tbuckley/cabot-search huggingface dataset:
Abstract 1540: CARs and TCRs: Myth and reality
Authors: Xueyin Wang, Aaron D. Martin, Kathleen Negri, Michele McElvain, Julyun Oh, Ming-Lun Wu, Wen-Hua Lee, Agnes Hamburger, Han Xu, Alexander Kamb
Journal: Cancer Research (2021)

Abstract Here we address questions of comparative TCR and CAR function: How different are CARs from TCRs with regard to antigen sensitivity, selectivity, co-stimulation dependence, checkpoint control, cytokine sensitivity, and antigen-dependent exhaustion (defined as loss of cytotoxicity and proliferative capacity over time). We used optimized CARs and TCRs matched to the same target pMHCs, allowing direct comparison of these important parameters. We describe a large-scale, systematic comparison of 17 CARs and 5 TCRs directed at 5 different pMHC targets in both acute and chronic settings in vitro. Surprisingly, we find little fundamental difference between CARs and TCRs with respect to their relative sensitivity to known regulators of T cell activation, including co-stimulation, checkpoint, and cytokine control. Though TCRs often emerge from human blood directly as potent, selective receptors, CARs must be heavily optimized to attain these properties for pMHC targets. Nonetheless, when iteratively improved, CARs can achieve levels of sensitivity and selectivity similar to their vaunted counterparts. Thus, other than signaling sensitivity (and perhaps selectivity), there may be little to distinguish CARs from TCRs in the context of engineered-cell therapy. CARs appear similar to TCRs with regard to immune control, undermining the notion that CARs can, of themselves, overcome regulators that limit T cell activity. Nevertheless, CARs tolerate much more sequence variability within their structural components and this, coupled with their capability to bind different antigen classes, smaller size and subunit simplicity, confers advantages that may foster a leading role for CARs in the next generation of cell therapeutics. We believe that the major conclusions reached here should instruct thinking about the boundaries around therapeutic designs for CARs, which appear to be very wide, and those around differentiation from TCRs, which appear to be much narrower. Citation Format: Xueyin Wang, Aaron D. Martin, Kathleen Negri, Michele McElvain, Julyun Oh, Ming-Lun Wu, Wen-Hua Lee, Agnes Hamburger, Han Xu, Alexander Kamb. CARs and TCRs: Myth and reality [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 1540.
Heterogeneity-analysis of molecular subtypes of muscle-invasive bladder cancer and their precursor lesions in multiregion mapped whole-organ bladders
Authors: V. Weyerer, F. Lange, A. Wullweber, R. Stoehr, S. Bertz, S. Wach, H. Taubert, B. Wullich, D. Sikic, P. Strissel, R. Strick, A. Hartmann, M. Eckstein
Journal: European Urology (2021)
In older adults with subclinical hypothyroidism, levothyroxine therapy did not reduce depressive symptoms at 12 mo
Authors: Jennifer Watt
Journal: Annals of Internal Medicine (2021)

Source Citation Wildisen L, Feller M, Del Giovane C, et al. Effect of levothyroxine therapy on the development of depressive symptoms in older adults with subclinical hypothyroidism: an ancillary study of a randomized clinical trial. JAMA Netw Open. 2021;4:e2036645. 33566107
Abstract 2467: Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis
Authors: Sharon J. Manley, Jarrid Jack, Joseph Ambrose, Appolinaire A. Olou, Michael N. VanSaun
Journal: Cancer Research (2021)

