising novel therapeutic agent for effective clinical treatment of ovarian cancer.

  16. Induction of Immunogenic Cell Death with Non-Thermal Plasma for Cancer Immunotherapy

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    Lin, Abraham G.

    Even with the recent advancements in cancer immunotherapy, treatments are still associated with debilitating side effects and unacceptable fail rates. Induction of immunogenic cell death (ICD) in tumors is a promising approach to cancer treatment that may overcome these deficiencies. Cells undergoing ICD pathways enhance the interactions between cancerous cells and immune cells of the patient, resulting in the generation of anti-cancer immunity. The goal of this therapy relies on the engagement and reestablishment of the patient's natural immune processes to target and eliminate cancerous cells systemically. The main objective of this research was to determine if non-thermal plasma could be used to elicit immunogenic cancer cell death for cancer immunotherapy. My hypothesis was that plasma induces immunogenic cancer cell death through oxidative stress pathways, followed by development of a specific anti-tumor immune response. This was tested by investigating the interactions between plasma and multiple cancerous cells in vitro and validating anti-tumor immune responses in vivo. Following plasma treatment, two surrogate ICD markers, secreted adenosine triphosphate (ATP) and surface exposed calreticulin (ecto-CRT), were emitted from all three cancerous cell lines tested: A549 lung carcinoma cell line, CNE-1 radiation-resistant nasopharyngeal cell line and CT26 colorectal cancer cell line. When these cells were co-cultured with macrophages, cells of the innate immune system, the tumoricidal activity of macrophages was enhanced, thus demonstrating the immunostimulatory activity of cells undergoing ICD. The underlying mechanisms of plasma-induced ICD were also evaluated. When plasma is generated, four major components are produced: electromagnetic fields, ultraviolet radiation, and charged and neutral reactive species. Of these, we determined that plasma-generated charged and short-lived reactive oxygen species (ROS) were the major effectors of ICD. Following plasma

  17. Functionalized magnetic nanowires for chemical and magneto-mechanical induction of cancer cell death

    KAUST Repository

    Martinez Banderas, Aldo Isaac

    2016-10-24

    Exploiting and combining different properties of nanomaterials is considered a potential route for next generation cancer therapies. Magnetic nanowires (NWs) have shown good biocompatibility and a high level of cellular internalization. We induced cancer cell death by combining the chemotherapeutic effect of doxorubicin (DOX)-functionalized iron NWs with the mechanical disturbance under a low frequency alternating magnetic field. (3-aminopropyl)triethoxysilane (APTES) and bovine serum albumin (BSA) were separately used for coating NWs allowing further functionalization with DOX. Internalization was assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal analysis, BSA formulations demonstrated higher internalization and less agglomeration. The functionalized NWs generated a comparable cytotoxic effect in breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by free DOX and non-functionalized NWs formulations. A synergistic cytotoxic effect is obtained when a magnetic field (1 mT, 10 Hz) is applied to cells treated with DOX-functionalized BSA or APTES-coated NWs, (~70% at the highest concentration). In summary, a bimodal method for cancer cell destruction was developed by the conjugation of the magneto-mechanical properties of iron NWs with the effect of DOX producing better results than the individual effects.

  18. Functionalized magnetic nanowires for chemical and magneto-mechanical induction of cancer cell death.

    Science.gov (United States)

    Martínez-Banderas, Aldo Isaac; Aires, Antonio; Teran, Francisco J; Perez, Jose Efrain; Cadenas, Jael F; Alsharif, Nouf; Ravasi, Timothy; Cortajarena, Aitziber L; Kosel, Jürgen

    2016-10-24

    Exploiting and combining different properties of nanomaterials is considered a potential route for next generation cancer therapies. Magnetic nanowires (NWs) have shown good biocompatibility and a high level of cellular internalization. We induced cancer cell death by combining the chemotherapeutic effect of doxorubicin (DOX)-functionalized iron NWs with the mechanical disturbance under a low frequency alternating magnetic field. (3-aminopropyl)triethoxysilane (APTES) and bovine serum albumin (BSA) were separately used for coating NWs allowing further functionalization with DOX. Internalization was assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal analysis, BSA formulations demonstrated higher internalization and less agglomeration. The functionalized NWs generated a comparable cytotoxic effect in breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by free DOX and non-functionalized NWs formulations. A synergistic cytotoxic effect is obtained when a magnetic field (1 mT, 10 Hz) is applied to cells treated with DOX-functionalized BSA or APTES-coated NWs, (~70% at the highest concentration). In summary, a bimodal method for cancer cell destruction was developed by the conjugation of the magneto-mechanical properties of iron NWs with the effect of DOX producing better results than the individual effects.

  19. Autologous graft-versus-host disease induction in advanced breast cancer: role of peripheral bloodprogenitor cells

    NARCIS (Netherlands)

    Wall, E. van der; Horn, T.; Bright, E.; Passos-Coehlo, J-L.; Bond, S.; Clarke, B.; Altomonte, V.; McIntyre, K.; Vogelsang, G.; Noga, S.J.; Davis, J.M.; Thomassen, J.; Ohly, K.V.; Lee, S.M.; Fetting, J.; Armstrong, D.K.; Davidson, N.E.; Hess, A.D.; Kennedy, M.J.

    2000-01-01

    The purpose of the present study was to investigate the impact of the use of peripheral blood progenitor cells (PBPCs) on the induction of autologous graft-versus-host disease (GVHD) in patients with advanced breast cancer. 14 women with stage IIIB and 36 women with stage IV breast cancer received

  20. RGE of fission neutrons under the recessive mutation induction in Drosophila Melanogaster

    International Nuclear Information System (INIS)

    Aleksandrov, I.D.; Aleksandrova, M.V.; Lapidus, I.L.; Korablinova, S.V.; )

    2001-01-01

    The RCR-analysis of 81 γ- and neutron-induced vg recessive mutations in ripe sperm of Drosophila melanogaster males of combined with complementation assay with the vg[nw83b27] deletion mutation is used to detect precisely the RGE values of neutrons (0.85 MeV) under the chromosome and point mutation induction. The results obtained show that all genetic end-points increase linearly with γ-ray and neutron dose. Thereby, the efficacy of neutrons is found to be twice (and more) as large as that of γ-rays under the all macro- and micro-aberration mutation induction. Unlike that, the RGE of neutrons are more than twice as low as that of γ-rays under the gene/point mutation induction [ru

  1. Radiation promotes cancer cell metastasis via EMT induction in mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jongkuk; Kang, Sungwook; Hwang, Sanggu; Um, Hongduck [Department of Radiation Cancer, New York (United States); Jang, Su Jin; Kang, Joohyun [Molecular Imaging Research Center, Charlestown (United States); Park, Sunhoo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Wunjae [Chungbuk National Univ., Cheongju (Korea, Republic of)

    2013-05-15

    Whether γ-IR-induced invasion and metastasis are stimulated in our in vitro C6L cell line and in vivo systems, and further identify the associated changes in signal pathways or mice physiology. We constructed an animal model system with a view to clarifying the intracellular molecular events underlying the promotion of metastasis after γ-IR treatment for primary cancer and developing effective anti-metastatic reagents. Our results demonstrate that γ-IR treatment of cancer cell lines and mice xenografts triggers invasion and metastasis. In particular, γ-IR-treated cancer cells or mouse xenografts and metastatic lesions in mice bearing γ-IR-treated xenografts also display typical EMT marker expression patterns, such as increased venetum or MMP-2 expression, decreased E-chondron, and enhanced activity of MMP-2. Our results collectively suggest that γ-IR-induced invasion or metastasis results from induction of EMT, and inhibition of EMT may thus be a means to enhance the effectiveness of radiation therapy. Our results also suggested EMT might be one of the major therapeutic targets to block metastasis.

  2. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway.

    Science.gov (United States)

    Maeda, Masahiro; Moro, Hiroshi; Ushijima, Toshikazu

    2017-03-01

    Multiple pathogenic mechanisms by which Helicobacter pylori infection induces gastric cancer have been established in the last two decades. In particular, aberrant DNA methylation is induced in multiple driver genes, which inactivates them. Methylation profiles in gastric cancer are associated with specific subtypes, such as microsatellite instability. Recent comprehensive and integrated analyses showed that many cancer-related pathways are more frequently altered by aberrant DNA methylation than by mutations. Aberrant DNA methylation can even be present in noncancerous gastric mucosae, producing an "epigenetic field for cancerization." Mechanistically, H. pylori-induced chronic inflammation, but not H. pylori itself, plays a direct role in the induction of aberrant DNA methylation. The expression of three inflammation-related genes, Il1b, Nos2, and Tnf, is highly associated with the induction of aberrant DNA methylation. Importantly, the degree of accumulated aberrant DNA methylation is strongly correlated with gastric cancer risk. A recent multicenter prospective cohort study demonstrated the utility of epigenetic cancer risk diagnosis for metachronous gastric cancer. Suppression of aberrant DNA methylation by a demethylating agent was shown to inhibit gastric cancer development in an animal model. Induction of aberrant DNA methylation is the major pathway by which H. pylori infection induces gastric cancer, and this can be utilized for translational opportunities.

  3. Theoretical and Experimental Estimations of Volumetric Inductive Phase Shift in Breast Cancer Tissue

    Science.gov (United States)

    González, C. A.; Lozano, L. M.; Uscanga, M. C.; Silva, J. G.; Polo, S. M.

    2013-04-01

    Impedance measurements based on magnetic induction for breast cancer detection has been proposed in some studies. This study evaluates theoretical and experimentally the use of a non-invasive technique based on magnetic induction for detection of patho-physiological conditions in breast cancer tissue associated to its volumetric electrical conductivity changes through inductive phase shift measurements. An induction coils-breast 3D pixel model was designed and tested. The model involves two circular coils coaxially centered and a human breast volume centrally placed with respect to the coils. A time-harmonic numerical simulation study addressed the effects of frequency-dependent electrical properties of tumoral tissue on the volumetric inductive phase shift of the breast model measured with the circular coils as inductor and sensor elements. Experimentally; five female volunteer patients with infiltrating ductal carcinoma previously diagnosed by the radiology and oncology departments of the Specialty Clinic for Women of the Mexican Army were measured by an experimental inductive spectrometer and the use of an ergonomic inductor-sensor coil designed to estimate the volumetric inductive phase shift in human breast tissue. Theoretical and experimental inductive phase shift estimations were developed at four frequencies: 0.01, 0.1, 1 and 10 MHz. The theoretical estimations were qualitatively in agreement with the experimental findings. Important increments in volumetric inductive phase shift measurements were evident at 0.01MHz in theoretical and experimental observations. The results suggest that the tested technique has the potential to detect pathological conditions in breast tissue associated to cancer by non-invasive monitoring. Further complementary studies are warranted to confirm the observations.

  4. Tumor-targeted induction of oxystress for cancer therapy.

    Science.gov (United States)

    Fang, J; Nakamura, H; Iyer, A K

    2007-01-01

    Reactive oxygen species (ROS), such as superoxide anion radicals (O.-2) and hydrogen peroxide (H2O2) are potentially harmful by-products of normal cellular metabolism that directly affect cellular functions. ROS is generated by all aerobic organisms and it seems to be indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, overproduction of these highly reactive oxygen metabolites can initiate lethal chain reactions, which involve oxidation and damage to structures that are crucial for cellular integrity and survival. In fact, many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin and many others exhibit antitumor activity via ROS-dependent activation of apoptotic cell death, suggesting potential use of ROS as an antitumor principle. Thus, a unique anticancer strategy named "oxidation therapy" has been developed by inducing cytotoxic oxystress for cancer treatment. This goal could be achieved mainly by two methods, namely, (i) inducing the generation of ROS directly to solid tumors and (ii) inhibiting the antioxidative enzyme (defense) system of tumor cells. Since 1950s, many strategies have been employed based on the first method, namely, administration of ROS per se (e.g. H2O2) or ROS generating enzyme to tumor bearing animals. However no successful and practical results were obtained probably because of the lack of tumor selective ROS delivery and hence resulting in subsequent induction of severe side effects. To overcome these obstacles, we developed polyethylene glycol (PEG) conjugated O.-2 or H2O2-generating enzymes, xanthine oxidase (XO) and D-amino acid oxidase (DAO) (PEG-DAO) respectively. More recently, a pegylated (PEG) zinc protoporphyrin (PEG-ZnPP) and a highly water soluble micellar formulation of ZnPP based on amphiphilic styrene maleic acid (SMA) copolymer, SMA-ZnPP, are prepared, which are potent inhibitors of heme

  5. Laparoscopic Gastrectomy for Gastric Cancer with Peritoneal Dissemination after Induction Chemotherapy

    Directory of Open Access Journals (Sweden)

    Satoshi Tsutsumi

    2013-12-01

    Full Text Available Gastric cancer with peritoneal dissemination may be diagnosed as unresectable. More recently, as a result of progress in chemotherapy, some patients with peritoneal dissemination have exhibited extended survival. We report on our experience with three patients in whom induction chemotherapy allowed for totally laparoscopic total gastrectomy (TLTG. All three patients were diagnosed as having advanced gastric cancer with peritoneal dissemination using staging laparoscopy. As induction chemotherapy, S-1 combined with cisplatin was administered to two patients and trastuzumab plus capecitabine combined with cisplatin to one patient. TLTG was performed in all patients and there were no postoperative complications. Adjuvant chemotherapy was initiated within 3 weeks after surgery in all three patients. Laparoscopic gastrectomy undertaken after induction chemotherapy was found to be effective and safe; this treatment has the potential to achieve good treatment outcomes in patients with stage IV gastric cancer.

  6. The Role of Mitochondria in Cancer Induction, Progression and Changes in Metabolism.

    Science.gov (United States)

    Rogalinska, Malgorzata

    2016-01-01

    Mitochondria play important roles as energetic centers. Mutations in mitochondrial DNA (mtDNA) were found in several diseases, including cancers. Studies on cytoplasmic hybrids (cybrids) confirm that directed mutation introduced into mtDNA could be a reason for cancer induction. Mitochondria could also be a factor linking cancer transformation and progression. The importance of mitochondria in cancer also confirms their involvement in the resistance to treatment. Resistance to treatment of cancer cells can frequently be a reason for glycolysis acceleration. It could be explained by cancer cells' high proliferation index and high energy request. The involvement of mitochondria in metabolic disturbances of several metabolic diseases, including cancers, was reported. These data confirm that cancer induction, as well as cancer progression, could have metabolic roots. The aberrant products observed in prostate cells involved in the Krebs cycle could promote cancer progression. These multiple relationships between alterations on a genetic level translated into disturbances in cellular metabolism and their potential relation with epigenetic control of gene expression make cancerogenesis more complicated and prognoses' success in studies on cancer etiology more distant in time.

  7. Induction of artificial cancer stem cells from tongue cancer cells by defined reprogramming factors.

    Science.gov (United States)

    Harada, Koji; Ferdous, Tarannum; Cui, Dan; Kuramitsu, Yasuhiro; Matsumoto, Takuya; Ikeda, Eiji; Okano, Hideyuki; Ueyama, Yoshiya

    2016-07-27

    -2 (FGF-2) and epidermal Growth Factor (EGF). These findings suggest that artificial cancer stem cells obtained by the induction of cellular reprogramming may be useful for investigating the acquisition of potential malignancy as well as screening the CSCs-targeting drugs.

  8. Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent.

    Science.gov (United States)

    Davis, F M; Azimi, I; Faville, R A; Peters, A A; Jalink, K; Putney, J W; Goodhill, G J; Thompson, E W; Roberts-Thomson, S J; Monteith, G R

    2014-05-01

    Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia-induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium-permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. Although intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium-dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of

  9. High Order Sliding Mode Control of Doubly-fed Induction Generator under Unbalanced Grid Faults

    DEFF Research Database (Denmark)

    Zhu, Rongwu; Chen, Zhe; Wu, Xiaojie

    2013-01-01

    This paper deals with a doubly-fed induction generator-based (DFIG) wind turbine system under grid fault conditions such as: unbalanced grid voltage, three-phase grid fault, using a high order sliding mode control (SMC). A second order sliding mode controller, which is robust with respect...

  10. Apoptosis induction of epifriedelinol on human cervical cancer cell line

    African Journals Online (AJOL)

    Background: Present investigation evaluates the antitumor activity of epifriedelinol for the management of cervical cancer by inducing process of apoptosis. Methods: Human Cervical Cancer Cell Line, C33A and HeLa were selected for study and treated with epifriedelinol at a concentration of (50-1000 μg/ml). Cytotoxicity of ...

  11. Induction of DISE in ovarian cancer cells in vivo

    OpenAIRE

    Murmann, Andrea E.; McMahon, Kaylin M.; Haluck-Kangas, Ashley; Ravindran, Nandini; Patel, Monal; Law, Calvin Y.; Brockway, Sonia; Wei, Jian-Jun; Thaxton, C. Shad; Peter, Marcus E.

    2017-01-01

    The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3’UTRs of critical survival genes through canonical RNAi. We have named this unique form of off-target effect DISE (for death induced by survival gene elimination). DISE preferentially kills transformed cells and ...

  12. Studies on culture and osteogenic induction of human mesenchymal stem cells under CO2-independent conditions.

    Science.gov (United States)

    Chen, Jian; Zhang, Cui; Feng, Yiding; Zong, Chen; Chen, Jiarong; Tang, Zihua; Jia, Bingbing; Tong, Xiangming; Zheng, Qiang; Wang, Jinfu

    2013-04-01

    Human mesenchymal stem cells (hMSCs) are one of the important factors that regulate bone anabolism. Osteoporosis resulting from microgravity during spaceflight may possibly be due to a decrease in osteogenesis mediated by hMSCs. This speculation should be verified through culture and osteogenic induction of hMSCs in a microgravity environment during spaceflight. Control of CO2 is a key component in current experimental protocols for growth, survival, and proliferation of in vitro cultured cells. However, carrying CO2 tanks on a spaceflight and devoting space/mass allowances for classical CO2 control protocols make experimentation on culture and osteogenesis difficult during most missions. Therefore, an experimental culture and osteogenic medium was developed through modifying the components of buffer salts in conventional culture medium. This experimental medium was used to culture and induce hMSCs under CO2-independent conditions. The results showed that culture and induction of hMSCs with conventional culture medium and conventional osteogenic medium under CO2-independent conditions resulted in an increase of pH in medium. The proliferation of hMSCs was also inhibited. hMSCs cultured with experimental culture medium under CO2-independent conditions showed a proliferation potential that was the same as those cultured with conventional culture medium under CO2-dependent conditions. The experimental osteogenic medium could promote hMSCs to differentiate into osteoblast-like cells under CO2-independent conditions. Cells induced by this induction system showed high alkaline phosphatase activity. The expression levels of osteogenic genes in cells induced with experimental osteogenic medium under CO2-independent conditions were not significantly different from those cells induced with conventional osteogenic medium under CO2-dependent conditions. These results suggest that the experimental culture and induction system could be used to culture hMSCs and induce the

  13. Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yushuang Ding

    2016-04-01

    Full Text Available Cancer cells typically display higher than normal levels of reactive oxygen species (ROS, which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL, a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G1/S-CDK suppresser CDKN1B (p21 and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G1 and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway.

  14. Process strategies to improve heterologous protein production in Escherichia coli under lactose or IPTG induction

    DEFF Research Database (Denmark)

    Kilikian, B. V.; Surarez, I. D.; Liria, C. W.

    2000-01-01

    Cells of Escherichia coli BL21 bearing the chicken muscle Troponin C (TnC) gene under the control of the lacUV5 promoter were induced under different cultivation conditions and the consequences on growth and cell protein content were investigated. The type of inducer molecule (lactose or IPTG...... per gram dry cell weight (DCW), was achieved when isopropyl-beta-D-thiogalactoside (IPTG) was the inducer. Under lactose induction, a value of 96 mg per gram DCW was attained. However, the high metabolic load imposed by IPTG, when compared with lactose induction, as assessed by the cell protein...... content and stability, indicates that lactose is probably the most appropriate inducer for the synthesis of this heterologous protein. (C) 2000 Elsevier Science Ltd. All rights reserved....

  15. Induction of apoptosis in human breast cancer cell line MCF-7 by ...

    African Journals Online (AJOL)

    USER

    2010-07-12

    Jul 12, 2010 ... Induction of apoptosis in human breast cancer cell line. MCF-7 by phytochemicals from Gmelina asiatica. N. J. Merlin1, V. Parthasarathy1* and T. R. Santhoshkumar2. 1Department of Pharmacy, Annamalai University, Annamalai Nagar-608002, Tamil Nadu, India. 2Rajiv Gandhi Centre for Biotechnology, ...

  16. Cancer induction as a result of nuclear war

    International Nuclear Information System (INIS)

    Land, C.E.; Oftedal, P.

    1984-01-01

    A major nuclear war would involve some increase in radiation exposure to the entire world population from delayed fallout, but the major exposures would occur locally from early fallout close to, and downwind of, nuclear detonations in which the fireball touched the ground. Given the preponderance of multi-megaton weapons in the armament carried by intercontinental ballistic missiles and strategic bombers, it is likely that early fallout would be by far the most important source of radiation exposure. Those surviving beyond the first few years after a nuclear exchange would be subject to an increased cancer risk as a result of their exposure to ionizing radiation. This annex represents an attempt to quantify roughly this excess cancer risk in terms of the numbers of cancer deaths and cases, and the expected years of life lost

  17. Arsenic Exposure and the Induction of Human Cancers

    Directory of Open Access Journals (Sweden)

    Victor D. Martinez

    2011-01-01

    Full Text Available Arsenic is a metalloid, that is, considered to be a human carcinogen. Millions of individuals worldwide are chronically exposed through drinking water, with consequences ranging from acute toxicities to development of malignancies, such as skin and lung cancer. Despite well-known arsenic-related health effects, the molecular mechanisms involved are not fully understood; however, the arsenic biotransformation process, which includes methylation changes, is thought to play a key role. This paper explores the relationship of arsenic exposure with cancer development and summarizes current knowledge of the potential mechanisms that may contribute to the neoplastic processes observed in arsenic exposed human populations.

  18. Comparison of control strategies for Doubly fed induction generator under recurring grid faults

    DEFF Research Database (Denmark)

    Chen, Wenjie; Blaabjerg, Frede; Zhu, Nan

    2014-01-01

    The new grid codes demand the wind turbine systems to ride through recurring grid faults. Many control strategies have been proposed for the Doubly Fed Induction Generator under single grid fault, but their performance under recurring grid faults have not been studied yet. In this paper, five...... different control strategies for DFIG to ride through single grid faults are presented, and their performance under recurring grid faults are analyzed. The controllable range, stator time constant and torque fluctuations of the DFIG with different control strategies are compared. The results are verified...

  19. Inverter-fed induction motor simulation under overloading for regenerative braking management in electric vehicle

    Energy Technology Data Exchange (ETDEWEB)

    Papazacharopoulos, Z; Tatis, K.; Kladas, A.; Manias, S.; Tegopoulos, J. [National Technical University of Athens, Electric Power Division, Laboratory of Electrical Machines, Athens (Greece)

    2000-08-01

    The paper introduces a dynamic model for inverter-fed induction motor drive system, enabling accurate simulation under limited motor overloading during regenerative braking. This model includes a conveniently modified equivalent circuit for the motor analysis and has been checked by measurements on a 20 kW experimental set-up. The considered motor overloading may provide substantial energy savings in the domain of electromotion, in traction systems such as electric vehicles and relevant industrial applications. (orig.)

  20. Suppression of gastric cancer by extract from the tuber of amorphophallus konjac via induction of apoptosis and autophagy.

    Science.gov (United States)

    Chen, Xi; Yuan, Lin-Qing; Li, Lin-Jie; Lv, Yao; Chen, Pei-Feng; Pan, Lei

    2017-08-01

    The tuber of amorphophallus konjac (TuAK) is an antitumor herb used in traditional Chinese medicine. The present study investigated the inhibitory effect of TuAK against gastric cancer and the underlying mechanisms associated with two programmed cell death pathways, apoptosis and autophagy. TuAK was extracted by organic solvents including ethanol and ligarine. The extract of TuAK, shortened as TuAKe, significantly inhibited the growth of cultured gastric cancer cell lines SGC-7901 and AGS, with IC50 of 35-45 µg/ml. TuAKe could increase cell apoptosis and induce cell cycle arrest. For the apoptosis-associated proteins, expressions of survivin and Bcl-2 were decreased by treatment of TuAKe, and the expression of Bax and caspase-9 was increased. Furthermore, TuAKe could promote autophagy, and the antitumor efficacy of TuAKe was significantly hampered by targeted suppression of autophagy, suggesting that autophagy contributed to TuAKe-induced cell death. Furthermore, patients with gastric cancer who received TuAK-based medicinal decoction achieved improved scores in assessment of life quality compared with those without TuAK treatment. This study demonstrated the antitumor activity of TuAKe against gastric cancer, and is the first report to show that the underlying mechanism is associated with induction of autophagy. Our data provided support of the clinical use of amorphophallus konjac-based medication in combination with classical chemotherapy to achieve optimized outcome for gastric cancer.

  1. Inhibition of HAS2 induction enhances the radiosensitivity of cancer cells via persistent DNA damage

    International Nuclear Information System (INIS)

    Shen, Yan Nan; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Kim, Su-Hyeon; Hwang, Sang-Gu; Park, Sang Jun; Kim, Chun-Ho; Lee, Kee-Ho

    2014-01-01

    Highlights: •HAS2 may be a promising target for the radiosensitization of human cancer. •HAS2 is elevated (up to ∼10-fold) in irradiated radioresistant and -sensitive cancer cells. •HAS2 knockdown sensitizes cancer cells to radiation. •HAS2 knockdown potentiates irradiation-induced DNA damage and apoptotic death. •Thus, the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. -- Abstract: Hyaluronan synthase 2 (HAS2), a synthetic enzyme for hyaluronan, regulates various aspects of cancer progression, including migration, invasion and angiogenesis. However, the possible association of HAS2 with the response of cancer cells to anticancer radiotherapy, has not yet been elucidated. Here, we show that HAS2 knockdown potentiates irradiation-induced DNA damage and apoptosis in cancer cells. Upon exposure to radiation, all of the tested human cancer cell lines exhibited marked (up to 10-fold) up-regulation of HAS2 within 24 h. Inhibition of HAS2 induction significantly reduced the survival of irradiated radioresistant and -sensitive cells. Interestingly, HAS2 depletion rendered the cells to sustain irradiation-induced DNA damage, thereby leading to an increase of apoptotic death. These findings indicate that HAS2 knockdown sensitizes cancer cells to radiation via persistent DNA damage, further suggesting that the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. Thus, HAS2 could potentially be targeted for therapeutic interventions aimed at radiosensitizing cancer cells

  2. Model for the induction of bone cancer by 224Ra

    International Nuclear Information System (INIS)

    Groer, P.G.; Marshall, J.H.

    1976-01-01

    A mathematical model for the transformation of normal endosteal cells into malignant tumor cells by α irradiation is applied to 224 Ra. The model postulates that a normal endosteal cell near the bone surface is transformed into a malignant cell by three consecutive events. The first two events are the initiation events. The probability of their occurrence is proportional to the absorbed endosteal dose and they generate dormant tumor cells. These dormant tumor cells are promoted by the third event, the promotion event. The probability of this last event is proportional to the rate of bone remodeling but independent of the radiation dose. In competition with these transforming events is the killing of any endosteal cell by α irradiation. Killing is balanced by replacement of killed endosteal cells by normal stem cells. This model provides the following interesting predictions for the human 224 Ra cases: after the decay of 224 Ra the tumor rate decreases exponentially at a rate proportional to the bone turnover rate; for exposure to the same dose the model predicts an increased number of tumors for protracted exposure (i.e., exposure at a lower dose rate). Implications of this model for the therapy of ankylosing spondylitis are discussed. Statistical procedures are suggested for comparison of this theoretical model with the existing data on the induction of osteosarcomas by 224 Ra in man

  3. Induction of resident memory T cells enhances the efficacy of cancer vaccine.

    Science.gov (United States)

    Nizard, Mevyn; Roussel, Hélène; Diniz, Mariana O; Karaki, Soumaya; Tran, Thi; Voron, Thibault; Dransart, Estelle; Sandoval, Federico; Riquet, Marc; Rance, Bastien; Marcheteau, Elie; Fabre, Elizabeth; Mandavit, Marion; Terme, Magali; Blanc, Charlotte; Escudie, Jean-Baptiste; Gibault, Laure; Barthes, Françoise Le Pimpec; Granier, Clemence; Ferreira, Luis C S; Badoual, Cecile; Johannes, Ludger; Tartour, Eric

    2017-05-24

    Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. Although they are considered as early immune effectors in infectious diseases, their role in cancer immunosurveillance remains unknown. In a preclinical model of head and neck cancer, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin, induces local Trm and inhibits tumour growth. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. Blockade of TFGβ decreases the induction of Trm after mucosal vaccine immunization, resulting in the lower efficacy of cancer vaccine. In order to extrapolate this role of Trm in humans, we show that the number of Trm correlates with a better overall survival in lung cancer in multivariate analysis. The induction of Trm may represent a new surrogate biomarker for the efficacy of cancer vaccine. This study also argues for the development of vaccine strategies designed to elicit them.

  4. Lichen Secondary Metabolites in Flavocetraria cucullata Exhibit Anti-Cancer Effects on Human Cancer Cells through the Induction of Apoptosis and Suppression of Tumorigenic Potentials

    Science.gov (United States)

    Nguyen, Thanh Thi; Yoon, Somy; Yang, Yi; Lee, Ho-Bin; Oh, Soonok; Jeong, Min-Hye; Kim, Jong-Jin; Yee, Sung-Tae; Crişan, Florin; Moon, Cheol; Lee, Kwang Youl; Kim, Kyung Keun; Hur, Jae-Seoun; Kim, Hangun

    2014-01-01

    Lichens are symbiotic organisms which produce distinct secondary metabolic products. In the present study, we tested the cytotoxic activity of 17 lichen species against several human cancer cells and further investigated the molecular mechanisms underlying their anti-cancer activity. We found that among 17 lichens species, F. cucullata exhibited the most potent cytotoxicity in several human cancer cells. High performance liquid chromatography analysis revealed that the acetone extract of F. cucullata contains usnic acid, salazinic acid, Squamatic acid, Baeomycesic acid, d-protolichesterinic acid, and lichesterinic acid as subcomponents. MTT assay showed that cancer cell lines were more vulnerable to the cytotoxic effects of the extract than non-cancer cell lines. Furthermore, among the identified subcomponents, usnic acid treatment had a similar cytotoxic effect on cancer cell lines but with lower potency than the extract. At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials. In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected. Overall, the anti-cancer activity of the extract is more potent than that of usnic acid alone. Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT. PMID:25360754

  5. Synergy of radon inhalation and tobacco smoking in the induction of lung cancer

    International Nuclear Information System (INIS)

    Sedlak, Antonin

    2010-01-01

    The problem of contribution of tobacco smoking to the induction of lung cancer in persons living in environments with the enhanced radon concentrations is treated. An attempt is made to interpret the sub-multiplicative mechanism of the synergy of the two factors, i.e. a situation where the contribution of the two factors acting jointly is larger than their simple addition but lower than their multiplication, as currently assumed to hold. (P.A.)

  6. Risks for cancer induction by pion radiation in the peak- and plateau region

    International Nuclear Information System (INIS)

    Cottier, H.; Fritz-Niggli, H.; Froehlich, E.; Heinzell, F.; Nichel, C.; Rao, K.

    In the foreground of an evaluation of the suitability of negative protons for cancer therapy there is, beside the analysis of pion effect on malignant cells, also the reaction of healthy tissue. The observation that neutrons at the lowest dose-rate can induce breast cancer and our own results after pion radiation in the peak-region necessitate a broadly planned, urgent investigation of these delayed damages. We will consider radiations at the plateau- and peak-region, the results of which should be of utmost interest for the comparison of neutron- and pion therapy. There are indications that the RBE of a high LET radiation is extremely large for the tumor induction. We will investigate especially the development of mammary cancers in variously aged mice with a low spontaneous tumor rate and C 3 H mice with a high cancer expectancy

  7. Induction of Rhizopus oryzae germination under starvation using host metabolites increases spore susceptibility to heat stress.

    Science.gov (United States)

    Turgeman, Tidhar; Kakongi, Nathan; Schneider, Avishai; Vinokur, Yakov; Teper-Bamnolker, Paula; Carmeli, Shmuel; Levy, Maggie; Skory, Christopher D; Lichter, Amnon; Eshel, Dani

    2014-03-01

    Sweetpotato is a nutritional source worldwide. Soft rot caused by Rhizopus spp. is a major limiting factor in the storage of produce, rendering it potentially unsafe for human consumption. In this study, Rhizopus oryzae was used to develop a concept of postharvest disease control by weakening the pathogen through induction of spore germination under starvation conditions. We isolated the sweetpotato active fractions (SPAFs) that induce spore germination and used them at a low dose to enhance spore weakening caused by starvation. Germination in SPAF at 1 mg/ml weakened the pathogen spores by delaying their ability to form colonies on rich media and by increasing their sensitivity to heat stress. The weakening effect was also supported by reduced metabolic activity, as detected by Alarmar Blue fluorescent dye assays. Spores incubated with SPAF at 1 mg/ml showed DNA fragmentation in some of their nuclei, as observed by TUNEL assay. In addition, these spores exhibited changes in ultrastructural morphology (i.e., shrinkage of germ tubes, nucleus deformation, and vacuole formation) which are hallmarks of programmed cell death. We suggest that induction of spore germination under starvation conditions increases their susceptibility to stress and, therefore, might be considered a new strategy for pathogen control.

  8. Induction of transposon TN1 translocation under the action of different mutagens

    International Nuclear Information System (INIS)

    Kubanejshvili, M.G.; Smirnov, S.P.; Tarasov, V.A.

    1983-01-01

    Migration of ampicillin transposon Tn1 under normal conditions in Escherichia coli cells proceeds with low frequency (10 -4 transpositions for cell). The low transposition frequency is conditioned by the transposition repression, realized by the gene-repressor in transposon structure and, probably, by other regulating genes of the bacterium-host. E. coli cell treatment by physical and chemical mutagens resulted in induction of translocation of ampicillin transposon Tn1 from plasmid RP4 into other replicons. Mitomycin C and ultraviolet radiation produced stronger inducing effect as compared to nitroso-guanidine (NG). The effect of the given mutagens on transposition Tn1 correlated with their activating capacity with respect to inducible SOS-functions of E coli. The mutation of rec A didn't influence on spontaneous Tn1 transposition, but blocked completely the induction of transposition process under mutagen effect. The relationship of inducible transposition with SOS-functions in E. coli cells, controlled by recA and lexA genes, as well as the possible role of the process in genetic microorganism variability are discussed in the paper

  9. Passivity-Based Control of a Doubly Fed Induction Generator System under Unbalanced Grid Voltage Conditions

    Directory of Open Access Journals (Sweden)

    Jiawei Huang

    2017-08-01

    Full Text Available According to the theory of passivity-based control (PBC, this paper establishes a port-controlled Hamiltonian system with dissipation (PCHD model for a doubly fed induction generator (DFIG system under unbalanced grid voltage conditions and proposes a method of interconnection and damping assignment passivity-based control (IDA-PBC of the system under such conditions. By using this method, the rotor-side converter and grid-side converter can be controlled simultaneously in order to improve fault ride-through capability of the DFIG system. Simulation results indicate that this IDA-PBC strategy effectively suppresses fluctuations of output current and power in the DFIG system during unbalanced grid voltage sag/swell, enhances dynamic performance, and improves the robustness of the system.

  10. Dose-dependent deterioration of swallowing function after induction chemotherapy and definitive chemoradiotherapy for laryngopharyngeal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Haderlein, M.; Semrau, S.; Ott, O.; Speer, S.; Fietkau, R. [University Hospital Erlangen, Department of Radiation Oncology, Erlangen (Germany); Bohr, C. [University Hospital Erlangen, Department of Otorhinolaryngology, Head and Neck Surgery, Erlangen (Germany)

    2014-02-15

    To evaluate the influence of clinical, treatment- and dose-dependent factors on posttreatment swallowing function after induction chemotherapy and definitive chemoradiotherapy in a group of homogeneously treated laryngopharyngeal cancer patients. From 28 May 2008 to 15 February 2013, 45 patients with borderline inoperable laryngopharyngeal cancer that had responded well to induction chemotherapy were treated with definitive chemoradiotherapy. Median follow-up was 22 months. Swallowing function and clinical data were prospectively analyzed using the EORTC QLQ-C30 questionnaire. Swallowing structures were retrospectively delineated on the original treatment planning CT. Dose-volume histograms were calculated for swallowing structures and D{sub mean}, D{sub max} and V50-V64 values (in 2 Gy increments) were determined for each patient. Tumor volume and infiltration of the swallowing apparatus was defined by CT before induction chemotherapy. Of the 45 patients, 26 (57.8 %) fully regained swallowing function after chemoradiotherapy. A further 12 patients (26.7 %) were able to manage soft, pureed and/or liquid foods; the remaining 7 (15.6 %) were completely dependent on percutaneous endoscopic gastrostomy (PEG). Posttreatment swallowing function was significantly influenced by D{sub mean} to the superior pharyngeal constrictor muscle (PCM, p = 0.041). Correlations between late dysphagia and dose-volume relationships in the superior PCM and soft palate were also observed, which were significant from V60 (p = 0.043) and V58 for the soft palate and superior PCM, respectively. Of the evaluated clinical and tumor-related factors, only alcohol abuse (p = 0.024) had an influence on posttreatment swallowing function. Almost 50 % of patients had deterioration of swallowing function after definitive chemoradiotherapy for laryngopharyngeal cancer. The dose to anatomical structures responsible for swallowing function appears to play a role. Therefore, in selected patients, target

  11. Aphid wing induction and ecological costs of alarm pheromone emission under field conditions.

    Directory of Open Access Journals (Sweden)

    Eduardo Hatano

    2010-06-01

    Full Text Available The pea aphid, Acyrthosiphon pisum Harris, (Homoptera: Aphididae releases the volatile sesquiterpene (E-beta-farnesene (EBF when attacked by a predator, triggering escape responses in the aphid colony. Recently, it was shown that this alarm pheromone also mediates the production of the winged dispersal morph under laboratory conditions. The present work tested the wing-inducing effect of EBF under field conditions. Aphid colonies were exposed to two treatments (control and EBF and tested in two different environmental conditions (field and laboratory. As in previous experiments aphids produced higher proportion of winged morphs among their offspring when exposed to EBF in the laboratory but even under field conditions the proportion of winged offspring was higher after EBF application (6.84+/-0.98% compared to the hexane control (1.54+/-0.25%. In the field, the proportion of adult aphids found on the plant at the end of the experiment was lower in the EBF treatment (58.1+/-5.5% than in the control (66.9+/-4.6%, in contrast to the climate chamber test where the numbers of adult aphids found on the plant at the end of the experiment were, in both treatments, similar to the numbers put on the plant initially. Our results show that the role of EBF in aphid wing induction is also apparent under field conditions and they may indicate a potential cost of EBF emission. They also emphasize the importance of investigating the ecological role of induced defences under field conditions.

  12. Liver cancer induction by 241Am and thorotrast in deer mice and grasshopper mice

    International Nuclear Information System (INIS)

    Taylor, G.N.; Mays, C.W.; Lloyd, R.D.; Jones, C.W.; Rojas, J.; Wrenn, M.E.; Ayoroa, G.; Kaul, A.; Riedel, W.

    1986-01-01

    The carcinogenicity of 241 Am, relative to thorotrast, has been determined in two species of mice: the grasshopper mouse (Onychomys leucogaster) and the deer mouse (Peromyscus maniculatus). These species were used since both have high uptakes of Pu and Am and, unlike conventional mice and rats, both retain relatively high concentrations of plutonium and americium in their livers. The study indicated that the liver carcinogenicity of comparable rad doses of 241 Am or thorotrast is approximately equal. The toxicity ratio ( 241 Am/thorotrast) for liver cancer induction approximated 1.2 with a range of about 0.6 to 1.6. This suggested that nonradiation factors of thorotrast were not significant in liver tumor induction. (orig.)

  13. Induction of alternative respiratory pathway involves nitric oxide, hydrogen peroxide and ethylene under salt stress.

    Science.gov (United States)

    Wang, Huahua; Huang, Junjun; Bi, Yurong

    2010-12-01

    Alternative respiratory pathway (AP) plays an important role in plant thermogenesis, fruit ripening and responses to environmental stresses. AP may participate in the adaptation to salt stress since salt stress increased the activity of the AP. Recently, new evidence revealed that ethylene and hydrogen peroxide (H(2)O(2)) are involved in the salt-induced increase of the AP, which plays an important role in salt tolerance in Arabidopsis callus, and ethylene may be acting downstream of H(2)O(2). Recent observations also indicated both ethylene and nitric oxide (NO) act as signaling molecules in responses to salt stress, and ethylene may be a part of the downstream signal molecular in NO action. In this addendum, a hypothetical model for NO function in regulation of H(2)O(2)- and ethylene-mediated induction of AP under salt stress is presented.

  14. Theoretical and experimental analysis of inverter fed induction motor system under DC link capacitor failure

    Directory of Open Access Journals (Sweden)

    Hadeed A. Sher

    2017-04-01

    Full Text Available In this paper theoretical and experimental analysis of an AC–DC–AC inverter under DC link capacitor failure is presented. The failure study conducted for this paper is the open circuit of the DC link capacitor. The presented analysis incorporates the results for both single and three phase AC input. It has been observed that the higher ripple frequency provides better ride through capability for this fault. Furthermore, the effects of this fault on electrical characteristics of AC–DC–AC inverter and mechanical properties of the induction motor are also presented. Moreover, the effect of pulsating torque as a result of an open circuited DC link capacitor is also taken into consideration. Theoretical analysis is supported by computer aided simulation as well as with a real time experimental prototype.

  15. Development Procedure in Mutation Induction and Tracer Technique for Good Agriculture Practices for Under used Crops

    International Nuclear Information System (INIS)

    Faiz Ahmad; Rusli Ibrahim; Khairuddin Abdul Rahim

    2015-01-01

    Under used crops are those crop species which have high potential value in the supply of important raw material for secondary economy sector in food processing. The yield production of new Under used crops varieties can be used as an important input in food production process for export products. The optimum production cost can be minimized since the price of raw material supplied from agriculture sector is cheaper compared with the international markets. Agriculture output can be increased through the development of Under used crops using radiation mutagenesis and tracer technique for good agricultural practices. This paper work will discuss the development procedure of mutation induction method which includes irradiation of samples such as seeds of groundnut and in vitro shoots of banana using gamma rays and application of N-15 for nutrient use efficiency and screening of potential mutant lines with high yield and resistance to drought. These management practices using established procedures of water and nutrient use efficiency will be recommended to the growers. (author)

  16. Sensorless speed control of a five-phase induction machine under open-phase condition

    Directory of Open Access Journals (Sweden)

    Ahmed S. Morsy

    2014-05-01

    Full Text Available Recently, multiphase machines have been promoted as competitors to their three-phase counterparts in high-power safety-critical drive applications. Among numerous advantages of multiphase induction machine (IM drives, self-starting and operation under open phase(s stand as the most salient features. With open phase(s, optimal current control provides disturbance- free operation given a set of objective functions. Although hysteresis current control was merely employed in the literature as it offers a simple controller structure to control the remaining healthy phases, it is not suitable for high-power applications. In the literature, multiple synchronous reference frame (dq control can be an alternative; however, it requires back and forth transformations with several calculations and additional sophistication. In this paper, a simple technique employing adaptive proportional resonant (PR current controllers is presented to control a five-phase IM under open-phase conditions. Results for both volt/hertz (V/f and field oriented control (FOC systems are presented. Moreover, sensorless operation under fault condition is also demonstrated by estimating the machine speed using a rotor flux-based model reference adaptive system (MRAS speed estimator. The proposed controllers are experimentally verified and compared. Although FOC provides better dynamic performance, V/f control offers a simpler control structure and a lower number of PR controllers.

  17. Apoptosis induction with electric pulses - A new approach to cancer therapy with drug free

    International Nuclear Information System (INIS)

    Tang, Liling; Yao, Chenguo; Sun, Caixin

    2009-01-01

    Electrical pulses have been widely used in biomedical fields, whose applications depend on the parameters such as durations and electric intensity. Conventional electroporation (0.1-1 kV/cm, 100 μs) has been used in cell fusion, transfection and electrochemotherapy. Recent studies with high-intensity (MV/cm) electric field applications with durations of several tens of nanoseconds can affect intracellular signal transduction and intracellular structures with plasma intact, resulting in an application of intracellular manipulation. The most recent development is the finding that parameters between those two ranges could be used to induce apoptosis of cancer cells. Proposal of apoptosis induction and tumor inhibition has advantages to pursue the treatment of cancer free of cytotoxic drugs.

  18. Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintainance of epilepsy.

    Science.gov (United States)

    Delorenzo, Robert J; Sun, David A; Deshpande, Laxmikant S

    2005-03-01

    Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury (central nervous system [CNS] insult), (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels [Ca(2+)](i) and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but they share a common molecular mechanism for producing brain damage-an increase in extracellular glutamate concentration that causes increased intracellular neuronal calcium, leading to neuronal injury and/or death. Neurons that survive the injury induced by glutamate and are exposed to increased [Ca(2+)](i) are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca(2+)](i) and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel

  19. Beliefs Underlying Messages of Anti-Cancer-Screening Websites in Japan: A Qualitative Analysis

    Science.gov (United States)

    Okuhara, Tsuyoshi; Ishikawa, Hirono; Okada, Masahumi; Kato, Mio; Kiuchi, Takahiro

    2018-02-26

    Background: Cancer screening rates are lower in Japan than in Western countries. Meanwhile, anti-cancer-screening activists take to the internet to spread their messages that cancer screening has little or no efficacy, poses substantial health risks such as side effects from radiation exposure, and that people should forgo cancer screening. We applied a qualitative approach to explore the beliefs underlying the messages of anti-cancer-screening websites, by focusing on perceived value the beliefs provided to those who held them. Methods: We conducted online searches using Google Japan and Yahoo! Japan, targeting websites we classified as “pro,” “anti,” or “neutral” depending on their claims. We applied a dual analytic approach- inductive thematic analysis and deductive interpretative analysis- to the textual data of the anti websites. Results: Of the 88 websites analyzed, five themes that correspond to beliefs were identified: destruction of common knowledge, denial of standard cancer control, education about right cancer control, education about hidden truths, and sense of superiority that only I know the truth. Authors of anti websites ascribed two values (“safety of people” and “self-esteem”) to their beliefs. Conclusion: The beliefs of authors of anti-cancer-screening websites were supposed to be strong. It would be better to target in cancer screening promotion not outright screening refusers but screening hesitant people who are more amenable to changing their attitudes toward screening. The possible means to persuade them were discussed. Creative Commons Attribution License

  20. SOLAR RADIATION AND INDUCTION OF DNA DAMAGE, MUTATIONS AND SKIN CANCERS.

    Energy Technology Data Exchange (ETDEWEB)

    SETLOW,R.B.

    2007-05-10

    An understanding of the effects of sunlight on human skin begins with the effects on DNA and extends to cells, animals and humans. The major DNA photoproducts arising from UVB (280-320 nm) exposures are cyclobutane pyrimidine dimers. If unrepaired, they may kill or mutate cells and result in basal and squamous cell carcinomas. Although UVA (320-400 nm) and visible wavelengths are poorly absorbed by DNA, the existing data indicate clearly that exposures to these wavelengths are responsible, in an animal model, for {approx}95 % of the incidence of cutaneous malignant melanoma (CMM). Six lines of evidence, to be discussed in detail, support the photosensitizing role of melanin in the induction of this cancer. They are: (1) Melanomas induced in backcross hybrids of small tropical fish of the genus Xiphophorus, exposed to wavelengths from 302-547 nm, indicate that {approx}95% of the cancers induced by exposure to sunlight would arise from UVA + visible wavelengths; (2) The action spectrum for inducing melanin-photosensitized oxidant production is very similar to the spectrum for inducing melanoma; (3) Albino whites and blacks, although very sensitive to sunburn and the sunlight induction of non-CMM, have very low incidences of CMM; (4) The incidence of CMM as a function of latitude is very similar to that of UVA, but not UVB; (5) Use of UVA-exposing sun-tanning parlors by the young increases the incidence rate of CMM and (6) Major mutations observed in CMM are not UVB-induced.

  1. Induction chemotherapy followed by concurrent radiotherapy and chemotherapy in stage III non-small cell lung cancer

    International Nuclear Information System (INIS)

    Bouillet, T.; MOrere, J.F.; Piperno-Neuman, S.; Boaziz, C.; Breau, J.L.; Mazeron, J.J.; Haddad, E.

    1997-01-01

    The purpose was to determine the efficacy and safety of induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of stage III non-small cell lung cancer and whether the response to induction chemotherapy can predict the response to subsequent chemoradiotherapy and survival. In conclusion, there is a statistically significant relationship not only between the response to ICT and the response to CCrt, but also between the response to ICT and the local outcome and survival. (authors)

  2. Motion of isolated open vortex filaments evolving under the truncated local induction approximation

    Science.gov (United States)

    Van Gorder, Robert A.

    2017-11-01

    The study of nonlinear waves along open vortex filaments continues to be an area of active research. While the local induction approximation (LIA) is attractive due to locality compared with the non-local Biot-Savart formulation, it has been argued that LIA appears too simple to model some relevant features of Kelvin wave dynamics, such as Kelvin wave energy transfer. Such transfer of energy is not feasible under the LIA due to integrability, so in order to obtain a non-integrable model, a truncated LIA, which breaks the integrability of the classical LIA, has been proposed as a candidate model with which to study such dynamics. Recently Laurie et al. ["Interaction of Kelvin waves and nonlocality of energy transfer in superfluids," Phys. Rev. B 81, 104526 (2010)] derived truncated LIA systematically from Biot-Savart dynamics. The focus of the present paper is to study the dynamics of a section of common open vortex filaments under the truncated LIA dynamics. We obtain the analog of helical, planar, and more general filaments which rotate without a change in form in the classical LIA, demonstrating that while quantitative differences do exist, qualitatively such solutions still exist under the truncated LIA. Conversely, solitons and breather solutions found under the LIA should not be expected under the truncated LIA, as the existence of such solutions relies on the existence of an infinite number of conservation laws which is violated due to loss of integrability. On the other hand, similarity solutions under the truncated LIA can be quite different to their counterparts found for the classical LIA, as they must obey a t1/3 type scaling rather than the t1/2 type scaling commonly found in the LIA and Biot-Savart dynamics. This change in similarity scaling means that Kelvin waves are radiated at a slower rate from vortex kinks formed after reconnection events. The loss of soliton solutions and the difference in similarity scaling indicate that dynamics emergent under

  3. Staging laparoscopy leads to rapid induction of chemotherapy for unresectable pancreatobiliary cancers.

    Science.gov (United States)

    Hashimoto, Daisuke; Chikamoto, Akira; Sakata, Kazuya; Nakagawa, Shigeki; Hayashi, Hiromitsu; Ohmuraya, Masaki; Hirota, Masahiko; Yoshida, Naoya; Beppu, Toru; Baba, Hideo

    2015-02-01

    Preoperatively evaluating the resectability of pancreatobiliary cancers is difficult. The aim of this study was to investigate the benefit of staging laparoscopy in unresectable pancreatobiliary cancers. Between 2010 and 2013, 25 patients with pancreatobiliary cancers underwent staging laparoscopy after conventional tumor staging; they were compared with 10 patients who had unresectable or metastatic tumors that were found during laparotomy. Staging laparoscopy did not show unresectable factors in 11 patients, and resections were performed in these patients. Unresectable factors were found in other 14 patients who underwent staging laparoscopy. In these patients, chemotherapy was started after median postoperative day 3 (range, 2-10 days). This period was significantly longer in patients who received unnecessary laparotomy; chemotherapy was started after median postoperative day 11 (range, 6-15 days). These results suggest that staging laparoscopy, while avoiding laparotomy with unsuccessful resection, can lead to rapid induction of chemotherapy for unresectable pancreatobiliary cancers. © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.

  4. Hypoxia-inducible factor 1-mediated human GATA1 induction promotes erythroid differentiation under hypoxic conditions.

    Science.gov (United States)

    Zhang, Feng-Lin; Shen, Guo-Min; Liu, Xiao-Ling; Wang, Fang; Zhao, Ying-Ze; Zhang, Jun-Wu

    2012-08-01

    Hypoxia-inducible factor promotes erythropoiesis through coordinated cell type-specific hypoxia responses. GATA1 is essential to normal erythropoiesis and plays a crucial role in erythroid differentiation. In this study, we show that hypoxia-induced GATA1 expression is mediated by HIF1 in erythroid cells. Under hypoxic conditions, significantly increased GATA1 mRNA and protein levels were detected in K562 cells and erythroid induction cultures of CD34(+) haematopoietic stem/progenitor cells. Enforced HIF1α expression increased GATA1 expression, while HIF1α knockdown by RNA interference decreased GATA1 expression. In silico analysis revealed one potential hypoxia response element (HRE). The results from reporter gene and mutation analysis suggested that this element is necessary for hypoxic response. Chromatin immunoprecipitation (ChIP)-PCR showed that the putative HRE was recognized and bound by HIF1 in vivo. These results demonstrate that the up-regulation of GATA1 during hypoxia is directly mediated by HIF1.The mRNA expression of some erythroid differentiation markers was increased under hypoxic conditions, but decreased with RNA interference of HIF1α or GATA1. Flow cytometry analysis also indicated that hypoxia, desferrioxamine or CoCl(2) induced expression of erythroid surface markers CD71 and CD235a, while expression repression of HIF1α or GATA1 by RNA interference led to a decreased expression of CD235a. These results suggested that HIF1-mediated GATA1 up-regulation promotes erythropoiesis in order to satisfy the needs of an organism under hypoxic conditions. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  5. Radiation fields, dosimetry, biokinetics and biophysical models for cancer induction by ionising radiation 1996-1999. Executive summary

    International Nuclear Information System (INIS)

    Jacob, P.; Paretzke, H.G.; Roth, P.

    2000-01-01

    The Association Contract covers a range of research domains that are important to the Radiation Protection Research Action, especially in the areas 'Evaluation of Radiation Risks' and 'Understanding Radiation Mechanisms and Epidemiology'. Three research projects concentrate on radiation dosimetry research and two projects on the modelling of radiation carcinogenesis. The following list gives an overview on the topics and responsible scientific project leaders of the Association Contract: Study of radiation fields and dosimetry at aviation altitudes. Biokinetics and dosimetry of incorporated radionuclides. Dose reconstruction. Biophysical models for the induction of cancer by radiation. Experimental data for the induction of cancer by radiation of different qualities. (orig.)

  6. Dose and induction to cancer risk evaluation associated to use of X ray body scanners by transmission at airports

    International Nuclear Information System (INIS)

    Correa, Samanda Cristine Arruda; Aquino, Josilto Oliveira de; Souza, Edmilson Monteiro de; Silva, Ademir Xavier da

    2011-01-01

    This paper uses the Monte Carlo MCNPX and the phantoms in male voxel and female voxel to evaluate the absorbed doses effective doses and the induction risk and the mortality due to cancer associated to exposures of individual submitted to X ray body scanners by transmission at various projections. The values of effective dose were calculated according to the recommended by the new ICRP 103 and the values of induction risks and mortality due to cancer were estimated through the document BEIR VII. (author)

  7. Proteoglycans remodeling in cancer: Underlying molecular mechanisms.

    Science.gov (United States)

    Theocharis, Achilleas D; Karamanos, Nikos K

    2017-11-08

    Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural organization and cell signaling contributing to the control of numerous normal and pathological processes. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Their interactions with matrix effectors, cell surface receptors and enzymes enable them with unique properties. In malignancy, extensive remodeling of tumor stroma is associated with marked alterations in proteoglycans' expression and structural variability. Proteoglycans exert diverse functions in tumor stroma in a cell-specific and context-specific manner and they mainly contribute to the formation of a permissive provisional matrix for tumor growth affecting tissue organization, cell-cell and cell-matrix interactions and tumor cell signaling. Proteoglycans also modulate cancer cell phenotype and properties, the development of drug resistance and tumor stroma angiogenesis. This review summarizes the proteoglycans remodeling and their novel biological roles in malignancies with particular emphasis to the underlying molecular mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models.

    Science.gov (United States)

    Ornelas, Argentina; McCullough, Christopher R; Lu, Zhen; Zacharias, Niki M; Kelderhouse, Lindsay E; Gray, Joshua; Yang, Hailing; Engel, Brian J; Wang, Yan; Mao, Weiqun; Sutton, Margie N; Bhattacharya, Pratip K; Bast, Robert C; Millward, Steven W

    2016-10-26

    Autophagy is a bulk catabolic process that modulates tumorigenesis, therapeutic resistance, and dormancy. The tumor suppressor ARHI (DIRAS3) is a potent inducer of autophagy and its expression results in necroptotic cell death in vitro and tumor dormancy in vivo. ARHI is down-regulated or lost in over 60 % of primary ovarian tumors yet is dramatically up-regulated in metastatic disease. The metabolic changes that occur during ARHI induction and their role in modulating death and dormancy are unknown. We employed Nuclear Magnetic Resonance (NMR)-based metabolomic strategies to characterize changes in key metabolic pathways in both cell culture and xenograft models of ARHI expression and autophagy. These pathways were further interrogated by cell-based immunofluorescence imaging, tracer uptake studies, targeted metabolic inhibition, and in vivo PET/CT imaging. Induction of ARHI in cell culture models resulted in an autophagy-dependent increase in lactate production along with increased glucose uptake and enhanced sensitivity to glycolytic inhibitors. Increased uptake of glutamine was also dependent on autophagy and dramatically sensitized cultured ARHI-expressing ovarian cancer cell lines to glutaminase inhibition. Induction of ARHI resulted in a reduction in mitochondrial respiration, decreased mitochondrial membrane potential, and decreased Tom20 staining suggesting an ARHI-dependent loss of mitochondrial function. ARHI induction in mouse xenograft models resulted in an increase in free amino acids, a transient increase in [ 18 F]-FDG uptake, and significantly altered choline metabolism. ARHI expression has previously been shown to trigger autophagy-associated necroptosis in cell culture. In this study, we have demonstrated that ARHI expression results in decreased cellular ATP/ADP, increased oxidative stress, and decreased mitochondrial function. While this bioenergetic shock is consistent with programmed necrosis, our data indicates that the accompanying up

  9. The usefulness of three-dimensional cell culture in induction of cancer stem cells from esophageal squamous cell carcinoma cell lines

    International Nuclear Information System (INIS)

    Fujiwara, Daisuke; Kato, Kazunori; Nohara, Shigeo; Iwanuma, Yoshimi; Kajiyama, Yoshiaki

    2013-01-01

    Highlights: •Spheroids were created from esophageal carcinoma cells using NanoCulture® Plates. •The proportion of strongly ALDH-positive cells increased in 3-D culture. •Expression of cancer stem cell-related genes was enhanced in 3-D culture. •CA-9 expression was enhanced, suggesting hypoxia had been induced in 3-D culture. •Drug resistance was increased. 3-D culture is useful for inducing cancer stem cells. -- Abstract: In recent years, research on resistance to chemotherapy and radiotherapy in cancer treatment has come under the spotlight, and researchers have also begun investigating the relationship between resistance and cancer stem cells. Cancer stem cells are assumed to be present in esophageal cancer, but experimental methods for identification and culture of these cells have not yet been established. To solve this problem, we created spheroids using a NanoCulture® Plate (NCP) for 3-dimensional (3-D) cell culture, which was designed as a means for experimentally reproducing the 3-D structures found in the body. We investigated the potential for induction of cancer stem cells from esophageal cancer cells. Using flow cytometry we analyzed the expression of surface antigen markers CD44, CD133, CD338 (ABCG2), CD318 (CDCP1), and CD326 (EpCAM), which are known cancer stem cell markers. None of these surface antigen markers showed enhanced expression in 3-D cultured cells. We then analyzed aldehyde dehydrogenase (ALDH) enzymatic activity using the ALDEFLUOR reagent, which can identify immature cells such as stem cells and precursor cells. 3-D-cultured cells were strongly positive for ALDH enzyme activity. We also analyzed the expression of the stem cell-related genes Sox-2, Nanog, Oct3/4, and Lin28 using RT-PCR. Expression of Sox-2, Nanog, and Lin28 was enhanced. Analysis of expression of the hypoxic surface antigen marker carbonic anhydrase-9 (CA-9), which is an indicator of cancer stem cell induction and maintenance, revealed that CA-9 expression

  10. Cotton Defense Induction Patterns Under Spatially, Temporally and Quantitatively Varying Herbivory Levels.

    Science.gov (United States)

    Eisenring, Michael; Meissle, Michael; Hagenbucher, Steffen; Naranjo, Steven E; Wettstein, Felix; Romeis, Jörg

    2017-01-01

    In its defense against herbivores, cotton ( Gossypium sp.) relies in part on the production of a set of inducible, non-volatile terpenoids. Under uniform damage levels, in planta allocation of induced cotton terpenoids has been found to be highest in youngest leaves, supporting assumptions of the optimal defense theory (ODT) which predicts that plants allocate defense compounds to tissues depending on their value and the likelihood of herbivore attack. However, our knowledge is limited on how varying, and thus more realistic, damage levels might affect cotton defense organization. We hypothesized that the allocation of terpenoids and densities of terpenoid-storing glands in leaves aligns with assumptions of the ODT, even when plants are subjected to temporally, spatially and quantitatively varying caterpillar ( Heliothis virescens ) damage. As expected, cotton plants allocated most of their defenses to their youngest leaves regardless of damage location. However, defense induction in older leaves varied with damage location. For at least 14 days after damage treatments ended, plants reallocated defense resources from previously young leaves to newly developed leaves. Furthermore, we observed a positive hyperbolic relationship between leaf damage area and both terpenoid concentrations and gland densities, indicating that cotton plants can fine-tune defense allocation. Although it appears that factors like vascular constraints and chemical properties of individual defense compounds can affect defense levels, our results overall demonstrate that induced defense organization of cotton subjected to varying damage treatments is in alignment with key assumptions of the ODT.

  11. Comparison and analysis of transient performances for doubly fed induction generator wind turbine under grid voltage dip

    DEFF Research Database (Denmark)

    Li, H.; Ye, R.; Han, L.

    2010-01-01

    In order to entirely analyze the transient performances of a grid-connected doubly fed induction generator (DFIG) wind turbine under the different operational states, based on the transient models of DFIG, a two-mass wind turbine electrical equivalent model considering the torsional flexibility o...

  12. The Identification of Senescence-Specific Genes during the Induction of Senescence in Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Steven R. Schwarze

    2005-09-01

    Full Text Available Classic mechanisms of tumor response to chemotherapy include apoptosis, mitotic catastrophe. Recent studies have suggested that cellular senescence, a terminal proliferation arrest seen in vitro, may be invoked during the exposure of cancer cells to chemotherapeutic agents. To identify markers associated specifically with the cellular senescence phenotype, we utilized expression data from cDNA microarray experiments identifying transcripts whose expression levels increased as human prostate epithelial cells progressed to senescence. When screened against other growth-inhibitory conditions, including quiescence, apoptosis, many of these transcripts were also upregulated, indicating that similar pathways occur between apoptosis, senescence. A senescent-like phenotype was then induced in several prostate cancer cell lines using 5-aza-2′-deoxycytidine, doxorubicin, or Docetaxel. Treatment with these agents resulted in a significant increase in the induction of senescence-specific genes when compared to nonsenescent conditions. The performance of the panel was improved with fluorescence-activated cell sorting using PKH26 to isolate nonproliferating, viable, drug-treated populations, indicating that a heterogeneous response occurs with chemotherapy. We have defined an RNA-based gene panel that characterizes the senescent phenotype induced in cancer cells by drug treatment. These data also indicate that a panel of genes, rather than one marker, needs to be utilized to identify senescence.

  13. Performance Analysis of Doubly Fed Induction Generator Based Wind turbine under Faulty and RLC Load Conditions

    OpenAIRE

    Rekha Parashar; Shashikant

    2015-01-01

    This paper presents the performance of Doubly Fed Induction Generator based wind turbine system during different types of grid fault. The doubly fed induction generator (DFIG) based wind turbine (WT) system provides better power delivery towards the demand. The design and response of the DFIG based wind turbine system during different fault conditions, various load conditions and integrated system consisting of DFIG based WT system have been verified using MATLAB/ Simulink. The simulation re...

  14. Time-lapse electromagnetic induction surveys under olive tree canopies reveal soil moisture dynamics and controls

    Science.gov (United States)

    Martínez, Gonzalo; Giraldez Cervera, Juan Vicente; Vanderlinden, Karl

    2015-04-01

    Soil moisture (θ) is a critical variable that exerts an important control on plant status and development. Soil sampling, neutron attenuation and electromagnetic methods such as TDR or FDR have been used widely to measure θ and provide point data at a possible range of temporal resolutions. However, these methods require either destructive sampling or permanently installed devices with often limiting measurement depths, or are extremely time-consuming. Moreover, the small support of such measurements compromises its value in heterogeneous soils. To overcome such limitations electromagnetic induction (EMI) can be tested to monitor θ at different spatial and temporal scales. This work investigates the potential of EMI to characterize the spatio-temporal variability of soil moisture from apparent electrical conductivity (ECa) under the canopy of individual olive trees. During one year we measured θ with a frequency of 5 min and ECa on an approximately weekly basis along transects from the tree trunk towards the inter-row area. CS-616 soil moisture sensors where horizontally installed in the walls of a trench at depths of 0.1, 0.2, 0.4, 0.6 and 0.8 m at five locations along the transect, with a separation of 0.8 m. The Dualem-21S sensor was used to measure weekly the ECa at 0.2 m increments, from the tree trunk to a distance of 4.4 m. The results showed similar drying and wetting patterns for θ and ECa. Both variables showed a decreasing pattern from the tree trunk towards the drip line, followed by a sharp increment and constant values towards the center of the inter-row space. This pattern reflects clearly the influence of root-zone water uptake under the tree canopy and higher θ values in the inter-row area where root-water uptake is smaller. Time-lapse ECa data responded to evaporation and infiltration fluxes with the highest sensitivity for the 1 and 1.5 m ECa signals, as compared to the 0.5 and 3.0 m signals. Overall these preliminary results revealed the

  15. A generalized electron energy probability function for inductively coupled plasmas under conditions of nonlocal electron kinetics

    Science.gov (United States)

    Mouchtouris, S.; Kokkoris, G.

    2018-01-01

    A generalized equation for the electron energy probability function (EEPF) of inductively coupled Ar plasmas is proposed under conditions of nonlocal electron kinetics and diffusive cooling. The proposed equation describes the local EEPF in a discharge and the independent variable is the kinetic energy of electrons. The EEPF consists of a bulk and a depleted tail part and incorporates the effect of the plasma potential, Vp, and pressure. Due to diffusive cooling, the break point of the EEPF is eVp. The pressure alters the shape of the bulk and the slope of the tail part. The parameters of the proposed EEPF are extracted by fitting to measure EEPFs (at one point in the reactor) at different pressures. By coupling the proposed EEPF with a hybrid plasma model, measurements in the gaseous electronics conference reference reactor concerning (a) the electron density and temperature and the plasma potential, either spatially resolved or at different pressure (10-50 mTorr) and power, and (b) the ion current density of the electrode, are well reproduced. The effect of the choice of the EEPF on the results is investigated by a comparison to an EEPF coming from the Boltzmann equation (local electron kinetics approach) and to a Maxwellian EEPF. The accuracy of the results and the fact that the proposed EEPF is predefined renders its use a reliable alternative with a low computational cost compared to stochastic electron kinetic models at low pressure conditions, which can be extended to other gases and/or different electron heating mechanisms.

  16. Solar ultraviolet radiation from cancer induction to cancer prevention: solar ultraviolet radiation and cell biology.

    Science.gov (United States)

    Tuorkey, Muobarak J

    2015-09-01

    Although decades have elapsed, researchers still debate the benefits and hazards of solar ultraviolet radiation (UVR) exposure. On the one hand, humans derive most of their serum 25-hydroxycholecalciferol [25(OH)D3], which has potent anticancer activity, from solar UVB radiation. On the other hand, people are more aware of the risk of cancer incidence associated with harmful levels of solar UVR from daily sunlight exposure. Epidemiological data strongly implicate UV radiation exposure as a major cause of melanoma and other cancers, as UVR promotes mutations in oncogenes and tumor-suppressor genes. This review highlights the impact of the different mutagenic effects of solar UVR, along with the cellular and carcinogenic challenges with respect to sun exposure.

  17. Cyclin K dependent regulation of Aurora B affects apoptosis and proliferation by induction of mitotic catastrophe in prostate cancer.

    Science.gov (United States)

    Schecher, Sabrina; Walter, Britta; Falkenstein, Michael; Macher-Goeppinger, Stephan; Stenzel, Philipp; Krümpelmann, Kristina; Hadaschik, Boris; Perner, Sven; Kristiansen, Glen; Duensing, Stefan; Roth, Wilfried; Tagscherer, Katrin E

    2017-10-15

    Cyclin K plays a critical role in transcriptional regulation as well as cell development. However, the role of Cyclin K in prostate cancer is unknown. Here, we describe the impact of Cyclin K on prostate cancer cells and examine the clinical relevance of Cyclin K as a biomarker for patients with prostate cancer. We show that Cyclin K depletion in prostate cancer cells induces apoptosis and inhibits proliferation accompanied by an accumulation of cells in the G2/M phase. Moreover, knockdown of Cyclin K causes mitotic catastrophe displayed by multinucleation and spindle multipolarity. Furthermore, we demonstrate a Cyclin K dependent regulation of the mitotic kinase Aurora B and provide evidence for an Aurora B dependent induction of mitotic catastrophe. In addition, we show that Cyclin K expression is associated with poor biochemical recurrence-free survival in patients with prostate cancer treated with an adjuvant therapy. In conclusion, targeting Cyclin K represents a novel, promising anti-cancer strategy to induce cell cycle arrest and apoptotic cell death through induction of mitotic catastrophe in prostate cancer cells. Moreover, our results indicate that Cyclin K is a putative predictive biomarker for clinical outcome and therapy response for patients with prostate cancer. © 2017 UICC.

