A note on inflation targeting and economic growth in Brazil

Directory of Open Access Journals (Sweden)

Gilberto Libânio

2010-03-01

Full Text Available This paper analyzes the relation between monetary policy and economic performance in Brazil during the period 1999-2006. In particular, it discusses the growth effects of the inflation targeting regime through its effects on aggregate demand. It is argued that monetary policy under IT reacts in a procyclical and asymmetric way to fluctuations in economic activity (too "tight" during recessions, not so "loose" during expansions. Such pattern may generate a downward bias in aggregate demand, with negative real effects on output growth and employment. Our results suggest that monetary policy has been procyclical and asymmetrical in Brazil under inflation targeting. The main economic policy implication of this study is that central banks should consider more seriously the real effects of monetary policy on output and employment.

Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth.

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Gururajan, Murali; Dasu, Trivikram; Shahidain, Seif; Jennings, C Darrell; Robertson, Darrell A; Rangnekar, Vivek M; Bondada, Subbarao

2007-01-01

Curcumin (diferuloylmethane), a component of dietary spice turmeric (Curcuma longa), has been shown in recent studies to have therapeutic potential in the treatment of cancer, diabetes, arthritis, and osteoporosis. We investigated the ability of curcumin to modulate the growth of B lymphomas. Curcumin inhibited the growth of both murine and human B lymphoma in vitro and murine B lymphoma in vivo. We also demonstrate that curcumin-mediated growth inhibition of B lymphoma is through inhibition of the survival kinase Akt and its key target Bad. However, in vitro kinase assays show that Akt is not a direct target of curcumin. We identified a novel target for curcumin in B lymphoma viz spleen tyrosine kinase (Syk). Syk is constitutively activated in primary tumors and B lymphoma cell lines and curcumin down-modulates Syk activity accompanied by down-regulation of Akt activation. Moreover, we show that overexpression of Akt, a target of Syk, or Bcl-x(L), a target of Akt can overcome curcumin-induced apoptosis of B lymphoma cells. These observations suggest a novel growth promoting role for Syk in lymphoma cells.

MiR-422a targets MAPKK6 and regulates cell growth and apoptosis in colorectal cancer cells.

Science.gov (United States)

Li, Peng; Li, Qingmin; Zhang, Yanqiang; Sun, Shaojun; Liu, Shuntao; Lu, Zhaoxi

2018-03-19

The important role of miR-422a in tumor has been reported in several studies. Recent research discovered that the expression of miR-422a was significantly decreased in colorectal cancer tissues, providing miR-422a as a tumor suppressor in CRC. However, the concrete mechanism of miR-422a regulating CRC cell is still unclear. In this study, we demonstrated that miR-422a could inhibit CRC cell growth and promote cell apoptosis via in vitro analyses. Moreover, computational methods were adopted to identify the targets of miR-422a. We found MAPKK6 was the direct target of miR-422a. Consequently, we further elucidated that miR-422a inhibited CRC cell growth and induced cell apoptosis by inhibiting p38/MAPK pathway. Besides that, we established the tumor xenograft model using nude mice and the inhibitory effects on tumor volumes and weights by miR-422a mimic transfection were also detected. Taken together, these findings demonstrated miR-422a exerted anti-cancer activities on CRC, which could be potentially used for CRC prognosis prediction and treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance.

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Lee, Jin-Ku; Chang, Nakho; Yoon, Yeup; Yang, Heekyoung; Cho, Heejin; Kim, Eunhee; Shin, Yongjae; Kang, Wonyoung; Oh, Young Taek; Mun, Gyeong In; Joo, Kyeung Min; Nam, Do-Hyun; Lee, Jeongwu

2016-01-01

Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy

Directory of Open Access Journals (Sweden)

Szlachcic A

2016-08-01

Full Text Available Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland Abstract: Fibroblast growth factor receptors (FGFRs are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V, was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE, and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality. Keywords: fibroblast growth factor 1, FGF receptor, targeted cancer therapy, cytotoxic conjugates, FGFR-dependent cancer, MMAE, auristatin

MicroRNA-375 inhibits colorectal cancer growth by targeting PIK3CA

Energy Technology Data Exchange (ETDEWEB)

Wang, Yihui [Department of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, 150 Haping Road, 150081 Harbin (China); Tang, Qingchao [Cancer Center, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, 150086 Harbin (China); Li, Mingqi; Jiang, Shixiong [Department of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, 150 Haping Road, 150081 Harbin (China); Wang, Xishan, E-mail: wxshan12081@163.com [Cancer Center, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, 150086 Harbin (China)

2014-02-07

Highlights: • miR-375 is downregulated in colorectal cancer cell lines and tissues. • miR-375 inhibits colorectal cancer cell growth by targeting PIK3CA. • miR-375 inhibits colorectal cancer cell growth in xenograft nude mice model. - Abstract: Colorectal cancer (CRC) is the second most common cause of death from cancer. MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression by triggering RNA degradation or interfering with translation. Aberrant miRNA expression is involved in human disease including cancer. Herein, we showed that miR-375 was frequently down-regulated in human colorectal cancer cell lines and tissues when compared to normal human colon tissues. PIK3CA was identified as a potential miR-375 target by bioinformatics. Overexpression of miR-375 in SW480 and HCT15 cells reduced PIK3CA protein expression. Subsequently, using reporter constructs, we showed that the PIK3CA untranslated region (3′-UTR) carries the directly binding site of miR-375. Additionally, miR-375 suppressed CRC cell proliferation and colony formation and led to cell cycle arrest. Furthermore, miR-375 overexpression resulted in inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. SiRNA-mediated silencing of PIK3CA blocked the inhibitory effect of miR-375 on CRC cell growth. Lastly, we found overexpressed miR-375 effectively repressed tumor growth in xenograft animal experiments. Taken together, we propose that overexpression of miR-375 may provide a selective growth inhibition for CRC cells by targeting PI3K/Akt signaling pathway.

Natural gas reserve growth in Canada

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Woronuk, R. [Canadian Gas Potential Committee, Calgary, AB (Canada)]|[GasEnergy Strategies Inc., Calgary, AB (Canada)

2003-07-01

An appreciation study of a natural gas reservoir is a component of assessing its ultimate reserve potential. The Canadian Gas Potential Committee (CGPC) defines appreciation as the change in a reserve estimate from a previously booked pool or basin. Basins cannot appreciate through the addition of new pools. Ultimate potential includes all of the following: cumulative production; remaining discovered reserves; adjustments to remaining discovered reserves; and, full appreciated undiscovered reserves. This presentation outlined the procedures used by the CGPC in its appreciation studies. It also reviewed data supplier issues, regulatory practices, and booking issues. A series of graphs were also included depicting pools discovered in 1993 and the average pool gas in place. Reservoir loss from 1993 to 1998 was attributed to the fact that enhanced recovery technology cannot keep pace with the degradation in pool quality. It was noted that beyond 1998, significant increases in gas prices should increase recovery factors. Special studies by the Alberta Energy and Utilities Board have included the depreciation of unconnected gas pools and the appreciation of sheet sands. The challenge of tracking pool appreciation was discussed with reference to estimating new pool discoveries in established fields. 2 tabs., 6 figs.

Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer.

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Brown, Wells S; Tan, Li; Smith, Andrew; Gray, Nathanael S; Wendt, Michael K

2016-09-01

Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096-106. ©2016 AACR. ©2016 American Association for Cancer Research.

Approaches to identifying reservoir heterogeneity and reserve growth opportunities from subsurface data: The Oficina Formation, Budare field, Venezuela

Energy Technology Data Exchange (ETDEWEB)

Hamilton, D.S.; Raeuchle, S.K.; Holtz, M.H. [Bureau of Economic Geology, Austin, TX (United States)] [and others

1997-08-01

We applied an integrated geologic, geophysical, and engineering approach devised to identify heterogeneities in the subsurface that might lead to reserve growth opportunities in our analysis of the Oficina Formation at Budare field, Venezuela. The approach involves 4 key steps: (1) Determine geologic reservoir architecture; (2) Investigate trends in reservoir fluid flow; (3) Integrate fluid flow trends with reservoir architecture; and (4) Estimate original oil-in-place, residual oil saturation, and remaining mobile oil, to identify opportunities for reserve growth. There are three main oil-producing reservoirs in the Oficina Formation that were deposited in a bed-load fluvial system, an incised valley-fill, and a barrier-strandplain system. Reservoir continuity is complex because, in addition to lateral facies variability, the major Oficina depositional systems were internally subdivided by high-frequency stratigraphic surfaces. These surfaces define times of intermittent lacustrine and marine flooding events that punctuated the fluvial and marginal marine sedimentation, respectively. Syn and post depositional faulting further disrupted reservoir continuity. Trends in fluid flow established from initial fluid levels, response to recompletion workovers, and pressure depletion data demonstrated barriers to lateral and vertical fluid flow caused by a combination of reservoir facies pinchout, flooding shale markers, and the faults. Considerable reserve growth potential exists at Budare field because the reservoir units are highly compartment by the depositional heterogeneity and structural complexity. Numerous reserve growth opportunities were identified in attics updip of existing production, in untapped or incompletely drained compartments, and in field extensions.

miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A

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Chang, Xiao; Zhang, Haiping [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Lian, Shi [Department of Dermatology and Venereal Disease, Capital Medical University, Beijing 100069 (China); Zhu, Wei, E-mail: zhuwei_2020@163.com [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

2016-07-01

As an oncogene, aurora kinase A (AURKA) is overexpressed in various types of human cancers. However, the expression and roles of AURKA in malignant melanoma are largely unknown. In this study, a miR-137-AURKA axis was revealed to regulate melanoma growth. We found a significant increase in levels of AURKA in melanoma. Both genetic knockdown and pharmacologic inhibition of AURKA decreased tumor cell growth in vitro and in vivo. Further found that miR-137 reduced AURKA expression through interaction with its 3′ untranslated region (3′UTR) and that miR-137 was negatively correlated with AURKA expression in melanoma specimens. Overexpression of miR-137 decreased cell proliferation and colony formation in vitro. Notably, re-expression of AURKA significantly rescued miR-137-mediated suppression of cell growth and clonality. In summary, these results reveal that miR-137 functions as a tumor suppressor by targeting AURKA, providing new insights into investigation of therapeutic strategies against malignant melanoma. -- Highlights: •First reported overexpression of AURKA in melanoma. •Targeting AURKA inhibits melanoma growth in vitro and in vivo. •Further found miR-137 suppressed cell growth by binding to AURKA 3′UTR. •Re-expression of AURKA rescued miR-137-mediated suppression. •miR-137-AURKA axis may be potential therapeutic targets of melanoma.

The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways.

Science.gov (United States)

Rengarajan, Thamaraiselvan; Yaacob, Nik Soriani

2016-10-15

Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeted therapies in the treatment of urothelial cancers.

Science.gov (United States)

Aragon-Ching, Jeanny B; Trump, Donald L

2017-07-01

Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

Small Open Economies with Frictions in Credit Markets: Target inflation or money growth when floating?

OpenAIRE

Paula Hernandez-Verme

2009-01-01

I compare the relative merits of a policy of inflation targeting for small open economies with frictions in financial markets with an alternative floating regime that has a constant rate of domestic money growth. The differences between these two policies appear only in the dynamic properties of equilibria with credit rationing. When the probability of loan repayment is low, inflation targeting eliminates endogenous volatility when compared with a constant money growth, but equilibria remain ...

Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals.

Science.gov (United States)

Weisman, Ronit

2016-10-01

All organisms can respond to the availability of nutrients by regulating their metabolism, growth, and cell division. Central to the regulation of growth in response to nutrient availability is the target of rapamycin (TOR) signaling that is composed of two structurally distinct complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The TOR genes were first identified in yeast as target of rapamycin, a natural product of a soil bacterium, which proved beneficial as an immunosuppressive and anticancer drug and is currently being tested for a handful of other pathological conditions including diabetes, neurodegeneration, and age-related diseases. Studies of the TOR pathway unraveled a complex growth-regulating network. TOR regulates nutrient uptake, transcription, protein synthesis and degradation, as well as metabolic pathways, in a coordinated manner that ensures that cells grow or cease growth in response to nutrient availability. The identification of specific signals and mechanisms that stimulate TOR signaling is an active and exciting field of research that has already identified nitrogen and amino acids as key regulators of TORC1 activity. The signals, as well as the cellular functions of TORC2, are far less well understood. Additional open questions in the field concern the relationships between TORC1 and TORC2, as well as the links with other nutrient-responsive pathways. Here I review the main features of TORC1 and TORC2, with a particular focus on yeasts as model organisms.

Reserve growth of the world's giant oil fields

Science.gov (United States)

Klett, T.R.; Schmoker, J.W.

2005-01-01

Analysis of estimated total recoverable oil volume (field size) of 186 well-known giant oil fields of the world (>0.5 billion bbl of oil, discovered prior to 1981), exclusive of the United States and Canada, demonstrates general increases in field sizes through time. Field sizes were analyzed as a group and within subgroups of the Organization of Petroleum Exporting Countries (OPEC) and non-OPEC countries. From 1981 through 1996, the estimated volume of oil in the 186 fields for which adequate data were available increased from 617 billion to 777 billion bbl of oil (26%). Processes other than new field discoveries added an estimated 160 billion bbl of oil to known reserves in this subset of the world's oil fields. Although methods for estimating field sizes vary among countries, estimated sizes of the giant oil fields of the world increased, probably for many of the same reasons that estimated sizes of oil fields in the United States increased over the same time period. Estimated volumes in OPEC fields increased from a total of 550 billion to 668 billion bbl of oil and volumes in non-OPEC fields increased from 67 billion to 109 billion bbl of oil. In terms of percent change, non-OPEC field sizes increased more than OPEC field sizes (63% versus 22%). The changes in estimated total recoverable oil volumes that occurred within three 5-year increments between 1981 and 1996 were all positive. Between 1981 and 1986, the increase in estimated total recoverable oil volume within the 186 giant oil fields was 11 billion bbl of oil; between 1986 and 1991, the increase was 120 billion bbl of oil; and between 1991 and 1996, the increase was 29 billion bbl of oil. Fields in both OPEC and non-OPEC countries followed trends of substantial reserve growth.

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

Science.gov (United States)

Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

2017-11-01

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

Energy Technology Data Exchange (ETDEWEB)

Ludwig, Joseph A., E-mail: jaludwig@mdanderson.org; Lamhamedi-Cherradi, Salah-Eddine [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Lee, Ho-Young [Departments of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Naing, Aung [Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Benjamin, Robert [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States)

2011-07-26

The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

International Nuclear Information System (INIS)

Ludwig, Joseph A.; Lamhamedi-Cherradi, Salah-Eddine; Lee, Ho-Young; Naing, Aung; Benjamin, Robert

2011-01-01

The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas

Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

Directory of Open Access Journals (Sweden)

Aung Naing

2011-07-01

Full Text Available The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R, in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

Predicting the dynamics of bacterial growth inhibition by ribosome-targeting antibiotics

Science.gov (United States)

Greulich, Philip; Doležal, Jakub; Scott, Matthew; Evans, Martin R.; Allen, Rosalind J.

2017-12-01

Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance—yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding (‘low-affinity antibiotic’) or, in contrast, irreversible transport and/or high affinity ribosome binding (‘high-affinity antibiotic’). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance.

Complete adrenocorticotropin deficiency after radiation therapy for brain tumor with a normal growth hormone reserve

Energy Technology Data Exchange (ETDEWEB)

Sakai, Haruna; Yoshioka, Katsunobu; Yamagami, Keiko [Osaka City General Hospital (Japan)] (and others)

2002-06-01

A 34-year-old man with neurofibromatosis type 1, who had received radiation therapy after the excision of a brain tumor 5 years earlier, was admitted to our hospital with vomiting and weight loss. Cortisol and adrenocorticotropin (ACTH) were undetectable before and after administration of 100 {mu}g corticotropin releasing hormone. The level of growth hormone without stimulation was 24.7 ng/ml. We diagnosed him to have complete ACTH deficiency attributable to radiation therapy. This is the first known case of a patient with complete ACTH deficiency after radiation therapy and a growth hormone reserve that remained normal. (author)

Complete adrenocorticotropin deficiency after radiation therapy for brain tumor with a normal growth hormone reserve

International Nuclear Information System (INIS)

Sakai, Haruna; Yoshioka, Katsunobu; Yamagami, Keiko

2002-01-01

A 34-year-old man with neurofibromatosis type 1, who had received radiation therapy after the excision of a brain tumor 5 years earlier, was admitted to our hospital with vomiting and weight loss. Cortisol and adrenocorticotropin (ACTH) were undetectable before and after administration of 100 μg corticotropin releasing hormone. The level of growth hormone without stimulation was 24.7 ng/ml. We diagnosed him to have complete ACTH deficiency attributable to radiation therapy. This is the first known case of a patient with complete ACTH deficiency after radiation therapy and a growth hormone reserve that remained normal. (author)

Evidence for protection of targeted reef fish on the largest marine reserve in the Caribbean

Directory of Open Access Journals (Sweden)

Fabián Pina-Amargós

2014-02-01

Full Text Available Marine reserves can restore fish abundance and diversity in areas impacted by overfishing, but the effectiveness of reserves in developing countries where resources for enforcement are limited, have seldom been evaluated. Here we assess whether the establishment in 1996 of the largest marine reserve in the Caribbean, Gardens of the Queen in Cuba, has had a positive effect on the abundance of commercially valuable reef fish species in relation to neighboring unprotected areas. We surveyed 25 sites, including two reef habitats (reef crest and reef slope, inside and outside the marine reserve, on five different months, and over a one-and-a-half year period. Densities of the ten most frequent, highly targeted, and relatively large fish species showed a significant variability across the archipelago for both reef habitats that depended on the month of survey. These ten species showed a tendency towards higher abundance inside the reserve in both reef habitats for most months during the study. Average fish densities pooled by protection level, however, showed that five out of these ten species were at least two-fold significantly higher inside than outside the reserve at one or both reef habitats. Supporting evidence from previously published studies in the area indicates that habitat complexity and major benthic communities were similar inside and outside the reserve, while fishing pressure appeared to be homogeneous across the archipelago before reserve establishment. Although poaching may occur within the reserve, especially at the boundaries, effective protection from fishing was the most plausible explanation for the patterns observed.

Evidence for protection of targeted reef fish on the largest marine reserve in the Caribbean.

Science.gov (United States)

Pina-Amargós, Fabián; González-Sansón, Gaspar; Martín-Blanco, Félix; Valdivia, Abel

2014-01-01

Marine reserves can restore fish abundance and diversity in areas impacted by overfishing, but the effectiveness of reserves in developing countries where resources for enforcement are limited, have seldom been evaluated. Here we assess whether the establishment in 1996 of the largest marine reserve in the Caribbean, Gardens of the Queen in Cuba, has had a positive effect on the abundance of commercially valuable reef fish species in relation to neighboring unprotected areas. We surveyed 25 sites, including two reef habitats (reef crest and reef slope), inside and outside the marine reserve, on five different months, and over a one-and-a-half year period. Densities of the ten most frequent, highly targeted, and relatively large fish species showed a significant variability across the archipelago for both reef habitats that depended on the month of survey. These ten species showed a tendency towards higher abundance inside the reserve in both reef habitats for most months during the study. Average fish densities pooled by protection level, however, showed that five out of these ten species were at least two-fold significantly higher inside than outside the reserve at one or both reef habitats. Supporting evidence from previously published studies in the area indicates that habitat complexity and major benthic communities were similar inside and outside the reserve, while fishing pressure appeared to be homogeneous across the archipelago before reserve establishment. Although poaching may occur within the reserve, especially at the boundaries, effective protection from fishing was the most plausible explanation for the patterns observed.

Targeting Insulin-Like Growth Factor 1 Receptor Inhibits Pancreatic Cancer Growth and Metastasis

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Subramani, Ramadevi; Lopez-Valdez, Rebecca; Arumugam, Arunkumar; Nandy, Sushmita; Boopalan, Thiyagarajan; Lakshmanaswamy, Rajkumar

2014-01-01

Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer. PMID:24809702

Feasible climate targets. The roles of economic growth, coalition development and expectations

International Nuclear Information System (INIS)

Blanford, Geoffrey J.; Richels, Richard G.; Rutherford, Thomas F.

2009-01-01

The analysis presented here follows the design specified by the Energy Modeling Forum (EMF) Transition Scenarios study on achieving climate stabilization goals with delayed participation by developing countries. We use the MERGE model to evaluate the core EMF scenarios for both the international and the US-specific studies. Our results indicate that a radiative forcing target equivalent to 450 ppmv CO 2 -e cannot be met even allowing for full participation and overshoot during the entire 21st century. With delayed participation of developing countries, a target of 550 ppmv CO 2 -e is only attainable with pessimistic assumptions about economic growth, and even then only at very high cost. A target of 650 ppmv CO 2 -e can be met with delayed participation for a more affordable cost. We highlight sensitivities to the core scenarios in two key dimensions: (1) the effect of the unfolding global financial crisis on the rate of economic growth and (2) the willingness of initially non-participating countries to agree at the beginning of the next commitment period (i.e. 2012) to join the coalition at a pre-specified date in the future. We find that while the recession does not fundamentally change the crucial role of developing country involvement, advance agreement on their part to future targets could substantially reduce costs for all countries. (author)

Targeting the erythropoietin receptor on glioma cells reduces tumour growth

International Nuclear Information System (INIS)

Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

2011-01-01

Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

Plant lectin can target receptors containing sialic acid, exemplified by podoplanin, to inhibit transformed cell growth and migration.

Directory of Open Access Journals (Sweden)

Jhon Alberto Ochoa-Alvarez

Full Text Available Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors that have not been identified. We report here that a lectin from the seeds of Maackia amurensis (MASL with affinity for O-linked carbohydrate chains containing sialic acid targets PDPN to inhibit transformed cell growth and motility at nanomolar concentrations. Interestingly, the biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular system to inhibit melanoma cell growth, migration, and tumorigenesis. These studies demonstrate how lectins may be used to help develop dietary agents that target specific receptors to combat malignant cell growth.

Inverse Problems and Data Fusion for crop production applications targeting optimal growth - Fertilization

DEFF Research Database (Denmark)

Kaur, Bipjeet; Owusu, Robert K. A.

2015-01-01

of the crop growth process based on information on soil quality, field seeding, spraying/fertilization and environmental information in general. Finally, references to software tools, which could form the basis for an open source platform for a planning and monitoring system for optimal crop growth......, such that the crop yield is optimized with respect to several parameters (e.g. high end user value and minimum environmental impact), thus obtaining a sustainable production. The growth process optimization is based on information, including sensor based measurements with sensor quality monitoring, from previous......This work in progress is a contribution to crop growth systems for planning and monitoring of farm activities and practices by farmers. The work outlines the initial findings related to modelling, simulation and visualization techniques for crop growth, specifically targeting the barley crop...

Diffusion tensor magnetic resonance imaging driven growth modeling for radiotherapy target definition in glioblastoma

DEFF Research Database (Denmark)

Jensen, Morten B; Guldberg, Trine L; Harbøll, Anja

2017-01-01

the microscopic tumor cell spread. Gliomas favor spread along the white matter fiber tracts. Tumor growth models incorporating the MRI diffusion tensors (DTI) allow to account more consistently for the glioma growth. The aim of the study was to investigate the potential of a DTI driven growth model to improve...... target definition in glioblastoma (GBM). MATERIAL AND METHODS: Eleven GBM patients were scanned using T1w, T2w FLAIR, T1w + Gd and DTI. The brain was segmented into white matter, gray matter and cerebrospinal fluid. The Fisher-Kolmogorov growth model was used assuming uniform proliferation...

Segmentation of foreground apple targets by fusing visual attention mechanism and growth rules of seed points

Energy Technology Data Exchange (ETDEWEB)

Qu, W.; Shang, W.; Shao, Y.; Wang, D.; Yu, X.; Song, H.

2015-07-01

Accurate segmentation of apple targets is one of the most important problems to be solved in the vision system of apple picking robots. This work aimed to solve the difficulties that background targets often bring to foreground targets segmentation, by fusing the visual attention mechanism and the growth rule of seed points. Background targets could be eliminated by extracting the ROI (region of interest) of apple targets; the ROI was roughly segmented on the HSV color space, and then each of the pixels was used as a seed growing point. The growth rule of the seed points was adopted to obtain the whole area of apple targets from seed growing points. The proposed method was tested with 20 images captured in a natural scene, including 54 foreground apple targets and approximately 84 background apple targets. Experimental results showed that the proposed method can remove background targets and focus on foreground targets, while the k-means algorithm and the chromatic aberration algorithm cannot. Additionally, its average segmentation error rate was 13.23%, which is 2.71% higher than that of the k-means algorithm and 2.95% lower than that of the chromatic aberration algorithm. In conclusion, the proposed method contributes to the vision system of apple-picking robots to locate foreground apple targets quickly and accurately under a natural scene. (Author)

Preparation and Characterization of an Antibody Antagonist That Targets the Porcine Growth Hormone Receptor

Directory of Open Access Journals (Sweden)

Huanzhong Cui

2016-10-01

Full Text Available A series of antagonists specifically targeting growth hormone receptors (GHR in different species, such as humans, rats, bovines, and mice, have been designed; however, there are currently no antagonists that target the porcine growth hormone (GH. Therefore, in this study, we developed and characterized a porcine GHR (pGHR antibody antagonist (denoted by AN98 via the hybridoma technique. The results from enzyme-linked immunosorbent assay, fluorescence activated cell sorter, indirect immunoinfluscent assay, and competitive receptor binding analysis showed that AN98 could specifically recognize pGHR, and further experiments indicated that AN98 could effectively inhibit pGH-induced signalling in CHO-pGHR cells and porcine hepatocytes. In addition, AN98 also inhibited GH-induced insulin-like growth factor-1 (IGF-1 secretion in porcine hepatocytes. In summary, these findings indicated that AN98, as a pGHR-specific antagonist, has potential applications in pGH-pGHR-related research on domestic pigs.

The postnatal growth of ICRP target organs in reference humans: Spleen and liver

International Nuclear Information System (INIS)

Walker, J.T.

1989-01-01

Attempts to improve radiation dose estimates to infants and children are hampered because of the lack of mathematical models that describe the age variation in anatomical and physiological parameters. Specifically, for one anatomical parameter, organ size, there are no growth models available to the health physics community. In this paper, an empirical mathematical model is introduced for estimating age-specific masses of two ICRP target organs: the spleen and liver. That model, the Power Logistic Additive (PLA) growth model, is fitted to ICRP 23 organ growth data to determine five growth parameters. This model assumes that organs grow under the influence of two main processes: a primary (power function) and a sexual maturation (logistic function) process, which are additive from birth to adulthood. The results show that the model describes the ICRP growth data quite well. Growth parameters and tables listing the predicted masses and mass velocities as a function of age for each organ are provided for application in the ICRP modeling system

Development of epidermal growth factor receptor targeted therapy in pancreatic cancer.

Science.gov (United States)

Qing, Liu; Qing, Wang

2018-02-01

The epidermal growth factor receptor (EGFR) family are a series of important cancer therapeutic targets involved in cancer biology. These genes play an important role in tumor biological characteristics including angiogenesis, cell survival, invasion and glucose metabolism. In recent years, progresses have been achieved upon the cellular and molecular biological characteristics of EGFR and its role in cancer development based on the study of tumor specimens and experimental animal model. EGFR(HER1/ErbB) is overexpressed in over sixty percent of triple-negative breast cancers and occurs in pancreatic, bladder, lung and head-and-neck cancers. Up to now, EGFR inhibitors have been applied in various of cancer, such as lung, breast, bladder and head and neck cancers etc., in which the combination of EGFR inhibitors plus chemotherapeutic agents is now seen as the standard of care for advanced/metastatic pancreatic cancer. For these reasons, EGFR inhibitors and their therapeutic effect for pancreatic cancer is becoming the focus in Laboratory and clinical research. In this paper, research progress of the development of epidermal growth factor receptor targeted therapy in pancreatic cancer is introduced.

The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases?

Science.gov (United States)

Garcia-Huerta, Paula; Troncoso-Escudero, Paulina; Jerez, Carolina; Hetz, Claudio; Vidal, Rene L

2016-10-15

One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer.

Science.gov (United States)

Philip, Philip A; Lutz, Manfred P

2015-10-01

Pancreatic cancer is aggressive, chemoresistant, and characterized by complex and poorly understood molecular biology. The epidermal growth factor receptor (EGFR) pathway is frequently activated in pancreatic cancer; therefore, it is a rational target for new treatments. However, the EGFR tyrosine kinase inhibitor erlotinib is currently the only targeted therapy to demonstrate a very modest survival benefit when added to gemcitabine in the treatment of patients with advanced pancreatic cancer. There is no molecular biomarker to predict the outcome of erlotinib treatment, although rash may be predictive of improved survival; EGFR expression does not predict the biologic activity of anti-EGFR drugs in pancreatic cancer, and no EGFR mutations are identified as enabling the selection of patients likely to benefit from treatment. Here, we review clinical studies of EGFR-targeted therapies in combination with conventional cytotoxic regimens or multitargeted strategies in advanced pancreatic cancer, as well as research directed at molecules downstream of EGFR as alternatives or adjuncts to receptor targeting. Limitations of preclinical models, patient selection, and trial design, as well as the complex mechanisms underlying resistance to EGFR-targeted agents, are discussed. Future clinical trials must incorporate translational research end points to aid patient selection and circumvent resistance to EGFR inhibitors.

Genome-scale reconstruction of the Streptococcus pyogenes M49 metabolic network reveals growth requirements and indicates potential drug targets.

Science.gov (United States)

Levering, Jennifer; Fiedler, Tomas; Sieg, Antje; van Grinsven, Koen W A; Hering, Silvio; Veith, Nadine; Olivier, Brett G; Klett, Lara; Hugenholtz, Jeroen; Teusink, Bas; Kreikemeyer, Bernd; Kummer, Ursula

2016-08-20

Genome-scale metabolic models comprise stoichiometric relations between metabolites, as well as associations between genes and metabolic reactions and facilitate the analysis of metabolism. We computationally reconstructed the metabolic network of the lactic acid bacterium Streptococcus pyogenes M49. Initially, we based the reconstruction on genome annotations and already existing and curated metabolic networks of Bacillus subtilis, Escherichia coli, Lactobacillus plantarum and Lactococcus lactis. This initial draft was manually curated with the final reconstruction accounting for 480 genes associated with 576 reactions and 558 metabolites. In order to constrain the model further, we performed growth experiments of wild type and arcA deletion strains of S. pyogenes M49 in a chemically defined medium and calculated nutrient uptake and production fluxes. We additionally performed amino acid auxotrophy experiments to test the consistency of the model. The established genome-scale model can be used to understand the growth requirements of the human pathogen S. pyogenes and define optimal and suboptimal conditions, but also to describe differences and similarities between S. pyogenes and related lactic acid bacteria such as L. lactis in order to find strategies to reduce the growth of the pathogen and propose drug targets. Copyright © 2016 Elsevier B.V. All rights reserved.

Marine reserves: fish life history and ecological traits matter.

Science.gov (United States)

Claudet, J; Osenberg, C W; Domenici, P; Badalamenti, F; Milazzo, M; Falcón, J M; Bertocci, I; Benedetti-Cecchi, L; García-Charton, J A; Goñi, R; Borg, J A; Forcada, A; De Lucia, G A; Perez-Ruzafa, A; Afonso, P; Brito, A; Guala, I; Le Diréach, L; Sanchez-Jerez, P; Somerfield, P J; Planes, S

2010-04-01

Marine reserves are assumed to protect a wide range of species from deleterious effects stemming from exploitation. However, some species, due to their ecological characteristics, may not respond positively to protection. Very little is known about the effects of life history and ecological traits (e.g., mobility, growth, and habitat) on responses of fish species to marine reserves. Using 40 data sets from 12 European marine reserves, we show that there is significant variation in the response of different species of fish to protection and that this heterogeneity can be explained, in part, by differences in their traits. Densities of targeted size-classes of commercial species were greater in protected than unprotected areas. This effect of protection increased as the maximum body size of the targeted species increased, and it was greater for species that were not obligate schoolers. However, contrary to previous theoretical findings, even mobile species with wide home ranges benefited from protection: the effect of protection was at least as strong for mobile species as it was for sedentary ones. Noncommercial bycatch and unexploited species rarely responded to protection, and when they did (in the case of unexploited bentho-pelagic species), they exhibited the opposite response: their densities were lower inside reserves. The use of marine reserves for marine conservation and fisheries management implies that they should ensure protection for a wide range of species with different life-history and ecological traits. Our results suggest this is not the case, and instead that effects vary with economic value, body size, habitat, depth range, and schooling behavior.

Action of a diffusible target-derived chemoattractant on cortical axon branch induction and directed growth.

Science.gov (United States)

Sato, M; Lopez-Mascaraque, L; Heffner, C D; O'Leary, D D

1994-10-01

Cortical axons innervate their brainstem target, the basilar pons, by the initiation and extension of collateral branches interstitially along their length. To address whether a diffusible pons-derived chemoattractant controls these events, we used cocultures in collagen matrices and time-lapse microscopy. Pontine explants enhanced by 5-fold the de novo initiation of transient branches along cortical axons; most branches were directed toward pons. Of the branches extended toward pons, 2%-3% were stabilized; those extended away were not. Pontine explants also enhanced the stable bifurcation of growth cones and prompted directional changes by growth cone turning and collateral extension. These effects were distance dependent and mimicked by pons-conditioned medium. This evidence indicates that the pons activity promotes branch initiation interstitially along cortical axons, a novel property for a chemoattractant, and provides a directional cue for their growth. These findings suggest that the pons chemoattractant serves as a diffusible target-recognition molecule.

Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice

International Nuclear Information System (INIS)

Cheng, Pei-Hsin; Rao, Xiao-Mei; Wechman, Stephen L.; Li, Xiao-Feng; McMasters, Kelly M.; Zhou, Heshan Sam

2015-01-01

Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads. Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies. Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment. Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor. The online version of this article (doi:10.1186/s12885-015-1731-x) contains supplementary material, which is available to authorized users

A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment

Science.gov (United States)

Nör, Jacques Eduardo

2018-01-01

Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth. PMID:29351275

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

Science.gov (United States)

Unkelbach, Jan; Menze, Bjoern H.; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Ayache, Nicholas; Shih, Helen A.

2014-02-01

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation

International Nuclear Information System (INIS)

Unkelbach, Jan; Dittmann, Florian; Le, Matthieu; Shih, Helen A; Menze, Bjoern H; Ayache, Nicholas; Konukoglu, Ender

2014-01-01

Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher–Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most

Experimental reduction of laser imprinting and Rayleigh–Taylor growth in spherically compressed, medium-Z-doped plastic targets

International Nuclear Information System (INIS)

Fiksel, G.; Hu, S. X.; Goncharov, V. A.; Meyerhofer, D. D.; Sangster, T. C.; Yaakobi, B.; Bonino, M. J.; Jungquist, R.; Smalyuk, V. A.

2012-01-01

The effect of medium-Z doping of plastic ablators on laser imprinting and Rayleigh–Taylor (RT) instability growth was studied using spherical direct-drive implosions on the OMEGA Laser System [T. R. Boehly et al., Opt. Commun. 133, 495 (1977)]. The targets were spherical plastic (CH) shells, with an outer diameter of 860 μm and a thickness of 22 μm, volume doped with a varied concentration of Si (4.3% and 7.4%) and Ge (3.9%). The targets were imploded with 48 beams with a low-adiabat, triple-picket laser shape pulse with a peak intensity of 4×10 14 W/cm 2 , and a pulse duration of 2.5 ns. The shells were x-ray radiographed through a 400 -μm opening in the side of the target. The results show that volumetric impurity doping strongly reduces the shell density modulation and the instability growth rate. The amplitude of the initial imprint is reduced by a factor of 2.5 ± 0.5 for CH[4.3% Si] targets and by a factor of 3 ± 0.5 for CH[7.4% Si] and CH[3.9% Ge] targets. At the end of the acceleration phase, the reduction factor becomes 3 ± 0.5 and 5 ± 0.5, correspondingly. The RT instability growth rate in doped targets is reduced by a factor of 1.5 compared to undoped ones. Simulations using the two-dimensional, radiation-hydrodynamics code draco show good agreement with the measurements.

Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth

Science.gov (United States)

Al-Ali, Hassan; Lee, Do-Hun; Danzi, Matt C.; Nassif, Houssam; Gautam, Prson; Wennerberg, Krister; Zuercher, Bill; Drewry, David H.; Lee, Jae K.; Lemmon, Vance P.; Bixby, John L.

2016-01-01

Mammalian Central Nervous System (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multi-target drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds’ kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth, as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology, was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line, as well as targets recently shown to mediate drug resistance. PMID:26056718

Epidermal Growth Factor Receptor targeting in non-small cell lung cancer: revisiting different strategies against the same target.

Science.gov (United States)

Castañón, Eduardo; Martín, Patricia; Rolfo, Christian; Fusco, Juan P; Ceniceros, Lucía; Legaspi, Jairo; Santisteban, Marta; Gil-Bazo, Ignacio

2014-01-01

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the paradigm of treatment in non-small cell lung cancer (NSCLC). The molecular biology study of EGFR has led to clinical trials that select patients more accurately, regarding the presence of EGFR activating mutations. Nonetheless, a lack of response or a temporary condition of the response has been detected in patients on EGFR TKIs. This has urged to study potential resistance mechanisms underneath. The most important ones are the presence of secondary mutations in EGFR, such as T790M, or the overexpression of mesenchymal-epithelial transition factor (MET) that may explain why patients who initially respond to EGFR TKIs, may ultimately become refractory. Several approaches have been taken and new drugs both targeting EGFR resistance-mutation or MET are currently being developed. Here we review and update the EGFR biological pathway as well as the clinical data leading to approval of the EGFR TKIs currently in the market. New compounds under investigation targeting resistance mutations or dually targeting EGFR and other relevant receptors are also reviewed and discussed.

International strategies for growth : monetizing gas reserves to add value to the bottom line

International Nuclear Information System (INIS)

Mihaichuk, G.

1998-01-01

The direction taken by oil and gas companies, including TransCanada International, in their strategy for growth in global energy markets was discussed. The role that gas plays in meeting the objectives was examined and the different ways in which gas reserves and investments in the gas sector are being turned into high-performing vehicles for adding value to the bottom line were described. Deregulation of, and competition within, the gas and electric power industries are the driving factors for changes within the energy industries. Natural gas will be a winner because it is the first choice for new power generation. Many companies have entered the international playing field to take advantage of the opportunities in international markets. The problems and solutions to monetizing natural gas reserves, some of the international political issues such as regulatory uncertainty, cross-border disputes, lack of regional integration, and sanctions, and how these adverse effects may be mitigated through mergers, acquisitions, or joint ventures, are explored. 14 figs

Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

Science.gov (United States)

Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

2012-07-15

Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines

International Nuclear Information System (INIS)

Xu, Ling; Hausmann, Martin; Dietmaier, Wolfgang; Kellermeier, Silvia; Pesch, Theresa; Stieber-Gunckel, Manuela; Lippert, Elisabeth; Klebl, Frank; Rogler, Gerhard

2010-01-01

Cholangiocarcinoma (CC) is a malignant neoplasm of the bile ducts or the gallbladder. Targeting of growth factor receptors showed therapeutic potential in palliative settings for many solid tumors. The aim of this study was to determine the expression of seven growth factor receptors in CC cell lines and to assess the effect of blocking the EGFR receptor in vitro. Expression of EGFR (epithelial growth factor receptor), HGFR (hepatocyte growth factor receptor) IGF1R (insulin-like growth factor 1 receptor), IGF2R (insulin-like growth factor 2 receptor) and VEGFR1-3 (vascular endothelial growth factor receptor 1-3) were examined in four human CC cell lines (EGI-1, HuH28, OZ and TFK-1). The effect of the anti-EGFR-antibody cetuximab on cell growth and apoptosis was studied and cell lines were examined for KRAS mutations. EGFR, HGFR and IGFR1 were present in all four cell lines tested. IGFR2 expression was confirmed in EGI-1 and TFK-1. No growth-inhibitory effect was found in EGI-1 cells after incubation with cetuximab. Cetuximab dose-dependently inhibited growth in TFK-1. Increased apoptosis was only seen in TFK-1 cells at the highest cetuximab dose tested (1 mg/ml), with no dose-response-relationship at lower concentrations. In EGI-1 a heterozygous KRAS mutation was found in codon 12 (c.35G>A; p.G12D). HuH28, OZ and TFK-1 lacked KRAS mutation. CC cell lines express a pattern of different growth receptors in vitro. Growth factor inhibitor treatment could be affected from the KRAS genotype in CC. The expression of EGFR itself does not allow prognoses on growth inhibition by cetuximab

Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines

Directory of Open Access Journals (Sweden)

Kellermeier Silvia

2010-06-01

Full Text Available Abstract Background Cholangiocarcinoma (CC is a malignant neoplasm of the bile ducts or the gallbladder. Targeting of growth factor receptors showed therapeutic potential in palliative settings for many solid tumors. The aim of this study was to determine the expression of seven growth factor receptors in CC cell lines and to assess the effect of blocking the EGFR receptor in vitro. Methods Expression of EGFR (epithelial growth factor receptor, HGFR (hepatocyte growth factor receptor IGF1R (insulin-like growth factor 1 receptor, IGF2R (insulin-like growth factor 2 receptor and VEGFR1-3 (vascular endothelial growth factor receptor 1-3 were examined in four human CC cell lines (EGI-1, HuH28, OZ and TFK-1. The effect of the anti-EGFR-antibody cetuximab on cell growth and apoptosis was studied and cell lines were examined for KRAS mutations. Results EGFR, HGFR and IGFR1 were present in all four cell lines tested. IGFR2 expression was confirmed in EGI-1 and TFK-1. No growth-inhibitory effect was found in EGI-1 cells after incubation with cetuximab. Cetuximab dose-dependently inhibited growth in TFK-1. Increased apoptosis was only seen in TFK-1 cells at the highest cetuximab dose tested (1 mg/ml, with no dose-response-relationship at lower concentrations. In EGI-1 a heterozygous KRAS mutation was found in codon 12 (c.35G>A; p.G12D. HuH28, OZ and TFK-1 lacked KRAS mutation. Conclusion CC cell lines express a pattern of different growth receptors in vitro. Growth factor inhibitor treatment could be affected from the KRAS genotype in CC. The expression of EGFR itself does not allow prognoses on growth inhibition by cetuximab.

Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen

Energy Technology Data Exchange (ETDEWEB)

Khan, S.H.; Sorof, S. (Fox Chase Cancer Center, Philadelphia, PA (United States))

1990-12-01

Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ{sub 2}, and {Delta}{sup 12}-PGJ{sub 2}, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA{sub 2} and {Delta}{sup 12}-PGJ{sub 2} in primary cultures of purified rat hepatocytes. As a model ligand, ({sup 3}H)PGA{sub 1} bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 {mu}M (low affinity). The high-affinity finding of ({sup 3}H)PGA{sup 1} correlated with their growth inhibitory activities reported previously and here. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.

Status of fossil fuel reserves; Etat des reserves des combustibles fossiles

Energy Technology Data Exchange (ETDEWEB)

Laherrere, J

2005-07-01

Reserves represent the sum of past and future productions up to the end of production. In most countries the reserve data of fields are confidential. Therefore, fossil fuel reserves are badly known because the published data are more political than technical and many countries make a confusion between resources and reserves. The cumulated production of fossil fuels represents only between a third and a fifth of the ultimate reserves. The production peak will take place between 2020 and 2050. In the ultimate reserves, which extrapolate the past, the fossil fuels represent three thirds of the overall energy. This document analyses the uncertainties linked with fossil fuel reserves: reliability of published data, modeling of future production, comparison with other energy sources, energy consumption forecasts, reserves/production ratio, exploitation of non-conventional hydrocarbons (tar sands, extra-heavy oils, bituminous shales, coal gas, gas shales, methane in overpressure aquifers, methane hydrates), technology impacts, prices impact, and reserves growth. (J.S.)

Forest structure, stand composition, and climate-growth response in montane forests of Jiuzhaigou National Nature Reserve, China.

Directory of Open Access Journals (Sweden)

Mark W Schwartz

Full Text Available Montane forests of western China provide an opportunity to establish baseline studies for climate change. The region is being impacted by climate change, air pollution, and significant human impacts from tourism. We analyzed forest stand structure and climate-growth relationships from Jiuzhaigou National Nature Reserve in northwestern Sichuan province, along the eastern edge of the Tibetan plateau. We conducted a survey to characterize forest stand diversity and structure in plots occurring between 2050 and 3350 m in elevation. We also evaluated seedling and sapling recruitment and tree-ring data from four conifer species to assess: 1 whether the forest appears in transition toward increased hardwood composition; 2 if conifers appear stressed by recent climate change relative to hardwoods; and 3 how growth of four dominant species responds to recent climate. Our study is complicated by clear evidence of 20(th century timber extraction. Focusing on regions lacking evidence of logging, we found a diverse suite of conifers (Pinus, Abies, Juniperus, Picea, and Larix strongly dominate the forest overstory. We found population size structures for most conifer tree species to be consistent with self-replacement and not providing evidence of shifting composition toward hardwoods. Climate-growth analyses indicate increased growth with cool temperatures in summer and fall. Warmer temperatures during the growing season could negatively impact conifer growth, indicating possible seasonal climate water deficit as a constraint on growth. In contrast, however, we found little relationship to seasonal precipitation. Projected warming does not yet have a discernible signal on trends in tree growth rates, but slower growth with warmer growing season climates suggests reduced potential future forest growth.

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer.

Science.gov (United States)

Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T

2017-04-01

Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

Directory of Open Access Journals (Sweden)

Bin Zhang

2017-08-01

Full Text Available Background: MicroRNAs (miRNAs have emerged as key players in various human biological processes, including tumorigenesis. Here, we investigated the roles of miR-375 in the pathogenesis of oral squamous cell carcinoma (OSCC. Methods: We performed quantitative real-time PCR (qRT-PCR to detect miR-375 expression in OSCC tissues and corresponding normal oral epithelial tissues and analyze the correlation of miR-375 expression with OSCC metastasis and patient’s survival. Then, the effects of miR-375 expression on proliferation, cell cycle, apoptosis and radiosensitivity in OSCC cells were determined by using MTT, flow cytometry and clonogenic survival assays. A dual-luciferase reporter assay was performed to test whether miR-375 binds to the 3’-untranslated region (3’-UTR of target mRNA. Results: The expression level of miR-375 in OSCC tissues was significantly lower than that in normal oral epithelial tissues, and low miR-375 expression was correlated with higher incidence of lymph node metastasis and poor survival of OSCC patients. Upregulation of miR-375 significantly inhibits growth, induces cell cycle arrest in G0/G1 phase, increases apoptosis and enhances radiosensitivity in OSCC cells. Analysis of luciferase activity demonstrated that miR-375 binds to the 3’-UTR of insulin like growth factor 1 receptor (IGF-1R. Small interfering RNA (shRNA-mediated IGF-1R knockdown mimics the effects of miR-375 upregulation, while overexpression of IGF-1R partially reverses those effects in OSCC cells. Conclusion: It was obviously demonstrated that miRNA-375 inhibits growth and enhances radiosensitivity in OSCC cells by targeting IGF-1R, suggesting that miR-375 may be a potential therapeutic target for OSCC patients.

miRNA-497 Negatively Regulates the Growth and Motility of Chondrosarcoma Cells by Targeting Cdc25A.

Science.gov (United States)

Lu, Yandong; Li, Fangguo; Xu, Tao; Sun, Jie

2016-01-01

Chondrosarcoma (CHS) is the second most common malignant bone sarcoma with increased risk of invasion and metastasis. However, the regulatory mechanisms of CHS tumorigenesis remain unknown. Here we investigated the novel role of miR-497 in regulating chondrosarcoma cell growth and cell cycle arrest. RT-PCR analysis showed that the expression of miR-497 is aberrantly downregulated in human chondrosarcoma samples and cells. After transfection with miR-497 mimic or antagomir, the proliferation and apoptosis of JJ012 and OUMS-27 chondrosarcoma cells were determined by CCK-8 assay and flow cytometric analysis, respectively. Results showed that the proliferation capacity of JJ012 and OUMS-27 cells was significantly decreased by miR-497 overexpression but increased by miR-497 repression. Apoptosis in both cell types was remarkably enhanced by miR-497 mimic but inhibited by miR-497 antagomir. By bioinformatics and luciferase reporter analysis, Cdc25A was proven to be a direct target of miR-497 in chondrosarcoma cells. Further studies indicated that miR-497 modulates the growth of chondrosarcoma cells by targeting Cdc25A, in which the cell cycle inhibitor p21 is involved through a p53-independent pathway. In conclusion, we demonstrated that miR-497 represents a potential tumor suppressor in human chondrosarcoma that regulates the growth of chondrosarcoma cells by targeting Cdc25A. This may provide a novel therapeutic target for chondrosarcoma.

Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis.

Science.gov (United States)

Chiu, Christopher W; Nozawa, Hiroaki; Hanahan, Douglas

2010-10-10

Pancreatic neuroendocrine tumors (PNETs), although rare, often metastasize, such that surgery, the only potentially curative therapy, is not possible. There is no effective systemic therapy for patients with advanced PNETs. Therefore, new strategies are needed. Toward that end, we investigated the potential benefit of dual therapeutic targeting of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) kinases, using a preclinical mouse model of PNET. Rapamycin and erlotinib, inhibitors of mTOR and EGFR, respectively, were used to treat RIP-Tag2 transgenic mice bearing advanced multifocal PNET. Tumor growth and survival were monitored, and tumors were surveyed for potential biomarkers of response to the therapeutics. Rapamycin monotherapy was notably efficacious, prolonging survival concomitant with tumor stasis (stable disease). However, the tumors developed resistance, as evidenced by eventual relapse to progressive tumor growth. Erlotinib monotherapy slowed tumor growth and elicited a marginal survival benefit. In combination, there was an unprecedented survival benefit in the face of this aggressive multifocal cancer and, in contrast to either monotherapy, the development of adaptive resistance was not apparent. Additionally, the antiapoptotic protein survivin was implicated as a biomarker of sensitivity and beneficial responses to the dual targeted therapy. Preclinical trials in a mouse model of endogenous PNET suggest that combined targeting of the mTOR and EGFR signaling pathways could have potential clinical benefit in treating PNET. These results have encouraged development of an ongoing phase II clinical trial aimed to evaluate the efficacy of this treatment regimen in human neuroendocrine tumors.

miR-216b suppresses breast cancer growth and metastasis by targeting SDCBP

International Nuclear Information System (INIS)

Jana, Samir; Sengupta, Suman; Biswas, Subir; Chatterjee, Annesha; Roy, Himansu; Bhattacharyya, Arindam

2017-01-01

Breast cancer is the most deadly cancer among women and the second leading cause of cancer death worldwide. Treatment effectiveness is complicated with tumor invasiveness/drug resistance. To tailor treatments more effectively to individual patients, it is important to define tumor growth and metastasis at molecular levels. SDCBP is highly overexpressed and associated with a strikingly poor prognosis in breast cancer. However the post transcriptional regulation of SDCBP overexpression remains to be an unexplored area. Our study reveals that miR-216b directly regulates SDCBP expression by binding to its 3′UTR region. miR-216b is a tumor suppressive miRNA and it is underexpressed during metastatic breast cancer. Consequently, overexpression of miR-216b resulted in decreased proliferation, migration and invasion in BC cell lines by modulating the expression of SDCBP. Inhibition of miR-216b divergent the tumor suppressive role by inducing the growth proliferation, migration and invasion in vitro. There is therefore a negative correlation between the expression of miR-216b and its target gene SDCBP in the BC tissue samples as well as cell lines. Simultaneous expression of miR-216b and SDCBP rescued the growth, migration and invasion effect suggesting that tumor suppressive action of miR-216b may be directly mediated by SDCBP. In summary, the study identifies miR-216b as a regulator of SDCBP expression in breast cancer which can potentially be targeted for developing newer therapies for the effective treatment of this killer disease.

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

Science.gov (United States)

Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T.

2018-01-01

Introduction Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted. PMID:28271910

Growth and reproductive performance of sambar deer in Sabal Forest Reserve of Sarawak, Malaysia.

Science.gov (United States)

Dahlan, Ismail; Dawend, Jiwan

2013-10-01

We examined the growth, reproduction, rutting behavior, and health status of sambar deer (Cervus unicolor brookei) in secondary Acacia mangium plantation. The data were collected over 11 years from a breeding herd of 21 stags and 33 hinds in Sabal Forest Reserve, Sarawak, Malaysia. Brody's growth model of the pooled data is Y t  = 148.56 (1 - 0.98e(-0.023t)), which estimates that maximum weights of adults are 184 and 115 kg for males and females respectively. Sambar deer are nonseasonal breeders with the breeding peak in February. Although the earliest age at which a female reached sexual maturity was 11 months, the mean age was 23 ± 7 months. Mean age of first fawning was 32 ± 8 months. Mean gestation period was 259 ± 12 days (n = 82). Stags shed antlers mostly between March and July. Velvet hardens at 103 ± 27 days (n = 23), and velvet harvesting is best at 7-9 weeks when antler length is 25-30 cm. Sambar deer are suitable as a farm species in forest plantations and have a vast potential to uplift rural living standards.

