tbuckley/cabot-search huggingface dataset:
β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
Authors: Linyong Du, Jong-Ho Lee, Hongfei Jiang, Chengde Wang, Silu Wang, Zhihong Zheng, Fei Shao, Daqian Xu, Yan Xia, Jing Li, Yanhua Zheng, Xu Qian, Xinjian Li, Hyung-Ryong Kim, Dongming Xing, Pengyuan Liu, Zhimin Lu, Jianxin Lyu
Journal: The Journal of Experimental Medicine (2020)

PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8+ T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti–PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8+ T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion.
Cost-effectiveness of Universal and Targeted Hepatitis C Virus Screening in the United States
Authors: Moosa Tatar, Susana W. Keeshin, Mark Mailliard, Fernando A. Wilson
Journal: JAMA Network Open (2020)

Between 2 and 3.5 million people live with chronic hepatitis C virus (HCV) infection in the US, most of whom (approximately 75%) are not aware of their disease. Despite the availability of effective HCV treatment in the early stages of infection, HCV will result in thousands of deaths in the next decade in the US.To investigate the cost-effectiveness of universal screening for all US adults aged 18 years or older for HCV in the US and of targeted screening of people who inject drugs.This simulated economic evaluation used cohort analyses in a Markov model to perform a 10 000-participant Monte Carlo microsimulation trail to evaluate the cost-effectiveness of HCV screening programs, and compared screening programs targeting people who inject drugs with universal screening of US adults age 18 years or older. Data were analyzed in December 2019.Cost per quality-adjusted life-year (QALY).Cost per QALY gained.In a 10 000 Monte Carlo microsimulation trail that compared a baseline of individuals aged 40 years (men and women) and people who inject drugs in the US, screening and treatment for HCV were estimated to increase total costs by $10 457 per person and increase QALYs by 0.23 (approximately 3 months), providing an incremental cost-effectiveness ratio of $45 465 per QALY. Also, universal screening and treatment for HCV are estimated to increase total costs by $2845 per person and increase QALYs by 0.01, providing an incremental cost-effectiveness ratio of $291 277 per QALY.The findings of this study suggest that HCV screening for people who inject drugs may be a cost-effective intervention to combat HCV infection in the US, which could potentially decrease the risk of untreated HCV infection and liver-related mortality.
FRI0624-HPR A SYSTEMATIC REVIEW OF JOB LOSS PREVENTION INTERVENTIONS FOR PERSONS WITH INFLAMMATORY ARTHRITIS.
Authors: C. M. T. Madsen, S. Kjaer, J. Primdahl, J. R. Christensen, C. Von Bülow
Journal: Annals of the Rheumatic Diseases (2020)

Background: Persons with inflammatory arthritis (IA) have a higher level of absenteeism from work than those without IA and up to 20-30% become permanently work-disabled during the first years after being diagnosed with IA. Despite developments of new pharmacological and surgical treatments, people with IA still report reduced work ability. It is therefore relevant to offer effective interventions designed to prevent job loss and improve work function (i.e. job loss prevention interventions) to support people with IA to stay connected to the labour market. Initial effects of job loss prevention interventions have been established in a Cochrane review by Hoving et al. 2014 (1), but as only three randomized controlled trials (RCT) were identified, it seems relevant to investigate if new evidence has emerged. Objectives: The aim of this study was to present an overview of the evidence of the effect of job loss prevention interventions, which can improve work participation and decrease absenteeism and job loss in persons with IA. Methods: A systematic literature search was performed in the databases PubMed, EMBASE, CINAHL, PsycINFO and the Cochrane Library in two steps: 1) an update of the Cochrane review, restricted to studies published from January 2014 to February 2019 and 2) an additional search with updated keywords with no time restriction. Quality assessment and data extraction were performed independently by two authors. The results were summarized narratively. Results: The first search identified 1276 titles and the second search identified 2384 titles. Six studies (including the three RCT´s included in the Cochrane review (1)) were included. The results indicated that job loss prevention interventions may have effect on work ability, absenteeism and in particular job loss, but the results across study outcomes, were not consistent. This may be due to heterogeneity in the interventions delivered (i.e. dose, duration and setting) and outcome measures used. Most of the studies were of low quality. Therefore, the results should be interpreted with caution. Conclusion: Job loss prevention interventions may have an effect on work ability, absenteeism and in particular job loss among persons with IA. Further studies of high quality regarding job loss prevention interventions for people with IA are recommended. References: [1] Hoving, J.L. et al. 2014, “Non-pharmacological interventions for preventing job loss in workers with inflammatory arthritis”, The Cochrane database of systematic reviews, vol. 11;2014;, no. 11, pp. CD010208. Disclosure of Interests: Christina Merete Tvede Madsen: None declared, Sara Kjaer: None declared, Jette Primdahl Speakers bureau: BMS and Pfizer, Jeanette Reffstrup Christensen: None declared, Cecilie von Bülow: None declared
Clinical Pharmacology and Interplay of Immune Checkpoint Agents: A Yin-Yang Balance
Authors: Arthur Geraud, Paul Gougis, Aurore Vozy, Celine Anquetil, Yves Allenbach, Emanuela Romano, Elisa Funck-Brentano, Javid J. Moslehi, Douglas B. Johnson, Joe-Elie Salem
Journal: The Annual Review of Pharmacology and Toxicology (2020)

