tbuckley/cabot-search huggingface dataset:
Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling
Authors: Tian Lan, Yufeng Hu, Fengjiao Hu, Haonan Li, Yinghua Chen, Jing Zhang, Yang Yu, Shuo Jiang, Qiqing Weng, Song Tian, Tengfei Ma, Guizhi Yang, Duosheng Luo, Lexun Wang, Kunping Li, Shenghua Piao, Xianglu Rong, Jiao Guo
Journal: Journal of Hepatology (2021)

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme. However, the roles of GSTM2 in NASH have not been elucidated.Multiple RNA-seq analyses were used to identify hepatic GSTM2 expression in NASH. In vitro and in vivo gain- or loss-of-function approaches were used to investigate the role and molecular mechanism of GSTM2 in NASH.We identified GSTM2 as a sensitive responder and effective suppressor of NASH progression. GSTM2 was significantly downregulated during NASH progression. Hepatocyte GSTM2 deficiency markedly aggravated insulin resistance, hepatic steatosis, inflammation and fibrosis induced by a high-fat diet and a high-fat/high-cholesterol diet. Mechanistically, GSTM2 sustained MAPK pathway signaling by directly interacting with apoptosis signal-regulating kinase 1 (ASK1). GSTM2 directly bound to the N-terminal region of ASK1 and inhibited ASK1 N-terminal dimerization to subsequently repress ASK1 phosphorylation and the activation of its downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction.These data demonstrated that hepatocyte GSTM2 is an endogenous suppressor that protects against NASH progression by blocking ASK1 N-terminal dimerization and phosphorylation. Activating GSTM2 holds promise as a therapeutic strategy for NASH.IIT-2021-277.New therapeutic strategies for non-alcoholic steatohepatitis are urgently needed. We identified that the protein GSTM2 exerts a protective effect in response to metabolic stress. Therapies that aim to increase the activity of GSTM2 could hold promise for the treatment of non-alcoholic steatohepatitis.
Outcomes of triple class (proteasome inhibitor, IMiDs and monoclonal antibody) refractory patients with multiple myeloma
Authors: Saurabh Zanwar, Matthew Ho, Prashant Kapoor, Angela Dispenzieri, Martha Q. Lacy, Morie A. Gertz, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Taxiarchis Kourelis, Amie Fonder, Miriam Hobbs, Yi Hwa, Wilson Gonsalves, Rahma Warsame, Eli Muchtar, Nelson Leung, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar
Journal: Leukemia (2021)
Lethal variants in humans: lessons learned from a large molecular autopsy cohort
Authors: Hanan E. Shamseldin, Lama AlAbdi, Sateesh Maddirevula, Hessa S. Alsaif, Fatema Alzahrani, Nour Ewida, Mais Hashem, Firdous Abdulwahab, Omar Abuyousef, Hiroyuki Kuwahara, Xin Gao, Hesham Aldhalaan, Abdullah Alfaifi, Amal Alhashem, Khalid Alhasan, Maha Alnemer, Nada Alsahan, Suad Alyamani, Hamad Alzaidan, Kerr Brownyn, Angela Condie, Eissa Faqeih, Rubina Khan, Wesam Kurdi, Osama Muthaffar, Amira Nabil, William Newman, Mohammad M. Al-Qattan, Zuhair Rahbeeni, Rawda Sunbul, Mohamad-Hani Temsah, Maha Tulbah, Mohammed Zain, Fowzan S. Alkuraya
Journal: Genome Medicine (2021)

Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans. We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels. The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results. Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.
Correction: Mapping and role of T cell response in SARS-CoV-2–infected mice
Authors: Zhen Zhuang, Xiaomin Lai, Jing Sun, Zhao Chen, Zhaoyong Zhang, Jun Dai, Donglan Liu, Yuming Li, Fang Li, Yanqun Wang, Airu Zhu, Junxiang Wang, Wenhui Yang, Jicheng Huang, Xiaobo Li, Lingfei Hu, Liyan Wen, Jianfen Zhuo, Yanjun Zhang, Dingbin Chen, Suxiang Li, Shuxiang Huang, Yongxia Shi, Kui Zheng, Nanshan Zhong, Jingxian Zhao, Dongsheng Zhou, Jincun Zhao
Journal: The Journal of Experimental Medicine (2021)

The authors regret that the amino acid sequence of one of the T epitopes in Table 1 was incorrect.The corrected table is shown here, with new data in red.
Variation in severity-adjusted resource use and outcome in intensive care units
Authors: Jukka Takala, André Moser, Rahul Raj, Ville Pettilä, Irina Irincheeva, Tuomas Selander, Olli Kiiski, Tero Varpula, Matti Reinikainen, Stephan M. Jakob
Journal: Intensive Care Medicine (2021)

