tbuckley/cabot-search huggingface dataset:
Omics guided small molecule inhibitor screen for the identification of therapeutic vulnerabilities in metastatic lung adenocarcinoma.
Authors: Benjamin B. Morris, Lisa G. Gray, Ryan D. Gentzler, David Randolph Jones, Marty W. Mayo
Journal: Journal of Clinical Oncology (2021)

e21015 Background: Recent studies from our lab and others have demonstrated that double-strand DNA break accumulation, error-prone repair, and genomic instability are strongly linked to increased metastasis to distant organs. Our lab has shown that lung adenocarcinomas overexpressing the transcription factor MYBL2 display chronic replication stress, elevated error-prone repair, and widespread genomic instability. Importantly, this MYBL2-driven phenotype accounts for ̃21% of all lung adenocarcinomas and identifies aggressive disease enriched for metastases to brain, liver, and kidney. This study was performed to identify clinically actionable therapeutic vulnerabilities in MYBL2-driven metastatic lung adenocarcinoma. Methods: RNA-sequencing and proteomic data from the TCGA and ORIEN consortiums were mined to identify highly expressed druggable targets in MYBL2-driven lung adenocarcinomas. Identified targets were used to assemble a custom inhibitor library of 50 small molecules targeting DNA repair effectors, epigenetic factors, protein translation, kinase-signaling, autophagy, and post-translational modifications. Omics data from the Cancer Cell Line Encyclopedia was used to identify human cell line models (H1650 (pleura), H1568 (lymph node), H1299 (lymph node)) of MYBL2-driven metastatic disease. Inhibitors were tested at two doses, 5 uM and 500 nM, in triplicate, across replicate experiments. The PrestoBlue HS viability reagent was used to quantify cell viability in a 96 well plate format. The primary endpoint of this study was statistically significant cancer cell death, compared to vehicle controls. Results: Screen results demonstrated that, at nanomolar doses, inhibitors of protein translation have strong anti-tumor effects in MYBL2-driven disease. Interestingly, small molecules targeting EIF4G1 (SBI-0640756), ribosome biogenesis/RNA export (YM155), and rRNA synthesis (CX5461) were effective in inducing cell death while inhibitors blocking mTOR signaling, EIF2A phosphorylation, and EIF4F complex assembly were not. Bioinformatic analysis revealed that ̃60% of MYBL2-driven transcripts are dependent on EIF4G1 for translation. Importantly, effected transcripts include effectors controlling DNA repair, cell cycle coordination, and cell survival. Conclusions: Our data demonstrates that MYBL2-driven metastatic disease is uniquely sensitive to inhibitors of the protein translation machinery. Importantly, these inhibitors significantly outperform current standard-of-care agents cisplatin and pemetrexed. To our knowledge, our study is the first to demonstrate that blocking EIF4G1 effectively induces widespread cell death in metastatic lung adenocarcinoma models. Collectively, our work supports initiation of clinical trials testing the efficacy of SBI-0640756 in MYBL2-driven metastatic lung adenocarcinoma.
Advances and highlights in allergic rhinitis
Authors: Yuan Zhang, Feng Lan, Luo Zhang
Journal: Allergy (2021)