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

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Anca Maria Cimpean

2010-03-01

Full Text Available Angiogenesis in normal and pathological conditions is a multi-step process governed by positive and negative endogenous regulators. Many growth factors are involved in different steps of angiogenesis, like vascular endothelial growth factors (VEGF, fibroblast growth factor (FGF-2 or platelet-derived growth factors (PDGF. From these, VEGF and FGF-2 were extensively investigated and it was shown that they significantly contribute to the induction and progression of angiogenesis. A lot of evidence has been accumulated in last 10 years that supports the contribution of PDGF/PDGFR axis in developing angiogenesis in both normal and tumoral conditions. The crucial role of PDGF-B and PDGFR-β in angiogenesis has been demonstrated by gene targeting experiments, and their expression correlates with increased vascularity and maturation of the vascular wall. PDGF and their receptors were identified in a large variety of human tumor cells. In experimental models it was shown that inhibition of PDGF reduces interstitial fluid pressure in tumors and enhances the effect of chemotherapy. PDGFR have been involved in the cardiovascular development and their loss leads to a disruption in yolk sac blood vessels development. PDGFRβ expression by pericytes is necessary for their recruitment and integration in the wall of tumor vessels. Endothelial cells of tumor-associated blood vessels can express PDGFR. Based on these data, it was suggested the potential benefit of targeting PDGFR in the treatment of solid tumors. The molecular mechanisms of PDGF/PDGFR-mediated angiogenesis are not fully understood, but it was shown that tyrosine kinase inhibitors reduce tumor growth and angiogenesis in experimental xenograft models, and recent data demonstrated their efficacy in chemoresistant tumors. The in vivo effects of PDGFR inhibitors are more complex, based on the cross-talk with other angiogenic factors. In this review, we summarize data regarding the mechanisms and

Monoclonal Antibody Fragments for Targeting Therapeutics to Growth Plate Cartilage | NCI Technology Transfer Center | TTC

Science.gov (United States)

Researchers at The Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD) have discovered monoclonal antibodies that bind to matrilin-3, a protein specifically expressed in cartilage tissue, that could be used for treating or inhibiting growth plate disorders, such as a skeletal dysplasia or short stature. The monoclonal antibodies can also be used to target therapeutic agents, such as anti-arthritis agents, to cartilage tissue. NICHD seeks statements of capability or interest from parties interested in collaborative research to co-develop, evaluate, or commercialize treatment of skeletal disorders using targeting antibodies.

Population growth changes targets for immunization.

Science.gov (United States)

Tuljapurkar, S; John, A M

1995-01-01

The faster the rate of population growth in developing countries, the less likely it is that current protocols for immunization against measles, rubella, and mumps will eradicate these childhood diseases. Standard protocols (timing, percentage of children to be immunized) do not take into account the rapid rates of population growth in developing countries (3.0% per year on average in sub-Saharan Africa and 2.0% in the rest of Africa, in Latin America, and in Asia, excluding China). Most public health planning models in this area were created based on static infant populations. The World Health Organization advises vaccinating at least 85% of children aged 6 to 9 months, a 3-month immunization window during which maternal antibodies are low (so the vaccination takes) and herd immunity is high (the probability that a child will encounter the disease is low because most children have been immunized). In practice, the immunization window in developing countries is 1 year or more. More susceptible children are present than assumed by the models. A larger number of susceptible babies are added each year during rapid population growth. As the age range for immunization widens, a higher percentage of children must be vaccinated to eradicate disease (chart). The proportion of each birth cohort that must be immunized rises as the population growth rate increases. At zero population growth, 94% must be vaccinated; at population growth rates greater than 3%, 98% must be vaccinated.

Population Connectivity Measures of Fishery-Targeted Coral Reef Species to Inform Marine Reserve Network Design in Fiji.

Science.gov (United States)

Eastwood, Erin K; López, Elora H; Drew, Joshua A

2016-01-25

Coral reef fish serve as food sources to coastal communities worldwide, yet are vulnerable to mounting anthropogenic pressures like overfishing and climate change. Marine reserve networks have become important tools for mitigating these pressures, and one of the most critical factors in determining their spatial design is the degree of connectivity among different populations of species prioritized for protection. To help inform the spatial design of an expanded reserve network in Fiji, we used rapidly evolving mitochondrial genes to investigate connectivity patterns of three coral reef species targeted by fisheries in Fiji: Epinephelus merra (Serranidae), Halichoeres trimaculatus (Labridae), and Holothuria atra (Holothuriidae). The two fish species, E. merra and Ha. trimaculatus, exhibited low genetic structuring and high amounts of gene flow, whereas the sea cucumber Ho. atra displayed high genetic partitioning and predominantly westward gene flow. The idiosyncratic patterns observed among these species indicate that patterns of connectivity in Fiji are likely determined by a combination of oceanographic and ecological characteristics. Our data indicate that in the cases of species with high connectivity, other factors such as representation or political availability may dictate where reserves are placed. In low connectivity species, ensuring upstream and downstream connections is critical.

PANC-1 pancreatic cancer cell growth inhibited by cucurmosin alone and in combination with an epidermal growth factor receptor-targeted drug.

Science.gov (United States)

Wang, Congfei; Yang, Aiqin; Zhang, Baoming; Yin, Qiang; Huang, Heguang; Chen, Minghuang; Xie, Jieming

2014-03-01

To investigate the inhibition of PANC-1 pancreatic cancer cell growth by cucurmosin (CUS) and its possible mechanism. We observed the inhibition of PANC-1 cell growth by sulforhodamine B and colony-forming experiments in vitro and established nonobese diabetic/severe combined immunodeficiency mouse subcutaneous tumor models in vivo. We used Western blot to analyze protein levels related to apoptosis and epidermal growth factor receptor (EGFR) signaling pathways after drug intervention, whereas the messenger RNA expression of EGFR was analyzed by quantitative real-time polymerase chain reaction. Sulforhodamine B and colony-forming experiments indicated that CUS inhibited PANC-1 cell proliferation in a dose- and time-dependent manner. A stronger inhibitory effect was observed when CUS was combined with gefitinib. The subcutaneous tumor growth was also inhibited. Western blot showed that all the examined proteins decreased, except for 4E-BP1 and the active fragments of caspase 3 and caspase 9 increased. Epidermal growth factor receptor expression did not change significantly in quantitative real-time polymerase chain reaction. Cucurmosin can strongly inhibit the growth of PANC-1 cells in vitro and in vivo. Cucurmosin can down-regulate EGFR protein expression, but not at the messenger RNA level. Cucurmosin can also inhibit the ras/raf and phosphatidylinositol 3-kinase/Akt downstream signaling pathways and enhance the sensitivity of the EGFR-targeted drug gefitinib.

TOR, the Gateway to Cellular Metabolism, Cell Growth, and Disease.

Science.gov (United States)

Blenis, John

2017-09-21

Michael N. Hall is this year's recipient of the Lasker Basic Medical Research Award for the identification of the target of rapamycin, TOR. TOR is a master regulator of the cell's growth and metabolic state, and its dysregulation contributes to a variety of diseases, including diabetes, obesity, neurodegenerative disorders, aging, and cancer, making the TOR pathway an attractive therapeutic target. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons.

OpenAIRE

Flavell, D M; Wells, T; Wells, S E; Carmignac, D F; Thomas, G B; Robinson, I C

1996-01-01

Expression of human growth hormone (hGH) was targeted to growth hormone-releasing (GRF) neurons in the hypothalamus of transgenic rats. This induced dominant dwarfism by local feedback inhibition of GRF. One line, bearing a single copy of a GRF-hGH transgene, has been characterized in detail, and has been termed Tgr (for Transgenic growth-retarded). hGH was detected by immunocytochemistry in the brain, restricted to the median eminence of the hypothalamus. Low levels were also detected in the...

Growth of PETROBRAS international gas reserves in Latin America; Crescimento das reservas internacionais de gas da PETROBRAS na America Latina

Energy Technology Data Exchange (ETDEWEB)

Rabe, Claudio [Pontificia Univ. Catolica do Rio de Janeiro (PUC-Rio), RJ (Brazil); Syrio, Julio Cesar; Pizarro, Jorge Oscar de Sant' Anna [PETROBRAS, Rio de Janeiro, RJ (Brazil)

2004-07-01

This paper presents the work developed at PETROBRAS International to increase the natural gas reserves and production in Latin America. The results indicate that the company's new strategic focus has been providing an increase of its production of natural gas in 270%, in which daily production in September reached 84192 boed. The same happened with reserves in 2002, that increased in 37,2 billions m{sup 3}. This growth was mainly due to incorporation of Perez Conpanc and Petrolera Santa Fe. (author)

Diffusion tensor magnetic resonance imaging driven growth modeling for radiotherapy target definition in glioblastoma.

Science.gov (United States)

Jensen, Morten B; Guldberg, Trine L; Harbøll, Anja; Lukacova, Slávka; Kallehauge, Jesper F

2017-11-01

The clinical target volume (CTV) in radiotherapy is routinely based on gadolinium contrast enhanced T1 weighted (T1w + Gd) and T2 weighted fluid attenuated inversion recovery (T2w FLAIR) magnetic resonance imaging (MRI) sequences which have been shown to over- or underestimate the microscopic tumor cell spread. Gliomas favor spread along the white matter fiber tracts. Tumor growth models incorporating the MRI diffusion tensors (DTI) allow to account more consistently for the glioma growth. The aim of the study was to investigate the potential of a DTI driven growth model to improve target definition in glioblastoma (GBM). Eleven GBM patients were scanned using T1w, T2w FLAIR, T1w + Gd and DTI. The brain was segmented into white matter, gray matter and cerebrospinal fluid. The Fisher-Kolmogorov growth model was used assuming uniform proliferation and a difference in white and gray matter diffusion of a ratio of 10. The tensor directionality was tested using an anisotropy weighting parameter set to zero (γ0) and twenty (γ20). The volumetric comparison was performed using Hausdorff distance, Dice similarity coefficient (DSC) and surface area. The median of the standard CTV (CTVstandard) was 180 cm 3 . The median surface area of CTVstandard was 211 cm 2 . The median surface area of respective CTV γ0 and CTV γ20 significantly increased to 338 and 376 cm 2 , respectively. The Hausdorff distance was greater than zero and significantly increased for both CTV γ0 and CTV γ20 with respective median of 18.7 and 25.2 mm. The DSC for both CTV γ0 and CTV γ20 were significantly below one with respective median of 0.74 and 0.72, which means that 74 and 72% of CTVstandard were included in CTV γ0 and CTV γ20, respectively. DTI driven growth models result in CTVs with a significantly increased surface area, a significantly increased Hausdorff distance and decreased overlap between the standard and model derived volume.

Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

Energy Technology Data Exchange (ETDEWEB)

Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

2013-06-14

Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

A novel oncolytic adenovirus targeting Wnt signaling effectively inhibits cancer-stem like cell growth via metastasis, apoptosis and autophagy in HCC models.

Science.gov (United States)

Zhang, Jian; Lai, Weijie; Li, Qiang; Yu, Yang; Jin, Jin; Guo, Wan; Zhou, Xiumei; Liu, Xinyuan; Wang, Yigang

2017-09-16

Cancer stem cells (CSCs), which are highly differentiated and self-renewing, play an important role in the occurrence, therapeutic resistant and metastasis of hepatacellular carcinoma (HCC). Oncolytic adenoviruses have targeted killing effect on tumor cells, and are invoked as candidate drugs for cancer treatment. We designed a dual-regulated oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 that targets Wnt and Rb signaling pathways respectively, and carries the tumor suppressor gene, TSLC1. Previous studies have demonstrated that oncolytic adenovirus mediated TSLC1can target liver cancer and exhibit significant cytotoxicity. However, whether Ad.wnt-E1A(△24bp)-TSLC1 can effectively eliminate liver CSCs remains to be explored. We first used the spheroid culture to enrich the liver CSCs-like cells, and detected the self-renewal capacity, differentiation, drug resistance and tumorigenicity. The results showed that Ad-wnt-E1A(△24bp)-TSLC1 could effectively lead to autophagic death. In addition, recombinant adenovirus effectively induced the apoptosis, inhibit metastasis of hepatic CSCs-like cells in vivo. Further animal experiments indicated that Ad-wnt-E1A(△24bp)-TSLC1could effectively inhibit the growth of transplanted tumor of hepatic CSCs and prolong the survival time of mice. Therefore, the novel oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 has potential application as a therapeutic target for HCC stem cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways

NARCIS (Netherlands)

van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Heukers, R.; Pieters, Ebel H.E.; van Bergen en Henegouwen, Paul M.P.; Storm, Gerrit; Hennink, Wim E.; Kok, Robbert J.; Schiffelers, Raymond M.

2013-01-01

The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be

HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

Science.gov (United States)

Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

2016-08-01

The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models

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Pinar Kanlikilicer

2017-12-01

Full Text Available Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER, and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.] administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.

Quantifying the importance of MSP1-19 as a target of growth-inhibitory and protective antibodies against Plasmodium falciparum in humans.

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Danny W Wilson

Full Text Available BACKGROUND: Antibodies targeting blood stage antigens are important in protection against malaria, but the key targets and mechanisms of immunity are not well understood. Merozoite surface protein 1 (MSP1 is an abundant and essential protein. The C-terminal 19 kDa region (MSP1-19 is regarded as a promising vaccine candidate and may also be an important target of immunity. METHODOLOGY/FINDINGS: Growth inhibitory antibodies against asexual-stage parasites and IgG to recombinant MSP1-19 were measured in plasma samples from a longitudinal cohort of 206 children in Papua New Guinea. Differential inhibition by samples of mutant P. falciparum lines that expressed either the P. falciparum or P. chabaudi form of MSP1-19 were used to quantify MSP1-19 specific growth-inhibitory antibodies. The great majority of children had detectable IgG to MSP1-19, and high levels of IgG were significantly associated with a reduced risk of symptomatic P. falciparum malaria during the 6-month follow-up period. However, there was little evidence of PfMSP1-19 specific growth inhibition by plasma samples from children. Similar results were found when testing non-dialysed or dialysed plasma, or purified antibodies, or when measuring growth inhibition in flow cytometry or microscopy-based assays. Rabbit antisera generated by immunization with recombinant MSP1-19 demonstrated strong MSP1-19 specific growth-inhibitory activity, which appeared to be due to much higher antibody levels than human samples; antibody avidity was similar between rabbit antisera and human plasma. CONCLUSIONS/SIGNIFICANCE: These data suggest that MSP1-19 is not a major target of growth inhibitory antibodies and that the protective effects of antibodies to MSP1-19 are not due to growth inhibitory activity, but may instead be mediated by other mechanisms. Alternatively, antibodies to MSP1-19 may act as a marker of protective immunity.

Structure and Composition of Old-Growth and Unmanaged Second-Growth Riparian Forests at Redwood National Park, USA

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Christopher R. Keyes

2014-02-01

Full Text Available Restoration of second-growth riparian stands has become an important issue for managers of redwood (Sequoia sempervirens [D. Don] Endl. forest reserves. Identifying differences between old-growth and second-growth forest vegetation is a necessary step in evaluating restoration needs and targets. The objective of this study was to characterize and contrast vegetation structure and composition in old-growth and unmanaged second-growth riparian forests in adjacent, geomorphologically similar watersheds at Redwood National Park. In the old-growth, redwood was the dominant overstory species in terms of stem density, basal area, and importance values. Second-growth was dominated by red alder (Alnus rubra Bong., Douglas-fir (Pseudotsuga menziesii [Mirbel] Franco, and redwood. Understory species were similar in both forests, with several key differences: Oxalis oregana Nutt. and Trillium ovatum Pursh had greater importance values in the old-growth, and Vaccinium parvifolium Sm., Dryopteris spp. and sedges Carex spp. had greater importance values in the second-growth. Notable differences in structure and composition suggest that restoration practices such as thinning could expedite the acquisition of old-growth characteristics in second-growth riparian forests.

Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

International Nuclear Information System (INIS)

Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, André; Gnanasekar, Munirathinam

2012-01-01

Highlights: ► Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. ► Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. ► Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. ► Knock down of RAGE abrogates prostate tumor growth in vivo. ► Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

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David Olmos

2011-01-01

Full Text Available Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response.

Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

Science.gov (United States)

Olmos, David; Martins, Ana Sofia; Jones, Robin L.; Alam, Salma; Scurr, Michelle; Judson, Ian R.

2011-01-01

Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response. PMID:21647361

Comparison of low-normal and high-normal IGF-1 target levels during growth hormone replacement therapy : A randomized clinical trial in adult growth hormone deficiency

NARCIS (Netherlands)

van Bunderen, Christa C; Lips, Paul; Kramer, Mark H H; Drent, Madeleine L

BACKGROUND: Current guidelines state that the goals of growth hormone (GH) therapy in adults should be an appropriate clinical response, avoidance of side effects, and an IGF-1 value within the age-adjusted reference range. There are no published studies on the target level for IGF-1 that offer

A novel small peptide as an epidermal growth factor receptor targeting ligand for nanodelivery in vitro

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Han CY

2013-04-01

Full Text Available Cui-yan Han,1,2 Li-ling Yue,2 Ling-yu Tai,1 Li Zhou,2 Xue-yan Li,2 Gui-hua Xing,2 Xing-gang Yang,1 Ming-shuang Sun,1 Wei-san Pan1 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2Qiqihar Medical University, Qiqihar, People’s Republic of China Abstract: The epidermal growth factor receptor (EGFR serves an important function in the proliferation of tumors in humans and is an effective target for the treatment of cancer. In this paper, we studied the targeting characteristics of small peptides (AEYLR, EYINQ, and PDYQQD that were derived from three major autophosphorylation sites of the EGFR C-terminus domain in vitro. These small peptides were labeled with fluorescein isothiocyanate (FITC and used the peptide LARLLT as a positive control, which bound to putative EGFR selected from a virtual peptide library by computer-aided design, and the independent peptide RALEL as a negative control. Analyses with flow cytometry and an internalization assay using NCI-H1299 and K562 with high EGFR and no EGFR expression, respectively, indicated that FITC-AEYLR had high EGFR targeting activity. Biotin-AEYLR that was specifically bound to human EGFR proteins demonstrated a high affinity for human non-small-cell lung tumors. We found that AEYLR peptide-conjugated, nanostructured lipid carriers enhanced specific cellular uptake in vitro during a process that was apparently mediated by tumor cells with high-expression EGFR. Analysis of the MTT assay indicated that the AEYLR peptide did not significantly stimulate or inhibit the growth activity of the cells. These findings suggest that, when mediated by EGFR, AEYLR may be a potentially safe and efficient delivery ligand for targeted chemotherapy, radiotherapy, and gene therapy. Keywords: EGFR, small peptide, tumor targeting, lung cancer, NLC

Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy.

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Dharmawardana, Pathirage G; Peruzzi, Benedetta; Giubellino, Alessio; Burke, Terrence R; Bottaro, Donald P

2006-01-01

Growth factor receptor-bound 2 (Grb2) is a ubiquitously expressed adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. As such, it has been implicated in the oncogenesis of several important human malignancies. In addition to this function, research over the last decade has revealed other fundamental roles for Grb2 in cell motility and angiogenesis--processes that also contribute to tumor growth, invasiveness and metastasis. This functional profile makes Grb2 a high priority target for anti-cancer drug development. Knowledge of Grb2 protein structure, its component Src homology domains and their respective structure-function relationships has facilitated the rapid development of sophisticated drug candidates that can penetrate cells, bind Grb2 with high affinity and potently antagonize Grb2 signaling. These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics.

A novel mouse monoclonal antibody targeting ErbB2 suppresses breast cancer growth

Energy Technology Data Exchange (ETDEWEB)

Kawa, Seiji [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan); Matsushita, Hirohisa; Ohbayashi, Hirokazu [Department of Research and Development, Nichirei Biosciences Inc., Tokyo 104-8402 (Japan); Semba, Kentaro [Department of Life Science and Medical Bio-Science, School of Science and Engineering, Waseda University, Tokyo 169-8555 (Japan); Yamamoto, Tadashi, E-mail: tyamamot@ims.u-tokyo.ac.jp [Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639 (Japan)

2009-07-03

Overexpression of ErbB2 in breast cancer is associated with increased recurrence and worse prognosis. Accumulating evidences suggest that molecular targeted therapy is a promising anticancer strategy. In this study, we produced a novel anti-ErbB2 monoclonal antibody, 6G10, that recognized an epitope distinct from the trastuzumab binding site. 6G10 induced aggregation of BT474 breast cancer cells and inhibited proliferation of various breast cancer cell lines including BT474. A growth inhibition assay showed that 6G10 had EC{sub 50} values comparable to trastuzumab, indicating that the drugs have a similar level of potency. Furthermore, intraperitoneal administration of 6G10 completely inhibited the growth of xenografted tumors derived from BT474 and SK-BR-3 cells. These data suggested that 6G10 has great therapeutic potential and could be administered to patients alternatively, or synergistically, with trastuzumab.

FGFR a promising druggable target in cancer: Molecular biology and new drugs.

Science.gov (United States)

Porta, Rut; Borea, Roberto; Coelho, Andreia; Khan, Shahanavaj; Araújo, António; Reclusa, Pablo; Franchina, Tindara; Van Der Steen, Nele; Van Dam, Peter; Ferri, Jose; Sirera, Rafael; Naing, Aung; Hong, David; Rolfo, Christian

2017-05-01

The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations. Copyright © 2017 Elsevier B.V. All rights reserved.

The use of stored carbon reserves in growth of temperate tree roots and leaf buds: Analyses using radiocarbon measurements and modeling

Energy Technology Data Exchange (ETDEWEB)

Gaudinski, J.B.; Torn, M.S.; Riley, W.J.; Swanston, C.; Trumbore, S.E.; Joslin, J.D.; Majdi, H.; Dawson, T.E.; Hanson, P.J.

2009-02-01

Characterizing the use of carbon (C) reserves in trees is important for understanding regional and global C cycles, stress responses, asynchrony between photosynthetic activity and growth demand, and isotopic exchanges in studies of tree physiology and ecosystem C cycling. Using an inadvertent, whole-ecosystem radiocarbon ({sup 14}C) release in a temperate deciduous oak forest and numerical modeling, we estimated that the mean age of stored C used to grow both leaf buds and new roots is 0.7 years and about 55% of new-root growth annually comes from stored C. Therefore, the calculated mean age of C used to grow new-root tissue is {approx}0.4 years. In short, new roots contain a lot of stored C but it is young in age. Additionally, the type of structure used to model stored C input is important. Model structures that did not include storage, or that assumed stored and new C mixed well (within root or shoot tissues) before being used for root growth, did not fit the data nearly as well as when a distinct storage pool was used. Consistent with these whole-ecosystem labeling results, the mean age of C in new-root tissues determined using 'bomb-{sup 14}C' in three additional forest sites in North America and Europe (one deciduous, two coniferous) was less than 1-2 years. The effect of stored reserves on estimated ages of fine roots is unlikely to be large in most natural abundance isotope studies. However, models of root C dynamics should take stored reserves into account, particularly for pulse-labeling studies and fast-cycling roots (<1 years).

The Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin.

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Margret H Bülow

2010-12-01

Full Text Available Forkhead transcription factors of the FoxO subfamily regulate gene expression programs downstream of the insulin signaling network. It is less clear which proteins mediate transcriptional control exerted by Target of rapamycin (TOR signaling, but recent studies in nematodes suggest a role for FoxA transcription factors downstream of TOR. In this study we present evidence that outlines a similar connection in Drosophila, in which the FoxA protein Fork head (FKH regulates cellular and organismal size downstream of TOR. We find that ectopic expression and targeted knockdown of FKH in larval tissues elicits different size phenotypes depending on nutrient state and TOR signaling levels. FKH overexpression has a negative effect on growth under fed conditions, and this phenotype is not further exacerbated by inhibition of TOR via rapamycin feeding. Under conditions of starvation or low TOR signaling levels, knockdown of FKH attenuates the size reduction associated with these conditions. Subcellular localization of endogenous FKH protein is shifted from predominantly cytoplasmic on a high-protein diet to a pronounced nuclear accumulation in animals with reduced levels of TOR or fed with rapamycin. Two putative FKH target genes, CG6770 and cabut, are transcriptionally induced by rapamycin or FKH expression, and silenced by FKH knockdown. Induction of both target genes in heterozygous TOR mutant animals is suppressed by mutations in fkh. Furthermore, TOR signaling levels and FKH impact on transcription of the dFOXO target gene d4E-BP, implying a point of crosstalk with the insulin pathway. In summary, our observations show that an alteration of FKH levels has an effect on cellular and organismal size, and that FKH function is required for the growth inhibition and target gene induction caused by low TOR signaling levels.

Effects of sex change on the implications of marine reserves for fisheries.

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Chan, Neil C S; Connolly, Sean R; Mapstone, Bruce D

2012-04-01

Marine reserves have become widely used in biodiversity conservation and are increasingly proposed as fisheries management tools. Previous modeling studies have found that reserves may increase or decrease yields, depending on local environmental conditions and on the specific life-history traits of the fishery species. Sex-changing (female-to-male) fish are targets of some of the most important commercial and recreational fisheries in the world. The potential for disproportionate removal of the larger, older sex of such species requires new theory to facilitate our understanding of how reserves will affect the yields of surrounding fisheries, relative to fishes with separate sexes. We investigated this question by modeling the effects of marine reserves on a non-sex-changing and a sex-changing population. We used demographic parameter estimates for the common coral trout as a baseline, and we conducted extensive sensitivity analyses to determine how sustainable yields of sex-changing species are likely to be affected by reserves across a broad range of life-history parameters. Our findings indicate that fisheries for sex-changing species are unlikely to receive the same yield-enhancing benefit that non-sex-changing fisheries enjoy from marine reserves, and that often reserves tend to reduce sustainable yields for a given overall population size. Specifically, the increased egg production and high fertilization success within reserves is more than offset by the reduced egg production and fertilization success in the fished areas, relative to a system in which fishing mortality is distributed more evenly over the entire system. A key reason for this appears to be that fertilization success is reduced, on average, when males are unevenly distributed among subpopulations, as is the case when reserves are present. These findings suggests that, for sex-changing populations, reserves are more suited to rebuilding overfished populations and sustaining fishery viability

Prioritizing plant defence over growth through WRKY regulation facilitates infestation by non-target herbivores

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Li, Ran; Zhang, Jin; Li, Jiancai; Zhou, Guoxin; Wang, Qi; Bian, Wenbo; Erb, Matthias; Lou, Yonggen

2015-01-01

Plants generally respond to herbivore attack by increasing resistance and decreasing growth. This prioritization is achieved through the regulation of phytohormonal signaling networks. However, it remains unknown how this prioritization affects resistance against non-target herbivores. In this study, we identify WRKY70 as a specific herbivore-induced, mitogen-activated protein kinase-regulated rice transcription factor that physically interacts with W-box motifs and prioritizes defence over growth by positively regulating jasmonic acid (JA) and negatively regulating gibberellin (GA) biosynthesis upon attack by the chewing herbivore Chilo suppressalis. WRKY70-dependent JA biosynthesis is required for proteinase inhibitor activation and resistance against C. suppressalis. In contrast, WRKY70 induction increases plant susceptibility against the rice brown planthopper Nilaparvata lugens. Experiments with GA-deficient rice lines identify WRKY70-dependent GA signaling as the causal factor in N. lugens susceptibility. Our study shows that prioritizing defence over growth leads to a significant resistance trade-off with important implications for the evolution and agricultural exploitation of plant immunity. DOI: http://dx.doi.org/10.7554/eLife.04805.001 PMID:26083713

Status of fossil fuel reserves

International Nuclear Information System (INIS)

Laherrere, J.

2005-01-01

Reserves represent the sum of past and future productions up to the end of production. In most countries the reserve data of fields are confidential. Therefore, fossil fuel reserves are badly known because the published data are more political than technical and many countries make a confusion between resources and reserves. The cumulated production of fossil fuels represents only between a third and a fifth of the ultimate reserves. The production peak will take place between 2020 and 2050. In the ultimate reserves, which extrapolate the past, the fossil fuels represent three thirds of the overall energy. This document analyses the uncertainties linked with fossil fuel reserves: reliability of published data, modeling of future production, comparison with other energy sources, energy consumption forecasts, reserves/production ratio, exploitation of non-conventional hydrocarbons (tar sands, extra-heavy oils, bituminous shales, coal gas, gas shales, methane in overpressure aquifers, methane hydrates), technology impacts, prices impact, and reserves growth. (J.S.)

Pannus growth regulators as potential targets for biological therapy in rheumatoid arthritis

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A. S. Mikhaylova

2018-01-01

Full Text Available The main goal of treatment for rheumatoid arthritis (RA is to suppress inflammation using basic and symptomatic therapies. At the same time, the above strategy does not significantly stop joint  destruction that leads to disability in patients. The review analyzes  publications dealing with a search for intercellular interaction  regulators among the main effector cells in the pannus – fibroblast- like synoviocytes (FLSs. It assesses the influence of FLS aggression  factors on invasive pannus behavior, the possibility of their targeted deactivation during biological therapy, and the preliminary  results of similar treatment by the examples of animal models. It is  shown that the most promising targets for biological therapy may be FLS adhesion molecules, such as transmembrane receptor cadherin  11, integrins α5/β1, and VCAM1, ICAM1, which actively participate in the attachment of FLSs to the cartilage surface and activate their production of cytokines, growth factors and aggression factors.

Impact of water stress on growth reserves and re-growth of Themeda ...

African Journals Online (AJOL)

Four water stress treatments (T1 = 0–25%, T2 = 25–50%, T3 = 50–75% and T4 = 75–100% depletion of plant available water) were applied to the plants in pots in a glasshouse. The TNCC declined drastically after severe defoliation over all the water treatments (P < 0.05), in all the plant parts (P < 0.05) and for all the growth ...

Long-term effect of carbohydrate reserves on growth and reproduction of Prosopis denudans (Fabaceae): implications for conservation of woody perennials

Science.gov (United States)

Vilela, Alejandra E.; Agüero, Paola R.; Ravetta, Damián; González-Paleo, Luciana

2016-01-01

Prosopis denudans, an extreme xerophyte shrub, is consumed by ungulates and threatened by firewood gathering, because it is one of the preferred species used by Mapuche indigenous people of Patagonia. In a scenario of uncontrolled use of vegetation, it is very difficult to develop a conservation plan that jointly protects natural resources and its users. We performed a field experiment to assess the impact of defoliation on growth, reproduction and stores of a wild population of P. denudans. We imposed four levels of defoliation (removal of 100, 66, 33 and 0% of leaves) and evaluated the short- and long-term (3 years) effects of this disturbance. Seasonal changes in shoot carbohydrates suggested that they support leaf-flush and blooming. Severely defoliated individuals also used root reserves to support growth and leaf-flush after clipping. Vegetative growth was not affected by defoliation history. Leaf mass area increased after the initial clipping, suggesting the development of structural defenses. The depletion of root reserves at the end of the first year affected inflorescence production the following spring. We conclude that P. denudans shrubs could lose up to one-third of their green tissues without affecting growth or inflorescence production. The removal of a higher proportion of leaves will diminish stores, which in turn, will reduce or completely prevent blooming and, therefore, fruit production the following seasons. Very few studies integrate conservation and plant physiology, and we are not aware, so far, of any work dealing with long-term plant carbon economy of a long-lived perennial shrub as an applied tool in conservation. These results might help the development of management strategies that consider both the use and the conservation of wild populations of P. denudans. PMID:27293747

miRNA and Degradome Sequencing Reveal miRNA and Their Target Genes That May Mediate Shoot Growth in Spur Type Mutant “Yanfu 6”

Science.gov (United States)

Song, Chunhui; Zhang, Dong; Zheng, Liwei; Zhang, Jie; Zhang, Baojuan; Luo, Wenwen; Li, Youmei; Li, Guangfang; Ma, Juanjuan; Han, Mingyu

2017-01-01

The spur-type growth habit in apple trees is characterized by short internodes, increased number of fruiting spurs, and compact growth that promotes flowering and facilitates management practices, such as pruning. The molecular mechanisms responsible for regulating spur-type growth have not been elucidated. In the present study, miRNAs and the expression of their potential target genes were evaluated in shoot tips of “Nagafu 2” (CF) and spur-type bud mutation “Yanfu 6” (YF). A total of 700 mature miRNAs were identified, including 202 known apple miRNAs and 498 potential novel miRNA candidates. A comparison of miRNA expression in CF and YF revealed 135 differentially expressed genes, most of which were downregulated in YF. YF also had lower levels of GA, ZR, IAA, and ABA hormones, relative to CF. Exogenous applications of GA promoted YF shoot growth. Based on the obtained results, a regulatory network involving plant hormones, miRNA, and their potential target genes is proposed for the molecular mechanism regulating the growth of YF. miRNA164, miRNA166, miRNA171, and their potential targets, and associated plant hormones, appear to regulate shoot apical meristem (SAM) growth. miRNA159, miRNA167, miRNA396, and their potential targets, and associated plant hormones appear to regulate cell division and internode length. This study provides a foundation for further studies designed to elucidate the mechanism underlying spur-type apple architecture. PMID:28424721

Hepatoma-derived growth factor: A survival-related protein in prostate oncogenesis and a potential target for vitamin K2.

Science.gov (United States)

Shetty, Aditya; Dasari, Subramanyam; Banerjee, Souresh; Gheewala, Taher; Zheng, Guoxing; Chen, Aoshuang; Kajdacsy-Balla, Andre; Bosland, Maarten C; Munirathinam, Gnanasekar

2016-11-01

Hepatoma-derived growth factor (HDGF) is a heparin-binding growth factor, which has previously been shown to be expressed in a variety of cancers. HDGF overexpression has also previously been correlated with a poor prognosis in several cancers. The significance of HDGF in prostate cancer, however, has not been investigated. Here, we show that HDGF is overexpressed in both androgen-sensitive LNCaP cells and androgen-insensitive DU145, 22RV1, and PC-3 cells. Forced overexpression enhanced cell viability of RWPE-1 cells, whereas HDGF knockdown reduced cell proliferation in human prostate cancer cells. We also show that HDGF may serve as a survival-related protein as ectopic overexpression of HDGF in RWPE cells up-regulated the expression of antiapoptosis proteins cyclin E and BCL-2, whereas simultaneously down-regulating proapoptotic protein BAX. Western blot analysis also showed that HDGF overexpression modulated the activity of phospho-AKT as well as NF-kB, and these results correlated with in vitro migration and invasion assays. We next assessed the therapeutic potential of HDGF inhibition with a HDGF monoclonal antibody and vitamin k 2 , showing reduced cell proliferation as well as inhibition of NF-kB expression in HDGF overexpressed RWPE cells treated with a HDGF monoclonal antibody and vitamin K 2 . Collectively, our results suggest that HDGF is a relevant protein in prostate oncogenesis and may serve as a potential therapeutic target in prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice

DEFF Research Database (Denmark)

Kamoun, Walid S; Ley, Carsten D; Farrar, Christian T

2009-01-01

anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. METHODS: We treated...... mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis...... by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation -- as measured by MRI and by dry/wet weight measurement of water content -- but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage...

Targeting S100P Inhibits Colon Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference and Proteomic Analysis

Science.gov (United States)

Jiang, Lei; Lai, Yiu-Kay; Zhang, Jinfang; Wang, Hua; Lin, Marie CM; He, Ming-liang; Kung, Hsiang-fu

2011-01-01

S100P was recently found to be overexpressed in a variety of cancers and is considered a potential target for cancer therapy, but the functional role or mechanism of action of S100P in colon cancer is not fully understood. In the present study, we knocked down the gene expression of S100P in colon cancer cells using lentivirus-mediated RNA interference. This step resulted in significant inhibition of cancer cell growth, migration and invasion in vitro and tumor growth and liver metastasis in vivo. Moreover, S100P downstream target proteins were identified by proteomic analysis in colon cancer DLD-1 cells with deletion of S100P. Knockdown of S100P led to downregulation of thioredoxin 1 and β-tubulin and upregulation of Rho guanosine diphosphate (GDP) dissociation inhibitor α (RhoGDIA), all potential therapeutic targets in cancer. Taken together, these findings suggest that S100P plays an important role in colon tumorigenesis and metastasis, and the comprehensive and comparative analyses of proteins associated with S100P could contribute to understanding the downstream signal cascade of S100P, leading to tumorigenesis and metastasis. PMID:21327297

Growth Defects in the Dorsal Pallium after Genetically Targeted Ablation of Principal Preplate Neurons and Neuroblasts: A Morphometric Analysis

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Robin Fisher

2010-09-01

Full Text Available The present study delineates the large-scale, organic responses of growth in the dorsal pallium to targeted genetic ablations of the principal PP (preplate neurons of the neocortex. Ganciclovir treatment during prenatal development [from E11 (embryonic age 11 to E13] of mice selectively killed cells with shared S-phase vulnerability and targeted expression of a GPT [golli promoter transgene; GPT linked to HSV-TK (herpes simplex virus-thymidine kinase, τ-eGFP and lacZ reporters] localized in PP neurons and their intermediate progenitor neuroblasts. The volume, area and thickness of the pallium were measured in an E12-P4 (postnatal age 4 longitudinal study with comparisons between ablated (HSV-TK+/0 and control (HSV-TK0/0 littermates. The extent of ablations was also systematically varied, and the effect on physical growth was assessed in an E18 cross-sectional study. The morphological evidence obtained in the present study supports the conclusion that genetically targeted ablations delay the settlement of the principal PP neurons of the dorsal pallium. This leads to progressive and substantial reductions of growth, despite compensatory responses that rapidly replace the ablated cells. These growth defects originate from inductive cellular interactions in the proliferative matrix of the ventricular zone of the pallium, but are amplified by subsequent morphogenic and trophic cellular interactions. The defects persist during the course of prenatal and postnatal development to demonstrate a constrained dose-response relationship with the extent of specific killing of GPT neurons. The defects propagate simultaneously in both the horizontal and vertical cytoarchitectural dimensions of the developing pallium, an outcome that produces a localized shortfall of volume in the telencephalic vesicles.

Tree Nonstructural Carbohydrate Reserves Across Eastern US Temperate Forests

Science.gov (United States)

Mantooth, J.; Dietze, M.

2015-12-01

Understanding the roles, importance, and dynamics of tree non-structural carbohydrates (NSCs) is currently an active area of research. The question of how the relationships between NSCs, growth, and mortality can be used to develop more accurate projections of forest dynamics is central to this research. To begin to address this question, we have asked an even more fundamental question: How much are trees allocating carbon to storage, in the form of NSCs, versus new growth? Ecological theory predicts that there should be trade-offs between different plant life history strategies provided that there are the carbon mass-balance constraints to enforce these trade-offs. Current data on tree NSCs lack the spatial and taxonomic extent required to properly address this question. Therefore, we established a network of forest inventory plots at ten sites across the eastern US and measured growth in adult trees using increment cores and repeat measures of diameter at breast height (DBH). Increment cores were also used to measure sapwood NSCs. We hypothesized that across the eastern US, shade tolerant species, e.g. Sugar Maple (Acer saccharum) have the largest NSC reserves and that shade intolerant species have the lowest reserves. We also hypothesized that NSC reserves increase with temperature and precipitation, as with growth, and that within species NSC reserves increase with growth rate. Initial analyses of tree NSCs indicates that trees of intermediate shade tolerance, e.g. Red Oak (Quercus rubra) have the highest concentrations of sapwood NSCs, and among the highest growth rates. Across the entire study region, NSC concentrations are positively correlated with tree size and growth rate. Within species, NSC concentrations are also positively correlated with growth rate. Across functional groups healthy individuals have significantly higher sapwood NSC concentrations than visibly stressed individuals. There are also significantly lower NSC concentrations in sapwood of

Inflation Targeting and Quantitative Tightening: Effects of Reserve Requirements in Peru

OpenAIRE

Adrián Armas; Paul Castillo; Marco Vega

2014-01-01

This paper provides an overview of the reserve requirement measures undertaken by the Central Bank of Peru. It provides a rationale for the use of these instruments as well as empirical evidence of their effectiveness. In general, the results show that tightening reserve requirements has the desired effects on interest rates and credit levels at both banks and smaller financial institutions (cajas municipales).

Targeting Insulin and Insulin-Like Growth Factor Pathways in Epithelial Ovarian Cancer

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Marie-Claude Beauchamp

2010-01-01

Full Text Available Ovarian cancer is the most lethal of all gynecological malignancies, due in part to the diagnosis at an advanced stage caused by the lack of specific signs and symptoms and the absence of reliable tests for screening and early detection. Most patients will respond initially to treatment but about 70% of them will suffer a recurrence. Therefore, new therapeutic modalities are urgently needed to overcome chemoresistance observed in ovarian cancer patients. Evidence accumulates suggesting that the insulin/insulin growth factor (IGF pathways could act as a good therapeutic target in several cancers, including ovarian cancer. In this paper, we will focus on the role of insulin/IGF in ovarian cancer tumorigenesis and treatment.

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

Science.gov (United States)

Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

2017-09-18

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

microRNA-495 promotes bladder cancer cell growth and invasion by targeting phosphatase and tensin homolog

International Nuclear Information System (INIS)

Tan, Mingyue; Mu, Xingyu; Liu, Zhihong; Tao, Le; Wang, Jun; Ge, Jifu; Qiu, Jianxin

2017-01-01

Accumulating evidence has linked deregulation of microRNA-495 (miR-495) to tumorigenesis; however, its function in tumor progression is controversial. This work was undertaken to explore the expression and biological roles of miR-495 in bladder cancer. The expression of miR-495 was examined in 67 pairs of bladder cancer and adjacent normal bladder tissues. The roles of miR-495 in bladder cancer cell proliferation and invasion in vitro and tumorigenesis in vivo were determined. Direct target gene(s) mediating the activity of miR-495 in bladder cancer cells was identified. It was found that miR-495 was expressed at greater levels in bladder tissues and cell lines. High expression of miR-495 was significantly associated with larger tumor size, advanced TNM stage, and lymph node metastasis. Overexpression of miR-495 significantly promoted bladder cancer cell proliferation and invasion, whereas inhibition of miR-495 suppressed cell proliferation and invasion. PTEN, a well-defined tumor suppressor was identified to be a target gene of miR-495. A significant inverse correlation between miR-495 and PTEN expression was noted in bladder cancer tissues (r = −0.3094, P = 0.0125). Overexpression of miR-495 led to reduction of PTEN expression in bladder cancer cells. Rescue experiments showed that enforced expression of PTEN impaired miR-495-mediated bladder cancer proliferation and invasion. In vivo mouse studies demonstrated that overexpression of miR-495 accelerated the growth of subcutaneous bladder cancer xenografts, which was associated with downregulation of PTEN. Overall, these findings indicate that miR-495 upregulation contributes to bladder cancer cell growth, invasion, and tumorigenesis by targeting PTEN and offer a potential therapeutic target for bladder cancer. - Highlights: • miR-495 upregulation induces aggressive phenotype in bladder cancer. • miR-495 is inversely correlated with PTEN in bladder cancer. • miR-495 promotes bladder cancer cell

MicroRNA-338 inhibits growth, invasion and metastasis of gastric cancer by targeting NRP1 expression.

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Yang Peng

Full Text Available NRP1 as multifunctional non-tyrosine-kinase receptors play critical roles in tumor progression. MicroRNAs (miRNAs are an important class of pervasive genes that are involved in a variety of biological functions, particularly cancer. It remains unclear whether miRNAs can regulate the expression of NRP1. The goal of this study was to identify miRNAs that could inhibit the growth, invasion and metastasis of gastric cancer by targeting NRP1 expression. We found that miR-338 expression was reduced in gastric cancer cell lines and in gastric cancer tissues. Moreover, we found that miR-338 inhibited gastric cancer cell migration, invasion, proliferation and promoted apoptosis by targeting NRP1 expression. As an upstream regulator of NRP1, miR-338 directly targets NRP1. The forced expression of miR-338 inhibited the phosphorylation of Erk1/2, P38 MAPK and Akt; however, the expression of phosphorylated Erk1/2, P38 MAPK and Akt was restored by the overexpression of NRP1. In AGS cells infected with miR-338 or transfected with SiNRP1, the protein levels of fibronectin, vimentin, N-cadherin and SNAIL were decreased, but the expression of E-cadherin was increased. The expression of mesenchymal markers in miR-338-expressing cells was restored to normal levels by the restoration of NRP1 expression. In vivo, miR-338 also decreased tumor growth and suppressed D-MVA by targeting NRP1. Therefore, we conclude that miR-338 acts as a novel tumor suppressor gene in gastric cancer. miR-338 can decrease migratory, invasive, proliferative and apoptotic behaviors, as well as gastric cancer EMT, by attenuating the expression of NRP1.

MicroRNA 128a increases intracellular ROS level by targeting Bmi-1 and inhibits medulloblastoma cancer cell growth by promoting senescence.

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Sujatha Venkataraman

Full Text Available BACKGROUND: MicroRNAs (miRNAs are a class of short non-coding RNAs that regulate cell homeostasis by inhibiting translation or degrading mRNA of target genes, and thereby can act as tumor suppressor genes or oncogenes. The role of microRNAs in medulloblastoma has only recently been addressed. We hypothesized that microRNAs differentially expressed during normal CNS development might be abnormally regulated in medulloblastoma and are functionally important for medulloblastoma cell growth. METHODOLOGY AND PRINCIPAL FINDINGS: We examined the expression of microRNAs in medulloblastoma and then investigated the functional role of one specific one, miR-128a, in regulating medulloblastoma cell growth. We found that many microRNAs associated with normal neuronal differentiation are significantly down regulated in medulloblastoma. One of these, miR-128a, inhibits growth of medulloblastoma cells by targeting the Bmi-1 oncogene. In addition, miR-128a alters the intracellular redox state of the tumor cells and promotes cellular senescence. CONCLUSIONS AND SIGNIFICANCE: Here we report the novel regulation of reactive oxygen species (ROS by microRNA 128a via the specific inhibition of the Bmi-1 oncogene. We demonstrate that miR-128a has growth suppressive activity in medulloblastoma and that this activity is partially mediated by targeting Bmi-1. This data has implications for the modulation of redox states in cancer stem cells, which are thought to be resistant to therapy due to their low ROS states.

Dynamic contents of energy and organic nutrient in steppe growths of the Mohelenská Serpentine Steppe National Nature Reserve

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Pavel Veselý

2006-01-01

Full Text Available The aim of the study was to determine the dynamics in the content of organic nutrients, ash and energy in dry matter of growths within the Mohelenská Serpentine Steppe National Nature Reserve (NPR, and to document their initial nutritive value before the intended grazing. Plant samples in 1995 and 1996 during the growing season in 14-days intervals from the area of 3 × 1 m2. Amounts of dry matter, fibre, nitrogen substances, fat and ashes were determined in growths according to the ANONYM (2001. Nitrogen-free extract substances (BNLV were determined by final calculating; BE, ME, NEL, NEV, PDIN and PDIE were calculated using the regression equations (VESELÝ and ZEMAN, 1995, 1997. Combining ratio (SP was calculated according to the relation: SP = PDIN (g/NEL (MJ. The dynamics of the contents of dry matter, organic nutrients, ashes and energy were assessed in the growth during the vegetation period and the dynamics was compared with standardized requirements of sheep (no pregnant ewe. Regression and correlation relations for nutrition value of the growths during vegetation period were calculated by use of mathematical-statistical analysis. Only statistically significantly (P<0.05 different parameters form the zero are presented in the paper. The content of dry matter in the growths culminated in summer months (places D8, E13, B17 and it was accompanied by depression in autumn months. After the highest content of crude protein, PDIN and PDIE recorded in spring months summer depression (August followed, this depression was partly balanced by autumn growth of vegetation. The content of ash in steppe growths increased during evaluated period. Similar tendency was registered for fat. Also the contents of fibre and BNLV linearly increased. The contents of nitrogen nutrients and energy corresponded with standardized requirements for sheep during whole vegetation period. Conversely the content of fibre highly exceeded the requirement except in spring

Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth.

Science.gov (United States)

Lu, Hongbo; Kojima, Kensuke; Battula, Venkata Lokesh; Korchin, Borys; Shi, Yuexi; Chen, Ye; Spong, Suzanne; Thomas, Deborah A; Kantarjian, Hagop; Lock, Richard B; Andreeff, Michael; Konopleva, Marina

2014-03-01

Connective tissue growth factor (CTGF/CCN2) is involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in precursor B-acute lymphoblastic leukemia (ALL) and that increased expression of CTGF is associated with inferior outcome in B-ALL. In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knockdown CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA. Silencing of CTGF resulted in significant suppression of leukemia cell growth compared to control vector, which was associated with AKT/mTOR inactivation and increased levels of cyclin-dependent kinase inhibitor p27. CTGF knockdown sensitized ALL cells to vincristine and methotrexate. Treatment with an anti-CTGF monoclonal antibody, FG-3019, significantly prolonged survival of mice injected with primary xenograft B-ALL cells when co-treated with conventional chemotherapy (vincristine, L-asparaginase and dexamethasone). Data suggest that CTGF represents a targetable molecular aberration in B-ALL, and blocking CTGF signaling in conjunction with administration of chemotherapy may represent a novel therapeutic approach for ALL patients.

Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

Science.gov (United States)

Ma, Shao; Yin, Ning; Qi, Xiaomei; Pfister, Sandra L; Zhang, Mei-Jie; Ma, Rong; Chen, Guan

2015-05-30

Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.

MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2

Energy Technology Data Exchange (ETDEWEB)

Xia, Ying; Gao, Yan, E-mail: gaoyanhdhos@126.com

2014-05-09

Highlights: • miR-181b is upregulated in human ovarian cancer tissues. • miR-181b promotes ovarian cancer cell proliferation and invasion. • LATS2 is a direct target of miR-181b. • LATS2 is involved in miR-181b-induced ovarian cancer cell growth and invasion. - Abstract: MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (large tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3′-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer.

Autophagy as a potential target for sarcoma treatment.

Science.gov (United States)

Min, Li; Choy, Edwin; Pollock, Raphael E; Tu, Chongqi; Hornicek, Francis; Duan, Zhenfeng

2017-08-01

Autophagy is a constitutively active, evolutionary conserved, catabolic process for maintaining homeostasis in cellular stress responses and cell survival. Although its mechanism has not been fully illustrated, recent work on autophagy in various types of sarcomas has demonstrated that autophagy exerts an important role in sarcoma cell growth and proliferation, in pro-survival response to therapies and stresses, and in therapeutic resistance of sarcoma. Thus, the autophagic process is being seen as a possibly novel therapeutic target of sarcoma. Additionally, some co-regulators of autophagy have also been investigated as promising biomarkers for the diagnosis and prognosis of sarcoma. In this review, we summarize contemporary advances in the role of autophagy in sarcoma and discuss the potential of autophagy as a new target for sarcoma treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Preconditions for Introduction and Prospects for Implementation of the Inflation Targeting Regime in Ukraine

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Hladkykh Dmytro M.

2017-07-01

Full Text Available The article is aimed at studying the preconditions for introduction, the main problems and prospects for implementation of the inflation targeting regime in Ukraine. In 2014, the country got into a crisis that affected at once the currency market, the banking system and the real sector, resulting in devaluations, bank failures, decreasing GDP, growing prices. One of the responses to the financial challenges was the transition to inflationary targeting, which led to a slowdown in inflation in 2016-2017. Goals of an inflation targeting are both price growth and international reserves. Achieving these goals implies a policy of «expensive money», exclusive smoothing by interventions of excessive fluctuations, lack of fiscal dominance, prudent fiscal policies, and elimination of quasi-fiscal imbalances. The risks of current monetary policy are the slow implementation of reforms, which can stop external lending, «pre-election» increases in social spending, debt burden growth, and the escalation of hostilities in the east of the country. Further actions by the State should include: minimization of monetary emissions, further reduction of the interest rate, providing the positive level of rates by the National Bank of Ukraine in terms of inflation, increased use of compulsory reservation of the funds involved, restriction of sales of domestic bonds and the NBU certificates to banks.

