tbuckley/cabot-search huggingface dataset:
Essential Role of Regulatory T Cells on Early B Cell Reconstitution after Haploidentical BMT with Posttransplant Cyclophosphamide
Authors: Miki Iwamoto, Ken-ichi Matsuoka, Yusuke Meguri, Shuntaro Ikegawa, Hiroyuki Sugiura, Yasuhisa Sando, Makoto Nakamura, Takeru Asano, Yoshinobu Maeda
Journal: Blood (2017)
Abstract 2140: Delineating a functional link between a phosphoserine aminotransferase (PSAT1)-associated gene signature and EGFR-mutant NSCLC
Authors: Rumeysa Biyik-Sit, Brian F. Clem
Journal: Cancer Research (2021)

Abstract Phosphoserine aminotransferase 1 (PSAT1) catalyzes the second enzymatic step within the serine synthetic pathway and its expression is elevated in numerous human cancers, such as NSCLC. While PSAT1 suppression decreases SSP activity and cell proliferation, non-canonical activities have recently been suggested that may contribute to its pro-tumorigenic function, as is seen with other metabolic enzymes such as pyruvate kinase. Thus, we conducted a genome wide expression screen to uncover potential unknown cellular processes impacted by PSAT1 and to identify a PSAT1-associated gene signature that might inform patient outcomes in NSCLC. Loss of PSAT1 in EGFR-mutant PC9 lung cancer cells led to 491 differentially expressed genes (279-down; 212-up). KEGG and gene ontology analysis identified biological pathways such as metabolic processes, cell cycle regulation, cell adhesion, and cell motility. Transcript analysis confirmed inhibitory effects on the Rb/E2F1 and β-catenin pathways as well as expression of effectors on the actin cytoskeleton upon loss of PSAT1. Importantly, these could be rescued by PSAT1 restoration, including the loss of F-actin stress fibers as observed with phalloidin staining. Lastly, a bioinformatics approach utilizing transcriptomic data from human lung cancer patients was used to define genes altered between EGFR-mutant lung cancers and normal lung and that were differentially expressed in our PSAT1 depletion RNA-seq study. From this, we identified a PSAT1-associated gene signature that was then used to assign risk survival scores to these NSCLC patients. Subsequent, Kaplan Meier analysis demonstrated the prognostic ability of this gene signature for both relapse free and overall survival in EGFR-mutant NSCLC but was unable to predict risk groups in other NSCLC subtypes. Together, transcriptomic analysis under PSAT1 silencing identified its impact on various biological processes, including actin cytoskeleton rearrangement, and led to identification of a gene signature that has predictive ability towards survival outcomes in EGFR-mutant lung cancer. Citation Format: Rumeysa Biyik-Sit, Brian F. Clem. Delineating a functional link between a phosphoserine aminotransferase (PSAT1)-associated gene signature and EGFR-mutant NSCLC [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 2140.
Abstract 314: Highly polymeric grape seed proanthocyanidins: A call for establishing the safe dose
Authors: Wasitha Thilakarathna, H.P. Vasantha Rupasinghe
Journal: Cancer Research (2021)