Abstract Understanding the impact of risk factors on the progression of pancreatic cancer is critical for the development of novel therapeutics. Multiple studies have clearly shown that obesity positively correlates with increased progression of pancreatic adenocarcinoma (PDAC). We have demonstrated that individual adipose derived cytokines (aka adipokines) can elicit either pro-tumorigenic or anti-tumorigenic effects on PDAC progression. We previously demonstrated that adiponectin receptor agonism effectively suppresses pancreatic cancer growth in vitro as well as in vivo, through suppression of MAPK as well as STAT3 pathways. Yet, adiponectin is well known to stimulate the AMPK pathway and therefore we hypothesized that adiponectin agonism could also be affecting metabolic function in PDAC. In our current studies, we defined multiple metabolic alterations in pancreatic cancer cells in response to adiponectin receptor agonism using a seahorse-based assay. Human and murine PDAC cell lines were seeded into XFe96 microplates and subjected to a mitochondrial stress test as well as the glycolysis stress test. Our results demonstrate that adiponectin receptor activation impairs pancreatic cancer mitochondrial function leading to a metabolic switch from mitochondrial respiration to glycolysis. We further demonstrate that this switch is associated with AMPK phosphorylation-mediated inhibition of Acetyl Coenzyme A Carboxylase (ACC), the lipogenic enzyme whose inhibition induces fatty acid breakdown. Thus, our results support a role for adipose-secreted factors to influence the metabolic phenotype of pancreatic cancer. Since metabolic rewiring is often associated with development of chemotherapeutic resistance in cancer, we are currently testing whether dual therapeutic targeting of the mitochondrial respiration, via adiponectin receptor agonism, and glycolysis would provide an efficacious therapeutic. Citation Format: Sharon J. Manley, Jarrid Jack, Joseph Ambrose, Appolinaire A. Olou, Michael N. VanSaun. Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis [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 2467.
Subgroup analyses of the phase 3 study of intravesical nadofaragene firadenovec in patients with high-grade, BCG-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)
Authors: V. Narayan, S. Boorjian, M. Alemozaffer, B.R. Konety, L. Gomella, A.M. Kamat, S.P. Lerner, R.S. Svatek, L. Karsh, D. Canter, Y. Lotan, B.A. Inman, M. Yang, V. Garcia-Horton, D. Sawutz, N. Parker, C.P.N. Dinney
Journal: European Urology (2021)
Abstract 9365: Left Ventricular Dysfunction and Cardiac Hypertrophy in Kit Mutant Mice During Aging
Authors: Lei Ye, Eric Y Zhang, Qiang Xiong, Mike Astle, Pengyuan Zhang, David E Harrison, Jianyi J Zhang
Journal: Circulation (2011)

Aim: Cardiac progenitor cells marked with c-Kit play an important role in maintaining normal cardiac function. This study aims at comparing effects of Kit mutants, including W/Wv, W41/W41, and W41/W42, on myocardial c-kit + cells profile and their association with left ventricular contractile function , hypertrophy during normal aging. Methods: LV function of W/Wv, W41/W41 and W41/W42 mice at age of 4 months and 12 months were determined by echocardiogram using age matched wide type (WT) mice as normal controls. Bone marrow (BM) from normal donor of green fluorescent protein (GFP) marked mice, was transplanted into Kit mutant mice after irradiation to determine whether normal BM repopulation could rescue the LV dysfunction by the regeneration of myocytes from BM cells, or by promote migration of endogenous c-Kit + progenitor cells into heart of Kit mutant mice. In addition, cardiac hypertrophy was determined and myocardial c-Kit + cells in myocardium were quantified. Results: Young mice with the Kit mutations showed no defects in LV functional studies in regard of LV ejection fraction (EF) and fractional shortening (FS). However EF and FS were significantly decreased in 12 months aged W41/W42 mice compared with the other three groups. Cardiac hypertrophy, indexed by heart weight/body weight was also significantly increased in W41/W42 mice compared with WT, W/Wv and W41/W41 at 12 months of age. Numbers of myocardial c-Kit + cells were significantly reduced in all three Kit mutant mice hearts compared with WT. BM transplantation did not increase c-Kit + progenitor cells into Kit mutated mice heart and also did not rescue decreased EF and FS of aged W41/W42 mutated mice. Conclusions: The W41/W42 mutants show decreased LV function during normal aging that is accompanied by a significant reduction of myocardial c-Kit+ cell count. Repopulation with normal BM does not increase c-Kit + progenitor cells in heart nor prevent reduction of LV function in aged W41/W42 mice. These data demonstrate that heart is not a post mitotic organ, and a normal myocytes turnover rate and normal LV function are supported by a pool of resident KIT+ progenitor during aging.
Abstract 2881: Snail-mediated regulation of MMP1 expression in the context of ovarian cancer invasiveness
Authors: Tise Suzuki, Casey Curow, Hanmin Wang, Asis Martinez, Nozomi Hojo, Juli Unternaehrer
Journal: Cancer Research (2021)

