tbuckley/cabot-search huggingface dataset:
Composition of the Sepsis Definitions Task Force—Reply
Authors: Todd Dorman, Daniel De Backer
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 5164: Protein kinase C epsilon is a mediator of KRAS-driven lung tumorigenesis
Authors: Rachana Garg, Veena Kapoor, Martin Abba, David M. Feldser, Steven M. Albelda, Marcelo G. Kazanietz
Journal: Cancer Research (2016)

Abstract Exposure to a number of environmental carcinogens, such as polycyclic aromatic hydrocarbons (PAHs), are the major causative agents of lung cancer, the leading cause of cancer related deaths in the U.S. Oncogenic mutations in KRAS, one of the most common alteration found in non-small cell lung cancer (NSCLC), are induced in high frequency by PAHs and environmental carcinogens. Studies from many laboratories, including ours, established key roles for PKCϵ, a member of the protein kinase C (PKC) family, in mitogenesis and survival of cancer cells. Notably, PKCϵ is up-regulated in several epithelial cancers, including human NSCLC, suggesting a role in the development and/or maintenance of the malignant phenotype. We observed that PKCϵ inhibition/depletion blunt the proliferative, motile, and invasive properties of lung cancer cells with KRAS mutation (PLoS One;7(2):e31714,2012). More importantly, silencing PKCϵ reduced the ability of human NSCLC cells with KRAS mutation to form tumors in nude mice as well as impaired their metastatic potential (Oncogene 31(20):2593-600, 2011). As Ras-transformed cells have enhanced DAG levels and signaling, we hypothesized that genetic targeting of PKCϵ reverses lung tumorigenesis driven by oncogenic Ras. To address this, we intercrossed lung-specific mutant Ras mice (KrasLSL-G12D/+) with PKCϵ knockout mice. Notably, significant inhibition occurred in the formation of lung tumors upon loss of either one or both PKCϵ gene (PRKCE) alleles, with significant extension of mice lifespan, suggesting a role for PKCϵ in the initiation of lung tumorigenesis driven by oncogenic mutant KRas. Furthermore, in silico database analysis of KRAS mutated human lung adenocarcinomas revealed a significant association between high PRKCE expression and poor patient outcome. As environmental lung carcinogens (PAHs) induce mutations in Ras, we next intended to test the hypothesis that PKCϵ is implicated in the action of these carcinogens. Interestingly, alveolar hyperplasia as well as pulmonary adenomas induced by benzo(a)pyrene, a prototypical PAH, were significantly reduced upon loss of one or two PKCϵ alleles, suggesting that genetic ablation of PKCϵ impairs chemically-induced lung carcinogenesis. Overall, our results indicate that PKCϵ is a novel effector of KRAS in lung cancer that may represent a promising target for disease treatment. Citation Format: Rachana Garg, Veena Kapoor, Martin Abba, David M. Feldser, Steven M. Albelda, Marcelo G. Kazanietz. Protein kinase C epsilon is a mediator of KRAS-driven lung tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5164.
Four Roles of Ethical Theory in Clinical Ethics Consultation
Authors: Morten Magelssen, Reidar Pedersen, Reidun Førde
Journal: The American Journal of Bioethics (2016)

When clinical ethics committee members discuss a complex ethical dilemma, what use do they have for normative ethical theories? Members without training in ethical theory may still contribute to a pointed and nuanced analysis. Nonetheless, the knowledge and use of ethical theories can play four important roles: aiding in the initial awareness and identification of the moral challenges, assisting in the analysis and argumentation, contributing to a sound process and dialogue, and inspiring an attitude of reflexivity. These four roles of ethical theory in clinical ethics consultation are described and their significance highlighted, while an example case is used as an illustration throughout.
Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells
Authors: Dhifaf Sarhan, Frank Cichocki, Bin Zhang, Ashley Yingst, Stephen R. Spellman, Sarah Cooley, Michael R. Verneris, Bruce R. Blazar, Jeffrey S. Miller
Journal: Cancer Research (2016)

Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immunoregulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor T-cell Ig and ITIM domain (TIGIT), which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome. In contrast, conventional NK cells were potently suppressed by MDSCs, an effect abrogated completely by TIGIT blockade. Mechanistically, TIGIT signaling in NK cells after MDSC coculture led to a decrease in the phosphorylation of ZAP70/Syk and ERK1/2. These effects were reversed by blocking TIGIT on NK cells or by inhibiting production of reactive oxygen species (ROS) by MDSCs, the latter of which upregulated the TIGIT ligand CD155 on MDSCs. Accordingly, the blunted cytotoxicity of NK cells cocultured with MDSCs against tumor cells could be reversed by blocking TIGIT or ROS production. Overall, our results show how adaptive NK cells arising in response to CMV infection can escape MDSC-mediated suppression, and defined TIGIT antagonists as a novel type of checkpoint inhibitor to enhance NK-cell-mediated responses against cancer and infection. Cancer Res; 76(19); 5696-706. ©2016 AACR.
Definitions for Sepsis and Septic Shock
Authors: Verena Schneider-Lindner, Holger A. Lindner, Manfred Thiel
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 758: Modulating function of tumor associated macrophages by CSF1R inhibitor suppressed tumor growth in hepatocellular carcinoma
Authors: Hui-Chuan Sun, Jian-Yang Ao, Hao Cai, Zong-Tao Chai, Xiao-Dong Zhu
Journal: Cancer Research (2016)

Abstract Aims: To investigate the effect of colony stimulating factor 1 receptor (CSF1R) inhibitor on macrophages and tumor pathogenesis. Methods: CSF1 and CSF2 stimulated macrophages were obtained from mouse bone marrow derived monocytes cultured with CSF1 and CSF2. Mouse hepatoma cell line Hepa 1-6, and human hepatoma cell lines, HCCLM3 and HepG2 were used to established a allograft or xenograft tumor models to examine the effect of CSF1R inhibitor on tumor growth and distribution of macrophages. The characteristics of macrophages were determined by flow cytometry, immunohistochemistry, cell motility and Western blotting assays. Results: CSF1R inhibitor suppressed tumor growth in the tumor models derived from three hepatoma cell lines, and prolonged hosts’ survival, but CSF1R inhibitor did not decreased the number of macrophages in Hepa1-6 allograft tumors. in vitro study showed CSF1R inhibitor suppressed proliferation and motility of CSF1 stimulated macrophages but not CSF2 stimulated macrophages. Furthermore, we found CSF1R inhibitor treatment decreased the ability of THP-1 macrophages to promote migration and invasion of tumor cells. Conclusions: CSF1R inhibitor suppressed tumor growth in hepatoma animal models by modulating function of tumor associating macrophages. Citation Format: Hui-Chuan Sun, Jian-Yang Ao, Hao Cai, Zong-Tao Chai, Xiao-Dong Zhu. Modulating function of tumor associated macrophages by CSF1R inhibitor suppressed tumor growth in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 758.
Abstract LB-028: CIRP promotes keratinocytes survival following low-dose UVB irradiation through Stat3-mediated Bag-1/S expression
Authors: Yi Liao, Liling Tang, Shiyong Wu
Journal: Cancer Research (2016)

Abstract UV induces CIRP expression and subsequent Stat3 activation, but the biological function and mechanism of CIRP and Stat3 in mediating UVB-induced skin carcinogenesis have not been fully elucidated. In this study, we demonstrate that CIRP is elevated in all tested melanoma and non-melanoma skin cancer cell lines; and the expression of CIRP is upregulated in keratinocytes after being irradiated with relatively low dose (&amp;lt;5 mJ/cm2), but not high dose (50 mJ/cm2), UVB acutely and chronically. The increased expression of CIRP, either induced by UVB or through overexpression, leads to resistance of keratinocytes to UVB-induced growth arrest and death; and reduced expression of CIRP by RNA knockdown sensitizes keratinocyte cells to the low dose UVB irradiation. We also demonstrated that CIRP expression is required for the low dose UVB-induced Tyr705-phosphorylation, but not total amount, of Stat3. The p-Stat3 level is correlated with the expression levels of cyclin D1 and VEGF, two known downstream cell growth regulators of Stat3, as well as Bag-1/S, an apoptosis regulator. Inhibition of Stat3 DNA-binding activity by S3I-201 leads to a reduction of the p-Stat3 and Bag-1/S along with growth and survival of keratinocytes post-UVB; and the effect of S3I-201 on the UVB-irradiated cells can be partially inhibited by overexpression of CIRP or Bag-1/S. Furthermore, the overexpression of Bag-1/S can totally inhibit UVB-induced PARP cleavage and caspase 3 activation. The results presented above led us to propose that CIRP-p(705)-Stat3 cascade promotes cell proliferation and survival post-UVB via upregulating the expression of cyclin D1 and Bag-1/S respectively. Citation Format: Yi Liao, Liling Tang, Shiyong Wu. CIRP promotes keratinocytes survival following low-dose UVB irradiation through Stat3-mediated Bag-1/S expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-028.
“Prediabetes”: Are There Problems With This Label? Yes, the Label Creates Further Problems!
Authors: John S. Yudkin
Journal: Diabetes Care (2016)