Abstract Introduction: Proanthocyanidins (PC) are the oligomers and polymers of flavan-3-ols, especially catechin and epicatechin. PC in general are proven to be beneficial against cancers and widely available as over the counter (OTC) supplements. However, role of highly polymeric PC (HP-PC) on human cancer prevention remain unknown. Therefore, the effects of HP-PC supplementation on hepatic pathology in the context of hepatocellular carcinoma (HCC) were evaluated. HP-PC supplementation on mice gut microbiota was also evaluated considering the association of dysbiosis-mediated inflammation with HCC. Methodology: Crude PC was extracted from grape seeds (GS) using 70% acetone (in water) as the extraction solvent. PC mixture was purified and fractionated by flash chromatography. Monomeric and oligomeric PC was eluted with 100% ethanol and the HP-PC was collected by eluting with 70% acetone. C57BL/6 mice (49 - 56 days old) were supplemented with HP-PC (200 mg/kg body weight per day) for 14 days and sacrificed to collect livers and blood serum. Feces samples were collected from mice colon to evaluate the composition of gut microbiota using the 16S rRNA sequencing technology. Mice liver histopathology was examined by staining with hematoxylin and eosin. The level of alanine aminotransferase (ALT) in mice blood serum was measured as a marker of liver damage. Results: Evaluation of liver histopathology revealed signs of steatosis in the mice supplemented with HP-PC. Interestingly, rare foci of monocytic lobular inflammation was visible in the hepatic tissues of the mice supplemented with HP-PC. The alpha diversity of the mice gut microbiome was evaluated in terms of Shannon Index, Pielou's evenness, Faith's phylogenic diversity, and observed operational taxonomic units. A significant difference was not observed for the alpha diversity between the HP-PC supplemented and control group mice gut microbiota. The levels of ALT in the mice blood serum were not significantly different between HP-PC supplemented and control group mice. Conclusions: The preliminary experimental data suggests the potential of HP-PC to promote steatosis and hepatic inflammation. However, further studies must be conducted to understand potential harmful effect of HP-PC (if any) in hepatic toxicity and safer dose to use for potential health benefits. Furthermore, the results of this study emphasize the critical importance of establishing the safe dose of HP-PC or any OTC supplements. Citation Format: Wasitha Thilakarathna, H.P. Vasantha Rupasinghe. Highly polymeric grape seed proanthocyanidins: A call for establishing the safe dose [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 314.
Abstract 1514: Engineering off-the-shelf T Cell Receptor Fusion Construct (TRuC) T cells
Authors: Julie Donaghey, Philippe Kieffer-Kwon, Julio Gomez-Rodriguez, Troy Patterson, Jessica Gierut, Tiffany Chan, Ryan Milione, Joshua Daniel, Holly Horton, Robert Tighe, Robert Hofmeister, Dario A. Gutierrez
Journal: Cancer Research (2021)

Abstract The natural T cell receptor (TCR) recognizes its cognate peptide antigen only when presented on human leukocyte antigen (HLA) molecules and requires HLA matching of α/β TCR-engineered T cells for cancer therapy. To bypass the need for HLA matching, we have previously described the generation of autologous T Cell Receptor Fusion Construct (TRuC™) T cells which are engineered to express a fusion protein that comprises an antibody-derived binder tethered to the CD3ϵ signaling subunit. Upon integration of the TRuC into the TCR, it recognizes tumor surface antigens independent of HLA and uses the complete receptor complex to trigger a comprehensive T cell response. Here, we report the engineering of off-the-shelf TRuC-T cells directed against CD19 and mesothelin, respectively. To eliminate the alloreactivity of α/β T cells and reduce the risk of graft-versus-host-disease (GvHD), the TRAC locus is knocked-out. To enable the re-assembly of the TCR, the endogenous TCRα and β subunits are replaced with fusion proteins comprising antibody binders fused to the murine TCRα or β constant domains, or alternatively, to the TCRγ and δ constant domains. Similar to their autologous counterparts, allogeneic CD19 and MSLN-targeting TRuC-T cells upregulate activation markers, secrete cytokines, and lyse tumor cells in an antigen-specific manner. Importantly, TRuC-T cells lack alloreactivity as demonstrated in mixed lymphocyte reactions and clear tumors in NSG xenograft model comparable to autologous anti-CD19 TRuC-T cells, but without signs of GvHD. Likewise, the functional activity and efficacy of allogeneic TRuC-T cells directed against mesothelin is similar to that of autologous anti-MSLN TRuC-T cells. To reduce host rejection and enhance the persistence of the allogeneic TRuC-T cells, MHC class I expression on the surface of the TRuC-T cells was down-regulated by means of RNAi. In summary we have engineered allogeneic TRuC-T cells that maintain the signaling properties of the TCR complex with comparable efficacy as donor-matched autologous TRuC-T cells; moreover, these T cells have the potential to persist in an allogeneic host by diminishing the risk of rejection by the host. Citation Format: Julie Donaghey, Philippe Kieffer-Kwon, Julio Gomez-Rodriguez, Troy Patterson, Jessica Gierut, Tiffany Chan, Ryan Milione, Joshua Daniel, Holly Horton, Robert Tighe, Robert Hofmeister, Dario A. Gutierrez. Engineering off-the-shelf T Cell Receptor Fusion Construct (TRuC) T 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 1514.
The epidemiology of alopecia areata: a population‐based cohort study in UK primary care*
Authors: M. Harries, A.E. Macbeth, S. Holmes, W.S. Chiu, W.R. Gallardo, M. Nijher, S. de Lusignan, C. Tziotzios, A.G. Messenger
Journal: British Journal of Dermatology (2021)