Downregulation of miR-497 promotes tumor growth and angiogenesis by targeting HDGF in non-small cell lung cancer

International Nuclear Information System (INIS)

Zhao, Wen-yan; Wang, Yan; An, Zhong-jun; Shi, Chang-guo; Zhu, Guang-ai; Wang, Bin; Lu, Ming-yan; Pan, Chang-kun; Chen, Peng

2013-01-01

Highlights: •MiR-497 is down-regulated in NSCLC cells and tissues. •MiR-497 inhibits NSCLC cell growth in vitro. •HDGF is a target gene of miR-497. •MiR-497 inhibits NSCLC cell growth by downregulating HDGF. •miR-497 inhibits tumor growth and angiogenesis in vivo. -- Abstract: MicroRNAs (miRNAs) play important roles in the development of various cancers. MiRNA-497 functions as a tumor-suppressor that is downregulated in several malignancies; however, its role in non-small cell lung cancer (NSCLC) has not been examined in detail. Here, we showed that miR-497 is downregulated in NSCLC tumors and cell lines and its ectopic expression significantly inhibits cell proliferation and colony formation. Integrated analysis identified HDGF as a downstream target of miR-497, and the downregulation of HDGF by miR-497 overexpression confirmed their association. Rescue experiments showed that the inhibitory effect of miR-497 on cell proliferation and colony formation is predominantly mediated by the modulation of HDGF levels. Furthermore, tumor samples from NSCLC patients showed an inverse relationship between miR-497 and HDGF levels, and ectopic expression of miR-497 significantly inhibited tumor growth and angiogenesis in a SCID mouse xenograft model. Our results suggest that miR-497 may serve as a biomarker in NSCLC, and the modulation of its activity may represent a novel therapeutic strategy for the treatment of NSCLC patients

Can the Growth/Differentiation Factor-15 Be a Surrogate Target in Chronic Heart Failure Biomarker-Guided Therapy?

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Alexander E. Berezin

2017-03-01

Full Text Available Heart failure (HF biomarker-guided therapy is a promising method, which directs to the improvement of clinical status, attenuation of admission/readmission to the hospital and reduction in mortality rate. Many biological markers, like inflammatory cytokines, are under consideration as a surrogate target for HF treatment, while there are known biomarkers with established predictive value, such as natriuretic peptides. However, discovery of new biomarkers reflecting various underlying mechanisms of HF and appearing to be surrogate targets for biomarker-guided therapy is fairly promising. Nowadays, growth/differentiation factor 15 (GDF-15 is suggested a target biomarker for HF treatment. Although elevated level of GDF-15 is associated with HF development, progression, and prognosis, there is no represented evidence regarding the direct comparison of this biomarker with other clinical risk predictors and biomarkers. Moreover, GDF-15 might serve as a contributor to endothelial progenitor cells (EPC dysfunction by inducing EPC death/autophagy and limiting their response to angiopoetic and reparative effects. The short communication was discussed whether GDF-15 is good molecular target for HF biomarker-guided therapy.

Restoration of Degraded Soil in the Nanmangalam Reserve Forest with Native Tree Species: Effect of Indigenous Plant Growth-Promoting Bacteria.

Science.gov (United States)

Ramachandran, Andimuthu; Radhapriya, Parthasarathy

Restoration of a highly degraded forest, which had lost its natural capacity for regeneration, was attempted in the Nanmangalam Reserve Forest in Eastern Ghats of India. In field experiment, 12 native tree species were planted. The restoration included inoculation with a consortium of 5 native plant growth-promoting bacteria (PGPB), with the addition of small amounts of compost and a chemical fertilizer (NPK). The experimental fields were maintained for 1080 days. The growth and biomass varied depending on the plant species. All native plants responded well to the supplementation with the native PGPB. The plants such as Pongamia pinnata, Tamarindus indica, Gmelina arborea, Wrightia tinctoria, Syzygium cumini, Albizia lebbeck, Terminalia bellirica, and Azadirachta indica performed well in the native soil. This study demonstrated, by using native trees and PGPB, a possibility to restore the degraded forest.

Restoration of Degraded Soil in the Nanmangalam Reserve Forest with Native Tree Species: Effect of Indigenous Plant Growth-Promoting Bacteria

Directory of Open Access Journals (Sweden)

Andimuthu Ramachandran

2016-01-01

Full Text Available Restoration of a highly degraded forest, which had lost its natural capacity for regeneration, was attempted in the Nanmangalam Reserve Forest in Eastern Ghats of India. In field experiment, 12 native tree species were planted. The restoration included inoculation with a consortium of 5 native plant growth-promoting bacteria (PGPB, with the addition of small amounts of compost and a chemical fertilizer (NPK. The experimental fields were maintained for 1080 days. The growth and biomass varied depending on the plant species. All native plants responded well to the supplementation with the native PGPB. The plants such as Pongamia pinnata, Tamarindus indica, Gmelina arborea, Wrightia tinctoria, Syzygium cumini, Albizia lebbeck, Terminalia bellirica, and Azadirachta indica performed well in the native soil. This study demonstrated, by using native trees and PGPB, a possibility to restore the degraded forest.

rights reserved Modelling Growth Kinetics of Klebsiella sp. FIRD 2

African Journals Online (AJOL)

ADOWIE PERE

... most toxic anthropogenic compounds deliberately introduced ... Due of its toxicity to marine organisms, the. International ... There are a lot of published papers describing ... The rate of bacterial growth and degradation can be represented as ...

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells

OpenAIRE

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-01-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation o...

Demand for Reserves and the Central Bank's Management of Interest Rates

OpenAIRE

Martin Schlegel; Sébastien Kraenzlin

2009-01-01

The implementation of monetary policy is prevalently done by interest rate targeting with a short term market rate serving as operational target. The instruments for achieving the operational target are the provision of reserves and the interest rate charged in these transactions. This paper presents a model for the estimation of the demand curve for reserves, derived from the central bank's fixed rate tender auction and the interbank money market. Using data from Switzerland, the slope of th...

Corruption of phage display libraries by target-unrelated clones: diagnosis and countermeasures.

Science.gov (United States)

Thomas, William D; Golomb, Miriam; Smith, George P

2010-12-15

Phage display is used to discover peptides or proteins with a desired target property-most often, affinity for a target selector molecule. Libraries of phage clones displaying diverse surface peptides are subject to a selection process designed to enrich for the target behavior and subsequently propagated to restore phage numbers. A recurrent problem is enrichment of clones, called target-unrelated phages or peptides (TUPs), that lack the target behavior. Many TUPs are propagation related; they have mutations conferring a growth advantage and are enriched during the propagations accompanying selection. Unlike other filamentous phage libraries, fd-tet-based libraries are relatively resistant to propagation-related TUP corruption. Their minus-strand origin is disrupted by a large cassette that simultaneously confers resistance to tetracycline and imposes a rate-limiting growth defect that cannot be bypassed with simple mutations. Nonetheless, a new type of propagation-related TUP emerged in the output of in vivo selections from an fd-tet library. The founding clone had a complex rearrangement that restored the minus-strand origin while retaining tetracycline resistance. The rearrangement involved two recombination events, one with a contaminant having a wild-type minus-strand origin. The founder's infectivity advantage spread by simple recombination to clones displaying different peptides. We propose measures for minimizing TUP corruption. Copyright © 2010 Elsevier Inc. All rights reserved.

miR-449 overexpression inhibits papillary thyroid carcinoma cell growth by targeting RET kinase-β-catenin signaling pathway.

Science.gov (United States)

Li, Zongyu; Huang, Xin; Xu, Jinkai; Su, Qinghua; Zhao, Jun; Ma, Jiancang

2016-10-01

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and represent approximately 80% of all thyroid cancers. The present study is aimed to investigate the role of microRNA (miR)-449 in the progression of PTC. Our results revealed that miR-449 was underexpressed in the collected PTC specimens compared with non-cancerous PTC tissues. Overexpression of miR-449 induced a cell cycle arrest at G0/G1 phase and inhibited PTC cell growth in vitro. Further studies revealed that RET proto-oncogene (RET) is a novel miR-449 target, due to miR-449 bound directly to its 3'-untranslated region and miR-449 mimic reduced the protein expression of RET. Similar to the effects of miR-449 overexpression, RET downregulation inhibited cell growth, whereas RET overexpression reversed the inhibitive effect of miR-449 mimic. Furthermore, miR-449 overexpression inhibited the nuclear translocation of β-catenin and reduced the expression of several downstream genes, including c-Myc, cyclin D1, T cell-specific transcription factor (TCF) and lymphoid enhancer-binding factor 1 (LEF-1), and inactivated the β-catenin pathway in TPC-1 cells. Moreover, overexpression of β-catenin prevented miR-449-reduced cell cycle arrest and cell viability. In xenograft animal experiments, miR-449 overexpression effectively suppressed the tumor growth of PTC. Taken together, our research indicated that miR-449 functions as an anti-oncogene by targeting RET, and that miR-449 overexpression inhibited the growth of PTC by inactivating the β-catenin pathway. Thus, miR-449 may serve as a potential therapeutic strategy for the treatment of PTC.

Nerve growth factor alters microtubule targeting agent-induced neurotransmitter release but not MTA-induced neurite retraction in sensory neurons.

Science.gov (United States)

Pittman, Sherry K; Gracias, Neilia G; Fehrenbacher, Jill C

2016-05-01

Peripheral neuropathy is a dose-limiting side effect of anticancer treatment with the microtubule-targeted agents (MTAs), paclitaxel and epothilone B (EpoB); however, the mechanisms by which the MTAs alter neuronal function and morphology are unknown. We previously demonstrated that paclitaxel alters neuronal sensitivity, in vitro, in the presence of nerve growth factor (NGF). Evidence in the literature suggests that NGF may modulate the neurotoxic effects of paclitaxel. Here, we examine whether NGF modulates changes in neuronal sensitivity and morphology induced by paclitaxel and EpoB. Neuronal sensitivity was assessed using the stimulated release of calcitonin gene-related peptide (CGRP), whereas morphology of established neurites was evaluated using a high content screening system. Dorsal root ganglion cultures, maintained in the absence or presence of NGF, were treated from day 7 to day 12 in culture with paclitaxel (300nM) or EpoB (30nM). Following treatment, the release of CGRP was stimulated using capsaicin or high extracellular potassium. In the presence of NGF, EpoB mimicked the effects of paclitaxel: capsaicin-stimulated release was attenuated, potassium-stimulated release was slightly enhanced and the total peptide content was unchanged. In the absence of NGF, both paclitaxel and EpoB decreased capsaicin- and potassium-stimulated release and the total peptide content, suggesting that NGF may reverse MTA-induced hyposensitivity. Paclitaxel and EpoB both decreased neurite length and branching, and this attenuation was unaffected by NGF in the growth media. These differential effects of NGF on neuronal sensitivity and morphology suggest that neurite retraction is not a causative factor to alter neuronal sensitivity. Copyright © 2016 Elsevier Inc. All rights reserved.

Deep sequencing of small RNA libraries from human prostate epithelial and stromal cells reveal distinct pattern of microRNAs primarily predicted to target growth factors.

Science.gov (United States)

Singh, Savita; Zheng, Yun; Jagadeeswaran, Guru; Ebron, Jey Sabith; Sikand, Kavleen; Gupta, Sanjay; Sunker, Ramanjulu; Shukla, Girish C

2016-02-28

Complex epithelial and stromal cell interactions are required during the development and progression of prostate cancer. Regulatory small non-coding microRNAs (miRNAs) participate in the spatiotemporal regulation of messenger RNA (mRNA) and regulation of translation affecting a large number of genes involved in prostate carcinogenesis. In this study, through deep-sequencing of size fractionated small RNA libraries we profiled the miRNAs of prostate epithelial (PrEC) and stromal (PrSC) cells. Over 50 million reads were obtained for PrEC in which 860,468 were unique sequences. Similarly, nearly 76 million reads for PrSC were obtained in which over 1 million were unique reads. Expression of many miRNAs of broadly conserved and poorly conserved miRNA families were identified. Sixteen highly expressed miRNAs with significant change in expression in PrSC than PrEC were further analyzed in silico. ConsensusPathDB showed the target genes of these miRNAs were significantly involved in adherence junction, cell adhesion, EGRF, TGF-β and androgen signaling. Let-7 family of tumor-suppressor miRNAs expression was highly pervasive in both, PrEC and PrSC cells. In addition, we have also identified several miRNAs that are unique to PrEC or PrSC cells and their predicted putative targets are a group of transcription factors. This study provides perspective on the miRNA expression in PrEC and PrSC, and reveals a global trend in miRNA interactome. We conclude that the most abundant miRNAs are potential regulators of development and differentiation of the prostate gland by targeting a set of growth factors. Additionally, high level expression of the most members of let-7 family miRNAs suggests their role in the fine tuning of the growth and proliferation of prostate epithelial and stromal cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth

Science.gov (United States)

Vittorio, Orazio; Brandl, Miriam; Cirillo, Giuseppe; Kimpton, Kathleen; Hinde, Elizabeth; Gaus, Katharina; Yee, Eugene; Kumar, Naresh; Duong, Hien; Fleming, Claudia; Haber, Michelle; Norris, Murray; Boyer, Cyrille; Kavallaris, Maria

2016-01-01

Neuroblastoma is frequently diagnosed at advanced stage disease and treatment includes high dose chemotherapy and surgery. Despite the use of aggressive therapy survival rates are poor and children that survive their disease experience long term side effects from their treatment, highlighting the need for effective and less toxic therapies. Catechin is a natural polyphenol with anti-cancer properties and limited side effects, however its mechanism of action is unknown. Here we report that Dextran-Catechin, a conjugated form of catechin that increases serum stability, is preferentially and markedly active against neuroblastoma cells having high levels of intracellular copper, without affecting non-malignant cells. Copper transporter 1 (CTR1) is the main transporter of copper in mammalian cells and it is upregulated in neuroblastoma. Functional studies showed that depletion of CTR1 expression reduced intracellular copper levels and led to a decrease in neuroblastoma cell sensitivity to Dextran-Catechin, implicating copper in the activity of this compound. Mechanistically, Dextran-Catechin was found to react with copper, inducing oxidative stress and decreasing glutathione levels, an intracellular antioxidant and regulator of copper homeostasis. In vivo, Dextran-Catechin significantly attenuated tumour growth in human xenograft and syngeneic models of neuroblastoma. Thus, Dextran-Catechin targets copper, inhibits tumour growth, and may be valuable in the treatment of aggressive neuroblastoma and other cancers dependent on copper for their growth. PMID:27374085

miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis.

Science.gov (United States)

Sun, Xiaojuan; Charbonneau, Cherie; Wei, Lei; Chen, Qian; Terek, Richard M

2015-09-01

Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16. Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma. ©2015 American Association for Cancer Research.

US uranium reserves

International Nuclear Information System (INIS)

Hansen, M.V.

1981-01-01

The current low level of demand, compounded by rapidly rising costs and low prices, has caused a significant reduction in drilling for uranium in the United States, and the trend is likely to continue for a few more years. The effect on uranium reserves will be fewer additions to reserves because less exploration is being done. Further reductions will occur, especially in low-cost reserves, because of increasing costs, continuing depletion through production, and erosion through the high grading of deposits to fulfill previous contractual commitments. During the past several years, it has been necessary to increase the upper reserve cost level twice to compensate for rising costs. Rising costs are reducing the $15 reserves, the cost category corresponding most closely to the present market price, to an insignificant level. An encouraging factor related to US uranium reserves is that the US position internationally, as far as quantity is concerned, is not bad for the longer term. Also, there is a general opinion that US consumers would rather contract for domestic uranium than for foreign because of greater assurance of supply. Still another factor, nearly impossible to assess, is what effect rising costs in other countries will have on their uranium reserves. The annual conferences between the Grand Junction Area Office staff and major uranium companies provide a broad overview of the industry's perception of the future. It is not optimistic for the short term. Many companies are reducing their exploration and mining programs; some are switching to other more marketable mineral commodities, and a few are investing more heavily in foreign ventures. However, there is general optimism for the long term, and many predict a growth in demand in the mid-1980s. If the industry can survive the few lean years ahead, rising prices may restore its viability to former levels

Effects of Sb-doping on the grain growth of Cu(In, Ga)Se2 thin films fabricated by means of single-target sputtering

International Nuclear Information System (INIS)

Zhang, Shu; Wu, Lu; Yue, Ruoyu; Yan, Zongkai; Zhan, Haoran; Xiang, Yong

2013-01-01

To investigate the effects of Sb doping on the kinetics of grain growth in Cu(In,Ga)Se 2 (CIGS) thin films during annealing, CIGS thin films were sputtered onto Mo coated substrates from a single CIGS alloy target, followed by chemical bath deposition of Sb 2 S 3 thin layers on top of CIGS layers and subsequent annealing at different temperatures for 30 min in Se vapors. X-ray diffraction results showed that CIGS thin films were obtained directly using the single-target sputtering method. After annealing, the In/Ga ratio in Sb-doped CIGS thin films remained stable compared to undoped film, possibly because Sb can promote the incorporation of Ga into CIGS. The grain growth in CIGS thin films was enhanced after Sb doping, exhibiting significantly larger grains after annealing at 400 °C or 450 °C compared to films without Sb. In particular, the effect was strikingly significant in grain growth across the film thickness, resulting in columnar grain structure in Sb-doped films. This grain growth improvement may be led by the diffusion of Sb from the front surface to the CIGS-Mo back interface, which promoted the mass transport process in CIGS thin films. - Highlights: ► Cu(In,Ga)Se 2 (CIGS) thin films made by sputtering from a single CIGS target. ► Chemical bath deposition used to introduce antimony into CIGS absorber layers. ► In/Ga ratio decreases in Sb-doped annealed films, comparatively to undoped films. ► Sb-doped CIGS films are superior to undoped films in terms of grain-growth kinetics

miR-409-3p suppresses breast cancer cell growth and invasion by targeting Akt1

Energy Technology Data Exchange (ETDEWEB)

Zhang, Guoqiang [Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan 250012 (China); Department of Thyroid and Breast Surgery, Hospital Affiliated to Binzhou Medical University, 661 Second Huanghe Street, Binzhou 256603 (China); Liu, Zengyan [Department of Hematology, Hospital Affiliated to Binzhou Medical University, 661 Second Huanghe Street, Binzhou 256603 (China); Xu, Hao [Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (China); Yang, Qifeng, E-mail: qifengy_sdu1@163.com [Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan 250012 (China)

2016-01-08

Altered levels and functions of microRNAs (miRNAs) are correlated with carcinogenesis. While miR-409-3p has been shown to play important roles in several cancer types, its function in the context of breast cancer (BC) remains unknown. In this study, miR-409-3p was significantly downregulated in BC tissues and cell lines, compared with the corresponding control counterparts. Overexpression of miR-409-3p inhibited BC cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Notably, miR-409-3p induced downregulation of Akt1 protein through binding to its 3′ untranslated region (UTR). Conversely, restoring Akt1 expression rescued the suppressive effects of miR-409-3p. Our data collectively indicate that miR-409-3p functions as a tumor suppressor in BC through downregulating Akt1, supporting the targeting of the novel miR-409-3p/Akt1 axis as a potentially effective therapeutic approach for BC. - Highlights: • miR-409-3p inhibits proliferation, migration and invasion of BC cells. • miR-409-3p suppresses tumor growth in nude mice. • Akt1 is a direct downstream target of miR-409-3p. • Ectopic expression of Akt1 reverses the effects of miR-409-3p on cell proliferation, migration and invasion.

Molecular Imaging of Hepatocellular Carcinoma Xenografts with Epidermal Growth Factor Receptor Targeted Affibody Probes

Directory of Open Access Journals (Sweden)

Ping Zhao

2013-01-01

Full Text Available Hepatocellular carcinoma (HCC is a highly aggressive and lethal cancer. It is typically asymptomatic at the early stage, with only 10%–20% of HCC patients being diagnosed early enough for appropriate surgical treatment. The delayed diagnosis of HCC is associated with limited treatment options and much lower survival rates. Therefore, the early and accurate detection of HCC is crucial to improve its currently dismal prognosis. The epidermal growth factor receptor (EGFR has been reported to be involved in HCC tumorigenesis and to represent an attractive target for HCC imaging and therapy. In this study, an affibody molecule, Ac-Cys-ZEGFR:1907, targeting the extracellular domain of EGFR, was used for the first time to assess its potential to detect HCC xenografts. By evaluating radio- or fluorescent-labeled Ac-Cys-ZEGFR:1907 as a probe for positron emission tomography (PET or optical imaging of HCC, subcutaneous EGFR-positive HCC xenografts were found to be successfully imaged by the PET probe. Thus, affibody-based PET imaging of EGFR provides a promising approach for detecting HCC in vivo.

Estimating Foreign Exchange Reserve Adequacy

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Abdul Hakim

2013-04-01

Full Text Available Accumulating foreign exchange reserves, despite their cost and their impacts on other macroeconomics variables, provides some benefits. This paper models such foreign exchange reserves. To measure the adequacy of foreign exchange reserves for import, it uses total reserves-to-import ratio (TRM. The chosen independent variables are gross domestic product growth, exchange rates, opportunity cost, and a dummy variable separating the pre and post 1997 Asian financial crisis. To estimate the risky TRM value, this paper uses conditional Value-at-Risk (VaR, with the help of Glosten-Jagannathan-Runkle (GJR model to estimate the conditional volatility. The results suggest that all independent variables significantly influence TRM. They also suggest that the short and long run volatilities are evident, with the additional evidence of asymmetric effects of negative and positive past shocks. The VaR, which are calculated assuming both normal and t distributions, provide similar results, namely violations in 2005 and 2008.

Novel targeted agents for gastric cancer

Directory of Open Access Journals (Sweden)

Liu Lian

2012-06-01

Full Text Available Abstract Contemporary advancements have had little impact on the treatment of gastric cancer (GC, the world’s second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs and receptor tyrosine kinase inhibitors (TKIs. Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2 gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF, mammalian target of rapamycin (mTOR, and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers.

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells12

OpenAIRE

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-01-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation ...

Kinase Screening in Pichia pastoris Identified Promising Targets Involved in Cell Growth and Alcohol Oxidase 1 Promoter (PAOX1 Regulation.

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Wei Shen

Full Text Available As one of the most commonly used eukaryotic recombinant protein expression systems, P. pastoris relies heavily on the AOX1 promoter (PAOX1, which is strongly induced by methanol but strictly repressed by glycerol and glucose. However, the complicated signaling pathways involved in PAOX1 regulation when supplemented with different carbon sources are poorly understood. Here we constructed a kinase deletion library in P. pastoris and identified 27 mutants which showed peculiar phenotypes in cell growth or PAOX1 regulation. We analyzed both annotations and possible functions of these 27 targets, and then focused on the MAP kinase Hog1. In order to locate its potential downstream components, we performed the phosphoproteome analysis on glycerol cultured WT and Δhog1 strains and identified 157 differentially phosphorylated proteins. Our results identified important kinases involved in P. pastoris cell growth and PAOX1 regulation, which could serve as valuable targets for further mechanistic studies.

Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS.

Science.gov (United States)

Sumowski, James F; Rocca, Maria A; Leavitt, Victoria M; Dackovic, Jelena; Mesaros, Sarlota; Drulovic, Jelena; DeLuca, John; Filippi, Massimo

2014-05-20

Based on the theories of brain reserve and cognitive reserve, we investigated whether larger maximal lifetime brain growth (MLBG) and/or greater lifetime intellectual enrichment protect against cognitive decline over time. Forty patients with multiple sclerosis (MS) underwent baseline and 4.5-year follow-up evaluations of cognitive efficiency (Symbol Digit Modalities Test, Paced Auditory Serial Addition Task) and memory (Selective Reminding Test, Spatial Recall Test). Baseline and follow-up MRIs quantified disease progression: percentage brain volume change (cerebral atrophy), percentage change in T2 lesion volume. MLBG (brain reserve) was estimated with intracranial volume; intellectual enrichment (cognitive reserve) was estimated with vocabulary. We performed repeated-measures analyses of covariance to investigate whether larger MLBG and/or greater intellectual enrichment moderate/attenuate cognitive decline over time, controlling for disease progression. Patients with MS declined in cognitive efficiency and memory (p improve prediction of future cognitive decline in patients with MS. © 2014 American Academy of Neurology.

Estimation of gas reserves in North America

International Nuclear Information System (INIS)

Laherrere, J.

2001-01-01

If the oil market is global, the gas market is divided into three zones: North America, Europe and Asia. The official forecast of the future demand of North America gas is optimist as it is based on estimates of resources which are ten times those of the proved reserves. The poor practice (SEC rules) of proved reserves (when the rest of the world uses proven+probable) leads to a constant revision and a growth of the past discoveries, showing well a wrong evaluation. The official databases are then very poor, even those of the US federal domain, which have to be public. The study of the technical data of reserves of US, Canada and Mexico leads to a more pessimistic estimation of the ultimate reserves and then to the future local supply. In the Gulf of Mexico (the main hope), the production of natural gas in shallow water decline and the discoveries in the deep-water are mainly oil. The non-conventional gas seems to level. But the future demand is also too optimistic, based on cheap price and on a steady growth. However the local gas supply will be likely insufficient, and the demand will need imported liquefied natural gas. (author)

Required reserves as a credit policy tool

OpenAIRE

Mimir, Yasin; Sunel, Enes; Taskin, Temel

2012-01-01

This paper conducts a quantitative investigation of the role of reserve requirements as a macroprudential policy tool. We build a monetary DSGE model with a banking sector in which (i) an agency problem between households and banks leads to endogenous capital constraints for banks in obtaining funds from households, (ii) banks are subject to time-varying reserve requirements that countercyclically respond to expected credit growth, (iii) households face cash-in-advance constraints, requiring ...

Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging.

Science.gov (United States)

Liu, Heng; Chen, Xiao; Xue, Wei; Chu, Chengchao; Liu, Yu; Tong, Haipeng; Du, Xuesong; Xie, Tian; Liu, Gang; Zhang, Weiguo

The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

Financial Security and Optimal Scale of Foreign Exchange Reserve in China

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Guangyou Zhou

2018-05-01

Full Text Available The study of how foreign exchange reserves maintain financial security is of vital significance. This paper provides simulations and estimations of the optimal scale of foreign exchange reserves under the background of possible shocks to China’s economy due to the further opening of China’s financial market and the sudden stop of capital inflows. Focused on the perspective of financial security, this article tentatively constructs an optimal scale analysis framework that is based on a utility maximization of the foreign exchange reserve, and selects relevant data to simulate the optimal scale of China’s foreign exchange reserves. The results show that: (1 the main reason for the fast growth of the Chinese foreign exchange reserve scale is the structural trouble of its double international payment surplus, which creates long-term appreciation expectations for the exchange rate that make it difficult for international capital inflows and excess foreign exchange reserves to enter the real economic growth mechanism under the model of China’s export-driven economy growth; (2 the average optimal scale of the foreign exchange reserve in case of the sudden stop of capital inflows was calculated through parameter estimation and numerical simulation to be 13.53% of China’s gross domestic product (GDP between 1994 and 2017; (3 with the function of the foreign exchange reserves changing from meeting basic transaction demands to meeting financial security demands, the effect of the foreign exchange reserve maintaining the state’s financial security is becoming more and more obvious. Therefore, the structure of foreign exchange reserve assets should be optimized in China, and we will give full play to the special role of foreign exchange reserve in safeguarding a country’s financial security.

European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy

NARCIS (Netherlands)

Powles, Thomas; Staehler, Michael; Ljungberg, Börje; Bensalah, Karim; Canfield, Steven E; Dabestani, Saeed; Giles, Rachel H; Hofmann, Fabian; Hora, Milan; Kuczyk, Markus A; Lam, Thomas; Marconi, Lorenzo; Merseburger, Axel S; Volpe, Alessandro; Bex, Axel

2016-01-01

The European Association of Urology renal cancer guidelines panel recommends nivolumab and cabozantinib over the previous standard of care in patients who have failed one or more lines of vascular endothelial growth factor-targeted therapy. New data have recently become available showing a survival

Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

Science.gov (United States)

Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

2011-02-10

Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

Development growth of uranium reserves during mining

International Nuclear Information System (INIS)

Giroux, M.

1989-01-01

According to the 1988 issue of the Nuclear Energy Agency report 'Uranium Resources, Production and Demand' (the Red Book), total uranium resources remained constant, and compare with those given in the 1986 issue. However, the low cost category of the Reasonably Assured Resources (RAR), that is to say potentially mineable reserves under present market conditions, presents a different picture. These show a decrease of 54 000 tonnes U, or about 3.5%, from the 1 January 1985 level. It seems insignificant until compared with what was removed from the ground - only a quarter of the 71 500 tonnes U of the low cost uranium that was extracted during 1985 and 1986 was renewed by the industry. This is probably related to the low level of exploration activity since 1983. Moreover, new uranium might be not as easy to find as some past discoveries have led us to believe. While in 1988 it appears there is enough low cost uranium to supply existing reactors, the picture quickly changes. From 1991 onwards, for 30 years' supply for existing reactors, uranium will have to come from RAR in the higher cost category. (author)

Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

Science.gov (United States)

Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

2015-12-29

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review

Directory of Open Access Journals (Sweden)

Guiramand Jérôme

2011-10-01

Full Text Available Abstract Background Chordomas are very rare low-grade malignant bone tumors that arise from the embryonic rests of the notochord. They are characterized by slow growth and long history with frequent local relapses, and sometimes metastases. While chemotherapy is not efficient, imatinib has shown antitumor activity. Case presentation We report on a 76-year-old patient with EGFR-overexpressing advanced chordoma that progressed on imatinib and subsequently responded to erlotinib during 12 months. Conclusions We report the fourth case of advanced chordoma treated with an EGFR inhibitor. We also review the literature concerning the rationale and potential of EGFR targeting in chordoma.

Impact of marine reserve on maximum sustainable yield in a traditional prey-predator system

Science.gov (United States)

Paul, Prosenjit; Kar, T. K.; Ghorai, Abhijit

2018-01-01

Multispecies fisheries management requires managers to consider the impact of fishing activities on several species as fishing impacts both targeted and non-targeted species directly or indirectly in several ways. The intended goal of traditional fisheries management is to achieve maximum sustainable yield (MSY) from the targeted species, which on many occasions affect the targeted species as well as the entire ecosystem. Marine reserves are often acclaimed as the marine ecosystem management tool. Few attempts have been made to generalize the ecological effects of marine reserve on MSY policy. We examine here how MSY and population level in a prey-predator system are affected by the low, medium and high reserve size under different possible scenarios. Our simulation works shows that low reserve area, the value of MSY for prey exploitation is maximum when both prey and predator species have fast movement rate. For medium reserve size, our analysis revealed that the maximum value of MSY for prey exploitation is obtained when prey population has fast movement rate and predator population has slow movement rate. For high reserve area, the maximum value of MSY for prey's exploitation is very low compared to the maximum value of MSY for prey's exploitation in case of low and medium reserve. On the other hand, for low and medium reserve area, MSY for predator exploitation is maximum when both the species have fast movement rate.

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

Science.gov (United States)

Amin, A.R.M. Ruhul; Karpowicz, Phillip A.; Carey, Thomas E.; Arbiser, Jack; Nahta, Rita; Chen, Zhuo G.; Dong, Jin-Tang; Kucuk, Omer; Khan, Gazala N.; Huang, Gloria S.; Mi, Shijun; Lee, Ho-Young; Reichrath, Joerg; Honoki, Kanya; Georgakilas, Alexandros G.; Amedei, Amedeo; Amin, Amr; Helferich, Bill; Boosani, Chandra S.; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I.; Azmi, Asfar S.; Keith, W Nicol; Bhakta, Dipita; Halicka, Dorota; Niccolai, Elena; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S. Salman; Nowsheen, Somaira; Yang, Xujuan; Bilsland, Alan; Shin, Dong M.

2015-01-01

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting. PMID:25749195

The RNA-binding protein PCBP2 facilitates gastric carcinoma growth by targeting miR-34a

International Nuclear Information System (INIS)

Hu, Cheng-En; Liu, Yong-Chao; Zhang, Hui-Dong; Huang, Guang-Jian

2014-01-01

Highlights: • PCBP2 is overexpressed in human gastric cancer. • PCBP2 high expression predicts poor survival. • PCBP2 regulates gastric cancer growth in vitro and in vivo. • PCBP2 regulates gastric cancer apoptosis by targeting miR-34a. - Abstract: Gastric carcinoma is the fourth most common cancer worldwide, with a high rate of death and low 5-year survival rate. However, the mechanism underling gastric cancer is still not fully understood. Here in the present study, we identify the RNA-binding protein PCBP2 as an oncogenic protein in human gastric carcinoma. Our results show that PCBP2 is up-regulated in human gastric cancer tissues compared to adjacent normal tissues, and that high level of PCBP2 predicts poor overall and disease-free survival. Knockdown of PCBP2 in gastric cancer cells inhibits cell proliferation and colony formation in vitro, whereas opposing results are obtained when PCBP2 is overexpressed. Our in vivo subcutaneous xenograft results also show that PCBP2 can critically regulate gastric cancer cell growth. In addition, we find that PCBP2-depletion induces apoptosis in gastric cancer cells via up-regulating expression of pro-apoptotic proteins and down-regulating anti-apoptotic proteins. Mechanically, we identify that miR-34a as a target of PCBP2, and that miR-34a is critically essential for the function of PCBP2. In summary, PCBP2 promotes gastric carcinoma development by regulating the level of miR-34a

U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo

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Rafal Goraczniak

2013-01-01

Full Text Available U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2 and metabotropic glutamate receptor 1 (GRM1, in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6 indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases.

Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function.

Science.gov (United States)

Hennig, Maria; Fiedler, Saskia; Jux, Christian; Thierfelder, Ludwig; Drenckhahn, Jörg-Detlef

2017-08-04

Fetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of mTORC1 in intrauterine growth restriction and prenatal heart growth. We inhibited mTORC1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces mTORC1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin-treated neonates exhibit a 16% reduction in body weight compared with vehicle-treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin- versus vehicle-treated mice at birth. Although proliferation rates in neonatal rapamycin-treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle-treated neonates. Rapamycin-treated mice exhibit postnatal catch-up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal mTORC1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling. Prenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of mTORC1 in perinatal cardiac growth. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Overlapping activities of TGF-β and Hedgehog signaling in cancer: therapeutic targets for cancer treatment.

Science.gov (United States)

Perrot, Carole Y; Javelaud, Delphine; Mauviel, Alain

2013-02-01

Recent advances in the field of cancer therapeutics come from the development of drugs that specifically recognize validated oncogenic or pro-metastatic targets. The latter may be mutated proteins with altered function, such as kinases that become constitutively active, or critical components of growth factor signaling pathways, whose deregulation leads to aberrant malignant cell proliferation and dissemination to metastatic sites. We herein focus on the description of the overlapping activities of two important developmental pathways often exacerbated in cancer, namely Transforming Growth Factor-β (TGF-β) and Hedgehog (HH) signaling, with a special emphasis on the unifying oncogenic role played by GLI1/2 transcription factors. The latter are the main effectors of the canonical HH pathway, yet are direct target genes of TGF-β/SMAD signal transduction. While tumor-suppressor in healthy and pre-malignant tissues, TGF-β is often expressed at high levels in tumors and contributes to tumor growth, escape from immune surveillance, invasion and metastasis. HH signaling regulates cell proliferation, differentiation and apoptosis, and aberrant HH signaling is found in a variety of cancers. We discuss the current knowledge on HH and TGF-β implication in cancer including cancer stem cell biology, as well as the current state, both successes and failures, of targeted therapeutics aimed at blocking either of these pathways in the pre-clinical and clinical settings. Copyright © 2012 Elsevier Inc. All rights reserved.

Growth inhibition of head and neck squamous cell carcinoma cells by sgRNA targeting the cyclin D1 mRNA based on TRUE gene silencing.

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Satoshi Iizuka

Full Text Available Head and neck squamous cell carcinoma (HNSCC exhibits increased expression of cyclin D1 (CCND1. Previous studies have shown a correlation between poor prognosis of HNSCC and cyclin D1 overexpression. tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing is one of the RNA-mediated gene expression control technologies that have therapeutic potential. This technology is based on a unique enzymatic property of mammalian tRNase ZL, which is that it can cleave any target RNA at any desired site by recognizing a pre-tRNA-like complex formed between the target RNA and an artificial small guide RNA (sgRNA. In this study, we designed several sgRNAs targeting human cyclin D1 mRNA to examine growth inhibition of HNSCC cells. Transfection of certain sgRNAs decreased levels of cyclin D1 mRNA and protein in HSC-2 and HSC-3 cells, and also inhibited their proliferation. The combination of these sgRNAs and cisplatin showed more than additive inhibition of cancer cell growth. These findings demonstrate that TRUE gene silencing of cyclin D1 leads to inhibition of the growth of HNSCC cells and suggest that these sgRNAs alone or combined with cisplatin may be a useful new therapy for HNSCCs.

Targeted deletion of hepatocyte Ikkβ confers growth advantages

International Nuclear Information System (INIS)

Koch, Katherine S.; Maeda, Shin; He, Guobin; Karin, Michael; Leffert, Hyam L.

2009-01-01

Mice lacking hepatocyte IKKβ (Ikkβ Δhep ) are defective in TNFα-activation of hepatocellular transcription factor NF-κB, and highly susceptible to hepatotoxicity. Following diethylnitrosamine (DEN) exposure, Ikkβ Δhep mice develop more hepatocellular carcinoma (HCC) than control mice due partly to enhanced DEN-induced hepatocyte death. Here we show that Ikkβ Δhep hepatocytes display growth advantages over normal hepatocytes consisting of precocious PCNA and cyclin D1 expression during liver regeneration (shortened hepatocyte G 0 → G 1 transitions), and enhanced recovery efficiency, cyclin D1 expression and cell proliferation after plating. Ex vivo deletion of Ikkβ also accelerates hepatocyte growth. Ikkβ Δhep hepatocyte proliferative responses show heightened sensitivity to TGFα and TNFα, and heightened expression of fibronectin, collagens I/III, nidogen, β-actin and integrin β1 mRNAs. These findings suggest that altered mitogen signaling and expression of extracellular matrix and its associated components underlie growth advantages. Increased HCC development in Ikkβ Δhep mice may also be caused by growth advantages of surviving Ikkβ-deleted hepatocytes.

Serum insulin-like growth factor-I (IGF-I) and growth in children born after assisted reproduction

DEFF Research Database (Denmark)

Kai, Claudia Mau; Main, Katharina M; Andersen, Anders Nyboe

2006-01-01

CONTEXT: Concern has been raised about the safety of assisted reproduction techniques for the offspring. OBJECTIVES: The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF...... their target height (sd score) at 3 yr of age [mean -0.91 (1.2)], compared with NC children [-0.61 (0.9), P = 0.033]. In the child cohort, target height attainment (sd score) and growth factors did not differ among the three groups. CONCLUSIONS: The overall growth pattern of ICSI and IVF children in both...... cohorts was normal. Our findings of subtle differences in target height attainment and serum IGF-I levels between infants born after assisted reproduction techniques and controls may not be clinically significant. However, these observations indicate that further systematic follow-up of growth and puberty...

Targeting mesothelin receptors with drug-loaded bacterial nanocells suppresses human mesothelioma tumour growth in mouse xenograft models.

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Mohamed A Alfaleh

Full Text Available Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant mesothelioma incidence rates in European countries are still rising and Australia has one of the highest burdens of malignant mesothelioma on a population basis in the world. Therapy using systemic delivery of free cytotoxic agents is associated with many undesirable side effects due to non-selectivity, and is thus dose-limited which limits its therapeutic potential. Therefore, increasing the selectivity of anti-cancer agents has the potential to dramatically enhance drug efficacy and reduce toxicity. EnGeneIC Dream Vectors (EDV are antibody-targeted nanocells which can be loaded with cytotoxic drugs and delivered to specific cancer cells via bispecific antibodies (BsAbs which target the EDV and a cancer cell-specific receptor, simultaneously. BsAbs were designed to target doxorubicin-loaded EDVs to cancer cells via cell surface mesothelin (MSLN. Flow cytometry was used to investigate cell binding and induction of apoptosis, and confocal microscopy to visualize internalization. Mouse xenograft models were used to assess anti-tumour effects in vivo, followed by immunohistochemistry for ex vivo evaluation of proliferation and necrosis. BsAb-targeted, doxorubicin-loaded EDVs were able to bind to and internalize within mesothelioma cells in vitro via MSLN receptors and induce apoptosis. In mice xenografts, the BsAb-targeted, doxorubicin-loaded EDVs suppressed the tumour growth and also decreased cell proliferation. Thus, the use of MSLN-specific antibodies to deliver encapsulated doxorubicin can provide a novel and alternative modality for treatment of mesothelioma.

Is insulin-like growth factor 1 (IGF-1) system an attractive target inflammatory bowel diseases? Benefits and limitation of potential therapy.

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Zatorski, Hubert; Marynowski, Mateusz; Fichna, Jakub

2016-08-01

Inflammatory bowel diseases (IBD) are chronic gastrointestinal disorders with unknown etiology, whose incidence dramatically increased over the past 50 years. Currently available strategies for IBD treatment, such as biological therapies, corticosteroids, and immunosuppressive agents are effective, but their side effects and economic costs cannot be ignored. Better understanding of IBD etiology and new therapeutics are thus needed. The aim of this paper is to briefly discuss IGF-1 dependent functions, with particular focus on IGF-1 use in IBD therapy. Data collection was based on records found in medical literature. Data analysis included records published between 1984 and 2014. The IGF-1 system is involved in major physiological functions, such as cell proliferation and metabolism, and growth promotion. Most importantly IGF-1 has anti-inflammatory properties and its use in IBD treatment can be recommended. However, potential IGF-1 therapy has some limitations, which include aggravation of fibrosis in Crohn's patients and facilitated transformation to malignancy. Taken into consideration their possible side effects, IGF-1 analogs and recombinants are nonetheless a promising target for IBD therapy for a specific group of patients. Further studies, at the clinical level are thus recommended. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Effects of mistletoe removal on growth, N and C reserves, and carbon and oxygen isotope composition in Scots pine hosts.

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Yan, Cai-Feng; Gessler, Arthur; Rigling, Andreas; Dobbertin, Matthias; Han, Xing-Guo; Li, Mai-He

2016-05-01

Most mistletoes are xylem-tapping hemiparasites, which derive their resources from the host's xylem solution. Thus, they affect the host's water relations and resource balance. To understand the physiological mechanisms underlying the mistletoe-host relationship, we experimentally removed Viscum album ssp. austriacum (Wiesb.) Vollmann from adult Pinus sylvestris L. host trees growing in a Swiss dry valley. We analyzed the effects of mistletoe removal over time on host tree growth and on concentrations of nonstructural carbohydrates (NSC) and nitrogen (N) in needles, fine roots and sapwood. In addition, we assessed the δ(13)C and δ(18)O in host tree rings. After mistletoe removal, δ(13)C did not change in newly produced tree rings compared with tree rings in control trees (still infected with mistletoe), but δ(18)O values increased. This pattern might be interpreted as a decrease in assimilation (A) and stomatal conductance (gs), but in our study, it most likely points to an inadequacy of the dual isotope approach. Instead, we interpret the unchanged δ(13)C in tree rings upon mistletoe removal as a balanced increase in A and gs that resulted in a constant intrinsic water use efficiency (defined as A/gs). Needle area-based concentrations of N, soluble sugars and NSC, as well as needle length, single needle area, tree ring width and shoot growth, were significantly higher in trees from which mistletoe was removed than in control trees. This finding suggests that mistletoe removal results in increased N availability and carbon gain, which in turn leads to increased growth rates of the hosts. Hence, in areas where mistletoe is common and the population is large, mistletoe management (e.g., removal) may be needed to improve the host vigor, growth rate and productivity, especially for relatively small trees and crop trees in xeric growth conditions. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth.

Science.gov (United States)

Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M; Yang, Jun; Starbuck, Michael W; Ravoori, Murali K; Kundra, Vikas; Vazquez, Elba; Navone, Nora M

2012-03-01

Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth

Inhibiting the growth of methicillin-resistant Staphylococcus aureus in vitro with antisense peptide nucleic acid conjugates targeting the ftsZ gene

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Shumei Liang

2015-01-01

Conclusion: Our results demonstrate that the potent effects of PNAs on bacterial growth and cell viability were mediated by the down-regulation or even knock-out of ftsZ gene expression. This highlights the utility of ftsZ as a promising target for the development of new antisense antibacterial agents to treat MRSA infections.

Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRalpha.

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Baumgartner, Christian; Gleixner, Karoline V; Peter, Barbara; Ferenc, Veronika; Gruze, Alexander; Remsing Rix, Lily L; Bennett, Keiryn L; Samorapoompichit, Puchit; Lee, Francis Y; Pickl, Winfried F; Esterbauer, Harald; Sillaber, Christian; Superti-Furga, Giulio; Valent, Peter

2008-10-01

Chronic eosinophilic leukemia (CEL) is a myeloproliferative disorder characterized by molecular and/or cytogenetic evidence of clonality of eosinophils, marked eosinophilia, and organ damage. In many patients, the transforming mutation FIP1L1-PDGFRalpha and the related CHIC2 deletion are found. The respective oncoprotein, FIP1L1-PDGFRalpha, is considered to play a major role in malignant cell growth in CEL. The tyrosine kinase (TK) inhibitor imatinib (STI571) has been described to counteract the TK activity of FIP1L1-PDGFRalpha in most patients. However, not all patients with CEL show a response to imatinib. Therefore, several attempts have been made to identify other TK inhibitors that counteract growth of neoplastic eosinophils. We provide evidence that dasatinib, a multi-targeted kinase inhibitor, blocks the growth and survival of EOL-1, an eosinophil leukemia cell line carrying FIP1L1-PDGFRalpha. The effects of dasatinib on proliferation of EOL-1 cells were dose-dependent, with an IC50 of 0.5 to 1 nM, which was found to be in the same range when compared to IC50 values produced with imatinib. Dasatinib was also found to induce apoptosis in EOL-1 cells in a dose-dependent manner (IC50: 1-10 nM). The apoptosis-inducing effects of dasatinib on EOL-1 cells were demonstrable by light microscopy, flow cytometry, and in a TUNEL assay. In Western blot experiments, dasatinib completely blocked the phosphorylation of FIP1L1-PDGFRalpha in EOL-1 cells. Dasatinib inhibits the growth of leukemic eosinophils through targeting of the disease-related oncoprotein FIP1L1-PDGFRalpha. Based on this observation, dasatinib may be considered as a new interesting treatment option for patients with CEL.

Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro

International Nuclear Information System (INIS)

Cardillo, Thomas M; Trisal, Preeti; Arrojo, Roberto; Goldenberg, David M; Chang, Chien-Hsing

2013-01-01

Advanced or metastatic renal cell carcinoma (RCC) has a poor prognosis, because it is relatively resistant to conventional chemotherapy or radiotherapy. Treatments with human interferon-α2b alone or in combination with mammalian target of rapamycin (mTOR) inhibitors have led to only a modest improvement in clinical outcome. One observation made with mTOR inhibitors is that carcinomas can overcome these inhibitory effects by activating the insulin-like growth factor-I (IGF-I) signaling pathway. Clinically, there is an association of IGF-I receptor (IGF-IR) expression in RCC and poor long-term patient survival. We have developed a humanized anti-IGF-IR monoclonal antibody, hR1, which binds to RCC, resulting in effective down-regulation of IGF-IR and moderate inhibition of cell proliferation in vitro. In this work, we evaluate the anti-tumor activity of two novel IGF-1R-targeting agents against renal cell carcinoma given alone or in combination with an mTOR inhibitor. hR1 was linked by the DOCK-AND-LOCK™ (DNL™) method to four Fabs of hR1, generating Hex-hR1, or to four molecules of interferon-α2b, generating 1R-2b. Eight human RCC cell lines were screened for IGF-1R expression and sensitivity to treatment with hR1 in vitro. Synergy with an mTOR inhibitor, temsirolimus, was tested in a cell line (ACHN) with low sensitivity to hR1. Hex-hR1 induced the down-regulation of IGF-IR at 10-fold lower concentrations compared to the parental hR1. Sensitivity to growth inhibition mediated by hR1 and Hex-hR1 treatments correlated with IGF-1R expression (higher expression was more sensitive). The potency of 1R-2b to inhibit the in vitro growth of RCC was also demonstrated in two human cell lines, ACHN and 786-O, with EC 50 –values of 63 and 48 pM, respectively. When combined with temsirolimus, a synergistic growth-inhibition with hR1, Hex-hR1, and 1R-2b was observed in ACHN cells at concentrations as low as 10 nM for hR1, 1 nM for Hex-hR1, and 2.6 nM for 1R-2b. Both Hex-hR1

On the Chinese Carbon Reduction Target

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Michinori Uwasu

2010-06-01

Full Text Available In November 2009, China pledged a 40–45% decrease in CO2 emissions per GDP by 2020, as compared with the 2005 level. Although carbon intensity (emission targets by nature are ambiguous, this study demonstrates that China’s pledge is consistent with the current Chinese domestic agenda that simultaneously pursues economic growth and energy security. The target numbers in the pledge seem reasonable, given the technological feasibility and measures, considered along with the assumption that moderate economic growth will occur. However, the study also argues that financial and institutional constraints exist as potential obstacles to achieving the target if the trend of the current economic tendencies continues.

Lithium reserves and resources

International Nuclear Information System (INIS)

Evans, R.K.

1978-01-01

As a result of accelerating research efforts in the fields of secondary batteries and thermonuclear power generation, concern has been expressed in certain quarters regarding the availability, in sufficient quantities, of lithium. As part of a recent study by the National Research Council on behalf of the Energy Research and Development Administration, a subpanel was formed to consider the outlook for lithium. Principal areas of concern were reserves, resources and the 'surplus' available for energy applications after allowing for the growth in current lithium applications. Reserves and resources were categorized into four classes ranging from fully proved reserves to resources which are probably dependent upon the marketing of co-products to become economically attractive. Because of the proprietary nature of data on beneficiation and processing recoveries, the tonnages of available lithium are expressed in terms of plant feed. However, highly conservative assumptions have been made concerning mining recoveries and these go a considerable way to accounting for total losses. Western World reserves and resources of all classes are estimated at 10.6 million tonnes Li of which 3.5 million tonnes Li are located in the United States. Current United States capacity, virtually equivalent to Western World capacity, is 4700 tonnes Li and production in 1976 approximated to 3500 tonnes Li. Production for current applications is expected to grow to approx. 10,000 tonnes in year 2000 and 13,000 tonnes a decade later. The massive excess of reserves and resources over that necessary to support conventional requirements has limited the amount of justifiable exploration expenditures; on the last occasion, there was a a major increase in demand (by the USAEA) reserves and capacity were increased rapidly. There are no foreseeable reasons why this shouldn't happen again when the need is clear. (author)

Epidermal growth factor (EGF) as a potential targeting agent for delivery of boron to malignant gliomas

International Nuclear Information System (INIS)

Capala, J.; Barth, R.F.; Adams, D.M.; Bailey, M.Q.; Soloway, A.H.; Carlsson, J.

1994-01-01

The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of 10 B to tumor cells with an amplified number of EGFR. Human glioma cells can expresses as many as 10 5 -10 6 EGF receptors per cell, and if these could be saturated with boronated EGF, then > 10 8 boron atoms would be delivered per cell. Since EGF has a comparatively low molecular weight (∼ 6 kD), this has allowed us to construct relatively small bioconjugates containing ∼ 900 boron atoms per EGF molecule 3 , which also had high affinity for EGFR on tumor cells. In the present study, the feasibility of using EGF receptors as a potential target for therapy of gliomas was investigated by in vivo scintigraphic studies using 131 I- or 99m T c -labeled EGF in a rat brain tumor model. Our results indicate that intratumorally delivered boron- EGF conjugates might be useful for targeting EGFR on glioma cells if the boron containing moiety of the conjugates persisted intracellularly. Further studies are required, however, to determine if this approach can be used for BNCT of the rat glioma

Serum Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) as a Biomarker for Primary Ovarian Cancer.

Science.gov (United States)

Miyata, Kohei; Yotsumoto, Fusanori; Fukagawa, Satoshi; Kiyoshima, Chihiro; Ouk, Nam Sung; Urushiyama, Daichi; Ito, Tomohiro; Katsuda, Takahiro; Kurakazu, Masamitsu; Araki, Ryota; Sanui, Ayako; Miyahara, Daisuke; Murata, Masaharu; Shirota, Kyoko; Yagi, Hiroshi; Takono, Tadao; Kato, Kiyoko; Yaegashi, Nobuo; Akazawa, Kohei; Kuroki, Masahide; Yasunaga, Shin'ichiro; Miyamoto, Shingo

2017-07-01

Ovarian cancer is the most lethal malignancy among gynaecological cancers. Although many anticancer agents have been developed for the treatment of ovarian cancer, it continues to have an extremely poor prognosis. Heparin-binding epidermal growth factor-like grown factor (HB-EGF) has been reported to be a rational therapeutic target for ovarian cancer. Here, we evaluated the clinical significance of serum HB-EGF by examining the association between prognosis and serum HB-EGF levels in patients with primary ovarian cancer. We found that high serum HB-EGF concentrations were significantly associated with poor prognosis in a combined cohort of patients with all stages of ovarian cancer, as well as in a subset of patients with advanced disease. In addition, serum HB-EGF levels increased as the cancer advanced. These data suggest that serum HB-EGF may be a target for the design of novel therapies for ovarian cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Randomized controlled trial of SecondStory, an intervention targeting posttraumatic growth, with bereaved adults.

