tbuckley/cabot-search huggingface dataset:
Suppression of Melatonin Secretion in Totally Visually Blind People by Ocular Exposure to White Light
Authors: Joseph T. Hull, Charles A. Czeisler, Steven W. Lockley
Journal: Ophthalmology (2018)

Although most totally visually blind individuals exhibit nonentrained circadian rhythms due to an inability of light to entrain the circadian pacemaker, a small proportion retain photic circadian entrainment, melatonin suppression, and other nonimage-forming responses to light. It is thought that these responses to light persist because of the survival of melanospin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), which project primarily to the circadian pacemaker and are functionally distinct from the rod and cone photoreceptors that mediate vision. We aimed to assess the integrity of nonimage-forming photoreception in totally visually blind patients with a range of ocular disorders.Within-subject, dark-controlled design.A total of 18 totally visually blind individuals (7 females; mean age ± standard deviation = 49.8±11.0 years) with various causes of blindness, including 3 bilaterally enucleated controls.Melatonin concentrations were compared during exposure to a 6.5-hour bright white light (∼7000 lux) with melatonin concentrations measured 24 hours earlier at the corresponding clock times under dim-light (4 lux) conditions.Area under the curve (AUC) for melatonin concentration.Melatonin concentrations were significantly suppressed (defined as ≥33% suppression) during the bright-light condition compared with the dim-light condition in 5 of 15 participants with eyes (retinitis pigmentosa, n = 2; retinopathy of prematurity [ROP], n = 2; bilateral retinal detachments, n = 1). Melatonin concentrations remained unchanged in response to light in the remaining 10 participants with eyes (ROP, n = 3; optic neuritis/neuropathy, n = 2; retinopathy unknown, n = 2; congenital glaucoma, n = 1; congenital rubella syndrome, n = 1; measles retinopathy, n = 1) and in all 3 bilaterally enucleated participants.These data confirm that light-induced suppression of melatonin remains functionally intact in a minority of totally visually blind individuals with eyes. None of the bilaterally enucleated individuals or those with phthisis bulbi was responsive to light; of the remainder, half were responsive to light. Although inner retinal damage is associated with a high likelihood that nonimage-forming photoreception is absent, the impact of outer retinal damage is more ambiguous, and therefore the assessment of the presence, attenuation, or absence of nonimage-forming light responses in totally blind patients requires careful individual confirmation and cannot simply be assumed from the type of blindness.
An open-label, phase II study of intravenous anetumab ravtansine, an anti-mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer.
Authors: Saurin Chokshi, Howard S. Hochster
Journal: Journal of Clinical Oncology (2018)

TPS540 Background: Advanced pancreatic cancer remains one of the deadliest malignancies with median OS of 11 months with the most aggressive therapy regimen. Hence, a need exists for more effective, durable, and targeted therapies. Mesothelin is a membrane associated antigen overexpressed in most pancreatic adenocarcinomas. The biological function of mesothelin remains unknown but it is an internalizing antigen. Given its limited expression in normal tissue and high expression in malignant cells, mesothelin is an excellent target for antibody directed cytotoxic drug delivery. Anetumab ravtansine (AR) is an ADC consisting of a fully human IgG1 antibody directed at mesothelin and conjugated to tubulin-binding toxophore, DM4 (maytansine derivative). Preclinical efforts have shown antiproliferative activity in mesothelin positive cancer cell lines and 75% tumor regression in pancreatic xenograft models (Golfier S, et al. Mol Cancer Ther 13(6):1537-48, 2014). Methods: This is a multicenter, non-randomized, Phase II study evaluating the efficacy of AR in pretreated mesothelin-expressing advanced pancreatic cancer. The study utilizes minimax, Simon 2-stage design testing 5% null hypothesis versus 21% alternative. If no response among the first 20, trial will terminate early. If at least one response among the first 20, trial will accrue additional 10 patients for maximum of 30. Four or more responses out of 30 will reject the null hypothesis. Significance level (alpha) is 0.1 and power is 90%. Probability of stopping early is 36% if the response rate is 5% or lower. Patients will receive AR infusion at 6.5 mg/kg on Day 1 of 21-day cycle. Primary objective: response rate per RECIST 1.1. Secondary objectives: time to progression; toxicity. Eligibility: measurable disease per RECIST 1.1; no more than two prior chemotherapy regimens; 30% of cells with 2+/3+ mesothelin staining per IHC; no history of keratitis or corneal disease. Correlative studies: serum soluble mesothelin levels and apoptotic factors (CK18, caspase-cleaved fragments) at baseline and throughout the study to predict treatment response/outcome. Enrollment is on-going. Clinical trial information: NCT03023722.
Immune related adverse events and their treatment in melanoma patients receiving ipilimumab.
Authors: Gerardo Cabanillas
Journal: Journal of Clinical Oncology (2017)