  18. Antiproliferative and apoptosis induction of α-mangostin in T47D breast cancer cells.

    Science.gov (United States)

    Kritsanawong, Somchai; Innajak, Sukanda; Imoto, Masaya; Watanapokasin, Ramida

    2016-05-01

    α-Mangostin extracted from mangosteen, Garcinia mangostana Linn. is known as 'queen of fruits'. The anticancer activity of α-mangostin through apoptosis induction and related signaling pathways in human breast cancer T47D cells was investigated. Human epidermal growth factor receptor 2 (HER2) and mitogen-activated protein kinase (MAPK) signaling have been shown to play important roles in apoptosis. The results showed that α-mangostin induced cell proliferation inhibition, DNA fragmentation, nuclear condensation, increased cleaved caspase-3 and cleaved caspase-9, but decreased Bcl-2 and Mcl-1 expression. Mitochondrial dysfunction and cytochrome c release were also detected. In addition, phosphorylation of ERα, HER2, PI3K, Akt and ERK1/2 were downregulated whereas p-JNK1/2 and p-p38 were upregulated. These results indicated that α-mangostin induced apoptosis associated with HER2/PI3K/Akt and MAPK signaling pathways suggesting that α-mangostin may be used as food supplement or a potential therapeutic compound for breast cancer.

  19. A Combined Chemical and Magneto-Mechanical Induction of Cancer Cell Death by the Use of Functionalized Magnetic Iron Nanowires

    KAUST Repository

    Martinez Banderas, Aldo

    2016-04-01

    Cancer prevails as one of the most devastating diseases being at the top of death causes for adults despite continuous development and innovation in cancer therapy. Nanotechnology may be used to achieve therapeutic dosing, establish sustained-release drug profiles, and increase the half-life of drugs. In this context, magnetic nanowires (NWs) have shown a good biocompatibility and cellular internalization with a low cytotoxic effect. In this thesis, I induced cancer cell death by combining the chemotherapeutic effect of iron NWs functionalized with Doxorubicin (DOX) with mechanical disturbance under a low frequency alternating magnetic field. Two different agents, APTES and BSA, were separately used for coating NWs permitting further functionalization with DOX. Internalization was qualitatively and quantitatively assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal reflection analysis, BSA formulations demonstrate to have a higher internalization degree and a broader distribution within the cells in comparison to APTES formulations. Both groups of functionalized NWs generated a comparable cytotoxic effect in MDA-MB-231 breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by the free DOX (~95% at the same concentration) and non-functionalized NWs formulations (~10% at the same NWs concentration). A synergistic cytotoxic effect is obtained when a low frequency magnetic field (1 mT, 10 Hz) is applied to cells treated with the two formulations that is again comparable (~70% at the highest concentration). Furthermore, the cytotoxic effect of both groups of coated NWs without the drug increased notoriously when the field is applied (~25% at the highest concentration tested). Here, a novel bimodal method for cancer cell destruction was developed by the conjugation of the magneto

  20. Regulation of an Induction Motor under Broad Changes in DC-Link Voltage

    Czech Academy of Sciences Publication Activity Database

    Kokeš, Petr; Semerád, Radko

    2006-01-01

    Roč. 51, č. 4 (2006), s. 363-394 ISSN 0001-7043 Institutional research plan: CEZ:AV0Z20570509 Keywords : induction motor (IM) * DC-link voltage drop * stator flux vector control (SFVC) Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering

  1. Induction chemotherapy followed by concurrent chemoradiotherapy in stage III unresectable non-small cell lung cancer

    International Nuclear Information System (INIS)

    Tan, E.H.; Ang, P.T.; Leong, S.S.; Khoo, K.S.; Wee, J.; Fong, K.W.; Tan, T.; Lee, K.S.; Chua, E.J.; Eng, P.; Hsu, A.; Tan, Y.K.; Ong, Y.Y.

    1999-01-01

    che favourable experience with the combination regimen of vinorelbine, ifosfamide and cisplatin (NIP) in patients with metastatic non-small cell lung cancer (NSCLC) has led to a protocol assessing this regimen as an induction treatment in patients with stage III unresectable NSCLC, followed by thoracic radiotherapy with concurrent daily cisplatin as a radiosensitizer. Two cycles of NIP were administered 21 days apart; each cycle comprised i.v. vinorelbine 25 mg/m 2 on days 1 and 8, i.v. ifosfamide 3 g/m 2 on day 1 with MESNA as uroprotection, and i.v. cisplatin 50 mg/m 2 on day 1. Radical thoracic radiotherapy commenced on day 43 to a total dose of 64 Gy and i.v. cisplatin 6 mg/m 2 was given concurrently prior to each fraction of radiation as a sensitiser. Two more cycles of NIP were given to patients who responded favourably to the induction treatment about 2 weeks after completion of radiation. Between July 1995 and July 1997, 44 patients were treated with this protocol. This treatment schedule was generally well tolerated. Grade 3-4 neutropenia occurred in 50% of the patients and neutropenic sepsis was seen in 8. Grade 3-4 oesophagitis was uncommon. Most of the patients were able to complete the induction and concurrent chemoradiotherapy phase. Major response occurred in 75% of the patients with 2 (4.5%) complete responses (CR). A total of 6 patients achieved CR after chemoradiotherapy. At a median follow-up of 35 months, the median overall survival for all patients was 15 months with a 3-year survival rate of 24%. The median overall survival for stage IIIA patients was 19 months with a 3-year survival rate of 39% in contrast to 13 months' median overall survival and only 15% 3-year survival rate for stage IIIB. The NIP regimen results in a high response rate in NSCLC and this treatment programme seems to benefit selected patients with stage III disease. (orig.)

  2. Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS

    Directory of Open Access Journals (Sweden)

    Zhen-Wei Zou

    2018-06-01

    Full Text Available Thyroid cancer is the most common endocrine carcinoma with increasing incidence worldwide and anaplastic subtypes are frequently associated with cancer related death. Radioresistance of thyroid cancer often leads to therapy failure and cancer-related death. In this study, we found that melatonin showed potent suppressive roles on NF-κB signaling via inhibition of p65 phosphorylation and generated redox stress in thyroid cancer including the anaplastic subtypes. Our data showed that melatonin significantly decreased cell viability, suppressed cell migration and induced apoptosis in thyroid cancer cell lines in vitro and impaired tumor growth in the subcutaneous mouse model in vivo. By contrast, irradiation of thyroid cancer cells resulted in elevated level of phosphorylated p65, which could be reversed by cotreatment with melatonin. Consequently, melatonin synergized with irradiation to induce cytotoxicity to thyroid cancer, especially in the undifferentiated subgroups. Taken together, our results suggest that melatonin may exert anti-tumor activities against thyroid carcinoma by inhibition of p65 phosphorylation and induction of reactive oxygen species. Radio-sensitization by melatonin may have clinical benefits in thyroid cancer. Keywords: Melatonin, Thyroid cancer, Radioresistance, p65, Reactive oxygen species

  3. Electrical Activity in a Time-Delay Four-Variable Neuron Model under Electromagnetic Induction

    Directory of Open Access Journals (Sweden)

    Keming Tang

    2017-11-01

    Full Text Available To investigate the effect of electromagnetic induction on the electrical activity of neuron, the variable for magnetic flow is used to improve Hindmarsh–Rose neuron model. Simultaneously, due to the existence of time-delay when signals are propagated between neurons or even in one neuron, it is important to study the role of time-delay in regulating the electrical activity of the neuron. For this end, a four-variable neuron model is proposed to investigate the effects of electromagnetic induction and time-delay. Simulation results suggest that the proposed neuron model can show multiple modes of electrical activity, which is dependent on the time-delay and external forcing current. It means that suitable discharge mode can be obtained by selecting the time-delay or external forcing current, which could be helpful for further investigation of electromagnetic radiation on biological neuronal system.

  4. Non-chemotoxic induction of cancer cell death using magnetic nanowires

    Directory of Open Access Journals (Sweden)

    Contreras MF

    2015-03-01

    Full Text Available Maria F Contreras,1 Rachid Sougrat,2 Amir Zaher,3 Timothy Ravasi,1,3 Jürgen Kosel3 1Division of Biological and Environmental Sciences and Engineering, 2Advanced Nanofabrication Imaging and Characterization, 3Division of Computer, Electrical and Mathematical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Kingdom of Saudi Arabia Abstract: In this paper, we show that magnetic nanowires with weak magnetic fields and low frequencies can induce cell death via a mechanism that does not involve heat production. We incubated colon cancer cells with two concentrations (2.4 and 12 µg/mL of nickel nanowires that were 35 nm in diameter and exposed the cells and nanowires to an alternating magnetic field (0.5 mT and 1 Hz or 1 kHz for 10 or 30 minutes. This low-power field exerted a force on the magnetic nanowires, causing a mechanical disturbance to the cells. Transmission electron microscopy images showed that the nanostructures were internalized into the cells within 1 hour of incubation. Cell viability studies showed that the magnetic field and the nanowires separately had minor deleterious effects on the cells; however, when combined, the magnetic field and nanowires caused the cell viability values to drop by up to 39%, depending on the strength of the magnetic field and the concentration of the nanowires. Cell membrane leakage experiments indicated membrane leakage of 20%, suggesting that cell death mechanisms induced by the nanowires and magnetic field involve some cell membrane rupture. Results suggest that magnetic nanowires can kill cancer cells. The proposed process requires simple and low-cost equipment with exposure to only very weak magnetic fields for short time periods. Keywords: cell death induction, low frequency alternating magnetic field, nanomedicine, nanowire internalization, nickel nanowires

  5. Prostate cancer induction in autoimmune rats and modulation of T cell apoptosis.

    Science.gov (United States)

    Gilardoni, M B; Rabinovich, G A; Oviedo, M; Depiante-Depaoli, M

    1999-12-01

    In this study we present an experimental model of prostate gland cancer induced by long term hormonal treatment with testosterone in combination with a chemical carcinogenic agent in male Wistar rats with autoimmune prostatitis (AIP). This system is particularly attractive in order to study the factors involved in the transition from a non-invasive to an invasive carcinoma, decisive in the risk of human cancer. At first, autoimmune prostatitis was induced by immunization in 3 months-old male Wistar rats with autologous accessory glands. Then, rats were treated with continuous intradermal implants of testosterone propionate (TP) and with single doses of the chemical carcinogen 7, 12 dimethylbenz (alpha) anthracene (DMBA) by intraperitoneal injection. Histopathological studies of the prostate gland revealed the presence of pre-malignant lesions, particularly the so-called prostatic intraepithelial neoplasm (PIN) in 50% of animals. Moreover, we observed the development of carcinomas in 50% of treated-animals, which could be histologically discriminated in adenocarcinomas, carcinoma of epidermal origin and undifferentiated carcinoma. In autoimmune rats which did not receive any other treatment, exposure to autoantigens gave rise to an atypical hyperplasia of the prostatic gland which could be attributed to the hyperactive state of the gland. Control groups constituted by autoimmune rats treated with TP or DMBA, and normal rats which were exposed to TP and/or DMBA evidenced the presence of PINs at different degrees, but did not develop carcinomas. Moreover, serum acid phosphatase significantly increased as treatment was accomplished, reaching its maximum levels in animals with carcinoma, in which DNA content, determined by image cytometry, showed to be aneuploid. Finally, we provided biochemical and cytofluorometrical evidence of the induction of apoptosis of spleen T cells in carcinoma-bearing hosts, and to a lesser extent in animals with PIN, but not in autoimmune or

  6. Studies on Culture and Osteogenic Induction of Human Mesenchymal Stem Cells under CO2-Independent Conditions

    OpenAIRE

    Chen, Jian; Zhang, Cui; Feng, Yiding; Zong, Chen; Chen, Jiarong; Tang, Zihua; Jia, Bingbing; Tong, Xiangming; Zheng, Qiang; Wang, Jinfu

    2013-01-01

    Human mesenchymal stem cells (hMSCs) are one of the important factors that regulate bone anabolism. Osteoporosis resulting from microgravity during spaceflight may possibly be due to a decrease in osteogenesis mediated by hMSCs. This speculation should be verified through culture and osteogenic induction of hMSCs in a microgravity environment during spaceflight. Control of CO2 is a key component in current experimental protocols for growth, survival, and proliferation of in vitro cultured cel...

  7. Selective cytotoxicity of Aniba rosaeodora essential oil towards epidermoid cancer cells through induction of apoptosis.

    Science.gov (United States)

    Sœur, Jérémie; Marrot, Laurent; Perez, Philippe; Iraqui, Ismail; Kienda, Guy; Dardalhon, Michèle; Meunier, Jean-Roch; Averbeck, Dietrich; Huang, Meng-Er

    2011-01-10

    Essential oils are complex mixtures of odorous and volatile compounds derived from secondary plant metabolism. They can be isolated from many plants by mechanical pressing or hydro- and steam-distillation and are known to induce a wide range of biological effects through their antibacterial, antifungal, cytotoxic, antioxidant and antimutagenic activities. In order to explore their beneficial properties on human skin cells, we investigated the effects of an essential oil from rosewood Aniba rosaeodora (REO) on the human epidermoid carcinoma cell line A431, on immortal HaCaT cells thought to represent an early stage of skin carcinogenesis, on transformed normal HEK001 keratinocytes and on primary normal NHEK keratinocytes. In a defined range of concentrations, REO selectively killed A431 and HaCaT cells. The same treatments had only a minor cytotoxic effect on HEK001 and NHEK cells. Preferentially in A431 and HaCaT cells, REO triggered the production of reactive oxygen species, induced depolarization of the mitochondrial membrane and caused caspase-dependent cell death characterized by phosphatidylserine externalization, an early marker of apoptosis. Both intrinsic and extrinsic apoptotic pathways were implicated in REO-induced cell death. The identification of selective induction of apoptosis in precancerous and cancerous skin cells by REO highlights the potential anticancer activity of this essential oil. 2010 Elsevier B.V. All rights reserved.

  8. The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Wen-Ying [Department of Pathology, Chi-Mei Hospital, Tainan, Taiwan (China); Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Chen, Yen-Chou [Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Shih, Chwen-Ming; Lin, Chun-Mao; Cheng, Chia-Hsiung; Chen, Ku-Chung [Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Lin, Cheng-Wei, E-mail: cwlin@tmu.edu.tw [Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)

    2014-01-01

    Heme oxygenase (HO)-1 is an oxidative stress-response enzyme which catalyzes the degradation of heme into bilirubin, ferric ion, and carbon monoxide (CO). Induction of HO-1 was reported to have antitumor activity; the inhibitory mechanism, however, is still unclear. In the present study, we found that treatment with [Ru(CO){sub 3}Cl{sub 2}]{sub 2} (RuCO), a CO-releasing compound, reduced the growth of human MCF7 and MDA-MB-231 breast cancer cells. Analysis of growth-related proteins showed that treatment with RuCO down-regulated cyclinD1, CDK4, and hTERT protein expressions. Interestingly, RuCO treatment resulted in opposite effects on wild-type and mutant p53 proteins. These results were similar to those of cells treated with geldanamycin (a heat shock protein (HSP)90 inhibitor), suggesting that RuCO might affect HSP90 activity. Moreover, RuCO induced mutant p53 protein destabilization accompanied by promotion of ubiquitination and proteasome degradation. The induction of HO-1 by cobalt protoporphyrin IX (CoPP) showed consistent results, while the addition of tin protoporphyrin IX (SnPP), an HO-1 enzymatic inhibitor, diminished the RuCO-mediated effect. RuCO induction of HO-1 expression was reduced by a p38 mitogen-activated protein kinase inhibitor (SB203580). Additionally, treatment with a chemopreventive compound, curcumin, induced HO-1 expression accompanied with reduction of HSP90 client protein expression. The induction of HO-1 by curcumin inhibited 12-O-tetradecanoyl-13-acetate (TPA)-elicited matrix metalloproteinase-9 expression and tumor invasion. In conclusion, we provide novel evidence underlying HO-1's antitumor mechanism. CO, a byproduct of HO-1, suppresses HSP90 protein activity, and the induction of HO-1 may possess potential as a cancer therapeutic. - Highlights: • CO and HO-1 inhibited the growth of human breast cancer cells. • CO and HO-1 attenuated HSP90 and its client proteins expression. • CO induced mutant p53 protein

  9. Induction period

    International Nuclear Information System (INIS)

    Land, C.E.; Tokunaga, M.

    1984-01-01

    Induction period is the temporal aspect of the excess cancer risk that follows an exposure to ionizing radiation. Operationally, it can be thought of as the time from an exposure of brief duration to the diagnosis of any resultant cancer. Whereas the magnitude of excess risk can be described by a single number, such as the average yearly excess risk over some fixed time interval after exposure, the temporal distribution requires a histogram or a curve, that is, an array or continuum of numbers. The study of induction period involves a search for a simple way of describing the temporal distribution of risk, that is, a way of describing a continuum by using only one or two numbers. In other words, the goal is to describe induction period probabilistically, using a parametric model with a few parameters

  10. Shikonin enhances efficacy of a gene-based cancer vaccine via induction of RANTES

    Directory of Open Access Journals (Sweden)

    Chen Hui-Ming

    2012-04-01

    effectively enhance anti-tumor potency of a gene-based cancer vaccine via the induction of RANTES expression at the skin immunization site.

  11. CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid‐specific cancer cell death through autophagy induction

    DEFF Research Database (Denmark)

    Lee, Alvin J. X.; Roylance, Rebecca; Sander, Jil

    2012-01-01

    to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CERT‐specific multidrug sensitization is associated with enhanced autophagosome–lysosome flux, resulting from the expression of LAMP2 following CERT silencing in colorectal and HER2+ breast cancer cell lines. Live...... cell microscopy analysis revealed that CERT depletion induces LAMP2‐dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CERT is relatively over‐expressed in HER2+ breast cancer and CERT protein expression acts as an independent prognostic variable...... and predictor of outcome in adjuvant chemotherapy‐treated patients with primary breast cancer. These data suggest that the induction of LAMP2‐dependent autophagic flux through CERT targeting may provide a rational approach to enhance multidrug sensitization and potentiate the death of polyploid cells following...

  12. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer.

    NARCIS (Netherlands)

    Meerbeeck, J.P. van; Kramer, G.W.P.M.; Schil, P.E. van; Legrand, C.; Smit, E.F.; Schramel, F.M.; Tjan-Heijnen, V.C.; Biesma, B.; Debruyne, C.; Zandwijk, N. van; Splinter, T.A.; Giaccone, G.

    2007-01-01

    BACKGROUND: Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to

  13. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer

    NARCIS (Netherlands)

    J.P. van Meerbeeck (Jan); G.W.P.M. Kramer (Gijs); P.E.Y. van Schil (Paul); C. Legrand; E.F. Smit (Egbert); F.M.N.H. Schramel (Franz); V.C.G. Tjan-Heijnen (Vivianne); B. Biesma (Bonne); C. Debruyne (Channa); N. van Zandwijk (Nico); T.A.W. Splinter (Ted); G. Giaccone (Giuseppe)

    2007-01-01

    textabstractBackground: Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non - small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be

  14. Advanced modelling of doubly fed induction generator wind turbine under network disturbance

    DEFF Research Database (Denmark)

    Seman, S.; Iov, Florin; Niiranen, J.

    This paper presents a variable speed wind turbine simulator. The simulator is used for a 2 MW wind turbine transient behavior study during a short-term symmetrical network disturbance. The mechanical part of wind turbine model consists of the rotor aerodynamic model, the wind turbine control...... and the drive train model. The Doubly Fed Induction Generator (DFIG) is represented by an analytical two-axis model with constant lumped parameters and by Finite Element Method (FEM) based model. The model of the DFIG is coupled with the model of the passive crowbar protected and DTC controlled frequency...

  15. Modelling high frequency phenomena in the rotor of induction motors under no-load test conditions

    International Nuclear Information System (INIS)

    Boglietti, Aldo; Bottauscio, Oriano.; Chiampi, Mario; Lazzari, Mario

    2003-01-01

    The paper aims to deep the electromagnetic phenomena in the rotor of induction motors produced during the no-load test by the high-order harmonics of the spatial distribution of magnetic flux. The analysis is carried out by a flux driven finite element procedure, which can take into account the hysteresis of magnetic material, the induced currents in rotor cage and the eddy currents in the laminations. The computed results, including losses and local waveforms of electrical and magnetic quantities, are finally discussed

  16. Glomerular diseases and cancer: evaluation of underlying malignancy.

    Science.gov (United States)

    Pani, Antonello; Porta, Camillo; Cosmai, Laura; Melis, Patrizia; Floris, Matteo; Piras, Doloretta; Gallieni, Maurizio; Rosner, Mitchell; Ponticelli, Claudio

    2016-04-01

    Onconephrology is an emerging medical subspecialty focused on the numerous interconnections between cancer and kidney diseases. Patient with malignancies commonly experience kidney problems including acute kidney injury, tumor lysis syndrome, fluid and electrolyte disorders and chronic kidney disease, often as a consequence of the anti-cancer treatment. Conversely, a number of glomerulopathies, tubulopathies and vascular renal diseases can early signal the presence of an underlying cancer. Furthermore, the administration of immunosuppressive drugs, especially cytotoxic drugs and calcineurin inhibitors, may strongly impair the immune response increasing the risk of cancer. The objective of this review article is to: (i) discuss paraneoplastic glomerular disease, (ii) review cancer as an adverse effect of immunosuppressive agents used to treat glomerulopathies, and (iii) in the absence of international approved guidelines, propose a screening program based on expert opinion aimed at guiding nephrologists to early detect malignancies during their clinical practice.

  17. Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression

    International Nuclear Information System (INIS)

    Paschall, Amy V; Bielawska, Alicja; Liu, Kebin; Zimmerman, Mary A; Torres, Christina M; Yang, Dafeng; Chen, May R; Li, Xia; Bieberich, Erhard; Bai, Aiping; Bielawski, Jacek

    2014-01-01

    Ceramide is a bioeffector that mediates various cellular processes, including apoptosis. However, the mechanism underlying ceramide function in apoptosis is apparently cell type-dependent and is not well-understood. We aimed at identifying molecular targets of ceramide in metastatic human colon and breast cancer cells, and determining the efficacy of ceramide analog in suppression of colon and breast cancer metastasis. The activity of and mechanism underlying ceramide as a cytotoxic agent, and as a sensitizer for Fas-mediated apoptosis was analyzed in human cell lines established from primary or metastatic colon and breast cancers. The efficacy of ceramide analog LCL85 in suppression of metastasis was examined in preclinical mouse tumor models. Exposure of human colon carcinoma cells to ceramide analog LCL85 results in apoptosis in a dose-dependent manner. Interestingly, a sublethal dose of LCL85 increased C16 ceramide content and overcame tumor cell resistance to Fas-mediated apoptosis. Subsequently, treatment of tumor cells with exogenous C16 ceramide resulted in increased tumor cell sensitivity to Fas-mediated apoptosis. LCL85 resembles Smac mimetic BV6 in sensitization of colon carcinoma cells to Fas-mediated apoptosis by inducing proteasomal degradation of cIAP1 and xIAP proteins. LCL85 also decreased xIAP1 and cIAP1 protein levels and sensitized metastatic human breast cancer cells to Fas-mediated apoptosis. Silencing xIAP and cIAP1 with specific siRNAs significantly increased the metastatic human colon carcinoma cell sensitivity to Fas-mediated apoptosis, suggesting that IAP proteins mediate apoptosis resistance in metastatic human colon carcinoma cells and ceramide induces IAP protein degradation to sensitize the tumor cells to apoptosis induction. Consistent with its apoptosis sensitization activity, subtoxic doses of LCL85 suppressed colon carcinoma cell metastatic potential in an experimental lung metastasis mouse model, as well as breast cancer growth

  18. LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis.

    Science.gov (United States)

    Wang, Zhi-Yu; Loo, Tjing Yung; Shen, Jian-Gang; Wang, Neng; Wang, Dong-Mei; Yang, De-Po; Mo, Sui-Lin; Guan, Xin-Yuan; Chen, Jian-Ping

    2012-02-01

    LDH-A, as the critical enzyme accounting for the transformation from pyruvate into lactate, has been demonstrated to be highly expressed in various cancer cells and its silencing has also been approved relating to increased apoptosis in lymphoma cells. In this study, we intend to investigate the correlation between LDH-A and other clinicopathological factors of breast cancer and whether LDH-A silencing could suppress breast cancer growth, and if so the potential mechanisms. 46 breast cancer specimens were collected to study the relation between LDH-A expression and clinicopathological characteristics including menopause, tumor size, node involvement, differentiation, and pathological subtypes classified by ER, PR, and Her-2. shRNAs were designed and applied to silence LDH-A expression in breast cancer cell lines MCF-7 and MDA-MB-231. The effects of LDH-A reduction on cancer cells were studied by a series of in vitro and in vivo experiments, including cell growth assay, apoptosis evaluation, oxidative stress detection, transmission electron microscopy observation, and tumor formation assay on nude mice. LDH-A expression was found to correlate significantly with tumor size and to be independent for other clinicopathological factors. LDH-A reduction resulted in an inhibited cancer cell proliferation, elevated intracellular oxidative stress, and induction of mitochondrial pathway apoptosis. Meanwhile, the tumorigenic ability of LDH-A deficient cancer cells was significantly limited in both breast cancer xenografts. The Ki67 positive cancer cells were significantly reduced in LDH-A deficiency tumor samples, while the apoptosis ratio was enhanced. Our results suggested that LDH-A inhibition might offer a promising therapeutic strategy for breast cancer.

  19. Apoptosis induction by Pleurotus sajor-caju (Fr.) Singer extracts on colorectal cancer cell lines.

    Science.gov (United States)

    Finimundy, Tiane C; Abreu, Rui M V; Bonetto, Natalia; Scariot, Fernando J; Dillon, Aldo J P; Echeverrigaray, Sergio; Barros, Lillian; Ferreira, Isabel C F R; Henriques, João A P; Roesch-Ely, Mariana

    2018-02-01

    Pleurotus sajor-caju (PSC) is an edible mushroom used in food supplements, presenting antitumor properties through induction of cell death pathways. The PSC potential against colorectal cancer was analyzed by exposing HCT116 wt cells to different PSC extracts. The PSC n-hexane extract (PSC-hex) showed the highest cytotoxicity effect (IC 50 value 0.05 mg/mL). The observed cytotoxicity was then associated to apoptosis-promoting and cell cycle-arrest pathways. PSC-hex was able to induce apoptosis related to breakdown of mitochondrial membrane potential and ROS generation. The absence of cytotoxicity in HTC116 -p53 and HTC116 -Bax cells, alongside with an increase in p53, Bax and Caspase-3 expression, and decrease in Bcl-2 expression, supports that the pro-apoptotic effect is probably induced through a p53 associated pathway. PSC-hex induced cell cycle arrest at G2/M in HCT116 wt without cytotoxicity in HTC116 -p21  cells. These findings suggest that a p21/p53 cell cycle regulation pathway is probably disrupted by compounds present on PSC-hex. Identification of the major components was then performed with ergosta-5,7,22-trien-3β-ol representing 30.6% of total weight. In silico docking studies of ergosta-5,7,22-trien-3β against Bcl-2 were performed and results show a credible interaction with the Bcl-2 hydrophobic cleft. The results show that PSC-hex can be used as supplementary food for adjuvant therapy in colorectal carcinoma. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Subcritical Hopf Bifurcation and Stochastic Resonance of Electrical Activities in Neuron under Electromagnetic Induction

    Directory of Open Access Journals (Sweden)

    Yu-Xuan Fu

    2018-02-01

    Full Text Available The FitzHugh–Nagumo model is improved to consider the effect of the electromagnetic induction on single neuron. On the basis of investigating the Hopf bifurcation behavior of the improved model, stochastic resonance in the stochastic version is captured near the bifurcation point. It is revealed that a weak harmonic oscillation in the electromagnetic disturbance can be amplified through stochastic resonance, and it is the cooperative effect of random transition between the resting state and the large amplitude oscillating state that results in the resonant phenomenon. Using the noise dependence of the mean of interburst intervals, we essentially suggest a biologically feasible clue for detecting weak signal by means of neuron model with subcritical Hopf bifurcation. These observations should be helpful in understanding the influence of the magnetic field to neural electrical activity.

  1. [A Case of Advanced Rectal Cancer Resected Successfully after Induction Chemotherapy with Modified FOLFOX6 plus Panitumumab].

    Science.gov (United States)

    Yukawa, Yoshimi; Uchima, Yasutake; Kawamura, Minori; Takeda, Osami; Hanno, Hajime; Takayanagi, Shigenori; Hirooka, Tomoomi; Dozaiku, Toshio; Hirooka, Takashi; Aomatsu, Naoki; Hirakawa, Toshiki; Iwauchi, Takehiko; Nishii, Takafumi; Morimoto, Junya; Nakazawa, Kazunori; Takeuchi, Kazuhiro

    2016-05-01

    We report a case of advanced colon cancer that was effectively treated with mFOLFOX6 plus panitumumab combination chemotherapy. The patient was a 54-year-old man who had type 2 colon cancer of the rectum. An abdominal CT scan demonstrated rectal cancer with bulky lymph node metastasis and 1 hepatic node (rectal cancer SI [bladder retroperitoneum], N2M0H1P0, cStage IV). He was treated with mFOLFOX6 plus panitumumab as neoadjuvant chemotherapy. After 4 courses of chemotherapy, CT revealed that the primary lesion and regional metastatic lymph nodes had reduced in size (rectal cancer A, N1H1P0M0, cStage IV). Anterior rectal resection with D3 nodal dissection and left lateral segmentectomy of the liver was performed. The histological diagnosis was tubular adenocarcinoma (tub2-1), int, INF a, pMP, ly0, v0, pDM0, pPM0, R0. He was treated with 4 courses of mFOLFOX6 after surgery. The patient has been in good health without a recurrence for 2 years and 5 months after surgery. This case suggests that induction chemotherapy with mFOLFOX6 plus panitumumab is a potentially effective regimen for advanced colon cancer.

  2. Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.

    Directory of Open Access Journals (Sweden)

    W Joost Lesterhuis

    Full Text Available Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+ and CD8(+ T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.

  3. Modulatory Effects of Polyphenols on Apoptosis Induction: Relevance for Cancer Prevention

    Directory of Open Access Journals (Sweden)

    Claudio Giovannini

    2008-02-01

    Full Text Available Polyphenols, occurring in fruit and vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products, have been demonstrated to have clear antioxidant properties in vitro, and many of their biological actions have been attributed to their intrinsic reducing capabilities. However, it has become clear that, in complex biological systems, polyphenols exhibit several additional properties which are yet poorly understood. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathological processes, since too little or too much apoptosis can lead to proliferative or degenerative diseases, respectively. Cancer cells are characterized by a deregulated proliferation, and/or an inability to undergo programmed cell death. A large body of evidence indicates that polyphenols can exert chemopreventive effects towards different organ specific cancers, affecting the overall process of carcinogenesis by several mechanisms: inhibition of DNA synthesis, modulation of ROS production, regulation of cell cycle arrest, modulation of survival/proliferation pathways. In addition, polyphenols can directly influence different points of the apoptotic process, and/or the expression of Int. J. Mol. Sci. 2008, 9 214 regulatory proteins. Although the bulk of data has been obtained in in vitro systems, a number of clinical studies suggesting a preventive and therapeutic effectiveness of polyphenols in vivo is available. However, a deeper knowledge of the underlying mechanisms responsible for the modulation of apoptosis by polyphenols, and their real effectiveness, is necessary in order to propose them as potential chemopreventive and chemotherapeutic candidates for cancer treatment.

  4. Preoperative chemoradiation with or without induction oxaliplatin plus 5-fluorouracil in locally advanced rectal cancer. Long-term outcome analysis

    International Nuclear Information System (INIS)

    Calvo, F.A.; Sole, C.V.; Serrano, J.; Valle, E. del; Rodriguez, M.; Munoz-Calero, A.; Garcia-Sabrido, J.L.; Garcia-Alfonso, P.; Peligros, I.; Alvarez, E.

    2014-01-01

    It has been previously reported that a short FOLFOX-4 induction significantly improves pathologic complete response in locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiation (CRT). In a larger and updated patient series, we analyzed FOLFOX-4 efficacy in terms of sphincter preservation and long-term outcomes. From January 1995 to December 2010, 335 LARC patients were treated with preoperative chemoradiation (4500-5040 cGy). Starting in May 2001, 207 consecutive patients additionally received induction FOLFOX-4. Surgery was performed 6 weeks (range 3-12 weeks) after chemoradiation. Incidence of total tumor (63 vs. 54 %, p = 0.02) and nodal downstaging (60 vs. 43 %, p = 0.002) was significantly increased by induction FOLFOX-4. In an analysis of tumors located below 5 cm from the anal verge (n = 114, 34 %), sphincter preservation was feasible in 30 % in the FOLFOX-4 versus 13 % in the upfront CRT group (p = 0.04). Median follow-up time for the entire cohort of patients was 72.6 months (range 4-205 months). FOLFOX-4 was not associated with superior locoregional control (HR 0.88, p = 0.78), disease-free survival (HR 0.83, p = 0.55), distant metastases-free survival (HR 0.94, p = 0.81), or cancer-specific survival (HR 0.70, p = 0.15). Short-intense induction FOLFOX-4 significantly improves downstaging and sphincter preservation in low rectal tumors. Long-term outcomes were not improved in the FOLFOX-4 group of patients. (orig.) [de

  5. Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer.

    Science.gov (United States)

    Meltzer, Sebastian; Kalanxhi, Erta; Hektoen, Helga Helseth; Dueland, Svein; Flatmark, Kjersti; Redalen, Kathrine Røe; Ree, Anne Hansen

    2016-06-07

    In colorectal cancer, immune effectors may be determinative for disease outcome. Following curatively intended combined-modality therapy in locally advanced rectal cancer metastatic disease still remains a dominant cause of failure. Here, we investigated whether circulating immune factors might correlate with outcome. An antibody array was applied to assay changes of approximately 500 proteins in serial serum samples collected from patients during oxaliplatin-containing induction chemotherapy and sequential chemoradiotherapy before final pelvic surgery. Array data was analyzed by the Significance Analysis of Microarrays software and indicated significant alterations in serum osteoprotegerin (TNFRSF11B) during the treatment course, which were confirmed by osteoprotegerin measures using a single-parameter immunoassay. Patients experiencing increase in circulating osteoprotegerin during the chemotherapy had significantly better 5-year progression-free survival than those without increase (78% versus 48%; P = 0.009 by log-rank test). Hence, systemic release of this soluble tumor necrosis factor decoy receptor following the induction phase of neoadjuvant therapy was associated with favorable long-term outcome in patients given curatively intended chemoradiotherapy and surgery but with metastatic disease as the main adverse event. This finding suggests that osteoprotegerin may mediate or reflect systemic anti-tumor immunity invoked by combined-modality therapy in locally advanced rectal cancer.

  6. NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction.

    Science.gov (United States)

    Yang, Shida; Li, Xin; Guan, Wenchang; Qian, Mingqin; Yao, Zhicheng; Yin, Xiaoxue; Zhao, Hongmei

    2017-10-10

    NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP-BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications.

  7. Induction of cancer cell death by proton beam in tumor hypoxic region

    International Nuclear Information System (INIS)

    Hur, T. R.; Lee, Y. M.; Park, J. W.; Sohn, E. J.

    2006-05-01

    The physical properties of charged particles such as protons are uniquely suited to target the radiation dose precisely in the tumor. In proton therapy, the Bragg peak is spread out by modulating or degrading the energy of the particles to cover a well defined target volume at a given depth. Due to heterogeneity in the various tumors and end-points as well as in the physical properties of the beams considered, it is difficult to fit the various results into a clear general description of the biological effect of proton in tumor therapy. Tumor hypoxia is a main obstacle to radiotherapy, including gamma-ray. Survived tumor cells under hypoxic region are resistant to radiation and more aggressive to be metastasized. To investigate the dose of proton beam to induce cell death of various tumor cells and hypoxic tumor cells at the Bragg peak in vitro, we used 3 kinds of tumor cells, lung cancer, leukemia and hepatoma cells. Proton beam induces apoptosis in Lewis lung carcinoma cells dose dependently and, slightly in leukemia but not in hepatoma cells at all. Above 1000 gray of proton beam, 60% of cells died even the hypoxic cells in Lewis lung carcinoma cells. But the Molt-4 leukemia cells showed milder effect, 20% cell death by the above 1000 Gray of proton beam and typical resistant pattern (5-10%) of hypoxia in desferrioxamine treated cells. Hepatoma cells (HepG2) were not responsive to proton beam even in rather higher dose (4000G). However, by the gamma-irradiation, Molt-4 was more sensitive than hepatoma or lung cancer cells, but still showed hypoxic resistance. The cell death by proton beam in Lewis lung carcinoma cells was confirmed by PARP cleavage and may be mediated by increased p53. Pro-caspases were also activated and cleaved by the proton beam irradiations for lung cancer cell death. In conclusion, high dose of proton beam (above 1000 gray) may be a good therapeutic radiation even in hypoxic region at the Bragg peak, but further investigations about the

  8. Callitriche cophocarpa (water starwort) proteome under chromate stress: evidence for induction of a quinone reductase.

    Science.gov (United States)

    Kaszycki, Paweł; Dubicka-Lisowska, Aleksandra; Augustynowicz, Joanna; Piwowarczyk, Barbara; Wesołowski, Wojciech

    2018-01-13

    Chromate-induced physiological stress in a water-submerged macrophyte Callitriche cophocarpa Sendtn. (water starwort) was tested at the proteomic level. The oxidative stress status of the plant treated with 1 mM Cr(VI) for 3 days revealed stimulation of peroxidases whereas catalase and superoxide dismutase activities were similar to the control levels. Employing two-dimensional electrophoresis, comparative proteomics enabled to detect five differentiating proteins subjected to identification with mass spectrometry followed by an NCBI database search. Cr(VI) incubation led to induction of light harvesting chlorophyll a/b binding protein with a concomitant decrease of accumulation of ribulose bisphosphate carboxylase (RuBisCO). The main finding was, however, the identification of an NAD(P)H-dependent dehydrogenase FQR1, detectable only in Cr(VI)-treated plants. The FQR1 flavoenzyme is known to be responsive to oxidative stress and to act as a detoxification protein by protecting the cells against oxidative damage. It exhibits the in vitro quinone reductase activity and is capable of catalyzing two-electron transfer from NAD(P)H to several substrates, presumably including Cr(VI). The enhanced accumulation of FQR1 was chromate-specific since other stressful conditions, such as salt, temperature, and oxidative stresses, all failed to induce the protein. Zymographic analysis of chromate-treated Callitriche shoots showed a novel enzymatic protein band whose activity was attributed to the newly identified enzyme. We suggest that Cr(VI) phytoremediation with C. cophocarpa can be promoted by chromate reductase activity produced by the induced quinone oxidoreductase which might take part in Cr(VI) → Cr(III) bioreduction process and thus enable the plant to cope with the chromate-generated oxidative stress.

  9. New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

    Directory of Open Access Journals (Sweden)

    Roleira Fernanda MF

    2008-07-01

    Full Text Available Abstract Background Aromatase, the cytochrome P-450 enzyme (CYP19 responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI, which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells. Results The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death. Conclusion Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

  10. Induction of apoptosis by the medium-chain length fatty acid lauric acid in colon cancer cells due to induction of oxidative stress.

    Science.gov (United States)

    Fauser, J K; Matthews, G M; Cummins, A G; Howarth, G S

    2013-01-01

    Fatty acids are classified as short-chain (SCFA), medium-chain (MCFA) or long-chain and hold promise as adjunctive chemotherapeutic agents for the treatment of colorectal cancer. The antineoplastic potential of MCFA remains underexplored; accordingly, we compared the MCFA lauric acid (C12:0) to the SCFA butyrate (C4:0) in terms of their capacity to induce apoptosis, modify glutathione (GSH) levels, generate reactive oxygen species (ROS), and modify phases of the cell cycle in Caco-2 and IEC-6 intestinal cell lines. Caco-2 and IEC-6 cells were treated with lauric acid, butyrate, or vehicle controls. Apoptosis, ROS, and cell cycle analysis were determined by flow cytometry. GSH availability was assessed by enzymology. Lauric acid induced apoptosis in Caco-2 (p lauric acid reduced GSH availability and generated ROS compared to butyrate (p Lauric acid reduced Caco-2 and IEC-6 cells in G0/G1and arrested cells in the S and G2/M phases. Lauric acid induced apoptosis in IEC-6 cells compared to butyrate (p lauric acid induced high levels of ROS compared to butyrate. Compared to butyrate, lauric acid displayed preferential antineoplastic properties, including induction of apoptosis in a CRC cell line.

  11. Induction of heat shock-like proteins in Vigna sinensis seedlings growing under ultraviolet-B (280-320 nm) enhanced radiation

    International Nuclear Information System (INIS)

    Nedunchezhian, N.; Annamalainathan, K.; Kulandaivelu, G.

    1992-01-01

    The effect of ultraviolet-B (UV-B) enhanced fluorescent radiation on protein profile and protein synthesis has been investigated in Vigna sinensis L. cv. Walp seedlings growing at various temperatures. In seedlings growing at 30°C, UV-B radiation decreased the level of several proteins as seen in Coomassie brilliant blue stained gel. However, fluorography of the same gel indicates induction of three sets of proteins in the range of 70. 53 and 16 k Da. Such induction under UV-B enhanced radiation resembled that found after heat shock treatments. In seedlings at 10 and 20°C, induction of such proteins varied both qualitatively and quantitatively. At 40°C. UV-B enhanced radiation caused a cumulative effect with temperature. Strong induction of specific proteins by UV-B radiation in seedlings growing under normal temperature indicates a possible protective role

  12. RNAi mediated gene silencing of ITPA using a targeted nanocarrier: Apoptosis induction in SKBR3 cancer cells.

    Science.gov (United States)

    Charbgoo, Fahimeh; Behmanesh, Mehrdad; Nikkhah, Maryam; Kane, Eric G

    2017-08-01

    A pure nucleotide pool is required for high-fidelity DNA replication and prevention of carcinogenesis in living cells. Human inosine triphosphatase (ITPase), encoded by the ITPA gene, plays a critical role in maintaining the purity of the cellular nucleotide pool by excluding nucleotides that enhance mutagenesis. ITPase is a nucleoside triphosphate pyrophosphatase that hydrolyzes the non-canonical nucleotides inosine triphosphate (ITP) and xanthine triphosphate (XTP). The monophosphate products of ITPase reactions are subsequently excluded from the nucleotide pool and the improper substitution of ITP and XTP into DNA and RNA is prevented. Previous studies show that deficiency in ITPA can suppress cellular growth and enhance DNA instability. In this study, we evaluated the influence of effective ITPA down-regulation on the induction of apoptosis in a human cancer cell line using folate-single wall nanotubes (SWNT) as a targeted nanocarrier. We assessed whether SWNT enhances IPTA-siRNA transfection efficiency in cancer cells using folate as a homing device. Since folate receptor is considerably overexpressed in cancer cells, conjugation of SWNTs to folate could enhance their cancer-specific penetrance. We found that nanocarrier mediated ITPA-siRNA transfection into SKBR3 cells caused significant reduction of ITPA mRNA expression level and complete down-regulation of the ITPase protein product. The silencing of ITPA led to promotion of apoptosis in SWNT-treated SKBR3 cancer cells. © 2017 John Wiley & Sons Australia, Ltd.

  13. Induction of Mitochondria Mediated Apoptosis in Human Breast Cancer Cells (T-47D) by Annona reticulata L. Leaves Methanolic Extracts.

    Science.gov (United States)

    Roham, Pratiksha H; Kharat, Kiran R; Mungde, Priyanka; Jadhav, Mahadev A; Makhija, Surinder J

    2016-01-01

    Annona reticulata Linn. (Common name: Bullock's-heart) (Annonaceae family) is a semi-evergreen and small deciduous tree. The extracts of various parts of Annona reticulata L. have been reported as cytotoxic to many cancer cells. Annona reticulata L. leaves' methanolic extract (ARME) was prepared and used against the breast cancer cells. The breast cancer cells (T-47D) viability and IC50 were evaluated by Vybrant® MTT Cell Proliferation Assay Kit. Detection of phosphatidylserine on membranes of apoptotic cells was done by Attune flow cytometer. RNA transcripts were quantified in ARME treated and untreated cells. Finally, the Vybrant® FAM Poly Caspases assay kit was used for analysis of polycaspases activity in T-47D cells. The IC50 (5 ± 0.5 µg/mL) of the ARME was found against breast cancer cells (T-47D). The Paclitaxel was used as a control standard drug for the study. The downregulation of Bcl-2 and upregulation of Bax and Bak, and caspases activation suggested induction of apoptosis in T-47D cells by ARME through mitochondrial pathway. The cell cycle halted at G2/M phase in the ARME treated cells. The ARME was found to be effective against Breast cancer cells (T-47D).

  14. Direct micro-CT observation confirms the induction of embolism upon xylem cutting under tension

    Science.gov (United States)

    We used two different Synchrotron-based micro-CT facilities (SLS: Swiss Light Source, Villigen, Switzerland, and ALS: Advanced Light Source, Berkeley, CA USA) to test the excision artifact described by Wheeler et al. (2013). Specifically, we examined the impact of cutting xylem under tension and und...

  15. Depletion of membrane cholesterol compromised caspase-8 imparts in autophagy induction and inhibition of cell migration in cancer cells.

    Science.gov (United States)

    Kumar, Mukesh; Irungbam, Karuna; Kataria, Meena

    2018-01-01

    Cholesterol in lipid raft plays crucial role on cancer cell survival during metastasis of cancer cells. Cancer cells are reported to enrich cholesterol in lipid raft which make them more susceptible to cell death after cholesterol depletion than normal cells. Methyl-β-cyclodextrin (MβCD), an amphipathic polysaccharide known to deplete the membrane cholesterol, induces cell death selectively in cancer cells. Present work was designed to identify the major form of programmed cell death in membrane cholesterol depleted cancer cells (MDA-MB 231 and 4T1) and its impact on migration efficiency of cancer cells. Membrane cholesterol alteration and morphological changes in 4T1 and MDA-MB 231 cancer cells by MβCD were measured by fluorescent microscopy. Cell death and cell proliferation were observed by PI, AO/EB and MTT assay respectively. Programme cell death was confirmed by flow cytometer. Caspase activation was assessed by MTT and PI after treatments with Z-VAD [OME]-FMK, mitomycin c and cycloheximide. Necroptosis, autophagy, pyroptosis and paraptosis were examined by cell proliferation assay and flow cytometry. Relative quantitation of mRNA of caspase-8, necroptosis and autophagy genes were performed. Migration efficiency of cancer cells were determined by wound healing assay. We found caspase independent cell death in cholesterol depleted MDA-MB 231 cells which was reduced by (3-MA) an autophagy inhibitor. Membrane cholesterol depletion neither induces necroptosis, paraptosis nor pyroptosis in MDA-MB 231 cells. Subsequent activation of caspase-8 after co-incubation of mitomycin c and cycloheximide separately, restored the cell viability in cholesterol depleted MDA-MB 231 cells. Down regulation of caspase-8 mRNA in cholesterol depleted cancer cells ensures that caspase-8 indirectly promotes the induction of autophagy. In another experiment we have demonstrated that membrane cholesterol depletion reduces the migration efficiency in cancer cells. Together our

  16. Effect of Doubly Fed Induction GeneratorTidal Current Turbines on Stability of a Distribution Grid under Unbalanced Voltage Conditions

    Directory of Open Access Journals (Sweden)

    Dahai Zhang

    2017-02-01

    Full Text Available This paper analyses the effects of doubly fed induction generator (DFIG tidal current turbines on a distribution grid under unbalanced voltage conditions of the grid. A dynamic model of an electrical power system under the unbalanced network is described in the paper, aiming to compare the system performance when connected with and without DFIG at the same location in a distribution grid. Extensive simulations of investigating the effect of DFIG tidal current turbine on stability of the distribution grid are performed, taking into account factors such as the power rating, the connection distance of the turbine and the grid voltage dip. The dynamic responses of the distribution system are examined, especially its ability to ride through fault events under unbalanced grid voltage conditions. The research has shown that DFIG tidal current turbines can provide a good damping performance and that modern DFIG tidal current power plants, equipped with power electronics and low-voltage ride-through capability, can stay connected to weak electrical grids even under the unbalanced voltage conditions, whilst not reducing system stability.

  17. Inhibition of Topoisomerase IIα and Induction of Apoptosis in Gastric Cancer Cells by 19-Triisopropyl Andrographolide

    OpenAIRE

    Monger, Adeep; Boonmuen, Nittaya; Suksen, Kanoknetr; Saeeng, Rungnapha; Kasemsuk, Teerapich; Piyachaturawat, Pawinee; Saengsawang, Witchuda; Chairoungdua, Arthit

    2017-01-01

    Gastric cancer is the most common cancer in Eastern Asia. Increasing chemoresistance and general systemic toxicities have complicated the current chemotherapy leading to an urgent need of more effective agents. The present study reported a potent DNA topoisomerase IIα inhibitory activity of an andrographolide analogue (19-triisopropyl andrographolide, analogue-6) in gastric cancer cells; MKN-45, and AGS cells. The analogue was potently cytotoxic to both gastric cancer cell lines with the half...

  18. Herbal extract of Artemisia vulgaris (mugwort) induces antitumor effects in HCT-15 human colon cancer cells via autophagy induction, cell migration suppression and loss of mitochondrial membrane potential.

    Science.gov (United States)

    Lian, Guanghui; Li, Fujun; Yin, Yani; Chen, Linlin; Yang, Junwen

    2018-01-01

    Artemisia vulgaris (A.vulgaris) belonging to family Compositae, commonly known as mugwort, has been used as a medicinal herb in Chinese traditional medicine for treatment of diseases. Studies have reported a diversity of activities for this plant which include antiseptic, antispasmodic, antigastric, anticancer and nervous system diseases. However, the anticancer activity of A.vulgaris in HCT-15 human colon cancer cells has not been scientifically validated. Therefore the present study aimed at evaluating the anticancer activity of methanolic extract of A.vulgaris against HCT-15 human colon cancer cell line. Cell cytotoxicity effects of the extract were evaluated by MTT cell viability assay, while clonogenic assay assessed the effects on cancer cell colony formation. Effects on reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) were evaluated by flow cytometry. In vitro wound healing assay was used to evaluate the effects on cell migration. To confirm autophagy, we evaluated the expression of several autophagy-associated proteins using Western blot assay. Results indicated that the methanolic extract of A.vulgaris exhibited an IC50 value of 50 μg/ml and exerted its cytotoxic effects in a dose-dependent manner. Moreover, it was observed that the extract inhibits colony formation and induces autophagy dose-dependently. The underlying mechanism for the induction of autophagy was found to be ROS-mediated MMP and significant inhibition of cell migration potential of colon cancer cells at the IC50 was observed. These results strongly stress that the methanolic extract may prove a source for the isolation of novel anticancer lead molecules for the management of colon cancer.

  19. Activation of ERK signaling and induction of colon cancer cell death by piperlongumine

    Science.gov (United States)

    Piperlongumine (PPLGM) is a bioactive compound isolated from long peppers that shows selective toxicity towards a variety of cancer cell types including colon cancer. The signaling pathways that lead to cancer cell death in response to PPLGM exposure have not been previously identified. Our objectiv...

  20. Therapeutic immunization strategies against cervical cancer : induction of cell-mediated immunity in murine models

    NARCIS (Netherlands)

    Bungener, Laura Barbara

    2004-01-01

    The aim of the study described in this thesis is the development of a therapeutic immunization strategy against cervical cancer and pre-malignant precursor lesions of cervical cancer (CIN lesions). Cervical cancer is caused by high risk human papillomavirus (HPV). Two of the early proteins of high

  1. Radiation fields, dosimetry, biokinetics and biophysical models for cancer induction by ionising radiation 1996-1999. Biophysical models for the induction of cancer by radiation. Final report

    International Nuclear Information System (INIS)

    Paretzke, H.G.; Ballarini, F.; Brugmans, M.

    2000-01-01

    The overall project is organised into seven work packages. WP1 concentrates on the development of mechanistic, quantitative models for radiation oncogenesis using selected data sets from radiation epidemiology and from experimental animal studies. WP2 concentrates on the development of mechanistic, mathematical models for the induction of chromosome aberrations. WP3 develops mechanistic models for radiation mutagenesis, particularly using the HPRT-mutation as a paradigm. WP4 will develop mechanistic models for damage and repair of DNA, and compare these with experimentally derived data. WP5 concentrates on the improvement of our knowledge on the chemical reaction pathways of initial radiation chemical species in particular those that migrate to react with the DNA and on their simulation in track structure codes. WP6 models by track structure simulation codes the production of initial physical and chemical species, within DNA, water and other components of mammalian cells, in the tracks of charged particles following the physical processes of energy transfer, migration, absorption, and decay of excited states. WP7 concentrates on the determination of the start spectra of those tracks considered in WP6 for different impinging radiation fields and different irradiated biological objects. (orig.)

  2. Novel failure mechanism and improvement for split-gate trench MOSFET with large current under unclamped inductive switch stress

    Science.gov (United States)

    Tian, Ye; Yang, Zhuo; Xu, Zhiyuan; Liu, Siyang; Sun, Weifeng; Shi, Longxing; Zhu, Yuanzheng; Ye, Peng; Zhou, Jincheng

    2018-04-01

    In this paper, a novel failure mechanism under unclamped inductive switch (UIS) for Split-Gate Trench Metal Oxide Semiconductor Field Effect Transistor (MOSFET) with large current is investigated. The device sample is tested and analyzed in detail. The simulation results demonstrate that the nonuniform potential distribution of the source poly should be responsible for the failure. Three structures are proposed and verified available to improve the device UIS ruggedness by TCAD simulation. The best one of the structures the device with source metal inserting into source poly through contacts in the field oxide is carried out and measured. The results demonstrate that the optimized structure can balance the trade-off between the UIS ruggedness and the static characteristics.

  3. Induction of L-form-like cell shape change of Bacillus subtilis under microculture conditions.

    Science.gov (United States)

    Shingaki, Ryuji; Kasahara, Yasuhiro; Iwano, Megumi; Kuwano, Masayoshi; Takatsuka, Tomomasa; Inoue, Tetsuyoshi; Kokeguchi, Susumu; Fukui, Kazuhiro

    2003-09-01

    A remarkable cell shape change was observed in Bacillus subtilis strain 168 under microculture conditions on CI agar medium (Spizizen's minimal medium supplemented with a trace amount of yeast extract and Casamino acids). Cells cultured under a cover glass changed in form from rod-shaped to spherical, large and irregular shapes that closely resembled L-form cells. The cell shape change was observed only with CI medium, not with Spizizen's minimum medium alone or other rich media. The whole-cell protein profile of cells grown under cover glass and cells grown on CI agar plates differed in several respects. Tandem mass analysis of nine gel bands which differed in protein expression between the two conditions showed that proteins related to nitrate respiration and fermentation were expressed in the shape-changed cells grown under cover glass. The cell shape change of CI cultures was repressed when excess KNO3 was added to the medium. Whole-cell protein analysis of the normal rod-shaped cells grown with 0.1% KNO3 and the shape-changed cells grown without KNO3 revealed that the expression of the branched-chain alpha-keto acid dehydrogenase complex (coded by the bfmB gene locus) was elevated in the shape-changed cells. Inactivation of the bfmB locus resulted in the repression of cell shape change, and cells in which bfmB expression was induced by IPTG did show changes in shape. Transmission electron microscopy of ultrathin sections demonstrated that the shape-changed cells had thin walls, and plasmolysis of cells fixed with a solution including 0.1 M sucrose was observed. Clarifying the mechanism of thinning of the cell wall may lead to the development of a new type of cell wall biosynthetic inhibitor.

  4. Astaxanthin induction in Microalga H. pluvialis with flat panel airlift photobioreactors under indoor and outdoor conditions.

    Science.gov (United States)

    Poonkum, Woradej; Powtongsook, Sorawit; Pavasant, Prasert

    2015-01-01

    Astaxanthin was induced from Haematococcus pluvialis (NIES-144) under indoor and outdoor conditions using 17-, 50-, and 90-L flat-panel airlift photobioreactors (FP-APBRs). Preliminary experiments in 1.5-L bubble column photobioreactors (BC-PBRs) revealed that sterilized clean water with 3% CO2 aeration (1.47 cm(3) s(-1) CO2 loading) could best encourage astaxanthin accumulation at 18.21 g m(-3) (3.63% by weight). Operating 17-L FP-APBRs with these bubble column parameters under indoor conditions could further enhance astaxanthin to 26.63 g m(-3) (5.34% by weight). This was potentially due to the inherited up-lift force from the reactor that helped avoid cell precipitation by allowing the cells to be circulated within the reactor. In addition, the various sizes of FP-APBRs exhibited similar performance, implying a potential scale-up opportunity. However, similar operation under outdoor condition exhibited slightly poorer performance due to the light inhibition effect. The best outdoor performance was obtained with the FP-APBR covered with one layer of shading net, where 20.11 g m(-3) (4.47% by weight) of astaxanthin was resulted.

  5. Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer

    Directory of Open Access Journals (Sweden)

    Fuady JH

    2014-03-01

    Full Text Available Jerry H Fuady,1,* Mattia R Bordoli,1,* Irene Abreu-Rodríguez,1,* Glen Kristiansen,2 David Hoogewijs,1,** Daniel P Stiehl,1,** Roland H Wenger1,**1Institute of Physiology and Zurich Center for Human Physiology, University of Zurich, Zurich, Switzerland; 2University Hospital Bonn, Institute of Pathology, Bonn, Germany*,**These authors contributed equally to this workAbstract: Hypoxia and the hypoxia-inducible factor (HIF signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2, which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2α-dependent manner. HIF-2-driven regulation of the WISP2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2α, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low-invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2α silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2α tumor levels with prolonged overall survival of patients with breast cancer.Keywords: invasion, metastasis, motility, oxygen, tumor, transcriptional

  6. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

    Directory of Open Access Journals (Sweden)

    Lili Chen

    Full Text Available BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL staining and decreased Ki-67 expression in tumors. Through natural killer (NK cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria

  7. Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity

    Science.gov (United States)

    Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

    2011-01-01

    Background Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Methodology/Principal Findings Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Conclusions/Significance Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a

  8. Selective killing of ovarian cancer cells through induction of apoptosis by nonequilibrium atmospheric pressure plasma

    International Nuclear Information System (INIS)

    Iseki, Sachiko; Tanaka, Hiromasa; Kondo, Hiroki; Hori, Masaru; Nakamura, Kae; Hayashi, Moemi; Kajiyama, Hiroaki; Kikkawa, Fumitaka; Kano, Hiroyuki

    2012-01-01

    Two independent ovarian cancer cell lines and fibroblast controls were treated with nonequilibrium atmospheric pressure plasma (NEAPP). Most ovarian cancer cells were detached from the culture dish by continuous plasma treatment to a single spot on the dish. Next, the plasma source was applied over the whole dish using a robot arm. In vitro cell proliferation assays showed that plasma treatments significantly decreased proliferation rates of ovarian cancer cells compared to fibroblast cells. Flow cytometry and western blot analysis showed that plasma treatment of ovarian cancer cells induced apoptosis. NEAPP could be a promising tool for therapy for ovarian cancers.

  9. Lipopolysaccharide (LPS)-stimulated iNOS Induction Is Increased by Glucosamine under Normal Glucose Conditions but Is Inhibited by Glucosamine under High Glucose Conditions in Macrophage Cells*

    Science.gov (United States)

    Hwang, Ji-Sun; Kwon, Mi-Youn; Kim, Kyung-Hong; Lee, Yunkyoung; Lyoo, In Kyoon; Kim, Jieun E.; Oh, Eok-Soo; Han, Inn-Oc

    2017-01-01

    We investigated the regulatory effect of glucosamine (GlcN) for the production of nitric oxide (NO) and expression of inducible NO synthase (iNOS) under various glucose conditions in macrophage cells. At normal glucose concentrations, GlcN dose dependently increased LPS-stimulated production of NO/iNOS. However, GlcN suppressed NO/iNOS production under high glucose culture conditions. Moreover, GlcN suppressed LPS-induced up-regulation of COX-2, IL-6, and TNF-α mRNAs under 25 mm glucose conditions yet did not inhibit up-regulation under 5 mm glucose conditions. Glucose itself dose dependently increased LPS-induced iNOS expression. LPS-induced MAPK and IκB-α phosphorylation did not significantly differ at normal and high glucose conditions. The activity of LPS-induced nuclear factor-κB (NF-κB) and DNA binding of c-Rel to the iNOS promoter were inhibited under high glucose conditions in comparison with no significant changes under normal glucose conditions. In addition, we found that the LPS-induced increase in O-GlcNAcylation as well as DNA binding of c-Rel to the iNOS promoter were further increased by GlcN under normal glucose conditions. However, both O-GlcNAcylation and DNA binding of c-Rel decreased under high glucose conditions. The NF-κB inhibitor, pyrrolidine dithiocarbamate, inhibited LPS-induced iNOS expression under high glucose conditions but it did not influence iNOS induction under normal glucose conditions. In addition, pyrrolidine dithiocarbamate inhibited NF-κB DNA binding and c-Rel O-GlcNAcylation only under high glucose conditions. By blocking transcription with actinomycin D, we found that stability of LPS-induced iNOS mRNA was increased by GlcN under normal glucose conditions. These results suggest that GlcN regulates inflammation by sensing energy states of normal and fuel excess. PMID:27927986

  10. The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

    Science.gov (United States)

    Colletta, A A; Wakefield, L M; Howell, F V; Danielpour, D; Baum, M; Sporn, M B

    1991-01-01

    Recent experimental work has identified a novel intracellular binding site for the synthetic progestin, Gestodene, that appears to be uniquely expressed in human breast cancer cells. Gestodene is shown here to inhibit the growth of human breast cancer cells in a dose-dependent fashion, but has no effect on endocrine-responsive human endometrial cancer cells. Gestodene induced a 90-fold increase in the secretion of transforming growth factor-beta (TGF-beta) by T47D human breast cancer cells. Other synthetic progestins had no effect, indicating that this induction is mediated by the novel Gestodene binding site and not by the conventional progesterone receptor. Furthermore, in four breast cancer cell lines, the extent of induction of TGF-beta correlated with intracellular levels of Gestodene binding site. No induction of TGF-beta was observed with the endometrial cancer line, HECl-B, which lacks the Gestodene binding site, but which expresses high levels of progesterone receptor. The inhibition of growth of T47D cells by Gestodene is partly reversible by a polyclonal antiserum to TGF-beta. These data indicate that the growth-inhibitory action of Gestodene may be mediated in part by an autocrine induction of TGF-beta. Images PMID:1985102

  11. Lichen secondary metabolites are responsible for induction of apoptosis in HT-29 and A2780 human cancer cell lines.

    Science.gov (United States)

    Bačkorová, M; Jendželovský, R; Kello, M; Bačkor, M; Mikeš, J; Fedoročko, P

    2012-04-01

    Lichens are a known source of approximately 800 unique secondary metabolites, many of which play important ecological roles, including regulating the equilibrium between symbionts. However, only a few of these compounds have been assessed for their effectiveness against various in vitro cancer models. Moreover, the mechanisms of biological activity of lichen secondary metabolites on living cells (including cancer cells) are still almost entirely unknown. In the present study, we investigated the mechanisms of cytotoxicity of four lichen secondary metabolites (parietin, atranorin, usnic acid and gyrophoric acid) on A2780 and HT-29 cancer cell lines. We found that usnic acid and atranorin were more effective anti-cancer compounds when compared to parietin and gyrophoric acid. Usnic acid and atranorin were capable of inducing a massive loss in the mitochondrial membrane potential, along with caspase-3 activation (only in HT-29 cells) and phosphatidylserine externalization in both tested cell lines. Induction of both ROS and especially RNS may be responsible, at least in part, for the cytotoxic effects of the tested compounds. Based on the detection of protein expression (PARP, p53, Bcl-2/Bcl-xL, Bax, p38, pp38) we found that usnic acid and atranorin are activators of programmed cell death in A2780 and HT-29, probably through the mitochondrial pathway. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Anticancer Effect and Apoptosis Induction of Cymbopogon citratus Plant on Head and Neck HTB43 Cancer Cell Lines

    International Nuclear Information System (INIS)

    Yen, N.; Zainah Adam; Arapoc, D.J.; Mohamed Zaffar Ali Mohamed Amiroudine; Shafii Khamis

    2016-01-01

    Lemongrass (Cymbopogon citratus) is a major crop in Asia, South and Central America, Africa and other tropical countries. It is commonly used as a culinary herb in Asian cuisine and also as medicinal herb in India. The objective of the present study was to investigate the anticancer effect of Cymbopogon citratus essential oil on human head and neck cancer cell lines. Lemongrass essential oil was obtained from fresh lemongrass leaves using the microwave extractor. The yield of the highly purified oil obtained was 0.62 %. The oil was investigated for its in-vitro cytotoxicity and apoptosis induction against human head and neck HTB43 cancer cell lines. The results showed promising cytotoxic effects with IC 50 value of 15.42 ± 6.10 μg/ ml (HTB43) respectively. In addition, the essential oil has found inducing apoptotic effect within HTB43 cells (25.71 ± 1.43 %). These preliminary results indicated that the oil had apoptosis-based cytotoxicity against head and neck cancer cells. However, further investigations need to be carried out in order to elucidate the anti-cancer properties of the oil. The phytochemicals properties of the active compounds found in the oil also need to be studied. (author)

  13. General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Tomoharu Tanaka

    Full Text Available Erythropoietin (EPO, originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS. EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes.BALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10-1.0%. Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2α protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2α protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2α protein and EPO mRNA.Taken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes.

  14. Modifications of fungal membrane proteins profile under pathogenicity induction: A proteomic analysis of Botrytis cinerea membranome.

    Science.gov (United States)

    Liñeiro, Eva; Chiva, Cristina; Cantoral, Jesús M; Sabidó, Eduard; Fernández-Acero, Francisco Javier

    2016-09-01

    Botrytis cinerea is a model fungus for the study of phytopathogenicity that exhibits a wide arsenal of tools to infect plant tissues. Most of these factors are related to signal transduction cascades, in which membrane proteins play a key role as a bridge between environment and intracellular molecular processes. This work describes the first description of the membranome of Botrytis under different pathogenicity conditions induced by different plant-based elicitors: glucose and tomato cell wall (TCW). A discovery proteomics analysis of membrane proteins was carried out by mass spectrometry. A total of 2794 proteins were successfully identified, 46% of them were classified as membrane proteins based on the presence of transmembrane regions and lipidation. Further analyses showed significant differences in the membranome composition depending on the available carbon source: 804 proteins were exclusively identified when the fungus was cultured with glucose as a sole carbon source, and 251 proteins were exclusively identified with TCW. Besides, among the 1737 common proteins, a subset of 898 proteins presented clear differences in their abundance. GO enrichment and clustering interaction analysis revealed changes in the composition of membranome with increase of signalling function in glucose conditions and carbohydrate degradation process in TCW conditions. All MS data have been deposited in the ProteomeXchange with identifier PXD003099 (http://proteomecentral.proteomexchange.org/dataset/PXD003099). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. CONSTITUTIVE PHOTOMORPHOGENIC 10 (COP10 Contributes to Floral Repression under Non-Inductive Short Days in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Min-Young Kang

    2015-11-01

    Full Text Available In Arabidopsis, CONSTITUTIVE PHOTOMORPHOGENIC/DE-ETIOLATED/FUSCA (COP/DET/FUS genes act in repression of photomorphogenesis in darkness, and recent reports revealed that some of these genes, such as COP1 and DET1, also have important roles in controlling flowering time and circadian rhythm. The COP/DET/FUS protein COP10 interacts with DET1 and DNA DAMAGE-BINDING PROTEIN 1 (DDB1 to form a CDD complex and represses photomorphogenesis in darkness. The cop10-4 mutants flower normally in inductive long days (LD but early in non-inductive short days (SD compared with wild type (WT; however, the role of COP10 remains unknown. Here, we investigate the role of COP10 in SD-dependent floral repression. Reverse transcription-quantitative PCR revealed that in SD, expression of the LD-dependent floral inducers GI, FKF1, and FT significantly increased in cop10-4 mutants, compared with WT. This suggests that COP10 mainly regulates FT expression in a CO-independent manner. We also show that COP10 interacts with GI in vitro and in vivo, suggesting that COP10 could also affect GI function at the posttranslational level. Moreover, FLC expression was repressed drastically in cop10-4 mutants and COP10 interacts with MULTICOPY SUPPRESSOR OF IRA1 4 (MSI4/FVE (MSI4/FVE, which epigenetically inhibits FLC expression. These data suggest that COP10 contributes to delaying flowering in the photoperiod and autonomous pathways by downregulating FT expression under SD.

  16. Induction of reactive oxygen species in marine phytoplankton under crude oil exposure.

    Science.gov (United States)

    Ozhan, Koray; Zahraeifard, Sara; Smith, Aaron P; Bargu, Sibel

    2015-12-01

    Exposure of phytoplankton to the water-accommodated fraction of crude oil can elicit a number of stress responses, but the mechanisms that drive these responses are unclear. South Louisiana crude oil was selected to investigate its effects on population growth, chlorophyll a (Chl a) content, antioxidative defense, and lipid peroxidation, for the marine diatom, Ditylum brightwellii, and the dinoflagellate, Heterocapsa triquetra, in laboratory-based microcosm experiments. The transcript levels of several possible stress-responsive genes in D. brightwellii were also measured. The microalgae were exposed to crude oil for up to 96 h, and Chl a content, superoxide dismutase (SOD), the glutathione pool (GSH and GSSG), and lipid peroxidation content were analyzed. The cell growth of both phytoplankton species was inhibited with increasing crude oil concentrations. Crude oil exposure did not affect Chl a content significantly in cells. SOD activities showed similar responses in both species, being enhanced at 4- and 8-mg/L crude oil exposure. Only H. triquetra demonstrated enhanced activity in GSSG pool and lipid peroxidation at 8-mg/L crude oil exposure, suggesting that phytoplankton species have distinct physiological responses and tolerance levels to crude oil exposure. This study indicated the activation of reactive oxygen species (ROS) in phytoplankton under crude oil exposure; however, the progressive damage in cells is still unknown. Thus, ROS-related damage in nucleic acid, lipids, proteins, and DNA, due to crude oil exposure could be a worthwhile subject of study to better understand crude oil toxicity at the base of the food web.