Allergic rhinitis (AR) is a growing public health, medical and economic problem worldwide. The current review describes the major discoveries related to AR during the past 2 years, including risk factors for the prevalence of AR, the corresponding diagnostic strategy, precise underlying immunological mechanisms, and efficient therapies for AR during the ongoing global "coronavirus disease 2019" (COVID-19) pandemic. The review further attempts to highlight future research perspectives. Increasing evidence suggests that environmental exposures, climate changes, and lifestyle are important risk factors for AR. Consequently, detailed investigation of the exposome and the connection between environmental exposures and health in the future should provide better risk profiles instead of single predictors, and also help mitigate adverse health outcomes in allergic diseases. Although patients with dual AR, a newly defined AR phenotype, display perennial and seasonal allergens-related nasal symptoms, they are only allergic to seasonal allergens, indicating the importance of measuring inflammation at the local sites. Herein, we suggest that a combination of precise diagnosis in local sites and traditional diagnostic methods may enhance the precision medicine-based approach for management of AR; however, this awaits further investigations. Apart from traditional treatments, social distancing, washing hands, and disinfection are also required to better manage AR patients in the ongoing global COVID-19 pandemic. Despite recent advances in understanding the immune mechanisms underlying the effects of allergen immunotherapy (AIT), further understanding changes of cell profiles after AIT and accurately evaluate the efficacy of AIT are required.
Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype
Authors: Laura Lecce, Yang Xu, Bhargavi V’Gangula, Nirupama Chandel, Venu Pothula, Axelle Caudrillier, Maria Paola Santini, Valentina d’Escamard, Delaine K. Ceholski, Przemek A. Gorski, Lijiang Ma, Simon Koplev, Martin Mæng Bjørklund, Johan L.M. Björkegren, Manfred Boehm, Jacob Fog Bentzon, Valentin Fuster, Ha Won Kim, Neal L. Weintraub, Andrew H. Baker, Emily Bernstein, Jason C. Kovacic
Journal: Journal of Clinical Investigation (2021)

Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class IIa HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease.
Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis
Authors: Soongu Kwak, Russell J. Everett, Thomas A. Treibel, Seokhun Yang, Doyeon Hwang, Taehoon Ko, Michelle C. Williams, Rong Bing, Trisha Singh, Shruti Joshi, Heesun Lee, Whal Lee, Yong-Jin Kim, Calvin W.L. Chin, Miho Fukui, Tarique Al Musa, Marzia Rigolli, Anvesha Singh, Lionel Tastet, Laura E. Dobson, Stephanie Wiesemann, Vanessa M. Ferreira, Gabriella Captur, Sahmin Lee, Jeanette Schulz-Menger, Erik B. Schelbert, Marie-Annick Clavel, Sung-Ji Park, Tobias Rheude, Martin Hadamitzky, Bernhard L. Gerber, David E. Newby, Saul G. Myerson, Phillipe Pibarot, João L. Cavalcante, Gerry P. McCann, John P. Greenwood, James C. Moon, Marc R. Dweck, Seung-Pyo Lee
Journal: Journal of the American College of Cardiology (2021)
Decrease in acetyl-CoA pathway utilizing butyrate-producing bacteria is a key pathogenic feature of alcohol-induced functional gut microbial dysbiosis and development of liver disease in mice
Authors: Richa Singhal, Hridgandh Donde, Smita Ghare, Kendall Stocke, Jingwein Zhang, Manicka Vadhanam, Sreelatha Reddy, Leila Gobejishvili, Paula Chilton, Swati Joshi-Barve, Wenke Feng, Craig McClain, Kristi Hoffman, Joseph Petrosino, Marius Vital, Shirish Barve
Journal: Gut Microbes (2021)

