tbuckley/cabot-search huggingface dataset:
RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer
Authors: C. Cruz, M. Castroviejo-Bermejo, S. Gutiérrez-Enríquez, A. Llop-Guevara, Y.H. Ibrahim, A. Gris-Oliver, S. Bonache, B. Morancho, A. Bruna, O.M. Rueda, Z. Lai, U.M. Polanska, G.N. Jones, P. Kristel, L. de Bustos, M. Guzman, O. Rodríguez, J. Grueso, G. Montalban, G. Caratú, F. Mancuso, R. Fasani, J. Jiménez, W.J. Howat, B. Dougherty, A. Vivancos, P. Nuciforo, X. Serres-Créixams, I.T. Rubio, A. Oaknin, E. Cadogan, J.C. Barrett, C. Caldas, J. Baselga, C. Saura, J. Cortés, J. Arribas, J. Jonkers, O. Díez, M.J. O’Connor, J. Balmaña, V. Serra
Journal: Annals of Oncology (2018)

BackgroundBRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity.Patients and methodsWe investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi.ResultsRAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor.ConclusionDetection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.
A pilot study of vinorelbine safety and pharmacokinetics (PKs) in patients (pts) with varying degrees of liver dysfunction (LD).
Authors: Jun Gong, May Thet Cho, Rohan Gupta, Timothy W. Synold, Paul Henry Frankel, Christopher Ruel, Marwan Fakih, Vincent M. Chung, Dean Lim, Joseph Chao
Journal: Journal of Clinical Oncology (2018)

432 Background: Prospective data to support dosing guidelines for intravenous (IV) vinorelbine in pts with LD are limited. One study recommends standard 30 mg/m 2 weekly for total bilirubin ≤2 mg/dL and a 50% dose reduction for bilirubin &gt; 2 mg/dL. Another study recommends no dose modifications for bilirubin up to 3X the upper limit of normal (ULN). This phase I study describes the safety and PKs of vinorelbine in pts with varying degrees of hepatic impairment. Methods: Pts with treatment-refractory solid tumors received weekly IV 30 mg/m 2 vinorelbine for normal liver function, 20 mg/m 2 for mild LD defined as bilirubin &lt; 1.5 mg/dL but aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 1.5-2.5X ULN or alkaline phosphatase (ALK) 1.5-3X ULN, 15 mg/m 2 or 30 mg/m 2 for moderate LD defined as bilirubin 1.5-3.0 mg/dL and/or AST/ALT &gt; 2.5 or ALK &gt; 3X ULN, and 7.5 mg/m 2 or 20 mg/m 2 for severe LD defined as bilirubin &gt; 3.0 mg/dL. Vinorelbine PKs were evaluated to describe its relationship with liver function. Results: 47 patients were enrolled (61.7% gastrointestinal and hepatobiliary cancers) and a total of 248 treatment-related adverse events (AEs) occurred. All-grade myelosuppression was the most common AE overall (41.1%). Out of 71 grade ≥3 AEs, 17 (23.9%) were grade 4 in severity with the majority (15/17) being myelosuppression. Rates of grade 4 hematologic AEs in the normal liver function and the 7.5 mg/m 2 severe LD group were low ( &lt; 10%). 4/17 grade 4 hematologic AEs were observed in the mild LD group while the remainder and majority occurred in the moderate-severe LD groups. Vinorelbine PKs were not correlated with the degree of LD, however free drug levels or levels of the active metabolite 4-O-deacetylvinorelbine were not measured. Conclusions: Weekly vinorelbine at 30 mg/m 2 and 7.5 mg/m 2 appears safe with normal liver function and severe LD, respectively. High rates of grade 4 myelosuppression with 15-30 mg/m 2 vinorelbine in moderate-severe LD raise concerns for its safety in this population. Vinorelbine PKs are not affected by LD. However, it is possible that levels of the active metabolite could be higher in pts with LD if its elimination is impacted by LD to a greater extent than the parent drug. Clinical trial information: NCT00540982.
New Stent for Small Vessels
Authors: Rebecca Voelker
Journal: JAMA (2018)

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
Next-generation expression analysis (NanoString) to develop prognostic and predictive gene signatures for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.
Authors: Annalisa Milano, Marina Borro, Emanuela Pilozzi, Andrea Montori, Marco Mazzotta, Laura Lorenzon, Donatella Caivano, Giuditta Chiloiro, Andrea Botticelli, Federica Mazzuca, Mattia Falchetto Osti, Maurizio Simmaco, Luigi Ruco, Vincenzo Valentini, Paolo Marchetti
Journal: Journal of Clinical Oncology (2018)

