tbuckley/cabot-search huggingface dataset:
Abstract 1040: Imipridones exhibit synergy with sorafenib, HDAC inhibition, PARP inhibition, and proteasome inhibition in liver cancer cell lines
Authors: Joshua N. Honeyman, Wen-I Chang, Varun V. Prabhu, Joshua E. Allen, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2021)

Abstract Liver cancer is a significant cause of cancer-related death worldwide. We previously showed that the imipridone class of small molecule therapeutics is active against hepatocellular malignancies. ONC201, the first imipridone to reach clinical trials, antagonizes the G protein-coupled receptor DRD2 and is an agonist of mitochondrial caseinolytic protease ClpP. ONC206 also antagonizes DRD2 and is a ClpP agonist. ONC212 is an agonist of both the orphan G protein-coupled receptor GPR132 and ClpP. We investigated the efficacy of ONC201, ONC206, and ONC212 in combination with histone deacetylase inhibition (HDACi), poly ADP ribose polymerase inhibition (PARPi), proteasome inhibition, and current standard of care multi-kinase inhibitor sorafenib. Liver cancer cell lines Hep3B and HepG2 were treated with ONC201, ONC206, and ONC212 to determine dose-response effect. Both cell lines were also treated with each imipridone in combination with sorafenib. Combination treatment effect was also tested between ONC201 and the HDACi vorinostat, PARPi nariparib, and the proteasome inhibitor marizomib. Cell viability was measured with CellTiter-Glo. Synergy was quantified using the combination index (CI). Protein expression was assessed using Western blot. As has been previously reported, both HepG2 and Hep3B cell lines were sensitive to ONC201 (Hep3B IC50 = 2.29μM; HepG2 IC50 = 2.69μM), ONC206 (Hep3B IC50 = 0.11μM; HepG2 IC50 = 0.15μM), and ONC212 (Hep3B IC50 = 0.07μM; HepG2 IC50 = 0.05μM) administered as single-agent therapy with ONC212 demonstrating the greatest potency. In combination with sorafenib, all three imipridones demonstrated synergy in both cell lines. ONC201 and ONC206 exhibited stronger synergy with CI &amp;lt; 0.3 at multiple dose combinations. ONC201 was also found to exert a synergistic reduction in cell viability when Hep3B and HepG2 cells were treated with vorinostat, nariparib, and marizomib. These results suggest that the imipridone family of small molecules is a novel therapy for liver cancer with efficacy as a single agent and in combination with existing targeted agents. Future studies will clarify the mechanisms of synergy and expand the findings into small animal models. Citation Format: Joshua N. Honeyman, Wen-I Chang, Varun V. Prabhu, Joshua E. Allen, Lanlan Zhou, Wafik S. El-Deiry. Imipridones exhibit synergy with sorafenib, HDAC inhibition, PARP inhibition, and proteasome inhibition in liver cancer cell lines [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 1040.
Prospective assessment of two-gene urinary test with multiparametric magnetic resonance imaging of the prostate for men undergoing primary prostate biopsy
Authors: G.M. Busetto, M. Maggi, F. Del Giudice, U. Falagario, E. De Berardinis, L. Cormio, G. Carrieri, A. Sciarra
Journal: European Urology (2021)
YC-1 inhibits endothelial cell functions induced by angiogenic factors in vitro and angiogenesis in vivo model
Authors: Shiow-Lin Pan, Che-Ming Teng, Chieh-Yu Peng, Jih-Hwa Guh
Journal: Cancer Research (2005)

3961  Angiogenesis is a process that involves endothelial cell proliferation, migration, invasion, and tube formation, and inhibition of these processes has implications for angiogenesis-mediated disorders. The purpose of this study was to evaluate the antiangiogenic efficacy of YC-1 in well-characterized in vitro and in vivo systems. YC-1, in a dose-dependent manner, inhibited the ability of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) to induce proliferation, migration and tube formation in human umbilical vascular endothelial cell (HUVEC); these outcomes were evaluated using [3H]thymidine incorporation, transwell chamber, and Matrigel-coated slides assays, respectively. YC-1 inhibited VEGF- and bFGF-induced p42/p44 mitogen-activated protein kinase and Akt phosphorylation as well as PKCα translocation (Western blots). The effect of YC-1 on angiogenesis in vivo was evaluated using the mouse Matrigel implant model. YC-1 administered orally in doses of 1-100 mg/kg/day inhibited VEGF- and bFGF-induced neovascularization in a dose-dependent manner over 7 days. These results indicate that YC-1 has antiangiogenic activity at very low doses. Moreover, in transplantable murine tumor models, YC-1 administered orally displayed a high degree of anti-tumor activity (treatment to control life span ratio > 175%) without cytotoxicity. YC-1 may be useful for treating angiogenesis-dependent human diseases such as cancer.
Adaptive servo ventilation for sleep apnoea in heart failure: the FACE study 3-month data
Authors: Renaud Tamisier, Thibaud Damy, Sebastien Bailly, Jean-Marc Davy, Johan Verbraecken, Florent Lavergne, Alain Palot, Frederic Goutorbe, Marie-Pia d'Ortho, Jean Louis Pépin
Journal: Thorax (2021)

