tbuckley/cabot-search huggingface dataset:
MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation
Authors: Candela Diaz-Canestro, Yustina M Puspitasari, Luca Liberale, Tomasz J Guzik, Andreas J Flammer, Nicole R Bonetti, Patricia Wüst, Sarah Costantino, Francesco Paneni, Alexander Akhmedov, Zsuzsanna Varga, Stefano Ministrini, Jürg H Beer, Frank Ruschitzka, Matthias Hermann, Thomas F Lüscher, Isabella Sudano, Giovanni G Camici
Journal: Cardiovascular Research (2021)

Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small-interfering RNA (siRNA) on age-dependent arterial stiffness.Pulse wave velocity (PWV) was assessed in right carotid artery of wild-type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18- to 21-month old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2-treated mice showed increased elastin-to-collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS), and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness.MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.
Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction
Authors: Qing-Jun Zhang, Yu He, Yongnan Li, Huali Shen, Ling Lin, Min Zhu, Zhaoning Wang, Xiang Luo, Joseph A. Hill, Dian Cao, Richard L. Luo, Raymond Zou, John McAnally, Jun Liao, Pietro Bajona, Qun S. Zang, Yonghao Yu, Zhi-Ping Liu
Journal: Circulation Research (2021)

Rationale: Cilp1 (cartilage intermediate layer protein 1) is a secreted extracellular matrix protein normally associated with bone and cartilage development. Its function and mechanism of action in adult heart disease remain elusive. Objective: To establish the function and mechanism of action of Cilp1 in postmyocardial infarction (MI) cardiac remodeling. Methods and Results: We investigated the expression of Cilp1 in mouse models of pathological cardiac remodeling and human heart failure patients. Cilp1 was expressed predominantly in cardiac fibroblasts and upregulated in response to cardiac injury and in the heart and blood of patients with heart failure. We generated Cilp1 knock out (KO) and transgenic (Tg) mice with NCilp1 (N-terminal half of the protein) overexpressed in myofibroblasts. Cilp1 KO mice had better cardiac function, reduced number of immune cells and myofibroblasts, and enhanced microvascular survival after MI compared with wild-type littermates. Conversely, NCilp1-transgenic mice had augmented loss of cardiac function, increased number of myofibroblasts and infarct size after the MI injury. RNA-seq and gene ontology analysis indicated that cell proliferation and mTORC1 (mammalian Target of Rapamycin Complex 1) signaling were downregulated in KO hearts compared with wild-type hearts. In vivo BrdU labeling and immunofluorescence staining showed that myofibroblast proliferation in the Cilp1 KO heart was downregulated. Biaxial mechanical testing and extracellular matrix gene expression analysis indicated that while MI caused significant stiffness in wild-type hearts it had little effect on KO hearts. Upregulation of collagen expression after MI injury was attenuated in KO hearts. Recombinant CILP1 protein or NCilp1-conditioned medium promoted proliferation of neonatal rat ventricular cardiac fibroblasts via the mTORC1 signaling pathway. Conclusions: Our studies established a pathological role of Cilp1 in promoting post-MI remodeling, identified a novel function of Cilp1 in promoting myofibroblast proliferation, and suggested that Cilp1 may serve as a potential biomarker for pathological cardiac remodeling and target for fibrotic heart disease.
