tbuckley/cabot-search huggingface dataset:
Abstract 1360: Exposure-response safety analysis of avelumab in patients with locally advanced or metastatic urothelial carcinoma
Authors: Jerry Li, Carlo Bello, Akash Khandelwal, Yulia Vugmeyster, Dana Nickens, Swan Lin
Journal: Cancer Research (2021)

Abstract BACKGROUND: Avelumab is a human IgG1 monoclonal antibody targeting PD-L1 that is approved in the US for second-line locally advanced or metastatic urothelial carcinoma (UC) and first-line maintenance (1LM) treatment of patients with UC that has not progressed with first-line platinum-containing chemotherapy. The current analysis was conducted to evaluate the relationships between avelumab exposure and the probability of experiencing adverse events in 1LM-UC patients. METHODS: Avelumab exposures following 10-mg/kg every-2-weeks (Q2W) dosing in 1LM-UC patients were derived from post hoc parameter estimates from a population pharmacokinetic model. Safety endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs), and any-grade immune-related adverse events (irAEs). For each safety endpoint, avelumab exposures were assessed by univariate screen followed by a full model including influence of all potential covariates and a final model that retained statistically significant covariates (α=0.01) after backwards elimination. Safety analyses were performed with R version 3.5.0 by binomial logistic regression. RESULTS: A total of 344 1LM-UC patients treated with avelumab were included in the analyses. Of these patients, 163 (47%), 101 (29%), and 74 (21.5%) experienced grade ≥3 TEAE, any-grade IRR, and any-grade irAE, respectively. Avelumab exposure did not demonstrate statistically significant relationships with grade ≥3 TEAE or any-grade irAE. Any-grade IRR demonstrated a potentially confounded inverse relationship with avelumab exposure (p=0.009), a trend also seen in patients with advanced renal cell carcinoma. In all models, immunogenicity and PD-L1 status were tested as covariates but were not predictors for any safety endpoint. CONCLUSIONS: The exposure range associated with avelumab 10-mg/kg Q2W dosing demonstrated no clinically meaningful relationships with any of the safety endpoints. Given the similarity in avelumab exposures between the flat 800-mg Q2W and weight-based 10-mg/kg dosing, the findings of this analysis support the use of the flat-dosing regimen for 1LM-UC patients. Citation Format: Jerry Li, Carlo Bello, Akash Khandelwal, Yulia Vugmeyster, Dana Nickens, Swan Lin. Exposure-response safety analysis of avelumab in patients with locally advanced or metastatic urothelial 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 1360.
Multi-omics profiling predicts allograft function after lung transplantation
Authors: Martin L. Watzenboeck, Anna-Dorothea Gorki, Federica Quattrone, Riem Gawish, Stefan Schwarz, Christopher Lambers, Peter Jaksch, Karin Lakovits, Sophie Zahalka, Nina Rahimi, Philipp Starkl, Dörte Symmank, Tyler Artner, Céline Pattaroni, Nikolaus Fortelny, Kristaps Klavins, Florian Frommlet, Benjamin J. Marsland, Konrad Hoetzenecker, Stefanie Widder, Sylvia Knapp
Journal: European Respiratory Journal (2021)

Rationale Lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (CLAD). The mechanisms leading to CLAD remain elusive due to an insufficient understanding of the complex post-transplant adaptation processes. Objectives To better understand these lung adaptation processes after transplantation and to investigate their association with future changes in allograft function. Methods We performed an exploratory cohort study of bronchoalveolar lavage samples from 78 lung recipients and donors. We analysed the alveolar microbiome using 16S rRNA sequencing, the cellular composition using flow cytometry, as well as metabolome and lipidome profiling. Measurements and main results We established distinct temporal dynamics for each of the analysed data sets. Comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. We further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. A decline in forced expiratory volume during the first second (FEV 1 ) is a major characteristic of lung allograft dysfunction in transplant recipients. By using a machine learning approach, we could accurately predict future changes in FEV 1 from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. Conclusion Bronchoalveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The lung microbiome can predict future changes in lung function with high precision.
Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
Authors: Abhishek K. Singh, Balkrishna Chaube, Xinbo Zhang, Jonathan Sun, Kathryn M. Citrin, Alberto Canfrán-Duque, Binod Aryal, Noemi Rotllan, Luis Varela, Richard G. Lee, Tamas L. Horvath, Nathan L. Price, Yajaira Suárez, Carlos Fernández-Hernando
Journal: Journal of Clinical Investigation (2021)