Intensive care patients have increased risk of death and their care is expensive. We investigated whether risk-adjusted mortality and resources used to achieve survivors change over time and if their variation is associated with variables related to intensive care unit (ICU) organization and structure.Data of 207,131 patients treated in 2008-2017 in 21 ICUs in Finland, Estonia and Switzerland were extracted from a benchmarking database. Resource use was measured using ICU length of stay, daily Therapeutic Intervention Scoring System Scores (TISS) and purchasing power parity-adjusted direct costs (2015-2017; 17 ICUs). The ratio of observed to severity-adjusted expected resource use (standardized resource use ratio; SRUR) was calculated. The number of expected survivors and the ratio of observed to expected mortality (standardized mortality ratio; SMR) was based on a mortality prediction model covering 2015-2017. Fourteen a priori variables reflecting structure and organization were used as explanatory variables for SRURs in multivariable models.SMR decreased over time, whereas SRUR remained unchanged, except for decreased TISS-based SRUR. Direct costs of one ICU day, TISS score and ICU admission varied between ICUs 2.5-5-fold. Differences between individual ICUs in both SRUR and SMR were up to > 3-fold, and their evolution was highly variable, without clear association between SRUR and SMR. High patient turnover was consistently associated with low SRUR but not with SMR.The wide and independent variation in both SMR and SRUR suggests that they should be used together to compare the performance of different ICUs or an individual ICU over time.
OA11.01 Neoadjuvant Pembrolizumab for Early Stage Non-Small Cell Lung Cancer
Authors: J. Bar, D. Urban, I. Redinsky, A. Ackerstein, S. Daher, I. Kamer, A. Onn, T. Shulimzon, M. Peled, N. Zeitlin, R. Kremer, S. Raskin, A. Ben-Nun, M. Perelman, E. Ofek
Journal: Journal of Thoracic Oncology (2021)
Can static hyperinflation predict exercise capacity in COPD?
Authors: I. Ladeira, P. Oliveira, J. Gomes, R. Lima, M. Guimarães
Journal: Pulmonology (2021)

The diagnosis and severity assessment of COPD relies on spirometry, and in particular the FEV1. However, it has been proposed that hyperinflation and air-trapping are better predictors of exercise capacity and mortality than the FEV1.QUESTION: Does static hyperinflation predict exercise capacity?We conducted an observational prospective study. Patients with COPD referred to the lung function laboratory were consecutively recruited. Patients with hyperinflation (the experimental group) were compared to patients without hyperinflation (the control group). The sample sizes were determined assuming an effect size of 0.5 and a power of 0.80.We recruited 124 participants, of whom 87% were male, the mean age was 66.1 ± 8.8 years. 67% were symptomatic (GOLD B or D). Airflow limitation was moderate to severe in the majority of patients (median FEV1 47%, IQR 38-65%) and 43% of patients had static hyperinflation. The median 6MWD was 479 meters (404-510) and peak workload in CPET was 64 watts (46-88) with peak VO2 1.12 L/min, 0.89-1.31 L/min. Patients with lower FEV1, DLCO and IC/TLC and higher RV/TLC had reduced exercise capacity in both 6MWT and CPET, measured as lower distance, greater desaturation and ∆Borg dyspnoea, and reduced workload, peak VO2 and peak VE and higher desaturation and ventilatory limitation (VE/MVV). An IC/TLC < 0.33 predicted reduced exercise performance (peak O2 <60%). Dyspnoea assessed by mMRC and QoL measured by CAT and CCQ were also worse in the hyperinflation in COPD patients.In COPD patients, IC/TLC and RV/TLC are valuable predictors of exercise performance in both 6MWT and CPET and PRO.
P06.09 Lobectomy for Lung Cancer, What Is the Brazilian reality? Brazilian Society of Thoracic Surgeons Analysis
Authors: M.T. Tsukazan, M. Soares, A. Miotto, M. Saueressig, G. Fortunato, S. Camargo, H. Oliveira, A. Vigo, L. Brand, S. De Sateles, R. Terra
Journal: Journal of Thoracic Oncology (2021)
Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis
Authors: Raymond Chen, Charles A. Ishak, Daniel D. De Carvalho
Journal: Cancer Discovery (2021)