  17. Cytoplasmic CXCR4 expression in breast cancer: induction by nitric oxide and correlation with lymph node metastasis and poor prognosis

    Directory of Open Access Journals (Sweden)

    Kodama Rieko

    2008-11-01

    Full Text Available Abstract Background Lymph nodes constitute the first site of metastasis for most malignancies, and the extent of lymph node involvement is a major criterion for evaluating patient prognosis. The CXC chemokine receptor 4 (CXCR4 has been shown to play an important role in lymph node metastasis. Nitric oxide (NO may also contribute to induction of metastatic ability in human cancers. Methods CXCR4 expression was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels (a biomarker for peroxynitrate formation from NO in vivo and lymph node status, CXCR4 immunoreactivity, and other established clinico-pathological parameters, as well as prognosis, was analyzed. Nitrite/nitrate levels and CXCR4 expressions were assessed in MDA-MB-231 and SK-BR-3 breast cancer cell lines after induction and/or inhibition of NO synthesis. Results CXCR4 staining was predominantly cytoplasmic; this was observed in 50%(56/113 of the tumors. Cytoplasmic CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis. Kaplan-Meier survival curves showed that cytoplasmic CXCR4 expression was associated with reduced disease-free and overall survival. In multivariate analysis, cytoplasmic CXCR4 expression emerged as a significant independent predictor for overall and disease-free survival. Cytoplasmic expression of functional CXCR4 in MDA-MB-231 and SK-BR-3 cells was increased by treatment with the NO donor DETA NONOate. This increase was abolished by L-NAME, an inhibitor of NOS. Conclusion Our data showed a role for NO in stimulating cytoplasmic CXCR4 expression in vitro. Formation of the biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in vivo. In addition, cytoplasmic CXCR4 expression may serve as a significant prognostic factor for long-term survival in breast cancer.

  18. Cytoplasmic CXCR4 expression in breast cancer: induction by nitric oxide and correlation with lymph node metastasis and poor prognosis

    International Nuclear Information System (INIS)

    Yasuoka, Hironao; Tsujimoto, Masahiko; Yoshidome, Katsuhide; Nakahara, Masaaki; Kodama, Rieko; Sanke, Tokio; Nakamura, Yasushi

    2008-01-01

    Lymph nodes constitute the first site of metastasis for most malignancies, and the extent of lymph node involvement is a major criterion for evaluating patient prognosis. The CXC chemokine receptor 4 (CXCR4) has been shown to play an important role in lymph node metastasis. Nitric oxide (NO) may also contribute to induction of metastatic ability in human cancers. CXCR4 expression was analyzed in primary human breast carcinoma with long-term follow-up. The relationship between nitrotyrosine levels (a biomarker for peroxynitrate formation from NO in vivo) and lymph node status, CXCR4 immunoreactivity, and other established clinico-pathological parameters, as well as prognosis, was analyzed. Nitrite/nitrate levels and CXCR4 expressions were assessed in MDA-MB-231 and SK-BR-3 breast cancer cell lines after induction and/or inhibition of NO synthesis. CXCR4 staining was predominantly cytoplasmic; this was observed in 50%(56/113) of the tumors. Cytoplasmic CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis. Kaplan-Meier survival curves showed that cytoplasmic CXCR4 expression was associated with reduced disease-free and overall survival. In multivariate analysis, cytoplasmic CXCR4 expression emerged as a significant independent predictor for overall and disease-free survival. Cytoplasmic expression of functional CXCR4 in MDA-MB-231 and SK-BR-3 cells was increased by treatment with the NO donor DETA NONOate. This increase was abolished by L-NAME, an inhibitor of NOS. Our data showed a role for NO in stimulating cytoplasmic CXCR4 expression in vitro. Formation of the biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in vivo. In addition, cytoplasmic CXCR4 expression may serve as a significant prognostic factor for long-term survival in breast cancer

  19. EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia.

    Science.gov (United States)

    Jiang, Xingkang; Gao, Ming; Chen, Yue; Liu, Jing; Qi, Shiyong; Ma, Juan; Zhang, Zhihong; Xu, Yong

    2016-05-01

    Hemolytic anemia is a common form of anemia due to hemolysis, resulting in disordered iron homeostasis. In this study, a dose of 40mg/kg phenylhydrazine (PHZ) was injected into mice to successfully establish a pronounced anemia animal model, which resulted in stress erythropoiesis and iron absorption. We found that serum erythropoietin (EPO) concentration was dramatically elevated by nearly 5000-fold for the first 2days, and then drop to the basal level on day 6 after PHZ injection. Mirrored with serum EPO concentration, the mRNA expression of erythroferrone (ERFE) was rapidly increased in the bone marrow and spleen 3days after injection of PHZ, and then gradually decreased but was still higher than baseline on day 6. In addition, we also found that the hepcidin mRNA levels were gradually reduced almost up to 8-fold on day 5, and then was ameliorated compared to the untreated control. Mechanistic investigation manifested that the increase of serum EPO essentially determined the induction of ERFE expression particular at the first 3days after PHZ treatment. Lentiviral mediated ERFE knockdown significantly restrained hepcidin suppression under PHZ treatment. Thus, our data unearthed EPO-dependent ERFE expression acts as an erythropoiesis-driven regulator of iron metabolism under PHZ-induced hemolytic anemia. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Genetic evidence that induction of root Fe(III) chelate reductase activity is necessary for iron uptake under iron deficiency.

    Science.gov (United States)

    Yi, Y; Guerinot, M L

    1996-11-01

    Reduction of Fe(III) to Fe(II) by Fe(III) chelate reductase is thought to be an obligatory step in iron uptake as well as the primary factor in making iron available for absorption by all plants except grasses. Fe(III) chelate reductase has also been suggested to play a more general role in the regulation of cation absorption. In order to experimentally address the importance of Fe(III) chelate reductase activity in the mineral nutrition of plants, three Arabidopsis thaliana mutans (frd1-1, frd1-2 and frd1-3), that do not show induction of Fe(III) chelate reductase activity under iron-deficient growth conditions, have been isolated and characterized. These mutants are still capable of acidifying the rhizosphere under iron-deficiency and accumulate more Zn and Mn in their shoots relative to wild-type plants regardless of iron status. frd1 mutants do not translocate radiolabeled iron to the shoots when roots are presented with a tightly chelated form of Fe(III). These results: (1) confirm that iron must be reduced before it can be transported, (2) show that Fe(III) reduction can be uncoupled from proton release, the other major iron-deficiency response, and (3) demonstrate that Fe(III) chelate reductase activity per se is not necessarily responsible for accumulation of cations previously observed in pea and tomato mutants with constitutively high levels of Fe(III) chelate reductase activity.

  1. Detergent Induction of HEK 293A Cell Membrane Permeability Measured under Quiescent and Superfusion Conditions Using Whole Cell Patch Clamp

    Science.gov (United States)

    2015-01-01

    Detergents have several biological applications but present cytotoxicity concerns, since they can solubilize cell membranes. Using the IonFlux 16, an ensemble whole cell planar patch clamp, we observed that anionic sodium dodecyl sulfate (SDS), cationic cetyltrimethylammonium bromide (CTAB), and cationic, fluorescent octadecyl rhodamine B (ORB) increased the membrane permeability of cells substantially within a second of exposure, under superfusion conditions. Increased permeability was irreversible for 15 min. At subsolubilizing detergent concentrations, patched cells showed increased membrane currents that reached a steady state and were intact when imaged using fluorescence microscopy. SDS solubilized cells at concentrations of 2 mM (2× CMC), while CTAB did not solubilize cells even at concentrations of 10 mM (1000× CMC). The relative activity for plasma membrane current induction was 1:20:14 for SDS, CTAB, and ORB, respectively. Under quiescent conditions, the relative ratio of lipid to detergent in cell membranes at the onset of membrane permeability was 1:7:5 for SDS, CTAB, and ORB, respectively. The partition constants (K) for SDS, CTAB, and ORB were 23000, 55000, and 39000 M–1, respectively. Combining the whole cell patch clamp data and XTT viability data, SDS ≤ 0.2 mM and CTAB and ORB ≤ 1 mM induced cell membrane permeability without causing acute toxicity. PMID:24548291

  2. Induction of apoptosis in human breast cancer cell line MCF-7 by ...

    African Journals Online (AJOL)

    Currently, breast cancer is the leading cause of cancer-related death in women. Therefore, there is an urgent need to develop alternative therapeutic measures against this deadly disease. Many components from dietary or medicinal plants have been identified that possess substantial chemopreventive properties. India has ...

  3. Metallothionein-3 Increases Triple-Negative Breast Cancer Cell Invasiveness via Induction of Metalloproteinase Expression.

    Directory of Open Access Journals (Sweden)

    Alicja M Kmiecik

    Full Text Available It has been recently found that metallothionein-3 (MT3 enhances the invasiveness and tumorigenesis of prostate cancer cells. This finding is in contrast to those of earlier studies, which indicated that overexpression of MT3 in breast cancer and prostate cancer cell lines inhibits their growth in vitro. Therefore, to clarify the role of MT3 in breast cancer progression, we analyzed the effect of MT3-overexpression on proliferation, invasiveness, migration, and tumorigenesis of breast cancer MDA-MB-231/BO2 cells. It was found that MDA-MB-231/BO2 cells overexpressing MT3 were characterized by increased invasiveness in vitro, compared to the control cells. Interestingly, this increased invasiveness correlated with a highly increased concentration of MMP3 in the culture supernatants (p<0.0001. Our data suggest that MT3 may regulate breast cancer cell invasiveness by modulating the expression of MMP3. These experimental results, obtained using triple-negative MDA-MB-231/BO2 cells, were further supported by clinical data. It was found that, in triple-negative breast cancer (TNBC, nuclear MT3 immunoreactivity in cancer cells tended to be associated with patients' shorter disease-specific survival, suggesting that nuclear MT3 expression may be a potential marker of poor prognosis of triple-negative TNBC cases.

  4. Metallothionein-3 Increases Triple-Negative Breast Cancer Cell Invasiveness via Induction of Metalloproteinase Expression.

    Science.gov (United States)

    Kmiecik, Alicja M; Pula, Bartosz; Suchanski, Jaroslaw; Olbromski, Mateusz; Gomulkiewicz, Agnieszka; Owczarek, Tomasz; Kruczak, Anna; Ambicka, Aleksandra; Rys, Janusz; Ugorski, Maciej; Podhorska-Okolow, Marzena; Dziegiel, Piotr

    2015-01-01

    It has been recently found that metallothionein-3 (MT3) enhances the invasiveness and tumorigenesis of prostate cancer cells. This finding is in contrast to those of earlier studies, which indicated that overexpression of MT3 in breast cancer and prostate cancer cell lines inhibits their growth in vitro. Therefore, to clarify the role of MT3 in breast cancer progression, we analyzed the effect of MT3-overexpression on proliferation, invasiveness, migration, and tumorigenesis of breast cancer MDA-MB-231/BO2 cells. It was found that MDA-MB-231/BO2 cells overexpressing MT3 were characterized by increased invasiveness in vitro, compared to the control cells. Interestingly, this increased invasiveness correlated with a highly increased concentration of MMP3 in the culture supernatants (p<0.0001). Our data suggest that MT3 may regulate breast cancer cell invasiveness by modulating the expression of MMP3. These experimental results, obtained using triple-negative MDA-MB-231/BO2 cells, were further supported by clinical data. It was found that, in triple-negative breast cancer (TNBC), nuclear MT3 immunoreactivity in cancer cells tended to be associated with patients' shorter disease-specific survival, suggesting that nuclear MT3 expression may be a potential marker of poor prognosis of triple-negative TNBC cases.

  5. [The effect of solar ultraviolet radiation (UVR) on induction of skin cancers].

    Science.gov (United States)

    Pacholczyk, Marta; Czernicki, Jan; Ferenc, Tomasz

    Ultraviolet radiation is a physical mutagenic and cancerogenic factor. About 95% of ultraviolet A (UVA) (320-400 nm) and 5% of UVB (280-320 nm) reach the Earth's surface. Melanin is a natural skin protective factor against UV radiation. Skin cancers associated with long-term exposure to UV radiation are: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). The high risk of BCC development is related to acute and repeated exposure to UV causing sunburn. Molecular studies of BBC demonstrated disorders in sonic hedgehog (SHH) cell signaling regulation pathway, associated with the suppressor protein patched homolog 1 gene (PTCH1) mutations. The risk of the BCC development is related to the polymorphism of melanokortin-1 receptor gene (MC1R). Tumor P53 gene mutations observed in BCC cells has been classified as secondary genetic changes. In SCC cells UV-induced mutations were mostly related to P53 gene. Increased expression of cyclooxigenase- 2 gene (COX-2) plays a significant role in the development of SCC. Other pathogenetic factors include intensification of the synthesis of pro-inflammatory cytokines (tumor necrosis factor α (TNF-α), interleukin-1 α (IL-1α), IL-1β and IL-6). Currently, the role of UVB has been recognized in the pathogenesis of CMM. In CMM cells the following gene mutations were noted: cyclindependent kinase inhibitor 2A INK4A (p16INK4A), cyclin-dependent kinase 4 (CDK4), Ras, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and proto-oncogene B-Raf (BRAF). The BRAF gene mutations were observed in ~50% of CMM cases. Mutations of P53 gene are not characteristic of CMM cells. Med Pr 2016;67(2):255-266. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

  6. Irradiation effect on the apoptosis induction in the human cancer cell lines and the gingival fibroblast

    International Nuclear Information System (INIS)

    Park, Mu Soon; Lee, Sam Sun; Choi, Soon Chul; Park, Tae Won; You, Dong Soo

    1998-01-01

    The radiation-induced apoptosis was studied for two human cancer cell lines (KB cells, RPMI 2650 cells) and the human gingival fibroblast cell line (HGF-1 cells). The single irradiation of 2, 10, 20 Gy was done with 241.5 cGy/min dose rate using the 137 Cs MK cell irradiator. The cell were stained with propidium iodide and examined under the fluoro-microscope and assayed with the flow cytometry a day after irradiation. Also, the LDH assay was done to determine the amount of necrotic cells. The obtained results were as follows : 1. On the fluoro-microscope, many fragmented nuclei were detected in the KB, RPMI 2650, and HGF-1 cells after irradiation. 2. On the DNA content histogram obtained from the flow cytometry, the percentages of the pre-G1 peak of the control and 2, 10 and 20 Gy irradiation group were 4.5, 55.0, 52.3, and 66.6% on KB cells, 2.7, 3.3, 31.8, and 32.6% on RPMI 2650 cells and 2.8, 21.8, 30.4, and 40.2% on HGF-1 cells respectively. 3. The number of G1-stage cells was abruptly decreased after 2 Gy irradiation on KB cells and 10 Gy irradiation on RPMI 2650 cells, But there was a slight decrease without regard to irradiation dose on HGF-1 cells. 4. There was no significantly different absorbance in extracellular LDH assay along the experimental cell lines

  7. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

    International Nuclear Information System (INIS)

    Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya; An, Byeong Jun; Song, Ho Sueb; Han, Sang Bae; Kim, Jang Heub; Song, Min Jong; Hong, Jin Tae

    2012-01-01

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1–5 μg/ml) and melittin (0.5–2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ► Some studies have showed that bee venom and/or melittin have anti-cancer effects. ► We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ► Bee venom and melittin induce apoptosis in SKOV3 and PA-1.

  8. Propolis extracts from the northern region of Thailand suppress cancer cell growth through induction of apoptosis pathways.

    Science.gov (United States)

    Khacha-Ananda, Supakit; Tragoolpua, Khajornsak; Chantawannakul, Panuwan; Tragoolpua, Yingmanee

    2016-12-01

    The continual increase in mortality rates and number of cancer cases is a matter of serious concern in developing countries. The incorporation of natural products into classical cancer treatment approaches is a promising direction. The mechanisms of A549 and HeLa cancer cell death induction by ethanolic extracts of propolis samples from Phayao, Chiang Mai, and Nan provinces in northern Thailand were investigated in this study. The propolis extract from Chiang Mai showed the highest antioxidant activity and the greatest total phenolic content. The propolis extract from Nan also exhibited the highest total flavonoid content. The proliferation of A549 and HeLa cells grown in the presence of the propolis extracts was suppressed in a dose- and time-dependent manner. Moreover, treatment of both cancer cells with the propolis extracts showed DNA fragmentation and significantly increased the number of the apoptotic cells. On A549 cells, the extrinsic and intrinsic pathways of caspase enzymes were activated by the propolis extracts from Phayao and Chiang Mai. In the case of the propolis extract from Nan, the mechanisms involved apoptosis on the A549 cells were caspase-independent pathway. The extrinsic pathway of the caspase enzyme was triggered by all of the propolis extracts on HeLa cells. Finally, oral administration of the propolis granule produced from the propolis extract from Nan resulted in extended survival of tumour-bearing mice. Therefore, propolis extracts from the northern region of Thailand demonstrated pharmacological properties, both antioxidant and anticancer activities. From these findings, it is evident that propolis extracts can be considered as a naturally obtained agent extremely useful in cancer treatment.

  9. FoxD3 deficiency promotes breast cancer progression by induction of epithelial–mesenchymal transition

    Energy Technology Data Exchange (ETDEWEB)

    Chu, Tian-Li [Department of General Surgery, The People’s Hospital of Wuqing, Tianjin (China); Zhao, Hong-Meng [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Li, Yue [Department of Respiration, Affiliated Hospital of Medical College of Chinese People’s Armed Police Force, Tianjin (China); Chen, Ao-Xiang; Sun, Xuan [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Ge, Jie, E-mail: gejie198003@163.com [Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China)

    2014-04-04

    Highlights: • FOXD3 is down-regulated in breast cancer tissues. • FOXD3 inhibits breast cancer cell proliferation and invasion. • FoxD3 deficiency induces epithelial–mesenchymal transition. - Abstract: The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3 expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial–mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy.

  10. FoxD3 deficiency promotes breast cancer progression by induction of epithelial–mesenchymal transition

    International Nuclear Information System (INIS)

    Chu, Tian-Li; Zhao, Hong-Meng; Li, Yue; Chen, Ao-Xiang; Sun, Xuan; Ge, Jie

    2014-01-01

    Highlights: • FOXD3 is down-regulated in breast cancer tissues. • FOXD3 inhibits breast cancer cell proliferation and invasion. • FoxD3 deficiency induces epithelial–mesenchymal transition. - Abstract: The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3 expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial–mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy

  11. Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival.

    Science.gov (United States)

    Fink, Stephen P; Myeroff, Lois L; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K V; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S; Wang, Zhenghe; Markowitz, Sanford D

    2015-10-13

    Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target.

  12. Inhibition of class I histone deacetylases in non-small cell lung cancer by honokiol leads to suppression of cancer cell growth and induction of cell death in vitro and in vivo.

    Science.gov (United States)

    Singh, Tripti; Prasad, Ram; Katiyar, Santosh K

    2013-01-01

    Non-small-cell lung cancer (NSCLC) represents approximately 80% of all types of lung cancer. Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia grandiflora, on NSCLC cells and the molecular mechanisms underlying these effects using in vitro and in vivo models. Treatment of NSCLC cells (A549, H1299, H460 and H226) with honokiol (20, 40 and 60 µM) inhibited histone deacetylase (HDAC) activity, reduced the levels of class I HDAC proteins and enhanced histone acetyltransferase activity in a dose-dependent manner. These effects of honokiol were associated with a significant reduction in the viability of NSCLC cells. Concomitant treatment of cells with a proteasome inhibitor, MG132, prevented honokiol-induced degradation of class I HDACs, suggesting that honokiol reduced the levels of HDACs in NSCLC cells through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of NSCLC cells. Treatment of A549 and H1299 cells with honokiol resulted in an increase in G 1 phase arrest, and a decrease in the levels of cyclin D1, D2 and cyclin dependent kinases. Further, administration of honokiol by oral gavage significantly inhibited the growth of subcutaneous A549 and H1299 tumor xenografts in athymic nude mice, which was associated with the induction of apoptotic cell death and marked inhibition of class I HDACs proteins and HDAC activity in the tumor xenograft tissues. Together, our study provides new insights into the role of class I HDACs in the chemotherapeutic effects of honokiol on lung cancer cells.

  13. Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer.

    Directory of Open Access Journals (Sweden)

    Wieslawa H Dragowska

    Full Text Available Gefitinib (Iressa(®, ZD1839 is a small molecule inhibitor of the epidermal growth factor receptor (EGFR tyrosine kinase. We report on an early cellular response to gefitinib that involves induction of functional autophagic flux in phenotypically diverse breast cancer cells that were sensitive (BT474 and SKBR3 or insensitive (MCF7-GFPLC3 and JIMT-1 to gefitinib. Our data show that elevation of autophagy in gefitinib-treated breast cancer cells correlated with downregulation of AKT and ERK1/2 signaling early in the course of treatment. Inhibition of autophagosome formation by BECLIN-1 or ATG7 siRNA in combination with gefitinib reduced the abundance of autophagic organelles and sensitized SKBR3 but not MCF7-GFPLC3 cells to cell death. However, inhibition of the late stage of gefitinib-induced autophagy with hydroxychloroquine (HCQ or bafilomycin A1 significantly increased (p0.05, when compared to vehicle-treated controls. Our results also show that elevated autophagosome content following short-term treatment with gefitinib is a reversible response that ceases upon removal of the drug. In aggregate, these data demonstrate that elevated autophagic flux is an early response to gefitinib and that targeting EGFR and autophagy should be considered when developing new therapeutic strategies for EGFR expressing breast cancers.

  14. Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line.

    Science.gov (United States)

    Moongkarndi, Primchanien; Kosem, Nuttavut; Kaslungka, Sineenart; Luanratana, Omboon; Pongpan, Narongchai; Neungton, Neelobol

    2004-01-01

    This study was designed to determine the antiproliferative, apoptotic and antioxidative properties of crude methanolic extract (CME) from the pericarp of Garcinia mangostana (family Guttiferae) using human breast cancer (SKBR3) cell line as a model system. SKBR3 cells were cultured in the presence of CME at various concentrations (0-50 microg/ml) for 48 h and the percentage of cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-di phenyl tetrazolium bromide (MTT) assay. CME showed a dose-dependent inhibition of cell proliferation with ED(50) of 9.25+/-0.64 microg/ml. We found that antiproliferative effect of CME was associated with apoptosis on breast cancer cell line by determinations of morphological changes and oligonucleosomal DNA fragments. In addition, CME at various concentrations and incubation times were also found to inhibit ROS production. These investigations suggested that the methanolic extract from the pericarp of Garcinia mangostana had strong antiproliferation, potent antioxidation and induction of apoptosis. Thus, it indicates that this substance can show different activities and has potential for cancer chemoprevention which were dose dependent as well as exposure time dependent.

  15. Mitochondrial and caspase pathways are involved in the induction of apoptosis by nardosinen in MCF-7 breast cancer cell line.

    Science.gov (United States)

    Shahali, Amirhosein; Ghanadian, Mustafa; Jafari, Seyyed Mehdi; Aghaei, Mahmoud

    2018-02-01

    Natural products isolated from plants provide a valuable source for expansion of new anticancer drugs. Nardosinen (4,9-dihydroxy-nardosin-6-en) is a natural sesquiterpene extracted from Juniperus foetidissima . Recently, we have reported the cytotoxic effects of nardosinen in various cancer cells. The aim of the current study was to investigate the anticancer features of nardosinen as well as its possible molecular mechanisms of the nardosinen cytotoxic effect on breast tumor cells. MTT assay showed that nardosinen notably inhibited cell proliferation in a dose-dependent manner in MCF-7 breast cancer cells. The growth inhibitory effect of nardosinen was associated with the induction of cell apoptosis, activation of caspase-6, increase of reactive oxygen species (ROS), and loss of mitochondrial membrane potentials (ΔΨm). Western blot assay following treatment with nardosinen showed that the expression levels of the Bax were significantly up-regulated and the expression levels of the Bcl-2 were significantly down-regulated. Our results finally exhibited that nardosinen induces apoptosis in breast cancer cells via the mitochondrial and caspase pathways.

  16. Involvement of the mitogen-activated protein kinase kinase 2 in the induction of cell dissociation in pancreatic cancer.

    Science.gov (United States)

    Tan, Xiaodong; Egami, Hiroshi; Kamohara, Hidenobu; Ishikawa, Shinji; Kurizaki, Takashi; Yoshida, Naoya; Tamori, Yasuhiko; Takai, Eiji; Hirota, Masahiko; Ogawa, Michio

    2004-01-01

    In our previous investigation, mitogen-activated protein kinase kinase 2 (MEK2) was detected as a factor which was correlated to the potential of invasion-metastasis. In this study, the immunocytochemical, immunohistochemical and mRNA expressions of MEK2 were examined in pancreatic cancer cell lines and tissue samples, respectively. Constitutive expressions of MEK2 and phosphorylated MEK (p-MEK) were observed in PC-1.0 and ASPC-1 cells, which exhibited a growth pattern of single cells, whereas the relevant expressions were quite faint in PC-1 cells and CAPAN-2 cells, which exhibited a growth pattern of island-like clonies. Simultaneous inductions of MEK2 expressions and cell dissociation were observed after the treatment with a conditioned medium (CM) of PC-1.0 cells. The expression of MEK2 and p-MEK were reduced and the cell aggregation was found in PC-1.0 and ASPC-1 cells after U0126 (a MEK inhibitor) treatment. In vivo, both the MEK2 and p-MEK overexpressed in human pancreatic cancer tissues and p-MEK was found to be more strongly expressed in the invasive front than that in the center of tumor (Pcell dissociation. MEK2 activation is probably involved in the first step of the cascade in the invasion-metastasis of pancreatic cancer.

  17. Induction of tumor stem cell differentiation--novel strategy to overcome therapy resistance in gastric cancer.

    Science.gov (United States)

    Zieker, Derek; Bühler, Sarah; Ustündag, Zeynep; Königsrainer, Ingmar; Manncke, Sebastian; Bajaeifer, Khaled; Vollmer, Jörg; Fend, Falko; Northoff, Hinnak; Königsrainer, Alfred; Glatzle, Jörg

    2013-04-01

    Metastases are a frequent finding in gastric cancer and are associated with poor prognosis. A recently discovered link between metabolic changes, differentiation, and therapy resistance due to tumor stem cells could depict a novel approach in cancer research and therapy. Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme and is known to be involved in enabling gastric cancer cells to be invasive and to disseminate. In this study, we investigated if PGK1 is a promising candidate in inducing stem cell differentiation in gastric cancer. MKN45 gastric cancer cells were used due to their known cancer stem cell population, which is defined by the surface marker CD44. MKN45 cells were separated between CD44+ and CD44- cells and, in equal parts, incubated with shRNA anti-PGK1 using fluorescence-activated cell sorting (FACS) analysis; they were then injected into nude mice to evaluate their tumor growth behavior in vivo. Further, the invasive potential of gastric cancer cells was evaluated in vitro using the xCelligence analyzing system. CD44+ gastric cancer cells treated with and without shRNA anti-PGK1 were capable to cause tumor growth in vivo, whereas tumor growth in CD44+ cells treated with shRNA anti-PGK1 was considerably smaller in comparison with that in CD44+ cells without treatment. CD44- cells did not show any noticeable tumor growth in vivo. By targeting PGK1, the invasive potential of gastric cancer cells was impressively reduced in vitro. In all our cells, which were targeted with shRNA anti-PGK1, we did not find any change that is in accordance with the phenotype of the cells using FACS analysis. Our findings suggest that targeting the key metabolic enzyme PGK1 in gastric cancer cells may open a new chapter in cancer treatment, which is well worth for further exploration in combination with recent chemotherapy, and might be a promising possibility to overcome therapy resistance in gastric cancer.

  18. High dose and low dose radiation exposure in the induction of breast cancer

    International Nuclear Information System (INIS)

    Fernandez-Vicioso, E.; Ruiz-Cruces, R.; Pastor Vega, Jose M.

    2001-01-01

    In today's modern practice of Radiation Oncology it is becoming increasingly common to follow many patients with breast cancer. There is a proven association between prior radiation and the development of breast cancer, although in many instances the available sources of data are confusing. Characteristic features of radiation induced breast cancer are the importance of age at first exposure to radiation and the long latency period. The risk of breast cancer is highest in women exposed in the first decade of life and lessens progressively with increased age at exposure. The latency period is typically 10 years or more; a time in which other age dependent factors may influence the expression of the malignant phenotype. Genetic factors may also (in theory) increase a particular patient's susceptibility. (author)

  19. Screening Doses for Induction of Cancers Calculated with the Interactive RadioEpidemiological Program (IREP)

    National Research Council Canada - National Science Library

    Kocher, David C; Apostoaei, Julian A

    2007-01-01

    .... Screening doses for 32 cancer types were calculated with the Interactive RadioEpidemiological Program, which is used by the Department of Veterans Affairs in adjudicating claims for compensation...

  20. Induction of the p75NTR by Aryl Propionic Acids in Prostate Cancer Cells

    National Research Council Canada - National Science Library

    Quann, Emily

    2007-01-01

    .... I have found that treatment of prostate cancer cells with the aryl propionic acids R-flurbiprofen and ibuprofen induces reexpression of p75NTR, decreases cell survival, and increases apoptosis...

  1. ZEB1 Promotes Oxaliplatin Resistance through the Induction of Epithelial - Mesenchymal Transition in Colon Cancer Cells.

    Science.gov (United States)

    Guo, Cao; Ma, Junli; Deng, Ganlu; Qu, Yanlin; Yin, Ling; Li, Yiyi; Han, Ying; Cai, Changjing; Shen, Hong; Zeng, Shan

    2017-01-01

    Background: Oxaliplatin (OXA) chemotherapy is widely used in the clinical treatment of colon cancer. However, chemo-resistance is still a barrier to effective chemotherapy in cases of colon cancer. Accumulated evidence suggests that the epithelial mesenchymal transition (EMT) may be a critical factor in chemo-sensitivity. The present study investigated the effects of Zinc finger E-box binding homeobox 1 (ZEB1) on OXA-sensitivity in colon cancer cells. Method: ZEB1expression and its correlation with clinicopathological characteristics were analyzed using tumor tissue from an independent cohort consisting of 118 colon cancer (CC) patients who receiving OXA-based chemotherapy. ZEB1 modulation of OXA-sensitivity in colon cancer cells was investigated in a OXA-resistant subline of HCT116/OXA cells and the parental colon cancer cell line: HCT116. A CCK8 assay was carried out to determine OXA-sensitivity. qRT-PCR, Western blot, Scratch wound healing and transwell assays were used to determine EMT phenotype of colon cells. ZEB1 knockdown using small interfering RNA (siRNA) was used to determine the ZEB1 contribution to OXA-sensitivity in vitro and in vivo (in a nude mice xenograft model). Result: ZEB1 expression was significantly increased in colon tumor tissue, and was correlated with lymph node metastasis and the depth of invasion. Compared with the parental colon cancer cells (HCT116), HCT116/OXA cells exhibited an EMT phenotype characterized by up-regulated expression of ZEB1, Vimentin, MMP2 and MMP9, but down-regulated expression of E-cadherin. Transfection of Si-ZEB1 into HCT116/OXA cells significantly reversed the EMT phenotype and enhanced OXA-sensitivity in vitro and in vivo . Conclusion: HCT116/OXA cells acquired an EMT phenotype. ZEB1 knockdown effectively restored OXA-sensitivity by reversing EMT. ZEB1 is a potential therapeutic target for the prevention of OXA-resistance in colon cancer.

  2. The Yin and Yang aspects of IL-27 in induction of cancer-specific T-cell responses and immunotherapy.

    Science.gov (United States)

    Li, Ming-Song; Liu, Zhenzhen; Liu, Jin-Qing; Zhu, Xiaotong; Liu, Zhihao; Bai, Xue-Feng

    2015-01-01

    Accumulating evidences from animal studies have indicated that both endogenous and exogenous IL-27, an IL-12 family of cytokine, can increase antitumor T-cell activities and inhibit tumor growth. IL-27 can modulate Treg responses, and program effector T cells into a unique T-effector stem cell (TSEC) phenotype, which enhances T-cell survival in the tumor microenvironment. However, animal studies also suggest that IL-27 induces molecular pathways such as IL-10, PD-L1 and CD39, which may downregulate tumor-specific T-cell responses. In this review paper, we will discuss the Yin and Yang aspects of IL-27 in the induction of tumor-specific T-cell responses, and the potential impacts of these functions of IL-27 in the design of cancer immunotherapy.

  3. Electrothermal simulations of high-power SOI vertical DMOS transistors with lateral drain contacts under unclamped inductive switching test

    Science.gov (United States)

    Pinardi, Kuntjoro; Heinle, Ulrich; Bengtsson, Stefan; Olsson, Jörgen; Colinge, Jean-Pierre

    2004-07-01

    Electrothermal effects during the unclamped inductive switching (UIS) of silicon-on-insulator (SOI) high power vertical double diffused MOS (VDMOS) transistors have been studied by device simulation. In the UIS test all the energy stored in the inductor during the on state is dumped directly into the device when the device is turned off. This extreme condition during the UIS test will give ratings for the power device and gives a measure for the stability of the device in the breakdown regime. Electrothermal simulations of this device are evaluated under boundary conditions imposed by the UIS circuit. Simulations show that UIS involves a substantial risk of turning the parasitic bipolar transistor (BJT) on. Our measurements of the fabricated SOI VDMOSFET in the static region are in good agreement with the expected impact of the self-heating on the saturation behaviour. The experiments at ambient temperature of 100 °C show that the breakdown voltage decreases as the drain voltage increases. This indicates that the parasitic BJT has been turned on and causes an open-base bipolar transistor breakdown voltage.

  4. Retracted: Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis

    Science.gov (United States)

    2017-11-17

    Retraction: Retracted: Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis Asian Pacific Journal of Cancer Prevention has retracted the article titled “Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis”(1) for reason of similarity with a series of articles identified by Byrne and Labbé (2). Xue-Mei Wang, Jiu-Wei Cui1&, Wei Li , Lu Cai, Wei Song , Guan-Jun Wang 1. Xue-Mei Wang, Jiu-Wei Cui1&, Wei Li , Lu Cai, Wei Song , Guan-Jun Wang. Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis. Asian Pac J Cancer Prev. 2012;13(5):1823-7. 2. J. A. Byrne and C. Labbé, “Striking similarities between publications from China describing single gene knockdown experiments in human cancer cell lines,” Scientometrics, vol. 110, no. 3, pp. 1471–1493, 2017. Authors did not respond to request for comment.

  5. Wavelength-dependent induction of UV absorbing mycosporine-like amino acids in the red alga Chondrus crispus under natural solar radiation

    NARCIS (Netherlands)

    Krabs, G; Bischof, K; Hanelt, D; Karsten, U; Wiencke, C

    2002-01-01

    Polychromatic response spectra for the induction of UV absorbing mycosporine-like amino acids (MAAs) were calculated after exposing small thalli of the red alga Chondrus crispus under various cut-off filters to natural solar radiation on the North Sea island Helgoland, Germany. The laboratory-grown

  6. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Hagman, H; Frödin, J-E; Berglund, Å

    2016-01-01

    BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies...

  7. Effectiveness of gaseous and intravenous inductions on children′s anxiety and distress during extraction of teeth under general anesthesia

    Directory of Open Access Journals (Sweden)

    Giath Gazal

    2015-01-01

    Full Text Available Context: Anxiety and distress regarding dental treatment is a major issue for dental patients and can be exaggerated in pediatric dental patients. Aims: The aim was to investigate how different methods of induction for general anesthesia affect children′s distress for dental procedures such as extraction of teeth. Subjects and Methods: This was an observational clinical study conducted at Manchester University Dental Hospital. The induction of anesthesia in children was achieved with either intravenous (I.V. or a gaseous induction. The Modified Child Smiley Faces Scales were completed for children at various times intervals. Statistical Analysis Used: There were statistically significant differences between the mean distress scores for the I.V. and inhalation groups (P values from independent t-test: P < 0.001 was applied. Results: In gaseous induction group, the number of children who scored severe and very severe distress was greater than those who were in I.V. group. Gaseous induction was used for 23 children. Preoperatively, 56.5% children were in very severe distress, 17.4% in severe distress, 13% in moderate distress, 8.7% in mild distress and only one (4.3% showed no distress. For I.V. induction, 11.2% children were in very severe distress, 9% in severe distress, and 9.6% in moderate distress, 24.2% in mild distress and 46.1% showed no distress. Conclusions: Gaseous induction anesthesia for extractions of teeth does produce high levels of distress than I.V. induction in children for dental extractions. There was no significant difference between both induction methods in terms of distress levels at the time of recovery and 15 min postoperatively.

  8. Analysis of indirect rotor field oriented control-based induction machine performance under inaccurate field-oriented condition

    DEFF Research Database (Denmark)

    Liu, Yang; Tao, Geng; Wang, Huai

    2017-01-01

    Indirect rotor field oriented control (IRFOC) plays an important role in the high performance induction machine drives. In the indirect rotor field oriented control — based induction machine adjustable speed control system, the rotor field angle is usually obtained by the rotor angular velocity...... used in the indirect rotor field oriented control may have considerable error. In the paper, the angle error caused by rotor resistance variation is analyzed and the impact on the output torque and the rotor field intensity of the induction machine is studied. Simulations and experimental verification...

  9. Induction of apoptosis in colon cancer cells by a novel topoisomerase I inhibitor TopIn

    International Nuclear Information System (INIS)

    Bae, Soo Kyung; Gwak, Jungsug; Song, Im-Sook; Park, Hyung-Soon; Oh, Sangtaek

    2011-01-01

    Highlights: → TopIn activates p53-dependent transcription in colon cancer cells. → TopIn induces apoptosis in colon cancer cells. → TopIn selectively inhibits topoisomerase I activity. → TopIn does not affect the activity of BCRP and MDR-1. -- Abstract: The tumor suppressor p53 plays an important role in cellular emergency mechanisms through regulating the genes involved in cell cycle arrest and apoptosis. To identify small molecules that can activate p53-responsive transcription, we performed chemical screening using genetically engineered HCT116 reporter cells. We found that TopIn (7-phenyl-6H-[1,2,5]oxadiazolo[3,4-e]indole 3-oxide) efficiently activated p53-mediated transcriptional activity and induced phosphorylation of p53 at Ser15, thereby stabilizing the p53 protein. Furthermore, TopIn upregulated the expression of p21 WAF1/CIP1 , a downstream target of p53, and suppressed cellular proliferation in various colon cancer cells. Additionally, TopIn induced DNA fragmentation, caspase-3/7 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis, in p53 wild-type and mutated colon cancer cells. Finally, we found that TopIn inhibited topoisomerase I activity, but not topoisomerase II, in vitro and induced the formation of the topoisomerase I-DNA complex in HCT116 colon cancer cells. Unlike camptothecin (CPT) and its derivative SN38, TopIn did not affect the activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP) or multidrug-resistant protein-1 (MDR-1). These results suggest that TopIn may present a promising new topoisomerase I-targeting anti-tumor therapeutics.

  10. Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258 and its Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Shalini S. Yadav

    2017-06-01

    Full Text Available Prostate cancer (PCa remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT; however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC. With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258 is a pan receptor tyrosine kinase (RTK inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.

  11. TGF-Beta Induction of PMEPA1: Role in Bone Metastasis Due to Prostate Cancer

    Science.gov (United States)

    2009-01-01

    ASBMR John Haddad Young Investigator award, American Society for Bone and Mineral Research. 2008 Noa Siris Schwartz Research Award, Bone and Cancer...Riggins for their technical assistance . 40 Funding Disclosure This work was supported by a Department of Defense (DoD) predoctoral fellowship

  12. Induction of autophagy by proteasome inhibitor is associated with proliferative arrest in colon cancer cells

    International Nuclear Information System (INIS)

    Wu, William Ka Kei; Wu Yachun; Yu Le; Li Zhijie; Sung, Joseph Jao Yiu; Cho, C.H.

    2008-01-01

    The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Blockade of UPS by proteasome inhibitors has been shown to activate autophagy. Recent evidence also suggests that proteasome inhibitors may inhibit cancer growth. In this study, the effect of a proteasome inhibitor MG-132 on the proliferation and autophagy of cultured colon cancer cells (HT-29) was elucidated. Results showed that MG-132 inhibited HT-29 cell proliferation and induced G 2 /M cell cycle arrest which was associated with the formation of LC3 + autophagic vacuoles and the accumulation of acidic vesicular organelles. MG-132 also increased the protein expression of LC3-I and -II in a time-dependent manner. In this connection, 3-methyladenine, a Class III phosphoinositide 3-kinase inhibitor, significantly abolished the formation of LC3 + autophagic vacuoles and the expression of LC3-II but not LC3-I induced by MG-132. Taken together, this study demonstrates that inhibition of proteasome in colon cancer cells lowers cell proliferation and activates autophagy. This discovery may shed a new light on the novel function of proteasome in the regulation of autophagy and proliferation in colon cancer cells

  13. WAVELENGTH DEPENDENCE OF SKIN-CANCER INDUCTION BY ULTRAVIOLET-IRRADIATION OF ALBINO HAIRLESS MICE

    NARCIS (Netherlands)

    de Gruijl, F. R.; Sterenborg, H. J.; Forbes, P. D.; Davies, R. E.; Cole, C.; Kelfkens, G.; van Weelden, H.; Slaper, H.; van der Leun, J. C.

    1993-01-01

    Information on the variation in carcinogenicity with wavelength is crucial in risk assessments for skin cancers induced by UV radiation. Until recently the wavelength (lambda) dependencies of other detrimental UV effects, such as sunburn, have been used as substitutes. Direct information on the

  14. Targeting the Mitochondrial Electron Transport Chain Complexes for the Induction of Apoptosis and Cancer Treatment

    Czech Academy of Sciences Publication Activity Database

    Rohlena, Jakub; Dong, L. F.; Neužil, Jiří

    2013-01-01

    Roč. 14, č. 3 (2013), s. 377-389 ISSN 1389-2010 Institutional research plan: CEZ:AV0Z50520701 Keywords : Cancer * mitochondria * electron transport chain Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.511, year: 2013

  15. Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited.

    Science.gov (United States)

    Schulz, Tim J; Thierbach, René; Voigt, Anja; Drewes, Gunnar; Mietzner, Brun; Steinberg, Pablo; Pfeiffer, Andreas F H; Ristow, Michael

    2006-01-13

    More than 80 years ago Otto Warburg suggested that cancer might be caused by a decrease in mitochondrial energy metabolism paralleled by an increase in glycolytic flux. In later years, it was shown that cancer cells exhibit multiple alterations in mitochondrial content, structure, function, and activity. We have stably overexpressed the Friedreich ataxia-associated protein frataxin in several colon cancer cell lines. These cells have increased oxidative metabolism, as shown by concurrent increases in aconitase activity, mitochondrial membrane potential, cellular respiration, and ATP content. Consistent with Warburg's hypothesis, we found that frataxin-overexpressing cells also have decreased growth rates and increased population doubling times, show inhibited colony formation capacity in soft agar assays, and exhibit a reduced capacity for tumor formation when injected into nude mice. Furthermore, overexpression of frataxin leads to an increased phosphorylation of the tumor suppressor p38 mitogen-activated protein kinase, as well as decreased phosphorylation of extracellular signal-regulated kinase. Taken together, these results support the view that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals.

  16. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway.

    Science.gov (United States)

    Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya; An, Byeong Jun; Song, Ho Sueb; Han, Sang Bae; Kim, Jang Heub; Song, Min Jong; Hong, Jin Tae

    2012-01-01

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1-5 μg/ml) and melittin (0.5-2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Inhibition of Topoisomerase IIα and Induction of Apoptosis in Gastric Cancer Cells by 19-Triisopropyl Andrographolide

    Science.gov (United States)

    Monger, Adeep; Boonmuen, Nittaya; Suksen, Kanoknetr; Saeeng, Rungnapha; Kasemsuk, Teerapich; Piyachaturawat, Pawinee; Saengsawang, Witchuda; Chairoungdua, Arthit

    2017-10-26

    Gastric cancer is the most common cancer in Eastern Asia. Increasing chemoresistance and general systemic toxicities have complicated the current chemotherapy leading to an urgent need of more effective agents. The present study reported a potent DNA topoisomerase IIα inhibitory activity of an andrographolide analogue (19-triisopropyl andrographolide, analogue-6) in gastric cancer cells; MKN-45, and AGS cells. The analogue was potently cytotoxic to both gastric cancer cell lines with the half maximal inhibitory concentration (IC50 values) of 6.3±0.7 μM, and 1.7±0.05 μM at 48 h for MKN-45, and AGS cells, respectively. It was more potent than the parent andrographolide and the clinically used, etoposide with the IC50 values of >50 μM in MKN-45 and 11.3±2.9 μM in AGS cells for andrographolide and 28.5±4.4 μM in MKN-45 and 4.08±0.5 μM in AGS cells for etoposide. Analogue-6 at 2 μM significantly inhibited DNA topoisomerase IIα enzyme in AGS cells, induced DNA damage, activated cleaved PARP-1, and Caspase3 leading to late cellular apoptosis. Interestingly, the expression of tumor suppressor p53 was not activated. These results show the importance of 19-triisopropyl-andrographolide in its emerging selectivity to primary target on topoisomerase IIα enzyme, inducing DNA damage and apoptosis by p53- independent mechanism. Thereby, the results provide insights of the potential of 19-triisopropyl andrographolide as an anticancer agent for gastric cancer. The chemical transformation of andrographolide is a promising strategy in drug discovery of a novel class of anticancer drugs from bioactive natural products. Creative Commons Attribution License

  18. Induction of uterine cancer with inactivated herpes simplex virus, types 1 and 2

    International Nuclear Information System (INIS)

    Wentz, W.B.; Reagan, J.W.; Heggie, A.D.; Fu, Y.S.; Anthony, D.D.

    1981-01-01

    A series of studies were performed to evaluate the oncogenic potential of inactivated herpes simplex viruses types 1 (HSV-1) and 2 (HSV-2) in the mouse cervix. HSV-1 or HSV-2 prepared in HEp-2 cell cultures and inactivated by exposure to formalin or ultraviolet light was applied to the mouse cervix for periods ranging from 20 to 90 weeks. Control mice were exposed for the same period to control fluids. Vaginal cytologic preparations from all animals were examined weekly to detect epithelial abnormalities. Animals were sacrificed and histopathological studies were carried out when cellular changes seen on vaginal smears resembled those indicative of premalignant or malignant changes as previously established in a similar model system using coal tar hydrocarbons. Other animals were exposed for periods up to 90 weeks, or until there was cellular evidence of invasive cancer. Cytologic and histologic materials were coded and evaluated without knowledge of whether they were from virus-exposed or control animals. Premalignant and malignant cervical lesions similar to those that occur in women were encountered in 78 to 90% of the virus-exposed animals. All controls were normal. Invasive cancer was detected in 24 to 60% of the animals and dysplasia was found in 18 to 66%. The yield of invasive cancer was twice as great after exposure to ultraviolet-inactivated HSV-2 as compared with formalin-inactivated virus. Various histologic grades of carcinoma of the cervix and endometrium were found. No primary lesions were found in the vagina or ovaries

  19. Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer

    Science.gov (United States)

    Kosaka, Takeo; Hongo, Hiroshi; Miyazaki, Yasumasa; Nishimoto, Koshiro; Miyajima, Akira; Oya, Mototsugu

    2017-01-01

    Reactive oxygen species (ROS) production induced by taxanes in cancer cells may influence the taxane-induced cell death or the drug resistance. We investigated the correlation between the cytotoxic effect of taxanes and ROS production in human castration-resistant prostate cancer (CRPC) cell lines. Three human prostate cancer cell lines were treated with increasing concentrations of docetaxel or cabazitaxel in vitro. Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production detected by FACS analysis. To investigate whether cabazitaxel-mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel. We found that ROS elimination by Sestrin-3 (SESN3) was significantly inhibited by cabazitaxel, but not by docetaxel. These results indicate higher sensitivity of human CRPC to cabazitaxel compared to docetaxel involves ROS production through inhibiting the expression of antioxidant enzyme SESN3. PMID:29152111

  20. Immobilization of silver nanoparticles in Zr-based MOFs: induction of apoptosis in cancer cells

    Science.gov (United States)

    Han, Congcong; Yang, Jian; Gu, Jinlou

    2018-03-01

    Silver nanoparticles (AgNPs) are a potential class of nanomaterial for antibiosis and chemotherapeutic effects against human carcinoma cells. However, the DNA-damaging ability of free AgNPs pose the critical issues in their biomedical applications. Herein, we demonstrated a facile method to capture Ag+ ions and reduce them into active AgNPs within Zr-based metal-organic frameworks (MOFs) of UiO-66 with a mild reductant of DMF (AgNPs@UiO-66(DMF)). The average diameters of UiO-66 carriers and AgNPs were facilely controlled to be 140 and 10 nm, respectively. The obtained UiO-66 nanocarriers exhibited excellent biocompatibility and could be effectively endocytosed by cancer cells. Additionally, the AgNPs@UiO-66(DMF) could rapidly release Ag+ ions and efficiently inhibit the growth of cancer cells. The half maximal inhibitory concentration (IC50) values of the encapsulated AgNPs were calculated to be 2.7 and 2.45 μg mL-1 for SMMC-7721 and HeLa cells, respectively, which were much lower than those of free AgNPs in the reported works. Therefore, the developed AgNPs@UiO-66(DMF) not only maintained the therapeutic effect against cancer cells but also reduced the dosage of free AgNPs in chemotherapy treatment. [Figure not available: see fulltext.

  1. Preoperative chemoradiation with or without induction oxaliplatin plus 5-fluorouracil in locally advanced rectal cancer. Long-term outcome analysis

    Energy Technology Data Exchange (ETDEWEB)

    Calvo, F.A. [Hospital General Universitario Gregorio Maranon, Department of Oncology, Madrid (Spain); Complutense University, School of Medicine, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Instituto de Investigacion Sanitaria, Madrid (Spain); Sole, C.V. [Hospital General Universitario Gregorio Maranon, Department of Oncology, Madrid (Spain); Complutense University, School of Medicine, Madrid (Spain); Instituto de Radiomedicina, Service of Radiation Oncology, Santiago (Chile); Hospital General Universitario Gregorio Maranon, Instituto de Investigacion Sanitaria, Madrid (Spain); Serrano, J. [Complutense University, School of Medicine, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Service of Radiation Oncology, Madrid (Spain); Valle, E. del; Rodriguez, M. [Hospital General Universitario Gregorio Maranon, Service of General Surgery I, Madrid (Spain); Munoz-Calero, A.; Garcia-Sabrido, J.L. [Complutense University, School of Medicine, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Service of General Surgery I, Madrid (Spain); Garcia-Alfonso, P. [Complutense University, School of Medicine, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Service of Medical Oncology, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Instituto de Investigacion Sanitaria, Madrid (Spain); Peligros, I. [Hospital General Universitario Gregorio Maranon, Department of Pahology, Madrid (Spain); Alvarez, E. [Complutense University, School of Medicine, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Department of Pahology, Madrid (Spain); Hospital General Universitario Gregorio Maranon, Instituto de Investigacion Sanitaria, Madrid (Spain)

    2014-02-15

    It has been previously reported that a short FOLFOX-4 induction significantly improves pathologic complete response in locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiation (CRT). In a larger and updated patient series, we analyzed FOLFOX-4 efficacy in terms of sphincter preservation and long-term outcomes. From January 1995 to December 2010, 335 LARC patients were treated with preoperative chemoradiation (4500-5040 cGy). Starting in May 2001, 207 consecutive patients additionally received induction FOLFOX-4. Surgery was performed 6 weeks (range 3-12 weeks) after chemoradiation. Incidence of total tumor (63 vs. 54 %, p = 0.02) and nodal downstaging (60 vs. 43 %, p = 0.002) was significantly increased by induction FOLFOX-4. In an analysis of tumors located below 5 cm from the anal verge (n = 114, 34 %), sphincter preservation was feasible in 30 % in the FOLFOX-4 versus 13 % in the upfront CRT group (p = 0.04). Median follow-up time for the entire cohort of patients was 72.6 months (range 4-205 months). FOLFOX-4 was not associated with superior locoregional control (HR 0.88, p = 0.78), disease-free survival (HR 0.83, p = 0.55), distant metastases-free survival (HR 0.94, p = 0.81), or cancer-specific survival (HR 0.70, p = 0.15). Short-intense induction FOLFOX-4 significantly improves downstaging and sphincter preservation in low rectal tumors. Long-term outcomes were not improved in the FOLFOX-4 group of patients. (orig.) [German] Es wurde bereits berichtet, dass eine kurze FOLFOX-4-Induktion das gesamte pathologische Ansprechen bei Patienten mit lokal fortgeschrittenem Rektumkarzinom (LARC), die praeoperativ mittels Strahlenchemotherapie (CRT) behandelt wurden, signifikant verbessert. In einer groesseren und aktualisierten Patientengruppe analysierten wir die FOLFOX-4-Wirksamkeit hinsichtlich Sphinktererhalt und Langzeitergebnissen. Von Januar 1995 bis Dezember 2010 wurden 335 LARC-Patienten praeoperativ mit einer

  2. Cancer prostatae hos maend under 65 år. Forekomst og behov for udredning

    DEFF Research Database (Denmark)

    Brasso, K; Friis, S; Kjaer, S K

    1997-01-01

    Based on information from the nationwide Danish Cancer Registry, the development in prostate cancer incidence among Danish men under 65 years is reviewed. Changes in incidence rate, clinical stage and the number of possible candidates for radical treatment are discussed.......Based on information from the nationwide Danish Cancer Registry, the development in prostate cancer incidence among Danish men under 65 years is reviewed. Changes in incidence rate, clinical stage and the number of possible candidates for radical treatment are discussed....

  3. Measurement of sliding velocity and induction time of a single micro-bubble under an inclined collector surface

    Energy Technology Data Exchange (ETDEWEB)

    Najafi, A.S.; Xu, Z.; Masliyah, J. [Alberta Univ., Edmonton, AB (Canada). Dept. of Chemical and Materials Engineering

    2008-12-15

    Flotation is a major process by which bitumens are recovered from oil sands slurries, and air bubble-bitumen attachment is necessary for the effective separation of aerated bitumen. This study investigated the interactions between a gas bubble and a solid, flat surface. Various physical and chemical conditions were studied in order to determine their impact on the sliding velocity and induction times of the micro-bubble as it slid underneath an inclined solid surface. The bubble's trajectory was monitored by a high-speed video imaging system. Tests were conducted using de-aerated process water in order to study the effect of dissolved gases on bubble sliding velocity. Simulated process water was also used to study the role of the natural surfactants contained in recycle process water. The study showed that terminal and sliding velocities of the bubbles were functions of temperature. Sliding velocities increased with increases in liquid temperature. Increases in liquid temperature also reduced the induction time used to quantify bubble-solid attachment. Induction times were also reduced with increases in surface hydrophobicity. Induction times measured for CO{sub 2} bubbles were shorter than those observed with air, oxygen, and hydrogen bubbles. It was concluded that the use of natural surface active agents in process water reduced bubble terminal rising velocity and increased the induction times of bubble-solid attachment. 36 refs., 2 tabs., 15 figs.

  4. A model for the induction of bone cancer by 224Ra

    International Nuclear Information System (INIS)

    Groer, P.G.; Marshall, J.H.

    1976-01-01

    A mathematical model for the transformation of normal endosteal cells into malignant tumor cells by α-irradiation is applied to 224 Ra. The model postulates that a normal endosteal cell near the bone surface is transformed into a malignant cell by three consecutive events. The first two events are the initiation events. The probability of their occurrence is proportional to the absorbed endosteal dose and they generate dormant tumor cells. These dormant tumor cells are promoted by the third event, the promotion event. The probability of this last event is proportional to the rate of bone remodeling but independent of the radiation dose. In competition with these transformig events is the killing of any endosteal cell by α-irradiation. Killing is balanced by replacement of killed endosteal cells by normal stem cells. This model provides the following interesting predictions for the human 224 Ra cases. 1) After the decay of 224 Ra the tumor rate decreases exponentially at a rate proportional to the bone turnover rate. 2) For exposure to the same dose the model predicts an increased number of tumors for protacted exposure (i.e. exposure at a lower dose rate). Implications of this model for the therapy of ankylosing spondylitis are discussed. Statistical procedures are suggested for comparison of this theoretical model with the existing data on the induction of osteosarcomas by 224 Ra in man. (orig.) [de

  5. Antiproliferative activity and induction of apoptosis by Annona muricata (Annonaceae) extract on human cancer cells.

    Science.gov (United States)

    Pieme, Constant Anatole; Kumar, Santosh Guru; Dongmo, Mireille Sylviane; Moukette, Bruno Moukette; Boyoum, Fabrice Fekam; Ngogang, Jeanne Yonkeu; Saxena, Ajit Kumar

    2014-12-24

    Annona muricata (A. muricata) is widely distributed in Asia, Africa and South America. Different parts of this plant are used to treat several diseases in Cameroon. The aim of this study is to determine the in vitro anti-proliferative effects and apoptotic events of A. muricata extracts on HL-60 cells as well as to quantify its phenols content. The cell viability was measured by using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay while the changes in morphology of HL-60 cells, membrane mitochondrial potential (MMP) and the cell cycle were used for assessment apoptosis induction. The results show that the concentration of phenols, flavonoids and flavonols in the extracts varied depending on the part of the plant. All the extracts tested inhibited the proliferation of HL-60 cells in a concentration dependent manner with IC50 varied from 6-49 μg/mL. The growth inhibition of the cells by extracts was associated with the disruption of MMP, reactive oxygen species (ROS) generation and the G0/G1 cell arrest. These findings suggest that the extracts from A. muricata have strong antiproliferation potential and can induce apoptosis through loss of MMP and G0/G1 phase cell arrest.

  6. Induction of apoptosis in breast cancer cells in vitro by Fas ligand reverse signaling.

    Science.gov (United States)

    Kolben, Thomas; Jeschke, Udo; Reimer, Toralf; Karsten, Nora; Schmoeckel, Elisa; Semmlinger, Anna; Mahner, Sven; Harbeck, Nadia; Kolben, Theresa M

    2018-02-01

    The Fas-antigen is a cell surface receptor that transduces apoptotic signals into cells. The purpose of this study was to evaluate FasL expression in breast cancer and to elucidate the role of its signaling in different breast cancer cell lines. T47D and MCF7 cells were used and cultured in Dulbecco's modified Eagle's medium. FasL translocation to the membrane was achieved by culturing the cells in the presence of human interferon-γ (IFNγ). Translocation was detected by immunofluorescence. The ability of a Fas:Fc fusion protein to trigger apoptosis in these cells was investigated by cell death detection ELISA. After incubation with IFNγ for 4 h and 18 h, apoptosis was assessed in response to treatment with Fas:Fc. Immunofluorescence revealed that the used cell lines were positive for FasL which was increased and changed to more membrane-bound FasL expression after IFNγ stimulation. After stimulation with 50 IU/ml IFNγ, Fas:Fc significantly increased MCF7 apoptosis (1.39 ± 0.06-fold, p = 0.0004) after 18 h. After stimulation with 100 IU/ml, Fas:Fc significantly increased apoptosis both after 4 h (1.49 ± 0.15-fold, p = 0.018) and 18 h (1.30 ± 0.06-fold, p = 0.013). In T47D cells this effect was seen after 4 h of stimulation with 50 IU/ml and addition of Fas:Fc (1.6 ± 0.08-fold, p = 0.03). Membrane-bound FasL expression could be induced by IFNγ in a breast cancer cell model. More importantly, in the presence of IFNγ the Fas:Fc fusion protein was able to transmit pro-apoptotic signals to T47D and MCF7 cells, significantly inducing apoptosis. The current findings support further in vivo studies regarding FasL activation as a potential target for therapeutic intervention in breast cancer.

  7. Comparative cellular and molecular analysis of cytotoxicity and apoptosis induction by doxorubicin and Baneh in human breast cancer T47D cells.

    Science.gov (United States)

    Rezaei, P Fathi; Fouladdel, Sh; Cristofanon, Silvia; Ghaffari, S M; Amin, G R; Azizi, E

    2011-10-01

    It is now widely accepted that dietary phytochemicals inhibit cancer progression and enhance the effects of conventional chemotherapy. In this report, we comparatively studied the cellular and molecular aspects of apoptosis induction by the methanolic extract of Baneh fruit skin in comparison to Doxorubicin (Dox), a well-known anticancer drug, in human breast cancer T47D cells. The MTT assay was used to determine the antiproliferative effects. The flow cytometric and microscopic analyses were done to evaluate the apoptosis induction. Furthermore, western blot analyses have been done to study the role of key molecular players of apoptosis including caspase 3 and PARP. The Baneh extract showed strong antiproliferative activity against T47D cells in a dose- and time-dependent manner that was comparable to and even stronger than Dox in certain concentrations. Analysis of Baneh-treated cells by flow cytometry and fluorescence microscopy indicated strong apoptosis induction and nuclear morphological alterations similar to or greater than Dox. Finally, molecular analysis of apoptosis by western blotting proved activation of caspase 3 followed by poly ADP ribose polymerase (PARP) cleavage more efficiently in Baneh than in Dox treated cancer cells. These findings indicate that Baneh extract contains phytochemicals which act as inhibitor of cell proliferation and inducer of apoptosis in human breast cancer T47D cells that makes it a potentially good candidate for new anticancer drug development.

  8. Non-chemotoxic induction of cancer cell death using magnetic nanowires

    KAUST Repository

    Contreras, Maria F.

    2015-03-01

    In this paper, we show that magnetic nanowires with weak magnetic fields and low frequencies can induce cell death via a mechanism that does not involve heat production. We incubated colon cancer cells with two concentrations (2.4 and 12 μg/mL) of nickel nanowires that were 35 nm in diameter and exposed the cells and nanowires to an alternating magnetic field (0.5 mT and 1 Hz or 1 kHz) for 10 or 30 minutes. This low-power field exerted a force on the magnetic nanowires, causing a mechanical disturbance to the cells. Transmission electron microscopy images showed that the nanostructures were internalized into the cells within 1 hour of incubation. Cell viability studies showed that the magnetic field and the nanowires separately had minor deleterious effects on the cells; however, when combined, the magnetic field and nanowires caused the cell viability values to drop by up to 39%, depending on the strength of the magnetic field and the concentration of the nanowires. Cell membrane leakage experiments indicated membrane leakage of 20%, suggesting that cell death mechanisms induced by the nanowires and magnetic field involve some cell membrane rupture. Results suggest that magnetic nanowires can kill cancer cells. The proposed process requires simple and low-cost equipment with exposure to only very weak magnetic fields for short time periods. © 2015 Contreras et al.

  9. Induction of apoptosis in prostate cancer cells by pachymic acid from Poria cocos

    International Nuclear Information System (INIS)

    Gapter, Leslie; Wang, Zaisen; Glinski, Jan; Ng, Ka-yun

    2005-01-01

    Pachymic acid (PA) is a natural triterpenoid known to inhibit the phospholipase A2 (PLA 2 ) family of arachidonic acid (AA)-producing enzymes. PLA 2 is elevated in prostatic adenocarcinoma and conversion of AA to prostaglandins leads to AKT pro-survival activity. In this study, we investigated the effect of PA on the growth of human prostate cancer cells. PA significantly reduced cell proliferation and induced apoptosis in a dose- and time-dependent fashion, with androgen-insensitive DU145 prostate cancer cells showing greater growth inhibition relative to androgen-responsive LNCaP. Despite elevated protein expression of the cell cycle inhibitor, p21, apoptosis occurred in the absence of cell cycle arrest. PA-treatment decreased Bad phosphorylation, increased Bcl-2 phosphorylation, and activated caspases-9 and -3, suggesting that PA initiated apoptosis through mitochondria dysfunction. PA-treatment also decreased the expression and activation of proteins within the AKT signal pathway. We speculate that PA influenced apoptosis by reducing prostaglandin synthesis and AKT activity

  10. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer.

    Science.gov (United States)

    Roh, Jong-Lyel; Kim, Eun Hye; Jang, Hye Jin; Park, Jin Young; Shin, Daiha

    2016-10-10

    Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy-resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cystine or glutamine excess induced ferroptosis of both cisplatin-sensitive and -resistant HNC cells without any apparent changes to necrosis and apoptosis markers. The cystine/glutamate antiporter inhibitors erastin and sulfasalazine inhibited HNC cell growth and accumulated lipid reactive oxygen species, thereby inducing ferroptosis. Genetic silencing of cystine/glutamate antiporter with siRNA or shRNA treatment also induced effective ferroptotic cell death of resistant HNC cells and enhanced the cisplatin cytotoxicity of resistant HNC cells. Pharmacological and genetic inhibition of cystine/glutamate antiporter significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Pharmacological and genetic inhibition of cystine/glutamate antiporter overcomes the cisplatin resistance of HNC cells by inducing ferroptosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. A study of the induction of chromosomal aberrations in human breast cancer cells with Californium-252

    Energy Technology Data Exchange (ETDEWEB)

    Byrne, T.E. [Roane State, Harriman, Tennessee (United States); Khan, M.K.; Kabalka, G.W.; MacCabe, J.A.; Miller, L.F. [Univ. of Tennessee, TN (United States); Martin, R.C. [Oak Ridge National Laboratory, Oak Ridge, Tennessee (United States)

    2000-10-01

    A system for testing potential BNCT pharmaceuticals in cell cultures has been developed with the cooperation of Oak Ridge National Laboratory (ORNL), the University of Tennessee Chemistry Department, the University of Tennessee Biochemistry, Cellular and Molecular Biology Department and the University of Tennessee Nuclear Engineering Department. The scope of this research is to build upon the established cellular studies and determine the role of thermalized neutrons from Cf-252 in causing chromosomal aberrations. Following standard laboratory treatment the human breast cancer cell line (ATTC HTB-129, MDA-MB-435s) was exposed to Cf-252 neutron sources provided by the Californium User Facility for Neutron Science at ORNL. The neutron spectrum and beam characteristics are similar to those of reactor fission sources with an average energy of 2.1 MeV. A 50 mg source of Cf-252 moderated by a large mass of water provides a source on the order of 1 x 10{sup 9} thermal neutrons/cm{sup 2}/s at a distance of 3 cm complemented by a larger flux of fast neutrons. The half-life of Cf-252 is 2.65 years, and thus provides a simple and reliable source of neutrons for cancer treatments in locations without suitable nuclear reactors. (author)

  12. Induction of immunological changes induced by photodynamic therapy (PDT) for cancer

    International Nuclear Information System (INIS)

    Reginato, E.

    2014-01-01

    Photodynamic therapy (PDT) is a clinically approved procedure for treatment of cancer and certain non-malignant diseases. PDT consists of systemic or topical administration of a photosensitizer (PS) or a PS precursor (prodrug) such as aminolevulinic acid, followed by irradiation of the diseased area with light of wavelengths corresponding to the absorbance band of the PS. When the PS is activated to its excited state by the light, it can react with the surrounding environment and transfer energy to the molecular tissue oxygen, triggering a photochemical reaction and causing cell death. Besides causing direct cytotoxic effects on illuminated cancer cells, PDT is known to cause damage to the tumor vasculature and to induce the release of pro-inflammatory mediators. Previous studies in mouse models and patients have demonstrated that PDT is capable of affecting both innate and adaptive arms of the immune system. It has been shown that besides stimulating tumor-specific cytotoxic T-cells capable to destroy distant untreated tumor cells, PDT can lead to development of anti-tumor memory immunity that potentially prevents the recurrence of cancer. Moreover, several lines of evidence suggest that PDT may also interfere with the immune-suppressive regulatory T cells (Treg). In the present work we thoroughly investigated the intricate immune profile of PDT in both preclinical and clinical studies, involving (1) a colon adenocarcinoma CT26 wild-type tumor mouse model, (2) patients suffering from esophageal squamous cell carcinoma (ESCC) treated with porfimer sodium (Photofrin) and Laser and (3) patients with actinic keratoses (AK), treated with the porphyrin precursor methyl aminolevulinate and red LED light. Our results from the animal model suggested that PDT did not cause any long-term effect on the levels of Treg in the spleen or lymph nodes. However, Treg cells depletion via administration of cyclophosphamide (CY) prior PDT potentiated anti-tumor immunity, leading to

  13. Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line.

    Directory of Open Access Journals (Sweden)

    Giuseppe Pirozzi

    Full Text Available Cancer Stem Cells (CSCs hypothesis asserts that only a small subset of cells within a tumour is capable of both tumour initiation and sustainment. The Epithelial-Mesenchymal Transition (EMT is an embryonic developmental program that is often activated during cancer invasion and metastasis. The aim of this study is to shed light on the relationship between EMT and CSCs by using LC31 lung cancer primary cell line.A549 and LC31 cell lines were treated with 2 ng/ml TGFβ-1 for 30 days, and 80 days, respectively. To evaluate EMT, morphological changes were assessed by light microscopy, immunofluorescence and cytometry for following markers: cytokeratins, e-cadherin, CD326 (epithelial markers and CD90, and vimentin (mesenchymal markers. Moreover, RT-PCR for Slug, Twist and β-catenin genes were performed. On TGFβ-1 treated and untreated LC31 cell lines, we performed stemness tests such as pneumospheres growth and stem markers expression such as Oct4, Nanog, Sox2, c-kit and CD133. Western Blot for CD133 and tumorigenicity assays using NOD/SCID mice were performed.TGFβ-1 treated LC31 cell line lost its epithelial morphology assuming a fibroblast-like appearance. The same results were obtained for the A549 cell line (as control. Immunofluorescence and cytometry showed up-regulation of vimentin and CD90 and down-regulation of cytocheratin, e-cadherin and CD326 in TGFβ-1 treated LC31 and A549 cell lines. Slug, Twist and β-catenin m-RNA transcripts were up-regulated in TGFβ-1 treated LC31 cell line confirming EMT. This cell line showed also over-expression of Oct4, Nanog, Sox2 and CD133, all genes of stemness. In addition, in TGFβ-1 treated LC31 cell line, an increased pneumosphere-forming capacity and tumours-forming ability in NOD/SCID mice were detectable.The induction of EMT by TGFβ-1 exposure, in primary lung cancer cell line results in the acquisition of mesenchymal profile and in the expression of stem cell markers.

  14. Anti-proliferation and Apoptosis Induction of Aqueous Leaf Extract of Carica papaya L. on Human Breast Cancer Cells MCF-7.

    Science.gov (United States)

    Zuhrotun Nisa, Fatma; Astuti, Mary; Murdiati, Agnes; Mubarika Haryana, Sofia

    2017-01-01

    Breast cancer is the most frequently diagnosed cancer in women. Chemotherapy is the main method of breast cancer treatment but there are side effects. Carica papaya leaves is vegetable foods consumed by most people of Indonesia have potential as anticancer. The aim of this study was to investigate anti-proliferative and apoptotic induced effect of aqueous papaya leaves extracts on human breast cancer cell lines MCF-7. Inhibitory on cell proliferation was measured by MTT assay while apoptosis induction was measured using Annexin V. The results showed that papaya leaf can inhibit the proliferation of human breast cancer cells MCF-7 with IC50 in 1319.25 μg mL-1. The IC50 values of papaya leaf extract was higher than the IC50 value quercetin and doxorubicin. Papaya leaf extract can also induce apoptosis of breast cancer cells MCF-7 about 22.54% for concentration 659.63 μg mL-1 and about 20.73% for concentration 329.81 μg mL-1. The percentage of cell apoptosis of papaya leaf extract lower than doxorubicin but higher than quercetin. This study indicated that papaya leaf extract have potential as anticancer through mechanism anti-proliferation and apoptosis induction.

