tbuckley/cabot-search huggingface dataset:
Response to Terlipressin and Albumin Is Associated With Improved Liver Transplant Outcomes in Patients With Hepatorenal Syndrome
Authors: Salvatore Piano, Carmine Gambino, Elia Vettore, Valeria Calvino, Marta Tonon, Patrizia Boccagni, Enrico Gringeri, Giacomo Germani, Patrizia Burra, Umberto Cillo, Paolo Angeli
Journal: Hepatology (2020)

Although terlipressin and albumin are effective at treating acute kidney injury-hepatorenal syndrome (AKI-HRS), liver transplantation (LT) is the best treatment. However, it is unclear if an effective treatment with terlipressin and albumin improves post-LT outcomes in these patients. The aim of this study was to evaluate the impact of response to treatment with terlipressin and albumin on posttransplant outcomes in patients with AKI-HRS.We analyzed two cohorts of patients with cirrhosis listed for LT between 2012 and 2016: 82 patients who developed AKI-HRS before LT and were treated with terlipressin and albumin and 259 patients without AKI-HRS who received transplants during the study period (control group). After LT, patients were followed up until discharge, every month for the first 3 months, and every 3 months thereafter. Of the patients, 43 (52%) responded to terlipressin and albumin. Responders had a better 30-day transplant-free survival (60% vs. 33%, P = 0.006), longer LT waiting list time (37 vs. 17 days, P = 0.041), and lower Model for End-Stage Liver Disease score at the time of LT (23 vs. 29, P = 0.007). Among patients with AKI-HRS receiving transplant, nonresponders required renal replacement therapy (RRT) more frequently than responders (20% vs. 0%, P = 0.024). Nonresponders had a significantly higher incidence of chronic kidney disease (CKD) at 1 year after LT than responders (65% vs. 31%, P = 0.019). In multivariate analysis, nonresponse to terlipressin and albumin was found to be an independent predictor for CKD at 1 year after LT (subdistribution hazard ratio [SHR] = 2.76, P = 0.001), whereas responders did not have an increased risk (SHR = 1.53, P = 0.210).In patients with AKI-HRS, response to terlipressin and albumin reduces the need for RRT after LT and reduces the risk of CKD at 1 year after LT.
Abstract LB-077: Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis
Authors: Jeffrey H. Lin, Robert H. Vonderheide
Journal: Cancer Research (2020)

Abstract Dysfunction of type 1 conventional dendritic cells (cDC1s) - the dendritic cell subtype crucial for spontaneous anti-tumor T cell immunity - has long been hypothesized to develop secondarily to invasive cancer. Here, we reveal that cDC1 dysfunction instead develops in the earliest stages of cancer development upon formation of preinvasive pancreatic intraepithelial neoplasias (PanINs) in the KrasG12D Trp53R172H Pdx1-Cre-driven (KPC) mouse model of pancreatic ductal adenocarcinoma. This results in systemically increased cDC1 apoptosis and insufficient upregulation of T cell-polarizing cytokines during cDC1 maturation. CD8+ T cell activation following vaccination is subsequently impaired in PanIN- and tumor-bearing mice. Yet, combination therapy with CD40 agonist and Flt3 ligand in tumor-bearing mice returns cDC1 abundance to normal levels and induces an IFNg response signature, repairing cDC1 maturation and restoring full CD8+ T cell activation. This study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation while elaborating therapeutically tractable strategies towards cDC1 repair. Citation Format: Jeffrey H. Lin, Robert H. Vonderheide. Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-077.
