tbuckley/cabot-search huggingface dataset:
Abstract 1646: Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responses
Authors: George Katibah, Yamini Ohol, Cyril Bucher, Lavanya Adusumilli, Deepika Kaveri, Omar Robles, Michael Sun, Cynthia Cho, Heather Milestone, Rachel Ames, Scott Jacobson, Dan Nebalasca, Justy Gomez- Guagua, Jerick Sanchez, Molly Grandcolas, Steve Wong, Martin Brovarney, Chandru Ramana, Thant Zaw, Lan Nguyen, Parcharee Tivitmahaisoon, Andrew Ng, Anqi Ma, Blanca Gomez, Michelle Ko, Paul Leger, Jeffrey Jackson, Grant Shibuya, Anton Shakhmin, Delia Bradford, Mengshu Xu, Mikhail Zibinsky, Daniel Poon, David Wustrow, Paul Kassner, Dirk Brockstedt
Journal: Cancer Research (2021)

Abstract Hematopoietic progenitor kinase 1 (HPK1) is an intracellular protein kinase that negatively regulates T cell signaling and proliferation. Upon T cell receptor (TCR) activation, active HPK1 phosphorylates the adaptor protein SLP76 in the TCR complex, recruiting the negative regulator 14-3-3 and targeting components of the TCR signaling complex for degradation. HPK1 thus limits the TCR signaling important for mounting an effective immune response against tumor cells. We are employing structure-guided drug design to develop potent small-molecule inhibitors of HPK1. Our compounds potently inhibit HPK1 in biochemical assays, reduce levels of phosphorylated SLP76 and concomitantly increase IL-2 production by Jurkat T cells. Importantly, our HPK1 inhibitors enhance cytokine production by human and mouse primary T cells above that observed with TCR activation alone. Treatment of mice with orally available HPK1 inhibitors results in increased activation of antigen-specific CD8+ T cells in vivo and decreased tumor growth as single agent and in combination with clinically relevant checkpoint inhibitor antibodies. Our work confirms the importance of HPK1 for T cell function and supports HPK1 as a promising next generation immuno-oncology target. Citation Format: George Katibah, Yamini Ohol, Cyril Bucher, Lavanya Adusumilli, Deepika Kaveri, Omar Robles, Michael Sun, Cynthia Cho, Heather Milestone, Rachel Ames, Scott Jacobson, Dan Nebalasca, Justy Gomez- Guagua, Jerick Sanchez, Molly Grandcolas, Steve Wong, Martin Brovarney, Chandru Ramana, Thant Zaw, Lan Nguyen, Parcharee Tivitmahaisoon, Andrew Ng, Anqi Ma, Blanca Gomez, Michelle Ko, Paul Leger, Jeffrey Jackson, Grant Shibuya, Anton Shakhmin, Delia Bradford, Mengshu Xu, Mikhail Zibinsky, Daniel Poon, David Wustrow, Paul Kassner, Dirk Brockstedt. Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responses [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 1646.
Abstract 344: Correlative biomarker analyses: Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in an open-label, single arm phase 2 trial in locally advanced esophageal squamous carcinoma
Authors: Wenwu He, Lin Peng, Yu Bao, Wenguang Xiao, Qiang Fang, Xuefeng Leng, Jiaxin Yan, Tianqin Mao, Xudong Shen, Depei Huang, Hushan Zhang, Xueke She, Yongtao Han
Journal: Cancer Research (2021)

Abstract Background: NCT04177797 was an open-label, single arm phase 2 trial in locally advanced esophageal squamous carcinoma (ESCC), which adopted toripalimab, plus paclitaxel and carboplatin as neoadjuvant immunotherapy regimen. Here we report correlative biomarker analyses for all 18 included patients. Methods: After two cycles of neoadjuvant immunotherapy, sixteen patients underwent surgery and seven of them achieved major pathological response (MPR). Two patients did not receive surgery but their imaging evaluation were both clinical complete response (cCR). We defined MPR or cCR as responders, and others as non-responders. Peripheral blood, gastroscopic tumor and adjacent normal tissues were collected before the first dose of drug and so did surgery samples. Whole exome sequencing (WES) and RNA-seq were conducted for the pretreatment tissues, and surgery samples were performed for multiplex immunohistochemistry (mIHC) with 5 markers. Results: In pretreatment tumor tissues, there was no significant difference either in the CD8+ (p=0.19) or CD68+HLA-DR- (p=0.57) density between responders and non-responders. However, CD8+ density increased (p=0.0078) and CD68+HLA-DR- density decreased (p=0.039) significantly in responders after neoadjuvant combined immunotherapy, whereas these two markers did not in non-responders (p=0.13 and p=0.36, respectively). Meanwhile, responders were associated with higher baseline gene expression levels of CXCL 5 (p=0.03) and lower baseline CCL 19 (p=0.017) and UMODL1 (p=0.03). Conclusions: The mechanism of tumor response may be associated reduction of M2 macrophages and CD8 cells recruitment after combined immunotherapy in locally advanced resectable ESCC. Citation Format: Wenwu He, Lin Peng, Yu Bao, Wenguang Xiao, Qiang Fang, Xuefeng Leng, Jiaxin Yan, Tianqin Mao, Xudong Shen, Depei Huang, Hushan Zhang, Xueke She, Yongtao Han. Correlative biomarker analyses: Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in an open-label, single arm phase 2 trial in locally advanced esophageal squamous carcinoma [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 344.
Toward Antiracist Reimbursement Policy in End-Stage Kidney Disease: From Equality to Equity
Authors: Kathryn Taylor, Deidra C. Crews
Journal: Journal of the American Society of Nephrology (2021)