  15. Inducible Hsp70 in the Regulation of Cancer Cell Survival: Analysis of Chaperone Induction, Expression and Activity

    Energy Technology Data Exchange (ETDEWEB)

    Zorzi, Elisa [OncoHematology Clinic of Pediatrics, University-Hospital of Padova, 35100 Padova (Italy); Bonvini, Paolo, E-mail: paolo.bonvini@unipd.it [OncoHematology Clinic of Pediatrics, University-Hospital of Padova, 35100 Padova (Italy); Fondazione Città della Speranza, 36030 Monte di Malo, Vicenza (Italy)

    2011-10-21

    Understanding the mechanisms that control stress is central to realize how cells respond to environmental and physiological insults. All the more important is to reveal how tumour cells withstand their harsher growth conditions and cope with drug-induced apoptosis, since resistance to chemotherapy is the foremost complication when curing cancer. Intensive research on tumour biology over the past number of years has provided significant insights into the molecular events that occur during oncogenesis, and resistance to anti-cancer drugs has been shown to often rely on stress response and expression of inducible heat shock proteins (HSPs). However, with respect to the mechanisms guarding cancer cells against proteotoxic stresses and the modulatory effects that allow their survival, much remains to be defined. Heat shock proteins are molecules responsible for folding newly synthesized polypeptides under physiological conditions and misfolded proteins under stress, but their role in maintaining the transformed phenotype often goes beyond their conventional chaperone activity. Expression of inducible HSPs is known to correlate with limited sensitivity to apoptosis induced by diverse cytotoxic agents and dismal prognosis of several tumour types, however whether cancer cells survive because of the constitutive expression of heat shock proteins or the ability to induce them when adapting to the hostile microenvironment remains to be elucidated. Clear is that tumours appear nowadays more “addicted” to heat shock proteins than previously envisaged, and targeting HSPs represents a powerful approach and a future challenge for sensitizing tumours to therapy. This review will focus on the anti-apoptotic role of heat shock 70kDa protein (Hsp70), and how regulatory factors that control inducible Hsp70 synthesis, expression and activity may be relevant for response to stress and survival of cancer cells.

  16. Inducible Hsp70 in the Regulation of Cancer Cell Survival: Analysis of Chaperone Induction, Expression and Activity

    Science.gov (United States)

    Zorzi, Elisa; Bonvini, Paolo

    2011-01-01

    Understanding the mechanisms that control stress is central to realize how cells respond to environmental and physiological insults. All the more important is to reveal how tumour cells withstand their harsher growth conditions and cope with drug-induced apoptosis, since resistance to chemotherapy is the foremost complication when curing cancer. Intensive research on tumour biology over the past number of years has provided significant insights into the molecular events that occur during oncogenesis, and resistance to anti-cancer drugs has been shown to often rely on stress response and expression of inducible heat shock proteins (HSPs). However, with respect to the mechanisms guarding cancer cells against proteotoxic stresses and the modulatory effects that allow their survival, much remains to be defined. Heat shock proteins are molecules responsible for folding newly synthesized polypeptides under physiological conditions and misfolded proteins under stress, but their role in maintaining the transformed phenotype often goes beyond their conventional chaperone activity. Expression of inducible HSPs is known to correlate with limited sensitivity to apoptosis induced by diverse cytotoxic agents and dismal prognosis of several tumour types, however whether cancer cells survive because of the constitutive expression of heat shock proteins or the ability to induce them when adapting to the hostile microenvironment remains to be elucidated. Clear is that tumours appear nowadays more “addicted” to heat shock proteins than previously envisaged, and targeting HSPs represents a powerful approach and a future challenge for sensitizing tumours to therapy. This review will focus on the anti-apoptotic role of heat shock 70kDa protein (Hsp70), and how regulatory factors that control inducible Hsp70 synthesis, expression and activity may be relevant for response to stress and survival of cancer cells. PMID:24213118

  17. Analytical closed-form investigation of PWM inverter induction motor drive performance under DC bus voltage pulsation

    Czech Academy of Sciences Publication Activity Database

    Klíma, J.; Chomát, Miroslav; Schreier, Luděk

    2008-01-01

    Roč. 2, č. 6 (2008), s. 341-352 ISSN 1751-8660 R&D Projects: GA ČR GA102/08/0424 Institutional research plan: CEZ:AV0Z20570509 Keywords : DC-link voltage pulsations * torque ripple * induction motor Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering Impact factor: 0.660, year: 2008

  18. Effect of Kolb's Learning Styles under Inductive Guided-Inquiry Learning on Learning Outcomes

    Science.gov (United States)

    Sudria, Ida Bagus Nyoman; Redhana, I. Wayan; Kirna, I. Made; Aini, Diah

    2018-01-01

    This study aimed to examine the effect of Kolb's learning styles on chemical learning activities and achievement of reaction rate taught by inductive guided inquiry learning. The population was eleventh grade Science students of a senior secondary school having relatively good academic input based on national testing results in Bali, Indonesia.…

  19. Cytotoxic Induction and Photoacoustic Imaging of Breast Cancer Cells Using Astaxanthin-Reduced Gold Nanoparticles

    Directory of Open Access Journals (Sweden)

    Subramaniyan Bharathiraja

    2016-04-01

    Full Text Available Astaxanthin, a kind of photosynthetic pigment, was employed for gold nanoparticle formation. Nanoparticles were characterized using Ulteraviolet-Visible (UV-Vis spectroscopy, transmission electron microscopy, and X-ray diffraction, and the possible presence of astaxanthin functional groups were analyzed by Fourier transform infrared spectroscopy (FTIR. The cytotoxic effect of synthesized nanoparticles was evaluated against MDA-MB-231 (human breast cancer cells using a tetrazolium-based assay, and synthesized nanoparticles exhibited dose-dependent toxicity. The morphology upon cell death was differentiated through fluorescent microscopy using different stains that predicted apoptosis. The synthesized nanoparticles were applied in ultrasound-coupled photoacoustic imaging to obtain good images of treated cells. Astaxanthin-reduced gold nanoparticle has the potential to act as a promising agent in the field of photo-based diagnosis and therapy.

  20. Induction of apoptosis by pinostrobin in human cervical cancer cells: Possible mechanism of action.

    Directory of Open Access Journals (Sweden)

    Alka Jaudan

    Full Text Available Pinostrobin (PN is a naturally occurring dietary bioflavonoid, found in various medicinal herbs/plants. Though anti-cancer potential of many such similar constituents has been demonstrated, critical biochemical targets and exact mechanism for their apoptosis-inducing actions have not been fully elucidated. The present study was aimed to investigate if PN induced apoptosis in cervical cancer cells (HeLa of human origin. It is demonstrated that PN at increasing dose effectivity reduced the cell viability as well as GSH and NO2- levels. Condensed nuclei with fragmented chromatin and changes in mitochondrial matrix morphology clearly indicated the role of mitochondria in PN induced apoptosis. A marked reduction in mitochondrial membrane potential and increased ROS production after PN treatment showed involvement of free radicals, which in turn further augment ROS levels. PN treatment resulted in DNA damage, which could have been triggered by an increase in ROS levels. Decrease in apoptotic cells in the presence of caspase 3 inhibitor in PN-treated cells suggested that PN induced apoptosis via caspase dependent pathways. Additionally, a significant increase in the expression of proteins of extrinsic (TRAIL R1/DR4, TRAIL R2/DR5, TNF RI/TNFRSF1A, FADD, Fas/TNFRSF6 and intrinsic pathway (Bad, Bax, HTRA2/Omi, SMAC/Diablo, cytochrome C, Pro-Caspase-3, Cleaved Caspase-3 was observed in the cells exposed to PN. Taken together, these observations suggest that PN efficiently induces apoptosis through ROS mediated extrinsic and intrinsic dependent signaling pathways, as well as ROS mediated mitochondrial damage in HeLa cells.

  1. Induction of apoptosis by pinostrobin in human cervical cancer cells: Possible mechanism of action.

    Science.gov (United States)

    Jaudan, Alka; Sharma, Sapna; Malek, Sri Nurestri Abd; Dixit, Aparna

    2018-01-01

    Pinostrobin (PN) is a naturally occurring dietary bioflavonoid, found in various medicinal herbs/plants. Though anti-cancer potential of many such similar constituents has been demonstrated, critical biochemical targets and exact mechanism for their apoptosis-inducing actions have not been fully elucidated. The present study was aimed to investigate if PN induced apoptosis in cervical cancer cells (HeLa) of human origin. It is demonstrated that PN at increasing dose effectivity reduced the cell viability as well as GSH and NO2- levels. Condensed nuclei with fragmented chromatin and changes in mitochondrial matrix morphology clearly indicated the role of mitochondria in PN induced apoptosis. A marked reduction in mitochondrial membrane potential and increased ROS production after PN treatment showed involvement of free radicals, which in turn further augment ROS levels. PN treatment resulted in DNA damage, which could have been triggered by an increase in ROS levels. Decrease in apoptotic cells in the presence of caspase 3 inhibitor in PN-treated cells suggested that PN induced apoptosis via caspase dependent pathways. Additionally, a significant increase in the expression of proteins of extrinsic (TRAIL R1/DR4, TRAIL R2/DR5, TNF RI/TNFRSF1A, FADD, Fas/TNFRSF6) and intrinsic pathway (Bad, Bax, HTRA2/Omi, SMAC/Diablo, cytochrome C, Pro-Caspase-3, Cleaved Caspase-3) was observed in the cells exposed to PN. Taken together, these observations suggest that PN efficiently induces apoptosis through ROS mediated extrinsic and intrinsic dependent signaling pathways, as well as ROS mediated mitochondrial damage in HeLa cells.

  2. Induction of proapoptotic antibodies to triple-negative breast cancer by vaccination with TRAIL death receptor DR5 DNA.

    Science.gov (United States)

    Piechocki, Marie P; Wu, Gen Sheng; Jones, Richard F; Jacob, Jennifer B; Gibson, Heather; Ethier, Stephen P; Abrams, Judith; Yagita, Hideo; Venuprasad, K; Wei, Wei-Zen

    2012-12-01

    TNF-related apoptosis-inducing ligand receptor 2 [TRAIL-R2 or death receptor 5 (DR5)] is expressed at elevated levels in a broad range of solid tumors to mediate apoptotic signals from TRAIL or agonist antibodies. We tested the hypothesis that DR5 DNA vaccination will induce proapoptotic antibody to trigger apoptosis of tumor cells. BALB/c mice were electrovaccinated with DNA-encoding wild-type human DR5 (phDR5) or its derivatives. Resulting immune serum or purified immune IgG induced apoptosis in triple-negative breast cancer (TNBC) cells, which were also TRAIL sensitive. The proapoptotic activity of immune serum at dilutions of 0.5-2% was comparable to that of 1-2 μg/ml of TRAIL. Apoptotic activity of immune serum was enhanced by antibody crosslinking. Apoptotic cell death induced by anti-DR5 antibody was shown by the cleavage of PARP and caspase-3. In contrast, immune serum had no effect on the proliferation of activated human T cells, which expressed low levels of DR5. In vivo, hDR5 reactive immune serum prevented growth of SUM159 TNBC cells in severe combined immune-deficient mice. DR5-specific IFN-γ-secreting T cells were also induced by DNA vaccination. Furthermore, the feasibility to overcome immune tolerance to self DR5 was shown by the induction of mouse DR5-binding antibody after electrovaccination of BALB/c mice with pmDR5ectm-Td1 encoding a fusion protein of mouse DR5 and an immunogenic fragment of tetanus toxin. These findings support DR5 as a promising vaccine target for controlling TNBC and other DR5-positive cancers. Copyright © 2012 UICC.

  3. Induction of chromosomal aberrations in human primary fibroblasts and immortalized cancer cells exposed to extremely-low-frequency electromagnetic fields

    International Nuclear Information System (INIS)

    Seyyedi, S. S.; Mozdarani, H.; Rezaei Tavirani, M.; Heydari, S.

    2010-01-01

    Rapidly increasing possibilities of exposure to environmental extremely low-frequency electromagnetic fields have become a topic of worldwide investigation. Epidemiological and laboratory studies suggest that exposure to extremely low-frequency electromagnetic fields may increase cancer risk therefore assessment of chromosomal damage in various cell lines might be of predictive value for future risk estimation. Materials and Methods: Primary cultures of fibroblasts from human skin biopsy were exposed to continuous extremely low-frequency electromagnetic fields (3, 50 and 60 Hz, sinusoidal, 3h, and 4 m T). Also immortalized cell lines, SW480, MCF-7 and 1321N1 were exposed to continuous extremely low-frequency electromagnetic fields (50 Hz, sinusoidal, 3 h, 4 m T). Metaphase plates Were prepared according to standard methods and stained in 5% Giemsa solution. Chromosomal aberrations of both chromosome and chromatid types were scored to evaluate the effects of extremely low-frequency electromagnetic fields on primary or established cell lines. Results: Results indicate that by increasing the frequency of extremely low-frequency electromagnetic fields, chromosomal aberrations were increased up to 7-fold above background levels in primary human fibroblast cells. In addition, continuous exposure to a 50 Hz electromagnetic field led to a significant increase in chromosomal aberrations in SW480, MCF-7 and 1321N1 cell lines compared to sham control. Conclusion: Results obtained indicate that extremely low-frequency electromagnetic fields has the potential for induction of chromosomal aberrations in all cell types.

  4. The induction of autophagy against mitochondria-mediated apoptosis in lung cancer cells by a ruthenium (II) imidazole complex

    Science.gov (United States)

    Peng, Fa; Jie, Xinming; Dongye, Guangzhi; Cai, Kangrong; Feng, Ruibing; Li, Baojun; Zeng, Qingwang; Lun, Kaiyi; Chen, Jincan; Xu, Bilian

    2016-01-01

    In the present study, it was found that the ruthenium (II) imidazole complex [Ru(Im)4(dppz)]2+ (Ru1) could induce significant growth inhibition and apoptosis in A549 and NCI-H460 cells. Apart from the induction of apoptosis, it was reported for the first time that Ru1 induced an autophagic response in A549 and NCI-H460 cells as evidenced by the formation of autophagosomes, acidic vesicular organelles (AVOs), and the up-regulation of LC3-II. Furthermore, scavenging of reactive oxygen species (ROS) by antioxidant NAC or Tiron inhibited the release of cytochrome c, caspase-3 activity, and eventually rescued cancer cells from Ru1-mediated apoptosis, suggesting that Ru1 inducing apoptosis was partially caspase 3-dependent by triggering ROS-mediated mitochondrial dysfunction in A549 and NCI-H460 cells. Further study indicated that the extracellular signal-regulated kinase (ERK) signaling pathway was involved in Ru1-induced autophagy in A549 and NCI-H460 cells. Moreover, blocking autophagy using pharmacological inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhanced Ru1-induced apoptosis, indicating the cytoprotective role of autophagy in Ru1-treated A549 and NCI-H460 cells. Finally, the in vivo mice bearing A549 xenografts, Ru1 dosed at 10 or 20 mg/kg significantly inhibited tumor growth. PMID:27811372

  5. Prostaglandin E2 and the protein kinase A pathway mediate arachidonic acid induction of c-fos in human prostate cancer cells

    Science.gov (United States)

    Chen, Y.; Hughes-Fulford, M.

    2000-01-01

    Arachidonic acid (AA) is the precursor for prostaglandin E2 (PGE2) synthesis and increases growth of prostate cancer cells. To further elucidate the mechanisms involved in AA-induced prostate cell growth, induction of c-fos expression by AA was investigated in a human prostate cancer cell line, PC-3. c-fos mRNA was induced shortly after addition of AA, along with a remarkable increase in PGE2 production. c-fos expression and PGE2 production induced by AA was blocked by a cyclo-oxygenase inhibitor, flurbiprofen, suggesting that PGE2 mediated c-fos induction. Protein kinase A (PKA) inhibitor H-89 abolished induction of c-fos expression by AA, and partially inhibited PGE2 production. Protein kinase C (PKC) inhibitor GF109203X had no significant effect on c-fos expression or PGE2 production. Expression of prostaglandin (EP) receptors, which mediate signal transduction from PGE2 to the cells, was examined by reverse transcription polymerase chain reaction in several human prostate cell lines. EP4 and EP2, which are coupled to the PKA signalling pathway, were expressed in all cells tested. Expression of EP1, which activates the PKC pathway, was not detected. The current study showed that induction of the immediate early gene c-fos by AA is mediated by PGE2, which activates the PKA pathway via the EP2/4 receptor in the PC-3 cells.

  6. Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism

    Science.gov (United States)

    Goodman, C R; Sato, T; Peck, A R; Girondo, M A; Yang, N; Liu, C; Yanac, A F; Kovatich, A J; Hooke, J A; Shriver, C D; Mitchell, E P; Hyslop, T; Rui, H

    2016-01-01

    Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers. PMID:26096934

  7. Breast cancer under age 40: a different approach.

    Science.gov (United States)

    Ribnikar, D; Ribeiro, J M; Pinto, D; Sousa, B; Pinto, A C; Gomes, E; Moser, E C; Cardoso, M J; Cardoso, F

    2015-04-01

    Breast cancer (BC) under age 40 is a complex disease to manage due to the additionally fertility-related factors to be taken in consideration. More than 90% of young patients with BC are symptomatic. Womenmanagement strategies for every individual patient with BC before the start of any therapy including surgery. This applies to both early (early breast cancer (EBC)) and advanced (advanced breast cancer (ABC)) disease, before the start of any therapy. Mastectomy even in young patients confers no overall survival advantage when compared to breast-conserving treatment (BCT), followed by radiotherapy. Regarding axillary approach, indications are identical to other age groups. Young age is one of the most important risk factors for local recurrence after both breast-conserving surgery (BCS) and mastectomy, associated with a higher risk of distant metastasis and death. Radiation after BCS reduces local recurrence from 19.5 to 10.2% in BC patients 40 years and younger. The indications for and the choice of systemic treatment for invasive BC (both early and advanced disease) should not be based on age alone but driven by the biological characteristics of the individual tumor (including hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, grade, and proliferative activity), disease stage, and patient's comorbidities. Recommendations regarding the use of genomic profiles such as MammaPrint, Oncotype Dx, and Genomic grade index in young women are similar to the general BC population. Especially in the metastatic setting, patient preferences should always be taken into account, as the disease is incurable. The best strategy for these patients is the inclusion into well-designed, independent, prospective randomized clinical trials. Metastatic disease should always be biopsied whenever feasible for histological confirmation and reassessment of biology. Endocrine therapy is the preferred option for hormone receptor-positive disease (HR+ve), even in

  8. Unraveling the microenvironmental influences on the normal mammary gland and induction and progression of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Weigelt, Britta; Bissell, Mina J.

    2008-06-26

    The normal mammary gland and invasive breast cancer are both complex 'organs' composed of multiple cell types as well as extracellular matrix (ECM) in three-dimensional (3D) space. Conventionally, both normal and malignant breast cells are studied in vitro as two-dimensional (2D) monolayers of epithelial cells, which results in the loss of structure and tissue function. Many laboratories are now investigating regulation of signaling function in normal mammary gland using 3D cultures. However, it is important also to assay malignant breast cells ex vivo in a physiologically relevant environment to more closely mimic tumor architecture, signal transduction regulation and tumor behavior in vivo. Here we present the potential of these 3D models for drug testing, target validation and guidance of patient selection for clinical trials. We argue also that in order to get full insight into the biology of the normal and malignant breast, and to create in vivo-like models for therapeutic approaches in humans, we need to continue to create more complex heterotypic models to approach the full context the cells encounter in the human body.

  9. Randomized Phase 2 Trial of S1 and Oxaliplatin-Based Chemoradiotherapy With or Without Induction Chemotherapy for Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Dok Hyun [Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jang, Geundoo [Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Department of Internal Medicine, Hallym Medical Center, Hallym University College of Medicine, Seoul (Korea, Republic of); Kim, Jong Hoon [Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Yong-Hee [Department of Thoracic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Ji Youn [Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Hyeong Ryul [Department of Thoracic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jung, Hwoon-Yong; Lee, Gin-Hyug [Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Song, Ho Young [Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Cho, Kyung-Ja [Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Ryu, Jin-Sook [Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Sung-Bae, E-mail: sbkim3@amc.seoul.kr [Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2015-03-01

    Purpose: To assess, in a randomized, phase 2 trial, the efficacy and safety of chemoradiotherapy with or without induction chemotherapy (ICT) of S1 and oxaliplatin for esophageal cancer. Patients and Methods: Patients with stage II, III, or IVA esophageal cancer were randomly allocated to either 2 cycles of ICT (oxaliplatin 130 mg/m{sup 2} on day 1 and S1 at 40 mg/m{sup 2} twice daily on days 1-14, every 3 weeks) followed by concurrent chemoradiotherapy (CCRT) (46 Gy, 2 Gy/d with oxaliplatin 130 mg/m{sup 2} on days 1 and 21 and S1 30 mg/m{sup 2} twice daily, 5 days per week during radiation therapy) and esophagectomy (arm A), or the same CCRT followed by esophagectomy without ICT (arm B). The primary endpoint was the pathologic complete response (pCR) rate. Results: A total of 97 patients were randomized (arm A/B, 47/50), 70 of whom underwent esophagectomy (arm A/B, 34/36). The intention-to-treat pCR rate was 23.4% (95% confidence interval [CI] 11.2-35.6%) in arm A and 38% (95% CI 24.5% to 51.5%) in arm B. With a median follow-up duration of 30.3 months, the 2-year progression-free survival rate was 58.4% in arm A and 58.6% in arm B, whereas the 2-year overall survival rate was 60.7% and 63.7%, respectively. Grade 3 or 4 thrombocytopenia during CCRT was more common in arm A than in arm B (35.4% vs 4.1%). The relative dose intensity of S1 (89.5% ± 20.6% vs 98.3% ± 5.2%, P=.005) and oxaliplatin (91.4% ± 16.8% vs 99.0% ± 4.2%, P=.007) during CCRT was lower in arm A compared with arm B. Three patients in arm A, compared with none in arm B, died within 90 days after surgery. Conclusions: Combination chemotherapy of S1 and oxaliplatin is an effective chemoradiotherapy regimen to treat esophageal cancer. However, we failed to show that the addition of ICT to the regimen can improve the pCR rate.

  10. Analysis of field-oriented controlled induction motor drives under sensor faults and an overview of sensorless schemes.

    Science.gov (United States)

    Arun Dominic, D; Chelliah, Thanga Raj

    2014-09-01

    To obtain high dynamic performance on induction motor drives (IMD), variable voltage and variable frequency operation has to be performed by measuring speed of rotation and stator currents through sensors and fed back them to the controllers. When the sensors are undergone a fault, the stability of control system, may be designed for an industrial process, is disturbed. This paper studies the negative effects on a 12.5 hp induction motor drives when the field oriented control system is subjected to sensor faults. To illustrate the importance of this study mine hoist load diagram is considered as shaft load of the tested machine. The methods to recover the system from sensor faults are discussed. In addition, the various speed sensorless schemes are reviewed comprehensively. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

  11. Myricetin and methyl eugenol combination enhances the anticancer activity, cell cycle arrest and apoptosis induction of cis-platin against HeLa cervical cancer cell lines.

    Science.gov (United States)

    Yi, Jin-Ling; Shi, Song; Shen, Yan-Li; Wang, Ling; Chen, Hai-Yan; Zhu, Jun; Ding, Yan

    2015-01-01

    Drug combination therapies are common practice in the treatment of cancer. In this study, we evaluated the anticancer effects of myricetin (MYR), methyl eugenol (MEG) and cisplatin (CP) both separately as well as in combination against cervical cancer (HeLa) cells. To demonstrate whether MYR and MEG enhance the anticancer activity of CP against cervical cancer cells, we treated HeLa cells with MYR and MEG alone or in combination with cisplatin and evaluated cell growth and apoptosis using MTT (3 (4, 5 dimethyl thiazol 2yl) 2, 5 diphenyltetrazolium bromide) assay, LDH release assay, flow cytometry and fluorescence microscopy. The results revealed that, as compared to single drug treatment, the combination of MYR or MEG with CP resulted in greater effect in inhibiting cancer cell growth and inducing apoptosis. Cell apoptosis induction, Caspase-3 activity, cell cycle arrest and mitochondrial membrane potential loss were systematically studied to reveal the mechanisms of synergy between MYR, MEG and CP. Combination of MYR or MEG with CP resulted in more potent apoptosis induction as revealed by fluorescence microscopy using Hoechst 33258 and AO-ETBR staining. The combination treatment also increased the number of cells in G0/G1 phase dramatically as compared to single drug treatment. Mitochondrial membrane potential loss (ΛΨm) as well as Caspase-3 activity was much higher in combination treatment as compared to single drug treatment. Findings of this investigation suggest that MYR and MEG combined with cisplatin is a potential clinical chemotherapeutic approach in human cervical cancer.

  12. The effect of solar ultraviolet radiation (UVR on induction of skin cancers

    Directory of Open Access Journals (Sweden)

    Marta Pacholczyk

    2016-04-01

    Full Text Available Ultraviolet radiation is a physical mutagenic and cancerogenic factor. About 95% of ultraviolet A (UVA (320–400 nm and 5% of UVB (280–320 nm reach the Earth’s surface. Melanin is a natural skin protective factor against UV radiation. Skin cancers associated with long-term exposure to UV radiation are: basal cell carcinoma (BCC, squamous cell carcinoma (SCC and cutaneous malignant melanoma (CMM. The high risk of BCC development is related to acute and repeated exposure to UV causing sunburn. Molecular studies of BBC demonstrated disorders in sonic hedgehog (SHH cell signaling regulation pathway, associated with the suppressor protein patched homolog 1 gene (PTCH1 mutations. The risk of the BCC development is related to the polymorphism of melanokortin-1 receptor gene (MC1R. Tumor P53 gene mutations observed in BCC cells has been classified as secondary genetic changes. In SCC cells UV-induced mutations were mostly related to P53 gene. Increased expression of cyclooxigenase- 2 gene (COX-2 plays a significant role in the development of SCC. Other pathogenetic factors include intensification of the synthesis of pro-inflammatory cytokines (tumor necrosis factor α (TNF-α, interleukin-1 α (IL-1α, IL-1β and IL-6. Currently, the role of UVB has been recognized in the pathogenesis of CMM. In CMM cells the following gene mutations were noted: cyclindependent kinase inhibitor 2A INK4A (p16INK4A, cyclin-dependent kinase 4 (CDK4, Ras, phosphatase and tensin homolog deleted on chromosome 10 (PTEN and proto-oncogene B-Raf (BRAF. The BRAF gene mutations were observed in ~50% of CMM cases. Mutations of P53 gene are not characteristic of CMM cells. Med Pr 2016;67(2:255–266

  13. Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and gemcitabine in pancreatic cancer.

    Science.gov (United States)

    Angelova, Assia L; Grekova, Svitlana P; Heller, Anette; Kuhlmann, Olga; Soyka, Esther; Giese, Thomas; Aprahamian, Marc; Bour, Gaétan; Rüffer, Sven; Cziepluch, Celina; Daeffler, Laurent; Rommelaere, Jean; Werner, Jens; Raykov, Zahari; Giese, Nathalia A

    2014-05-01

    Novel therapies employing oncolytic viruses have emerged as promising anticancer modalities. The cure of particularly aggressive malignancies requires induction of immunogenic cell death (ICD), coupling oncolysis with immune responses via calreticulin, ATP, and high-mobility group box protein B1 (HMGB1) release from dying tumor cells. The present study shows that in human pancreatic cancer cells (pancreatic ductal adenocarcinoma [PDAC] cells n=4), oncolytic parvovirus H-1 (H-1PV) activated multiple interconnected death pathways but failed to induce calreticulin exposure or ATP release. In contrast, H-1PV elevated extracellular HMGB1 levels by 4.0±0.5 times (58%±9% of total content; up to 100 ng/ml) in all infected cultures, whether nondying, necrotic, or apoptotic. An alternative secretory route allowed H-1PV to overcome the failure of gemcitabine to trigger HMGB1 release, without impeding cytotoxicity or other ICD activities of the standard PDAC medication. Such broad resistance of H-1PV-induced HMGB1 release to apoptotic blockage coincided with but was uncoupled from an autocrine interleukin-1β (IL-1β) loop. That and the pattern of viral determinants maintained in gemcitabine-treated cells suggested the activation of an inflammasome/caspase 1 (CASP1) platform alongside DNA detachment and/or nuclear exclusion of HMGB1 during early stages of the viral life cycle. We concluded that H-1PV infection of PDAC cells is signaled through secretion of the alarmin HMGB1 and, besides its own oncolytic effect, might convert drug-induced apoptosis into an ICD process. A transient arrest of cells in the cyclin A1-rich S phase would suffice to support compatibility of proliferation-dependent H-1PV with cytotoxic regimens. These properties warrant incorporation of the oncolytic virus H-1PV, which is not pathogenic in humans, into multimodal anticancer treatments. The current therapeutic concepts targeting aggressive malignancies require an induction of immunogenic cell death

  14. Comparative study of 1,2-dimethylhydrazine and azoxymethane on the induction of colorectal cancer in rats

    Directory of Open Access Journals (Sweden)

    Mario Jorge Jucá

    2014-07-01

    Full Text Available The induced colorectal carcinogenesis in rodents has a long history and currently uses the substances 1,2-dimethylhydrazine and azoxymethane. Objective: The aim of this study was to compare the inductive effect of the substances azoxymethane and 1,2-dimethylhydrazine in colorectal carcinogenesis. Method: 30 randomly chosen male Wistar rats were divided into four groups. G1 group was treated with 1,2-dimethylhydrazine and C1 was its control group; G2 group was treated azoxymethane and C2 was its control group. The animals were weekly weighed until euthanasia, when their intestines were removed, processed and analyzed by an experienced pathologist. Results: Among the control groups (C1 and C2 no histologic changes were observed; moderate dysplasia was detected in G2 group; hyperplasia, mild dysplasia, severe dysplasia and carcinoma were observed in G1 group. When this study compared the cost of the substances, 1,2-dimethylhydrazine was more than 50 times less expensive than azoxymethane. Conclusion: Azoxymethane is able to promote histological changes consistent with colorectal carcinogenesis. 1,2-Dimethylhydrazine produced neoplasia and dysplasia, and, compared to the azoxymethane, was more efficient in the induction of colorectal cancer. Resumo: A carcinogênese colorretal induzida em roedores tem longa história e utiliza, atualmente, as substâncias 1,2 dimetil-hidrazina (DMH e azoximetano (AOM. Objetivo: Comparar o efeito indutivo das substâncias AOM e DMH para o câncer colorretal (CCR. Método: 30 ratos Wistar machos foram randomizados em quatro grupos. O grupo G1 foi inoculado com DMH, o grupo C1 foi seu controle; G2 recebeu o AOM e C2 foi seu controle. Os animais foram pesados semanalmente até a eutanásia, quando tiveram seus intestinos retirados, processados e analisados por um patologista experiente. Resultados: Os animais dos grupos de controle apresentaram tecido colorretal normal e os animais do grupo G2 apresentaram um padrão de

  15. Prediction of distant metastasis in head neck cancer patients: implications for induction chemotherapy and pre-treatment staging?

    International Nuclear Information System (INIS)

    Studer, G.; Glanzmann, C.; Seifert, B.

    2008-01-01

    Background and purpose: intensity modulated radiation therapy (IMRT) combined treatment approaches, surgical and radiodiagnostic advances, respectively, lead to improved local-regional control in head neck cancer (HNC). With increasing local-regional control, distant metastases (DM) become more meaningful. In some trials without concomitant chemotherapy, induction chemotherapy (IC) resulted in an absolute reduction of DM by ∝10-15%. In order to define a more efficient selection of patients at risk for DM with respect to IC and M-staging, we analysed our patients treated by contemporary standards. Patients and methods: between 1/2002 to 12/2007, 409 HNC patients were treated with IMRT; 303/409 (74%) underwent definitive, 106 (26%) postoperative IMRT. The mean/median follow-up was 23/20 months (3-72). 70% tolerated 4-7, 9% 1-3 cycles of simultaneous cisplatin. Treatment followed a prospectively designed protocol. In a previous study with 172 HNC IMRT patients, gross tumor volume (GTV) was found the strongest predictor for local-regional control. In the current study, this criterion has been prospectively tested for DM. Numbers needed to treat were calculated for IC. Results: DM developed in 28/399 (7%) patients; 10 presented initially with DM (total 38/409). In 13/28 (46%), DM remained the only manifestation of disease. GTV was the strongest predictor for DM (p 70 cc; only 6 of them (6/73, 8%) developed isolated DM. Conclusion: GTV was the most significant predictor for DM, that could guide selective pre-treatment M-staging. The subgroup with isolated DM in the high risk group, that could benefit from IC, is small. (orig.)

  16. Evaluation of the cytotoxicity, cell-cycle arrest, and apoptotic induction by Euphorbia hirta in MCF-7 breast cancer cells.

    Science.gov (United States)

    Kwan, Yuet Ping; Saito, Tamio; Ibrahim, Darah; Al-Hassan, Faisal Muti Saleh; Ein Oon, Chern; Chen, Yeng; Jothy, Subramanion L; Kanwar, Jagat R; Sasidharan, Sreenivasan

    2016-07-01

    Euphorbia hirta L. (Euphorbiaceae) has been used as a folk remedy in Southeast Asia for the treatment of various ailments. The current study evaluates the cytotoxicity, cell-cycle arrest, and apoptotic induction by E. hirta in MCF-7 breast cancer cells. Cytotoxic activity of methanol extract of whole part of E. hirta was determined by the MTT assay at various concentrations ranging from 1.96 to 250.00 µg/mL in MCF-7 cells. Cell morphology was assessed by light and fluorescence microscopy. Apoptosis and cell-cycle distribution were determined by annexin V staining and flow cytometry. DNA fragmentation, caspase activity, and reactive oxygen species (ROS) assays were performed using the commercially available kits. To identify the cytotoxic fraction, E. hirta extract was subjected to bioassay-guided fractionation. Euphorbia hirta exhibited significant inhibition of the survival of MCF-7 cells and the half inhibitory concentration (IC50) values was 25.26 µg/mL at 24 h. Microscopic studies showed that E. hirta-treated cells exhibited marked morphological features characteristic of apoptosis. Euphorbia hirta extract also had an ignorable influence on the LDH leakage and generating intracellular ROS. The flow cytometry study confirmed that E. hirta extract induced apoptosis in MCF-7 cells. Euphorbia hirta also resulted in DNA fragmentation in MCF-7 cells. Moreover, E. hirta treatment resulted in the accumulation of cells at the S and G2/M phases as well as apoptosis. The caspase activity study revealed that E. hirta extract induced apoptosis through the caspase-3-independent pathway by the activation of caspase-2, 6, 8, and 9. Euphorbia hirta hexane fraction, namely HFsub4 fraction, demonstrated highest activity among all the fractions tested with an IC50 value of 10.01 µg/mL at 24 h. This study revealed that E. hirta induced apoptotic cell death and suggests that E. hirta could be used as an apoptosis-inducing anticancer agent for breast cancer treatment

  17. The interplay between GRP78 expression and Akt activation in human colon cancer cells under celecoxib treatment.

    Science.gov (United States)

    Tian, Shaobo; Chang, Weilong; Du, Hansong; Bai, Jie; Sun, Zhenhai; Zhang, Qing; Wang, Hui; Zhu, Guangsheng; Tao, Kaixiong; Long, Yueping

    2015-10-01

    It has been reported previously that celecoxib shows antitumor effects in many types of cancers. Here, we detected its effects on DLD-1 and SW480 (two human colon cancer cell lines) and investigated the dynamic relationship between the 78-kDa glucose-regulatory protein (GRP78) and the phosphoinositide 3-kinase (PI3K)/Akt pathway. Gene expression was detected by real-time PCR and western blot analysis; the cytotoxicity was determined by the MTT assay and flow cytometry. First, the results showed that celecoxib induced cytotoxicity in a dose-dependent and time-dependent manner. Furthermore, we found the celecoxib-triggered unfolded protein response and the bidirectional regulation of Akt activation in both cell lines. Inhibiting the Akt activation by the PI3K inhibitor LY294002 markedly enhanced GRP78 expression. Besides, silencing the GRP78 expression regulated Akt activation in a time-dependent manner and increased the induction of the C/EBP homologous protein (CHOP) as well as considerably promoted celecoxib-induced apoptosis. In conclusion, these findings provide evidence that under the celecoxib treatment, GRP78 plays a protective role by modulating Akt activation and abrogating CHOP expression. However, Akt activation can provide a feedback loop to inhibit GRP78 expression. These studies can lead to novel therapeutic strategies for human colon cancer.

  18. Randomized Study of Concurrent Carboplatin, Paclitaxel, and Radiotherapy with or Without Prior Induction Chemotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Gouda, Y.S.; Eldeeb, N.A.; Omar, A.M.; Kohail, H.M.; El-Geneidy, M.M.; Elkerm, Y.M.

    2006-01-01

    Background: Multiple concepts of combined modality therapy for locally advanced inoperable non-small cell lung cancer have been investigated. These include induction chemotherapy, concomitant chemo-radiotherapy, and radiation only. To date, combined modality therapy specially the use of concomitant chemo-radiotherapy has led to promising results and was shown to be superior to radiotherapy alone in phase II studies. However the optimum chemo-therapeutic regimen to be used as well as the benefit of induction chemotherapy before concomitant chemo-radiotherapy are yet to be determined. Based on these observations, we investigated the use of paclitaxel and carboplatin concomitantly with radiotherapy and the benefit of prior two cycles induction chemotherapy. Materials and Methods: In this trial 50 patients with locally advanced inoperable non small cell lung cancer, good performance status and minimal weight loss have been randomized into 3 groups each of 20 patients. Group A received induction 2 cycles paclitaxel (175 mg/m 2 ) and carboplatin (AUC 6) on day I and 28 th followed by concomitant paclitaxel (45 mg/m 2 ) and carboplatin (AUC 2) weekly with radiotherapy. Group B received concomitant carboplatin, paclitaxel (same doses as in group A) and radiotherapy with no prior induction chemotherapy. Group C received only radiotherapy to a total dose of 60 Gy in conventional fractionation. Results: A total of 60 patients were enrolled in this study between 1998 and 2000. Pretreatment characteristics, including age, gender, performance status, histological features and stage were comparable in each group. The incidence of oesophagi tis was significantly higher in group A and B than in group C (ρ=0.023). Hematological toxicities was also significantly higher in group A and B than in group C (ρ=0.003). The response rate was significantly higher in group A and B than in group C (75%,79%, and 40% respectively) (ρ =0.020). The time to in-field progresion was significantly

  19. Clinical T2N0 Esophageal Cancer: Identifying Pretreatment Characteristics Associated with Pathologic Upstaging and the Potential Role for Induction Therapy

    Science.gov (United States)

    Samson, Pamela; Puri, Varun; Robinson, Clifford; Lockhart, Craig; Carpenter, Danielle; Broderick, Stephen; Kreisel, Daniel; Krupnick, A. Sasha; Patterson, G. Alexander; Meyers, Bryan; Crabtree, Traves

    2016-01-01

    Background While studies have suggested standard therapy for clinical T2N0 esophageal cancer should be primary surgery, we hypothesize there is a subgroup for whom induction therapy may result in improved overall survival (OS). Methods cT2N0 esophageal cancer patients receiving induction therapy or upfront esophagectomy (UE) were identified in the National Cancer Data Base (NCDB). UE patients were dichotomized as 1) pathologically upstaged or 2) same-or down-staged. Logistic regression models identified variables associated with upstaging and Kaplan-Meier analysis compared median OS. Results From 2006–2012, 932 (52.2%) cT2N0 patients received UE, while 853 (47.8%) received induction therapy first. 326/713 (45.7%) UE patients were upstaged. 87/326 (26.7%) patients had T upstaging, 98/326 (30.1%) had N upstaging, and 141/326 (43.3%) had both. Patients upstaged after UE had a higher tumor grade (35.1% versus 57.1% Grade 3), and a higher rate of lymphovascular invasion (LVI, 57.1% versus 17.7%), both p<0.001. Variables associated with upstaging included LVI (OR 6.0, 95% CI 2.9 – 12.5, p<0.001) and tumor grade 3 (OR 9.4, 1.8 – 48.4, p=0.007). Of upstaged UE patients, only 144 (44.2%) received adjuvant therapy. The median OS for cT2N0 patients upstaged after UE was 27.5 ± 2.5 months versus 43.9 ± 2.9 months for induction therapy patients (any resultant pathologic stage, p<0.001). Conclusions Half of all cT2N0 patients were pathologically upstaged after UE with worse survival compared to patients receiving induction therapy. Refining an upstaging model would help select patients for induction therapy and increase the rate of chemotherapy in patients at risk for systemic disease. PMID:27083246

  20. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

    DEFF Research Database (Denmark)

    Lu, Yi; Cuellar-Partida, Gabriel; Painter, Jodie N

    2015-01-01

    Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address...... this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested...... that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We...

  1. Chemopreventive Activity of MGN-3/Biobran Against Chemical Induction of Glandular Stomach Carcinogenesis in Rats and Its Apoptotic Effect in Gastric Cancer Cells.

    Science.gov (United States)

    Badr El-Din, Nariman K; Abdel Fattah, Salma M; Pan, Deyu; Tolentino, Lucilene; Ghoneum, Mamdooh

    2016-12-01

    In the current study, we investigated the chemopreventive activity of arabinoxylan rice bran, MGN-3/Biobran, against chemical induction of glandular stomach carcinogenesis in rats. Gastric cancer was induced by carcinogen methylnitronitrosoguanidine (MNNG), and rats received MNNG alone or MNNG plus Biobran (40 mg/kg body weight) for a total of 8 months. Averaged results from 2 separate readings showed that exposure to MNNG plus Biobran caused gastric dysplasia and cancer (adenocarcinoma) in 4.5/12 rats (9/24 readings, 37.5%), with 3.5/12 rats (7/24 readings, 29.2%) showing dysplasia and 1/12 rats (8.3%) developing adenocarcinoma. In contrast, in rats treated with MNNG alone, 8/10 (80%) developed dysplasia and adenocarcinoma, with 6/10 rats (60%) showing dysplasia and 2/10 rats (20%) developing adenocarcinoma. The effect of combining both agents was also associated with significant suppression of the expression of the tumor marker Ki-67 and remarkable induction in the apoptotic gastric cancer cells via mitochondrial-dependent pathway as indicated by the upregulation in p53 expression, Bax expression, downregulation in Bcl-2 expression, an increase in Bax/Bcl-2 ratio, and an activation of caspase-3. In addition, Biobran treatment induced cell-cycle arrest in the subG1 phase, where the hypodiploid cell population was markedly increased. Moreover, Biobran treatment protected rats against MNNG-induced significant decrease in lymphocyte levels. We conclude that Biobran provides protection against chemical induction of glandular stomach carcinogenesis in rats and may be useful for the treatment of human patients with gastric cancer. © The Author(s) 2016.

  2. Poly(I:C) induces intense expression of c-IAP2 and cooperates with an IAP inhibitor in induction of apoptosis in cancer cells

    International Nuclear Information System (INIS)

    Friboulet, Luc; Gourzones, Claire; Tsao, Sai Wah; Morel, Yannis; Paturel, Carine; Témam, Stéphane; Uzan, Catherine; Busson, Pierre

    2010-01-01

    There is increasing evidence that the toll-like receptor 3 (TLR3) is an interesting target for anti-cancer therapy. Unfortunately, most laboratory investigations about the impact of TLR3 stimulation on human malignant cells have been performed with very high concentrations - 5 to 100 μg/ml - of the prototype TLR3 ligand, poly(I:C). In a previous study focused on a specific type of human carcinoma - nasopharyngeal carcinoma - we have shown that concentrations of poly(I:C) as low as 100 ng/ml are sufficient to induce apoptosis of malignant cells when combined to a pharmacological antagonist of the IAP family based on Smac mimicry. This observation prompted us to investigate the contribution of the IAP family in cell response to poly(I:C) in a variety of human malignant cell types. We report a rapid, intense and selective increase in c-IAP2 protein expression observed under stimulation by poly(I:C)(500 ng/ml) in all types of human malignant cells. In most cell types, this change in protein expression is underlain by an increase in c-IAP2 transcripts and dependent on the TLR3/TRIF pathway. When poly(I:C) is combined to the IAP inhibitor RMT 5265, a cooperative effect in apoptosis induction and/or inhibition of clonogenic growth is obtained in a large fraction of carcinoma and melanoma cell lines. Currently, IAP inhibitors like RMT 5265 and poly(I:C) are the subject of separate therapeutic trials. In light of our observations, combined use of both types of compounds should be considered for treatment of human malignancies including carcinomas and melanomas

  3. Poly(I:C induces intense expression of c-IAP2 and cooperates with an IAP inhibitor in induction of apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Uzan Catherine

    2010-06-01

    Full Text Available Abstract Background There is increasing evidence that the toll-like receptor 3 (TLR3 is an interesting target for anti-cancer therapy. Unfortunately, most laboratory investigations about the impact of TLR3 stimulation on human malignant cells have been performed with very high concentrations - 5 to 100 μg/ml - of the prototype TLR3 ligand, poly(I:C. In a previous study focused on a specific type of human carcinoma - nasopharyngeal carcinoma - we have shown that concentrations of poly(I:C as low as 100 ng/ml are sufficient to induce apoptosis of malignant cells when combined to a pharmacological antagonist of the IAP family based on Smac mimicry. Methods This observation prompted us to investigate the contribution of the IAP family in cell response to poly(I:C in a variety of human malignant cell types. Results We report a rapid, intense and selective increase in c-IAP2 protein expression observed under stimulation by poly(I:C(500 ng/ml in all types of human malignant cells. In most cell types, this change in protein expression is underlain by an increase in c-IAP2 transcripts and dependent on the TLR3/TRIF pathway. When poly(I:C is combined to the IAP inhibitor RMT 5265, a cooperative effect in apoptosis induction and/or inhibition of clonogenic growth is obtained in a large fraction of carcinoma and melanoma cell lines. Conclusions Currently, IAP inhibitors like RMT 5265 and poly(I:C are the subject of separate therapeutic trials. In light of our observations, combined use of both types of compounds should be considered for treatment of human malignancies including carcinomas and melanomas.

  4. Labor Induction

    Science.gov (United States)

    f AQ FREQUENTLY ASKED QUESTIONS FAQ154 LABOR, DELIVERY, AND POSTPARTUM CARE Labor Induction • What is labor induction? • Why is labor induced? • What is the Bishop score? • What is “ripening ...

  5. Bone marrow-derived mesenchymal stromal cells promote colorectal cancer cell death under low-dose irradiation.

    Science.gov (United States)

    Feng, Hao; Zhao, Jing-Kun; Schiergens, Tobias S; Wang, Pu-Xiongzhi; Ou, Bao-Chi; Al-Sayegh, Rami; Li, Ming-Lun; Lu, Ai-Guo; Yin, Shuai; Thasler, Wolfgang E

    2018-02-06

    Radiotherapy remains one of the cornerstones to improve the outcome of colorectal cancer (CRC) patients. Radiotherapy of the CRC not only help to destroy cancer cells but also remodel the tumour microenvironment by enhancing tumour-specific tropism of bone marrow-derived mesenchymal stromal cell (BM-MSC) from the peripheral circulation. However, the role of local MSCs and recruited BM-MSC under radiation were not well defined. Indeed, the functions of BM-MSC without irradiation intervention remained controversial in tumour progression: BM-MSC was previously shown to modulate the immune function of major immune cells, resulting in an impaired immunological sensitivity and to induce an increased risk of tumour recurrence. In contrast, it could also secrete various cytokines and possess anticancer effect. Three co-cultivation modules, 3D culture modules, and cancer organoids were established. The induction of cytokines secretion in hBM-MSCs after irradiation was analysed by ELISA array and flow cytometry. AutoMac separator was used to separate hBM-MSC and CRC automatically. Cells from the co-cultured group and the control group were then irradiated by UV-C lamp and X-ray. Proliferation assay and viability assay were performed. In this study, we show that BM-MSCs can induce the EMT progression of CRC cells in vitro. When irradiated with low doses of ultraviolet radiation and X-rays, BM-MSCs show an anti-tumour effect by secreting certain cytokine (TNF-α, IFN-γ) that lead to the inhibition of proliferation and induction of apoptosis of CRC cells. This was further verified in a 3D culture model of a CRC cell in vitro. Furthermore, irradiation on the co-culture system induced the cleavage of caspase3, and attenuated the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase in cancer cells. The signal pathways above might contribute to the cancer cell death. Taken together, we show that BM-MSC can potentially promote the

  6. Usefulness of ultrasonography for detection of breast cancer in patients under 30 years of age

    International Nuclear Information System (INIS)

    Kim, Ji Hyung; Oh, Ki Keun; Yoon, Sang Wook

    1995-01-01

    The purpose of this study was to compare mammography and breast sonography in detection of breast cancer and to suggest reasonable guideline of breast imaging in breast cancer patients under 30 years of age in whom breast cancer shows different clinicopathologic characteristics compared with breast cancer in older women. Authors reviewed medical records of 27 patients under 30 years of age with pathologically-proven breast cancer. Age, family history, physical examination findings, indications for breast sonography were reviewed. Cases in whom breast cancer lesion is detectable and cases in whom not detectable using mammography or breast sonography were reviewed. And then, authors evaluated the usefulness of each method and reasons for nonvisualization of lesion on mammography. Among 27 patients, 25 patients had palpable breast mass as indication of mammography and breast sonography. Cancer lesions were detectable in 16 of 25 patients (64%) on mammography and 24 of 25 patients (96%) on breast ultrasonography. Reasons for nonvisualization of cancer lesions on mammography were dense breast with nodular parenchyma pattern and minimal breast change of ductal carcinoma in situ. In breast cancer patients under 30 years of age who have palpable breast mass as a initial, and main clinical problem, breast ultrasonography is superior to mammography in detecting and diagnosing breast cancer. We suggest that guidelines can avoid unnecessary mammography in these patients

  7. BRAFV600E Efficient Transformation and Induction of Microsatellite Instability Versus KRASG12V Induction of Senescence Markers in Human Colon Cancer Cells

    Directory of Open Access Journals (Sweden)

    Eftychia Oikonomou

    2009-11-01

    Full Text Available In colorectal cancer, BRAF and KRAS oncogenes are mutated in about 15% and 35% respectively at approximately the same stage of the adenoma-carcinoma sequence. Since these two mutations rarely coexist, further analysis to dissect their function of transformation in colon cancer is required. Caco-2 human colon adenocarcinoma cells were stably transfected with BRAFV600E (Caco-BR cells or KRASG12V (Caco-K cells oncogenes. BRAFV600E is more efficient in transforming Caco-2 cells and altering their morphology. The dominant nature of BRAFV600E is evident by its ability to render Caco-2 cells tumorigenic in vivo all be it through selective extracellular signal-related kinase (ERK 2 phosphorylation and high levels of cyclin D1. As a consequence, the cell cycle distribution of parental cells is altered and microsatellite instability is introduced. Attenuated ERK activation observed correlated with KSR downregulation by BRAFV600E without further implications to signaling. Highly activated ERK in case of KRASG12V (Caco-K cells leads to mild transformation causing Caco-K cells to express premature senescence-related markers and acquire growth factor-dependent viability. Interestingly, BRAFWTgets equally activated by upstream KRAS mutations present in colon adenocarcinoma cells such as DLD-1 and SW620. Taken together, these results suggest that the two oncogenes have different transforming capability in colon cancer, although they both use the mitogen-activated protein (MAP kinase pathway to carry out their effect. In general, BRAFV600E presents greater potential in mediating tumorigenic effect as compared to KRASG12V both in vivo and in vitro. These findings may have implications in personalised diagnosis and targeted therapeutics.

  8. Sensorless Doubly-Fed Induction Generator Control Under Power System Transients and Faults: The Influence of Magnetic Saturation

    DEFF Research Database (Denmark)

    Serban, Ioan; Boldea, Ion; Blaabjerg, Frede

    2004-01-01

    -circuit at the middle of a typical local power grid is investigated. A computer program in Matlab-Simulink package for the whole system has been developed and applied to simulate transients as described above with and without considering the magnetic saturation in the machine. It is shown by digital simulations......The present paper investigates the influence of magnetic saturation on the rotor position and speed estimators and the machine behavior during transients and short-circuit faults for a doubly-fed induction generator (DFIG) connected to the power grid. The DFIG is considered driven by a wind turbine...... whose torque vs. generator speed at different wind speed is optimised. The DFIG is connected to the grid, at a certain initial speed, simultaneously in the stator and in the rotor for given values of active and reactive stator power references. Subsequently a sudden three-phase short...

  9. Induction cooking

    Energy Technology Data Exchange (ETDEWEB)

    Grosbety, Y. [Ugine Aciers, 73 (France)

    1994-10-01

    The principles of heating by electromagnetic induction, the large families of induction hobs and key figures of the rapidity developing market. Performances and interests of induction (energy savings, rapidity and precision of heating, safety). Steels used: ferritic stainless steels alone or three-layer materials. (author). 4 refs., 8 figs., 2 tabs.

  10. The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation.

    Science.gov (United States)

    Mendes, Fernando; Domingues, Cátia; Rodrigues-Santos, Paulo; Abrantes, Ana Margarida; Gonçalves, Ana Cristina; Estrela, Jéssica; Encarnação, João; Pires, Ana Salomé; Laranjo, Mafalda; Alves, Vera; Teixo, Ricardo; Sarmento, Ana Bela; Botelho, Maria Filomena; Rosa, Manuel Santos

    2016-04-01

    Immune surveillance seems to represent an effective tumor suppressor mechanism. However, some cancer cells survive and become variants, being poorly immunogenic and able to enter a steady-state phase. These cells become functionally dormant or remain hidden clinically throughout. Neoplastic cells seem to be able to instruct immune cells to undergo changes promoting malignancy. Radiotherapy may act as a trigger of the immune response. After radiotherapy a sequence of reactions occurs, starting in the damage of oncogenic cells by multiple mechanisms, leading to the immune system positive feedback against the tumor. The link between radiotherapy and the immune system is evident. T cells, macrophages, Natural Killer cells and other immune cells seem to have a key role in controlling the tumor. T cells may be dysfunctional and remain in a state of T cell exhaustion, nonetheless, they often retain a high potential for successful defense against cancer, being able to be mobilized to become highly functional. The lack of clinical trials on a large scale makes data a little robust, in spite of promising information, there are still many variables in the studies relating to radiation and immune system. The clarification of the mechanisms underlying immune response to radiation exposure may contribute to treatment improvement, gain of life quality and span of patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Quality of life of elderly cancer patients under radiotherapy

    International Nuclear Information System (INIS)

    Peres de Oliveira, Patricia; Corte Pereira, Beltrina da Purificacao

    2004-01-01

    This research analyzed the effects of radiotherapy in the quality of life of elderly patients suffering from prostatic cancer. Our aim was to verify the psychometric properties of the Quality of Life Index (QLI), by Ferrans and Powers, describing the social-demographic characteristics that affect the quality of life; and patients concept of quality of life and their perception of how radiotherapy interferes with the quality of life. Interviews were carried out with a sample of seven elderly patients suffering from prostatic cancer. Two different approaches were utilized: descriptive and qualitative statistics. The results show that the QLI may have useful application in our field in the identification of those aspects of quality of life affected by cancer. (author)

  12. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Zhiwen Xiao

    2014-01-01

    Full Text Available As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer.

  13. Survival of Mexican Children with Acute Lymphoblastic Leukaemia under Treatment with the Protocol from the Dana-Farber Cancer Institute 00-01

    Science.gov (United States)

    Jiménez-Hernández, Elva; Jaimes-Reyes, Ethel Zulie; Arellano-Galindo, José; García-Jiménez, Xochiketzalli; Tiznado-García, Héctor Manuel; Sánchez-Jara, Berenice; Bekker-Méndez, Vilma Carolina; Ortíz-Torres, María Guadalupe; Ortíz-Fernández, Antonio; Marín-Palomares, Teresa; Mejía-Aranguré, Juan Manuel

    2015-01-01

    Our aim in this paper is to describe the results of treatment of acute lymphoblastic leukaemia (ALL) in Mexican children treated from 2006 to 2010 under the protocol from the Dana-Farber Cancer Institute (DFCI) 00-01. The children were younger than 16 years of age and had a diagnosis of ALL de novo. The patients were classified as standard risk if they were 1–9.9 years old and had a leucocyte count 100 × 109/L. The poor outcomes were associated with toxic death during induction, complete remission, and relapse. These factors remain the main obstacles to the success of this treatment in our population. PMID:25922837

  14. Radiosensitivity and gene expression of human lung cancer cells dividing in nude tumor before (anoxic) and after vascular induction

    International Nuclear Information System (INIS)

    Miyamoto, Tadaaki; Ishii, Sachiko; Koto, Masashi; Imai, Reiko; Saegusa, Kimiko; Michikawa, Yuichi; Imai, Takashi

    2003-01-01

    We cloned H2 cell line from IA cell line (human large cell lung cancer) in anoxic cell culture. AH2 nude tumor develops a poor vascular system with rich fibrous component and shows low radiosensitivity compared with IA tumor. In relation to radiosensitivity, we studied the gene expression of the both cell lines grown in culture under an oxic or anoxic condition, and in a nude tumor with a microarray method using 22K custom oligoallele. As a result, we found that the both cells depressed CXCL1 and CXCL gene in anoxic culture condition and depressed or expressed IF127, EBI3, and cytokine like protein C17 gene in a nude tumor. (author)

  15. Radiosensitivity and gene expression of human lung cancer cells dividing in nude tumor before (anoxic) and after vascular induction

    International Nuclear Information System (INIS)

    Miyamoto, Tadaaki; Ishii, Sachiko; Baba, Masayuki; Sugawara, Toshiyuki; Furuno, Aki; Saegusa, Kimiko; Michikawa, Y.; Imai, Takashi

    2004-01-01

    We cloned H2 cell line from IA cell line (human large cell lung cancer) in anoxic cell culture. AH2 nude tumor develops a poor vascular system with rich fibrous component and shows low radiosensitivity compared with IA tumor. In relation to radiosensitivity, we studied the gene expression of the both cell lines grown in culture under an oxic or anoxic condition, and in a nude tumor with a microarray method using 22K custom oligoallele. As a result, we found that the both cells depressed CXCL1 and CXCL gene in anoxic culture condition and depressed or expressed IFI27, EBI3, and cytokine like protein C17 gene in a nude tumor. (author)

  16. The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5.

    Science.gov (United States)

    Hilton, H N; Kalyuga, M; Cowley, M J; Alles, M C; Lee, H J; Caldon, C E; Blazek, K; Kaplan, W; Musgrove, E A; Daly, R J; Naylor, M J; Graham, J D; Clarke, C L; Ormandy, C J

    2010-07-01

    Prolactin and progesterone act together to regulate mammary alveolar development, and both hormones have been implicated in breast cancer initiation and progression. Here we show that Elf5, a prolactin-induced ETS transcription factor that specifies the mammary secretory cell lineage, is also induced by progestins in breast cancer cells via a direct mechanism. To define the transcriptional response to progestin elicited via Elf5, we made an inducible Elf5 short hairpin-RNA knock-down model in T47D breast cancer cells and used it to prevent the progestin-induction of Elf5. Functional analysis of Affymetrix gene expression data using Gene Ontologies and Gene Set Enrichment Analysis showed enhancement of the progestin effects on cell cycle gene expression. Cell proliferation assays showed a more efficacious progestin-induced growth arrest when Elf5 was kept at baseline levels. These results showed that progestin induction of Elf5 expression tempered the antiproliferative effects of progestins in T47D cells, providing a further mechanistic link between prolactin and progestin in the regulation of mammary cell phenotype.

  17. Estrogen induction of telomerase activity through regulation of the mitogen-activated protein kinase (MAPK dependent pathway in human endometrial cancer cells.

    Directory of Open Access Journals (Sweden)

    Chunxiao Zhou

    Full Text Available Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2 induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs, and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.

  18. Dermatomyositis presenting as a paraneoplastic syndrome due to underlying breast cancer.

    Science.gov (United States)

    Sandhu, Nicole P; Zakaria, Shaheen; Degnim, Amy C; Boughey, Judy C

    2011-02-02

    Breast cancer most often presents as a palpable mass or with an abnormal mammogram. Much less commonly, breast cancer may present as a paraneoplastic syndrome. Dermatomyositis (DM) is a rare disease most often considered a complement-mediated idiopathic inflammatory myopathy manifested by classic skin findings and proximal muscle weakness. However, DM may also be due to a paraneoplastic syndrome associated with an underlying malignancy. The authors present a case report of a woman with presumed contact dermatitis who was diagnosed with breast cancer in the setting of progressive fatigue and muscle weakness. DM was subsequently diagnosed. Treatment of DM simultaneous with treatment of the breast cancer led to regression of DM. The diagnosis of DM in an adult should raise suspicion of an underlying malignancy. Breast cancer is a common disease that may rarely present with uncommon features that may divert attention from the underlying malignancy.

  19. Induction linacs

    International Nuclear Information System (INIS)

    Keefe, D.

    1986-07-01

    The principle of linear induction acceleration is described, and examples are given of practical configurations for induction linacs. These examples include the Advanced Technology Accelerator, Long Pulse Induction Linac, Radial Line Accelerator (RADLAC), and Magnetically-Insulated Electron-Focussed Ion Linac. A related concept, the auto accelerator, is described in which the high-current electron-beam technology in the sub-10 MeV region is exploited to produce electron beams at energies perhaps as high as the 100 to 1000 MeV range. Induction linacs for ions are also discussed. The efficiency of induction linear acceleration is analyzed

  20. Comparison of growth inhibition profiles and mechanisms of apoptosis induction in human colon cancer cell lines by isothiocyanates and indoles from Brassicaceae

    Energy Technology Data Exchange (ETDEWEB)

    Pappa, Gerlinde [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg (Germany); Lichtenberg, Maike [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg (Germany); Iori, Renato [Consiglio per la Ricerca e la Sperimentazione in Agricoltura, Istituto Sperimentale Colture Industriali, 40129 Bologna (Italy); Barillari, Jessica [Consiglio per la Ricerca e la Sperimentazione in Agricoltura, Istituto Sperimentale Colture Industriali, 40129 Bologna (Italy); Bartsch, Helmut [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg (Germany); Gerhaeuser, Clarissa [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), 69120 Heidelberg (Germany)]. E-mail: c.gerhauser@dkfz.de

    2006-07-25

    The isothiocyanates sulforaphane and PEITC ({beta}-phenethyl isothiocyanate) as well as the indoles indole-3-carbinol and its condensation product 3,3'-diindolylmethane are known to inhibit cancer cell proliferation and induce apoptosis. In this study, we compared the cell growth inhibitory potential of the four compounds on the p53 wild type human colon cancer cell line 40-16 (p53{sup +/+}) and its p53 knockout derivative 379.2 (p53{sup -/-}) (both derived from HCT116). Using sulforhodamin B staining to assess cell proliferation, we found that the isothiocyanates were strongly cytotoxic, whereas the indoles inhibited cell growth in a cytostatic manner. Half-maximal inhibitory concentrations of all four compounds in both cell lines ranged from 5-15 {mu}M after 24, 48 and 72 h of treatment. Apoptosis induction was analyzed by immunoblotting of poly(ADP-ribose)polymerase (PARP). Treatment with sulforaphane (15 {mu}M), PEITC (10 {mu}M), indole-3-carbinol (10 {mu}M) and 3,3'-diindolylmethane (10 {mu}M) induced PARP cleavage after 24 and 48 h in both 40-16 and the 379.2 cell lines, suggestive of a p53-independent mechanism of apoptosis induction. In cultured 40-16 cells, activation of caspase-9 and -7 detected by Western blotting indicated involvement of the mitochondrial pathway. We detected time- and concentration-dependent changes in protein expression of anti-apoptotic Bcl-x{sub L} as well as pro-apoptotic Bax and Bak proteins. Of note is that for sulforaphane only, ratios of pro- to anti-apoptotic Bcl-2 family protein levels directly correlated with apoptosis induction measured by PARP cleavage. Taken together, we demonstrated that the glucosinolate breakdown products investigated in this study have distinct profiles of cell growth inhibition, potential to induce p53-independent apoptosis and to modulate Bcl-2 family protein expression in human colon cancer cell lines.

  1. Mechanisms underlying social inequality in post-menopausal breast cancer.

    Science.gov (United States)

    Hvidtfeldt, Ulla Arthur

    2014-10-01

    This thesis is based on studies conducted in the period 2010-2014 at Department of Public Health, University of Copenhagen and at Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York. The results are presented in three scientific papers and a synopsis. The main objective of the thesis was to determine mechanisms underlying social inequality (defined by educational level) in postmenopausal breast cancer (BC) by addressing mediating effects through hormone therapy (HT) use, BMI, lifestyle and reproductive factors. The results of previous studies suggest that the higher risk of postmenopausal BC among women of high socioeconomic position (SEP) may be explained by reproductive factors and health behaviors. Women of higher SEP generally have fewer children and give birth at older ages than women of low SEP, and these factors have been found to affect the risk of BC - probably through altered hormone levels. Adverse effects on BC risk have also been documented for modifiable health behaviors that may affect hormone levels, such as alcohol consumption, high BMI, physical inactivity, and HT use. Alcohol consumption and HT use are likewise more common among women of higher SEP. The analyses were based on the Social Inequality in Cancer (SIC) cohort and a subsample of the Women's Health Initiative Observational Study (WHI-OS). The SIC cohort was derived by pooling 6 individual studies from the Copenhagen area including 33,562 women (1,733 BC cases) aged 50-70 years at baseline. The subsample of WHI-OS consisted of two case-cohort studies with measurements of endogenous estradiol (N = 1,601) and insulin (N = 791). Assessment of mediation often relies on comparing multiplicative models with and without the potential mediator. Such approaches provide potentially biased results, because they do not account for mediator-outcome confounding, exposure-dependent mediator-outcome confounding, exposure-mediator interaction and interactions

  2. Frequency-tuning radiofrequency plasma source operated in inductively-coupled mode under a low magnetic field

    Science.gov (United States)

    Takahashi, Kazunori; Nakano, Yudai; Ando, Akira

    2017-07-01

    A radiofrequency (rf) inductively-coupled plasma source is operated with a frequency-tuning impedance matching system, where the rf frequency is variable in the range of 20-50 MHz and the maximum power is 100 W. The source consists of a 45 mm-diameter pyrex glass tube wound by an rf antenna and a solenoid providing a magnetic field strength in the range of 0-200 Gauss. A reflected rf power for no plasma case is minimized at the frequency of ˜25 MHz, whereas the frequency giving the minimum reflection with the high density plasma is about 28 MHz, where the density jump is observed when minimizing the reflection. A high density argon plasma above 1× {{10}12} cm-3 is successfully obtained in the source for the rf power of 50-100 W, where it is observed that an external magnetic field of a few tens of Gauss yields the highest plasma density in the present configuration. The frequency-tuning plasma source is applied to a compact and high-speed silicon etcher in an Ar-SF6 plasma; then the etching rate of 8~μ m min-1 is obtained for no bias voltage to the silicon wafer, i.e. for the case that a physical ion etching process is eliminated.

  3. Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6.

    Science.gov (United States)

    Chiu, Hui-Wen; Lin, Shu-Wen; Lin, Li-Ching; Hsu, Yung-Ho; Lin, Yuh-Feng; Ho, Sheng-Yow; Wu, Yuan-Hua; Wang, Ying-Jan

    2015-09-01

    Ninety percent of human pancreatic cancer is characterized by activating K-RAS mutations. TRAF6 is an oncogene that plays a vital role in K-RAS-mediated oncogenesis. We investigated the synergistic effect of combining ionizing radiation (IR) and proteasome inhibitor (MG132). Furthermore, following combined treatment with IR and MG132, we analyzed the expression of TRAF6 and the mechanism of human pancreatic cancer cell death in vitro and in an orthotopic pancreatic cancer mouse model. The combined treatment groups displayed synergistic cell killing effects and induced endoplasmic reticulum stress in human pancreatic cancer cells. The combined treatment groups were characterized by enhanced cytotoxicity, which resulted from increased autophagy induction through the inhibition of TRAF6. Significantly reduced cytotoxicity was observed following MG132 and IR treatment of MIA PaCa-2 cells pre-treated with 3-MA (an autophagy inhibitor). Down-regulation of TRAF6 led to a significant increase in apoptosis and autophagy. In an orthotopic xenograft model of SCID mice, combination MG132 and IR therapy resulted in a significant increase in the tumor growth delay time and a decreased tumor tissue expression of TRAF6. IR combined with a proteasome inhibitor or TRAF6 inhibition could represent a new therapeutic strategy for human pancreatic cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Apoptotic induction activity of Dactyloctenium aegyptium (L. P.B. and Eleusine indica (L. Gaerth. extracts on human lung and cervical cancer cell lines

    Directory of Open Access Journals (Sweden)

    Pintusorn Hansakul

    2009-08-01

    Full Text Available Dactyloctenium aegyptium (L. P.B. (Yaa paak khwaai and Eleusine indica (L. Gaerth. (Yaa teen-ka have long been used in traditional Thai medicine because of their diuretic, anti-inflamatory, and antipyretic effects. The present study examined the antiproliferative and cytotoxic effects of the hexane and butanolic extracts of these two grass species. All the grass extracts exhibited selective growth inhibition effect on human lung cancer (A549 and cervical cancer (HeLa cells relative to normal human lung MRC-5 fibroblasts with IC50 values in a range of 202 to 845 mg/ml. Apparently, HeLa cellswere more sensitive to the extracts than A549 cells. Moreover, all the extracts induced lethality in both cancer cell lines atconcentrations close to 1,000 mg/ml, indicating their selective cytotoxicity effects. ELISA assay showed that only the hexaneextract of D. aegyptium (L. P.B. and E. indica (L. Gaerth. significantly increased the apoptotic level in extract-treatedA549 cells. However, DNA ladder assay detected classic DNA ladder patterns, a characteristic feature of apoptosis, in both cancer cell lines treated with all the extracts in a dose- and time-dependent manner. Taken together, these results indicatethat the cytotoxic activity of the grass extracts against lung and cervical cancer cells is mediated through the induction ofapoptosis.