Hepatic uptake and biosynthesis of fatty acids (FAs), as well as the partitioning of FAs into oxidative, storage, and secretory pathways, are tightly regulated processes. Dysregulation of one or more of these processes can promote excess hepatic lipid accumulation, ultimately leading to systemic metabolic dysfunction. Angiopoietin-like-4 (ANGPTL4) is a secretory protein that inhibits lipoprotein lipase (LPL) and modulates triacylglycerol (TAG) homeostasis. To understand the role of ANGPTL4 in liver lipid metabolism under normal and high-fat–fed conditions, we generated hepatocyte-specific Angptl4 mutant mice (Hmut). Using metabolic turnover studies, we demonstrate that hepatic Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Consequently, depletion of hepatocyte Angptl4 protects against diet-induced obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that loss of Angptl4 in hepatocytes promotes FA uptake, which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage, which likely occur via increased HL activity. Notably, this inhibition strategy does not cause any of the deleterious effects previously observed with neutralizing antibodies.
Abstract 1015: mTOR inhibitor induces non-apoptotic, autophagy dependent cell death (ADCD) in TP53 mutant HNSCC
Authors: Md Maksudul Alam, Janmaris Marin Fermin, Patrick T. Spiller, Channing Dorr, Xiaohua Rong, Tara-Moore Medlin, Alok R. Khandelwal, Cherie-Ann Nathan
Journal: Cancer Research (2021)

Abstract TP53 is the most frequently mutated gene in Head and Neck Squamous Cell Carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis. A phase II multi-institutional clinical trial, determined that, adjuvant therapy with an mTOR inhibitor significantly increased 2-year progression free survival (PFS) in patients with p53 mutant tumors. Previous studies have shown that mutant p53 causes sustained activation of PI3K/AKT/mTOR pathway in cancer. We investigated the mechanism by which the mTOR inhibitor CCI-779 inhibits cell growth of TP53 mutant HNSCC in vitro. HPV-negative HNSCC cell lines harboring TP53 mutations at different positions were treated with CCI-779.CCI-779 significantly reduced cell viability and colony forming ability of all the cell lines tested. CCI-779 did not induce apoptosis or cell cycle arrest in these cells. However, the reduction in cell viability was associated with increase in autophagy as demonstrated by increased levels of LC3-II. The autophagy inhibitors, 3-methyl adenine (3-MA) and ULK-101 restored the cell viability by inhibiting CCI-779 induced autophagy. Therefore, we postulate that CCI-779 induces nonapototic autophagy dependent cell death (ADCD) in HPV-negative TP53 mutant HNSCC cell lines. CCI-779 induced autophagy is accompanied by increased level of ULK1 and Beclin1 as well as increased phosphorylation of ULK1 at Serine 555. However, ULK101 (ULK1 inhibitor) and 3-MA (PI3K inhibitor) when combined with CCI-779 reduced the level of both total and phosphorylated levels of ULK1, which resulted in inhibition of autophagy and improved cell viability. However, combination of CCI-779 and bafilomycin A1 treatment showed increased level of LC3-II, ULK1 and phospho-ULK1 (S555) with concomitant decrease in cell viability. Our data suggests that rapalog induces ADCD by facilitating autophagy initiation through the stabilization and activation of ULK1. Moreover our data demonstrated that CCI-779 mediated activation of ULK1 is associated with down regulation of mTORC1 but not mTORC2 signaling. This is a novel mechanism of how rapalogues induce ADCD through the stabilization/activation of ULK1 in HPV-negative TP53 mutant HNSCC cells. Together these data highlight the importance of how mTORi can be used to accelerate tumor cell death in HPV-negative TP53 mutant HNSCC. Citation Format: Md Maksudul Alam, Janmaris Marin Fermin, Patrick T. Spiller, Channing Dorr, Xiaohua Rong, Tara-Moore Medlin, Alok R. Khandelwal, Cherie-Ann Nathan. mTOR inhibitor induces non-apoptotic, autophagy dependent cell death (ADCD) in TP53 mutant HNSCC [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 1015.
The potential prognostic role of pre-biopsy MRI: An example with PIRADS 5 lesions
Authors: G. Fiard, A. Seigneurin, G. Ploussard, R. Diamand, G. Assenmacher, A. Peltier, M. Oderda, P. Gontero, T. Roumeguere, S. Albisinni, C. Dariane, N. Barry Delongchamps, J. Anract, J. Van Damme, A. Feyaerts, T. Saussez, R. Mastroianni, G. Simone, A. Fourcade, G. Fournier, M. Roumiguie, J-L. Descotes
Journal: European Urology (2021)
Adrenalectomy for pheochromocytoma: Complications and predictive factors of intraoperative hemodynamic instability
Authors: F. Tariel, C. Dourmap, J. Hascoet, T. Denolle, J.F. Heautot, T. Frouget, C. Bendavid, B. Moreau, I. Guilhem, A. Guenego, K. Bensalah, A. Manunta, B. Peyronnet
Journal: European Urology (2021)
Abstract 1692: A novel immunoregulatory role of tumor treating fields (TTFields) on macrophage polarization
Authors: Boris Brant, Tali Voloshin, Alexandra Volodin, Lilach Koren, Anat Klein-Goldberg, Efrat Zemer-Tov, Rom Paz, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2021)

