tbuckley/cabot-search huggingface dataset:
Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth
Authors: Xin Chen, Norhan Amar, Yuankui Zhu, Chunguang Wang, Chunjiao Xia, Xiaoqing Yang, Dongde Wu, Mingqian Feng
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Small cell lung cancer (SCLC) accounts for 15% of lung cancers, and the primary treatment of this malignancy is chemotherapy and radiotherapy. Delta-like 3 (DLL3) is an attractive target for SCLC immunotherapy since its expression is highly restricted to SCLC with a neglectable appearance on normal adult tissues. In the current study, we aimed to explore the efficacy of DLL3-targeted SCLC immunotherapy via the engagement of T cell. Methods As a proof of concept, we constructed DLL3-targeted bispecific antibody and chimeric antigen receptor (CAR)-modified T cells. In vitro and in vivo tumor-suppression activity of these treatments alone or in combination with a Program Death-1 (PD-1) inhibitory antibody was evaluated. Results In vitro studies showed that both DLL3 bispecific antibody and CAR-T efficiently killed DLL3-positive cancer cells, including the native SCLC cell lines H446, H196, H82, and the artificial A431 cells that were forcefully overexpressing DLL3. In vivo studies in xenograft mouse models demonstrated that both bispecific antibody and CAR-T suppressed the tumor growth, and combination therapy with PD-1 inhibitory antibody dramatically improved the efficacy of the DLL3 bispecific antibody, but not the CAR-T cells. Conclusions Our results demonstrated that DLL3-targeted bispecific antibody plus PD-1 inhibition was effective in controlling SCLC growth.
Abstract A06: Multiplatform analysis of early-stage cancer signatures in blood
Authors: Bingsi Li, Chenyang Wang, Jiayue Xu, Shuai Fang, Fujun Qiu, Jing Su, Huiling Chu, Han Han-Zhang, Xinru Mao, Hao Liu, Xianling Liu, Wei Zhang, Heng Zhao, Zhihong Zhang
Journal: Clinical Cancer Research (2020)

