tbuckley/cabot-search huggingface dataset:
Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy
Authors: Clara H. Karches, Mohamed-Reda Benmebarek, Moritz L. Schmidbauer, Mathias Kurzay, Richard Klaus, Martina Geiger, Felicitas Rataj, Bruno L. Cadilha, Stefanie Lesch, Constanze Heise, Ramona Murr, Johannes vom Berg, Martin Jastroch, Daniel Lamp, Jian Ding, Peter Duewell, Gerhard Niederfellner, Claudio Sustmann, Stefan Endres, Christian Klein, Sebastian Kobold
Journal: Clinical Cancer Research (2019)

Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing.BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell-induced lysis were characterized in three murine and human tumor models in vitro and in vivo.Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo.We describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.
Size and temporal-dependent efficacy of oltipraz-loaded PLGA nanoparticles for treatment of acute kidney injury and fibrosis
Authors: Hang Yu, Tingsheng Lin, Wei Chen, Wenmin Cao, Chengwei Zhang, Tianwei Wang, Meng Ding, Sheng Zhao, Hui Wei, Hongqian Guo, Xiaozhi Zhao
Journal: Biomaterials (2019)
Correction to: Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case–Control Consortium
Authors: M. Waterhouse, H.A. Risch, C. Bosetti, K.E. Anderson, G.M. Petersen, W.R. Bamlet, M. Cotterchio, S.P. Cleary, T.I. Ibiebele, C. La Vecchia, H.G. Skinner, L. Strayer, P.M. Bracci, P. Maisonneuve, H.B. Bueno-de-Mesquita, W. Zatoński, L. Lu, H. Yu, K. Janik-Koncewicz, J. Polesel, D. Serraino, R.E. Neale
Journal: Annals of Oncology (2015)
Does intensity of induction chemotherapy affect the impact of measurable residual disease (MRD) on prognosis in acute myeloid leukemia (AML)?
Authors: Michael Jamie Hochman, Megan Othus, Carole Shaw, Kelda Gardner, Mary-Elizabeth M. Percival, Paul C. Hendrie, Elihu Estey
Journal: Journal of Clinical Oncology (2019)

7031 Background: Absence of MRD in first complete remission (CR1) of AML decreases the probability of subsequent relapse both in patients given more (e.g. 7+3 or FLAG) or less (e.g. azacitidine) intense induction. Although high-intensity induction seems to increase the chance of CR without MRD, it is unknown whether induction intensity affects outcomes beyond eradication of MRD. Methods: We retrospectively studied adults with newly diagnosed AML or MDS with 10-20% blasts who received induction at the University of Washington from 2008 through 2015. Induction was classified as high or low intensity, CR defined by standard criteria, and marrow MRD by presence of blasts on multiparameter flow cytometry within 1-2 weeks of CR. Post-remission therapy in 10 patients included allogeneic hematopoietic cell transplant (HCT). Multivariate regression analysis examined the independent effects of age, initial cytogenetics (favorable, intermediate, adverse), performance status, de novo vs secondary AML, induction intensity, and MRD on post-CR outcomes. Results: 217 patients received high- and 38 low-intensity induction. 75% of the former vs. 42% of the latter achieved CR without MRD. Although high-intensity therapy was associated with longer overall survival (OS), this difference disappeared after accounting for the above covariates (HR 0.94, 95% CI 0.58  1.52, P = 0.8) and OS was poor regardless of chemotherapy intensity if MRD was present. Multivariate analysis found no interaction between the presence or absence of MRD and induction intensity (HR 0.95, 95% CI 0.4  2.29, P = 0.9). Conclusions: Receiving high-intensity induction chemotherapy does not appear to confer a separate advantage in long-term outcomes once CR without MRD is achieved, at least in patients mostly not receiving HCT. We are currently including more such patients who received HCT. Our results suggest that any effect of high-intensity induction largely reflects its association with a higher probability of achieving an MRD-negative CR.
Biomarker Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Jennifer Abbasi
Journal: JAMA (2019)

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Sustained efficacy of secukinumab in patients with moderate‐to‐severe palmoplantar psoriasis: 2·5‐year results from <scp>GESTURE</scp> , a randomized, double‐blind, placebo‐controlled trial
Authors: A.B. Gottlieb, A. Kubanov, M. Doorn, J. Sullivan, K.A. Papp, R. You, P. Regnault, J.A. Frueh
Journal: British Journal of Dermatology (2019)