The year 2020 saw ongoing police violence against Black people; their disproportionate burden of coronavirus disease 2019 morbidity and mortality; and subsequent national protests. In the context of calls for racial justice, the kidney community is grappling with how its established policies and
Abstract 2257: Effect ofALDH1L1folate enzyme on hepatocellular carcinoma inachemical carcinogenesismodel
Authors: Jaspreet Sharma, Natalia I. Krupenko, Peter Pediaditakis, Kristi Helke, Kyle C. Strickland, Sergey A. Krupenko
Journal: Cancer Research (2021)

Abstract Background: ALDH1L1 (aldehyde dehydrogenase 1 family member L1, or cytosolic 10-formyltetrahydrofolate dehydrogenase) is an abundant enzyme in folate metabolism representing about 1% of total soluble protein in hepatocytes. Expression of this protein is strongly and ubiquitously downregulated in human cancers through the promoter methylation. Several studies indicate that patients with hepatocellular carcinoma who had low expression of ALDH1L1 had poorer prognosis than those with high expression. Hypothesis: We propose that in the absence of ALDH1L1, liver tumors proliferate faster and grow to a larger size. Methods: The effect of the Aldh1l1 knockout (Aldh1l1−/−) on hepatocellular carcinoma was investigated using DEN (diethyl nitrosamine) model of chemical carcinogenesis. Fifteen-days-old male Aldh1l1−/- mice and their wild-type littermate controls (Aldh1l1+/+) were injected intraperitoneally with DEN at the dose of 15 mg/kg body weight. Mice were sacrificed 10, 20, 28- and 36-weeks post-injection and livers were examined for for histopathology. Results: Significant reduction in total body weight was observed in the DEN-injected knockout compared to wild type animals at 28 and 36 weeks. Immunohistochemical analysis reveals that tumor size was significantly bigger in Aldh1l1−/− compared to Aldh1l1+/+ mice and also indicated fibrosis in livers of knockout vs wild-type mice. Vascular involvement, highlighted by reticulin staining, was present in both Aldh1l1−/− and Aldh1l1+/+ mice as early as 20 weeks after the injection. Tumor multiplicity did not differ significantly between the Aldh1l1−/− and Aldh1l1+/+ animals. Conclusion:. Aldh1l1 knockout promoted aggressiveness of liver tumors without affecting the tumor initiation. Acknowledgement: These studies were supported by the National Institutes of Health grants DK54388 and CA095030 (S.A.K.). Citation Format: Jaspreet Sharma, Natalia I. Krupenko, Peter Pediaditakis, Kristi Helke, Kyle C. Strickland, Sergey A. Krupenko. Effect ofALDH1L1folate enzyme on hepatocellular carcinoma inachemical carcinogenesismodel [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 2257.
Abstract 972: Pharmacological targeting CDC7 sensitizes oxaliplatin treatment in colorectal cancer
Authors: Yufeng Chen, Zhaoliang Yu, Peng Deng, Xiaojian Wu
Journal: Cancer Research (2021)