Science.gov (United States)

Roepke, Ann Marie; Tsukayama, Eli; Forgeard, Marie; Blackie, Laura; Jayawickreme, Eranda

2018-06-01

People often report positive psychological changes after adversity, a phenomenon known as posttraumatic growth (PTG). Few PTG-focused interventions have been rigorously tested, and measurement strategies have had significant limitations. This study evaluated the effects of a new group-format psychosocial intervention, SecondStory, aimed at facilitating PTG by helping participants make meaning of the past and plan a purposeful future. In a randomized controlled trial, adults (N = 112, 64% women) bereaved within 5 years were randomly assigned to SecondStory or an active control, expressive writing. The primary outcome, PTG, was measured using two contrasting methods: the Posttraumatic Growth Inventory, which asks participants retrospectively how much they believe they have changed due to struggling with adversity, and the Current-Standing Posttraumatic Growth Inventory, which tracks quantifiable change in participants' standing in PTG domains over time. Secondary outcomes included depression symptoms, posttraumatic stress symptoms, and life satisfaction. Outcomes were measured at 2-week intervals: pretest, posttest, and three follow-up occasions. Hierarchical linear modeling was used to assess whether SecondStory participants experienced greater gains in primary and/or secondary outcomes over the 8-week trial. Results indicated that SecondStory participants did not show significantly greater improvements than control participants on measures of PTG, posttraumatic stress, or life satisfaction, but they did show greater decreases in depression symptoms by the first follow-up. These findings suggest that SecondStory may not facilitate PTG more effectively than existing interventions but may be promising for addressing depression. Positive interventions may productively be refined to support people experiencing trauma and loss. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Targeted Cancer Therapies

Science.gov (United States)

... are sometimes referred to as the product of "rational" drug design.) One approach to identify potential targets ... molecules that stimulate new blood vessel growth. Immunotherapies trigger the immune system to destroy cancer cells. Some ...

Targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin squamous cell carcinoma cell growth in vitro and in vivo.

Science.gov (United States)

Zou, Ying; Ge, Minggai; Wang, Xuemin

2017-08-19

Abnormal activation of PI3K-AKT-mTOR signaling is detected in human skin squamous cell carcinoma (SCC). LY3023414 is a novel, potent, and orally bio-available PI3K-AKT-mTOR inhibitor. Its activity against human skin SCC cells was tested. We demonstrated that LY3023414 was cytotoxic when added to established (A431 line) and primary (patient-derived) human skin SCC cells. LY3023414 induced G0/1-S arrest and inhibited proliferation of skin SCC cells. Moreover, LY3023414 induced activation of caspase-3/-9 and apoptosis in skin SCC cells. Intriguingly, LY3023414 was yet non-cytotoxic nor pro-apoptotic to normal human skin cells (melanocytes, keratinocytes and fibroblasts). At the molecular level, LY3023414 blocked PI3K-AKT-mTOR activation in skin SCC cells, as it dephosphorylated PI3K-AKT-mTOR substrates: P85, AKT and S6K1. In vivo studies showed that oral administration of LY3023414 at well-tolerated doses inhibited A431 xenograft tumor growth in severe combined immunodeficiency (SCID) mice. AKT-mTOR activation in LY3023414-treated tumors was also largely inhibited. Together, these results suggest that targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin SCC cell growth in vitro and in vivo, establishing the rationale for further clinical testing. Copyright © 2017 Elsevier Inc. All rights reserved.

Specific and Efficient Regression of Cancers Harboring KRAS Mutation by Targeted RNA Replacement.

Science.gov (United States)

Kim, Sung Jin; Kim, Ju Hyun; Yang, Bitna; Jeong, Jin-Sook; Lee, Seong-Wook

2017-02-01

Mutations in the KRAS gene, which persistently activate RAS function, are most frequently found in many types of human cancers. Here, we proposed and verified a new approach against cancers harboring the KRAS mutation with high cancer selectivity and efficient anti-cancer effects based on targeted RNA replacement. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically target and reprogram the mutant KRAS G12V transcript to induce therapeutic gene activity in cells. Adenoviral vectors containing the specific ribozymes with downstream suicide gene were constructed and then infection with the adenoviruses specifically downregulated KRAS G12V expression and killed KRAS G12V-harboring cancer cells additively upon pro-drug treatment, but it did not affect the growth of wild-type KRAS-expressing cells. Minimal liver toxicity was noted when the adenoviruses were administered systemically in vivo. Importantly, intratumoral injection of the adenoviruses with pro-drug treatment specifically and significantly impeded the growth of xenografted tumors harboring KRAS G12V through a trans-splicing reaction with the target RNA. In contrast, xenografted tumors harboring wild-type KRAS were not affected by the adenoviruses. Therefore, RNA replacement with a mutant KRAS-targeting trans-splicing ribozyme is a potentially useful therapeutic strategy to combat tumors harboring KRAS mutation. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Effect of an insecticide on growth and metabolism of some non-target soil micro-organisms

International Nuclear Information System (INIS)

Balasubramanian, A.; Nilakantan, Gita

1975-01-01

Aldicarb, a systemic insecticide, enhanced the growth of Rhizobium japonicum in vitro at 1 ppm concentration but inhibited it at 5 ppm level. The cell yields of Azotobacter chroococcum and Pseudomonas solanacearum were reduced by both the concentrations of the chemical. 1 and 5 ppm levels of the insecticide the incorporation of 14 C-glucose by R. japonicum, but it was stimulated in the case of R. chroococcum. In the case of P. solanacearum, however, 1 ppm level of the insecticide enhanced the incorporation of the label. Uptake of 32 P-di-potassium hydrogen phosphate by the cells was also significantly reduced indicating that the metabolic activities of these non-target soil micro-organisms are altered by the insecticide treatment. (author)

Future Targets for Female Sexual Dysfunction.

Science.gov (United States)

Farmer, Melissa; Yoon, Hana; Goldstein, Irwin

2016-08-01

Female sexual function reflects a dynamic interplay of central and peripheral nervous, vascular, and endocrine systems. The primary challenge in the development of novel treatments for female sexual dysfunction is the identification and targeted modulation of excitatory sexual circuits using pharmacologic treatments that facilitate the synthesis, release, and/or receptor binding of neurochemicals, peptides, and hormones that promote female sexual function. To develop an evidence-based state-of-the-art consensus report that critically integrates current knowledge of the therapeutic potential for known molecular and cellular targets to facilitate the physiologic processes underlying female sexual function. State-of-the-art review representing the opinions of international experts developed in a consensus process during a 1-year period. Expert opinion was established by grading the evidence-based medical literature, intensive internal committee discussion, public presentation, and debate. Scientific investigation is urgently needed to expand knowledge and foster development of future treatments that maintain genital tissue integrity, enhance genital physiologic responsiveness, and optimize positive subjective appraisal of internal and external sexual cues. This article critically condenses the current knowledge of therapeutic manipulation of molecular and cellular targets within biological systems responsible for female sexual physiologic function. Future treatment targets include pharmacologic modulation of emotional learning circuits, restoration of normal tactile sensation, growth factor therapy, gene therapy, stem cell-based therapies, and regenerative medicine. Concurrent use of centrally and peripherally acting therapies could optimize treatment response. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: A new concept of dual targeting drugs

International Nuclear Information System (INIS)

Dubois, Ludwig; Peeters, Sarah G.J.A.; Kuijk, Simon J.A. van; Yaromina, Ala; Lieuwes, Natasja G.; Saraya, Ruchi; Biemans, Rianne; Rami, Marouan; Parvathaneni, Nanda Kumar; Vullo, Daniela; Vooijs, Marc; Supuran, Claudiu T.; Winum, Jean-Yves

2013-01-01

Background and purpose: Carbonic anhydrase IX (CAIX) plays an important role in pH regulation processes critical for tumor cell growth and metastasis. We hypothesize that a dual targeting bioreductive nitroimidazole based anti-CAIX sulfamide drug (DH348) will reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner. Material and methods: The effect of the dual targeting anti-CAIX (DH348) and its single targeting control drugs on extracellular acidification and radiosensitivity was examined in HT-29 colorectal carcinoma cells. Tumor growth and time to reach 4× start volume (T4×SV) was monitored for animals receiving DH348 (10 mg/kg) combined with tumor single dose irradiation (10 Gy). Results: In vitro, DH348 reduced hypoxia-induced extracellular acidosis, but did not change hypoxic radiosensitivity. In vivo, DH348 monotherapy decreased tumor growth rate and sensitized tumors to radiation (enhancement ratio 1.50) without systemic toxicity only for CAIX expressing tumors. Conclusions: A newly designed nitroimidazole and sulfamide dual targeting drug reduces hypoxic extracellular acidification, slows down tumor growth at nontoxic doses and sensitizes tumors to irradiation all in a CAIX dependent manner, suggesting no “off-target” effects. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting

Galangin inhibits human osteosarcoma cells growth by inducing transforming growth factor-β1-dependent osteogenic differentiation.

Science.gov (United States)

Liu, Chunhong; Ma, Mingming; Zhang, Junde; Gui, Shaoliu; Zhang, Xiaohai; Xue, Shuangtao

2017-05-01

Osteosarcoma is the most common primary malignancy of the musculoskeletal system, and is associated with excessive proliferation and poor differentiation of osteoblasts. Currently, despite the use of traditional chemotherapy and radiotherapy, no satisfactory and effective agent has been developed to treat the disease. Herein, we found that a flavonoid natural product, galangin, could significantly attenuate human osteosarcoma cells proliferation, without causing obvious cell apoptosis. Moreover, galangin enhanced the expression of osteoblast differentiation markers (collagen type I, alkaline phosphatase, osteocalcin and osteopontin) remarkably and elevated the alkaline phosphatase activity in human osteosarcoma cells. And galangin could also attenuated osteosarcoma growth in vivo. These bioactivities of galangin resulted from its selective activation of the transforming growth factor (TGF)-β1/Smad2/3 signaling pathway, which was demonstrated by pathway blocking experiments. These findings suggested that galangin could be a promising agent to treat osteosarcoma. In addition, targeting TGF-β1 to induce osteogenic differentiation might represent a novel therapeutic strategy to treat osteosarcoma with minimal side effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A Two-Layer Gene Circuit for Decoupling Cell Growth from Metabolite Production.

Science.gov (United States)

Lo, Tat-Ming; Chng, Si Hui; Teo, Wei Suong; Cho, Han-Saem; Chang, Matthew Wook

2016-08-01

We present a synthetic gene circuit for decoupling cell growth from metabolite production through autonomous regulation of enzymatic pathways by integrated modules that sense nutrient and substrate. The two-layer circuit allows Escherichia coli to selectively utilize target substrates in a mixed pool; channel metabolic resources to growth by delaying enzymatic conversion until nutrient depletion; and activate, terminate, and re-activate conversion upon substrate availability. We developed two versions of controller, both of which have glucose nutrient sensors but differ in their substrate-sensing modules. One controller is specific for hydroxycinnamic acid and the other for oleic acid. Our hydroxycinnamic acid controller lowered metabolic stress 2-fold and increased the growth rate 2-fold and productivity 5-fold, whereas our oleic acid controller lowered metabolic stress 2-fold and increased the growth rate 1.3-fold and productivity 2.4-fold. These results demonstrate the potential for engineering strategies that decouple growth and production to make bio-based production more economical and sustainable. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

MicroRNA-9 suppresses the growth, migration, and invasion of malignant melanoma cells via targeting NRP1

Directory of Open Access Journals (Sweden)

Xu D

2016-11-01

overexpression decreased the tumor growth, while overexpression of NRP1 increased MM growth. In summary, our findings suggest that the miR-9/NRP1 axis may serve as a potential target for the treatment of MM. Keywords: malignant melanoma, microRNA, neuropilin1, proliferation, migration, invasion

Dynamics of International Reserve Accumulation in Turkish Economy

Directory of Open Access Journals (Sweden)

Duygu Ayhan

2015-05-01

Full Text Available Many of the emerging market economies embody macroeconomic and structural vulnerabilities due to large deficits, high inflation, slowing growth and heavy reliance on short-term capital inflows. Therefore, accumulation of international reserve holdings has been frequently used by authorities to serve as an insurance against the volatility of the capital flows and strengthen the fragile nature of these economies. Turkish economy, classified as one of the most fragile of the emerging economies, has been experiencing a similar process of international reserve accumulation. The chronically high current account deficit and low savings rate boost the importance of international reserves. Thus, the aim of this paper is to investigate the determinants of international reserves in Turkey. The dataset covers the 2000-2013 period. Consequently, we find that the international reserve accumulation is mainly explained by current account balance, per capita income and past crisis experience.

Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

Energy Technology Data Exchange (ETDEWEB)

Pagan, Jonathan, E-mail: jdpagan@uams.edu; Przybyla, Beata; Jamshidi-Parsian, Azemat [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States); Gupta, Kalpna [Vascular Biology Center and Division of Hematology-Oncology Transplantation, Department of Medicine, University of Minnesota Medical School, MN 72223 (United States); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States)

2013-02-18

Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm{sup 3}) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

International Nuclear Information System (INIS)

Pagan, Jonathan; Przybyla, Beata; Jamshidi-Parsian, Azemat; Gupta, Kalpna; Griffin, Robert J.

2013-01-01

Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm 3 ) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

Characterization of the sulfate uptake and assimilation pathway from Xanthomonas citri - targets for bacterial growth inhibitors

Energy Technology Data Exchange (ETDEWEB)

Tambascia, C.; Balan, A. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil)

2012-07-01

Full text: Microorganisms require sulfur for growth and obtain it either for inorganic sulfate or organosulfur compounds. ATP-Binding Cassete (SulT family) or major facilitator superfamily-type (SulP) transporters are responsible for the sulfate transport into the cell. In Xanthomonas citri, the phytopathogenic bacterium that causes the canker citrus disease, there are no reports related to the importance of these transporters during in vitro or in vivo infection. We identified in X. citri genome all the genes that belong to the well-characterized cys regulon from Escherichia coli and Salmonella typhimurium, which includes three ABC transporters and all the enzymes necessary for sulfate oxide reduction to sulfide and cysteine. Once these genes have been shown to be extremely important for bacteria growth and development in different environments, we chose the sbpcysWUA and cysDNCHIJG operons, which encodes the ABC inorganic sulfate ABC transporter and all the enzymes necessary for conversion of sulfate in cysteine, respectively. As a step for crystallization trials and resolution of their tridimensional structures, the referred genes were amplified and cloned into the cloning vector pGEM T-easy. In addition, using bioinformatics tools and molecular modeling we characterized all the protein functions as well as built tridimensional models of their structure for determination of the active sites. The importance of each protein is discussed aiming the discovery of a good target for development of inhibitors that could block the bacterium growth. (author)

Characterization of the sulfate uptake and assimilation pathway from Xanthomonas citri - targets for bacterial growth inhibitors

International Nuclear Information System (INIS)

Tambascia, C.; Balan, A.

2012-01-01

Full text: Microorganisms require sulfur for growth and obtain it either for inorganic sulfate or organosulfur compounds. ATP-Binding Cassete (SulT family) or major facilitator superfamily-type (SulP) transporters are responsible for the sulfate transport into the cell. In Xanthomonas citri, the phytopathogenic bacterium that causes the canker citrus disease, there are no reports related to the importance of these transporters during in vitro or in vivo infection. We identified in X. citri genome all the genes that belong to the well-characterized cys regulon from Escherichia coli and Salmonella typhimurium, which includes three ABC transporters and all the enzymes necessary for sulfate oxide reduction to sulfide and cysteine. Once these genes have been shown to be extremely important for bacteria growth and development in different environments, we chose the sbpcysWUA and cysDNCHIJG operons, which encodes the ABC inorganic sulfate ABC transporter and all the enzymes necessary for conversion of sulfate in cysteine, respectively. As a step for crystallization trials and resolution of their tridimensional structures, the referred genes were amplified and cloned into the cloning vector pGEM T-easy. In addition, using bioinformatics tools and molecular modeling we characterized all the protein functions as well as built tridimensional models of their structure for determination of the active sites. The importance of each protein is discussed aiming the discovery of a good target for development of inhibitors that could block the bacterium growth. (author)

Inhibition of prostate cancer growth using doxorubicin assisted by ultrasound-targeted nanobubble destruction

Directory of Open Access Journals (Sweden)

Fan X

2016-07-01

Full Text Available Xiaozhou Fan,1,* Luofu Wang,2,* Yanli Guo,1 Xingyu Xiong,1 Lianhua Zhu,1 Kejing Fang1 1Department of Ultrasound, Southwest Hospital, 2Department of Urology, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China *These authors contributed equally to this work Abstract: Ultrasound (US-targeted microbubble destruction has been widely used as an effective drug-delivery system. However, nanobubbles (NBs have better stability and stronger penetration than microbubbles, and drug delivery assisted by US-targeted NB destruction (UTND still needs to be investigated. Our aim was to investigate the effect of doxorubicin (DOX on the inhibition of prostate cancer growth under UTND. Contrast-enhanced US imaging of transplanted PC3 prostate cancer in mice showed that under a combination of 1 W/cm2 US power and a 100 Hz intermittent pulse with a “5 seconds on, 5 seconds off” mode, NBs with an average size of (485.7±33 nm were effectively destroyed within 15 minutes in the tumor location. PC3 cells and 20 tumor-bearing mice were divided into four groups: a DOX group, a DOX + NB group, a DOX + US group, and a DOX + NB + US group. The cell growth-inhibition rate and DOX concentration of xenografts in the DOX + NB + US group were highest. Based on another control group and these four groups, another 25 tumor-bearing mice were used to observe the treatment effect of nine DOX injections under UTND. The xenografts in the DOX + NB + US group decreased more obviously and had more cellular apoptosis than other groups. Finally, electron microscopy was used to estimate the cavitation effect of NBs under US irradiation in the control group, NB group, US group, and NB + US group. The results of scanning electron microscopy showed that PC3 cells in the DOX + NB + US group had more holes and significantly increased cell-surface folds. Meanwhile, transmission electric microscopy confirmed that more lanthanum nitrate particles entered

The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer.

Science.gov (United States)

Lai, Yi-Hua; Yu, Sung-Liang; Chen, Hsuan-Yu; Wang, Chi-Chung; Chen, Huei-Wen; Chen, Jeremy J W

2013-05-01

HLJ1 is a novel tumour suppressor and is a potential druggable target for non-small-cell lung cancer (NSCLC). In this report, using a promoter-containing enhancer region as the HLJ1-targeting drug-screening platform, we identified several herbal compounds from a Chinese herbal bank with the capacity to enhance HLJ1 promoter activity and suppress tumour growth and invasion of NSCLC. Among the herbal drugs identified, the andrographolide (from Andrographis paniculata [Burm. f.] Nees.) most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulates HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. In addition, silencing of HLJ1 partially reverses the inhibition of cancer-cell invasion by andrographolide. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect 939 genes (analysis of variance, false discovery rate andrographolide on anticancer invasion and proliferation. In conclusion, the HLJ1-targeting drug-screening platform is useful for screening of novel anticancer compounds. Using this platform, we identified andrographolide is a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC.

Targeted delivery of polyamidoamine-paclitaxel conjugate functionalized with anti-human epidermal growth factor receptor 2 trastuzumab

Directory of Open Access Journals (Sweden)

Ma P

2015-03-01

Full Text Available Pengkai Ma,1 Xuemei Zhang,1 Ling Ni,2 Jinming Li,2 Fengpu Zhang,1 Zheng Wang,1 Shengnan Lian,1 Kaoxiang Sun1 1School of Pharmacy, Yantai University, Yantai, Shandong Province, People’s Republic of China; 2State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, Shandong Province, People’s Republic of China Background: Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB, which binds to human epidermal growth factor receptor 2 (HER2, was used as a targeting agent in a TMAB-polyamidoamine (PAMAM conjugate carrying paclitaxel (PTX specifically to cells overexpressing HER2. Methods: TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG. PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively. Results: Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was

Deterministic claims reserving in short-term insuarance contracts ...

African Journals Online (AJOL)

Claims reserving for general insurance business has developed significantly over the recent past. This has been occasioned by the growth of the insurance market, with the risk underwriting process becoming more and more complex. New insurance products have been developed that cater for the more specific needs of ...

Wind offering in energy and reserve markets

DEFF Research Database (Denmark)

Soares, Tiago; Pinson, Pierre; Morais, Hugo

2016-01-01

The increasing penetration of wind generation in power systems to fulfil the ambitious European targets will make wind power producers to play an even more important role in the future power system. Wind power producers are being incentivized to participate in reserve markets to increase...... their revenue, since currently wind turbine/farm technologies allow them to provide ancillary services. Thus, wind power producers are to develop offering strategies for participation in both energy and reserve markets, accounting for market rules, while ensuring optimal revenue. We consider a proportional...... offering strategy to optimally decide upon participation in both markets by maximizing expected revenue from day-ahead decisions while accounting for estimated regulation costs for failing to provide the services. An evaluation of considering the same proportional splitting of energy and reserve in both...

Altered decorin leads to disrupted endothelial cell function: a possible mechanism in the pathogenesis of fetal growth restriction?

Science.gov (United States)

Chui, A; Murthi, P; Gunatillake, T; Brennecke, S P; Ignjatovic, V; Monagle, P T; Whitelock, J M; Said, J M

2014-08-01

Fetal growth restriction (FGR) is a key cause of adverse pregnancy outcome where maternal and fetal factors are identified as contributing to this condition. Idiopathic FGR is associated with altered vascular endothelial cell functions. Decorin (DCN) has important roles in the regulation of endothelial cell functions in vascular environments. DCN expression is reduced in FGR. The objectives were to determine the functional consequences of reduced DCN in a human microvascular endothelial cell line model (HMVEC), and to determine downstream targets of DCN and their expression in primary placental microvascular endothelial cells (PLECs) from control and FGR-affected placentae. Short-interference RNA was used to reduce DCN expression in HMVECs and the effect on proliferation, angiogenesis and thrombin generation was determined. A Growth Factor PCR Array was used to identify downstream targets of DCN. The expression of target genes in control and FGR PLECs was performed. DCN reduction decreased proliferation and angiogenesis but increased thrombin generation with no effect on apoptosis. The array identified three targets of DCN: FGF17, IL18 and MSTN. Validation of target genes confirmed decreased expression of VEGFA, MMP9, EGFR1, IGFR1 and PLGF in HMVECs and PLECs from control and FGR pregnancies. Reduction of DCN in vascular endothelial cells leads to disrupted cell functions. The targets of DCN include genes that play important roles in angiogenesis and cellular growth. Therefore, differential expression of these may contribute to the pathogenesis of FGR and disease states in other microvascular circulations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Targets of curcumin

Science.gov (United States)

Zhou, Hongyu; Beevers, Christopher S.; Huang, Shile

2010-01-01

Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here. PMID:20955148

TARGET Research Goals

Science.gov (United States)

TARGET researchers use various sequencing and array-based methods to examine the genomes, transcriptomes, and for some diseases epigenomes of select childhood cancers. This “multi-omic” approach generates a comprehensive profile of molecular alterations for each cancer type. Alterations are changes in DNA or RNA, such as rearrangements in chromosome structure or variations in gene expression, respectively. Through computational analyses and assays to validate biological function, TARGET researchers predict which alterations disrupt the function of a gene or pathway and promote cancer growth, progression, and/or survival. Researchers identify candidate therapeutic targets and/or prognostic markers from the cancer-associated alterations.

The combi-targeting concept: synthesis of stable nitrosoureas designed to inhibit the epidermal growth factor receptor (EGFR).

Science.gov (United States)

Domarkas, Juozas; Dudouit, Fabienne; Williams, Christopher; Qiyu, Qiu; Banerjee, Ranjita; Brahimi, Fouad; Jean-Claude, Bertrand Jacques

2006-06-15

According to the "combi-targeting" concept, the EGFR tyrosine kinase (TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds (3'-Cl and Br series) with small angles (0.5-3 degrees ) were generally stronger EGFR TK inhibitors than those with large angles (18-21 degrees ). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC(50) values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line (Pearson r = 0.8). On the basis of stability (t(1/2)), EGFR TK inhibitory potency (IC(50)), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.

Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma.

Science.gov (United States)

Johnson, Jennifer; Ascierto, Maria Libera; Mittal, Sandeep; Newsome, David; Kang, Liang; Briggs, Michael; Tanner, Kirk; Marincola, Francesco M; Berens, Michael E; Vande Woude, George F; Xie, Qian

2015-09-17

Constitutive MET signaling promotes invasiveness in most primary and recurrent GBM. However, deployment of available MET-targeting agents is confounded by lack of effective biomarkers for selecting suitable patients for treatment. Because endogenous HGF overexpression often causes autocrine MET activation, and also indicates sensitivity to MET inhibitors, we investigated whether it drives the expression of distinct genes which could serve as a signature indicating vulnerability to MET-targeted therapy in GBM. Interrogation of genomic data from TCGA GBM (Student's t test, GBM patients with high and low HGF expression, p ≤ 0.00001) referenced against patient-derived xenograft (PDX) models (Student's t test, sensitive vs. insensitive models, p ≤ 0.005) was used to identify the HGF-dependent signature. Genomic analysis of GBM xenograft models using both human and mouse gene expression microarrays (Student's t test, treated vs. vehicle tumors, p ≤ 0.01) were performed to elucidate the tumor and microenvironment cross talk. A PDX model with EGFR(amp) was tested for MET activation as a mechanism of erlotinib resistance. We identified a group of 20 genes highly associated with HGF overexpression in GBM and were up- or down-regulated only in tumors sensitive to MET inhibitor. The MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall impede tumor growth by inhibiting cell cycle progression. EGFR (amp) tumors undergo erlotinib resistance responded to a combination of MET and EGFR inhibitors. Combining TCGA primary tumor datasets (human) and xenograft tumor model datasets (human tumor grown in mice) using therapeutic efficacy as an endpoint may serve as a useful approach to discover and develop molecular signatures as therapeutic biomarkers for targeted therapy. The HGF dependent signature may serve as a candidate predictive signature for patient enrollment in clinical trials using MET inhibitors

Platelet-camouflaged nanococktail: Simultaneous inhibition of drug-resistant tumor growth and metastasis via a cancer cells and tumor vasculature dual-targeting strategy.

Science.gov (United States)

Jing, Lijia; Qu, Haijing; Wu, Dongqi; Zhu, Chaojian; Yang, Yongbo; Jin, Xing; Zheng, Jian; Shi, Xiangsheng; Yan, Xiufeng; Wang, Yang

2018-01-01

Multidrug resistance (MDR) poses a great challenge to cancer therapy. It is difficult to inhibit the growth of MDR cancer due to its chemoresistance. Furthermore, MDR cancers are more likely to metastasize, causing a high mortality among cancer patients. In this study, a nanomedicine RGD-NPVs@MNPs/DOX was developed by encapsulating melanin nanoparticles (MNPs) and doxorubicin (DOX) inside RGD peptide (c(RGDyC))-modified nanoscale platelet vesicles (RGD-NPVs) to efficiently inhibit the growth and metastasis of drug-resistant tumors via a cancer cells and tumor vasculature dual-targeting strategy. Methods: The in vitro immune evasion potential and the targeting performance of RGD-NPVs@MNPs/DOX were examined using RAW264.7, HUVECs, MDA-MB-231 and MDA-MB-231/ADR cells lines. We also evaluated the pharmacokinetic behavior and the in vivo therapeutic performance of RGD-NPVs@MNPs/DOX using a MDA-MB-231/ADR tumor-bearing nude mouse model. Results: By taking advantage of the self-recognizing property of the platelet membrane and the conjugated RGD peptides, RGD-NPVs@MNPs/DOX was found to evade immune clearance and target the αvβ3 integrin on tumor vasculature and resistant breast tumor cells. Under irradiation with a NIR laser, RGD-NPVs@MNPs/DOX produced a multipronged effect, including reversal of cancer MDR, efficient killing of resistant cells by chemo-photothermal therapy, elimination of tumor vasculature for blocking metastasis, and long-lasting inhibition of the expressions of VEGF, MMP2 and MMP9 within the tumor. Conclusion: This versatile nanomedicine of RGD-NPVs@MNPs/DOX integrating unique biomimetic properties, excellent targeting performance, and comprehensive therapeutic strategies in one formulation might bring opportunities to MDR cancer therapy.

Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

Science.gov (United States)

Bianchi, Enrica; Taurone, Samanta; Bardella, Lia; Signore, Alberto; Pompili, Elena; Sessa, Vincenzo; Chiappetta, Caterina; Fumagalli, Lorenzo; Di Gioia, Cira; Pastore, Francesco S; Scarpa, Susanna; Artico, Marco

2015-10-01

Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD). © 2015 Authors; published by Portland Press Limited.

Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

Science.gov (United States)

Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

2010-05-14

Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)

Science.gov (United States)

Zhou, Yihua; Xu, Bixiong C.; Maheshwari, Hiralal G.; He, Li; Reed, Michael; Lozykowski, Maria; Okada, Shigeru; Cataldo, Lori; Coschigamo, Karen; Wagner, Thomas E.; Baumann, Gerhard; Kopchick, John J.

1997-01-01

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans. PMID:9371826

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse).

Science.gov (United States)

Zhou, Y; Xu, B C; Maheshwari, H G; He, L; Reed, M; Lozykowski, M; Okada, S; Cataldo, L; Coschigamo, K; Wagner, T E; Baumann, G; Kopchick, J J

1997-11-25

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.

Brassinosteriod Insensitive 2 (BIN2) acts as a downstream effector of the Target of Rapamycin (TOR) signaling pathway to regulate photoautotrophic growth in Arabidopsis.

Science.gov (United States)

Xiong, Fangjie; Zhang, Rui; Meng, Zhigang; Deng, Kexuan; Que, Yumei; Zhuo, Fengping; Feng, Li; Guo, Sundui; Datla, Raju; Ren, Maozhi

2017-01-01

The components of the target of rapamycin (TOR) signaling pathway have been well characterized in heterotrophic organisms from yeast to humans. However, because of rapamycin insensitivity, embryonic lethality in tor null mutants and a lack of reliable ways of detecting TOR protein kinase in higher plants, the key players upstream and downstream of TOR remain largely unknown in plants. Using engineered rapamycin-sensitive Binding Protein 12-2 (BP12-2) plants, the present study showed that combined treatment with rapamycin and active-site TOR inhibitors (asTORis) results in synergistic inhibition of TOR activity and plant growth in Arabidopsis. Based on this system, we revealed that TOR signaling plays a crucial role in modulating the transition from heterotrophic to photoautotrophic growth in Arabidopsis. Ribosomal protein S6 kinase 2 (S6K2) was identified as a direct downstream target of TOR, and the growth of TOR-suppressed plants could be rescued by up-regulating S6K2. Systems, genetic, and biochemical analyses revealed that Brassinosteriod Insensitive 2 (BIN2) acts as a novel downstream effector of S6K2, and the phosphorylation of BIN2 depends on TOR-S6K2 signaling in Arabidopsis. By combining pharmacological with genetic and biochemical approaches, we determined that the TOR-S6K2-BIN2 signaling pathway plays important roles in regulating the photoautotrophic growth of Arabidopsis. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma

International Nuclear Information System (INIS)

Baumann, Philipp; Mandl-Weber, Sonja; Oduncu, Fuat; Schmidmaier, Ralf

2009-01-01

NVP-BEZ235 is a new inhibitor of phosphoinositol-3-kinase (PI3 kinase) and mammalian target of rapamycin (mTOR) whose efficacy in advanced solid tumours is currently being evaluated in a phase I/II clinical trial. Here we show that NVP-BEZ235 inhibits growth in common myeloma cell lines as well as primary myeloma cells at nanomolar concentrations in a time and dose dependent fashion. Further experiments revealed induction of apoptosis in three of four cell lines. Inhibition of cell growth was mainly due to inhibition of myeloma cell proliferation, as shown by the BrdU assay. Cell cycle analysis revealed induction of cell cycle arrest in the G1 phase, which was due to downregulation of cyclin D1, pRb and cdc25a. NVP-BEZ235 inhibited phosphorylation of protein kinase B (Akt), P70S6k and 4E-BP-1. Furthermore we show that the stimulatory effect of CD40-ligand (CD40L), insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6) and conditioned medium of HS-5 stromal cells on myeloma cell growth is completely abrogated by NVP-BEZ235. In addition, synergism studies revealed synergistic and additive activity of NVP-BEZ235 together with melphalan, doxorubicin and bortezomib. Taken together, inhibition of PI3 kinase/mTOR by NVP-BEZ235 is highly effective and NVP-BEZ235 represents a potential new candidate for targeted therapy in multiple myeloma

Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor

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Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun; Feng, Jian-Quan; Kobayashi, Tatsuya; Merregaert, Joseph; Liu, Chuan-Ju

2016-01-01

Chondrogenesis and endochondral ossification are precisely controlled by cellular interactions with surrounding matrix proteins and growth factors that mediate cellular signaling pathways. Here, we report that extracellular matrix protein 1 (ECM1) is a previously unrecognized regulator of chondrogenesis. ECM1 is induced in the course of chondrogenesis and its expression in chondrocytes strictly depends on parathyroid hormone–related peptide (PTHrP) signaling pathway. Overexpression of ECM1 suppresses, whereas suppression of ECM1 enhances, chondrocyte differentiation and hypertrophy in vitro and ex vivo. In addition, target transgene of ECM1 in chondrocytes or osteoblasts in mice leads to striking defects in cartilage development and endochondral bone formation. Of importance, ECM1 seems to be critical for PTHrP action in chondrogenesis, as blockage of ECM1 nearly abolishes PTHrP regulation of chondrocyte hypertrophy, and overexpression of ECM1 rescues disorganized growth plates of PTHrP-null mice. Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an interaction network and act in concert in the regulation of chondrogenesis.—Kong, L., Zhao, Y.-P., Tian, Q.-Y., Feng, J.-Q., Kobayashi, T., Merregaert, J., Liu, C.-J. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. PMID:27075243

Role of nature reserves in giant panda protection.

Science.gov (United States)

Kang, Dongwei; Li, Junqing

2018-02-01

Giant panda (Ailuropoda melanoleuca) is a flagship species in nature conservation of the world; to protect this species, 67 nature reserves have been established in China. To evaluate the protection effect of giant panda nature reserves, we analyzed the variation of giant panda number and habitat area of 23 giant panda nature reserves of Sichuan province based on the national survey data released by State Forestry Administration and Sichuan Forestry Department. Results showed that from the third national survey to the fourth, giant panda number and habitat area of 23 giant panda nature reserves of Sichuan province failed to realize the significant increase. Furthermore, we found that the total population growth rate of 23 nature reserves in the last 12 years was lower than those of the province total of Sichuan and the national total of China, and the total habitat area of the 23 nature reserves was decreasing in the last 12 years, but the province total and national total were all increasing. We propose that giant panda protection should pay more attention to how to improve the protective effects of nature reserves.

Fibroblast growth factor receptors in breast cancer.

Science.gov (United States)

Wang, Shuwei; Ding, Zhongyang

2017-05-01

Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.

Macronutrient intake in preschoolers with cystic fibrosis and the relationship between macronutrients and growth.

Science.gov (United States)

Filigno, Stephanie S; Robson, Shannon M; Szczesniak, Rhonda D; Chamberlin, Leigh A; Baker, Meredith A; Sullivan, Stephanie M; Kroner, John; Powers, Scott W

2017-07-01

Adequate nutrition is essential for growth in children with cystic fibrosis (CF). The new CF Foundation Clinical Practice Guidelines bring attention to monitoring macronutrient intake as well as total energy. Dietary intake of 75 preschool children with CF and pancreatic insufficiency was examined and compared to the Clinical Practice Guidelines. Regression analyses examined relationships between macronutrient intake and growth. Approximately 45% of children met the 110% minimum recommended dietary allowance (RDA) recommendation. Children consumed 35.3% (6.1) of total daily energy intake from fat, 12.7% (1.7) from protein, and 52.0% (6.1) from carbohydrates. Percent energy from protein was associated with height growth. Many preschoolers with CF are not meeting nutrition benchmarks for total energy and fat. To optimize nutrition early, dietary monitoring with frequent individualized feedback is needed. Optimizing intake of macronutrients that promote growth, especially fat and protein, should be a primary clinical target. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer

International Nuclear Information System (INIS)

Li, Weina; He, Fei

2014-01-01

Highlights: • Expression of MMD is increased in lung cancer tissues. • Knockdown of MMD inhibits growth of A549 and LLC cells in vitro and in vivo. • MMD is a direct functional target of miR-140-5p. • MiR-140-5p/MMD axis regulates Erk1/2 signaling. - Abstract: Monocyte to macrophage differentiation-associated (MMD) is identified in macrophages as a gene associated with the differentiation from monocytes to macrophages. Recent microarray analysis for non-small cell lung cancer (NSCLC) suggests that MMD is an important signature associated with relapse and survival among patients with NSCLC. Therefore, we speculate that MMD likely plays a role in lung cancer. In this study, we found that the protein level of MMD was increased in lung cancer compared to benign lung tissues, and knockdown of MMD inhibited the growth of A549 and Lewis lung cancer cells (LLC) in vitro and in vivo. Integrated analysis demonstrated that MMD was a direct functional target of miR-140-5p. Furthermore, we found that miR-140-5p/MMD axis could affect the cell proliferation of lung cancer cells by regulating Erk signaling. Together, our results highlight the significance of miR-140-5p/MMD axis in lung cancer, and miR-140-5p/MMD axis could serve as new molecular targets for the therapy against lung cancer

Anthropogenic disturbances jeopardize biodiversity conservation within tropical rainforest reserves.

Science.gov (United States)

Martínez-Ramos, Miguel; Ortiz-Rodríguez, Iván A; Piñero, Daniel; Dirzo, Rodolfo; Sarukhán, José

2016-05-10

Anthropogenic disturbances affecting tropical forest reserves have been documented, but their ecological long-term cumulative effects are poorly understood. Habitat fragmentation and defaunation are two major anthropogenic threats to the integrity of tropical reserves. Based on a long-term (four decades) study, we document how these disturbances synergistically disrupt ecological processes and imperil biodiversity conservation and ecosystem functioning at Los Tuxtlas, the northernmost tropical rainforest reserve in the Americas. Deforestation around this reserve has reduced the reserve to a medium-sized fragment (640 ha), leading to an increased frequency of canopy-gap formation. In addition, hunting and habitat loss have caused the decline or local extinction of medium and large herbivores. Combining empirical, experimental, and modeling approaches, we support the hypothesis that such disturbances produced a demographic explosion of the long-lived (≈120 y old, maximum height of 7 m) understory palm Astrocaryum mexicanum, whose population has increased from 1,243-4,058 adult individuals per hectare in only 39 y (annual growth rate of ca 3%). Faster gap formation increased understory light availability, enhancing seed production and the growth of immature palms, whereas release from mammalian herbivory and trampling increased survival of seedlings and juveniles. In turn, the palm's demographic explosion was followed by a reduction of tree species diversity, changing forest composition, altering the relative contribution of trees to forest biomass, and disrupting litterfall dynamics. We highlight how indirect anthropogenic disturbances (e.g., palm proliferation) on otherwise protected areas threaten tropical conservation, a phenomenon that is currently eroding the planet's richest repositories of biodiversity.

Targeting long non-coding RNA-TUG1 inhibits tumor growth and angiogenesis in hepatoblastoma.

Science.gov (United States)

Dong, R; Liu, G-B; Liu, B-H; Chen, G; Li, K; Zheng, S; Dong, K-R

2016-06-30

Hepatoblastoma is the most common liver tumor of early childhood, which is usually characterized by unusual hypervascularity. Recently, long non-coding RNAs (lncRNA) have emerged as gene regulators and prognostic markers in several cancers, including hepatoblastoma. We previously reveal that lnRNA-TUG1 is upregulated in hepatoblastoma specimens by microarray analysis. In this study, we aim to elucidate the biological and clinical significance of TUG1 upregulation in hepatoblastoma. We show that TUG1 is significantly upregulated in human hepatoblastoma specimens and metastatic hepatoblastoma cell lines. TUG1 knockdown inhibits tumor growth and angiogenesis in vivo, and decreases hepatoblastoma cell viability, proliferation, migration, and invasion in vitro. TUG1, miR-34a-5p, and VEGFA constitutes to a regulatory network, and participates in regulating hepatoblastoma cell function, tumor progression, and tumor angiogenesis. Overall, our findings indicate that TUG1 upregulation contributes to unusual hypervascularity of hepatoblastoma. TUG1 is a promising therapeutic target for aggressive, recurrent, or metastatic hepatoblastoma.

Thermophilic growth and enzymatic thermostability are polyphyletic traits within Chaetomiaceae.

Science.gov (United States)

van den Brink, Joost; Facun, Kryss; de Vries, Michel; Stielow, J Benjamin

2015-12-01

Thermophilic fungi have the potential to produce industrial-relevant thermostable enzymes, in particular for the degradation of plant biomass. Sordariales is one of the few fungal orders containing several thermophilic taxa, of which many have been associated with the production of thermostable enzymes. The evolutionary affiliation of Sordariales fungi, especially between thermophiles and non-thermophilic relatives, is however poorly understood. Phylogenetic analysis within the current study was based on sequence data, derived from a traditional Sanger and highly multiplexed targeted next generation sequencing approach of 45 isolates. The inferred phylogeny and detailed growth analysis rendered the trait 'thermophily' as polyphyletic within Chaetomiaceae (Sordariales, Sordariomycetes), and characteristic to: Myceliophthora spp., Thielavia terrestris, Chaetomium thermophilum, and Mycothermus thermophilus. Compared to mesophiles, the isolates within thermophilic taxa produced enzyme mixtures with the highest thermostability of known cellulase activities. Temperature profiles of the enzyme activities correlated strongly with the optimal growth temperatures of the isolates but not with their phylogenetic relationships. This strong correlation between growth and enzyme characteristics indicated that detailed analysis of growth does give predictive information on enzyme physiology. The variation in growth and enzyme characteristics reveals these fungi as an excellent platform to better understand fungal thermophily and enzyme thermostability. Copyright © 2015 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Recent Advances in Targetable Therapeutics in Metastatic Non-Squamous NSCLC

Directory of Open Access Journals (Sweden)

Pranshu eBansal

2016-05-01

Full Text Available Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC. With the discovery of epidermal growth factor receptor (EGFR mutations, anaplastic lymphoma kinase (ALK rearrangements and effective targeted therapies, therapeutic options are expanding for patients with lung adenocarcinoma. Here, we review novel therapies in non-squamous NSCLC, which are directed against oncogenic targets, including EGFR, ALK, ROS1, BRAF, MET, human epidermal growth factor receptor 2 (HER2, vascular endothelial growth factor receptor 2 (VEGFR2, RET and NTRK. With the rapidly evolving molecular testing and development of new targeted agents, our ability to further personalize therapy in non-squamous NSCLC is rapidly expanding.

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.

Science.gov (United States)

Pérez-Pérez, María-Jesús; Priego, Eva-María; Bueno, Oskía; Martins, Maria Solange; Canela, María-Dolores; Liekens, Sandra

2016-10-13

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

Regeneration of cervical reserve cell-like cells from human induced pluripotent stem cells (iPSCs): A new approach to finding targets for cervical cancer stem cell treatment.

Science.gov (United States)

Sato, Masakazu; Kawana, Kei; Adachi, Katsuyuki; Fujimoto, Asaha; Yoshida, Mitsuyo; Nakamura, Hiroe; Nishida, Haruka; Inoue, Tomoko; Taguchi, Ayumi; Ogishima, Juri; Eguchi, Satoko; Yamashita, Aki; Tomio, Kensuke; Wada-Hiraike, Osamu; Oda, Katsutoshi; Nagamatsu, Takeshi; Osuga, Yutaka; Fujii, Tomoyuki

2017-06-20

Cervical reserve cells are epithelial progenitor cells that are pathologically evident as the origin of cervical cancer. Thus, investigating the characteristics of cervical reserve cells could yield insight into the features of cervical cancer stem cells (CSCs). In this study, we established a method for the regeneration of cervical reserve cell-like properties from human induced pluripotent stem cells (iPSCs) and named these cells induced reserve cell-like cells (iRCs). Approximately 70% of iRCs were positive for the reserve cell markers p63, CK5 and CK8. iRCs also expressed the SC junction markers CK7, AGR2, CD63, MMP7 and GDA. While iRCs expressed neither ERα nor ERβ, they expressed CA125. These data indicated that iRCs possessed characteristics of cervical epithelial progenitor cells. iRCs secreted higher levels of several inflammatory cytokines such as macrophage migration inhibitory factor (MIF), soluble intercellular adhesion molecule 1 (sICAM-1) and C-X-C motif ligand 10 (CXCL-10) compared with normal cervical epithelial cells. iRCs also expressed human leukocyte antigen-G (HLA-G), which is an important cell-surface antigen for immune tolerance and carcinogenesis. Together with the fact that cervical CSCs can originate from reserve cells, our data suggested that iRCs were potent immune modulators that might favor cervical cancer cell survival. In conclusion, by generating reserve cell-like properties from iPSCs, we provide a new approach that may yield new insight into cervical cancer stem cells and help find new oncogenic targets.

Small interfering RNA targeted to IGF-IR delays tumor growth and induces proinflammatory cytokines in a mouse breast cancer model.

Directory of Open Access Journals (Sweden)

Tiphanie Durfort

Full Text Available Insulin-like growth factor I (IGF-I and its type I receptor (IGF-IR play significant roles in tumorigenesis and in immune response. Here, we wanted to know whether an RNA interference approach targeted to IGF-IR could be used for specific antitumor immunostimulation in a breast cancer model. For that, we evaluated short interfering RNA (siRNAs for inhibition of in vivo tumor growth and immunological stimulation in immunocompetent mice. We designed 2'-O-methyl-modified siRNAs to inhibit expression of IGF-IR in two murine breast cancer cell lines (EMT6, C4HD. Cell transfection of IGF-IR siRNAs decreased proliferation, diminished phosphorylation of downstream signaling pathway proteins, AKT and ERK, and caused a G0/G1 cell cycle block. The IGF-IR silencing also induced secretion of two proinflammatory cytokines, TNF- α and IFN-γ. When we transfected C4HD cells with siRNAs targeting IGF-IR, mammary tumor growth was strongly delayed in syngenic mice. Histology of developing tumors in mice grafted with IGF-IR siRNA treated C4HD cells revealed a low mitotic index, and infiltration of lymphocytes and polymorphonuclear neutrophils, suggesting activation of an antitumor immune response. When we used C4HD cells treated with siRNA as an immunogen, we observed an increase in delayed-type hypersensitivity and the presence of cytotoxic splenocytes against wild-type C4HD cells, indicative of evolving immune response. Our findings show that silencing IGF-IR using synthetic siRNA bearing 2'-O-methyl nucleotides may offer a new clinical approach for treatment of mammary tumors expressing IGF-IR. Interestingly, our work also suggests that crosstalk between IGF-I axis and antitumor immune response can mobilize proinflammatory cytokines.

10 years anniversary of the Poles'e state radioecological reserve (collected articles)

International Nuclear Information System (INIS)

Parfenov, V.I.

1998-01-01

The results of long time investigations of radionuclide contamination dynamics of soils, flora and fauna conducted by research workers of the reserve and National Academy of Sciences of Belarus on the territory of the reserve are offered. The different aspects of plant growth and animal behaviour in new ecological conditions are estimated

Growth and metabolic characteristics of oleaginous microalgal isolates from Nilgiri biosphere Reserve of India.

Science.gov (United States)

Thangavel, Kalaiselvi; Radha Krishnan, Preethi; Nagaiah, Srimeena; Kuppusamy, Senthil; Chinnasamy, Senthil; Rajadorai, Jude Sudhagar; Nellaiappan Olaganathan, Gopal; Dananjeyan, Balachandar

2018-01-03

Renewable energy for sustainable development is a subject of a worldwide debate since continuous utilization of non-renewable energy sources has a drastic impact on the environment and economy; a search for alternative energy resources is indispensable. Microalgae are promising and potential alternate energy resources for biodiesel production. Thus, our efforts were focused on surveying the natural diversity of microalgae for the production of biodiesel. The present study aimed at identification, isolation, and characterization of oleaginous microalgae from shola forests of Nilgiri Biosphere Reserve (NBR), the biodiversity hot spot of India, where the microalgal diversity has not yet been systematically investigated. Overall the higher biomass yield, higher lipid accumulation and thermotolerance observed in the isolated microalgal strains have been found to be the desirable traits for the efficient biodiesel production. Species composition and diversity analysis yielded ten potential microalgal isolates belonging to Chlorophyceae and Cyanophyceae classes. The chlorophytes exhibited higher growth rate, maximum biomass yield, and higher lipid accumulation than Cyanophyceae. Among the chlorophytes, the best performing strains were identified and represented by Acutodesmus dissociatus (TGA1), Chlorella sp. (TGA2), Chlamydomonadales sp. (TGA3) and Hindakia tetrachotoma (PGA1). The Chlamydomonadales sp. recorded with the highest growth rate, lipid accumulation and biomass yield of 0.28 ± 0.03 day -1 (μ exp ), 29.7 ± 0.69% and 134.17 ± 16.87 mg L -1  day -1 , respectively. It was also found to grow well at various temperatures, viz., 25 °C, 35 °C, and 45 °C, indicating its suitability for open pond cultivation. The fatty acid methyl ester (FAME) analysis of stationary phase cultures of selected four algal strains by tandem mass spectrograph showed C16:0, C18:1 and C18:3 as dominant fatty acids suitable for biodiesel production. All the three

Targeted therapy in lung and breast cancer: a big deal

OpenAIRE

Caffarra, Cristina

2015-01-01

Great strides have been done in treating cancer. For decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy which targets all dividing cells. In the last ten years the identification of different driver oncogenic mutations has allowed the development of targeted drugs. Targeted cancer therapies are based on the use of drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. The ...

Can we protect the gut in critical illness? The role of growth factors and other novel approaches.

Science.gov (United States)

Dominguez, Jessica A; Coopersmith, Craig M

2010-07-01

The intestine plays a central role in the pathophysiology of critical illness and is frequently called the "motor" of the systemic inflammatory response. Perturbations to the intestinal barrier can lead to distant organ damage and multiple organ failure. Therefore, identifying ways to preserve intestinal integrity may be of paramount importance. Growth factors and other peptides have emerged as potential tools for modulation of intestinal inflammation and repair due to their roles in cellular proliferation, differentiation, migration, and survival. This review examines the involvement of growth factors and other peptides in intestinal epithelial repair during critical illness and their potential use as therapeutic targets. Copyright 2010 Elsevier Inc. All rights reserved.

A33 antibody-functionalized exosomes for targeted delivery of doxorubicin against colorectal Cancer.

Science.gov (United States)

Li, Yan; Gao, Yuan; Gong, Chunai; Wang, Zhuo; Xia, Qingming; Gu, Fenfen; Hu, Chuling; Zhang, Lijuan; Guo, Huiling; Gao, Shen

2018-06-20

Exosomes have emerged as a promising drug carrier with low immunogenicity, high biocompatibility and delivery efficiency. Here in, we isolated exosomes from A33-positive LIM1215 cells (A33-Exo) and loaded them with doxorubicin (Dox). Furthermore, we coated surface-carboxyl superparamagnetic iron oxide nanoparticles (US) with A33 antibodies (A33Ab-US), expecting that these A33 antibodies on the surface of the nanoparticles could bind to A33-positive exosomes and form a complex (A33Ab-US-Exo/Dox) to target A33-positive colon cancer cells. The results showed that A33Ab-US-Exo/Dox had good binding affinity and antiproliferative effect in LIM1215 cells, as shown by increased uptake of the complex. In vivo study showed that A33Ab-US-Exo/Dox had an excellent tumor targeting ability, and was able to inhibit tumor growth and prolong the survival of the mice with reduced cardiotoxicity. In summary, exosomes functionalized by targeting ligands through coating with high-density antibodies may prove to be a novel delivery system for targeted drugs against human cancers. Copyright © 2018 Elsevier Inc. All rights reserved.

Optimal design of compact and connected nature reserves for multiple species.

Science.gov (United States)

Wang, Yicheng; Önal, Hayri

2016-04-01

When designing a conservation reserve system for multiple species, spatial attributes of the reserves must be taken into account at species level. The existing optimal reserve design literature considers either one spatial attribute or when multiple attributes are considered the analysis is restricted only to one species. We built a linear integer programing model that incorporates compactness and connectivity of the landscape reserved for multiple species. The model identifies multiple reserves that each serve a subset of target species with a specified coverage probability threshold to ensure the species' long-term survival in the reserve, and each target species is covered (protected) with another probability threshold at the reserve system level. We modeled compactness by minimizing the total distance between selected sites and central sites, and we modeled connectivity of a selected site to its designated central site by selecting at least one of its adjacent sites that has a nearer distance to the central site. We considered structural distance and functional distances that incorporated site quality between sites. We tested the model using randomly generated data on 2 species, one ground species that required structural connectivity and the other an avian species that required functional connectivity. We applied the model to 10 bird species listed as endangered by the state of Illinois (U.S.A.). Spatial coherence and selection cost of the reserves differed substantially depending on the weights assigned to these 2 criteria. The model can be used to design a reserve system for multiple species, especially species whose habitats are far apart in which case multiple disjunct but compact and connected reserves are advantageous. The model can be modified to increase or decrease the distance between reserves to reduce or promote population connectivity. © 2015 Society for Conservation Biology.

