tbuckley/cabot-search huggingface dataset:
Abstract 5839: The unfolded protein response gene Ire1α is required for tissue renewal and normal differentiation in the mouse tongue and esophagus
Authors: Fiona E. Chalmers, Douglas B. Stairs, Adam B. Glick
Journal: Cancer Research (2020)

Abstract IRE1α is a well-characterized stress response signaling protein that adapts the cell to conditions of endoplasmic reticulum (ER) stress. In addition to well-established sources of ER stress such as viral infection, hypoxia and nutrient deprivation, it has recently been proposed that the morphological and epigenetic changes associated with routine cell differentiation are also a source of ER stress for the cell, and that IRE1α has an important role in adapting the cell to its newly differentiated state. Here, we provide evidence that IRE1α is essential for the differentiation of stratified squamous epithelium. We utilized mice expressing K14CreERT2 and floxed IRE1α to enable tamoxifen-inducible deletion of IRE1α targeted to the basal layer and stem cells of stratified squamous epithelium. After tamoxifen injection, IRE1α knockout mice displayed severe weight loss resulting in death within 10 days of treatment. Histological analysis revealed that epithelial homeostasis in the tongue and esophagus was severely disrupted leading to significantly decreased food intake and, as a result, death. The tongue epithelium and esophageal mucosal layer were found to be significantly thinner, and filiform papillae were lost from the tongue. Immunohistochemical staining showed significant downregulation of the proliferative marker Ki67, as well as a marker of differentiation, Sox2, suggesting an almost complete loss of tissue renewal as early as four days after IRE1α deletion. This work highlights the complexity of IRE1α signaling beyond adaptation to external sources of stress and proposes a role of IRE1α in the normal physiology of tissue homeostasis. As inhibition of the IRE1α signaling pathway has been proposed as a therapeutic target in certain cancers, an increased understanding of how broad the scope of IRE1α activity is may provide insight into potential side effects resulting from these treatments. Citation Format: Fiona E. Chalmers, Douglas B. Stairs, Adam B. Glick. The unfolded protein response gene Ire1α is required for tissue renewal and normal differentiation in the mouse tongue and esophagus [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5839.
USMLE Step 1 Scoring System Change to Pass/Fail—Implications for International Medical Graduates
Authors: Faisal Aziz, Carlos F. Bechara
Journal: JAMA Surgery (2020)

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Abstract 3621: Characterization of BRAF mutation in Chinese colorectal cancer patients using next generation sequencing
Authors: Hui Wang, Hao Wu, Yifan Zhou, Bei Zhang, Danpeng Sun, LIihua Jiang, Hui Chen, Yuezong Bai, Zhe Zhang
Journal: Cancer Research (2020)