Adaptive servo ventilation (ASV) is contraindicated in patients with systolic heart failure (HF) who have a left ventricular ejection fraction (LVEF) below 45% and predominant central sleep apnoea (CSA). However, the effects of ASV in other HF subgroups have not been clearly defined.The European, multicentre, prospective, observational cohort trial, FACE, evaluated the effects of ASV therapy on morbidity and mortality in patients with HF with sleep-disordered breathing (SDB); 3-month outcomes in patient subgroups defined using latent class analysis (LCA) are presented.Consecutive patients with HF with predominant CSA (±obstructive sleep apnoea) indicated for ASV were included from 2009 to 2018; the non-ASV group included patients who refused/were noncompliant with ASV. The primary endpoint was time to composite first event (all-cause death, lifesaving cardiovascular intervention or unplanned hospitalisation for worsening of chronic HF).Baseline assessments were performed in 503 patients, and 482 underwent 3-month follow-up. LCA identified six discrete patient clusters characterised by variations in LVEF, SDB type, age, comorbidities and ASV acceptance. The 3- month rate of primary outcome events was significantly higher in cluster 1 patients (predominantly men, low LVEF, severe HF, CSA; 13.9% vs 1.5%-5% in other clusters, p<0.01).For the first time, our data identified homogeneous patient clusters representing clinically relevant subgroups relating to SDB management in patients with HF with different ASV usage, each with a different prognosis. This may improve patient phenotyping in clinical practice and allow individualisation of therapy.
Abstract 3159: Targeting the TGFΒ/TIMP-1/2 axes to re-educate pro-inflammatory/pro angiogenic NK cells in cancer patients
Authors: Matteo Gallazzi, Antonino Bruno, Douglas M. Noonan, William G. Stetler-Stevenson, Adriana Albini
Journal: Cancer Research (2021)

Abstract Tissue inhibitors of metalloproteases (TIMPs) have been reported to exert dual roles in cancer, based on the different cancer type and interactions with the tumor microenvironments. As inhibitors of Matrix metalloproteases (MMP) they downregulate invasion, metastasis and angiogenesis. However, TIMP1 levels have been found increased in patients with different types of cancer. Natural Killer cells have been found to be phenotypically and functionally compromised in several solid and hematological cancers. We were the first in characterizing NK pro-angiogenic phenotype in the peripheral blood and tumor tissues of patients with Non-small Cell Lung cancer (NSCLC), colorectal cancers (CRC) and in pleural effusion (PE) of patients with metastatic cancers. Also, we found that pro-angiogenic NK cells in the peripheral blood of colorectal cancer patients release of TIMP-1 and TIMP-2, in a STAT3/STAT5-independent manner. Here, we investigated the effects of TIMP-1 and TIMP-2 recombinant proteins, using a TGFβ-mediated NK cell polarization model, in vitro. The effects of TGFβ, alone or in combination with TIMP-1 or TIMP-2 peptides, was determined by multicolor flow cytometry for surface antigens and cytokine productions, on cytolytic NK cells isolated from healthy subjects. Commercially available antibody membrane arrays was used to determine the modulation of the secretome, on FACS-sorted NK cells, from healthy subjects, following 72 hours of exposure to TGFβ, alone or in combination with TIMP-1 or TIMP-2 peptide. We found that NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like phenotype, together with decreased levels of the activation marker NKG2D. Administration of TIMP1 or TIMP2 peptides was effective in interfering with TGFβ-induced NK cell polarization towards the CD56brightCD9+CD49a+ decidual-like phenotype and in restoration of the levels of the NKG2D activation marker. We also observed that TGFβ-polarized NK cell, when co-treated with TIMP1 or TIMP2, exhibit a trend toward decreased production of VEGF and increased production of the anti-tumor cytokines IFNγ and TNFα Our results suggest a potential role of TIMPs in contrasting the angiogenic switch in NK cells and suggest a possible use of TIMPs peptides in the re-education of anergic/pro-angiogenic NK cells in cancer patients. Citation Format: Matteo Gallazzi, Antonino Bruno, Douglas M. Noonan, William G. Stetler-Stevenson, Adriana Albini. Targeting the TGFΒ/TIMP-1/2 axes to re-educate pro-inflammatory/pro angiogenic NK cells in cancer patients [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 3159.
Abstract 10167: Diversity of Ryanodine Receptor 1-mediated Ca2+ Signaling in Pulmonary and Systemic (aortic) Artery Smooth Muscle Cells
Authors: Yun Min Zheng, Yong-Xiao Wang
Journal: Circulation (2019)