Abstract Features of the cancer epigenome distinguish cancers from their respective cell of origin and establish therapeutic vulnerabilities that can be exploited through pharmacologic inhibition of DNA- or histone-modifying enzymes. Epigenetic therapies converge with cancer immunotherapies through “viral mimicry,” a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons. This review describes the initial characterization and expansion of viral mimicry–inducing approaches as well as features that “prime” cancers for viral mimicry induction. Increased understanding of viral mimicry in therapeutic contexts suggests potential physiologic roles in cellular homeostasis. Significance: Recent literature establishes elevated cytosolic double strand RNA (dsRNA) levels as a cancer-specific therapeutic vulnerability that can be elevated by viral mimicry–inducing therapies beyond tolerable thresholds to induce antiviral signaling and increase dependence on dsRNA stress responses mediated by ADAR1. Improved understanding of viral mimicry signaling and tolerance mechanisms reveals synergistic treatment combinations with epigenetic therapies that include inhibition of BCL2, ADAR1, and immune checkpoint blockade. Further characterization of viral mimicry tolerance may identify contexts that maximize efficacy of conventional cancer therapies.
MA08.02 Outcomes of Early Stage ALK-positive NSCLC patients in a Real-World Cohort
Authors: S. Schmid, S. Chotai, S. Cheng, L. Zhan, K. Balaratnam, K. Khan, D. Patel, M.C. Brown, W. Xu, P. Moriarty, O. Kaidanovich-Beilin, F.A. Shepherd, A. Sacher, N. Leighl, P. Bradbury, G. Liu
Journal: Journal of Thoracic Oncology (2021)
FP16.04 A Nationwide Population-Based Mapping of Mutations and Gene Fusions in Lung Cancer Among Never-Smokers
Authors: A. Salomonsson, M. Jönsson, A. Behndig, B. Bergman, J. Botling, E. Brandén, H. Koyi, H. Brunnström, L. De Petris, G. Helenius, A. Hussein, M. Johansson, M. Kentson, K. Lamberg, R. Lewensohn, U. Mager, N. Monsef, C. Ortiz-Villalon, A. Patthey, J. Sundh, A. Vikström, G. Wagenius, J. Staaf, M. Planck
Journal: Journal of Thoracic Oncology (2021)
The unfolded protein response sensitizes human melanoma cells to TRAIL-induced apoptosis by selective up-regulation of TRAIL-R2
Authors: Xu Dong Zhang, Chen Chen Jiang, Li Hua Chen, Susan Gillespie, Kelly Kiejda, Peter Hersey
Journal: Cancer Research (2007)

4576  Our past studies have shown that melanoma may not respond to treatment with TRAIL unless given with agents that increase the cell surface expression of TRAIL death receptors, in particular, TRAIL-R2. In the course of searching for such agents, we examined a large array of currently available chemotherapeutic drugs and those in development for clinical applications, and found none of the agents tested could up-regulate TRAIL death receptor expression on melanoma cells. In contrast, treatment with the ER stress inducer Tunicamycin (TM) or Thapsigargin (TG) selectively up-regulated TRAIL-R2 on the melanoma cell surface and sensitized melanoma cells to TRAIL-induced apoptosis. Although this was associated with an increase in TRAIL-R2 transcription and up-regulation of the TRAIL-R2 total protein levels, kinetic studies indicated that the increase in TRAIL-R2 on the cell surface occurred as rapidly as up-regulation of TRAIL-R2 mRNA and the total protein contents. In addition, inhibition of protein synthesis by CHX did not appreciably block up-regulation of TRAIL-R2 on the cell surface at early stages after exposure to TM or TG. The unfolded protein response (UPR) appeared to be the up-stream signaling of up-regulation of TRAIL-R2 by either TM or TG, as inhibition of the UPR mediators IRE1α, ATF6, and PERK, respectively, by siRNA blocked the increase in TRAIL-2 to varying degrees in a cell line-dependent manner. Notably, siRNA knockdown of the UPR effector, the transcription factor CHOP, had only a minor effect on the initiation of up-regulation of TRAIL-2 on the cell surface. However, it markedly blocked the increase in TRAIL-R2 at late stages after exposure to TM or TG. Taken together, the UPR induced by TM or TG sensitizes melanoma cells to TRAIL-induced apoptosis by selective up-regulation of TRAIL-R2 via increasing its transcription and translocation onto the cell surface. These results suggest that the role of the UPR in sensitization of melanoma cells to TRAIL-induced apoptosis is worthy of further investigation for development of effective treatment of melanoma with TRAIL.
Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment
Authors: Youmna Kfoury, Ninib Baryawno, Nicolas Severe, Shenglin Mei, Karin Gustafsson, Taghreed Hirz, Thomas Brouse, Elizabeth W Scadden, Anna A Igolkina, Konstantinos Kokkaliaris, Bryan D Choi, Nikolas Barkas, Mark A Randolph, John H Shin, Philip J Saylor, David T Scadden, David B Sykes, Peter V Kharchenko
Journal: Cancer Cell (2021)
Abstract 232: Three-Dimensional Models of Complex Interactions Between Age, Prehospital Blood Pressure, and Mortality in Major Traumatic Brain Injury
Authors: Daniel W Spaite, Chengcheng Hu, Bentley J Bobrow, Bruce J Barnhart, Vatsal Chikani, Joshua B Gaither, Kurt R Denninghoff, Amber D Rice, Samuel M Keim
Journal: Circulation (2018)