Emerging research evidence has established the critical role of the gut-liver axis in the development of alcohol-associated liver disease (ALD). The present study employed 16S rRNA gene and whole genome shotgun (WGS) metagenomic analysis in combination with a revised microbial dataset to comprehensively detail the butyrate-producing microbial communities and the associated butyrate metabolic pathways affected by chronic ethanol feeding. Specifically, the data demonstrated that a decrease in several butyrate-producing bacterial genera belonging to distinct families within the Firmicutes phyla was a significant component of ethanol-induced dysbiosis. WGS analysis of total bacterial genomes encompassing butyrate synthesizing pathways provided the functional characteristics of the microbiome associated with butyrate synthesis. The data revealed that in control mice microbiome, the acetyl-coenzyme A (CoA) butyrate synthesizing pathway was the most prevalent and was significantly and maximally decreased by chronic ethanol feeding. Further WGS analysis i) validated the ethanol-induced decrease in the acetyl-CoA pathway by identifying the decrease in two critical genes but – (butyryl-CoA: acetate CoA transferase) and buk – (butyrate kinase) that encode the terminal condensing enzymes required for converting butyryl-CoA to butyrate and ii) detection of specific taxa of butyrate-producing bacteria containing but and buk genes. Notably, the administration of tributyrin (Tb) – a butyrate prodrug - significantly prevented ethanol-induced decrease in butyrate-producing bacteria, hepatic steatosis, inflammation, and injury. Taken together, our findings strongly suggest that the loss of butyrate-producing bacteria using the acetyl-CoA pathway is a significant pathogenic feature of ethanol-induced microbial dysbiosis and ALD and can be targeted for therapy.
1434TiP MOUNTAINEER-02: Phase II/III study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC): Trial in progress
Authors: D.V. Catenacci, J.H. Strickler, K. Shitara, Y. Nakamura, Y.Y. Janjigian, A. Barzi, T. Bekaii-Saab, H.J. Lenz, H.C. Chung, J. Tabernero, T. Yoshino, S. Siena, J.G. Mayor, M.C. Palanca-Wessels, D. Xie, J.L. Marshall
Journal: Annals of Oncology (2021)
抗酸化剤、N-2-メルカプトプロピオニルグリシンは、マウス圧過負荷モデルの左心室肥大を防ぐ。
Authors: Morita T, Nishida K, Hirotani S, Tada M, Date M, Otsu K, Nakayama H, Hori M, Matsumura Y
Journal: Circulation (2002)
International consensus recommendations on key outcome measures for organ preservation after (chemo)radiotherapy in patients with rectal cancer
Authors: Emmanouil Fokas, Ane Appelt, Robert Glynne-Jones, Geerard Beets, Rodrigo Perez, Julio Garcia-Aguilar, Eric Rullier, J. Joshua Smith, Corrie Marijnen, Femke P. Peters, Maxine van der Valk, Regina Beets-Tan, Arthur S. Myint, Jean-Pierre Gerard, Simon P. Bach, Michael Ghadimi, Ralf D. Hofheinz, Krzysztof Bujko, Cihan Gani, Karin Haustermans, Bruce D. Minsky, Ethan Ludmir, Nicholas P. West, Maria A. Gambacorta, Vincenzo Valentini, Marc Buyse, Andrew G. Renehan, Alexandra Gilbert, David Sebag-Montefiore, Claus Rödel
Journal: Nature Reviews Clinical Oncology (2021)
Secretoglobins in the big picture of immunoregulation in airway diseases
Authors: Martine Mootz, Constanze A. Jakwerth, Carsten B. Schmidt‐Weber, Ulrich M. Zissler
Journal: Allergy (2021)

Abstract The proteins of the secretoglobin (SCGB) family are expressed by secretory tissues of barrier organs. They are embedded in immunoregulatory and anti‐inflammatory processes of airway diseases. This review particularly illustrates the immune regulation of SCGBs by cytokines and their implication in the pathophysiology of airway diseases. The biology of SCGBs is a complex topic of increasing importance, as they are highly abundant in the respiratory tract and can also be detected in malignant tissues and as elements of immune control. In addition, SCGBs react to cytokines, they are embedded in Th1 and Th2 immune responses, and they are expressed in a manner dependent on cell maturation. The big picture of the SCGB family identifies these factors as critical elements of innate immune control at the epithelial barriers and highlights their potential for diagnostic assessment of epithelial activity. Some members of the SCGB family have so far only been superficially examined, but have high potential for translational research.
Abstract 16585: Monocytes Up-Regulate Tlr2 Levels and Enhance Inflammatory Responses in Aortic Valve Interstitial Cells Through Paracrine Effect
Authors: Peijian Zhang, Balachandar Nedumaran, Lihua Ao, Dingli Xu, David A. Fullerton, Xianzhong Meng
Journal: Circulation (2018)

Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. Chronic valvular inflammation associated monocyte infiltration and resident macrophage activation is ...
One‐Pot Approach to Fe<sup>2+</sup>/Fe<sup>3+</sup>‐Based MOFs with Enhanced Catalytic Activity for Fenton Reaction
Authors: Xin Meng, Fan Zhang, Huanling Guo, Chunyang Zhang, Hangtong Hu, Wei Wang, Jie Liu, Xintao Shuai, Zhong Cao
Journal: Advanced Healthcare Materials (2021)

Abstract Smart theragnostic nanoplatforms exhibit great promise in clinical tumor treatment. The Fe‐based Fenton reaction in tumor sites may generate reactive oxygen species to kill cancer cells with negligible side effects on normal tissues. However, its efficiency and duration are limited by the low intracellular concentration of H 2 O 2 , weak acidicity of tumor tissue, and low catalytic activity of conventional Fenton reagents. Herein, a facile strategy is proposed to efficiently overcome these obstacles. An efficient enzymatic/Fenton‐starvation nanoreactor PMs loaded with glucose oxidase and perfluoropentane (PGPMs) is constructed through synthesizing methoxy‐PEG‐carboxymethy‐modified iron (Fe 2+ /Fe 3+ )‐based metal–organic frameworks (PMs), followed by loading glucose oxidase (GOx) and perfluoropentane (PFP). PGPMs accumulating in the tumor tissue exhibit tumor microenvironment‐responsive biodegradable behavior and unusual catalytic activity for Fenton reaction advantageous over Fe 3+ ‐based MOFs. Meanwhile, encapsulation of GOx into PGPMs further significantly increases the catalytic activity for Fenton reaction and also induces starvation therapy. PGPMs also exhibit considerable capabilities of ultrasound and tumor microenvironment‐responsive T2 MR imaging applicable for contrast‐enhanced diagnosis. Both in vitro and in vivo studies demonstrate the great diagnostic and therapeutic potentials of this nanoreactor in tumor.
Soluble and Microparticle‐Based Delivery of TLR4 and TLR9 Agonists Differentially Modulate 3D Chemotaxis of Bone Marrow‐Derived Dendritic Cells (Adv. Healthcare Mater. 15/2021)
Authors: Alexandra Atalis, J. Brandon Dixon, Krishnendu Roy
Journal: Advanced Healthcare Materials (2021)

Dendritic Cells Migration of dendritic cells (DCs) from peripheral tissues to the draining lymph-node is critical for our immune responses to vaccines and against various pathogens. In article 2001899, Alexandra Atalis, J. Brandon Dixon, and Krishnendu Roy develop a method using a microfluidic device and related statistical analyses tools to study DC migration in 3D in response to vaccine adjuvants and lymphatic chemokines. The work shows how DCs differentially respond to soluble versus particulate carriers of adjuvants and to various adjuvant types. The cover image is an artistic view depicting the interface of engineering and biology to model and study the fundamental mechanisms of immune cell migration to lymphatics from peripheral tissues. Cover art by: Victoria Lozano Escarra, Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA.
Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial
Authors: Ly-Mee Yu, Mona Bafadhel, Jienchi Dorward, Gail Hayward, Benjamin R Saville, Oghenekome Gbinigie, Oliver Van Hecke, Emma Ogburn, Philip H Evans, Nicholas P B Thomas, Mahendra G Patel, Duncan Richards, Nicholas Berry, Michelle A Detry, Christina Saunders, Mark Fitzgerald, Victoria Harris, Milensu Shanyinde, Simon de Lusignan, Monique I Andersson, Peter J Barnes, Richard E K Russell, Dan V Nicolau, Sanjay Ramakrishnan, F D Richard Hobbs, Christopher C Butler, Ly-Mee Yu, Mona Bafadhel, Jienchi Dorward, Gail Hayward, Benjamin R Saville, Oghenekome Gbinigie, Oliver van Hecke, Emma Ogburn, Philip H Evans, Nicholas PB Thomas, Mahendra G Patel, Duncan Richards, Nicholas Berry, Michelle A Detry, Christina T Saunders, Mark Fitzgerald, Victoria Harris, Milensu Shanyinde, Simon de Lusignan, Monique I Andersson, Peter J Barnes, Richard EK Russell, Dan V Nicolau, Sanjay Ramakrishnan, FD Richard Hobbs, Christopher C Butler
Journal: The Lancet (2021)
Discovery of a Carbamoyl Phosphate Synthetase 1–Deficient HCC Subtype With Therapeutic Potential Through Integrative Genomic and Experimental Analysis
Authors: Tong Wu, Guijuan Luo, Qiuyu Lian, Chengjun Sui, Jing Tang, Yanjing Zhu, Bo Zheng, Zhixuan Li, Yani Zhang, Yangqianwen Zhang, Jinxia Bao, Ji Hu, Siyun Shen, Zhao Yang, Jianmin Wu, Kaiting Wang, Yan Zhao, Shuai Yang, Shan Wang, Xinyao Qiu, Wenwen Wang, Xuan Wu, Hongyang Wang, Jin Gu, Lei Chen
Journal: Hepatology (2021)

