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The serrated pathway in colorectal carcinogenesis

Yamine, Letícia; Scapulatempo-Neto, Cristovam; Reis, R. M.; Guimarães, Denise Peixoto
Fonte: Baishideng Publishing Group Publicador: Baishideng Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 14/12/2014 POR
Relevância na Pesquisa
35.67%
Serrated adenocarcinoma is a recently described subset of colorectal cancer (CRC), which account for about 10% of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC. Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps (HPs), sessile serrated adenoma (SSA), traditional serrated adenoma (TSA) and mixed polyps. HPs are the most common serrated polyp followed by SSA and TSA. This distinct histogenesis is believed to have a major influence in prevention strategies, patient prognosis and therapeutic impact. Genetically, serrated polyps exhibited also a distinct pattern, with KRAS and BRAF having an important contribution to its development. Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype. In the present review we will address the current knowledge of serrated polyps, clinical pathological features and will update the most recent findings of its molecular pathways. The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development.

A critical pathway for electronic medical record selection.

Holbrook, A.; Keshavjee, K.; Langton, K.; Troyan, S.; Millar, S.; Olantunji, S.; Pray, M.; Tytus, R.; Ford, P. T.;
Fonte: American Medical Informatics Association Publicador: American Medical Informatics Association
Tipo: Artigo de Revista Científica
Publicado em //2001 EN
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35.6%
Electronic medical records (EMRs) are increasingly becoming a necessary tool in health care. Given their potential to influence every aspect of health care, there has been surprisingly little rigorous research applied to this important piece of emerging health technology. An initial phase of the COMPETE study, which is examining the impact of EMRs on efficiency, quality of care and privacy concerns, involved a rigorous "critical pathway" approach to EMR selection for the study. A multidisciplinary team with clinical, technical and research expertise led an 8-stage evaluation process with direct input from user physicians at each stage. An iterative sequence of review of EMR specifications and features, live product demonstrations, site visits, and negotiations with vendors led to a progressive narrowing of the field of eligible EMR systems. Final scoring was based on 3 main themes of clinical usability, data quality and support/vendor issues. We believe that a rigorous, multidisciplinary process such as this is required to maximize success of any EMR implementation project.

A critical role for the NFkB pathway in multiple myeloma

Demchenko, Yulia N.; Kuehl, W. Michael
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 07/05/2010 EN
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35.68%
NFkB transcription factors play a key role in the survival and proliferation of many kinds of B-cell tumors, including multiple myeloma (MM). It was shown that NFkB activation in MM tumors results mainly from extrinsic signaling by APRIL and BAFF ligands that stimulate receptors on normal plasma cells as well as on pre-malignant monoclonal gammopathy of undetermined significance (MGUS) and MM tumors. However, the mutations that occur during MM progression and that constitutively activate NFkB would be expected to decrease dependence of tumor cells on the bone marrow microenvironment. These mutations can activate the classical or alternative NFkB pathways selectively, but usually both pathways are activated in MM. Significantly, activation of either NFkB pathway leads to a similar response of MM cell lines. This frequent activation of the alternative pathway distinguishes MM from other B-cell tumors, which more frequently have mutations that are predicted to activate only the classical NFkB pathway. Given the strong dependence of MGUS and MM tumors on NFkB pathway activation, inhibition by a combination of targeting extrinsic signaling plus both NFkB pathways appears to be an attractive therapeutic approach in MM tumors.

The NFκB pathway: a therapeutic target in glioblastoma

Nogueira, Lorena; Ruiz-Ontañon, Patricia; Vazquez-Barquero, Alfonso; Moris, Francisco; Fernandez-Luna, Jose L.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 05/09/2011 EN
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35.64%
Cancer initiating cells have been described to be the only cell population with tumorigenic capacity in glioblastoma multiforme, one of the most aggressive and untreatable cancers. Recent work from our group described that NFκB pathway was activated in glioblastoma initiating cells undergoing differentiation, and that blockade of this activation promoted senescence of differentiating cells. NFκB activation in cancer may be the result of either exposure to proinflammatory stimuli in the tumor microenvironment or upregulation of the signaling pathway by upstream regulators. Appropriate control of NFκB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NFκB related tumors, including glioblastoma. Here, we summarize the current knowledge of the relevance of NFκB in cancer and its possible role as a target of therapeutic intervention.