74P A predictive signature for response to immunotherapy in non-small cell lung cancer based on plasma proteomics and clinical parameters
Authors: Y. Shaked, C. Lahav, M. Harel, E. Jacob, I. Sela, G. Yahalom, Y. Elon, O. Sharon, I. Kamer, A. Dicker, J. Bar, R. Katzenelson, I. Wolf, M. Gottfried, M. Abu-Amana, A. Agbarya, H. Nechushtan, M.T. Moskovits, A. Zer
Journal: Annals of Oncology (2021)
696P Is it possible to improve the prognostic ability of the IMDC score? Validation of the Meet-URO score in metastatic renal cell carcinoma (mRCC) patients (pts) receiving first-line nivolumab plus ipilimumab in the Italian Expanded Access Program (EAP)
Authors: S.E. Rebuzzi, A. Signori, M. Maruzzo, G. Tortora, L. Galli, M. Rizzo, U. De Giorgi, L. Antonuzzo, S. Bracarda, G. Cartenì, F. Atzori, S. Tamberi, G. Procopio, L. Fratino, M. Santoni, C. Baldessari, A. Astone, F. Calabro', S. Buti, G. Fornarini
Journal: Annals of Oncology (2021)
Genome-wide analyses of multiple obesity-related cytokines and hormones informs biology of cardiometabolic traits
Authors: Karlijn A. C. Meeks, Amy R. Bentley, Mateus H. Gouveia, Guanjie Chen, Jie Zhou, Lin Lei, Adebowale A. Adeyemo, Ayo P. Doumatey, Charles N. Rotimi
Journal: Genome Medicine (2021)

Abstract Background A complex set of perturbations occur in cytokines and hormones in the etiopathogenesis of obesity and related cardiometabolic conditions such as type 2 diabetes (T2D). Evidence for the genetic regulation of these cytokines and hormones is limited, particularly in African-ancestry populations. In order to improve our understanding of the biology of cardiometabolic traits, we investigated the genetic architecture of a large panel of obesity- related cytokines and hormones among Africans with replication analyses in African Americans. Methods We performed genome-wide association studies (GWAS) in 4432 continental Africans, enrolled from Ghana, Kenya, and Nigeria as part of the Africa America Diabetes Mellitus (AADM) study, for 13 obesity-related cytokines and hormones, including adipsin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), interleukin-1 receptor antagonist (IL1-RA), interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, visfatin, insulin, glucagon, and ghrelin. Exact and local replication analyses were conducted in African Americans ( n = 7990). The effects of sex, body mass index (BMI), and T2D on results were investigated through stratified analyses. Results GWAS identified 39 significant ( P value &lt; 5 × 10 −8 ) loci across all 13 traits. Notably, 14 loci were African-ancestry specific. In this first GWAS for adipsin and ghrelin, we detected 13 and 4 genome-wide significant loci respectively. Stratified analyses by sex, BMI, and T2D showed a strong effect of these variables on detected loci. Eight novel loci were successfully replicated: adipsin (3), GIP (1), GLP-1 (1), and insulin (3). Annotation of these loci revealed promising links between these adipocytokines and cardiometabolic outcomes as illustrated by rs201751833 for adipsin and blood pressure and locus rs759790 for insulin level and T2D in lean individuals. Conclusions Our study identified genetic variants underlying variation in multiple adipocytokines, including the first loci for adipsin and ghrelin. We identified population differences in variants associated with adipocytokines and highlight the importance of stratification for discovery of loci. The high number of African-specific loci detected emphasizes the need for GWAS in African-ancestry populations, as these loci could not have been detected in other populations. Overall, our work contributes to the understanding of the biology linking adipocytokines to cardiometabolic traits.
Metal transporter Slc30a1 controls pharyngeal neural crest differentiation via the zinc‐Snai2‐Jag1 cascade
Authors: Zhidan Xia, Xinying Bi, Sisi Yang, Xiu Yang, Zijun Song, Jiayu Wei, Pengfei Xu, Lothar Rink, Junxia Min, Fudi Wang
Journal: MedComm (2021)

Abstract The pharyngeal arch (PA) is a neural crest (NC)‐derived organ that is transiently developed during embryogenesis and is required for the subsequent development of various tissues. However, the role of zinc during PA differentiation from NC progenitor cells is unknown. Here, we found that the metal transporters Slc30a1a and Slc30a1b mediate zinc homeostasis during PA differentiation. Slc30a1‐deficient zebrafish develop zinc accumulation in NC cells, with increased expression of stemness markers and PA dorsal genes, and SMART‐seq analyses revealed that the genes snai2 and jag1b may serve as downstream targets. Furthermore, functional studies showed that knocking down either snai2 or jag1b rescues PA development in Slc30a1‐deficient zebrafish. Notably, we identified the double zinc‐finger domain in the transcription factor Snai2 as a zinc‐responsive element that regulates jag1b expression. Our findings indicate that the Slc30a1/zinc‐ snai2 ‐ jag1b axis is an essential regulatory network controlling PA differentiation, shedding new light on the function of zinc homeostasis in maintaining NC cell stemness and multipotency in vertebrates.
