tbuckley/cabot-search huggingface dataset:
Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL
Authors: Tingting Zhang, Hengqi Liu, Lei Jiao, Zhenzhen Zhang, Jin He, Lanfang Li, Lihua Qiu, Zhengzi Qian, Shiyong Zhou, Wenchen Gong, Bin Meng, Xiubao Ren, Huilai Zhang, Xianhuo Wang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Targeting the PD-1/PD-L1/L2 (programmed cell death protein 1/programmed cell death ligand 1/ligand 2) pathway combined with other immunosuppressive signalings, such as CD73/A2aR (A2a adenosine receptor) adenosine signaling, has emerged as a promising strategy for cancer treatment. The genetic characteristics of these immune checkpoints need to be further investigated in diffuse large B-cell lymphoma (DLBCL). Methods We performed whole-exome sequencing/targeted deep sequencing to investigate the genetic characteristics of PD-1/PD-L1/L2 and CD73/A2aR. The immunosuppressive effect of these two pathways on the tumor microenvironment was evaluated via RNA sequencing. Single-cell RNA sequencing was further applied to investigate the dysfunctional CD8+ T cells. In addition, multiplex immunofluorescence staining was used to quantitatively assess the expression of dysfunctional CD8 + T cells in DLBCL. Results SP140 was identified as a novel translocation partner for PD-L1, and a new inversion was detected between PD-L1 and PD-L2, both leading to the upregulation of PD-L1 expression. CD73 genetic mutations did not increase mRNA and protein expression. Patients with genetically altered CD73 tended to have a better overall survival than patients with wild-type CD73. Both PD-1/PD-L1 and CD73/A2aR signaling mediated the immunosuppressive microenvironment in DLBCL. The numbers of CD8 + T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8 + T cells (R 2 =0.974, p = 0.013). According to the grades of dysfunctional CD8 + T cells we defined, grade 1 dysfunctional CD8 + T cells, with either PD-1 + or A2aR + , were significantly associated with poorer survival than grade 0 dysfunctional CD8 + T cells, with both PD-1 − and A2aR − ; and patients with grade 2 dysfunctional CD8 + T cells showed the worst clinical outcomes. Conclusions This study describes the additional genetic basis of PD-L1 overexpression and characterizes certain genetic alterations of CD73/A2aR in DLBCL. The degree of T-cell dysfunction is correlated with clinical outcomes. Strategies that reverse T-cell dysfunction by inhibiting PD-1/PD-L1/L2, particularly in combination with CD73/A2aR, may show potential as effective therapeutic options for DLBCL.
Are there outcome differences between NAFLD and metabolic‐associated fatty liver disease?
Authors: Zobair M. Younossi, James M. Paik, Reem Al Shabeeb, Pegah Golabi, Issah Younossi, Linda Henry
Journal: Hepatology (2022)

Given the association of NAFLD with metabolic risks, a name change to MAFLD is proposed. We compared the long-term outcomes of NAFLD and MAFLD.We included patients with fatty liver disease (FLD) from NHANES III and NHANES 2017-2018 (FLD defined as moderate to severe hepatic steatosis by ultrasound for NHANES III and as having a controlled attenuation parameter ≥285 dB/m for NHANES 2017-2018). NAFLD was defined as FLD without other liver diseases and excess alcohol use. Metabolic-associated fatty liver disease (MAFLD) was defined as FLD and metabolic dysfunction per criteria. All NHANES III participants had linked mortality data through December 31, 2015.NHANES III participants (n = 12,878): mean age 43.1 years old; 49.5% male; 20.3% with FLD, 16.5% with NAFLD, and 18.1% with MAFLD. NHANES 2017-2018 participants (n = 4328): mean age 48.0 years old; 49.1% male; 36.8% with FLD, 34.2% with NAFLD, and 36.3% with MAFLD. Excellent concordance was noted between MAFLD and NAFLD diagnosis in both data sets (kappa coefficient = 0.83-0.94). Except for components of each definition (e.g., alcohol use for MAFLD), no other major differences in clinical characteristics were noted. During up to 27 years of follow-up (median of 22.8 years), no differences in cumulative all-cause and cause-specific mortality were noted. In addition to the stage of fibrosis, insulin resistance was a predictor of liver mortality in NAFLD, and alcohol-associated liver disease (ALD) was a predictor of mortality in MAFLD.MAFLD and NAFLD have similar clinical profiles and long-term outcomes. The increased liver-related mortality among NAFLD is driven by insulin resistance, and among MAFLD is primarily driven by ALD.
