tbuckley/cabot-search huggingface dataset:
Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness
Authors: Weiqiu Cheng, Oleksandr Frei, Dennis van der Meer, Yunpeng Wang, Kevin S. O’Connell, Yunhan Chu, Shahram Bahrami, Alexey A. Shadrin, Dag Alnæs, Guy F. L. Hindley, Aihua Lin, Naz Karadag, Chun-Chieh Fan, Lars T. Westlye, Tobias Kaufmann, Espen Molden, Anders M. Dale, Srdjan Djurovic, Olav B. Smeland, Ole A. Andreassen
Journal: JAMA Psychiatry (2021)

Schizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive.To investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci.Independent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021.The primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci.Based on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified.This study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.
Dose Continuing Warfarin Therapy during Catheter Ablation Reduce the Thromboembolism in Patients with Atrial Fibrillation
Authors: Hioki Mika, Matsuo Seiichiro, Tokutake Kenichi, Narui Ryohsuke, Ito Keiichi, Tanigawa Shinichi, Fujii Shinya, Yamashita Seigo, Inada Keiichi, Shibayama Kenri, Miyanaga Satoru, Date Taro, Sugimoto Kenichi, Yamane Teiichi, Yoshimura Michihiro
Journal: Circulation (2012)
Liposomes and Extracellular Vesicles as Drug Delivery Systems: A Comparison of Composition, Pharmacokinetics, and Functionalization
Authors: Luke van der Koog, Timea B. Gandek, Anika Nagelkerke
Journal: Advanced Healthcare Materials (2021)

Over the past decades, lipid-based nanoparticle drug delivery systems (DDS) have caught the attention of researchers worldwide, encouraging the field to rapidly develop improved ways for effective drug delivery. One of the most prominent examples is liposomes, which are spherical shaped artificial vesicles composed of lipid bilayers and able to encapsulate both hydrophilic and hydrophobic materials. At the same time, biological nanoparticles naturally secreted by cells, called extracellular vesicles (EVs), have emerged as promising more complex biocompatible DDS. In this review paper, the differences and similarities in the composition of both vesicles are evaluated, and critical mediators that affect their pharmacokinetics are elucidate. Different strategies that have been assessed to tweak the pharmacokinetics of both liposomes and EVs are explored, detailing the effects on circulation time, targeting capacity, and cytoplasmic delivery of therapeutic cargo. Finally, whether a hybrid system, consisting of a combination of only the critical constituents of both vesicles, could offer the best of both worlds is discussed. Through these topics, novel leads for further research are provided and, more importantly, gain insight in what the liposome field and the EV field can learn from each other.
Abstract LB071: Tuning the tumor myeloid microenvironment (TME) by targeting TREM2+ tumor-associated macrophages to overcome resistance to immune checkpoint inhibitors
Authors: Nadine S. Jahchan, Mikhail Binnewies, Joshua L. Pollack, Ranna Mehta, Subhadra Dash, Christine Tun, Erick Lu, Xiaoyan Du, Kevin P. Baker, Len Reyno, Venkataraman Sriram
Journal: Cancer Research (2021)

Abstract The tumor microenvironment (TME) often contains high levels of suppressive myeloid cells that may contribute to innate checkpoint inhibitor (CPI) resistance. Pionyr's Myeloid Tuning approach involves altering the composition and/or the function of myeloid cells in the TME. To this end, therapeutic targeting of tumor-associated macrophages (TAMs) is a promising strategy to increase CPI response rates in solid tumor indications, as well as to overcome resistance to CPI therapies. Pionyr and others identified the transmembrane protein triggering receptor expressed on myeloid cells-2 (TREM2) as a highly enriched TAMs target. Furthermore, TREM2 mRNA expression negatively correlates with patient survival in a variety of tumor types, supporting the involvement of TAMs in tumor progression. Pionyr developed a lead anti-TREM2 monoclonal antibody (mAb), termed PY314, as well as a murinized version of PY314, termed PY314m. PY314m demonstrated significant anti-tumor activity either as single agent in CPI-sensitive syngeneic tumor models or in combination with anti-PD-1 in CPI-resistant syngeneic tumor models. Mechanistically, PY314m reduced the pro-tumorigenic MHC class II-low, M2-like TAMs, induced pro-inflammatory cytokine production, significant increased CD8+ T cell infiltration into the TME. These findings suggest that PY314 therapy could be used to overcome CPI resistance in humans. To select patients most likely to benefit from PY314 therapy, Pionyr developed a qualitative IHC assay that detects TREM2 expression levels in formalin-fixed, paraffin-embedded human tumor tissues. Screening for TREM2 expression in tumor tissues demonstrated that TREM2+ TAMs were present in multiple solid tumor indications and their number increased with disease grade in a selected set of indications. Ongoing efforts are aimed at better understanding localization of TREM2+ TAMs within the TME, and spatial relationship of the TREM2+ TAMs to other immune cells present in the TME. The TREM2 IHC assay will be used to test our hypothesis that patients with tumors with high level of TREM2+ TAMs are most likely to benefit from PY314 treatment. Citation Format: Nadine S. Jahchan, Mikhail Binnewies, Joshua L. Pollack, Ranna Mehta, Subhadra Dash, Christine Tun, Erick Lu, Xiaoyan Du, Kevin P. Baker, Len Reyno, Venkataraman Sriram. Tuning the tumor myeloid microenvironment (TME) by targeting TREM2+ tumor-associated macrophages to overcome resistance to immune checkpoint inhibitors [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 LB071.
Association of the COVID-19 Pandemic With Patterns of Statewide Cancer Services
Authors: K Robin Yabroff, Xiao-Cheng Wu, Serban Negoita, Jennifer Stevens, Linda Coyle, Jingxuan Zhao, Brent J Mumphrey, Ahmedin Jemal, Kevin C Ward
Journal: JNCI Journal of the National Cancer Institute (2021)

