tbuckley/cabot-search huggingface dataset:
Abstract 1819: The immunosuppressive role of YAP1 on the tumor immune microenvironment
Authors: Ling-Ling Zhu, Jiewei Liu, Jiang Chen
Journal: Cancer Research (2021)

Abstract Background and aims: Lung adenocarcinoma (LUAD), the most prevalent histologic subtype of non-small cell lung cancer, is one of the most fatal malignancies. Despite the reported direct link between Hippo pathway and suppression of CD8+ and CD4+ T cell function in the context of cancer, its dynamic modulation and tumor microenvironment (TME) in LUAD remain unclear. We aim to investigate the correlation between YAP1 (a major component of Hippo signalling pathway), TME, and the overall survival of patients with LUAD. Methods: The SsGSEA, CIBERSORT, and ESTIMATE algorithms were applied, and gene set enrichment analysis (GSEA) was conducted to screen Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways between patients with LUAD expressing low and high levels of YAP1 utilizing data downloaded from The Cancer Genome Atlas database. Flow cytometry was performed to detect the immune cell infiltration in LUAD mice model and patients. Western blot and qRT-PCR were used to investigate the mRNA and protein expression of YAP1 from mice model and patients. Results: In this study, we demonstrated that YAP1 was negatively related to activated CD4/CD8 T cells and positively linked to immature dendritic cell, Tregs, and MDSC in 497 LUAD patients from TCGA, while it was not associated with signatures of 37 immunoregulatory and effector molecules, 37 cytokines. GSEA revealed that the high YAP1 group was not enriched in GO terms and KEGG pathways related to the immune response. However, high level of YAP1 positively correlated to immune score. In LUAD mice model, YAP1 knockout was associated with a reduced Treg cell intratumoural representation, and with higher production of interferon-γ and tumour necrosis factor by CD8+ and CD4+ effector cells (markers of increased cytotoxic activity). Moreover, YAP1 level was negatively related to overall survival in patients. Conclusion: YAP1 expression within the TME might be useful as a predictive biomarker for immune response and a novel immunotherapeutic prognostic biomarker for LUAD. Citation Format: Ling-Ling Zhu, Jiewei Liu, Jiang Chen. The immunosuppressive role of YAP1 on the tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1819.
Abstract 1033: The anticancer compound avicin D targets lysosomal functions
Authors: Friederike Braig, Jordan U. Gutterman, Diego Acosta-Alvear
Journal: Cancer Research (2021)

Abstract This study investigates the mechanism by which avicins—plant-derived triterpenes with potent anticancer activity—alter lysosomal functions. The anticancer properties of avicins have been known for over two decades, yet the precise mechanism of action of avicins remains unknown. To elucidate their mechanism of action, we conducted a pooled CRISPR interference (CRISPRi) genetic screen in Jurkat T-cell leukemia cells treated with avicin D. Our screen revealed that the depletion of genes encoding lysosomal components protected cells from the drug's cytotoxic effects. Consistent with this finding, blocking lysosomal functions with chloroquine protected cells from avicins. Moreover, blocking the lysosomal cholesterol transporter NPC1 abolished avicin cytotoxicity, hinting that avicins—which resemble steroidogenic molecules—use the same cellular factors required for cholesterol transport. Together, these results suggest a causal relationship between a requirement for lysosomal functions and avicin cytotoxicity. The top hit whose depletion sensitized cells to avicin D was the endoplasmic reticulum (ER) stress sensor ATF6, which is a membrane-tethered transcription factor capable of detecting sphingolipid lipotoxicity in the ER membrane. Consistent with this result, recent observations indicate that avicins alter the cell's sphingolipid and cholesterol balance (1), suggesting that avicins induce ER stress by disrupting ER membrane homeostasis. Together, our results support a potential mechanism of action wherein avicins are pro-drugs activated in lysosomes and induce organelle stress by altering the cell's lipid balance. We are currently working on elucidating the molecular mechanisms by which avicins and their putative metabolic products disrupt organelle homeostasis. We anticipate that our study will reveal the molecular circuitry that controls the cell's response to avicins and may open new avenues for therapeutic intervention in cancer. 1. Garrido CM, Henkels KM, Rehl KM, Liang H, Zhou Y, Gutterman JU, Cho K-J. Avicin G is a potent sphingomyelinase inhibitor and blocks oncogenic K- and H-Ras signaling. PMC7272413 Citation Format: Friederike Braig, Jordan U. Gutterman, Diego Acosta-Alvear. The anticancer compound avicin D targets lysosomal functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1033.
A high-throughput cell- and virus-free assay shows reduced neutralization of SARS-CoV-2 variants by COVID-19 convalescent plasma
Authors: Craig Fenwick, Priscilla Turelli, Céline Pellaton, Alex Farina, Jérémy Campos, Charlène Raclot, Florence Pojer, Valeria Cagno, Semira Gonseth Nusslé, Valerie D’Acremont, Jan Fehr, Milo Puhan, Giuseppe Pantaleo, Didier Trono
Journal: Science Translational Medicine (2021)

The detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies in the serum of an individual indicates previous infection or vaccination. However, it provides limited insight into the protective nature of this immune response. Neutralizing antibodies recognizing the viral spike protein are more revealing, yet their measurement traditionally requires virus- and cell-based systems that are costly, time-consuming, inflexible, and potentially biohazardous. Here, we present a cell-free quantitative neutralization assay based on the competitive inhibition of trimeric SARS-CoV-2 spike protein binding to the angiotensin-converting enzyme 2 (ACE2) receptor. This high-throughput method matches the performance of the gold standard live virus infection assay, as verified with a panel of 206 seropositive donors with varying degrees of infection severity and virus-specific immunoglobulin G titers, achieving 96.7% sensitivity and 100% specificity. Furthermore, it allows for the parallel assessment of neutralizing activities against multiple SARS-CoV-2 spike protein variants of concern. We used our assay to profile serum samples from 59 patients hospitalized with coronavirus disease 2019 (COVID-19). We found that although most sera had high activity against the 2019-nCoV parental spike protein and, to a lesser extent, the α (B.1.1.7) variant, only 58% of serum samples could efficiently neutralize a spike protein derivative containing mutations present in the β (B.1.351) variant. Thus, we have developed an assay that can evaluate effective neutralizing antibody responses to SARS-CoV-2 spike protein variants of concern after natural infection and that can be applied to characterize vaccine-induced antibody responses or to assess the potency of monoclonal antibodies.
Recent advances in clinical practice: epidemiology of autoimmune liver diseases
Authors: Palak J Trivedi, Gideon M Hirschfield
Journal: Gut (2021)

Autoimmune liver diseases are chronic inflammatory hepatobiliary disorders that when classically defined encompass three distinctive clinical presentations; primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Meaningful changes in disease epidemiology are reported, with increasing incidence and prevalence of AIH and PSC in Europe, and rising prevalence of PBC across Europe, North America and the Asia-Pacific region. However, there appears to be very significant global variation with contemporary incidence rates of disease per 100 000 ranging from 0.84 to 2.75 for PBC, 0.1 to 4.39 for PSC and 0.4 to 2.39 for AIH. Prevalence corresponds, and per 100 000 estimates for PBC range from 1.91 to 40.2, for PSC between 0.78 and 31.7 and for AIH from 4.8 to 42.9. Population-based studies and multicentre observational cohort series provide improved understanding of the clinical course that patients experience, highlighting variations in presenting phenotypes geographically and temporally. Collectively, while autoimmune liver diseases are rare, the clinical burden is disproportionately high relative to population incidence and prevalence. Age, sex and race also impact clinical outcomes, and patient morbidity and mortality are reflected by high need for gastroenterology, hepatology and organ transplant services.
Abstract 2387: Targeting PVT1 exon 9 transcript is not pro-apoptotic but induces claudin 4 expression and inhibits migration in triple negative breast cancer cells
Authors: Fayola A. Levine, Olorunseun O. Ogunwobi
Journal: Cancer Research (2021)

