tbuckley/cabot-search huggingface dataset:
Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients
Authors: Jiayi Yu, Xiaowen Wu, Junya Yan, Huan Yu, Longwen Xu, Zhihong Chi, Xinan Sheng, Lu Si, Chuanliang Cui, Jie Dai, Meng Ma, Tianxiao Xu, Yan Kong, Jun Guo
Journal: Journal of Hematology & Oncology (2018)

Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells to test their cytotoxicity in melanoma in vitro and in vivo. Moreover, we reported the expression of ganglioside GD2 in non-Caucasian melanoma populations for the first time, thus providing a basis for future clinical research. This study included tumor samples from 288 melanoma patients at the Peking University Cancer Hospital & Institute. Clinical data were collected. Immunohistochemical assays using antibodies against ganglioside GD2 were performed on formalin-fixed, paraffin-embedded specimens. The ability of ganglioside GD2 CAR-T cells to kill ganglioside GD2+ melanoma cells was evaluated in vitro and in a patient-derived xenograft (PDX) model. Among the 288 samples, 49.3% of cases (142/288) demonstrated positive staining with ganglioside GD2. The median survival time in patients exhibiting ganglioside GD2 expression was significantly shorter than that in patients without ganglioside GD2 expression (31 vs. 47.1 months, P < 0.001). In the present study, CAR was constructed using a GD2-specific scFv (14.G2a), T cell receptor CD3ζ chain, and the CD137 (4-1BB) costimulatory motif. In addition, the GD2.BBζ CAR-T cells demonstrated specific lysis of ganglioside GD2-expressing melanoma cells in vitro. In two PDX models, mice that received intravenous or local intratumor injections of GD2.BBζ CAR-T cells experienced rapid tumor regression. These data demonstrate that the rate of GD2 expression in Chinese patients is 49.3%. GD2.BBζ CAR-T cells can both efficiently lyse melanoma in a GD2-specific manner and release Th1 cytokines in an antigen-dependent manner in vitro and in vivo. Anti-GD2/4-1BB CAR-T cells represent a clinically appealing treatment strategy for Chinese melanoma patients exhibiting GD2 expression and provide a basis for future studies of the clinical application of immunotherapy for melanoma.
Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors
Authors: Julius Strauss, Christopher R. Heery, Jeffrey Schlom, Ravi A. Madan, Liang Cao, Zhigang Kang, Elizabeth Lamping, Jennifer L. Marté, Renee N. Donahue, Italia Grenga, Lisa Cordes, Olaf Christensen, Lisa Mahnke, Christoph Helwig, James L. Gulley
Journal: Clinical Cancer Research (2018)

Abstract Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ “trap.” Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at &amp;gt;1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR.
Abstract 15711: Mitochondrial Metabolic Remodeling of Cardiac Fibroblasts Promotes Right Ventricular Fibrosis in Pulmonary Arterial Hypertension
Authors: Lian Tian, Asish Dasgupta, Danchen Wu, Kuang-Hueih Chen, Jeffrey Mewburn, Stephen L Archer
Journal: Circulation (2016)

Introduction: In pulmonary arterial hypertension (PAH), fibrosis of pulmonary arteries (PAs) and the right ventricle (RV) is associated with reduced PA and RV compliance, respectively. The role of ...
miR-145 Antagonizes SNAI1-Mediated Stemness and Radiation Resistance in Colorectal Cancer
Authors: Yun Zhu, Cindy Wang, Scott A. Becker, Katie Hurst, Lourdes M. Nogueira, Victoria J. Findlay, E. Ramsay Camp
Journal: Molecular Therapy (2018)