e14598 Background: Ipilimumab is an immune checkpoint inhibitor approved for the treatment of melanoma. Immune-related adverse events (irAEs) may occur as adverse effects. Most reports on irAEs are from clinical trials, which may not reflect community clinical practice and outcomes. We used a health insurance based database to identify irAEs and their treatment among patients with melanoma that received Ipilimumab, as part of regular care. Methods: We identified all melanoma patients aged 18 and older who received Ipilimumab from the Truven Health Analytics Marketscan database between 2011 and 2014. Patients had continuous insurance coverage from the period of six months prior to Ipilimumab and three months after. We further assessed the treatment for each irAEs. IrAEs were defined base on claims with one or more 228 ICD-9 codes; irAEs had to occur within a 6-month window before treatment. We used summary statistics such as means and standard deviations for continuous variables, frequencies and percentages for categorical variables. Results: The cohort included 1225 patients. Median age was 60 years, 62% were male; 343 (35.44%) patients had one or more irAEs, and 48.6% (211) were treated at least once. Young age and female gender were associated with a higher likelihood of having an irAEs. Endocrinopathies and gastrointestinal diseases were the most common irAEs. The most frequent irAEs was colitis in 27% of patients, followed by hypothyroidism 26%. Six different drugs were used to treat irAEs, and corticosteroids being the most frequently prescribed. Few patients with colitis received Infliximab 14%; and cyclosporine was prescribed in one patient with pancreatitis Conclusions: One third of the patients with melanoma treated with Ipilimumab in the community developed irAEs. Corticosteroids were the most frequent drugs used to treat irAEs. Our results show that toxicity remains high with the use of this agent in clinical practice.
Src activation decouples cell division orientation from cell geometry in mammalian cells
Authors: Xiaoyan Sun, Hongsheng Qi, Xiuzhen Zhang, Li Li, Jiaping Zhang, Qunli Zeng, George S. Laszlo, Bo Wei, Tianhong Li, Jianxin Jiang, Alex Mogilner, Xiaobing Fu, Min Zhao
Journal: Biomaterials (2018)
Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids
Authors: Clara Vilches, Emilia Boiadjieva-Knöpfel, Susanna Bodoy, Simone Camargo, Miguel López de Heredia, Esther Prat, Aida Ormazabal, Rafael Artuch, Antonio Zorzano, François Verrey, Virginia Nunes, Manuel Palacín
Journal: Journal of the American Society of Nephrology (2018)

Background Reabsorption of amino acids (AAs) across the renal proximal tubule is crucial for intracellular and whole organism AA homeostasis. Although the luminal transport step is well understood, with several diseases caused by dysregulation of this process, the basolateral transport step is not understood. In humans, only cationic aminoaciduria due to malfunction of the basolateral transporter y + LAT1/CD98hc (SLC7A7/SLC3A2), which mediates the export of cationic AAs, has been described. Thus, the physiologic roles of basolateral transporters of neutral AAs, such as the antiporter LAT2/CD98hc (SLC7A8/SLC3A2), a heterodimer that exports most neutral AAs, and the uniporter TAT1 (SLC16A10), which exports only aromatic AAs, remain unclear. Functional cooperation between TAT1 and LAT2/CD98hc has been suggested by in vitro studies but has not been evaluated in vivo . Methods To study the functional relationship of TAT1 and LAT2/CD98hc in vivo , we generated a double-knockout mouse model lacking TAT1 and LAT2, the catalytic subunit of LAT2/CD98hc (dKO LAT2-TAT1 mice). Results Compared with mice lacking only TAT1 or LAT2, dKO LAT2-TAT1 mice lost larger amounts of aromatic and other neutral AAs in their urine due to a tubular reabsorption defect. Notably, dKO mice also displayed decreased tubular reabsorption of cationic AAs and increased expression of y + LAT1/CD98hc. Conclusions The LAT2/CD98hc and TAT1 transporters functionally cooperate in vivo , and y + LAT1/CD98hc may compensate for the loss of LAT2/CD98hc and TAT1, functioning as a neutral AA exporter at the expense of some urinary loss of cationic AAs. Cooperative and compensatory mechanisms of AA transporters may explain the lack of basolateral neutral aminoacidurias in humans.
Abstract P316: Multiple Vulnerabilities to Health Disparities and Incident Coronary Heart Disease in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Monika M Safford, Laura Pinheiro, Madeline Sterling, Joshua Richman, Paul Muntner, Raegan Durant, John Booth, Evgeniya Reshetnyak
Journal: Circulation (2018)