Our previous studies have shown the importance of ryanodine receptor 1 (RyR1) in spontaneous local Ca2+ event, global Ca2+ release and contraction in pulmonary artery smooth muscle cells (PASMCs). ...
Long-term survival benefit with dual kidney transplantation: analysis of French cohort between 2002 and 2014 and strategies to optimize the allocation of very extended criteria donor kidneys
Authors: E. Savoye, C. Legendre, Y. Neuzillet, M. Peraldi, P. Grimbert, N. Ouali, M. Durand, L. Badet, F. Kerbaul, M. Pastural, C. Legeai, M. Macher, R. Snanoudj
Journal: European Urology (2021)
バンド3とグリコホリンAの新たな糖鎖異常:バンド3正常遺伝子と突然変異(L751)グリコホリン遺伝子によるグリコシル化の減少、損なわれたアニオン輸送、変形能の低下に伴い著しく乱された細胞骨格タンパク網と遺伝性有口赤血球症
Authors: Kanzaki A, Wada H, Yawata A, Uchikawa M, Fujimoto T, Fujimura K, Yawata Y
Journal: Blood (1996)
Implications of sex-related differences in central nervous system disorders for drug research and development
Authors: Florence Butlen-Ducuing, Ewa Balkowiec-Iskra, Christina Dalla, David A. Slattery, Maria Teresa Ferretti, Nikolaos Kokras, Pavel Balabanov, Corinne De Vries, Simona Mellino, Antonella Santuccione Chadha
Journal: Nature Reviews Drug Discovery (2021)
The multifaceted role of cathepsins in liver disease
Authors: Paloma Ruiz-Blázquez, Valeria Pistorio, María Fernández-Fernández, Anna Moles
Journal: Journal of Hepatology (2021)

Proteases are the most abundant enzyme gene family in vertebrates and they execute essential functions in all living organisms. Their main role is to hydrolase the peptide bond within proteins, a process also called proteolysis. Contrary to the conventional paradigm, proteases are not only random catalytic devices, but can perform highly selective and targeted cleavage of specific substrates, finely modulating multiple essential cellular processes. Lysosomal protease cathepsins comprise 3 families of proteases that preferentially act within acidic cellular compartments, but they can also be found in other cellular locations. They can operate alone or as part of signalling cascades and regulatory circuits, playing important roles in apoptosis, extracellular matrix remodelling, hepatic stellate cell activation, autophagy and metastasis, contributing to the initiation, development and progression of liver disease. In this review, we comprehensively summarise current knowledge on the role of lysosomal cathepsins in liver disease, with a particular emphasis on liver fibrosis, non-alcoholic fatty liver disease and hepatocellular carcinoma.
Independent role of dose-escalation and prophylactic lymph-nodal irradiation in salvage radiotherapy after prostatectomy. A retrospective, multi-institute analysis on 725 men treated with high-dose radiotherapy and eight years follow-up
Authors: C. Cozzarini, A. Magli, D. Cante, B. Noris Chiorda, F. Munoz, A. Faiella, E. Olivetta, M.A. Signor, C. Piva, B. Avuzzi, L. Ferella, A. Pastorino, A. Fodor, C. Deantoni, F. Nicola, G. Gandaglia, G. Sanguineti, R. Valdagni, C. Fiorino, A. Briganti, F. Montorsi, N. Di Muzio
Journal: European Urology (2021)
Quality of Early Essential Newborn Care in hospitals in Gaza: a pre-intervention and post-intervention study
Authors: Shireen N Abed, Sireen Al Attar, Bothaina Shaikh Khalil, Laila Al Masharfa, Nashwa Skaik, Luca Ronfani, Silvia Pivetta, John C S Murray, Ahmed Shatat, Hasan Al Louh, Hani Mahdi, Waleed Abu Hatab, Walid Afana, Walid Madi, Fadya Melhes, Imtethal Araj, Taghreed Abu Mousa, Khawla Al Madhoon, Nawal Ghalban, Reem Al Aloul, Rohaifa Al Farra, Doaa Oweda, Wesam Shaltout, Haleema Nabhan, Naser Bolbol, Ayman Al Rabae
Journal: The Lancet (2021)
Global Microbiota‐Dependent Histone Acetylation Patterns Are Irreversible and Independent of Short Chain Fatty Acids
Authors: Yedidya Saiman, Ting‐Chin David Shen, Peder J. Lund, Victoria M. Gershuni, Cholsoon Jang, Shivali Patel, Sunhee Jung, Emma E. Furth, Elliot S. Friedman, Lillian Chau, Benjamin A. Garcia, Gary D. Wu
Journal: Hepatology (2021)