Background: Traumatic brain injury (TBI) studies with extensive prehospital data linked to trauma center (TC) outcomes have been small. Thus, risk adjusters like age and systolic BP have been treated dichotomously (e.g. age ≥55, SBP &lt;90). In contrast, the size and linkage rate (98%) of the EPIC Study allows complex analysis. Hypothesis: The interactions between age, SBP, and mortality are neither simple nor dichotomous. Methods and Inclusion: Major TBI cases, age ≥10, in EPIC (NIH 1R01NS071049) before TBI guideline implementation (1/07-3/14). Logistic regression was used to associate death with age and lowest EMS SBP, adjusted for confounders, and fitted nonparametrically using penalized thin plate regression splines through the generalized additive model. Results: Included were 13,435 cases (Excl: 6.2% missing data; Med. age 46; 67.8% male). The Figure shows 3D planar images of the associations between adjusted risk of death (vertical axis), age and SBP. Fig A reveals: 1) there is no “hypotension threshold” below 120 mmHg at any age and this inflection point increases to 135 in older adults; 2) the optimal SBP vs outcome “valley” is very broad (e.g. ~120-180 in the young) and increases with age (~135-190 in the elderly). Figs B/C reveal: 1) mortality increases across the entire spectrum of age, 2) in hypotensive cases (SBP &lt;90), mortality increases linearly with increasing age, 3) in non -hypotensive patients, the adjusted risk of death increases much more rapidly after age 40. Conclusion: Due to the small size of extant EMS studies, the evidence supporting parameters in triage guidelines (e.g. “older adults”) and EMS treatment guidelines (e.g. SBP &lt;90) is weak. This analysis reveals that: 1) the interactions between age and SBP are far more complex than previously understood, 2) the rapidly-increasing risk for “older adults” with TBI begins around age 40, 3) the inflection point for hypotension is much higher than current guidelines suggest and increases steadily with age.
QIAreach QuantiFERON-TB for the diagnosis of <i>Mycobacterium tuberculosis</i> infection
Authors: Francesca Saluzzo, Paola Mantegani, Valeria Poletti de Chaurand, Daniela Maria Cirillo
Journal: European Respiratory Journal (2021)

<b>QIAreach QFT demonstrated a good performance in diagnosing TB infection. This tool may offer technical and operational benefits over more complex IGRA ELISA-based assays, granting timely TB diagnosis in decentralised settings with limited infrastructure.</b>https://bit.ly/3n6Dxll
Retinal Artery Thrombosis and Aortic Valve Vegetations
Authors: Shree K. Kurup, Miroslav Sekulic, Alan H. Markowitz
Journal: JAMA (2021)

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Biomimetic Scaffolds Modulate the Posttraumatic Inflammatory Response in Articular Cartilage Contributing to Enhanced Neoformation of Cartilaginous Tissue In Vivo
Authors: Guillermo Bauza‐Mayol, Marcos Quintela, Ava Brozovich, Michael Hopson, Shazad Shaikh, Fernando Cabrera, Aaron Shi, Federica Banche Niclot, Francesca Paradiso, Emman Combellack, Tom Jovic, Paul Rees, Ennio Tasciotti, Lewis W. Francis, Patrick Mcculloch, Francesca Taraballi
Journal: Advanced Healthcare Materials (2021)

Focal chondral lesions of the knee are the most frequent type of trauma in younger patients and are associated with a high risk of developing early posttraumatic osteoarthritis. The only current clinical solutions include microfracture, osteochondral grafting, and autologous chondrocyte implantation. Cartilage tissue engineering based on biomimetic scaffolds has become an appealing strategy to repair cartilage defects. Here, a chondrogenic collagen-chondroitin sulfate scaffold is tested in an orthotopic Lapine in vivo model to understand the beneficial effects of the immunomodulatory biomaterial on the full chondral defect. Using a combination of noninvasive imaging techniques, histological and whole transcriptome analysis, the scaffolds are shown to enhance the formation of cartilaginous tissue and suppression of host cartilage degeneration, while also supporting tissue integration and increased tissue regeneration over a 12 weeks recovery period. The results presented suggest that biomimetic materials could be a clinical solution for cartilage tissue repair, due to their ability to modulate the immune environment in favor of regenerative processes and suppression of cartilage degeneration.
Peritoneal metastasis of colorectal cancer (pmCRC): identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models
Authors: Mathias Dahlmann, Guido Gambara, Bernadette Brzezicha, Oliver Popp, Eva Pachmayr, Lena Wedeken, Alina Pflaume, Margarita Mokritzkij, Safak Gül-Klein, Andreas Brandl, Caroline Schweiger-Eisbacher, Philipp Mertins, Jens Hoffmann, Ulrich Keilholz, Wolfgang Walther, Christian Regenbrecht, Beate Rau, Ulrike Stein
Journal: Molecular Cancer (2021)