tbuckley/cabot-search huggingface dataset:
Rethinking the Belmont Report?
Authors: Phoebe Friesen, Lisa Kearns, Barbara Redman, Arthur L. Caplan
Journal: The American Journal of Bioethics (2017)

This article reflects on the relevance and applicability of the Belmont Report nearly four decades after its original publication. In an exploration of criticisms that have been raised in response to the report and of significant changes that have occurred within the context of biomedical research, five primary themes arise. These themes include the increasingly vague boundary between research and practice, unique harms to communities that are not addressed by the principle of respect for persons, and how growing complexity and commodification in research have shed light on the importance of transparency. The repercussions of Belmont's emphasis on the protection of vulnerable populations is also explored, as is the relationship between the report's ethical principles and their applications. It is concluded that while the Belmont Report was an impressive response to the ethical issues of its day, the field of research ethics involving human subjects may have outgrown it.
Conflict of Interest, Conflicting Interests, and Effective Collaboration Between Academia and Industry on Preclinical and Clinical Cancer Research
Authors: Mace L. Rothenberg, David H. Johnson
Journal: JAMA Oncology (2017)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Oncology journal
Complement Recognition Pathways in Renal Transplantation
Authors: Christopher L. Nauser, Conrad A. Farrar, Steven H. Sacks
Journal: Journal of the American Society of Nephrology (2017)

The complement system, consisting of soluble and cell membrane–bound components of the innate immune system, has defined roles in the pathophysiology of renal allograft rejection. Notably, the unavoidable ischemia-reperfusion injury inherent to transplantation is mediated through the terminal complement activation products C5a and C5b-9. Furthermore, biologically active fragments C3a and C5a, produced during complement activation, can modulate both antigen presentation and T cell priming, ultimately leading to allograft rejection. Earlier work identified renal tubule cell synthesis of C3, rather than hepatic synthesis of C3, as the primary source of C3 driving these effects. Recent efforts have focused on identifying the local triggers of complement activation. Collectin-11, a soluble C-type lectin expressed in renal tissue, has been implicated as an important trigger of complement activation in renal tissue. In particular, collectin-11 has been shown to engage L-fucose at sites of ischemic stress, activating the lectin complement pathway and directing the innate immune response to the distressed renal tubule. The interface between collectin-11 and L-fucose, in both the recipient and the allograft, is an attractive target for therapies intended to curtail renal inflammation in the acute phase.
The WISDOM study pilot: Evaluating a preference-tolerant RCT of risk-based vs. annual breast cancer screening.
Authors: Sarah Theiner, Celia Kaplan, Setareh Sarrafan, Julissa Cabrera, Sarah Dilys Sawyer, April S Liang, Sarah Rosenberg-Wohl, Miya Frick, Emily Claire Wong, Jeffrey Tice, Elad Ziv, Alexander D. Borowsky, Hoda Anton-Culver, Arash Naeim, Andrea LaCroix, Thomas Cink, Laura Esserman, Laura Van't Veer, Allison S Fiscalini
Journal: Journal of Clinical Oncology (2016)