Comment and reply on: Vasohibin-1 and its emerging role in the evolution and progression of systemic tumors besides renal cell carcinomas Response
Authors: Monica Chan, Lin Wang, Niramol Chanplakorn, Kentaro Tamaki, Takayuki Ueno, Masakazu Toi, Wings Loo, Louis Wc Chow, Takashi Suzuki, Hironobu Sasano
Journal: Thorax (2013)
Integrated Omics of Metastatic Colorectal Cancer
Authors: Chen Li, Yi-Di Sun, Guan-Yu Yu, Jing-Ru Cui, Zheng Lou, Hang Zhang, Ya Huang, Chen-Guang Bai, Lu-Lu Deng, Peng Liu, Kuo Zheng, Yan-Hua Wang, Qin-Qin Wang, Qing-Run Li, Qing-Qing Wu, Qi Liu, Yu Shyr, Yi-Xue Li, Luo-Nan Chen, Jia-Rui Wu, Wei Zhang, Rong Zeng
Journal: Cancer Cell (2020)
Abstract 238: Targeting glutaminolysis potentiates the efficacy of chemotherapy in RAS-driven pancreatic cancers
Authors: Suman Mukhopadhyay, Debanjan Goswami, Dwight V. Nissley, Frank McCormick
Journal: Cancer Research (2020)

Abstract Pancreatic cancer is an extremely aggressive and deadly malignancy. Despite a detailed understanding of pancreatic ductal adenocarcinoma (PDAC)'s biology, the outcome of the current therapeutic regimen remains grim. Chemotherapeutic treatment is one of the first-line systemic treatments for PDAC. However, creating resistance against chemotherapy remains a major challenge. Oncogenic K-Ras mutation is one of the most common events responsible for the initiation and progression of PDAC. K-Ras mutation also promotes the activation of a transcription factor called NRF2 that is crucial for tumor development and pancreatic cancer proliferation. Our study detects differential basal levels of NRF2 in a panel of PDAC cell lines. We hypothesized that this phenomenon might reflect a greater intrinsic capacity of PDAC cells to become resistant to chemotherapy. We then demonstrated that up-regulation of NRF2 creates resistance against chemotherapy in PDAC cells. Consequently, NRF2 activation rewires metabolic pathway networks. Importantly, our metabolomics analysis revealed that, upon NRF2 activation, several metabolic pathways are reprogrammed. Recent advances in tumor metabolism signify the critical role of glutamine as a key regulator of cancer therapy. Moreover, we observed that inhibiting glutamine metabolism enhances the efficacy of chemotherapeutic drugs in PDAC cells. Taken together, our finding holds promise as a novel combination therapy for patients with pancreatic cancer marked by developed resistance against chemotherapy. Finally, this treatment strategy further establishes the potential for exploiting metabolic changes in RAS-driven cancer cells that confer novel therapeutic opportunities. Citation Format: Suman Mukhopadhyay, Debanjan Goswami, Dwight V. Nissley, Frank McCormick. Targeting glutaminolysis potentiates the efficacy of chemotherapy in RAS-driven pancreatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 238.
Abstract B71: Investigating the role of PAX8 in modulating the tumor microenvironment of high-grade serous ovarian cancer
Authors: Amrita Salvi, Laura Hardy, Samantha Watry, Melissa Pergande, Stephanie M. Cologna, Joanna E. Burdette
Journal: Clinical Cancer Research (2020)

Abstract High-grade serous ovarian cancer (HGSOC), the most common and lethal form of ovarian cancer, is a highly heterogeneous disease. HGSOC is rarely detected early, and likely arises from the fimbriated end of the fallopian tube epithelium (FTE), and in some cases, the ovarian surface epithelium (OSE). PAX8 is a commonly used biomarker for ovarian serous tumors and is expressed in 80-96% of HGSOC. Although the OSE does not express PAX8, murine models of HGSOC derived from the OSE acquire PAX8, suggesting that it is not only a marker of Müllerian origin, but also an essential part of HGSOC progression, potentially from both the OSE and FTE. Previously, we showed that PAX8 deletion by CRISPR and shRNA in HGSOC cell lines caused apoptosis and reduced cell migration and invasion. We performed secretome analysis of PAX8 deleted cells and found a reduction of the extracellular matrix (ECM) component fibronectin. This finding was validated by immunoblotting and immunofluorescence in PAX8 deleted HGSOC cells. We have generated several murine FTE-derived tumor models (PTEN/KRAS/p53 alterations) and knocked down PAX8 in these models. These syngeneic fallopian tube-derived tumor models will be allografted into immune intact FVB mice and the tumors will be used to determine if PAX8 loss impacts immune cell infiltration via changes in ECM. Additionally, we are using a novel high-throughput screening (HTS) assay to identify small molecules that can function to inhibit PAX8 promoter activation and lead to reduced PAX8 expression. We have generated a stable cell line using murine FTE cells expressing the PAX8 promoter-luciferase reporter, which will be used to screen a library of FDA-approved drugs (Prestwick Library, ca. 1,200 members). Overall, this study would help us to validate PAX8 as a regulator of ECM deposition in the tumor microenvironment and identify an effective drug for treatment of ovarian cancers derived from both the FTE and OSE. Citation Format: Amrita Salvi, Laura Hardy, Samantha Watry, Melissa Pergande, Stephanie M. Cologna, Joanna E. Burdette. Investigating the role of PAX8 in modulating the tumor microenvironment of high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B71.