The category of “prediabetes” defined by the American Diabetes Association comprises a range of intermediate hyperglycemia based on fasting or 2-h postload glucose or on HbA1c. Over the recent past, the “cut points” identifying this stage have changed, i.e., a lower fasting glucose level is used. On one hand, it can be argued that the change to a lower cut point identifies a group of individuals still at higher risk and provides heightened awareness for a condition associated with higher risk for cardiovascular disease. In addition, identification of individuals at this stage may represent a chance of earlier intervention in the disease. However, the argument against this definition of “prediabetes” is that it disguises the differences in the three subcategories and creates problems in interpreting observations on interventions and outcomes. In addition, it can be argued that the enormous numbers of people identified with the criteria far exceeds the capacity of health care systems to respond through individual care, particularly without evidence that interventions benefit any category other than impaired glucose tolerance. Thus, there does not appear to be consensus on the definition using the cut points identified. Controversy also remains as to whether there are glycemic metrics beyond HbA1c that can be used in addition to HbA1c to help assess risk of an individual developing diabetes complications. Given the current controversy, a Point-Counterpoint debate on this issue is provided herein. In the point narrative below, Dr. Yudkin provides his argument that there are significant problems with this label. In the counterpoint narrative that follows Dr. Yudkin’s contribution, Dr. Cefalu argues that the cut points are appropriate and do provide useful and important information in trying to reduce the future burden of diabetes. —William T. Cefalu Editor in Chief, Diabetes Care
Optimal cost-effective designs of randomized phase II proof of concept trials and associated go-no go decisions
Authors: R. A. Beckman, C. Chen
Journal: Journal of Clinical Oncology (2008)

14669 Background: In oncology, the number of possible combinations of therapeutic agents far exceeds available patients for clinical proof of concept (POC) studies. We have investigated optimal cost-effective designs for randomized (POC) trials. Unlike a Phase III confirmatory registration trial, a randomized POC trial is exploratory in nature, allowing flexibility in type I/II error rates. Methods: We have derived an efficiency score function representing the estimated probability of identifying a truly active treatment per patient exposure in the POC trial and in subsequent phase III trials. Optimization of the score function leads to type I/II error rates (and therefore sample size) for POC trials that are most cost-effective. This in turn leads to optimal cost-effective decision criteria for continuing to Phase 3 development and optimal allocation of fixed resources. The analysis has been done first assuming multiple investigational hypotheses of equal estimated likelihood of ultimate Phase 3 success and equal value, and then in the case where these parameters are unequal. Results: The optimal POC programs for equal hypotheses involve smaller randomized POC trials. Viewed as hypothesis testing, the type I error rates for optimal trials would be in the 0.05–0.1 range, but type II error rates would be 0.4 or higher. This translates into relatively high hurdles for continuation to Phase 3 for any individual trial. For unequal hypotheses, we can show when it is optimal to investigate only the more likely or valuable hypothesis. Conclusions: Generally, it is more efficient to investigate more of the credible hypotheses, even if at lesser statistical accuracy. No significant financial relationships to disclose.
Abstract 4727: ST7612AA1: focus on a drug candidate, front-runner of a new generation of HDAC inhibitors
Authors: Giuseppe Giannini, Ferdinando Maria Milazzo, Gianfranco Battistuzzi, Loredana Vesci
Journal: Cancer Research (2016)