e13035 Background: The goal of the WISDOM study (Women Informed to Screen Depending on Measures of risk) is to examine the effectiveness of a personalized approach to breast cancer screening and to bring clarity and objective recommendations to the current debate regarding mammography screening frequency. The WISDOM study, funded by PCORI, is a randomized trial with a preference-tolerant design that aims to determine if risk-based (RBS), vs. annual screening, is as safe, less morbid, enables prevention and is preferred by women. A pilot was conducted to test the logistics and examine the acceptance of the study. Methods: Women were recruited from the UCSF site of the Athena Breast Health Network, a clinical care-research cohort including 100,000 women from the 5 UC Medical Centers and Sanford Health. We recruited women 40 -74 years of age that had no history of breast cancer and had a normal mammogram in the past year. The Breast Cancer Surveillance Consortium model (standard risk factors, ethnicity, breast density and SNP risk alleles) in addition to gene panel testing was used to calculate breast cancer risks to inform the start and frequency of screening. Results: An online electronic enrollment process, e-Consent and patient engagement portal was successfully implemented. To date, 623 women were invited, 220 registered, and 159 have completed intake. 72% chose to be randomized, and 28% chose to self-assign, of whom 70% chose annual screening. Mean age of pilot participants was 56 years old. The ethnic breakdown of the cohort is: 80% White, 10% Asian, 4% Latino, 3% Black, and 3% other. 30% of participants identify as having Jewish ancestry. Initial patient interviews reveal overall enthusiasm for the study and provide ongoing feedback to improve the study materials. The pilot will conclude April 2016 when the full trial is launched. Additional data on distribution of personal risk estimates, and exit survey data evaluating uptake of screening recommendations will be presented. Conclusions: Our pilot reveals that the majority of women are willing to be randomized to answer the important question on optimal breast cancer screening. This pilot study is designed to inform the implementation of the 100,000 women WISDOM Study. Clinical trial information: NCT02620852.
Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis
Authors: Joseph Jacob, Brian J. Bartholmai, Srinivasan Rajagopalan, Maria Kokosi, Toby M. Maher, Arjun Nair, Ronald Karwoski, Elisabetta Renzoni, Simon L.F. Walsh, David M. Hansell, Athol U. Wells
Journal: European Respiratory Journal (2017)

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis. Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide ( D LCO ), transfer coefficient of the lung for carbon monoxide ( K CO ), composite physiologic index (CPI)) and mortality. The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using D LCO , and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p&lt;0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p&lt;0.0001) reduced gas transfer ( D LCO ). There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema.
Abstract P205: The Role of Nuclear Nox4 in Mediating Oxidation of HDAC4 in Response to Phenylephrine Stimulation
Authors: Shouji Matsushima, Junya Kuroda, Tetsuro Ago, Junichi Sadoshima
Journal: Circulation Research (2011)

Reduction and oxidation (Redox) stress is involved in the pathogenesis of cardiac hypertrophy and heart failure. We have shown previously that oxidation of conserved cysteine residues in histone deacetylase 4 (HDAC4) induces nuclear-to-cytoplasmic translocation of HDAC4, thereby mediating phenylephrine (PE)-induced cardiac hypertrophy. NAD(P)H oxidase 4 (Nox4) is a major source of oxidative stress in cardiomyocytes (CMs) in response to pressure overload. We hypothesized that Nox4 plays an essential role in mediating cardiac hypertrophy by regulating the redox state of HDAC4. Nox4 exists on intracellular membranes, including the mitochondria and nucleus in CMs. A subpressor dose of phenylephrine (PE, 20 mg/kg per day) or saline alone (control) was continuously infused into wild type (WT) and cardiac specific Nox4 knockout (Nox4-/-) mice subcutaneously via an osmotic minipumps. After 14 days, mean aortic pressure was similar between WT and Nox4-/- mice. Left ventricular (LV) wall thickness (1.04±0.03 vs. 1.27±0.06 mm, p&lt;0.05) and LV weight/ tibial length (LVW/TL 5.7±0.14 vs. 6.4±0.05 mg/mm, p&lt;0.05) were significantly lower in Nox4-/- than in WT mice. CM cross sectional area (MCA: 223±13 vs. 258±12 μm 2 , p&lt;0.05) was significantly smaller in Nox4-/- than in WT mice. Superoxide production from the nuclear membrane, as evaluated by lucigenin chemiluminescent assays, was also significantly lower in Nox4-/- than in WT mice (4116±314 vs. 7057±1710 RLU, p&lt;0.05). On the other hand, PE infusion induced significantly greater cardiac hypertrophy in transgenic mice with cardiac specific overexpression of Nox4 than in control mice. In cultured neonatal rat CMs, PE (100μM) treatment induced upregulation of Nox4 (2.8 fold vs. control, p&lt;0.05) within 5 min, which was accompanied by increases in superoxide production (6 fold, p&lt;0.01) and rapid (&lt; 5min) nuclear export of HDAC4. Knockdown of Nox4 with shRNA-Nox4, but not Nox2 knockdown, attenuated superoxide production in the nucleus and prevented PE-induced nuclear export of HDAC4. These results suggest that Nox4 plays an essential role in mediating PE-induced cardiac hypertrophy. Nox4 mediates PE-induced superoxide production in the nucleus and nuclear export of HDAC4, possibly through cysteine oxidation.
Integration of Plasticity Mechanisms within a Single Sensory Neuron of C. elegans Actuates a Memory
Authors: Josh D. Hawk, Ana C. Calvo, Ping Liu, Agustin Almoril-Porras, Ahmad Aljobeh, María Luisa Torruella-Suárez, Ivy Ren, Nathan Cook, Joel Greenwood, Linjiao Luo, Zhao-Wen Wang, Aravinthan D.T. Samuel, Daniel A. Colón-Ramos
Journal: Neuron (2018)
Abstract 120: Epidermal Growth Factor Receptor (EGFR) Family Dimeric Partners Switch During Pathological Stress in microRNA-7 Transgenic Mice
Authors: Manveen Gupta, Xi Wang, Elizabeth Martelli, Sathyamangla V Naga Prasad
Journal: Circulation Research (2015)