Background There is a lack of population-based information on the disease burden and management of alopecia areata (AA). Objectives To describe the epidemiology of AA, focusing on incidence, demographics and patterns of healthcare utilization. Methods Population-based cohort study of 4·16 million adults and children, using UK electronic primary care records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database, 2009–2018. The incidence and point prevalence of AA were estimated. Variation in AA incidence by age, sex, deprivation, geographical distribution and ethnicity was examined. Patterns of healthcare utilization were evaluated in people with incident AA. Results The AA incidence rate was 0·26 per 1000 person-years. AA point prevalence in 2018 was 0·58% in adults. AA onset peaked at age 25–29 years for both sexes, although the peak was broader in females. People of nonwhite ethnicity were more likely to present with AA, especially those of Asian ethnicity [incidence rate ratio (IRR) 3·32 (95% confidence interval 3·11–3·55)]. Higher AA incidence was associated with social deprivation [IRR most vs. least deprived quintile 1·47 (1·37–1·59)] and urban living [IRR 1·23 (1·14–1·32)]. People of higher social deprivation were less likely to be referred for specialist dermatology review. Conclusions By providing the first large-scale estimates of the incidence and point prevalence of AA, our study helps to understand the burden of AA on the population. Understanding the variation in AA onset between different population groups may give insight into the pathogenesis of AA and its management.
Abstract 3154: Host and neoplastic cell Axl inhibition impair prostate and breast cancer bone metastasis
Authors: Mai Tanaka, Dietmar W. Siemann
Journal: Cancer Research (2021)

Abstract Prostate and breast cancers are the most prevalent and the second leading causes of cancer-deaths for men and women in the United States. Cancer survival rates generally worsen significantly with advanced and disseminated disease with nearly 90% of all cancer deaths resulting from metastasis. For breast and prostate cancers, bone is the most common site of metastasis. A key signaling pathway involved in metastatic dissemination of tumor cells is the receptor tyrosine kinase Axl. Axl belongs to the Tyro3, Axl, and MerTK (TAM) subfamily, is expressed in a variety of tumor types, including breast and prostate, and is associated with poor prognosis, metastasis, and outcome. The goal of the present study was to characterize the role of Axl signaling in prostate and breast cancer cell dissemination to bone. This was accomplished using Axl knockdown neoplastic cells, a selective small molecule Axl inhibitor (BGB324), and osteoclast progenitor cells in vitro, as well as intracardiac injection of Axl knockdown tumor cells in vivo. The results showed that Axl inhibition significantly decreases tumor cell migration and invasion in vitro, and suppression of Axl signaling in osteoclast precursor cells reduces the formation of mature osteoclasts. In vivo, Axl knockdown in prostate and breast cancer cells significantly suppressed the formation of neoplastic bone lesions. Taken together our findings indicate that therapeutic targeting of Axl may impair tumor metastasis to the bones through neoplastic and host cell signaling axes. Citation Format: Mai Tanaka, Dietmar W. Siemann. Host and neoplastic cell Axl inhibition impair prostate and breast cancer bone metastasis [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 3154.
Abstract 1079: A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab-resistance in HER2-positive cancers
Authors: Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Hye-Rim Seo, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
Journal: Cancer Research (2021)