Differential effect of long-term leucine supplementation on skeletal muscle and adipose tissue in old rats: an insulin signaling pathway approach

Zeanandin, Gilbert; Balage, Michèle; Schneider, Stéphane M.; Dupont, Joëlle; Hébuterne, Xavier; Mothe-Satney, Isabelle; Dardevet, Dominique
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
EN
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35.64%
Leucine acts as a signal nutrient in promoting protein synthesis in skeletal muscle and adipose tissue via mTOR pathway activation, and may be of interest in age-related sarcopenia. However, hyper-activation of mTOR/S6K1 has been suggested to inhibit the first steps of insulin signaling and finally promote insulin resistance. The impact of long-term dietary leucine supplementation on insulin signaling and sensitivity was investigated in old rats (18 months old) fed a 15% protein diet supplemented (LEU group) or not (C group) with 4.5% leucine for 6 months. The resulting effects on muscle and fat were examined. mTOR/S6K1 signaling pathway was not significantly altered in muscle from old rats subjected to long-term dietary leucine excess, whereas it was increased in adipose tissue. Overall glucose tolerance was not changed but insulin-stimulated glucose transport was improved in muscles from leucine-supplemented rats related to improvement in Akt expression and phosphorylation in response to food intake. No change in skeletal muscle mass was observed, whereas perirenal adipose tissue mass accumulated (+45%) in leucine-supplemented rats. A prolonged leucine supplementation in old rats differently modulates mTOR/S6K pathways in muscle and adipose tissue. It does not increase muscle mass but seems to promote hypertrophy and hyperplasia of adipose tissue that did not result in insulin resistance.

MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway

Bouillez, Audrey; Gnemmi, Viviane; Gaudelot, Kelly; Hémon, Brigitte; Ringot, Bélinda; Pottier, Nicolas; Glowacki, François; Butruille, Caroline; Cauffiez, Christelle; Hamdane, Malika; Sergeant, Nicolas; Seuningen, Isabelle Van; Leroy, Xavier; Aubert, S
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 02/02/2014 EN
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35.67%
MUC1 is a membrane-anchored mucin and its cytoplasmic tail (CT) can interact with many signaling pathways and act as a co-transcription factor to activate genes involved in tumor progression and metastasis. MUC1 is overexpressed in renal cell carcinoma with correlation to prognosis and has been implicated in the hypoxic pathway, the main renal carcinogenetic pathway. In this context, we assessed the effects of MUC1 overexpression on renal cancer cells properties. Using shRNA strategy and/or different MUC1 constructs, we found that MUC1-extracellular domain and MUC1-CT are involved in increase of migration, cell viability, resistance to anoikis and in decrease of cell aggregation in cancer cells. Invasiveness depends only on MUC1-CT. Then, by using siRNA strategy and/or pharmacological inhibitors or peptides, we showed that sheddases ADAM10, ADAM17 and gamma-secretase are necessary for MUC1 C-terminal subunit (MUC1-C) nuclear location and in increase of invasion property. Finally, MUC1 overexpression increases ADAM10/17 protein expression suggesting a positive regulatory loop. In conclusion, we report that MUC1 acts in renal cancer progression and MUC1-C nuclear localization drives invasiveness of cancer cells through a sheddase/gamma secretase dependent pathway. MUC1 appears as a therapeutic target by blocking MUC1 cleavage or nuclear translocation by using pharmacological approach and peptide strategies.