miRNA-7 is known to target epidermal growth factors receptor 1(EGFR1) in cancer cells. EGFR family members (EGFR 1, 2, 3 and 4) are known to form homo- and/or hetero-dimers to mediate downstream signals . Our previous study in human heart failure (Naga Prasad etal., JBC, 2009) showed that EGFR2 (ERBB2) was targeted by miRNA-7. Based on this study, we developed transgenic (Tg) mice with cardiomyocyte-specific overexpression of miRNA-7. miRNA-7 Tg mice have age dependent deterioration in cardiac dysfunction and is associated with cardiac dilation as measured by echocardiography (3 months - 60% FS, 6 month -52% FS &amp;12 months - 24%FS) and yet, they survive well for more than a year. To investigate whether pathological stress would accelerate the deterioration in cardiac function, miRNA-7 Tg mice were subjected to transverse aortic constriction (TAC) for two weeks. In contrast to the wild type littermates which undergo hypertrophic response following TAC, miRNA-7 Tg mice have accelerated cardiac dysfunction and dilation within two weeks. Biochemical analysis interestingly showed differential switching of dimeric EGFR partners in hearts of the miRNA-7 Tg mice compared to their sham controls. Our presentation will discuss the differential downstream signaling induced by changing of EGFR dimeric partners induced by pathological stress like TAC in the wildtype and miRNA-7 Tg mice.
Abstract 267: Opposing Functions of Two Splice Variants of the Human Transcription Factor Grainyhead-like 3 in Endothelial Cells And in vivo
Authors: Joachim Altschmied, Nicole Büchner, Sascha Jakob, Sabrina Farrokh, Christine Goy, Heiner Schaal, Judith Haendeler
Journal: Circulation Research (2013)

Grainyhead-like 3 (GRHL3) is a member of the evolutionary conserved Grainyhead family of transcription factors. In humans, three isoforms are derived from differential first exon usage and alternative splicing, which differ only in their N-terminus. Isoform 2, the only variant also present in mouse, is required for endothelial cell (EC) migration and protects against apoptosis. The functions of the human specific isoforms 1 and 3, which are derived from an alternatively spliced pre-mRNA, have not yet been investigated, although all three isoforms are expressed in EC. Therefore, we have assessed their effects on EC migration and apoptosis. Overexpression of the two proteins had opposite effects on EC migration, with isoform 1 acting pro-migratory. This protein also protected EC against apoptosis in an eNOS-dependent manner, whereas isoform 3 had no effect. These opposing outcomes with respect to apoptosis EC were corroborated by isoform-specific knockdowns. With reporter assays using a GRHL3-specific luciferase reporter we demonstrated that both are active transcription factors. Microarray analyses revealed that they induce divergent target gene sets in EC. Two validated targets, Akt2 and Mxi1, which are upregulated by isoform1, are regulators of Akt1-, and thus eNOS-phosphorylation and apoptosis, which could explain the effects of this protein on these processes. In vivo, overexpression of isoform 3 in zebrafish embryos resulted in increased lethality and severe deformations, while isoform 1 had no deleterious effect. In conclusion, our data demonstrate that the splice variant derived isoforms 1 and 3 of the human transcription factor GRHL3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes.
Liquid biopsy in the clinic: A prospective study of plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) in patients with advanced non-small cell lung cancers to match targeted therapy.
Authors: Joshua K. Sabari, Ai Ni, Adrian Lee, Nick Pavlakis, Stephen John Clarke, Nidhi Tandon, Sutirtha Datta, Mariel A. DuBoff, Andres Martinez, Michael D. Offin, James M. Isbell, Valerie W. Rusch, David Randolph Jones, Samantha Henderson, Lee Lim, Chris Raymond, Mark Li, Gregory J. Riely, Charles M. Rudin, Bob T. Li
Journal: Journal of Clinical Oncology (2017)

