tbuckley/cabot-search huggingface dataset:
Abstract P378: Association Between an Ideal Cardiovascular Health (ICH) Profile and Coronary Artery Calcium (CAC) in South Asians: Implications for the Role of Lifestyle Factors in the Prevention of Cardiovascular Disease in a Minority Population.
Authors: Akhil Mehta
Journal: Circulation (2017)

The goal of this study was to evaluate cross sectionally the association between an ideal cardiovascular risk factor (IRF) profile and the presence and severity of subclinical atherosclerosis measured in the form of coronary artery calcium (CAC) at the El Camino Hospital South Asian Heart Center. We included 515 participants of South Asian origin with no prior history of cardiovascular disease aged 36 to 88 years who underwent CAC measurement. The 2010 Task Force of the American Heart Association (AHA) cutoffs were used to define ideal level of smoking, physical activity, diet, blood pressure, glucose, cholesterol levels, and body mass index (BMI). Participants were categorized according their number of IRFs: 0 to 1 (n = 45, 8.7%), 2 (n = 103, 20%), 3 (n = 144, 28%), 4 (n = 128, 24.9%), 5 (n = 70, 13.6%), and 6 to 7 (n = 25, 4.8%). Compared to individuals with 0 to 1 IRFs, the odds ratio of participants with 6 to 7 IRFs presenting with a CAC &gt;0 was 0.16 (95% CI 0.04-0.69). Moving forward, participants were also categorized according to their number of ideal lifestyle factors (BMI, physical activity, smoking status, and healthy diet) and clinical factors (blood pressure, total cholesterol, and blood sugar). Compared to individuals with 0 ideal lifestyle factors, the odds ratio of participants with all 4 ideal lifestyle factors presenting with a CAC &gt;0 was .12 (95% CI .03-.50). Amongst the individual ideal lifestyle factors though, only non-smoking status, 0.47 (95% CI 0.30-.75), and a BMI &lt;23 kg/m^2, 0.60 (95% CI 0.38-.95), conferred a statistically significant protective effect from having a non-zero CAC score. In contrast, compared to those with 0 ideal clinical factors, the odds ratio of participants with all 3 ideal clinical factors presenting with a CAC &gt;0 was .16 (95% CI .06-.44). That said, amongst the individual ideal clinical factors, normal BP produced the strongest protective effect from having a non-zero CAC score, 0.37 (95% CI 0.25-.57), followed by total cholesterol &lt;200 mg/dL, 0.69 (95% CI 0.44-.90), and blood glucose &lt;100 mg/dL, 0.69 (95% CI 0.47-.90).
Hierarchical assembly and disassembly of a transcriptionally active RAG locus in CD4+CD8+ thymocytes
Authors: Abani Kanta Naik, Aaron T. Byrd, Aaron C.K. Lucander, Michael S. Krangel
Journal: The Journal of Experimental Medicine (2018)

Expression of Rag1 and Rag2 is tightly regulated in developing T cells to mediate TCR gene assembly. Here we have investigated the molecular mechanisms governing the assembly and disassembly of a transcriptionally active RAG locus chromatin hub in CD4+CD8+ thymocytes. Rag1 and Rag2 gene expression in CD4+CD8+ thymocytes depends on Rag1 and Rag2 promoter activation by a distant antisilencer element (ASE). We identify GATA3 and E2A as critical regulators of the ASE, and Runx1 and E2A as critical regulators of the Rag1 promoter. We reveal hierarchical assembly of a transcriptionally active chromatin hub containing the ASE and RAG promoters, with Rag2 recruitment and expression dependent on assembly of a functional ASE-Rag1 framework. Finally, we show that signal-dependent down-regulation of RAG gene expression in CD4+CD8+ thymocytes depends on Ikaros and occurs with disassembly of the RAG locus chromatin hub. Our results provide important new insights into the molecular mechanisms that orchestrate RAG gene expression in developing T cells.
Spatiotemporally-controlled transgene expression in hydroxyapatite-fibrin composite scaffolds using high intensity focused ultrasound
Authors: Alexander Moncion, Jennifer N. Harmon, Yan Li, Sam Natla, Easton C. Farrell, Oliver D. Kripfgans, Jan P. Stegemann, Francisco M. Martín-Saavedra, Nuria Vilaboa, Renny T. Franceschi, Mario L. Fabiilli
Journal: Biomaterials (2018)
Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories
Authors: Clarissa Gerhauser, Francesco Favero, Thomas Risch, Ronald Simon, Lars Feuerbach, Yassen Assenov, Doreen Heckmann, Nikos Sidiropoulos, Sebastian M. Waszak, Daniel Hübschmann, Alfonso Urbanucci, Etsehiwot G. Girma, Vladimir Kuryshev, Leszek J. Klimczak, Natalie Saini, Adrian M. Stütz, Dieter Weichenhan, Lisa-Marie Böttcher, Reka Toth, Josephine D. Hendriksen, Christina Koop, Pavlo Lutsik, Sören Matzk, Hans-Jörg Warnatz, Vyacheslav Amstislavskiy, Clarissa Feuerstein, Benjamin Raeder, Olga Bogatyrova, Eva-Maria Schmitz, Claudia Hube-Magg, Martina Kluth, Hartwig Huland, Markus Graefen, Chris Lawerenz, Gervaise H. Henry, Takafumi N. Yamaguchi, Alicia Malewska, Jan Meiners, Daniela Schilling, Eva Reisinger, Roland Eils, Matthias Schlesner, Douglas W. Strand, Robert G. Bristow, Paul C. Boutros, Christof von Kalle, Dmitry Gordenin, Holger Sültmann, Benedikt Brors, Guido Sauter, Christoph Plass, Marie-Laure Yaspo, Jan O. Korbel, Thorsten Schlomm, Joachim Weischenfeldt
Journal: Cancer Cell (2018)
Iduronate-2-Sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1/2 Trial
Authors: Torayuki Okuyama, Yoshikatsu Eto, Norio Sakai, Kohtaro Minami, Tatsuyoshi Yamamoto, Hiroyuki Sonoda, Mariko Yamaoka, Katsuhiko Tachibana, Tohru Hirato, Yuji Sato
Journal: Molecular Therapy (2018)

