tbuckley/cabot-search huggingface dataset:
Safety and Efficacy of Apixaban vs Enoxaparin for Preventing Postoperative Venous Thromboembolism in Women Undergoing Surgery for Gynecologic Malignant Neoplasm
Authors: Saketh R. Guntupalli, Alyse Brennecke, Kian Behbakht, Anna Tayebnejad, Christopher A. Breed, Lisa Marie Babayan, Georgina Cheng, Amin A. Ramzan, Lindsay J. Wheeler, Bradley R. Corr, Carolyn Lefkowits, Jeanelle Sheeder, Koji Matsuo, Dina Flink
Journal: JAMA Network Open (2020)

Current guidelines recommend a 28-day course of enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The high cost of this medication and the low adherence rates observed in prior studies provide an opportunity to benefit patients by demonstrating the safety of a more cost-effective, easier to use thromboprophylactic.
Single nucleotide polymorphism (SNP) rs3751143 in P2RX7 is associated with therapy failure in chronic Q fever while rs7125062 in MMP1 is associated with fewer complications
Authors: S.B. Buijs, A.F.M. Jansen, J.J. Oosterheert, T. Schoffelen, P.C. Wever, A.I.M. Hoepelman, E. van de Vosse, M. van Deuren, C.P. Bleeker-Rovers
Journal: Clinical Microbiology and Infection (2020)

ObjectivesChronic Q fever is a persistent infection with the intracellular bacterium Coxiella burnetii. Development of chronic Q fever is associated with single nucleotide polymorphisms (SNPs) in genes encoding for pattern recognition receptors, for phagolysosomal pathway components and for matrix metalloproteinases (MMPs). We evaluated the association of SNPs in these innate-immunity and MMP genes with clinical outcomes.MethodsSNPs were selected from previous association studies and analysed in a cohort of patients with chronic Q fever. The primary outcome was all-cause mortality; secondary outcomes were therapy failure and chronic Q fever–related complications. Subdistribution hazard ratios (SHR) were calculated.ResultsNineteen SNPs were analysed in 134 patients with proven and 29 with probable chronic Q fever. In multivariable analysis, none of the selected SNPs was associated with all-cause mortality. However, SNP rs3751143 located in P2RX7 appeared to be associated with therapy failure (SHR 2.42; 95% confidence interval, 1.16–5.05; p 0.02), which is in line with other reports, showing that a loss of function of the P2X7 receptor leads to inefficient killing of intracellular organisms. In addition, SNP rs7125062 located in MMP1, involved in the cleavage of extracellular matrix, was associated with fewer chronic Q fever–related complications such as acute aneurysms (SHR 0.49; 95% confidence interval, 0.29–0.83; p 0.008).ConclusionsA polymorphism in P2RX7, known to lead to loss of function of the receptor and inefficient killing of intracellular organisms, and a polymorphism in MMP1 were respectively associated with more therapy failures and fewer complications such as acute aneurysms in patients with chronic Q fever.
On tuberculosis and COVID-19 co-infection
Authors: Marina Tadolini, José-María García-García, François-Xavier Blanc, Sergey Borisov, Delia Goletti, Ilaria Motta, Luigi Ruffo Codecasa, Simon Tiberi, Giovanni Sotgiu, Giovanni Battista Migliori
Journal: European Respiratory Journal (2020)

Tuberculosis is a chronic infectious disease endemic in Argentina most often localized in the lungs, caused by Mycobacterium tuberculosis. It usually afflicts poor population groups and has a significant impact on public health. COVID-19 is an acute viral disease caused by SARS-CoV-2 presenting with a typical respiratory localization, which eventually displays clinical and radiological similarities with pulmonary tuberculosis. Both entities can have a fatal outcome if they are not diagnosed and treated on time. We present a case series where pulmonary tuberculosis and COVID-19 were diagnosed simultaneously.La tuberculosis es una enfermedad infecciosa crónica endémica en la República Argentina causada por Mycobacterium tuberculosis, cuya localización más frecuente es la pulmonar. Suele afectar grupos poblacionales carenciados y tiene gran repercusión sobre la salud pública. COVID-19 es una infección viral aguda caus 101-ada por SARS-CoV-2 que tiene típico compromiso respiratorio y, en ocasiones, puede presentar similitudes clínicas y radiológicas con la tuberculosis pulmonar. Ambas entidades pueden tener desenlace fatal si no son diagnosticadas y tratadas a tiempo. Presentamos una serie de casos en los que se diagnosticó tuberculosis pulmonar y COVID-19 en forma simultánea.
Treatment options in type-2 low asthma
Authors: Timothy S.C. Hinks, Stewart J. Levine, Guy G. Brusselle
Journal: European Respiratory Journal (2020)