700 Background: The standard of care for locally advanced rectal cancer (RC) is neoadjuvant chemoradiotherapy (CRT) with 5FU aimed to tumor downstaging prior to radical resection but there is a wide spectrum of responses to it, from none to complete. The aim of this project is to validate top candidate genes previously identified by microarray studies as prognostic and predictive classifiers of locally advanced RC, using the NanoString nCounter Platform. Methods: Two cohorts of RC patients were identified according to tumor regression grade (TRG) of AJCC Staging Manual (7th) system: 1) good prognosis: patients that after neoadjuvant CRT obtained TRG0 (complete response); 2) poor prognosis: patients with TRG1 (moderate response), patients with TRG2 (minimum response rate) and patients with TRG3 (poor response). Pre-treatment biopsies tissues from ten TRG0 patients (ID TRG0bio) and thirteen TRG1-3 patients (ID TRG1-3bio) were macro-dissected from FFPE sections, RNA isolated and used for expression profiling of a 305 genes custom code set consisting of 12 normalizer genes, 101 prognostic genes (markers of stemness, invasiveness, proliferation, drug-resistance), 192 predictive genes (involved in response to 5-FU, to radiation therapy and in the response to CRT). All samples were normalized using the geometric mean of the housekeeper genes. P-values were calculated by student’s t-test and was consider significance if was less than 0.05. Gene-specific RNA expression profiles were compared using Spearman's correlation. The heat map was generated using MeV 4.9.0. Results: When we compared TRG0bio to TRG1-3bio tissues, among the 305 genes assayed, changes in expression levels of 18 genes (SSB, GAPDH, TXNDC9, DUT, PKM, STAT1,SLC28A3, DAG1, TYMS, FERMT1, ARNT,SLC6A6, SMAD3, SCRN1, POU5F1, GNG4, PDRG1, ATP5E) were statistically significant. Conclusions: Results suggest that TRG0 RC is characterized by distinct molecular events compared TRG1-3 disease. Next steps will be: to amplify sample size, to understand signaling pathways of top differentially expressed genes and to validate prospectively our gene signature.
Ventilatory practices in extremely low birth weight infants in a level III neonatal intensive care unit
Authors: S. Abreu-Pereira, R. Pinto-Lopes, F. Flôr-de-Lima, G. Rocha, H. Guimarães
Journal: Pulmonology (2018)

Although non-invasive forms of ventilation have recently spread in neonatology, invasive ventilation still plays a key role in the support of extremely low birth weight (ELBW) infants. The purpose of this study was to assess changes in neonatal ventilation practices for ELBW infants and compare outcomes between two epochs (2005–2009 vs. 2010–2015) to analyze progression stemming from the implementation of newer clinical guidelines. We conducted a retrospective study with data collection from all ELBW infants born between 2005 and 2015 in our center through their individual clinical records. The main outcome was the prevalence of bronchopulmonary dysplasia (BPD) in both periods. Assessment of other morbidities and survival were secondary outcomes. A hundred and thirty-one infants were included; median gestational age of 27 weeks (23–33) and mean birth weight of 794.58 g (±149.37). Invasive mechanical ventilation (IMV) was performed on 103 (78.6%) infants. Non-significant increases in the use of non-invasive mechanical ventilation (NIMV) were observed between epochs both exclusively and following IMV. In conventional ventilation there were significant variations between epochs, namely a decrease in synchronized intermittent mandatory ventilation (SIMV) and a major growth in the addition of volume guarantee (VG). Significant decreases in BPD (from 50.9% to 32.0%) and cystic periventricular leukomalacia (cPVL) (from 27.5% to 10.7%) were observed between epochs, with no major changes in other morbidities and survival. Changes in our neonatal intensive care unit's ventilatory practices according to the most up-to-date guidelines, have led to a decrease in BPD and cPVL, over an 11-year period.
Further Questions Regarding Electrocardiogram Prior to Liver Transplant—Reply
Authors: Laszlo Littmann, Jennifer K. Potter, Jessica R. Hoglund
Journal: JAMA Internal Medicine (2018)

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 Internal Medicine 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 Internal Medicine journal
Modeling the diffusion of D-2-hydroxyglutarate from IDH1 mutant gliomas in the central nervous system
Authors: Andreas Linninger, Grant A Hartung, Benjamin P Liu, Snezana Mirkov, Kevin Tangen, Rimas V Lukas, Dusten Unruh, C David James, Jann N Sarkaria, Craig Horbinski
Journal: Neuro-Oncology (2018)