Social determinants contribute to disparities in incident CHD but it is not known if they have an additive effect. We hypothesized that having more socially determined vulnerabilities to health disparities is associated with increased risk of incident CHD in the REGARDS study, a large biracial prospective cohort with physiological and survey measures. Experts adjudicated incident fatal and nonfatal CHD over 10 years of follow-up. Vulnerabilities included black race, low education, low income, and Southeastern US residence. The risks for CHD outcomes associated with 1, 2, and 3+ vs 0 vulnerabilities were calculated with Cox proportional hazards models adjusted for medical conditions, functional status, health behaviors, and physiologic variables. Of the 19,645 participants free of CHD at baseline (mean age 64 years, 57% women), 16% had 0 vulnerabilities, 36% had 1, 29% had 2, and 18% had 3+. Increasing numbers of vulnerabilities were associated with higher incidence (Figure) and risk of CHD that attenuated somewhat after multivariable adjustment (Table). These findings may provide a method of risk stratification useful for population health management.
Annals Story Slam - Just Another Day in the Emergency Department
Authors: Judd Hollander
Journal: Annals of Internal Medicine (2018)

Web Exclusives3 April 2018Annals Story Slam - Just Another Day in the Emergency DepartmentFREEJudd Hollander, MDJudd Hollander, MDThomas Jefferson University, Philadelphia, Pennsylvania (J.H.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W18-0004 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Just Another Day in the Emergency Department "Just Another Day in the Emergency Department," by Dr. Judd Hollander (Duration 5:10)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Thomas Jefferson University, Philadelphia, Pennsylvania (J.H.)Corresponding Author: Judd Hollander, MD; e-mail, judd.[email protected]edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 3 April 2018Volume 168, Issue 7Page: SS1 ePublished: 3 April 2018 Issue Published: 3 April 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.Loading ...
Prognostic significance of RASSF1A, CST6 and KLK10 methylation status in early breast cancer.
Authors: Magdalini Kioulafa, Loukas Kaklamanis, Stathis Stathopoulos, Georgia Sotiropoulou, Vassilis Georgoulias, Evi Lianidou
Journal: Cancer Research (2008)

