tbuckley/cabot-search huggingface dataset:
Abstract 2521: Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome
Authors: Aloran Mazumder, Athena Jimenez, Rachel Ellsworth, Stephen Freedland, Sophia George, Matthew Bainbridge, Svasti Haricharan
Journal: Cancer Research (2021)

Abstract African American (AA) estrogen receptor positive (ER+) breast cancer patients have worse outcomes than Caucasian Americans (CA) being 42 % more likely to die from the disease. However, AAs are severely underrepresented in currently available datasets of patient tumors, which precludes comprehensive approaches to identify race-specific molecular drivers of these poor outcomes. Endocrine therapy (ET) is the first line standard of care for ER+ breast cancer. Nevertheless, 1 in 4 patients develop ET resistance. Specific DNA damage/repair (DDR) defects have been shown to associate with poor outcome in CA patients, and to induce ET resistance. Whether these or other DDR defects contribute to poor outcomes observed in AA patients remains unknown. For the purpose of this investigation, we assessed the DDR dysregulation landscape of AA ER+ tumors using three independent tumor datasets (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA) and two normal breast datasets (1) GSE43973 (2) GSE50939. This analysis identified a distinct set of AA ER+ tumors with simultaneous dysregulation of genes from multiple DDR pathways, rarely seen in CA tumors. This simultaneous dysregulation also associated with worse patient outcomes in all three datasets analyzed. This work constitutes the first systematic analysis of race-specific DDR dysregulation in ER+ breast cancer, and identifies DDR as a potential predictive biomarker for worse outcome seen in AA patients. Citation Format: Aloran Mazumder, Athena Jimenez, Rachel Ellsworth, Stephen Freedland, Sophia George, Matthew Bainbridge, Svasti Haricharan. Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome [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 2521.
Fatty Acid Synthase–Suppressor Screening Identifies Sorting Nexin 8 as a Therapeutic Target for NAFLD
Authors: Yufeng Hu, Wenzhi He, Yongping Huang, Hui Xiang, Juan Guo, Yan Che, Xu Cheng, Fengjiao Hu, Manli Hu, Tengfei Ma, Jie Yu, Han Tian, Song Tian, Yan‐Xiao Ji, Peng Zhang, Zhi‐Gang She, Xiao‐Jing Zhang, Zan Huang, Juan Yang, Hongliang Li
Journal: Hepatology (2021)

NAFLD is the most prevalent chronic liver disease without any Food and Drug Administration-approved pharmacological intervention in clinic. Fatty acid synthase (FASN) is one of the most attractive targets for NAFLD treatment because of its robust rate-limiting capacity to control hepatic de novo lipogenesis. However, the regulatory mechanisms of FASN in NAFLD and potential therapeutic strategies targeting FASN remain largely unknown.Through a systematic interactomics analysis of FASN-complex proteins, we screened and identified sorting nexin 8 (SNX8) as a binding partner of FASN. SNX8 directly bound to FASN and promoted FASN ubiquitination and subsequent proteasomal degradation. We further demonstrated that SNX8 mediated FASN protein degradation by recruiting the E3 ligase tripartite motif containing 28 (TRIM28) and enhancing the TRIM28-FASN interaction. Notably, Snx8 interference in hepatocytes significantly deteriorated lipid accumulation in vitro, whereas SNX8 overexpression markedly blocked hepatocyte lipid deposition. Furthermore, the aggravating effect of Snx8 deletion on NAFLD was validated in vivo as hepatic steatosis and lipogenic pathways in the liver were significantly exacerbated in Snx8-knockout mice compared to wild-type controls. Consistently, hepatocyte-specific overexpression of Snx8 in vivo markedly suppressed high-fat, high-cholesterol diet (HFHC)-induced hepatic steatosis. Notably, the protective effect of SNX8 against NAFLD was largely dependent on FASN suppression.These data indicate that SNX8 is a key suppressor of NAFLD that promotes FASN proteasomal degradation. Targeting the SNX8-FASN axis is a promising strategy for NAFLD prevention and treatment.
Sodium<sup>+</sup>/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
Authors: Ahmad Salhab, Johnny Amer, Yinying Lu, Rifaat Safadi
Journal: Gut (2021)