Abstract Background: Detection of cancer in its early stages is likely to be the most effective way to improve clinical outcome. In patients with cancer, a portion of cell-free DNA (cfDNA) in the blood stream is tumor derived, providing an opportunity to analyze the cancer genome in real time noninvasively. MERMAID is a retrospective multicenter case-control study to investigate early tumor signatures in blood using different platforms. Methods: The study was conducted among 452 surgery-resectable patients with lung cancer (N=180), colorectal cancer (N=210), liver cancer (N=62), and 290 age-/sex- matched non-cancer controls. Patients who were recognized to have anemia, autoimmune diseases, treated with neoadjuvant therapy were excluded from the study. The non-cancer controls were recruited with the criteria of showing no clinical symptoms or history of cancer at time of administration. The participants were divided into subgroups and analyzed by ultra-deep mutation sequencing (HS-UMI), droplet digital PCR (ddPCR), and deep methylation sequencing (ELSA-seq) singly or in combination. Results: Overall, the highest accuracy was achieved using ELSA-seq and will be reported in full. Highly similar classification results were obtained in training and test sets, with the area under the curve (AUC) value ranging from 0.90-0.97. The specificity for each cancer type ranged from 96-99%, and the average sensitivities with 95CI were lung cancer (61%, 53-70%), colorectal cancer (82%, 76-87%), and hepatocellular cancer (91%, 80-96%). Moreover, incorporation of somatic variants and epigenetic alterations improved the overall accuracy. Conclusions: This study highlighted the potential of machine learning-aided deep methylation sequencing as a sensitive ctDNA profiling approach for early cancer detection. Further investigation in large-scale clinical studies is ongoing. Citation Format: Bingsi Li, Chenyang Wang, Jiayue Xu, Shuai Fang, Fujun Qiu, Jing Su, Huiling Chu, Han Han-Zhang, Xinru Mao, Hao Liu, Xianling Liu, Wei Zhang, Heng Zhao, Zhihong Zhang. Multiplatform analysis of early-stage cancer signatures in blood [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A06.
Targeting the coding sequence: opposing roles in regulating classical and non-classical MHC class I molecules by miR-16 and miR-744
Authors: Michael Friedrich, Christoforos K Vaxevanis, Katharina Biehl, Anja Mueller, Barbara Seliger
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background To control gene expression, microRNAs (miRNAs) are of key importance and their deregulation is associated with the development and progression of various cancer types. In this context, a discordant messenger RNA/protein expression pointing to extensive post-transcriptional regulation of major histocompatibility complex (MHC) class I molecules was already shown. However, only a very limited number of miRNAs targeting these molecules have yet been identified. Despite an increasing evidence of coding sequence (CDS)-located miRNA binding sites, there exists so far, no detailed study of the interaction of miRNAs with the CDS of MHC class I molecules. Methods Using an MS2-tethering approach in combination with small RNA sequencing, a number of putative miRNAs binding to the CDS of human leukocyte antigen (HLA)-G were identified. These candidate miRNAs were extensively screened for their effects in the HLA-G-positive JEG3 cell line. Due to the high sequence similarity between HLA-G and classical MHC class I molecules, the impact of HLA-G candidate miRNAs on HLA class I surface expression was also analyzed. The Cancer Genome Atlas data were used to correlate candidate miRNAs and HLA class I gene expression. Results Transfection of candidate miRNAs revealed that miR-744 significantly downregulates HLA-G protein levels. In contrast, overexpression of the candidate miRNAs miR-15, miR-16, and miR-424 sharing the same seed sequence resulted in an unexpected upregulation of HLA-G. Comparable results were obtained for classical MHC class I members after transfection of miRNA mimics into HEK293T cells. Analyses of The Cancer Genome Atlas data sets for miRNA and MHC class I expression further validated the results. Conclusions Our data expand the knowledge about MHC class I regulation and showed for the first time an miRNA-dependent control of MHC class I antigens mediated by the CDS. CDS-located miRNA binding sites could improve the general use of miRNA-based therapeutic approaches as these sites are highly independent of structural variations (e.g. mutations) in the gene body. Surprisingly, miR-16 family members promoted MHC class I expression potentially in a gene activation-like mechanism.
Restoring glucose uptake rescues neutrophil dysfunction and protects against systemic fungal infection in mouse models of kidney disease
Authors: Chetan V. Jawale, Kritika Ramani, De-dong Li, Bianca M. Coleman, Rohan S. Oberoi, Saran Kupul, Li Lin, Jigar V. Desai, Greg M. Delgoffe, Michail S. Lionakis, Filitsa H. Bender, Alexander J. Prokopienko, Thomas D. Nolin, Sarah L. Gaffen, Partha S. Biswas
Journal: Science Translational Medicine (2020)

Metabolic reprogramming with a GSK3β inhibitor corrects neutrophil dysfunction and improves antifungal function in mouse models of kidney disease.
International trends in oesophageal cancer survival by histological subtype between 1995 and 2014
Authors: Eileen Morgan, Isabelle Soerjomataram, Anna T Gavin, Mark J Rutherford, Piers Gatenby, Aude Bardot, Jacques Ferlay, Oliver Bucher, Prithwish De, Gerda Engholm, Christopher Jackson, Serena Kozie, Alana Little, Bjorn Møller, Lorraine Shack, Hanna Tervonen, Vicky Thursfield, Sally Vernon, Paul M Walsh, Ryan R Woods, Christian Finley, Neil Merrett, Dianne L O’Connell, John V Reynolds, Freddie Bray, Melina Arnold
Journal: Gut (2020)