Wind offering in energy and reserve markets

Science.gov (United States)

Soares, T.; Pinson, P.; Morais, H.

2016-09-01

The increasing penetration of wind generation in power systems to fulfil the ambitious European targets will make wind power producers to play an even more important role in the future power system. Wind power producers are being incentivized to participate in reserve markets to increase their revenue, since currently wind turbine/farm technologies allow them to provide ancillary services. Thus, wind power producers are to develop offering strategies for participation in both energy and reserve markets, accounting for market rules, while ensuring optimal revenue. We consider a proportional offering strategy to optimally decide upon participation in both markets by maximizing expected revenue from day-ahead decisions while accounting for estimated regulation costs for failing to provide the services. An evaluation of considering the same proportional splitting of energy and reserve in both day- ahead and balancing market is performed. A set of numerical examples illustrate the behavior of such strategy. An important conclusion is that the optimal split of the available wind power between energy and reserve strongly depends upon prices and penalties on both market trading floors.

The epidermal growth factor receptor as a target for gastrointestinal cancer therapy.

Science.gov (United States)

Tedesco, Karen L; Lockhart, A Craig; Berlin, Jordan D

2004-10-01

The epidermal growth factor receptor (EGFR) is a member of the family of transmembrane protein kinase receptors known as the erbB or HER receptor family. When activated, EGFR phosphorylates and activates other intracellular proteins that affect cell signaling pathways, cellular proliferation, control of apoptosis and angiogenesis. EGFR signaling is best thought of as a network of activating and inactivating proteins with EGFR as the entry point into the network. EGFR overexpression occurs in most GI malignancies and while data are not entirely consistent, EGFR overexpression often confers a poor prognosis in those GI malignancies that have been studied. It often correlates with poorly differentiated histology, more advanced stage and other known poor prognostic markers. The EGFR is a tempting target because of its presence and overexpression on so many tumor types. However, downstream of the EGFR are several proteins that may be activated without EGFR thus allowing blockade to be overcome. Therefore, while blocking the activity of the EGFR protein appears to be a promising anticancer strategy, a simplistic strategy of blocking only EGFR is likely to only impact a minority of patients. It is time for the laboratory and clinical researchers to work closely together to develop this treatment strategy, moving back and forth from clinical to laboratory to best understand how to block this network effectively enough to produce a broader antitumor effect. While multiple methods of targeting the EGFR pathway are under development, including the inhibition of downstream proteins, only two modalities have entered clinical trials in GI malignancies: small molecule inhibitors of the intracellular kinase domain of EGFR and antibodies designed to block the extracellular ligand-binding domain of EGFR. EGFR inhibitors are still experimental in every GI malignancy with the notable exception of cetuximab that is approved for second or third-line therapy of metastatic colorectal

Targeting the epidermal growth factor receptor in solid tumor malignancies

DEFF Research Database (Denmark)

Nedergaard, Mette K; Hedegaard, Chris J; Poulsen, Hans S

2012-01-01

been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind...... to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal...... agents to the EGFR/EGFRvIII-positive cells; among these are radio-labelled mAbs and immunotoxins. This article reviews the current status and efficacy of EGFR/EGFRvIII-targeted therapies....

Reciprocal Regulation of the TOR Kinase and ABA Receptor Balances Plant Growth and Stress Response.

Science.gov (United States)

Wang, Pengcheng; Zhao, Yang; Li, Zhongpeng; Hsu, Chuan-Chih; Liu, Xue; Fu, Liwen; Hou, Yueh-Ju; Du, Yanyan; Xie, Shaojun; Zhang, Chunguang; Gao, Jinghui; Cao, Minjie; Huang, Xiaosan; Zhu, Yingfang; Tang, Kai; Wang, Xingang; Tao, W Andy; Xiong, Yan; Zhu, Jian-Kang

2018-01-04

As sessile organisms, plants must adapt to variations in the environment. Environmental stress triggers various responses, including growth inhibition, mediated by the plant hormone abscisic acid (ABA). The mechanisms that integrate stress responses with growth are poorly understood. Here, we discovered that the Target of Rapamycin (TOR) kinase phosphorylates PYL ABA receptors at a conserved serine residue to prevent activation of the stress response in unstressed plants. This phosphorylation disrupts PYL association with ABA and with PP2C phosphatase effectors, leading to inactivation of SnRK2 kinases. Under stress, ABA-activated SnRK2s phosphorylate Raptor, a component of the TOR complex, triggering TOR complex dissociation and inhibition. Thus, TOR signaling represses ABA signaling and stress responses in unstressed conditions, whereas ABA signaling represses TOR signaling and growth during times of stress. Plants utilize this conserved phospho-regulatory feedback mechanism to optimize the balance of growth and stress responses. Copyright © 2017 Elsevier Inc. All rights reserved.

Foreign acquisition, plant survival, and employment growth

DEFF Research Database (Denmark)

Bandick, Roger; Görg, Holger

2010-01-01

This paper analyzes the effect of foreign acquisition on survival and employment growth of targets using data on Swedish manufacturing plants.We separate targeted plants into those within Swedish MNEs, Swedish exporting non-MNEs, and purely domestic firms. The results, controlling for possible...... acquisitions. We find robust positive employment growth effects only for exporters and only if the takeover is vertical....

Targeted drugs in radiation therapy

International Nuclear Information System (INIS)

Favaudon, V.; Hennequin, C.; Hennequin, C.

2004-01-01

New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neo-angiogenesis promoters, TGF-β, cyclooxygenase or the transcription factor NF-κB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms. (authors)

Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.

Science.gov (United States)

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-07-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells

Directory of Open Access Journals (Sweden)

Xing-Cheng Zhao

2013-07-01

Full Text Available The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD motif targeting endothelial cells (ECs. We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2+ perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

OPTIMIZATION OF MANAGEMENT APPROACHES: RESERVES GROWTH OF EFFICIENCY OF NR-MANAGEMENT IN THE BUSINESS

Directory of Open Access Journals (Sweden)

F. Sh. Fedorova

2016-01-01

Full Text Available The article describes one of the possible ways of building more eff ective relationships between managers and subordinates, taking into account variable range of individual motivation, capabilities and potential of people belonging to diff erent types of employees.The topic is urgent due to the changes in modern business processes that require new approaches to management. Goal/objectives. Our aim is to develop an approach to the creation of human resources management model that takes into account not only the knowledge and skills of employees, but also their deeper individual characteristics. The approach accounts for the hierarchy of one's life values and drives, temperament, strains, habitual and unfamiliar social roles, way of thinking, preferred pattern of communication, peculiarities of the behavior in power relations and a host of other features. We suggest that asking them into account is an incredible opportunity for productivity growth and team eff ectiveness improvements.Methodology. The theoretical basis of the article are studies of Russian and foreign authors on the classifications and typologies of personality, of social roles, roles in the team, as well as subordinate types. The article refl ects the results of studies and observations of the authors on the peculiarities of manifestation of diff erent types of people in decision-making and business communications.Results. We suggest the typology of subordinates describing the key characteristics and preferences of representatives of the types. The typology allows to build relationships between managers and subordinates more eff ectively.Conclusions/significance. We propose typology of subordinates that can be used to develop management models focused on certain types of employees. This, in turn, may be useful for structuring of human management, retrieval of unused but eff ective management tools, and for building an eff ective staff -management relations network as a whole to

Development, implementation, and impact of a collaborative junior faculty engagement and professional growth program: The Young Faculty Leadership Initiative.

Science.gov (United States)

Pate, Adam; Smith, Jennifer; Caldwell, David; Horace, Alexis; Zagar, Michelle

2018-03-01

To develop, implement, and evaluate the effect of a faculty engagement and professional growth program targeted at junior faculty members. A faculty engagement and growth program based on adult learning theory was piloted in a clinical sciences department. Effect of the model was evaluated using a pre/post-survey evaluating faculty output and work engagement using the Utrecht Work Engagement Scale (UWES). Average number of publications/projects with cross-campus collaboration increased (0.58 versus 1.25, P = 0.03, 95%CI 0.059-1.264). Involvement in national/state organizations, number of accepted poster presentations, and grants submitted and/or funded all increased (p>0.05). Total UWES score increased (4.13 vs. 4.495 p = 0.21) with the greatest subscale increase in vigor (3.833 vs 4.347, P = 0.1). A faculty engagement and growth program targeting junior faculty members using adult learning theory as a framework may provide a novel and economic way for schools to support the development of these critical team members. Copyright © 2017 Elsevier Inc. All rights reserved.

Bioimpact of application of pesticides with plant growth hormone (gibberellic acid on target and non-target microorganisms

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Mohamed Abdullah Al Abboud

2014-12-01

Full Text Available The objective of this investigation was to determine the impacts of fungicide, insecticide, plant growth hormone (gibberellic acid on soil microbiota, and the growth characteristics of Aspergillus flavus. In the fungicide or insecticide mixed with plant growth hormone treated soil sample, the total viable number of soil microbiota was found to be higher than that of the soil treated with fungicide or insecticide alone. Moderate effect of insecticide used on the total number of fungi was observed. On the other hand the effect of insecticide on soil bacteria was more than effect of fungicide, and the negative effect of fungicide on soil bacteria was observed particularly at latent periods (15 and 20 days of application. A great sensitivity to fungicide and insecticide was observed in the case of nitrogen fixing bacteria. At 15 days after fungicide and insecticide application the adverse effect was found. Morphological deformations were clear in A. flavus cultivated on medium containing fungicide, the fungus failed to form conidiospores, conidiophores and vesicles. Intermediate and terminal outgrowths like blisters and terminal vesicle originate from hyphae. The addition of plant growth hormone reduced the effect of fungicide on fungus.

Target post-evaluation of China's “12th Five-Year” oil and gas exploration and development planning and its “13th Five-Year” target prediction

Directory of Open Access Journals (Sweden)

Jiping Pan

2016-03-01

Full Text Available In the turn of 12th and 13th “Five-Year Plan” of China, the global oil and gas market changes greatly. In this regard, the target post-evaluation of the “12th Five-Year” oil and gas exploration and development planning was conducted, which is of significant importance to scientifically and reasonably making the specific “13th Five-Year” oil and gas exploration and development target planning. The post-evaluation results indicate that, in the period of “12th Five-Year Plan”, the oil and gas exploration and development targets of China were satisfactorily completed, but some deficiencies still existed. For example, the target of oil production (2 × 108 t was overfulfilled, while the target of oil reserves (65 × 108 t remained 6.4% outstanding. The target of gas reserves (3.5 × 1012 m3 was overfulfilled, while the target of gas production (1385 × 108 m3 remained 6.2% outstanding. Moreover, the targets of unconventional gases were not satisfactorily completed-shale gas being better than coalbed methane (CBM. Failures to fulfill some targets in “12th Five-Year Plan” were primarily attributed to the slowdown of oil and gas consumption growth, sharp drop of oil price, downgrading of resources, and changes of statistic basis under the new normal. The forecast results suggest that, in the period of “13th Five-Year Plan”, given USD50–70/bbl of world oil price, China's annual average incremental conventional oil and gas in place will be 10.0 × 108–12.0 × 108 t and 6000 × 108–8000 × 108 m3 respectively, annual average incremental shale gas and CBM in place will be 1000 × 108–2000 × 108 m3 and 500 × 108–1000 × 108 m3 respectively, and annual oil production will be about 2.0 × 108 t. By 2020, China's annual gas production will approach 1800 × 108–2000 × 108 m3 (shale gas: 200 × 108 m3, and CBM: 150 × 108 m3.

Factors Affecting Tufa Degradation in Jiuzhaigou National Nature Reserve, Sichuan, China

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Lixia Liu

2017-09-01

Full Text Available Water and tufa samples were collected from Arrow Bamboo Lake, the stream from Panda Lake to Five-Color Lake, Pearl Shoal and Shuzheng Lakes in Jiuzhaigou National Nature Reserve, China, between October 2013 and September 2014, to investigate tufa growth rate and water environment (water temperature, pH, electric conductivity, major ions and nutrients, and analyzed to explore the main causes of tufa degradation. The mean annual rate of tufa growth was low and varied within lakes, with the maximum deposit thickness of 332 μm/y. The calcite saturation index ranged from 0.65 to 0.83. Scanning electron microscope images showed that the tufa deposits had non-isopachous structures, and diatoms were the dominant microorganisms that participated in tufa deposition. Porous and crystalline structures of deposits were linked with a high tufa growth and small amounts of diatoms. Conversely, tufa deposits with amorphous and loose structures showed a low crystal growth rate and a high number of diatoms. A one-way analysis of variance and a least significant difference test were applied to identify site differences in water chemistry. Linear correlations indicated that nitrate, phosphate and sulfate inhibit tufa growth (p < 0.05. Increased nitrogen and phosphorus concentrations that originate mainly from atmospheric pollution and tourist activities at scenic attractions could trigger excessive diatom growth, which inhibits tufa precipitation. A series of measures should be implemented (e.g., the visitor number and vehicles should be regulated and controlled to minimize tufa degradation in the Jiuzhaigou National Nature Reserve.

The targets of curcumin.

Science.gov (United States)

Zhou, Hongyu; Beevers, Christopher S; Huang, Shile

2011-03-01

Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here.

Rural Sprawl and the Impact of Human Land Use on the Pine Ridge Indian Reservation, South Dakota

Science.gov (United States)

Campbell, R.; Bennett, T.

2005-12-01

The most important impact on global land cover is human use and development. With the recent population growth occurring on the reservations in South Dakota, specifically Pine Ridge Indian Reservation, the towns and communities of the reservation are undergoing change. Although urban sprawl certainly is not a consideration on the reservations, the population explosion currently underway has seen a subsequent increase in rural sprawl. In this case, rural sprawl is defined as exponential population growth and geographic expansion of remote reservation communities. The capacity of satellite imagery to encompass large land tracts make the use of this technology a cost effective way to visualize and investigate population growth in rural communities. Likewise, integrating remotely sensed data into a Geographic Information Systems (GIS) can be a powerful tool to identify environmental and other land use issues that impact the people and communities in and around the Pine Ridge area. The objective of this research is to (1) observe and calculate land cover change around three communities on the Pine Ridge Indian reservation using remotely sensed data (Landsat MSS, TM and ETM+) and Geographic Information Systems over a 20 year span, and (2) to discuss the potential impacts of rural sprawl on the Pine Ridge Reservation, SD. Preliminary results indicate that land cover has changed in relationship to increased population growth within three communities on the reservation. New housing developments, roads and buildings have appeared and these changes were detectable using Landsat imagery. These results will be discussed along with the experiences and education through the NASA Goddard Internship sponsored by the North Dakota Association of Tribal Colleges.

Impact of pesticides on plant growth promotion of Vigna radiata and non-target microbes: comparison between chemical- and bio-pesticides.

Science.gov (United States)

Gupta, Sukriti; Gupta, Rashi; Sharma, Shilpi

2014-08-01

To compare the target and non-target effects of two chemical-pesticides (chlorpyrifos and endosulfan) with that of a bio-pesticide (azadirachtin), Vigna radiata (mung bean) was grown in a randomized pot experiment with recommended and higher application rates of pesticides. Colony counts enumerating specific microbial populations, viz. fungi, Pseudomonas, nitrogen-fixing bacteria, and phosphate-solubilizing microorganisms, were performed. In addition, several plant growth parameters such as root and shoot lengths were also monitored. It was observed that the pesticides exerted a suppressive effect on different microbial communities under study in the initial 30 days period. The bacterial and fungal populations in chlorpyrifos treated plants increased thereafter. Endosulfan resulted in enhancement of fungi and nitrogen-fixing bacteria, although phosphate-solubilizing microorganisms were suppressed at higher application rates. Azadirachtin, which is gaining popularity owing to its biological origin, did not result in enhancement of any microbial populations; on the other hand, it had a deleterious effect on phosphate-solubilizing bacteria. This study is the first to evaluate the non-target effects of pesticides with a comparison between chemical- and bio-pesticides, and also stresses the importance of critical investigation of bio-pesticides before their wide spread application in agriculture.

Experimental study on ablative stabilization of Rayleigh-Taylor instability of laser-irradiated targets

Science.gov (United States)

Shigemori, Keisuke; Sakaiya, Tatsuhiko; Otani, Kazuto; Fujioka, Shinsuke; Nakai, Mitsuo; Azechi, Hiroshi; Shiraga, Hiroyuki; Tamari, Yohei; Okuno, Kazuki; Sunahara, Atsushi; Nagatomo, Hideo; Murakami, Masakatsu; Nishihara, Katsunobu; Izawa, Yasukazu

2004-09-01

Hydrodynamic instabilities are key issues of the physics of inertial confinement fusion (ICF) targets. Among the instabilities, Rayleigh-Taylor (RT) instability is the most important because it gives the largest growth factor in the ICF targets. Perturbations on the laser irradiated surface grow exponentially, but the growth rate is reduced by ablation flow. The growth rate γ is written as Takabe-Betti formula: γ = [kg/(1+kL)]1/2-βkm/pa, where k is wave number of the perturbation, g is acceleration, L is density scale-length, β is a coefficient, m is mass ablation rate per unit surface, and ρa is density at the ablation front. We experimentally measured all the parameters in the formula for polystyrene (CH) targets. Experiments were done on the HIPER laser facility at Institute of Laser Engineering, Osaka University. We found that the β value in the formula is ~ 1.7, which is in good agreements with the theoretical prediction, whereas the β for certain perturbation wavelengths are larger than the prediction. This disagreement between the experiment and the theory is mainly due to the deformation of the cutoff surface, which is created by non-uniform ablation flow from the ablation surface. We also found that high-Z doped plastic targets have multiablation structure, which can reduce the RT growth rate. When a low-Z target with high-Z dopant is irradiated by laser, radiation due to the high-Z dopant creates secondary ablation front deep inside the target. Since, the secondary ablation front is ablated by x-rays, the mass ablation rate is larger than the laser-irradiated ablation surface, that is, further reduction of the RT growth is expected. We measured the RT growth rate of Br-doped polystyrene targets. The experimental results indicate that of the CHBr targets show significantly small growth rate, which is very good news for the design of the ICF targets.

Pemetrexed With Platinum Combination as a Backbone for Targeted Therapy in Non-Small-Cell Lung Cancer.

Science.gov (United States)

Stinchcombe, Thomas E; Borghaei, Hossein; Barker, Scott S; Treat, Joseph Anthony; Obasaju, Coleman

2016-01-01

Standard platinum-based chemotherapy combinations for advanced non-small-cell lung cancer (NSCLC) have reached a plateau in terms of the survival benefit they offer for patients. In addition, the emerging clinical trend of tailored treatment based on patient characteristics has led to the development of therapeutic strategies that target specific cancer-related molecular pathways, including epidermal growth factor receptor (EGFR), angiogenesis, and anaplastic lymphoma kinase inhibitors. Current research is focused on combining targeted therapy with platinum-based chemotherapy in an endeavor to achieve an additional benefit in specific patient populations. Currently, pemetrexed is indicated for use in the first-line, maintenance, and second-line settings for the treatment of nonsquamous NSCLC. The combination of pemetrexed and cisplatin is well tolerated and is the approved standard first-line therapy. Thus, the pemetrexed-platinum backbone provides an attractive option for combination with targeted therapies. This review aims to summarize the current knowledge and future prospects of the use of pemetrexed-platinum as a backbone for combination with targeted therapies for NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

Entrepreneurship Education and Economic Growth

DEFF Research Database (Denmark)

Pedersen, Jonna; Lindquist, Carl Rickard

. This paper addresses the presumptions behind the project. The presumptions in relation to entrepreneurship demonstrate that the effort should target both growth entrepreneurs and SMEs in a wide sense; there is a need for growth entrepreneurs with ambitions to generate breakthrough innovation as well...

Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma.

Science.gov (United States)

Johnson, Thomas G; Schelch, Karin; Cheng, Yuen Y; Williams, Marissa; Sarun, Kadir H; Kirschner, Michaela B; Kao, Steven; Linton, Anthony; Klebe, Sonja; McCaughan, Brian C; Lin, Ruby C Y; Pirker, Christine; Berger, Walter; Lasham, Annette; van Zandwijk, Nico; Reid, Glen

2018-02-01

Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM. Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, and growth, colony formation, migration and invasion assays were conducted. MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference-mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion. MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Therapeutic Approaches to Target Cancer Stem Cells

International Nuclear Information System (INIS)

Diaz, Arlhee; Leon, Kalet

2011-01-01

The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC

Anti-PDGF receptor β antibody-conjugated squarticles loaded with minoxidil for alopecia treatment by targeting hair follicles and dermal papilla cells.

Science.gov (United States)

Aljuffali, Ibrahim A; Pan, Tai-Long; Sung, Calvin T; Chang, Shu-Hao; Fang, Jia-You

2015-08-01

This study developed lipid nanocarriers, called squarticles, conjugated with anti-platelet-derived growth factor (PDGF)-receptor β antibody to determine whether targeted Minoxidil (MXD) delivery to the follicles and dermal papilla cells (DPCs) could be achieved. Squalene and hexadecyl palmitate (HP) were used as the matrix of the squarticles. The PDGF-squarticles showed a mean diameter and zeta potential of 195 nm and -46 mV, respectively. Nanoparticle encapsulation enhanced MXD porcine skin deposition from 0.11 to 0.23 μg/mg. The antibody-conjugated nanoparticles ameliorated follicular uptake of MXD by 3-fold compared to that of the control solution in the in vivo mouse model. Both vertical and horizontal skin sections exhibited a wide distribution of nanoparticles in the follicles, epidermis, and deeper skin strata. The encapsulated MXD moderately elicited proliferation of DPCs and vascular endothelial growth factor (VEGF) expression. The active targeting of PDGF-squarticles may be advantageous to improving the limited success of alopecia therapy. Topical use of minoxidil is only one of the very few treatment options for alopecia. Nonetheless, the current delivery method is far from ideal. In this article, the authors developed lipid nanocarriers with anti-platelet-derived growth factor receptor ? antibody to target dermal papilla cells, and showed enhanced uptake of minoxidil. Copyright © 2015 Elsevier Inc. All rights reserved.

Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting.

Science.gov (United States)

Wang, Hao; Mann, Paul A; Xiao, Li; Gill, Charles; Galgoci, Andrew M; Howe, John A; Villafania, Artjohn; Barbieri, Christopher M; Malinverni, Juliana C; Sher, Xinwei; Mayhood, Todd; McCurry, Megan D; Murgolo, Nicholas; Flattery, Amy; Mack, Matthias; Roemer, Terry

2017-05-18

Riboswitches are bacterial-specific, broadly conserved, non-coding RNA structural elements that control gene expression of numerous metabolic pathways and transport functions essential for cell growth. As such, riboswitch inhibitors represent a new class of potential antibacterial agents. Recently, we identified ribocil-C, a highly selective inhibitor of the flavin mononucleotide (FMN) riboswitch that controls expression of de novo riboflavin (RF, vitamin B2) biosynthesis in Escherichia coli. Here, we provide a mechanistic characterization of the antibacterial effects of ribocil-C as well as of roseoflavin (RoF), an antimetabolite analog of RF, among medically significant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis. We provide genetic, biophysical, computational, biochemical, and pharmacological evidence that ribocil-C and RoF specifically inhibit dual FMN riboswitches, separately controlling RF biosynthesis and uptake processes essential for MRSA growth and pathogenesis. Such a dual-targeting mechanism is specifically required to develop broad-spectrum Gram-positive antibacterial agents targeting RF metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design of ignition targets for the National Ignition Facility

International Nuclear Information System (INIS)

Haan, S.W.; Dittrich, T.R.; Marinak, M.M.; Hinkel, D.E.

1999-01-01

This is a brief update on the work being done to design ignition targets for the National Ignition Facility. Updates are presented on three areas of current activity : improvements in modeling, work on a variety of targets spanning the parameter space of possible ignition targets ; and the setting of specifications for target fabrication and diagnostics. Highlights of recent activity include : a simulation of the Rayleigh-Taylor instability growth on an imploding capsule, done in 3D on a 72degree by 72degree wedge, with enough zones to resolve modes out to 100 ; and designs of targets at 250eV and 350eV, as well as the baseline 300 eV ; and variation of the central DT gas density, which influences both the Rayleigh-Taylor growth and the smoothness of the DT ice layer

Development of antibody-based c-Met inhibitors for targeted cancer therapy

Directory of Open Access Journals (Sweden)

Lee D

2015-02-01

Full Text Available Dongheon Lee, Eun-Sil Sung, Jin-Hyung Ahn, Sungwon An, Jiwon Huh, Weon-Kyoo You Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea Abstract: Signaling pathways mediated by receptor tyrosine kinases (RTKs and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics. Keywords: hepatocyte growth factor, ligands, receptor tyrosine kinase, signaling pathway, therapeutic agent

Nutritional catch-up growth.

Science.gov (United States)

Gat-Yablonski, Galia; Pando, Rakefet; Phillip, Moshe

2013-01-01

Malnutrition, marked by variant nutrient deficiencies, is considered a leading cause of stunted growth worldwide. In developing countries, malnutrition is caused mainly by food shortage and infectious diseases. Malnutrition may also be found in the developed world, where it is due mostly to prematurity, chronic diseases, and anorexia nervosa. In most cases, when food consumption is corrected, spontaneous catch-up (CU) growth occurs. However, CU growth is not always complete, leading to growth deficits. Therefore, it is important to understand the mechanisms that govern this process. Using a rat model of food restriction followed by refeeding, we established a nutrition-induced CU growth model. Levels of leptin and insulin-like growth factor-1 were found to significantly decrease when food was restricted and to increase already 1 day after refeeding. Gene expression analysis of the growth plate revealed that food restriction specifically affects transcription factors such as the hypoxia inducible factor-1 and its downstream targets on the one hand, and global gene expression, indicating epigenetic regulation, on the other. Food restriction also reduced the level of several microRNAs, including the chondrocyte-specific miR-140, which led to an increase in its target, SIRT1, a class III histone deacetylase. These findings may explain the global changes in gene expression observed under nutritional manipulation. We suggest that multiple levels of regulation, including transcription factors, epigenetic mechanisms, and microRNAs respond to nutritional cues and offer a possible explanation for some of the effects of food restriction on epiphyseal growth plate growth. The means whereby these components sense changes in nutritional status are still unknown. Deciphering the role of epigenetic regulation in growth may pave the way for the development of new treatments for children with growth disorders. Copyright © 2013 S. Karger AG, Basel.

Peptide deformylase as an antibacterial drug target: target validation and resistance development.

Science.gov (United States)

Apfel, C M; Locher, H; Evers, S; Takács, B; Hubschwerlen, C; Pirson, W; Page, M G; Keck, W

2001-04-01

New inhibitors of peptide deformylase (PDF) which are very potent against the isolated enzyme and show a certain degree of antibacterial activity have recently been synthesized by our group. Several lines of experimental evidence indicate that these inhibitors indeed interfere with the target enzyme in the bacterial cell. (i) The inhibition of Escherichia coli growth could be counteracted by overexpression of PDF from different organisms, including E. coli, Streptococcus pneumoniae, and Haemophilus influenzae. Conversely, reduced expression of PDF in S. pneumoniae resulted in an increased susceptibility to the inhibitors. (ii) Proteome analysis on two-dimensional gels revealed a shift for many proteins towards lower pI in the presence of PDF inhibitors, as would be expected if the proteins still carry their N-formyl-Met terminus. (iii) PDF inhibitors show no antimicrobial activity against E. coli under conditions that make growth independent of formylation and deformylation. The antibacterial activity in E. coli was characterized as bacteriostatic. Furthermore, the development of resistance in E. coli was observed to occur with high frequency (10(-7)). Resistant mutants show a reduced growth rate, and DNA sequence analysis revealed mutations in their formyl transferase gene. Taking all these aspects into account, we conclude that PDF may not be an optimal target for broad-spectrum antibacterial agents.

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)

OpenAIRE

Zhou, Yihua; Xu, Bixiong C.; Maheshwari, Hiralal G.; He, Li; Reed, Michael; Lozykowski, Maria; Okada, Shigeru; Cataldo, Lori; Coschigamo, Karen; Wagner, Thomas E.; Baumann, Gerhard; Kopchick, John J.

1997-01-01

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/...

Memory for found targets interferes with subsequent performance in multiple-target visual search.

Science.gov (United States)

Cain, Matthew S; Mitroff, Stephen R

2013-10-01

Multiple-target visual searches--when more than 1 target can appear in a given search display--are commonplace in radiology, airport security screening, and the military. Whereas 1 target is often found accurately, additional targets are more likely to be missed in multiple-target searches. To better understand this decrement in 2nd-target detection, here we examined 2 potential forms of interference that can arise from finding a 1st target: interference from the perceptual salience of the 1st target (a now highly relevant distractor in a known location) and interference from a newly created memory representation for the 1st target. Here, we found that removing found targets from the display or making them salient and easily segregated color singletons improved subsequent search accuracy. However, replacing found targets with random distractor items did not improve subsequent search accuracy. Removing and highlighting found targets likely reduced both a target's visual salience and its memory load, whereas replacing a target removed its visual salience but not its representation in memory. Collectively, the current experiments suggest that the working memory load of a found target has a larger effect on subsequent search accuracy than does its perceptual salience. PsycINFO Database Record (c) 2013 APA, all rights reserved.

miR-613 inhibits the growth and invasiveness of human hepatocellular carcinoma via targeting DCLK1

Energy Technology Data Exchange (ETDEWEB)

Wang, Wenyao, E-mail: wangwy117@163.com; Zhang, Hongfei; Wang, Lichao; Zhang, Shaojun; Tang, Miao

2016-05-13

microRNAs (miRNAs) play key regulatory roles in various biological processes. In this study, we aimed to determine the expression and biological roles of miR-613 in hepatocellular carcinoma (HCC). Compared with non-cancerous liver tissues, miR-613 was significantly downregulated in HCC tissues. Ectopic expression of miR-613 significantly suppressed the proliferation and invasion of Hep3B and SMMC-7721 HCC cells. Bioinformatic and luciferase reporter analysis identified doublecortin-like kinase 1 (DCLK1) as a direct target of miR-613. Overexpression of miR-613 inhibited the expression of DCLK1 in HCC cells. There was a significant inverse correlation between miR-613 and DCLK1 protein expression in HCC samples. Small interfering RNA-mediated silencing of DCLK1 phenocopied the suppressive effects of miR-613 in HCC cells. Rescue experiments demonstrated that co-transfection of DCLK1 lacking the 3′-untranslated region partially prevented miR-613-induced suppression of HCC cell proliferation and invasion. In vivo studies confirmed that miR-613 overexpression retarded the growth of Hep3B xenograft tumors in nude mice, coupled with a reduction in the percentage of Ki67-positive tumor cells and DCLK1 protein expression. In conclusion, we provide first evidence for the suppressive activity of miR-613 in HCC, which is causally linked to targeting of DCLK1. Restoration of miR-613 may provide a potential therapeutic strategy for HCC. - Highlights: • miR-613 inhibits the aggressive phenotypes of HCC cells. • DCLK1 is a direct target of miR-613 in HCC. • miR-613 impairs HCC tumorigenesis in vivo.

Phenotypic indications of FtsZ inhibition in hok/sok-induced bacterial growth changes and stress response.

Science.gov (United States)

Chukwudi, Chinwe Uzoma; Good, Liam

2018-01-01

The hok/sok locus has been shown to enhance the growth of bacteria in adverse growth conditions such as high temperature, low starting-culture densities and antibiotic treatment. This is in addition to their well-established plasmid-stabilization effect via post-segregational killing of plasmid-free daughter cells. It delays the onset of growth by prolonging the lag phase of bacterial culture, and increases the rate of exponential growth when growth eventually begins. This enables the cells adapt to the prevailing growth conditions and enhance their survival in stressful conditions. These effects functionally complement defective SOS response mechanism, and appear analogous to the growth effects of FtsZ in the SOS pathway. In this study, the role of FtsZ in the hok/sok-induced changes in bacterial growth and cell division was investigated. Morphologic studies of early growth-phase cultures and cells growing under temperature stress showed elongated cells typical of FtsZ inhibition/deficiency. Both ftsZ silencing and over-expression produced comparable growth effects in control cells, and altered the growth changes observed otherwise in the hok/sok + cells. These changes were diminished in SOS-deficient strain containing mutant FtsZ. The involvement of FtsZ in the hok/sok-induced growth changes may be exploited as drug target in host bacteria, which often propagate antibiotic resistance elements. Copyright © 2017 Elsevier Ltd. All rights reserved.

The multilayer nanoparticles formed by layer by layer approach for cancer-targeting therapy.

Science.gov (United States)

Oh, Keun Sang; Lee, Hwanbum; Kim, Jae Yeon; Koo, Eun Jin; Lee, Eun Hee; Park, Jae Hyung; Kim, Sang Yoon; Kim, Kwangmeyung; Kwon, Ick Chan; Yuk, Soon Hong

2013-01-10

The multilayer nanoparticles (NPs) were prepared for cancer-targeting therapy using the layer by layer approach. When drug-loaded Pluronic NPs were mixed with vesicles (liposomes) in the aqueous medium, Pluronic NPs were incorporated into the vesicles to form the vesicle NPs. Then, the multilayer NPs were formed by freeze-drying the vesicle NPs in a Pluronic aqueous solution. The morphology and size distribution of the multilayer NPs were observed using a TEM and a particle size analyzer. In order to apply the multilayer NPs as a delivery system for docetaxel (DTX), which is a model anticancer drug, the release pattern of the DTX was observed and the tumor growth was monitored by injecting the multilayer NPs into the tail veins of tumor (squamous cell carcinoma)-bearing mice. The cytotoxicity of free DTX (commercial DTX formulation (Taxotere®)) and the multilayer NPs was evaluated using MTT assay. We also evaluated the tumor targeting ability of the multilayer NPs using magnetic resonance imaging. The multilayer NPs showed excellent tumor targetability and antitumor efficacy in tumor-bearing mice, caused by the enhanced permeation and retention (EPR) effect. These results suggest that the multilayer NPs could be a potential drug delivery system for cancer-targeting therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

Endocrine Regulation of Compensatory Growth in Fish

Directory of Open Access Journals (Sweden)

Eugene T. Won

2013-07-01

Full Text Available Compensatory growth (CG is a period of accelerated growth that occurs following the alleviation of growth-stunting conditions during which an organism can make up for lost growth opportunity and potentially catch-up in size with non-stunted cohorts. Fish show a particularly robust capacity for the response and have been the focus of numerous studies that demonstrate their ability to compensate for periods of fasting once food is made available again. Compensatory growth is characterized by an elevated growth rate resulting from enhanced feed intake, mitogen production and feed conversion efficiency. Because little is known about the underlying mechanisms that drive the response, this review describes the sequential endocrine adaptations that lead to CG; namely during the precedent catabolic phase (fasting that taps endogenous energy reserves, and the following hyperanabolic phase (refeeding when accelerated growth occurs. In order to elicit a CG response, endogenous energy reserves must first be moderately depleted, which alters endocrine profiles that enhance appetite and growth potential. During this catabolic phase, elevated ghrelin and growth hormone (GH production increase appetite and protein-sparing lipolysis, while insulin-like growth factors (IGFs are suppressed, primarily due to hepatic GH resistance. During refeeding, temporal hyperphagia provides an influx of energy and metabolic substrates that are then allocated to somatic growth by resumed IGF signaling. Under the right conditions, refeeding results in hyperanabolism and a steepened growth trajectory relative to constantly fed controls. The response wanes as energy reserves are re-accumulated and homeostasis is restored. We ascribe possible roles for select appetite and growth-regulatory hormones in the context of these catabolic and hyperanabolic phases of the CG response in teleosts, with emphasis on GH, IGFs, cortisol, somatostatin, neuropeptide Y, ghrelin and leptin.

Gene co-expression analysis identifies gene clusters associated with isotropic and polarized growth in Aspergillus fumigatus conidia.

Science.gov (United States)

Baltussen, Tim J H; Coolen, Jordy P M; Zoll, Jan; Verweij, Paul E; Melchers, Willem J G

2018-04-26

Aspergillus fumigatus is a saprophytic fungus that extensively produces conidia. These microscopic asexually reproductive structures are small enough to reach the lungs. Germination of conidia followed by hyphal growth inside human lungs is a key step in the establishment of infection in immunocompromised patients. RNA-Seq was used to analyze the transcriptome of dormant and germinating A. fumigatus conidia. Construction of a gene co-expression network revealed four gene clusters (modules) correlated with a growth phase (dormant, isotropic growth, polarized growth). Transcripts levels of genes encoding for secondary metabolites were high in dormant conidia. During isotropic growth, transcript levels of genes involved in cell wall modifications increased. Two modules encoding for growth and cell cycle/DNA processing were associated with polarized growth. In addition, the co-expression network was used to identify highly connected intermodular hub genes. These genes may have a pivotal role in the respective module and could therefore be compelling therapeutic targets. Generally, cell wall remodeling is an important process during isotropic and polarized growth, characterized by an increase of transcripts coding for hyphal growth and cell cycle/DNA processing when polarized growth is initiated. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Marine reserves and reproductive biomass: a case study of a heavily targeted reef fish.

Directory of Open Access Journals (Sweden)

Brett M Taylor

Full Text Available Recruitment overfishing (the reduction of a spawning stock past a point at which the stock can no longer replenish itself is a common problem which can lead to a rapid and irreversible fishery collapse. Averting this disaster requires maintaining a sufficient spawning population to buffer stochastic fluctuations in recruitment of heavily harvested stocks. Optimal strategies for managing spawner biomass are well developed for temperate systems, yet remain uncertain for tropical fisheries, where the danger of collapse from recruitment overfishing looms largest. In this study, we explored empirically and through modeling, the role of marine reserves in maximizing spawner biomass of a heavily exploited reef fish, Lethrinus harak around Guam, Micronesia. On average, spawner biomass was 16 times higher inside the reserves compared with adjacent fished sites. Adult density and habitat-specific mean fish size were also significantly greater. We used these data in an age-structured population model to explore the effect of several management scenarios on L. harak demography. Under minimum-size limits, unlimited extraction and all rotational-closure scenarios, the model predicts that preferential mortality of larger and older fish prompt dramatic declines in spawner biomass and the proportion of male fish, as well as considerable declines in total abundance. For rotational closures this occurred because of the mismatch between the scales of recovery and extraction. Our results highlight how alternative management scenarios fall short in comparison to marine reserves in preserving reproductively viable fish populations on coral reefs.

Breast cancer stem cells, EMT and therapeutic targets

Energy Technology Data Exchange (ETDEWEB)

Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: s.bhattacharya@jiit.ac.in

2014-10-10

Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.

Overexpression of microRNA-375 impedes platelet-derived growth factor-induced proliferation and migration of human fetal airway smooth muscle cells by targeting Janus kinase 2.

Science.gov (United States)

Ji, Yamei; Yang, Xin; Su, Huixia

2018-02-01

The abnormal proliferation and migration of airway smooth muscle (ASM) cells play a critical role in airway remodeling during the development of asthma. MicroRNAs (miRNAs) have emerged as critical regulators of ASM cell proliferation and migration in airway remodeling. In this study, we aimed to investigate the potential role of miR-375 in the regulation of platelet-derived growth factor (PDGF)-induced fetal ASM cell proliferation and migration. Our results showed that miR-375 expression was significantly decreased in fetal ASM cells that were treated with PDGF. Functional data showed that overexpression of miR-375 inhibited the proliferation and migration of fetal ASM cells, whereas inhibition of miR-375 enhanced the proliferation and migration of fetal ASM cells. The results of bioinformatics analysis and a dual-luciferase reporter assay showed that miR-375 binds directly to the 3'-untranslated region of Janus kinase 2 (JAK2). Further data confirmed that miR-375 negatively regulates the expression of JAK2 in fetal ASM cells. Moreover, miR-375 also impeded the PDGF-induced activation of signal transducer and activator of transcription 3 (STAT3) in fetal ASM cells. However, restoration of JAK2 expression partially reversed the inhibitory effect of miR-375 on fetal ASM cell proliferation and migration. Overall, our results demonstrate that miR-375 inhibits fetal ASM cell proliferation and migration by targeting JAK2/STAT3 signaling. Our study provides a potential therapeutic target for the development of novel treatment strategies for pediatric asthma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Oil, gas field growth projections: Wishful thinking or reality?

Science.gov (United States)

Attanasi, E.D.; Mast, R.F.; Root, D.H.

1999-01-01

The observed `field growth' for the period from 1992 through 1996 with the US Geological Survey's (USGS) predicted field growth for the same period are compared. Known field recovery of field size is defined as the sum of past cumulative field production and the field's proved reserves. Proved reserves are estimated quantities of hydrocarbons which geologic and engineering data demonstrate with reasonable certainty to recoverable from known fields under existing economic and operating conditions. Proved reserve estimates calculated with this definition are typically conservative. The modeling approach used by the USGS to characterize `field growth phenomena' is statistical rather that geologic in nature.

Metastatic gastric cancer – focus on targeted therapies

Directory of Open Access Journals (Sweden)

Meza-Junco J

2012-06-01

Full Text Available Judith Meza-Junco, Michael B SawyerDepartment of Oncology, Cross Cancer Institute, Edmonton, Alberta, CanadaAbstract: Gastric cancer (GC is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.Keywords: gastric cancer, targeted therapy, antiangiogenesis drugs, anti-EGFR drugs

Hydrocarbon Reserves: Abundance or Scarcity

Energy Technology Data Exchange (ETDEWEB)

NONE

2005-07-01

IFP and the OAPEC jointly organize a regular international seminar dealing with world oil-related problems appearing in the news. For the first time, this seminar has been opened to oil and gas company specialists, service companies, research centers and independents. This year's theme concerns oil and gas reserves: are they abundant or are we headed towards the shortages announced by some experts? This theme is especially topical in that: oil and gas currently meet two thirds of world energy needs and almost completely dominate the transport sector; the reserves declared by the OAPEC countries account for nearly half of world reserves; the price of a barrel of oil went through the roof in 2004; world energy demand is growing fast and alternative sources of energy are far from ready to take over from oil and gas in the next few decades. Since the reserves correspond to the volume it is technically and economically viable to produce, the seminar has, of course, dealt with the technical and economic questions that arise in connection with exploration and production, but it has also considered changes in the geopolitical context. Presentations by the leading companies of the OAPEC countries and by the IFP group were completed by presentation from the International Energy Agency (IEA), the United States Geological Survey (USGS), the IHS Energy Group, Total and Gaz de France. This document gathers the transparencies of the following presentations: Hydrocarbon reserves in OAPEC members countries: current and future (M. Al-Lababidi); Non OAPEC liquid reserves and production forecasts (Y. Mathieu); World oil and gas resources and production outlook (K. Chew); Global investments in the upstream (F. Birol); Total's policy in the oil and gas sector (C. de Margerie); Gaz de France's policy in the oil and gas sector (J. Abiteboul); NOC/IOC's opportunities in OPEC countries (I. Sandrea); Relationships between companies, countries and investors: How they may impact on the growth

Hydrocarbon Reserves: Abundance or Scarcity

International Nuclear Information System (INIS)

2005-01-01

IFP and the OAPEC jointly organize a regular international seminar dealing with world oil-related problems appearing in the news. For the first time, this seminar has been opened to oil and gas company specialists, service companies, research centers and independents. This year's theme concerns oil and gas reserves: are they abundant or are we headed towards the shortages announced by some experts? This theme is especially topical in that: oil and gas currently meet two thirds of world energy needs and almost completely dominate the transport sector; the reserves declared by the OAPEC countries account for nearly half of world reserves; the price of a barrel of oil went through the roof in 2004; world energy demand is growing fast and alternative sources of energy are far from ready to take over from oil and gas in the next few decades. Since the reserves correspond to the volume it is technically and economically viable to produce, the seminar has, of course, dealt with the technical and economic questions that arise in connection with exploration and production, but it has also considered changes in the geopolitical context. Presentations by the leading companies of the OAPEC countries and by the IFP group were completed by presentation from the International Energy Agency (IEA), the United States Geological Survey (USGS), the IHS Energy Group, Total and Gaz de France. This document gathers the transparencies of the following presentations: Hydrocarbon reserves in OAPEC members countries: current and future (M. Al-Lababidi); Non OAPEC liquid reserves and production forecasts (Y. Mathieu); World oil and gas resources and production outlook (K. Chew); Global investments in the upstream (F. Birol); Total's policy in the oil and gas sector (C. de Margerie); Gaz de France's policy in the oil and gas sector (J. Abiteboul); NOC/IOC's opportunities in OPEC countries (I. Sandrea); Relationships between companies, countries and investors: How they may impact on the growth

Stoichiometry control of complex oxides by sequential pulsed-laser deposition from binary-oxide targets

Energy Technology Data Exchange (ETDEWEB)

Herklotz, A. [ORNL, Materials Science and Technology Division, Bethel Valley Road, Oak Ridge, Tennessee 37831-6056 (United States); Martin Luther University Halle-Wittenberg, Institute for Physics, Von-Danckelmann-Platz 3, 06120 Halle (Germany); Dörr, K. [Martin Luther University Halle-Wittenberg, Institute for Physics, Von-Danckelmann-Platz 3, 06120 Halle (Germany); Ward, T. Z.; Eres, G. [ORNL, Materials Science and Technology Division, Bethel Valley Road, Oak Ridge, Tennessee 37831-6056 (United States); Christen, H. M.; Biegalski, M. D. [ORNL, Center for Nanophase Materials Sciences, Bethel Valley Road, Oak Ridge, Tennessee 37831-6496 (United States)

2015-03-30

To have precise atomic layer control over interfaces, we examine the growth of complex oxides through the sequential deposition from binary targets by pulsed laser deposition. In situ reflection high-energy electron diffraction (RHEED) is used to control the growth and achieve films with excellent structural quality. The growth from binary oxide targets is fundamentally different from single target growth modes and shows more similarities to shuttered growth by molecular beam epitaxy. The RHEED intensity oscillations of non-stoichiometric growth are consistent with a model of island growth and accumulation of excess material on the surface that can be utilized to determine the correct stoichiometry for growth. Correct monolayer doses can be determined through an envelope frequency in the RHEED intensity oscillations. In order to demonstrate the ability of this growth technique to create complex heterostructures, the artificial n = 2 and 3 Sr{sub n+1}Ti{sub n}O{sub 3n+1} Ruddlesden-Popper phases are grown with good long-range order. This method enables the precise unit-cell level control over the structure of perovskite-type oxides, and thus the growth of complex materials with improved structural quality and electronic functionality.

Assessment of current and proposed nature reserves of Mexico based on their capacity to protect geophysical features and biodiversity

Science.gov (United States)

Cantu, C.; Wright, R.G.; Scott, J.M.; Strand, Espen

2004-01-01

Mexico currently has 144 nature reserves covering approximately 9.1% of its land area. These reserves were established for a variety of reasons - often unrelated to the protection of biodiversity. In 2000 in response to a growing concern about the lack of organized conservation reserve planning to protect the important threatened biological and physical features of Mexico, the Mexican Commission for Knowledge and Use of Biodiversity (CONABIO) proposed the establishment of 151 new reserves for Mexico covering 51,429,500 ha. We compiled a GIS analysis using digital thematic maps of physical and biological features to examine how the existing and proposed reserves serve to protect the biodiversity and physical features of the country. Using a conservation target of placing a minimum of 12% of the land area of each important biophysical feature in nature reserves, we found that the 144 existing nature reserves covering 18 million ha (9% of the country) only meet that target for elevation ranges >3000 m and areas with poor soils. These mountainous areas represent less than 1% of the country. The gaps in the existing nature reserves network occur mainly at lower and intermediate elevations (<3000 m) areas with xeric, tropical, and temperate ecosystems, and high productivity soils. The areas proposed by CONABIO increase the proportion of protected lands in the country to over 27% and most of the conservation targets for geophysical features, and land cover, categories are met. Whether this area would be sufficient to maintain viable populations and ecological integrity of species and ecosystems is unknown. Even with the new reserves, low elevation coastal lands would be below the conservation target in the nature reserves. To include a representative sample of these lands would be difficult as these are the same areas where the majority of people live. ?? 2003 Elsevier Ltd. All rights reserved.

Improving the Design of a Conservation Reserve for a Critically Endangered Species.

Science.gov (United States)

Taylor, Chris; Cadenhead, Natasha; Lindenmayer, David B; Wintle, Brendan A

2017-01-01

Setting aside protected areas is a key strategy for tackling biodiversity loss. Reserve effectiveness depends on the extent to which protected areas capture both known occurrences and areas likely to support the species. We assessed the effectiveness of the existing reserve network for Leadbeater's Possum (Gymnobelideus leadbeateri) and other forest-dependent species, and compared the existing reserve system to a set of plausible reserve expansion options based on area targets implied in a recent Population Viability Analysis (PVA). The existing Leadbeater's Reserve and surrounding reserve system captured 7.6% and 29.6% of cumulative habitat suitability, respectively, across the landscape. Expanded reserve scenarios captured 34% to 62% of cumulative habitat suitability. We found acute trade-offs between conserving Leadbeater's Possum habitat and conserving habitat of other forest-dependent species. Our analysis provides a template for systematically expanding and evaluating reserve expansion options in terms of trade-offs between priority species' needs.

Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center.

Science.gov (United States)

Bechtold, S; Beyerlein, A; Ripperger, P; Roeb, J; Dalla Pozza, R; Häfner, R; Haas, J P; Schmidt, H

2012-10-01

Growth failure is a permanent sequelae in juvenile idiopathic arthritis (JIA). The aim of the study was to compare pubertal growth in control and growth hormone (GH) treated JIA subjects. 64 children with JIA at a mean age of 10.38 ± 2.80 years were enrolled and followed until final height (measured in standard deviation (SD) scores). 39 children (20 m) received GH therapy and 24 (9 m) served as controls. GH dose was 0.33 mg/kg/week. Linear regression analysis was performed to identify factors influencing total pubertal growth. Mean total pubertal growth was 21.1 ± 1.3 cm (mean ± SD) in GH treated JIA patients and 13.8 ± 1.5 cm in controls. Final height was significantly higher with GH treatment (-1.67 ± 1.20 SD) compared to controls (-3.20 ± 1.84 SD). Linear regression model identified age at onset of puberty (ß=-4.2,CI: -5.9, -2.6 in controls and ß=-2.3,CI: -3.6, -1.1 in GH treated) as the main factor for total pubertal growth. Final height SDS was determined by the difference to target height at onset of puberty (ß=-0.59;CI: -0.80, -0.37 in controls and ß=-0.30,CI: -0.52, -0.08 in GH treated), age at onset of puberty (ß=0.47;CI:0.02,0.93 in controls and 0.23;CI: -0.00,0.46 in GH treated) and height gain during puberty (ß=0.13;CI:0.05,0.21 in controls and ß=0.11;CI:0.07,0.16 in GH treated). Total pubertal growth in JIA patients treated with GH was increased by a factor of 1.5 greater in comparison to controls leading to a significantly better final height. To maximize final height GH treatment should be initiated early to reduce the height deficit at onset of puberty. Copyright © 2012 Elsevier Ltd. All rights reserved.

Habitat damage, marine reserves, and the value of spatial management

KAUST Repository

Moeller, Holly V.

2013-07-01

The biological benefits of marine reserves have garnered favor in the conservation community, but "no-take" reserve implementation is complicated by the economic interests of fishery stakeholders. There are now a number of studies examining the conditions under which marine reserves can provide both economic and ecological benefits. A potentially important reality of fishing that these studies overlook is that fishing can damage the habitat of the target stock. Here, we construct an equilibrium bioeconomic model that incorporates this habitat damage and show that the designation of marine reserves, coupled with the implementation of a tax on fishing effort, becomes both biologically and economically favorable as habitat sensitivity increases. We also study the effects of varied degrees of spatial control on fisheries management. Together, our results provide further evidence for the potential monetary and biological value of spatial management, and the possibility of a mutually beneficial resolution to the fisherman-conservationist marine reserve designation dilemma. © 2013 by the Ecological Society of America.

Cohort Profile: The Applied Research Group for Kids (TARGet Kids!).

Science.gov (United States)

Carsley, Sarah; Borkhoff, Cornelia M; Maguire, Jonathon L; Birken, Catherine S; Khovratovich, Marina; McCrindle, Brian; Macarthur, Colin; Parkin, Patricia C

2015-06-01

The Applied Research Group for Kids (TARGet Kids!) is an ongoing open longitudinal cohort study enrolling healthy children (from birth to 5 years of age) and following them into adolescence. The aim of the TARGet Kids! cohort is to link early life exposures to health problems including obesity, micronutrient deficiencies and developmental problems. The overarching goal is to improve the health of Canadians by optimizing growth and developmental trajectories through preventive interventions in early childhood. TARGet Kids!, the only child health research network embedded in primary care practices in Canada, leverages the unique relationship between children and families and their trusted primary care practitioners, with whom they have at least seven health supervision visits in the first 5 years of life. Children are enrolled during regularly scheduled well-child visits. To date, we have enrolled 5062 children. In addition to demographic information, we collect physical measurements (e.g. height, weight), lifestyle factors (nutrition, screen time and physical activity), child behaviour and developmental screening and a blood sample (providing measures of cardiometabolic, iron and vitamin D status, and trace metals). All data are collected at each well-child visit: twice a year until age 2 and every year until age 10. Information can be found at: http://www.targetkids.ca/contact-us/. © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Identification of microRNAs and their targets in Finger millet by high throughput sequencing.