The coronavirus disease 2019 (COVID-19) pandemic led to delayed medical care in the United States. We examined changes in patterns of cancer diagnosis and surgical treatment between January 1 and December 31 in 2020 and 2019 with real-time electronic pathology report data from population-based Surveillance, Epidemiology, and End Results cancer registries from Georgia and Louisiana. During 2020, there were 29 905 fewer pathology reports than in 2019, representing a 10.2% decline. Declines were observed in all age groups, including children and adolescents younger than 18 years. The nadir was early April 2020, with 42.8% fewer reports than in April 2019. Numbers of reports through December 2020 never consistently exceeded those in 2019 after first declines. Patterns were similar by age group and cancer site. Findings suggest substantial delays in diagnosis and treatment services for cancers during the pandemic. Ongoing evaluation can inform public health efforts to minimize any lasting adverse effects of the pandemic on cancer diagnosis, stage, treatment, and survival.
Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma
Authors: Haijing Deng, Anna Kan, Ning Lyu, Meng He, Xin Huang, Shuang Qiao, Shaolong Li, Wenhua Lu, Qiankun Xie, Huiming Chen, Jinfa Lai, Qifeng Chen, Xiongying Jiang, Shousheng Liu, Zhenfeng Zhang, Ming Zhao
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Neutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1 + ) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1 + neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1 + neutrophils in hepatocellular carcinoma. Methods Neutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1 + neutrophil infiltration. Further in vivo assays were used for verification. Results Lenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1 + neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1 + neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1 + neutrophil and promoted the antitumor effect of lenvatinib. Conclusions PD-L1 + neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1 + neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.
Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling
Authors: Vik Meadows, Lindsey Kennedy, Burcin Ekser, Konstantina Kyritsi, Debjyoti Kundu, Tianhao Zhou, Lixian Chen, Linh Pham, Nan Wu, Jennifer Demieville, Laura Hargrove, Shannon Glaser, Gianfranco Alpini, Heather Francis
Journal: Hepatology (2021)