Abstract Ovarian cancer ranks fifth among the causes of cancer death in US women. Despite initial positive response to cytoreductive surgery and chemotherapy treatments with platinum-based therapies, over 80% of patients with high-grade serous ovarian cancer (HGSOC), the most common type of ovarian cancer, exhibit relapse. Most recurrent cases of HGSOC are resistant to chemotherapy, and cells are highly invasive. Therefore, further studies are required to understand the mechanisms of invasiveness and chemoresistance in relapse patients. In HGSOC, invasiveness can result when epithelial cancer cells undergo epithelial-mesenchymal transition (EMT). The transcription factor SNAI1 (Snail) initiates the EMT process and increased Snail expression can result in enhancement of metastatic potential, acquisition of stem cell-like characteristics, and resistance to chemotherapeutic drugs. However, the mechanism of activation of invasiveness in ovarian cancer by Snail has not been defined. In OVCAR8, a HGSOC cell line, comparison of shSnail knockdown to control through RNA-sequencing revealed that Snail expression is directly correlated to matrix metalloprotease 1 (MMP1) expression. MMP1 is an extracellular matrix remodeler known to digest interstitial collagens. High MMP1 expression has been linked to increased cancer invasion, metastasis, angiogenesis, and apoptosis. Furthermore, in breast cancer, MMP1 has been reported to be a downstream target of Slug, another major EMT transcription factor. Some evidence for Snail activation of MMPs in liver cancer has been presented, but a direct relationship has not been established. Therefore, we hypothesize that overexpression of Snail in ovarian cancer cells results in MMP1 upregulation, leading to increased invasion. RT-qPCR was performed to analyze relative mRNA expression levels of Snail and MMP1 in eight cell lines. We found that Snail and MMP1 levels were higher in the more mesenchymal-like cell lines, some of which are known to be more invasive. Additionally, Snail overexpression led to a significant corresponding increase in MMP1 mRNA expression and resistance to cisplatin. Chromatin immunoprecipitation (ChIP) experiments demonstrate Snail binding to the MMP1 promoter. Thus, our preliminary findings have shown strong evidence of a Snail-mediated regulation of MMP1 expression in the context of HGSOC invasiveness. Citation Format: Tise Suzuki, Casey Curow, Hanmin Wang, Asis Martinez, Nozomi Hojo, Juli Unternaehrer. Snail-mediated regulation of MMP1 expression in the context of ovarian cancer invasiveness [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 2881.
Abstract 2255: The impact of primary immunodeficiency informed molecular landscape on the biology and prognosis of refractory malignancies
Authors: Son Tran, Luis Murguia-Favela, Aru Narendran
Journal: Cancer Research (2021)