Science.gov (United States)

Usha, S; Jyothi, M N; Sharadamma, N; Dixit, Rekha; Devaraj, V R; Nagesh Babu, R

2015-12-15

MicroRNAs are short non-coding RNAs which play an important role in regulating gene expression by mRNA cleavage or by translational repression. The majority of identified miRNAs were evolutionarily conserved; however, others expressed in a species-specific manner. Finger millet is an important cereal crop; nonetheless, no practical information is available on microRNAs to date. In this study, we have identified 95 conserved microRNAs belonging to 39 families and 3 novel microRNAs by high throughput sequencing. For the identified conserved and novel miRNAs a total of 507 targets were predicted. 11 miRNAs were validated and tissue specificity was determined by stem loop RT-qPCR, Northern blot. GO analyses revealed targets of miRNA were involved in wide range of regulatory functions. This study implies large number of known and novel miRNAs found in Finger millet which may play important role in growth and development. Copyright © 2015 Elsevier B.V. All rights reserved.

Transforming growth factor alpha, Shope fibroma growth factor, and vaccinia growth factor can replace myxoma growth factor in the induction of myxomatosis in rabbits.

Science.gov (United States)

Opgenorth, A; Nation, N; Graham, K; McFadden, G

1993-02-01

The epidermal growth factor (EGF) homologues encoded by vaccinia virus, myxoma virus, and malignant rabbit fibroma virus have been shown to contribute to the pathogenicity of virus infection upon inoculation of susceptible hosts. However, since the primary structures of these growth factors and the disease profiles induced by different poxvirus genera vary substantially, the degree to which the various EGF homologues perform similar roles in viral pathogenesis remains unclear. In order to determine whether different EGF-like growth factors can perform qualitatively similar functions in the induction of myxomatosis in rabbits, we created recombinant myxoma virus variants in which the native growth factor, myxoma growth factor (MGF), was disrupted and replaced with either vaccinia virus growth factor, Shope fibroma growth factor, or rat transforming growth factor alpha. Unlike the control virus containing an inactivated MGF gene, which caused marked attenuation of the disease syndrome and substantially less proliferation of the epithelial cell layers in the conjunctiva and respiratory tract, the recombinant myxoma virus strains expressing heterologous growth factors produced infections which were both clinically and histopathologically indistinguishable from wild-type myxomatosis. We conclude that these poxviral and cellular EGF-like growth factors, which are diverse with respect to primary structure and origin, have similar biological functions in the context of myxoma virus pathogenesis and are mitogenic for the same target cells.

New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

Science.gov (United States)

Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

2016-01-01

Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their

Chimeric Monoclonal Antibody Cetuximab Targeting Epidermal Growth Factor-Receptor in Advanced Non-Melanoma Skin Cancer.

Science.gov (United States)

Wollina, Uwe; Tchernev, Georgi; Lotti, Torello

2018-01-25

Non-melanoma skin cancer (NMSC) is the most common malignancy in humans. Targeted therapy with monoclonal antibody cetuximab is an option in case of advanced tumor or metastasis. We present and update of the use of cetuximab in NMSC searching PUBMED 2011-2017. The monoclonal antibody cetuximab against epidermal growth factor receptor (EGFR) has been investigated for its use in NMSC during the years 2011 to 2017 by a PUBMED research using the following items: "Non-melanoma skin cancer AND cetuximab," "cutaneous squamous cell carcinoma AND cetuximab," and "basal cell carcinoma AND cetuximab", and "cetuximab AND skin toxicity". Available data were analyzed including case reports. Current evidence of cetuximab efficacy in NMSC was mainly obtained in cutaneous SCC and to a lesser extend in BCC. Response rates vary for neoadjuvant, adjuvant, mono- and combined therapy with cetuximab. Management of cutaneous toxicities is necessary. Guidelines are available. Cetuximab is an option for recurrent or advanced NMSC of the skin. It seems to be justified particularly in very high-risk tumors. There is a need for phase III trials.

The impact of oil price on additions to US proven reserves

International Nuclear Information System (INIS)

Farzin, Y.H.

2001-01-01

Departing from Hotelling's assumption of fixed and known reserves, this paper develops an economic model of additions to proven reserves that explicitly incorporates the effects of expected resource price, cumulative reserves development, and technological progress on reserve additions. The model treats additions to proven oil reserves as output of a production process in which drilling wells is a primary input to transform some of oil-in-place into the economic category of proven reserves. Application of the model to US data for the 1950-1995 period provides strong statistical support for the existence of all the three salient effects. We obtain an estimate of the price elasticity of reserve additions (absent from previous studies) which, although statistically highly significant, is rather small. Using this price elasticity estimate, it is shown that if in the face of steady economic growth, and hence, oil consumption, US oil import dependence is to be kept from rising in the future, ceteris paribus, a steady oil price increase in the range of 1.5-4.5% a year is essential

Rapid effects of marine reserves via larval dispersal.

Directory of Open Access Journals (Sweden)

Richard Cudney-Bueno

Full Text Available Marine reserves have been advocated worldwide as conservation and fishery management tools. It is argued that they can protect ecosystems and also benefit fisheries via density-dependent spillover of adults and enhanced larval dispersal into fishing areas. However, while evidence has shown that marine reserves can meet conservation targets, their effects on fisheries are less understood. In particular, the basic question of if and over what temporal and spatial scales reserves can benefit fished populations via larval dispersal remains unanswered. We tested predictions of a larval transport model for a marine reserve network in the Gulf of California, Mexico, via field oceanography and repeated density counts of recently settled juvenile commercial mollusks before and after reserve establishment. We show that local retention of larvae within a reserve network can take place with enhanced, but spatially-explicit, recruitment to local fisheries. Enhancement occurred rapidly (2 yrs, with up to a three-fold increase in density of juveniles found in fished areas at the downstream edge of the reserve network, but other fishing areas within the network were unaffected. These findings were consistent with our model predictions. Our findings underscore the potential benefits of protecting larval sources and show that enhancement in recruitment can be manifested rapidly. However, benefits can be markedly variable within a local seascape. Hence, effects of marine reserve networks, positive or negative, may be overlooked when only focusing on overall responses and not considering finer spatially-explicit responses within a reserve network and its adjacent fishing grounds. Our results therefore call for future research on marine reserves that addresses this variability in order to help frame appropriate scenarios for the spatial management scales of interest.

Bone marrow-derived cultured mast cells and peritoneal mast cells as targets of a growth activity secreted by BALB/3T3 fibroblasts

International Nuclear Information System (INIS)

Jozaki, K.; Kuriu, A.; Hirota, S.; Onoue, H.; Ebi, Y.; Adachi, S.; Ma, J.Y.; Tarui, S.; Kitamura, Y.

1991-01-01

When fibroblast cell lines were cultured in contact with bone marrow-derived cultured mast cells (CMC), both NIH/3T3 and BALB/3T3 cell lines supported the proliferation of CMC. In contrast, when contact between fibroblasts and CMC was prohibited by Biopore membranes or soft agar, only BALB/3T3 fibroblasts supported CMC proliferation, suggesting that BALB/3T3 but not NIH/3T3 cells secreted a significant amount of a mast cell growth activity. Moreover, the BALB/3T3-derived growth activity induced the incorporation of [3H]thymidine by CMC and the clonal growth of peritoneal mast cells in methylcellulose. The mast cell growth activity appeared to be different from interleukin 3 (IL-3) and interleukin 4 (IL-4), because mRNAs for these interleukins were not detectable in BALB/3T3 fibroblasts. Although mast cells are genetically deficient in tissues of W/Wv mice, CMC did develop when bone marrow cells of W/Wv mice were cultured with pokeweed mitogen-stimulated spleen cell-conditioned medium. Because BALB/3T3 fibroblast-conditioned medium (BALB-FCM) did not induce the incorporation of [3H]thymidine by W/Wv CMC, the growth activity in BALB-FCM appeared to be a ligand for the receptor encoded by the W (c-kit) locus. Because CMC and peritoneal mast cells are obtained as homogeneous suspensions rather easily, these cells may be potentially useful as targets for the fibroblast-derived mast cell growth activity

Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation

Science.gov (United States)

Chen, Shuowen; Khan, Muhammad J.; Loor, Juan J.

2013-01-01

Characterization and biological roles of the peroxisome proliferator-activated receptor (PPAR) isotypes are well known in monogastrics, but not in ruminants. However, a wealth of information has accumulated in little more than a decade on ruminant PPARs including isotype tissue distribution, response to synthetic and natural agonists, gene targets, and factors affecting their expression. Functional characterization demonstrated that, as in monogastrics, the PPAR isotypes control expression of genes involved in lipid metabolism, anti-inflammatory response, development, and growth. Contrary to mouse, however, the PPARγ gene network appears to controls milk fat synthesis in lactating ruminants. As in monogastrics, PPAR isotypes in ruminants are activated by long-chain fatty acids, therefore, making them ideal candidates for fine-tuning metabolism in this species via nutrients. In this regard, using information accumulated in ruminants and monogastrics, we propose a model of PPAR isotype-driven biological functions encompassing key tissues during the peripartal period in dairy cattle. PMID:23737762

Antitumor activity of ZD6126, a novel vascular-targeting agent, is enhanced when combined with ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, and potentiates the effects of radiation in a human non-small cell lung cancer xenograft model.

Science.gov (United States)

Raben, David; Bianco, Cataldo; Damiano, Vincenzo; Bianco, Roberto; Melisi, Davide; Mignogna, Chiara; D'Armiento, Francesco Paolo; Cionini, Luca; Bianco, A Raffaele; Tortora, Giampaolo; Ciardiello, Fortunato; Bunn, Paul

2004-08-01

Targeting the tumor vasculature may offer an alternative or complementary therapeutic approach to targeting growth factor signaling in lung cancer. The aim of these studies was to evaluate the antitumor effects in vivo of the combination of ZD6126, a tumor-selective vascular-targeting agent; ZD1839 (gefitinib, Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor; and ionizing radiation in the treatment of non-small cell lung cancer xenograft model. Athymic nude mice with established flank A549 human non-small cell lung cancer xenograft model xenografts were treated with fractionated radiation therapy, ZD6126, ZD1839, or combinations of each treatment. ZD6126 (150 mg/kg) was given i.p. the day after each course of radiation. Animals treated with ZD1839 received 100 mg/kg per dose per animal, 5 or 7 days/wk for 2 weeks. Immunohistochemistry was done to evaluate the effects on tumor growth using an anti-Ki67 monoclonal antibody. Effects on tumor-induced vascularization were quantified using an anti-factor VIII-related antigen monoclonal antibody. ZD6126 attenuated the growth of human A549 flank xenografts compared with untreated animals. Marked antitumor effects were observed when animals were treated with a combination of ZD6126 and fractionated radiation therapy with protracted tumor regression. ZD6126 + ZD1839 resulted in a greater tumor growth delay than either agent alone. Similar additive effects were seen with ZD1839 + fractionated radiation. Finally, the addition of ZD6126 to ZD1839 and radiation therapy seemed to further improve tumor growth control, with a significant tumor growth delay compared with animals treated with single agent or with double combinations. Immunohistochemistry showed that ZD1839 induced a marked reduction in A549 tumor cell proliferation. Both ZD1839 and ZD6126 treatment substantially reduced tumor-induced angiogenesis. ZD6126 caused marked vessel destruction through loss of endothelial cells and thrombosis

The strength of small: Improved targeting of Insulin-like Growth Factor-1 Receptor (IGF-1R) with F(ab')2-R1507 fragments in Ewing sarcomas

NARCIS (Netherlands)

Fleuren, Emmy D. G.; Versleijen-Jonkers, Yvonne M. H.; Heskamp, Sandra; Roeffen, Melissa H. S.; Bouwman, Wilbert H.; Molkenboer-Kuenen, Janneke D. M.; van Laarhoven, Hanneke W. M.; Oyen, Wim J. G.; Boerman, Otto C.; van der Graaf, Winette T. A.

2013-01-01

To investigate whether F(ab')2-fragments of the monoclonal Insulin-like Growth Factor-1 Receptor (IGF-1R) antibody R1507 (F(ab')2-R1507) can successfully target IGF-1R in Ewing sarcomas (ES). BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human ES xenografts (EW-5 and EW-8)

Improving the Design of a Conservation Reserve for a Critically Endangered Species.

Directory of Open Access Journals (Sweden)

Chris Taylor

Full Text Available Setting aside protected areas is a key strategy for tackling biodiversity loss. Reserve effectiveness depends on the extent to which protected areas capture both known occurrences and areas likely to support the species. We assessed the effectiveness of the existing reserve network for Leadbeater's Possum (Gymnobelideus leadbeateri and other forest-dependent species, and compared the existing reserve system to a set of plausible reserve expansion options based on area targets implied in a recent Population Viability Analysis (PVA. The existing Leadbeater's Reserve and surrounding reserve system captured 7.6% and 29.6% of cumulative habitat suitability, respectively, across the landscape. Expanded reserve scenarios captured 34% to 62% of cumulative habitat suitability. We found acute trade-offs between conserving Leadbeater's Possum habitat and conserving habitat of other forest-dependent species. Our analysis provides a template for systematically expanding and evaluating reserve expansion options in terms of trade-offs between priority species' needs.

Hydrocarbon Reserves: Abundance or Scarcity

Energy Technology Data Exchange (ETDEWEB)

NONE

2005-07-01

impact on the growth of reserves and resources (H. Le Leuch); Additional reserves: the role of new technologies - A global perspective on EORIOR (G. Fries); - Updating reservoir models with dynamic data and uncertainty quantification: an integrated approach (F. Roggero); Seismic technology for the OAPEC countries (P. Canal); Exploration knowledge and technologies: impact of progress - Statistical results (N. Alazard); Stratigraphic modelling as a key to find new potentialities in exploration (D. Granjeon); Modelling hydrocarbon migration as a tool for reserve estimation (J-L. Rudkiewicz); The contribution of surface and near surface geology to hydrocarbon discoveries (S.M. Kumati); Contribution of the exploration activity in renewing reserves - The case of Algeria (R. Lounissi); Egypt's petroleum hydrocarbon potential (H. Hataba); Future of hydrocarbon reserves in Syria (T. Hemsh); Natural gas, the fuel of choice for decades to com (M.F. Chabrelie); The role and importance of Arab natural gas in world market (M. Al-Lababidi); LNG and GTL: two pathways for natural gas utilization (C. Cameron); Yet to find hydrocarbon potential (S. Al Menhali); Libyan context of hydrocarbon reserves: abundance or scarcity? (M. Elazi)

Testing mechanistic models of growth in insects.

Science.gov (United States)

Maino, James L; Kearney, Michael R

2015-11-22

Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg(-1)) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes. © 2015 The Author(s).

Ligand-targeted theranostic nanomedicines against cancer.

Science.gov (United States)

Yao, Virginia J; D'Angelo, Sara; Butler, Kimberly S; Theron, Christophe; Smith, Tracey L; Marchiò, Serena; Gelovani, Juri G; Sidman, Richard L; Dobroff, Andrey S; Brinker, C Jeffrey; Bradbury, Andrew R M; Arap, Wadih; Pasqualini, Renata

2016-10-28

Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human sc

VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis

Science.gov (United States)

Zhang, Fan; Tang, Zhongshu; Hou, Xu; Lennartsson, Johan; Li, Yang; Koch, Alexander W.; Scotney, Pierre; Lee, Chunsik; Arjunan, Pachiappan; Dong, Lijin; Kumar, Anil; Rissanen, Tuomas T.; Wang, Bin; Nagai, Nobuo; Fons, Pierre; Fariss, Robert; Zhang, Yongqing; Wawrousek, Eric; Tansey, Ginger; Raber, James; Fong, Guo-Hua; Ding, Hao; Greenberg, David A.; Becker, Kevin G.; Herbert, Jean-Marc; Nash, Andrew; Yla-Herttuala, Seppo; Cao, Yihai; Watts, Ryan J.; Li, Xuri

2009-01-01

VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a “survival,” rather than an “angiogenic” factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases. PMID:19369214

Targeted therapy in the treatment of malignant gliomas

Directory of Open Access Journals (Sweden)

Rimas V Lukas

2009-05-01

Full Text Available Rimas V Lukas1, Adrienne Boire2, M Kelly Nicholas1,2 1Department of Neurology; 2Department of Medicine, University of Chicago, Chicago, IL, USAAbstract: Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In addition, we will discuss strategies that target the extracellular matrix in which these cells reside as well as angiogenesis, a process emerging as central to tumor development and growth. Finally, we will briefly touch on the role of neural stem cells as both potential targets as well as delivery vectors for other therapies. Interdependence between these varied pathways, both in maintaining health and in causing disease, is clear. Thus, attempts to easily classify some targeted therapies are problematic.Keywords: glioma, EGFR, mTOR, HDAC, Ras, angiogenesis

Theranostic gas-generating nanoparticles for targeted ultrasound imaging and treatment of neuroblastoma.

Science.gov (United States)

Lee, Jangwook; Min, Hyun-Su; You, Dong Gil; Kim, Kwangmeyung; Kwon, Ick Chan; Rhim, Taiyoun; Lee, Kuen Yong

2016-02-10

The development of safe and efficient diagnostic/therapeutic agents for treating cancer in clinics remains challenging due to the potential toxicity of conventional agents. Although the annual incidence of neuroblastoma is not that high, the disease mainly occurs in children, a population vulnerable to toxic contrast agents and therapeutics. We demonstrate here that cancer-targeting, gas-generating polymeric nanoparticles are useful as a theranostic tool for ultrasound (US) imaging and treating neuroblastoma. We encapsulated calcium carbonate using poly(d,l-lactide-co-glycolide) and created gas-generating polymer nanoparticles (GNPs). These nanoparticles release carbon dioxide bubbles under acidic conditions and enhance US signals. When GNPs are modified using rabies virus glycoprotein (RVG) peptide, a targeting moiety to neuroblastoma, RVG-GNPs effectively accumulate at the tumor site and substantially enhance US signals in a tumor-bearing mouse model. Intravenous administration of RVG-GNPs also reduces tumor growth in the mouse model without the use of conventional therapeutic agents. This approach to developing theranostic agents with disease-targeting ability may provide useful strategy for the detection and treatment of cancers, allowing safe and efficient clinical applications with fewer side effects than may occur with conventional agents. Copyright © 2015 Elsevier B.V. All rights reserved.

Treating juvenile idiopathic arthritis to target: recommendations of an international task force.

Science.gov (United States)

Ravelli, Angelo; Consolaro, Alessandro; Horneff, Gerd; Laxer, Ronald M; Lovell, Daniel J; Wulffraat, Nico M; Akikusa, Jonathan D; Al-Mayouf, Sulaiman M; Antón, Jordi; Avcin, Tadej; Berard, Roberta A; Beresford, Michael W; Burgos-Vargas, Ruben; Cimaz, Rolando; De Benedetti, Fabrizio; Demirkaya, Erkan; Foell, Dirk; Itoh, Yasuhiko; Lahdenne, Pekka; Morgan, Esi M; Quartier, Pierre; Ruperto, Nicolino; Russo, Ricardo; Saad-Magalhães, Claudia; Sawhney, Sujata; Scott, Christiaan; Shenoi, Susan; Swart, Joost F; Uziel, Yosef; Vastert, Sebastiaan J; Smolen, Josef S

2018-06-01

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chitin synthases from Saprolegnia are involved in tip growth and represent a potential target for anti-oomycete drugs.

Directory of Open Access Journals (Sweden)

Gea Guerriero

Full Text Available Oomycetes represent some of the most devastating plant and animal pathogens. Typical examples are Phytophthora infestans, which causes potato and tomato late blight, and Saprolegnia parasitica, responsible for fish diseases. Despite the economical and environmental importance of oomycete diseases, their control is difficult, particularly in the aquaculture industry. Carbohydrate synthases are vital for hyphal growth and represent interesting targets for tackling the pathogens. The existence of 2 different chitin synthase genes (SmChs1 and SmChs2 in Saprolegnia monoica was demonstrated using bioinformatics and molecular biology approaches. The function of SmCHS2 was unequivocally demonstrated by showing its catalytic activity in vitro after expression in Pichia pastoris. The recombinant SmCHS1 protein did not exhibit any activity in vitro, suggesting that it requires other partners or effectors to be active, or that it is involved in a different process than chitin biosynthesis. Both proteins contained N-terminal Microtubule Interacting and Trafficking domains, which have never been reported in any other known carbohydrate synthases. These domains are involved in protein recycling by endocytosis. Enzyme kinetics revealed that Saprolegnia chitin synthases are competitively inhibited by nikkomycin Z and quantitative PCR showed that their expression is higher in presence of the inhibitor. The use of nikkomycin Z combined with microscopy showed that chitin synthases are active essentially at the hyphal tips, which burst in the presence of the inhibitor, leading to cell death. S. parasitica was more sensitive to nikkomycin Z than S. monoica. In conclusion, chitin synthases with species-specific characteristics are involved in tip growth in Saprolegnia species and chitin is vital for the micro-organisms despite its very low abundance in the cell walls. Chitin is most likely synthesized transiently at the apex of the cells before cellulose, the major

Molecular-targeted therapy for chemotherapy-refractory gastric cancer: a case report and literature review.

Science.gov (United States)

Kuo, Hung-Yang; Yeh, Kun-Huei

2014-07-01

The prognosis of advanced gastric cancer (AGC) remains poor despite therapeutic advances in recent decades. Several recent positive phase III trials established the efficacy of second-line chemotherapy for metastatic gastric cancer in prolonging overall survival. However, malnutrition and poor performance of AGC in late stages usually preclude such patients from intensive treatment. Many targeted-therapies failed to show a significant survival benefit in AGC, but have regained attention after the positive result of ramucirumab was announced last year. Among all targeted agents, only trastuzumab, a monoclonal antibody against Human epidermal growth factor receptor-2 (HER2) protein, has been proven as having survival benefit by addition to first-line chemotherapy. Herein we reported a patient who benefited from adding trastuzumab to the same second-line combination chemotherapy (paclitaxel, 5-fluorouracil, and leucovorin) upon progression of bulky liver metastases. At least five months of progression-free survival were achieved without any additional toxicity. We also reviewed literature of molecularly-targeted therapy for chemotherapy-refractory gastric cancer, including several large phase III trials (REGARD, GRANITE-1, EXPAND, and REAL-3) published in 2013-2014. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer

International Nuclear Information System (INIS)

Xu, Da-zhi; Sun, Xiao-wei; Guan, Yuan-xiang; Li, Yuan-fang; Lin, Tong-yu; Geng, Qi-rong; Tian, Ying; Cai, Mu-yan; Fang, Xin-juan; Zhan, You-qing; Zhou, Zhi-wei; Li, Wei; Chen, Ying-bo

2010-01-01

The mammalian target of rapamycin (mTOR) plays a key role in cellular growth and homeostasis. The purpose of our present study is to investigate the expression of activated mTOR (p-mTOR) in gastric cancer patients, their prognostic significance and the inhibition effect of RAD001 on tumor growth and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for gastric cancer. The expression of p-mTOR was detected in specimens of 181 gastric cancers who underwent radical resection (R0) by immunohistochemistry. The correlation of p-mTOR expression to clinicopathologic features and survival of gastric cancer was studied. We also determined the inhibition effect of RAD001 on tumor growth using BGC823 and AGS human gastric cancer cell lines. Immunostaining for p-mTOR was positive in 93 of 181 (51.4%) gastric cancers, closely correlated with lymph node status and pTNM stage. Patients with p-mTOR positive showed significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those with p-mTOR-negative tumors in univariable analyses, and there was a trend toward a correlation between p-mTOR expression and survival in multivariable analyses. RAD001 markedly inhibited dose-dependently proliferation of human gastric carcinoma cells by down-regulating expression of p70s6k, p-p70s6k, C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53. In gastric cancer, p-mTOR is a potential therapeutic target and RAD001 was a promising treatment agent with inducing cell cycle arrest and apoptosis by down-regulating expression of C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2-Dependent Bladder Cancer Cell Migration and Invasion.

Science.gov (United States)

Gupta, Sounak; Hau, Andrew M; Al-Ahmadie, Hikmat A; Harwalkar, Jyoti; Shoskes, Aaron C; Elson, Paul; Beach, Jordan R; Hussey, George S; Schiemann, William P; Egelhoff, Thomas T; Howe, Philip H; Hansel, Donna E

2016-05-01

Our prior work identified the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether transforming growth factor (TGF)-β, which can function as a promotility factor in bladder cancer cells, could regulate mTORC2-dependent bladder cancer cell motility and invasion. In human bladder cancers, the highest levels of phosphorylated SMAD2, a TGF-β signaling intermediate, were present in high-grade invasive bladder cancers and associated with more frequent recurrence and decreased disease-specific survival. Increased expression of TGF-β isoforms, receptors, and signaling components was detected in invasive high-grade bladder cancer cells that expressed Vimentin and lacked E-cadherin. Application of TGF-β induced phosphorylation of the Ser473 residue of AKT, a selective target of mTORC2, in a SMAD2- and SMAD4-independent manner and increased bladder cancer cell migration in a modified scratch wound assay and invasion through Matrigel. Inhibition of TGF-β receptor I using SB431542 ablated TGF-β-induced migration and invasion. A similar effect was seen when Rictor, a key mTORC2 component, was selectively silenced. Our results suggest that TGF-β can induce bladder cancer cell invasion via mTORC2 signaling, which may be applicable in most bladder cancers. Copyright © 2016. Published by Elsevier Inc.

Effects of growth hormone treatment on growth in children with juvenile idiopathic arthritis.

Science.gov (United States)

Simon, D; Bechtold, S

2009-11-01

Several therapeutic trials have been conducted over the past decade to evaluate the role of exogenous growth hormone (GH) as a means of correcting the growth deficiency seen in children with juvenile idiopathic arthritis (JIA). Early studies showed the benefit of GH treatment with respect to final height in patients with JIA. Of 13 patients receiving GH, 84% (11 patients) achieved a final height within their target range compared with only 22% (4 of 18 patients) of untreated patients. There are, however, factors that may limit the statural gains achieved with GH therapy including severe inflammation, severe statural deficiency at GH therapy initiation, long disease duration and delayed puberty. Data on the efficacy of GH replacement therapy in children with JIA and factors that influence the statural growth response will be reviewed. Results from therapeutic trials show that treatment with GH can decrease the statural deficit that occurs during the active phase of JIA, producing an adult height that is close to the genetically determined target height. Copyright 2009 S. Karger AG, Basel.

The adipose organ and multiple myeloma: Impact of adipokines on tumor growth and potential sites for therapeutic intervention.

Science.gov (United States)

Allegra, Alessandro; Innao, Vanessa; Gerace, Demetrio; Allegra, Andrea Gaetano; Vaddinelli, Doriana; Bianco, Oriana; Musolino, Caterina

2018-07-01

In addition to its capacity to store lipids the adipose tissue is now identified as a real organ with both endocrine and metabolic roles. Preclinical results indicate that modifying adipose tissue and bone marrow adipose tissue (BMAT) could be a successful multiple myeloma (MM) therapy. BMAT interrelates with bone marrow cells and other immune cells, and may influence MM disease progression. The BM adipocytes may have a role in MM progression, bone homing, chemoresistance, and relapse, due to local endocrine, paracrine, or metabolic factors. BM adipocytes isolated from MM subjects have been shown to increase myeloma growth in vitro and may preserve cells from chemotherapy-induced apoptosis. By producing free fatty acids and emitting signaling molecules such as growth factors and adipokines, BM adipocytes are both an energy font and an endocrine signaling factory. This review should suggest future research approaches toward developing novel treatments to target MM by targeting BMAT and its products. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

HomoTarget: a new algorithm for prediction of microRNA targets in Homo sapiens.

Science.gov (United States)

Ahmadi, Hamed; Ahmadi, Ali; Azimzadeh-Jamalkandi, Sadegh; Shoorehdeli, Mahdi Aliyari; Salehzadeh-Yazdi, Ali; Bidkhori, Gholamreza; Masoudi-Nejad, Ali

2013-02-01

MiRNAs play an essential role in the networks of gene regulation by inhibiting the translation of target mRNAs. Several computational approaches have been proposed for the prediction of miRNA target-genes. Reports reveal a large fraction of under-predicted or falsely predicted target genes. Thus, there is an imperative need to develop a computational method by which the target mRNAs of existing miRNAs can be correctly identified. In this study, combined pattern recognition neural network (PRNN) and principle component analysis (PCA) architecture has been proposed in order to model the complicated relationship between miRNAs and their target mRNAs in humans. The results of several types of intelligent classifiers and our proposed model were compared, showing that our algorithm outperformed them with higher sensitivity and specificity. Using the recent release of the mirBase database to find potential targets of miRNAs, this model incorporated twelve structural, thermodynamic and positional features of miRNA:mRNA binding sites to select target candidates. Copyright © 2012 Elsevier Inc. All rights reserved.

Molecular Targets for Targeted Radionuclide Therapy

International Nuclear Information System (INIS)

Mather, S.J.

2009-01-01

radiolabelled regulatory peptides and their metabolically stabilised analogues. Antigen epitopes: Antibodies, as unlabelled biological drugs, are becoming of increasing interest. They exert an antibody-dependent cellular cytotoxicity which leads to lysis of tumour cells. Radiolabelled versions of these (and other) antibodies are being developed worldwide. The disadvantage of the long circulating time of antibodies can be solved by engineering fragments such as diabodies, bivalent single chain variable fragments (scFv), minibodies or by pretargeting approaches. Transmembrane transporters: Other interesting targets are transporters for radiolabelled amino acids and nutrients. Cancer cells require an increased supply of many such nutrients and obtain these by increased expression of some types of amino-acid transporter. A more detailed analysis of the relationship between amino-acid uptake and transporter expression in normal and malignant cells would be very valuable in identifying the clinical therapeutic potential of this class of tracer. Tumour blood supply: Tumours require an efficient blood supply to grow and metastatise and active angiogenesis of new blood vessels is a feature of many tumours. Specific receptors expressed during this process represent a novel class of targets for TRT. Extra-cellular matrix: Recently, another relevant class of target antigens has raised interest. Lectins, or carbohydrate binding proteins, recognize specific oligosaccharide structures on glycoproteins and glycolipids. It is well known that protein and lipid glycosylation are consistently altered in cancer cells for the aberrant activity of specific glycosyltransferase and glycosydases. Experimental evidence demonstrated that tumor growth and progression may depend, at least in part, on the presence of altered glycoproteins on the cell surface, which can mediate aberrant receptor-ligand interactions. (author)

CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth

Energy Technology Data Exchange (ETDEWEB)

Lee, Eunjung; Son, Joe Eun; Byun, Sanguine; Lee, Seung Joon; Kim, Yeong A [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Liu, Kangdong [The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912 (United States); Kim, Jiyoung [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Lim, Soon Sung; Park, Jung Han Yoon [Department of Food Science and Nutrition, College of Natural Science, Hallym University, Chuncheon, 200-702 (Korea, Republic of); Dong, Zigang [The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912 (United States); Lee, Ki Won, E-mail: kiwon@snu.ac.kr [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Korea, Republic of); Lee, Hyong Joo, E-mail: leehyjo@snu.ac.kr [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Korea, Republic of)

2013-10-01

Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phase cell cycle transition and the accumulation of p27{sup kip1}. The elevated p27{sup kip1} expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients. - Highlights: • Isoangustone A suppresses growth of PC3 and LNCaP prostate cancer cells. • Administration of isoangustone A inhibits tumor growth in mice. • Treatment of isoangustone A induces cell cycle arrest and accumulation of p27{sup kip1}. • Isoangustone A inhibits CDK2 and mTOR activity. • Isoangustone A directly binds with CDK2 and mTOR complex in prostate cancer cells.

Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab

Directory of Open Access Journals (Sweden)

Chen Gang

2012-03-01

Full Text Available Abstract Background The epidermal growth factor receptor (EGFR is a validated therapeutic target in non-small cell lung cancer (NSCLC. However, current single agent receptor targeting does not achieve a maximal therapeutic effect, and some mutations confer resistance to current available agents. In the current study we have examined, in different NSCLC cell lines, the combined effect of RNA interference targeting the EGFR mRNA, and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors (TKIs or a monoclonal antibody cetuximab. Methods NSCLC cells (cell lines HCC827, H292, H358, H1650, and H1975 were transfected with EGFR siRNA and/or treated with the TKIs gefitinib, erlotinib, and afatinib, and/or with the monoclonal antibody cetuximab. The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR. The down-regulation of EGFR protein expression was measured by western blot, and the proliferation, viability, caspase3/7 activity, and apoptotic morphology were monitored by spectrophotometry, fluorimetry, and fluorescence microscopy. The combined effect of EGFR siRNA and different drugs was evaluated using a combination index. Results EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied, albeit with a different magnitude. The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs. The effects of siRNA probably correlate with the overall oncogenic significance of the receptor, which is only partly inhibited by the TKIs. The cells which showed weak response to TKIs, such as the H1975 cell line containing the T790M resistance mutation, were found to be responsive to siRNA knockdown of EGFR, as were cell lines with downstream TKI resistance mutations. The cell line HCC827, harboring an exon 19 deletion mutation, was more than 10-fold

Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results

International Nuclear Information System (INIS)

Baumann, Michael; Krause, Mechthild

2004-01-01

Background and purpose: Inhibition of the epidermal growth factor receptor (EGFR) is a fastly developing field in preclinical and clinical cancer research. This review presents the current status of knowledge and discusses radiobiological mechanisms which may underly the efficacy of EGFR inhibitors combined with irradiation. Materials and methods: Preclinical and clinical results on combined targeting of the EGFR and irradiation from the literature and from this laboratory are reviewed. Focus is given to the radiobiological rationale of this approach and to endpoints of experimental radiotherapy. Results: Overexpression of the EGFR is associated with decreased local tumour control after radiotherapy, especially when the overall treatment time is long. Inhibition of the EGFR either alone or in combination with irradiation decreases the growth rate of tumours expressing this receptor. Preclinical data provide proof-of-principle that local tumour control may be improved by combining irradiation with C225 mAb. In a randomised phase III clinical trial, simultaneous irradiation and treatment with the EGFR antibody Cetuximab (Erbitux[reg]; C225) in head and neck cancer patients resulted in significantly improved locoregional tumour control and survival compared to curative irradiation alone. Acute skin reactions increased in the experimental arm. The underlying mechanisms of enhanced radiation effects of combined EGFR inhibition with irradiation and of the partly conflicting results in different studies are poorly understood. There is increasing evidence, that important intertumoral heterogeneity in the response to EGFR inhibition alone and combined with irradiation exists, which appears to be at least partly dependent on specific mutations of the receptor as well as of molecules that are involved in the intracellular signal transduction pathway. Conclusions and outlook: Further investigations at all levels of the translational research chain exploring the mechanisms of

Targeting of liposomes to cells bearing nerve growth factor receptors mediated by biotinylated NGF

International Nuclear Information System (INIS)

Rosenberg, M.B.

1986-01-01

Previous studies of liposome targeting have concentrated on immunological systems, the use of ligand-receptor interactions has received little attention. The protein hormone beta-nerve growth factor (NGF) was modified by biotinylation via carboxyl group substitution (C-bio-NGF) under reaction conditions that yielded an average of 3 biotin additions per NGF subunit. NGF was also biotinylated through amino group substitution to produce derivatives with ratios of 1, 2 and 4 biotin moieties per NGF subunit (N-bio-NGF). These derivatives were compared with native NGF for their ability to compete with 125 I-NGF for binding to NGF receptors on rat pheochromocytoma (PC 12) cells at 4 0 C. C-bio-NGF was as effective as native NGF in binding to NGF receptors, while N-bio-NGF containing 1 biotin per NGF subunit was only 28% as active in binding as native NGF. C-bio-NGF, but not N-bio-NGF, mediated the specific binding of 125 I-streptavidin to PC12 cells. Biocytin-NGF, a derivative of C-bio-NGF with an extended spacer chain, was also synthesized and retained full biological and receptor binding activities. C-bio-NGF and biocytin-NGF were as effective as native NGF in a bioassay involving induction of neurite outgrowth from PC12 cells

Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells.

Science.gov (United States)

Schneider, Craig S; Perez, Jimena G; Cheng, Emily; Zhang, Clark; Mastorakos, Panagiotis; Hanes, Justin; Winkles, Jeffrey A; Woodworth, Graeme F; Kim, Anthony J

2015-02-01

A major limitation in the treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to invading tumor cells outside of the area that is safe for surgical removal. A promising way to target invading GBM cells is via drug-loaded nanoparticles that bind to fibroblast growth factor-inducible 14 (Fn14), thereby potentially improving efficacy and reducing toxicity. However, achieving broad particle distribution and nanoparticle targeting within the brain remains a significant challenge due to the adhesive extracellular matrix (ECM) and clearance mechanisms in the brain. In this work, we developed Fn14 monoclonal antibody-decorated nanoparticles that can efficiently penetrate brain tissue. We show these Fn14-targeted brain tissue penetrating nanoparticles are able to (i) selectively bind to recombinant Fn14 but not brain ECM proteins, (ii) associate with and be internalized by Fn14-positive GBM cells, and (iii) diffuse within brain tissue in a manner similar to non-targeted brain penetrating nanoparticles. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved tumor cell co-localization in mice bearing human GBM xenografts compared to non-targeted nanoparticles. Minimizing non-specific binding of targeted nanoparticles in the brain may greatly improve the access of particulate delivery systems to remote brain tumor cells and other brain targets. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Novel NHE1-Centered Signaling Cassette Drives Epidermal Growth Factor Receptor–Dependent Pancreatic Tumor Metastasis and Is a Target for Combination Therapy

Directory of Open Access Journals (Sweden)

Rosa Angela Cardone

2015-02-01

Full Text Available Pancreatic ductal adenocarcinoma (PDAC is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na+/H+ exchanger (NHE1 associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib.

Sphingosine kinase 1 is a relevant molecular target in gastric cancer

DEFF Research Database (Denmark)

Fuereder, Thorsten; Hoeflmayer, Doris; Jaeger-Lansky, Agnes

2011-01-01

Sphingosine kinase 1 (Sphk1), a lipid kinase implicated in cell transformation and tumor growth, is overexpressed in gastric cancer and is linked with a poor prognosis. The biological relevance of Sphk1 expression in gastric cancer is unclear. Here, we studied the functional significance of Sphk1...... as a novel molecular target for gastric cancer by using an antisense oligonucleotide approach in vitro and in vivo. Gastric cancer cell lines (MKN28 and N87) were treated with Sphk1 with locked nucleic acid-antisense oligonucleotides (LNA-ASO). Sphk1 target regulation, cell growth, and apoptosis were...... assessed for single-agent Sphk1 LNA-ASO and for combinations with doxorubicin. Athymic nude mice xenografted with gastric cancer cells were treated with Sphk1 LNA and assessed for tumor growth and Sphk1 target regulation, in vivo. In vitro, nanomolar concentrations of Sphk1 LNA-ASO induced an approximately...

Active power reserves evaluation in large scale PVPPs

DEFF Research Database (Denmark)

Crăciun, Bogdan-Ionut; Kerekes, Tamas; Sera, Dezso

2013-01-01

The present trend on investing in renewable ways of producing electricity in the detriment of conventional fossil fuel-based plants will lead to a certain point where these plants have to provide ancillary services and contribute to overall grid stability. Photovoltaic (PV) power has the fastest...... growth among all renewable energies and managed to reach high penetration levels creating instabilities which at the moment are corrected by the conventional generation. This paradigm will change in the future scenarios where most of the power is supplied by large scale renewable plants and parts...... of the ancillary services have to be shared by the renewable plants. The main focus of the proposed paper is to technically and economically analyze the possibility of having active power reserves in large scale PV power plants (PVPPs) without any auxiliary storage equipment. The provided reserves should...

Real-time imaging of the growth-inhibitory effect of JS399-19 on Fusarium.

Science.gov (United States)

Wollenberg, Rasmus D; Donau, Søren S; Nielsen, Thorbjørn T; Sørensen, Jens L; Giese, Henriette; Wimmer, Reinhard; Søndergaard, Teis E

2016-11-01

Real-time imaging was used to study the effects of a novel Fusarium-specific cyanoacrylate fungicide (JS399-19) on growth and morphology of four Fusarium sp. This fungicide targets the motor domain of type I myosin. Fusarium graminearum PH-1, Fusarium solani f. sp. pisi 77-13-4, Fusarium avenaceum IBT8464, and Fusarium avenaceum 05001, which has a K216Q amino-acid substitution at the resistance-implicated site in its myosin type I motor domain, were analyzed. Real-time imaging shows that JS399-19 inhibits fungal growth but not to the extent previously reported. The fungicide causes the hypha to become entangled and unable to extend vertically. This implies that type I myosin in Fusarium is essential for hyphal and mycelia propagation. The K216Q substitution correlates with reduced susceptibility in F. avenaceum. Copyright © 2015 Elsevier B.V. All rights reserved.

Regulatory Circuits Linking Energy Status to Growth

NARCIS (Netherlands)

Jansen, W.M.

2017-01-01

Plant growth and development critically depend on carbon nutrient status. Over the past years several core regulatory systems that link plant carbon status to growth have emerged. The core regulatory systems studied include the trehalose 6-phosphate (T6P) signaling system and the Target of Rapamycin

Targeted inhibition of αvβ3 integrin with an RNA aptamer impairs endothelial cell growth and survival

International Nuclear Information System (INIS)

Mi Jing; Zhang Xiuwu; Giangrande, Paloma H.; McNamara, James O.; Nimjee, Shahid M.; Sarraf-Yazdi, Shiva; Sullenger, Bruce A.; Clary, Bryan M.

2005-01-01

αvβ3 integrin is a crucial factor involved in a variety of physiological processes, such as cell growth and migration, tumor invasion and metastasis, angiogenesis, and wound healing. αvβ3 integrin exerts its effect by regulating endothelial cell (EC) migration, proliferation, and survival. Inhibiting the function of αvβ3 integrin, therefore, represents a potential anti-cancer, anti-thrombotic, and anti-inflammatory strategy. In this study, we tested an RNA aptamer, Apt-αvβ3 that binds recombinant αvβ3 integrin, for its ability to bind endogenous αvβ3 integrin on the surface of cells in culture and to subsequently affect cellular response. Our data illustrate that Apt-αvβ3 binds αvβ3 integrin expressed on the surface of live HUVECs. This interaction significantly decreases both basal and PDGF-induced cell proliferation as well as inhibition of cell adhesion. Apt-αvβ3 can also reduce PDGF-stimulated tube formation and increase HUVEC apoptosis through inhibition of FAK phosphorylation pathway. Our results demonstrate that by binding to its target, Apt-αvβ3 can efficiently inhibit human EC proliferation and survival, resulting in reduced angiogenesis. It predicts that Apt-αvβ3 could become useful in both tumor imaging and the treatment of tumor growth, atherosclerosis, thrombosis, and inflammation

GE11 Peptide as an Active Targeting Agent in Antitumor Therapy: A Minireview

Directory of Open Access Journals (Sweden)

Ida Genta

2017-12-01

Full Text Available A lot of solid tumors are characterized by uncontrolled signal transduction triggered by receptors related to cellular growth. The targeting of these cell receptors with antitumor drugs is essential to improve chemotherapy efficacy. This can be achieved by conjugation of an active targeting agent to the polymer portion of a colloidal drug delivery system loaded with an antitumor drug. The goal of this minireview is to report and discuss some recent results in epidermal growth factor receptor targeting by the GE11 peptide combined with colloidal drug delivery systems as smart carriers for antitumor drugs. The minireview chapters will focus on explaining and discussing: (i Epidermal growth factor receptor (EGFR structures and functions; (ii GE11 structure and biologic activity; (iii examples of GE11 conjugation and GE11-conjugated drug delivery systems. The rationale is to contribute in gathering information on the topic of active targeting to tumors. A case study is introduced, involving research on tumor cell targeting by the GE11 peptide combined with polymer nanoparticles.

CD47-CAR-T Cells Effectively Kill Target Cancer Cells and Block Pancreatic Tumor Growth.

Science.gov (United States)

Golubovskaya, Vita; Berahovich, Robert; Zhou, Hua; Xu, Shirley; Harto, Hizkia; Li, Le; Chao, Cheng-Chi; Mao, Mike Ming; Wu, Lijun

2017-10-21

CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen. In addition, CD47-CAR-T cells significantly blocked BxPC3 pancreatic xenograft tumor growth after intratumoral injection into NSG mice. Moreover, we humanized mouse CD47 ScFv and showed that it effectively bound CD47 antigen. The humanized CD47-CAR-T cells also specifically killed ovarian, pancreatic, and cervical cancer cell lines and produced IL-2 that correlated with expression of CD47. Thus, CD47-CAR-T cells can be used as a novel cellular therapeutic agent for treating different types of cancer.

Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?

Science.gov (United States)

Xu, Xiao-juan; Liu, Liang; Yao, Shu-kun

2016-01-01

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.

Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development.

Science.gov (United States)

Kim, Seonwook; Yang, Lihua; Kim, Seongu; Lee, Richard G; Graham, Mark J; Berliner, Judith A; Lusis, Aldons J; Cai, Lei; Temel, Ryan E; Rateri, Debra L; Lee, Sangderk

2017-01-01

The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model. Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin II (AngII, 1,000ng/kg/min) for the last 4 weeks of ASO administration. We confirmed that the HB-EGF ASO administration significantly downregulated HB-EGF expression in multiple tissues including the liver. Importantly, the HB-EGF ASO administration significantly suppressed development of aortic aneurysms including thoracic and abdominal types. Interestingly, the HB-EGF ASO administration induced a remarkable anti-hyperlipidemic effect by suppressing very low density lipoprotein (VLDL) level in the blood. Mechanistically, the HB-EGF targeting suppressed hepatic VLDL secretion rate without changing heparin-releasable plasma triglyceride (TG) hydrolytic activity or fecal neutral cholesterol excretion rate. This result suggested that the HB-EGF targeting induced protection against aneurysm development through anti-hyperlipidemic effects. Suppression of hepatic VLDL production process appears to be a key mechanism for the anti-hyperlipidemic effects by the HB-EGF targeting.

Environmental and economic effects of the Copenhagen pledges and more ambitious emission reduction targets. Interim report

Energy Technology Data Exchange (ETDEWEB)

Schleich, Joachim; Duscha, Vicki; Peterson, Everett B. [Fraunhofer-Institut fuer System- und Innovationsforschung, Karlsruhe (Germany); Virginia Tech, Blacksburg, VA (United States). Dept. of Agricultural and Applied Economics

2010-06-15

Equilibrium Model DYE-CLIP, which accounts for economic and environmental effects resulting from changes in income, prices, exports and imports, or from carbon leakage in response to climate policy. The main findings are: (a) Economic costs (in terms of reduced GDP compared to baseline GDP) in 2020 for industrialized and developing countries with ''pledges'' are - on average - no higher than 0.25 %, assuming that these countries are allowed to trade emission certificates unrestrictedly. The average GDP growth for industrialized countries with ''pledges'' remains at 27 %, while for developing countries with ''pledges'' it decreases slightly from 102 % to 100 % between 2004 and 2020. Economic effects for the most ambitious scenario are also rather low; (b) If the EU adopts an unconditioned 30 % emission reduction target in 2020 while all other countries stick with their ''weak'' pledges, the reduction in GDP growth in the EU will be rather small (less than 0.005 percentage points); (c) All policy scenarios lead to relatively larger reductions in GDP growth for developing countries than for industrialized countries. In general, annual GDP growth rates in developing countries remain significantly above those for industrialized countries; (d) Losses in economic growth tend to be above average in regions which depend highly on their reserves of fossil fuels. Because climate policies result in lower global demand for these resources, their world prices fall (compared to the baseline) translating into lower incomes for the respective countries. Revenues from selling excess certificates (stemming from ''new hot air'' implied by the Russian pledge) are not sufficient to compensate for these losses in economic growth; (d) Some large developing countries such as China and India experience larger losses in GDP growth for tighter global emission targets because their industrial sectors are

Democracy and growth in divided societies: A health-inequality trap?

Science.gov (United States)

Powell-Jackson, Timothy; Basu, Sanjay; Balabanova, Dina; McKee, Martin; Stuckler, David

2011-07-01

governance are insufficient to achieve child and maternal health targets in communities with high levels of persistent social inequality. To reduce child and maternal mortality in highly divided societies, it will be necessary not only to increase growth and promote democratic elections, but also empower disenfranchised communities. Copyright © 2011 Elsevier Ltd. All rights reserved.

Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance

International Nuclear Information System (INIS)

Jotte, Robert M; Spigel, David R

2015-01-01

Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance

BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury.

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Lopes, Cátia D F; Gonçalves, Nádia P; Gomes, Carla P; Saraiva, Maria J; Pêgo, Ana P

2017-03-01

Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain-derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nanoparticle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Discovery of functional monoclonal antibodies targeting G-protein-coupled receptors and ion channels.

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Wilkinson, Trevor C I

2016-06-15

The development of recombinant antibody therapeutics is a significant area of growth in the pharmaceutical industry with almost 50 approved monoclonal antibodies on the market in the US and Europe. Despite this growth, however, certain classes of important molecular targets have remained intractable to therapeutic antibodies due to complexity of the target molecules. These complex target molecules include G-protein-coupled receptors and ion channels which represent a large potential target class for therapeutic intervention with monoclonal antibodies. Although these targets have typically been addressed by small molecule approaches, the exquisite specificity of antibodies provides a significant opportunity to provide selective modulation of these target proteins. Given this opportunity, substantial effort has been applied to address the technical challenges of targeting these complex membrane proteins with monoclonal antibodies. In this review recent progress made in the strategies for discovery of functional monoclonal antibodies for these challenging membrane protein targets is addressed. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1

International Nuclear Information System (INIS)

Ha, Jung Min; Yun, Sung Ji; Kim, Young Whan; Jin, Seo Yeon; Lee, Hye Sun; Song, Sang Heon; Shin, Hwa Kyoung; Bae, Sun Sik

2015-01-01

Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. - Graphical abstract: Regulation of VSMC phenotype by PDGF-dependent activation of mTORC1. - Highlights: • The expression of contractile marker proteins was reduced by PDGF stimulation. • PDGF-dependent phenotypic conversion of VSMCs was blocked by inhibition of mTOR. • PDGF-induced proliferation of VSMCs was attenuated by inhibition of mTORC1. • mTORC1 plays a critical role in PDGF-dependent phenotypic conversion of VSMCs

Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1

Energy Technology Data Exchange (ETDEWEB)

Ha, Jung Min; Yun, Sung Ji; Kim, Young Whan; Jin, Seo Yeon; Lee, Hye Sun [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Song, Sang Heon [Department of Internal Medicine, Pusan National University Hospital, Busan (Korea, Republic of); Shin, Hwa Kyoung [Department of Anatomy, Pusan National University School of Korean Medicine, Yangsan (Korea, Republic of); Bae, Sun Sik, E-mail: sunsik@pusan.ac.kr [Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan (Korea, Republic of)

2015-08-14

Mammalian target of rapamycin complex (mTORC) regulates various cellular processes including proliferation, growth, migration and differentiation. In this study, we showed that mTORC1 regulates platelet-derived growth factor (PDGF)-induced phenotypic conversion of vascular smooth muscle cells (VSMCs). Stimulation of contractile VSMCs with PDGF significantly reduced the expression of contractile marker proteins in a time- and dose-dependent manner. In addition, angiotensin II (AngII)-induced contraction of VSMCs was completely blocked by the stimulation of VSMCs with PDGF. PDGF-dependent suppression of VSMC marker gene expression was significantly blocked by inhibition of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and mTOR whereas inhibition of p38 MAPK had no effect. In particular, inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked the PDGF-dependent phenotypic change of VSMCs whereas silencing of Rictor had no effect. In addition, loss of AngII-dependent contraction by PDGF was significantly retained by silencing of Raptor. Inhibition of mTORC1 by rapamycin or by silencing of Raptor significantly blocked PDGF-induced proliferation of VSMCs. Taken together, we suggest that mTORC1 plays an essential role in PDGF-dependent phenotypic changes of VSMCs. - Graphical abstract: Regulation of VSMC phenotype by PDGF-dependent activation of mTORC1. - Highlights: • The expression of contractile marker proteins was reduced by PDGF stimulation. • PDGF-dependent phenotypic conversion of VSMCs was blocked by inhibition of mTOR. • PDGF-induced proliferation of VSMCs was attenuated by inhibition of mTORC1. • mTORC1 plays a critical role in PDGF-dependent phenotypic conversion of VSMCs.