Abstract Triple negative breast cancer (TNBC) is a lethal molecular subtype of invasive breast cancer (BC) that is ER-, PR- and HER2-. Claudin low (CL) TNBC, a distinct molecular subtype of TNBC, has the worst prognosis compared to other BC subtypes. Aberrant expression of claudin proteins disrupts the function of tight junctions. Consequently, inducing epithelial-to-mesenchymal transition (EMT) in cancers, an important factor for enhanced motility and metastasis. Therefore, understanding the molecular mechanisms that modulate claudin expression in TNBC is crucial. The 8q24 genomic locus is an important cancer susceptibility locus that is associated with poor clinical outcomes in cancer due to common amplification events that occur in many malignant diseases. This locus contains the PVT1 gene, which encodes a long noncoding RNA (lncRNA) that has been implicated in multiple cancers including BC. PVT1 consists of 12 exons that are alternatively spliced to generate lncRNAs. Although previous research has implicated PVT1 as an important player in BC, the underlying molecular mechanisms of PVT1 in CL TNBC is unknown. To examine the role of PVT1 in CL TNBC, we assessed PVT1 expression in T47D (ER+), MDA MB 231 (CL) and MDA MB 468 (claudin high (CH)) BC cells. We observed that PVT1 exons 4A, 4B, and 9 are significantly overexpressed in CL MDA MB 231 and significantly underexpressed in CH MDA MB 468 in comparison to T47D cells, suggesting a protumorigenic role of PVT1 in CL TNBC. We analyzed the functional consequences of siRNA targeting of PVT1 exon 9 expression in CL TNBC cells. siRNA targeting of PVT1 exon 9 expression in the MDA MB 231 CL TNBC cells led to a significant reduction in migration and the re-expression of claudin 4. To determine the role of PVT1 on EMT, we assessed the expression of EMT markers (vimentin, fibronectin, and E-cadherin) in MDA MB 231 cells. We observed no changes in the expression of EMT markers when PVT1 exon 9 is knocked down. However, our data show that mesenchymal markers are more highly expressed in MDA MB 231 cells in comparison to MDA MB 468 cells. Further, knockdown of PVT1 exon 9 did not induce apoptosis in MDA MB 231 cells as assessed by caspase 3 and caspase 9 expression. Taken together, our data indicate that PVT1 exon 9 regulates claudin expression and migration in CL TNBC, and may have implications for clinical outcomes in TNBC. Citation Format: Fayola A. Levine, Olorunseun O. Ogunwobi. Targeting PVT1 exon 9 transcript is not pro-apoptotic but induces claudin 4 expression and inhibits migration in triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2387.
Abstract 2860: NOSTRIN-induced inhibition of pancreatic cancer progression involves CCBE1 in an eNOS-independent manner
Authors: Lin Zhang, Shouhui Yang, Limin Wang, Peijun He, Ohara Yuuki, Paloma Valenzuela, Wei Tang, Jochen Gaedcke, B. Michael Ghadim, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, Brid M Ryan, S. Perwez Hussain
Journal: Cancer Research (2021)

Abstract NOSTRIN represses disease aggressiveness in pancreatic cancer by suppressing eNOS-mediated NO production. We have further explored the NOSTRIN-mediated eNOS-independent pathways that contribute to its tumor inhibitory function. Gene expression analysis identified CCBE1 as a target of NOSTRIN. We provide experimental and clinical evidence that NOSTRIN functions a negative regulator in pancreatic cancer progression through inhibiting the expression of CCBE1. Furthermore, CCBE1 expression is regulated by NOSTRIN independent of eNOS. NOSTRIN attenuates protein-protein interaction between ABL1 and PKD2 resulting in the suppression of PKD2 and NFkB p50 activation. Inhibition of PKD2 and NFkB p50 activation results in the suppression of CTCF, which is as a transcription factor of CCBE1. CCBE1 expression is decreased as the down-stream gene of CTCF. Taken together, CCBE1 may be a potential therapeutic target in pancreatic cancer. Citation Format: Lin Zhang, Shouhui Yang, Limin Wang, Peijun He, Ohara Yuuki, Paloma Valenzuela, Wei Tang, Jochen Gaedcke, B. Michael Ghadim, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, Brid M Ryan, S. Perwez Hussain. NOSTRIN-induced inhibition of pancreatic cancer progression involves CCBE1 in an eNOS-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2860.
An opportunity for men with positive prostate mpMRI studies to safely avoid biopsy – Results from the INNOVATE Study
Authors: S. Singh, H. Rogers, B. Kanber, J. Clemente, H. Pye, A. Grey, E. Dineen, G. Shaw, A. Haider, A. Freeman, D. Atkinson, C.M. Moore, H.C. Whitaker, D.C. Alexander, E. Panagiotaki, S. Punwani
Journal: European Urology (2021)
Abstract 1568: A2aR inhibition enhances the antitumor activity of CTLA4 blockade in mouse Pten-deficient prostate cancer
Authors: Marco A. De Velasco, Yurie Kura, Noriko Sako, Naomi Ando, Kazuko Sakai, Alwin Schuller, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2021)