Abstract Introduction: Cancer is one of the most common causes of death in patients with primary immunodeficiencies (PIDs). The immune surveillance concept postulates that PIDs are an important contributor to cancer growth and outcomes. Although several immunodeficiency syndromes are known to be associated with malignancies in children and adults, currently, the molecular mechanisms that link immune functions to cancers are poorly understood. Here we describe distinct molecular characteristics in adult cancers with respect to PID-associated genes that impact survival outcomes in affected patients. Methods: In this study, we integrated transcriptome data of 28 adult cancers from the public database The Cancer Genome Atlas (TCGA) with respective healthy tissues as control from the Genotype-Tissue Expression (GTEx) project. Unified datasets integrating GTEx healthy samples and TCGA cancer data were provided by the Recount2 protocol and differential expression analyses (DEA) were carried out using the integrated limma-voom and edgeR pipelines in the TCGAbiolinks R package. Gene ontology (GO) enrichment analyses were performed using the pathfindR R package. Mutational and clinical data of adult cancer patient samples in TCGA and the AACR Project GENIE were consolidated using cBioPortal and the maftools R package. PID-associated genes were curated from the latest registry by the European Society for Immunodeficiencies (ESID). Results: Of 307 PID-associated genes, 151 (32.0%) up-regulated and 88 (18.6%) down-regulated genes were identified across the 28 unified TCGA-GTEx datasets. From the identified differentially expressed gene sets, GO analysis revealed enrichment in immunological pathways related to complement and coagulation cascades (27/28 datasets), systemic lupus erythematosus (25/28), in addition to Fanconi anemia (22/28). The greatest frequency of mutations in PID-associated genes from the consolidated TCGA and GENIE datasets were KRAS (14.83%), KMT2D (10.03%), TERT (8.99%), PRKDC (7.59%) and PTEN (6.18%) across all cancer types, with a total of 259 affected PID-associated genes. Survival analyses using Cox proportional-hazards and Kaplan-Meier models will assess the clinical implications of the identified molecular alterations in affected patients. Conclusion: Our integrative approach aids in the elucidation of molecular mechanisms that bridge PIDs to tumour biology. These data may help identify important biomarkers and potential future targeted therapeutics. Citation Format: Son Tran, Luis Murguia-Favela, Aru Narendran. The impact of primary immunodeficiency informed molecular landscape on the biology and prognosis of refractory 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 2255.
SAKK 16/14: Anti-PD-L1 antibody durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small cell lung cancer (NSCLC)—A multicenter single-arm phase II trial.
Authors: Sacha Rothschild, Alfred Zippelius, Eric I Eboulet, Spasenija Savic, Daniel C. Betticher, Adrienne Bettini, Martin Frueh, Markus Joerger, Christian Britschgi, Solange Peters, Michael Thomas Mark, Adrian Ochsenbein, Wolf Dieter Janthur, Christine Waibel, Nicolas Mach, Michel Gonzalez, Patrizia Froesch, Gilles Godar, Corinne Rusterholz, Miklos Pless
Journal: Journal of Clinical Oncology (2020)

9016 Background: For patients (pts) with resectable stage IIIA(N2) non-small cell lung cancer (NSCLC) neoadjuvant chemotherapy (chemo) with 3 cycles cisplatin (cis)/docetaxel (doc) followed by surgery is an accepted standard of care leading to a 1-year (yr) event-free survival (EFS) of 48% and a 5-yr overall survival (OS) of 37%. PD-1/PD-L1 inhibitors have recently shown to lead to high response rates in resectable NSCLC. Methods: SAKK 16/14 is an open-label single-arm phase II study including 68 pts with resectable NSCLC stage IIIA(N2) (T1-3 N2 M0), irrespective of histological subtype, genomic aberrations or PD-L1 expression status. Neoadjuvant treatment consisted of 3 cycles of cis 100 mg/m 2 and doc 85 mg/m 2 q3w followed by 2 cycles of durvalumab 750 mg q2w. Durvalumab was continued after surgery q2w for 1 yr. The primary endpoint is EFS at 1 yr. The statistical hypothesis is to improve EFS at 1 yr from 48% based on the SAKK 16/00 study to 65%. Here, we report the primary endpoint and response data from 67 evaluable pts included in the study. Results: 68 pts were included from 06/16 to 01/19 and 67 pts (35 males, 32 females) were evaluable. Median age was 61 yrs (range, 41-74). 52 pts (77.6%) had a WHO PS of 0. 95.5% were current or former smokers. The majority of tumors were adenocarcinoma (55.2%) followed by squamous cell histology (32.8%). Clinical stage T1, T2 and T3 were present at diagnosis in 22.4%, 49.3% and 28.4%, respectively. 81.1% of pts underwent resection. The main reason for not undergoing surgery was disease progression (33.3%). Pneumonectomy was performed in 5 pts (9.1%), 43 pts underwent lobectomy and 7 pts bilobectomy. 30-day postoperative mortality was observed in one patient (1.8%). One patient died due to a bleeding complication after surgery most likely not related to neoadjuvant therapy. Radiographic response was 44.8% (95%CI: 32.6-57.4) after neoadjuvant chemo and 59.7% (95%CI: 46.4-71.9) after additional neoadjuvant immunotherapy. 1-yr EFS was 73.3% (90%CI: 62.5-81.4). Results for pathologic remission rate as well as correlation with PD-L1 status will be presented during the meeting. Conclusions: We report on treatment outcomes of the largest cohort of pts with resectable stage IIIA(N2) NSCLC receiving perioperative immune checkpoint inhibitor therapy. The addition of perioperative durvalumab to standard of care cis/doc is safe and leads to a high response rate and a very encouraging 1-yr EFS rate that appears substantially higher than with chemo alone. Clinical trial information: NCT 02572843.
Effect of prostate biopsy technique on nerve sparing during radical prostatectomy: Do transperineal template mapping biopsies in combination with mpMRI translate into more nerve sparing?
Authors: M.S. Wettstein, J.B. Grogg, C. Cruz, A. Affentranger, G.S. Kulkarni, T. Sulser, C. Poyet, C.D. Fankhauser, T. Hermanns
Journal: European Urology (2021)
Delivery Before 39 Weeks’ Gestation for Suspected Fetal Growth Restriction
Authors: Robert M. Silver, Nathan R. Blue
Journal: JAMA (2021)