Background and Aims Although germ-free mice are an indispensable tool in studying the gut microbiome and its effects on host physiology, they are phenotypically different than their conventional counterparts. While antibiotic-mediated microbiota depletion in conventional mice leads to physiologic alterations that often mimic the germ-free state, the degree to which the effects of microbial colonization on the host are reversible is unclear. The gut microbiota produce abundant short chain fatty acids (SCFAs), and previous studies have demonstrated a link between microbial-derived SCFAs and global hepatic histone acetylation in germ-free mice. Approach and Results We demonstrate that global hepatic histone acetylation states measured by mass spectrometry remained largely unchanged despite loss of luminal and portal vein SCFAs after antibiotic-mediated microbiota depletion. In contrast to stable hepatic histone acetylation states, we see robust hepatic transcriptomic alterations after microbiota depletion. Additionally, neither dietary supplementation with supraphysiologic levels of SCFA nor the induction of hepatocyte proliferation in the absence of microbiota-derived SCFAs led to alterations in global hepatic histone acetylation. Conclusions These results suggest that microbiota-dependent landscaping of the hepatic epigenome through global histone acetylation is static in nature, while the hepatic transcriptome is responsive to alterations in the gut microbiota.
Abstract 2824: SHP2-PDHA metabolic axis is critical for adipocyte function by mitigating ER stress-induced adipocytes dysfunction: Implication for obesity-driven pancreatic ductal adenocarcinoma progression
Authors: Appolinaire A. Olou, Jarrid Jack, Sharon Manley, Joseph Ambrose, McKinnon Walsh, Austin Eades, Michael N. VanSaun
Journal: Cancer Research (2021)

Abstract Obesity remains a major risk factor for the development of pancreatic cancer. Animal studies demonstrated that obese mice develop larger and more metastatic pancreatic cancer compared to their lean counterpart. Within the tumor environment are adipocytes that secrete adipokines, which promote inflammation and directly stimulate pancreatic cancer cells. Understanding the mechanisms that alter adipocyte function and adipokine secretion is critical for circumventing adipocyte-mediated influence on pancreatic cancer progression. Targeting of the Src homology region 2 containing protein tyrosine phosphatase (SHP-2) in the cancer cells has recently shown promising potential, yet the effect of SHP2 inhibition on stromal components has not been addressed. Here we demonstrate that SHP2 and the mitochondrial protein pyruvate dehydrogenase (PDHA) are critical mediators of adipocyte function, through mitigation of ER stress in adipocytes. In order to understand the role of SHP2 and PDHA in adipocytes, we performed Oil Red O staining and western blot assays on cultured adipocytes. We found that the transition from pre-adipocytes to fully developed adipocytes is marked by significant accumulation of phospho-SHP2, PDHA and the ER stress marker Bip. Chemical inhibition of SHP2 or PDHA augmented ER stress and impaired lipid production in the adipocytes; these effects were reversed by the ER stress inhibitor, 4-Phenylbyturic acid (4-PBA). Moreover, pancreatic cancer cells exposed to conditioned media from differentiated adipocytes, in which either SHP2 or PDHA was inhibited, are less aggressive and invasive compared to PDAC cells grown in conditioned media from control adipocytes with no inhibitor treatment. Therefore, our studies indicate that SHP2 and PDHA, in adipocytes, are key mediators of obesity-driven pancreatic cancer progression. Future studies will focus on understanding the SHP2-PDHA axis in adipocytes and further to elucidate how cancer cell extrinsic effects of SHP2 inhibition could alter PDAC progression. Citation Format: Appolinaire A. Olou, Jarrid Jack, Sharon Manley, Joseph Ambrose, McKinnon Walsh, Austin Eades, Michael N. VanSaun. SHP2-PDHA metabolic axis is critical for adipocyte function by mitigating ER stress-induced adipocytes dysfunction: Implication for obesity-driven pancreatic ductal adenocarcinoma progression [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 2824.
Abstract 2206: Investigation of DNA damage repair mutated characteristics and correlation with immunogenic biomarker in Chinese head and neck cancer patients
Authors: Yong Chen, Yan Wang, Yating Zheng, Wenzhuan Xie, Mengli Huang
Journal: Cancer Research (2021)

