tbuckley/cabot-search huggingface dataset:
Modulating lncRNA NKILA in tumor-reactive T cells to enhance their trafficking to breast cancer by inhibition of FasL-induced T-cell apoptosis.
Authors: Di Huang, Shicheng Su, Erwei Song
Journal: Journal of Clinical Oncology (2017)

143 Background: Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the autologous tumor-reactive lymphocytes with direct anticancer activity. In addition to the effective application of ACT for cancer treatment to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors, many of the ACT therapy has failed because of the trafficking barrier of T cells. Methods: In vitro, we established tumor-reactive CTL by vaccination with autologous DCs pulsed with MUC1-derived peptides. Moreover, tumor-reactive T cells were transferred to the immunocompromised mice inoculated with autologous patient derived breast cancer xenografts (PDX). Results: In our study, we found that during the induction of tumor-reactive T cells, cytotoxic T lymphocytes (CTL) may undergo massive expansion and have the ability of specific lysis to tumor cells upon appropriate antigenic stimulation via NF-κB pathway activation. However, hyperactive tumor-specific lymphocytes were hypersensitivity to apoptosis signals in tumor milieu, such as Fas ligand. In this research, we showed that NKILA, an NF-κB interacting lncRNA, is up-regulated at the later phase of CTL activation. The up-regulated NKILA suppresses NF-κB activity and sensitizes T cells to apoptosis. In vivo, NKILA knockdown in tumor-reactive T cells upon transferring to the immunocompromised mice inoculated with autologous PDX enhances CTL in xenografts, and thus effectively inhibits tumor growth. Conclusions: Collectively, our findings suggested that NKILA upregulation is responsible for the apoptosis of tumor-responsive CTLs and targeting the lncRNA may provide a novel strategy to enhance the therapeutic efficacy of immune cell transferring for breast cancer.
Phase 1 studies of 3- and 6-peptide vaccine cocktail derived from GPC3, WDRPUH, and NEIL3 in patients with advanced hepatocellular carcinoma (HCC).
Authors: Masafumi Ikeda, Takuji Okusaka, Izumi Ohno, Shuichi Mitsunaga, Hideaki Takahashi, Shunsuke Kondo, Chigusa Morizane, Junji Furuse
Journal: Journal of Clinical Oncology (2018)