Monoclonal antibodies targeting IgE or the type-2 cytokines interleukin (IL)-4, IL-5 and IL-13 are proving highly effective in reducing exacerbations and symptoms in people with severe allergic and eosinophilic asthma, respectively. However, these therapies are not appropriate for 30–50% of patients in severe asthma clinics who present with non-allergic, non-eosinophilic, “type-2 low” asthma. These patients constitute an important and common clinical asthma phenotype, driven by distinct, yet poorly understood pathobiological mechanisms. In this review we describe the heterogeneity and clinical characteristics of type-2 low asthma and summarise current knowledge on the underlying pathobiological mechanisms, which includes neutrophilic airway inflammation often associated with smoking, obesity and occupational exposures and may be driven by persistent bacterial infections and by activation of a recently described IL-6 pathway. We review the evidence base underlying existing treatment options for specific treatable traits that can be identified and addressed. We focus particularly on severe asthma as opposed to difficult-to-treat asthma, on emerging data on the identification of airway bacterial infection, on the increasing evidence base for the use of long-term low-dose macrolides, a critical appraisal of bronchial thermoplasty, and evidence for the use of biologics in type-2 low disease. Finally, we review ongoing research into other pathways including tumour necrosis factor, IL-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells. We suggest that type-2 low disease frequently presents opportunities for identification and treatment of tractable clinical problems; it is currently a rapidly evolving field with potential for the development of novel targeted therapeutics.
MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy
Authors: Xiaoyu Jiang, Stephanie Dudzinski, Kathryn E Beckermann, Kirsten Young, Eliot McKinley, J Oliver McIntyre, Jeffrey C Rathmell, Junzhong Xu, John C Gore
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors, the most widespread class of immunotherapies, have demonstrated unique response patterns that are not always adequately captured by traditional response criteria such as the Response Evaluation Criteria in Solid Tumors or even immune-specific response criteria. These response metrics rely on monitoring tumor growth, but an increase in tumor size and/or appearance after starting immunotherapy does not always represent tumor progression, but also can be a result of T cell infiltration and thus positive treatment response. Therefore, non-invasive and longitudinal monitoring of T cell infiltration are needed to assess the effects of immunotherapies such as checkpoint inhibitors. Here, we proposed an innovative concept that a sufficiently large influx of tumor infiltrating T cells, which have a smaller diameter than cancer cells, will change the diameter distribution and decrease the average size of cells within a volume to a degree that can be quantified by non-invasive MRI. Methods We validated our hypothesis by studying tumor response to combination immune-checkpoint blockade (ICB) of anti-PD-1 and anti-CTLA4 in a mouse model of colon adenocarcinoma (MC38). The response was monitored longitudinally using Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED), a diffusion MRI-based method which has been previously shown to non-invasively map changes in intracellular structure and cell sizes with the spatial resolution of MRI, in cell cultures and in animal models. Tumors were collected for immunohistochemical and flow cytometry analyzes immediately after the last imaging session. Results Immunohistochemical analysis revealed that increased T cell infiltration of the tumors results in a decrease in mean cell size (eg, a 10% increase of CD3 + T cell fraction results a ~1 µm decrease in the mean cell size). IMPULSED showed that the ICB responders, mice with tumor volumes were less than 250 mm 3 or had tumors with stable or decreased volumes, had significantly smaller mean cell sizes than both Control IgG-treated tumors and ICB non-responder tumors. Conclusions IMPULSED-derived cell size could potentially serve as an imaging marker for differentiating responsive and non-responsive tumors after checkpoint inhibitor therapies, a current clinical challenge that is not solved by simply monitoring tumor growth.
Antiphospholipid Antibodies in Critically Ill Patients With COVID‐19
Authors: Meng Xiao, Yan Zhang, Shulan Zhang, Xuzhen Qin, Peng Xia, Wei Cao, Wei Jiang, Huan Chen, Xin Ding, Hua Zhao, Hongmin Zhang, Chunyao Wang, Jing Zhao, Xuefeng Sun, Ran Tian, Wei Wu, Dong Wu, Jie Ma, Yu Chen, Dong Zhang, Jing Xie, Xiaowei Yan, Xiang Zhou, Zhengyin Liu, Jinglan Wang, Bin Du, Yan Qin, Peng Gao, Minya Lu, Xin Hou, Xian Wu, Huadong Zhu, Yingchun Xu, Wen Zhang, Taisheng Li, Fengchun Zhang, Yongqiang Zhao, Yongzhe Li, Shuyang Zhang
Journal: Arthritis & Rheumatology (2020)