Epithelial-to-mesenchymal transition (EMT) has been closely linked with therapy resistance and cancer stem cells (CSCs). However, EMT pathways have proven challenging to therapeutically target. MicroRNA 145 (miR-145) targets multiple stem cell transcription factors and its expression is inversely correlated with EMT. Therefore, we hypothesized that miR-145 represents a therapeutic target to reverse snail family transcriptional repressor 1 (SNAI1)-mediated stemness and radiation resistance (RT). Stable expression of SNAI1 in DLD1 and HCT116 cells (DLD1-SNAI1; HCT116-SNAI1) increased expression of Nanog and decreased miR-145 expression compared to control cells. Using a miR-145 luciferase reporter assay, we determined that ectopic SNAI1 expression significantly repressed the miR-145 promoter. DLD1-SNAI1 and HCT116-SNAI1 cells demonstrated decreased RT sensitivity and, conversely, miR-145 replacement significantly enhanced RT sensitivity. Of the five parental colon cancer cell lines, SW620 cells demonstrated relatively high endogenous SNAI1 and low miR-145 levels. In the SW620 cells, miR-145 replacement decreased CSC-related transcription factor expression, spheroid formation, and radiation resistance. In rectal cancer patient-derived xenografts, CSC identified by EpCAM+/aldehyde dehydrogenase (ALDH)+ demonstrated high expression of SNAI1, c-Myc, and Nanog compared with non-CSCs (EpCAM+/ALDH-). Conversely, patient-derived CSCs demonstrated low miR-145 expression levels relative to non-CSCs. These results suggest that the SNAI1:miR-145 pathway represents a novel therapeutic target in colorectal cancer to overcome RT resistance.
Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease
Authors: Patrick Mallia, Jessica Webber, Simren K. Gill, Maria-Belen Trujillo-Torralbo, Maria Adelaide Calderazzo, Lydia Finney, Eteri Bakhsoliani, Hugo Farne, Aran Singanayagam, Joseph Footitt, Richard Hewitt, Tatiana Kebadze, Julia Aniscenko, Vijay Padmanaban, Philip L. Molyneaux, Ian M. Adcock, Peter J. Barnes, Kazihuro Ito, Sarah L. Elkin, Onn Min Kon, William O. Cookson, Miriam F. Moffat, Sebastian L. Johnston, John S. Tregoning
Journal: Journal of Allergy and Clinical Immunology (2018)

Patients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear.
Adalimumab concentration-based tapering strategy: as good as the recommended dosage
Authors: Denis Mulleman, Alejandro Balsa
Journal: Annals of the Rheumatic Diseases (2018)

Table 1 Arguments for therapeutic drug monitoring of a tumour necrosis factor inhibitor in rheumatic diseases and requirements Rationale Requirement Pharmacokinetic interindividual variability Valid assay for drug concentration measurement and anti-drug antibody detection Dose-concentration relationship Algorithm based on clinical and biological assessment Risk of adverse events, outside the target concentration range* Personalised dosing-schedule modelling tool, to achieve the target concentration and response *Immunogenicity with low concentrations and infection with high concentrations.
2018 EULAR recommendations for a core data set to support observational research and clinical care in giant cell arteritis
Authors: Lisa Ehlers, Johan Askling, Hans WJ Bijlsma, Maria Cinta Cid, Maurizio Cutolo, Bhaskar Dasgupta, Christian Dejaco, William G Dixon, Nils Feltelius, Axel Finckh, Kate Gilbert, Sarah Louise Mackie, Alfred Mahr, Eric L Matteson, Lorna Neill, Carlo Salvarani, Wolfgang A Schmidt, Anja Strangfeld, Ronald F van Vollenhoven, Frank Buttgereit
Journal: Annals of the Rheumatic Diseases (2019)

Giant cell arteritis (GCA) represents the most common form of primary systemic vasculitis and is frequently associated with comorbidities related to the disease itself or induced by the treatment. Systematically collected data on disease course, treatment and outcomes of GCA remain scarce. The aim of this EULAR Task Force was to identify a core set of items which can easily be collected by experienced clinicians, in order to facilitate collaborative research into the course and outcomes of GCA. A multidisciplinary EULAR task force group of 20 experts including rheumatologists, internists, epidemiologists and patient representatives was assembled. During a 1-day meeting, breakout groups discussed items from a previously compiled collection of parameters describing GCA status and disease course. Feedback from breakout groups was further discussed. Final consensus was achieved by means of several rounds of email discussions after the meeting. A three-round Delphi survey was conducted to determine a core set of parameters including the level of agreement. 117 parameters were regarded as relevant. Potential items were subdivided into the following categories: General, demographics, GCA-related signs and symptoms, other medical conditions and treatment. Possible instruments and assessment intervals were proposed for documentation of each item. To facilitate implementation of the recommendations in clinical care and clinical research, a minimum core set of 50 parameters was agreed. This proposed core set intends to ensure that relevant items from different GCA registries and databases can be compared for the dual purposes of facilitating clinical research and improving clinical care.
Self-regulation of the Medical Profession and Maintenance of Certification—Reply
Authors: David H. Johnson
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 Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Characteristics of tumors detected by screen-film and digital mammography during breast cancer screening.
Authors: Maira M Caleffi, Ademar M Bedin, Dakir L Duarte Filho, Luis Antonio de Moraes Neto, Clarissa M Ferreira, Rodrigo Antonini Ribeiro, Daniela Dornelles Rosa, Eliana M Wendland
Journal: Journal of Clinical Oncology (2014)

