tbuckley/cabot-search huggingface dataset:
Abstract 850: Multivitamin use and risk of overall and site-specific cancer in the National Institutes of Health - AARP Diet and Health Study
Authors: Jungeun Lim, Stephanie J. Weinstein, Linda M. Liao, Jiaqi Huang, Demetrius Albanes
Journal: Cancer Research (2021)

Abstract Although multivitamins are among the most commonly used supplements in the U.S., their effectiveness in preventing cancer and other chronic diseases is unclear. To help address this uncertainty, we prospectively investigated the association between multivitamin use and risk of overall and site-specific cancer in 489,640 participants enrolled in the National Institutes of Health (NIH) - AARP Diet and Health Study. We defined site-specific cancers using the Surveillance Epidemiology and End Results (SEER) incidence and the International Classification of Diseases for Oncology coding (3rd ed.). Multivitamin use was assessed by questionnaire at baseline and categorized as never, &amp;lt;3 times per week, 3-6 times per week, daily, and &amp;gt;1 per day. Cox proportional hazards regression models of multivitamin use estimated hazard ratios (HRs) and 95% confidence intervals (CIs) that adjusted for multiple potential confounders including gender, age, body mass index, smoking status, and Healthy Eating Index-2015 (HEI-2015) score. We observed no association between increasing multivitamin use and overall cancer risk (HRs 1.0 (reference, never use) 0.94, 0.96, 1.01, 1.00; trend P-value=0.42). Multivitamin use was, however, inversely associated with colon cancer risk: HR=0.79, 95% CI=0.70-0.89 (trend P-value&amp;lt;0.0001) among participants taking &amp;gt;1 multivitamin daily compared with never users, a finding that was identical in men and women (HR=0.79, 95% CI=0.68-0.92 and HR=0.79, 95% CI=0.65-0.95, respectively). Although there were some additional suggestive findings (e.g., for oropharyngeal cancer and leukemia), multivitamin use was not associated with the risk of cancer of the breast, prostate, or lung. In this study that comprehensively evaluated multivitamin use in relation to the risk of overall and site-specific malignancies in both men and women, we found little evidence to support beneficial associations, with the exception of colon cancer risk in both sexes. Citation Format: Jungeun Lim, Stephanie J. Weinstein, Linda M. Liao, Jiaqi Huang, Demetrius Albanes. Multivitamin use and risk of overall and site-specific cancer in the National Institutes of Health - AARP Diet and Health Study [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 850.
Abstract CT213: NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies
Authors: Mark Voskoboynik, Justin C. Moser, Nehal Lakhani, Michael Millward, Diwakar Davar, Wael A. Harb, Jing Yang, Gary Means, Kristi Manjarrez, Almudena Tercero, Hany Zayed, Jan Hillson, Christine Dela Cruz, Graciela Perez, Stanford L. Peng
Journal: Cancer Research (2021)