Objective Sodium + / taurocholate cotransporting polypeptide (NTCP) is a membrane transporter affecting the enterohepatic circulation of bile acids (BAs). We aimed to evaluate NTCP’s roles in humans and animal models of liver fibrosis (LF). Design Primary hepatic stellate cells (pHSCs) isolated from livers biopsies of patients with LF with different fibrosis grading were stained for NTCP. NTCP gene silencing, taurocholic acid (TCA), obeticholic acid (OCA), epigallocatechin gallate (EGCG) and HA-100 dihydrochloride (HA-100) were used as tools to modulate NTCP expression on human HSC line (LX2). BA trafficking/uptake were assessed extracellularly (LX2 culture medium) and intracellularly following treatment with/without NTCP neutralizing antibody. LF models of C57/BL6 mice of carbon tetrachloride (CCl 4 ) and leptin-deficient ( Ob/Ob ) fed with high-fat diet ( Ob/Ob HFD ) were evaluated for pHSCs-NTCP expressions, metabolic and LF profiles following intraperitoneal injections of NTCP neutralizing antibody. Results pHSCs from F3/F4-scored patients of LF exhibit threefold increased NTCP expressions compared with F0-scored patients (p&lt;0.0001). Sorted-activated HSCs (LX2 αSMA+ ) showed high expressions of NTCP and high TCA uptake in vitro and triggered a further increase in their activations. This phenomenon was inhibited with NTCP small interfering RNA and the NTCP neutralizing antibody. Sorted LX2 NTCP+ (high alpha smooth muscle actin (αSMA)/high NTCP) cells showed high phosphorylated pathways of AKT/mTOR and protein kinase C (PKC) accompanied with a decrease in farnesoid X receptor expression. Moreover, LX2 NTCP+ cells treated with EGCG, OCA and PKC inhibitor HA-100 significantly decreased NTCP and αSMA. NTCP neutralizing antibody inhibited NTCP (less TCA uptake); it attenuated LF in both CCl 4 and Ob/Ob HFD animal models with ameliorated metabolic profile. Conclusion NTCP expression is linearly correlated with fibrosis severity. Modulated BA trafficking could be an important step in LF pathogenesis. Antagonising BA uptake may suggest a therapeutic strategy for preventing disease progression.
Abstract 60: Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment
Authors: Charly R. Good, Shunichiro Kuramitsu, Parisa Samareh, Greg Donahue, Kenichi Ishiyama, Yujie Ma, Nils Wellhausen, Lifeng Tian, Sangya Agarwal, Sonia Guedan, M. Angela Aznar, Katherine A. Alexander, Zhen Zhang, Nathan Singh, Max W. Richardson, Keisuke Watanabe, Janos L. Tanyi, Mark H. O'Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June
Journal: Cancer Research (2021)

Abstract Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains largely ineffective in solid tumors. A major factor leading to the reduced efficacy of CAR T cell therapy is T cell dysfunction, and the mechanisms mediating this dysfunction are under investigation. Here we establish a robust model to study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer. Continuous antigen exposure results in hallmark features of exhaustion including reduced proliferation capacity and cytotoxicity, and severe defects in cytokine production. Here we identified a transcriptional signature at both population and single-cell levels in CAR T cells after continuous antigen exposure. In addition, TCR lineage tracing revealed a CD8+ T-to-NK-like T cell plasticity that results in reduced tumor cell killing. The transcription factors SOX4 and ID3 are specifically expressed in the dysfunctional CAR NK-like T cells and are predicted to be master regulators of the dysfunction gene expression signature and the post-thymic acquisition of an NK-like T cell fate. Finally, we identified the emergence of NK-like CAR T cells in a subset of patients after infusion of CAR T cells. The findings gleaned from this study shed light on the plasticity of human CAR T cells and suggest new approaches to improve the efficacy of CAR T cell therapy in solid tumors by preventing or revitalizing CAR T cell dysfunction. Citation Format: Charly R. Good, Shunichiro Kuramitsu, Parisa Samareh, Greg Donahue, Kenichi Ishiyama, Yujie Ma, Nils Wellhausen, Lifeng Tian, Sangya Agarwal, Sonia Guedan, M. Angela Aznar, Katherine A. Alexander, Zhen Zhang, Nathan Singh, Max W. Richardson, Keisuke Watanabe, Janos L. Tanyi, Mark H. O'Hara, Marco Ruella, Simon F. Lacey, Edmund K. Moon, Stephen J. Schuster, Steven M. Albelda, Lewis L. Lanier, Regina M. Young, Shelley L. Berger, Carl H. June. Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment [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 60.
A Text-Book on Practical Obstetrics.
Journal: JAMA (1899)