Abstract Introduction: Tumor Treating Fields (TTFields) therapy is a clinically applied anti-neoplastic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. In this study we investigated the potential of TTFields for regulating macrophage phenotype skewing, with or without lipopolysaccharide (LPS) and interferon-γ (IFN-γ) or IL-4 activation. Methods: Bone marrow cells were flushed from the femurs and tibias of 5-8 week old Balb\C mice to generate bone marrow-derived macrophages (BMDMs). To study individual macrophage responses to TTFields, we profiled macrophages that were stimulated with LPS+IFN-γ (M1 polarization) or IL-4 (M2 polarization), followed by treatment with TTFields (150 kHz) for 24 hours. Flow cytometry was used to assess surface expression of F4/80 (a macrophage biomarker) and the activation markers that included major histocompatibility complex class II (MHC II), CD80, and inducible nitric oxide synthase (iNOS). A multiplexed secretion assay was used to measure the heterogeneity of the stimulated macrophages. We captured the secretion of 13 different proteins including CXCL1 (KC), IL-18, IL-23, IL-12p70, IL6, TNF-α, IL-12p40, free active TGF-β1, CCL22 (MDC), IL-10, IL-6, G-CSF, CCL17 (TARC) and IL-1β. Results: TTFields treatment polarized IL-4 stimulated M2 macrophages to the M1 phenotype, as indicated by a significant increase in the percentage of CD80+MHC IIhigh cells. Treatment with TTFields of BMDMs that were either stimulated with IFN-γ and LPS (M1 phenotype) or had remained unstimulated increased the percentage of CD80+MHC IIhigh cells to a lesser degree. Moreover, treatment with TTFields significantly increased intracellular iNOS levels in M1 polarized BMDMs. In unstimulated BMDMs, application of TTFields resulted in significant increases in secretion of the pro-inflammatory cytokines CXCL1, IL-18, IL-23, IL-12p70, TNF-α, IL-12p40, CCL22, G-CSF, CCL17 and IL-1β. Also, a similar pattern was observed in cell supernatants of M1 and M2 stimulated BMDMs after TTFields application. Conclusions: These results elucidate a novel immunoregulatory role of TTFields on macrophage polarization. Future studies will aim to focus on the mechanism governing phenotypic skewing of macrophages treated with TTFields and to explore the effect of TTFields on macrophage in the tumor microenvironment. Citation Format: Boris Brant, Tali Voloshin, Alexandra Volodin, Lilach Koren, Anat Klein-Goldberg, Efrat Zemer-Tov, Rom Paz, Moshe Giladi, Uri Weinberg, Yoram Palti. A novel immunoregulatory role of tumor treating fields (TTFields) on macrophage polarization [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 1692.
Abstract 760: Analysis of ERG and SPOP subtypes in prostate cancer in the Colombian population and their possible implications on prognosis
Authors: Wendy Montero Ovalle, Yenifer Segura Moreno, María Carolina Sanabria-Salas, Jorge Mesa López de Mesa, Rodolfo Varela Ramírez, Vilma Medina Boada, Martha Lucía Serrano López
Journal: Cancer Research (2021)