387 Background: Glypican 3 (GPC3), WD-Repeat-containing Protein Up-regulated in HCC (WDRPUH), and Nei Endonuclease VIII-Like 3 (NEIL3) are tumor antigens in HCC. We conducted two phase 1 multicenter open-label studies for advanced HCC: one to evaluate the HLA-A*24-restricted 3-epitope peptide vaccine cocktail named ONO-7268MX1 (MX1); the other to evaluate the HLA-A*24 and -A*02-restricted 6-epitope peptide vaccine cocktail named ONO-7268MX2 (MX2). Both vaccines contain epitope peptides derived from GPC3, WDRPUH, and NEIL3. MX1 and MX2 cover most of Japanese HCC patients (pts). Safety is the primary, and efficacy and immunological response are the exploratory objectives. Methods: Pts received SC MX1 or MX2 once weekly. In MX1 study, pts received each of 3 peptides at 0.3 mg (cohort 1), 1 mg (cohort 2), and 3 mg of GPC3, 1.1 mg of WDRPUH and 3 mg of NEIL3 (cohort 3). In MX2 study, pts received each of 6 peptides at 1 mg. Results: In MX1 study, 3, 8, and 7 pts with HLA-A*24 were enrolled to cohort 1, 2, and 3, respectively. In MX2 study, 14 pts (7 with HLA-A*24, 6 with HLA-A*02, and 1 with HLA-A*24/A*02) were enrolled. No dose limiting toxicities were observed in both studies. The most commonly related AEs were Grade 1/2 injection site reaction (erythema, induration, pain, and pruritus), 44.4% (8/18) in MX1 and 78.6% (11/14) in MX2. Grade 3-related AEs occurred only in MX2 study; neutrophil count decreased, white blood cell count decreased, and decreased appetite (each 1 patient). No grade 4-related AEs occurred in both studies. No response (CR or PR) were seen in both studies. In MX1 study, median and mean of PFS [range], median duration of SD were 2.8, 3.4 [0.5-16.8], 3.7 months respectively, in MX2 study those were 1.9 and 2.8 [0.4-8.3], 5.7 respectively. In both studies, some pts showed long disease control (≥6 months). For those pts, each peptide-specific Cytotoxic T Lymphocyte (CTL) responses were shown by the ELISPOT assay. Conclusions: MX1 and MX2 showed good tolerability. Both vaccines induced CTL responses which may be related to antitumor effect. In addition, some pts showed long disease control. These results implied the potential usefulness of these vaccines for the treatment of HCC. Clinical trial information: JapicCTI-121933 and JapicCTI-142477.
OP0122 Tumour necrosis factor-receptor associated periodic syndrome in a finnish family
Authors: T Pettersson, H Nevala, L Karenko, S Stjernberg, M Raatikainen, H Suomalainen, J Rauta, MF McDermott, P Peterson, A Ranki
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> TNF receptor-associated periodic syndrome (TRAPS) is a recently defined dominantly inherited autoinflammatory syndrome, which is caused by mutations in the extracellular domains of the 55 kDa TNF receptor, TNFRSF1A. TRAPS is characterised by periodic fevers, sterile peritonitis, pleurisy, arthritis, erysipeloid erythema of the skin, and conjunctivitis. Affected individuals have shown a shedding defect of TNFRSF1A upon stimulation and, consequently, low levels of soluble TNFRSF1A in serum. <h3>Objectives</h3> We studied a three-generation Finnish family, where recurrent attacks of fever and abdominal pain appeared to segregate as an autosomal dominant trait. <h3>Methods</h3> The TNFRSF1A gene was sequenced in both affected and unaffected family members. Flow cytometric analysis and ELISA analyses were used to assess membrane expression and serum levels of TNFRSF1A, respectively. <h3>Results</h3> A missense mutation of exon 4, resulting in an amino acid substitution (F112I) close to a conserved cysteine and disulphide bond, was detected in 4 affected family members and in one asymptomatic family member. Impaired shedding of TNFRSF1A after phorbol myristate acetate stimulation was detected in peripheral blood monocytes and granulocytes from affected individuals. The soluble TNFRSF1A levels of individuals carrying the mutation (n = 5) were about half of soluble TNFRSF1A levels of individuals not carrying the mutation (n = 4). <h3>Conclusion</h3> Dominantly inherited autoinflammatory syndrome should be suspected whenever a patient presents with a history of intermittent fevers accompanied by abdominal pain, arthritis or skin rashes, particularly in the presence of a positive family history. Among such patients, low serological levels of soluble TNFRSF1A give an indication of those individuals who are likely to have TRAPS. <h3>Reference</h3> McDermott MF, Aksentijevich I, Galon J, <i>et al</i>. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 1999;97:133–44
Inhibitory Receptor Expression on T Cells as a Marker of Disease Activity and Target to Regulate Effector Cellular Responses in Rheumatoid Arthritis
Authors: Luisina I. Onofrio, Estefania R. Zacca, Paola Ferrero, Cristina Acosta, Eduardo Mussano, Laura Onetti, Isaac Cadile, M. Victoria Gazzoni, Raúl Jurado, Jimena Tosello Boari, Maria C. Ramello, Carolina L. Montes, Adriana Gruppi, Eva V. Acosta Rodríguez
Journal: Arthritis & Rheumatology (2018)

Objective Inhibitory receptors are essential for the regulation of effector immune responses and may play critical roles in autoimmune diseases. We evaluated whether inhibitory receptor expression on T cells from patients with rheumatoid arthritis ( RA ) were correlated with immune activation, disease activity, and response to treatment, as well as whether inhibitory receptor–mediated pathways were functional. Methods Using flow cytometry, we performed extensive phenotypic and functional evaluation of CD 4+ and CD 8+ T cells from the blood and synovial fluid ( SF ) of RA patients ex vivo and after culture. The relationship of each parameter with the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ( DAS 28‐ ESR ) and response to treatment was examined. Results In RA patients with low levels of T cell activation, inhibitory receptor expression showed an inverse relationship with the DAS 28‐ ESR . The frequency of T cells expressing multiple inhibitory receptors was reduced in untreated RA patients but returned to normal levels in treated patients. RA patients who responded to treatment showed an augmented frequency of inhibitory receptor–expressing T cells that correlated with reduced inflammatory cytokine production in comparison to nonresponders. Higher frequencies of effector and memory T cells that expressed multiple inhibitory receptors were seen in SF than in peripheral blood. Notably, inhibitory pathways were operative in blood and synovial T cells from all RA patients, although cells from nonresponder patients were less sensitive to inhibition. Conclusion Inhibitory receptor expression on T cells from RA patients is inversely correlated with effector T cell function and disease activity and may predict response to treatment. Furthermore, different inhibitory pathways are functional and cooperatively suppress synovial T cells, providing a rationale for new treatment strategies to regulate acute local inflammation.
Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018
Authors: Adam Meijer, Corien M Swaan, Martin Voerknecht, Edin Jusic, Sharon van den Brink, Lisa A Wijsman, Bettie CG Voordouw, Gé A Donker, Jacqueline Sleven, Wendelien W Dorigo-Zetsma, Sanela Svraka, Michiel van Boven, Manon R Haverkate, Aura Timen, Jaap T van Dissel, Marion PG Koopmans, Theo M Bestebroer, Ron AM Fouchier
Journal: Eurosurveillance (2018)