Abstract The cell division cycle 7 (CDC7) is a serine/threonine kinase that plays a critical role in the initiation of DNA replication by phosphorylating MCM 2-7 complex, which is frequently overexpressed in various human cancers. This study aimed to investigate the roles of CDC7 in colorectal cancer (CRC) and its potential pharmacological value. We found CDC7 expression was associated with tumor recurrence and poor outcome in CRC patients. We depleted CDC7 expression with siRNA and found CDC7 depletion dramatically inhibits colony formation in CRC cells treated with oxaliplatin. Importantly, pharmacological inhibition of CDC7 with inhibitor (XL413 or PHA767491) could overcome oxaliplatin resistance of CRC cells in cells proliferation, clone formation and tumorsphere formation. To further validated these findings in vivo, we examined the efficacy of CDC7 inhibitor and oxaliplatin in a DLD1-derived xenograft mouse model and two PDX models. The combination of oxaliplatin and XL413 significantly inhibit xenograft tumor growth, which showed remarkably decreased Ki-67 and increased cleaved-caspase 3 by IHC analysis. Collectively, our findings unveil the critical role of CDC7 in colon cancer cells and targeting CDC7 is a potential effective therapeutic for CRC patients. Citation Format: Yufeng Chen, Zhaoliang Yu, Peng Deng, Xiaojian Wu. Pharmacological targeting CDC7 sensitizes oxaliplatin treatment 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 972.
Abstract CT150: Humanized CD19 CAR-T cells in the treatment of relapsed and refractory diffuse large B-cell lymphoma: A case report
Authors: Tan Li, Yi Wang, Bin Li, Xueying Hu, Liu Liu, Yangyi Bao, Qiao Li, Lin Yang, Hongxia Li
Journal: Cancer Research (2021)

Abstract The authors did not submit an updated abstract. The original abstract should be considered final. Citation Format: Tan Li, Yi Wang, Bin Li, Xueying Hu, Liu Liu, Yangyi Bao, Qiao Li, Lin Yang, Hongxia Li. Humanized CD19 CAR-T cells in the treatment of relapsed and refractory diffuse large B-cell lymphoma: A case report [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 CT150.
A qualitative study of patient and carer experiences with home respiratory therapies: Long-term oxygen therapy and home mechanical ventilation
Authors: Cátia Caneiras, Cristina Jácome, Emília Moreira, Daniela Oliveira, Cláudia Camila Dias, Liliane Mendonça, Sagrario Mayoralas-Alises, João Almeida Fonseca, Salvador Diaz-Lobato, Joan Escarrabill, João Carlos Winck
Journal: Pulmonology (2021)

Studies exploring the experience of patients receiving home respiratory therapies (HRT), such as long-term oxygen therapy (LTOT) and home mechanical ventilation (HMV), are still limited. This study focused on patients' and carers' experience with LTOT and HMV. An exploratory, cross-sectional qualitative study, using semi-structured focus groups, was carried out with 18 patients receiving HRT (median 71y, 78% male, 56% on both LTOT and HMV) and 6 carers (median age 67y, 67% female). Three focus groups were conducted in three regions of Portugal. Thematic analysis was performed by two independent researchers. Patients' and carers' experience was reflected in seven major topics, linked to specific time points and settings of the treatment: Initial symptoms/circumstances (n = 41), Prescription (n = 232), Implementation (n = 184), Carer involvement (n = 34), Quality of life impact (n = 301), Health care support/navigability (n = 173) and Suggestions (n = 14). Our findings demonstrate a general good perception of the HRT by patients and carers recognizing a significative quality of life impact improvement, while identifying specific points where improvements in healthcare are needed, particularly about navigability issues, articulation between the hospital, primary care and homecare teams, especially regardingprescriptionrenewal. This knowledge is crucial to promote a long-term HRT adherence and to optimize HRT delivery in line with patients' experience, needs, and values. Moreover, these key points can inform the development of a specific patient-reported experience measure (PREM) for patients on HRT, which is not currently available, and foster a more integrated respiratory care model.
Abstract 1923: Modulation of apoptosis in glioblastoma U87-MG cancer cells by aqueous extract of <i>Bryophyllum pinnatum</i>
Authors: Kristin Ferrer, Joshua Li, Camille Kordas, Jasmine Cha, Sung Been Han, Joon Seo, Nathaly Manrique, Min Seo Kang, Yi Shan Jin, Si Won Choi, Ben Hiramoto, Denise Smith, Brian Yuen Wong
Journal: Cancer Research (2021)