A partial form of inherited human USP18 deficiency underlies infection and inflammation
Authors: Marta Martin-Fernandez, Sofija Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, Françoise Vuillier, Lina Franklin, Fatima Ailal, Alice Muglia Amancio, Louise Malle, Conor Gruber, Ibtihal Benhsaien, Jennie Altman, Justin Taft, Caroline Deswarte, Manon Roynard, Alejandro Nieto-Patlan, Kunihiko Moriya, Jérémie Rosain, Nathalie Boddaert, Aziz Bousfiha, Yanick J. Crow, Dragana Jankovic, Alan Sher, Jean-Laurent Casanova, Sandra Pellegrini, Jacinta Bustamante, Dusan Bogunovic
Journal: The Journal of Experimental Medicine (2022)

Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I–mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ–dependent induction of IL-12 and IL-23 is reduced owing to IFN-I–mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease.
Immunotherapy combining tumor and endothelium cell lysis with immune enforcement by recombinant MIP-3α Newcastle disease virus in a vessel-targeting liposome enhances antitumor immunity
Authors: Jin-Yan Wang, Hengyu Chen, Shu-Zhen Dai, Feng-Ying Huang, Ying-Ying Lin, Cai-Chun Wang, Lei Li, Wu-Ping Zheng, Guang-Hong Tan
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Several agents for oncolytic immunotherapy have been approved for clinical use, but monotherapy is modest for most oncolytic agents. The combination of several therapeutic strategies through recombinant and nanotechnology to engineer multifunctional oncolytic viruses for oncolytic immunotherapy is a promising strategy. Methods An endothelium-targeting iRGD-liposome encapsulating a recombinant Newcastle disease virus (NDV), which expresses the dendritic cell (DC) chemokine MIP-3α (iNDV3α-LP), and three control liposomes were constructed. MIP-3α, HMGB1, IgG, and ATP were detected by western blotting or ELISA. The chemotaxis of DCs was examined by Transwell chambers. The phenotypes of the immune cells were analyzed by flow cytometry. The antitumor efficiency was investigated in B16 and 4T1 tumor-bearing mice. Immunofluorescence and immunohistochemistry were used to observe the localization of liposomes, molecular expression and angiogenesis. Synergistic index was calculated using the data of tumor volume, tumor angiogenesis and tumor-infiltrating lymphocytes. Results Compared with NDV-LP, treatment with iNDV3α-LP and NDV3α-LP induced stronger virus replication and cell lysis in B16 and 4T1 tumor cells and human umbilical vein endothelial cells (HUVECs) with the best response observed following iNDV3α-LP treatment. B16 and 4T1 cells treated with iNDV3α-LP produced more damage-associated molecular pattern molecules, including secreted HMGB1, ATP, and calreticulin. Moreover, iNDV3α-LP specifically bound to αvβ3-expressing 4T1 cells and HUVECs and to tumor neovasculature. Tumor growth was significantly suppressed, and survival was longer in iNDV3α-LP-treated B16-bearing and 4T1-bearing mice. A mechanism study showed that iNDV3α-LP treatment initiated the strongest tumor-specific cellular and humoral immune response. Moreover, iNDV3α-LP treatment could significantly suppress tumor angiogenesis and reverse the tumor immune suppressive microenvironment in both B16-bearing and 4T1-bearing mice. Conclusions In this study, iNDV3α-LP had several functions, such as tumor and vessel lysis, MIP-3α immunotherapy, and binding to αvβ3-expressing tumor and its neovasculature. iNDV3α-LP treatment significantly suppressed tumor angiogenesis and reversed the tumor immunosuppressive microenvironment. These findings offer a strong rationale for further clinical investigation into a combination strategy for oncolytic immunotherapy, such as the formulation iNDV3α-LP in this study.
HSR22-141: Treatment Patterns and Clinical Outcomes Among Metastatic Non-Small Cell Lung Cancer Patients Without Actionable Genomic Alterations (AGAs) Previously Treated With Platinum-Based Chemotherapy and Immunotherapy
Authors: Jerome H Goldschmidt, Anupama Vasudevan, Michelle Silver, Jackie Kwong, Elizabeth Marrett
Journal: Journal of the National Comprehensive Cancer Network (2022)

"HSR22-141: Treatment Patterns and Clinical Outcomes Among Metastatic Non-Small Cell Lung Cancer Patients Without Actionable Genomic Alterations (AGAs) Previously Treated With Platinum-Based Chemotherapy and Immunotherapy" published on 31 Mar 2022 by National Comprehensive Cancer Network.