Background and Aims Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in‐depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)‐deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. Approach and Results A pan‐cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver‐specific and was down‐regulated in HCC. A large‐scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in‐house hepatectomy cohort identified a specific CPS1‐deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography–mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate–activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient‐derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. Conclusions In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1‐deficient HCC subtype through big‐data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.
Levels of pneumococcal conjugate vaccine coverage and indirect protection against invasive pneumococcal disease and pneumonia hospitalisations in Australia: An observational study
Authors: Jocelyn Chan, Heather F. Gidding, Christopher C. Blyth, Parveen Fathima, Sanjay Jayasinghe, Peter B. McIntyre, Hannah C. Moore, Kim Mulholland, Cattram D. Nguyen, Ross Andrews, Fiona M. Russell
Journal: PLoS Medicine (2021)

Background There is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children. Methods and findings Birth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged &lt;5 years, born between 2001 and 2012 in 2 Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD; (2) all-cause pneumonia; and (3) pneumococcal and lobar pneumonia hospitalisation in undervaccinated children. Undervaccinated children received &lt;2 doses of PCV at &lt;12 months of age and no doses at ≥12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph. There were strong inverse associations between PCV coverage and the incidence of PCV7-type IPD (adjusted incidence rate ratio [aIRR] 0.967, 95% confidence interval [CI] 0.958 to 0.975, p -value &lt; 0.001), and pneumonia hospitalisations (all-cause pneumonia: aIRR 0.991 95% CI 0.990 to 0.994, p -value &lt; 0.001) among undervaccinated children. Subgroup analyses for children &lt;4 months old, urban, rural, and Indigenous populations showed similar trends, although effects were smaller for rural and Indigenous populations. Approximately 50% coverage of PCV7 among children &lt;5 years of age was estimated to prevent up to 72.5% (95% CI 51.6 to 84.4) of PCV7-type IPD among undervaccinated children, while 90% coverage was estimated to prevent 95.2% (95% CI 89.4 to 97.8). The main limitations of this study include the potential for differential loss to follow-up, geographical misclassification of children (based on residential address at birth only), and unmeasured confounders. Conclusions In this study, we observed substantial indirect protection at lower levels of PCV coverage than previously described—challenging assumptions that high levels of PCV coverage (i.e., greater than 90%) are required. Understanding the association between PCV coverage and indirect protection is a priority since the control of vaccine-type pneumococcal disease is a prerequisite for reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to substantially reduce program costs while maintaining vaccine impact.
Association of Adjuvant Immunotherapy Duration With Chronic Immune-Related Adverse Events—Reply
Authors: Douglas B. Johnson, J. Randall Patrinely, Fei Ye
Journal: JAMA Oncology (2021)

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