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Abstract 10596: Multiparametric Cardiac Magnetic Resonance Imaging to Detect Cardiac Allograft Vasculopathy Beyond the First Year Post-heart Transplantation
Authors: Muhannad Abbasi, Roberto Sarnari, Arif Jivan, Rahim Gulamali, Julie Blaisdell, Kongkiat Chaikriangkrai, Alexander Ruh, Daniel Lee, Kambiz Ghafourian, Jane E Wilcox, Sadiya S Khan, Esther Vorovich, Jonathan Rich, Allen S Anderson, Clyde W Yancy, James C carr, Michael Markl
Journal: Circulation (2019)

Introduction: Cardiac allograft vasculopathy (CAV) is a leading cause of mortality post-heart transplant (HTx). Invasive coronary angiography (ICA) may miss early disease. Cardiac magnetic resonanc...
Abstract 4: Temporal and spatial topography of cell proliferation in cancer
Authors: Giorgio Gaglia, Sheheryar Kabraji, Danae Argyropoulou, Yang Dai, Johann Bergholz, Shannon Coy, Jia-Ren Lin, Eric P. Winer, Deborah Dillon, Jean J. Zhao, Peter K. Sorger, Sandro Santagata
Journal: Cancer Research (2021)

Abstract Uncontrolled cell proliferation is a defining feature of malignancy. Current understanding of proliferation, particularly in humans, derives primarily from studying cells growing rapidly in the non-physiological conditions of cell culture. However, tumors are exceedingly complex admixtures of different cell types and subclonal malignant populations comprising proliferative, non-proliferative, and arrested states that are influenced by physical, metabolic, and molecular conditions. Images of single or small sets of protein markers from fixed tissue samples only provide limited and static views into the nature of these complex states. Here we identify proliferation states and develop a quantitative framework to extract cell cycle dynamics from multiplexed, spatially-resolved tissue images of millions of tumor cells from human cancers and genetically engineered tumors in mice. Across spatial scales, tumors display intrinsic regional variability in proliferation patterns and in the coherence of cell cycle markers in high-dimensional space. Cell cycle dynamics and cell cycle coherence are not solely a function of tumor growth and oncogene expression and rapidly adapt following genetic and therapeutic perturbations. Replacing binary metrics with multivariate traits provides a quantitative framework for extracting multidimensional dynamic information from static images that is broadly applicable to the study of temporal processes within the native architecture of human disease tissues. Citation Format: Giorgio Gaglia, Sheheryar Kabraji, Danae Argyropoulou, Yang Dai, Johann Bergholz, Shannon Coy, Jia-Ren Lin, Eric P. Winer, Deborah Dillon, Jean J. Zhao, Peter K. Sorger, Sandro Santagata. Temporal and spatial topography of cell proliferation in 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 4.
Patient-derived preclinical models of castration resistant prostate cancer: Xenografts and PDX-derived organoids to recapitulate patients’ disease profiles
Authors: A. Van Hemelryk, I. Tomljanovic, C.M.A. De Ridder, D. Stuurman, S. Erkens-Schulze, W.J. Teubel, E.I. Verhoef, G.J.L.H. Van Leenders, M. Cangiano, I.J. Beumer, H.J.G. Van De Werken, M.E. Van Royen, M. Grudniewska, W.M. Van Weerden
Journal: European Urology (2021)