Abstract Objective: BRAF alterations were characterized into three classes according to their dependency with upstream gene alterations in activating the MARK signaling pathway, giving clinical doctors clues of inhibitors selection for therapy. However, the characterization of BRAF mutation in Chinese colorectal cancer patients was unknown. Methods: Colorectum tissue samples were collected from 2155 patients and performed the next generation sequencing (NGS) using a validated commercial panel containing essential genes in RAS-RAF-MARK and PI3K-AKT-mTOR pathways. BRAF mutations were characterized into Class I (kinase-activated, codon 600), II (kinase-activated, non-codon 600) and III (kinase-impaired). Results: There were 9031 pathogenic and likely pathogenic somatic mutations were detected in 2137 out of 2155 samples, among which 149 (7.0%), 1048 (48.6%), 82 (3.8%), 2 (0.1%), 8 (0.4%), 362 (16.8%), 90 (4.2%) were found caring BRAF, KRAS, NRAS, HRAS, EGFR, PIK3CA and PTEN mutations, respectively. A total of 19 unique BRAF mutations were detected. The Class I (BRAFV600E), Class II and Class III accounted for 76.0%, 6.7% and 13.3% of all BRAF mutations. Higher incidence of co-occurrence of Class III mutations and RAS mutations were observed in our study, which might be due to their RAS-dependent way in activating downstream signaling pathway. Class III patients might be more sensitive to EGFR inhibitor and receive more benefits from survival than other classes. Conclusions: In our study, the mutation type, frequency, classification of BRAF mutations and co-occurrence with BRAF and other driver gene mutations were explored in a large cohort of Chinese colorectal cancer patients, which might help to suggest proper therapy methods. Citation Format: Hui Wang, Hao Wu, Yifan Zhou, Bei Zhang, Danpeng Sun, LIihua Jiang, Hui Chen, Yuezong Bai, Zhe Zhang. Characterization of BRAF mutation in Chinese colorectal cancer patients using next generation sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3621.
Poor Agreement between Commercially Available Anti-Cardiolipin and Anti-β2glycoprotein I IgG and IgM Solid Phase Assays Hampers Uniformity in the Classification of Antiphospholipid Syndrome Patients
Authors: Walid Chayouâ, Hilde Kelchtermans, Gary Moore, Jean-Christophe Gris, Jacek Musial, Denis Wahl, Stéphane Zuily, Armando Tripodi, Pierre Fontana, Jasper A. Remijn, Bas De Laat, Katrien Devreese
Journal: Blood (2017)
Expansion of atypical memory B cells is a prominent feature of COVID-19
Authors: Barbara Oliviero, Stefania Varchetta, Dalila Mele, Stefania Mantovani, Antonella Cerino, Cesare G. Perotti, Serena Ludovisi, Mario U. Mondelli
Journal: Cellular and Molecular Immunology (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus responsible for a pandemic that causes asymptomatic or paucisymptomatic infection in most individuals but may be responsible for severe interstitial pneumonia, myocarditis, acute kidney injury, hepatitis, acute respiratory distress syndrome (ARDS), multiorgan failure (MOF), and death. 1 Patients with severe coronavirus disease (COVID-19) typically show signs of hyperinflammation characterized by an exuberant host immune response leading to a virus-driven cytokine release syndrome. 2A hallmark of COVID-19 is lymphopenia, involving virtually all cell lineages, and a number of studies have provided evidence in support of altered innate and adaptive immune responses in COVID-19. 2With respect to the latter, most studies focused on phenotypic and molecular T-cell alterations; however, little or no information is available for B cells, apart from the possible role of SARS-CoV-2specific neutralizing antibodies in controlling the infection and clinical outcome.An altered distribution of B-cell subsets is usually observed in chronic viral infections, including hepatitis C and B 3,4 and HIV. 5 In an effort to identify characteristic changes that may be associated with favorable or poor outcomes in patients with COVID-19, we studied peripheral blood B-cell subsets in 17 patients presenting with severe SARS-CoV-2 infection and interstitial pneumonia with a viral RNA-positive nasopharyngeal swab or bronchoalveolar lavage.All were admitted to the hospital because of severe dyspnea requiring at least a Venturi type of mask for oxygen ventilation.Four patients required a ventilation upgrade to continuous positive airway pressure with high positive end-expiratory pressure or transfer to the ICU and intubation.Ten of these patients died because of ARDS and/or MOF.Follow-up peripheral blood mononuclear cells were available from seven recovered patients ~45 days after discharge.Seven convalescent (Conv) individuals who donated hyperimmune plasma because of serum high-titer neutralizing antibodies immediately after hospital discharge or after home quarantine were also investigated.Laboratory findings are reported in Supplementary Table 1.Thirteen clinically healthy, SARS-CoV-2 RNA-negative subjects of the same age group as the patients served as controls (HD).The study was approved by the Institutional Review Board of Fondazione IRCCS Policlinico San Matteo (prot.N. 20200038910).B cells (CD19+) were examined by flow cytometry (FACS Celesta, BD Bioscience, San Diego, CA, USA) and are shown as frequencies and absolute numbers that largely overlapped, with only a few exceptions.B cells were categorized according to the expression of CD21, CD27, and CD10 molecules as immature
Abstract 4145: Performance of IntelliPlexTM companion diagnostics application in cancer management
Authors: Lara Felicioni, Fiamma Buttitta, Antonio Marchetti, ShianPin Hu, ChenHung Chao, WenKai Liang, JuiYu Hu, Stuart Palmer, ChinShiou Huang
Journal: Cancer Research (2020)