Background and Aims Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)/FGF15. Patients with primary sclerosing cholangitis (PSC) typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis. In bile‐duct‐ligated (BDL) MC‐deficient mice (B6.Cg‐ KitW‐sh /HNihrJaeBsmJ [ KitW‐sh ]), ductular reaction (DR) and liver fibrosis decrease compared with BDL wild type, and MC injection exacerbates liver damage in normal mice. Approach and Results In this study, we demonstrated that MC‐FXR regulates biliary FXR/FGF15, DR, and hepatic fibrosis and alters intestinal FXR/FGF15. We found increased MC number and biliary FXR expression in patients with liver injury compared with control. Histamine and FGF19 serum levels and small heterodimer partner expression increase in patients PSC and PSC‐IBD compared with healthy controls. MC injection increased liver damage, DR, inflammation, biliary senescence/senescence‐associated secretory phenotype (SASP), fibrosis, and histamine in KitW‐sh mice. Inhibition of MC‐FXR before injection reduced these parameters. BDL and KitW‐sh mice injected with MCs displayed increased TBA content, biliary FXR/FGF15, and intestinal inflammation, which decreased in BDL KitW‐sh and KitW‐sh mice injected with MC‐FXR. MCs increased ileal FXR/FGF15 expression in KitW‐sh mice that was reduced following FXR inhibition. BDL and multidrug resistance 2/ATP‐binding cassette family 2 member 4 knockout ( Mdr2 −/− ) mice, models of PSC, displayed increased intestinal MC infiltration and FXR/FGF15 expression. These were reduced following MC stabilization with cromolyn sodium in Mdr2 −/− mice. In vitro , MC‐FXR inhibition decreased biliary proliferation/SASP/FGF and hepatic stellate cell activation. Conclusions Our studies demonstrate that MC‐FXR plays a key role in liver damage and DR, including TBA regulation through alteration of intestinal and biliary FXR/FGF15 signaling.
Respiratory disease, and treatment / thematic poster session a novel approach to medical monitoring during the sars-cov-2 pandemic supporting the activ 4b outpatient anticoagulation trial
Authors: J. C. Hulbert, J. A. Krishnan, E. Heather, N. Shapiro, S. O'Neal, A. Baucom, L. Castro, B. Kirwan, S. Wisniewski, F. C. Sciurba, P. Ridker, J. Connors
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale The ACTIV 4B (OWS/NHLBI supported) clinical trial addresses the use of anti-platelet and anticoagulant agents in symptomatic COVID-19 positive non-hospitalized patients with regards to safety and prevention of macro- and micro-thrombotic events using a composite outcome (symptomatic DVT/PE, arterial thromboembolism, MI, CVA, hospitalization for CV/pulmonary events, mortality). Concerns regarding SARS-CoV- 2 transmission risk to research staff and overburdened institutional environments create challenges for standard event monitoring. In addition, safety or outcome events often occur at other institutions rather than the enrollment site. Therefore, research methodology was adapted to effectively evaluate and categorize safety events using a remote low touch approach. Methods Trial over can be found at NCT04498273. Potential adverse events identified through patient electronic data capture survey or call center assessments are handled remotely by central clinical study staff. If an event is identified as a possible endpoint or SAE by the central study staff the electronic data collection (EDC) system notifies the central medical monitoring team, and the enrolling site coordinator if patient enrolled from an acute care setting, that additional source documents are necessary. The medical coordinator works with the site coordinator, or will reach out independently to treating institutions to obtain necessary source documents. Based on a review of clinical data from the EDC and all available source documents, final arbitration of seriousness, relatedness and expectedness is be made by the study's Medical Monitor, and appropriate study entities (NIH, FDA, IRB, study leadership, pharmaceutical co.) are notified.Results The process as described has been successfully and effectively implemented in >50 patients with anticipation of 7000 patient eventual enrollment. Events have been captured, source documentation has been procured and events have been reported as per established protocol processes. Conclusion We have effectively implemented a medical safety event monitoring methodology in a “low touch” study design to assess events in the complex COVID-19 outpatient space. Elements of our system can be effectively replicated in other COVID and non-COVID clinical trials. .
Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes
Authors: Sheng-Chieh Hsu, Chia-Lin Chen, Mei-Ling Cheng, Cheng-Ying Chu, Chun A. Changou, Yen-Ling Yu, Shauh-Der Yeh, Tse-Chun Kuo, Cheng-Chin Kuo, Chih-Pin Chuu, Chien-Feng Li, Lu-Hai Wang, Hong-Wu Chen, Yun Yen, David K. Ann, Hung-Jung Wang, Hsing-Jien Kung
Journal: Theranostics (2021)