Abstract 1478: Endothelial-specific loss of glutaminase normalizes tumor blood vessels and inhibits tumor growth
Authors: Verra Ngwa, Deanna Edwards, Jin Chen
Journal: Cancer Research (2020)

Abstract Abnormal tumor blood vessels with chaotic angiogenic sprouting result in spontaneous hemorrhages and increased interstitial fluid pressure in the tumor microenvironment. These defects of intra-tumoral vessels lead to poor leukocyte trafficking and drug delivery. Although there is a solid published premise for tumor blood vessel normalization, mechanisms of improved tumor vessel quality are only beginning to be investigated. Because tumor vascular endothelial cells are fast growing, they require nutrients to generate biomass that support their proliferative program. Indeed, inhibition of glucose metabolism has been shown to normalize tumor vasculature and improve drug delivery. In addition to glucose, glutamine is also essential for endothelial cell proliferation and angiogenic sprouting. Thus, we hypothesized that tumor associated endothelium may require glutamine metabolism to support their rapid proliferation and blocking glutaminolysis would normalize tumor vasculature. To test this hypothesis, we crossed glutaminase (GLS) floxed (GLS f/f) animals with CDH5 (VE-Cad)-CreER transgenic mice to induce endothelial-specific deletion of GLS upon tamoxifen administration (GLSECKO). We found that there is a decrease in tumor growth in GLSECKO animals compared to WT recipients. Loss of GLS in endothelium leads to a decrease in CD31+ angiogenic sprouts, and a better coverage of SMA+ pericytes in capillaries. We also observed an increase in tomato-lectin perfused blood vessels and a decrease in tissue hypoxia, as judged by pimonidazole stain. Together, these results suggest that endothelial-specific loss of glutaminase normalizes tumor blood vessels. We are currently investigating the effects of endothelial-specific deletion of GLS on endothelial cell metabolism, tumor metastasis, lymphocytes infiltration, and the response to chemotherapy. Success of this project will uncover the role of endothelial glutaminase in tumor vessels. Further, chemotherapies are currently the main treatment for TNBC patients, so improvements in drug delivery will have significant clinical impact. Finally, TNBCs lacking tumor infiltrating lymphocytes (TILS) are poorly responsive to immune checkpoint inhibitors (ICIs). Investigating ways to normalize tumor blood vessels will lay foundation for developing novel therapeutics to increase TILs in immunologically cold TNBCs to increase their response to ICIs. Citation Format: Verra Ngwa, Deanna Edwards, Jin Chen. Endothelial-specific loss of glutaminase normalizes tumor blood vessels and inhibits tumor growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1478.
A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Authors: Kun Lyu, Ye Zhang, Dongyan Zhang, Mario Kahn, Kasper W. ter Horst, Marcos R.S. Rodrigues, Rafael C. Gaspar, Sandro M. Hirabara, Panu K. Luukkonen, Seohyuk Lee, Sanjay Bhanot, Jesse Rinehart, Niels Blume, Morten Grønbech Rasch, Mireille J. Serlie, Jonathan S. Bogan, Gary W. Cline, Varman T. Samuel, Gerald I. Shulman
Journal: Cell Metabolism (2020)
Phenotypical and functional alteration of unconventional T cells in severe COVID-19 patients
Authors: Youenn Jouan, Antoine Guillon, Loïc Gonzalez, Yonatan Perez, Chloé Boisseau, Stephan Ehrmann, Marion Ferreira, Thomas Daix, Robin Jeannet, Bruno François, Pierre-François Dequin, Mustapha Si-Tahar, Thomas Baranek, Christophe Paget
Journal: The Journal of Experimental Medicine (2020)

COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19–driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS–CoV-2–driven ARDS.