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Characteristics and mid-term follow-up of COVID-19 patients with hematological diseases: a retrospective study from a French tertiary care hospital
Authors: Nicolas Vallet, Sylvie Chevret, Linda Feghoul, Lorea Aguinaga, Louise Bondeelle, Eleonore Kaphan, Rémi Bertinchamp, Juliette Soret, Camille Villesuzanne, Nathalie De Castro, Marie Sebert, David Boutboul, Etienne Lengline, Jean-Jacques Tudesq, Florence Rabian, Lionel Adès, Alienor Xhaard, Roberta Di Blasi, Emmanuel Raffoux, Lionel Galicier, Jérôme Le Goff, Constance Delaugerre, Anne Bergeron, Stéphanie Harel, Nathalie De Castro, Jérôme Le Goff, Constance Delaugerre
Journal: Blood Cancer Journal (2021)
Abstract 2087: Breast tissue-specific DNA methylation levels predicted by genetic variants in association with breast cancer
Authors: Chunyan He, James Castle, Nan Lin, Jinpeng Liu, Chi Wang, Yunlong Liu
Journal: Cancer Research (2021)

Abstract Aberrant DNA methylation (DNAm) contributes to the development of breast cancer. Both genetic and environmental factors influence DNAm levels in a tissue-specific fashion. Previously studies have reported that genetically predicted DNAm levels at CpGs were associated with breast cancer risk. However, the prediction models were built based on DNAm measured in blood, which may not be the most relevant tissue for breast cancer. In this study, we aim to build statistical models to predict breast tissue-specific DNAm levels using genetic data and DNAm sequencing data of normal breast tissue from healthy women (N=293). We applied these models to the GWAS data from the Breast Cancer Association Consortium that includes 46,785 breast cancer patients and 42,892 controls. We evaluated the association of genetically predicted breast tissue-specific DNAm levels at CpGs with breast cancer risk using MetaXcan. Due to our small sample size of normal breast tissue samples, we restricted our statistical models to those that were well-validated and highly correlated between predicted and measured DNAm levels (r≥0.6). We thus identified 45 CpGs that were significantly associated with breast cancer risk after correction for multiple testings, and many of these CpGs were also differentially methylation between breast tumor and normal tissue samples. Genes annotated to these CpG sites are enriched in Wnt signaling, cell cycle, and stem cell proliferation pathways, including known genes such as FGFR2, KLF4, CASC8, TERT, and EMBP1. We also identified novel putative DNAm markers for the development of breast cancer. Our study provides insight into tissue-specific genetic regulation of DNAm in normal breast tissue. Citation Format: Chunyan He, James Castle, Nan Lin, Jinpeng Liu, Chi Wang, Yunlong Liu. Breast tissue-specific DNA methylation levels predicted by genetic variants in association with breast 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 2087.
Single-cell RNA sequencing reveals distinct cellular factors for response to immunotherapy targeting CD73 and PD-1 in colorectal cancer
Authors: Miok Kim, Yong Ki Min, Jinho Jang, Hyejin Park, Semin Lee, Chang Hoon Lee
Journal: Journal for ImmunoTherapy of Cancer (2021)