Abstract Prostate cancer (PCa) is the type of cancer with the highest incidence and mortality in our country. Current disease prognostic factors do not differentiate aggressive from indolent cases with sufficient certainty and for this reason, it has worked on a characterization of molecular subtypes that allows for a better classification. In localized PCa, fusions between the gene regulated by androgens TMPRSS2 and ERG, or mutations in SPOP (speckle type POZ, the gene that codes for an adapter protein of the Cullin-3-RING-Box1 complex) have been detected in different populations, which has been related to prognosis; however, we do not know the relevance of these molecular alterations in affected Colombians. These two alterations are described within the 7 subtypes reported by the TCGA and are considered mutually exclusive. Objective: Evaluate the presence of ERG and SPOP subtypes in prostate cancer in the Colombian population and correlate these findings with clinicopathological parameters. Methodology: For this study, FFPE radical prostatectomy samples from 112 patients with PCa were used, where the TMPRSS2-ERG fusions were studied by FISH, and in negative cases for fusion, mutations in exons 6 and 7 of SPOP were evaluated by sanger sequencing. Results: Fusion was detected in 71 patients (63.4%), this frequency of the ERG subtype was similar to that observed in the Caucasian population (40-60%). No statistically significant differences were found between the fusion state and the clinicopathological variables analyzed such as age, initial PSA, Gleason score, Gleason grade group, clinical and pathological tumor stage, lymph node involvement, biochemical recurrence-free survival, and overall survival. In the 41 (36.6%) cases negative for fusion, only one mutation (F133L) was detected in exon 7, which has previously been reported in 34 cases. Conclusions: The frequency of fusion of the ERG subtype detected in our population was 63.4%, no associations were found between the fusion state and the prognosis of the disease. Until now, 1 case has been detected a mutation of exon 7 of SPOP (2.4%). The low frequency of this subtype in Colombians could be explained by the reported variability in the frequency of these mutations according to the population (5% -20%). Citation Format: Wendy Montero Ovalle, Yenifer Segura Moreno, María Carolina Sanabria-Salas, Jorge Mesa López de Mesa, Rodolfo Varela Ramírez, Vilma Medina Boada, Martha Lucía Serrano López. Analysis of ERG and SPOP subtypes in prostate cancer in the Colombian population and their possible implications on prognosis [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 760.
Neural and Molecular Mechanisms of Biological Embedding of Social Interactions
Authors: Ian M. Traniello, Gene E. Robinson
Journal: Annual Review of Neuroscience (2021)