  5. Taxane-containing induction chemotherapy followed by definitive chemoradiotherapy. Outcome in patients with locally advanced head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Broemme, J.O.; Schmuecking, M.; Leiser, D.; Geretschlaeger, A.; Ghadjar, P.; Aebersold, D.M. [Bern Univ. Hospital and Bern Univ. (Switzerland). Dept. of Radiation Oncology; Arnold, A.; Giger, R. [Bern Univ. (Switzerland). Head and Neck Surgery; Rauch, D. [Bern Univ. (Switzerland). Medical Oncology; Plasswilm, L. [Kantonsspital, St. Gallen (Switzerland). Radiation Oncology

    2013-08-15

    Background: Induction chemotherapy followed by definitive chemoradiotherapy is an intensified treatment approach for locally advanced squamous cell carcinoma of the head and neck (HNSCC) that might be associated with high rates of toxicity. Materials and methods: The data of 40 consecutive patients who underwent induction chemotherapy with docetaxel-containing regimens followed by intensity-modulated radiotherapy (IMRT) and concomitant systemic therapy for unresectable locally advanced HNSCC were retrospectively analyzed. Primary objectives were RT-related acute and late toxicity. Secondary objectives were response to induction chemotherapy, locoregional recurrence-free survival (LRRFS), overall survival (OS), and influencing factors for LRRFS and OS. Results: The median follow-up for surviving patients was 21 months (range, 2-53 months). Patients received a median of three cycles of induction chemotherapy followed by IMRT to 72 Gy. Three patients died during induction chemotherapy and one during chemoradiotherapy. Acute RT-related toxicity was of grade 3 and 4 in 72 and 3 % of patients, respectively, mainly dysphagia and dermatitis. Late RT-related toxicity was mainly xerostomia and bone/cartilage necrosis and was of grade 3 and 4 in 15 % of patients. One- and 2-year LRRFS and OS were 72 and 49 % and 77 and 71 %, respectively. Conclusion: Induction chemotherapy followed by chemoradiotherapy using IMRT was associated with a high rate of severe acute and late RT-related toxicities in this selected patient cohort. Four patients were lost because of fatal complications. Induction chemotherapy did not compromise the delivery of full-dose RT; however, the use of three cycles of concomitant cisplatin was impaired. (orig.)

  6. Inductive reasoning.

    Science.gov (United States)

    Hayes, Brett K; Heit, Evan; Swendsen, Haruka

    2010-03-01

    Inductive reasoning entails using existing knowledge or observations to make predictions about novel cases. We review recent findings in research on category-based induction as well as theoretical models of these results, including similarity-based models, connectionist networks, an account based on relevance theory, Bayesian models, and other mathematical models. A number of touchstone empirical phenomena that involve taxonomic similarity are described. We also examine phenomena involving more complex background knowledge about premises and conclusions of inductive arguments and the properties referenced. Earlier models are shown to give a good account of similarity-based phenomena but not knowledge-based phenomena. Recent models that aim to account for both similarity-based and knowledge-based phenomena are reviewed and evaluated. Among the most important new directions in induction research are a focus on induction with uncertain premise categories, the modeling of the relationship between inductive and deductive reasoning, and examination of the neural substrates of induction. A common theme in both the well-established and emerging lines of induction research is the need to develop well-articulated and empirically testable formal models of induction. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website. Copyright © 2010 John Wiley & Sons, Ltd.

  7. Trichostatin A enhances estrogen receptor-alpha repression in MCF-7 breast cancer cells under hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Hyunggyun; Park, Joonwoo; Shim, Myeongguk; Lee, YoungJoo, E-mail: yjlee@sejong.ac.kr

    2016-02-12

    Estrogen receptor (ER) is a crucial determinant of resistance to endocrine therapy, which may change during the progression of breast cancer. We previously showed that hypoxia induces ESR1 gene repression and ERα protein degradation via proteasome-mediated pathway in breast cancer cells. HDAC plays important roles in the regulation of histone and non-histone protein post-translational modification. HDAC inhibitors can induce epigenetic changes and have therapeutic potential for targeting various cancers. Trichostatin A exerts potent antitumor activities against breast cancer cells in vitro and in vivo. In this report, we show that TSA augments ESR1 gene repression at the transcriptional level and downregulates ERα protein expression under hypoxic conditions through a proteasome-mediated pathway. TSA-induced estrogen response element-driven reporter activity in the absence of estrogen was synergistically enhanced under hypoxia; however, TSA inhibited cell proliferation under both normoxia and hypoxia. Our data show that the hypoxia-induced repression of ESR1 and degradation of ERα are enhanced by concomitant treatment with TSA. These findings expand our understanding of hormone responsiveness in the tumor microenvironment; however, additional in-depth studies are required to elucidate the detailed mechanisms of TSA-induced ERα regulation under hypoxia. - Highlights: • TSA augments ESR1 gene repression at the transcriptional level under hypoxia. • TSA downregulates ERα protein expression under hypoxia. • TSA-induced ERα regulation under hypoxia is essential for understanding the behavior and progression of breast cancer.

  8. [The systems of molecular genetic markers under cancer of stomach].

    Science.gov (United States)

    Nemtsova, M V; Bykov, I I; Tchekinova, N V; Zaletaev, D V; Glikhov, A I; Khorobrykh, T V

    2013-11-01

    The study was organized to investigate the anomalous methylation of genes NA?1, RASSF1A, MLH1, N33, DAPK, the expression of genes hTERT. metalloproteinase MMP7, MMP9, survivin. COX-2, p53. The activity of telomerase in 106 samples of stomach tumors taken through intra-operation way and 53 samples of stomach tumors taken through endoscopic way and 50 samples of biopsy taken from patients with chronic calculous cholecystitis (comparison group) was analyzed too. These changes can be used as additional markers both in diagnostic of cancer of stomach and dynamic monitoring of operated patients.

  9. A rare DNA contact mutation in cancer confers p53 gain-of-function and tumor cell survival via TNFAIP8 induction.

    Science.gov (United States)

    Monteith, Jessica A; Mellert, Hestia; Sammons, Morgan A; Kuswanto, Laudita A; Sykes, Stephen M; Resnick-Silverman, Lois; Manfredi, James J; Berger, Shelley L; McMahon, Steven B

    2016-10-01

    The p53 tumor suppressor gene encodes a sequence-specific transcription factor. Mutations in the coding sequence of p53 occur frequently in human cancer and often result in single amino acid substitutions (missense mutations) in the DNA binding domain (DBD), blocking normal tumor suppressive functions. In addition to the loss of canonical functions, some missense mutations in p53 confer gain-of-function (GOF) activities to tumor cells. While many missense mutations in p53 cluster at six "hotspot" amino acids, the majority of mutations in human cancer occur elsewhere in the DBD and at a much lower frequency. We report here that mutations at K120, a non-hotspot DNA contact residue, confer p53 with the previously unrecognized ability to bind and activate the transcription of the pro-survival TNFAIP8 gene. Mutant K120 p53 binds the TNFAIP8 locus at a cryptic p53 response element that is not occupied by wild-type p53. Furthermore, induction of TNFAIP8 is critical for the evasion of apoptosis by tumor cells expressing the K120R variant of p53. These findings identify induction of pro-survival targets as a mechanism of gain-of-function activity for mutant p53 and will likely broaden our understanding of this phenomenon beyond the limited number of GOF activities currently reported for hotspot mutants. Published by Elsevier B.V.

  10. Green tea polyphenols induce cell death in breast cancer MCF-7 cells through induction of cell cycle arrest and mitochondrial-mediated apoptosis.

    Science.gov (United States)

    Liu, Shu-Min; Ou, Shi-Yi; Huang, Hui-Hua

    In order to study the molecular mechanisms of green tea polyphenols (GTPs) in treatment or prevention of breast cancer, the cytotoxic effects of GTPs on five human cell lines (MCF-7, A549, Hela, PC3, and HepG2 cells) were determined and the antitumor mechanisms of GTPs in MCF-7 cells were analyzed. The results showed that GTPs exhibited a broad spectrum of inhibition against the detected cancer cell lines, particularly the MCF-7 cells. Studies on the mechanisms revealed that the main modes of cell death induced by GTPs were cell cycle arrest and mitochondrial-mediated apoptosis. Flow cytometric analysis showed that GTPs mediated cell cycle arrest at both G1/M and G2/M transitions. GTP dose dependently led to apoptosis of MCF-7 cells via the mitochondrial pathways, as evidenced by induction of chromatin condensation, reduction of mitochondrial membrane potential (ΔΨ m ), improvement in the generation of reactive oxygen species (ROS), induction of DNA fragmentation, and activations of caspase-3 and caspase-9 in the present paper.

  11. Superiority of cisplatin or carboplatin in combination with teniposide and vincristine in the induction chemotherapy of small-cell lung cancer. A randomized trial with 5 years follow up

    DEFF Research Database (Denmark)

    Lassen, U; Kristjansen, P E; Osterlind, K

    1996-01-01

    PURPOSE: The introduction of platinum compounds and epipodophyllotoxins in combination with vincristine as induction chemotherapy in small-cell lung cancer (SCLC) was investigated in order to: (1) compare the efficacy of cisplatin with that of carboplatin in combination with teniposide and vincri....... CONCLUSION: Cisplatin and carboplatin produced similar response and survival rates and similar toxicity. Induction with platinum and epipodophyllotoxins did not improve objective response rates, but significantly improved survival without increasing the toxicity....

  12. Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma) Independent Novel Function of IFNgammaR2 as a Bax Inhibitor

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-12-1-0331 TITLE: Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand...DATE October 2016 2. REPORT TYPE Final report 3. DATES COVERED 1 Aug 2012 - 31 Jul 2016 4. TITLE AND SUBTITLE Apoptosis Induction by Targeting...IFNγR2 has previously unknown function as an inhibitor of Bax. Bax is a key mediator of apoptosis . We found that IFNγR2 is overexpressed in prostate

  13. Feasibility Study of Moderately Accelerated Intensity-Modulated Radiotherapy Plus Concurrent Weekly Cisplatin After Induction Chemotherapy in Locally Advanced Head-and Neck Cancer

    International Nuclear Information System (INIS)

    Morganti, Alessio G.; Mignogna, Samantha; Deodato, Francesco; Massaccesi, Mariangela; Cilla, Savino; Calista, Franco; Serafini, Giovanni; Digesu, Cinzia; Macchia, Gabriella; Picardi, Vincenzo; Caravatta, Luciana; Di Lullo, Liberato; Giglio, Gianfranco; Sallustio, Giuseppina; Piermattei, Angelo

    2011-01-01

    Purpose: To evaluate the feasibility and efficacy of moderately accelerated intensity-modulated radiation therapy (IMRT) along with weekly cisplatin, after induction chemotherapy, in patients with locally advanced unresectable head and neck cancer (HNC). Methods and Materials: Patients with Stage III or IV locally advanced HNC, without progressive disease after three courses of induction chemotherapy, received concurrent chemo-IMRT (weekly cisplatin 30 mg/m 2 plus simultaneous integrated boost IMRT). A total of 67.5 Gy in 30 fractions were delivered to primary tumor and involved nodes, 60 Gy in 30 fractions to high-risk nodal areas, and 55.5 Gy in 30 fractions to low-risk nodal areas. Results: In all, 36 patients (median age, 56 years) with International Union Against Cancer (UICC) Stage III (n = 5) and IV (n = 31) were included. Of the 36 patients, 17 had received CF (cisplatin and 5-fluorouracil (CF) and 19 had received docetaxel cisplatin and 5-fluorouracil (DCF). During concurrent chemoradiation, 11 of 36 patients (30.5%) experienced Grade III mucositis (CF, 47%; DCF, 15%; p < 0.04). Grade III pharyngeal-esophageal toxicity was observed in 5 of 19 patients (26.3%; CF, 0.0%; DCF, 26.3%; p = 0.02). Two patients died of complications (5.5%). After chemoradiation, the complete response rate was 63.8%. Two-year local control was 88.7%. Two-year progression free survival and overall survival were 74.5% and 60.9%, respectively. Conclusions: In our experience, a moderately accelerated chemo-IMRT was feasible after induction chemotherapy. However, a noteworthy early death rate of 5.5% was observed. Intensive supportive care strategies should be defined to better manage radiation-induced toxic effects. Longer follow-up is required to determine the incidence of late radiation toxicities and tumor control rates.

  14. Loss of PINK1 attenuates HIF-1α induction by preventing 4E-BP1-dependent switch in protein translation under hypoxia.

    Science.gov (United States)

    Lin, William; Wadlington, Natasha L; Chen, Linan; Zhuang, Xiaoxi; Brorson, James R; Kang, Un Jung

    2014-02-19

    Parkinson's disease (PD) has multiple proposed etiologies with implication of abnormalities in cellular homeostasis ranging from proteostasis to mitochondrial dynamics to energy metabolism. PINK1 mutations are associated with familial PD and here we discover a novel PINK1 mechanism in cellular stress response. Using hypoxia as a physiological trigger of oxidative stress and disruption in energy metabolism, we demonstrate that PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1α protein, HIF-1α transcriptional activity, and hypoxia-responsive gene upregulation. Loss of PINK1 impairs both hypoxia-induced 4E-BP1 dephosphorylation and increase in the ratio of internal ribosomal entry site (IRES)-dependent to cap-dependent translation. These data suggest that PINK1 mediates adaptive responses by activating IRES-dependent translation, and the impairments in translation and the HIF-1α pathway may contribute to PINK1-associated PD pathogenesis that manifests under cellular stress.

  15. Compensation of negative sequence stator flux of doubly-fed induction generator using polar voltage control-based direct torque control under unbalanced grid voltage condition

    Directory of Open Access Journals (Sweden)

    Badrinarayan Bansilal Pimple

    2015-02-01

    Full Text Available This study proposes a polar voltage control-based direct torque control method to reduce the effects of unbalanced grid voltage on doubly-fed induction generator (DFIG-based wind turbine system. Under unbalanced grid voltage, the stator flux has a negative sequence component which leads to second harmonic pulsation in torque, stator active power, stator reactive power, stator current and rotor current. In the control scheme, the negative sequence rotor voltage vector is controlled to compensate the negative sequence stator flux by negative sequence rotor flux. Simulation study is carried out on a 2 MW DFIG system using MATLAB/SIMULINK. Feasibility of the proposed control strategy is experimentally verified on a 1.5 kW DFIG system.

  16. Formation of distinctive structures of GaN by inductively-coupled-plasma and reactive ion etching under optimized chemical etching conditions

    Directory of Open Access Journals (Sweden)

    N. Okada

    2017-06-01

    Full Text Available We focused on inductively coupled plasma and reactive ion etching (ICP–RIE for etching GaN and tried to fabricate distinctive GaN structures under optimized chemical etching conditions. To determine the optimum chemical etching conditions, the flow rates of Ar and Cl2, ICP power, and chamber pressure were varied in the etching of c-plane GaN layers with stripe patterns. It was determined that the combination of Ar and Cl2 flow rates of 100 sccm, chamber pressure of 7 Pa, and ICP power of 800 W resulted in the most enhanced reaction, yielding distinctive GaN structures such as pillars with inverted mesa structures for c-plane GaN and a semipolar GaN layer with asymmetric inclined sidewalls. The selectivity and etching rate were also investigated.

  17. Induction of CD44 variant 9-expressing cancer stem cells might attenuate the efficacy of chemoradioselection and Worsens the prognosis of patients with advanced head and neck cancer.

    Directory of Open Access Journals (Sweden)

    Takeichiro Aso

    Full Text Available At our institute, a chemoradioselection strategy has been used to select patients for organ preservation on the basis of response to an initial 30-40 Gy concurrent chemoradiotherapy (CCRT. Patients with a favorable response (i.e., chemoradioselected; CRS have demonstrated better outcomes than those with an unfavorable response (i.e., nonchemoradioselected; N-CRS. Successful targeting of molecules that attenuate the efficacy of chmoradioselection may improve results. Thus, the aim of this study was to evaluate the association of a novel cancer stem cell (CSC marker, CD44 variant 9 (CD44v9, with cellular refractoriness to chemoradioselection in advanced head and neck squamous cell carcinoma (HNSCC.Through a medical chart search, 102 patients with advanced HNSCC treated with chemoradioselection from 1997 to 2008 were enrolled. According to our algorithm, 30 patients were CRC following induction CCRT and 72 patients were N-CRS. Using the conventional immunohistochemical technique, biopsy specimens and surgically removed tumor specimens were immunostained with the anti-CD44v9 specific antibodies.The intrinsic expression levels of CD44v9 in the biopsy specimens did not correlate with the chemoradioselection and patient survival. However, in N-CRS patients, the CD44v9-positive group demonstrated significantly (P = 0.008 worse prognosis, than the CD44v9-negative group. Multivariate analyses demonstrated that among four candidate factors (T, N, response to CCRT, and CD44v9, CD44v9 positivity (HR: 3.145, 95% CI: 1.235-8.008, P = 0.0163 was significantly correlated with the poor prognosis, along with advanced N stage (HR: 3.525, 95% CI: 1.054-9.060, P = 0.0228. Furthermore, the survival rate of the CD44v9-induced group was significantly (P = 0.04 worse than the CD44v9-non-induced group.CCRT-induced CD44v9-expressing CSCs appear to be a major hurdle to chemoradioselection. CD44v9-targeting seems to be a promising strategy to enhance the efficacy of

  18. [Rectal cancer - local staging and imaging under neoadjuvant therapy].

    Science.gov (United States)

    Karpitschka, M

    2012-06-01

    Rectal cancer restaging after neoadjuvant therapy is based on two principles: an anatomic definition of the tumor allowing surgical planning and prognostic stage grouping. Emerging data suggest that reassessment using a combination of different imaging modalities may help to provide valuable prognostic information before definitive surgery. Perfusion computed tomography (CT) may provide special information regarding tumor vascularity. Evaluation of therapy response, especially of the circumferential resection margin (CRM) is necessary for surgical planning. For local staging high-resolution and diffusion-weighted magnetic resonance imaging has proven to be of high diagnostic accuracy. The M status should be assessed using multidetector computed tomography (MDCT) according to response evaluation criteria in solid tumors (RECIST) while lymph node evaluation requires either magnetic resonance imaging or positron emission tomography/computed tomography scanning.

  19. Nursing workload for cancer patients under palliative care.

    Science.gov (United States)

    Fuly, Patrícia Dos Santos Claro; Pires, Livia Márcia Vidal; Souza, Claudia Quinto Santos de; Oliveira, Beatriz Guitton Renaud Baptista de; Padilha, Katia Grillo

    2016-01-01

    To verify the nursing workload required by cancer patients undergoing palliative care and possible associations between the demographic and clinical characteristics of the patients and the nursing workload. This is a quantitative, cross-sectional, prospective study developed in the Connective Bone Tissue (TOC) clinics of Unit II of the Brazilian National Cancer Institute José Alencar Gomes da Silva with patients undergoing palliative care. Analysis of 197 measures of the Nursing Activities Score (NAS) revealed a mean score of 43.09% and an association between the performance status of patients undergoing palliative care and the mean NAS scores. The results of the study point to the need to resize the team of the unit. The NAS has proven to be a useful tool in oncologic clinical units for patients undergoing palliative care. Verificar a carga de trabalho de enfermagem requerida por pacientes com câncer sob cuidados paliativos e possíveis associações entre as características demográficas e clínicas dos pacientes e a carga de trabalho de enfermagem. Trata-se de um estudo de abordagem quantitativa, transversal, prospectivo, desenvolvido na clínica de Tecido Ósseo Conectivo (TOC) da Unidade II do Instituto Nacional de Câncer José Alencar Gomes da Silva, com pacientes em cuidados paliativos. A análise de 197 medidas do Nursing Activities Score (NAS) revelou um escore médio de 43,09% e uma associação entre a performance status de pacientes em cuidados paliativos com os valores médios do NAS. Os resultados do estudo apontam para a necessidade de redimensionamento da equipe da Unidade. O NAS mostrou-se um instrumento passível de utilização em unidades clínicas oncológicas, com pacientes em cuidados paliativos.

  20. Induction of human microsomal prostaglandin E synthase 1 by activated oncogene RhoA GTPase in A549 human epithelial cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Hye Jin [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Lee, Dong-Hyung [Department of Obstetrics and Gynecology, Medical Research Institute, Pusan National University, Busan (Korea, Republic of); Park, Seong-Hwan; Kim, Juil; Do, Kee Hun [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); An, Tae Jin; Ahn, Young Sup; Park, Chung Berm [Department of Herbal Crop Research, NIHHS, RDA, Eumseong (Korea, Republic of); Moon, Yuseok, E-mail: moon@pnu.edu [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Medical Research Institute and Research Institute for Basic Sciences, Pusan National University, Busan (Korea, Republic of)

    2011-09-30

    Highlights: {yields} As a target of oncogene RhoA-linked signal, a prostaglandin metabolism is assessed. {yields} RhoA activation increases PGE{sub 2} levels and its metabolic enzyme mPGES-1. {yields} RhoA-activated NF-{kappa}B and EGR-1 are positively involved in mPGES-1 induction. -- Abstract: Oncogenic RhoA GTPase has been investigated as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Among the various targets of RhoA-linked signals, pro-inflammatory prostaglandin E{sub 2} (PGE{sub 2}), a major prostaglandin metabolite, was assessed in epithelial cancer cells. RhoA activation increased PGE{sub 2} levels and gene expression of the rate-limiting PGE{sub 2} producing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase 1 (mPGES-1). In particular, human mPGES-1 was induced by RhoA via transcriptional activation in control and interleukin (IL)-1{beta}-activated cancer cells. To address the involvement of potent signaling pathways in RhoA-activated mPGES-1 induction, various signaling inhibitors were screened for their effects on mPGES-1 promoter activity. RhoA activation enhanced basal and IL-1{beta}-mediated phosphorylated nuclear factor-{kappa}B and extracellular signal-regulated kinase1/2 proteins, all of which were positively involved in RhoA-induced gene expression of mPGES-1. As one potent down-stream transcription factor of ERK1/2 signals, early growth response gene 1 product also mediated RhoA-induced gene expression of mPGES-1 by enhancing transcriptional activity. Since oncogene-triggered PGE{sub 2} production is a critical modulator of epithelial tumor cells, RhoA-associated mPGES-1 represents a promising chemo-preventive or therapeutic target for epithelial inflammation and its associated cancers.

  1. Induction of strand breaks in DNA films by low energy electrons and soft X-ray under nitrous oxide atmosphere

    Energy Technology Data Exchange (ETDEWEB)

    Alizadeh, Elahe, E-mail: Elahe.Alizadeh@USherbrooke.ca [Groupe en science des radiations, Departement de medecine nucleaire et radiobiologie, Faculte de medecine et des sciences de la sante, Universite de Sherbrooke, Sherbrooke, J1H 5N4 (Canada); Sanche, Leon, E-mail: Leon.Sanche@USherbrooke.ca [Groupe en science des radiations, Departement de medecine nucleaire et radiobiologie, Faculte de medecine et des sciences de la sante, Universite de Sherbrooke, Sherbrooke, J1H 5N4 (Canada)

    2012-01-15

    Five-monolayer (5 ML) plasmid DNA films deposited on glass and tantalum substrates were exposed to Al K{sub {alpha}} X-rays of 1.5 keV under gaseous nitrous oxide (N{sub 2}O) at atmospheric pressure and temperature. Whereas the damage yields for DNA deposited on glass are due to soft X-rays, those arising from DNA on tantalum are due to both the interaction of low energy photoelectrons from the metal and X-rays. Then, the differences in the yields of damage on glass and tantalum substrates, essentially arises from interaction of essentially low-energy electrons (LEEs) with DNA molecules and the surrounding atmosphere. The G-values (i.e., the number of moles of product per Joule of energy absorbed) for DNA strand breaks induced by LEEs (G{sub LEE}) and the lower limit of G-values for soft X-ray photons (G{sub XL}) were calculated and the results compared to those from previous studies under atmospheric conditions and other ambient gases, such as N{sub 2} and O{sub 2}. Under N{sub 2}O, the G-values for loss of supercoiled DNA are 103{+-}15 nmol/J for X-rays, and 737{+-}110 nmol/J for LEEs. Compared to corresponding values in an O{sub 2} atmosphere, the effectiveness of X-rays to damage DNA in N{sub 2}O is less, but the G value for LEEs in N{sub 2}O is more than twice the corresponding value for an oxygenated environment. This result indicates a higher effectiveness for LEEs relative to N{sub 2} and O{sub 2} environments in causing SSB and DSB in an N{sub 2}O environment. Thus, the previously observed radiosensitization of cells by N{sub 2}O may not be only due to OH{sup {center_dot}} radicals but also to the reaction of LEE with N{sub 2}O molecules near DNA. The previous experiments with N{sub 2} and O{sub 2} and the present one demonstrate the possibility to investigate damage induced by LEEs to biomolecules under various types of surrounding atmospheres. - Highlights: > A completely different and new approach is applied to investigate the radiation chemistry of N

  2. Modulation of MicroRNAs by Phytochemicals in Cancer: Underlying Mechanisms and Translational Significance

    Science.gov (United States)

    Srivastava, Sanjeev K.; Arora, Sumit; Averett, Courey; Singh, Ajay P.

    2015-01-01

    MicroRNAs (miRNAs) are small, endogenous noncoding RNAs that regulate a variety of biological processes such as differentiation, development, and survival. Recent studies suggest that miRNAs are dysregulated in cancer and play critical roles in cancer initiation, progression, and chemoresistance. Therefore, exploitation of miRNAs as targets for cancer prevention and therapy could be a promising approach. Extensive evidence suggests that many naturally occurring phytochemicals regulate the expression of numerous miRNAs involved in the pathobiology of cancer. Therefore, an understanding of the regulation of miRNAs by phytochemicals in cancer, their underlying molecular mechanisms, and functional consequences on tumor pathophysiology may be useful in formulating novel strategies to combat this devastating disease. These aspects are discussed in this review paper with an objective of highlighting the significance of these observations from the translational standpoint. PMID:25853141

  3. Post-cancer Treatment with Condurango 30C Shows Amelioration of Benzo[a]pyrene-induced Lung Cancer in Rats Through the Molecular Pathway of Caspa- se-3-mediated Apoptosis Induction

    Directory of Open Access Journals (Sweden)

    Sikdar Sourav

    2013-09-01

    Full Text Available Objectives: The present investigation aimed at examining if post-cancer treatment with a potentized homeopathic drug, Condurango 30C, which is generally used to treat oesophageal cancer, could also show an ameliorating effect through apoptosis induction on lung cancer induced by benzo[a]pyrene (BaP in white rats (Rattus norvegicus. Methods: Lung cancer was induced after four months by chronic feeding of BaP to rats through gavage at a dose of 50 mg/kg body weight for one month. After four months, the lung-cancer-bearing rats were treated with Condurango 30C for the next one (5th, two (5th-6th and three (5th-7th months, respectively, and were sacrificed at the corresponding time- points. The ameliorating effect, if any, after Condurango 30C treatment for the various periods was evaluated by using protocols such as histology, scanning electron microscopy (SEM, annexinV-FITC/PI assay, flow cytometry of the apoptosis marker, DNA fragmentation, reverse transcriptase-polymerase chain reaction (RT-PCR, immunohistochemistry, and western blot analyses of lung tissue samples. Results: Striking recovery of lung tissue to a near normal status was noticed after post-cancerous drug treatment, as evidenced by SEM and histology, especially after one and two months of drug treatment. Data from the annexinV-FITC/PI and DNA fragmentation assays revealed that Condurango 30C could induce apoptosis in cancer cells after post-cancer treatment. A critical analysis of signalling cascade, evidenced through a RT-PCR study, demonstrated up-regulation and down-regulation of different pro- and anti-apoptotic genes, respectively, related to a caspase-3-mediated apoptotic pathway, which was especially discernible after one-month and two- month drug treatments. Correspondingly, Western blot and immunohistochemistry studies confirmed the ameliorative potential of Condurango 30C by its ability to down-regulate the elevated epidermal growth factor receptor (EGFR expression, a

  4. 14 CFR 27.1091 - Air induction.

    Science.gov (United States)

    2010-01-01

    ... STANDARDS: NORMAL CATEGORY ROTORCRAFT Powerplant Induction System § 27.1091 Air induction. (a) The air induction system for each engine must supply the air required by that engine under the operating conditions... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Air induction. 27.1091 Section 27.1091...

  5. Effect of Prior Immunization on Induction of Cervical Cancer in Mice by Herpes Simplex Virus Type 2

    Science.gov (United States)

    Budd Wentz, W.; Heggie, Alfred D.; Anthony, Donald D.; Reagan, James W.

    1983-12-01

    Previous studies at this laboratory showed that repeated application of inactivated herpes simplex virus type 2 to the mouse cervix produces premalignant and malignant lesions. In the present study mice were inoculated with inactivated herpes simplex virus type 2 or control solution and Freund's adjuvant by intraperitoneal and subcutaneous routes before exposure of the cervix to inactivated virus. It appears that immunization with inactivated virus conferred a protection against the induction of cervical carcinoma.

  6. The role of induction and adjuvant chemotherapy in combination with concurrent chemoradiotherapy for nasopharyngeal cancer: a Bayesian network meta-analysis of published randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Yu HL

    2016-01-01

    Full Text Available Hongliang Yu,1,* Dayong Gu,1,* Xia He,1 Xianshu Gao,2 Xiuhua Bian1 1Department of Radiation Oncology, Jiangsu Cancer Hospital affiliated with Nanjing Medical University, Nanjing, 2Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Whether the addition of induction chemotherapy (IC or adjuvant chemotherapy (AC to concurrent chemoradiotherapy (CCRT is superior to CCRT alone for locally advanced nasopharyngeal cancer is unknown. A Bayesian network meta-analysis was performed to investigate the efficacy of CCRT, IC + CCRT, and CCRT + AC on locally advanced nasopharyngeal cancer. The overall survival (OS with hazard ratios (HRs and locoregional recurrence rates (LRRs and distant metastasis rates (DMRs with risk ratios (RRs were investigated. After a comprehensive database search, eleven studies involving 2,626 assigned patients were included in this network meta-analysis. Compared with CCRT alone, IC + CCRT resulted in no significant improvement in OS or LRR and a marginal improvement in DMR (OS: HR =0.67, 95% credible interval (CrI 0.32–1.18; LRR: RR =1.79, 95% CrI 0.80–3.51; DMR: RR =1.79, 95% CrI 0.24–1.04 and CCRT + AC exhibited no beneficial effects on any of the endpoints of OS, LRR, or DMR (OS: HR =0.99, 95% CrI 0.64–1.43; LRR: RR =0.78, 95% CrI 0.43–1.32; DMR: RR =0.85, 95% CrI 0.57–1.24. As a conclusion, for locally advanced nasopharyngeal cancer, no significant differences in the treatment efficacies of CCRT, IC + CCRT, and CCRT + AC were found, with the exception of a marginally significant improvement in distant control observed following IC + CCRT compared with CCRT alone. Keywords: concurrent chemotherapy, induction chemotherapy, adjuvant chemotherapy, radiotherapy, nasopharyngeal cancer, network meta-analysis

  7. Anti-Lung Cancer Activity through Enhancement of Immunomodulation and Induction of Cell Apoptosis of Total Triterpenes Extracted from Ganoderma luncidum (Leyss. ex Fr. Karst.

    Directory of Open Access Journals (Sweden)

    Wei Cao

    2013-08-01

    Full Text Available Ganoderma luncidum (Leyss. ex Fr. Karst. (GLK has been used traditionally for the prevention and treatment of cancers or tumors for a long time in Traditional Chinese Medicine. The triterpenes as main effective components of GLK have been found to be beneficial for the efficacy. The purpose of this study was to examine the anti-lung cancer activity of triterpenes of GLK in vitro and in vivo and to explore their anti-lung cancer effects and potential mechanisms. A549 cells and Lewis tumor-bearing mice were used to evaluate the inhibition effects of triterpenes on cell proliferation and tumor growth. The IC50 of triterpenes of GLK on A549 cells was 24.63 μg/mL. Triterpenes of GLK could significantly inhibit tumor growth in mice (30, 60 and 120 mg/kg. The immune organs indexes including spleen and thymus were increased remarkedly by the treatment with triterpenes. Moreover, they were able to stimulate the immune response by increasing the expressions of IL-6 and TNF-α. Flow cytometric analysis revealed that cell arrest caused by triterpenes treatment (7.5, 15 and 30 μg/mL was in the G2/M phase in A549 cells. Triterpenes induced apoptosis by decreasing the expression of the antiapoptotic protein Bcl-2 and pro-caspase 9 and increasing the levels of cleaved-caspase 9. Our findings suggested that the triterpenes of GLK have anti-lung cancer activity in vitro and in vivo via enhancement of immunomodulation and induction of cell apoptosis. The study provides insights into the mechanism of GLK in the prevention and treatment of lung cancer.

  8. Evaluation of the efficacy & biochemical mechanism of cell death induction by Piper longum extract selectively in in-vitro and in-vivo models of human cancer cells.

    Science.gov (United States)

    Ovadje, Pamela; Ma, Dennis; Tremblay, Phillip; Roma, Alessia; Steckle, Matthew; Guerrero, Jose-Antonio; Arnason, John Thor; Pandey, Siyaram

    2014-01-01

    Currently chemotherapy is limited mostly to genotoxic drugs that are associated with severe side effects due to non-selective targeting of normal tissue. Natural products play a significant role in the development of most chemotherapeutic agents, with 74.8% of all available chemotherapy being derived from natural products. To scientifically assess and validate the anticancer potential of an ethanolic extract of the fruit of the Long pepper (PLX), a plant of the piperaceae family that has been used in traditional medicine, especially Ayurveda and investigate the anticancer mechanism of action of PLX against cancer cells. Following treatment with ethanolic long pepper extract, cell viability was assessed using a water-soluble tetrazolium salt; apoptosis induction was observed following nuclear staining by Hoechst, binding of annexin V to the externalized phosphatidyl serine and phase contrast microscopy. Image-based cytometry was used to detect the effect of long pepper extract on the production of reactive oxygen species and the dissipation of the mitochondrial membrane potential following Tetramethylrhodamine or 5,5,6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine chloride staining (JC-1). Assessment of PLX in-vivo was carried out using Balb/C mice (toxicity) and CD-1 nu/nu immunocompromised mice (efficacy). HPLC analysis enabled detection of some primary compounds present within our long pepper extract. Our results indicated that an ethanolic long pepper extract selectively induces caspase-independent apoptosis in cancer cells, without affecting non-cancerous cells, by targeting the mitochondria, leading to dissipation of the mitochondrial membrane potential and increase in ROS production. Release of the AIF and endonuclease G from isolated mitochondria confirms the mitochondria as a potential target of long pepper. The efficacy of PLX in in-vivo studies indicates that oral administration is able to halt the growth of colon cancer tumors in

  9. Apoptosis induction in Jurkat cells and sCD95 levels in women's sera are related with the risk of developing cervical cancer

    Directory of Open Access Journals (Sweden)

    Bravo-Cuellar Alejandro

    2008-04-01

    Full Text Available Abstract Background Currently, there is clear evidence that apoptosis plays an important role in the development and progression of tumors. One of the best characterized apoptosis triggering systems is the CD95/Fas/APO-1 pathway; previous reports have demonstrated high levels of soluble CD95 (sCD95 in serum of patients with some types of cancer. Cervical cancer is the second most common cancer among women worldwide. As a first step in an attempt to design a minimally invasive test to predict the risk of developing cervical cancer in patients with precancerous lesions, we used a simple assay based on the capacity of human serum to induce apoptosis in Jurkat cells. We evaluated the relationship between sCD95 levels and the ability to induce apoptosis in Jurkat cells in cervical cancer patients and controls. Methods Jurkat cells were exposed to serum from 63 women (20 healthy volunteers, 21 with cervical intraepithelial neoplasia grade I [CIN 1] and 22 with cervical-uterine carcinoma. The apoptotic rate was measured by flow cytometry using Annexin-V-Fluos and Propidium Iodide as markers. Serum levels of sCD95 and soluble CD95 ligand (sCD95L were measured by ELISA kits. Results We found that serum from almost all healthy women induced apoptosis in Jurkat cells, while only fifty percent of the sera from women with CIN 1 induced cell death in Jurkat cells. Interestingly, only one serum sample from a patient with cervical-uterine cancer was able to induce apoptosis, the rest of the sera protected Jurkat cells from this killing. We were able to demonstrate that elimination of Jurkat cells was mediated by the CD95/Fas/Apo-1 apoptotic pathway. Furthermore, the serum levels of sCD95 measured by ELISA were significantly higher in women with cervical cancer. Conclusion Our results demonstrate that there is a strong correlation between low levels of sCD95 in serum of normal women and higher apoptosis induction in Jurkat cells. We suggest that an analysis of

  10. Apoptosis induction in Jurkat cells and sCD95 levels in women's sera are related with the risk of developing cervical cancer

    International Nuclear Information System (INIS)

    Aguilar-Lemarroy, Adriana; Jave-Suarez, Luis F; Romero-Ramos, Jose E; Olimon-Andalon, Vicente; Hernandez-Flores, Georgina; Lerma-Diaz, Jose M; Ortiz-Lazareno, Pablo C; Morgan-Villela, Gilberto; Toro-Arreola, Susana del; Bravo-Cuellar, Alejandro

    2008-01-01

    Currently, there is clear evidence that apoptosis plays an important role in the development and progression of tumors. One of the best characterized apoptosis triggering systems is the CD95/Fas/APO-1 pathway; previous reports have demonstrated high levels of soluble CD95 (sCD95) in serum of patients with some types of cancer. Cervical cancer is the second most common cancer among women worldwide. As a first step in an attempt to design a minimally invasive test to predict the risk of developing cervical cancer in patients with precancerous lesions, we used a simple assay based on the capacity of human serum to induce apoptosis in Jurkat cells. We evaluated the relationship between sCD95 levels and the ability to induce apoptosis in Jurkat cells in cervical cancer patients and controls. Jurkat cells were exposed to serum from 63 women (20 healthy volunteers, 21 with cervical intraepithelial neoplasia grade I [CIN 1] and 22 with cervical-uterine carcinoma). The apoptotic rate was measured by flow cytometry using Annexin-V-Fluos and Propidium Iodide as markers. Serum levels of sCD95 and soluble CD95 ligand (sCD95L) were measured by ELISA kits. We found that serum from almost all healthy women induced apoptosis in Jurkat cells, while only fifty percent of the sera from women with CIN 1 induced cell death in Jurkat cells. Interestingly, only one serum sample from a patient with cervical-uterine cancer was able to induce apoptosis, the rest of the sera protected Jurkat cells from this killing. We were able to demonstrate that elimination of Jurkat cells was mediated by the CD95/Fas/Apo-1 apoptotic pathway. Furthermore, the serum levels of sCD95 measured by ELISA were significantly higher in women with cervical cancer. Our results demonstrate that there is a strong correlation between low levels of sCD95 in serum of normal women and higher apoptosis induction in Jurkat cells. We suggest that an analysis of the apoptotic rate induced by serum in Jurkat cells and the

  11. Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype.

    Science.gov (United States)

    Semenza, Gregg L

    2017-02-01

    Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species (ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 (HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production (NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer. © 2016 The Author.

  12. Induction of apoptosis in HeLa cancer cells by an ultrasonic-mediated synthesis of curcumin-loaded chitosan-alginate-STPP nanoparticles.

    Science.gov (United States)

    Ahmadi, Fatemeh; Ghasemi-Kasman, Maryam; Ghasemi, Shahram; Gholamitabar Tabari, Maryam; Pourbagher, Roghayeh; Kazemi, Sohrab; Alinejad-Mir, Ali

    2017-01-01

    Natural herbal compounds have been widely introduced as an alternative therapeutic approach in cancer therapy. Despite potent anticancer activity of curcumin, its clinical application has been limited because of low water solubility and resulting poor bioavailability. In this study, we designed a novel ultrasonic-assisted method for the synthesis of curcumin-loaded chitosan-alginate-sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). Furthermore, antitumor effect of curcumin-loaded NPs was evaluated in vitro. Field emission scanning electron microscopy (FE-SEM) and atomic force microscopy (AFM) were used to characterize the properties of NPs. Antitumor activity of curcumin-loaded NPs was assessed by using MTT and quantitative real-time polymerase chain reaction (qRT-PCR). FE-SEM and AFM data revealed the spherical morphology, and the average size of NPs was <50 nm. In vitro cytotoxicity assay suggested that curcumin-loaded CS-ALG-STPP NPs displayed significant antitumor activity compared with the free curcumin. Gene expression level analyses showed that curcumin NPs significantly increased the apoptotic gene expression. Collectively, our results suggest that curcumin-loaded NPs significantly suppressed proliferation and promoted the induction of apoptosis in human cervical epithelioid carcinoma cancer cells, which might be regarded as an effective alternative strategy for cancer therapy.

  13. Low-dose radiation pretreatment improves survival of human ceiling culture-derived proliferative adipocytes (ccdPAs) under hypoxia via HIF-1 alpha and MMP-2 induction

    International Nuclear Information System (INIS)

    Adachi, Naoki; Kubota, Yoshitaka; Kosaka, Kentarou; Akita, Shinsuke; Sasahara, Yoshitarou; Kira, Tomoe; Kuroda, Masayuki; Mitsukawa, Nobuyuki; Bujo, Hideaki; Satoh, Kaneshige

    2015-01-01

    Poor survival is a major problem of adipocyte transplantation. We previously reported that VEGF and MMPs secreted from transplanted adipocytes are essential for angiogenesis and adipogenesis. Pretreatment with low-dose (5 Gy) radiation (LDR) increased VEGF, MMP-2, and HIF-1 alpha mRNA expression in human ceiling culture-derived proliferative adipocytes (hccdPAs). Gene expression after LDR differed between adipose-derived stem cells (hASCs) and hccdPAs. Pretreatment with LDR improved the survival of hccdPAs under hypoxia, which is inevitable in the early stages after transplantation. Upregulation of VEGF and MMP-2 after LDR in hccdPAs is mediated by HIF-1 alpha expression. Our results suggest that pretreatment with LDR may improve adipocyte graft survival in a clinical setting through upregulation of VEGF and MMP-2 via HIF-1 alpha. - Highlights: • Ceiling culture-derived proliferative adipocytes (ccdPAs) react to radiation. • Low-dose radiation (LDR) pretreatment improves survival of ccdPAs under hypoxia. • Gene expression after LDR differs between ccdPAs and adipose-derived stem cells. • LDR-induced increase in MMP-2 and VEGF is dependent on HIF-1 alpha induction. • LDR pretreatment may improve the adipocyte graft survival rate in clinical settings

  14. Low-dose radiation pretreatment improves survival of human ceiling culture-derived proliferative adipocytes (ccdPAs) under hypoxia via HIF-1 alpha and MMP-2 induction

    Energy Technology Data Exchange (ETDEWEB)

    Adachi, Naoki [Department of Plastic Surgery, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677 (Japan); Kubota, Yoshitaka, E-mail: kubota-cbu@umin.ac.jp [Department of Plastic Surgery, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677 (Japan); Kosaka, Kentarou; Akita, Shinsuke; Sasahara, Yoshitarou; Kira, Tomoe [Department of Plastic Surgery, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677 (Japan); Kuroda, Masayuki [Center for Advanced Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677 (Japan); Mitsukawa, Nobuyuki [Department of Plastic Surgery, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677 (Japan); Bujo, Hideaki [Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University, Sakura Medical Center, 564-1 Shimoshizu, Sakura-shi, Chiba, #285-8741 (Japan); Satoh, Kaneshige [Department of Plastic Surgery, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-city, Chiba, #260-8677 (Japan)

    2015-08-07

    Poor survival is a major problem of adipocyte transplantation. We previously reported that VEGF and MMPs secreted from transplanted adipocytes are essential for angiogenesis and adipogenesis. Pretreatment with low-dose (5 Gy) radiation (LDR) increased VEGF, MMP-2, and HIF-1 alpha mRNA expression in human ceiling culture-derived proliferative adipocytes (hccdPAs). Gene expression after LDR differed between adipose-derived stem cells (hASCs) and hccdPAs. Pretreatment with LDR improved the survival of hccdPAs under hypoxia, which is inevitable in the early stages after transplantation. Upregulation of VEGF and MMP-2 after LDR in hccdPAs is mediated by HIF-1 alpha expression. Our results suggest that pretreatment with LDR may improve adipocyte graft survival in a clinical setting through upregulation of VEGF and MMP-2 via HIF-1 alpha. - Highlights: • Ceiling culture-derived proliferative adipocytes (ccdPAs) react to radiation. • Low-dose radiation (LDR) pretreatment improves survival of ccdPAs under hypoxia. • Gene expression after LDR differs between ccdPAs and adipose-derived stem cells. • LDR-induced increase in MMP-2 and VEGF is dependent on HIF-1 alpha induction. • LDR pretreatment may improve the adipocyte graft survival rate in clinical settings.

  15. Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1 in Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Cyril Sobolewski

    2015-08-01

    Full Text Available The RNA-binding protein tristetraprolin (TTP promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE. In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC inhibitors (Trichostatin A, SAHA and sodium butyrate promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells and cervix carcinoma cells (HeLa. We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1. Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer.

  16. Induction Chemotherapy and Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Patients With Locally Advanced Inoperable Non-Small-Cell Lung Cancer: The MRC INCH Randomized Trial

    International Nuclear Information System (INIS)

    Hatton, Matthew; Nankivell, Matthew; Lyn, Ethan; Falk, Stephen; Pugh, Cheryl; Navani, Neal; Stephens, Richard; Parmar, Mahesh

    2011-01-01

    Purpose: Recent clinical trials and meta-analyses have shown that both CHART (continuous hyperfractionated accelerated radiation therapy) and induction chemotherapy offer a survival advantage over conventional radical radiotherapy for patients with inoperable non-small cell-lung cancer (NSCLC). This multicenter randomized controlled trial (INCH) was set up to assess the value of giving induction chemotherapy before CHART. Methods and Materials: Patients with histologically confirmed, inoperable, Stage I-III NSCLC were randomized to induction chemotherapy (ICT) (three cycles of cisplatin-based chemotherapy followed by CHART) or CHART alone. Results: Forty-six patients were randomized (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Twenty-eight patients were male, 28 had squamous cell histology, 34 were Stage IIIA or IIIB, and all baseline characteristics were well balanced between the two treatment arms. Seventeen (74%) of the 23 ICT patients completed the three cycles of chemotherapy. All 42 (22 CHART + 20 ICT) patients who received CHART completed the prescribed treatment. Median survival was 17 months in the CHART arm and 25 months in the ICT arm (hazard ratio of 0.60 [95% CI 0.31-1.16], p = 0.127). Grade 3 or 4 adverse events (mainly fatigue, dysphagia, breathlessness, and anorexia) were reported for 13 (57%) CHART and 13 (65%) ICT patients. Conclusions: This small randomized trial indicates that ICT followed by CHART is feasible and well tolerated. Despite closing early because of poor accrual, and so failing to show clear evidence of a survival benefit for the additional chemotherapy, the results suggest that CHART, and ICT before CHART, remain important options for the treatment of inoperable NSCLC and deserve further study.

  17. The Effects of Davallic Acid from Davallia divaricata Blume on Apoptosis Induction in A549 Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Tsu-Liang Chang

    2012-11-01

    Full Text Available Traditional or folk medicinal herbs continue to be prescribed in the treatment of various diseases and conditions in many cultures. Recent scientific efforts have focused on the potential roles of extracts of traditional herbs as alternative and complementary medications for cancer treatment. In Taiwan, Davallia divaricata Blume has been traditionally employed in folk medicine for therapy of lung cancer, davallic acid being the major active compound of D. divaricata Blume. In this study, we investigated the inhibitory activity of davallic acid on the proliferation of A549 lung cancer cells. Davallic acid was extracted from D. divaricata Blume, and its effects on cell viability, cell cycle distribution, ROS level, and apoptotic protein expression in A549 cells were determined. Davallic acid significantly induced reactive oxygen species (ROS generation as well as caspase-3, -8, and -9 activation, thereby repressing A549 cell growth and elevating apoptotic activity. Since lung cancer has a high incidence of recurrence, these results indicate that davallic acid may have the potential to be a natural anti-lung cancer compound, and may provide a basis for further study of its use in combating cancer.

  18. Human thyroid cancer induction by ionizing radiation: summary of studies based on external irradiation and radioactive iodines

    International Nuclear Information System (INIS)

    Shore, R.E.

    1996-01-01

    To provide a context for the Chernobyl thyroid cancer experience, a summary of the findings from other studies is given. The data on external radiation and thyroid cancer come primarily from studies of children irradiated for a variety of benign medical conditions and the Japanese atomic bomb cohort. Unfortunately, only small amounts of data are currently available on thyroid cancer following radioactive iodine exposure in childhood. In order to predict the risk of thyroid cancer in the Chernobyl experience, a number of radiation-related factors need to be considered: the magnitude of radiation risk from available studies; shape of the dose-response curve; variations in risk by gender, time since irradiation, and age at irradiation; the effects of dose fractionation or dose protraction. Other considerations pertaining to the frequency of thyroid cancer and its outcome are thyroid-tumor surveillance effects and background iodine intake. The data to date suggest that 131 I produces less thyroid cancer than a comparable dose of external radiation, but the Chernobyl experience will provide extensive new information on this issue. Principles are discussed as to how to maximize the scientific validity and informativeness of Chernobyl thyroid studies

  19. Berberine Activates Aryl Hydrocarbon Receptor but Suppresses CYP1A1 Induction through miR-21-3p Stimulation in MCF-7 Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sheng-Nan Lo

    2017-10-01

    Full Text Available Berberine and the methylenedioxy ring-opening derivatives palmatine and jatrorrhizine are active ingredients in immunomodulatory plants, such as goldenseal. This study aimed to illustrate the effects of protoberberines on aryl hydrocarbon receptor (AhR activation and cytochrome P450 (CYP 1 in the estrogen receptor (ERα(+ MCF-7 breast cancer cells. Among protoberberines at non-cytotoxic concentrations (≤10 μM, berberine had the most potent and statistically significant effects on AhR activation and CYP1A1/1A2/1B1 mRNA induction. The 24-h exposure to 10 μM berberine did not change CYP1A1 mRNA stability, protein level and function. Berberine significantly increased micro RNA (miR-21-3p by 36% and the transfection of an inhibitor of miR-21-3p restored the induction of CYP1A1 protein with a 50% increase. These findings demonstrate that the ring opening of the methylenedioxyl moiety in berberine decreased AhR activation in MCF-7 cells. While CYP1A1 mRNA was elevated, berberine-induced miR-21-3p suppressed the increase of functional CYP1A1 protein expression.

  20. Cytotoxicity of trans-chalcone and licochalcone A against breast cancer cells is due to apoptosis induction and cell cycle arrest.

    Science.gov (United States)

    Bortolotto, Luis Felipe Buso; Barbosa, Flávia Regina; Silva, Gabriel; Bitencourt, Tamires Aparecida; Beleboni, Rene Oliveira; Baek, Seung Joon; Marins, Mozart; Fachin, Ana Lúcia

    2017-01-01

    Chalcones are precursors of flavonoids that exhibit structural heterogeneity and potential antitumor activity. The objective of this study was to characterize the cytotoxicity of trans-chalcone and licochalcone A (LicoA 1 ) against a breast cancer cell line (MCF-7) and normal murine fibroblasts (3T3). Also the mechanisms of the anti-cancer activity of these two compounds were studied. The alkaline comet assay revealed dose-dependent genotoxicity, which was more responsive against the tumor cell line, compared to the 3T3 mouse fibroblast cell line. Flow cytometry showed that the two chalcones caused the cell cycle arrest in the G1 phase and induced apoptosis in MCF-7 cells. Using PCR Array, we found that trans-chalcone and LicoA trigger apoptosis mediated by the intrinsic pathway as demonstrated by the inhibition of Bcl-2 and induction of Bax. In western blot assay, the two chalcones reduced the expression of cell death-related proteins such as Bcl-2 and cyclin D1 and promoted the cleavage of PARP. However, only trans-chalcone induced the expression of the CIDEA gene and protein in these two experiments. Furthermore, transient transfections of MCF-7 using a construction of a promoter-luciferase vector showed that trans-chalcone induced the expression of the CIDEA promoter activity in 24 and 48h. In conclusion, the results showed that trans-chalcone promoted high induction of the CIDEA promoter gene and protein, which is related to DNA fragmentation during apoptosis. Copyright © 2016. Published by Elsevier Masson SAS.

  1. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9

    Directory of Open Access Journals (Sweden)

    Song Xin

    2009-04-01

    Full Text Available Abstract Background Abberant aryl hydrocarbon receptor (AhR expression and AhR pathway activation are involved in gastric carcinogenesis. However, the relationship between AhR pathway activation and gastric cancer progression is still unclear. In present study, we used 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD, a classic and most potent ligand of AhR, to activate AhR pathway and investigated the effect of AhR pathway activation on human gastric cancer AGS cell invasion and explored the corresponding mechanism. Results To determine whether AhR pathway can be activated in AGS cells, we examined the expression of CYP1A1, a classic target gene of AhR pathway, following TCDD exposure. RT-PCR and western blot analysis showed that both CYP1A1 mRNA and protein expression were increased in a dose-dependent manner following TCDD treatment and AhR antagonist resveratrol (RSV could reverse this TCDD-induced CYP1A1 expression. To determine whether TCDD treatment of AGS cells results in an induction of MMP-9 expression, we detected MMP-9 mRNA using RT-PCR and detected MMP-9 enzymatic activity using gelatin zymography. The results showed that both MMP-9 mRNA expression and enzymatic activity were gradually increased with the concentration increase of TCDD in media and these changes could be reversed by RSV treatment in a dose-dependent manner. To examine whether AhR activation-induced MMP-9 expression and activity in AGS cells results in increased migration and invasion, we performed wound healing migration assay and transwell migration and invasion assay. After TCDD treatment, the migration distance and the migration and invasion abilities of AGS cells were increased with a dose-dependent manner. To demonstrate AhR activation-induced MMP-9 expression is mediated by c-Jun, siRNA transfection was performed to silence c-Jun mRNA in AGS cells. The results showed that MMP-9 mRNA expression and activity in untreated control AGS cells were very weak; After TCDD

  2. Skin cancer susceptibility genes and radiation: induction of macroscopic BCCs in Ptc1 heterozygous mice on different genetic backgrounds

    International Nuclear Information System (INIS)

    Pazzaglia, S.; Mancuso, M.; Merola, P.; Rebessi, S.; Covelli, V.; Saran, A.; Tanori, M.

    2003-01-01

    Full text: Individuals affected with the Gorlin syndrome inherit a germ-line mutation of the patched (Ptc1) developmental gene and, analogously to Ptc1 heterozygous mice, show an increased susceptibility to spontaneous tumor development. Gorlin patients show extensive variability of the phenotype and individuals with the same mutation may exhibit very different symptoms, suggesting an influence of genetic background. Similarly, in Ptc1 heterozygous mice, the tumor incidence and phenotype vary with their genetic background suggesting an influence of mouse strain-specific alleles. Human and mouse Ptc1 heterozygous have also been shown to be hypersensitive to ionizing radiation (IR)-induced tumorigenesis in terms of basal cell carcinoma (BCC) and medulloblastoma (MB) induction. The present study investigates the effects of genetic background in the context of radiation-induced BCC tumorigenesis. Ptc1 +/- mice on CD1 background were crossed with skin carcinogenesis susceptible (Car-S) and resistant (Car-R) mice to provide F1SPtc1 +/- and F1RPtc1 +/- and wild-type litter mates. The Car-S/R model interline difference in susceptibility is >100-fold. Here we show that F1SPtc1 +/- mice were extremely susceptible to BCC-induction following IR exposure. Conversely, F1RPtc1 +/- were refractory to BCC tumorigenesis, providing the indication that induction of BCC by IR in Ptc1 +/- mice is strongly dependent on genetic background. We also investigated the status of the remaining Ptc1 wild-type allele in BCCs from CD1 and F1S heterozygotes. The results of this analysis suggest that genetic background-dependent differences in the mechanisms of BCC induction may exist, since a higher frequency of Ptc1 wild-type allele loss was found in CD1 compared to F1S. The introduction of Ptc1 deficiency in a background susceptible to skin carcinogenesis (Car-S mice) offers the opportunity to easily induce macroscopic BCCs by radiation, thus providing a useful tool to study the pathogenesis of

  3. Clinicopathological and imaging features of breast cancer in Korean Women under 40 years of age

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jun Woo; Jang, Mi Jung; Kim, Sun Mi; Yun, Bo La; Lee, Jong Yoon; Kim, Eun Kyu; Kang, Eun Young; Park, So Yeon [Seoul National University Bundang Hospital, Seongnam (Korea, Republic of)

    2017-06-15

    To evaluate the clinicopathological and imaging features of mammography, ultrasonography, and magnetic resonance imaging (MRI) for breast cancer in Korean women under 40 years of age according to molecular subtypes. We included 183 breast cancers in 176 consecutive women under 40 years old who had been diagnosed with breast cancer between January 2012 and November 2014. The patients' clinical and pathologic records were available as electronic medical records. A retrospective review of the pre-operative imaging studies was performed with 177 mammographies, 183 ultrasonographies, and 178 MRIs. Eighty-six percent (158/183) of lesions were symptomatic, with masses (147/183) as the most common presentation. Eighty percent (22/25) of the asymptomatic lesions were diagnosed via screening ultrasonography. The luminal A subtype was the most common (n = 79, 43%), human epidermal growth factor receptor 2-enriched subtype showed indistinct margins on mammography (p = 0.006), the triple negative subtype depicted a posterior enhancement on ultrasonography (p < 0.001) and rim enhancement on MRI (p < 0.001). Breast cancers in Korean women under 40 years of age are commonly presented with a palpable mass, and luminal A is the most common molecular subtype. In our study, the imaging and pathologic characteristics of breast cancer in younger women were similar to those previously reported for older patients.

  4. Induction of the CLOCK Gene by E2-ERα Signaling Promotes the Proliferation of Breast Cancer Cells

    Science.gov (United States)

    Bi, Hailian; Li, Shujing; Wang, Miao; Xing, Xinrong; Wu, Huijian

    2014-01-01

    Growing genetic and epidemiological evidence suggests a direct connection between the disruption of circadian rhythm and breast cancer. Moreover, the expression of several molecular components constituting the circadian clock machinery has been found to be modulated by estrogen-estrogen receptor α (E2-ERα) signaling in ERα-positive breast cancer cells. In this study, we investigated the regulation of CLOCK expression by ERα and its roles in cell proliferation. Immunohistochemical analysis of human breast tumor samples revealed high expression of CLOCK in ERα-positive breast tumor samples. Subsequent experiments using ERα-positive human breast cancer cell lines showed that both protein and mRNA levels of CLOCK were up-regulated by E2 and ERα. In these cells, E2 promoted the binding of ERα to the EREs (estrogen-response elements) of CLOCK promoter, thereby up-regulating the transcription of CLOCK. Knockdown of CLOCK attenuated cell proliferation in ERα-positive breast cancer cells. Taken together, these results demonstrated that CLOCK could be an important gene that mediates cell proliferation in breast cancer cells. PMID:24789043

  5. Induction of apoptosis by tomato using space mutation breeding in human colon cancer SW480 and HT-29 cells.

    Science.gov (United States)

    Shi, Jiahui; Yang, Bin; Feng, Pan; Li, Duo; Zhu, Jiajin

    2010-03-15

    As far as we know, there have been no reports concerning the functional characteristics of tomatoes using space mutation breeding. The aim of this study was to evaluate the anti-colon cancer effect of tomatoes M1 and M2 using space mutation breeding. In the present study, obvious anti-cancer activity was shown with tomato juice of M1 and M2 and their parent CK treatment in colon cancer cell lines SW480 and HT-29 in cell growth inhibition. In addition, SW480 cells were more sensitive to M1 and M2 than HT-29 cells in cell apoptosis. Furthermore, M1 and M2 induced cell cycle arrest both in G0-G1 and G2/M phases. These data suggest that consumption of tomato using space mutation breeding may provide benefits to inhibit growth of colon cancer cells. Therefore, tomato production using space mutation breeding may be a good candidate for development as a dietary supplement in drug therapy for colon cancer.

  6. Glutamate production from ammonia via glutamate dehydrogenase 2 activity supports cancer cell proliferation under glutamine depletion.

    Science.gov (United States)

    Takeuchi, Yukiko; Nakayama, Yasumune; Fukusaki, Eiichiro; Irino, Yasuhiro

    2018-01-01

    Cancer cells rapidly consume glutamine as a carbon and nitrogen source to support proliferation, but the cell number continues to increase exponentially after glutamine is nearly depleted from the medium. In contrast, cell proliferation rates are strongly depressed when cells are cultured in glutamine-free medium. How cancer cells survive in response to nutrient limitation and cellular stress remains poorly understood. In addition, rapid glutamine catabolism yields ammonia, which is a potentially toxic metabolite that is secreted into the extracellular space. Here, we show that ammonia can be utilized for glutamate production, leading to cell proliferation under glutamine-depleted conditions. This proliferation requires glutamate dehydrogenase 2, which synthesizes glutamate from ammonia and α-ketoglutarate and is expressed in MCF7 and T47D cells. Our findings provide insight into how cancer cells survive under glutamine deprivation conditions and thus contribute to elucidating the mechanisms of tumor growth. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Linear induction accelerators for industrial applications

    International Nuclear Information System (INIS)

    Adler, R.J.; Bayless, J.R.

    1987-01-01

    Electron beams and x-rays have a variety of industrial and commercial applications including the sterilization of food, medical products and sludge, the detoxification of pollutant gases, the crosslinking and polymerization of plastics, the alteration of gemstone color, oil well logging, and cancer therapy. These requirements are presently met by chemical techniques, radioisotopes, electrostatic accelerators, or RF accelerators. Induction accelerators can be used in a number of these applications, with significant advantages in cost, efficiency, reliability and power handling capability. In this paper, the authors briefly discuss the principles of the induction accelerator and describe the development program. The goals of their program are to improve system reliability and to reduce system cost. An accelerator presently under construction which embodies a number of industrial improvements will be described. Unique features are a low cost accelerator design, and an SCR switched, tubeless pulsed power system

  8. Molecular mechanisms of synergistic induction of apoptosis by the combination therapy with hyperthermia and cisplatin in prostate cancer cells.

    Science.gov (United States)

    Zhang, Jian-Fu; Yan, Xiang-Ming; Lan, Bin; Lei, Yin-Rui; Li, Xiao-Hu; Gao, Shuai; Guo, Yi-Feng; Guo, Fang

    2016-10-14

    Prostate Cancer has become the second leading cause of male cancer-related incidence and mortality in United States. Hyperthermia (HT) is known to serve as a powerful tool in treatment of prostate cancer in clinical. The combination treatment with HT and cisplatin has a synergistic effect to inhibit prostate cancer progression and demonstrates better clinical effectiveness than HT or chemotherapy alone. But molecular mechanisms of this phenomenon have not been illuminated clearly. In this study, we used MTS assay to examine cell viabilities of PC-3, LNCaP, DU-145 and RM-1 cells after treated by HT and cisplatin. Then colony formation of PC-3 and DU-145 cells after treated with HT and cisplatin were photographed. To investigate whether the combination therapy would enhance apoptosis of PC-3 and DU-145 cells, we used Western blot analysis to detect expression level of proteins on apoptosis-regulated signaling pathway in PC-3 and DU-145 cells. Our results showed that the combination treatment decreased cell viabilities and colony formation of prostate cancer cells in a dose-dependent manner and this combination therapy enhanced apoptosis of PC-3 and DU-145 cells via activation of Caspase-3 and cleavage of PARP. We also found that the combination therapy could down-regulate the anti-apoptotic Bcl-2 and IAP family proteins. At last, the combination therapy activated AMPKα-JNK signaling pathway and inhibited Akt-mTOR-p70s6k signaling pathway to promote apoptosis of PC-3 and DU-145 cells. In conclusion, this study clearly elucidated how the combination therapy with HT and cisplatin promoted apoptosis of prostate cancer cells in synergy. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. The social experiences of cancer patients under treatment: a comparative study

    NARCIS (Netherlands)

    Tempelaar, R.; de Haes, J. C.; de Ruiter, J. H.; Bakker, D.; van den Heuvel, W. J.; van Nieuwenhuijzen, M. G.

    1989-01-01

    As part of a larger study on the quality of life of cancer patients under treatment, the positive and negative experiences in social interaction have been examined as compared to those of a control group (nonpatients, n = 201). Two patient groups were included: 109 patients who had recently

  10. 1,25D3 differentially suppresses bladder cancer cell migration and invasion through the induction of miR-101-3p.

    Science.gov (United States)

    Ma, Yingyu; Luo, Wei; Bunch, Brittany L; Pratt, Rachel N; Trump, Donald L; Johnson, Candace S

    2017-09-01

    Metastasis is the major cause of bladder cancer death. 1,25D 3 , the active metabolite of vitamin D, has shown anti-metastasis activity in several cancer model systems. However, the role of 1,25D 3 in migration and invasion in bladder cancer is unknown. To investigate whether 1,25D 3 affects migration and invasion, four human bladder cell lines with different reported invasiveness were selected: low-invasive T24 and 253J cells and highly invasive 253J-BV and TCCSUP cells. All of the four bladder cancer cells express endogenous and inducible vitamin D receptor (VDR) as examined by immunoblot analysis. 1,25D 3 had no effect on the proliferation of bladder cancer cells as assessed by MTT assay. In contrast, 1,25D 3 suppressed migration and invasion in the more invasive 253J-BV and TCCSUP cells, but not in the low-invasive 253J and T24 cells using "wound" healing, chemotactic migration and Matrigel-based invasion assays. 1,25D 3 promoted the expression of miR-101-3p and miR-126-3p in 253J-BV cells as examined by qRT-PCR. miR-101-3p inhibitor partially abrogated and pre-miR-101-3p further suppressed the inhibition of 1,25D 3 on migration and invasion in 253J-BV cells. Further, 1,25D 3 enhanced VDR recruitment to the promoter region of miR-101-3p using ChIP-qPCR assay. 1,25D 3 enhanced the promoter activity of miR-101-3p as evaluated by luciferase reporter assay. Taken together, 1,25D 3 suppresses bladder cancer cell migration and invasion in two invasive/migration competent lines but not in two less invasive/motile lines, which is partially through the induction of miR-101-3p expression at the transcriptional level.

  11. Induction of chromosome instability and stomach cancer by altering the expression pattern of mitotic checkpoint genes in mice exposed to areca-nut

    International Nuclear Information System (INIS)

    Kurkalang, Sillarine; Banerjee, Atanu; Ghoshal, Nitin; Dkhar, Hughbert; Chatterjee, Anupam

    2013-01-01

    There are strong indications for a causal association between areca-nut consumption and cancers. In Meghalaya, India, the variety of areca-nut is used as raw and unprocessed form whose chemical composition and pharmacological actions have been reported. Yet we know little on the initial pathway involved in areca-nut associated carcinogenesis since it is difficult to assess its effects on genetic alterations without interference of other compounding factors. Therefore, present study was undertaken in mice to verify the ability of raw areca-nut (RAN) to induce cancer and to monitor the expression of certain genes involved in carcinogenesis. This study was not intended to isolate any active ingredients from the RAN and to look its action. Three groups of mice (n = 25 in each) were taken and used at different time-points for different experimental analysis. The other three groups of mice (n = 15 in each) were considered for tumor induction studies. In each set, two groups were administered RAN-extract ad libitum in drinking water with or without lime. The expression of certain genes was assessed by conventional RT-PCR and immunoblotting. The mice were given the whole RAN-extract with and without lime in order to mimic the human consumption style of RAN. Histological preparation of stomach tissue revealed that RAN induced stomach cancer. A gradual increase in the frequency of precocious anaphase and aneuploid cells was observed in the bone marrow cells with a greater increment following RAN + lime administeration. Levels of p53, Bax, Securin and p65 in esophageal and stomach cells were elevated during early days of RAN exposure while those of different mitotic checkpoint proteins were downregulated. Apoptotic cell death was detected in non-cancerous stomach cells but not in tumor cells which showed overexpression of Bax and absence of PARP. Present study suggested (a) RAN induces stomach cancer, however, presence of lime promoted higher cell transformation and thereby

  12. Induction Brazing

    DEFF Research Database (Denmark)

    Henningsen, Poul

    Induction brazing is a fast and appropriate method for industrial joining of complex geometries and metal combinations. In all types of brazing processes it is important to heat the joint interface of the two materials to the same, high temperature. If one of the specimens is warmer than the other...... materials has large influence on the heating time and temperature distribution in induction heating. In order to ensure high and uniform temperature distribution near the interface of a joint between dissimilar materials the precise coil geometry and position is of great importance. The present report...... presents a combined numerical and experimental method for determination of appropriate/optimiged coil geometry and position in induction brazing tube-to-plate joints of different ratios between tube and plate thickness and different combinations of the materials stainless steel, brass and copper...

  13. Induction accelerators

    CERN Document Server

    Takayama, Ken

    2011-01-01

    A broad class of accelerators rests on the induction principle whereby the accelerating electrical fields are generated by time-varying magnetic fluxes. Particularly suitable for the transport of bright and high-intensity beams of electrons, protons or heavy ions in any geometry (linear or circular) the research and development of induction accelerators is a thriving subfield of accelerator physics. This text is the first comprehensive account of both the fundamentals and the state of the art about the modern conceptual design and implementation of such devices. Accordingly, the first part of the book is devoted to the essential features of and key technologies used for induction accelerators at a level suitable for postgraduate students and newcomers to the field. Subsequent chapters deal with more specialized and advanced topics.

  14. Induction practice -

    DEFF Research Database (Denmark)

    Rohde, Nicolas; Sprogøe, Jonas

    2007-01-01

    Research on induction of newcomers is primarily focused on individual processes, such as acquisition of knowledge and socialization in order to create a smooth and frictionless entry period. The interest of our research, however, is the processes that happen on the organizational level. We claim...... that induction potentially triggers both individual and organizational learning and by drawing on practice-based theory we discuss how the interplay between individual and the organization, what we call agenerative dance, ignites both kinds of learning. We focus on and describe the interplay , ignites both kinds...... of learning. We focus on and describe the interplay that takes place in particular induction events and analyze the "dance" through the lens of learning. The paper concludes with a brief discussion about the implications for practitioners and the challenges and future research prospects we have encountered...

  15. The action of a dietary retinoid on gene expression and cancer induction in electron-irradiated rat skin

    International Nuclear Information System (INIS)

    Burns, F.J.; Chen, S.; Xu, G.; Wu, F.; Tang, M.S.