WNT-pathway components as predictive markers useful for diagnosis, prevention and therapy in inflammatory bowel disease and sporadic colorectal cancer

Serafino, Annalucia; Moroni, Noemi; Zonfrillo, Manuela; Andreola, Federica; Mercuri, Luana; Nicotera, Giuseppe; Nunziata, Joseph; Ricci, Riccardo; Antinori, Armando; Rasi, Guido; Pierimarchi, Pasquale
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 11/01/2014 EN
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35.67%
The key role of the Wnt/β-catenin signaling in colorectal cancer (CRC) insurgence and progression is now recognized and several therapeutic strategies targeting this pathway are currently in developing. Wnt/β-catenin signaling not only dominates the early stages of sporadic colorectal cancer (SCC), but could also represent the connection between inflammatory bowel diseases (IBD) and increased risk of developing SCC. The knowledge on the sequential molecular events of Wnt-signaling cascade in IBD and during colorectal carcinogenesis, might provide new diagnostic/prognostic markers and could be helpful for optimizing the treatment protocols, thus improving the efficacy of Wnt-targeting therapies. We performed a comparative evaluation of the expression of some crucial molecules participating to Wnt signaling in an animal model of chemically-induced CRC and in human tissues obtained from patients suffering from IBD or at sequential stages of SCC. Specifically, we analyzed upstream events of Wnt signaling including β-catenin nuclear translocation and loss of E-cadherin and APC functions, and downstream events including c-Myc and Cyclin-D1 expression. We demonstrated that these crucial components of the Wnt/β-catenin pathway, when evaluated by immunohistochemistry using a multiparametric approach that includes the analyses of both expression and localization...

Novel mechanism of JNK pathway activation by adenoviral E1A

Romanov, Vasily S.; Brichkina, Anna I.; Morrison, Helen; Pospelova, Tatiana V.; Pospelov, Valery A.; Herrlich, Peter
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 25/03/2014 EN
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35.64%
The adenoviral oncoprotein E1A influences cellular regulation by interacting with a number of cellular proteins. In collaboration with complementary oncogenes, E1A fully transforms primary cells. As part of this action, E1A inhibits transcription of c-Jun:Fos target genes while promoting that of c-Jun:ATF2-dependent genes including jun. Both c-Jun and ATF2 are hyperphosphorylated in response to E1A. In the current study, E1A was fused with the ligand binding domain of the estrogen receptor (E1A-ER) to monitor the immediate effect of E1A activation. With this approach we now show that E1A activates c-Jun N-terminal kinase (JNK), the upstream kinases MKK4 and MKK7, as well as the small GTPase Rac1. Activation of the JNK pathway requires the N-terminal domain of E1A, and, importantly, is independent of transcription. In addition, it requires the presence of ERM proteins. Downregulation of signaling components upstream of JNK inhibits E1A-dependent JNK/c-Jun activation. Taking these findings together, we show that E1A activates the JNK/c-Jun signaling pathway upstream of Rac1 in a transcription-independent manner, demonstrating a novel mechanism of E1A action.

Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway

Potu, Harish; Peterson, Luke F.; Pal, Anupama; Verhaegen, Monique; Cao, Juxiang; Talpaz, Moshe; Donato, Nicholas J.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 26/06/2014 EN
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35.6%
Usp5 is a deubiquitinase (DUB) previously shown to regulate unanchored polyubiquitin (Ub) chains, p53 transcriptional activity and double-strand DNA repair. In BRAF mutant melanoma cells, Usp5 activity was suppressed by BRAF inhibitor (vemurafenib) in sensitive but not in acquired or intrinsically resistant cells. Usp5 knockdown overcame acquired vemurafenib resistance and sensitized BRAF and NRAS mutant melanoma cells to apoptosis initiated by MEK inhibitor, cytokines or DNA-damaging agents. Knockdown and overexpression studies demonstrated that Usp5 regulates p53 (and p73) levels and alters cell growth and cell cycle distribution associated with p21 induction. Usp5 also regulates the intrinsic apoptotic pathway by modulating p53-dependent FAS expression. A small molecule DUB inhibitor (EOAI3402143) phenocopied the FAS induction and apoptotic sensitization of Usp5 knockdown and fully blocked melanoma tumor growth in mice. Overall, our results demonstrate that BRAF activates Usp5 to suppress cell cycle checkpoint control and apoptosis by blocking p53 and FAS induction; all of which can be restored by small molecule-mediated Usp5 inhibition. These results suggest that Usp5 inhibition can provide an alternate approach in recovery of diminished p53 (or p73) function in melanoma and can add to the targeted therapies already used in the treatment of melanoma.