11536 Background: Liquid biopsy for plasma ctDNA NGS is a rapidly evolving science. Plasma ctDNA assays are commercially available and are increasingly adopted in the community with a paucity of evidence-based guidance. We set out to study the optimal timing and utility of plasma ctDNA NGS in clinic. Methods: Pts with advanced NSCLC who were driver unknown, defined as not having prior tissue NGS or clinical concern for tumor heterogeneity that may affect treatment decisions, were eligible. Peripheral blood was collected in a Streck tube (10mL), DNA extracted, and subjected to a bias-corrected hybrid-capture 21 gene targeted NGS assay in a CLIA lab with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1% (ResolutionBio Bellevue, WA). Pts also had concurrent tissue NGS via MSK IMPACT. Clinical endpoints included detection of oncogenic drivers in plasma, ability to match pts to targeted therapy, concordance and turnaround time of plasma and tissue NGS. Results: Forty-one pts were prospectively accrued. Plasma ctDNA detected an oncogenic driver in 39% (16/41) of pts, of whom 17% (7/41) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insertionYVMA, BRAF L597Q and MET exon14. Mean turnaround time for plasma was 7 days (4-12) and 28 days (20-43) for tissue. Plasma ctDNA was detected in 56% (23/41) of pts; detection was 40% (8/20) if blood was drawn on active therapy and 71% (15/21) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.28, 95% CI 0.06 - 1.16; p = 0.06). All pts had concurrent tissue NGS; of the 10 samples resulted, there was 100% driver concordance between tissue and plasma in pts drawn off therapy. Conclusions: In pts who were driver unknown or who had clinical concern for tumor heterogeneity, plasma ctDNA NGS identified a variety of oncogenic drivers with a short turnaround time and matched them to targeted therapy. Plasma ctDNA detection was more frequent at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific, but a negative finding may still require tissue biopsy.
Mutation Frequencies in Patients With Early-Onset Colorectal Cancer
Authors: Andrew D. Beggs
Journal: JAMA Oncology (2017)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Oncology journal
Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus
Authors: Justine Hum, Janice H. Jou, Pamela K. Green, Kristin Berry, James Lundblad, Barbara D. Hettinger, Michael Chang, George N. Ioannou
Journal: Diabetes Care (2017)