Secukinumab has shown sustained efficacy and safety in several manifestations of psoriasis.GESTURE investigated the long-term (2·5-year) safety and efficacy of 150 mg and 300 mg subcutaneous secukinumab in 205 patients with moderate-to-severe palmoplantar psoriasis.GESTURE was a randomized, double-blind, placebo-controlled, multicentre, phase IIIb trial conducted across 15 countries. The study was 140 weeks long and consisted of four periods: screening (up to 4 weeks), treatment period 1 (16 weeks), treatment period 2 (116 weeks) and post-treatment follow-up (8 weeks). Eligible patients were aged ≥ 18 years with moderate-to-severe palmoplantar psoriasis and at least one plaque outside of the palms and soles. Efficacy was assessed via a palmoplantar Investigator's Global Assessment (ppIGA) and the palmoplantar Psoriasis Area and Severity Index (PASI).The primary end point, a ppIGA score of 0 or 1, was met at week 16. The effect was sustained over 2·5 years with 59% [95% confidence interval (CI) 43·5-74·1] and 53% (95% CI 35·1-69·6) of patients in the secukinumab 300 mg and 150 mg groups, respectively, achieving clear or almost clear palms and soles (ppIGA 0 or 1). At 2·5 years, the mean palmoplantar PASI percentage was reduced in both the secukinumab 300 mg group (-74·7%) and the secukinumab 150 mg group (-61·6%). A total of 17% (secukinumab 300 mg group) and 18% (secukinumab 150 mg group) of patients experienced no difficulty in hands and feet functionality, as indicated by the palmoplantar quality of life instrument overall scores. The safety profile was favourable.GESTURE revealed that secukinumab provides a strong and sustained response over 2·5 years in challenging-to-treat palmoplantar psoriasis.
Tofacitinib in Amyopathic Dermatomyositis–Associated Interstitial Lung Disease
Authors: Zhiwei Chen, Xiaodong Wang, Shuang Ye
Journal: New England Journal of Medicine (2019)

Tofacitinib in Amyopathic Dermatomyositis-Associated Interstitial Lung DiseaseTo the Editor: Anti-melanoma differentiationassociated protein (MDA) 5 (anti-MDA5)-positive amyopathic dermatomyositis (ADM)-associated interstitial lung disease (ILD) (hereafter, ADM-ILD) is a rapidly progressive and life-threatening disease. 1 Despite aggressive conventional treatments with high-dose glucocorticoids in combination with cyclosporine, tacrolimus, or cyclophosphamide, the 6-month mortality is as high as 50%. 2,3Japanese investigators recently reported the possible efficacy of tofacitinib, a Janus kinase (JAK) inhibitor, as a rescue option for patients with high-risk ADM-ILD after failure of conventional treatment. 3 Our data have also suggested that a JAK inhibitor could abrogate the proinflammatory and profibrotic effects of ADM-ILDderived T cells in vitro. 4 Thus, we conducted a single-center, open-label clinical study (Chinese Clinical Trial Registry number, ChiCTR-1800016629) to evaluate the efficacy of tofacitinib in patients with early-stage anti-MDA5positive AMD-ILD.Patients were included in the trial if they were older than 18 years of age, met the criteria for a diagnosis of ADM 2 and were positive for anti-MDA5 antibodies, had had ILD (confirmed by pulmonary high-resolution computed tomography [CT]) for less than 3 months, and had a predicted forced vital capacity (FVC) of at least 50%.Patients were excluded if they had other connective-tissue diseases, an underlying cancer, a concomitant infection, or a liver aminotransferase level greater than 2 times the upper limit of the normal range.From July 2017 through September 2018, a total of 18 consecutive patients who were eligible to participate in the trial were prospectively enrolled at our center and received a glucocorticoid
LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY
Authors: Rui Zhang, Fan Zhang, Zeguo Sun, Pengpeng Liu, Xiao Zhang, Yingnan Ye, Beiqi Cai, Martin J. Walsh, Xiubao Ren, Xishan Hao, Weijia Zhang, Jinpu Yu
Journal: Cancer Research (2019)

Somatic long interspersed element-1 (LINE-1) retrotransposition is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of LINE-1 retrotransposition in lung squamous cell carcinoma (LUSC) remain unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas and observed LINE-1 retrotransposition in 90% of tumor samples. Thirteen LINE-1 retrotranspositions of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, LINE-1-FGGY (L1-FGGY) was identified as the most frequent LINE-1 retrotransposition in the Chinese cohort and significantly correlated with poor clinical outcome. L1-FGGY occurred with smoke-induced hypomethylation of the LINE-1 promoter and contributed to the development of local immune evasion and dysfunctional metabolism. Overexpression of L1-FGGY or knockdown of FGGY promoted cell proliferation and invasion in vitro, facilitated tumorigenesis in vivo, and dysregulated cell energy metabolism and cytokine/chemotaxin transcription. Importantly, specific reverse transcription inhibitors, nevirapine and efavirenz, dramatically countered L1-FGGY abundance, inhibited tumor growth, recovered metabolism dysfunction, and improved the local immune evasion. In conclusion, hypomethylation-induced L1-FGGY expression is a frequent genomic event that promotes the development and progression of LUSC and represents a promising predictive biomarker and therapeutic target in LUSC. SIGNIFICANCE: LINE-1-FGGY is a prognosis predictive biomarker and potential therapeutic target to overcome local immune evasion in lung squamous cell carcinoma.
The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression
Authors: Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I. Scher, Ouathek Ouerfelli, Filippo G. Giancotti
Journal: Cancer Cell (2019)
A Roadmap to Assess Myocardial Work
Authors: Pieter van der Bijl, Marina Kostyukevich, Mohammed El Mahdiui, Gunnar Hansen, Eigil Samset, Nina Ajmone Marsan, Jeroen J Bax, Victoria Delgado
Journal: JACC. Cardiovascular imaging (2019)