Objective Coagulopathy is one of the characteristics observed in critically ill patients with coronavirus disease 2019 (COVID‐19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, though their role in COVID‐19 remains unclear. This study was undertaken to determine the prevalence and characteristics of aPLs in patients with COVID‐19. Methods Sera collected from 66 COVID‐19 patients who were critically ill and 13 COVID‐19 patients who were not critically ill were tested by chemiluminescence immunoassay for anticardiolipin antibodies (aCLs), anti–β 2 ‐glycoprotein I (anti‐β 2 GPI) (IgG, IgM, and IgA), and IgG anti‐β 2 GPI–domain 1 (anti‐β 2 GPI–D1) and IgM and IgG anti–phosphatidylserine/prothrombin (anti‐PS/PT) antibodies were detected in the serum by enzyme‐linked immunosorbent assay. Results Of the 66 COVID‐19 patients in critical condition, aPLs were detected in 31 (47% ). Antiphospholipid antibodies were not present among COVID‐19 patients who were not in critical condition. The IgA anti‐β 2 GPI antibody was the most commonly observed aPL in patients with COVID‐19 and was present in 28.8% (19 of 66) of the critically ill patients, followed by IgA aCLs (17 of 66, or 25.8%) and IgG anti‐β 2 GPI (12 of 66, or 18.2%). For multiple aPLs, IgA anti‐β 2 GPI + IgA aCLs was the most common antibody profile observed (15 of 66, or 22.7%), followed by IgA anti‐β 2 GPI + IgA aCL + IgG anti‐β 2 GPI (10 of 66, or 15.2%). Antiphospholipid antibodies emerge ~35–39 days after disease onset. A dynamic analysis of aPLs revealed 4 patterns based on the persistence or transient appearance of the aPLs. Patients with multiple aPLs had a significantly higher incidence of cerebral infarction compared to patients who were negative for aPLs ( P = 0.023). Conclusion Antiphospholipid antibodies were common in critically ill patients with COVID‐19. Repeated testing demonstrating medium to high titers of aPLs and the number of aPL types a patient is positive for may help in identifying patients who are at risk of developing cerebral infarction. Antiphospholipid antibodies may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID‐19 may trigger the development of an autoimmune condition similar to the antiphospholipid syndrome (APS), referred to as “COVID‐19–induced APS‐like syndrome.” Long‐term follow‐up of COVID‐19 patients who are positive for aPLs would be of great importance in understanding the pathogenesis of this novel coronavirus.
Multisystem Inflammatory Syndrome in U.S. Children and Adolescents
Authors: Leora R. Feldstein, Erica B. Rose, Steven M. Horwitz, Jennifer P. Collins, Margaret M. Newhams, Mary Beth F. Son, Jane W. Newburger, Lawrence C. Kleinman, Sabrina M. Heidemann, Amarilis A. Martin, Aalok R. Singh, Simon Li, Keiko M. Tarquinio, Preeti Jaggi, Matthew E. Oster, Sheemon P. Zackai, Jennifer Gillen, Adam J. Ratner, Rowan F. Walsh, Julie C. Fitzgerald, Michael A. Keenaghan, Hussam Alharash, Sule Doymaz, Katharine N. Clouser, John S. Giuliano, Anjali Gupta, Robert M. Parker, Aline B. Maddux, Vinod Havalad, Stacy Ramsingh, Hulya Bukulmez, Tamara T. Bradford, Lincoln S. Smith, Mark W. Tenforde, Christopher L. Carroll, Becky J. Riggs, Shira J. Gertz, Ariel Daube, Amanda Lansell, Alvaro Coronado Munoz, Charlotte V. Hobbs, Kimberly L. Marohn, Natasha B. Halasa, Manish M. Patel, Adrienne G. Randolph
Journal: New England Journal of Medicine (2020)

Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).
cGAS-STING–mediated DNA sensing maintains CD8 <sup>+</sup> T cell stemness and promotes antitumor T cell therapy
Authors: Wenwen Li, Lu Lu, Juanjuan Lu, Xinran Wang, Chao Yang, Jingsi Jin, Lingling Wu, Xiaochuan Hong, Fanlin Li, Dongqing Cao, Yuanqin Yang, Meng Wu, Bing Su, Jinke Cheng, Xuanming Yang, Wen Di, Liufu Deng
Journal: Science Translational Medicine (2020)

Cell-intrinsic cGAS-STING–mediated DNA sensing promotes the formation of stem cell–like CD8 + T cells for effective cancer T cell therapy.
Alison E Mack
Authors: Alistair Mack
Journal: BMJ (2020)

Alison Mack, who died aged 83,was a determined and enthusiastic innovator in improving the healthcare of women. This was matched only by her dedication to her family.

Alison graduated MBChB in 1960, achieving a distinction in surgery in her finals examination. She gained experience in school health and general practice before she and the family accompanied her husband, Alistair, to Kenya, where he had been seconded to help establish …
Serum interleukin-6 and C-reactive protein are associated with survival in melanoma patients receiving immune checkpoint inhibition
Authors: Andressa S Laino, David Woods, Melinda Vassallo, Xiaozhong Qian, Hao Tang, Megan Wind-Rotolo, Jeffrey Weber
Journal: Journal for ImmunoTherapy of Cancer (2020)

Inflammatory mediators, including acute phase reactants and cytokines, have been reported to be associated with clinical efficacy in patients with melanoma and other cancers receiving immune checkpoint inhibitors (ICI). Analyses of patient sera from three large phase II/III randomized ICI trials, one of which included a chemotherapy arm, were performed to assess whether baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6) or neutrophil/lymphocyte (N/L) ratios were prognostic or predictive.Baseline and on-treatment sera were analyzed by multiplex protein assays from immunotherapy-naïve patients with metastatic melanoma randomized 1:1 on the Checkmate-064 phase II trial of sequential administration of nivolumab followed by ipilimumab or the reverse sequence. Baseline sera, and peripheral blood mononuclear cells using automated cell counting, were analyzed from treatment-naïve patients who were BRAF wild-type and randomly allocated 1:1 to receive nivolumab or dacarbazine on the phase III Checkmate-066 trial, and from treatment-naïve patients allocated 1:1:1 to receive nivolumab, ipilimumab or both ipilimumab and nivolumab on the phase III Checkmate-067 trial.Higher baseline levels of IL-6 and the N/L ratio, and to a lesser degree, CRP were associated with shorter survival in patients receiving ICI or chemotherapy. Increased on-treatment levels of IL-6 in patients on the Checkmate-064 study were also associated with shorter survival. IL-6 levels from patients on Checkmate-064, Checkmate-066 and Checkmate-067 were highly correlated with levels of CRP and the N/L ratio.IL-6, CRP and the N/L ratio are prognostic factors with higher levels associated with shorter overall survival in patients with metastatic melanoma receiving ICI or chemotherapy in large randomized trials. In a multi-variable analysis of the randomized phase III Checkmate-067 study, IL-6 was a significant prognostic factor for survival.
Bariatric gastric band removal using a gastric mural erosion technique induced with a fully covered self-expandable metal stent
Authors: Julio G. Velasquez-Rodriguez, Amador Garcia Ruiz de Gordejuela, Joan B. Gornals
Journal: Endoscopy (2020)