OBJECTIVE Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. We aimed to investigate whether eradication of HCV infection with direct-acting antiviral (DAA) agents is associated with improved glycemic control in patients with diabetes. RESEARCH DESIGN AND METHODS We identified 2,435 patients with diabetes who underwent interferon-free and ribavirin-free DAA-based antiviral treatment for HCV in the national Veterans Affairs health care system. Changes in average hemoglobin A1c (HbA1c) level and use of antidiabetic medications 1 year before and after antiviral treatment were compared between patients who achieved sustained virologic response (SVR) and those who did not. RESULTS Among patients with elevated baseline HbA1c, the drop in HbA1c associated with antiviral treatment was greater in those who achieved SVR (0.98%) than in those who sustained treatment failure (0.65%) (adjusted mean difference 0.34, P = 0.02). Use of antidiabetic medications decreased more in patients who achieved SVR than in those who sustained treatment failure, especially for the use of insulin, which dropped significantly from 41.3% to 38% in patients achieving SVR compared with a slight increase from 49.8% to 51% in those who sustained treatment failure. CONCLUSIONS DAA-based eradication of HCV is associated with improved glycemic control in patients with diabetes as evidenced by decreased mean HbA1c and decreased insulin use. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes.
Prognostic score to predict time to castration-resistance in underserved patients with metastatic prostate cancer.
Authors: Ankit Mangla, Muhammad Umair Mushtaq, Udit Yadav, Ahmed T Ahmed, Jiaxiang Liu, Muriel Tania Go, Ahmed S Hassan, Sara Bedrose, Hashim Mann, Michael Russell Mullane
Journal: Journal of Clinical Oncology (2017)

e16518 Background: This study aimed to identify predictors of time to castration-resistance prostate cancer (tCRPC) from initial diagnosis of metastatic prostate cancer (mPC) and develop a prognostic score in the underserved population of an inner-city tertiary care hospital. Methods: We retrospectively reviewed charts of 278 men diagnosed with mPC between 2001 and 2015, of which 155 patients were analyzed. Socio-demographic, clinical and pathologic factors were ascertained at the time of diagnosis. Kaplan-Meier and cox regression analyses were done to explore correlates tCRPC. Crude (HR) and adjusted (aHR) hazard ratios with 95% confidence intervals (CI) were obtained. Results: Over a median follow-up of 46 months (95% CI 23-69), 73.5% of men developed castration-resistance. Median tCRPC was 16 months (95% CI 12.5-19.5). All patients received medical or surgical castration at the time of diagnosis. Significant correlates of short tCRPC included: prostate specific antigen &gt;20 ng/mL (HR 2.56, 95% CI 1.25-5.23, P=0.010), core involvement &gt;50% (HR 2.11, 95% CI 1.43-3.11, P&lt;0.001), bone metastases (HR 2.94, 95% CI 1.36-6.35, P=0.006), visceral metastases (HR 01.65, 95% CI 1.08-2.53, P=0.021), hemoglobin &lt;10 g/dL (HR 2.02, 95% CI 1.26-3.23, P=0.003), alkaline phosphatase (ALP) &gt;240 U/L (HR 2.42, 95% CI 1.62-3.61, P&lt;0.001), lactate dehydrogenase (LDH) &gt;200 U/L (HR 1.68, 95% CI 1.16-2.43, P=0.006) and neutrophil-lymphocyte ratio &gt;2.4 (HR 1.50, 95% CI 1.03-2.20, P=0.035). In multivariate model, core involvement &gt;50% (aHR 2.99, 95% CI 1.79-5.01, P&lt;0.001), ALP &gt;240 U/L (aHR 2.08, 95% CI 1.13-3.84, P=0.019) and LDH &gt;200 U/L (aHR 1.71, 95% CI 1.02-2.86, P=0.043) independently predicted short tCRPC and each factor decreased tCRPC by almost 50%. Mean prognostic score (PS), based on 1 point for each independent predictor (scale 0-3), was 1.23 (SD 0.91) and significantly predicted short tCRPC (P&lt;0.001). [Table] Conclusions: Our PS based on core involvement (&gt;50%), high ALP (&gt;240 U/L) and high LDH (&gt;200 U/L) significantly predicts tCRPC in men with mPC. Prospective studies are warranted to further validate this score. [Table: see text]
Tet2 Loss Dysregulates the Behavior of Mesenchymal Stem Cells and Increases Their Ability to Promote Tet2-/--Driven Myeloid Malignancy Progression
Authors: Zhigang Zhao, Rong Li, Lin Liu, Jinhuan Wang, Zizhen Chen, Wen Xing, Weiping Yuan, Feng-Chun Yang, Yuan Zhou, Mingjiang Xu
Journal: Blood (2016)