Among diffusely infiltrative gliomas in adults, 20%–30% contain a point mutation in isocitrate dehydrogenase 1 (IDH1mut), which increases production of D-2-hydroxyglutarate (D2HG). This is so efficient that D2HG often reaches 30 mM within IDH1mut gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1mut glioma patients, the exposure of nonneoplastic cells within and surrounding an IDH1mut glioma to D2HG is unknown and difficult to measure directly. Conditioned medium from patient-derived wild type IDH1 (IDH1wt) and IDH1mut glioma cells was analyzed for D2HG by liquid chromatography–mass spectrometry (LC-MS). Mathematical models of D2HG release and diffusion around an IDH1mut glioma were independently generated based on fluid dynamics within the brain and on previously reported intratumoral and cerebrospinal D2HG concentrations. LC-MS analysis indicates that patient-derived IDH1mut glioma cells release 3.7–97.0 pg D2HG per cell per week. Extrapolating this to an average-sized tumor (30 mL glioma volume and 1 × 108 cells/mL tumor), the rate of D2HG release by an IDH1mut glioma (SA) is estimated at 3.2–83.0 × 10−12 mol/mL/sec. Mathematical models estimate an SA of 2.9–12.9 × 10−12 mol/mL/sec, within the range of the in vitro LC-MS data. In even the most conservative of these models, the extracellular concentration of D2HG exceeds 3 mM within a 2 cm radius from the center of an IDH1mut glioma. The microenvironment of an IDH1mut glioma is likely being exposed to high concentrations of D2HG, in the low millimolar range. This has implications for understanding how D2HG affects nonneoplastic cells in an IDH1mut glioma.
State Medicaid Coverage for Tobacco Cessation Treatments and Barriers to Accessing Treatments — United States, 2015–2017
Authors: Anne DiGiulio, Zach Jump, Annie Yu, Stephen Babb, Anna Schecter, Kisha-Ann S. Williams, Debbie Yembra, Brian S. Armour
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Cigarette smoking prevalence among Medicaid enrollees (25.3%) is approximately twice that of privately insured Americans (11.8%), placing Medicaid enrollees at increased risk for smoking-related disease and death (1). Medicaid spends approximately $39 billion annually on treating smoking-related diseases (2). Individual, group, and telephone counseling and seven Food and Drug Administration (FDA)-approved medications* are effective in helping tobacco users quit (3). Although state Medicaid coverage of tobacco cessation treatments improved during 2014-2015, coverage was still limited in most states (4). To monitor recent changes in state Medicaid cessation coverage for traditional (i.e., nonexpansion) Medicaid enrollees, the American Lung Association collected data on coverage of a total of nine cessation treatments: individual counseling, group counseling, and seven FDA-approved cessation medications† in state Medicaid programs during July 1, 2015-June 30, 2017. The American Lung Association also collected data on seven barriers to accessing covered treatments, such as copayments and prior authorization. As of June 30, 2017, 10 states covered all nine of these treatments for all enrollees, up from nine states as of June 30, 2015; of these 10 states, Missouri was the only state to have removed all seven barriers to accessing these cessation treatments. State Medicaid programs that cover all evidence-based cessation treatments, remove barriers to accessing these treatments, and promote covered treatments to Medicaid enrollees and health care providers would be expected to reduce smoking, smoking-related disease, and smoking-attributable federal and state health care expenditures (5-7).
Complementary Tuning of Na+ and K+ Channel Gating Underlies Fast and Energy-Efficient Action Potentials in GABAergic Interneuron Axons
Authors: Hua Hu, Fabian C. Roth, David Vandael, Peter Jonas
Journal: Neuron (2018)

Fast-spiking, parvalbumin-expressing GABAergic interneurons (PV+-BCs) express a complex machinery of rapid signaling mechanisms, including specialized voltage-gated ion channels to generate brief action potentials (APs). However, short APs are associated with overlapping Na+ and K+ fluxes and are therefore energetically expensive. How the potentially vicious combination of high AP frequency and inefficient spike generation can be reconciled with limited energy supply is presently unclear. To address this question, we performed direct recordings from the PV+-BC axon, the subcellular structure where active conductances for AP initiation and propagation are located. Surprisingly, the energy required for the AP was, on average, only ∼1.6 times the theoretical minimum. High energy efficiency emerged from the combination of fast inactivation of Na+ channels and delayed activation of Kv3-type K+ channels, which minimized ion flux overlap during APs. Thus, the complementary tuning of axonal Na+ and K+ channel gating optimizes both fast signaling properties and metabolic efficiency.
Shamanism and the social nature of cumulative culture
Authors: Mark Nielsen, Ronald Fischer, Yoshihisa Kashima
Journal: Behavioral and Brain Sciences (2018)