A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes
Authors: Sally Mortlock, Rosario I. Corona, Pik Fang Kho, Paul Pharoah, Ji-Heui Seo, Matthew L. Freedman, Simon A. Gayther, Matthew T. Siedhoff, Peter A.W. Rogers, Ronald Leuchter, Christine S. Walsh, Ilana Cass, Beth Y. Karlan, B.J. Rimel, Grant W. Montgomery, Kate Lawrenson, Siddhartha P. Kar
Journal: Cell Reports Medicine (2022)
REAL-WORLD COMPARISON BETWEEN INSPIRON SIROLIMUS-ELUTING STENT AND OTHER THIRD-GENERATION DRUG-ELUTING STENTS IN PATIENTS WITH ST-ELEVATION MYOCARDIAL INFARCTION SUBMITTED TO PRIMARY PERCUTANEOUS CORONARY INTERVENTION: INSTEMI REGISTRY
Authors: Gustavo Neves De Araujo, Guilherme P. Machado, Marcia Moura, Eduarda R. Guazzelli, Luiz Carlos Bergoli, Rodrigo V. Wainstein, Felipe C. Fuchs, Ana M. Krepsky, Bruno Matte, Sandro C. Goncalves, Alexandre Schaan Quadros, Marco Wainstein
Journal: Journal of the American College of Cardiology (2022)
TYPE 2 DIABETES SIGNIFICANTLY MODULATES THE POWER OF LIPOPROTEIN(A) TO PREDICT CARDIOVASCULAR EVENTS AND MORTALITY IN YOUNG CORONARY ARTERY DISEASE PATIENTS
Authors: Arthur Mader, Maximilian Maechler, Barbara Larcher, Lukas Sprenger, Valentin Grabher, Andreas Leiherer, Axel Muendlein, Alexander Vonbank, Heinz Drexel, Christoph H. Saely
Journal: Journal of the American College of Cardiology (2022)
ADVERSE CARDIOVASCULAR EVENTS ASSOCIATED WITH KINASE INHIBITORS IN THE TREATMENT OF CANCER REVEAL SPECIFIC RISK BASED ON THE KINASE INHIBITOR - A SINGLE-CENTER RETROSPECTIVE COHORT STUDY
Authors: Jennifer Kwan, Miles Shen, Michael Mankbadi, Peter Wang, Saif Zaman, Seohyuk Lee, Matthew Jiang, Weiwei Tao, Wei Wei, Narjes Akhlaghi
Journal: Journal of the American College of Cardiology (2022)
AI-GUIDED QUANTITATIVE CT: MORE ACCURATE THAN STRESS PERFUSION IMAGING FOR OBSTRUCTIVE CAD? CREDENCE SUB-ANALYSIS
Authors: Isabella Lipkin, Anha Telluri, Yumin Kim, Alfateh Sidahmed, Joseph Michael Krepp, Brian G. Choi, James P. Earls, Andrew D. Choi
Journal: Journal of the American College of Cardiology (2022)
Gentamicin Inhibits Ca2+ Channel TRPV5 and Induces Calciuresis Independent of the Calcium-Sensing Receptor–Claudin-14 Pathway
Authors: Wouter H. van Megen, Megan R. Beggs, Sung-Wan An, Patrícia G. Ferreira, Justin J. Lee, Matthias T. Wolf, R. Todd Alexander, Henrik Dimke
Journal: Journal of the American Society of Nephrology (2022)

Treatment with the aminoglycoside antibiotic gentamicin can be associated with severe adverse effects, including renal Ca2+ wasting. The underlying mechanism is unknown but it has been proposed to involve activation of the Ca2+-sensing receptor (CaSR) in the thick ascending limb, which would increase expression of claudin-14 (CLDN14) and limit Ca2+ reabsorption. However, no direct evidence for this hypothesis has been presented.We studied the effect of gentamicin in vivo using mouse models with impaired Ca2+ reabsorption in the proximal tubule and the thick ascending limb. We used a Cldn14 promoter luciferase reporter assay to study CaSR activation and investigated the effect of gentamicin on activity of the distal nephron Ca2+ channel transient receptor potential vanilloid 5 (TRPV5), as determined by patch clamp in HEK293 cells.Gentamicin increased urinary Ca2+ excretion in wild-type mice after acute and chronic administration. This calciuretic effect was unaltered in mice with genetic CaSR overactivation and was present in furosemide-treated animals, whereas the calciuretic effect in Cldn14-/- mice and mice with impaired proximal tubular Ca2+ reabsorption (claudin-2 [CLDN2]-deficient Cldn2-/- mice) was equivalent to that of wild-type mice. In vitro, gentamicin failed to activate the CaSR. In contrast, patch clamp analysis revealed that gentamicin strongly inhibited rabbit and human TRPV5 activity and chronic gentamicin administration downregulated distal nephron Ca2+ transporters.Gentamicin does not cause hypercalciuria via activation of the CaSR-CLDN14 pathway or by interfering with proximal tubular CLDN2-dependent Ca2+ reabsorption. Instead, gentamicin blocks distal Ca2+ reabsorption by direct inhibition of the Ca2+ channel TRPV5. These findings offer new insights into Ca2+ wasting in patients treated with gentamicin.