T cells have a central role in immune system balance. When activated, they may lead to autoimmune diseases. When too anergic, they contribute to infection spread and cancer proliferation. Immune checkpoint proteins regulate T cell function, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1). These nodes of self-tolerance may be exploited pharmacologically to downregulate (CTLA-4 agonists) and activate [CTLA-4 and PD-1/PD-L1 antagonists, also called immune checkpoint inhibitors (ICIs)] the immune system.CTLA-4 agonists are used to treat rheumatologic immune disorders and graft rejection. CTLA-4, PD-1, and PD-L1 antagonists are approved for multiple cancer types and are being investigated for chronic viral infections. Notably, ICIs may be associated with immune-related adverse events (irAEs), which can be highly morbid or fatal. CTLA-4 agonism has been a promising method to reverse such life-threatening irAEs. Herein, we review the clinical pharmacology of these immune checkpoint agents with a focus on their interplay in human diseases.
Abstract 4388: Weighted gene co-expression network analysis identified cell cycle signaling pathway associated hub genes correlated with progression and prognosis of multiple myeloma
Authors: Olayinka O. Adebayo, Tiara Griffen, Corey Young, Eric Dammer, James W. Lillard
Journal: Cancer Research (2020)

Abstract There is a gap in understanding the molecular mechanisms behind early relapse / multiple myeloma (MM) progression in the newly diagnosed patient on standard treatment for MM, i.e., lenalidomide, bortezomib, and dexamethasone (RVD). As a result, the relatively high percentage of patients that progress after early treatment with RVD is significant. Therefore, identification of clinically relevant clusters of co-expressed genes or representative biomarkers for MM progression, while on RVD, would help identify new molecular mechanisms and drug targets. The objective of this study is to use weighted gene co-expression network analysis (WGCNA) to identify gene-signaling networks associated with early relapse / MM progression. To this end, we performed a WGCNA to determine module-trait correlations. We next examined the overrepresentation of upstream regulators and signal pathway networks from MM patients in the MMRF CoMMpass dataset (n = 175, gene transcripts= 30,598). WGCNA constructed 48 modules based on the correlations between patients on RVD and death. We are using death as a biomarker for MM progression and two years as cut off for treatment. We identified two modules, Green (p &amp;lt; 4.6 x 10-8), and Pale Turquoise (p &amp;lt; 8.8 x 10-7), that significantly and positively correlated with overall survival of &amp;lt; 2 years following initial treatment with RVD. Further analysis identified HDAC8, PARPBP, HSPG2, MAGE, KIF, and FOXM1 as the top six hub genes having tight variations in positive correlations. The signatures for these cell cycle signaling pathway related hub genes were found to be largely associated with the biological process for proliferation. Future studies will use connectivity mapping to identify drug signatures that can target any of the identified hub genes. The selective targeting of these hub genes is expected to improve response to RVD in MM patients. This transcriptome study is the first using this approach to identify gene signaling networks associated with MM progression. Citation Format: Olayinka O. Adebayo, Tiara Griffen, Corey Young, Eric Dammer, James W. Lillard. Weighted gene co-expression network analysis identified cell cycle signaling pathway associated hub genes correlated with progression and prognosis of multiple myeloma [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 4388.
High‐dose dexamethasone plus recombinant human thrombopoietin vs high‐dose dexamethasone alone as frontline treatment for newly diagnosed adult primary immune thrombocytopenia: A prospective, multicenter, randomized trial
Authors: Yafei Yu, Miaomiao Wang, Yu Hou, Ping Qin, Qingshu Zeng, Wenzheng Yu, Xinhong Guo, Jingxia Wang, Xiaomin Wang, Guoqiang Liu, Xiaoxia Chu, Lan Yang, Ying Feng, Fang Zhou, Zhaogang Sun, Mei Zhang, Xin Wang, Zhencheng Wang, Xuehong Ran, Hongguo Zhao, Lei Wang, Haiyan Zhang, Kehong Bi, Daqi Li, Chenglu Yuan, Ruirong Xu, Yili Wang, Yuhong Zhou, Jun Peng, Xin‐guang Liu, Ming Hou
Journal: American Journal of Hematology (2020)