2627    Introduction . Epigenetic silencing of tumor suppressor genes during mammary tumorigenesis is an aberrant event that can occur before the development of invasive breast cancer. The aim of our study was to evaluate the prognostic significance of RAS association domain family 1A ( RASSF1A) , cystatin M ( CST6)  and kallikrein 10 ( KLK10)  methylation status in early breast cancer.   Patients and methods.  Paraffin-embedded breast carcinomas were collected from 93 patients diagnosed with early stage breast cancer (median follow-up 6 years). A representative block of paraffin-embedded tumor tissues containing >80% tumor cells was used for DNA extraction. The extracted DNAs were subjected to a sodium bisulfite conversion reaction. Nested methylation specific polymerase chain reaction (MSP) was used to analyze methylated alleles of these three genes.   Results.   RASSF1A  and   CST6  promoters were found methylated in 66/93 (71.0%) and  KLK10  exon 3 in 65/93 (69.9%) of breast tumor tissues. During the follow up period, 22 patients relapsed and 11 out of them died from disease relapse.  RASSF1A, CST6  and  KLK10  methylation was detected in all patients (100%) that died and in 21/22 (95.4%), 19/22 (86.4%) and 19/22 (86.4%) of patients that relapsed, respectively. Kaplan Meier analysis showed that the detection of RASSF1A promoter methylation did not have prognostic implication, since it was not associated with decreased disease free interval (DFI) (p=0.076). On the contrary,  CST6  promoter  methylation (p=0.008) and  KLK10  exon 3 methylation (p=0.050) did have prognostic implication for early breast cancer patients, since it was associated with decreased DFI. The Kaplan Meier estimates of the overall survival (OS) rates for patients with methylated  RASSF1A  promoter were significantly different (p=0.036) in favor of patients with non-methylated  RASSF1A  promoter. Similarly, the Kaplan Meier estimates of the overall survival (OS) rates for patients with methylated  CST6  promoter (p=0.043) and for patients with methylated  KLK10  exon 3 (p=0.028) were significantly different in favor of patients with non-methylated  CST6  promoter and non-methylated  KLK10  exon3, respectively.   Conclusions.  CST6  and  RASSF1A  promoter and  KLK10  exon 3 methylation are frequent and early events in the process of mammary tumorigenesis. We show, for the first time, that they can provide important prognostic information in early stage breast cancer patients. The methylation status of these genes should be further evaluated as a promising prognostic biomarker in a larger number of patients, in respect to their clinical outcome and overall survival.
Agency is realized by subpersonal mechanisms too
Authors: Neil Levy
Journal: Behavioral and Brain Sciences (2018)

Abstract John Doris argues that, when behaviors are caused by processes that we would not endorse, our agency is defeated. I argue that this test for defeaters is inappropriate. What matters is not what we would but what we should endorse. The subpersonal mechanisms he identifies as defeaters enable us to track and respond to reasons. They realize agency, rather than defeating it.
Tumour necrosis factor: out of my heart!
Authors: Lars Vereecke, Dirk Elewaut
Journal: Annals of the Rheumatic Diseases (2018)

Increasing evidence points to cardiovascular comorbidities in patients with rheumatic diseases, particularly in rheumatoid arthritis (RA) and spondyloarthritis (SpA).1 Ischaemic heart disease, valvular involvement including insufficiency and stenosis and arrhythmias can be observed as typical manifestations. They are a major cause of increased morbidity and mortality. While the epidemiological evidence is overwhelming, the underlying mechanisms why chronic inflammatory diseases affect the cardiovascular system are only partially understood. Treatment with anti-tumour necrosis factor (TNF) biologics ameliorates the risk for these comorbidities.1 However, insights into the underlying mechanisms and information on responsible cell-type linking arthritis and cardiac disease are yet unclear.

In this issue, Ntari et al describe spontaneous cardiac pathology in a preclinical model of arthritis driven by chronic human TNF expression. They show that TNF signalling in mesenchymal cells is both necessary and sufficient for the development of heart valve pathology in the presented mouse model.2 

Human TNF transgenic mice which develop spontaneous arthritis (Tg197 line)3 were backcrossed to colVI-Cre TNFR1fl/fl versus TNFR1cneo/cneo mutant mice. This approach permits selective mesenchymal-specific genetic ablation versus reactivation of TNF/TNF-receptor 1 (TNFR1), including valve interstitial cells (VICs) of the heart. The same group previously showed that TNF signalling in mesenchymal cells is sufficient to drive chronic gut and joint pathology in an alternative TNF-overexpressing mouse model.4 In humans, synovial fibroblasts in the joints and intestinal mesenchymal cells in the gut regulate pathological mechanisms during arthritis5 and inflammatory bowel disease (IBD),6 which indicates …
Management of Metastatic Melanoma in 2018
Authors: Howard L. Kaufman, Kim Margolin, Ryan Sullivan
Journal: JAMA Oncology (2018)

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Response to: ‘ “Evaluation of the impact of concomitant fibromyalgia on TNF alpha blockers’ effectiveness in axial spondyloarthritis: results of a prospective, multicentre study” by Moltó<i>et al</i>: still a long way to go in the assessment of patients with spondyloarthritis and concomitant fibromyalgia?’ by Altobelli<i>et al</i>
Authors: Anna Moltó, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2018)

We would like to thank Altobelli et al 1 for the interest they have expressed in our recently published article ‘Evaluation of the impact of concomitant fibromyalgia on tumor necrosis factor (TNF) alpha blockers’ effectiveness in axial spondyloarthritis (axSpA) : results of a prospective multicentre study’2 and the ARD editorial team to give us the opportunity to address their comments in this present letter.