Noninvasive left ventricular (LV) myocardial work (MW) is a novel LV function parameter. It overcomes the load dependency of LV ejection fraction (LVEF) and LV strain by incorporating afterload. LVMW can be quantified noninvasively by integrating speckle tracking strain echocardiography and
RNA-sequencing reveals immunotherapy targets in gynecological cancer.
Authors: Antonios Papanicolau-Sengos, Ting-Tai Yen, Devin Dressman, Paul DePietro, Sarabjot Pabla, Mary Nesline, Jeffrey M. Conroy, Sean T. Glenn, Felicia L. Lenzo, Kunle Odunsi, Tian-Li Wang, Carl Morrison
Journal: Journal of Clinical Oncology (2019)

8 Background: We performed microsatellite instability testing and expression immune profiling of endometrioid and serous carcinomas to identify immunotherapeutic targets and histologic attribute correlates. Methods: Microsatellite instability and RNA-seq of 395 immune-related genes were performed in 37 endometrioid and 53 serous carcinomas. Each gene was ranked against a reference population and subsequently compared to a separate clinical database reference of diverse neoplasms to perform Wilcoxon ranked sum test comparisons. Benjamin-Hochberg corrected p-values are reported. Results: VTCN1, IDO1, LAG3, and components of the mTOR/AKT1 pathway were overexpressed in both endometrioid and serous carcinomas compared to the clinical database population. CD276 and NT5E were uniquely overexpressed in the endometrioid set (Table). In the endometrioid set ADGRE5 was overexpressed in endometrioid primaries when compared to their metastatic counterparts. Serous metastases relatively overexpressed HLA-DPA1 compared to their primary counterparts. Ten of 26 endometrioid cancers with available microsatellite instability status were microsatellite unstable. All serous carcinomas were microsatellite stable. There was no correlation between microsatellite instability status and expression of any gene in either endometrioid or serous cancers. Conclusions: We identified high RNA-expression of VTCN1, IDO1, CD276, and LAG3 in endometrioid and serous carcinomas while NT5E (ADORA2A ligand) was found to be uniquely upregulated in endometrioid carcinomas. These markers may play a role in immune suppression in gynecological cancers and are potential immunotherapeutic targets. The upregulation of ADGRE5 in primary endometrioid cancers and upregulation of HLA-DPA1 in metastatic serous cancers suggests immunologic differences which may be relevant to the formation of metastatic disease.
Cancer-immune checkpoint inhibition and autoimmune-related adverse events.
Authors: Joerg Rathmann, James J. Vredenburgh, Racha Demesropian, Dorothy Wakefield, Kendra Williams, Archana Purushothaman, Jessica Bello, Latha Dulipsingh
Journal: Journal of Clinical Oncology (2019)