Abstract BACKGROUND: Checkpoint inhibitors (CPI) targeting the PD-1 and CTLA-4 pathways have demonstrated significant clinical benefit in multiple tumors, but the majority of patients exhibit or develop resistance, at least in part due to insufficient activation and/or excessive exhaustion of tumor-specific T cells. Strong preclinical rationale exists to combine CPIs with T cell costimulatory agonists, but such approaches have not yet translated into significantly improved clinical benefit. The majority of these approaches, though, have not targeted CD28, a critical T cell costimulator recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. As monotherapy, ALPN-202 has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating a favorable safety profile in preclinical toxicology studies. METHODS: This is a cohort-based, open-label dose escalation and expansion study in adults with advanced solid tumors or lymphoma (NCT04186637). The objectives of this study are to evaluate the safety, efficacy, pharmacokinetics, anti-drug antibodies, and pharmacodynamics of ALPN-202. Subjects who are refractory or resistant to standard therapy (including approved CPIs), or without available standard or curative therapy are eligible. ALPN-202 is administered by IV infusion. After two single-subject cohorts (0.001 mg/kg, 0.01 mg/kg), a standard 3+3 dose escalation (0.1-20 mg/kg) has been implemented with two dose schedules in parallel, Q1W and Q3W. Thereafter, expansion cohorts are planned to enroll subjects at a selected dose regimen(s) in selected indications. Biomarkers include tumor measurements of PD-L1, CD28, CD80 and CD86 to explore the possible relationship between baseline expression and outcomes. Other pharmacodynamic analyses include target saturation, inflammatory cytokines and immunophenotyping of circulating leukocytes. As of January 2021, the trial is continuing as planned; no DLTs have been observed through the 0.3 mg/kg cohorts (dose level 4). Citation Format: Mark Voskoboynik, Justin C. Moser, Nehal Lakhani, Michael Millward, Diwakar Davar, Wael A. Harb, Jing Yang, Gary Means, Kristi Manjarrez, Almudena Tercero, Hany Zayed, Jan Hillson, Christine Dela Cruz, Graciela Perez, Stanford L. Peng. NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies [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 CT213.
Impact of whole-cell bacterial immunoprophylaxis in the management of recurrent urinary tract infections in the frail elderly
Authors: M.F. Lorenzo Gomez, B.Y. Padilla-Fernández, J. Flores-Fraile, S. Valverde-Martínez, I. González-Casado, J.M. De Dios-Hernández, A. Sánchez-Escudero, M.J. Vicente-Arroyo, M. Martínez-Huélamo, F. Herrera-Criado, E. Blanco-Tarrío, M. Márquez-Sánchez, M.C. Flores-Fraile, P. Saz-Leal, J.A. Mirón-Canelo, H.A. García-Perdomo, M.B. García-Cenador
Journal: European Urology (2021)
Abstract 1899: Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting
Authors: Adham S. Bear, Tatiana Blanchard, Mark H. O'Hara, John Scholler, Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno
Journal: Cancer Research (2021)

Abstract Activating missense mutations within RAS oncogenes are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here, we employ multi-omic approaches to characterize optimal HLA class I-restricted mKRAS epitopes. Using in silico epitope prediction, we identify candidate mKRAS G12 epitopes with high predicted binding affinity to prevalent HLA class I alleles. We utilize biochemical approaches to identify mKRAS epitopes with high measured binding affinity and stability to HLA-A*03:01, -A*11:01 and -B*07:02. Furthermore, we provide proteomic validation of epitope processing and presentation by these alleles. We report mKRAS G12V and G12R epitopes are immunogenic as evidenced by the isolation of mKRAS G12V- and G12R-specific TCRαβ from healthy donors. The transfer of mKRAS-TCRs to primary CD8+ T cells serves as sensitive probes to validate mKRAS epitope processing and presentation by tumor cells and confers cytotoxicity against mKRAS human tumor cell lines of various histologies. The kinetics of lytic activity correlate with measured TCR avidity and mKRAS/HLA class I complex abundance expressed on the tumor cell surface. Finally, the adoptive transfer of mKRAS-TCR engineered primary CD8+ T cells to NOD scid gamma mice leads to tumor eradication in an orthotopic mKRAS lung cancer model. This study validates mKRAS as a bona fide tumor neoantigen and supports strategies to identify recurrent driver alterations for immunological targeting. Based on this work, clinical studies targeting mKRAS in cancer patients using vaccines and adoptive T cell therapy are under active investigation. Citation Format: Adham S. Bear, Tatiana Blanchard, Mark H. O'Hara, John Scholler, Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno. Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting [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 1899.
Ann Kinloch Maclennan
Authors: Betty Anderson
Journal: BMJ (2021)

Ann Kinloch Maclennan (nee Smith) was born in Glasgow. After being educated at Hillhead High School she enrolled at Glasgow University in 1938. Too young to study medicine, she studied mathematics, natural philosophy, and chemistry for a year, passing first class in all three subjects. Ann graduated in 1944. She was awarded the Asher Asher gold medal in laryngology and rhinology in 1943.