Abstract After more than 20 years of research in the field of HDAC inhibitors, the oncological armamentarium has significantly enriched with new approved drugs. Currently, four drugs, Vorinostat (Zolinza; 2006), Romidepsin (Istodax; 2009) Belinostat (Beleodaq; 2014) and Panobinostat (Farydak; 2015) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and multiple myeloma, respectively. A fifth, Chidamide (Epidaza; 2015), has been recently approved by the China Food and Drug Administration for the treatment of PTCL. Beyond them, more than twenty are currently under pre-clinical and clinical investigation as single agent and in combination therapies against different cancers and in other several novel therapeutic indications. However, it is to emphasize a feature: among all these, no one, with the exception of the natural product Romidepsin, is a thiol derivative. After efforts lasted years, now we have selected ST7612AA1 - a new thiol-ω(γ-lactam amide) SAHA analogues, potential front-runner of a new generation of HDAC inhibitors, [1] highly competitive respect to other HDAC inhibitors drugs, orally administered with a negligible toxicity. ST7612AA1 displays low-nanomolar inhibitor activity on HDACs, being especially powerful on HDAC6 isoform, associated to a wide spectrum of antitumor activity, both in vitro and in vivo [2]; it can be industrially developed with a quick and easy synthetic process [3]. Moreover, it has also been investigated as an enhancer in antiretroviral therapy against HIV, aimed to eradicate the viral reservoirs [4]. All these results encouraged further enrichment experiments with ST7612AA1 as a drug candidate, which is currently in a phase of pre-clinical evaluation. The overall profile of ST7612AA1, including synthesis and a comprehensive pharmacological characterization, will be presented. [1] G. Giannini et al. J Med Chem. 2014, 57, 8358-8377 [2] L. Vesci et al. Oncotarget 2015, 6, 5735-48 [3] G. Battistuzzi, G. Giannini. Bioorg. Med. Chem .Lett. 2015, submitted [4] R. Badia Antiviral Research 2015, 123, 62-69 Citation Format: Giuseppe Giannini, Ferdinando Maria Milazzo, Gianfranco Battistuzzi, Loredana Vesci. ST7612AA1: focus on a drug candidate, front-runner of a new generation of HDAC inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4727.
Abstract 1974: Consequence of the tumor-associated deletion of CHD1 on transcriptional output and tumor progression
Authors: Michael A. Augello, Mirjam Blattner-Johnson, Mark Rubin, Christopher Barbieri
Journal: Cancer Research (2016)

Abstract CHD1 is a member of the super-family of chromatin modifier proteins, and is characterized by the presence of several chromo-domains as well as an ATP dependent helicase domain. A multitude of studies across several model systems have demonstrated that CHD1 functions as a transcriptional co-activator, responsible for efficient RNA polymerase II (RNA pol II) ejection from the transcriptional start site as well as maintenance of RNA pol II processivity across the gene body. This is accomplished largely though nucleosome remodeling ahead of RNA pol II, which efficiently reorganizes nucleosome position to allow for optimal RNA pol II function. Consequently, as CHD1 plays a critical role in transcriptional competency, tumor associated deletions and/or mutations of the CHD1 gene that compromise its function are rare. Interestingly, prostate cancer proves to be the exception, where the CHD1 locus is deleted with high frequency in primary disease. Tumors harboring homozygous deletion of CHD1 belong to a subclass of prostate cancer that are enriched for either SPOP or FOXA1 mutations, suggesting a prostate-specific, tumor suppressive role for CHD1 in this genomic context. Importantly, while the oncogenic functions of both FOXA1 and SPOP mutations have been largely defined, little is known as to how CHD1 loss contributes to tumor initiation or progression. Here, using 3D organoid cultures derived from GEM models of inducible CHD1 loss, prostate specific cells were found to have dramatically altered transcriptionally competency upon CHD1 depletion. These events were correlated with an aberrant, tumor-associated transcriptome, resulting in changes in morphology and growth. Furthermore, while genome wide assessment of CHD1 occupancy in human prostate cancer models uncovered an enrichment of CHD1 at sites of active transcription, loss of CHD1 did not dramatically affect expression of genes associated with tumor progression. Inversely, genomic loss of CHD1 was associated with changes in lineage dependent markers, suggesting that a major function of CHD1 is to regulate the differentiation state of prostate cells. Collectively, these data help to define the tumor suppressive role for CHD1 in prostate cancer tumorigenesis, and suggest that loss of CHD1 could alter the function of key transcriptional regulators associated with prostate cancer initiation and progression. Citation Format: Michael A. Augello, Mirjam Blattner-Johnson, Mark Rubin, Christopher Barbieri. Consequence of the tumor-associated deletion of CHD1 on transcriptional output and tumor progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1974.