Abstract OT2-02-01: Utilization of patient reported outcomes generated by electronic medical record and smart pill bottles with follow up telehealth encounters to improve adherence to adjuvant endocrine therapy in breast cancer patients
Journal: Cancer Research (2022)

Abstract Background: The use of adjuvant endocrine therapy (ET) in the form of tamoxifen (TAM) or an aromatase inhibitor (AI) for up to 10 years is the standard of care (SOC) for women with hormone receptor positive (HR+) breast cancer (BC). These agents can reduce recurrence by 30-50% and reduce mortality by approximately 1/3 irrespective of the use of chemotherapy (CT). Many women have difficulty with long-term compliance and persistence due to side effects and may ultimately self-discontinue. In the EBCTCG meta-analysis, evaluating 20 separate trials of adjuvant TAM for 5 years versus no adjuvant TAM, there was an estimated 80% adherence. Other BC trials have demonstrated lower adherence to TAM, dropping to 50% by years 4-5. Additionally, within the first year, discontinuation rates have been reported to be as high as 20-23%. In this investigator-initiated clinical trial we aim to evaluate the utility of one of two interventions a) serial electronic medical record (EPIC) generated patient (pt) reported outcomes (PRO)and pt surveys, OR b) a smart pill bottle, in increasing adherence to adjuvant ET over a 12-month interval during the first 4 years of adjuvant ET. The study also includes research-specific Telehealth (TH) visits when indicated in response to reports of increased toxicity or non-compliance. Methods: This is the Phase II, randomized, open-label, three-arm, multi-site study that will randomize 285 pts ≥18 years of age with stage 0-III HR+ BC in a 1:1:1 fashion with 95 patients in each arm. Arm A includes standard of care (SOC) quarterly visits (in-person or TH) with the treating provider during 12 months follow-up. Arm B is SOC quarterly visits during 12 months follow up, 18 electronic surveys every 3 weeks in between the SOC visits. Arm C is SOC quarterly visits during for 12 months follow up and use of electronic smart pill bottle with daily reminders to take ET. Primary Objective is to evaluate if the intervention of utilization of automated PROs and follow up TH encounters or the utilization of Smart Pill Bottles and follow up TH encounters can improve patient adherence with adjuvant ET within 12 months of study participation during the first 4 years of ET. The secondary objective is to evaluate if these interventions can improve quality of life and decrease side effects of adjuvant ET. The trial is open with 119 patients enrolled at the time of this abstract submission. ClinicalTrials.gov Identifier: NCT04054557 Citation Format: Utilization of patient reported outcomes generated by electronic medical record and smart pill bottles with follow up telehealth encounters to improve adherence to adjuvant endocrine therapy in breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-02-01.