Suppression of the Rayleigh-Taylor instability due to self-radiation in a multiablation target

International Nuclear Information System (INIS)

Fujioka, Shinsuke; Sunahara, Atsushi; Nishihara, Katsunobu; Johzaki, Tomoyuki; Shiraga, Hiroyuki; Shigemori, Keisuke; Nakai, Mitsuo; Ikegawa, Tadashi; Murakami, Masakatsu; Nagai, Keiji; Norimatsu, Takayoshi; Azechi, Hiroshi; Yamanaka, Tatsuhiko; Ohnishi, Naofumi

2004-01-01

A scheme to suppress the Rayleigh-Taylor instability has been investigated for a direct-drive inertial fusion target. In a high-Z doped-plastic target, two ablation surfaces are formed separately--one driven by thermal radiation and the other driven by electron conduction. The growth of the Rayleigh-Taylor instability is significantly suppressed on the radiation-driven ablation surface inside the target due to the large ablation velocity and long density scale length. A significant reduction of the growth rate was observed in simulations and experiments using a brominated plastic target. A new direct-drive pellet was designed using this scheme

Targeting of GIT1 by miR-149* in breast cancer suppresses cell proliferation and metastasis in vitro and tumor growth in vivo

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Dong Y

2017-12-01

Full Text Available Yan Dong,1,* Cai Chang,2,* Jingtian Liu,3 Jinwei Qiang4 1Department of Ultrasonography, Jinshan Hospital, 2Department of Ultrasonography, Cancer Center, 3Department of General Surgery, 4Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China *These authors contributed equally to this work Abstract: Breast cancer remains a major cause of cancer-related death in women worldwide. Dysregulation of microRNAs (miRNAs is involved in the initiation and progression of breast cancer. Moreover, it was found that GIT1 was widely involved in the development of many human cancers. Herein, we aimed to investigate the expression changes of miR-149* and GIT1 and the functional effects of miR-149*/GIT1 link in breast cancer. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR and Western blot (WB were used to examine the expression levels of miR-149* and GIT1. Dual luciferase reporter assay was utilized to confirm the target interaction between miR-149* and GIT1. The biological functions, including cell proliferation, invasion, and migration, of miR-149* and GIT1 were determined by MTT assay and Transwell assays, respectively. Eventually, the tumor xenograft model in nude mice injected with stable transfected MDA-MB-231 cells was established to verify the effects of miR-149* and GIT1 on tumor growth. Our results showed that miR-149* expression was decreased, whereas GIT1 expression was increased in clinical samples of breast cancer. Based on the inverse expression trend between miR-149* and GIT1, we further demonstrated that miR-149* indeed directly targets GIT1. Subsequently, it was observed that inhibition of miR-149* significantly promoted cell proliferation, invasion, and migration, but the ability of cell proliferation, invasion, and migration was obviously declined after silencing of GIT1 in MDA-MB-231 cells transfected with miR-149* mimic and/or si-GIT1. Finally, it was also found that elevated miR-149* decelerated

The influence of government targeted procurement strategies on the growth performance of construction small and medium-sized contractors (SMCs in South Africa

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Abdurauf Adediran

2017-12-01

Full Text Available This paper examines government targeted procurement (TP strategies in South Africa and whether these strategies have an influence on the growth performance of Small and medium-sized contractors (SMCs in the construction industry. The rationale for this study stems from reports that while TP has been widely used as an instrument to improve the position of SMCs in the South African construction industry, three out of five SMCs do not become established firms. In addition, the nature of the influence of TP strategies on the growth performance of SMCs is not known. Following a review of existing literature, the study mainly adopted a quantitative research approach. Questionnaire surveys were administered to Construction Industry Development Board (cidb Grades 3 to 6 contractors that have executed TP projects within the last 5 years. The collected data was subjected to descriptive and inferential statistical analyses – Spearman’s rank order correlation was used as an index of association between the study variables. The study found that tendering equity is the most frequently used TP strategy, closely followed by preferencing and mandatory subcontracting. The study also found that positive significant associations exists among preferencing and turnover; third-party management and company assets; tendering equity, turnover and number of employees; as well as accelerated rotations, turnover and number of employees. The study concluded that government intervention through targeted procurement has the potential to achieve its intended results of improving the position of historically disadvantaged SMCs in the construction industry in South Africa if selected and implemented appropriately.

Risk spreading, connectivity, and optimal reserve spacing.

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Blowes, Shane A; Connolly, Sean R

2012-01-01

Two important processes determining the dynamics of spatially structured populations are dispersal and the spatial covariance of demographic fluctuations. Spatially explicit approaches to conservation, such as reserve networks, must consider the tension between these two processes and reach a balance between distances near enough to maintain connectivity, but far enough to benefit from risk spreading. Here, we model this trade-off. We show how two measures of metapopulation persistence depend on the shape of the dispersal kernel and the shape of the distance decay in demographic covariance, and we consider the implications of this trade-off for reserve spacing. The relative rates of distance decay in dispersal and demographic covariance determine whether the long-run metapopulation growth rate, and quasi-extinction risk, peak for adjacent patches or intermediately spaced patches; two local maxima in metapopulation persistence are also possible. When dispersal itself fluctuates over time, the trade-off changes. Temporal variation in mean distance that propagules are dispersed (i.e., propagule advection) decreases metapopulation persistence and decreases the likelihood that persistence will peak for adjacent patches. Conversely, variation in diffusion (the extent of random spread around mean dispersal) increases metapopulation persistence overall and causes it to peak at shorter inter-patch distances. Thus, failure to consider temporal variation in dispersal processes increases the risk that reserve spacings will fail to meet the objective of ensuring metapopulation persistence. This study identifies two phenomena that receive relatively little attention in empirical work on reserve spacing, but that can qualitatively change the effectiveness of reserve spacing strategies: (1) the functional form of the distance decay in covariance among patch-specific demographic rates and (2) temporal variation in the shape of the dispersal kernel. The sensitivity of metapopulation

Antigen-Addicted T Cell Reserves Trickle Charge the Frontline Killers.

Science.gov (United States)

Kalia, Vandana; Sarkar, Surojit

2016-07-19

Highly active killer T cells mediate a stable standoff during controlled persistent infections. In this issue of Immunity, Robey and colleagues describe a unique antigen-addicted T cell population bearing characteristics of both effector and memory CD8(+) T cells that provides a continuous supply of potent killer T cells to curb Toxoplasma gondii growth during latency. Copyright © 2016 Elsevier Inc. All rights reserved.

Drosophila photoreceptor axon guidance and targeting requires the dreadlocks SH2/SH3 adapter protein.

Science.gov (United States)

Garrity, P A; Rao, Y; Salecker, I; McGlade, J; Pawson, T; Zipursky, S L

1996-05-31

Mutations in the Drosophila gene dreadlocks (dock) disrupt photoreceptor cell (R cell) axon guidance and targeting. Genetic mosaic analysis and cell-type-specific expression of dock transgenes demonstrate dock is required in R cells for proper innervation. Dock protein contains one SH2 and three SH3 domains, implicating it in tyrosine kinase signaling, and is highly related to the human proto-oncogene Nck. Dock expression is detected in R cell growth cones in the target region. We propose Dock transmits signals in the growth cone in response to guidance and targeting cues. These findings provide an important step for dissection of signaling pathways regulating growth cone motility.

Analysing growth and development of plants jointly using developmental growth stages.

Science.gov (United States)

Dambreville, Anaëlle; Lauri, Pierre-Éric; Normand, Frédéric; Guédon, Yann

2015-01-01

Plant growth, the increase of organ dimensions over time, and development, the change in plant structure, are often studied as two separate processes. However, there is structural and functional evidence that these two processes are strongly related. The aim of this study was to investigate the co-ordination between growth and development using mango trees, which have well-defined developmental stages. Developmental stages, determined in an expert way, and organ sizes, determined from objective measurements, were collected during the vegetative growth and flowering phases of two cultivars of mango, Mangifera indica. For a given cultivar and growth unit type (either vegetative or flowering), a multistage model based on absolute growth rate sequences deduced from the measurements was first built, and then growth stages deduced from the model were compared with developmental stages. Strong matches were obtained between growth stages and developmental stages, leading to a consistent definition of integrative developmental growth stages. The growth stages highlighted growth asynchronisms between two topologically connected organs, namely the vegetative axis and its leaves. Integrative developmental growth stages emphasize that developmental stages are closely related to organ growth rates. The results are discussed in terms of the possible physiological processes underlying these stages, including plant hydraulics, biomechanics and carbohydrate partitioning. © The Author 2014. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Urdaibai Biosphere Reserve (Biscay, Spain): Conservation against development?

Science.gov (United States)

Castillo-Eguskitza, Nekane; Rescia, Alejandro J; Onaindia, Miren

2017-08-15

The protected area approach has extended from conserving biodiversity to improving human well-being. However, the relationship between conservation and socioeconomic and cultural development continues to be controversial. This paper combines land use variables with socioeconomic and cultural variables through multivariate ordination analysis and evaluates their evolution in two areas inside and outside a Biosphere Reserve since the approval of the Governance Plan for Use and Management in the Reserve. The results indicate a similar tendency in the two areas, from the abandonment of traditional rural activities and decline in pine plantations to naturalness, urban sprawl and the growth of the tertiary economic sector, welfare indicators and sustainability index. However, it can be broadly observed that the region included inside the protected area presents better conservation features (native forest) and rural systems (forestry and primary economic sector) than the region outside the protected area while maintaining similar socioeconomic and cultural conditions. We suggest that the designation of the Biosphere Reserve does not influence the local population negatively but does safeguard its conservation, which could have enhanced socioeconomic and cultural development. Thus, even though certain changes must be made to replace the conifer plantations and encourage agricultural activities, the designation of the protected area fulfills its sustainability goal and enhances the local population's quality of life. Copyright © 2017 Elsevier B.V. All rights reserved.

Small-scale habitat structure modulates the effects of no-take marine reserves for coral reef macroinvertebrates.

Directory of Open Access Journals (Sweden)

Pascal Dumas

Full Text Available No-take marine reserves are one of the oldest and most versatile tools used across the Pacific for the conservation of reef resources, in particular for invertebrates traditionally targeted by local fishers. Assessing their actual efficiency is still a challenge in complex ecosystems such as coral reefs, where reserve effects are likely to be obscured by high levels of environmental variability. The goal of this study was to investigate the potential interference of small-scale habitat structure on the efficiency of reserves. The spatial distribution of widely harvested macroinvertebrates was surveyed in a large set of protected vs. unprotected stations from eleven reefs located in New Caledonia. Abundance, density and individual size data were collected along random, small-scale (20×1 m transects. Fine habitat typology was derived with a quantitative photographic method using 17 local habitat variables. Marine reserves substantially augmented the local density, size structure and biomass of the target species. Density of Trochus niloticus and Tridacna maxima doubled globally inside the reserve network; average size was greater by 10 to 20% for T. niloticus. We demonstrated that the apparent success of protection could be obscured by marked variations in population structure occurring over short distances, resulting from small-scale heterogeneity in the reef habitat. The efficiency of reserves appeared to be modulated by the availability of suitable habitats at the decimetric scale ("microhabitats" for the considered sessile/low-mobile macroinvertebrate species. Incorporating microhabitat distribution could significantly enhance the efficiency of habitat surrogacy, a valuable approach in the case of conservation targets focusing on endangered or emblematic macroinvertebrate or relatively sedentary fish species.

Targeted Drug-Carrying Bacteriophages as Antibacterial Nanomedicines▿

Science.gov (United States)

Yacoby, Iftach; Bar, Hagit; Benhar, Itai

2007-01-01

While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of ∼20,000 compared to the free drug. PMID:17404004

In vivo tumor targeting and imaging with anti-vascular endothelial growth factor antibody-conjugated dextran-coated iron oxide nanoparticles

Directory of Open Access Journals (Sweden)

Hsieh WJ

2012-06-01

Full Text Available Wan-Ju Hsieh,1 Chan-Jung Liang,1 Jen-Jie Chieh,4 Shu-Huei Wang,1 I-Rue Lai,1 Jyh-Horng Chen,2 Fu-Hsiung Chang,3 Wei-Kung Tseng,4–6 Shieh-Yueh Yang,4 Chau-Chung Wu,7 Yuh-Lien Chen11Institute of Anatomy and Cell Biology, College of Medicine, 2Department of Electrical Engineering, 3Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan; 4Institute of Electro-Optical Science and Technology, National Taiwan Normal University, Taipei, Taiwan; 5Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Taipei, Taiwan; 6Department of Medical Imaging and Radiological Sciences, I-Shou University, Taipei, Taiwan; 7Department of Internal Medicine and Primary Care Medicine, National Taiwan University Hospital, Taipei, TaiwanBackground: Active targeting by specific antibodies combined with nanoparticles is a promising technology for cancer imaging and detection by magnetic resonance imaging (MRI. The aim of the present study is to investigate whether the systemic delivery of antivascular endothelial growth factor antibodies conjugating to the surface of functionalized supermagnetic iron oxide nanoparticles (anti-VEGF-NPs led to target-specific accumulation in the tumor.Methods: The VEGF expression in human colon cancer and in Balb/c mice bearing colon cancers was examined by immunohistochemistry. The distribution of these anti-VEGF-NPs particles or NPs particles were evaluated by MRI at days 1, 2, or 9 after the injection into the jugular vein of Balb/c mice bearing colon cancers. Tumor and normal tissues (liver, spleen, lung, and kidney were collected and were examined by Prussian blue staining to determine the presence and distribution of NPs in the tissue sections.Results: VEGF is highly expressed in human and mouse colon cancer tissues. MRI showed significant changes in the T*2 signal and T2 relaxation in the anti-VEGF-NP- injected-mice, but not in mice injected with NP alone. Examination of paraffin

'Intensity' targets. Pathway or roadblock to preventing climate change while enhancing economic growth?

International Nuclear Information System (INIS)

Dudek, D.; Golub, A.

2003-12-01

After establishing the operative definitions of greenhouse gas emissions 'intensity' targets and 'absolute' targets for greenhouse gas emissions limits, we identify examples of these approaches in current laws and policies. We focus in particular on the US experience with the sulfur dioxide emissions 'cap and trade' program as an example of the use of an 'absolute' target approach. We compare and contrast this example with 'performance standard' programs under the US Clean Air Act and the Corporate Average Fuel Economy standards for motor vehicles, which embody the emissions rate or 'intensity' concept. These case studies give us insights into the pros and cons of the intensity versus absolute approaches. Moving from retrospective to prospective, we consider the possible application of alternative absolute and intensity targets (IT) to global, national and firm-level emissions. We then identify criteria for evaluating the use of 'intensity' targets as a tool for achieving both environmental and economic goals. These include success in limiting climate change, achieving cost certainty and manageability, providing flexibility for public and private sector decision-makers in responding to new information, stimulating technological progress and sustaining a global climate regime

Prostate Tumor Growth Can Be Modulated by Dietarily Targeting the 15-Lipoxygenase-1 and Cyclooxygenase-2 Enzymes

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Uddhav P. Kelavkar

2009-07-01

Full Text Available The main objectives of our study were to determine the bioavailability of omega-3 (ω-3 to the tumor, to understand its mechanisms, and to determine the feasibility of targeting the ω-6 polyunsaturated fatty acids (PUFAs metabolizing 15-lipoxygenase-1 (15-LO-1 and cyclooxygenase-2 (COX-2 pathways. Nude mice injected subcutaneously with LAPC-4 prostate cancer cells were randomly divided into three different isocaloric (and same percent [%] of total fat diet groups: high ω-6 linoleic acid (LA, high ω-3 stearidonic acid (SDA PUFAs, and normal (control diets. Tumor growth and apoptosis were examined as end points after administration of short-term (5 weeks ω-3 and ω-6 fatty acid diets. Tumor tissue membranes were examined for growth, lipids, enzyme activities, apoptosis, and proliferation. Tumors from the LA diet-fed mice exhibited the most rapid growth compared with tumors from the control and SDA diet-fed mice. Moreover, a diet switch from LA to SDA caused a dramatic decrease in the growth of tumors in 5 weeks, whereas tumors grew more aggressively when mice were switched from an SDA to an LA diet. Evaluating tumor proliferation (Ki-67 and apoptosis (caspase-3 in mice fed the LA and SDA diets suggested increased percentage proliferation index from the ω-6 diet-fed mice compared with the tumors from the ω-3 SDA-fed mice. Further, increased apoptosis was observed in tumors from ω-3 SDA diet-fed mice versus tumors from ω-6 diet-fed mice. Levels of membrane phospholipids of red blood cells reflected dietary changes and correlated with the levels observed in tumors. Linoleic or arachidonic acid and metabolites (eicosanoid/prostaglandins were analyzed for 15-LO-1 and COX-2 activities by high-performance liquid chromatography. We also examined the percent unsaturated or saturated fatty acids in the total phospholipids, PUFA ω-6/ω-3 ratios, and other major enzymes (elongase, Delta [Δ]-5-desaturase, and Δ-6-desaturase of ω-6 catabolic

The role of insulin-like growth factor-1 (IGF-1) in growth and reproduction in female brown house snakes (Lamprophis fuliginosus).

Science.gov (United States)

Sparkman, A M; Byars, D; Ford, N B; Bronikowski, A M

2010-09-15

Insulin-like growth factor-1 (IGF-1) is a peptide hormone critically involved in the regulation of key life-history traits such as growth and reproduction. Its structure and function are well-characterized among diverse mammal, fish, and bird species; however, little is known regarding the activities of IGF-1 in non-avian reptiles, particularly snakes and lizards. Nevertheless, several unique characteristics of reptiles, such as high metabolic flexibility and remarkable diversity in life-history strategy, suggest that they are of great interest in the study of endocrinological mechanisms underlying the regulation and evolution of life-history traits. Here we test for a relationship between IGF-1 and individual feeding rate, growth rate and reproductive stage in lab-reared female offspring of wild-caught oviparous house snakes, Lamprophis fuliginosus. We confirm a positive correlation between IGF-1 and both feeding and growth rates in sexually immature snakes, similar to that reported in other taxa. We also show a family effect on IGF-1, suggesting that IGF-1 levels may be heritable in these snakes, and serve as an important target of selection to produce divergent life-history strategies. Furthermore, we provide evidence that suggests that IGF-1 may peak rapidly after first mating, and subsequently decline prior to egg-laying, a phenomenon not previously reported in other taxa. These findings suggest that further comparative study of IGF-1 in snakes may reveal both the extent to which IGF-1 function is conserved across major taxonomic groups, as well as novel and intriguing roles for IGF-1 in the regulation of reproductive activities. Copyright (c) 2010 Elsevier Inc. All rights reserved.

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma.

Science.gov (United States)

Arora, Shilpi; Gonzales, Irma M; Hagelstrom, R Tanner; Beaudry, Christian; Choudhary, Ashish; Sima, Chao; Tibes, Raoul; Mousses, Spyro; Azorsa, David O

2010-08-18

Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells. Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis. In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.

Morphology targets: What do seedling morphological attributes tell us?

Science.gov (United States)

Jeremiah R. Pinto

2011-01-01

Morphology is classically defined as the form and structure of individual organisms, as distinct from their anatomy or physiology. We use morphological targets in the nursery because they are easy to measure, and because we can often quantitatively link seedling morphological traits with survival and growth performance in the field. In the 20 years since the Target...

Population Growth and National Population Policy of India

Science.gov (United States)

Thukral, A. K.; Singh, B. P.

2008-01-01

The population growth in India may overtake China by the year 2030. The National Population Policy of India targets population stabilization in India by the year 2045. The present paper carries out objective analysis of the population growth in India in terms of change in specific growth. At the present rate of specific growth rate decline, the population by the end of the century will be 2.49 billion. For the population to achieve zero growth by the year 2045, a decline in specific growth rate will have to be achieved at the rate of 0.000428 per year.

Development and Characterization of a Camelid Single Domain Antibody-Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2.

Science.gov (United States)

Tian, Baomin; Wong, Wah Yau; Uger, Marni D; Wisniewski, Pawel; Chao, Heman

2017-01-01

Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs). In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21) and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody-urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MS E peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3) pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[( N -maleimidopropionamido)-diethyleneglycol] ester (SM(PEG) 2 ), which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis(maleimido)diethylene glycol

Development and Characterization of a Camelid Single Domain Antibody–Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2

Directory of Open Access Journals (Sweden)

Baomin Tian

2017-08-01

Full Text Available Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs. In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21 and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody–urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MSE peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3 pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[(N-maleimidopropionamido-diethyleneglycol] ester (SM(PEG2, which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis

Podoplanin - an emerging cancer biomarker and therapeutic target.

Science.gov (United States)

Krishnan, Harini; Rayes, Julie; Miyashita, Tomoyuki; Ishii, Genichiro; Retzbach, Edward P; Sheehan, Stephanie A; Takemoto, Ai; Chang, Yao-Wen; Yoneda, Kazue; Asai, Jun; Jensen, Lasse; Chalise, Lushun; Natsume, Atsushi; Goldberg, Gary S

2018-03-25

Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts (CAFs), and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition (EMT), migration, invasion, metastasis, and inflammation. Antibodies, CAR-T cells, biologics, and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer including glioma, squamous cell carcinoma, mesothelioma, and melanoma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

77 FR 21846 - Reserve Requirements of Depository Institutions: Reserves Simplification

Science.gov (United States)

2012-04-12

... Requirements of Depository Institutions: Reserves Simplification AGENCY: Board of Governors of the Federal Reserve System. ACTION: Final rule. SUMMARY: The Board is amending Regulation D, Reserve Requirements of Depository Institutions, to simplify the administration of reserve requirements. The final rule creates a...

A Novel indole compound that inhibits Pseudomonas aeruginosa growth by targeting MreB is a substrate for MexAB-OprM.

Science.gov (United States)

Robertson, Gregory T; Doyle, Timothy B; Du, Qun; Duncan, Leonard; Mdluli, Khisimuzi E; Lynch, A Simon

2007-10-01

Drug efflux systems contribute to the intrinsic resistance of Pseudomonas aeruginosa to many antibiotics and biocides and hamper research focused on the discovery and development of new antimicrobial agents targeted against this important opportunistic pathogen. Using a P. aeruginosa PAO1 derivative bearing deletions of opmH, encoding an outer membrane channel for efflux substrates, and four efflux pumps belonging to the resistance nodulation/cell division class including mexAB-oprM, we identified a small-molecule indole-class compound (CBR-4830) that is inhibitory to growth of this efflux-compromised strain. Genetic studies established MexAB-OprM as the principal pump for CBR-4830 and revealed MreB, a prokaryotic actin homolog, as the proximal cellular target of CBR-4830. Additional studies establish MreB as an essential protein in P. aeruginosa, and efflux-compromised strains treated with CBR-4830 transition to coccoid shape, consistent with MreB inhibition or depletion. Resistance genetics further suggest that CBR-4830 interacts with the putative ATP-binding pocket in MreB and demonstrate significant cross-resistance with A22, a structurally unrelated compound that has been shown to promote rapid dispersion of MreB filaments in vivo. Interestingly, however, ATP-dependent polymerization of purified recombinant P. aeruginosa MreB is blocked in vitro in a dose-dependent manner by CBR-4830 but not by A22. Neither compound exhibits significant inhibitory activity against mutant forms of MreB protein that bear mutations identified in CBR-4830-resistant strains. Finally, employing the strains and reagents prepared and characterized during the course of these studies, we have begun to investigate the ability of analogues of CBR-4830 to inhibit the growth of both efflux-proficient and efflux-compromised P. aeruginosa through specific inhibition of MreB function.

Proangiogenic Tie2(+) macrophages infiltrate human and murine endometriotic lesions and dictate their growth in a mouse model of the disease.

Science.gov (United States)

Capobianco, Annalisa; Monno, Antonella; Cottone, Lucia; Venneri, Mary Anna; Biziato, Daniela; Di Puppo, Francesca; Ferrari, Stefano; De Palma, Michele; Manfredi, Angelo A; Rovere-Querini, Patrizia

2011-11-01

Endometriosis affects women of reproductive age, causing infertility and pain. Although immune cells are recruited in endometriotic lesions, their role is unclear. Tie2-expressing macrophages (TEMs) have nonredundant functions in promoting angiogenesis and growth of experimental tumors. Here we show that human TEMs infiltrate areas surrounding newly formed endometriotic blood vessels. We set up an ad hoc mouse model in which TEMs, and not Tie2-expressing endothelial cells, are targeted. We transplanted in wild-type recipients bone marrow cells expressing a suicide gene (Herpes simplex virus type 1 thymidine kinase) under the Tie2 promoter/enhancer. TEMs infiltrated endometriotic lesions. TEM depletion by ganciclovir administration arrested the growth of established lesions, without toxicity. Lesion architecture was disrupted, with: i) loss of glandular organization, ii) reduced neovascularization, and iii) activation of caspase 3 in CD31(+) endothelial cells. Thus, TEMs are important for maintaining the viability of newly formed vessels and represent a potential therapeutic target in endometriosis. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Climate targets for all countries: the options

International Nuclear Information System (INIS)

Philibert, C.; Pershing, J.

2001-01-01

This paper assesses five options for targets that could be taken by all countries to meet the ultimate objective of the Climate Change Convention: fixed, binding targets, dynamic targets; non-binding targets; sectoral targets, policies and measures. Each is evaluated according to criteria of environmental effectiveness, cost-effectiveness, contribution to economic growth and sustainable development, and equity. While fixed, binding targets continue to be viable for industrialized countries, they do not seem suitable for many developing countries in the near future. Dynamic targets could alleviate developing countries' concerns about constraining their development as well as broader concerns about possible introduction of 'hot air' in a world trading regime; they could also be considered for some or all industrialized countries. Non-binding targets could be politically appealing to developing counties, alleviate fears about development and/or hot air, but might only allow conditional participation in emissions trading by developing countries. Sectoral targets could offer a pragmatic first step - although their cost-effectiveness might be questioned. Finally, targets based on commitments to implement specific policies and measures might drive mitigation action and be part of negotiated packages including financial and technological cooperation. All these options may coexist in the future. (authors)

Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Mediates Liver Fibrosis in Transgenic Mice.

Science.gov (United States)

Guo, Yongze; Ding, Qian; Chen, Lei; Ji, Chenguang; Hao, Huiyao; Wang, Jia; Qi, Wei; Xie, Xiaoli; Ma, Junji; Li, Aidi; Jiang, Xiaoyu; Li, Xiaotian; Jiang, Huiqing

2017-08-01

The role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver fibrosis is not clear and is sometimes even contradictory. To clarify this role, a HB-EGF transgenic (Tg) mouse model was, for the first time, used to evaluate the functions of HB-EGF in liver fibrosis. For the in vivo study, carbon tetrachloride injection and bile duct ligation treatment were used to induce liver fibrosis in HB-EGF Tg mice and wild-type (WT) mice, respectively. Primary hepatic satellite cells (HSCs) were isolated from HB-EGF Tg and WT mice for the in vitro study. Compared with the WT mice, HB-EGF Tg mice were shown to develop more severe liver fibrosis when treated with carbon tetrachloride or bile duct ligation, with increased matrix metalloproteinases 13 activity and enhanced expression of fibrogenic genes including α-smooth muscle actin and collagen I. HB-EGF gene transfer led to an increase in proliferation and a decrease in apoptosis in primary HSCs. The ERK signaling pathway was more highly activated in primary HSCs from HB-EGF Tg mice than in those from WT mice. Our investigation confirmed the profibrotic effect of HB-EGF on the liver using a Tg mouse model. This result may contribute to the elucidation of HB-EGF as a therapeutic target in liver fibrosis. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury.

Science.gov (United States)

Terabayashi, Takeshi; Ito, Yasuhiko; Mizuno, Masashi; Suzuki, Yasuhiro; Kinashi, Hiroshi; Sakata, Fumiko; Tomita, Takako; Iguchi, Daiki; Tawada, Mitsuhiro; Nishio, Ryosuke; Maruyama, Shoichi; Imai, Enyu; Matsuo, Seiichi; Takei, Yoshifumi

2015-09-01

Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-β1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and -D, might be a new target to improve net ultrafiltration by using adenovirus-expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (Ptarget to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption.

Emissions intensity targeting: From China's 12th Five Year Plan to its Copenhagen commitment

International Nuclear Information System (INIS)

Lu, Yingying; Stegman, Alison; Cai, Yiyong

2013-01-01

China is currently the world's largest single source of fossil fuel related CO 2 emissions. In response to pressure from the international community, and in recognition of its role in global climate change mitigation, the Chinese government has announced a series of climate policy commitments, in both the Copenhagen Accord and its domestic 12th 5 Year Plan, to gradually reduce emissions intensity by 2020. Emissions intensity reduction commitments differ significantly from emission level reduction commitments that are commonly adopted by developed economies. In this paper, we investigate the economic implications of China's recent commitments to reduce emissions intensity, and highlight the complexities involved in modelling intensity targets under uncertainty. Using G-Cubed, an intertemporal, computable general equilibrium model of the world economy, we show that China's emissions intensity targets could be achieved with a range of low and high growth emissions level trajectories corresponding to low and high growth GDP scenarios, which lead to different welfare consequences. - Highlights: • We investigate the economic implication of China's recent climate commitments. • We address the complexity of modelling reduction in emissions intensity. • The 2015 target gives China more flexibility towards its 2020 target. • The policy restriction is eased in high growth periods. • In low growth periods an intensity target places a further restriction on the economy

Target innervation is necessary for neuronal polyploidization in the terrestrial slug Limax.

Science.gov (United States)

Matsuo, Ryota; Yamagishi, Miki; Wakiya, Kyoko; Tanaka, Yoko; Ito, Etsuro

2013-08-01

The brain of gastropod mollusks contains many giant neurons with polyploid genomic DNAs. Such DNAs are generated through repeated DNA endoreplication during body growth. However, it is not known what triggers DNA endoreplication in neurons. There are two possibilities: (1) DNAs are replicated in response to some unknown molecules in the hemolymph that reflect the nutritive status of the animal; or (2) DNAs are replicated in response to some unknown factors that are retrogradely transported through axons from the innervated target organs. We first tested whether hemolymph with rich nutrition could induce DNA endoreplication. We tested whether the transplanted brain exhibits enhanced DNA endoreplication like an endogenous brain does when transplanted into the homocoel of the body of a slug whose body growth is promoted by an increased food supply. However, no enhancement was observed in the frequency of DNA endoreplication when we compared the transplanted brains in the growth-promoted and growth-suppressed host slugs, suggesting that the humoral environment is irrelevant to triggering the body growth-dependent DNA endoreplication. Next, we tested the requirement of target innervation by surgically dissecting a unilateral posterior pedal nerve of an endogenous brain. Substantially lower number of neurons exhibited DNA endoreplication in the pedal ganglion ipsilateral to the dissected nerve. These results support the view that enhanced DNA endoreplication is mediated by target innervation and is not brought about through the direct effect of humoral factors in the hemolymph during body growth. Copyright © 2013 Wiley Periodicals, Inc.

Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins.

Science.gov (United States)

Eng, M S; Kaur, J; Prasmickaite, L; Engesæter, B Ø; Weyergang, A; Skarpen, E; Berg, K; Rosenblum, M G; Mælandsmo, G M; Høgset, A; Ferrone, S; Selbo, P K

2018-05-16

Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS2a (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS2a + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.

Rayleigh-Taylor instability in multi-structured spherical targets

International Nuclear Information System (INIS)

Gupta, N.K.; Lawande, S.V.

1986-01-01

An eigenvalue equation for the exponential growth rate of the Rayleigh-Taylor instability is derived in spherical geometry. The free surface and jump boundary conditions are obtained from the eigenvalue equation. The eigenvalue equation is solved in the cases where the initial fluid density profile has a step function or exponential variation in space and analytical formulae for growth rate of the instability are obtained. The solutions for the step function are generalized for any number N of spherical zones forming an arbitrary fluid density profile. The results of the numerical calculations for N spherical zones are compared with the exact analytical results for exponential fluid density profile with N=10 and a good agreement is observed. The formalism is further used to study the effects of density gradients on Rayleigh-Taylor instability in spherical geometry. Also analytical formulae are presented for a particular case of N=3 and shell targets. The formalism developed here can be used to study the growth of the instability in present day multi-structured shell targets. (author)

Genome-wide placental DNA methylation analysis of severely growth-discordant monochorionic twins reveals novel epigenetic targets for intrauterine growth restriction.

Science.gov (United States)

Roifman, Maian; Choufani, Sanaa; Turinsky, Andrei L; Drewlo, Sascha; Keating, Sarah; Brudno, Michael; Kingdom, John; Weksberg, Rosanna

2016-01-01

Intrauterine growth restriction (IUGR), which refers to reduced fetal growth in the context of placental insufficiency, is etiologically heterogeneous. IUGR is associated not only with perinatal morbidity and mortality but also with adult-onset disorders, such as cardiovascular disease and diabetes, posing a major health burden. Placental epigenetic dysregulation has been proposed as one mechanism that causes IUGR; however, the spectrum of epigenetic pathophysiological mechanisms leading to IUGR remains to be elucidated. Monozygotic monochorionic twins are particularly affected by IUGR, in the setting of severe discordant growth. Because monozygotic twins have the same genotype at conception and a shared maternal environment, they provide an ideal model system for studying epigenetic dysregulation of the placenta. We compared genome-wide placental DNA methylation patterns of severely growth-discordant twins to identify novel candidate genes for IUGR. Snap-frozen placental samples for eight severely growth-discordant monozygotic monochorionic twin pairs were obtained at delivery from each twin. A high-resolution DNA methylation array platform was used to identify methylation differences between IUGR and normal twins. Our analysis revealed differentially methylated regions in the promoters of eight genes: DECR1, ZNF300, DNAJA4, CCL28, LEPR, HSPA1A/L, GSTO1, and GNE. The largest methylation differences between the two groups were in the promoters of DECR1 and ZNF300. The significance of these group differences was independently validated by bisulfite pyrosequencing, implicating aberrations in fatty acid beta oxidation and transcriptional regulation, respectively. Further analysis of the array data identified methylation changes most prominently affecting the Wnt and cadherin pathways in the IUGR cohort. Our results suggest that IUGR in monozygotic twins is associated with impairments in lipid metabolism and transcriptional regulation as well as cadherin and Wnt

Sortase A: an ideal target for anti-virulence drug development.

Science.gov (United States)

Cascioferro, Stella; Totsika, Makrina; Schillaci, Domenico

2014-12-01

Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance. Copyright © 2014 Elsevier Ltd. All rights reserved.

Bacterial proteases: targets for diagnostics and therapy

NARCIS (Netherlands)

Kaman, W.E.; Hays, J.P.; Endtz, H.P.; Bikker, F.J.

2014-01-01

Proteases are essential for the proliferation and growth of bacteria, and are also known to contribute to bacterial virulence. This makes them interesting candidates as diagnostic and therapeutic targets for infectious diseases. In this review, the authors discuss the most recent developments and

The inhibitory effect of disulfiram encapsulated PLGA NPs on tumor growth: Different administration routes.

Science.gov (United States)

Fasehee, Hamidreza; Zarrinrad, Ghazaleh; Tavangar, Seyed Mohammad; Ghaffari, Seyed Hamidollah; Faghihi, Shahab

2016-06-01

The strong anticancer activity of disulfiram is hindered by its rapid degradation in blood system. A novel folate-receptor-targeted poly (lactide-co-glycolide) (PLGA)-polyethylene glycol (PEG) nanoparticle (NP) is developed for encapsulation and delivery of disulfiram into breast cancer tumor using passive (EPR effect) and active (folate receptor) targeting. The anticancer activity of disulfiram and its effect on caspase-3 activity and cell cycle are studied. The administration of encapsulated PLGA NPs using intra-peritoneal, intravenous and intra-tumor routes is investigated using animal model. Disulfiram shows strong cytotoxicity against MCF7 cell line. The activity of caspase-3 inhibited with disulfiram via dose dependent manner while the drug causes cell cycle arrest in G0/G1 and S phase time-dependently. The encapsulated disulfiram shows higher activity in apoptosis induction as compared to free drug. In nontoxic dose of encapsulated disulfiram, the highest and lowest efficacy of NPs in tumor growth inhibition is observed for intravenous injection and intraperitoneal injection. It is suggested that administration of disulfiram by targeted PLGA nanoparticles using intravenous injection would present an alternative therapeutic approach for solid tumor treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Onco-miR-24 regulates cell growth and apoptosis by targeting BCL2L11 in gastric cancer

Directory of Open Access Journals (Sweden)

Haiyang Zhang

2016-01-01

Full Text Available ABSTRACT Gastric cancer is one of the most common malignancies worldwide; however, the molecular mechanism in tumorigenesis still needs exploration. BCL2L11 belongs to the BCL-2 family, and acts as a central regulator of the intrinsic apoptotic cascade and mediates cell apoptosis. Although miRNAs have been reported to be involved in each stage of cancer development, the role of miR-24 in GC has not been reported yet. In the present study, miR-24 was found to be up-regulated while the expression of BCL2L11 was inhibited in tumor tissues of GC. Studies from both in vitro and in vivo shown that miR-24 regulates BCL2L11 expression by directly binding with 3′UTR of mRNA, thus promoting cell growth, migration while inhibiting cell apoptosis. Therefore, miR-24 is a novel onco-miRNA that can be potential drug targets for future clinical use.

Application of a Mathematical Model to an Advertisement Reservation Problem

Directory of Open Access Journals (Sweden)

Ozlem COSGUN

2013-01-01

Full Text Available Television networks provide TV programs free of charge to the public. However, they acquire their revenue by telecasting advertisements in the midst of continuing programs or shows. A key problem faced by the TV networks in Turkey is how to accept and televise the advertisements reserved by a client on a specified advertisement break which we called “Advertisement Reservation Problem” (ARP. The problem is complicated by limited time inventory, by different rating points for different target groups, competition avoidance and the relationship between TV networks and clients. In this study we have developed a mathematical model for advertisement reservation problem and extended this model for some cases encountered in real business life. We have also discussed how these cases affect the decisions of a TV network. Mixed integer linear programming approach is proposed to solve these problems. This approach has been implemented to a case taken from one of the biggest TV networks of Turkey.

Lipid for biodiesel production from attached growth Chlorella vulgaris biomass cultivating in fluidized bed bioreactor packed with polyurethane foam material.

Science.gov (United States)

Mohd-Sahib, Ainur-Assyakirin; Lim, Jun-Wei; Lam, Man-Kee; Uemura, Yoshimitsu; Isa, Mohamed Hasnain; Ho, Chii-Dong; Kutty, Shamsul Rahman Mohamed; Wong, Chung-Yiin; Rosli, Siti-Suhailah

2017-09-01

The potential to grow attached microalgae Chlorella vulgaris in fluidized bed bioreactor was materialized in this study, targeting to ease the harvesting process prior to biodiesel production. The proposed thermodynamic mechanism and physical property assessment of various support materials verified polyurethane to be suitable material favouring the spontaneous adhesion by microalgae cells. The 1-L bioreactor packed with only 2.4% (v/v) of 1.00-mL polyurethane foam cubes could achieve the highest attached growth microalgae biomass and lipid weights of 812±122 and 376±37mg, respectively, in comparison with other cube sizes. The maturity of attached growth microalgae biomass for harvesting could also be determined from the growth trend of suspended microalgae biomass. Analysis of FAME composition revealed that the harvested microalgae biomass was dominated by C16-C18 (>60%) and mixture of saturated and mono-unsaturated fatty acids (>65%), satiating the biodiesel standard with adequate cold flow property and oxidative stability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Do we understand the linkages between economic growth, poverty targets and poverty reduction?

DEFF Research Database (Denmark)

Casse, Thorkil; Jensen, Stig Eduard Breitenstein

2009-01-01

This article contributes to the debate on poverty trends in Africa, looking at the argument for a correspondence between economic growth and poverty reduction. It questions whether a link between economic growth and poverty reduction can be established. We first look at the general picture...... appears more obvious, social and political unrest in 2009 casts doubt on the reliability of the data. Indeed, it is probable that an increase in poverty contributed to the crisis in Madagascar. Furthermore, there a signs that in both countries poverty strategies are increasingly giving way to Poverty...... Reduction Growth Facility programmes, closely related to former structural adjustment loans. We conclude, first, that analysing poverty strategies through Poverty Reduction Strategy Papers does not help in resolving the uncertainty, since these strategies assume a priori the existence of a link between...

RNA as a small molecule druggable target.

Science.gov (United States)

Rizvi, Noreen F; Smith, Graham F

2017-12-01

Small molecule drugs have readily been developed against many proteins in the human proteome, but RNA has remained an elusive target for drug discovery. Increasingly, we see that RNA, and to a lesser extent DNA elements, show a persistent tertiary structure responsible for many diverse and complex cellular functions. In this digest, we have summarized recent advances in screening approaches for RNA targets and outlined the discovery of novel, drug-like small molecules against RNA targets from various classes and therapeutic areas. The link of structure, function, and small-molecule Druggability validates now for the first time that RNA can be the targets of therapeutic agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

Status of Shanxi Province's power and coal reserves

International Nuclear Information System (INIS)

Wu, D.C.; Shang, J.Y.

1995-01-01

An introduction to Shanxi's coal reserve, production, transportation utilization, electric power generation and transmission capacities is presented with the intention of providing outsiders a clear understanding of Shanxi's coal and power industries. Quantitative sketches of Shanxi's role in China's energy resource production and power generation are included. The province of Shanxi invites investors to visit Shanxi to gain first-hand knowledge. The authors have also taken the liberty of providing the high points of Shanxi's indigenous sceneries and local customs. They believe that in the future, Shanxi's coal based power development will be one of the principal drivers of China's economic growth

Transcriptome-wide identification of Rauvolfia serpentina microRNAs and prediction of their potential targets.

Science.gov (United States)

Prakash, Pravin; Rajakani, Raja; Gupta, Vikrant

2016-04-01

MicroRNAs (miRNAs) are small non-coding RNAs of ∼ 19-24 nucleotides (nt) in length and considered as potent regulators of gene expression at transcriptional and post-transcriptional levels. Here we report the identification and characterization of 15 conserved miRNAs belonging to 13 families from Rauvolfia serpentina through in silico analysis of available nucleotide dataset. The identified mature R. serpentina miRNAs (rse-miRNAs) ranged between 20 and 22nt in length, and the average minimal folding free energy index (MFEI) value of rse-miRNA precursor sequences was found to be -0.815 kcal/mol. Using the identified rse-miRNAs as query, their potential targets were predicted in R. serpentina and other plant species. Gene Ontology (GO) annotation showed that predicted targets of rse-miRNAs include transcription factors as well as genes involved in diverse biological processes such as primary and secondary metabolism, stress response, disease resistance, growth, and development. Few rse-miRNAs were predicted to target genes of pharmaceutically important secondary metabolic pathways such as alkaloids and anthocyanin biosynthesis. Phylogenetic analysis showed the evolutionary relationship of rse-miRNAs and their precursor sequences to homologous pre-miRNA sequences from other plant species. The findings under present study besides giving first hand information about R. serpentina miRNAs and their targets, also contributes towards the better understanding of miRNA-mediated gene regulatory processes in plants. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mineral Resources: Reserves, Peak Production and the Future

Directory of Open Access Journals (Sweden)

Lawrence D. Meinert

2016-02-01

Full Text Available The adequacy of mineral resources in light of population growth and rising standards of living has been a concern since the time of Malthus (1798, but many studies erroneously forecast impending peak production or exhaustion because they confuse reserves with “all there is”. Reserves are formally defined as a subset of resources, and even current and potential resources are only a small subset of “all there is”. Peak production or exhaustion cannot be modeled accurately from reserves. Using copper as an example, identified resources are twice as large as the amount projected to be needed through 2050. Estimates of yet-to-be discovered copper resources are up to 40-times more than currently-identified resources, amounts that could last for many centuries. Thus, forecasts of imminent peak production due to resource exhaustion in the next 20–30 years are not valid. Short-term supply problems may arise, however, and supply-chain disruptions are possible at any time due to natural disasters (earthquakes, tsunamis, hurricanes or political complications. Needed to resolve these problems are education and exploration technology development, access to prospective terrain, better recycling and better accounting of externalities associated with production (pollution, loss of ecosystem services and water and energy use.

Price-related sensitivities of greenhouse gas intensity targets

International Nuclear Information System (INIS)

Muller, Benito; Muller-Furstenberger, Georg

2003-12-01

Greenhouse gas intensities are an appealing tool to foster abatement without imposing constraints on economic growth. This paper shows, however, that the computation of intensities is subject to some significant statistical and conceptual problems which relate to the inflation proofing of GDP growth. It is shown that the choice of price-index, the updating of quantity weights and the choice of base year prices can have a significant impact upon the commitment of intensity targets

Advances and advantages of nanomedicine in the pharmacological targeting of hyaluronan-CD44 interactions and signaling in cancer.

Science.gov (United States)

Skandalis, Spyros S; Gialeli, Chrisostomi; Theocharis, Achilleas D; Karamanos, Nikos K

2014-01-01

Extensive experimental evidence in cell and animal tumor models show that hyaluronan-CD44 interactions are crucial in both malignancy and resistance to cancer therapy. Because of the intimate relationship between the hyaluronan-CD44 system and tumor cell survival and growth, it is an increasingly investigated area for applications to anticancer chemotherapeutics. Interference with the hyaluronan-CD44 interaction by targeting drugs to CD44, targeting drugs to the hyaluronan matrix, or interfering with hyaluronan matrix/tumor cell-associated CD44 interactions is a viable strategy for cancer treatment. Many of these methods can decrease tumor burden in animal models but have yet to show significant clinical utility. Recent advances in nanomedicine have offered new valuable tools for cancer detection, prevention, and treatment. The enhanced permeability and retention effect has served as key rationale for using nanoparticles to treat solid tumors. However, the targeted and uniform delivery of these particles to all regions of tumors in sufficient quantities requires optimization. An ideal nanocarrier should be equipped with selective ligands that are highly or exclusively expressed on target cells and thus endow the carriers with specific targeting capabilities. In this review, we describe how the hyaluronan-CD44 system may provide such an alternative in tumors expressing specific CD44 variants. © 2014 Elsevier Inc. All rights reserved.

Statistical analysis of joint toxicity in biological growth experiments

DEFF Research Database (Denmark)

Spliid, Henrik; Tørslev, J.

1994-01-01

The authors formulate a model for the analysis of designed biological growth experiments where a mixture of toxicants is applied to biological target organisms. The purpose of such experiments is to assess the toxicity of the mixture in comparison with the toxicity observed when the toxicants are...... is applied on data from an experiment where inhibition of the growth of the bacteria Pseudomonas fluorescens caused by different mixtures of pentachlorophenol and aniline was studied.......The authors formulate a model for the analysis of designed biological growth experiments where a mixture of toxicants is applied to biological target organisms. The purpose of such experiments is to assess the toxicity of the mixture in comparison with the toxicity observed when the toxicants...

Direct drive acceleration of planar liquid deuterium targets

International Nuclear Information System (INIS)

Sethian, J.D.; Bodner, S.E.; Colombant, D.G.; Dahlburg, J.P.; Obenschain, S.P.; Pawley, C.J.; Serlin, V.; Gardner, J.H.; Aglitskiy, Y.; Chan, Y.; Deniz, A.V.; Lehecka, T.; Klapisch, M.

1999-01-01

The Nike laser (∼2 - 3 kJ, ∼10 14 W/cm 2 ) has been used to ablatively accelerate planar liquid deuterium targets. These experiments are designed to test some aspects of a high gain direct drive target design. The target consists of a low-density foam that is filled with liquid deuterium and covered with a thin polyimide membrane. The measured target trajectory agrees well with one-dimensional (1D) simulations. The growth of the areal mass modulations were measured with a new, 1.26 keV x-ray backlighter. The modulations appear later and grow to a smaller amplitude when the foot of the laser pulse is made spatially smoother. A thin layer of gold on the front of the target reduces the modulations. The results are compared with 2D modeling

Effect of young maternal age and skeletal growth on placental growth and development.

Science.gov (United States)

Hayward, C E; Greenwood, S L; Sibley, C P; Baker, P N; Jones, R L

2011-12-01

Teenagers are susceptible to delivering small-for-gestational-age infants. Previous studies implicate continued skeletal growth as a contributory factor, and impaired placental development was the primary cause of fetal growth restriction in growing adolescent sheep. The aims of this study were to examine the impact of young maternal age and growth on placental development. Placentas were collected from 31 teenagers, of which 12 were growing and 17 non-growing based on knee height measurements. An adult control group (n = 12) was included. Placental weight and morphometric measurements of villous, syncytiotrophoblast, fibrin and vessel areas, as well as indices of proliferation and apoptosis, were analysed in relation to maternal growth and age. Growing teenagers had a higher birthweight:placental weight ratio than non-growing teenagers (p adult and teenage pregnancies. Maternal smoking, a potential confounding factor, did not exert a major influence on the placental parameters examined, except for a stimulatory effect on placental proliferation (p development, and is consistent with our recent observations that maternal growth was not detrimental to fetal growth. Copyright © 2011 Elsevier Ltd. All rights reserved.

Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA.

Science.gov (United States)

Zhang, Haiyang; Wang, Yi; Bai, Ming; Wang, Junyi; Zhu, Kegan; Liu, Rui; Ge, Shaohua; Li, JiaLu; Ning, Tao; Deng, Ting; Fan, Qian; Li, Hongli; Sun, Wu; Ying, Guoguang; Ba, Yi

2018-03-01

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

TOR Signaling Promotes Accumulation of BZR1 to Balance Growth with Carbon Availability in Arabidopsis.

Science.gov (United States)

Zhang, Zhenzhen; Zhu, Jia-Ying; Roh, Jeehee; Marchive, Chloé; Kim, Seong-Ki; Meyer, Christian; Sun, Yu; Wang, Wenfei; Wang, Zhi-Yong

2016-07-25

For maintenance of cellular homeostasis, the actions of growth-promoting hormones must be attenuated when nutrient and energy become limiting. The molecular mechanisms that coordinate hormone-dependent growth responses with nutrient availability remain poorly understood in plants [1, 2]. The target of rapamycin (TOR) kinase is an evolutionarily conserved master regulator that integrates nutrient and energy signaling to regulate growth and homeostasis in both animals and plants [3-7]. Here, we show that sugar signaling through TOR controls the accumulation of the brassinosteroid (BR)-signaling transcription factor BZR1, which is essential for growth promotion by multiple hormonal and environmental signals [8-11]. Starvation, caused by shifting of light-grown Arabidopsis seedlings into darkness, as well as inhibition of TOR by inducible RNAi, led to plant growth arrest and reduced expression of BR-responsive genes. The growth arrest caused by TOR inactivation was partially recovered by BR treatment and the gain-of-function mutation bzr1-1D, which causes accumulation of active forms of BZR1 [12]. Exogenous sugar promoted BZR1 accumulation and seedling growth, but such sugar effects were largely abolished by inactivation of TOR, whereas the effect of TOR inactivation on BZR1 degradation is abolished by inhibition of autophagy and by the bzr1-1D mutation. These results indicate that cellular starvation leads sequentially to TOR inactivation, autophagy, and BZR1 degradation. Such regulation of BZR1 accumulation by glucose-TOR signaling allows carbon availability to control the growth promotion hormonal programs, ensuring supply-demand balance in plant growth. Copyright © 2016 Elsevier Ltd. All rights reserved.

Targeted tumor theranostics using folate-conjugated and camptothecin-loaded acoustic nanodroplets in a mouse xenograft model.

Science.gov (United States)

Chen, Wei-Tsung; Kang, Shih-Tsung; Lin, Jian-Liang; Wang, Chung-Hsin; Chen, Ran-Chou; Yeh, Chih-Kuang

2015-01-01

In this study, we aimed to validate the feasibility of receptor-targeted tumor theranostics with folate-conjugated (FA) and camptothecin-loaded (CPT) acoustic nanodroplets (NDs) (collectively termed FA-CPT-NDs). The ND formulation was based on lipid-stabilized low-boiling perfluorocarbon that can undergo acoustic droplet vaporization (ADV) under ultrasound (US) exposure. Conjugation of folate enhanced the selective delivery to tumors expressing high levels of folate receptor (FR) under mediation by the enhanced permeability and retention effect. In vitro and in vivo studies were performed using FR-positive KB and FR-negative HT-1080 cell lines and mouse xenograft tumor models. Simultaneous therapy and imaging were conducted with a clinical US imaging system at mechanical indices of up to 1.4 at a center frequency of 10 MHz. The results demonstrated that FA-CPT-NDs selectively attached to KB cells, but not HT-1080 cells. The targeted ADV caused instant and delayed damage via mechanical disruption and chemical toxicity to decrease the viability of KB cells by up to 45%, a much higher decrease than that achieved by the NDs without folate conjugation. The in vivo experiments showed that FR-mediated targeting successfully enhanced the EPR of FA-CPT-NDs in KB tumors mainly on the tumor periphery as indicated by immunofluorescence microscopy and US B-mode imaging. Treatments with FA-CPT-NDs at a CPT dose of 50 μg/kg inhibited the growth of KB tumors for up to six weeks, whereas treatment with NDs lacking folate produced a 4.6-fold increase in tumor volume. For HT-1080 tumors, neither the treatments with FA-CPT-NDs nor those with the NDs lacking folate presented tumor growth inhibition. In summary, FR-targeted tumor theranostics has been successfully implemented with FA-CPT-NDs and a clinical US unit. The ligand-directed and EPR-mediated accumulation provides active and passive targeting capabilities, permitting the antitumor effects of FA-CPT-NDs to be exerted

Double targeting and aptamer-assisted controlled release delivery of epirubicin to cancer cells by aptamers-based dendrimer in vitro and in vivo.