Abstract Background: DNA damage response (DDR) pathway is essential for maintaining genomic stability, cell survival, and tumorigenesis. However, the roles of DDR pathway in HER2-positive tumors remain unclear. This study aims to discover the function of DDR in trastuzumab-resistant (TR) cells to better understand HER2-biology and to suggest novel treatment strategy using DDR-targeting agents in HER2-positive TR tumors. Methods: Four HER2-positive TR cell lines (NCI-N87TR, SNU-216TR, SNU-2670TR, and SNU-2773TR) and their corresponding parental cells (NCI-N87, SNU-216, SNU-2670, and SNU-2773) were subject to immunoblotting to identify expression profiles of DDR proteins. Proteasome inhibitor MG-132 and cycloheximide chase assay were used for understanding PARP1 dynamics in TR cells. MTT assay and colony-forming assay were performed to evaluate antiproliferative effect of PARP inhibitor (PARPi, olaparib), ATM inhibitor (ATMi, AZD0156) and ATR inhibitor (ATRi, Ceralasertib). DNA damage and homologous recombination repair (HRR) efficiency were measured by comet assay and immunofluorescence respectively. Cell cycle analysis using flow cytometry was performed to assess drug-induced apoptosis. Results: Increase of PARP1 expression was observed in all four TR cells. Decreased proteasomal degradation of PARP1 was found in TR cells compared to parental cells. Olaparib showed better anti-proliferative effect in TR cells compared to parental cells. After treating with olaparib, there was a defect in formation of Rad51 foci, instead, there was induction of phosphorylation of ATM and ATR in TR cells, which might attenuate the effects of olaparib in TR cells. Combination of olaparib with AZD0156 showed stronger anti-tumor effect than olaparib monotherapy in TR cells. Moreover, synthetic lethal interaction was observed by olaparib/AZD0156 combination in TR cells. Interestingly, this synthetic lethal interaction was exclusively occurred in TR cells not in parental cells. Even though olaparib and ceralasertib combination showed better anti-tumor effect than each single drug in some TR cells, synthetic lethal interaction was not observed by olaparib/ceralasertib combination in TR cells. Conclusion: Dual inhibition of PARP1 and ATM could be a good strategy to overcome the resistance to trastuzumab in HER2-positive cancers using its synthetic lethal interaction. Citation Format: Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Hye-Rim Seo, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab-resistance in HER2-positive cancers [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 1079.
BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel
Authors: Tal Brosh-Nissimov, Efrat Orenbuch-Harroch, Michal Chowers, Meital Elbaz, Lior Nesher, Michal Stein, Yasmin Maor, Regev Cohen, Khetam Hussein, Miriam Weinberger, Oren Zimhony, Bibiana Chazan, Ronza Najjar, Hiba Zayyad, Galia Rahav, Yonit Wiener-Well
Journal: Clinical Microbiology and Infection (2021)
Abstract LB106: The EGF domains of MUC4 oncomucin interact with ErbB2 and mediate tumorigenic activity of cancer cells represent new potential therapeutic targets
Authors: Nicolas STOUP, Maxime LIBERELLE, Céline SCHULZ, Romain VASSEUR, Romain MAGNEZ, Xavier THURU, Patricia MELNYK, Nicolas RENAULT, Nicolas JONCKHEERE, Nicolas LEBEGUE, Isabelle VAN SEUNINGEN
Journal: Cancer Research (2021)

Abstract The MUC4 mucin and its membrane partner ErbB2 form an oncogenic complex at the surface of epithelial cancer cells that promotes tumor progression. They directly physically interact via an extracellular region of MUC4 encompassing three EGF domains opening the route to therapeutic targeting of ErbB2 over-expressing cancers in which MUC4-ErbB2 is present. However, before small inhibitory molecules may be designed, it is mandatory (i) to decipher at the molecular level which amino acid regions are involved in the interaction and (ii) show that they mediate cancer cell tumorigenicity. By using in vitro (2D cell culture, Micro Scale Thermophoresis, PLA assay, Co-IP, GST pull down, Molecular Dynamics simulations) and in vivo (xenograft model of pancreatic cancer) approaches, we show that the EGF1 domain of MUC4 is central both in the interaction with ErbB2 and in the activation of cell proliferation and migration and tumor growth via activation of key oncogenic pathways (Src, Ras, p70S6K/AKT/mTOR, β-catenin, FAK). Finally, we have identified hotspots of interaction paving the way to the design of therapeutic inhibitory molecules targeting the EGF domains of MUC4 which may represent a new alternative strategy to overcome ErbB2 therapeutic failure in cancer. Citation Format: Nicolas STOUP, Maxime LIBERELLE, Céline SCHULZ, Romain VASSEUR, Romain MAGNEZ, Xavier THURU, Patricia MELNYK, Nicolas RENAULT, Nicolas JONCKHEERE, Nicolas LEBEGUE, Isabelle VAN SEUNINGEN. The EGF domains of MUC4 oncomucin interact with ErbB2 and mediate tumorigenic activity of cancer cells represent new potential therapeutic targets [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 LB106.
Reduced IL‐31 receptor alpha splice variant mRNA following allergen challenge in a canine model of atopic dermatitis
Authors: Nicky Craig, Kim Ahrens, Rachel Wilkes, Rosanna Marsella
Journal: Allergy (2021)