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases.
Albert Sézary—The Man, the Cell, and the Syndrome
Authors: Aria Shakeri
Journal: JAMA Dermatology (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 Dermatology 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 Dermatology journal
Synaptic dysfunction in complex psychiatric disorders: from genetics to mechanisms
Authors: Xinyuan Wang, Kimberly M. Christian, Hongjun Song, Guo-li Ming
Journal: Genome Medicine (2018)

Breakthroughs on many fronts have provided strong evidence to support synaptic dysfunction as a causal factor for neuropsychiatric diseases. Genetic studies have identified variants implicated in novel biological and synaptic pathways, and animal and patient-derived induced pluripotent stem cell-based models have allowed mechanistic investigations of synaptic dysfunction in pathological processes.
Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study
Authors: Antoine Italiano, Jean-Charles Soria, Maud Toulmonde, Jean-Marie Michot, Carlo Lucchesi, Andrea Varga, Jean-Michel Coindre, Stephen J Blakemore, Alicia Clawson, Benjamin Suttle, Alice A McDonald, Mark Woodruff, Scott Ribich, Eric Hedrick, Heike Keilhack, Blythe Thomson, Takashi Owa, Robert A Copeland, Peter T C Ho, Vincent Ribrag
Journal: The Lancet Oncology (2018)
Signatures of negative selection in the genetic architecture of human complex traits
Authors: Jian Zeng, Ronald de Vlaming, Yang Wu, Matthew R. Robinson, Luke R. Lloyd-Jones, Loic Yengo, Chloe X. Yap, Angli Xue, Julia Sidorenko, Allan F. McRae, Joseph E. Powell, Grant W. Montgomery, Andres Metspalu, Tonu Esko, Greg Gibson, Naomi R. Wray, Peter M. Visscher, Jian Yang
Journal: Nature Genetics (2018)
Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome
Authors: Andrea Mazzanti, Riccardo Maragna, Gaetano Vacanti, Nicola Monteforte, Raffaella Bloise, Maira Marino, Lorenzo Braghieri, Patrick Gambelli, Mirella Memmi, Eleonora Pagan, Massimo Morini, Alberto Malovini, Martin Ortiz, Luciana Sacilotto, Riccardo Bellazzi, Lorenzo Monserrat, Carlo Napolitano, Vincenzo Bagnardi, Silvia G. Priori
Journal: Journal of the American College of Cardiology (2018)
Abstract 11153: Association of β1-Adrenergic,M2-Muscarinic Receptor Autoantibody With Occurrence of Nonvalvular Atrial Fibrillation
Authors: Bing Hu, Yanxiang Sun, Sha Li, Jie Sun, Tong Liu, Zidi Wu, Li Feng
Journal: Circulation (2016)