Abstract We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high‐dose dexamethasone (HD‐DXM) plus recombinant human thrombopoietin (rhTPO), vs HD‐DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4‐day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD‐DXM plus rhTPO arm and 96 patients in the HD‐DXM monotherapy arm were included in the full analysis set. So, HD‐DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs 66.7%, P &lt; .001) and complete response (CR, 75.0% vs 42.7%, P &lt; .001) compared with HD‐DXM monotherapy. Response rate at 6 months was also higher in the HD‐DXM plus rhTPO arm than that in the HD‐DXM monotherapy arm (51.0% vs 36.5%, P = .02; sustained CR: 46.0% vs 32.3%, P = .043). Throughout the follow‐up period, the overall duration of response was greater in the HD‐DXM plus rhTPO arm compared to the HD‐DXM monotherapy arm ( P = .04), as estimated by the Kaplan‐Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD‐DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044.
Abstract 3379: Cancer dependency signatures for line of sight genomic alterations in squamous cell lung cancer yield rational targets
Authors: Miika Ahdesmäki, Joshua Armenia, Krishna Bulusu, Ben Sidders, Jonathan Dry, Ultan McDermott
Journal: Cancer Research (2020)

Abstract The Cancer Dependency Map Portal enables combined analyses of genomic and phenomic data such as genomic alterations and CRISPR gene dependencies but focuses on single genes or cell lines. This is well suited for verifying previously generated hypotheses such as the dependency of cells on PRMT5 in the setting of loss of function mutations in MTAP. To identify additional actionable de-novo vulnerabilities in-silico, we refined the genomic status of 1000 cell lines by 1. focusing on variants (driver mutations and copy number alterations) that have higher prevalence in a given cancer type in TCGA and 2. reclassifying variants as actionable only if they cause loss of function in known tumour suppressor genes or gain of function in oncogenes. This gives a clear line of sight, a more manageable set of variants and is analogous to Mendelian randomization. This approach was applied to lung squamous cell carcinoma to form a binary event matrix for the shortlisted genes and copy number alterations across a panel of lung squamous cell lines. For each of the variants, we used machine learning approaches to define a dependency signature from CRISPR dependencies for the matching cell lines that distinguish altered vs non-altered cell lines. The top ranking dependencies were further examined for biological relevance and potential toxicity, yielding novel targets to follow up on. The approach generalises well and can be applied to any other cancers with unmet needs. All data in this study was derived from public databases. By combining TCGA cancer specific prevalent genomic alterations in tumor suppressor and oncogenes we drew clear line of sight and associated these alterations to CRISPR based vulnerabilities. This yielded a manageable set of alterations, and for each of these we identified a set of essential genes/pathways to use in machine learning. These signatures were further refined by biological enrichment, targetability and toxicity in order to build a process for rational novel target ID generation. Citation Format: Miika Ahdesmäki, Joshua Armenia, Krishna Bulusu, Ben Sidders, Jonathan Dry, Ultan McDermott. Cancer dependency signatures for line of sight genomic alterations in squamous cell lung cancer yield rational targets [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 3379.
Abstract 6686: SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner
Authors: Irena Adkins, Romana Mikyskova, Nada Hradilova, Guy de Martynoff, David Bechard, Ulrich Moebius, Milan Reinis, Radek Spisek
Journal: Cancer Research (2020)