Introduction Survival from oesophageal cancer remains poor, even across high-income countries. Ongoing changes in the epidemiology of the disease highlight the need for survival assessments by its two main histological subtypes, adenocarcinoma (AC) and squamous cell carcinoma (SCC). Methods The ICBP SURVMARK-2 project, a platform for international comparisons of cancer survival, collected cases of oesophageal cancer diagnosed 1995 to 2014, followed until 31 st December 2015, from cancer registries covering seven participating countries with similar access to healthcare (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK). 1-year and 3-year age-standardised net survival alongside incidence rates were calculated by country, subtype, sex, age group and period of diagnosis. Results 111 894 cases of AC and 73 408 cases of SCC were included in the analysis. Marked improvements in survival were observed over the 20-year period in each country, particularly for AC, younger age groups and 1 year after diagnosis. Survival was consistently higher for both subtypes in Australia and Ireland followed by Norway, Denmark, New Zealand, the UK and Canada. During 2010 to 2014, survival was higher for AC compared with SCC, with 1-year survival ranging from 46.9% (Canada) to 54.4% (Ireland) for AC and 39.6% (Denmark) to 53.1% (Australia) for SCC. Conclusion Marked improvements in both oesophageal AC and SCC survival suggest advances in treatment. Less marked improvements 3 years after diagnosis, among older age groups and patients with SCC, highlight the need for further advances in early detection and treatment of oesophageal cancer alongside primary prevention to reduce the overall burden from the disease.
Impact of Left Atrial Phasic Function in Heart Failure With Preserved Ejection Fraction
Authors: Robert Schönbauer, Andreas A. Kammerlander, Franz Duca, Stefan Aschauer, Christina Binder, Caroline Zotter-Tufaro, Christian Nitsche, Lukas Fiedler, Franz Xaver Roithinger, Christian Loewe, Diana Bonderman, Christian Hengstenberg, Julia Mascherbauer
Journal: JACC. Cardiovascular imaging (2020)
Comparing the efficacy and tolerability of biologic therapies in psoriasis: an updated network meta‐analysis
Authors: S.K. Mahil, M.C. Ezejimofor, L.S. Exton, L. Manounah, A.D. Burden, L.C. Coates, M. Brito, A. McGuire, R. Murphy, C.M. Owen, R. Parslew, R.T. Woolf, Z.Z.N. Yiu, O.A. Uthman, M.F. Mohd Mustapa, C.H. Smith
Journal: British Journal of Dermatology (2020)

The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development.To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis.We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10-16 weeks, followed by assessments of study quality, heterogeneity and inconsistency.We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10-16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution.Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.
Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage
Authors: Juan Antonio Fafián-Labora, Jose Antonio Rodríguez-Navarro, Ana O’Loghlen
Journal: Cell Metabolism (2020)

Aging is a process of cellular and tissue dysfunction characterized by different hallmarks, including cellular senescence. However, there is proof that certain features of aging and senescence can be ameliorated. Here, we provide evidence that small extracellular vesicles (sEVs) isolated from primary fibroblasts of young human donors ameliorate certain biomarkers of senescence in cells derived from old and Hutchinson-Gilford progeria syndrome donors. Importantly, sEVs from young cells ameliorate senescence in a variety of tissues in old mice. Mechanistically, we identified sEVs to have intrinsic glutathione-S-transferase activity partially due to the high levels of expression of the glutathione-related protein (GSTM2). Transfection of recombinant GSTM2 into sEVs derived from old fibroblasts restores their antioxidant capacity. sEVs increase the levels of reduced glutathione and decrease oxidative stress and lipid peroxidation both in vivo and in vitro. Altogether, our data provide an indication of the potential of sEVs as regenerative therapy in aging.
How to interpret MICs of antifungal compounds according to the revised clinical breakpoints v. 10.0 European committee on antimicrobial susceptibility testing (EUCAST)
Authors: M.C. Arendrup, N. Friberg, M. Mares, G. Kahlmeter, J. Meletiadis, J. Guinea, M.C. Arendrup, J. Meletiadis, J. Guinea, N. Friberg, M. Mares, G. Kahlmeter, C.T. Andersen, S. Arikan-Akdagli, F. Barchiesi, E. Chryssanthou, P. Hamal, H. Järv, N. Klimko, O. Kurzai, K. Lagrou, C. Lass-Flörl, T. Matos, K. Muehlethaler, T.R. Rogers, A. Velegraki, S. Arikan
Journal: Clinical Microbiology and Infection (2020)
ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: A rodent model rescued from neonatal death
Authors: Mingming Gao, Chun Yang, Xiaowei Wang, Mengmeng Guo, Liu Yang, Shanshan Gao, Xin Zhang, Guiyun Ruan, Xiangping Li, Wenhong Tian, Guotao Lu, Xiaoyan Dong, Sisi Ma, Weiqin Li, Yuhui Wang, Haibo Zhu, Jiuming He, Hongyuan Yang, George Liu, Xunde Xian
Journal: Metabolism (2020)
Value of 3D Versus 2D Speckle-Tracking Echocardiography for RV Strain Measurement
Authors: Yuman Li, Xiaojing Wan, Qiuyue Xiao, Yanting Zhang, Wei Sun, Yuji Xie, Qingyu Zeng, Zhenxing Sun, Yali Yang, Jing Wang, Qing Lv, Heshui Shi, Li Zhang, Mingxing Xie
Journal: JACC. Cardiovascular imaging (2020)
Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial
Authors: Matthew J. Frank, Michael S. Khodadoust, Debra K. Czerwinski, Ole A.W. Haabeth, Michael P. Chu, David B. Miklos, Ranjana H. Advani, Ash A. Alizadeh, Neel K. Gupta, Lauren S. Maeda, Sunil A. Reddy, Ginna G. Laport, Everett H. Meyer, Robert S. Negrin, Andrew R. Rezvani, Wen-Kai Weng, Kevin Sheehan, Malek Faham, Ami Okada, A. Holliston Moore, Destiny L. Phillips, Irene L. Wapnir, Joshua D. Brody, Ronald Levy
Journal: The Journal of Experimental Medicine (2020)

Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.
Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine
Authors: Claire Smalley Rumfield, Samuel T Pellom, Y Maurice Morillon II, Jeffrey Schlom, Caroline Jochems
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background While prophylactic human papillomavirus (HPV) vaccines will certainly reduce the incidence of HPV-associated cancers, these malignancies remain a major health issue. PDS0101 is a liposomal-based HPV therapeutic vaccine consisting of the immune activating cationic lipid R-DOTAP and HLA-unrestricted HPV16 peptides that has shown in vivo CD8+ T cell induction and safety in a phase I study. In this report, we have employed the PDS0101 vaccine with two immune modulators previously characterized in preclinical studies and which are currently in phase II clinical trials. Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domains of the transforming growth factor-β receptor type II (TGFβRII) fused to a human IgG 1 monoclonal antibody blocking programmed cell death protein-1 ligand (PDL1), designed both as a checkpoint inhibitor and to bring the TGFβRII ‘trap’ to the tumor microenvironment (TME). NHS-interleukin-12 (NHS-IL12) is a tumor targeting immunocytokine designed to bring IL-12 to the TME and thus enhance the inflammatory Th1 response. Methods We employed TC-1 carcinoma (expressing HPV16 E6 and E7 and devoid of PDL1 expression) in a syngeneic mouse model in monotherapy and combination therapy studies to analyze antitumor effects and changes in immune cell types in the spleen and the TME. Results As a monotherapy, the PDS0101 vaccine generated HPV-specific T cells and antitumor activity in mice bearing HPV-expressing mEER oropharyngeal and TC-1 lung carcinomas. When used as a monotherapy in the TC-1 model, NHS-IL12 elicited antitumor effects as well as an increase in CD8+ T cells in the TME. When used as a monotherapy, bintrafusp alfa did not elicit antitumor effects or any increase in T cells in the TME. When all three agents were used in combination, maximum antitumor effects were observed, which correlated with increases in T cells and T-cell clonality in the TME. Conclusion These studies provide the rationale for the potential clinical use of combinations of agents that can (1) induce tumor-associated T-cell responses, (2) potentiate immune responses in the TME and (3) reduce immunosuppressive entities in the TME.
Creating misinformation: how a headline in <i>The BMJ</i> about covid-19 spread virally
Authors: Maike Winters, Ben Oppenheim, Jonas Pick, Helena Nordenstedt
Journal: BMJ (2020)

Tryptophan was measured in the cisternal CSF and brains of rats. In untreated rats there was a significant but not very close correlation between the tryptophan concentration in these two compartments. Factors that change the brain tryptophan concentration such as starvation, glucose feeding, and lithium treatment affected the CSF tryptophan in the same way as the brain tryptophan. Diurnal changes were parallel for brain and CSF. When we take into account our knowledge of the disposition of tryptophan in human CSF, these data suggest that measurement of lumbar CSF tryptophan in man may be a useful approach to the study of human brain tryptophan. However, because the correlation between brain and CSF is not very close, measurements on CSF tryptophan would be more meaningful in groups of patients than in individuals.
Simulation of Pool Testing to Identify Patients With Coronavirus Disease 2019 Under Conditions of Limited Test Availability
Authors: Alhaji Cherif, Nadja Grobe, Xiaoling Wang, Peter Kotanko
Journal: JAMA Network Open (2020)