GAPS IN GUIDELINE-BASED LIPID-LOWERING THERAPY FOR SECONDARY PREVENTION IN THE UNITED STATES: A NATIONWIDE ANALYSIS OF 227,824 PATIENTS
Authors: Ahmed A. Kolkailah, Eric D. Peterson, Anand Gupta, Tasha Marie Boshears, Ethan Schneider, Yiqing Wang, Kristin Gillard, Marc Israel, Ann Marie Navar
Journal: Journal of the American College of Cardiology (2022)
Development and validation of a model to predict incident chronic liver disease in the general population: The CLivD score
Authors: Fredrik Åberg, Panu K. Luukkonen, Anna But, Veikko Salomaa, Annie Britton, Kasper Meidahl Petersen, Stig Egil Bojesen, Mie Balling, Børge G. Nordestgaard, Pauli Puukka, Satu Männistö, Annamari Lundqvist, Markus Perola, Antti Jula, Martti Färkkilä
Journal: Journal of Hepatology (2022)

Current screening strategies for chronic liver disease focus on detection of subclinical advanced liver fibrosis but cannot identify those at high future risk of severe liver disease. Our aim was to develop and validate a risk prediction model for incident chronic liver disease in the general population based on widely available factors.Multivariable Cox regression analyses were used to develop prediction models for liver-related outcomes with and without laboratory measures (Modellab and Modelnon-lab) in 25,760 individuals aged 40-70 years. Their data were sourced from the Finnish population-based health examination surveys FINRISK 1992-2012 and Health 2000 (derivation cohort). The models were externally validated in the Whitehall II (n = 5,058) and Copenhagen City Heart Study (CCHS) (n = 3,049) cohorts.The absolute rate of incident liver outcomes per 100,000 person-years ranged from 53 to 144. The final prediction model included age, sex, alcohol use (drinks/week), waist-hip ratio, diabetes, and smoking, and Modellab also included gamma-glutamyltransferase values. Internally validated Wolbers' C-statistics were 0.77 for Modellab and 0.75 for Modelnon-lab, while apparent 15-year AUCs were 0.84 (95% CI 0.75-0.93) and 0.82 (95% CI 0.74-0.91). The models identified a small proportion (<2%) of the population with >10% absolute 15-year risk for liver events. Of all liver events, only 10% occurred in participants in the lowest risk category. In the validation cohorts, 15-year AUCs were 0.78 (Modellab) and 0.65 (Modelnon-lab) in the CCHS cohort, and 0.78 (Modelnon-lab) in the Whitehall II cohort.Based on widely available risk factors, the Chronic Liver Disease (CLivD) score can be used to predict risk of future advanced liver disease in the general population.Liver disease often progresses silently without symptoms and thus the diagnosis is often delayed until severe complications occur and prognosis becomes poor. In order to identify individuals in the general population who have a high risk of developing severe liver disease in the future, we developed and validated a Chronic Liver Disease (CLivD) risk prediction score, based on age, sex, alcohol use, waist-hip ratio, diabetes, and smoking, with or without measurement of the liver enzyme gamma-glutamyltransferase. The CLivD score can be used as part of health counseling, and for planning further liver investigations and follow-up.
A DEADLY MATCH: A CASE OF ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY/DYSPLASIA
Authors: Jennifer Forbes, Alex K. Patel, George Abreut, Lauren Vaughan, Tasha Heller, Ahmed Osman, Yordanka I. Reyna, Arnoux Blanchard
Journal: Journal of the American College of Cardiology (2022)
Microenvironmental stiffness mediates cytoskeleton re-organization in chondrocytes through laminin-FAK mechanotransduction
Authors: Chenchen Zhou, Mengmeng Duan, Daimo Guo, Xinmei Du, Demao Zhang, Jing Xie
Journal: International Journal of Oral Science (2022)

Abstract Microenvironmental biophysical factors play a fundamental role in controlling cell behaviors including cell morphology, proliferation, adhesion and differentiation, and even determining the cell fate. Cells are able to actively sense the surrounding mechanical microenvironment and change their cellular morphology to adapt to it. Although cell morphological changes have been considered to be the first and most important step in the interaction between cells and their mechanical microenvironment, their regulatory network is not completely clear. In the current study, we generated silicon-based elastomer polydimethylsiloxane (PDMS) substrates with stiff (15:1, PDMS elastomer vs. curing agent) and soft (45:1) stiffnesses, which showed the Young’s moduli of ~450 kPa and 46 kPa, respectively, and elucidated a new path in cytoskeleton re-organization in chondrocytes in response to changed substrate stiffnesses by characterizing the axis shift from the secreted extracellular protein laminin β1, focal adhesion complex protein FAK to microfilament bundling. We first showed the cellular cytoskeleton changes in chondrocytes by characterizing the cell spreading area and cellular synapses. We then found the changes of secreted extracellular linkage protein, laminin β1, and focal adhesion complex protein, FAK, in chondrocytes in response to different substrate stiffnesses. These two proteins were shown to be directly interacted by Co-IP and colocalization. We next showed that impact of FAK on the cytoskeleton organization by showing the changes of microfilament bundles and found the potential intermediate regulators. Taking together, this modulation axis of laminin β1-FAK-microfilament could enlarge our understanding about the interdependence among mechanosensing, mechanotransduction, and cytoskeleton re-organization.