Although cancer immunotherapy is one of the most effective advanced-stage cancer therapies, no clinically approved cancer immunotherapies currently exist for colorectal cancer (CRC). Recently, programmed cell death protein 1 (PD-1) blockade has exhibited clinical benefits according to ongoing clinical trials. However, ongoing clinical trials for cancer immunotherapies are focused on PD-1 signaling inhibitors such as pembrolizumab, nivolumab, and atezolizumab. In this study, we focused on revealing the distinct response mechanism for the potent CD73 ectoenzyme selective inhibitor AB680 as a promising drug candidate that functions by blocking tumorigenic ATP/adenosine signaling in comparison to current therapeutics that block PD-1 to assess the value of this drug as a novel immunotherapy for CRC.To understand the distinct mechanism of AB680 in comparison to that of a neutralizing antibody against murine PD-1 used as a PD-1 blocker, we performed single-cell RNA sequencing of CD45+ tumor-infiltrating lymphocytes from untreated controls (n=3) and from AB680-treated (n=3) and PD-1-blockade-treated murine CRC in vivo models. We also used flow cytometry, Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) models, and in vitro functional assays to validate our new findings.We initially observed that the expressions of Nt5e (a gene for CD73) and Entpd1 (a gene for CD39) affect T cell receptor (TCR) diversity and transcriptional profiles of T cells, thus suggesting their critical roles in T cell exhaustion within tumor. Importantly, PD-1 blockade significantly increased the TCR diversity of Entpd1-negative T cells and Pdcd1-positive T cells. Additionally, we determined that AB680 improved the anticancer functions of immunosuppressed cells such as Treg and exhausted T cells, while the PD-1 blocker quantitatively reduced Malat1high Treg and M2 macrophages. We also verified that PD-1 blockade induced Treg depletion in AOM/DSS CRC in vivo models, and we confirmed that AB680 treatment caused increased activation of CD8+ T cells using an in vitro T cell assay.The intratumoral immunomodulation of CD73 inhibition is distinct from PD-1 inhibition and exhibits potential as a novel anticancer immunotherapy for CRC, possibly through a synergistic effect when combined with PD-1 blocker treatments. This study may contribute to the ongoing development of anticancer immunotherapies targeting refractory CRC.
Abstract 1084: Targeting MET and RON to overcome cetuximab resistance in colorectal cancer
Authors: Ramona Graves-Deal, Galina Bogatcheva, Vishnu Damalanka, Lidija Klampfer, James W. Janetka, Robert J. Coffey, Bhuminder Singh
Journal: Cancer Research (2021)

Abstract Using a novel 3D culture system, we previously showed that activation of receptor tyrosine kinases (RTKs) MET and RON contributed to cetuximab resistance in colorectal cancer (CRC) cells. CC derived from HCA-7 cells were sensitive to cetuximab, whereas similarly derived SC were resistant; we also generated cetuximab-resistant (CC-CR) upon prolonged exposure of CC to cetuximab. Both de novo and acquired modes of cetuximab resistance in SC and CC-CR, respectively, could be overcome by crizotinib, a multi-RTK inhibitor that also targets MET and RON. Moreover, MET and RON ligands, HGF and HGFL, respectively are synthesized as inactive precursors and require cleavage by proteases (HGFA, Matriptase, and Hepsin) to be biologically active. Herein, to inhibit HGF/HGFL cleavage in cetuximab-resistant cells, we employed inhibitors of proteases of HGF/HGFL (ZFH7116 and VD2173) and were able to overcome both de novo and acquired cetuximab resistance. We are now in the process of engineering cetuximab-sensitive CC cells to overexpress HGF or HGFL to test if ligand overexpression imparts cetuximab resistance and if this resistance can be overcome by inhibition of HGF/HGFL proteases and/or by crizotinib. To understand the broader significance of these resistance mechanisms, we have identified a set of KRAS wild-type human CRC patient-derived tumor xenografts (PDXs) that show increased MET/RON phosphorylation. A comparative RNA-seq analysis showed that PDXs with high pMET/pRON levels could be segregated from PDXs with low pMET/pRON levels. Differential response of these PDXs and their organoid (PDO) derivatives for cetuximab resistance and response to crizotinib addition based on their pMET/pRON levels will be presented. Citation Format: Ramona Graves-Deal, Galina Bogatcheva, Vishnu Damalanka, Lidija Klampfer, James W. Janetka, Robert J. Coffey, Bhuminder Singh. Targeting MET and RON to overcome cetuximab resistance in colorectal 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 1084.
Abstract 1699: Direct and indirect immune effects of CMP-001, a virus like particle containing a TLR9 agonist
Authors: Shakoora Sabree, Andrew Voigt, George J. Weiner, Sue Blackwell
Journal: Cancer Research (2021)