Abstract Bryophyllum pinnatum (BP) has been used in anthroposophic medicine to treat “hyperactivity diseases” such as tocolytic symptom and overactive bladder syndrome since the beginning of 20th century with no side effect. Its major secondary metabolites include bufadienolides, flavonoids, triterpenes, and steroids. BP has been widely used in tropical regions as traditional medicine. It is reported to have antioxidant, immunomodulatory, antidiabetic, anti-inflammatory, antihypertensive, wound healing, cytotoxic, and antitumor promoting activities. Glioblastoma is an aggressive and lethal tumor of the brain with few treatment options. In this study, the effects of aqueous extracts of BP on the induction and modulation of apoptosis in glioblastoma U87-MG cells were assessed using the green/red/blue fluorescent Apoptosis/Necrosis Detection Kit and the Human Apoptosis Antibody Array - Membrane (43 Targets) test by the Abcam cooperation. Our data revealed that 3-hours of 1 mg/mL and 2 mg/mL BP treatment induced statistically similar amounts of apoptosis observed as green apoptotic cells and red necrotic cells in U87-MG cells respectively (apoptotic cells = 86.0 ± 6%, necrotic cells = 14.0 ± 6.0% ; apoptotic cells = 85.0 ± 4.0% , necrotic cells = 14.5 ± 3.5%). The percent of apoptosis was not significantly different as compared to that of the positive control induced by 1µMol Staurosporine (94.5 ± 0.5%, 5.5 ± 0.5%); while significantly different from the negative control which had none apoptotic cells. Slightly less induction of apoptosis was obtained from 6-hours of 1 mg/mL and 2 mg/mL BP treatment with more necrotic cells (81.5 ± 2.5%, 18.5 ± 2.5%; 78.0 ± 3.0%, 21.5 ± 2.5% respectively). Modulation of various apoptosis markers such as up-regulation of Bax, p53, Caspase 3; and down-regulation of Bcl-2 and Bcl-w was also observed. These results suggest that BP contains phytochemicals which induce apoptosis in glioblastoma U87-MG cells by modulating these apoptotic pathway markers. Further study of the specific modulation effects of BP on apoptosis is warranted to reveal its potential chemopreventive and therapeutic properties against glioblastoma and other cancers. Citation Format: Kristin Ferrer, Joshua Li, Camille Kordas, Jasmine Cha, Sung Been Han, Joon Seo, Nathaly Manrique, Min Seo Kang, Yi Shan Jin, Si Won Choi, Ben Hiramoto, Denise Smith, Brian Yuen Wong. Modulation of apoptosis in glioblastoma U87-MG cancer cells by aqueous extract of Bryophyllum pinnatum [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 1923.
The new chronic lithiasic disease management and risk classification model, based on a Kaiser Permanente Pyramid (KPP) design. The 3-year results
Authors: F. Gómez Palomo, D.G. Ordaz Jurado, A. Budía Alba, D. Vivas-Consuelo, P. Bahilo Mateu, M. Trassierra Villa, D. López Acón, F. Boronat Tormo
Journal: European Urology (2021)
Abstract 1854: A Fc-competent anti-human TIGIT blocking antibody BGB-A1217 elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models
Authors: Xin Chen, Liu Xue, Xiao Ding, Qi Liu, Jing Zhang, Lei Jiang, Sha Liu, Hongjia Hou, Qing Zhu, Bin Jiang, Lijie Zhang, Xiaosui Zhou, Jie Ma, Yucheng Li, Wei Jin, Min Wei, Zhirong Shen, Mike Liu, Kang Li, Tong Zhang
Journal: Cancer Research (2021)

Abstract Background: TIGIT (T-cell immunoglobulin and ITIM domain) is a “checkpoint” inhibitory receptor, which is primarily expressed on activated and “exhausted” T and NK cells. Engagement of TIGIT to its ligands (i.e., PVR and PVR-L2) leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. BGB-A1217 is a novel humanized IgG1 anti-TIGIT antibody under clinical development. The immunomodulatory activity of BGB-A1217 was evaluated both in vitro and in vivo. Materials and methods: BGB-A1217 was generated through hybridoma fusion, humanized by CDR grafting and structural simulation. The binding affinity and specificity were studied by FACS and SPR. The immunomodulatory functions of BGB-A1217 were evaluated using primary immune cells as well as using animal models. Results: BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity. In a competition assay, BGB-A1217 efficiently blocks the interaction between TIGIT and PVR. In vitro, BGB-A1217 significantly enhances T-cell functions and induces potential ADCC against TIGITHi targets. In a human T-cell assay, BGB-A1217 enhances IFN-γ production of CMV-specific T cells. In a PBMC assay, BGB-A1217 augments T cell response, either alone or in combination with an anti-PD-1 antibody BGB-A317. Besides blocking TIGIT signaling, BGB-A1217 can also remove TIGIT from cell surface through trogocytosis. This activity is Fc-dependent. In vivo, the Fc effector function is critical for the activity of BGB-A1217 against CT26WT tumor implanted in humanized TIGIT knock-in mice. The observed anti-tumor efficacy is associated with pharmacodynamic change of TIGIT down-regulation, CD226 upregulation and Treg depletion at 48hrs after first dosing. Conclusions: BGB-A1217, either alone or in combination with anti-PD-1 mAb promotes immune cell activation both in vitro and in vivo, supporting its clinical development for the treatment of human cancers. Citation Format: Xin Chen, Liu Xue, Xiao Ding, Qi Liu, Jing Zhang, Lei Jiang, Sha Liu, Hongjia Hou, Qing Zhu, Bin Jiang, Lijie Zhang, Xiaosui Zhou, Jie Ma, Yucheng Li, Wei Jin, Min Wei, Zhirong Shen, Mike Liu, Kang Li, Tong Zhang. A Fc-competent anti-human TIGIT blocking antibody BGB-A1217 elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models [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 1854.
Intestinal Phosphorus Absorption in Moderate CKD and Healthy Adults Determined Using a Radioisotopic Tracer
Authors: Elizabeth R. Stremke, Gretchen N. Wiese, Sharon M. Moe, Meryl E. Wastney, Ranjani N. Moorthi, Kathleen M. Hill Gallant
Journal: Journal of the American Society of Nephrology (2021)