Rationale: One of the most common metabolic defects in cancers is the deficiency in arginine synthesis, which has been exploited therapeutically. Yet, challenges remain, and the mechanisms of arginine-starvation induced killing are largely unclear. Here, we sought to demonstrate the underlying mechanisms by which arginine starvation-induced cell death and to develop a dietary arginine-restriction xenograft model to study the in vivo effects. Methods: Multiple castration-resistant prostate cancer cell lines were treated with arginine starvation followed by comprehensive analysis of microarray, RNA-seq and ChIP-seq were to identify the molecular and epigenetic pathways affected by arginine starvation. Metabolomics and Seahorse Flux analyses were used to determine the metabolic profiles. A dietary arginine-restriction xenograft mouse model was developed to assess the effects of arginine starvation on tumor growth and inflammatory responses. Results: We showed that arginine starvation coordinately and epigenetically suppressed gene expressions, including those involved in oxidative phosphorylation and DNA repair, resulting in DNA damage, chromatin-leakage and cGAS-STING activation, accompanied by the upregulation of type I interferon response. We further demonstrated that arginine starvation-caused depletion of α-ketoglutarate and inactivation of histone demethylases are the underlying causes of epigenetic silencing. Significantly, our dietary arginine-restriction model showed that arginine starvation suppressed prostate cancer growth in vivo, with evidence of enhanced interferon responses and recruitment of immune cells. Conclusions: Arginine-starvation induces tumor cell killing by metabolite depletion and epigenetic silencing of metabolic genes, leading to DNA damage and chromatin leakage. The resulting cGAS-STING activation may further enhance these killing effects.
Peripheral neuropathy symptoms, pain, and functioning in previously treated multiple myeloma patients treated with selinexor, bortezomib, and dexamethasone
Authors: Larysa Sanchez, Xavier Leleu, Jennifer L. Beaumont, Hailin Yu, Stacie Hudgens, Maryana Simonova, Holger W. Auner, Hang Quach, Sosana Delimpasi, Ivan Špička, Ludĕk Pour, Iryna Kriachok, Meletios A. Dimopoulos, Ganna Usenko, Roman Hájek, Reuben Benjamin, Dinesh Kumar Sinha, Christopher Venner, Thomas Illmer, Mamta Krishnan Garg, Don Ambrose Stevens, Sundar Jagannath, Moshe Levy, Larry D. Anderson, Nizar Jacques Bahlis, Thierry Facon, Michele Cavo, Yi Chai, Xiwen Ma, Shijie Tang, Hoyee Leong, Jatin Shah, Sharon Shacham, Michael Kauffman, Paul Richardson, Sebastian Grosicki
Journal: American Journal of Hematology (2021)
Evaluation of Sympathetic Nerve Activity and Aldosterone Suppression in Decompensated Heart Failure Patients on the Treatment with Atrial Natriuretic Peptide
Authors: Kasama Shu, Araki Yoshihiro, Niwano Kazuo, Kanai Hiroyoshi, Itoh Toshio, Iwasaki Toshiya, Kumakura Hisao, Takayama Yoshiaki, Minami Kazutomo, Ichikawa Shuichi, Kurabayashi Masahiko
Journal: Circulation (2011)
Association of Preterm Birth With Myocardial Fibrosis and Diastolic Dysfunction in Young Adulthood
Authors: Adam J. Lewandowski, Betty Raman, Mariane Bertagnolli, Afifah Mohamed, Wilby Williamson, Joana Leal Pelado, Angus McCance, Winok Lapidaire, Stefan Neubauer, Paul Leeson
Journal: Journal of the American College of Cardiology (2021)

Preterm birth affects about 10% of live births worldwide and is associated with cardiac alterations. Animal models of preterm birth suggest that left ventricular functional impairment may be due to an up-regulation of myocardial fibrosis. The aim of this study was to determine whether diffuse left ventricular fibrosis is evident in young adults born preterm. One hundred one normotensive young adults born preterm (n = 47, mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) were included from YACHT (Young Adult Cardiovascular Health sTudy). Left ventricular structure and function were quantified by cardiovascular magnetic resonance and echocardiography. Intravenous administration of a gadolinium-based contrast agent during cardiovascular magnetic resonance was used to quantify focal myocardial fibrosis on the basis of late gadolinium enhancement and, in combination with T1 mapping, to quantify diffuse myocardial fibrosis on the basis of assessment of myocardial extracellular volume fraction. Adults born preterm had smaller left ventricular end-diastolic and stroke volumes, with greater left ventricular mass and wall thickness (P < 0.001). In addition, longitudinal peak systolic strain and diastolic strain rate by both cardiovascular magnetic resonance and echocardiography, and E/A ratio measured by echocardiography, were lower in preterm-born compared to term-born adults (P < 0.05). Extracellular volume fraction was greater in preterm-born compared with term-born adults (27.81% ± 1.69% vs 25.48% ± 1.41%; P < 0.001) and was a significant mediator in the relationship between gestational age and both longitudinal peak diastolic strain rate and E/A ratio. Preterm-born young adults have greater extracellular volume fraction in the left ventricle that is inversely related with gestational age and may underlie their diastolic functional impairments.
High-Resolution SNP-Array Profiling of “Ultra-High Risk” CLL Cases Reveals New Recurrent Genomic Alterations
Authors: Jennifer Edelmann, Karlheinz Holzmann, Eugen Tausch, Anna Dolnik, Tamara J. Blätte, Stefan Ibach, Jenny Saub, Daniel Mertens, Lars Bullinger, Kirsten Fischer, Valentin Goede, John G. Gribben, Michael J. Hallek, Hartmut Döhner, Stephan Stilgenbauer
Journal: Blood (2017)