Pleiotropic Mechanisms Drive Endocrine Resistance in the Three-Dimensional Bone Microenvironment
Authors: Eugen Dhimolea, Ricardo de Matos Simoes, Dhvanir Kansara, Xiang Weng, Shruti Sharma, Pallavi Awate, Zhiyi Liu, Dong Gao, Nicholas Mitsiades, Joseph H. Schwab, Yu Chen, Rinath Jeselsohn, Aedín C. Culhane, Myles Brown, Irene Georgakoudi, Constantine S. Mitsiades
Journal: Cancer Research (2020)

Abstract Although hormonal therapy (HT) inhibits the growth of hormone receptor–positive (HR+) breast and prostate cancers, HT resistance frequently develops within the complex metastatic microenvironment of the host organ (often the bone), a setting poorly recapitulated in 2D culture systems. To address this limitation, we cultured HR+ breast cancer and prostate cancer spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSC). In 3D monocultures, antiestrogens and antiandrogens induced anoikis by abrogating anchorage-independent growth of HR+ cancer cells but exhibited only modest effects against tumor cells residing in the ECM niche. In contrast, BMSC induced hormone-independent growth of breast cancer and prostate cancer spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of BMSC-induced hormone independence and HT resistance in anchorage-independent cells revealed distinct context-dependent mechanisms. Cocultures of ZR75-1 and LNCaP with BMSCs exhibited paracrine IL6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL6 or JAK signaling. Paracrine IL6/JAK/STAT3-mediated HT resistance was confirmed in patient-derived organoids cocultured with BMSCs. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures but acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in a non–IL6-dependent manner. Collectively, these data characterize the pleiotropic hormone-independent mechanisms underlying acquisition and restoration of anchorage-independent growth in HR+ tumors. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help refine treatment approaches. Significance: This study uncovers a previously underappreciated dependency of tumor cells on HR signaling for anchorage-independent growth and highlights how the metastatic microenvironment restores this malignant property of cancer cells during hormone therapy.
Symptoms of Anxiety, Depression, and Peritraumatic Dissociation in Critical Care Clinicians Managing Patients with COVID-19. A Cross-Sectional Study
Authors: Elie Azoulay, Alain Cariou, Fabrice Bruneel, Alexandre Demoule, Achille Kouatchet, Danielle Reuter, Virginie Souppart, Alain Combes, Kada Klouche, Laurent Argaud, François Barbier, Mercé Jourdain, Jean Reignier, Laurent Papazian, Bertrand Guidet, Guillaume Géri, Matthieu Resche-Rigon, Olivier Guisset, Vincent Labbé, Bruno Mégarbane, Guillaume Van Der Meersch, Christophe Guitton, Diane Friedman, Frédéric Pochard, Michael Darmon, Nancy Kentish-Barnes
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Frontline healthcare providers (HCPs) during the coronavirus disease (COVID-19) pandemic are at high risk of mental morbidity.Objectives: To assess the prevalence of symptoms of anxiety, depression, and peritraumatic dissociation in HCPs.Methods: This was a cross-sectional study in 21 ICUs in France between April 20, 2020, and May 21, 2020. The Hospital Anxiety and Depression Scale and the Peritraumatic Dissociative Experience Questionnaire were used. Factors independently associated with reported symptoms of mental health disorders were identified.Measurements and Main Results: The response rate was 67%, with 1,058 respondents (median age 33 yr; 71% women; 68% nursing staff). The prevalence of symptoms of anxiety, depression, and peritraumatic dissociation was 50.4%, 30.4%, and 32%, respectively, with the highest rates in nurses. By multivariable analysis, male sex was independently associated with lower prevalence of symptoms of anxiety, depression, and peritraumatic dissociation (odds ratio of 0.58 [95% confidence interval, 0.42-0.79], 0.57 [95% confidence interval, 0.39-0.82], and 0.49 [95% confidence interval, 0.34-0.72], respectively). HCPs working in non-university-affiliated hospitals and nursing assistants were at high risk of symptoms of anxiety and peritraumatic dissociation. Importantly, we identified the following six modifiable determinants of symptoms of mental health disorders: fear of being infected, inability to rest, inability to care for family, struggling with difficult emotions, regret about the restrictions in visitation policies, and witnessing hasty end-of-life decisions.Conclusions: HCPs experience high levels of psychological burden during the COVID-19 pandemic. Hospitals, ICU directors, and ICU staff must devise strategies to overcome the modifiable determinants of adverse mental illness symptoms.
AB0027 ARE RHEUMATOID FACTORS AND ANTINUCLEAR ANTIBODIES ASSOCIATED WITH FRAILTY IN ELDERLY TUNISIAN POPULATION?