59 40.61 0 0 0.2 3 0.82 17.87 0 0 0.3 3 0.99 0.97
Clinical characteristics and 28-day mortality of medical patients admitted with COVID-19 to a central London teaching hospital
Authors: K. Khalil, K. Agbontaen, D. McNally, A. Love, S. Mandalia, W. Banya, E. Starren, R. Dhunnookchand, H. Farne, R. Morton, G. Davies, O. Orhan, D Lai, M. Nelson, P.L. Shah, J.L. Garner
Journal: Journal of Infection (2020)
AB0335 PATIENTS IN REMISSION FREE OF DIRECTED BIOLOGICAL / SYNTHETIC DRUG. ANALYSIS OF A COHORT OF PATIENTS TREATED BY OBJECTIVES IN OPTIMIZATION FOR 6 YEARS
Authors: P. Castro, A. Aragón
Journal: Annals of the Rheumatic Diseases (2020)

Background: The goal of treatment with biological DMARDs (bDMARDs) should be the use for a limited period of time, during the called “therapeutic window of opportunity” to induce disease remission, followed by the maintenance of low activity with conventional DMARDs. We study if we achieve this goal in a cohort of patients treated by objectives in the last 6 years. Objectives: To assess the frequency and characteristics of patients with rheumatoid arthritis (RA), spondyloarthropathies (SA) and psoriatic arthritis (PsA)) treated with FB / SD who achieve remission without FB / SD. Methods: Observational and prospective study, which included a cohort of patients with RA, SA and PsA treated by objectives with FB / SD and optimized from January 2014 to December 2019. Optimization, defined as the reduction or prolongation of the interval of at least one dose, it was indicated when patients had received&gt; 6 months of treatment and were in clinical remission / low activity defined as DAS28 &lt;3.2 for RA and PsA, and BASDAI &lt;4 for SpA. All patients who managed to maintain remission without receiving FB / SD were also collected. Results: A total of 260 patients (115 RA, 69 SA and 76 PsA) were included in the study. Of the total of these patients, 32.7% received at least two treatments (“switch”). Of all the patients, 53% were optimized and according to the diagnosis: 60.9% had RA, 52.2% SA and 39.4% PsA. 5.3% of the patients were free of FB / SD: 5 patients with RA (4.34%), 8 patients with SA (11.6%) and 1 patient with PsA (1.3%). Among patients who entered clinical remission without FB / SD, 57% had received only one treatment with FB / SD while 43% of the patients had received two or more FB / SD. Only 3 of the patients with RA and 1 patient with PsA managed to be free of treatment without FB / SD or conventional DMARD. Conclusion: Remission without FB / SD treatment was rare, being higher in SA than in RA and in PsA, maintaining the same severity and frequency patterns in achieving optimization according to different pathologies (EspA&gt; AR&gt; APs). Except in the APs, more than 50% of the patients with RA and SA entered into optimization. Clinical remission without FB / SD was less frequent in the PsA probably because the MDA is more demanding than the other outcome measures and because it is a more complex and heterogeneous disease with domains controlled by various cytokines. Patients with disease-free RA or APs without FB / SD or conventional DMARD were the exception. Disclosure of Interests: None declared
Effect of JAK1/2 inhibition on High-Output Heart Failure Associated With Myeloproliferative Disease
Authors: Yuki Fujii, MD, Makoto Takei, MD, Risa Hayashi, MD, Ryuichiro Yagi, MD, Megumi Kawano, MD, Ayaka Endo, MD, Kenji Suzuki, MD, Naoki Hirata, MD, Tasuku Hasegawa, MD, Toshiyuki Takahashi, MD
Journal: JACC CardioOncology (2020)

There are reports of some patients with myeloproliferative disease (MPD) developing high-output heart failure (HOHF) ([1][1]). Another hematological disorder, multiple myeloma, is also known to be related to HOHF ([2][2]). According to the common pathological conditions in these 2 hematologic