e12516 Background: Screening mammography is the single most effective method of breast cancer (BC) detection, and the introduction of full-field digital mammography (FFDM) was suggested to be superior to screen-film mammography (SFM) to detect BC in early stages. Therefore, the aim of this study was to describe the clinical characteristics of patients with BC diagnosed at a screening cohort in southern Brazil, according with the type of mammography (FFDM or SFM). Methods: After accrual period, women from 40 to 69 years old were followed annually through clinical examination and mammograms. Clinical and immunohistochemical characteristics were evaluated according to the type of mammography performed: SFM (2006-2010) and FFDM (2011-2013). All mammograms were interpreted by the same radiologist. Complementary diagnostic procedures were done in the same screening day as needed and surgical treatment was performing on study site. The ●2 or Fisher test were used to compare categories and t-test was used to compare means. Results: From circa 2,800 women, 41 cases of invasive BC were detected from 2006 to 2013. Although the overall incidence of BC did not change after digital transition, an increase was observed in women from 40-49 years old (from 45.8 to 184.4/100,000; p<0.01) and a decrease in women 50-69 years old with a non-significant tendency of lower mean age in the FFDM period (52.7 vs. 57.2; p=0.07). There was no differences in the proportion of women in advanced stages, tumor size and histological grade according with mammogram type. A higher proportion of women had positive progesterone receptor in the FFDM period (p=0.03). There were no differences in Cerb2, p53, Ki-67 and estrogen receptors. All BC detected after digital transition were ductal invasive carcinomas (versus 76.9% in SFM period). Conclusions: The use of FFDM increases the detection of breast cancer in young women but the transition to FFDM did not modify tumor clinical and immunohistochemical characteristics.
Cancer fatty acid metabolism regulates Her-2/neu (erbB-2) oncogene expression via formation of “PEA3 transcription factor-PEA3 DNA binding site” complexes on the Her-2/neu gene promoter
Authors: Javier A. Menendez, Adriana Papadimitropoulou, Luciano Vellon, Ruth Lupu
Journal: Cancer Research (2006)

1718  Cancer fatty acid metabolism may represent a previously unrecognized regulator of the Her-2/neu oncogene. Specific inhibition of Fatty Acid Synthase (FAS)-catalyzed de novo fatty acid biogenesis or exogenous supplementation with oleic acid (OA) was found to equally suppress Her-2/neu overexpression. Noteworthy reductions in the expression of Her-2/neu-coded p185Her-2/neu tyrosin kinase orphan receptor were observed following treatment of cancer cells naturally bearing Her-2/neu gene amplification with either chemical FAS blockers, silencing RNA (siRNA)-targeting FAS gene or OA. The ultimate molecular mechanisms linking cancer fatty cell metabolism and Her-2/neu expression remained, however, largely obscure. Here, transient transfection experiments established the ability of C75 (a specific inhibitor of FAS activity) and OA to specifically repress the transcriptional activity of Her-2/neu gene promoter in a panel of breast, ovarian and stomach cancer cell lines exhibiting Her-2/neu oncogene amplification. Conversely, marginal decreases on the Her-2/neu promoter activity were observed in cancer cells expressing low to undetectable levels of Her-2/neu gene. Interestingly, treatments with C75 or OA were found to exclusively induce the up-regulation of the Ets protein PEA3 (a transcriptional repressor of Her-2/neu promoter activity) in all the cancer cell lines demonstrating Her-2/neu gene amplification. Moreover, an intact PEA3 DNA-binding site on the endogenous Her-2/neu promoter was essential for C75- and OA-induced transcriptional repression of Her-2/neu gene expression. Thus, a human Her-2/neu promoter bearing a PEA3 binding site-mutated sequence was not subjected to negative regulation by C75 or OA, while treatments with C75 or OA failed to repress the expression of a full-length Her-2/neu cDNA controlled by a SV40 viral promoter. Specific depletion of FAS protein following transient transfection with siRNA-targeting FAS gene strongly antagonized the inhibitory effects of C75 and OA on Her-2/neu gene promoter activity, while C75 and OA, as single agents, were found to significantly down-regulate FAS protein expression by attenuating FAS gene promoter activity. Exogenous supplementation with the FAS substrate Malonyl-CoA dramatically decreased the promoter activity of Her-2/neu and FAS genes while concomitantly promoting the up-regulation of PEA3 expression, thus recapitulating the regulatory actions of C75 and OA. Malonyl-CoA may represent a novel signal of fuel availability able to suppress Her-2/neu overexpression via formation of inhibitory “PEA3 protein-PEA3 DNA binding site” complexes on the endogenous Her-2/neu promoter, thus supporting the notion of fatty acid metabolism as a valuable molecular target in the management of Her-2/neu-overexpressing human carcinomas.
Abstract 17948: Reduced Loop Diuretic Use in Patients Taking Sacubitril/Valsartan Compared With Enalapril: The Paradigm-HF Study
Authors: Orly Vardeny, Brian Claggett, Jessica Kachadourian, Milton Packer, Michael Zile, Jean Rouleau, Karl Swedberg, Victor Shi, Martin Lefkowitz, John McMurray, Scott D Solomon
Journal: Circulation (2016)