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia and confers an independent increased risk of stroke and death. Although the exact mechanisms behind AF are not completely elucidated, A large number of evidence demonstrates that autoimmunity may play an important role in the initiation, the progression and the maintenance of AF. Hypothesis: In this study, we aimed to compare anti-β 1 -R and anti-M 2 -R levels between non-valvular AF patients and healthy control subjects Methods: Seventy-one patients with non-valve atrial fibrillation(age: 62.69±11.23 years, 54% male),along with 71healthy control subjects(age: 61.86±11.90 years, 52% male) were included . Enzyme-linked immunosorbent assay tests to measure serum anti-β 1 -R and anti-M 2 -R levels were performed in both groups. Hs-CRP concentration was measured by immunoturbidimetry.IL-6 concentration was measured by chemiluminescence. Results: Anti-β 1 -R and anti-M 2 -R levels were significantly higher in patients with non-valvular AF compared to healthy controls[anti-β 1 -R 221.11(132.38-291.69) vs. 198.14(125.70-278.40) ng/ml, P&lt;0.01; anti-M 2 -R 271.81(144.99-378.20) vs. 235.01(121.53-358.99) ng/ml, P&lt;0.01]. Compared with the control group, the serum level of IL-6,hs-CRP were higher in the non-valvular AF group(IL-6 19.65±5.6pg/mL vs 6.79±1.09pg/mL,hs-CRP 6.03±1.35mg/Lvs 2.73±0.63mg/L P&lt;0.05).After multivariable analyses , the baseline value of serum anti-β 1 -R (OR: 13.176, p&lt;0.001),anti-M 2 -R (OR:4.41, p&lt;0.001),IL-6(OR:6.126, p&lt;0.05) levels and LA diameter(OR:5.781, p&lt;0.05) were independently predictors of non-valvular AF. Conclusions: We found a significant association between circulating serum anti-β1-R,anti-M2-R,IL-6 levels and non-valvular AF. The possible mechanism is that the autoimmunity and inflammation might take part in electrical remodeling and structural remodeling of left atrium. Larger studies are warranted to further investigate their role in these settings.
Abstract 13820: Diastolic Dysfunction is Not Associated With Increased Diastolic Calcium During Experimental Uremic Cardiomyopathy
Authors: Pamela D Winterberg, Rong Jiang, Bo Wang, Sonal Harbaran, Mary B Wagner
Journal: Circulation (2014)

Introduction: The underlying mechanisms contributing to uremic cardiomyopathy during chronic kidney disease (CKD) are poorly understood, limiting treatment options. Hypothesis: We aimed to determine if altered calcium (Ca2+) handling in cardiomyocytes contributes to diastolic dysfunction in a mouse model of CKD. Methods: CKD was induced in male 129X1/SvJ mice through five-sixths nephrectomy in a two-stage surgery. Age-matched mice served as controls. Transthoracic echocardiography and speckle-tracking based strain analysis (Vevo2100, VisualSonics, Toronto, Canada) were performed at 8 weeks post-CKD (n=7-8) to assess heart structure and function. Cardiomyocytes isolated from mice with or without CKD (n=3 mice per group, 10-12 cells/mouse) were loaded with Fura 2-AM, paced by field stimulation (1 Hz), and imaged with a dual-excitation fluorescence photomultiplier system (IonOptix Inc, Milton, MA) to measure Ca2+ transients and sarcomere length. Sarcoplasmic reticulum Ca2+ content was determined following rapid application of caffeine.[[Unable to Display Character: &amp;#8232;]] Results: CKD mice displayed left ventricular hypertrophy (LVAW;d 1.46 ± 0.134 vs 1.04 ± 0.129 mm; p&lt;0.001) and decreased longitudinal strain (19 ± 4.1% vs 30 ± 2.3%; p&lt;0.0001) compared to control mice. Resting sarcomere length was significantly shorter in cardiomyocytes isolated from CKD mice compared to normal mice (1.86 ± 0.054 vs 1.89 ± 0.047 nm; p = 0.016), but relaxation time was unchanged (0.21 ± 0.12 vs 0.21 ± 0.15 seconds, p=0.4). Unexpectedly, the baseline cytosolic Ca2+ content was lower in uremic myocytes (1.22 ± 0.353 vs 1.46 ± 0.252 AU, p=0.002). However, the Ca2+ transient amplitude (0.39 ± 0.177 vs 0.41 ± 0.167 AU, p=0.4) and sarcoplasmic reticulum Ca2+ content (1.15 ± 0.321 vs 1.24 ± 0.550 AU, p=0.4) were comparable between CKD and normal cardiomyocytes.[[Unable to Display Character: &amp;#8232;]] Conclusions: Mice with CKD have signs of left ventricular hypertrophy and diastolic dysfunction on echocardiography. Cardiomyocytes isolated from mice with CKD have shorter diastolic sarcomere length implying impaired relaxation, yet paradoxically have decreased diastolic calcium. Thus Ca2+ accumulation during diastole does not appear to contribute to impaired relaxation in this model.
Outcomes with immune checkpoint inhibitor use in lung cancer patients with hepatic metastases.
Authors: Srikala Addepalli, Chipman Robert Geoffrey Stroud, Sulochana Devi Cherukuri, Cynthia R. Cherry, Nitika Sharma, Teresa Parent, Jessica Hardin, Paul R. Walker
Journal: Journal of Clinical Oncology (2017)