    2002-01-01

    Current models of radiation carcinogenesis generally assume that the DNA is damaged in a variety of ways by the radiation and that subsequent cell divisions contribute to the conversion of the damage to heritable mutations. Cancer may seem complex and intractable, but its complexity provides multiple opportunities for preventive interventions. Mitotic inhibitors are among the strongest cancer preventive agents, not only slowing the growth rate of preneoplasias but also increasing the fidelity of DNA repair processes. Ionizing radiation, including electrons, is a strong inducer of cancer in rat skin, and dietary retinoids have shown potent cancer preventive activity in the same system. A non-toxic dietary dose of retinyl acetate altered gene expression levels 24 hours after electron irradiation of rat skin. Of the 8740 genes on an Affymetrix rat expression array, the radiation significantly (5 fold or higher) altered 188, while the retinoid altered 231, including 16 radiation-altered genes that were reversely altered. While radiation strongly affected the expression of stress response, immune/inflammation and nucleic acid metabolism genes, the retinoid most strongly affected proliferation-related genes, including some significant reversals, such as, keratin 14, retinol binding protein, and calcium binding proteins. These results point to reversal of proliferation-relevant genes as a likely basis for the anti-radiogenic effects of dietary retinyl acetate. (author)

  16. Heregulin-beta1 promotes metastasis of breast cancer cell line SKBR3 through upregulation of Snail and induction of epithelial-mesenchymal transition.

    Science.gov (United States)

    Cheng, Liansheng; Zha, Zhao; Lang, Bo; Liu, Jing; Yao, Xuebiao

    2009-07-18

    HRG-beta1 stimulation of breast cancer cell line SKBR3 resulted in not only increased cell migration and invasion, upregulation of some mesenchymal markers, and downregulation of epithelial marker, but also upregulation of transcription factor Snail and its nuclear translocation. Similar results were acquired for cells transfected with Snail cDNA. Furthermore, downregulation of Snail by siRNA attenuated HRG-beta1 induced EMT-like phenotype. Inhibition of Akt kinase activation by a PI3K inhibitor LY294002, or exogenous expression of a kinase-dead mutant of Akt abrogated the increase of Snail expression induced by HRG-beta1. Conversely, expression of a constitutively active Akt resulted in increase of Snail expression. These results indicated that Snail upregulation by HRG-beta1 is mediated via the PI3K/Akt signaling pathway and that Snail plays a key role in HRG-beta1 induced breast cancer cell metastasis through induction of EMT.

  17. Major triterpenoids in Chinese hawthorn "Crataegus pinnatifida" and their effects on cell proliferation and apoptosis induction in MDA-MB-231 cancer cells.

    Science.gov (United States)

    Wen, Lingrong; Guo, Ruixue; You, Lijun; Abbasi, Arshad Mehmood; Li, Tong; Fu, Xiong; Liu, Rui Hai

    2017-02-01

    The cytotoxicity and antiproliferative effect of phytochemicals presenting in the fruits of Chinese hawthorn (Crataegus pinnatifida) were evaluated. Shanlihong (Crataegus pinnatifida Bge. var. major N.E.Br.) variety possessed significant levels of flavonoids and triterpenoids, and showed potent antiproliferative effect against HepG 2 , MCF-7 and MDA-MB- 231 human cancer cells lines. Triterpenoids-enriched fraction (S9) prepared by Semi-preparative HPLC, and its predominant ingredient ursolic acid (UA) demonstrated remarkably antiproliferative activities for all the tested cancer cell lines. DNA flow cytometric analysis showed that S9 fraction and UA significantly induced G1 arrest in MDA-MB-231 cells in a dose-dependent manner. Western blotting analysis revealed that S9 fraction and UA significantly induced PCNA, CDK4, and Cyclin D1 downregulation in MDA-MB-231 cells, followed by p21 Waf1/Cip1 up-regulation. Additionally, flow cytometer and DNA ladder assays indicated that S9 fraction and UA significantly induced MDA-MB-231 cells apoptosis. Mitochondrial death pathway was involved in this apoptosis as significantly induced caspase-9 and caspase-3 activation. These results suggested that triterpenoids-enriched fraction and UA exhibited antiproliferative activity through the cell cycle arrest and apoptosis induction, and was majorly responsible for the potent anticancer activity of Chinese hawthorn. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Induction of the cell cycle arrest and apoptosis by flavonoids isolated from Korean Citrus aurantium L. in non-small-cell lung cancer cells.

    Science.gov (United States)

    Park, Kwang Il; Park, Hyeon Soo; Nagappan, Arulkumar; Hong, Gyeong Eun; Lee, Do Hoon; Kang, Sang Rim; Kim, Jin A; Zhang, Jue; Kim, Eun Hee; Lee, Won Sup; Shin, Sung Chul; Hah, Young Sool; Kim, Gon Sup

    2012-12-15

    This study investigated the anti-proliferative and apoptotic effect of flavonoids isolated from Korean Citrus aurantium L. using A549 lung cancer cells. Flavonoids potently inhibited of A549 cells in a dose-dependent manner, whereas flavonoids had a weak inhibitory effect on proliferation of WI-38 cells. Flow cytometry and Western blot analysis showed that flavonoids induced cell cycle arrest at the G2/M checkpoint by controlling the proteins expression level of cyclin B1, cdc2, cdc25c and p21(WAF1/CIP1). Also, flavonoids induced apoptosis through the regulation of the expression of caspases, cleaved PARP and Bax/Bcl-xL ratio. The activity of caspase-3 on A549 cells increased in a dose-dependent manner. These results clearly indicated that the anti-cancer effect of flavonoids on A549 cells follows multiple cellular pathways through G2/M arrest and the induction of apoptosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Dose–response analysis of acute oral mucositis and pharyngeal dysphagia in patients receiving induction chemotherapy followed by concomitant chemo-IMRT for head and neck cancer

    International Nuclear Information System (INIS)

    Bhide, Shreerang A.; Gulliford, Sarah; Schick, Ulrike; Miah, Aisha; Zaidi, Shane; Newbold, Katie; Nutting, Christopher M.; Harrington, Kevin J.

    2012-01-01

    Dose–response curves (DRCs) and the quantitative parameters describing these curves were generated for grade 3 oral mucositis and dysphagia in 144 patients using individual patient DVHs. Curve fits to the oral mucositis clinical data yielded parameter values of mean dose in 2 Gy equivalent, MD 50 = 51 Gy (95% CI 40–61), slope of the curve, k = 1(95% CI 0.6–1.5). R 2 value for the goodness of fit was 0.80. Fits to the grade 3 dysphagia clinical data yielded parameter values of MD 50 = 44.5 Gy (95% CI 36–53), k = 2.6 (95% CI 0.8–4.5). R 2 value for the goodness of fit was 0.65. This is the first study to derive DRCs in patients receiving induction chemotherapy followed by chemo-radiation (IC-C-IMRT) for head and neck cancer. The dose–response model described in this study could be useful for comparing acute mucositis rates for different dose–fractionation schedules when using IMRT for head and neck cancer.

  20. Expression of LRP and MDR1 in locally advanced breast cancer predicts axillary node invasion at the time of rescue mastectomy after induction chemotherapy

    International Nuclear Information System (INIS)

    Schneider, José; Gonzalez-Roces, Severino; Pollán, Marina; Lucas, Raul; Tejerina, Armando; Martin, Miguel; Alba, Alfonso

    2001-01-01

    Axillary node status after induction chemotherapy for locally advanced breast cancer has been shown on multivariate analysis to be an independent predictor of relapse. However, it has been postulated that responders to induction chemotherapy with a clinically negative axilla could be spared the burden of lymphadenectomy, because most of them will not show histological nodal invasion. P-glycoprotein expression in the rescue mastectomy specimen has finally been identified as a significant predictor of patient survival. We studied the expression of the genes encoding multidrug resistance associated protein (MDR1) and lung cancer associated resistance protein (LRP) in formalin-fixed, paraffin-embedded tumor samples from 52 patients treated for locally advanced breast cancer by means of induction chemotherapy followed by rescue mastectomy. P-glycoprotein expression was assessed by means of immunohistochemistry before treatment in 23 cases, and by means of reverse-transcriptase-mediated polymerase chain reaction (RT-PCR) after treatment in 46 (6 failed). LRP expression was detected by means of immunohistochemistry, with the LRP-56 monoclonal antibody, in 31 cases before treatment. Immunohistochemistry for detecting the expression of c-erb-B2, p53, Ki67, estrogen receptor and progesterone receptor are routinely performed in our laboratory in every case, and the results obtained were included in the study. All patients had received between two and six cycles of standard 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) chemotherapy, with two exceptions [one patient received four cycles of a docetaxel-adriamycin combination, and the other four cycles of standard cyclophosphamide-methotrexate-5-fluorouracil (CMF) polychemotherapy]. Response was assessed in accordance with the Response Evaluation Criteria In Solid Tumors (RECIST). By these, 2 patients achieved a complete clinical response, 37 a partial response, and the remaining 13 showed stable disease. This makes a

  1. Routine TP53 testing for breast cancer under age 30: ready for prime time?

    Science.gov (United States)

    McCuaig, Jeanna M; Armel, Susan R; Novokmet, Ana; Ginsburg, Ophira M; Demsky, Rochelle; Narod, Steven A; Malkin, David

    2012-12-01

    It is well known that early-onset breast cancer may be due to an inherited predisposition. When evaluating women diagnosed with breast cancer under age 30, two important syndromes are typically considered: Hereditary Breast and Ovarian Cancer Syndrome and Li-Fraumeni syndrome. Many women are offered genetic testing for mutations in the BRCA1 and BRCA2 genes; however, few are offered genetic testing for mutations in the TP53 gene. There is a concern that overly restrictive testing of TP53 may fail to recognize families with Li-Fraumeni syndrome. We reviewed the genetic test results and family histories of all women with early-onset breast cancer who had genetic testing of the TP53 gene at the Toronto Hospital for Sick Children. Of the 28 women tested, six (33.3 %) had a mutation in the TP53 gene; a mutation was found in 7.7 % of women who did not meet current criteria for Li-Fraumeni syndrome. By reviewing similar data published between 2000 and 2011, we estimate that 5-8 % of women diagnosed with early-onset breast cancer, and who have a negative family history, may have a mutation in the TP53 gene. Given the potential benefits versus harms of this testing, we discuss the option of simultaneous testing of all three genes (BRCA1, BRCA2, and TP53) for women diagnosed with breast cancer before age 30.

  2. Oxidative Stress and Mitochondrial Activation as the Main Mechanisms Underlying Graphene Toxicity against Human Cancer Cells

    Directory of Open Access Journals (Sweden)

    Anna Jarosz

    2016-01-01

    Full Text Available Due to the development of nanotechnology graphene and graphene-based nanomaterials have attracted the most attention owing to their unique physical, chemical, and mechanical properties. Graphene can be applied in many fields among which biomedical applications especially diagnostics, cancer therapy, and drug delivery have been arousing a lot of interest. Therefore it is essential to understand better the graphene-cell interactions, especially toxicity and underlying mechanisms for proper use and development. This review presents the recent knowledge concerning graphene cytotoxicity and influence on different cancer cell lines.

  3. BCG strain S4-Jena: An early BCG strain is capable to reduce the proliferation of bladder cancer cells by induction of apoptosis

    Directory of Open Access Journals (Sweden)

    Hermann Inge-Marie

    2010-06-01

    Full Text Available Abstract Background Intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guérin has been established as the most effective adjuvant treatment for high risk non-muscle-invasive bladder cancer (NMIBC. We investigated the differences between the S4-Jena BCG strain and commercially available BCG strains. We tested the genotypic varieties between S4-Jena and other BCG strains and analysed the effect of the BCG strains TICE and S4-Jena on two bladder cancer cell lines. Results In contrast to commercially available BCG strains the S4-Jena strain shows genotypic differences. Spoligotyping verifies the S4-Jena strain as a BCG strain. Infection with viable S4-Jena or TICE decreased proliferation in the T24 cell line. Additionally, hallmarks of apoptosis were detectable. In contrast, Cal29 cells showed only a slightly decreased proliferation with TICE. Cal29 cells infected with S4-Jena, though, showed a significantly decreased proliferation in contrast to TICE. Concordantly with these results, infection with TICE had no effect on the morphology and hallmarks of apoptosis of Cal29 cells. However, S4-Jena strain led to clearly visible morphological changes and caspases 3/7 activation and PS flip. Conclusions S4-Jena strain has a direct influence on bladder cancer cell lines as shown by inhibition of cell proliferation and induction of apoptosis. The data implicate that the T24 cells are responder for S4-Jena and TICE BCG. However, the Cal29 cells are only responder for S4-Jena and they are non-responder for TICE BCG. S4-Jena strain may represent an effective therapeutic agent for NMIBC.

  4. Myofascial Induction Effects on Neck-Shoulder Pain in Breast Cancer Survivors: Randomized, Single-Blind, Placebo-Controlled Crossover Design.

    Science.gov (United States)

    Castro-Martín, Eduardo; Ortiz-Comino, Lucía; Gallart-Aragón, Tania; Esteban-Moreno, Bernabé; Arroyo-Morales, Manuel; Galiano-Castillo, Noelia

    2017-05-01

    To (1) investigate the immediate effects of myofascial induction (MI), with placebo electrotherapy as a control, on perceived pain, cervical/shoulder range of motion (ROM), and mood state in breast cancer survivors (BCSs) with shoulder/arm morbidity; and (2) examine the relationships between pain modifications and cervical/shoulder ROM on the side affected by breast cancer. Randomized, single-blind, placebo-controlled crossover study. Physical therapy laboratory. BCSs (N=21) who had a diagnosis of stage I-IIIA breast cancer and had completed adjuvant therapy (except hormonal treatment). During each session, the BCSs received either an MI (fascial unwinding) intervention focused on the upper limb area following the Pilat approach or placebo pulsed shortwave therapy (control group). Each session lasted 30 minutes, and an adequate washout period of 4 weeks between sessions was established. The visual analog scale (VAS) for pain and anxiety, shoulder-cervical goniometry for ROM, the Profile of Mood States for psychological distress, and the Attitudes Towards Massage Scale were used. An analysis of covariance (ANCOVA) revealed significant time × group interactions for VAS affected arm (P=.031) but not for VAS cervical (P=.332), VAS nonaffected arm (P=.698), or VAS anxiety (P=.266). The ANCOVA also revealed significant interactions for affected shoulder flexion (P<.001), abduction (P<.001), external rotation (P=.004), and internal rotation (P=.001). Significant interactions for affected cervical rotation (P=.022) and affected cervical lateral flexion (P=.038) were also found. A significant negative correlation was found between changes in VAS affected arm and shoulder/arm internal rotation ROM (r=-.46; P=.03). A single MI session decreases pain intensity and improves neck-shoulder ROM to a greater degree than placebo electrotherapy for BCSs experiencing pain. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  5. Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression.

    Science.gov (United States)

    Zakraoui, Ons; Marcinkiewicz, Cezary; Aloui, Zohra; Othman, Houcemeddine; Grépin, Renaud; Haoues, Meriam; Essafi, Makram; Srairi-Abid, Najet; Gasmi, Ammar; Karoui, Habib; Pagès, Gilles; Essafi-Benkhadir, Khadija

    2017-01-01

    Lebein, is an heterodimeric disintegrin isolated from Macrovipera lebetina snake venom that was previously characterized as an inhibitor of ADP-induced platelet aggregation. In this study, we investigated the effect of Lebein on the p53-dependent growth of human colon adenocarcinoma cell lines. We found that Lebein significantly inhibited LS174 (p53wt), HCT116 (p53wt), and HT29 (p53mut) colon cancer cell viability by inducing cell cycle arrest through the modulation of expression levels of the tumor suppression factor p53, cell cycle regulating proteins cyclin D1, CDK2, CDK4, retinoblastoma (Rb), CDK1, and cyclin-dependent kinase inhibitors p21 and p27. Interestingly, Lebein-induced apoptosis of colon cancer cells was dependent on their p53 status. Thus, in LS174 cells, cell death was associated with PARP cleavage and the activation of caspases 3 and 8 while in HCT116 cells, Lebein induced caspase-independent apoptosis through increased expression of apoptosis inducing factor (AIF). In LS174 cells, Lebein triggers the activation of the MAPK ERK1/2 pathway through induction of reactive oxygen species (ROS). It also decreased cell adhesion and migration to fibronectin through down regulation of α5β1 integrin. Moreover, Lebein significantly reduced the expression of two angiogenesis stimulators, Vascular Endothelial Growth Factor (VEGF) and Neuropilin 1 (NRP1). It inhibited the VEGF-induced neovascularization process in the quail embryonic CAM system and blocked the development of human colon adenocarcinoma in nude mice. Overall, our work indicates that Lebein may be useful to design a new therapy against colon cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Induction of apoptosis and cell cycle arrest by ethyl acetate fraction of Phoenix dactylifera L. (Ajwa dates) in prostate cancer cells.

    Science.gov (United States)

    Mirza, Muqtadir Baig; Elkady, Ayman I; Al-Attar, Atef M; Syed, Fareeduddin Quadri; Mohammed, Furkhan Ahmed; Hakeem, Khalid Rehman

    2018-02-21

    Phoenix dactylifera L. (Ajwa date) has high nutritive value and are consumed in Arabian Peninsula as an essential diet. Phoenix dactylifera L. have been mentioned in folk remedies of traditional Egyptian medicine and alternative medicine, for numerous health benefits including cancer treatment. The aim of the study is to evaluate the anticancer effects of the extract of Ajwa Date on human Prostate cancer cell line (PC3). Antiproliferative effect was measured using MTT assay. The long-term effect of EAFAD was determined using colony assay. Different stains like Giemsa and fluorescent stains (DAPI and acridine orange / Ethidium bromide) measured morphological changes. Loss of mitochondrial membrane potential and increased oxidative stress were measured using JC-1 and DCFH-DA dyes. DNA degradation was analyzed by comet assay. Cell cycle distribution was measured by flow cytometer. The apoptotic cell was quantified by annexin V-FITC and Propidium iodide dual staining using flow cytometer. PC3 cell line was treated with ethyl acetate fractions of Ajwa dates (EAFAD) to study their morphological and cellular changes and induction of apoptosis. MTT assay showed the strong inhibitory effect of EAFAD on PC3 cells. Loss of mitochondrial membrane potential and increased oxidative stress were observed in EAFAD treated cells, which suggested mitochondrial involvement in apoptosis. Comet assay proved DNA fragmentation induced by EAFAD. Flow Cytometer results demonstrated that Annexin V-FITC and propidium iodide staining showed that EAFAD induced apoptosis and arrest the cell cycle in S phase. Our results suggested EAFAD has potential therapeutics properties for prostate cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Induction of Apoptosis in Human Colon Cancer Cells by Methanol Fraction of Leaves of Plectranthus amboinicus (Lour) Spreng

    OpenAIRE

    Preeja G Pillai; P. Suresh; Gitanjali Mishra

    2013-01-01

    To evaluate the cytotoxicity and apoptosis inducing activities of the methanol extract from leaves of Plectranthus amboinicus (Lour) Spreng in an attempt to determine whether the medicinal uses are supported by pharmacological effects. Cytotoxicity was determined by sulforhodamine B assay method. Cytotoxicity and apoptosis inducing effect were evaluated in- vitro using human colon cancer cell line, COLO 205. There was statistically significant cell growth inhibition at the doses of 10, 20, 40...

  8. Induction of Apoptosis in Human Breast Cancer (MCF7) Cells by n-Hexane Extract of Plectranthus amboinicus (Lour.) Spreng.

    OpenAIRE

    Hasibuan, Poppy Anjelisa Z.

    2016-01-01

    The n-hexane extract of Plectranthus amboinicus, (Lour.) Spreng. reduced the proliferation of MCF7 cells. The present study was carried out to evaluate the effect of the extract on human breast cancer cells viability and apoptosis. To detect apoptotic cells, MCF7 cells were stained with etydium bromide-acrydine orange (double staining method). Quantitative detectin of apoptotic cells was performed by fluorescens microscope. The growth of MCF7 was inhibited by treatment with n-h...

  9. 6-Gingerol Inhibits Growth of Colon Cancer Cell LoVo via Induction of G2/M Arrest

    Directory of Open Access Journals (Sweden)

    Ching-Bin Lin

    2012-01-01

    Full Text Available 6-Gingerol, a natural component of ginger, has been widely reported to possess antiinflammatory and antitumorigenic activities. Despite its potential efficacy against cancer, the anti-tumor mechanisms of 6-gingerol are complicated and remain sketchy. In the present study, we aimed to investigate the anti-tumor effects of 6-gingerol on colon cancer cells. Our results revealed that 6-gingerol treatment significantly reduced the cell viability of human colon cancer cell, LoVo, in a dose-dependent manner. Further flow cytometric analysis showed that 6-gingerol induced significant G2/M phase arrest and had slight influence on sub-G1 phase in LoVo cells. Therefore, levels of cyclins, cyclin-dependent kinases (CDKs, and their regulatory proteins involved in S-G2/M transition were investigated. Our findings revealed that levels of cyclin A, cyclin B1, and CDK1 were diminished; in contrast, levels of the negative cell cycle regulators p27Kip1 and p21Cip1 were increased in response to 6-gingerol treatment. In addition, 6-gingerol treatment elevated intracellular reactive oxygen species (ROS and phosphorylation level of p53. These findings indicate that exposure of 6-gingerol may induce intracellular ROS and upregulate p53, p27Kip1, and p21Cip1 levels leading to consequent decrease of CDK1, cyclin A, and cyclin B1 as result of cell cycle arrest in LoVo cells. It would be suggested that 6-gingerol should be beneficial to treatment of colon cancer.

  10. Monocytopenia; Induction by Vinorelbine, Cisplatin and Doxorubicin in Breast, Non-Small Cell Lung and Cervix Cancer Patients

    Science.gov (United States)

    Nazir, Taha; Taha, Nida; Islam, Azahrul; Abraham, Suraj; Mahmood, Adeel; Mustafa, Mazhar

    2016-01-01

    Background The neoplasm is still a potential threat for breast, Non-Small Cell Lung (NSCL) and cervix cancer patients. Those gradually invade into other body organs, inducing complex pathological complications. Whereas, the anticancer drugs suppress the bone marrow, resulting serious hematological toxicities. Thus, the monocytic toxicity may the chance of infections, particularly in AID’s patients. Objective We aimed this retrospective study to investigate the monocytopenia induced by vinorelbine following chemotherapy in cancer patients. Patients and method A total 60 adult cancer patients were divided into two groups; Group-1 patients received the treatment of Vinorelbine alone while group 2 patients received Vinorelbine based combination chemotherapy. Result The overall comparison of mean monocyte count (×103 per μl) with time showed a significant statistical difference (p value <0.001) for G-I and no significant difference for G-II (p value <0.08). The independent comparison of mean values for two groups at every week confirms the non-significant statistical difference during all of the five weeks (p values 0.551, 0.112, 0.559, 0.372, 0.468 respectively). In addition of that, the comparison of mean values observed before therapy with that of week 4 (after therapy) showed significant difference in G-I (p value <0.001) and non-significant in G-II (p value 0.053). Conclusion Monocytopenia is induced in both of the chemotherapy protocols allows the clinical oncologists and consultant physicians to select either of the chemotherapy protocol. The therapeutic efficacy should constitute the intervening consideration to treat the breast, cervix and NSCL (Non-Small Cell Lung’s) cancers. PMID:27833519

  11. Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction

    OpenAIRE

    Chia-Ming Liu; Chih-Yu Peng; Yi-Wen Liao; Ming-Yi Lu; Meng-Lun Tsai; Jung-Chun Yeh; Chuan-Hang Yu; Cheng-Chia Yu

    2017-01-01

    Background/Purpose: Cancer stem cells (CSCs) are deemed as the driving force of tumorigenesis in oral squamous cell carcinomas (OSCCs). In this study, we investigated the chemotherapeutic effect of sulforaphane, a dietary component from broccoli sprouts, on targeting OSCC-CSCs. Methods: The effect of sulforaphane on normal oral epithelial cells (SG) and sphere-forming OSCC-CSCs isolated from SAS and GNM cells was examined. ALDH1 activity and CD44 positivity of OSCC-CSCs with sulforaphane t...

  12. Adrenaline promotes cell proliferation and increases chemoresistance in colon cancer HT29 cells through induction of miR-155

    Energy Technology Data Exchange (ETDEWEB)

    Pu, Jun [Department of General Surgery, Tangdu Hospital of the Fourth Military Medical University, Xi' an 710038 (China); Bai, Danna [Department of Cardiology, 323 Hospital of PLA, Xi' an 710054 (China); Yang, Xia [Department of Teaching and Medical Administration, Tangdu Hospital of the Fourth Military Medical University, Xi' an 710038 (China); Lu, Xiaozhao [Department of Nephrology, The 323 Hospital of PLA, Xi' an 710054 (China); Xu, Lijuan, E-mail: 13609296272@163.com [Department of Nephrology, The 323 Hospital of PLA, Xi' an 710054 (China); Lu, Jianguo, E-mail: lujianguo029@yahoo.com.cn [Department of General Surgery, Tangdu Hospital of the Fourth Military Medical University, Xi' an 710038 (China)

    2012-11-16

    Highlights: Black-Right-Pointing-Pointer Adrenaline increases colon cancer cell proliferation and its resistance to cisplatin. Black-Right-Pointing-Pointer Adrenaline activates NF{kappa}B in a dose dependent manner. Black-Right-Pointing-Pointer NF{kappa}B-miR-155 pathway contributes to cell proliferation and resistance to cisplatin. -- Abstract: Recently, catecholamines have been described as being involved in the regulation of cancer genesis and progression. Here, we reported that adrenaline increased the cell proliferation and decreased the cisplatin induced apoptosis in HT29 cells. Further study found that adrenaline increased miR-155 expression in an NF{kappa}B dependent manner. HT29 cells overexpressing miR-155 had a higher cell growth rate and more resistance to cisplatin induced apoptosis. In contrast, HT29 cells overexpressing miR-155 inhibitor displayed decreased cell proliferation and sensitivity to cisplatin induced cell death. In summary, our study here revealed that adrenaline-NF{kappa}B-miR-155 pathway at least partially contributes to the psychological stress induced proliferation and chemoresistance in HT29 cells, shedding light on increasing the therapeutic strategies of cancer chemotherapy.

  13. Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction.

    Science.gov (United States)

    Liu, Chia-Ming; Peng, Chih-Yu; Liao, Yi-Wen; Lu, Ming-Yi; Tsai, Meng-Lun; Yeh, Jung-Chun; Yu, Chuan-Hang; Yu, Cheng-Chia

    2017-01-01

    Cancer stem cells (CSCs) are deemed as the driving force of tumorigenesis in oral squamous cell carcinomas (OSCCs). In this study, we investigated the chemotherapeutic effect of sulforaphane, a dietary component from broccoli sprouts, on targeting OSCC-CSCs. The effect of sulforaphane on normal oral epithelial cells (SG) and sphere-forming OSCC-CSCs isolated from SAS and GNM cells was examined. ALDH1 activity and CD44 positivity of OSCC-CSCs with sulforaphane treatment was assessed by flow cytometry analysis. In vitro and in vivo tumorigenicity assays of OSCC-CSCs with sulforaphane treatment were presented. We observed that the sulforaphane dose-dependently eliminated the proliferation rate of OSCC-CSCs, whereas the inhibition on SG cells proliferation was limited. Cancer stemness properties including self-renewal, CD44 positivity, and ALDH1 activity were also decreased in OSCC-CSCs with different doses of sulforaphane treatment. Moreover, sulforaphane treatment of OSCC-CSCs decreased the migration, invasion, clonogenicity, and in vivo tumorigenicity of xenograghts. Sulforaphane treatment resulted in a dose-dependent increase in the levels of tumor suppressive miR200c. These lines of evidence suggest that sulforaphane can suppress the cancer stemness and tumor-initiating properties in OSCC-CSCs both in vitro and in vivo. Copyright © 2016. Published by Elsevier B.V.

  14. Adrenaline promotes cell proliferation and increases chemoresistance in colon cancer HT29 cells through induction of miR-155

    International Nuclear Information System (INIS)

    Pu, Jun; Bai, Danna; Yang, Xia; Lu, Xiaozhao; Xu, Lijuan; Lu, Jianguo

    2012-01-01

    Highlights: ► Adrenaline increases colon cancer cell proliferation and its resistance to cisplatin. ► Adrenaline activates NFκB in a dose dependent manner. ► NFκB–miR-155 pathway contributes to cell proliferation and resistance to cisplatin. -- Abstract: Recently, catecholamines have been described as being involved in the regulation of cancer genesis and progression. Here, we reported that adrenaline increased the cell proliferation and decreased the cisplatin induced apoptosis in HT29 cells. Further study found that adrenaline increased miR-155 expression in an NFκB dependent manner. HT29 cells overexpressing miR-155 had a higher cell growth rate and more resistance to cisplatin induced apoptosis. In contrast, HT29 cells overexpressing miR-155 inhibitor displayed decreased cell proliferation and sensitivity to cisplatin induced cell death. In summary, our study here revealed that adrenaline–NFκB–miR-155 pathway at least partially contributes to the psychological stress induced proliferation and chemoresistance in HT29 cells, shedding light on increasing the therapeutic strategies of cancer chemotherapy.

  15. The effect of under-treatment of breast cancer in women 80 years of age and older

    NARCIS (Netherlands)

    Van Leeuwen, Barbara L.; Rosenkranz, K. M.; Feng, L. Lei; Bedrosian, I.; Hartmann, K.; Hunt, K. K.; Kuerer, H. M.; Ross, M.; Singletary, S. E.; Babiera, Gildy V.

    Background: Several authors have demonstrated a trend toward the under-treatment of elderly and very elderly women with breast cancer. This study was undertaken to determine the impact of under-treatment of breast cancer in women age 80 and older. Methods: A retrospective chart review of all

  16. Covariation in Natural Causal Induction.

    Science.gov (United States)

    Cheng, Patricia W.; Novick, Laura R.

    1991-01-01

    Biases and models usually offered by cognitive and social psychology and by philosophy to explain causal induction are evaluated with respect to focal sets (contextually determined sets of events over which covariation is computed). A probabilistic contrast model is proposed as underlying covariation computation in natural causal induction. (SLD)

  17. Evaluation of the efficacy & biochemical mechanism of cell death induction by Piper longum extract selectively in in-vitro and in-vivo models of human cancer cells.

    Directory of Open Access Journals (Sweden)

    Pamela Ovadje

    Full Text Available Currently chemotherapy is limited mostly to genotoxic drugs that are associated with severe side effects due to non-selective targeting of normal tissue. Natural products play a significant role in the development of most chemotherapeutic agents, with 74.8% of all available chemotherapy being derived from natural products.To scientifically assess and validate the anticancer potential of an ethanolic extract of the fruit of the Long pepper (PLX, a plant of the piperaceae family that has been used in traditional medicine, especially Ayurveda and investigate the anticancer mechanism of action of PLX against cancer cells.Following treatment with ethanolic long pepper extract, cell viability was assessed using a water-soluble tetrazolium salt; apoptosis induction was observed following nuclear staining by Hoechst, binding of annexin V to the externalized phosphatidyl serine and phase contrast microscopy. Image-based cytometry was used to detect the effect of long pepper extract on the production of reactive oxygen species and the dissipation of the mitochondrial membrane potential following Tetramethylrhodamine or 5,5,6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine chloride staining (JC-1. Assessment of PLX in-vivo was carried out using Balb/C mice (toxicity and CD-1 nu/nu immunocompromised mice (efficacy. HPLC analysis enabled detection of some primary compounds present within our long pepper extract.Our results indicated that an ethanolic long pepper extract selectively induces caspase-independent apoptosis in cancer cells, without affecting non-cancerous cells, by targeting the mitochondria, leading to dissipation of the mitochondrial membrane potential and increase in ROS production. Release of the AIF and endonuclease G from isolated mitochondria confirms the mitochondria as a potential target of long pepper. The efficacy of PLX in in-vivo studies indicates that oral administration is able to halt the growth of colon cancer

  18. Cytotoxic effects of escin on human castration-resistant prostate cancer cells through the induction of apoptosis and G2/M cell cycle arrest.

    Science.gov (United States)

    Piao, Songzhe; Kang, Minyong; Lee, Young Ju; Choi, Woo Suk; Chun, Yang-Sook; Kwak, Cheol; Kim, Hyeon Hoe

    2014-10-01

    To evaluate the in vitro and in vivo effects of escin on human castration-resistant prostate cancer (CRPC) cells, PC-3 and DU-145. The inhibition of cell proliferation and its mechanism were assessed through a cytotoxicity assay, flow cytometry, and Western blot. The in vivo efficacy of escin in CRPC cells was assessed using a xenograft tumor model subcutaneously established in BALB/c nude mice. The treatment with escin significantly reduced cell viability of CRPC cells in a dose- and time-dependent manner. Escin induced apoptosis in a time-dependent manner, which was accompanied by increases in pro-apoptotic (BCL-2 associated X protein, cleaved-caspase3, and cleaved-poly [adenosine diphosphate-ribose] polymerase) proteins and decreases in antiapoptotic (X-linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis protein-1, cellular inhibitor of apoptosis protein-2B-cell leukemia/lymphoma-2, and B-cell lymphoma-extra large) proteins. Escin induced G2/M-phase cell cycle arrest and thus led to a significant decrease in the expression of cyclinB1 and its activating partner cyclin-dependent kinase 1, with the concomitant induction of p21. In addition, escin significantly inhibited the growth of CRPC cells in xenograft models. The results show that escin induced cytotoxic effects on CRPC cells through the induction of apoptosis and G2/M cell cycle arrest, indicating it may be a novel therapeutic agent for CRPC. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. VP-16 resistance in the NCI-H460 human lung cancer cell line is significantly associated with glucose-regulated protein78 (GRP78) induction.

    Science.gov (United States)

    Wang, Qi; Wang, Tao; Wang, Yingyan; Wang, Wei; Wang, Yanyan; Hu, Xiujuan; Shao, Shujuan; Zhang, Jinhui; Suo, Zhenhe

    2007-01-01

    To investigate the relationship between the expression of glucose-regulated protein (GRP78) and resistance to VP-16 in the NCI-H460 cell line. RT-PCR, real-time RT-PCR and Western blotting were used in analyzing the expression of GRP78 at mRNA and protein levels in the NCI-H460 cell line induced by A23187 at different concentrations. Cell survival with VP-16 was determined using a colony-formation assay with the account of IC50. The expression of GRP78 at both the mRNA and protein levels was higher in the NCI-H460 cell line induced by A23187. A23187 treatment resulted in up to 4.8-fold elevation of GRP78 mRNA and up to 3.2-fold elevation of GRP78 protein in the experimental cells compared to the controls, all in a dose-dependent manner. The IC50s for VP-16 in the cells pretreated with different concentrations of A23187 (0, 1, 2, 4 and 6 microM) were: 12.11 +/- 0.83, 12.68 +/- 1.04, 25.82 +/- 1.83, 37.46 +/- 1.89 and 45.19 +/- 2.34 microM, respectively. Compared to the control, there was a significant elevation of IC50 for VP-16 in the cells pretreated with A23187. Survival curve analysis also showed that the induction of A23187 caused a significantly longer survival for the cells subjected to VP-16 treatment (p VP-16 in the human lung cancer NCI-H460 cell line. Based on the trend of the change in IC50 and the expression of GRP78 in differently exposed cells, we conclude that the induction of GRP78 by A23187 is significantly associated with the resistance to VP-16.

  20. Chemoprevention of skin cancer with 1,1-Bis (3'-indolyl-1-(aromatic methane analog through induction of the orphan nuclear receptor, NR4A2 (Nurr1.

    Directory of Open Access Journals (Sweden)

    Cedar H A Boakye

    Full Text Available The objective of this study was to demonstrate the anti-skin cancer and chemopreventive potential of 1,1-bis(3'-indolyl-1-(p-chlorophenyl methane (DIM-D using an in vitro model.In vitro cell cytotoxicity and viability assays were carried out in A431 human epidermoid carcinoma cell line and normal human epidermal keratinocytes (NHEK respectively by crystal violet staining. Apoptosis induction in A431 cells (DIM-D treated and NHEK cells pretreated with DIM-D (2 hr prior to UVB irradiation, were assessed. The accumulation of reactive oxygen species (ROS in DIM-D pretreated NHEK cells (2 hr prior to UVB exposure was also determined. Immunocytochemistry and western blot analysis was performed to determine cleaved caspase 3 and DNA damage markers in DIM-D treated A431 cells and in DIM-D pretreated NHEK cells prior to UVB irradiation.The IC50 values of DIM-D were 68.7 ± 7.3, 48.3 ± 10.1 and 11.5 ± 3.1 μM whilst for Epigallocatechin gallate (EGCG were 419.1 ± 8.3, 186.1 ± 5.2 and 56.7 ± 3.1 μM for 24, 48 and 72 hr treatments respectively. DIM-D exhibited a significantly (p<0.05 greater induction of DNA fragmentation in A431 cells compared to EGCG with percent cell death of 38.9. In addition, DIM-D induced higher expression in A431 cells compared to EGCG of cleaved caspase 3 (3.0-fold vs. 2.4-fold changes, Nurr1 (2.7-fold vs. 1.7-fold changes and NFκB (1.3-fold vs. 1.1-fold changes. DIM-D also exhibited chemopreventive activity in UVB-irradiated NHEK cells by significantly (p<0.05 reducing UVB-induced ROS formation and apoptosis compared to EGCG. Additionally, DIM-D induced expression of Nurr1 but reduced expression of 8-OHdG significantly in UVB-irradiated NHEK cells compared to EGCG and UV only.Our results suggest that DIM-D exhibits Nurr1-dependent transactivation in the induction of apoptosis in A431 cells and it protects NHEK cells against UVB-induced ROS formation and DNA damage.

  1. Acridine orange exhibits photodamage in human bladder cancer cells under blue light exposure.

    Science.gov (United States)

    Lin, Yi-Chia; Lin, Ji-Fan; Tsai, Te-Fu; Chen, Hung-En; Chou, Kuang-Yu; Yang, Shan-Che; Tang, Ya-Ming; Hwang, Thomas I-Sheng

    2017-10-26

    Human bladder cancer (BC) cells exhibit a high basal level of autophagic activity with accumulation of acridine-orange(AO)-stained acidic vesicular organelles. The rapid AO relocalization was observed in treated BC cells under blue-light emission. To investigate the cytotoxic effects of AO on human BC cell lines under blue-light exposure, human immortalized uroepithelial (SV-Huc-1) and BC cell lines (5637 and T24) were treated with indicated concentrations of AO or blue-light exposure alone and in combination. The cell viability was then determined using WST-1, time-lapse imaging with a Cytosmart System and continuous quantification with a multi-mode image-based reader. Treatment of AO or blue-light exposure alone did not cause a significant loss of viability in BC cells. However, AO exhibited a dose-dependent increment of cytotoxicity toward BC cells under blue-light exposure. Furthermore, the tumor formation of BC cells with treatment was significantly reduced when evaluated in a mouse xenograft model. The photodamage caused by AO was nearly neglected in SV-Huc-1 cells, suggesting a differential effect of this treatment between cancer and normal cells. In summary, AO, as a photosensitizer, disrupts acidic organelles and induces cancer cell death in BC cells under blue-light irradiation. Our findings may serve as a novel therapeutic strategy against human BC.

  2. Plumericin inhibits the viability of cervical cancer cells by induction of apoptosis through degradation of DNA structure

    Directory of Open Access Journals (Sweden)

    Jing Sun

    2016-06-01

    Full Text Available The current study demonstrates the effect of plumericin on the viability and induction of apoptosis through degradation of double helical DNA structure in Bu25TK and HeLa cervical carcinoma cell lines. Plumericin treatment exhibited concentration- and time-dependent effect on the viability of Bu25TK and HeLa cells. Incubation of Bu25TK and HeLa cells with 40 µM concentration of plumericin decreased cell viability to 24 and 29%, respectively after 48 hours. Plumericin treatment also caused significant increase in the proportion of apoptotic cells in both the cell lines at 40 µM concentration compared to the control cells. Examination of the DNA double helical structure after 48 hours of treatment with plumericin at 40 µM concentration showed DNA degradation and formation of comets. Thus, plumericin exhibits inhibitory effect on the viability of Bu25TK and HeLa cells and induced apoptosis through DNA degradation. Therefore, plumericin is a potent candidate for the treatment of cervical carcinoma.

  3. Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy

    Directory of Open Access Journals (Sweden)

    Laviano Alessandro

    2010-03-01

    Full Text Available Abstract Objectives To determine the relationship between energy and nutrient consumption with chemosensory changes in cancer patients under chemotherapy. Methods We carried out a cross-sectional study, enrolling 60 subjects. Cases were defined as patients with cancer diagnosis after their second chemotherapy cycle (n = 30, and controls were subjects without cancer (n = 30. Subjective changes of taste during treatment were assessed. Food consumption habits were obtained with a food frequency questionnaire validated for Mexican population. Five different concentrations of three basic flavors --sweet (sucrose, bitter (urea, and a novel basic taste, umami (sodium glutamate-- were used to measure detection thresholds and recognition thresholds (RT. We determine differences between energy and nutrient consumption in cases and controls and their association with taste DT and RT. Results No demographic differences were found between groups. Cases showed higher sweet DT (6.4 vs. 4.4 μmol/ml; p = 0.03 and a higher bitter RT (100 vs. 95 μmol/ml; p = 0.04 than controls. Cases with sweet DT above the median showed significant lower daily energy (2,043 vs.1,586 kcal; p = 0.02, proteins (81.4 vs. 54 g/day; p = 0.01, carbohydrates (246 vs.192 g/day; p = 0.05, and zinc consumption (19 vs.11 mg/day; p = 0.01 compared to cases without sweet DT alteration. Cases with sweet DT and RT above median were associated with lower completion of energy requirements and consequent weight loss. There was no association between flavors DT or RT and nutrient ingestion in the control group. Conclusion Changes of sweet DT and bitter RT in cancer patients under chemotherapy treatment were associated with lower energy and nutrient ingestion. Taste detection and recognition thresholds disorders could be important factors in malnutrition development on patients with cancer under chemotherapy treatment.

  4. Endoplasmic Reticulum–Mitochondrial Ca2+ Fluxes Underlying Cancer Cell Survival

    Directory of Open Access Journals (Sweden)

    Hristina Ivanova

    2017-05-01

    Full Text Available Calcium ions (Ca2+ are crucial, ubiquitous, intracellular second messengers required for functional mitochondrial metabolism during uncontrolled proliferation of cancer cells. The mitochondria and the endoplasmic reticulum (ER are connected via “mitochondria-associated ER membranes” (MAMs where ER–mitochondria Ca2+ transfer occurs, impacting the mitochondrial biology related to several aspects of cellular survival, autophagy, metabolism, cell death sensitivity, and metastasis, all cancer hallmarks. Cancer cells appear addicted to these constitutive ER–mitochondrial Ca2+ fluxes for their survival, since they drive the tricarboxylic acid cycle and the production of mitochondrial substrates needed for nucleoside synthesis and proper cell cycle progression. In addition to this, the mitochondrial Ca2+ uniporter and mitochondrial Ca2+ have been linked to hypoxia-inducible factor 1α signaling, enabling metastasis and invasion processes, but they can also contribute to cellular senescence induced by oncogenes and replication. Finally, proper ER–mitochondrial Ca2+ transfer seems to be a key event in the cell death response of cancer cells exposed to chemotherapeutics. In this review, we discuss the emerging role of ER–mitochondrial Ca2+ fluxes underlying these cancer-related features.

  5. Antiproliferation and Induction of Apoptosis in Ca9-22 Oral Cancer Cells by Ethanolic Extract of Gracilaria tenuistipitata

    Directory of Open Access Journals (Sweden)

    Chi-Chen Yeh

    2012-09-01

    Full Text Available The water extract of Gracilaria tenuistipitata have been found to be protective against oxidative stress-induced cellular DNA damage, but the biological function of the ethanolic extracts of G. tenuistipitata (EEGT is still unknown. In this study, the effect of EEGT on oral squamous cell cancer (OSCC Ca9-22 cell line was examined in terms of the cell proliferation and oxidative stress responses. The cell viability of EEGT-treated OSCC cells was significantly reduced in a dose-response manner (p < 0.0001. The annexin V intensity and pan-caspase activity of EEGT-treated OSCC cells were significantly increased in a dose-response manner (p < 0.05 to 0.0001. EEGT significantly increased the reactive oxygen species (ROS level (p < 0.0001 and decreased the glutathione (GSH level (p < 0.01 in a dose-response manner. The mitochondrial membrane potential (MMP of EEGT-treated OSCC cells was significantly decreased in a dose-response manner (p < 0.005. In conclusion, we have demonstrated that EEGT induced the growth inhibition and apoptosis of OSCC cells, which was accompanied by ROS increase, GSH depletion, caspase activation, and mitochondrial depolarization. Therefore, EEGT may have potent antitumor effect against oral cancer cells.

  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. Crude aqueous extracts of Pluchea indica (L. Less. inhibit proliferation and migration of cancer cells through induction of p53-dependent cell death

    Directory of Open Access Journals (Sweden)

    Cho Jonathan J

    2012-12-01

    Full Text Available Abstract Background Pluchea indica (L. Less. (Asteraceae is a perennial shrub plant with anti-inflammatory and antioxidant medicinal properties. However, the anti-cancer properties of its aqueous extracts have not been studied. The aim of this study was to investigate the anti-proliferation, anti-migration, and pro-apoptotic properties of crude aqueous extracts of P. indica leaf and root on human malignant glioma cancer cells and human cervical cancer cells, and the underlying molecular mechanism. Methods GBM8401 human glioma cells and HeLa cervical carcinoma cells were treated with various concentrations of crude aqueous extracts of P. indica leaf and root and cancer cell proliferation and viability were measured by cell growth curves, trypan blue exclusions, and the tetrazolium reduction assay. Effects of the crude aqueous extracts on focus formation, migration, and apoptosis of cancer cells were studied as well. The molecular mechanism that contributed to the anti-cancer activities of crude aqueous extracts of P. indica root was also examined using Western blotting analysis. Results Crude aqueous extracts of P. indica leaf and root suppressed proliferation, viability, and migration of GBM8401 and HeLa cells. Treatment with crude aqueous extracts of P. indica leaf and root for 48 hours resulted in a significant 75% and 70% inhibition on proliferation and viability of GBM8401 and HeLa cancer cells, respectively. Crude aqueous extracts of P. indica root inhibited focus formation and promoted apoptosis of HeLa cells. It was found that phosphorylated-p53 and p21 were induced in GBM8401 and HeLa cells treated with crude aqueous extracts of P. indica root. Expression of phosphorylated-AKT was decreased in HeLa cells treated with crude aqueous extracts of P. indica root. Conclusion The in vitro anti-cancer effects of crude aqueous extracts of P. indica leaf and root indicate that it has sufficient potential to warrant further examination and

  8. Clinical trial insurance coverage for cancer patients under the Affordable Care Act

    Directory of Open Access Journals (Sweden)

    Christine B. Mackay

    2016-04-01

    Conclusion: Three main factors limit the effectiveness of the ACA provisions in expanding clinical trial coverage: 1 ‘grandfathered’ self-funded employer plans not subject to state Employee Retirement Income Security Act (ERISA regulations, 2 Medicaid coverage limits not addressed under the ACA, 3 populations that remain uninsured. Kansas saw a negligible increase in insurance coverage as a result of the ACA thus lack of insurance coverage is likely to remain a concern for cancer patients.

  9. Clusterin and chemotherapy sensitivity under normoxic and graded hypoxic conditions in colorectal cancer.

    LENUS (Irish Health Repository)

    Kevans, David

    2012-06-01

    In vitro studies have shown that clusterin modulates treatment sensitivity in a number of human cancers; however, the interaction between clusterin expression and hypoxia in controlling treatment response in CRC has not previously been examined. The aim of this study was to assess the effect of clusterin overexpression in CRC cells on sensitivity to 5-fluorouracil (5-FU), oxaliplatin and FOLFOX treatment under normoxic and graded hypoxic conditions.

  10. Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy.

    Science.gov (United States)

    Pelizzaro-Rocha, Karin Juliane; de Jesus, Marcelo Bispo; Ruela-de-Sousa, Roberta Regina; Nakamura, Celso Vataru; Reis, Fabiano Souza; de Fátima, Angelo; Ferreira-Halder, Carmen Veríssima

    2013-12-01

    Pancreatic cancer ranks fourth among cancer-related causes of death in North America. Minimal progress has been made in the diagnosis and treatment of patients with late-stage tumors. Moreover, pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid disease progression, resistance and metastasis. The main goal of this study was to define the mechanisms by which calix[6]arene, but not other calixarenes, efficiently decreases the aggressiveness of a drug resistant human pancreas carcinoma cell line (Panc-1). Calix[6]arene was more potent in reducing Panc-1 cell viability than gemcitabine and 5-fluorouracil. In relation to the underlying mechanisms of cytotoxic effects, it led to cell cycle arrest in the G0/G1 phase through downregulation of PIM1, CDK2, CDK4 and retinoblastoma proteins. Importantly, calix[6]arene abolished signal transduction of Mer and AXL tyrosine kinase receptors, both of which are usually overexpressed in pancreatic cancer. Accordingly, inhibition of PI3K and mTOR was also observed, and these proteins are positively modulated by Mer and AXL. Despite decreasing the phosphorylation of AKT at Thr308, calix[6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-α provide a molecular basis explaining the capacity of calix[6]arene to trigger endoplasmic reticulum stress and autophagic cell death. Our findings highlight calix[6]arene as a potential candidate for overcoming pancreatic cancer aggressiveness. Importantly, we provide evidence that calix[6]arene affects a broad array of key targets that are usually dysfunctional in pancreatic cancer, a highly desirable characteristic for chemotherapeutics. © 2013.

  11. Induction of cell proliferation and survival genes by estradiol-repressed microRNAs in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Yu Xinfeng

    2012-01-01

    Full Text Available Abstract Background In estrogen responsive MCF-7 cells, estradiol (E2 binding to ERα leads to transcriptional regulation of genes involved in the control of cell proliferation and survival. MicroRNAs (miRNAs have emerged as key post-transcriptional regulators of gene expression. The aim of this study was to explore whether miRNAs were involved in hormonally regulated expression of estrogen responsive genes. Methods Western blot and QPCR were used to determine the expression of estrogen responsive genes and miRNAs respectively. Target gene expression regulated by miRNAs was validated by luciferase reporter assays and transfection of miRNA mimics or inhibitors. Cell proliferation was evaluated by MTS assay. Results E2 significantly induced bcl-2, cyclin D1 and survivin expression by suppressing the levels of a panel of miRNAs (miR-16, miR-143, miR-203 in MCF-7 cells. MiRNA transfection and luciferase assay confirmed that bcl-2 was regulated by miR-16 and miR-143, cyclinD1 was modulated by miR-16. Importantly, survivin was found to be targeted by miR-16, miR-143, miR-203. The regulatory effect of E2 can be either abrogated by anti-estrogen ICI 182, 780 and raloxifene pretreatment, or impaired by ERα siRNA, indicating the regulation is dependent on ERα. In order to investigate the functional significance of these miRNAs in estrogen responsive cells, miRNAs mimics were transfected into MCF-7 cells. It revealed that overexpression of these miRNAs significantly inhibited E2-induced cell proliferation. Further study of the expression of the miRNAs indicated that miR-16, miR-143 and miR-203 were highly expressed in triple positive breast cancer tissues, suggesting a potential tumor suppressing effect of these miRNAs in ER positive breast cancer. Conclusions These results demonstrate that E2 induces bcl-2, cyclin D1 and survivin by orchestrating the coordinate downregulation of a panel of miRNAs. In turn, the miRNAs manifest growth suppressive effects

  12. Induction of protective and therapeutic anti-pancreatic cancer immunity using a reconstructed MUC1 DNA vaccine

    International Nuclear Information System (INIS)

    Rong, Yefei; Jin, Dayong; Wu, Wenchuan; Lou, Wenhui; Wang, Danshong; Kuang, Tiantao; Ni, Xiaoling; Qin, Xinyu

    2009-01-01

    Pancreatic cancer is a common, highly lethal disease with a rising incidence. MUC1 is a tumor-associated antigen that is over-expressed in pancreatic adenocarcinoma. Active immunotherapy that targets MUC1 could have great treatment value. Here we investigated the preventive and therapeutic effect of a MUC1 DNA vaccine on the pancreatic cancer. MUC1-various tandem repeat units(VNTR) DNA vaccine was produced by cloning one repeat of VNTR and inserting the cloned gene into the pcDNA3.1. In the preventive group, female C57BL/6 mice were immunized with the vaccine, pcDNA3.1 or PBS; and challenged with panc02-MUC1 or panc02 cell. In the therapeutic group the mice were challenged with panc02-MUC1 or panc02 cell, and then immunized with the vaccine, pcDNA3.1 or PBS. The tumor size and the survival time of the animals were compared between these groups. The DNA vaccine pcDNA3.1-VNTR could raise cytotoxic T lymphocyte (CTL) activity specific for MUC1. In the preventive experiment, the mice survival time was significantly longer in the vaccine group than in the control groups (P < 0.05). In the therapeutic experiment, the DNA vaccine prolonged the survival time of the panc02-MUC1-bearing mice (P < 0.05). In both the preventive and therapeutic experiments, the tumor size was significantly less in the vaccine group than in the control groups (P < 0.05). This pcDNA3.1-VNTR vaccine, however, could not prevent the mice attacked by panc02 cells and had no therapeutic effect on the mice attacked by panc02 cells. The MUC1 DNA vaccine pcDNA3.1-VNTR could induce a significant MUC1-specific CTL response; and had both prophylactic and therapeutic effect on panc02-MUC1 tumors. This vaccine might be used as a new adjuvant strategy against pancreatic cancer

  13. Lumpectomy and sentinel lymph node navigation surgery for breast cancer under local anesthesia

    International Nuclear Information System (INIS)

    Nakajima, Hiroo; Fujiwara, Ikuya; Mizuta, Naruhiko; Sakaguchi, Koichi; Hachimine, Yasushi; Nakatsukasa, Katsuhiro; Kobayashi, Aya

    2007-01-01

    We studied and analyzed therapeutic outcomes of a radical surgery under local anesthesia for breast cancer in our department. Subjects were 53 patients with breast cancer whose diagnoses were definitely made before surgery. Indications were: localized ductal carcinoma in situ (DCIS) diagnosed preoperatively; invasive carcinoma less than 3 cm in tumor diameter on ultrasound and magnetic resonance imaging scan; and clinically tumors with negative axillary lymph nodes. Operative procedures included microdochectomy or lumpectomy associated with sentinel lymph node navigation biopsy (SLNB). We could perform the operation under local anesthesia in all the 53 patients, and were not demanded to shift from local to general anesthesia. Surgical stumps were positive in 10 patients (18.9%). Of the ten patients, additional resection was performed in one, and irradiation was added to the remaining nine patients. SLNB was performed in a total of 39 patients, six (15.4%) patients of them had metastasis and two out of the six patients underwent additional axillary lymph node dissection. None of serious complications were encountered. Local recurrence and hepatic metastasis occurred in each one patient in an averaged observation period of 15.1 months. This day's radical operation under local anesthesia for breast cancer is a useful procedure as minimally invasive surgery as for the indications employed in this study. (author)

  14. Radiosensitivity and gene expression of human lung cancer cells dividing in nude tumor before (anoxic) and after vascular induction

    International Nuclear Information System (INIS)

    Miyamoto, Tadaaki; Baba, Masayuki; Sugawara, Toshiyuki; Yashiro, Tomoyasu; Saegusa, Kumiko; Furuno, Aki; Michikawa, Yuichi; Imai, Takashi

    2005-01-01

    Using cultured and nude mouse tumor cell (IA) derived frome a human lung cancer, we studied their radiosensitivity by focusing attention on the dynamics of tumor clonogens. The movement of clonogens in the regrowing IA tumor after X rays irradiation can be divided into three phases: first,: the early and rapid survival recovery (PLD repair) phase, second, the delay phase involving a certain lag in survival change, and third, the repopulation phase consisting of two stagea. Now we compare with the dynamics of tumor clonogens before or after exposure to X rays and carbon-ion beams. PLD repair was not observed in a carbon-ion beam. In relation to radiosensitivity and repair mechanism, we studied the gene expression of the cultured cell and nude tumor with a microarray method using 22K custom oligoallele. (author)

  15. Induction of heme oxygenase-1 with hemin alleviates cisplatin-induced reproductive toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line.

    Science.gov (United States)

    Heeba, Gehan Hussein; Hamza, Alaaeldin Ahmed; Hassanin, Soha Osama

    2016-12-15

    Cisplatin-induced testicular damage is a major obstacle in the application of cisplatin as chemotherapeutic agent. However, it remains as one of the most widely employed anticancer agents in treating various solid tumors including prostate cancer. Since heme-oxygenase-1 (HO-1) is a cytoprotective enzyme with anti-oxidative stress, anti-inflammatory and anticancer activities, we investigated the effects of up-regulation of HO-1 by hemin and its inhibition by zinc protoporphyrin-IX (ZnPP) on cisplatin-induced testicular toxicity in adult rats. Furthermore, the anticancer effect of hemin and ZnPP, with and without cisplatin, was evaluated on human prostate cancer cell line, PC3. Results of the animal study showed that hemin reversed cisplatin-induced perturbations in sperm characteristics, normalized serum testosterone level, and ameliorated cisplatin-induced alterations in testicular and epididymal weights, and restored normal testicular architecture. Moreover, hemin increased the expression and activity of HO-1 protein and prevented cisplatin-induced testicular toxicity by virtue of its antioxidant and anti-inflammatory effects. This effect was evidenced by amelioration of testicular oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione contents, and catalase activity) and inflammatory mediators (tumor necrosis factor-α and nitric oxide synthase expressions). In contrast, administration of ZnPP (HO-1 inhibitor) did not show significant improvement against cisplatin-induced testicular toxicity. Finally, in vitro analyses showed that, hemin augmented the anticancer efficacy of cisplatin, while ZnPP inhibited its apoptotic effect in PC3 cells. In conclusion, the induction of HO-1 represents a potential therapeutic approach to protect the testicular tissue from the detrimental effects of cisplatin without repressing, but rather augmenting, its cytotoxic effects on PC3 cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Synthesis of an anthraquinone derivative (DHAQC) and its effect on induction of G2/M arrest and apoptosis in breast cancer MCF-7 cell line.

    Science.gov (United States)

    Yeap, SweeKeong; Akhtar, Muhammad Nadeem; Lim, Kian Lam; Abu, Nadiah; Ho, Wan Yong; Zareen, Seema; Roohani, Kiarash; Ky, Huynh; Tan, Sheau Wei; Lajis, Nordin; Alitheen, Noorjahan Banu

    2015-01-01

    Anthraquinones are an important class of naturally occurring biologically active compounds. In this study, anthraquinone derivative 1,3-dihydroxy-9,10-anthraquinone-2- carboxylic acid (DHAQC) (2) was synthesized with 32% yield through the Friedel-Crafts condensation reaction. The mechanisms of cytotoxicity of DHAQC (2) in human breast cancer MCF-7 cells were further investigated. Results from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that DHAQC (2) exhibited potential cytotoxicity and selectivity in the MCF-7 cell line, comparable with the naturally occurring anthraquinone damnacanthal. DHAQC (2) showed a slightly higher IC50 (inhibitory concentration with 50% cell viability) value in the MCF-7 cell line compared to damnacanthal, but it is more selective in terms of the ratio of IC50 on MCF-7 cells and normal MCF-10A cells. (selective index for DHAQC (2) was 2.3 and 1.7 for damnacanthal). The flow cytometry cell cycle analysis on the MCF-7 cell line treated with the IC50 dose of DHAQC (2) for 48 hours showed that DHAQC (2) arrested MCF-7 cell line at the G2/M phase in association with an inhibited expression of PLK1 genes. Western blot analysis also indicated that the DHAQC (2) increased BAX, p53, and cytochrome c levels in MCF-7 cells, which subsequently activated apoptosis as observed in annexin V/propidium iodide and cell cycle analyses. These results indicate that DHAQC (2) is a synthetic, cytotoxic, and selective anthraquinone, which is less toxic than the natural product damnacanthal, and which demonstrates potential in the induction of apoptosis in the breast cancer MCF-7 cell line.

  17. "Hard" and "soft" lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy.

    Science.gov (United States)

    Garrido, Federico; Cabrera, Teresa; Aptsiauri, Natalia

    2010-07-15

    The ability of cancer cells to escape from the natural or immunotherapy-induced antitumor immune response is often associated with alterations in the tumor cell surface expression of Major Histocompatibility Complex (MHC) Class I antigens. Considerable knowledge has been gained on the prevalence of various patterns of MHC Class I defects and the underlying molecular mechanisms in different types of cancer. In contrast, few data are available on the changes in MHC Class I expression happening during the course of cancer immunotherapy. We have recently proposed that the progression or regression of a tumor lesion in cancer patients undergoing immunotherapy could be predetermined by the molecular mechanism responsible for the MHC Class I alteration and not by the type of immunotherapy used, i.e., interleukin-2 (IL-2), Bacillus Calmette-Guèrin (BCG), interferon-alpha (IFN-alpha), peptides alone, dendritic cells loaded with peptides, protein-bound polysaccharide etc. If the molecular alteration responsible for the changes in MHC Class I expression is reversible by cytokines ("soft" lesion), the MHC Class I expression will be upregulated, the specific T cell-mediated response will increase and the lesion will regress. However, if the molecular defect is structural ("hard" lesion), the MHC Class I expression will remain low, the escape mechanism will prevail and the primary tumor or the metastatic lesion will progress. According to this idea, the nature of the preexisting MHC Class I lesion in the cancer cell has a crucial impact determining the final outcome of cancer immunotherapy. In this article, we discuss the importance of these two types of molecular mechanisms of MHC Class I-altered expression.

  18. [The effect of As2O3 on induction of apoptosis and inhibition of telomerase activity in colon cancer LS-174T cells].

    Science.gov (United States)

    Wang, Xi-Shan; Wang, Gui-Yu; Xu, Hai-Tao; Wang, Kuan; Liu, Ming; Fu, Song-Bin; Geng, Jing-Shu; Zhang, Qi-Fan; Dong, Xin-Shu; Zhao, Jia-Hong

    2007-06-01

    To study the impact of arsenic trioxide (As2O3) on human colorectal carcinoma LS-174T cells and their activity of telomerase. LS-174T cells and xenograft model of nude mice were treated with As2O3. The inhibitory effect of As2O3 on survival of LS-174T cells was determined by MTT assay. Apoptosis was determined by electron microscopy and fluorescence microscopy. Cell cycle was assessed by flow cytometry. Telomerase activity in LS-174T cells was determined by PCR-ELISA kit. With the increasing concentration of As2O3, the ratio of living cells to dead cells decreased significantly, and the IC50 value was 5.23 micromol/L. Apoptosis curve appeared after 24 h and cells turned to apoptosis in a time-dependent manner. As2O3 inhibited the telomerase activity in cell extraction, obviously in a concentration-dependent and time-dependent manner. Inhibitiory effect of As2O3 on xenograft model of nude mice was observed by tumor volume and weight measurement, showing a significant difference between As2O3 and control groups (P colonrectal cancer S-174T cell growth, probably by induction of apoptosis and inhibition of telomerase activity.

  19. Correlation of DNA Repair Gene Polymorphisms With Clinical Outcome in Patients With Locally Advanced Non-Small-Cell Lung Cancer Receiving Induction Chemotherapy Followed by Surgery.

    Science.gov (United States)

    Santarpia, Mariacarmela; Ramirez, Jose Luis; de Aguirre, Itziar; Garrido, Pilar; Pérez Cano, Maria; Queralt, Cristina; Gonzalez-Larriba, Jose Luis; Insa, Amelia; Provencio, Mariano; Isla, Dolores; Camps, Carlos; Blanco, Remei; Moran, Teresa; Rosell, Rafael

    2017-03-01

    The aim of this study was to evaluate whether xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) polymorphisms influenced clinical outcome in patients with stage IIIA-B non-small-cell lung cancer (NSCLC) treated with neoadjuvant gemcitabine/cisplatin/docetaxel followed by surgery. A total of 109 patients with stage IIIA and IIIB NSCLC were prospectively genotyped to examine a potential association between XPD 312 (aspartic acid [Asp]/asparagine [Asn]), XPD 751 (lysine [Lys]/glutamine [Gln]), and RRM1 (-37 C/A) polymorphisms with response and survival. The median survival was 32.14 months for carriers of XPD 312 Asp/Asp and 12.04 months for those with the variant Asn allele (P = .05). In addition, event-free survival was longer for patients with the XPD 312 Asp/Asp genotype compared with patients with Asp/Asn or Asn/Asn (P = .03). A similar but nonsignificant trend was observed for the XPD 751 genotype. In a multivariate analysis, complete resection and age emerged as prognostic factors for overall survival; in patients with incomplete resection or exploratory thoracotomy, XPD 312 was the most significant prognostic factor (P = .03). The XPD 312 single nucleotide polymorphism is a prognostic factor for survival in patients with locally advanced NSCLC receiving induction chemotherapy followed by surgery. The Asn allele is associated with unfavorable outcome and could be used for better stratification of patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Dose and induction to cancer risk evaluation associated to use of X ray body scanners by transmission at airports; Avaliacao da dose e do risco de inducao ao cancer associados ao uso de escaneres corporais de raios X por transmissao em aeroportos

    Energy Technology Data Exchange (ETDEWEB)

    Correa, Samanda Cristine Arruda; Aquino, Josilto Oliveira de, E-mail: scorrea@cnen.gov.b, E-mail: josilto@cnen.gov.b [Comissao Nacional de Energia Nuclear (DIAPI/CGMI/CNEN), Rio de Janeiro, RJ (Brazil). Coordenacao Geral de Instalacoes Medicas e Industriais. Div. de Aplicacoes Industriais; Souza, Edmilson Monteiro de, E-mail: emonteiro@nuclear.ufrj.b [Centro Universitario Estadual da Zona Oeste (CAPI/UEZO), Campo Grande, RJ (Brazil). Colegiado da Area de Producao Industrial; Silva, Ademir Xavier da, E-mail: ademir@nuclear.ufrj.b [Coordenacao dos Programas de Pos-Graduacao de Engenharia (PEN/COPPE/UFRJ), RJ (Brazil). Programa de Engenharia Nuclear

    2011-07-01

    This paper uses the Monte Carlo MCNPX and the phantoms in male voxel and female voxel to evaluate the absorbed doses effective doses and the induction risk and the mortality due to cancer associated to exposures of individual submitted to X ray body scanners by transmission at various projections. The values of effective dose were calculated according to the recommended by the new ICRP 103 and the values of induction risks and mortality due to cancer were estimated through the document BEIR VII. (author)

  1. Phaseolus acutifolius Lectin Fractions Exhibit Apoptotic Effects on Colon Cancer: Preclinical Studies Using Dimethilhydrazine or Azoxi-Methane as Cancer Induction Agents

    Directory of Open Access Journals (Sweden)

    Ulisses Moreno-Celis

    2017-10-01

    Full Text Available Phaseolus acutifolius (Tepary bean lectins have been studied as cytotoxic molecules on colon cancer cells. The toxicological profile of a Tepary bean lectin fraction (TBLF has shown low toxicity in experimental animals; exhibiting anti-nutritional effects such as a reduction in body weight gain and a decrease in food intake when using a dose of 50 mg/kg on alternate days for six weeks. Taking this information into account, the focus of this work was to evaluate the effect of the TBLF on colon cancer using 1,2-dimethylhydrazine (DMH or azoxy-methane/dextran sodium sulfate (AOM/DSS as colon cancer inductors. Rats were treated with DMH or AOM/DSS and then administered with TBFL (50 mg/kg for six weeks. TBLF significantly decreased early tumorigenesis triggered by DMH by 70%, but without any evidence of an apoptotic effect. In an independent experiment, AOM/DSS was used to generate aberrant cryptic foci, which decreased by 50% after TBLF treatment. TBLF exhibited antiproliferative and proapoptotic effects related to a decrease of the signal transduction pathway protein Akt in its activated form and an increase of caspase 3 activity, but not to p53 activation. Further studies will deepen our knowledge of specific apoptosis pathways and cellular stress processes such as oxidative damage.

  2. Kinetics of mammary clonogenic cells and rat mammary cancer induction by X-rays or fission neutrons

    Energy Technology Data Exchange (ETDEWEB)

    Kamiya, Kenji [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine; Higgins, P.D.; Tanner, M.A.; Gould, M.N.; Clifton, K.H.

    1999-12-01

    Following the hormonal treatment of rats with high prolactin levels and glucocorticoid deficiency (Prl+/Glc-) for 48 days (Day +48), total recoverable mammary DNA was increased by more than sevenfold, tritiated thymidine uptake by nearly fourfold, and total mammary clonogens by about fivefold. Irradiation with 4, 40, and 80 cGy X-rays on Day +48 increased total mammary carcinomas per rat-day-at-risk linearly with dose, and 40 and 80 cGy significantly decreased first carcinoma latency. A dose of 40 cGy X-rays before hormone treatment (Day -1) yielded tumor latencies and frequencies insignificantly different from unirradiated controls but significantly different from those when the dose was given on Day +48. Total carcinomas per rat-day-at-risk were fitted better by a function of dose to the power 0.4 than by a linear function after exposure to 1, 10. and 20 cGy fission neutrons, and 10 and 20 cGy significantly shortened the time to appearance of the first cancer. In contrast to results with X-rays, 10 cGy neutrons on Day -1 yielded tumor frequencies and latencies insignificantly different from 10 cGy neutrons on Day +48. The carcinogenic action of X-rays, but not of neutrons, was thus influenced by total clonogen numbers and/or proliferation rates. (author)

  3. Effect of capilliposide for induction apoptosis in human nasopharyngeal cancer CNE-2 cells through up-regulating PUMA expression.