The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-Myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway

Wang, Jiabei; Yin, Dalong; Xie, Changming; Zheng, Tongsen; Liang, Yingjian; Hong, Xuehui; Lu, Zhaoyang; Song, Xuan; Song, Ruipeng; Yang, Haiyan; Sun, Boshi; Bhatta, Nishant; Meng, Xianzhi; Pan, Shangha; Jiang, Hongchi; Liu, Lianxin
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 08/08/2014 EN
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35.6%
Here we showed that hepatocellular carcinoma (HCC) cell lines with high metastatic potential had low levels of NDRG2. The iron chelator Dp44mT up-regulated NDRG2, suppressed epithelial-mesenchymal transition (EMT) and inhibited tumor metastasis in HCC having high metastatic potential. Also Dp44mT attenuated the TGF-β1-induced EMT in HCC having low metastatic potential. In agreement, silencing endogenous NDRG2 with shNDRG2 in HCC cells attenuated the effect of Dp44mT. We showed that the NDRG2/gp130/STAT3 pathway can mediate Dp44mT effects. In agreement, we found that a combination of NDRG2 expression and p-STAT3 levels is a strong predictor of prognosis in HCC patients. We suggest that up-regulation of NDRG2 by Dp44mT is a promising therapeutic approach in HCC.

The “Dual-Pathway” Strategy after Acute Coronary Syndrome: Rivaroxaban and Antiplatelet Agents in the ATLAS ACS 2-TIMI 51 Trial

Cohen, Marc; Iyer, Deepa
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
EN
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35.6%
Acute coronary syndrome (ACS) is a medical emergency often associated with an occlusive coronary event with consequent myocardial underperfusion. Patients require immediate antiplatelet therapy and long-term antithrombotic prophylaxis to reduce the risk of recurrence. Acetylsalicylic acid (ASA) alone or in combination with a platelet P2Y12 inhibitor (dual antiplatelet therapy [DAPT]) has become the clinically accepted antithrombotic prophylaxis for patients post-ACS. Historically, studies assessing the utility of adding oral anticoagulants (OACs) have not demonstrated a clinical benefit with regard to acceptable bleeding risk. Studies with vitamin K antagonists (VKAs) such as warfarin demonstrated a potential to reduce the risk of subsequent death by reinfarction but this benefit was offset by increases in bleeding. Results from studies of two targeted non-VKA OACs also proved disappointing, with little or no apparent reduction in the rate of ischemic events seen. However, the recent ATLAS studies assessing rivaroxaban (an oral factor Xa inhibitor) in patients with ACS demonstrated a reduction in the composite endpoint of deaths from cardiovascular causes, myocardial infarction (MI), or stroke, and a reduction in the rate of stent thrombosis. This review provides an overview of the pivotal studies in which the addition of OACs to antiplatelet therapy (the so-called “dual-pathway” approach) has been investigated for the management of patients post-ACS and considers the results of the ATLAS studies and their potential impact on the management of patients after an acute event.

The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway

Agnoletto, Chiara; Brunelli, Laura; Melloni, Elisabetta; Pastorelli, Roberta; Casciano, Fabio; Rimondi, Erika; Rigolin, Gian Matteo; Cuneo, Antonio; Secchiero, Paola; Zauli, Giorgio
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 10/12/2014 EN
Relevância na Pesquisa
35.6%
B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53mutated B-CLL cells and in p53mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53wild-type and p53mutated B-CLL patient cell cultures, as well as in p53mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53mutated leukemic cells...