38 Background: Immune checkpoint inhibitors have shown promising responses in advanced lung cancer as well as a number of other malignancies. However, efficacy appears to be variable based on the site of disease. We reviewed the outcomes of patients with lung cancer and hepatic metastases from a single institution. Methods: We performed a retrospective analysis of the lung cancer patients treated at East Carolina University with the PD1 inhibitor Nivolumab. Patients were enrolled in an IRB approved study designed to evaluate predictive markers of response to immune checkpoint blockade. Clinical characteristics, laboratory data, and imaging studies were analyzed and recorded. Results: Data for 75 patients with lung cancer who received anti-PD1 therapy was analyzed. Of the 75 patients included, 13% (n = 9) had liver metastases. Average age of the patients was 61.8 years, 66% patients were male, 22% had squamous cell, 33% had adenocarcinoma and 44 % small cell neuroendocrine histology. Average number of prior therapies was 1.7 (range 1-4). Thirty three percent of patients had modified Glasgow prognostic score of 2 and a mean CRP of 63.61mg/L (range 0.1-172.7mg/ L) at the initiation of anti-PD1 therapy. They received an average of 4 cycles of anti-PD1 therapy. Forty four percent of patients received adjunctive therapy such as ablative radiation (33%) or immune modulating chemotherapy with the aim of augmenting the effect of the anti-PD1 therapy. None of the analyzed patients with liver metastases had an objective decrease in liver metastases and the average survival in these patients after starting anti-PD1 therapy was 132 days. Conclusions: To our knowledge, this study is the largest reported series examining patients with hepatic metastases from lung cancer treated with PD-1 inhibitors. Our observations are consistent with prior reports indicating poor outcomes with anti-PD1 therapy in patients with liver metastases. The mechanisms underlying such resistance must be elucidated so that more effective treatment combinations can be developed.
Effective interventions for unintentional injuries: a systematic review and mortality impact assessment among the poorest billion
Authors: Andres I Vecino-Ortiz, Aisha Jafri, Adnan A Hyder
Journal: The Lancet Global Health (2018)

Between 1990 and 2015, the global injury mortality declined, but in countries where the poorest billion live, injuries are becoming an increasingly prevalent cause of death. The vulnerability of this population requires immediate attention from policy makers to implement effective interventions that lessen the burden of injuries in these countries. Our aim was two-fold; first, to review all the evidence on effective interventions for the five main types of unintentional injury; and second, to estimate the potential number of lives saved by effective injury interventions among the poorest billion.For our systematic review we used references in the Disability Control Priorities third edition, and searched PubMed and the Cochrane database for papers published until Sept 10, 2016, using a comprehensive search strategy to find interventions for the five major causes of unintentional injuries: road traffic crashes, falls, drowning, burns, and poisoning. Studies were included if they presented evidence with significant effects sizes for any outcome; no inclusions or exclusions made on the basis of where the study was carried out (ie, low-income, middle-income, or high-income country). Then we used data from the Global Burden of Disease 2015 study and a Monte Carlo simulation technique to estimate the potential annual attributable number of lives saved among the poorest billion by these evidence-based injury interventions. We estimated results for 84 countries where the poorest billion live.From the 513 papers identified, 47 were eligible for inclusion. We identified 11 interventions that had an effect on injury mortality. For road traffic deaths, the most successful interventions in preventing deaths are speed enforcement (>80 000 lives saved per year) and drink-driving enforcement (>60 000 lives saved per year). Interventions potentially most effective in preventing deaths from drowning are formal swimming lessons for children younger than 14 years (>25 000 lives saved per year) and the use of crèches to supervise younger children (younger than 5 years; >10 000 lives saved per year). We did not find sufficient evidence on interventions for other causes of unintentional injuries (poisoning, burns, and falls) to run similar simulations.Based on the little available evidence, key interventions have been identified to prevent lives lost from unintentional injuries among the poorest billion. This Article provides guidance to national authorities on evidence-based priority interventions that can reduce the burden of injuries among the most vulnerable members of the population. We also identify an important gap in knowledge on the effectiveness and the mortality impacts of injury interventions.Partly supported by the Fogarty International Center of the US National Institutes of Health (Chronic Consequences of Trauma, Injuries, Disability Across the Lifespan: Uganda; #D43TW009284).