388MO Tumor budding, an important prognostic factor in stage III colon cancer patients treated with oxaliplatin-based chemotherapy
Authors: D. Basile, C. Broudin, J-F. Emile, A. Falcoz, C. Toullec, J. Bennouna, C. Louvet, J. Desrame, S. Fratte, T. André, J. Taieb, M. Svrcek
Journal: Annals of Oncology (2021)
1272P First results of the early onset lung cancer (EOLUNG) study to characterize genomic alterations using FoundationOne CDx in young patients with non-small cell lung cancer
Authors: M. Jove Casulleras, J. Bosch Barrera, E. Sais, A. Hernandez, M. Gasusachs, E. Carcereny, T. Moran, M. Domenech Vinolas, R. Palmero, J. Brenes, N. Vilariño, J.C.C. Ruffinelli, C. Fina, S. Lorente, A. Teule, C. Lazaro, E. Nadal
Journal: Annals of Oncology (2021)
Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial
Authors: Chan Joon Kim, Mahn-Won Park, Min Chul Kim, Eun-Ho Choo, Byung-Hee Hwang, Kwan Yong Lee, Yun Seok Choi, Hee-Yeol Kim, Ki-Dong Yoo, Doo-Soo Jeon, Eun-Seok Shin, Young-Hoon Jeong, Ki-Bae Seung, Myung Ho Jeong, Hyeon Woo Yim, Youngkeun Ahn, Kiyuk Chang, Chan Joon Kim, Mahn-Won Park, Min Chul Kim, Eun-Ho Choo, Byung-Hee Hwang, Kwan Yong Lee, Yun Seok Choi, Hee-Yeol Kim, Ki-Dong Yoo, Doo-Soo Jeon, Eun-Seok Shin, Yong-Hoon Jeong, Ki-Bae Seung, Myung Ho Jeon, Youngkeun Ahn, Kiyuk Chang, Ju-Hyeon Oh, Sang Jin Ha, Ju Yeol Baek, Kyung Tae Jung, Joon-Hyung Doh, Won Kim, Dong-Bin Kim, Kwang Soo Cha, Myeong-Ho Yoon, Seung-Ho Hur, Seung-Hwan Lee, Byung-Ryul Cho, Jong-Seon Park, Jin Shin Koh, Sang-Hyun Kim, Jang Hyun Cho, Byung Joo Shim, Sang Wook Kim, Jae-Sik Jang, Kee-Sik Kim, Won-Yong Shin, Ki-Chul Sung
Journal: The Lancet (2021)
611P Pembrolizumab (pembro) monotherapy for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): Updated analyses with 4 years of follow-up from cohorts 1-3 of the KEYNOTE-199 study
Authors: E.S. Antonarakis, J.M. Piulats, M. Gross-Goupil, J.C. Goh, U.N. Vaishampayan, R. De Wit, T.V. Alanko, S. Fukasawa, K. Tabata, S. Feyerabend, R. Berger, K. Ojamaa, C.J. Hoimes, A. Sezer, A.G. Omlin, J. Yachnin, C. Niu, C.H. Poehlein, C. Schloss, J.S. de Bono
Journal: Annals of Oncology (2021)
212P HER2-low breast cancer: Evolution from primary tumor to residual disease after neoadjuvant treatment
Authors: F. Miglietta, G. Griguolo, M. Bottosso, T. Giarratano, M. Lo Mele, M. Fassan, M. Cacciatore, E. Genovesi, D. De Bartolo, G. Vernaci, O. Amato, F. Porra, P.F. Conte, V. Guarneri, M.V. Dieci
Journal: Annals of Oncology (2021)
1299P Effect of fat tissue composition on the outcome of patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors
Authors: K. Rounis, D. Makrakis, A-P. Tsigkas, A. Georgiou, N. Galanakis, G. Tsakonas, C. Papadaki, A. Monastirioti, M. Kontogianni, I. Gioulbasanis, D. Mavroudis, S. Agelaki
Journal: Annals of Oncology (2021)
If it quacks like a duck: The by-product account of music still stands
Authors: Debra Lieberman, Joseph Billingsley
Journal: Behavioral and Brain Sciences (2021)

Discerning adaptations from by-products is a defining feature of evolutionary science. Mehr, Krasnow, Bryant, and Hagen posit that music is an adaptation that evolved to function as a credible signal. We counter this claim, as we are not convinced they have dispelled the possibility that music is an elaboration of extant features of language.