Background: Diuretics are frequently used in patients with heart failure but can lead to neurohormonal activation, electrolyte abnormalities, and worsening renal function. Hypothesis: We hypothesiz...
Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non–Small-Cell Lung Cancer
Authors: Zhongxing Liao, J. Jack Lee, Ritsuko Komaki, Daniel R. Gomez, Michael S. O’Reilly, Frank V. Fossella, George R. Blumenschein, John V. Heymach, Ara A. Vaporciyan, Stephen G. Swisher, Pamela K. Allen, Noah Chan Choi, Thomas F. DeLaney, Stephen M. Hahn, James D. Cox, Charles S. Lu, Radhe Mohan
Journal: Journal of Clinical Oncology (2018)

Purpose This randomized trial compared outcomes of passive scattering proton therapy (PSPT) versus intensity-modulated (photon) radiotherapy (IMRT), both with concurrent chemotherapy, for inoperable non–small-cell lung cancer (NSCLC). We hypothesized that PSPT exposes less lung tissue to radiation than IMRT and thereby reduces toxicity without compromising tumor control. The primary end points were grade ≥ 3 radiation pneumonitis (RP) and local failure (LF). Patients and Methods Eligible patients had stage IIB to IIIB NSCLC (or stage IV NSCLC with a single brain metastasis or recurrent lung or mediastinal disease after surgery) who were candidates for concurrent chemoradiation therapy. Pairs of treatment plans for IMRT and PSPT were created for each patient. Patients were eligible for random assignment only if both plans satisfied the same prespecified dose-volume constraints for at-risk organs at the same tumor dose. Results Compared with IMRT (n = 92), PSPT (n = 57) exposed less lung tissue to doses of 5 to 10 Gy(RBE), which is the absorbed Gy dose multiplied by the relative biologic effectiveness (RBE) factor for protons; exposed more lung tissue to ≥ 20 Gy(RBE), but exposed less heart tissue at all dose levels between 5 and 80 Gy(RBE). The grade ≥ 3 RP rate for all patients was 8.1% (IMRT, 6.5%; PSPT, 10.5%); corresponding LF rates were 10.7% (all), 10.9% (IMRT), and 10.5% (PSPT). The posterior probability of IMRT being better than PSPT was 0.54. Exploratory analysis showed that the RP and LF rates at 12 months for patients enrolled before versus after the trial midpoint were 21.1% (before) versus 18.2% (after) for the IMRT group (P = .047) and 31.0% (before) versus 13.1% (after) for the PSPT group (P = .027). Conclusion PSPT did not improve dose-volume indices for lung but did for heart. No benefit was noted in RP or LF after PSPT. Improvements in both end points were observed over the course of the trial.
Thrombectomy Options for Acute Ischemic Stroke
Authors: Diederik W. J. Dippel
Journal: JAMA Neurology (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 Neurology 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 Neurology journal
Rituximab as Single Long-term Maintenance Therapy in Patients With Difficult-to-Treat Pemphigus
Authors: Julia Sanchez, Saskia Ingen-Housz-Oro, Olivier Chosidow, Frank Antonicelli, Philippe Bernard
Journal: JAMA Dermatology (2018)

intralesional triamcinolone to achieve control.Since then, she has initiated glycopyrrolate 1 mg 3 times per day and naltrexone 4.5 mg and achieved 30% clearance of HHD over the last 3 months.The patient is pleased because no lesions are exudative, eroded, or symptomatic.Discussion | Online testimonials and recent publications have documented dramatic responses of HHD to naltrexone. 2,3However, we demonstrate response variability and the possible use of adjunctive agents to achieve a desired effect.Clinicians should carefully manage patient expectations and explain the potential use of naltrexone in a multipronged approach to treatment.When used with topical steroids or acitretin, positive results can be observed with low frequency and dosages of these adjunctive agents, allowing for simplified regimens.Our cases suggest that the previously published 4.5-mg dose may not be sufficient, and that 12.5-mg to 50-mg doses can be safely attempted for an adequate response.Caution should be taken with immediate cessation of 12.5-mg to 50-mg doses, given evidence of flares following discontinuation.While no adverse effects were noted, we suggest monitoring patients on 12.5-mg to 50-mg doses for adverse effects such as depression, increased pain, and elevated liver function tests.