    Science.gov (United States)

    Hua, Yonghong; Hu, Qiaoying; Piao, Yongfeng; Tang, Qiu; Feng, Jiangguo

    2015-11-01

    To observe the apoptosis of capilliposide against human nasopharyngeal cancer CNE-2 cells and to study its primary mechanisms. Vectors pSilencer-PUMA-small interfering RNA (siRNA) were constructed to transcribe functional siRNA specially targeting PUMA. The interfering plasmids were used to transfect CNE-2 cells with lipofectamine 2000 transfection reagent. PUMA messenger RNA (mRNA) expression levels were analyzed by polymerase chain reaction. The proliferation of CNE-2 cells was detected using MTT colorimetry. Annexin V/propidium iodide double staining was applied to detect the apoptosis rate of CNE-2 cells. The protein levels of p53, PUMA, and Bax were detected using Western blot analysis. Recombinant siRNA expression vector targeting PUMA was constructed. MTT assays showed capilliposide inhibited the proliferation of CNE-2 cells in a concentration-dependent manner. The inhibition was strengthened along with increased concentrations. Apoptosis detected by flow cytometry in control group, drug group, siRNA group, and drug combined siRNA group was 9.3 ± 2.3%, 31.4 ± 5.6%, 12.3 ± 4.1%, and 13.2 ± 3.7%, respectively. After pretreated by capilliposide, PUMA protein was upregulated, and BAX was distributed to mitochondria in CNE-2 cells using Western blot analysis, but this effect can be interrupted by PUMA-siRNA. Capilliposide could induce the apoptosis of CNE-2 cells, which might be related with the increasing in PUMA-Bax pathway.

  4. Investigation of selective induction of breast cancer cells to death with treatment of plasma-activated medium

    Science.gov (United States)

    Hashizume, Hiroshi; Tanaka, Hiromasa; Nakamura, Kae; Kano, Hiroyuki; Ishikawa, Kenji; Kikkawa, Fumitaka; Mizuno, Masaaki; Hori, Masaru

    2015-09-01

    The applications of plasma in medicine have much attention. We previously showed that plasma-activated medium (PAM) induced glioblastoma cells to apoptosis. However, it has not been elucidated the selectivity of PAM in detail. In this study, we investigated the selective effect of PAM on the death of human breast normal and cancer cells, MCF10A and MCF7, respectively, and observed the selective death with fluorescent microscopy. For the investigation of cell viability with PAM treatment, we prepared various PAMs according to the strengths, and treated each of cells with PAMs. Week PAM treatment only decreased the viability of MCF7 cells, while strong PAM treatment significantly affected both viabilities of MCF7 and MCF10A cells. For the fluorescent observation, we prepared the mixture of MCF7 and fluorescent-probed MCF10A cells, and seeded them. After the treatment of PAMs, the images showed that only MCF7 cells damaged in the mixture with week PAM treatment. These results suggested that a specific range existed with the selective effect in the strength of PAM. This work was partly supported by a Grant-in-Aid for Scientific Research on Innovative Areas ``Plasma Medical Innovation'' Grant No. 24108002 and 24108008 from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

  5. Induction of endoplasmic reticulum-induced stress genes in Panc-1 pancreatic cancer cells is dependent on Sp proteins.

    Science.gov (United States)

    Abdelrahim, Maen; Liu, Shengxi; Safe, Stephen

    2005-04-22

    Endoplasmic reticulum (ER) stress plays a critical role in multiple diseases, and pharmacologically active drugs can induce cell death through ER stress pathways. Stress-induced genes are activated through assembly of transcription factors on ER stress response elements (ERSEs) in target gene promoters. Gel mobility shift and chromatin immunoprecipitation assays have confirmed interactions of NF-Y and YY1 with the distal motifs of the tripartite ERSE from the glucose-related protein 78 (GRP78) gene promoter. The GC-rich nonanucleotide (N(9)) sequence, which forms the ER stress response binding factor (ERSF) complex binds TFII-I and ATF6; however, we have now shown that in Panc-1 pancreatic cancer cells, this complex also binds Sp1, Sp3, and Sp4 proteins. Sp proteins are constitutively bound to the ERSE; however, activation of GRP78 protein (or reporter gene) by thapsigargin or tunicamycin is inhibited after cotransfection with small inhibitory RNAs for Sp1, Sp3, and Sp4. This study demonstrates that Sp transcription factors are important for stress-induced responses through their binding to ERSEs.

  6. WAF1 induction and infection by HPV E6 as a determinants of radiosensitivity in human cervical cancer

    International Nuclear Information System (INIS)

    Harima, Yoko; Oka, Atsutoshi; Harima, Keizo; Tanaka, Yoshimasa

    1998-01-01

    To establish a new predictor of outcome for human cervical carcinoma treatment, the relationship between WAF1 mRNA levels during treatment, human papilloma virus (HPV) infection and tumor radiosensitivity were investigated. Forty patients with uterine cervical carcinoma were treated with definitive radiotherapy. Only those patients who beard wild-type p53 were included into present clinical trial. p53 status was investigated using SSCP analysis. HPV E6 was determined by PCR, WAF1 mRNA was estimated by RT-PCR. Twenty-one patients achieved complete response (CR), 11 patients achieved partial response (PR), and 8 patients had no change (NC). The increase in WAF1 mRNA after irradiation at 10.8 Gy positively correlated both with better treatment response and improved survival. Although the infection by HPV did not directly influence on the survival rate, it decreased the inducibility of WAF1. p53-dependent activation of WAF1 gene expression during treatment may be a strong determinant of the efficacy of cervical cancer radiotherapy. (author)

  7. WAF1 induction and infection by HPV E6 as a determinants of radiosensitivity in human cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Harima, Yoko; Oka, Atsutoshi; Harima, Keizo; Tanaka, Yoshimasa [Kansai Medical Univ., Moriguchi, Osaka (Japan)

    1998-02-01

    To establish a new predictor of outcome for human cervical carcinoma treatment, the relationship between WAF1 mRNA levels during treatment, human papilloma virus (HPV) infection and tumor radiosensitivity were investigated. Forty patients with uterine cervical carcinoma were treated with definitive radiotherapy. Only those patients who beard wild-type p53 were included into present clinical trial. p53 status was investigated using SSCP analysis. HPV E6 was determined by PCR, WAF1 mRNA was estimated by RT-PCR. Twenty-one patients achieved complete response (CR), 11 patients achieved partial response (PR), and 8 patients had no change (NC). The increase in WAF1 mRNA after irradiation at 10.8 Gy positively correlated both with better treatment response and improved survival. Although the infection by HPV did not directly influence on the survival rate, it decreased the inducibility of WAF1. p53-dependent activation of WAF1 gene expression during treatment may be a strong determinant of the efficacy of cervical cancer radiotherapy. (author)

  8. Arctigenin anti-tumor activity in bladder cancer T24 cell line through induction of cell-cycle arrest and apoptosis.

    Science.gov (United States)

    Yang, Shucai; Ma, Jing; Xiao, Jianbing; Lv, Xiaohong; Li, Xinlei; Yang, Huike; Liu, Ying; Feng, Sijia; Zhang, Yafang

    2012-08-01

    Bladder cancer is the most common neoplasm in the urinary system. This study assesses arctigenin anti-tumor activity in human bladder cancer T24 cells in vitro and the underlying molecular events. The flow cytometry analysis was used to detect cell-cycle distribution and apoptosis. Western blotting was used to detect changes in protein expression. The data showed that arctigenin treatment reduced viability of bladder cancer T24 cells in a dose- and time-dependent manner after treatment with arctigenin (10, 20, 40, 80, and 100 μmol/L) for 24 hr and 48 hr. Arctigenin treatment clearly arrested tumor cells in the G1 phase of the cell cycle. Apoptosis was detected by hoechst stain and flow cytometry after Annexin-V-FITC/PI double staining. Early and late apoptotic cells were accounted for 2.32-7.01% and 3.07-7.35%, respectively. At the molecular level, arctigenin treatment decreased cyclin D1 expression, whereas CDK4 and CDK6 expression levels were unaffected. Moreover, arctigenin selectively altered the phosphorylation of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activated phosphorylation of p38 significantly in a dose-dependent manner. These results suggest that arctigenin may inhibit cell viability and induce apoptosis by direct activation of the mitochondrial pathway, and the mitogen-activated protein kinase pathway may play an important role in the anti-tumor effect of arctigenin. The data from the current study demonstrate the usefulness of arctigenin in bladder cancer T24 cells, which should further be evaluated in vivo before translation into clinical trials for the chemoprevention of bladder cancer. Copyright © 2012 Wiley Periodicals, Inc.

  9. Anemia During Sequential Induction Chemotherapy and Chemoradiation for Head and Neck Cancer: The Impact of Blood Transfusion on Treatment Outcome

    International Nuclear Information System (INIS)

    Bhide, Shreerang A.; Ahmed, Merina; Rengarajan, Vijayan; Powell, Ceri; Miah, Aisha; Newbold, Kate; Nutting, Christopher M.; Harrington, Kevin J.

    2009-01-01

    Purpose: Sequential treatment (chemotherapy followed by concomitant chemoradiation; CCRT) is increasingly being used for radical treatment of squamous cell cancer of the head and neck (SCCHN), which results in increased myelosuppression. In this study, we review the incidence of anemia and the effect of a policy of hemoglobin (Hb) maintenance by blood transfusion on disease outcomes in these patients. Methods and Materials: Retrospective review of the records of patients with SCCHN treated with sequential CCRT formed the basis of this study. The incidence of anemia and statistics on blood transfusion were documented. For the purpose of outcome analyses, patients were divided into four categories by (1) transfusion status, (2) nadir Hb concentration, (3) number of transfusion episodes, and (4) number of units of blood transfused (NOUT). Data on 3-year locoregional control (LRC), relapse-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were analyzed. Results: One hundred and sixty-nine patients were identified. The median follow-up was 23.6 months. The RFS (52% vs. 41%, p = 0.03), DSS (71% vs. 66%, p = 0.02), and OS (58% vs. 42% p = 0.005) were significantly better for patients who did not have a transfusion vs. those who did. The LRC, RFS, DSS, and OS were also significantly better for patients with nadir Hb level >12 vs. 4. Conclusion: Our study seems to suggest that blood transfusion during radical treatment for SCCHN might be detrimental. Further research should be undertaken into the complex interactions among tumor hypoxia, anemia, and the treatment of anemia before making treatment recommendations

  10. Hypoxia inducible factor-1α-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells.

    Science.gov (United States)

    Li, Mingchuan; Wang, Yong Xing; Luo, Yong; Zhao, Jiahui; Li, Qing; Zhang, Jiao; Jiang, Yongguang

    2016-07-01

    Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death. Hypoxia is an environmental stimulus that plays an important role in the development and cancer progression especially for solid tumors. The key regulator under hypoxic conditions is stabilized hypoxia-inducible factor (HIF)-1α. In the present study, immune-fluorescent staining, siRNAs, qRT-PC, immunoblotting, cell migration and invasion assays were carried out to test typical epithelial to mesenchymal transition under hypoxia and the key regulators of this process in PC3, a human prostate cancer cell line. Our data demonstrated that hypoxia induces diverse molecular, phenotypic and functional changes in prostate cancer cells that are consistent with EMT. We also showed that a cell signal factor such as HIF-1α, which might be stabilized under hypoxic environment, is involved in EMT and cancer cell invasive potency. The induced hypoxia could be blocked by HIF-1α gene silencing and reoxygenation of EMT in prostate cancer cells, hypoxia partially reversed accompanied by a process of mesenchymal-epithelial reverting transition (MErT). EMT might be induced by activation of HIF-1α-dependent cell signaling in hypoxic prostate cancer cells.

  11. Pro-oxidant activity of dietary chemopreventive agents: an under-appreciated anti-cancer property

    Science.gov (United States)

    Azmi, Asfar S

    2013-01-01

    “ Let food be thy medicine and medicine be thy food” was quoted by Hippocrates more than two thousand years ago and since ancient times the health benefits of different natural agents have been exploited. In modern research, the disease preventive benefits of many such natural agents, particularly dietary compounds and their derivatives, has been attributed to their well recognized activity as the regulators of redox state of the cell. Nevertheless, most of these studies have focused on their antioxidant activity. A large body of evidence indicates that a major fraction of these agents can elicit pro-oxidant (radical generating) behavior which has been linked to their anti-cancer effects. This editorial provides an overview of the under-appreciated pro-oxidant activity of natural products, with a special focus on their ability to generate reactive oxygen species in the presence of transition metal ions, and discusses their possible use as cancer chemotherapeutic agents. PMID:24358870

  12. mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells.

    Science.gov (United States)

    Pusapati, Raju V; Daemen, Anneleen; Wilson, Catherine; Sandoval, Wendy; Gao, Min; Haley, Benjamin; Baudy, Andreas R; Hatzivassiliou, Georgia; Evangelista, Marie; Settleman, Jeff

    2016-04-11

    Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. A TORC2-Akt feedforward topology underlies HER3 resiliency in HER2-amplified cancers

    Science.gov (United States)

    Amin, Dhara N.; Ahuja, Deepika; Yaswen, Paul; Moasser, Mark M.

    2015-01-01

    The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in-depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt-TORC2 feed-forward loop that functions as a self-perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus a critical pathophysiological event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2-amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers. PMID:26438156

  14. Breast cancer features in women under the age of 40 years

    Directory of Open Access Journals (Sweden)

    Deise Santiago Girão Eugênio

    Full Text Available Summary Objective: To describe the clinical features, imaging findings and pathological aspects of breast cancer diagnosed in women under the age of 40 years. Method: A retrospective, descriptive study was performed through analysis of medical records between November 2008 and August 2012. One hundred and twenty (120 patients were included, of whom 112 underwent mammography, 113 underwent ultrasonography, and 105 underwent magnetic resonance imaging (MRI. The histopathological data was obtained in most cases from post-surgical analysis, which was available for 113 patients. Results: The mean age at diagnosis of primary breast cancer was 34 years. Only 11 patients (9.0% had a family history of breast or ovarian cancer in first-degree relative. Ninety-two (92 patients sought medical attention after showing breast symptoms, and the presence of a palpable nodule was the main complaint. One hundred and twenty-two (122 primary tumors were diagnosed, of which 112 were invasive (95%. The most common histological type was invasive ductal carcinoma (73.8%. Luminal B was the predominant molecular subtype (42.6%. Ultrasonography was positive in 94.5% of the cases and the most common finding were nodules (94.8%. At mammography, the malignancy was observed in 92.8% and the presence of suggestive calcifications was the dominant feature. The MRI was positive in 98% of patients, and mass lesions were the most common. Conclusion: Most cases of breast cancer diagnosed in patients under the age of 40 years, in our population, had symptoms at diagnosis and tumor with more aggressive biological behavior. Despite the ultrasound has been the most widely used method, we found improved characterization of breast lesions when also used mammography and MRI.

  15. Induction of Apoptotic Effects of Antiproliferative Protein from the Seeds of Borreria hispida on Lung Cancer (A549 and Cervical Cancer (HeLa Cell Lines

    Directory of Open Access Journals (Sweden)

    S. Rupachandra

    2014-01-01

    Full Text Available A 35 KDa protein referred to as F3 was purified from the seeds of Borreria hispida by precipitation with 80% ammonium sulphate and gel filtration on Sephadex G-100 column. RP-HPLC analysis of protein fraction (F3 on an analytical C-18 column produced a single peak, detected at 220 nm. F3 showed an apparent molecular weight of 35 KDa by SDS PAGE and MALDI-TOF-MS analyses. Peptide mass fingerprinting analysis of F3 showed the closest homology with the sequence of 1-aminocyclopropane-1-carboxylate deaminase of Pyrococcus horikoshii. The protein (F3 exhibited significant cytotoxic activity against lung (A549 and cervical (HeLa cancer cells in a dose-dependent manner at concentrations ranging from 10 µg to 1000 µg/mL, as revealed by the MTT assay. Cell cycle analysis revealed the increased growth of sub-G0 population in both cell lines exposed to a concentration of 1000 µg/mL of protein fraction F3 as examined from flow cytometry. This is the first report of a protein from the seeds of Borreria hispida with antiproliferative and apoptotic activity in lung (A549 and cervical (HeLa cancer cells.

  16. [Clinical Benefits of Transurethral Resection Under Narrow Band Imaging for Non-Muscle Invasive Bladder Cancer].

    Science.gov (United States)

    Mita, Koji; Kobatake, Kohei; Ohara, Shinya; Kato, Masao

    2018-01-01

    The aim of this study was to reveal the clinical benefits of transurethral resection (TUR) under narrow band imaging (NBI-TUR) for non-muscle-invasive bladder cancer (NMIBC) compared with conventional white light imaging TUR (WLI-TUR). The subjects were 172 patients with NMIBC who were followed for more than 1 year after undergoing TUR with no additional postoperative treatment. In the WLI-TUR group (n=101), lesions that were detected as positive after systematic intravesical observation under WLI were resected completely under WLI. In the NBI-TUR group (n=71), similar observations under WLI were followed by systematic intravesical observation under NBI. After multiple site biopsy under NBI, TUR was performed for all lesions that were detected as positive under NBI. The sensitivity was calculated based on the results of cystoscopy and pathology of multiple site biopsy samples under WLI and NBI in the NBITUR group. The tumor recurrence rate was analyzed in both groups. Background factors did not differ significantly between the two groups, except for the observation period (63.3 months in the WLI-TUR group vs 42.0 months in the NBI-TUR group, p<0.01). The procedure under NBI had significantly higher sensitivity (94.6% vs 75.0%, p<0.01) compared with that under WLI. The recurrence-free rate in the NBITUR group was significantly higher than that in the WLI-TUR group (p=0.013). The tumor recurrencefree rate of NBI-TUR is higher than that of conventional WLI-TUR for patients with NMIBC.

  17. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress

    OpenAIRE

    Schug, Zachary T.; Peck, Barrie; Jones, Dylan T.; Zhang, Qifeng; Grosskurth, Shaun; Alam, Israt S.; Goodwin, Louise M.; Smethurst, Elizabeth; Mason, Susan; Blyth, Karen; McGarry, Lynn; James, Daniel; Shanks, Emma; Kalna, Gabriela; Saunders, Rebecca E.

    2015-01-01

    Summary A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and A...

  18. Experimental verification of the effect of cable length on voltage distribution in stator winding of an induction motor under surge condition

    Energy Technology Data Exchange (ETDEWEB)

    Oyegoke, B.S. [Helsinki Univ. of Technology, Otaniemi (Finland). Lab. of Electromechanics

    1997-12-31

    This paper presents the results of surge distribution tests performed on a stator of a 6 kV induction motor. The primary aim of these tests was to determine the wave propagation properties of the machine winding fed via cables of different lengths. Considering the measured resorts, conclusions are derived regarding the effect of cable length on the surge distribution within the stator winding of an ac motor. (orig.) 15 refs.

  19. Anti-cancer effect and the underlying mechanisms of gypenosides on human colorectal cancer SW-480 cells.

    Directory of Open Access Journals (Sweden)

    Han Yan

    Full Text Available BACKGROUND: Gypenosides (Gyp, the main components from Gynostemma pentaphyllum Makino, are widely used in traditional Chinese medicine. The present study aimed to investigate the anti-cancer effect and the underlying mechanisms of Gyp on human colorectal cancer cells SW-480. MATERIALS AND METHODS: The inhibitory effect of Gyp on SW-480 cells was evaluated by MTT assay. Apoptotic cell death was detected by nuclear Hoechst 33342 staining and DNA fragmentation analysis. Apoptosis was analyzed using Annexin V-PE/7-amino-actinomycin D staining. Cell membrane integrity was evaluated with flow cytometry following PI staining. Changes of mitochondrial membrane potential (Δψm were detected through flow cytometry analysis of rhodamine 123 (Rh123. The role of reactive oxygen species (ROS in Gyp induced cell death was investigated by intracellular ROS generation and general ROS scavenger. Wound-healing assay was carried out to investigate Gyp-inhibited migration of SW-480 cells in vitro. Additionally, the alterations in F-actin microfilaments were analyzed by FITC-labeled phalloidin toxin staining and the morphological changes were evaluated under scanning electron microscope (SEM. RESULTS: After the Gyp treatment, the plasma membrane permeability of SW-480 cell was increased, Δψm was decreased significantly, the level of intracellular ROS level was increased, DNA fragmentation and apoptotic morphology were observed. Cells treated with Gyp exert serious microfilament network collapse as well as the significant decrease in the number of microvilli. Gyp induced the changes of cell viability, cell migration, intracellular ROS generation and nuclear morphology were alleviated obviously by NAC. CONCLUSION: The results in this study implied that ROS play an important role in Gyp induced cell toxicity and apoptosis, and the mitochondria damage may be upstream of ROS generation post Gyp treatment. The findings of the present study provide new evidences for anti

  20. Quantitative gene expression underlying 18f-fluorodeoxyglucose uptake in colon cancer

    DEFF Research Database (Denmark)

    Engelmann, Bodil E.; Binderup, Tina; Kjær, Andreas

    2015-01-01

    Background: Positron emission tomography (PET) with the glucose analogue 18F-fluorodeoxyglucose (FDG) is widely used in oncologic imaging. This study examines the molecular mechanism underlying the detection of colon cancer (CC) by FDG-PET. Methods: Pre-operative PET/CT scans and tissue samples....... Mean gene expression levels of GLUT1, HK2, ki67, HIF1α, VEGF and CaIX, but not HK1, were significantly higher in primary tumours than in surrounding normal colonic mucosa. Linear regressions pairing tumour SUVmax with gene expression levels showed significant correlations between SUVmax and HK2, ki67...

  1. Nutritional status and feeding-tube placement in patients with locally advanced hypopharyngeal cancer included in an induction chemotherapy-based larynx preservation program.

    Science.gov (United States)

    Bozec, Alexandre; Benezery, Karen; Chamorey, Emmanuel; Ettaiche, Marc; Vandersteen, Clair; Dassonville, Olivier; Poissonnet, Gilles; Riss, Jean-Christophe; Hannoun-Lévi, Jean-Michel; Chand, Marie-Eve; Leysalle, Axel; Saada, Esma; Sudaka, Anne; Haudebourg, Juliette; Hebert, Christophe; Falewee, Marie-Noelle; Demard, François; Santini, José; Peyrade, Frédéric

    2016-09-01

    The objective of the study is to evaluate the nutritional status and determine its impact on clinical outcomes in patients with locally advanced hypopharyngeal cancer included in an induction chemotherapy (ICT)-based larynx preservation program without prophylactic feeding-tube placement. All patients with locally advanced (T3/4, N0-3, M0) hypopharyngeal squamous cell carcinoma, technically suitable for total pharyngolaryngectomy, treated by docetaxel, cisplatin and 5-fluorouracil (TPF)-ICT for larynx preservation at our institution between 2004 and 2013, were included in this retrospective study. Patients' nutritional status was closely monitored. Enteral nutrition was used if and when a patient was unable to sustain per-oral nutrition and hydration. The impact of nutritional status on clinical outcomes was investigated in univariate and multivariate analysis. A total of 53 patients (42 men and 11 women, mean age = 58.6 ± 8.2 years) were included in this study. Six (11.3 %) patients had lost more than 10 % of their usual body weight before therapy. Compared with patients' usual weight, the mean maximum patient weight loss during therapeutic management was 8.7 ± 4.5 kg. Enteral nutrition was required in 17 patients (32 %). We found no influence of the tested nutritional status-related factors on response to ICT, toxicity of ICT, overall, cause-specific and recurrence-free survival, and on post-therapeutic swallowing outcome. Maximum weight loss was significantly associated with a higher risk of enteral tube feeding during therapy (p = 0.03) and of complications (grade ≥3, p = 0.006) during RT. Without prophylactic feeding-tube placement, approximately one-third of the patients required enteral nutrition. There was no significant impact of nutritional status on oncologic or functional outcomes.

  2. The role of interim FDG PET-CT after induction chemotherapy as a predictor of concurrent chemoradiotherapy efficacy and prognosis for head and neck cancer

    International Nuclear Information System (INIS)

    Kim, Ka-Rham; Shim, Hyun-Jeong; Hwang, Jun-Eul; Cho, Sang-Hee; Chung, Ik-Joo; Park, Ki Seong; Kang, Sae-Ryung; Kwon, Seong Young; Chung, Woong-Ki; Bae, Woo Kyun

    2018-01-01

    Induction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes. Tumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS). We studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS. Using interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes. (orig.)

  3. Phase 2 Trial of Induction Gemcitabine, Oxaliplatin, and Cetuximab Followed by Selective Capecitabine-Based Chemoradiation in Patients With Borderline Resectable or Unresectable Locally Advanced Pancreatic Cancer

    International Nuclear Information System (INIS)

    Esnaola, Nestor F.; Chaudhary, Uzair B.; O'Brien, Paul; Garrett-Mayer, Elizabeth; Camp, E. Ramsay; Thomas, Melanie B.; Cole, David J.; Montero, Alberto J.; Hoffman, Brenda J.; Romagnuolo, Joseph; Orwat, Kelly P.; Marshall, David T.

    2014-01-01

    Purpose: To evaluate, in a phase 2 study, the safety and efficacy of induction gemcitabine, oxaliplatin, and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer (BRPC or LAPC, respectively). Methods and Materials: Patients received gemcitabine and oxaliplatin chemotherapy repeated every 14 days for 6 cycles, combined with weekly cetuximab. Patients were then restaged; “downstaged” patients with resectable disease underwent attempted resection. Remaining patients were treated with chemoradiation consisting of intensity modulated radiation therapy (54 Gy) and concurrent capecitabine; patients with borderline resectable disease or better at restaging underwent attempted resection. Results: A total of 39 patients were enrolled, of whom 37 were evaluable. Protocol treatment was generally well tolerated. Median follow-up for all patients was 11.9 months. Overall, 29.7% of patients underwent R0 surgical resection (69.2% of patients with BRPC; 8.3% of patients with LAPC). Overall 6-month progression-free survival (PFS) was 62%, and median PFS was 10.4 months. Median overall survival (OS) was 11.8 months. In patients with LAPC, median OS was 9.3 months; in patients with BRPC, median OS was 24.1 months. In the group of patients who underwent R0 resection (all of which were R0 resections), median survival had not yet been reached at the time of analysis. Conclusions: This regimen was well tolerated in patients with BRPC or LAPC, and almost one-third of patients underwent R0 resection. Although OS for the entire cohort was comparable to that in historical controls, PFS and OS in patients with BRPC and/or who underwent R0 resection was markedly improved

  4. Three-times-daily radiotherapy with induction chemotherapy in locally advanced non-small cell lung cancer. Feasibility and toxicity study

    Energy Technology Data Exchange (ETDEWEB)

    Catalano, G.; Jereczek-Fossa, B.A.; Pas, T. de [Div. of Radiotherapy, European Inst. of Oncology, Milan (Italy); Leon, M.E. [Div. of Epidemiology and Biostatistics, European Inst. of Oncology, Milan (Italy); Cattani, F. [Div. of Medical Physics, European Inst. of Oncology, Milan (Italy); Spaggiari, L.; Veronesi, G. [Div. of Thoracic Surgery, European Inst. of Oncology, Milan (Italy); Braud, F. de [Div. of Medical Oncology, European Inst. of Oncology, Milan (Italy); Orecchia, R. [Div. of Radiotherapy, European Inst. of Oncology, Milan (Italy); Radiotherapy, Univ. of Milan, Milan (Italy)

    2005-06-01

    Purpose: to evaluate the feasibility and toxicity of three-times-daily radiotherapy (3tdRT), preceded by induction chemotherapy (iCT), in stage IIIA-IIIB non-small cell lung cancer (NSCLC). Patients and methods: iCT consisted of three cycles of cisplatin and gemcitabine. Surgery was considered for stage IIIA patients responsive to iCT; definitive or postoperative 3tdRT was planned. Doses of 54.4 Gy and 64.6 Gy in postoperative and definitive treatments, respectively, were delivered in three daily fractions. Results: from February 1998 to October 2000, 37 patients received 3tdRT as definitive (n = 18) or postoperative treatment (n = 19). Toxicity was limited to RTOG grade 2 (25 patients, 67.6%) and grade 3 (four patients, 10.8%) acute esophagitis; no grade 3 late esophagitis occurred. Late lung toxicity was represented by one grade 3 pneumonitis. No correlation emerged between acute esophageal toxicity and irradiated esophageal volume or disease- and treatment-related factors. A significant correlation was found for stage (IIIA vs. IIIB; p = 0.03) and a trend for the N-class (N2 vs. N3; p = 0.08). Conclusion: in this experience of 3tdRT preceded by iCT, the low toxicity profile confirmed the feasibility of this combination. The limited statistical power does not permit a definition of predictors for radiation-induced esophagitis incidence and severity; additional studies are required to clarify the impact of volumetric and dosimetric parameters. Failure patterns and survival results are warranted to confirm the efficacy of this approach in locally advanced NSCLC. (orig.)

  5. Clinical Holistic Medicine: Induction of Spontaneous Remission of Cancer by Recovery of the Human Character and the Purpose of Life (the Life Mission

    Directory of Open Access Journals (Sweden)

    Søren Ventegodt

    2004-01-01

    Full Text Available The recovery of the human character and purpose of life with consciousness-based medicine seems to be able to induce spontaneous remissions in several diseases. On two different occasions, we observed breast tumors reduced to less than half their original diameters (clinically judged during a holistic session, when working with the patients in accordance with the holistic process theory of healing, the life mission theory, and the theory of human character. One tumor was histologically diagnosed as malign breast cancer prior to the session, while the other was under examination. As both patients had the affected regions of the breast surgically removed immediately after the session, we are unable to determine if they were actually healed by the holistic treatment. We find it extremely interesting that the size of a tumor can be reduced dramatically within a few hours of holistic treatment, when the patient is highly motivated for personal development. The reduction of tumor size is in accordance with the holistic view that many types of cancer are caused by emotional and existential disturbances. From a holistic perspective, cancer can be understood as a simple disturbance of the cells, arising from the tissue holding on to a trauma with strong emotional content. This is called “a blockage”, where the function of the cells is changed from their original function in the tissue to a function of holding emotions. The reduction of the tumor in the two cases happened when old painful emotions were identified in the tissues, in and around the tumor, and processed into understanding; when the patients finally did let go of negative beliefs and attitudes that had kept the feeling(s repressed to that part of the body, the tumor first softened and then disappeared, presumably by apoptosis. We believe that the consciousness-based/holistic medical toolbox has a serious additional offer to cancer patients, and we will therefore strongly encourage the

  6. Synthesis of an anthraquinone derivative (DHAQC and its effect on induction of G2/M arrest and apoptosis in breast cancer MCF-7 cell line

    Directory of Open Access Journals (Sweden)

    Yeap SK

    2015-02-01

    inhibited expression of PLK1 genes. Western blot analysis also indicated that the DHAQC (2 increased BAX, p53, and cytochrome c levels in MCF-7 cells, which subsequently activated apoptosis as observed in annexin V/propidium iodide and cell cycle analyses. These results indicate that DHAQC (2 is a synthetic, cytotoxic, and selective anthraquinone, which is less toxic than the natural product damnacanthal, and which demonstrates potential in the induction of apoptosis in the breast cancer MCF-7 cell line. Keywords: cytotoxic, selective index, cell cycle

  7. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Congcong Zhang

    2017-05-01

    Full Text Available Significant progress has been made in recent years toward realizing the potential of natural killer (NK cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future

  8. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity.

    Science.gov (United States)

    Zhang, Congcong; Oberoi, Pranav; Oelsner, Sarah; Waldmann, Anja; Lindner, Aline; Tonn, Torsten; Wels, Winfried S

    2017-01-01

    Significant progress has been made in recent years toward realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs) composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future prospects of CAR

  9. Lexicographic Path Induction

    DEFF Research Database (Denmark)

    Schürmann, Carsten; Sarnat, Jeffrey

    2009-01-01

    an induction principle that combines the comfort of structural induction with the expressive strength of transfinite induction. Using lexicographic path induction, we give a consistency proof of Martin-Löf’s intuitionistic theory of inductive definitions. The consistency of Heyting arithmetic follows directly...

  10. The short-term outcomes of induction SOX (S-1 + oxaliplatin) ± cetuximab chemotherapy followed by short-course chemoradiotherapy in patients with poor-risk locally advanced rectal cancer.

    Science.gov (United States)

    Beppu, Naohito; Yoshie, Hidenori; Kimura, Fumihiko; Aihara, Tsukasa; Doi, Hiroshi; Kamikonya, Norihiko; Matsubara, Nagahide; Tomita, Naohiro; Yanagi, Hidenori; Yamanaka, Naoki

    2016-10-01

    To evaluate the safety and efficacy of induction SOX (S-1 + oxaliplatin) ± cetuximab chemotherapy followed by short-course chemoradiotherapy and surgery in patients with poor-risk locally advanced rectal cancer. We enrolled eligible patients with poor-risk rectal cancer defined as T3 lower rectal cancer with mesorectal fascia involvement, T4a or T4b tumors or cases with lateral lymph node swelling. The primary endpoint was a pathological complete response (pCR), and the secondary endpoints were the objective response rate (ORR) and the pathological high response rate (Grade 2 plus 3). Twenty eligible patients were enrolled. The majority (75.0 %, 15/20) of the patients completed four cycles of induction chemotherapy, and all patients completed the radiotherapy (25 Gy/10 fractions/5 days). The global rate of Grade 3-4 toxicities was 30.0 % (6/20 patients). The ORRs were 85.0 % (17/20) and 95.0 % (19/20) in the patients who underwent R0 and R1 resection, respectively. The pathological high response rate was 70.0 % (14/20) and the pCR was 10.0 % (2/20). The regimen of induction SOX (S-1 + oxaliplatin) ± cetuximab chemotherapy followed by short-course chemoradiotherapy is safe and is associated with good tumor regression in patients with poor-risk locally advanced rectal cancer.

  11. Esophageal-gastric anastomosis in radical resection of esophageal cancer under thoracoscopy combined with laparoscopy.

    Science.gov (United States)

    Hao, Zhang; Zhenya, Shen; Lei, Wang

    2014-10-01

    To determine the feasibility of esophagogastric anastomosis in esophageal cancer radical resection under thoracoscopy combined with laparoscopy in terms of complications and operation time. Experimental study. Department of Thoracic Surgery, Affiliated with The First Hospital, Suzhou University, from June 2008 to June 2012. Clinical data of 136 patients operated for esophageal cancer by radical resection under thoracoscopy combined with laparoscopy was analyzed. Eighty one superior and middle segment esophageal carcinoma patients were operated through right thoracoscope, abdominoscope, and neck incision. The esophagogastric anastomosis was completed in the left side of neck by handiwork. Fifty five inferior segment esophageal carcinoma were operated through right thoracoscope, abdominoscope and the esophagogastric anastomosis was completed with stapler in right thoracic cavity through superior belly incision and diaphragmatic hiatus. The operation time and the intra-operative blood loss in patients with intrathoracic mechanical anastomosis was significantly lower than that of cervical anastomosis. Other variables were not significantly different. The practicability of this method of anastomosis that completed with stapler in right thoracic cavity through superior belly incision and diaphragmatic hiatus had been well confirmed.

  12. Esophageal - Gastric Anastomosis in Radical Resection of Esophageal Cancer under Thoracoscopy Combined with Laparoscopy

    International Nuclear Information System (INIS)

    Hao, Z.; Lei, W.; Zhenya, S.

    2014-01-01

    Objective: To determine the feasibility of esophagogastric anastomosis in esophageal cancer radical resection under thoracoscopy combined with laparoscopy in terms of complications and operation time. Study Design: Experimental study. Place and Duration of Study: Department of Thoracic Surgery, Affiliated with The First Hospital, Suzhou University, from June 2008 to June 2012. Methodology: Clinical data of 136 patients operated for esophageal cancer by radical resection under thoracoscopy combined with laparoscopy was analyzed. Eighty one superior and middle segment esophageal carcinoma patients were operated through right thoracoscope, abdominoscope, and neck incision. The esophagogastric anastomosis was completed in the left side of neck by handiwork. Fifty five inferior segment esophageal carcinoma were operated through right thoracoscope, abdominoscope and the esophagogastric anastomosis was completed with stapler in right thoracic cavity through superior belly incision and diaphragmatic hiatus. Results: The operation time and the intra-operative blood loss in patients with intrathoracic mechanical anastomosis was significantly lower than that of cervical anastomosis. Other variables were not significantly different. Conclusion: The practicability of this method of anastomosis that completed with stapler in right thoracic cavity through superior belly incision and diaphragmatic hiatus had been well confirmed. (author)

  13. Induction motors airgap-eccentricity detection through the discrete wavelet transform of the apparent power signal under non-stationary operating conditions.

    Science.gov (United States)

    Yahia, K; Cardoso, A J M; Ghoggal, A; Zouzou, S E

    2014-03-01

    Fast Fourier transform (FFT) analysis has been successfully used for fault diagnosis in induction machines. However, this method does not always provide good results for the cases of load torque, speed and voltages variation, leading to a variation of the motor-slip and the consequent FFT problems that appear due to the non-stationary nature of the involved signals. In this paper, the discrete wavelet transform (DWT) of the apparent-power signal for the airgap-eccentricity fault detection in three-phase induction motors is presented in order to overcome the above FFT problems. The proposed method is based on the decomposition of the apparent-power signal from which wavelet approximation and detail coefficients are extracted. The energy evaluation of a known bandwidth permits to define a fault severity factor (FSF). Simulation as well as experimental results are provided to illustrate the effectiveness and accuracy of the proposed method presented even for the case of load torque variations. Copyright © 2013 ISA. Published by Elsevier Ltd. All rights reserved.

  14. Anticancer action of lactucopicrin in SKMEL-5 human skin cancer cells is mediated via apoptosis induction, G2/M cell cycle arrest and downregulation of m=TOR/PI3K/AKT signalling pathway.

    Science.gov (United States)

    Zhang, Xue; Lan, Dong; Ning, Shuhua; Ruan, Liwen

    2018-01-01

    Skin cancer is one of the cancers responsible for significant morbidity and mortality across the globe. The treatment options for skin cancer are limited and associated with significant toxicity. Therefore, researches have been directed towards exploring molecules that could prove beneficial in the treatment of this disease. Lactucopicrin is an important sesquiterpene lactone with important pharmacological potential. In the present study the anticancer effects of lactucopicrin against human skin SKMEL-5 cancer cell line were investigated. Antiproliferative effects were examined by CCK-8 assay. Apoptosis was detected by DAPI and annexin V/propidium iodide (PI) staining. Cell cycle analysis was carried out by flow cytometry. Protein expression was determined by western blotting. The results indicated that lactucopicrin exerts significant anticancer effects on the SKMEL-5 cells with an IC50 of 7.5 μM. Its anticancer effects were due to induction of apoptosis. Lactucopicrin could upregulate the expression of Bax which was associated with concomitant downregulation of Bcl-2 expression. Additionally, lactucopicrin induced G2/M cell cycle arrest in SKMEL-5 cells in a dose-dependent manner and also inhibited the m-TOR/PI3K/AKT signalling pathway. These results indicate that lactucopicrin shows potent anticancer action in the tested skin cancer cells and may prove a prospective lead molecule for the treatment of skin cancer.

  15. The ability to generate senescent progeny as a mechanism underlying breast cancer cell heterogeneity.

    Directory of Open Access Journals (Sweden)

    Mine Mumcuoglu

    Full Text Available BACKGROUND: Breast cancer is a remarkably heterogeneous disease. Luminal, basal-like, "normal-like", and ERBB2+ subgroups were identified and were shown to have different prognoses. The mechanisms underlying this heterogeneity are poorly understood. In our study, we explored the role of cellular differentiation and senescence as a potential cause of heterogeneity. METHODOLOGY/PRINCIPAL FINDINGS: A panel of breast cancer cell lines, isogenic clones, and breast tumors were used. Based on their ability to generate senescent progeny under low-density clonogenic conditions, we classified breast cancer cell lines as senescent cell progenitor (SCP and immortal cell progenitor (ICP subtypes. All SCP cell lines expressed estrogen receptor (ER. Loss of ER expression combined with the accumulation of p21(Cip1 correlated with senescence in these cell lines. p21(Cip1 knockdown, estrogen-mediated ER activation or ectopic ER overexpression protected cells against senescence. In contrast, tamoxifen triggered a robust senescence response. As ER expression has been linked to luminal differentiation, we compared the differentiation status of SCP and ICP cell lines using stem/progenitor, luminal, and myoepithelial markers. The SCP cells produced CD24+ or ER+ luminal-like and ASMA+ myoepithelial-like progeny, in addition to CD44+ stem/progenitor-like cells. In contrast, ICP cell lines acted as differentiation-defective stem/progenitor cells. Some ICP cell lines generated only CD44+/CD24-/ER-/ASMA- progenitor/stem-like cells, and others also produced CD24+/ER- luminal-like, but not ASMA+ myoepithelial-like cells. Furthermore, gene expression profiles clustered SCP cell lines with luminal A and "normal-like" tumors, and ICP cell lines with luminal B and basal-like tumors. The ICP cells displayed higher tumorigenicity in immunodeficient mice. CONCLUSIONS/SIGNIFICANCE: Luminal A and "normal-like" breast cancer cell lines were able to generate luminal-like and

  16. Combination effects of sorafenib with PI3K inhibitors under hypoxia in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Bhatia DR

    2016-12-01

    Full Text Available Dimple R Bhatia, Padma Thiagarajan School of Biosciences and Technology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India Aim: This study reports the influence of hypoxia on response of colorectal cancer cells to anticancer effects of sorafenib in combination with PI3K inhibitors GDC-0941 and BEZ-235.Materials and methods: All hypoxic exposures were carried out at 1% O2/5% CO2. Antiproliferation activity was evaluated by 48 hours propidium iodide and 14 days clonogenic assay. Protein levels were evaluated by fluorescence ELISA. Metabolites lactate and glucose were evaluated biochemically.Results: In the 48-hour proliferation assay, sorafenib acted synergistically with GDC-0941 but not with BEZ-235. In long-term colony-forming assays, both GDC-0941 and BEZ-235 were shown to potentiate the antiproliferative activity of sorafenib. At the molecular level, the synergism is mediated through inhibition of pAKT, pS6, p4EBP1, pERK, cyclin D1, and Bcl-2. No change in hypoxia-inducible factor-1α (HIF-1α levels was observed in cells treated with the combination of compounds under hypoxia. A significant reduction in glucose uptake and lactate release was observed in cells treated with the combination of compounds under normoxia and hypoxia.Conclusion: Combinations of sorafenib with PI3K inhibitors BEZ-235 and GDC-0941 are efficacious under hypoxia. Thus, these anticancer combinations have a potential to overcome the hypoxia-mediated resistance mechanisms to antiproliferative agents in cancer therapy. Keywords: GDC-0941, BEZ-235, anticancer, antiproliferation

  17. Optimal healthcare decision making under multiple mathematical models: application in prostate cancer screening.

    Science.gov (United States)

    Bertsimas, Dimitris; Silberholz, John; Trikalinos, Thomas

    2018-03-01

    Important decisions related to human health, such as screening strategies for cancer, need to be made without a satisfactory understanding of the underlying biological and other processes. Rather, they are often informed by mathematical models that approximate reality. Often multiple models have been made to study the same phenomenon, which may lead to conflicting decisions. It is natural to seek a decision making process that identifies decisions that all models find to be effective, and we propose such a framework in this work. We apply the framework in prostate cancer screening to identify prostate-specific antigen (PSA)-based strategies that perform well under all considered models. We use heuristic search to identify strategies that trade off between optimizing the average across all models' assessments and being "conservative" by optimizing the most pessimistic model assessment. We identified three recently published mathematical models that can estimate quality-adjusted life expectancy (QALE) of PSA-based screening strategies and identified 64 strategies that trade off between maximizing the average and the most pessimistic model assessments. All prescribe PSA thresholds that increase with age, and 57 involve biennial screening. Strategies with higher assessments with the pessimistic model start screening later, stop screening earlier, and use higher PSA thresholds at earlier ages. The 64 strategies outperform 22 previously published expert-generated strategies. The 41 most "conservative" ones remained better than no screening with all models in extensive sensitivity analyses. We augment current comparative modeling approaches by identifying strategies that perform well under all models, for various degrees of decision makers' conservativeness.

  18. A cost-effectiveness analysis of first-line induction and maintenance treatment sequences in patients with advanced nonsquamous non-small-cell lung cancer in France

    Directory of Open Access Journals (Sweden)

    Taipale K

    2017-08-01

    Full Text Available Kaisa Taipale,1 Katherine B Winfree,2 Mark Boye,2 Mickael Basson,3 Ghassan Sleilaty,4 James Eaton,5 Rachel Evans,5 Christos Chouaid6 1Global Patient Outcomes and Real World Evidence International, Oy Eli Lilly Finland AB, Helsinki, Finland; 2Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, IN, USA; 3Corporate Affairs, Lilly France, Neuilly-sur-Seine, 4Bio-Medicines Medical Affairs, Lilly France, Neuilly-sur-Seine, France; 5ICON Health Economics and Epidemiology, ICON Plc, Milton Park, UK; 6Thoracic Oncology, Service de Pneumologie, Centre Hospitalier Intercommunal Créteil, Créteil, France Background: Comparative effectiveness and cost-effectiveness data for induction–maintenance (I–M sequences for the treatment of patients with nonsquamous non-small-cell lung cancer (nsqNSCLC are limited because of a lack of direct evidence. This analysis aimed to compare the cost-effectiveness of I–M pemetrexed with those of other I–M regimens used for the treatment of patients with advanced nsqNSCLC in the French health-care setting. Materials and methods: A previously developed global partitioned survival model was adapted to the France-only setting by restricting treatment sequences to include 12 I–M regimens most relevant to France, and incorporating French costs and resource-use data. Following a systematic literature review, network meta-analyses were performed to obtain hazard ratios for progression-free survival (PFS and overall survival (OS relative to gemcitabine + cisplatin (induction sequences or best supportive care (BSC (maintenance sequences. Modeled health-care benefits were expressed as life-years (LYs and quality-adjusted LYs (QALYs (estimated using French EuroQol five-dimension questionnaire tariffs. The study was conducted from the payer perspective (National Health Insurance. Cost- and benefit-model inputs were discounted at an annual rate of 4%. Results: Base-case results showed pemetrexed

  19. Addition of Bevacizumab to XELOX Induction Therapy Plus Concomitant Capecitabine-Based Chemoradiotherapy in Magnetic Resonance Imaging–Defined Poor-Prognosis Locally Advanced Rectal Cancer: The AVACROSS Study

    Science.gov (United States)

    Salud, Antonieta; Vicente, Pilar; Arriví, Antonio; Roca, José María; Losa, Ferran; Ponce, José; Safont, María José; Guasch, Inmaculada; Moreno, Isabel; Ruiz, Ana; Pericay, Carles

    2011-01-01

    Background. Concomitant chemoradiotherapy followed by total mesorectal excision is standard treatment for locally advanced rectal cancer. This approach, however, focuses on local disease control and delays systemic treatment. Induction chemotherapy has the advantage of earlier administration of systemic therapy and may improve distant control. The objective of the current study was to assess the efficacy and toxicity of adding bevacizumab to induction chemotherapy followed by preoperative bevacizumab-based chemoradiotherapy in patients with locally advanced rectal cancer. Patients and Methods. Eligible patients had high-risk rectal adenocarcinoma defined by magnetic resonance imaging criteria. Treatment consisted of four 21-day cycles of bevacizumab (7.5 mg/kg) and XELOX (capecitabine plus oxaliplatin), followed by concomitant radiotherapy (50.4 Gy) plus bevacizumab (5 mg/kg every 2 weeks) and capecitabine (825 mg/m2 twice daily on days 1–15). Surgery was scheduled for 6–8 weeks after chemoradiotherapy. The primary endpoint was pathologic complete response (pCR). Results. Between July 2007 and July 2008, 47 patients were recruited. Among 45 patients who underwent surgery, pCR was achieved in 16 patients (36%; 95% confidence interval: 22.29%–51.27%), and an additional 17 patients (38%) had Dworak tumor regression grade 3. R0 resection was performed in 44 patients (98%). Most grade 3/4 adverse events occurred during the induction phase and included diarrhea (11%), asthenia (4%), neutropenia (6%), and thrombocytopenia (4%). Eleven patients (24%) required surgical reintervention. Conclusions. Addition of bevacizumab to induction chemotherapy and chemoradiotherapy is feasible, with impressive activity and manageable toxicity. However, caution is recommended regarding surgical complications. PMID:21467148

  20. High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine.

    Science.gov (United States)

    Saito, Takuro; Wada, Hisashi; Yamasaki, Makoto; Miyata, Hiroshi; Nishikawa, Hiroyoshi; Sato, Eiichi; Kageyama, Shinichi; Shiku, Hiroshi; Mori, Masaki; Doki, Yuichiro

    2014-10-14

    We conducted a cancer vaccine clinical trial with MAGE-A4 protein. Safety, clinical response, and antigen-specific immune responses were analyzed and the prognostic factors by vaccination were investigated. Twenty patients with advanced esophageal, stomach or lung cancer were administered MAGE-A4 vaccine containing 300μg protein subcutaneously once every 2 weeks in six doses. Primary endpoints of this study were safety and MAGE-A4 immune responses. The vaccine was well tolerated. Fifteen of 20 patients completed one cycle of vaccination and two patients showed SD. A MAGE-A4-specific humoral immune response was observed in four patients who had high expression of MAGE-A4 and MHC class I on tumor cells. These four patients showed significantly longer overall survival than patients without an antibody response after vaccination (p=0.009). Patients with tumor cells expressing high MAGE-A4 or MHC class I antigen showed significantly longer overall survival than those with low expression. Induction of CD4 and CD8T cell responses was observed in three and six patients, respectively, and patients with induction of MAGE-A4-specific IFNγ-producing CD8T cells, but not CD4T cells, lived longer than those without induction. The CHP-MAGE-A4 vaccine was safe. Expression of MAGE-A4 and MHC class I in tumor tissue and the induction of a MAGE-A4-specific immune response after vaccination would be feasible prognostic markers for patients vaccinated with MAGE-A4. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. A Randomized study on the Effects of Paclitaxel Liposme and Cisplatin Induction Chemotherapy Followed Concurrent Chemoradiotherapy and Sequential Radiotherapy on Locally Advanced Non-small Cell Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Youyi DAI

    2011-02-01

    Full Text Available Background and objective Sequential and concurrent chemoradiotherapy were widely studied in locally advanced non-small cell lung cancer (NSCLC, but the reports of induction chemotherapy followed concurrent chemoradiotherapy are rare so far. The little side effects of paclitaxel liposme may be convenient to carry out induction chemotherapy followed concurrent chemoradiotherapy. The aim of this study is to compare the effects and side effects of TP regimen (Paclitaxel liposme and cisplatin induction chemotherapy followed concurrent chemoradiotherapy with sequential radiotherapy on locally advanced NSCLC. Methods Sixty locally advanced NSCLC patients were randomly divided into group A, induction chemotherapy followed concurrent chemoradiotherapy and group B, sequential radiotherapy group. The patients in group A received 2-3 cycles of induced chemotherapy included of Paclitaxel liposme 135 mg/m2-175 mg/m2, d1 and cisplatin 70 mg/m2-80 mg/m2, d2, 3 weeks repeat and after 2-3 cycles followed by concurrent chemoradiotherapy. The patients in group B received chemotherapy, (as described above in group A 4-6 cycles of chemotherapy followed one cycle of radiotherapy. The three-dimensional conformal radiotherapy at the total dose of 56 Gy-70 Gy was applied in all patients. Results The response rate in group A and group B were 80.3% and 60%, respectively (P=0.042. 1-year survival rates were 71.4% and 53.2%, respectively (P=0.18. And there were no significant difference of myelosuppression, radiation esophagitis and pulmonary fibrosis between the two groups (P=0.09, P=0.147, P=0.276, respectively. Conclusion The recent effects of induction chemotherapy followed by concurrent chemoradiotherapy group were better than sequential radiotherapy group on locally advanced NSCLC and there was no significant difference in side effects between the two groups.

  2. Final Results of a Randomized Phase 2 Trial Investigating the Addition of Cetuximab to Induction Chemotherapy and Accelerated or Hyperfractionated Chemoradiation for Locoregionally Advanced Head and Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Seiwert, Tanguy Y., E-mail: tseiwert@medicine.bsd.uchicago.edu [Departments of Medicine, University of Chicago, Chicago, Illinois (United States); Melotek, James M. [Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois (United States); Blair, Elizabeth A. [Department of Otolaryngology, University of Chicago, Chicago, Illinois (United States); Stenson, Kerstin M. [Department of Otolaryngology, Rush University, Chicago, Illinois (United States); Salama, Joseph K. [Department of Radiation Oncology, Duke University, Durham, North Carolina (United States); Witt, Mary Ellyn [Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois (United States); Brisson, Ryan J.; Chawla, Apoorva; Dekker, Allison [Departments of Medicine, University of Chicago, Chicago, Illinois (United States); Lingen, Mark W. [Department of Pathology, University of Chicago, Chicago, Illinois (United States); Kocherginsky, Masha [Department of Public Health Sciences, University of Chicago, Chicago, Illinois (United States); Villaflor, Victoria M. [Departments of Medicine, University of Chicago, Chicago, Illinois (United States); Cohen, Ezra E.W. [Moores Cancer Center, University of California, San Diego, San Diego, California (United States); Haraf, Daniel J. [Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois (United States); Vokes, Everett E. [Departments of Medicine, University of Chicago, Chicago, Illinois (United States)

    2016-09-01

    Purpose: The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation. Methods and Materials: Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%. Results: 110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P<.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients. Conclusions: The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further

  3. Final Results of a Randomized Phase 2 Trial Investigating the Addition of Cetuximab to Induction Chemotherapy and Accelerated or Hyperfractionated Chemoradiation for Locoregionally Advanced Head and Neck Cancer

    International Nuclear Information System (INIS)

    Seiwert, Tanguy Y.; Melotek, James M.; Blair, Elizabeth A.; Stenson, Kerstin M.; Salama, Joseph K.; Witt, Mary Ellyn; Brisson, Ryan J.; Chawla, Apoorva; Dekker, Allison; Lingen, Mark W.; Kocherginsky, Masha; Villaflor, Victoria M.; Cohen, Ezra E.W.; Haraf, Daniel J.; Vokes, Everett E.

    2016-01-01

    Purpose: The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation. Methods and Materials: Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%. Results: 110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P<.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients. Conclusions: The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further

  4. Effects of curcumin on growth of human cervical cancer xenograft in nude mice and underlying mechanism

    Directory of Open Access Journals (Sweden)

    Aixue LIU

    Full Text Available Abstract The present study investigated the effects of curcumin (Cur on growth of human cervical cancer xenograft in nude mice and underlying mechanism. The nude mice modeled with human cervical cancer HeLa cell xenograft were treated with normal saline (control, 3 mg/kg Cisplatin, 50, 100 and 200 mg/kg Cur, respectively. The animal body weight and growth of tumor were measured. The expressions of Bax, Bcl-2, p53, p21, HIF-1α, VEGF and MIF protein in tumor tissue were determined. Results showed that, after treatment for 20 days, the tumor mass and tumor volume in 100 and 200 mg/kg Cur group were significantly lower than control group (P < 0.05. The expressions of Bax, p53 and p21 protein in tumor tissue in 200 mg/kg Cur group were significantly higher than control group (P < 0.05, and the expressions of Bcl-2, HIF-1α, VEGF and MIF protein in tumor tissue in 200 mg/kg Cur group were significantly lower than control group (P < 0.05. Cur can inhibit the growth of HeLa cell xenograft in nude mice. The possible mechanism may be related to its up-regulation of Bax, p53 and p21 protein expression in tumor tissue, and down-regulation of Bcl-2, HIF-1α, VEGF and MIF protein expression.

  5. Mathematical modelling of the destruction degree of cancer under the influence of a RF hyperthermia

    Science.gov (United States)

    Paruch, Marek; Turchan, Łukasz

    2018-01-01

    The article presents the mathematical modeling of the phenomenon of artificial hyperthermia which is caused by the interaction of an electric field. The electric field is induced by the applicator positioned within the biological tissue with cancer. In addition, in order to estimate the degree of tumor destruction under the influence of high temperature an Arrhenius integral has been used. The distribution of electric potential in the domain considered is described by the Laplace system of equations, while the temperature field is described by the Pennes system of equations. These problems are coupled by source function being the additional component in the Pennes equation and resulting from the electric field action. The boundary element method is applied to solve the coupled problem connected with the heating of biological tissues.

  6. High risk of under-grading and -staging in prostate cancer patients eligible for active surveillance.

    Science.gov (United States)

    Heidegger, Isabel; Skradski, Viktor; Steiner, Eberhard; Klocker, Helmut; Pichler, Renate; Pircher, Andreas; Horninger, Wolfgang; Bektic, Jasmin

    2015-01-01

    Active surveillance (AS) is increasingly offered to patients with low risk prostate cancer. The present study was conducted to evaluate the risk of tumor under-grading and -staging for AS eligibility. Moreover, we analyzed possible biomarkers for predicting more unfavorable final tumor histology. 197 patients who underwent radical prostatectomy (RPE) but would have met the EAU (European Association of Urology) criteria for AS (PSA4-10 ng/ml), PSA density (6, extraprostatic extension and positive resection margin (R1) or correlated significantly with up-grading and/or extraprostatic extension in a multivariate model. Only R1 resections were predictable by combining intermediate PSA levels with two positive biopsy cores (p = 0.004). Sub-analyses showed that the number of biopsy cores (10 vs. 15 biopsy cores) had no influence on above mentioned results on predicting biopsy undergrading. Clinical courses of patients showed that 19.9% of patients had a biochemical relapse after RPE, among all of them were undergraded in the initial biopsy. In summary, this study shows that a multitude of patients fulfilling the criteria for AS are under-diagnosed. The use of preoperative PSA levels, PSA density and the number of positive cores were not predictable for undergrading in the present patient collective.

  7. Cellular deformation characterization of human breast cancer cells under hydrodynamic forces

    Directory of Open Access Journals (Sweden)

    Ahmad Sohrabi Kashani

    2017-06-01

    Full Text Available Understanding how cells sense mechanical forces, and how respond biologically to themis an interesting and quickly-progressing area. Cells within their microenvironment are subjected tovarious physical forces such as mechanical loads and shear stress. Cells respond and adjust to theseforces by mechanotransduction mechanism in which deformation and mechanical forces are convertedinto biomechanical signals. To quantify mechanotransduction responses and to correctly interpretthe behavior of cell under in vitro stimulation, magnitude and distribution of the stresses on the cellmembrane should be characterized. In this study, a 2D Finite Element Model is introduced to simulatethe deformation of individual benign (MCF10A and malignant (MCF7 human breast cancer cellsunder hydrodynamic forces. A fluid-structure interaction method is implemented to model fluid flowand the adherent single cells inside a microchannel to study the nature of mechanical forces (viscousand pressure and to determine their contribution to the deformation of cells. Due to the differentmechanical properties, cells respond differently to the forces exerted by the fluid flow. It was foundthat the maximum stress and strain take place at the interface of the adherent cell and channel wall. Also, under the same boundary conditions, nucleolus and cytoplasm of an individual malignant cellundergo more deformation comparing a single benign cell. Furthermore, it was observed that both two cell lines experience much more stress when their attached area to the substrate is reduced.

  8. Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism

    Science.gov (United States)

    Zielinski, Daniel C.; Jamshidi, Neema; Corbett, Austin J.; Bordbar, Aarash; Thomas, Alex; Palsson, Bernhard O.

    2017-01-01

    Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.

  9. Differential NF-κB and MAPK activation underlies fluoride- and TPA-mediated CXCL8 (IL-8 induction in lung epithelial cells

    Directory of Open Access Journals (Sweden)

    Refsnes M

    2014-12-01

    indispensable for CXCL8 induction. The early response, magnitude, and persistency of MAPK and NF-κB signaling seemed to be critical determinants for the potential to induce CXCL8. These findings underscore that a strong, rapid, and relatively transient activation of ERK1/2 in combination with NF-kB may be sufficient for a strong induction of CXCL8, which may exceed the effects of a more moderate ERK1/2 activation in combination with activation of p38, JNK1/2, and NF-κB. Keywords: TPA, sodium fluoride, CXCL8, MAPK, NF-κB, A549 cells

  10. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yu-Ching [Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan (China); Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Ho, Heng-Chien; Lee, Miau-Rong [Department of Biochemistry, China Medical University, Taichung 404, Taiwan (China); Lai, Kuang-Chi [Department of Surgery, China Medical University Beigang Hospital, Yunlin 651, Taiwan (China); School of Medicine, China Medical University, Taichung 404, Taiwan (China); Yeh, Chung-Min; Lin, Yueh-Min [Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan (China); Ho, Tin-Yun [School of Chinese Medicine, China Medical University, Taichung 404, Taiwan (China); Hsiang, Chien-Yun, E-mail: cyhsiang@mail.cmu.edu.tw [Department of Microbiology, China Medical University, Taichung 404, Taiwan (China); Chung, Jing-Gung, E-mail: jgchung@mail.cmu.edu.tw [Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China)

    2012-07-15

    The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9–18 fold) of induction in the microarray data, and its early induction was observed in a 2 h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

  11. Open switching of current varying inductance

    International Nuclear Information System (INIS)

    Zubkov, P.I.; Lukyanchikov, L.A.; Ten, K.A.

    1990-01-01

    The electromotive force of induction occurs in a varying inductance of a current circuit part. It can be used to control and switch the current. The effect, occurring under the forced inductance decrease, is used widely for explosive magnetic generators to produce high currents, to store high-density energy and to generate superhigh magnetic fields. This paper gives an analysis of open switching of the currents by varying inductance in some simple electrotechnical models of circuits used in pulse power engineering to obtain high energies

  12. Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin

    Directory of Open Access Journals (Sweden)

    Danica L. Rowe

    2009-09-01

    Full Text Available In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.

  13. The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

    OpenAIRE

    Colletta, A A; Wakefield, L M; Howell, F V; Danielpour, D; Baum, M; Sporn, M B

    1991-01-01

    Recent experimental work has identified a novel intracellular binding site for the synthetic progestin, Gestodene, that appears to be uniquely expressed in human breast cancer cells. Gestodene is shown here to inhibit the growth of human breast cancer cells in a dose-dependent fashion, but has no effect on endocrine-responsive human endometrial cancer cells. Gestodene induced a 90-fold increase in the secretion of transforming growth factor-beta (TGF-beta) by T47D human breast cancer cells. O...

  14. Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction

    Science.gov (United States)

    Tan, Li-Duan; Du, Xin; Li, Xiao-Qing; He, Rui; Wang, Qing-Shan; Feng, Yu-Mei

    2016-01-01

    Bone is one of the most common organs of breast cancer metastasis. Cancer cells that mimic osteoblasts by expressing bone matrix proteins and factors have a higher likelihood of metastasizing to bone. However, the molecular mechanisms of osteomimicry formation of cancer cells remain undefined. Herein, we identified a set of bone-related genes (BRGs) that are ectopically co-expressed in primary breast cancer tissues and determined that osteomimetic feature is obtained due to the osteoblast-like transformation of epithelial breast cancer cells that have undergone epithelial-mesenchymal transition (EMT) followed by bone morphogenetic protein-2 (BMP2) stimulation. Furthermore, we demonstrated that breast cancer cells that transformed into osteoblast-like cells with high expression of BRGs showed enhanced chemotaxis, adhesion, proliferation and multidrug resistance in an osteoblast-mimic bone microenvironment in vitro. During these processes, runt-related transcription factor 2 (RUNX2) functioned as a master mediator by suppressing or activating the transcription of BRGs that underlie the dynamic antagonism between the TGF-β/SMAD and BMP/SMAD signaling pathways in breast cancer cells. Our findings suggest a novel mechanism of osteomimicry formation that arises in primary breast tumors, which may explain the propensity of breast cancer to metastasize to the skeleton and contribute to potential strategies for predicting and targeting breast cancer bone metastasis and multidrug resistance. PMID:27806311

  15. Geospatial Disparities and the Underlying Causes of Major Cancers for Women in Taiwan

    Directory of Open Access Journals (Sweden)

    Chi-Ting Chiang

    2014-05-01

    Full Text Available Some specific types of cancer still pose a severe threat to the health of Taiwanese women. This study focuses on determining the geographical locations of hot spots and causal factors related to the major categories of cancers in Taiwanese women. Cancer mortality data from 1972 to 2001 of 346 townships in Taiwan were obtained from the Atlas of Cancer Mortality. Principal component analysis was conducted to determine the primary categories of female cancers. The spatial patterns of hot spots and cold spots for each major cancer category were identified using the local indicator of spatial association. Finally, the regional differences between the hot spots and cold spots were compared to confirm the possible factors causing cancer throughout Taiwan. A total of 21 cancer types in women were divided into seven major categories, which accounted for 68.0% of the total variance. The results from the spatial autocorrelation analysis showed significant spatial clusters of the cancer categories. Based on the overall consistency of results between this study and those of previous research, this study further identified the high-risk locations and some specific risk factors for major cancer types among Taiwanese women.

  16. Atypical presentation of Legionella pneumonia among patients with underlying cancer: A fifteen-year review.

    Science.gov (United States)

    del Castillo, Maria; Lucca, Anabella; Plodkowski, Andrew; Huang, Yao-Ting; Kaplan, Janice; Gilhuley, Kathleen; Babady, N Esther; Seo, Susan K; Kamboj, Mini

    2016-01-01

    Immunocompromised patients, especially those receiving treatment with corticosteroids and cytotoxic chemotherapy are at increased risk for developing Legionella pneumonia. The aim of this study was to determine clinical and radiographic characteristics of pulmonary infection due to Legionella in persons undergoing treatment for cancer and stem cell transplant (SCT) recipients. Retrospective review of Legionella cases at MSKCC over a fifteen-year study period from January 1999 and December 2013. Cases were identified by review of microbiology records. During the study period, 40 cases of Legionella infection were identified; nine among these were due to non-pneumophila species. Most cases occurred during the summer. The majority [8/9, (89%)] of patients with non-pneumophila infection had underlying hematologic malignancy, compared to 18/31 (58%) with Legionella pneumophila infections. Radiographic findings were varied-nodular infiltrates mimicking invasive fungal infection were seen only among patients with hematologic malignancy and hematopoietic stem cell transplant (SCT) recipients and were frequently associated with non-pneumophila infections (50% vs 16%; P = 0.0594). All cases of nodular Legionella pneumonia were found incidentally or had an indolent clinical course. Legionella should be considered in the differential diagnosis of nodular lung lesions in immunocompromised patients, especially those with hematologic malignancy and SCT recipients. Most cases of nodular disease due to Legionella are associated with non-pneumophila infections. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  17. The effect of marital status on breast cancer-related outcomes in women under 65: A SEER database analysis.

    Science.gov (United States)

    Hinyard, Leslie; Wirth, Lorinette Saphire; Clancy, Jennifer M; Schwartz, Theresa

    2017-04-01

    Marital status is strongly associated with improved health and longevity. Being married has been shown to be positively associated with survival in patients with multiple different types of malignancy; however, little is known about the relationship between marital status and breast cancer in younger women. The purpose of this study is to investigate the effect of marital status on diagnosis, and survival of women under the age of 65 with breast cancer. The SEER 18 regions database was used to identify women between the ages of 25-64 diagnosed with invasive breast cancer in the years 2004-2009. Logistic regression was used to predict later stage diagnosis by marital status and Cox proportional hazards models were used to compare breast cancer-related and all-cause survival by marital status classification. Models were stratified by AJCC stage. After adjusting for age, race, and ER status, unmarried women were 1.18 times more likely to be diagnosed at a later stage than married women (95% CI 1.15, 1.20). In adjusted analysis unmarried women were more likely to die of breast cancer and more likely to die of all causes than married women across all AJCC stages. Younger unmarried women with breast cancer may benefit from additional counseling, psychosocial support and case management at the time of diagnosis to ensure their overall outcomes are optimized. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Quality of life of elderly cancer patients under radiotherapy; Qualidade de vida de idosos com cancer de prostata em radioterapia

    Energy Technology Data Exchange (ETDEWEB)

    Peres de Oliveira, Patricia; Corte Pereira, Beltrina da Purificacao [Pontificia Univ. Catolica de Sao Paulo, SP (Brazil). Programa de Pos-graduacao em Gerontologia]. E-mail: patiperes@uol.com.br

    2004-07-01

    This research analyzed the effects of radiotherapy in the quality of life of elderly patients suffering from prostatic cancer. Our aim was to verify the psychometric properties of the Quality of Life Index (QLI), by Ferrans and Powers, describing the social-demographic characteristics that affect the quality of life; and patients concept of quality of life and their perception of how radiotherapy interferes with the quality of life. Interviews were carried out with a sample of seven elderly patients suffering from prostatic cancer. Two different approaches were utilized: descriptive and qualitative statistics. The results show that the QLI may have useful application in our field in the identification of those aspects of quality of life affected by cancer. (author)

  19. Understanding Cancer Prognosis

    Medline Plus

    Full Text Available ... Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic ... grade, which refers to how abnormal the cancer cells look under a microscope. Grade provides clues about ...

  20. Inductive Monitoring System (IMS)

    Data.gov (United States)

    National Aeronautics and Space Administration — IMS: Inductive Monitoring System The Inductive Monitoring System (IMS) is a tool that uses a data mining technique called clustering to extract models of normal...

  1. Flowering induction in the bioenergy grass Miscanthus sacchariflorus is a quantitative short-day response, whilst delayed flowering under long days increases biomass accumulation

    Science.gov (United States)

    Donnison, Iain

    2013-01-01

    Miscanthus sacchariflorus is a fast-growing C4 perennial grass that can naturally hybridize with M. sinensis to produce interspecific hybrids, such as the sterile triploid M.× giganteus. The creation of such hybrids is essential for the rapid domestication of this novel bioenergy crop. However, progress has been hindered by poor understanding of the environmental cues promoting floral transition in M. sacchariflorus, which flowers less readily than M. sinensis. The purpose of this work was to identify the flowering requirements of M. sacchariflorus genotypes in order to expedite the introduction of new germplasm optimized to different environments. Six M. sacchariflorus accessions collected from a range of latitudes were grown under controlled photoperiod and temperature conditions, and flowering, biomass, and morphological phenotypic data were captured. Results indicated that M. sacchariflorus, irrespective of origin, is a quantitative short-day plant. Flowering under static long days (15.3h daylength), compared with shorter photoperiods, was delayed by an average 61 d, with an average associated increase of 52% of above-ground biomass (DM plant–1). Timing of floral initiation occurred between photoperiods of 14.2h and 12.1h, and accumulated temperatures of 553–1157 °C above a base temperature of 10 °C. Miscanthus sacchariflorus flowering phenology closely resembles that of Sorghum and Saccharum, indicating potentially similar floral pathways and suggesting that determination of the underlying genetic mechanisms will be facilitated by the syntenic relationships existing between these important C4 grasses. PMID:23183254

  2. Using low-dose radiation to potentiate the effect of induction chemotherapy in head and neck cancer: Results of a prospective phase 2 trial

    Directory of Open Access Journals (Sweden)

    Susanne M. Arnold, MD

    2016-10-01

    Conclusion: Chemopotentiating LDFRT combined with paclitaxel and carboplatin is effective in SCCHN and provided an excellent median overall survival of 107.2 months, with median PFS not yet reached in this locally advanced SCCHN cohort. This compares favorably to prior investigations and caused fewer grade 3 and 4 toxicities than more intensive, 3-drug induction regimens. This trial demonstrates the innovative use of LDFRT as a potentiator of chemotherapy.