1402P Gastroesophageal cancer treatment patterns in Europe and the United States: An exploratory analysis using population-based cancer registry data
Authors: F. Giusti, C. Martos, L. Neamtiu, G. Randi, M. Flego, T.A. Dyba, R. Calvalho, N. Dimitrova, N. Nicholson, M. Bettio
Journal: Annals of Oncology (2021)
1859P Using deep learning with demographic and laboratory values from baseline to cycle 2 to predict subsequent renal and hepatic function
Authors: M.S. Watson, P. Chambers, K-K. Shiu, J.A. Bridgewater, M. Desai, R. Roylance, A. Tailor, S. Masento, M. Forster, N. Al Moubayed
Journal: Annals of Oncology (2021)
864MO Role of geriatric assessment in tailoring treatment of locally advanced head and neck cancer: The ELDERLY study
Authors: P. Bossi, A. Esposito, S. Vecchio, P. Nicolai, A. Tarsitano, A. Mirabile, S. Ursino, M.C. Cau, P. Bonomo, A. Marengoni, C. Piazza, M. Maddalo, L. Lorini, C. Gurizzan, M. Cossu Rocca, C.I. Ripamonti, M. Guglielmo, L.F. Licitra
Journal: Annals of Oncology (2021)
Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy
Authors: Mohammed G Ghonime, Uksha Saini, Michael C Kelly, Justin C Roth, Pin-Yi Wang, Chun-Yu Chen, Katherine Miller, Ilse Hernandez-Aguirre, Yeaseul Kim, Xiaokui Mo, Joseph R Stanek, Tim Cripe, Elaine Mardis, Kevin A Cassady
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection. Methods We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice. Results Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations. Conclusions Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.
LBA26 Darolutamide maintenance in metastatic castration resistant prostate cancer (mCRPC) previously treated with novel hormonal agents (NHA) and non-progressive disease after subsequent treatment with a taxane: A randomized double-blind placebo-controlled phase II trial (SAKK 08/16)
Authors: R. Cathomas, G. Procopio, S. Hayoz, E.A. Kremer, D. Kienle, O. Caffo, D. Lorente, A. Pedrazzini, G. Roubaud, S. Nenan, A.G. Omlin, C. Buttigliero, R.J. Pereira Mestre, K. Ribi, S. Gillessen
Journal: Annals of Oncology (2021)
1558O COVID-19 vaccine in participants (ptcpts) with cancer: Subgroup analysis of efficacy/safety from a global phase III randomized trial of the BNT162b2 (tozinameran) mRNA vaccine
Authors: S.J. Thomas, J.L. Perez, S.P. Lockhart, S. Hariharan, N. Kitchin, R. Bailey, K. Liau, E. Lagkadinou, Ö. Türeci, U. Şahin, X. Xu, S.S. Dychter, C. Lu, T. Gentile, W. Gruber
Journal: Annals of Oncology (2021)
家族性高脂血症におけるLDLアフェレーシスと薬物併用による集中的脂肪低下療法を用いた冠動脈硬化症退行:日本におけるLDLアフェレーシス冠動脈硬化の前向き研究(L-CAPS)
Authors: Nishimura S, Yamaguchi H
Journal: Circulation (1994)
389MO Risk of bowel obstruction in patients undergoing neoadjuvant chemotherapy for high-risk colon cancer: A nested case-control matched analysis of an international, multi-centre, randomised controlled trial (FOxTROT)
Authors: J. Glasbey, J. Seligmann, D.G. Morton, None The FOxTROT Collaborating Group
Journal: Annals of Oncology (2021)
Immune responses to two and three doses of the BNT162b2 mRNA vaccine in adults with solid tumors