First, we would like to emphasise that the purpose of this study was not to address the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs,) antidepressants or third-ladder analgesics, but to evaluate the effectiveness of TNF alpha blockers in an axSpA population and the potential impact of a concomitant fibromyalgia on such …
Sustained release of anti-PD-1 peptide for perdurable immunotherapy together with photothermal ablation against primary and distant tumors
Authors: Lihua Luo, Jie Yang, Chunqi Zhu, Mengshi Jiang, Xiaomeng Guo, Wei Li, Xiaoyi Yin, Hang Yin, Bin Qin, Xiaoling Yuan, Qingpo Li, Yongzhong Du, Jian You
Journal: Journal of Controlled Release (2018)
Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): Subanalyses of CheckMate-040.
Authors: Anthony B. El-Khoueiry, Ignacio Melero, Thomas Cheung Yau, Todd S. Crocenzi, Masatoshi Kudo, Chiun Hsu, SuPin Choo, Jorg Trojan, Theodore Welling, Tim Meyer, Yoon-Koo Kang, Winnie Yeo, Akhil Chopra, Huanyu Zhao, Adyb Baakili, Christine Marie Dela Cruz, Bruno Sangro
Journal: Journal of Clinical Oncology (2018)

475 Background: NIVO (anti–PD-1 mAb) has demonstrated durable responses, long-term OS, and manageable safety in pts with aHCC in CheckMate-040 (El-Khoueiry, Sangro et al. 2017). With anti–PD-1 therapies, meaningful OS benefit may be seen even in pts who do not achieve a conventional response by RECIST v1.1. Here we report nonconventional benefit with NIVO and effect of antitumor activity on OS in sorafenib-experienced (sor-exp) pts with aHCC, including pts with a best overall response (BOR) of progressive disease (PD). Methods: Sor-exp pts received NIVO (3 mg/kg Q2W) in a phase 1/2 dose-expansion cohort regardless of PD-L1 status. Impact of antitumor activity on median OS (mOS) was determined by calculating change in target lesion size from baseline using quartile analyses (25% cutoff). Nonconventional benefit was analyzed by reductions or stabilizations in target lesion size after progression in pts with a BOR of PD. Results: Sor-exp pts (N=145) had a median follow-up of 14.9 mo. The ORR (RECIST v1.1) was 14% and the DCR was 56%. Median duration of stable disease (SD) was 4.3 mo and the DCR with SD ≥6 mo was 27%. Overall, mOS was 15.6 mo. Degree of OS benefit corresponded with antitumor activity in pts with decreases (≥25%, mOS not reached; 0–25%, mOS 17.7 mo) or increases (0–25%, mOS 11.7 mo; ≥25%, mOS 8.9 mo) in target lesion size (Table). In non-responders (n=124; including pts with BOR of SD or PD), mOS was 13.4 mo. Nonconventional benefit was observed in 11 of 56 pts (20%) with a BOR of PD. Updated clinical data with additional follow-up will be presented. Conclusions: In sor-exp pts, mOS with NIVO corresponded to degree of antitumor activity, with OS benefit not limited to RECIST v1.1 responders. Improved OS in non-responders is likely due to nonconventional benefit, supported by disease reduction or stabilization even in pts with a BOR of PD. Clinical trial information: NCT01658878. [Table: see text]
Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain
Authors: Marie T. Fallon, Andrew Wilcock, Caroline A. Kelly, James Paul, Liz-Anne Lewsley, John Norrie, Barry J. A. Laird
Journal: JAMA Oncology (2018)

Ketamine hydrochloride is used as an adjuvant treatment for cancer-related neuropathic pain, but evidence of its effectiveness is limited.1 Findings of a large trial investigating the use of ketamine for general cancer pain were negative, but the population studied did not specifically have neuropathic pain. A randomized trial of oral ketamine for cancer-related neuropathic pain has been called for, and the present trial addresses that need.