Abstract Background: CMP-001, a virus-like particle (VLP) containing a TLR9 agonist encapsulated by the Qb capsid, is showing promise in early clinical trials when administered intratumorally. Prior work by our group has demonstrated the immunostimulatory effects of CMP-001 are dependent on generation of an anti-Qb antibody response which results in opsonization of CMP-001 by plasmacytoid dendritic cells (pDCs) and production of IFNa. The in vivo efficacy of CMP-001-mediated in situ immunization is T cell dependent. Here, we explore the mechanisms by which the initial effects of CMP-001 on pDCs can activate other cell populations that can contribute to development of an anti-tumor T cell response. Methods: Uptake of CMP-001 by various cell populations was evaluated by flow cytometry. Gene expression by various immune cell subsets in response to CMP-001 treatment was measured by single cell RNA sequencing (scRNAseq) of normal donor human PBMCs. Additional in vitro experiments were conducted to evaluate direct and secondary effects of CMP-001 on various immune cell subsets. Results: Anti-Qb antibody-coated CMP-001 were taken up extensively by monocytes with lower levels of uptake by B cells and pDCs. Antibody-coated CMP-001 induced upregulation of interferon-responsive genes and molecules by various cell types including CXCL10, PDL1, and IDO. Much of the impact of CMP-001 plus anti-Qb on monocytes was indirect and mediated by type I interferon. Expression by purified monocytes of PDL1 and IDO was increased in response to IFNa after treatment with CMP-001 plus anti-Qb whereas CXCL10 expression was decreased. Conclusions: CMP-001 plus anti-Qb induces production of type I interferon by pDCs. Type I interferon has secondary effects on a variety of cell types including monocytes which produce cytokines such as CXCL10 that can potentially impact the development of an anti-tumor T cell response. Uptake of anti-Qb-coated CMP-001 by monocytes has little direct effect on the monocytes. However, uptake of these particles by monocytes does alter the monocyte's response to type I interferon and results in enhanced expression of IDO and PDL1, and suppressed expression of CXCL10, consistent with generation of an immunosuppressive phenotype. These findings shed light on the complexity of the immune response to CMP-001, and provide insight into potential pathways that may be targeted in conjunction with CMP-001 to further enhance the efficacy of this novel approach to immunotherapy. Citation Format: Shakoora Sabree, Andrew Voigt, George J. Weiner, Sue Blackwell. Direct and indirect immune effects of CMP-001, a virus like particle containing a TLR9 agonist [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 1699.
Low Incidence of Osteonecrosis in Childhood Acute Lymphoblastic Leukemia Treated with ALL-97 and ALL-02 Study of Japan Association of Childhood Leukemia Study Group
Authors: Kenichi Sakamoto, Toshihiko Imamura, Kentaro Kihira, Hisashi Ishida, Suzuki Kouji, Hiromi Morita, Kanno Miyako, Takeshi Mori, Hidefumi Hiramatsu, Kousaku Matsubara, Kiminori Terui, Yoshihiro Takahashi, So-ichi Suenobu, Daiichiro Hasegawa, Yoshiyuki Kosaka, Koji Kato, Saito-Moriya Akiko, Atsushi Sato, Hirohide Kawasaki, Keiko Yumura Yagi, Jun-ichi Hara, Hiroki Hori, Keizo Horibe
Journal: Blood (2017)