Authors: Rachna T. Shroff, Pavani Chalasani, Ran Wei, Daniel Pennington, Grace Quirk, Marta V. Schoenle, Kameron L. Peyton, Jennifer L. Uhrlaub, Tyler J. Ripperger, Mladen Jergović, Shelby Dalgai, Alexander Wolf, Rebecca Whitmer, Hytham Hammad, Amy Carrier, Aaron J. Scott, Janko Nikolich-Žugich, Michael Worobey, Ryan Sprissler, Michael Dake, Bonnie J. LaFleur, Deepta Bhattacharya
Journal: Nature Medicine (2021)
Physical, cognitive and mental health outcomes in 1-year survivors of COVID-19-associated ARDS
Authors: Nicola Latronico, Elena Peli, Stefano Calza, Federica Rodella, Maria Paola Novelli, Andrea Cella, John Marshall, Dale M Needham, Frank Antony Rasulo, Simone Piva
Journal: Thorax (2021)

We report on the outcome of 114 COVID-19-associated acute respiratory distress syndrome (ARDS) survivors evaluated at 3, 6 and 12 months after intensive care unit discharge with assessment of physical, mental and cognitive impairments. Critical illness polyneuromyopathy was diagnosed in 23 patients (39%). Handgrip dynamometry was 70% predicted at 3 months and significantly improved over time, whereas the 6 min walk test (80% predicted) and severe fatigue (27% of patients) did not. Independence in activities of daily living (ADL) was achieved by 98% at 3 months. Cognitive impairment (28% at 3 months) improved over time, whereas depression, anxiety and post-traumatic stress disorder symptoms, present in 9%, 10% and 4% at 3 months, did not. Normalised health-related quality of life was good. COVID-19-associated ARDS leads to persisting impairment in performance-based measures of physical function, while ADL, cognitive and mental health status, and health-related quality of life may be less impaired. Trial registration number NCT04608994 .
861MO Spatial distribution of CD8+ and FoxP3+ in a window of opportunity for durvalumab (MEDI4736) plus metformin trial in squamous cell carcinoma of the head and neck (HNSCC)
Authors: J.M. Curry, A. Alnemri, S. Sussman, L. Harshyne, A. Linnenbach, R. Stapp, A. South, U. Nwagu, B. Swendseid, M. Tuluc, S. Gargano, D. Cognetti, V. Bar-Ad, A. Luginbuhl, R. Axelrod, D. Whitaker-Menezes, M.G. Mahoney, A. Argiris, U. Martinez-Outschoorn, J.M. Johnson
Journal: Annals of Oncology (2021)
Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study
Authors: Andrea Loehr, Akash Patnaik, David Campbell, Jeremy Shapiro, Alan H. Bryce, Ray McDermott, Brieuc Sautois, Nicholas J. Vogelzang, Richard M. Bambury, Eric Voog, Jingsong Zhang, Josep M. Piulats, Arif Hussain, Charles J. Ryan, Axel S. Merseburger, Gedske Daugaard, Axel Heidenreich, Karim Fizazi, Celestia S. Higano, Laurence E. Krieger, Cora N. Sternberg, Simon P. Watkins, Darrin Despain, Andrew D. Simmons, Melanie Dowson, Tony Golsorkhi, Simon Chowdhury, Wassim Abida
Journal: Clinical Cancer Research (2021)

Abstract Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA+), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA+ mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after next-generation androgen receptor–directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA+ identified by central plasma (n = 34), central tissue (n = 37), or local (n = 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA+ by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA+ mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.