Science.gov (United States)

Taghdisi, Seyed Mohammad; Danesh, Noor Mohammad; Ramezani, Mohammad; Lavaee, Parirokh; Jalalian, Seyed Hamid; Robati, Rezvan Yazdian; Abnous, Khalil

2016-05-01

Clinical use of epirubicin (Epi) in the treatment of cancer has been limited, due to its cardiotoxicity. Targeted delivery of chemotherapeutic agents could increase their efficacy and reduce their off-target effects. High drug loading and excellent stability of DNA dendrimers make these DNA nanostructures unique candidates for biological applications. In this study a modified and promoted dendrimer using three kinds of aptamers (MUC1, AS1411 and ATP aptamers) was designed for targeted delivery of Epi and its efficacy was evaluated in target cells including MCF-7 cells (breast cancer cell) and C26 cells (murine colon carcinoma cell). Aptamers (Apts)-Dendrimer-Epi complex formation was analyzed by fluorometric analysis and gel retardation assay. Release profiles of Epi from the designed complex were assessed at pHs 5.4 and 7.4. For MTT assay (cytotoxic study) MCF-7 and C26 cells (target cells) and CHO cells (Chinese hamster ovary cell, nontarget) were treated with Epi, Apts-Dendrimer-Epi complex and Apts-Dendrimer conjugate. Internalization was evaluated using flow cytometry analysis. Finally, the developed complex was used for inhibition of tumor growth in vivo. 25μM Epi was efficiently intercalated to 1μM dendrimer. Epi was released from the Apts-Dendrimer-Epi complex in a pH-sensitive manner (more release at pH 5.5). The results of flow cytometry analysis indicated that the designed complex was efficiently internalized into target cells, but not into control cells. The internalization data were confirmed by the results of MTT assay. Apts-Dendrimer-Epi complex had less cytotoxicity in CHO cells compared to Epi alone. The complex had more cytotoxicity in C26 and MCF-7 cells compared to Epi alone. Moreover, the Apts-Dendrimer-Epi complex could efficiently prohibit tumor growth in vivo. In conclusion, the designed targeted drug delivery system inherited characteristics of pH-dependent drug release, high drug loading and tumor targeting in vitro and in vivo

Targeted therapies in development for non-small cell lung cancer

Directory of Open Access Journals (Sweden)

Thanyanan Reungwetwattana

2013-01-01

Full Text Available The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC, the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2], RAS (rat sarcoma gene, BRAF (v-raf murine sarcoma viral oncogene homolog B1, MAPK (mitogen-activated protein kinase c-MET (c-mesenchymal-epithelial transition, FGFR (fibroblast growth factor receptor, DDR2 (discoidin domain receptor 2, PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha, PTEN (phosphatase and tensin homolog, AKT (protein kinase B, ALK (anaplastic lym phoma kinase, RET (rearranged during transfection, ROS1 (reactive oxygen species 1 and EPH (erythropoietin-producing hepatoma are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

Alanine rich peptide from Populus trichocarpa inhibit growth of Staphylococcus aureus via targetting its extracellular domain of Sensor Histidine Kinase YycGex protein.

Science.gov (United States)

Al Akeel, Raid; Mateen, Ayesha; Syed, Rabbani; Al-Qahtani, Mohammed S; Alqahtani, A

2018-05-11

Due to growing concern towards microbial resistance, ongoing search for developing novel bioactive compounds such as peptides is on rise. The aim of this study was to evaluate antimicrobial effect of Populus trichocarpa extract, chemically identify the active peptide fraction and finds its target in Staphylococcus aureus. In this study the active fraction of P. trichocarpa crude extract was purified and characterized using MS/MS. This peptide PT13 antimicrobial activity was confirmed by in-vitro agar based disk diffusion and in-vivo infection model of G. mellonella. The proteomic expression analysis of S. aureus under influence of PT13 was studied using LTQ-Orbitrap-MS in-solution digestion and identity of target protein was acquired with their quantified expression using label-free approach of Progenesis QI software. Docking study was performed with peptide PT13 and its target YycG protein using CABS-dock. The active fraction PT13 sequence was identified as KVPVAAAAAAAAAVVASSMVVAAAK, with 25 amino acid including 13 alanine having M/Z 2194.2469. PT13 was uniformly inhibited growth S. aureus SA91 and MIC was determined 16 μg/mL for SA91 S. aureus strain. Sensor histidine kinase (YycG) was most significant target found differentially expressed under influence of PT13. G. mellonella larvae were killed rapidly due to S aureus infection, whereas death in protected group was insignificant in compare to control. The docking models showed ten docking models with RMSD value 1.89 for cluster 1 and RMSD value 3.95 for cluster 2 which is predicted to be high quality model. Alanine rich peptide could be useful in constructing as antimicrobial peptide for targeting extracellular Domain of Sensor Histidine Kinase YycG from S. aureus used in the study. Copyright © 2018. Published by Elsevier Ltd.

Angiogenesis and vascular targeting: Relevance for hyperthermia

DEFF Research Database (Denmark)

Horsman, Michael R

2008-01-01

The creation of a functional blood supply from the normal tissue vasculature via the process of angiogenesis is critical for the continued growth and development of solid tumours. This importance has led to the concept of targeting the tumour vasculature as a therapeutic strategy, and two major...... types of vascular targeting agents (VTAs) have developed; those that inhibit the angiogenic process-angiogenesis inhibiting agents (AIAs)-and those that specifically damage the already established neovasculature-vascular disrupting agents (VDAs). The tumour vasculature also plays a critical role...

Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice

Directory of Open Access Journals (Sweden)

Teresa D. Elo

2010-11-01

Full Text Available Expression of fibroblast growth factor 8 (FGF-8 is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelialmorphology progressing fromatypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.

Urban growth management

DEFF Research Database (Denmark)

Jørgensen, Gertrud; Alexander Sick Nielsen, Thomas; Grünfelder, Julien

2011-01-01

, and finally urban attractivity policies. Effective regional bodies are needed to deal with urban expansion and peri-urbanisation at a relevant scale; European rural and agricultural policies makes up the main ‘policy complex’ targeting the non-urban area including its land uses; while lastly leverage of urban...... urban growth and curb urban sprawl in a wider sense. Methodology The main methodology of the paper is a desk-research based review of policy options supplemented with field study and interviews in selected cased study regions. This paper consists of two parts. The first part is based on literature...... there are contradictions in the evidence presented in the literature, we believe that it may be safely said that urban growth management policies have an influence on urban growth under certain preconditions including: sufficient time for implementation and continuity of efforts; choice of appropriate policy measures...

Targeting poverty : lessons from monitoring Ireland's National Anti-Poverty Strategy

OpenAIRE

Layte, Richard; Nolan, Brian; Whelan, Christopher T.

2000-01-01

In 1997 the Irish government adopted the National Anti-Poverty Strategy (NAPS), a global target for the reduction of poverty which illuminates a range of issues relating to official poverty targets. The Irish target is framed in terms of a relative poverty measure incorporating both relative income and direct measures of deprivation based on data on the extent of poverty from 1994. Since 1994 Ireland has experienced an unprecedented period of economic growth that makes it particularly importa...

Stiff mutant genes of Phycomyces target turgor pressure and wall mechanical properties to regulate elongation growth rate

Directory of Open Access Journals (Sweden)

Joseph K. E. Ortega

2012-05-01

Full Text Available Regulation of cell growth is paramount to all living organisms. In plants, algae and fungi, regulation of expansive growth of cells is required for development and morphogenesis. Also, many sensory responses of stage IVb sporangiophores of Phycomyces blakesleeanus are produced by regulating elongation growth rate (growth responses and differential elongation growth rate (tropic responses. Stiff mutant sporangiophores exhibit diminished tropic responses and are found to be defective in at least four genes; madD, madE, madF and madG. Prior experimental research suggests that the defective genes affect growth regulation, but this was not verified. All the growth of the single-celled stalk of the stage IVb sporangiophore occurs in a short region termed the growth zone. Prior experimental and theoretical research indicates that elongation growth rate of the stage IVb sporangiophore can be regulated by controlling the cell wall mechanical properties within the growth zone and the magnitude of the turgor pressure. A quantitative biophysical model for elongation growth rate is required to elucidate the relationship between wall mechanical properties and turgor pressure during growth regulation. In this study, it is hypothesized that the mechanical properties of the wall within the growth zone of stiff mutant sporangiophores are different compared to wild type. A biophysical equation for elongation growth rate is derived for fungal and plant cells with a growth zone. Two strains of stiff mutants are studied, C149 madD120 (- and C216 geo- (-. Experimental results demonstrate that turgor pressure is larger but irreversible deformation rates of the wall within the growth zone and growth zone length are smaller for stiff mutant sporangiophores compared to wild type. These findings explain the diminished tropic responses of the stiff mutant sporangiophores and suggest that the defective genes affect the amount of wall-building material delivered to the inner

APC functions at the centrosome to stimulate microtubule growth.

Science.gov (United States)

Lui, Christina; Ashton, Cahora; Sharma, Manisha; Brocardo, Mariana G; Henderson, Beric R

2016-01-01

The adenomatous polyposis coli (APC) tumor suppressor is multi-functional. APC is known to localize at the centrosome, and in mitotic cells contributes to formation of the mitotic spindle. To test whether APC contributes to nascent microtubule (MT) growth at interphase centrosomes, we employed MT regrowth assays in U2OS cells to measure MT assembly before and after nocodazole treatment and release. We showed that siRNA knockdown of full-length APC delayed both initial MT aster formation and MT elongation/regrowth. In contrast, APC-mutant SW480 cancer cells displayed a defect in MT regrowth that was unaffected by APC knockdown, but which was rescued by reconstitution of full-length APC. Our findings identify APC as a positive regulator of centrosome MT initial assembly and suggest that this process is disrupted by cancer mutations. We confirmed that full-length APC associates with the MT-nucleation factor γ-tubulin, and found that the APC cancer-truncated form (1-1309) also bound to γ-tubulin through APC amino acids 1-453. While binding to γ-tubulin may help target APC to the site of MT nucleation complexes, additional C-terminal sequences of APC are required to stimulate and stabilize MT growth. Copyright © 2015 Elsevier Ltd. All rights reserved.

Single-mode Rayleigh-Taylor growth-rate measurements with the OMEGA laser system

International Nuclear Information System (INIS)

Knauer, J.P.; Verdon, C.P.; Meyerhofer, D.D.; Boehly, T.R.; Bradley, D.K.; Smalyuk, V.A.; Ofer, D.; McKenty, P.W.; Glendinning, S.G.; Kalantar, D.H.; Watt, R.G.; Gobby, P.L.; Willi, O.; Taylor, R.J.

1997-01-01

The results from a series of single-mode Rayleigh-Taylor (RT) instability growth experiments performed on the OMEGA laser system using planar targets are reported. Planar targets with imposed mass perturbations were accelerated using five to six 351-nm laser beams overlapped with total intensities up to 2.5x10 14 W/cm 2 . Experiments were performed with both 3-ns ramp and 3-ns flat-topped temporal pulse shapes. The use of distributed phase plates and smoothing by spectral dispersion resulted in a laser-irradiation nonuniformity of 4%endash 7% over a 600-μm-diam region defined by the 90% intensity contour. The temporal growth of the modulation in optical depth was measured using through-foil radiography and was detected with an x-ray framing camera for CH targets with and without a foam buffer. The growth of both 31-μm and 60-μm wavelength perturbations was found to be in good agreement with ORCHID simulations when the experimental details, including noise, were included. The addition of a 30-mg/cc, 100-μm-thick polystyrene foam buffer layer resulted in reduced growth of the 31-μm perturbation and essentially unchanged growth for the 60-μm case when compared to targets without foam. copyright 1997 American Institute of Physics

The apical actin fringe contributes to localized cell wall deposition and polarized growth in the lily pollen tube.

Science.gov (United States)

Rounds, Caleb M; Hepler, Peter K; Winship, Lawrence J

2014-09-01

In lily (Lilium formosanum) pollen tubes, pectin, a major component of the cell wall, is delivered through regulated exocytosis. The targeted transport and secretion of the pectin-containing vesicles may be controlled by the cortical actin fringe at the pollen tube apex. Here, we address the role of the actin fringe using three different inhibitors of growth: brefeldin A, latrunculin B, and potassium cyanide. Brefeldin A blocks membrane trafficking and inhibits exocytosis in pollen tubes; it also leads to the degradation of the actin fringe and the formation of an aggregate of filamentous actin at the base of the clear zone. Latrunculin B, which depolymerizes filamentous actin, markedly slows growth but allows focused pectin deposition to continue. Of note, the locus of deposition shifts frequently and correlates with changes in the direction of growth. Finally, potassium cyanide, an electron transport chain inhibitor, briefly stops growth while causing the actin fringe to completely disappear. Pectin deposition continues but lacks focus, instead being delivered in a wide arc across the pollen tube tip. These data support a model in which the actin fringe contributes to the focused secretion of pectin to the apical cell wall and, thus, to the polarized growth of the pollen tube. © 2014 American Society of Plant Biologists. All Rights Reserved.

Endophytic bacterial effects on seed germination and mobilization of reserves in ammodendron biofolium

International Nuclear Information System (INIS)

Zhu, Y.; She, X.P.

2017-01-01

The main aim of this study was to analyze the mobilization of storage reserves during seed germination of Ammodendron bifolium by host plant-endophytic bacteria interaction and to determine the contribution of endophytic bacteria in plant establishment. The seeds were inoculated with three different endophytic bacteria from A. bifolium, Staphylococcus sp. AY3, Kocuria sp. AY9 and Bacillus sp. AG18, and they were germinated in the dark. Fresh weight changes and early seedling growth were assessed, and the content of storage compounds was quantified using biochemical assays in all germinated and non-germinated seeds. To understand the mechanism promoting seed germination, the activities of extracellular enzymes of bacterial isolates were also analyzed by the plate assay method. The results showed that treatment with endophytic bacteria accelerated seed germination; promoted further water absorption and radicle growth; and also promoted degradation of sucrose, protein and lipids during the germination process. At the same time, our results also showed that strain AG18 was able to produce protease and amylase, strain AY9 had only amylase activity, and strain AY3 had no extracellular enzyme activity. In summary, our current study showed that (i) endophytic bacteria improved seed germination and post-germination seedling growth of A. bifolium; (ii) inoculation with endophytic bacteria could promote storage reserve mobilization during or following germination; (iii) the degradation of protein, lipids and sucrose could provide essential energy for post-germination growth; and (iv) three bacterial isolates might have different action mechanisms on seed germination. (author)

[Double-ambient CO2 concentration affects the growth, development and sucking behavior of non-target brown plant hopper Nilaparvata lugens fed on transgenic Bt rice.

Science.gov (United States)

Lu, Yong Qing; Dai, Yang; Yu, Xiu Ying; Yu, Fu-Lan; Jiang, Shou Lin; Zhou, Zong Yuan; Chen, Fa Jun

2018-02-01

In recent years, the two issues of climate change including elevated CO 2 etc., and resistance of transgenic Bt crops against non-target insect pests have received widespread attention. Elevated CO 2 can affect the herbivorous insects. To date, there is no consensus about the effect of elevated CO 2 on the suck-feeding insect pests (non-target insect pests of transgenic Bt crops). Its effects on the suck-feeding behavior have rarely been reported. In this study, CO 2 levels were set up in artificial climate chamber to examined the effects of ambient (400 μL·L -1 ) and double-ambient (800 μL·L -1 ) CO 2 levels on the suck-feeding behavior, growth, development, and reproduction of the non-target insect pest of transgenic Bt rice, brown planthopper, Nilaparvata lugens. The results showed that CO 2 level significantly affected the egg and nymph duration, longevity and body mass of adults, and feeding behavior of the 4th and 5th instar nymphs, while had no effect on the fecundity of N. lugens. The duration of eggs and nymphs, and the longevity of female adults were significantly shortened by 4.0%, 4.2% and 6.6% respectively, the proportion of the macropterous adults was significantly increased by 11.6%, and the body mass of newly hatched female adults was significantly decreased by 2.2% by elevated CO 2 . In addition, elevated CO 2 significantly enhanced the stylet puncturing efficiency of the 4th and 5th instar nymphs of N. lugens. The duration ofphloem ingestion of the N4b waveform was significantly prolonged by 60.0% and 50.1%, and the frequency significantly was increased by 230.0% and 155.9% for the 4th and 5th instar nymphs of N. lugens by elevated CO 2 , respectively. It was concluded that double-ambient CO 2 could promote the growth and development of N. lugens through enhancing its suck-feeding, shorten the generation life-span and increase the macropertous adults' proportion of N. lugens. Thus, it could result in the occurrence of non-target rice

New perspectives on targeted therapy in ovarian cancer

Directory of Open Access Journals (Sweden)

Coward JIG

2015-02-01

Full Text Available Jermaine IG Coward,1–3 Kathryn Middleton,1 Felicity Murphy1 1Mater Health Services, Raymond Terrace, South Brisbane, QLD, Australia; 2Inflammtion and Cancer Therapeutics Group, Mater Research, University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, Australia; 3School of Medicine, University of Queensland, Brisbane, QLD, Australia Abstract: Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer. Keywords: antiangiogenic therapy, high-grade serous, low grade ovarian cancer, PARP inhibition, cancer-related inflammation

Microarray Cluster Analysis of Irradiated Growth Plate Zones Following Laser Microdissection

International Nuclear Information System (INIS)

Damron, Timothy A.; Zhang Mingliang; Pritchard, Meredith R.; Middleton, Frank A.; Horton, Jason A.; Margulies, Bryan M.; Strauss, Judith A.; Farnum, Cornelia E.; Spadaro, Joseph A.

2009-01-01

Purpose: Genes and pathways involved in early growth plate chondrocyte recovery after fractionated irradiation were sought as potential targets for selective radiorecovery modulation. Materials and Methods: Three groups of six 5-week male Sprague-Dawley rats underwent fractionated irradiation to the right tibiae over 5 days, totaling 17.5 Gy, and then were killed at 7, 11, and 16 days after the first radiotherapy fraction. The growth plates were collected from the proximal tibiae bilaterally and subsequently underwent laser microdissection to separate reserve, perichondral, proliferative, and hypertrophic zones. Differential gene expression was analyzed between irradiated right and nonirradiated left tibia using RAE230 2.0 GeneChip microarray, compared between zones and time points and subjected to functional pathway cluster analysis with real-time polymerase chain reaction to confirm selected results. Results: Each zone had a number of pathways showing enrichment after the pattern of hypothesized importance to growth plate recovery, yet few met the strictest criteria. The proliferative and hypertrophic zones showed both the greatest number of genes with a 10-fold right/left change at 7 days after initiation of irradiation and enrichment of the most functional pathways involved in bone, cartilage, matrix, or skeletal development. Six genes confirmed by real-time polymerase chain reaction to have early upregulation included insulin-like growth factor 2, procollagen type I alpha 2, matrix metallopeptidase 9, parathyroid hormone receptor 1, fibromodulin, and aggrecan 1. Conclusions: Nine overlapping pathways in the proliferative and hypertrophic zones (skeletal development, ossification, bone remodeling, cartilage development, extracellular matrix structural constituent, proteinaceous extracellular matrix, collagen, extracellular matrix, and extracellular matrix part) may play key roles in early growth plate radiorecovery.

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor.

Science.gov (United States)

Tiwari, Shruti Rakesh; Mishra, Prasun; Abraham, Jame

2016-10-01

HER2 gene amplification and receptor overexpression is identified in 20% to 25% of human breast cancers. Use of targeted therapy for HER2-amplified breast cancer has led to improvements in disease-free and overall survival in this subset of patients. Neratinib is an oral pan HER inhibitor, that irreversibly inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib is currently being tested in a number of clinical trials for its safety and efficacy in lung cancer, and colorectal, bladder, and breast cancers. In this review we discuss the available phase I, II, and III data for use of neratinib in the metastatic, adjuvant, neoadjuvant, and extended adjuvant settings along with the ongoing clinical trials of neratinib in breast cancer. We also elaborate on the side effect profile of this relatively new drug and provide guidelines for its use in clinical practice. Copyright © 2016 Elsevier Inc. All rights reserved.

77 FR 66361 - Reserve Requirements of Depository Institutions: Reserves Simplification

Science.gov (United States)

2012-11-05

... Requirements of Depository Institutions: Reserves Simplification AGENCY: Board of Governors of the Federal... (Reserve Requirements of Depository Institutions) published in the Federal Register on April 12, 2012. The... simplifications related to the administration of reserve requirements: 1. Create a common two-week maintenance...

Foreign Exchange Reserves and the Reserve Bank’s Balance Sheet

OpenAIRE

Christian Vallence

2012-01-01

The Reserve Bank of Australia holds and manages the nation’s foreign exchange reserve assets in order to meet its policy objectives. While Australia’s foreign exchange reserves are relatively modest by international standards, they nonetheless constitute a sizeable portion of the Bank’s balance sheet, and variations in the Australian dollar value of these reserves are usually the most volatile component of the Bank’s profit and loss statement. This article discusses some of the key decisions ...

Effects of the herbicide glyphosate on non-target plant native species from Chaco forest (Argentina).

Science.gov (United States)

Florencia, Ferreira María; Carolina, Torres; Enzo, Bracamonte; Leonardo, Galetto

2017-10-01

Agriculture based on transgenic crops has expanded in Argentina into areas formerly occupied by Chaco forest. Even though glyphosate is the herbicide most widely used in the world, increasing evidence indicates severe ecotoxicological effects on non-target organisms as native plants. The aim of this work is to determine glyphosate effects on 23 native species present in the remaining Chaco forests immersed in agricultural matrices. This is a laboratory/greenhouse approach studying acute effects on seedlings after 21 days. A gradient of glyphosate rates (525, 1050, 2100, 4200, and 8400g ai/Ha; recommended field application rate (RFAR) = 2100g ai/Ha) was applied on four-week seedlings cultivated in a greenhouse and response variables (phytotoxicity, growth reduction, and sensitivity to the herbicide) were measured. This gradient of herbicide rates covers realistic rates of glyphosate applications in the crop field and also those that can reach vegetation of forest relicts by off-target drift and overspray. Testing was performed following guidelines for vegetative vigour (post-germination spray). All species showed lethal or sublethal effects after the application of the 25% of RFAR (50% of species showed severe phytotoxicity or death and 70% of species showed growth reduction). The results showed a gradient of sensitivity to glyphosate by which some of the studied species are very sensitive to glyphosate and seedlings died with 25% of RFAR while other species can be classified as herbicide-tolerant. Thus, the vegetation present in the forest relicts could be strongly affected by glyphosate application on crops. Lethal and sublethal effects of glyphosate on non-target plants could promote both the loss of biodiversity in native forest relicts immersed in the agroecosystems and the selection of new crop weeds considering that some biotypes are continuously exposed to low doses of glyphosate. Copyright © 2017 Elsevier Inc. All rights reserved.

Chondroitin sulfate-functionalized polyamidoamine as a tumor-targeted carrier for miR-34a delivery.

Science.gov (United States)

Chen, Wenqi; Liu, Yong; Liang, Xiao; Huang, Yu; Li, Quanshun

2017-07-15

Chondroitin sulfate (CS) was modified on a polyamidoamine dendrimer (PAMAM) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The derivative CS-PAMAM was demonstrated to achieve an efficient cellular uptake of miR-34a in a CD44-dependent endocytosis way and further facilitate the endosomal escape of miR-34a after 4h. Through the miR-34a delivery, obvious inhibition of cell proliferation could be detected which was attributed to the enhancement of cell apoptosis and cell cycle arrest, and meanwhile the cell migration and invasion has been observed to be inhibited. Finally, the intravenous injection of CS-PAMAM/miR-34a formulation into mice bearing human lung adenocarcinoma cell A549 xenografts could efficiently inhibit the tumor growth and induce the tumor apoptosis owing to the enhanced accumulation of miR-34a in tumor tissue. Overall, CS-PAMAM is potential to be used as a tumor-targeted oligonucleotide carrier for achieving tumor gene therapy. The cationic dendrimer PAMAM was modified by chondroitin sulfate (CS) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The introduction of CS could achieve an efficient cellular uptake and intracellular transfection of miR-34a in a CD44-dependent endocytosis manner. The miR-34a delivery could execute the anti-proliferation activity by simultaneously inducing cell apoptosis and cell cycle arrest, and also the anti-migration activity. The CS-PAMAM-mediated systemic delivery of miR-34a showed significant inhibition of tumor growth and induction of tumor apoptosis using a mice model of subcutaneously implanted tumors. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

26 CFR 1.338-11 - Effect of section 338 election on insurance company targets.

Science.gov (United States)

2010-04-01

... premium for the contracts were equal to old target's tax reserves for the contracts. See § 1.197-2(g)(5... section. (2) Reinsurance premium. Old target is deemed to pay a gross amount of premium in the assumption... decrease in old T's reserves, which is taxable income to old T, the reinsurance premium paid by old T is...

Synergistic retention strategy of RGD active targeting and radiofrequency-enhanced permeability for intensified RF & chemotherapy synergistic tumor treatment.

Science.gov (United States)

Zhang, Kun; Li, Pei; He, Yaping; Bo, Xiaowan; Li, Xiaolong; Li, Dandan; Chen, Hangrong; Xu, Huixiong

2016-08-01

Despite gaining increasing attention, chelation of multiple active targeting ligands greatly increase the formation probability of protein corona, disabling active targeting. To overcome it, a synergistic retention strategy of RGD-mediated active targeting and radiofrequency (RF) electromagnetic field-enhanced permeability has been proposed here. It is validated that such a special synergistic retention strategy can promote more poly lactic-co-glycolic acid (PLGA)-based capsules encapsulating camptothecin (CPT) and solid DL-menthol (DLM) to enter and retain in tumor in vitro and in vivo upon exposure to RF irradiation, receiving an above 8 fold enhancement in HeLa retention. Moreover, the PLGA-based capsules can respond RF field to trigger the entrapped DLM to generate solid-liquid-gas (SLG) tri-phase transformation for enhancing RF ablation and CPT release. Therefore, depending on the enhanced RF ablation and released CPT and the validated synergistic retention effect, the inhibitory outcome for tumor growth has gained an over 10-fold improvement, realizing RF ablation & chemotherapy synergistic treatment against HeLa solid tumor, which indicates a significant promise in clinical RF ablation. Copyright © 2016 Elsevier Ltd. All rights reserved.

SL-401 and SL-501, Targeted Therapeutics Directed at the Interleukin-3 Receptor, Inhibit the Growth of Leukaemic Cells and Stem Cells in Advanced Phase Chronic Myeloid Leukaemia

Science.gov (United States)

Frolova, Olga; Benito, Juliana; Brooks, Chris; Wang, Rui-Yu; Korchin, Borys; Rowinsky, Eric K.; Cortes, Jorge; Kantarjian, Hagop; Andreeff, Michael; Frankel, Arthur E.; Konopleva, Marina

2014-01-01

SUMMARY While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38− BCR-ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388-IL3) and SL-501 (DT388-IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34+/CD38−/CD123+ CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk. PMID:24942980

What Is Green Growth Strategy for Government Link Company?

Science.gov (United States)

Jamilah Asha'ari, Maryam; Daud, Salina; Hassan, Hasmaizan

2016-03-01

Disasters around the world are very extreme because of the global warming and climate change. Malaysia firms have to play their role in handling the challenging of environmental problems in order to sustain. The feature of the new strategy which is green growth strategy has been identified. The study focuses on the features of the green growth strategy which discuss on the keys to sustaining the strategy, marketing emphasis, production emphasis, product line, basis of competitive advantage and strategic target. Business had contributed to the industrialisation era positively or negatively and therefore there is a must for business people to use the best strategy in reducing the environmental risks. By 2020, Malaysia will achieve the target in becoming an advanced economy by applying the right strategy. The objective of this paper is to propose a feature for new strategy known as green growth strategy. Future study is to propose to conduct an empirical analysis to confirm the green growth strategy features.

Common pitfalls in preclinical cancer target validation.

Science.gov (United States)

Kaelin, William G

2017-07-01

An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.

Rapid fabrication and characterization of sine wave targets

International Nuclear Information System (INIS)

Day, R.D.; Armijo, E.; Gobby, P.; Hatch, D.; Rivera, G.; Salzer, L.; Townsend, J.

1997-01-01

The effect of surface perturbations on Inertial Confinement Fusion target performance is currently being researched at Los Alamos National Laboratory (LANL). These perturbations can cause hydrodynamic instabilities which in turn reduce the targets' yield. To systematically measure the growth of these instabilities requires targets to be produced which have perturbations of a known amplitude and spatial frequency. The authors have recently assembled hardware onto one of their diamond turning lathes which enables them to machine and measure these sine waves in about 15 minutes. This is a significant reduction in time from the two and one half hours required by the previous method. This paper discusses the hardware, how it works, and how well the system is working for them to produce these targets

Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis

Directory of Open Access Journals (Sweden)

Yi-Chia Lin

2017-05-01

Full Text Available Chloroquine (CQ and hydroxychloroquine (HCQ, two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro. The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24 in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24 compared to immortalized uroepithelial cells (SV-Huc-1 or other reference cancer cell lines (PC3 and MCF-7. We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose polymerase (PARP, caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer.

Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis.

Science.gov (United States)

Lin, Yi-Chia; Lin, Ji-Fan; Wen, Sheng-I; Yang, Shan-Che; Tsai, Te-Fu; Chen, Hung-En; Chou, Kuang-Yu; Hwang, Thomas I-Sheng

2017-05-01

Chloroquine (CQ) and hydroxychloroquine (HCQ), two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro. The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24) in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24) compared to immortalized uroepithelial cells (SV-Huc-1) or other reference cancer cell lines (PC3 and MCF-7). We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose) polymerase (PARP), caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer. Copyright © 2017. Published by Elsevier Taiwan.

Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment.

Science.gov (United States)

van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Haselberg, Rob; van der Veeken, Joris; Roovers, Rob C; van Bergen en Henegouwen, Paul M P; Storm, Gert; Hennink, Wim E; Schiffelers, Raymond M; Kok, Robbert J

2012-04-30

The epidermal growth factor receptor (EGFR) is a validated target for anti-cancer therapy and several EGFR inhibitors are used in the clinic. Over the years, an increasing number of studies have reported on the crosstalk between EGFR and other receptors that can contribute to accelerated cancer development or even acquisition of resistance to anti-EGFR therapies. Combined targeting of EGFR and insulin-like growth factor 1 receptor (IGF-1R) is a rational strategy to potentiate anti-cancer treatment and possibly retard resistance development. In the present study, we have pursued this by encapsulating the kinase inhibitor AG538 in anti-EGFR nanobody-liposomes. The thus developed dual-active nanobody-liposomes associated with EGFR-(over)expressing cells in an EGFR-specific manner and blocked both EGFR and IGF-1R activation, due to the presence of the EGFR-blocking nanobody EGa1 and the anti-IGF-1R kinase inhibitor AG538 respectively. AG538-loaded nanobody-liposomes induced a strong inhibition of tumor cell proliferation even upon short-term exposure followed by a drug-free wash-out period. Therefore, AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobody-liposomes. Copyright © 2011 Elsevier B.V. All rights reserved.

Control of growth and development of the feto-placental unit

DEFF Research Database (Denmark)

Han, V K; Carter, Anthony Michael

2001-01-01

Classical gene targeting has identified many genes important for fetal and placental development. Null mutation of these genes may lead to fetal growth restriction, malformation or embryonic death. Growth restriction of epigenetic basis can predispose to adult-onset diseases. The mechanisms...

Report to the Congress on alternative methods for the Strategic Petroleum Reserve

Energy Technology Data Exchange (ETDEWEB)

1990-02-01

The purpose of this study is to fulfill the requirements of Public Law No. 101-46, approved June 30, 1989. The study describes and evaluates alternative methods for financing the future expansion of the Strategic petroleum Reserve (SPR), both to the current target level of 750 million barrels and to potential future levels of up to one billion barrels.

Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors.

Science.gov (United States)

Lobos-González, Lorena; Silva, Verónica; Araya, Mariela; Restovic, Franko; Echenique, Javiera; Oliveira-Cruz, Luciana; Fitzpatrick, Christopher; Briones, Macarena; Villegas, Jaime; Villota, Claudio; Vidaurre, Soledad; Borgna, Vincenzo; Socias, Miguel; Valenzuela, Sebastián; Lopez, Constanza; Socias, Teresa; Varas, Manuel; Díaz, Jorge; Burzio, Luis O; Burzio, Verónica A

2016-09-06

We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.

Pulsed-laser-deposited YBCO thin films using modified MTG processed targets

CERN Document Server

Kim, C H; Kim, I T; Hahn, T S

1999-01-01

YBCO thin films were deposited by pulsed laser deposition from targets fabricated using the modified melt-textured growth (MTG) method and the solid-state sintering (SSS) method. All of the films showed c-axis orientations, but the films from the MTG targets had better crystallinity than those from the SSS targets. As the substrate temperature was increased, T sub c and J sub c of the films increased. The films from the MTG targets showed better superconducting properties than those from the SSS targets. From the composition analysis of the targets, the Y-richer vapor species arriving at the substrate from the MTG targets are thought to form a thermodynamically more stable YBCO phase with less cation disorder.

Studies on the robustness of shock-ignited laser fusion targets

International Nuclear Information System (INIS)

Atzeni, S; Schiavi, A; Marocchino, A

2011-01-01

Several aspects of the sensitivity of a shock-ignited inertial fusion target to variation of parameters and errors or imperfections are studied by means of one-dimensional and two-dimensional numerical simulations. The study refers to a simple all-DT target, initially proposed for fast ignition (Atzeni et al 2007 Phys. Plasmas 7 052702) and subsequently shown to be also suitable for shock ignition (Ribeyre et al 2009 Plasma Phys. Control. Fusion 51 015013). It is shown that the growth of both Richtmyer-Meshkov and Rayleigh-Taylor instability (RTI) at the ablation front is reduced by laser pulses with an adiabat-shaping picket. An operating window for the parameters of the ignition laser spike is described; the threshold power depends on beam focusing and synchronization with the compression pulse. The time window for spike launch widens with beam power, while the minimum spike energy is independent of spike power. A large parametric scan indicates good tolerance (at the level of a few percent) to target mass and laser power errors. 2D simulations indicate that the strong igniting shock wave plays an important role in reducing deceleration-phase RTI growth. Instead, the high hot-spot convergence ratio (ratio of initial target radius to hot-spot radius at ignition) makes ignition highly sensitive to target mispositioning.

Replacing reserve requirements

OpenAIRE

Edward J. Stevens

1993-01-01

An examination of the fading significance of the Federal Reserve System's reserve requirements and the recent flowering of required clearing balances, a rapidly growing feature of Reserve Bank operations.

Genome-wide identification of microRNA targets in the neglected disease pathogens of the genus Echinococcus.

Science.gov (United States)

Macchiaroli, Natalia; Maldonado, Lucas L; Zarowiecki, Magdalena; Cucher, Marcela; Gismondi, María Inés; Kamenetzky, Laura; Rosenzvit, Mara Cecilia

2017-06-01

MicroRNAs (miRNAs), a class of small non-coding RNAs, are key regulators of gene expression at post-transcriptional level and play essential roles in biological processes such as development. MiRNAs silence target mRNAs by binding to complementary sequences in the 3'untranslated regions (3'UTRs). The parasitic helminths of the genus Echinococcus are the causative agents of echinococcosis, a zoonotic neglected disease. In previous work, we performed a comprehensive identification and characterization of Echinococcus miRNAs. However, current knowledge about their targets is limited. Since target prediction algorithms rely on complementarity between 3'UTRs and miRNA sequences, a major limitation is the lack of accurate sequence information of 3'UTR for most species including parasitic helminths. We performed RNA-seq and developed a pipeline that integrates the transcriptomic data with available genomic data of this parasite in order to identify 3'UTRs of Echinococcus canadensis. The high confidence set of 3'UTRs obtained allowed the prediction of miRNA targets in Echinococcus through a bioinformatic approach. We performed for the first time a comparative analysis of miRNA targets in Echinococcus and Taenia. We found that many evolutionarily conserved target sites in Echinococcus and Taenia may be functional and under selective pressure. Signaling pathways such as MAPK and Wnt were among the most represented pathways indicating miRNA roles in parasite growth and development. Genome-wide identification and characterization of miRNA target genes in Echinococcus provide valuable information to guide experimental studies in order to understand miRNA functions in the parasites biology. miRNAs involved in essential functions, especially those being absent in the host or showing sequence divergence with respect to host orthologs, might be considered as novel therapeutic targets for echinococcosis control. Copyright © 2017 Elsevier B.V. All rights reserved.

New diagnostic tests of GH reserve.

Science.gov (United States)

Martul, P; Pineda, J; Pombo, M; Peñalva, A; Bokser, L; Dieguez, C

1993-01-01

Pharmacological tests are essential for the diagnosis of growth hormone (GH) insufficiency. Obesity is a pathological state associated with blunted GH response to all the classical stimuli tested. In the present study, three new pharmacological stimuli for GH reserve were evaluated in three groups of subjects: Normal, GH-insufficient and normal growing obese children. Dexamethasone provokes a clear GH-response in normal children, whereas the response in the other 2 groups of patients is significantly diminished. Galanin-induced GH-secretion is significantly higher in normal than in obese children. GHRP-6 causes a potent GH release in normal children, higher than in GH-insufficiency or obesity. The overlap shown between GH-insufficient patients and normal children reduces the usefulness of the tests. Similar to the classical stimuli, the response to these new tests is also decreased in obesity.

Negative feedback and adaptive resistance to the targeted therapy of cancer.

Science.gov (United States)

Chandarlapaty, Sarat

2012-04-01

Mutational activation of growth factor signaling pathways is commonly observed and often necessary for oncogenic transformation. Under physiologic conditions, these pathways are subject to tight regulation through negative feedback, which limits the extent and duration of signaling events after physiologic stimulation. Until recently, the role of these negative feedback pathways in oncogene-driven cancers has been poorly understood. In this review, I discuss the evidence for the existence and relevance of negative feedback pathways within oncogenic signaling networks, the selective advantages such feedback pathways may confer, and the effects such feedback might have on therapies aimed at inhibiting oncogenic signaling. Negative feedback pathways are ubiquitous features of growth factor signaling networks. Because growth factor signaling networks play essential roles in the majority of cancers, their therapeutic targeting has become a major emphasis of clinical oncology. Drugs targeting these networks are predicted to inhibit the pathway but also to relieve the negative feedback. This loss of negative feedback can itself promote oncogenic signals and cancer cell survival. Drug-induced relief of feedback may be viewed as one of the major consequences of targeted therapy and a key contributor to therapeutic resistance.

Targeting protein kinases to reverse multidrug resistance in sarcoma.

Science.gov (United States)

Chen, Hua; Shen, Jacson; Choy, Edwin; Hornicek, Francis J; Duan, Zhenfeng

2016-02-01

Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma. Copyright © 2015 Elsevier Ltd. All rights reserved.

MicroRNA-20b-5p inhibits platelet-derived growth factor-induced proliferation of human fetal airway smooth muscle cells by targeting signal transducer and activator of transcription 3.

Science.gov (United States)

Tang, Jin; Luo, Lingying

2018-06-01

Pediatric asthma is still a health threat to the pediatric population in recent years. The airway remodeling induced by abnormal airway smooth muscle (ASM) cell proliferation is an important cause of asthma. MicroRNAs (miRNAs) are important regulators of ASM cell proliferation. Numerous studies have reported that miR-20b-5p is a critical regulator for cell proliferation. However, whether miR-20b-5p is involved in regulating ASM cell proliferation remains unknown. In this study, we aimed to investigate the potential role of miR-20b-5p in regulating the proliferation of fetal ASM cell induced by platelet-derived growth factor (PDGF). Here, we showed that miR-20b-5p was significantly decreased in fetal ASM cells treated with PDGF. Biological experiments showed that the overexpression of miR-20b-5p inhibited the proliferation while miR-20b-5p inhibition markedly promoted the proliferation of fetal ASM cells. Bioinformatics analysis and luciferase reporter assay showed that miR-20b-5p directly targeted the 3'-UTR of signal transducer and activator of transcription 3 (STAT3). Further data showed that miR-20b-5p negatively regulated the expression of STAT3 in fetal ASM cells. Moreover, miR-20b-5p regulates the transcriptional activity of STAT3 in fetal ASM cells. Overexpression of STAT3 reversed the inhibitory effect of miR-20b-5p overexpression on fetal ASM cell proliferation while the knockdown of STAT3 abrogated the promoted effect of miR-20b-5p inhibition on fetal ASM cell proliferation. Overall, our results show that miR-20b-5p impedes PDGF-induced proliferation of fetal ASM cells through targeting STAT3. Our study suggests that miR-20b-5p may play an important role in airway remodeling during asthma and suggests that miR-20b-5p may serve as a potential therapeutic target for pediatric asthma. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Advanced Research of Fibroblast Growth Factor Receptor 
in Non-small Cell Lung Cancer

Directory of Open Access Journals (Sweden)

Dan PU

2013-11-01

Full Text Available Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.

Financial repression, money growth, and seignorage: The Polish experience

NARCIS (Netherlands)

Aarle, B. van; Budina, N.

1997-01-01

Financial Repression, Money Growth and Seignorage: The Polish Experience. — A small analytical framework is developed to analyze the relation between reserve requirements, base money growth and seignorage revenues. From the analysis, the authors can derive of steady-state seignorage revenues as a

Monetary Policy Signaling from the Administration to the Federal Reserve.

OpenAIRE

Havrilesky, Thomas

1988-01-01

This paper develops an index of monetary policy signals from the Administration to the Federal Reserve based on articles which appeared in the Wall Street Journal in which Administration off icials express a desire for easier or tighter monetary policy. In reg ressions, the index has a significant effect on the money supply. In reaction functions, the index responds to variables which measure the state of the economy. Money growth does not respond to the same stat e-of-the-economy measures bu...

Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis.

Science.gov (United States)

El-Mezayen, Nesrine S; El-Hadidy, Wessam F; El-Refaie, Wessam M; Shalaby, Th I; Khattab, Mahmoud M; El-Khatib, Aiman S

2017-11-28

Liver fibrosis is a global health problem without approved treatment. Imatinib inhibits two key profibrotic pathways; platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) and thus can be used to treat liver fibrosis. However, conventional imatinib therapy is hampered by low concentration at target tissue and increased toxicity to other tissues especially heart, lung and liver. Since hepatic stellate cells (HSCs) are the main contributors to liver fibrosis pathogenesis and sole hepatic vitamin A (V A ) storage cells, they can be actively targeted by coupling liposomes to V A . In this study, novel V A -coupled imatinib-loaded liposomes (ILC) were prepared and optimized regarding V A -coupling efficiency, imatinib entrapment efficiency, and particle size. Preferential accumulation of the selected formula in liver was proved by tracing intraperitoneally (i.p.)-injected V A -coupled liposomes loaded with Nile Red (LCNR) to rats with CCl 4 -induced liver fibrosis using live animal imaging. Co-localization of LCNR with immunofluorescently-labeled PDGFR-β in frozen liver tissue sections confirmed HSCs targeting. ILC bio-distribution, following single i.p. injection, revealed 13.5 folds higher hepatic accumulation than conventional imatinib in addition to limited bio-distribution to other organs including heart and lung reflecting diminished adverse effects. ILC therapy resulted in a potent inhibition of phosphorylated PDGFR-β expression when compared to conventional imatinib. Subsequently, there was a statistically significant improvement in liver function tests and reversal of hepatotoxicity along with liver fibrosis. Anti-fibrotic effect was evident from histopathologic Ishak score reduction as well as normalization of the level of profibrotic mediators (hydroxyproline, TGF-B and matrix metalloproteinase-2). Thus, HSC-targeted imatinib therapy shows outstanding anti-fibrotic effects with reduced cytotoxicity compared to conventional

3-Bromopyruvate: targets and outcomes.

Science.gov (United States)

Shoshan, Maria C

2012-02-01

The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existant tumors in animal studies. We here review reported molecular targets of 3-BP and suggest that the very range of possible targets, which pertain to the altered energy metabolism of tumor cells, contributes both to the efficacy and the tumor specificity of the drug. Its in vivo efficacy is suggested to be due to a combination of glycolytic and mitochondrial targets, as well as to secondary effects affecting the tumor microenvironment. The cytotoxicity of 3-BP is less due to pyruvate mimicry than to alkylation of, e.g., key thiols. Alkylation of DNA/RNA has not been reported. More research is warranted to better understand the pharmacokinetics of 3-BP, and its potential toxic effects to normal cells, in particular those that are highly ATP-/mitochondrion-dependent.

Optimal management of nutrient reserves in microorganisms under time-varying environmental conditions.

Science.gov (United States)

Nev, Olga A; Nev, Oleg A; van den Berg, Hugo A

2017-09-21

Intracellular reserves are a conspicuous feature of many bacteria; such internal stores are often present in the form of inclusions in which polymeric storage compounds are accumulated. Such reserves tend to increase in times of plenty and be used up in times of scarcity. Mathematical models that describe the dynamical nature of reserve build-up and use are known as "cell quota," "dynamic energy/nutrient budget," or "variable-internal-stores" models. Here we present a stoichiometrically consistent macro-chemical model that accounts for variable stores as well as adaptive allocation of building blocks to various types of catalytic machinery. The model posits feedback loops linking expression of assimilatory machinery to reserve density. The precise form of the "regulatory law" at the heart of such a loop expresses how the cell manages internal stores. We demonstrate how this "regulatory law" can be recovered from experimental data using several empirical data sets. We find that stores should be expected to be negligibly small in stable growth-sustaining environments, but prominent in environments characterised by marked fluctuations on time scales commensurate with the inherent dynamic time scale of the organismal system. Copyright © 2017 Elsevier Ltd. All rights reserved.

Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets

Directory of Open Access Journals (Sweden)

Deepika Kanojia

2017-11-01

Full Text Available Abstract Background Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. Methods Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial. Results Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model. Conclusions Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor.

Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer.

Directory of Open Access Journals (Sweden)

Ibrahim Tekedereli

Full Text Available Eukaryotic elongation factor 2 kinase (eEF-2K, through its phosphorylation of elongation factor 2 (eEF2, provides a mechanism by which cells can control the rate of the elongation phase of protein synthesis. The activity of eEF-2K is increased in rapidly proliferating malignant cells, is inhibited during mitosis, and may contribute to the promotion of autophagy in response to anti-cancer therapies. The purpose of this study was to examine the therapeutic potential of targeting eEF-2K in breast cancer tumors. Through the systemic administration of liposomal eEF-2K siRNA (twice a week, i.v. 150 µg/kg, the expression of eEF-2K was down-regulated in vivo in an orthotopic xenograft mouse model of a highly aggressive triple negative MDA-MB-231 tumor. This targeting resulted in a substantial decrease in eEF2 phosphorylation in the tumors, and led to the inhibition of tumor growth, the induction of apoptosis and the sensitization of tumors to the chemotherapy agent doxorubicin. eEF-2K down-modulation in vitro resulted in a decrease in the expression of c-Myc and cyclin D1 with a concomitant increase in the expression of p27(Kip1. A decrease in the basal activity of c-Src (phospho-Tyr-416, focal adhesion kinase (phospho-Tyr-397, and Akt (phospho-Ser-473 was also detected following eEF-2K down-regulation in MDA-MB-231 cells, as determined by Western blotting. Where tested, similar results were seen in ER-positive MCF-7 cells. These effects were also accompanied by a decrease in the observed invasive phenotype of the MDA-MB-231 cells. These data support the notion that the disruption of eEF-2K expression in breast cancer cells results in the down-regulation of signaling pathways affecting growth, survival and resistance and has potential as a therapeutic approach for the treatment of breast cancer.

CAM and Cell Fate Targeting: Molecular and Energetic Insights into Cell Growth and Differentiation

Directory of Open Access Journals (Sweden)

Carlo Ventura

2005-01-01

Full Text Available Evidence-based medicine is switching from the analysis of single diseases at a time toward an integrated assessment of a diseased person. Complementary and alternative medicine (CAM offers multiple holistic approaches, including osteopathy, homeopathy, chiropractic, acupuncture, herbal and energy medicine and meditation, all potentially impacting on major human diseases. It is now becoming evident that acupuncture can modify the expression of different endorphin genes and the expression of genes encoding for crucial transcription factors in cellular homeostasis. Extremely low frequency magnetic fields have been found to prime the commitment to a myocardial lineage in mouse embryonic stem cells, suggesting that magnetic energy may direct stem cell differentiation into specific cellular phenotypes without the aid of gene transfer technologies. This finding may pave the way to novel approaches in tissue engineering and regeneration. Different ginseng extracts have been shown to modulate growth and differentiation in pluripotent cells and to exert wound-healing and antitumor effects through opposing activities on the vascular system, prompting the hypothesis that ancient compounds may be the target for new logics in cell therapy. These observations and the subtle entanglement among different CAM systems suggest that CAM modalities may deeply affect both the signaling and transcriptional level of cellular homeostasis. Such a perception holds promises for a new era in CAM, prompting reproducible documentation of biological responses to CAM-related strategies and compounds. To this end, functional genomics and proteomics and the comprehension of the cell signaling networks may substantially contribute to the development of a molecular evidence–based CAM.

Assessing Multiple Pathways for Achieving China’s National Emissions Reduction Target

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Mingyue Wang

2018-06-01

Full Text Available In order to achieve China’s target of carbon intensity emissions reduction in 2030, there is a need to identify a scientific pathway and feasible strategies. In this study, we used stochastic frontier analysis method of energy efficiency, incorporating energy structure, economic structure, human capital, capital stock and potential energy efficiency to identify an efficient pathway for achieving emissions reduction target. We set up 96 scenarios including single factor scenarios and multi-factors combination scenarios for the simulation. The effects of each scenario on achieving the carbon intensity reduction target are then evaluated. It is found that: (1 Potential energy efficiency has the greatest contribution to the carbon intensity emissions reduction target; (2 they are unlikely to reach the 2030 carbon intensity reduction target of 60% by only optimizing a single factor; (3 in order to achieve the 2030 target, several aspects have to be adjusted: the fossil fuel ratio must be lower than 80%, and its average growth rate must be decreased by 2.2%; the service sector ratio in GDP must be higher than 58.3%, while the growth rate of non-service sectors must be lowered by 2.4%; and both human capital and capital stock must achieve and maintain a stable growth rate and a 1% increase annually in energy efficiency. Finally, the specific recommendations of this research were discussed, including constantly improved energy efficiency; the upgrading of China’s industrial structure must be accelerated; emissions reduction must be done at the root of energy sources; multi-level input mechanisms in overall levels of education and training to cultivate the human capital stock must be established; investment in emerging equipment and accelerate the closure of backward production capacity to accumulate capital stock.

Seasonal carbon storage and growth in Mediterranean tree seedlings under different water conditions.

Science.gov (United States)

Sanz-Pérez, Virginia; Castro-Díez, Pilar; Joffre, Richard

2009-09-01

In all Mediterranean-type ecosystems, evergreen and deciduous trees differing in wood anatomy, growth pattern and leaf habit coexist, suggesting distinct adaptative responses to environmental constraints. This study examined the effects of summer water stress on carbon (C) storage and growth in seedlings of three coexisting Mediterranean trees that differed in phenology and wood anatomy characteristics: Quercus ilex subsp. ballota (Desf.) Samp., Quercus faginea Lam. and Pinus halepensis L. Seedlings were subjected to two levels of watering during two consecutive summers and achieved a minimum of -0.5 and -2.5 MPa of predawn water potential in the control and water stress treatment, respectively. Both Quercus species concentrated their growth in the early growing season, demanding higher C in early spring but replenishing C-stores in autumn. These species allocated more biomass to roots, having larger belowground starch and lipid reserves. Quercus species differed in seasonal storage dynamics from P. halepensis. This species allocated most of its C to aboveground growth, which occurred gradually during the growing season, leading to fewer C-reserves. Soluble sugar and starch concentrations sharply declined in August in P. halepensis, probably because reserves support respiration demands as this species closed stomata earlier under water stress. Drought reduced growth of the three species, mainly in Q. faginea and P. halepensis, but not C-reserves, suggesting that growth under water stress conditions is not limited by C-availability.

RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.