Abstract Background: Cancer is a group of various diseases with diverse causes which lead to the uncontrolled growth of abnormal cells. Understanding the genetic alteration in genes associated with cancer optimizes therapy outcomes by tailoring treatment based on each patient genetic basis. Molecular profiling is therefore a crucial tool for precision medicine to improve cancer management. Method: The IntelliPlexTM system, based on πCodeTM technology, provides a multiplexing solution for molecular profiling in just one reaction. PlexBio developed several single target gene assays utilizing DNA samples derived from formalin-fixed paraffin-embedded (FFPE) tumor tissues. The IntelliPlex EGFR Mutation kit is intended for detection of 40 mutations in the EGFR gene. The IntelliPlex BRAF V600 Mutation Kit is designed for identification of 7 nucleotide changes. The IntelliPlex KRAS Mutation Plus kit targets 25 single nucleotide changes in the KRAS gene and the IntelliPlex NRAS Mutation qualitative detects 33 single nucleotide changes in the NRAS gene. All IntelliPlex assays analyze the mutational status of each target in less than 5 hours (nucleic acid extraction not included) and allow high-throughput screening of up to 94 samples in parallel with minimal hands-on time. The performance of IntelliPlex system was evaluated on archived FFPE DNA specimens by comparing the results of the respective IntelliPlex assay with results previously obtained using the indicated commercially available molecular assays. All tests were conducted in a hospital lab located in Italy. Results: Among 76 FFPE DNA specimens tested, the overall agreement between IntelliPlex system and the comparison method was found to be 93.4%. The individual concordance for each assay kit is 90.0%, 95.8%, 93.8%, and 93.8% for EGFR, KRAS Plus, NRAS and BRAF, respectively. Conclusion: PlexBio's IntelliPlexTM system, a multiplex detection platform, is suitable to support precision medicine in cancer management. The system offers a rapid and cost-effective way to analyze patient specimens with high sensitivity and specificity in a clinical environment. Citation Format: Lara Felicioni, Fiamma Buttitta, Antonio Marchetti, ShianPin Hu, ChenHung Chao, WenKai Liang, JuiYu Hu, Stuart Palmer, ChinShiou Huang. Performance of IntelliPlexTM companion diagnostics application in cancer management [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4145.
Abrogated GADD45b-Mediated Integrity Control of Hematopoietic Stem Cells upon ER Stress and DNA Damage Triggers Lymphopoiesis over Granulopoiesis in Congenital Neutropenia
Authors: Perihan Mir, Masoud Nasri, Benjamin Dannenmann, Karin Haehnel, Maksim Klimiankou, Cornelia Zeidler, Lothar Kanz, Karl Welte, Julia Skokowa
Journal: Blood (2017)
Abstract 5060: Establishment and characterization of humanized mouse NPC-PDX model for testing immunotherapy
Authors: Wai Nam LIU, Shin Yie FONG, Wilson Wei Sheng TAN, Sue Yee TAN, Min LIU, Narayanan Gopalakrishna IYER, Darren Wan-Teck LIM, Qingfeng CHEN
Journal: Cancer Research (2020)

Abstract Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is common in Southern China and South-East Asia. Immune checkpoint blockade (ICB) is being studied in NPC and initial monotherapy ICB studies show early promise. Currently, lack of representative NPC models limit the preclinical studies to evaluate the efficacy and safety of novel ICB and combination regimens. Hence, there is a need to develop and characterize a mouse model with human immune system for testing immunotherapy. Here, we engrafted NPC-PDX in immunodeficient NSG mice, with a successful growth rate of 16.7% (6 out of 36), and humanized mouse NPC-PDX model was established subsequently. Of note, EBV latent membrane protein-1 was retained in the NPC in both NSG and humanized mice as revealed by IHC staining. There was an increase in tumor-infiltrating CD4+ T cells and a decrease in CD8+ cytotoxic T cells in humanized mice, when compared to the immune cells profile in circulation. Intriguingly, the expression levels of various exhaustion markers, namely PD-1, CTLA4 and TIM-3 were upregulated, particularly in the tumor-infiltrating T cells. Therefore, the use of ICB, either alone or in combination, may restore the function of anti-tumor immune effector cells. Taken together, we have established a humanized mouse NPC-PDX model, which plausibly provides a robust platform to test for the efficacy and safety of ICB and combination therapy regimens. Citation Format: Wai Nam LIU, Shin Yie FONG, Wilson Wei Sheng TAN, Sue Yee TAN, Min LIU, Narayanan Gopalakrishna IYER, Darren Wan-Teck LIM, Qingfeng CHEN. Establishment and characterization of humanized mouse NPC-PDX model for testing immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5060.
Abstract 953: Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic tumor cells induce anti-tumor immunity
Authors: Sho Umegaki, Hidekazu Shirota, Chikashi Ishioka
Journal: Cancer Research (2020)

Abstract Immune cells can recognize tumor antigen and elicit an adaptive immune response against tumor cells. It has been reported that apoptotic or necrotic death of tumor cells releases tumor antigen stimulating anti-tumor immunity. However, the immune responses against apoptotic tumor cells in vivo are poorly understood. To investigate whether apoptotic tumor cells affect anti-tumor immunity, local immune responses in tumor were evaluated by induction of apoptotic tumor cells with herpes simplex virus thymidine kinase (HSVtk)/ ganciclovir (GCV) system. HSVtk gene transduced tumor cells were resulted in apoptosis in vitro. Administration of GCV triggered apoptosis in HSVtk transfected tumor cells in vivo and regressed the tumor. Comprehensive gene expression analysis of the bulk tumor showed that IFNγ and IL-12 were upregulated. CD8+ T cells were increased in the treatment group compared to the control group. The tumor regression by induction of GCV-triggered apoptosis was inhibited by anti-CD8 depleting antibody. These findings indicate that apoptotic tumor cells induce CD8+ T cell-dependent anti-tumor immunity. Citation Format: Sho Umegaki, Hidekazu Shirota, Chikashi Ishioka. Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic tumor cells induce anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 953.
Identification of new susceptibility loci associated with rheumatoid arthritis
Authors: Rui-Xue Leng, Dong-Sheng Di, Jing Ni, Xiao-Xiao Wu, Lin-Lin Zhang, Xu-Fan Wang, Rui-Shan Liu, Qian Huang, Yin-Guang Fan, Hai-Feng Pan, Bin Wang, Dong-Qing Ye
Journal: Annals of the Rheumatic Diseases (2020)