Authors: Sonia Hammami, Ichrak Bennour, Imen Ghzaiel, Mourad Elghali, Sakly Nabil, Mohamed Hammami
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> An emerging concept is the 'frailty syndrome', which may explain diversity in clinical outcomes in the elderly population. <h3>Objectives:</h3> The aim of the study was to investigate the possible association between antinuclear autoantibodies, different isotypes of Rheumatoid Factor and frailty in aged individuals. <h3>Methods:</h3> Using a validated set of frailty criteria (the SEGA tool), we conducted a cross sectional observational study to evaluate the prevalence of antinuclear antibodies (ANA) (assessed by IFI) and different isotypes of Rheumatoid Factor (RF) (determined by ELISA) in 89 Tunisian individuals aged at least 65 years living in the community. The study population were categorized into three groups: severely frail (n=29), frail (n=31), and non frail (n=29) according to the validated and widely utilized frailty criteria (SEGA tool). <h3>Results:</h3> ANA were detected in 36 of the participants. No Significant difference was observed between the three groups. Immunofluorescence patterns observed were speckled in 34%, homogenous in 3.3%, and nucleolar in 3.3% of individuals. Nineteen of the severely frail patients had positive IgA RF compared to 11 from the Frail group and 6 only from the non-frail group (p&lt;0.02). RF isotypes showed low correlations with other features. Indeed, the IgA RF was correlated with the age (r= -0.22, p&lt;0.03), the C-Reactive Protein level (r= -0.45, p&lt;0.01), and the nutritional state of the patients assessed by the MNA score (r=0.27, p&lt;0.009). The IgG RF was correlated with hemoglobin (r= 0.22, p&lt;0.03) and creatinin (r= -0.36, p&lt;0.01) levels. <h3>Conclusion:</h3> Our study showed no significant difference in the frequency of ANA amongst nonfrail, prefrail, and frail aged individuals, whereas RF isotypes were found to be slightly correlated with several biological parameters and other features. <h3>References</h3> [1] Renato Nisihara, et al.Antinuclear Antibodies and Rheumatoid Factor Positivity in Healthy Elderly Adults: A Cross-Sectional Study in 336 Individuals. J American Geriatric Society2013; 61, P : 2044-46 <h3>Disclosure of Interests:</h3> None declared
Phase I/Ib Trial of the MUC1 Inhibitor GO-203-2C Alone and in Combination with Decitabine for Acute Myeloid Leukemia
Authors: Jessica Liegel, Jacalyn Rosenblatt, Richard M. Stone, Malgorzata McMasters, James D. Levine, Myrna Nahas, Robin M. Joyce, Salvia Jain, Daniel J. DeAngelo, Jacqueline S. Garcia, Josie Bazemore, Ilene Galinsky, Donna S. Neuberg, Lillian Werner, Emma Logan, Kaleb Mikami, Mary Paty Bryant, Victoria Allen, Dina Stroopinsky, Leandra Cole, Abigail J. Washington, Adam Ephraim, David E. Avigan
Journal: Blood (2017)
Abstract 1591: Single cell analysis of uveal melanoma reveals new evolutionary complexity
Authors: Michael A. Durante, Daniel A. Rodriguez, Stefan Kurtenbach, Jeffim N. Kuznetsoff, Margaret I. Sanchez, Christina L. Decatur, Helen Snyder, Lynn G. Feun, Alan S. Livingstone, J. William Harbour
Journal: Cancer Research (2020)

Abstract Uveal melanoma (UM) is a highly metastatic cancer that is largely unresponsive to molecular and immune therapy. We used scRNA-seq and other methods to analyze 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic UMs. This analysis confirmed the class 1/class 2 transcriptomic landscape established from bulk analysis and revealed newly identified subclonal genomic complexity and transcriptional states consistent with phenotype plasticity. The immune compartment comprised a previously unappreciated diversity of cell types. There was low expression of CTLA4 and PD1, but strong expression of a different checkpoint molecule. These findings revealed a dynamic ecosystem in which UM and immune cells co-evolve along trajectories associated with specific genomic aberrations, and they may explain the poor response of UM to current immunotherapy regimens. We identified a new promising candidate for immune checkpoint blockade in metastatic UM. Citation Format: Michael A. Durante, Daniel A. Rodriguez, Stefan Kurtenbach, Jeffim N. Kuznetsoff, Margaret I. Sanchez, Christina L. Decatur, Helen Snyder, Lynn G. Feun, Alan S. Livingstone, J. William Harbour. Single cell analysis of uveal melanoma reveals new evolutionary complexity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1591.