Ann’s successes at university weren’t limited to her academic pursuits. She was a first class sprinter and hurdler in the …
14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis
Authors: Wenyu Fu, Aubryanna Hettinghouse, Yujianan Chen, Wenhuo Hu, Xiang Ding, Meng Chen, Yuanjing Ding, Jyoti Mundra, Wenhao Song, Ronghan Liu, Young-Su Yi, Mukundan Attur, Jonathan Samuels, Eric Strauss, Philipp Leucht, Ran Schwarzkopf, Chuan-ju Liu
Journal: Annals of the Rheumatic Diseases (2021)

Objectives Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. Methods Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. Results Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN’s therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. Conclusions This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.
Abstract CT153: Correlation of <i>CDKN2A</i> genomic alterations with tumor response to palbociclib given before chemoradiation therapy to patients with human papillomavirus-unrelated, locally advanced head and neck squamous-cell carcinoma
Authors: Peter Oppelt, Jessica Ley, Kevin Palka, Randal C. Paniello, Sidharth V. Puram, Jason Rich, Ryan Jackson, Patrik Pipkorn, Hiram Gay, Jingxia Liu, Wade Thorstad, Jose Zevallos, Douglas R. Adkins
Journal: Cancer Research (2021)

Abstract The primary aims of this single-arm, phase 2 trial were to determine the objective response rate (ORR) of human papillomavirus (HPV)-unrelated, locally advanced head and neck squamous-cell carcinoma (LA-HNSCC) to palbociclib monotherapy, and to correlate responses to somatic genomic alterations in CDKN2A. HPV-unrelated disease was defined as 1) SCC of the larynx, hypopharynx or oral cavity, or 2) SCC of the oropharynx with &amp;lt;70% of tumor cells expressing p16 by immunohistochemistry and/or absence of high-risk HPV-RNA by in situ hybridization. Genome sequencing (FoundationOne CDx or Tempus xT) was performed on tumor tissue obtained before treatment. Patients received palbociclib 125 mg/d orally on days 1-21 of each 28-day cycle. Tumor response was assessed using RECIST 1.1 on CT scans performed before and after two cycles of palbociclib. After palbociclib, patients received chemoradiation therapy. A sample size of 24 patients yielded an 80% power if the ORR was &amp;gt;38% (alternative hypothesis), using an exact binomial test of one sample proportion comparison with an upper one-sided nominal significance level of 0.05 and null ORR of &amp;lt;17%. To date, 12 patients have enrolled and completed two cycles of palbociclib: primary site (larynx-7; hypopharynx-2; oropharynx-2, oral cavity-1), stage (III-3; IV-9), and smoking history (yes-11; no-1). The ORR to palbociclib monotherapy was 33%: CR (1 patient), PR (3), SD (7), and PD (1). CDKN2A alterations were identified in 6 patients (50%), and included loss-of-function mutations (4) or deletions (2). Tumor responses to palbociclib occurred in 4 of 6 patients (67%) with CDKN2A alterations versus 0 of 6 patients (0%) without CDKN2A alterations (p=0.06, Fisher's Exact Test). These preliminary results suggest that palbociclib may be an effective treatment for CDKN2A-altered, HPV-unrelated, LA-HNSCC, but not in disease that lacks CDKN2A alterations. Citation Format: Peter Oppelt, Jessica Ley, Kevin Palka, Randal C. Paniello, Sidharth V. Puram, Jason Rich, Ryan Jackson, Patrik Pipkorn, Hiram Gay, Jingxia Liu, Wade Thorstad, Jose Zevallos, Douglas R. Adkins. Correlation of CDKN2A genomic alterations with tumor response to palbociclib given before chemoradiation therapy to patients with human papillomavirus-unrelated, locally advanced head and neck squamous-cell 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 CT153.
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer
Authors: Matthew D Galsky, Arjun V Balar, Peter C Black, Matthew T Campbell, Gail S Dykstra, Petros Grivas, Shilpa Gupta, Christoper J Hoimes, Lidia P Lopez, Joshua J Meeks, Elizabeth R Plimack, Jonathan E Rosenberg, Neal Shore, Gary D Steinberg, Ashish M Kamat
Journal: Journal for ImmunoTherapy of Cancer (2021)

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.
Abstract 2770: Evaluation of tumor growth and baseline leukocyte infiltration in Charles River C57BL/6 and Balb/c mice engrafted with MC38, B16F10, RENCA and EMT6 cells
Authors: Christoph S. Eberle, Jenny Rowe, Ann Fiore, Robert Mihalek, Stephen Festin
Journal: Cancer Research (2021)