Objectives The present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA). Methods We performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function. Results We identified five new susceptibility loci ( IL12RB2 , BOLL-PLCL1 , CCR2 , TCF7 and IQGAP1 ; p meta &lt;5.00E−08) with same effect direction in each study cohort. The sensitivity analyses showed that the genetic association of at least three loci was reliable and robust. All these lead variants are expression quantitative trait loci and overlapped with epigenetic marks in immune cells. Furthermore, genes within the five loci are genetically associated with risk of other autoimmune diseases, and genes within four loci are known functional players in autoimmunity, which supports the validity of our findings. The reporter assay showed that the risk allele of rs8030390 in IQGAP1 have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in TCF7 was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets. Conclusion This study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.
Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP
Authors: Ciara L. Freeman, Kerry J. Savage, Diego R. Villa, David W. Scott, Line Srour, Alina S. Gerrie, Maura J. Brown, Graham W. Slack, Pedro Farinha, Brian Skinnider, James Morris, François Bénard, Christina Aquino-Parsons, Andrea Lo, Tom Pickles, Don C. Wilson, Petter Tonseth, Joseph M. Connors, Laurie H. Sehn
Journal: Blood (2020)
<i>E. coli</i> nitroreductase NfsA is a reporter gene for non-invasive PET imaging in cancer gene therapy applications
Authors: Alexandra Marie Mowday, Janine Naomi Copp, Sophie Philippa Syddall, Ludwig Jerome Dubois, Jingli Wang, Natasja Gabi Lieuwes, Rianne Biemans, Amir Ashoorzadeh, Maria Rosaria Abbattista, Elsie May Williams, Christopher Paul Guise, Philippe Lambin, David Francis Ackerley, Jeff Bruce Smaill, Jan Theys, Adam Vorn Patterson
Journal: Theranostics (2020)

The use of reporter genes to non-invasively image molecular processes inside cells has significant translational potential, particularly in the context of systemically administered gene therapy vectors and adoptively administered cells such as immune or stem cell based therapies.Bacterial nitroreductase enzymes possess ideal properties for reporter gene imaging applications, being of non-human origin and possessing the ability to metabolize a range of clinically relevant nitro(hetero)cyclic substrates.Methods: A library of eleven Escherichia coli nitroreductase candidates were screened for the ability to efficiently metabolize 2-nitroimidazole based positron emission tomography (PET) probes originally developed as radiotracers for hypoxic cell imaging.Several complementary methods were utilized to detect formation of cell-entrapped metabolites, including various in vitro and in vivo models to establish the capacity of the 2-nitroimidazole PET agent EF5 to quantify expression of a nitroreductase candidate.Proof-of-principle PET imaging studies were successfully conducted using 18 F-HX4.Results: Recombinant enzyme kinetics, bacterial SOS reporter assays, anti-proliferative assays and flow cytometry approaches collectively identified the major oxygen-insensitive nitroreductase NfsA from E. coli (NfsA_Ec) as the most promising nitroreductase reporter gene.Cells expressing NfsA_Ec were demonstrably labelled with the imaging agent EF5 in a manner that was quantitatively superior to hypoxia, in monolayers (2D), multicellular layers (3D), and in human tumor xenograft models.EF5 retention correlated with NfsA_Ec positive cell density over a range of EF5 concentrations in 3D in vitro models and in xenografts in vivo and was predictive of in vivo anti-tumor activity of the cytotoxic prodrug PR-104.Following PET imaging with 18 F-HX4, a significantly higher tumor-to-blood ratio was observed in two xenograft models for NfsA_Ec expressing tumors compared to the parental tumors thereof, providing verification of this reporter gene imaging approach. Conclusion:This study establishes that the bacterial nitroreductase NfsA_Ec can be utilized as an imaging capable reporter gene, with the ability to metabolize and trap 2-nitroimidazole PET imaging agents for non-invasive imaging of gene expression.