Abstract Extracellular adenosine impairs immune function in tumors and limits the efficacy of anti-CTAL4 immune checkpoint blockade. We previously showed that adenosine 2A receptor (A2aR) blockade with AZD4635 moderately inhibited tumor growth, in part by improving antigen presentation and cytotoxic T cell (CTL) activity in mouse Pten-deficient prostate cancer. Here, we continue to investigate the antitumor activity of AZD4635 and its effects when combined with CTLA4 blockade (aCTLA4) in preclinical models of Pten-deficient prostate cancer. Prostate tumors from Pten conditional knockout (KO) mice treated with aCTLA4 for five days had increased expression levels of adenosinergic genes. Furthermore, gene expression, flow cytometric and IHC analyses showed increased T regulatory cell differentiation and accumulation that was offset with the addition of AZD4635. Moreover, expression levels of genes associated with Th 1 cell differentiation and T cell-mediated cytotoxicity were increased in AZD4635/aCTLA4 treated tumors. Adding AZD4635 to a four-week regimen of aCTLA4 therapy improved the antitumor response by two-fold in an early-stage intervention model of Pten-deficient prostate cancer. Androgen deprivation (AD) has the potential to promote T cell infiltration in prostate tumors and using the AZD4635/aCTLA4 treatment combination as neoadjuvant therapy to AD via surgical castration led to a greater antitumor response. The antitumor activity of this treatment combination was further examined and confirmed in a subcutaneous syngeneic genome-derived allograft model using tumor-bearing conditional Pten-deficient knockout mice grafted with Pten-deficient CRPC tumor fragments. In a Pten/Trp53 conditional double knockout (DKO) mouse model of advanced prostate cancer, the AZD4635/aCTLA4 treatment combination did not improve overall survival rates. However, when AZD4635/aCTLA4 was used as neoadjuvant therapy to AR inhibition with the anti-androgen apalutamide, it improved median survival time from 21 days in monotherapy treated mice to 34 days in AZD4635/aCTLA4 treated mice. These results provide preclinical evidence to support the rational combination of A2AR blockade with AZD4635 and aCTLA4 immune checkpoint inhibition for PTEN-deficient prostate cancer. Citation Format: Marco A. De Velasco, Yurie Kura, Noriko Sako, Naomi Ando, Kazuko Sakai, Alwin Schuller, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. A2aR inhibition enhances the antitumor activity of CTLA4 blockade in mouse Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1568.
Biologics may have a beneficial effect in asthma patients with COVID-19
Authors: José L. Izquierdo, Joan B. Soriano
Journal: European Respiratory Journal (2021)

We take the opportunity to respond to P.A.B. Wark and co-workers, and their correspondence on the subject of our recent publication [1]. It is indeed worth exploring the relationships of respiratory disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential mechanisms involved to understand better the pathophysiology of coronavirus disease 2019 (COVID-19), and eventually consider new treatments. However, based on others and our own observations, we disagree with the statement that use of Th2 targeting biologics in patients with asthma may increase susceptibility to SARS-CoV-2 infection due to an increased expression of ACE2. The results in table 3 of our manuscript [1] with biologics (omalizumab n=641, mepolizumab n=308, benralizumab n=98, reslizumab n=26) point to a beneficial effect in asthmatics with COVID-19, as suggested elsewhere [2]. Biologics may have a beneficial effect in asthma patients with COVID-19 <https://bit.ly/3hkor8X>
Abstract 1694: Validation of GVHD in humanized mouse model for preclinical efficacy screen
Authors: Menglin Liu, Yingying Cai, Na Xu, Ya Zhang, Rou Xie, Lijun Jia, Qing Lin
Journal: Cancer Research (2021)