Reducing intestinal phosphorus absorption is a cornerstone in CKD-MBD management. Yet, knowledge gaps include how CKD pathophysiology affects intestinal phosphorus absorption.
Practice variation in the management of adult hydroceles: A multinational survey
Authors: K. Bolsunovskyi, M.T. Forss, T.P. Kilpeläinen, Y. Lee, Y. Aoki, S. Gudjonsson, F. Hervé, P. Järvinen, S. Malde, K. Miyazawa, J. Sairanen, L. Sander, L.P. Witte, G.H. Guyatt, K.A.O. Tikkinen
Journal: European Urology (2021)
Abstract 123: A CRISPR/Cas9-engineered ARID1A-deficient human gastric cancer organoid model reveals essential and non-essential modes of oncogenic transformation
Authors: Yuan-Hung Lo, Kevin S. Kolahi, Yuhong Du, Chiung-Ying Chang, Andrey Krokhotin, Ajay Nair, Walter D. Sobba, Kasper Karlsson, Sunny J. Jones, Teri A. Longacre, Amanda T. Mah, Alexandra Sockell, Jose A. Seoane, Jin Chen, Jonathan S. Weissman, Christina Curtis, Andrea Califano, Haian Fu, Gerald R. Crabtree, Calvin J. Kuo
Journal: Cancer Research (2021)

Abstract Mutations in ARID1A, encoding a subunit of the BAF chromatin remodeling complex, rank amongst the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward human genetic model systems. Here, CRISPR/Cas9 knockout of ARID1A in primary TP53-/- human gastric organoids induced morphologic dysplasia, tumorigenicity and mucinous differentiation but impaired Wnt/β-catenin signaling. Genetic Wnt pathway activation rescued mucinous differentiation, but not hyperproliferation, suggesting alternative essential pathways of ARID1A-mediated transformation. ARID1A loss induced transcriptional regulatory modules characteristic of MSI and EBV subtype human gastric cancer, including FOXM1 regulation of multiple mitotic regulatory genes and BIRC5/survivin. Convergently, high-throughput compound screening indicated selective vulnerability of ARID1A-deficient organoids to BIRC5/survivin inhibition, functionally implicating BIRC5/survivin as an essential mediator of proliferation following initial ARID1A loss. However, CRISPR inactivation of ARID1A in established gastric cancer cell lines did not elicit sensitivity to BIRC5/survivin inhibitors, suggesting that this pathway may be selectively required during the early establishment of tumorigenesis. Overall, we define distinct pathways downstream of oncogenic ARID1A mutation, with non-essential Wnt-inhibited mucinous differentiation in parallel with essential transcriptional FOXM1/BIRC5-stimulated proliferation, indicating the general utility of organoid-based forward genetic cancer analysis in human cells. Citation Format: Yuan-Hung Lo, Kevin S. Kolahi, Yuhong Du, Chiung-Ying Chang, Andrey Krokhotin, Ajay Nair, Walter D. Sobba, Kasper Karlsson, Sunny J. Jones, Teri A. Longacre, Amanda T. Mah, Alexandra Sockell, Jose A. Seoane, Jin Chen, Jonathan S. Weissman, Christina Curtis, Andrea Califano, Haian Fu, Gerald R. Crabtree, Calvin J. Kuo. A CRISPR/Cas9-engineered ARID1A-deficient human gastric cancer organoid model reveals essential and non-essential modes of oncogenic transformation [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 123.