Our species-unique capacity for cumulative culture relies on a complex interplay between social and cognitive motivations. Attempting to understand much of human behaviour will be incomplete if one of these motivations is the focus at the expense of the other. Anchored in gene-culture co-evolution theory, we stake a claim for the importance of social drivers in determining why shamans exist.
MiR-146a-5p correlates with clinical efficacy in patients with psoriasis treated with the tumour necrosis factor-alpha inhibitor adalimumab
Authors: E. Mensà, R. Recchioni, F. Marcheselli, K. Giuliodori, V. Consales, E. Molinelli, F. Prattichizzo, M. R. Rippo, A. Campanati, A.D. Procopio, F. Olivieri, A.M. Offidani
Journal: British Journal of Dermatology (2018)
Policy Approaches for Regulating Alcohol Marketing in a Global Context: A Public Health Perspective
Authors: Marissa B. Esser, David H. Jernigan
Journal: Annual Review of Public Health (2018)

Alcohol consumption is responsible for 3.3 million deaths globally or nearly 6% of all deaths. Alcohol use contributes to both communicable and noncommunicable diseases, as well as violence and injuries. The purpose of this review is to discuss, in the context of the expansion of transnational alcohol corporations and harms associated with alcohol use, policy options for regulating exposure to alcohol marketing. We first provide an overview of the public health problem of harmful alcohol consumption and describe the association between exposure to alcohol marketing and alcohol consumption. We then discuss the growth and concentration of global alcohol corporations and their marketing practices in low- and middle-income countries, as well as in higher-income societies. We review the use and effectiveness of various approaches for regulating alcohol marketing in various countries before discussing challenges and opportunities to protect public health.
Inflammatory demyelinating polyneuropathy versus leptomeningeal disease following Ipilimumab
Authors: Lorraine Cafuir, David Lawson, Nilesh Desai, Vita Kesner, Alfredo Voloschin
Journal: Journal for ImmunoTherapy of Cancer (2018)

Ipilimumab is an FDA-approved anti-CTLA-4 monoclonal antibody used in treatment of metastatic melanoma. We present an unusual neurological complication of Ipilimumab therapy and the diagnostic dilemma it caused.A 42 year old male with Stage IV metastatic melanoma developed lower extremity weakness and sensory neuropathy following three doses of Ipilimumab. MRI of the lumbar spine was initially interpreted as diffuse leptomeningeal disease, and patient began Dexamethasone and radiation with improvement in symptoms. However, subsequent completion imaging revealed smooth nerve root involvement with sparing of the spinal cord, findings more compatible with inflammatory demyelinating polyneuropathy. The absence of malignant cells in the cerebrospinal fluid (CSF) and nerve conduction study (NCS) showing lumbar polyradiculoneuropathy with axonal involvement and demyelinating features supported the diagnosis of inflammatory demyelinating polyneuropathy. Later in the course of his disease, the patient developed frank leptomeningeal melanoma.Ipilimumab immune-related toxicity presented as inflammatory demyelinating polyneuropathy, which was difficult to distinguish from leptomeningeal disease, a common complication of melanoma.
Improvement in 5-Year Survival Rates for the Most Common Types of Cancer, 1975-2012
Authors: Jennifer A Doherty, Allan Jensen, Linda E Kelemen, Celeste L Pearce, Elizabeth Poole, Joellen M Schildkraut, Kathryn L Terry, Shelley S Tworoger, Penelope M Webb, Nicolas Wentzensen
Journal: JNCI Journal of the National Cancer Institute (2017)

With recent ovarian cancer screening studies showing no clinically significant mortality benefit, preventing this disease, identifying high-risk populations, and extending survival remain priorities. However, several challenges are impeding progress in ovarian cancer research. With most studies capturing exposure information from 10 or more years ago, evaluation of how changing patterns of exposures, such as new oral contraceptive formulations and increased intrauterine device use, might influence ovarian cancer risk and survival is difficult. Risk factors for ovarian cancer should be evaluated in the context of tumor histotypes, which have unique molecular features and cells of origin; this is a task that requires large collaborative studies to achieve meaningful sample sizes. Importantly, identification of novel modifiable risk factors, in addition to those currently known to reduce risk (eg, childbearing, tubal ligation, oral contraceptive use), is needed; this is not feasibly implemented at a population level. In this Commentary, we describe important gaps in knowledge and propose new approaches to advance epidemiologic research to improve ovarian cancer prevention and survival, including updated classification of tumors, collection of data on changing and novel exposures, longer follow-up on existing studies, evaluation of diverse populations, development of better risk prediction models, and collaborating prospectively with consortia to develop protocols for new studies that will allow seamless integration for future pooled analyses.