Dynamic scenario of metabolic pathway adaptation in tumors and therapeutic approach

Peppicelli, Silvia; Bianchini, Francesca; Calorini, Lido
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 09/02/2015 EN
Relevância na Pesquisa
35.6%
Cancer cells need to regulate their metabolic program to fuel several activities, including unlimited proliferation, resistance to cell death, invasion and metastasis. The aim of this work is to revise this complex scenario. Starting from proliferating cancer cells located in well-oxygenated regions, they may express the so-called “Warburg effect” or aerobic glycolysis, meaning that although a plenty of oxygen is available, cancer cells choose glycolysis, the sole pathway that allows a biomass formation and DNA duplication, needed for cell division. Although oxygen does not represent the primary font of energy, diffusion rate reduces oxygen tension and the emerging hypoxia promotes “anaerobic glycolysis” through the hypoxia inducible factor-1α-dependent up-regulation. The acquired hypoxic phenotype is endowed with high resistance to cell death and high migration capacities, although these cells are less proliferating. Cells using aerobic or anaerobic glycolysis survive only in case they extrude acidic metabolites acidifying the extracellular space. Acidosis drives cancer cells from glycolysis to OxPhos, and OxPhos transforms the available alternative substrates into energy used to fuel migration and distant organ colonization.

Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo

Sharon, Chetna; Baranwal, Somesh; Patel, Nirmita J.; Rodriguez-Agudo, Daniel; Pandak, William M.; Majumdar, Adhip PN; Krystal, Geoffrey; Patel, Bhaumik B.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 29/03/2015 EN
Relevância na Pesquisa
35.69%
We observed a co-upregulation of the insulin-like growth factor receptor (IGF-1R)/AKT/mammalian target of rapamycin (mTOR) [InAT] axis and the mevalonate-isoprenoid biosynthesis (MIB) pathways in colorectal cancer stem cells (CSCs) in an unbiased approach. Hence, we hypothesized that the InAT axis might regulate the MIB pathway to govern colorectal CSCs growth. Stimulation (IGF-1) or inhibition (IGF-1R depletion and pharmacological inhibition of IGF-1R/mTOR) of the InAT axis produced induction or attenuation of CSC growth as well as expression of CSC markers and self-renewal factors respectively. Intriguingly, activation of the InAT axis (IGF-1) caused significant upregulation of the MIB pathway genes (both mRNA and protein); while its inhibition produced the opposite effects in colonospheres. More importantly, supplementation with dimethylallyl- and farnesyl-PP, MIB metabolites downstream of isopentenyl-diphosphate delta isomerase (IDI), but not mevalonate and isopentenyl-pp that are upstream of IDI, resulted in a near-complete reversal of the suppressive effect of the InAT axis inhibitors on CSCs growth. The latter findings suggest a specific regulation of the MIB pathway by the InAT axis distal to the target of statins that inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Effects of IGF-1R inhibition on colonic CSCs proliferation and the MIB pathway were confirmed in an ‘in vivo’ HCT-116 xenograft model. These observations establish a novel mechanistic link between the InAT axis that is commonly deregulated in colorectal cancer and the MIB pathway in regulation of colonic CSCs growth. Hence...

Updating the Poverty Estimates in Serbia in the Absence of Micro Data : A Microsimulation Approach

Cojocaru, Alexandru; Olivieri, Sergio
Fonte: World Bank, Washington, DC Publicador: World Bank, Washington, DC
EN_US
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35.71%
The continued poverty impact of the financial crisis in Serbia is difficult to establish beyond 2010 because of the lack of survey data. This paper tackles this difficulty. It uses a micro-simulation approach that accounts for a key pathway of the financial crisis in Serbia, the labor market. The results suggest a further increase in poverty in 2011 on account of a continued deterioration of the labor market indicators and despite a recovering gross domestic product. In order to evaluate the forecast, the model is applied to generate forecasts for previous years (2009 and 2010), which are compared with realized poverty estimates. The micro-simulation model performs well in predicting poverty dynamics during 2009-10 and less so during 2008-09. The accuracy of the predictions improves when the response of the social protection system is accounted for.

PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma

Luke, Jason J.; Ott, Patrick A.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
45.64%
Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors...

PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma

Luke, Jason J.; Ott, Patrick A.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 27/02/2015 EN
Relevância na Pesquisa
35.6%
Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors...

Downregulation of microRNA-23a suppresses prostate cancer metastasis by targeting the PAK6-LIMK1 signaling pathway

Cai, Songwang; Chen, Ruihan; Li, Xiaojuan; Cai, Yi; Ye, Zhiqiang; Li, Shigeng; Li, Jun; Huang, Huaiqiu; Peng, Shubin; Wang, Jun; Tao, Yiran; Huang, Hongxing; Wen, Xinglai; Mo, Jianfeng; Deng, Zhupeng; Wang, Jian; Zhang, Yangfan; Gao, Xin; Wen, Xingqiao
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 16/01/2015 EN
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35.6%
Here we found that levels of miR-23a were decreased in prostate cancer cell lines and tumor tissues. These low levels were associated with poor patients' prognosis. MiR-23a inhibited migration and invasion of prostate cancer in vivo and in orthotopic prostate cancer mice model. MiR-23a decreased levels of p21-activated kinase 6 (PAK6). Expression of miR-23a inhibited phosphorylation of LIM kinase 1 (LIMK1) and cofilin, in turn suppressing formation of stress fibers and actin filaments, which was required for cell motility and invasion. PAK6 bound to LIMK1 and activated it via phosphorylation at Thr-508. Also, PAK6 and LIMK1 were colocalized in the cytoplasma. Thus, miR-23a regulated cytoskeleton by affecting LIMK1 and cofilin. In summary, we have identified the miR-23a-PAK6-LIMK1 pathway of prostate cancer metastasis. Potential therapeutic approach by targeting miR-23 is suggested.

Theory-Driven Process Evaluation of the SHINE Trial Using a Program Impact Pathway Approach

Mbuya, Mduduzi N. N.; Jones, Andrew D.; Ntozini, Robert; Humphrey, Jean H.; Moulton, Lawrence H.; Stoltzfus, Rebecca J.; Maluccio, John A.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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55.79%
Two reasons for the lack of success of programs or interventions are poor alignment of interventions with the causes of the problem targeted by the intervention, leading to poor efficacy (theory failure), and failure to implement interventions as designed (program failure). These failures are important for both public health programs and randomized trials. In the Sanitation Hygiene and Infant Nutrition Efficacy (SHINE) Trial, we utilize the program impact pathway (PIP) approach to track intervention implementation and behavior uptake. In this article, we present the SHINE PIP including definitions and measurements of key mediating domains, and discuss the implications of this approach for randomized trials. Operationally, the PIP can be used for monitoring and strengthening intervention delivery, facilitating course-correction at various stages of implementation. Analytically, the PIP can facilitate a richer understanding of the mediating and modifying determinants of intervention impact than would be possible from an intention-to-treat analysis alone.

Projecting the external health costs of a coal-fired power plant: The case of Kusile

Riekert,Johannes W; Koch,Steven F
Fonte: Journal of Energy in Southern Africa Publicador: Journal of Energy in Southern Africa
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2012 EN
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65.73%
We examine an important subset of the expected health costs associated with the commissioning of Kusile, a new coal-fired electricity generation plant in South Africa. The subset of health impacts focuses on sulphur dioxides, nitrous oxides and large particulate matter (greater than 10 mm). The analysis makes use of the Impact Pathway Approach combined with the data transfer methodology. The plant, which is expected to contribute 4 800 MW of additional electricity to the South African grid is found to have modest health impacts, partly due to the limited additional pollutant emissions expected at the plant. Specifically, additional localised external health costs are found to be in the region of 0.09c/kWh to 6.08c/kWh. Limitations of the analysis are also examined.