Abstract Bone marrow transplantation has been successfully and widely used to treat diseases such as leukemia and lymphoma. However, the complication Graft vs Host Disease (GVHD) is a serious hindrance in patients' outcome. Immunosuppressant such as Cyclosporine A has been used to decrease the GVHD occurrence, but the associated side-effect such as transplant rejection and opportunistic infection outweigh its benefit. Therefore, new medication to suppress GVHD without severe toxicity is urgently in need now. To build better preclinical platform for drug efficacy evaluation in GVHD, we have validated the GVHD model in both mouse host and humanized mouse host. We collected bone marrow cells and splenocyte from C57BL/6J (H-2d) mice and transplant to irradiated BALB/c (H-2b) mice to induce GVHD. In humanized model, we injected humanized NPI mice (NOD-Prkdcscid-Il2rgem1lDMO with CD34+ hematopoeitc stem cells (HSCs) reconstitution) with PBMCs from MHCII mismatched donors to trigger GVHD occurrence. In both models, we observed the typical clinical symptoms such as hollow back, inactiveness, body weight loss in transplanted mice. Humanized mice with transplantation start to die in 2 weeks. In the endpoint, we used FACS to analyze the cell population change in whole blood, spleen and lymph nodes, and found histological changes in GI tract and skin. Thus, this model is suitable to screen potential human-specific antibodies or new small molecules. We are also going to explore extra parameters to characterize the disease progression. Citation Format: Menglin Liu, Yingying Cai, Na Xu, Ya Zhang, Rou Xie, Lijun Jia, Qing Lin. Validation of GVHD in humanized mouse model for preclinical efficacy screen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1694.
Should we delay covid-19 vaccination in children?
Authors: Dominic Wilkinson, Ilora Finlay, Andrew J Pollard, Lisa Forsberg, Anthony Skelton
Journal: BMJ (2021)

The net benefit of vaccinating children is unclear, and vulnerable people worldwide should be prioritised instead, say <b>Dominic Wilkinson</b>, <b>Ilora Finlay</b>, and <b>Andrew J Pollard</b>. But <b>Lisa Forsberg</b> and <b>Anthony Skelton</b> argue that covid-19 vaccines have been approved for some children and that children should not be disadvantaged because of policy choices that impede global vaccination
Abstract 16644: TGF-β/Smad3 Activation in the Diabetic Mouse Heart Induces Fibrotic Cardiac Remodeling and Diastolic Dysfunction While Protecting From Excessive Matrix Degradation and Preventing the Development of Systolic Dysfunction
Authors: Anna Biernacka, Carlos Gonzalez-Quesada, Qi Tian, Na Li, Marcin Dobaczewski, Xiao-Fan Wang, Nikolaos G Frangogiannis
Journal: Circulation (2011)

Hypertrophy, fibrosis and diastolic dysfunction are the main characteristics of diabetic cardiomyopathy. Our study examines the role of the pro-fibrotic TGF-β/Smad3 pathway in the diabetic heart using leptin resistant db/db mice. db/db mice developed diabetes and severe obesity and had marked elevation in circulating leptin levels. Despite exhibiting central leptin resistance (resulting in hyperphagia), db/db mice expressed a functional short-form leptin receptor in the myocardium. db/db hearts had concentric hypertrophy and diastolic dysfunction; systolic function was preserved. Collagen deposition was increased in db/db hearts; fibrotic changes were preceded by cytokine and chemokine induction and by activation of Smad3 signaling. In vitro, db/db cardiac fibroblasts exhibited marked upregulation of cytokines, chemokines and MMPs upon leptin stimulation indicating full responsiveness to the actions of leptin. In order to examine the role of Smad3 in morphology and function of the db/db heart we generated db/db Smad3 mutant mice. db/db Smad3 -/- mice exhibited high early mortality; the causes of early death are under investigation. In contrast, db/db Smad3 +/- heterozygotes (het) had similar survival curves, comparable weight gain and fat content with db/db Smad3+/+ animals. However, het mice had significant ventricular dilation (LVEDV, db/db: 82.9+4.7 vs. het: 125.6+6.4; p&lt;0.01) accompanied by systolic dysfunction (FS, db/db: 42.8+2.9 vs. het: 29.1+2.7; p&lt;0.01). Diastolic dysfunction, assessed through P:V loop analysis, was attenuated in het animals. In contrast, non-obese het mice had comparable chamber dimensions and function with WT Smad3 +/+ animals. The dilative remodeling, systolic dysfunction and attenuated diastolic dysfunction observed in obese diabetic het mice were associated with reduced collagen deposition, and increased MMP activity. Cardiac function and geometry in the diabetic heart are dependent on a balance between leptin and Smad3-mediated actions. Attenuation of Smad3 signaling in db/db mice prevents fibrosis and diastolic dysfunction, but also allows unopposed pro-inflammatory leptin-mediated effects resulting in impaired matrix preservation, chamber dilation and systolic dysfunction.