  3. Alzheimer's Disease as Subcellular `Cancer' --- The Scale-Invariant Principles Underlying the Mechanisms of Aging ---

    Science.gov (United States)

    Murase, M.

    1996-01-01

    with self-organization, has been thought to underlie `creative' aspects of biological phenomena such as the origin of life, adaptive evolution of viruses, immune recognition and brain function. It therefore must be surprising to find that the same principles will also underlie `non-creative' aspects, for example, the development of cancer and the aging of complex organisms. Although self-organization has extensively been studied in nonliving things such as chemical reactions and laser physics, it is undoubtedly true that the similar sources of the order are available to living things at different levels and scales. Several paradigm shifts are, however, required to realize how the general principles of natural selection can be extensible to non-DNA molecules which do not possess the intrinsic nature of self-reproduction. One of them is, from the traditional, genetic inheritance view that DNA (or RNA) molecules are the ultimate unit of heritable variations and natural selection at any organization level, to the epigenetic (nongenetic) inheritance view that any non-DNA molecule can be the target of heritable variations and molecular selection to accumulate in certain biochemical environment. Because they are all enriched with a β-sheet content, ready to mostly interact with one another, different denatured proteins like β-amyloid, PHF and prions can individually undergo self-templating or self-aggregating processes out of gene control. Other paradigm shifts requisite for a break-through in the etiology of neurodegenerative disorders will be discussed. As it is based on the scale-invariant principles, the present theory also predicts plausible mechanisms underlying quite different classes of disorders such as amyotrophic lateral sclerosis (ALS), atherosclerosis, senile cataract and many other symptoms of aging. The present theory, thus, provides the consistent and comprehensive account to the origin of aging by means of natural selection and self-organization.

  4. Induction of ROS formation, poly(ADP-ribose) polymerase-1 activation, and cell death by PCB126 and PCB153 in human T47D and MDA-MB-231 breast cancer cells.

    Science.gov (United States)

    Lin, Chia-Hua; Lin, Po-Hsiung

    2006-08-25

    The primary purpose of this research is to investigate whether exposure to polychlorinated biphenyls (PCBs), i.e. PCB153 and PCB126, is associated with induction of reactive oxygen species (ROS), poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cell death in human T47D and MDA-MB-231 breast cancer cells. Results indicated that PCB153 and PCB126 induced concentration- and time-dependent increases in cytotoxic response and ROS formation in both T47D and MDA-MB-231 cells. At non-cytotoxic concentrations both PCB153 and PCB126 induced decreases in intracellular NAD(P)H and NAD+ in T47D and MDA-MB-231 cells where T47D cells were more resistant to PCB-induced reduction in intracellular NAD(P)H than MDA-MB-231 cells. Further investigation indicated that three specific PARP inhibitors completely blocked PCB-induced decreases in intracellular NAD(P)H in both T47D and MDA-MB-231 cells. These results imply that decreases in intracellular NAD(P)H in PCB-treated cells may be, in part, due to depletion of intracellular NAD+ pool mediated by PARP-1 activation through formation of DNA strand breaks. Overall, the extent of cytotoxic response, ROS formation, and PARP-1 activation generated in T47D and MDA-MB-231 cells was greater for PCB153 than for PCB126. In addition, the cytotoxicity induced by PCB153 and PCB126 in both T47D and MDA-MB-231 cells was completely blocked by co-treatment of catalase, dimethylsulfoxide, cupper (I)-/iron (II)-specific chelators, and CYP1A/2B inhibitors. This evidence suggests the involvement of ROS, Cu(I), Fe(II), and CYP1A/2B enzymes in mediating the induction of cell death by PCB153 and PCB126. Further, antagonism was observed between PCB126 and PCB153 for effects on cytotoxic response and ROS formation in T47D and MDA-MB-231 cells. Antagonism was also observed between PCB153 and PCB126 in the induction of NAD(P)H depletion at lower concentration (T47D cells, but not in MDA-MB-231 cells. In conclusions, results from our investigation suggest

  5. Fourier transform infrared spectroscopy imaging of live epithelial cancer cells under non-aqueous media.

    Science.gov (United States)

    Soh, JunYi; Chueng, Adeline; Adio, Aminat; Cooper, Alan J; Birch, Brian R; Lwaleed, Bashir A

    2013-04-01

    Fourier transform infrared (FT-IR) imaging is increasingly being applied to biomedical specimens, but strong IR absorption by water complicates live cell imaging. This study investigates the viability of adherent epithelial cells maintained for short periods under mineral oils in order to facilitate live cell spectroscopy using FT-IR with subsequent imaging. The MGH-U1 urothelial or CaCo2 colorectal cancer cell lines were grown on plastic surfaces or mid-range infrared transparent windows. Medium in established cultures was replaced with paraffin mineral oil, or Fluorolube, for up to 2 h, and viability assessed by supravital staining. Drug handling characteristics were also assessed. Imaging of preparations was attempted by reflectance and transmission using a Varian FT-IR microscope. Cells covered by mineral oil remained viable for 2 h, with recovery into normal medium possible. MTT ((3-(4,5-dimethylthlazol-2-yl)-2,5-diphenyl tetrazolium) conversion to crystalline formazan and differential patterns of drug uptake were maintained. The combination of a calcium fluoride substrate, Fluorolube oil, and transmission optics proved best for spectroscopy. Spectral features were used to obtain images of live cells. The viability of cells overlaid with IR transparent oils was assessed as part of a technique to optimise conditions for FT-IR imaging. Images of untreated cells were obtained using both reflectance and transmission. This represents an effective means of imaging live cells by IR spectroscopy, and also means that imaging is not necessarily a terminal event. It also increases options for producing images based on real-time biochemistry in a range of in vitro experimental and 'optical biopsy' contexts.

  6. Induction machine handbook

    CERN Document Server

    Boldea, Ion

    2002-01-01

    Often called the workhorse of industry, the advent of power electronics and advances in digital control are transforming the induction motor into the racehorse of industrial motion control. Now, the classic texts on induction machines are nearly three decades old, while more recent books on electric motors lack the necessary depth and detail on induction machines.The Induction Machine Handbook fills industry's long-standing need for a comprehensive treatise embracing the many intricate facets of induction machine analysis and design. Moving gradually from simple to complex and from standard to

  7. Second primary cancers after adjuvant radiotherapy in early breast cancer patients: A national population based study under the Danish Breast Cancer Cooperative Group (DBCG)

    International Nuclear Information System (INIS)

    Grantzau, Trine; Mellemkjær, Lene; Overgaard, Jens

    2013-01-01

    Background and purpose: To analyze the long-term risk of second primary solid non-breast cancer in a national population-based cohort of 46,176 patients treated for early breast cancer between 1982 and 2007. Patients and methods: All patients studied were treated according to the national guidelines of the Danish Breast Cancer Cooperative Group. The risk of second primary cancers was estimated by Standardised incidence ratios (SIRs) and multivariate Cox regression models were used to estimate adjusted hazard ratios (HR) among irradiated women compared to non-irradiated. All irradiated patients were treated on linear accelerators. Second cancers were a priori categorized into two groups; radiotherapy-associated- (oesophagus, lung, heart/mediastinum, pleura, bones, and connective tissue) and non-radiotherapy-associated sites (all other cancers). Results: 2358 second cancers had occurred during the follow-up. For the radiotherapy-associated sites the HR among irradiated women was 1.34 (95% CI 1.11–1.61) with significantly increased HRs for the time periods of 10–14 years (HR 1.55; 95% CI 1.08–2.24) and ⩾15 years after treatment (HR 1.79; 95% CI 1.14–2.81). There was no increased risk for the non-radiotherapy-associated sites (HR 1.04; 95% CI 0.94–1.1). The estimated attributable risk related to radiotherapy for the radiotherapy-associated sites translates into one radiation-induced second cancer in every 200 women treated with radiotherapy. Conclusions: Radiotherapy treated breast cancer patients have a small but significantly excess risk of second cancers

  8. Incidence of childhood cancer among Mexican children registered under a public medical insurance program.

    Science.gov (United States)

    Rivera-Luna, Roberto; Correa-González, Cecilia; Altamirano-Alvarez, Eduardo; Sánchez-Zubieta, Fernando; Cárdenas-Cardós, Rocio; Escamilla-Asian, Gabriela; Olaya-Vargas, Alberto; Bautista-Marquez, Aurora; Aguilar-Romo, Manuel

    2013-04-01

    Prior to 2005, 51% of children in Mexico diagnosed with cancer received no standardized optimal multidisciplinary medical care. A government-subsidized national cancer treatment program was therefore created for these patients and a National Cooperative Childhood Cancer Treatment Group was consequently formed for these patients. Pediatric patients with a proven diagnosis of leukemia, lymphoma or solid tumor and who were registered in the Popular Medical Insurance (PMI) program from January 2007 to December 2010, are described in this report. These patients had been enrolled and registered in one of the 49 nationwide certified medical institutions in Mexico. The national incidence and frequency data for childhood cancers were analyzed for the whole program. At the end of a 4-year study, the analysis revealed that 8,936 children from across Mexico had been diagnosed with cancer. The incidence rate for the PMI patients was 150.3/million/year (2010) for children of 0-18 years. The highest age incidence rate was 51.9 between 0 and 4 years and boys were the predominant group for all types of cancer. The leukemia incidence was 75.3/million/year (2010), and an average frequency of 50.75% throughout the 4 years. The overall mortality rate was measured at 5.4/100,000/year (2010). This study demonstrates a high frequency and incidence of childhood cancer and a beneficial impact of the PMI program over the quality of life in these children. Copyright © 2012 UICC.

  9. PBX1 Genomic Pioneer Function Drives ERα Signaling Underlying Progression in Breast Cancer

    Science.gov (United States)

    Magnani, Luca; Ballantyne, Elizabeth B.; Zhang, Xiaoyang; Lupien, Mathieu

    2011-01-01

    Altered transcriptional programs are a hallmark of diseases, yet how these are established is still ill-defined. PBX1 is a TALE homeodomain protein involved in the development of different types of cancers. The estrogen receptor alpha (ERα) is central to the development of two-thirds of all breast cancers. Here we demonstrate that PBX1 acts as a pioneer factor and is essential for the ERα-mediated transcriptional response driving aggressive tumors in breast cancer. Indeed, PBX1 expression correlates with ERα in primary breast tumors, and breast cancer cells depleted of PBX1 no longer proliferate following estrogen stimulation. Profiling PBX1 recruitment and chromatin accessibility across the genome of breast cancer cells through ChIP-seq and FAIRE-seq reveals that PBX1 is loaded and promotes chromatin openness at specific genomic locations through its capacity to read specific epigenetic signatures. Accordingly, PBX1 guides ERα recruitment to a specific subset of sites. Expression profiling studies demonstrate that PBX1 controls over 70% of the estrogen response. More importantly, the PBX1-dependent transcriptional program is associated with poor-outcome in breast cancer patients. Correspondingly, PBX1 expression alone can discriminate a priori the outcome in ERα-positive breast cancer patients. These features are markedly different from the previously characterized ERα-associated pioneer factor FoxA1. Indeed, PBX1 is the only pioneer factor identified to date that discriminates outcome such as metastasis in ERα-positive breast cancer patients. Together our results reveal that PBX1 is a novel pioneer factor defining aggressive ERα-positive breast tumors, as it guides ERα genomic activity to unique genomic regions promoting a transcriptional program favorable to breast cancer progression. PMID:22125492

  10. Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin

    Directory of Open Access Journals (Sweden)

    Danielle D. Jandial

    2017-03-01

    Full Text Available HER2/neu positive breast tumors predict a high mortality and comprise 25%–30% of breast cancer. We have shown that Flavokawain A (FKA preferentially reduces the viabilities of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2 versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468. FKA at cytotoxic concentrations to breast cancer cell lines also has a minimal effect on the growth of non-malignant breast epithelial MCF10A cells. FKA induces G2M arrest in cell cycle progression of HER2-overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl2, BclX/L, XIAP, and survivin. FKA also downregulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to an enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through downregulation of Myt1, Wee1, Skp2, survivin, and XIAP. Our results suggest FKA as a promising and novel apoptosis inducer and G2 blocking agent that, in combination with Herceptin, enhances for the treatment of HER2-overexpressing breast cancer.

  11. gef Gene Expression in MCF-7 Breast Cancer Cells is Associated with a Better Prognosis and Induction of Apoptosis by p53-Mediated Signaling Pathway

    Science.gov (United States)

    Boulaiz, Houria; Álvarez, Pablo J.; Prados, Jose; Marchal, Juan; Melguizo, Consolación; Carrillo, Esmeralda; Peran, Macarena; Rodríguez, Fernando; Ramírez, Alberto; Ortíz, Raúl; Aránega, Antonia

    2011-01-01

    Breast cancer research has developed rapidly in the past few decades, leading to longer survival times for patients and opening up the possibility of developing curative treatments for advanced breast cancer. Our increasing knowledge of the biological pathways associated with the progression and development of breast cancer, alongside the failure of conventional treatments, has prompted us to explore gene therapy as an alternative therapeutic strategy. We previously reported that gef gene from E. coli has shown considerable cytotoxic effects in breast cancer cells. However, its action mechanism has not been elucidated. Indirect immunofluorescence technique using flow cytometry and immunocytochemical analysis were used to detect breast cancer markers: estrogen (ER) and progesterone (PR) hormonal receptors, human epidermal growth factor receptor-2 proto-oncogene (c-erbB-2), ki-67 antigen and p53 protein. gef gene induces an increase in ER and PR expressions and a decrease in ki-67 and c-erbB-2 gene expressions, indicating a better prognosis and response to treatment and a longer disease-free interval and survival. It also increased p53 expression, suggesting that gef-induced apoptosis is regulated by a p53-mediated signaling pathway. These findings support the hypothesis that the gef gene offers a new approach to gene therapy in breast cancer. PMID:22174609

  12. Depression and under-treatment of depression: potential risks and outcomes in black lung cancer patients

    Science.gov (United States)

    Traeger, Lara; Cannon, Sheila; Pirl, William F.; Park, Elyse R.

    2015-01-01

    In the U.S., black men are at higher risk than white men for lung cancer mortality whereas rates are comparable between black and white women. This paper draws from empirical work in lung cancer, mental health and health disparities to highlight that race and depression may overlap in predicting lower treatment access and utilization and poorer quality of life among patients. Racial barriers to depression identification and treatment in the general population may compound these risks. Prospective data are needed to examine whether depression plays a role in racial disparities in lung cancer outcomes. PMID:23514250

  13. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress.

    Science.gov (United States)

    Schug, Zachary T; Peck, Barrie; Jones, Dylan T; Zhang, Qifeng; Grosskurth, Shaun; Alam, Israt S; Goodwin, Louise M; Smethurst, Elizabeth; Mason, Susan; Blyth, Karen; McGarry, Lynn; James, Daniel; Shanks, Emma; Kalna, Gabriela; Saunders, Rebecca E; Jiang, Ming; Howell, Michael; Lassailly, Francois; Thin, May Zaw; Spencer-Dene, Bradley; Stamp, Gordon; van den Broek, Niels J F; Mackay, Gillian; Bulusu, Vinay; Kamphorst, Jurre J; Tardito, Saverio; Strachan, David; Harris, Adrian L; Aboagye, Eric O; Critchlow, Susan E; Wakelam, Michael J O; Schulze, Almut; Gottlieb, Eyal

    2015-01-12

    A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Maintenance based Bevacizumab versus complete stop or continuous therapy after induction therapy in first line treatment of stage IV colorectal cancer: A meta-analysis of randomized clinical trials.

    Science.gov (United States)

    Tamburini, Emiliano; Rudnas, Britt; Santelmo, Carlotta; Drudi, Fabrizio; Gianni, Lorenzo; Nicoletti, Stefania V L; Ridolfi, Claudio; Tassinari, Davide

    2016-08-01

    In stage IV colorectal cancer, bevacizumab-based maintenance therapy, complete stop therapy and continuous therapy are considered all possible approaches after first line induction chemotherapy. However, there are no clear data about which approach is preferable. All randomized phase III trials comparing bevacizumab-based maintenance therapy (MB) with complete stop therapy (ST) or with continuous therapy (CT) were considered eligible and included into the analysis. Primary endpoint was the Time to failure strategies (TFS). Secondary endpoints were Overall Survival (OS) and Progression free survival (PFS). Meta-analysis was performed in line with the PRISMA statement. 1892 patients of five trials were included into the analysis. A significant improvement in TFS (HR 0.79; CI 95% 0.7-0.9 p=0.0005) and PFS (HR 0.56; CI 95% 0.44-0.71 p<0.00001) were observed in favour of MB versus ST. A trend, but not statistically significant, in favour of MB versus ST was also observed for OS (HR 0.88; CI 95% 0.77-1.01, p=0.08). Comparing maintenance therapy versus continuous therapy no statistically differences were observed in the outcomes evaluated (OS 12 months OR 1.1 p=0.62, OS 24 months OR 1 p=1, OS 36 months OR 0.54 p=0.3, TFS 12 months OR 0.76 p=0.65). Our meta-analysis suggests that use of MB approach increases TFS, PFS compared to ST. Although without observing any statistically advantage, it should be highlighted that MB versus ST showed a trend in favour of MB. We observed no difference between MB and CT. MB should be considered the standard regimen in patients with stage IV colorectal cancer after first line induction therapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Combination of PTEN and γ-Ionizing Radiation Enhances Cell Death and G2/M Arrest Through Regulation of AKT Activity and p21 Induction in Non-Small-Cell Lung Cancer Cells

    International Nuclear Information System (INIS)

    Park, Jong Kuk; Jung, Hae-Yun; Park, Seon Ho; Kang, Seung Yi; Yi, Mi-Rang; Um, Hong Duck; Hong, Sung Hee

    2008-01-01

    Purpose: To identify the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) during γ-ionizing radiation (γ-IR) treatment for non-small-cell lung cancer cells. Methods and Materials: Wild-type PTEN or mutant forms of PTEN plasmids were transfected to construct stable transfectants of the NCI-H1299 non-small-cell lung cancer cell line. Combined effects of PTEN expression and IR treatment were tested using immunoblot, clonogenic, and cell-counting assays. Related signaling pathways were studied with immunoblot and kinase assays. Results: At steady state, stable transfectants showed almost the same proliferation rate but had different AKT phosphorylation patterns. When treated with γ-IR, wild-type PTEN transfectants showed higher levels of cell death compared with mock vector or mutant transfectants, and showed increased G 2 /M cell-cycle arrest accompanied by p21 induction and CDK1 inactivation. NCI-H1299 cells were treated with phosphosinositide-3 kinase (PI3K)/AKT pathway inhibitor (LY29002), resulting in reduced AKT phosphorylation levels. Treatment of NCI-H1299 cells with LY29002 and γ-IR resulted in increased cell-cycle arrest and p21 induction. Endogenous wild-type PTEN-containing NCI-H460 cells were treated with PTEN-specific siRNA and then irradiated with γ-IR: however reduced PTEN levels did not induce cell-cycle arrest or p21 expression. Conclusions: Taken together, these findings indicate that PTEN may modulate cell death or the cell cycle via AKT inactivation by PTEN and γ-IR treatment. We also propose that a PTEN-PI3K/AKT-p21-CDK1 pathway could regulate cell death and the cell cycle by γ-IR treatment

  16. Induction of cancer chemopreventive enzymes by coffee is mediated by transcription factor Nrf2. Evidence that the coffee-specific diterpenes cafestol and kahweol confer protection against acrolein

    International Nuclear Information System (INIS)

    Higgins, Larry G.; Cavin, Christophe; Itoh, Ken; Yamamoto, Masayuki; Hayes, John D.

    2008-01-01

    Mice fed diets containing 3% or 6% coffee for 5 days had increased levels of mRNA for NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase class Alpha 1 (GSTA1) of between 4- and 20-fold in the liver and small intestine. Mice fed 6% coffee also had increased amounts of mRNA for UDP-glucuronosyl transferase 1A6 (UGT1A6) and the glutamate cysteine ligase catalytic (GCLC) subunit of between 3- and 10-fold in the small intestine. Up-regulation of these mRNAs was significantly greater in mice possessing Nrf2 (NF-E2 p45 subunit-related factor 2) than those lacking the transcription factor. Basal levels of mRNAs for NQO1, GSTA1, UGT1A6 and GCLC were lower in tissues from nrf2 -/- mice than from nrf2 +/+ mice, but modest induction occurred in the mutant animals. Treatment of mouse embryonic fibroblasts (MEFs) from nrf2 +/+ mice with either coffee or the coffee-specific diterpenes cafestol and kahweol (C + K) increased NQO1 mRNA up to 9-fold. MEFs from nrf2 -/- mice expressed less NQO1 mRNA than did wild-type MEFs, but NQO1 was induced modestly by coffee or C + K in the mutant fibroblasts. Transfection of MEFs with nqo1-luciferase reporter constructs showed that induction by C + K was mediated primarily by Nrf2 and required the presence of an antioxidant response element in the 5'-upstream region of the gene. Luciferase reporter activity did not increase following treatment of MEFs with 100 μmol/l furan, suggesting that this ring structure within C + K is insufficient for gene induction. Priming of nrf2 +/+ MEFs, but not nrf2 -/- MEFs, with C + K conferred 2-fold resistance towards acrolein

  17. Gastric cancer in young people under 30 years of age: worse prognosis, or delay in diagnosis?

    International Nuclear Information System (INIS)

    López-Basave, Horacio Noé; Morales-Vásquez, Flavia; Ruiz-Molina, Juan Manuel; Ñamendys-Silva, Silvio A; Vela-Sarmiento, Itzel; Ruan, Javier Melchor; Rosciano, Alejandro E Padilla; Calderillo-Ruiz, German; Díaz-Romero, Consuelo; Herrera-Gómez, Angel; Meneses-García, Abelardo A

    2013-01-01

    Gastric cancer is an aggressive disease with nonspecific early symptoms. Its incidence and prognosis in young patients has shown considerable variability. Our objective was to retrospectively study patients from our institution aged <30 years with gastric carcinoma. The study was undertaken to describe the experience of gastric cancer in this population, and to demonstrate its specific clinical and pathological characteristics. We reviewed the cases of histologically confirmed gastric cancer between 1985 and 2006 at the Instituto Nacional de Cancerología of Mexico (INCan); emphasis in our review was placed on clinical presentation, diagnostic and therapeutic intervention, pathology, and the results. Thirty cases of gastric carcinoma were reviewed. The patients’ median age was 27 years (range, 18–30 years) and the male:female ratio was 1:1. Gastric cancer exhibits different behavior in patients aged, 30 years, but delay in diagnosis and the tumor’s behavior appear to be the most important factors in prognosis of the disease

  18. Elucidation of the Molecular Mechanisms Underlying Lymph Node Metastasis in Prostate Cancer

    National Research Council Canada - National Science Library

    Datta, Kaustubh

    2005-01-01

    .... This finding leads one to think that understanding the role of angiogenic molecules like VEGF-C and VEGF-D in molecular detail for lymphatic formation in prostate cancer will provide information...

  19. A comprehensive sensitivity analysis of microarray breast cancer classification under feature variability

    NARCIS (Netherlands)

    Sontrop, H.M.J.; Moerland, P.D.; Van den Ham, R.; Reinders, M.J.T.; Verhaegh, W.F.J.

    2009-01-01

    Background: Large discrepancies in signature composition and outcome concordance have been observed between different microarray breast cancer expression profiling studies. This is often ascribed to differences in array platform as well as biological variability. We conjecture that other reasons for

  20. The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions

    International Nuclear Information System (INIS)

    Mylonis, Ilias; Lakka, Achillia; Tsakalof, Andreas; Simos, George

    2010-01-01

    Research highlights: → Kaempferol inhibits HIF-1 activity in hepatocarcinoma cells; → Kaempferol causes cytoplasmic mislocalization of HIF-1α by impairing the MAPK pathway. → Viability of hepatocarcinoma cells under hypoxia is reduced by kaempferol. -- Abstract: Hepatocellular carcinoma (HCC) is characterized by high mortality rates and resistance to conventional treatment. HCC tumors usually develop local hypoxia, which stimulates proliferation of cancer cells and renders them resilient to chemotherapy. Adaptation of tumor cells to the hypoxic conditions depends on the hypoxia-inducible factor 1 (HIF-1). Over-expression of its regulated HIF-1α subunit, an important target of anti-cancer therapy, is observed in many cancers including HCC and is associated with severity of tumor growth and poor patient prognosis. In this report we investigate the effect of the dietary flavonoid kaempferol on activity, expression levels and localization of HIF-1α as well as viability of human hepatoma (Huh7) cancer cells. Treatment of Huh7 cells with kaempferol under hypoxic conditions (1% oxygen) effectively inhibited HIF-1 activity in a dose-dependent manner (IC 50 = 5.16 μM). The mechanism of this inhibition did not involve suppression of HIF-1α protein levels but rather its mislocalization into the cytoplasm due to inactivation of p44/42 MAPK by kaempferol (IC 50 = 4.75 μM). Exposure of Huh7 cells to 10 μΜ kaempferol caused significant reduction of their viability, which was remarkably more evident under hypoxic conditions. In conclusion, kaempferol, a non-toxic natural food component, inhibits both MAPK and HIF-1 activity at physiologically relevant concentrations (5-10 μM) and suppresses hepatocarcinoma cell survival more efficiently under hypoxia. It has, therefore, potential as a therapeutic or chemopreventive anti-HCC agent.

  1. The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions

    Energy Technology Data Exchange (ETDEWEB)

    Mylonis, Ilias; Lakka, Achillia; Tsakalof, Andreas [Laboratory of Biochemistry, School of Medicine, University of Thessaly, BIOPOLIS, 41110 Larissa (Greece); Institute of Biomedical Research and Technology (BIOMED), 51 Papanastasiou str., 41222 Larissa (Greece); Simos, George, E-mail: simos@med.uth.gr [Laboratory of Biochemistry, School of Medicine, University of Thessaly, BIOPOLIS, 41110 Larissa (Greece); Institute of Biomedical Research and Technology (BIOMED), 51 Papanastasiou str., 41222 Larissa (Greece)

    2010-07-16

    Research highlights: {yields} Kaempferol inhibits HIF-1 activity in hepatocarcinoma cells; {yields} Kaempferol causes cytoplasmic mislocalization of HIF-1{alpha} by impairing the MAPK pathway. {yields} Viability of hepatocarcinoma cells under hypoxia is reduced by kaempferol. -- Abstract: Hepatocellular carcinoma (HCC) is characterized by high mortality rates and resistance to conventional treatment. HCC tumors usually develop local hypoxia, which stimulates proliferation of cancer cells and renders them resilient to chemotherapy. Adaptation of tumor cells to the hypoxic conditions depends on the hypoxia-inducible factor 1 (HIF-1). Over-expression of its regulated HIF-1{alpha} subunit, an important target of anti-cancer therapy, is observed in many cancers including HCC and is associated with severity of tumor growth and poor patient prognosis. In this report we investigate the effect of the dietary flavonoid kaempferol on activity, expression levels and localization of HIF-1{alpha} as well as viability of human hepatoma (Huh7) cancer cells. Treatment of Huh7 cells with kaempferol under hypoxic conditions (1% oxygen) effectively inhibited HIF-1 activity in a dose-dependent manner (IC{sub 50} = 5.16 {mu}M). The mechanism of this inhibition did not involve suppression of HIF-1{alpha} protein levels but rather its mislocalization into the cytoplasm due to inactivation of p44/42 MAPK by kaempferol (IC{sub 50} = 4.75 {mu}M). Exposure of Huh7 cells to 10 {mu}{Mu} kaempferol caused significant reduction of their viability, which was remarkably more evident under hypoxic conditions. In conclusion, kaempferol, a non-toxic natural food component, inhibits both MAPK and HIF-1 activity at physiologically relevant concentrations (5-10 {mu}M) and suppresses hepatocarcinoma cell survival more efficiently under hypoxia. It has, therefore, potential as a therapeutic or chemopreventive anti-HCC agent.

  2. Induction Chemotherapy for p16 Positive Oropharyngeal Squamous Cell Carcinoma

    OpenAIRE

    Saito, Yuki; Ando, Mizuo; Omura, Go; Yasuhara, Kazuo; Yoshida, Masafumi; Takahashi, Wataru; Yamasoba, Tatsuya

    2016-01-01

    Objectives/Hypothesis We aimed to determine the effectiveness of induction chemotherapy for treating p16?positive oropharyngeal cancer in our department. Study Design This was a retrospective case series to assess treatment effectiveness. Methods We administered induction chemotherapy to patients with stage III to IV oropharyngeal p16?positive squamous cell carcinoma between 2008 and 2013. Induction chemotherapy was administered using combinations of docetaxel, cisplatin, and 5?fluorouracil. ...

  3. Involvement of Bax and Bcl-2 in Induction of Apoptosis by Essential Oils of Three Lebanese Salvia Species in Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Alessandra Russo

    2018-01-01

    Full Text Available Prostate cancer is one of the most common forms of cancer in men, and research to find more effective and less toxic drugs has become necessary. In the frame of our ongoing program on traditionally used Salvia species from the Mediterranean Area, here we report the biological activities of Salvia aurea, S. judaica and S. viscosa essential oils against human prostate cancer cells (DU-145. The cell viability was measured by 3(4,5-dimethyl-thiazol-2-yl2,5-diphenyl-tetrazolium bromide (MTT test and lactate dehydrogenase (LDH release was used to quantify necrosis cell death. Genomic DNA, caspase-3 activity, expression of cleaved caspase-9, B-cell lymphoma 2 (Bcl-2 and Bcl-2 associated X (Bax proteins were analyzed in order to study the apoptotic process. The role of reactive oxygen species in cell death was also investigated. We found that the three essential oils, containing caryophyllene oxide as a main constituent, are capable of reducing the growth of human prostate cancer cells, activating an apoptotic process and increasing reactive oxygen species generation. These results suggest it could be profitable to further investigate the effects of these essential oils for their possible use as anticancer agents in prostate cancer, alone or in combination with chemotherapy agents.

  4. Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells

    International Nuclear Information System (INIS)

    Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J; Mukherjee, Pinku

    2005-01-01

    Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E 2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G 0 /G 1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E 2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and

  5. Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells.

    Science.gov (United States)

    Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J; Mukherjee, Pinku

    2005-01-01

    Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and

  6. A TORC2-Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers.

    Science.gov (United States)

    Amin, Dhara N; Ahuja, Deepika; Yaswen, Paul; Moasser, Mark M

    2015-12-01

    The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in-depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt-TORC2 feed-forward loop that functions as a self-perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus, a critical pathophysiologic event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency, and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2-amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers. ©2015 American Association for Cancer Research.

  7. Sequential occurrence of dyspnea at the end of life in palliative care, according to the underlying cancer

    Science.gov (United States)

    Guirimand, Frédéric; Sahut d'izarn, Marine; Laporte, Lucy; Francillard, Marie; Richard, Jean-François; Aegerter, Philippe

    2015-01-01

    Dyspnea is a symptom that severely affects the quality of life of terminally ill patients. Its frequency differs considerably between studies. We aimed to characterize the frequency of dyspnea in a palliative care hospital (PCH) and to identify factors predisposing to dyspnea, particularly during the very last days of life, as a function of the underlying disease. Episodes of dyspnea were identified by the computerized extraction of prospectively collected data from the reports of care assistants or from medical observations recorded in the medical files for all stays at our PCH during the last 6 years. There were 6455 hospital stays, 88% ending in the death of the patient; 13,282 episodes of dyspnea were recorded during 2608 hospital stays (40%). Dyspnea was more frequently observed in cases of cancer than in other conditions (RR = 1.30; 95% CI: 1.14–1.48). Pulmonary metastasis increased the risk of dyspnea from 37% to 51% (RR = 1.37; 95% CI: 1.29–1.46). Dyspnea frequency varied with the primary cancer site, from 24% (brain cancer) to 60% (esophageal cancer). The data for cancer patients staying for more than 6 days who subsequently died indicated that 8% of patients experienced dyspnea exclusively during the last 4 days of the life, independently of the site of the primary cancer. Dyspnea during the last few days of life requires systematic assessment. Exclusively terminal dyspnea should be distinguished from more precocious dyspnea, as the pathophysiological mechanisms and treatments of these two forms are probably different. PMID:25644607

  8. Combination treatment of all-trans retinoic acid (ATRA) and γ-secretase inhibitor (DAPT) cause growth inhibition and apoptosis induction in the human gastric cancer cell line.

    Science.gov (United States)

    Patrad, Elham; Niapour, Ali; Farassati, Faris; Amani, Mojtaba

    2018-04-01

    Current medication for gastric cancer patients has a low success rate with resistance and side effects. According to recent studies, γ-secretase inhibitors is used as therapeutic drugs in cancer. Moreover, all-trans retinoic acid (ATRA) is a natural compound proposed for the treatment/chemo-prevention of cancers. The aim of this study was to explore the effects of ATRA in combination with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) as γ-secretase inhibitor on viability and apoptosis of the AGS and MKN-45 derived from human gastric cancer. AGS and MKN-45 gastric cancer cell lines were treated with different concentrations of ATRA or DAPT alone or ATRA plus DAPT. The viability, death detection and apoptosis of cells was examined by MTT assay and Ethidium bromide/acridine orange staining. The distribution of cells in different phases of cell cycle was also evaluated through flow cytometry analyses. In addition, caspase 3/7 activity and the expression of caspase-3 and bcl-2 were examined. DAPT and ATRA alone decreased gastric cancer cells viability in a concentration dependent manner. The combination of DAPT and ATRA exhibited significant synergistic inhibitory effects. The greater percentage of cells were accumulated in G0/G1 phase of cell cycle in combination treatment. The combination of DAPT and ATRA effectively increased the proportion of apoptotic cells and the level of caspase 3/7 activities compared to single treatment. Moreover, augmented caspase-3 up-regulation and bcl-2 down-regulation were found following combined application of DAPT and ATRA. The combination of DAPT and ATRA led to more reduction in viability and apoptosis in respect to DAPT or ATRA alone in the investigated cell lines.

  9. Expression of P2X7R in breast cancer tissue and the induction of apoptosis by the gene-specific shRNA in MCF-7 cells

    OpenAIRE

    TAN, CHAO; HAN, LI; ZOU, LILI; LUO, CHUNHUA; LIU, AIHUA; SHENG, XIEJING; XI, DEE

    2015-01-01

    The aim of the present study was to investigate the effects of P2X7R short hairpin (sh)RNA on the proliferation and apoptosis of MCF-7 cells, and to detect the expression of P2X7R in breast cancer and MCF-7 cells. In order to detect the expression of P2X7R in normal breast and breast cancer tissues, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot analysis and immunohistochemistry were performed. A P2X7-targeted shRNA sequence and a scrambled sequence were ...

  10. Sequential inductive learning

    Energy Technology Data Exchange (ETDEWEB)

    Gratch, J. [Univ. of Southern California, Marina del Rey, CA (United States)

    1996-12-31

    This article advocates a new model for inductive learning. Called sequential induction, it helps bridge classical fixed-sample learning techniques (which are efficient but difficult to formally characterize), and worst-case approaches (which provide strong statistical guarantees but are too inefficient for practical use). Learning proceeds as a sequence of decisions which are informed by training data. By analyzing induction at the level of these decisions, and by utilizing the only enough data to make each decision, sequential induction provides statistical guarantees but with substantially less data than worst-case methods require. The sequential inductive model is also useful as a method for determining a sufficient sample size for inductive learning and as such, is relevant to learning problems where the preponderance of data or the cost of gathering data precludes the use of traditional methods.

  11. Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia.

    Directory of Open Access Journals (Sweden)

    Toshiki Hirakawa

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs, the expression of insulin-like growth factor-1 (IGF1 and IGF1 receptor (IGF1R was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9 was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2 and hypoxia (1% O2. IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.

  12. The dietary flavonoid kaempferol effectively inhibits HIF-1 activity and hepatoma cancer cell viability under hypoxic conditions.

    Science.gov (United States)

    Mylonis, Ilias; Lakka, Achillia; Tsakalof, Andreas; Simos, George

    2010-07-16

    Hepatocellular carcinoma (HCC) is characterized by high mortality rates and resistance to conventional treatment. HCC tumors usually develop local hypoxia, which stimulates proliferation of cancer cells and renders them resilient to chemotherapy. Adaptation of tumor cells to the hypoxic conditions depends on the hypoxia-inducible factor 1 (HIF-1). Over-expression of its regulated HIF-1alpha subunit, an important target of anti-cancer therapy, is observed in many cancers including HCC and is associated with severity of tumor growth and poor patient prognosis. In this report we investigate the effect of the dietary flavonoid kaempferol on activity, expression levels and localization of HIF-1alpha as well as viability of human hepatoma (Huh7) cancer cells. Treatment of Huh7 cells with kaempferol under hypoxic conditions (1% oxygen) effectively inhibited HIF-1 activity in a dose-dependent manner (IC(50)=5.16microM). The mechanism of this inhibition did not involve suppression of HIF-1alpha protein levels but rather its mislocalization into the cytoplasm due to inactivation of p44/42 MAPK by kaempferol (IC(50)=4.75microM). Exposure of Huh7 cells to 10microM kaempferol caused significant reduction of their viability, which was remarkably more evident under hypoxic conditions. In conclusion, kaempferol, a non-toxic natural food component, inhibits both MAPK and HIF-1 activity at physiologically relevant concentrations (5-10microM) and suppresses hepatocarcinoma cell survival more efficiently under hypoxia. It has, therefore, potential as a therapeutic or chemopreventive anti-HCC agent. Copyright 2010 Elsevier Inc. All rights reserved.

  13. The melatonin action on stromal stem cells within pericryptal area in colon cancer model under constant light

    Energy Technology Data Exchange (ETDEWEB)

    Kannen, Vinicius, E-mail: kannen71@yahoo.com.br [Department of Pathology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto - Sao Paulo 14049-900 (Brazil); Marini, Tassiana [Department of Pathology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto - Sao Paulo 14049-900 (Brazil); Zanette, Dalila L. [National Institute of Science and Technology in Stem Cell and Cell Therapy, Center for Cell Therapy and Regional Blood Center, Ribeirao Preto - Sao Paulo (Brazil); Frajacomo, Fernando T.; Silva, Gyl E.B. [Department of Pathology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto - Sao Paulo 14049-900 (Brazil); Silva, Wilson A. [Department of Genetics, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto - Sao Paulo (Brazil); National Institute of Science and Technology in Stem Cell and Cell Therapy, Center for Cell Therapy and Regional Blood Center, Ribeirao Preto - Sao Paulo (Brazil); Garcia, Sergio B. [Department of Pathology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto - Sao Paulo 14049-900 (Brazil)

    2011-02-25

    Research highlights: {yields} We investigated melatonin against the malignant effects of constant light. {yields} Melatonin supplementation increased its serum levels and its receptor expression. {yields} Melatonin decreased cancer stem cells and dysplastic injuries in colon tissue. {yields} Melatonin controlled proliferative process and apoptosis induction. -- Abstract: Constant light (LL) is associated with high incidence of colon cancer. MLT supplementation was related to the significant control of preneoplastic patterns. We sought to analyze preneoplastic patterns in colon tissue from animals exposed to LL environment (14 days; 300 lx), MLT-supplementation (10 mg/kg/day) and DMH-treatment (1,2 dimethylhydrazine; 125 mg/kg). Rodents were sacrificed and MLT serum levels were measured by radioimmunoassay. Our results indicated that LL induced ACF development (p < 0.001) with a great potential to increase the number of CD133(+) and CD68(+) cells (p < 0.05 and p < 0.001). LL also increased the proliferative process (PCNA-Li; p < 0.001) as well as decreased caspase-3 protein (p < 0.001), related to higher COX-2 protein expression (p < 0.001) within pericryptal colonic stroma (PCCS). However, MLT-supplementation controlled the development of dysplastic ACF (p < 0.001) diminishing preneoplastic patterns into PCCS as CD133 and CD68 (p < 0.05 and p < 0.001). These events were relative to decreased PCNA-Li index and higher expression of caspase-3 protein. Thus, MLT showed a great potential to control the preneoplastic patterns induced by LL.

  14. The melatonin action on stromal stem cells within pericryptal area in colon cancer model under constant light

    International Nuclear Information System (INIS)

    Kannen, Vinicius; Marini, Tassiana; Zanette, Dalila L.; Frajacomo, Fernando T.; Silva, Gyl E.B.; Silva, Wilson A.; Garcia, Sergio B.

    2011-01-01

    Research highlights: → We investigated melatonin against the malignant effects of constant light. → Melatonin supplementation increased its serum levels and its receptor expression. → Melatonin decreased cancer stem cells and dysplastic injuries in colon tissue. → Melatonin controlled proliferative process and apoptosis induction. -- Abstract: Constant light (LL) is associated with high incidence of colon cancer. MLT supplementation was related to the significant control of preneoplastic patterns. We sought to analyze preneoplastic patterns in colon tissue from animals exposed to LL environment (14 days; 300 lx), MLT-supplementation (10 mg/kg/day) and DMH-treatment (1,2 dimethylhydrazine; 125 mg/kg). Rodents were sacrificed and MLT serum levels were measured by radioimmunoassay. Our results indicated that LL induced ACF development (p < 0.001) with a great potential to increase the number of CD133(+) and CD68(+) cells (p < 0.05 and p < 0.001). LL also increased the proliferative process (PCNA-Li; p < 0.001) as well as decreased caspase-3 protein (p < 0.001), related to higher COX-2 protein expression (p < 0.001) within pericryptal colonic stroma (PCCS). However, MLT-supplementation controlled the development of dysplastic ACF (p < 0.001) diminishing preneoplastic patterns into PCCS as CD133 and CD68 (p < 0.05 and p < 0.001). These events were relative to decreased PCNA-Li index and higher expression of caspase-3 protein. Thus, MLT showed a great potential to control the preneoplastic patterns induced by LL.

  15. Assessing oral bioaccessibility of trace elements in soils under worst-case scenarios by automated in-line dynamic extraction as a front end to inductively coupled plasma atomic emission spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Rosende, María [FI-TRACE group, Department of Chemistry, University of the Balearic Islands, Carretera de Valldemossa, km 7.5, Palma de Mallorca, Illes Balears E-07122 (Spain); Magalhães, Luis M.; Segundo, Marcela A. [REQUIMTE, Department of Chemistry, Faculty of Pharmacy, University of Porto, R. de Jorge Viterbo Ferreira, 228, Porto 4050-313 (Portugal); Miró, Manuel, E-mail: manuel.miro@uib.es [FI-TRACE group, Department of Chemistry, University of the Balearic Islands, Carretera de Valldemossa, km 7.5, Palma de Mallorca, Illes Balears E-07122 (Spain)

    2014-09-09

    Highlights: • Automatic oral bioaccessibility tests of trace metals under worst-case scenarios. • Use of intricate and realistic digestive fluids (UBM method). • Analysis of large amounts of soils (≥400 mg) in a flow-based configuration. • Smart interface to inductively coupled plasma atomic emission spectrometry. • Comparison of distinct flow systems mimicking physiological conditions. - Abstract: A novel biomimetic extraction procedure that allows for the in-line handing of ≥400 mg solid substrates is herein proposed for automatic ascertainment of trace element (TE) bioaccessibility in soils under worst-case conditions as per recommendations of ISO norms. A unified bioaccessibility/BARGE method (UBM)-like physiological-based extraction test is evaluated for the first time in a dynamic format for accurate assessment of in-vitro bioaccessibility of Cr, Cu, Ni, Pb and Zn in forest and residential-garden soils by on-line coupling of a hybrid flow set-up to inductively coupled plasma atomic emission spectrometry. Three biologically relevant operational extraction modes mimicking: (i) gastric juice extraction alone; (ii) saliva and gastric juice composite in unidirectional flow extraction format and (iii) saliva and gastric juice composite in a recirculation mode were thoroughly investigated. The extraction profiles of the three configurations using digestive fluids were proven to fit a first order reaction kinetic model for estimating the maximum TE bioaccessibility, that is, the actual worst-case scenario in human risk assessment protocols. A full factorial design, in which the sample amount (400–800 mg), the extractant flow rate (0.5–1.5 mL min{sup −1}) and the extraction temperature (27–37 °C) were selected as variables for the multivariate optimization studies in order to obtain the maximum TE extractability. Two soils of varied physicochemical properties were analysed and no significant differences were found at the 0.05 significance level

  16. Induction of Apoptosis in Human Breast Cancer by Adenoviral-Mediated Gene Transfer of the Transcription Factor E2F-1

    National Research Council Canada - National Science Library

    Hunt, Kelly K

    2000-01-01

    ... and evaluated our results using a two- dimensional isobologram statistical analysis. We observed marked synergistic growth inhibitory effects in breast cancer cell lines treated with a low-dose of adenovirus E2F-1 and low doses of Taxol or doxorubicin...

  17. Induction of PTEN-p53 crosstalk in mammary epithelial cells: A novel mechanism of breast cancer prevention by the dietary factor genistein

    Science.gov (United States)

    Consumption of soy foods either at an early age or for lifetime has been associated with reduced risk for developing breast cancer in humans and in animal models. However, this association continues to be controversial, and the precise mechanisms for protection remain elusive. Among the soy products...

  18. Mathematical Models of Androgen Resistance in Prostate Cancer Patients under Intermittent Androgen Suppression Therapy

    Directory of Open Access Journals (Sweden)

    Javier Baez

    2016-11-01

    Full Text Available Predicting the timing of a castrate resistant prostate cancer is critical to lowering medical costs and improving the quality of life of advanced prostate cancer patients. We formulate, compare and analyze two mathematical models that aim to forecast future levels of prostate-specific antigen (PSA. We accomplish these tasks by employing clinical data of locally advanced prostate cancer patients undergoing androgen deprivation therapy (ADT. While these models are simplifications of a previously published model, they fit data with similar accuracy and improve forecasting results. Both models describe the progression of androgen resistance. Although Model 1 is simpler than the more realistic Model 2, it can fit clinical data to a greater precision. However, we found that Model 2 can forecast future PSA levels more accurately. These findings suggest that including more realistic mechanisms of androgen dynamics in a two population model may help androgen resistance timing prediction.

  19. [Explore the influence factors on primary lung cancer in Fujian province Han population under the use of generalized linear model].

    Science.gov (United States)

    He, Fei; Xiao, Rendong; Yu, Tingting; Zhang, Xin; Liu, Zhiqiang; Cai, Lin

    2015-08-01

    The purpose of this study was to use the data on lung cancer in Han Chinese in Fujian province to explore the value of a generalized, linear model and to investigate the impact related to environment factors on lung cancer as well as the independent and interaction effects on the development of lung cancer. SAS 9.2 was used to build a generalized linear model to evaluate the influence factors and interaction of lung cancer on both smokers and non-smokers. Results showed that the relationship of the factors was multiplied. Under the logistic regression analysis, seven risk factors and nine risk factors were noticed in smokers or in non-smokers, respectively. Heavy smokers and lung diseases appeared a positive multiplying effect on smokers while passive smoking and fresh fruits showed positive multiplying effects on non-smokers. The generalized linear models could filter suitable models thus facilitating further research on the interaction between the two. It seemed easy to carry on the comprehensive and rational analysis on related epidemiological data.

  20. Hit by waves-living with local advanced or localized prostate cancer treated with endocrine therapy or under active surveillance.

    Science.gov (United States)

    Ervik, Bente; Nordøy, Tone; Asplund, Kenneth

    2010-01-01

    Previous studies of living with prostate cancer have shown that the illness and the treatment cause physical as well as psychosocial problems. The aim of this study was to illuminate men's experiences living with localized or local advanced prostate cancer when curative treatment such as surgery or radiation therapy is not an option at the time of diagnosis. The study was conducted via qualitative interviews, using a phenomenological hermeneutic approach. Ten men treated with endocrine therapy or under active surveillance were interviewed. Being diagnosed with prostate cancer was described as a shock, with different aspects of the illness revealed gradually. The limited amount of time available for meeting with health care providers contributed to patients' feelings of being left alone with difficulty getting information and help. Sexual and urinary problems were perceived as a threat to their manhood. The spouses provided the closest everyday support. The life situation of these patients can be understood as living in a "state of readiness," expecting something to happen regarding their illness, and not always knowing where to get help. The results confirm existing knowledge of patient's experiences in living with prostate cancer regarding the initial shock perceived by the patients, the bodily alterations, and the important role of their spouses. Nurses, as well as general practitioners, must play a more active role in follow-up to ensure that the men and their spouses receive better help and support.

  1. Mechanisms underlying UV-induced immune suppression

    Energy Technology Data Exchange (ETDEWEB)

    Ullrich, Stephen E. [Department of Immunology, University of Texas, MD Anderson Cancer Center, South Campus Research Building 1, 7455 Fannin St., P.O. Box 301402, Houston, TX 77030-1903 (United States)]. E-mail: sullrich@mdanderson.org

    2005-04-01

    Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression.

  2. Mechanisms underlying UV-induced immune suppression

    International Nuclear Information System (INIS)

    Ullrich, Stephen E.

    2005-01-01

    Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression

  3. Effectiveness of a Brief Health Education Intervention for Breast Cancer Prevention in Greece Under Economic Crisis

    Directory of Open Access Journals (Sweden)

    Kyriakoula Merakou

    2013-01-01

    Full Text Available Background: Prevalence rates in breast cancer have now reached epidemic levels. One of the main reasons behind onset of breast cancer is poor preventive beliefs and behavior of women towards cancer prevention. We examined the effectiveness of health education intervention in two communities of South Greece.Objective: The study investigates the effectiveness of a brief health education intervention on women’s beliefs and behaviour changes concerning breast cancer prevention.Methodology: A 90-minute, one-off encounter, health education study was designed for 300 women from Peloponissos, South Greece. A Health Belief Model questionnaire, was used before the intervention, immediately after and 6-months after the intervention.Results: Despite certain perception-related barriers (embarrassment, anxiety, ect women’s overall beliefs towards breast cancer prevention (perceived susceptibility, perceived benefits and perceived barriers changed positively after the health education intervention and this change was sustained at 6-month follow up. However, specific barriers (embarrassment, fear of pain, anxiety when anticipating tests’ results were not maintained at the same level of post-intervention during the same follow up. During the follow up period, women performed breast self-examination every month (73% and 55.10% had breast examination by a clinician and underwent a mammography.Conclusions: Short, low cost, health education interventions for breast cancer prevention to women can be effective in changing beliefs and behaviour. Tailored interventions are necessary to overcome relapsing of specific barriers. Emphasis should be given on the importance of doctor/nurse role in breast screening.

  4. d -Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis

    Directory of Open Access Journals (Sweden)

    Rabi Thangaiyan

    2009-01-01

    Full Text Available Background: Clinical trials have shown that docetaxel combined with other novel agents can improve the survival of androgen-independent prostate cancer patients. d -Limonene, a non-nutrient dietary component, has been found to inhibit various cancer cell growths without toxicity. We sought to characterize whether a non-toxic dose of d -limonene may enhance tumor response to docetaxel in an in vitro model of metastatic prostate cancer. Materials and Methods: Human prostate carcinoma DU-145 and normal prostate epithelial PZ-HPV-7 cells were treated with various concentrations of d -limonene, docetaxel or a combination of both, and cell viability was determined by MTT assay. Intracellular reactive oxygen species (ROS, reduced glutathione (GSH and caspase activity were measured. Apoptosis and apoptosis-related proteins were studied by enzyme-linked immunosorbent assay and Western blotting, respectively. Results: d -Limonene and docetaxel in combination significantly enhanced the cytotoxicity to DU-145 cells than PZ-HPV-7 cells. Exposure of DU-145 cells to a combined d -limonene and docetaxel resulted in higher ROS generation, depletion of GSH, accompanied by increased caspase activity than docetaxel alone. It also triggered a series of effects involving cytochrome c , cleavages of caspase-9, 3 and poly (ADP-ribose polymerase, and a shift in Bad:Bcl-xL ratio in favor of apoptosis. Apoptotic effect was significantly blocked on pretreatment with N -acetylcystein, indicating that antitumor effect is initiated by ROS generation, and caspase cascades contribute to the cell death. Conclusion: Our results show, for the first time, that d -limonene enhanced the antitumor effect of docetaxel against prostate cancer cells without being toxic to normal prostate epithelial cells. The combined beneficial effect could be through the modulation of proteins involved in mitochondrial pathway of apoptosis. d -Limonene could be used as a potent non-toxic agent to

  5. Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer

    International Nuclear Information System (INIS)

    Singh, Bhupendra; Chatterjee, Anwesha; Ronghe, Amruta M; Bhat, Nimee K; Bhat, Hari K

    2013-01-01

    Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis. Female ACI rats were treated with E2; Vit C; Vit C + E2; BHA; and BHA + E2 for up to 240 days. mRNA and protein levels of a DNA repair enzyme 8-Oxoguanine DNA glycosylase (OGG1) and a transcription factor NRF2 were quantified in the mammary and mammary tumor tissues of rats after treatment with E2 and compared with that of rats treated with antioxidants either alone or in combination with E2. The expression of OGG1 was suppressed in mammary tissues and in mammary tumors of rats treated with E2. Expression of NRF2 was also significantly suppressed in E2-treated mammary tissues and in mammary tumors. Vitamin C or BHA treatment prevented E2-mediated decrease in OGG1 and NRF2 levels in the mammary tissues. Chromatin immunoprecipitation analysis confirmed that antioxidant-mediated induction of OGG1 was through increased direct binding of NRF2 to the promoter region of OGG1. Studies using silencer RNA confirmed the role of OGG1 in inhibition of oxidative DNA damage. Our studies suggest that antioxidants Vit C and BHA provide protection against oxidative DNA damage and E2-induced mammary carcinogenesis, at least in part, through NRF2-mediated induction of OGG1

  6. Economic burden of gastrointestinal cancer under the protection of the New Rural Cooperative Medical Scheme in a region of rural China with high incidence of oesophageal cancer: cross-sectional survey.

    Science.gov (United States)

    Li, Xiang; Cai, Hong; Wang, Chaoyi; Guo, Chuanhai; He, Zhonghu; Ke, Yang

    2016-07-01

    To evaluate the financial burden of oesophageal cancer under the protection of the new Rural Cooperative Medical Scheme (NCMS) and to provide evidence and suggestions to policymakers in a high-incidence region in China. We analysed inpatient claim data for oesophageal cancer, gastric cancer and colorectal cancer from 1 January to 31 December 2013. The data were extracted from the NCMS management system of Hua County, Henan Province, a typical high-risk region for oesophageal cancer in China. Cancer-specific health economic indicators were calculated to evaluate the financial burden under the protection of the local NCMS. The total cost of oesophageal cancer was 2.7-3.6 times higher than that of gastric cancer and colorectal cancer, respectively, due to high incidence of oesophageal cancer. For each hospitalisation to treat oesophageal cancer, the average total cost and out-of-pocket expenses after reimbursement equalled an entire year's gross domestic product per capita and per capita disposable income, respectively, for the local area. The average total cost per hospitalisation for oesophageal cancer increased monotonically with hospital level for surgical hospitalisations, and it increased more rapidly for non-surgical hospitalisations (from $301 to $2589, 860%) than for gastric cancer (from $289 to $1453, 503%) and colorectal cancer (from $359 to $1610, 448%). Vulnerable groups with less access to high-level hospitals were found in different gender and age groups. Oesophageal cancer imposes serious financial burdens on communities and patients' households in this high-incidence region, and no preferential policy from the local NCMS has been designed to address this issue. A special supportive policy should be developed on the basis of local disease profiles and population characteristics to alleviate the financial burden of populations at high risk for certain high-cost diseases. © 2016 John Wiley & Sons Ltd.

  7. Descriptive Epidemiology in Mexican children with cancer under an open national public health insurance program.

    Science.gov (United States)

    Rivera-Luna, Roberto; Shalkow-Klincovstein, Jaime; Velasco-Hidalgo, Liliana; Cárdenas-Cardós, Rocio; Zapata-Tarrés, Marta; Olaya-Vargas, Alberto; Aguilar-Ortiz, Marco R; Altamirano-Alvarez, Eduardo; Correa-Gonzalez, Cecilia; Sánchez-Zubieta, Fernando; Pantoja-Guillen, Francisco

    2014-10-29

    All the children registered at the National Council for the Prevention and Treatment of Childhood Cancer were analyzed. The rationale for this Federal Government Council is to financially support the treatment of all children registered into this system. All patients are within a network of 55 public certified hospitals nationwide. In the current study, data from 2007 to 2012 are presented for all patients (0-18 years) with a pathological diagnosis of leukemia, lymphoma and solid tumors. The parameters analyzed were prevalence, incidence, mortality, and abandonment rate. A diagnosis of cancer was documented in 14,178 children. The incidence was of 156.9/million/year (2012). The median age was 4.9. The most common childhood cancer is leukemia, which occurs in 49.8% of patients (2007-2012); and has an incidence rate of 78.1/million/year (2012). The national mortality rate was 5.3/100,000 in 2012, however in the group between 15 to 18 years it reaches a level of 8.6. The study demonstrates that there is a high incidence of childhood cancer in Mexico. In particular, the results reveal an elevated incidence and prevalence of leukemia especially from 0 to 4 years. Only 4.7% of these patients abandoned treatment. The clinical outcome for all of the children studied improved since the establishment of this national program.

  8. Effect of residual stress relaxation by means of local rapid induction heating on stress corrosion cracking behavior and electrochemical characterization of welded Ti-6Al-4V alloy under slow strain rate test

    Science.gov (United States)

    Liu, Yan; Tang, Shawei; Liu, Guangyi; Sun, Yue; Hu, Jin

    2017-05-01

    In this study, a welded Ti-6Al-4V alloy was treated by means of local rapid induction heating in order to relax the residual stress existed in the weldment. The welded samples were heat treated at the different temperatures. The stress corrosion cracking behavior and electrochemical characterization of the as-welded samples before and after the post weld heat treatment as a function of residual stress were investigated. Electrochemical impedance spectroscopy measurements of the samples under slow strain rate test were performed in a LiCl-methanol solution. The results demonstrated that the residual stress in the as-welded sample was dramatically reduced after the post weld heat treatment, and the residual stress decreased with the increase in the heat treatment temperature. The stress corrosion cracking susceptibility and electrochemical activity of the as-welded sample were significantly reduced after the heat treatment due to the relaxation of the residual stress, which gradually decreased with the decreasing value of the residual stress distributed in the heat treated samples.

  9. NSAIDs may regulate EGR-1-mediated induction of reactive oxygen species and non-steroidal anti-inflammatory drug-induced gene (NAG)-1 to initiate intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer.

    Science.gov (United States)

    Vaish, Vivek; Piplani, Honit; Rana, Chandan; Vaiphei, Kim; Sanyal, Sankar Nath

    2013-06-01

    This study aims to investigate the unclear molecular relationship involved in the activation of intrinsic pathway of apoptosis and NSAID-activated gene-1 (NAG-1) induction as a putative target in NSAIDs-mediated chemoprevention of colorectal cancer. Male Sprague-Dawley rats were administered with a colon-specific pro-carcinogen, 1,2-dimethylhydrazine dihydrochloride to achieve the early stages of colorectal cancer. Histopathological examination was performed for the analysis of neoplastic lesions while flow cytometry was performed for the relative quantification of intracellular reactive oxygen species (ROS), differential mitochondrial membrane potential (MMP or ΔΨ(M)), and apoptotic events. Various target biomolecules were analyzed either for their mRNA or protein expression profiles via RT-PCR and quantitative Real-Time PCR, or Western blotting and immunofluorescence, respectively. Enhanced gene as well as protein expression of pro-apoptotic agents was observed with the daily oral administration of two NSAIDs viz. Sulindac (cyclooxygenase (COX)-non-specific) and Celecoxib (a selective COX-2 inhibitor). A significant increase in early growth response-1 (EGR-1) protein expression and nuclear localization in NSAIDs co-administered animals may have positively regulated the expression of NAG-1 with a significant enhancement of intracellular ROS in turn decreasing the ΔΨ(M) to initiate apoptosis. In silico molecular docking analysis also showed that Sulindac and Celecoxib can block the active site pocket of B-cell lymphoma-extra large (Bcl-xL, anti-apoptotic transmembrane mitochondrial protein) which could be a putative mechanism followed by these NSAIDs to overcome anti-apoptotic properties of the molecule. NSAIDs-mediated up-regulation of EGR-1 and thereby NAG-1 along with implication of higher ROS load may positively regulate the intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer.

  10. Chemosensitizing effects of carbon-based nanomaterials in cancer cells: enhanced apoptosis and inhibition of proliferation as underlying mechanisms

    International Nuclear Information System (INIS)

    Erdmann, Kati; Ringel, Jessica; Rieger, Christiane; Huebner, Doreen; Wirth, Manfred P; Fuessel, Susanne; Hampel, Silke

    2014-01-01

    Recent studies have shown that carbon nanomaterials such as carbon nanofibres (CNFs) and multi-walled carbon nanotubes (CNTs) can exert antitumor activities themselves and sensitize cancer cells to conventional chemotherapeutics such as carboplatin and cisplatin. In the present study, the chemosensitizing effect of CNFs and CNTs on cancer cells of urological origin was investigated regarding the underlying mechanisms. Prostate cancer (DU-145, PC-3) and bladder cancer (EJ28) cells were treated with carbon nanomaterials (CNFs, CNTs) and chemotherapeutics (carboplatin, cisplatin) alone as well as in combination for 24 h. Forty-eight (EJ28) or 72 h (DU-145, PC-3) after the end of treatment the effects on cellular proliferation, clonogenic survival, cell death rate and cell cycle distribution were evaluated. Depending on the cell line, simultaneous administration of chemotherapeutics and carbon nanomaterials produced an additional inhibition of cellular proliferation and clonogenic survival of up to 77% and 98%, respectively, compared to the inhibitory effects of the chemotherapeutics alone. These strongly enhanced antiproliferative effects were accompanied by an elevated cell death rate, which was predominantly mediated via apoptosis and not by necrosis. The antitumor effects of combinations with CNTs were less pronounced than those with CNFs. The enhanced effects of the combinatory treatments on cellular function were mostly of additive to partly synergistic nature. Furthermore, cell cycle analysis demonstrated an arrest at the G2/M phase mediated by a monotreatment with chemotherapeutics. Following combinatory treatments, mostly less than or nearly additive increases of cell fractions in the G2/M phase could be observed. In conclusion, the pronounced chemosensitizing effects of CNFs and CNTs were mediated by an enhanced apoptosis and inhibition of proliferation. The combination of carbon-based nanomaterials and conventional chemotherapeutics represents a novel

  11. Caffeic acid phenethyl ester causes p21 induction, Akt signaling reduction, and growth inhibition in PC-3 human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Hui-Ping Lin

    Full Text Available Caffeic acid phenethyl ester (CAPE treatment suppressed proliferation, colony formation, and cell cycle progression in PC-3 human prostate cancer cells. CAPE decreased protein expression of cyclin D1, cyclin E, SKP2, c-Myc, Akt1, Akt2, Akt3, total Akt, mTOR, Bcl-2, Rb, as well as phosphorylation of Rb, ERK1/2, Akt, mTOR, GSK3α, GSK3β, PDK1; but increased protein expression of KLF6 and p21(Cip1. Microarray analysis indicated that pathways involved in cellular movement, cell death, proliferation, and cell cycle were affected by CAPE. Co-treatment of CAPE with chemotherapeutic drugs vinblastine, paclitaxol, and estramustine indicated synergistic suppression effect. CAPE administration may serve as a potential adjuvant therapy for prostate cancer.

  12. Dose-response relationships and risk estimates for the induction of cancer due to low doses of low-LET radiation

    International Nuclear Information System (INIS)

    Elaguppillai, V.

    1981-01-01

    Risk estimates for radiation-induced cancer at low doses can be obtained only by extrapolation from the known effects at high doses and high dose rates, using a suitable dose-response model. The applicability of three different models, linear, sublinear and supralinear, are discussed in this paper. Several experimental studies tend to favour a sublinear dose-response model (linear-quadratic model) for low-LET radiation. However, human epidemiological studies do not exclude any of the dose-response relationships. The risk estimates based on linear and linear quadratic dose-response models are compared and it is concluded that, for low-LET radiation, the linear dose-response model would probably over-estimate the actual risk of cancer by a factor of two or more. (author)

  13. The induction of apoptosis in human melanoma, breast and ovarian cancer cell lines using an essential oil extract from the conifer Tetraclinis articulata.

    Science.gov (United States)

    Buhagiar, J A; Podesta, M T; Wilson, A P; Micallef, M J; Ali, S

    1999-01-01

    The cytotoxic effect of conifer Tetraclinis articulata essential oil (TAEO) on a number of human cancer cell lines and peripheral blood lymphocytes was assessed at various concentrations and time exposures. The cytotoxic effect showed the hallmarks of apoptosis confirmed by a variety of techniques including flow cytometry, an apoptosis- specific marker combined to fluorescent staining and DNA laddering. All cell lines tested were inhibited in a dose-dependent fashion and within a contact time of less than eight hours for the higher concentrations. Melanoma, breast and ovarian cancer cells gave IC50s of around 80 micrograms/ml whilst the IC50s on peripheral blood lymphocytes was almost double this value. We conclude that the essential oil contains components that are effective at inducing apoptosis. The advantages of using a mixture of monoterpenes (C10) as present in an EO over a single component, are discussed.

  14. Oxidative Stress Promotes Doxorubicin-Induced Pgp and BCRP Expression in Colon Cancer Cells Under Hypoxic Conditions.

    Science.gov (United States)

    Pinzón-Daza, Martha L; Cuellar-Saenz, Yenith; Nualart, Francisco; Ondo-Mendez, Alejandro; Del Riesgo, Lilia; Castillo-Rivera, Fabio; Garzón, Ruth

    2017-07-01

    P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are ATP binding cassette (ABC) transporters that are overexpressed in different drug-resistant cancer cell lines. In this study, we investigated whether doxorubicin promotes Pgp and/or BCRP expression to induce drug resistance in colon cancer cells under hypoxic conditions. We analyzed HIF-1α activity via ELISA, Pgp, and BCRP expression by qRT-PCR and the relationship between doxorubicin uptake and ABC transporter expression via confocal microscopy in HT-29WT and HT-29 doxorubicin-resistant colon cancer cells (HT-29DxR). These cells were treated with doxorubicin and/or CoCl 2 (chemical hypoxia), and reactive oxygen species inductors. We found that the combination of chemically induced hypoxia and doxorubicin promoted Pgp mRNA expression within 24 h in HT-29WT and HT-29DxR cells. Both doxorubicin and CoCl 2 alone or in combination induced Pgp and BCRP expression, as demonstrated via confocal microscopy in each of the above two cell lines. Thus, we surmised that Pgp and BCRP expression may result from synergistic effects exerted by the combination of doxorubicin-induced ROS production and HIF-1α activity under hypoxic conditions. However, HIF-1α activity disruption via the administration of E3330, an APE-1 inhibitor, downregulated Pgp expression and increased doxorubicin delivery to HT-29 cells, where it served as a substrate for Pgp, indicating the existence of an indirect relationship between Pgp expression and doxorubicin accumulation. Thus, we concluded that Pgp and BCRP expression can be regulated via cross-talk between doxorubicin and hypoxia, promoting drug resistance in HT-29 WT, and HT-29DxR cells and that this process may be ROS dependent. J. Cell. Biochem. 118: 1868-1878, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  15. Equol enhances tamoxifen’s anti-tumor activity by induction of caspase-mediated apoptosis in MCF-7 breast cancer cells

    International Nuclear Information System (INIS)

    Charalambous, Christiana; Pitta, Chara A; Constantinou, Andreas I

    2013-01-01

    Soy phytoestrogens, such as daidzein and its metabolite equol, have been proposed to be responsible for the low breast cancer rate in Asian women. Since the majority of estrogen receptor positive breast cancer patients are treated with tamoxifen, the basic objective of this study is to determine whether equol enhances tamoxifen’s anti-tumor effect, and to identify the molecular mechanisms involved. For this purpose, we examined the individual and combined effects of equol and tamoxifen on the estrogen-dependent MCF-7 breast cancer cells using viability assays, annexin-V/PI staining, cell cycle and western blot analysis. We found that equol (>50 μM) and 4-hydroxy-tamoxifen (4-OHT; >100 nM) significantly reduced the MCF-7 cell viability. Furthermore, the combination of equol (100 μM) and 4-OHT (10 μM) induced apoptosis more effectively than each compound alone. Subsequent treatment of MCF-7 cells with the pan-caspase inhibitor Z-VAD-FMK inhibited equol- and 4-OHT-mediated apoptosis, which was accompanied by PARP and α-fodrin cleavage, indicating that apoptosis is mainly caspase-mediated. These compounds also induced a marked reduction in the bcl-2:bax ratio, which was accompanied by caspase-9 and caspase-7 activation and cytochrome-c release to the cytosol. Taken together, these data support the notion that the combination of equol and tamoxifen activates the intrinsic apoptotic pathway more efficiently than each compound alone. Consequently, equol may be used therapeutically in combination treatments and clinical studies to enhance tamoxifen’s effect by providing additional protection against estrogen-responsive breast cancers

  16. Roles of p53 and caspases in induction of apoptosis in MCF- 7 breast cancer cells treated with a methanolic extract of Nigella sativa seeds.

    Science.gov (United States)

    Alhazmi, Mohammed I; Hasan, Tarique N; Shafi, Gowhar; Al-Assaf, Abdullah H; Alfawaz, Mohammed A; Alshatwi, Ali A

    2014-01-01

    Nigella Sativa (NS) is an herb from the Ranunculaceae family that exhibits numerous medicinal properties and has been used as important constituent of many complementary and alternative medicines (CAMs). The ability of NS to kill cancer cells such as PC3, HeLa and hepatoma cells is well established. However, our understanding of the mode of death caused by NS remains nebulous. The objective of this study was to gain further insight into the mode and mechanism of death caused by NS in breast cancer MCF-7 cells. Human breast cancer cells (MCF-7) were treated with a methanolic extract of NS, and a dose- and time-dependent study was performed. The IC50 was calculated using a Cell Titer Blue® viability assay assay, and evidence for DNA fragmentation was obtained by fluorescence microscopy TUNEL assay. Gene expression was also profiled for a number of apoptosis-related genes (Caspase-3, -8, -9 and p53 genes) through qPCR. The IC50 of MCF-7