107 Background: Immunotherapies effect adaptive or innate immune responses. Programmed-death 1 (PD-1), a cell surface protein on activated T cells, which, when bound to its ligands PD-L1 and PD-L2, inhibits T-cell activation. Inhibition can be associated with complicating immune-related adverse events (IRAEs). Immune checkpoint inhibitors (ICIs) are FDA approved for advanced NSCLC. Study aims: (1) determine if the use of ICIs nivolumab (N) and pembrolizumab (P) is associated with development of autoimmune diabetes and thyroid disease and (2) determine the impact of (N) and (P) on pre-existing autoimmunity. Methods: Prospective, biological and clinical end-point-driven study in subjects with NSCLC considered for 1st or 2nd-line treatment with N or P. Subjects were assessed for thyroid stimulation hormone (TSH), hemoglobin A1c (HbA1c), thyroid peroxidase antibodies (TPO), glutamic acid decarboxylase (GAD) antibodies and islet cell antibodies (IC) at time of treatment start and wk 16 end point. Results: 29 subjects enrolled with base-line laboratory testing of which 14 subjects could be assessed at wk 16. At baseline, 1/14 subject had abnl TSH but at week 16 all subjects had a nl TSH (p 0.0687). Subjects had nl TPO at baseline and only 1/14 had an abnl TPO at 16 weeks (p 0.1634 ) but TSH remained nl. All 14 subjects had nl GAD and IC antibodies at baseline and at 16 wks; however, 2/14 of subjects had abnl IC antibodies at 16 wks but had nl HbA1c. 6/14 had nl HbA1c at baseline and 1/6 went on to develop pre-diabetes and 1/6 developed diabetes at the 16 wks. 5/14 subjects had pre-diabetes at baseline: 1/5 had nl HbA1c while 1/5 developed diabetes at 16 wks. 2 subjects developing diabetes had no positive GAD or IC antibodies. 3/14 had diabetes at study start with no worsening of the HbA1c or diabetes-related complications at wk 16. Conclusions: ICIs can cause IRAEs. Study result suggests that treatments with N and P can cause new onset of non-immune diabetes mellitus. Clinical awareness is important while managing NSCLC patients on ICIs. Patient should be screened for diabetes and thyroid disease prior to therapy and with repeat testing so as to avoid treatment complications. Longer follow-up and further study of ICI-mediated auto-immune endocrinopathies is needed.
Abstract 18056: Modeling Duchenne Muscular Dystrophy (DMD) Cardiomyopathy Using Patient-specific Induced Pluripotent Stem Cell-derived Cardiomyocytes
Authors: Forum Kamdar, Andre Klaassen Kamdar, Christopher S Chapman, Timothy J Kamp, Joseph C Wu, Naoko Koyano-Nakagawa, Daniel J Garry
Journal: Circulation (2015)

Introduction: DMD is the most common muscular dystrophy and is characterized by the absence of dystrophin. Cardiomyopathy and associated arrhythmias have emerged as a leading cause of death in DMD. Hypothesis: We hypothesized that the pathophysiology of DMD cardiomyopathy can be modeled using DMD hiPSC-derived cardiomyocytes (CM), which can be interrogated at the cellular and molecular level. Methods: Dermal fibroblasts were obtained from patients with genetically confirmed DMD and healthy controls and reprogrammed to hiPSC using human reprogramming transcription factors. DMD and control hiPSC lines were differentiated to CMs using a directed differentiation protocol. Functional analysis including wheat-germ agglutinin co-immunoprecipitation and calcium handling was performed at d60. Results: DMD hiPSCs demonstrated DYSTROPHIN exon mutations consistent with patient mutations. DMD and control hiPSCs differentiated to beating, electrically coupled CM sheets. Quantitative western blot analysis for dystroglycan complex (DGC) components and novel cardiac DGC proteins Cryab and Cypher demonstrated expression of the majority of DGC and novel cardiac DGC proteins at d60 of differentiation in control hiPSC-derived CM. Dystrophin and DGC proteins including novel cardiac DGC proteins are associated with the DGC in all control hiPSC CM at d60. DMD hiPSC-derived CM have absence of dystrophin and a disrupted DGC. We identified that cypher is absent in DMD hiPSC CM and validated this in human DMD left ventricular tissue. Calcium imaging demonstrated significantly abnormal calcium transients in DMD hiPSC-derived CM correlating to arrhythmias. Conclusion: Our results suggest that the control hiPSC-derived CMs have a largely nucleated DGC at d60 including novel cardiac DGC associated proteins. DMD hiPSCs have the hallmark absence of dystrophin and a disrupted DGC. The phenotype of increased arrhythmias in DMD patients is also reflected in DMD hiPSC CM. DMD hiPSC-derived CMs can be used as a model for investigation of DMD cardiomyopathy and further evaluation of the molecular and physiologic phenotype of DMD hiPSC cardiomyocytes will serve as a platform for testing current therapies and developing novel therapies for patients with DMD cardiomyopathy.
Spliceosomal Dysfunction Is a Critical Mediator of IDH2 Mutant Leukemogenesis
Authors: Akihide Yoshimi, Kuan-Ting Lin, Daniel Wiseman, Andrew M Intlekofer, Bo Wang, Alessandro Pastore, Mohammad Rahman, Stanley Chun-Wei Lee, Bo Liu, Jean-Baptiste Micol, Stephane De Botton, Virginie Penard-Lacronique, Alan H. Shih, Eytan M. Stein, Benjamin H Durham, Daichi Inoue, Xiao Jing Zhang, Todd Albrecht, Young Rock Chung, Shouyong Peng, Silvia Buonamici, James Palacino, Peter Smith, Craig B. Thompson, Ross L. Levine, Eric Wagner, Adrian R. Krainer, Omar Abdel-Wahab
Journal: Blood (2017)