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Abstract 715: Flow cytometry analysis of immune response to COVID-19 vaccine candidates using an <i>in vitro</i> stimulation model
Authors: Xiaoshan Shi, Scott J. Bornheimer, Suraj Saksena, Stephanie Widmann, Aaron Tyznik
Journal: Cancer Research (2021)

Abstract T cell immunity is vital for the control of viral infections. Cytotoxic CD8 T cells play a crucial role in eliminating virus-infected cells while CD4 helper T cells mediate host immune responses and promote B cells to secrete antibodies. For both, T cell recognition of viral antigens in the form of short peptides presented by HLA complexes is a prerequisite for T cell activation. Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has become a global pandemic that has disrupted economies and resulted in an enormous burden on health care systems. Despite the worldwide intensive efforts on development of COVID-19 therapeutics, a safe and effective COVID-19 treatment or vaccine is not yet available. In this study, we established an in vitro stimulation system in which peripheral blood mononuclear cells were treated with putative SARS-CoV-2 immunogenic peptides. T cell immune responses were measured using different quantitative flow cytometry panels that were designed for evaluating cytokine production or identifying T cell subsets. Evaluation of host immune responses with a suite of flow cytometric panels may prove to be useful in the study of COVID-19. For Research Use Only. Not for use in diagnostic or therapeutic procedures. Class 1 Laser Product.BD-23276 (v1.0) 1120BD and the BD Logo are trademarks of Becton, Dickinson and Company. © 2020 BD. All rights reserved. Citation Format: Xiaoshan Shi, Scott J. Bornheimer, Suraj Saksena, Stephanie Widmann, Aaron Tyznik. Flow cytometry analysis of immune response to COVID-19 vaccine candidates using an in vitro stimulation model [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 715.
Abstract 166: Real world genomic data supports combined use of SHP-2 and PD-1/PD-L1 inhibitors in solid tumors
Authors: Keller Toral
Journal: Cancer Research (2021)

Abstract The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition of SHP-2, a tyrosine phosphatase, will improve the activity of immune checkpoint inhibitors (ICI) that target PD-1 or PD-L1 in lung cancers. We first collected protein expression data from the The Cancer Proteome Atlas (TCPA) to study the association of SHP-2 and PD-L1 expression in lung adenocarcinomas. RNA sequencing data was collected from the same subjects through the NCI Genetic Data Commons and evaluated for expression of the PTPN11 (SHP-2) and CD274 (PD-L1) genes. We then analyzed RNA sequencing data from a series of melanoma patients who were either treatment naïve or resistant to ICI therapy. PTPN11 and CD274 expression was compared between groups. Finally, we analyzed gene expression and drug response data collected from 21 non-small cell lung cancer (NSCLC) patients for PTPN11 and CD274 expression. From the three studies, we hypothesize that the activity of SHP-2, rather than the expression, likely controls the expression of PD-L1 as only a weak relationship between PTPN11 and CD274 expression in either lung adenocarcinomas or melanomas was observed. Lastly, the expression of CD274, not PTPN11, correlates with response to ICI in NSCLC. Citation Format: Keller Toral. Real world genomic data supports combined use of SHP-2 and PD-1/PD-L1 inhibitors in solid tumors [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 166.
Discrepancy between clinical and nephroureterectomy tumors stage as well as grade in upper tract urothelial carcinoma
Authors: K. Mori, S. Katayama, E. Laukhtina, V.M. Schuettfort, B. Pradere, F. Quhal, R. Sari Motlagh, H. Mostafaei, N.C. Grossmann, P. Rajwa, M. Rouprêt, V. Margulis, D.V. Enikeev, S. Egawa, S.F. Shariat
Journal: European Urology (2021)