Laparoscopic removal of non-eroded bariatric gastric bands may lead to major complications [1]. A minimally invasive approach involving endoscopic removal is a less risky option [2]. The stent-induced mural erosion technique using self-expandable plastic stents has been reported a few times [3] [4] [5]. The use of a fully covered self-expandable metal stent (FCSEMS) is anecdotally reported [1].
A Phase II Study of Allogeneic GM-CSF–Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer
Authors: Annie A. Wu, Katherine M. Bever, Won Jin Ho, Elana J. Fertig, Nan Niu, Lei Zheng, Rose M. Parkinson, Jennifer N. Durham, Beth Onners, Anna K. Ferguson, Cara Wilt, Andrew H. Ko, Andrea Wang-Gillam, Daniel A. Laheru, Robert A. Anders, Elizabeth D. Thompson, Elizabeth A. Sugar, Elizabeth M. Jaffee, Dung T. Le
Journal: Clinical Cancer Research (2020)

Abstract Purpose: This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting. Patients and Methods: Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8–12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms. Results: Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0–12.2] for Arm A and 14.7 months (95% CI, 11.6–20.0) for Arm B (HR, 1.75; P = 0.019). Using immune-related response criteria, two partial responses (5.7%) were observed in Arm A and four (13.8%) in Arm B. GVAX + ipilimumab promoted T-cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor. Conclusions: GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.
Repurposing old drugs to fight multidrug resistant cancers
Authors: Jelena Dinić, Thomas Efferth, Alfonso T. García-Sosa, Jelena Grahovac, José M. Padrón, Ilza Pajeva, Flavio Rizzolio, Simona Saponara, Gabriella Spengler, Ivanka Tsakovska
Journal: Drug Resistance Updates (2020)
CD3xCD19 DART molecule treatment induces non-apoptotic killing and is efficient against high-risk chemotherapy and venetoclax-resistant chronic lymphocytic leukemia cells
Authors: Anne W J Martens, Susanne R Janssen, Ingrid A M Derks, Homer C Adams III, Liat Izhak, Roel van Kampen, Sanne H Tonino, Eric Eldering, Gerritje J W van der Windt, Arnon P Kater
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Bispecific antibodies are promising new therapeutics in B cell malignancies. Whether they lead to potent T cell activation despite described T cell dysfunction in chronic lymphocytic leukemia (CLL), and are able to effectively target high-risk or venetoclax-resistant samples, is currently unknown. Methods CD19 + cell lines or primary (high-risk) CLL were cocultured in vitro with healthy donor (HD) or CLL-derived T cells in the presence of a CD3xCD19 dual affinity retargeting molecule (CD3xCD19 DART). Cell cytotoxicity, T cell activation, proliferation and effector molecule production were analyzed using flow cytometry. Results Here, we report that a bispecific CD3xCD19 DART mediates efficient killing by HD T cells of CD19 + cell-lines and primary CLL cells, regardless of immunoglobulin heavy chain variable region (IGHV) mutational status TP53 status or chemotherapy, ibrutinib or venetoclax sensitivity. Whereas TCR stimulation of CLL-derived T cells resulted in dysfunctional T cell activation and proliferation, treatment with CD3xCD19 DART led to a similar activation profile in CLL-derived and HD-derived T cells. Consistently, co-culture of CLL derived T cells with JeKo-1 or CLL cells in the presence of CD3xCD19 DART resulted in significant cytotoxicity by both CD4 + and CD8 + T cells. On stimulation of CLL cells with CD40L, CLL cells become resistant to the specific inhibitor of anti-apoptotic Bcl-2 protein venetoclax, due to upregulation of Bcl-2 family members such as Bcl-XL. Nevertheless, CD40L stimulated CLL cells were as efficiently lysed on CD3xCD19 DART treatment as unstimulated CLL cells. Further examination of the mechanism of CD3xCD19 DART mediated killing showed that lysis was dependent on granules, but was independent of BAX/BAK or caspase activity, indicating non-apoptotic cell death. Conclusions These data show that CD3xCD19 DART in CLL leads to robust T cell activation and lysis of high-risk venetoclax resistant CLL cells through a non-apoptotic mechanism.