Animals operate in complex environments, and salient social information is encoded in the nervous system and then processed to initiate adaptive behavior. This encoding involves biological embedding, the process by which social experience affects the brain to influence future behavior. Biological embedding is an important conceptual framework for understanding social decision-making in the brain, as it encompasses multiple levels of organization that regulate how information is encoded and used to modify behavior. The framework we emphasize here is that social stimuli provoke short-term changes in neural activity that lead to changes in gene expression on longer timescales. This process, simplified—neurons are for today and genes are for tomorrow—enables the assessment of the valence of a social interaction, an appropriate and rapid response, and subsequent modification of neural circuitry to change future behavioral inclinations in anticipation of environmental changes. We review recent research on the neural and molecular basis of biological embedding in the context of social interactions, with a special focus on the honeybee.
Abstract 645: Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat
Authors: Qingfei Pan, Tizita Zeleke, Cody Chiuzan, Maika Onishi, Mariano Alvarez, Erin Honan, Min Yang, Pei Ling Chia, Partha Mukhopadhyay, Sean Kelly, Ruby Wu, Kathleen Fenn, Meghna Trivedi, Melissa Accordino, Katherine Crew, Dawn Hershman, Matthew Maurer, Simon Jones, Andrea Califano, Kevin Kalinsky, Jiyang Yu, Jose Silva
Journal: Cancer Research (2021)

Abstract Despite the anticancer activity of pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors that selectively inhibit individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of ricolinostat (the leading HDAC6 inhibitor) in breast cancer (BC) patients. We have developed a computational network-based algorithm to evaluate the activity of the HDAC6 protein, based on the enrichment of its transcriptional targets in differentially expressed genes (HDAC6 score). Through preclinical in vitro and in vivo studies, we confirmed that the HDAC6 score can stratify the sensitivity of BC cells to ricolinostat treatment and may thus have value as a predictive biomarker. Moreover, analysis of ~3,000 primary human breast cancers showed that ~30% of them present high HDAC6 scores. Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Study results showed that the two agents can be safely combined, that clinical activity is identified specifically in patients with HR+/HER2- disease, and that the HDAC6 score was predictive of response. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective, CLIA certified predictive biomarker of ricolinostat sensitivity in multiple human cancers. Citation Format: Qingfei Pan, Tizita Zeleke, Cody Chiuzan, Maika Onishi, Mariano Alvarez, Erin Honan, Min Yang, Pei Ling Chia, Partha Mukhopadhyay, Sean Kelly, Ruby Wu, Kathleen Fenn, Meghna Trivedi, Melissa Accordino, Katherine Crew, Dawn Hershman, Matthew Maurer, Simon Jones, Andrea Califano, Kevin Kalinsky, Jiyang Yu, Jose Silva. Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [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 645.
Abstract 2764: Mechanisms of genomic-microenvironmental interactions in uveal melanoma
Authors: Christopher J. Kaler, James J. Dollar, Stefan Kurtenbach, Jeffim N. Kuznetsov, Michael A. Durante, J. William Harbour
Journal: Cancer Research (2021)

Abstract Uveal melanoma (UM) is the most common primary eye cancer and has a high rate of metastasis with liver tropism. UM can be stratified according to metastatic risk into low risk Class 1 and high risk Class 2 tumor. Biallelic mutational inactivation of the tumor suppressor BAP1 is the quintessential molecular feature of Class 2 UM, but the mechanism by which loss of BAP1 leads to metastasis is poorly understood. We recently showed using single-cell RNA sequencing that the tumor microenvironment of primary and metastatic Class 2 UM is characterized by large numbers of inhibitory T cells and macrophages. Taken together, these findings led us to hypothesize that loss of BAP1 triggers changes in tumor-immune cell interactions that lead to an immunosuppressive microenvironment. To test this hypothesis, we performed RNA-seq and proteomic mass spectrometry in uveal melanocytes and UM cells engineered to lack BAP1 expression. These experiments identified a small cassette of immune modulatory genes that are up-regulated at the mRNA and protein levels following BAP1 loss. These proteins are known to drive monocytes towards type 2 macrophage polarization, which secrete cytokines that can inhibit T cell activation. Our findings suggest that altered interaction between UM cells and monocytes may be key to the emergence of metastatic competence in UM, and we are exploring this possibility with function experiments that may open the door to targeted therapy to subvert this process. Citation Format: Christopher J. Kaler, James J. Dollar, Stefan Kurtenbach, Jeffim N. Kuznetsov, Michael A. Durante, J. William Harbour. Mechanisms of genomic-microenvironmental interactions in uveal melanoma [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 2764.