Abstract Background: In vivo syngeneic models continue to be an important tool in cancer biology research. Charles River C57BL/6 and Balb/c mice, two frequently used inbred strains, can be implanted with different murine tumor cell lines. One aspect of syngeneic model development is to characterize the extent and composition of infiltrating leukocytes (TIL) of tumor-bearing mice. The ability to analyze TILs is a relevant factor in preclinical model selection for studying immunomodulatory responses. Study Details: We evaluated growth rates and basal infiltrates in syngeneic models of solid mouse tumors. In four separate studies 7-week-old Charles River mice were implanted subcutaneously on the flank with either MC38 or B16F10 cells (C57BL/6) or with either RENCA or EMT6 cells (Balb/c), respectively. Mice were treated with isotype control IgG1 antibody (BioXcell clone MOPC-21) when tumors reached sizes of ~50-100 mm3. Surviving mice were euthanized when tumor burden reached or exceeded 2000 mm3 in line with internal IACUC guidelines. Spleen and tumors were then processed into single cell suspensions for immunophenotyping by multicolor acoustic-assisted flow cytometry. Results: Growth kinetics of all four tumor cell lines, MC38, B16F10, RENCA and EMT6, were monitored throughout each study. At study termination murine leukocyte infiltration was found in all models. These TILs were immune profiled to determine the frequencies and composition of murine immune cells in the lymphoid and myeloid compartments. Phenotyping data confirmed the presence of viable CD45+ cells with total T-cells (CD3+), T-cell subsets (CD4+, CD8+ and Treg) and myeloid populations (CD11b+) including M1 and M2 TAMs as well as CD11c+ cells. M1/M2 TAM, CD8/Treg and CD4/CD8 ratios were also calculated, and tumor models were assessed based on their baseline TIL composition. Conclusions: Four different allograft models of solid mouse tumors could be established using Charles River C57BL/6 and Balb/c mice. Their basal immune microenvironments could be characterized and therefore can be useful as pharmacodynamic readouts in efficacy studies of potential anti-cancer therapeutics. Citation Format: Christoph S. Eberle, Jenny Rowe, Ann Fiore, Robert Mihalek, Stephen Festin. Evaluation of tumor growth and baseline leukocyte infiltration in Charles River C57BL/6 and Balb/c mice engrafted with MC38, B16F10, RENCA and EMT6 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 2770.
Abstract 2694: An anatomic proteomic atlas of human glioblastoma
Authors: K.H. Brian Lam, Ugljesa Djuric, Ihor Batruch, Maxime Richer, Phedias Diamandis
Journal: Cancer Research (2021)

Abstract Glioblastoma (GBM) is an aggressive brain tumor with an expected survival of under 15 months despite spirited multimodal therapy. This grim outlook has remained virtually unchanged over the last 40 years and thus necessitates alternative research and therapeutic development strategies. Historically, traditional models of cancer biology have largely considered GBM tissue to be a homogenous mass. Emerging studies however now suggests that the interaction of tumor cells with various normal components of the brain and immune system play an important role in helping cancer grow and develop resistance to therapies. Better understanding of these hallmark features of GBM, collectively known as the “tumor microenvironment” (TME), could lead to the development of new and more effective therapies. In light of this, there is a renewed interest in revisiting our theories of cancer and preserving the microscopic anatomy of GBM in our molecular profiling efforts. Here we leverage laser capture microdissection (LCM) and mass spectrometry-based proteomics, in order to generate a detailed map of the distribution of proteins within tissues across a large number of patients. Specifically, we will isolate, and profile well-understood microscopic components of GBM: cellular tumor (CT), microvascular proliferation (MVP), infiltrating tumor (IT), palisading cells around necrosis (PAN) and normal brain tissue (LE). All of this data will be provided in an online-based GBM atlas as a publicly available resource. This atlas and the associated database for clinical and genomic data will serve as a useful platform for developing therapeutics and testing novel hypotheses related to GBM biology. Citation Format: K.H. Brian Lam, Ugljesa Djuric, Ihor Batruch, Maxime Richer, Phedias Diamandis. An anatomic proteomic atlas of human glioblastoma [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 2694.