Abstract SO-C101 (RLI-15) is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain designed to bypass the need of endogenous IL-15Rα, thereby leveraging the activity of IL-15 in vivo on target immune cells and reducing the toxicity of IL-15 as such. SO-C101 was previously shown to exhibit a potent anti-metastatic activity in Renca, B16F10 melanoma and delayed tumor growth in T cell-based mouse tumor models (CT26, MC38). Here we investigated the anti-tumor efficacy in predominantly natural killer (NK)-cell based mouse tumor models TC-1 and TRAMP-C2. We showed that SO-C101 monotherapy was effective in the treatment of established TC-1 tumors, which was dependent on the presence of both NK and CD8+ T cells, but not CD4+ T cells. In an early treatment setting SO-C101 significantly decreased the rate of tumor development also in dependence on NK and CD8+ T cells. SO-C101 effectively reduced tumor growth in TRAMP-C2 mice in early and advanced treatment settings. However, only in combination with anti-PD-1 antibody treatment the tumor development was prevented in majority of mice. This effect was durable, and the new tumor development was further significantly delayed after a tumor cell re-challenge, which suggests the involvement of memory T cells despite an important NK cell role in anti-tumor efficacy in these models. The efficacy of SO-C101 and anti-PD-1 treatment was not dependent on CD4+ T cells, but mainly on NK and CD8+ T cells. Interestingly, SO-C101 and anti-PD-1 treatment in double NK/CD8+ T cell-depleted mice decreased tumor growth which suggests an involvement of other immune cell populations in the anti-tumor efficacy. SO-C101 stimulated the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells without significant expansion of regulatory T cells. These data show the importance of various immune cell populations during SO-C101 monotherapy and the treatment in combination with anti-PD-1 antibodies, and set a base for further complex analysis of SO-C101 behavior. The therapeutic potential of SO-C101 is currently being tested in an ongoing Phase I clinical study in cancer patients. Citation Format: Irena Adkins, Romana Mikyskova, Nada Hradilova, Guy de Martynoff, David Bechard, Ulrich Moebius, Milan Reinis, Radek Spisek. SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner [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 6686.
THU0167 Correlations between the presence of rf, crp and aaf and the diagnosis and progression of ra
Authors: M Popa, D Stratan
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The aim of the study is to demonstrate the important role played by rheumatoid factor (RF), C reactive protein (CRP) and anti-philaggrin antibodies (APA) in the early diagnosis and in the follow-up of rheumatoid arthritis (RA). <h3>Methods</h3> Twelve patients were included in our study, all in an early stage of the disease, accomplishing the ARA criteria for the classification of RA. We tested the levels of RF, CRP and APA and we evaluated on the X-ray the erosions according to the Larsen score. <h3>Results</h3> The RF was present in 80% of the cases while CRP was present in 100% and APA only in 38%. However the APA have a specificity of 100% for RA and a strong correlation with the presence of HLA DR1. The high levels of RF and CRP are best associated with the presence and progression of the erosive lesions, the presence of the rheumatoid nodules and of the systemic involvement. CRP can be considered as a very good prognosis factor in the follow-up of RA. <h3>Conclusion</h3> RF and CRP are highly important factors in assessing of the evolutivity of the radiological lesions and in the follow-up of RA, while APA have a high specificity for RA and their presence is less correlated with the severity of the disease and more with an early diagnosis, before the ARA criteria of classification would be fulfilled.
P2RX7B is a new theranostic marker for lung adenocarcinoma patients
Authors: Valérie Vouret-Craviari
Journal: Theranostics (2020)

Rationale: The characterization of new theranostic biomarkers is crucial to improving the clinical outcome of patients with advanced lung cancer. Here, we aimed at characterizing the P2RX7 receptor, a positive modulator of the anti-tumor immune response, in patients with lung adenocarcinoma. Methods: The expression of P2RX7 and its splice variants was analyzed by RT-qPCR using areas of tumor and non-tumor lung adenocarcinoma (LUAD) tissues on both immune and non-immune cells. The biological activity of P2RX7 was studied by flow cytometry using fluorescent dyes. Bi-molecular fluorescence complementation and confocal microscopy were used to assess the oligomerization of P2RX7. Tumor immune infiltrates were characterized by immunohistochemistry. Results: Fifty-three patients with LUAD were evaluated. P2RX7A, and 3 alternative splice variants were expressed in LUAD tissues and expression was down regulated in tumor versus adjacent non-tumor tissues. The protein retained biological activity only in immune cells. The P2RX7B splice variant was differentially upregulated in immune cells (P < 0.001) of the tumor and strong evidence of oligomerization of P2RX7A and B was observed in the HEK expression model, which correlated with a default in the activity of P2RX7. Finally, LUAD patients with a high level of P2RX7B had non-inflamed tumors (P = 0.001). Conclusion: Our findings identified P2RX7B as a new theranostic tool to restore functional P2RX7 activity and open alternative therapeutic opportunities to improve LUAD patient outcome.