Abstract Background: DNA damage repair (DDR) pathway have been reported in several cancer, and known as a predictive biomarker of platinum-based chemotherapy, PARP inhibitor therapy, radiotherapy, and immunotherapy. However, the predictive value and mutated characteristics of DDR in patients with head and neck cancer (HNC) is still uncertain. The purpose of this study is to assess the frequency of DDR mutations, and the correlation between DDR mutations and immunogenic biomarker such as tumor mutation burden (TMB), microsatellite instability (MSI) and PD-L1 expression in Chinese HNC patients. Methods: Genomic profiling of DNA was performed through a next-generation sequencing (NGS) (panel on 381/733-gene) on tissue from Chinese patients with head and neck cancer between January 23, 2017 and April 10 2020. TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was determined by immunohistochemistry staining using Dako 22C3. Germline or somatic mutations of 35 DDR genes were classified as DDR gene mutations. Result: Genetic mutation of 319 HNC patients were analyzed using NGS, of which 32 (10.03%) harbored alterations in DDR genes. The most frequently mutated DDR genes were BRCA2 (3.23%), followed by FANCA (2.02%), BRCA1 (1.61%), RAD51 (0.81%), RAD50 (0.81%), PMS2 (0.81%), and PLAB2 (0.81%). The frequency of KMT2C, CD274, FBXW7, APC, NOTCH1, PDCD1LG2, RB1, LRP1B, and JAK2 mutations was higher in DDR mutations (DDRmut) than in DDR wild-type (DDRwt) patients. PD-L1 status analysis was performed in 265 HNC patients, including 24 DDRmut patients and 241 DDRwt patients. But there was no significant difference on PD-L1 expression between DDRmut t and DDRwt (P=0.93). 310 HNC patients (including 31 DDRmut patients and 279 DDRwt patients) could be evaluated for TMB, the results showed that DDRmut (10.13Muts/Mb) was associated with higher TMB than DDRwt (5.65Muts/Mb) (P = 0.0031). Of the 308 HNC patients (including 31 DDRmut patients and 277 DDRwt), only 3 (0.97%) were diagnosed as MSI-H, including 2 (6.45%) patients with DDRmut and 1 (0.36%) patient with DDRwt. Conclusions: The DDR pathway genes alteration characteristics was presented in Chinese HNC patients, and was associated with a higher TMB level. These findings provide a theoretical basis for future investigation of clinical therapy in DDR mutated Chinese HNC patients. Citation Format: Yong Chen, Yan Wang, Yating Zheng, Wenzhuan Xie, Mengli Huang. Investigation of DNA damage repair mutated characteristics and correlation with immunogenic biomarker in Chinese head and neck cancer patients [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 2206.
Transcriptome sequencing of BCG-treated T1HG bladder cancer patients identifies an EMT-basal subgroup with immune suppressive characteristics at high risk of BCG failure
Authors: F.C. De Jong, T.D. Laajala, R.F. Hoedemaeker, J.T.M. Mensink, A.C.J. Van Der Made, S. Rinaldetti, E.R. Boevé, D.K.E. Schoot, E.C. Zwarthoff, J.L. Boormans, D. Theodorescu, J.C. Costello, T.C.M. Zuiverloon
Journal: European Urology (2021)