Hunter syndrome (mucopolysaccharidosis II [MPS II]), a deficiency of iduronate-2-sulfatase (IDS), causes an accumulation of glycosaminoglycans, giving rise to multiple systemic and CNS symptoms. The currently available therapies, idursulfase and idursulfase beta, are ineffective against the CNS symptoms because they cannot pass the blood-brain barrier (BBB). A novel IDS fused with anti-human transferrin receptor antibody (JR-141) has been shown to penetrate the BBB and ameliorate learning deficits in model mice. This first-in-human study evaluated the pharmacokinetics, safety, and potential efficacy of JR-141 in 14 patients with MPS II. In a dose-escalation study performed in two patients, JR-141 plasma concentrations were dose dependent and peaked at 3 hr after initiation of each infusion, and no or only mild adverse reactions were exhibited. In a subsequent 4-week evaluation at two dose levels, the plasma concentration profiles were similar between the first and final administration, indicating no drug accumulation. Levels of heparan sulfate (HS) and dermatan sulfate (DS) were suppressed in both plasma and urine and HS levels were significantly decreased in cerebrospinal fluid. Two patients experienced some amelioration of neurocognitive and motor symptoms. These results suggest that the drug successfully penetrates the BBB and could have CNS efficacy.
Cardiovascular Disease in Chronic Kidney Disease
Authors: Joachim Jankowski, Jürgen Floege, Danilo Fliser, Michael Böhm, Nikolaus Marx
Journal: Circulation (2021)

Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk manifesting as coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Although the incidence and prevalence of cardiovascular events is already significantly higher in patients with early CKD stages (CKD stages 1–3) compared with the general population, patients with advanced CKD stages (CKD stages 4–5) exhibit a markedly elevated risk. Cardiovascular rather than end-stage kidney disease (CKD stage 5) is the leading cause of death in this high-risk population. CKD causes a systemic, chronic proinflammatory state contributing to vascular and myocardial remodeling processes resulting in atherosclerotic lesions, vascular calcification, and vascular senescence as well as myocardial fibrosis and calcification of cardiac valves. In this respect, CKD mimics an accelerated aging of the cardiovascular system. This overview article summarizes the current understanding and clinical consequences of cardiovascular disease in CKD.
Current Activities of the Coalition of Cancer Cooperative Groups
Authors: Monica M Bertagnolli, Susan M Blaney, Charles D Blanke, Walter J Curran, Janet Dancey, Robert S Mannel, Peter J O’Dwyer, Mitchell D Schnall, Norman Wolmark
Journal: JNCI Journal of the National Cancer Institute (2018)

The Coalition of Cancer Cooperative Groups is an organization representing the interests of patients and researchers who conduct research through the National Cancer Institute-supported National Clinical Trials Network (NCTN). The NCTN provides a crucial mechanism for executing practice-changing cancer clinical research to achieve both cancer control and development of new therapeutic agents or modality approaches. Public funding, largely through the National Cancer Institute, ensures that the work of the NCTN achieves important research that would not otherwise be accomplished in the private sector. In fall 2017, the Coalition of Cancer Cooperative Groups convened a Scientific Leadership Council to review the current state of the network with regard to research capabilities and to develop a list of research questions to be prioritized by the network. This report presents the results of this meeting, detailing a roadmap for future work by the NCTN.
NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology
Authors: Susan Schlenner, Emanuela Pasciuto, Vasiliki Lagou, Oliver Burton, Teresa Prezzemolo, Steffie Junius, Carlos P Roca, Cyril Seillet, Cynthia Louis, James Dooley, Kylie Luong, Erika Van Nieuwenhove, Ian P Wicks, Gabrielle Belz, Stéphanie Humblet-Baron, Carine Wouters, Adrian Liston
Journal: Annals of the Rheumatic Diseases (2018)

Objectives NFIL3 is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans. Methods Here, we characterised a kindred of two monozygotic twin girls with juvenile idiopathic arthritis at the genetic and immunological level, using whole exome sequencing, single cell sequencing and flow cytometry. Parallel studies were performed in a mouse model. Results The patients inherited a novel p.M170I in NFIL3 from each of the parents. The mutant form of NFIL3 demonstrated reduced stability in vitro. The potential contribution of this mutation to arthritis susceptibility was demonstrated through a preclinical model, where Nfil3-deficient mice upregulated IL-1β production, with more severe arthritis symptoms on disease induction. Single cell sequencing of patient blood quantified the transcriptional dysfunctions present across the peripheral immune system, converging on IL-1β as a pivotal cytokine. Conclusions NFIL3 mutation can sensitise for arthritis development, in mice and humans, and rewires the innate immune system for IL-1β over-production.
Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Luciano J. Costa, Edward Allen Stadtmauer, Gareth John Morgan, Gregory P. Monohan, Tibor Kovacsovics, Nicholas Burwick, Andrzej J. Jakubowiak, Mehrdad Mobasher, Kevin Freise, Jeremy A. Ross, John Carl Pesko, Wijith Munasinghe, Jaclyn Cordero, Lura Morris, Paulo Cesar Maciag, Orlando Bueno, Shaji Kumar
Journal: Journal of Clinical Oncology (2018)

8004 Background: The BCL-2 inhibitor venetoclax (VEN) has demonstrated efficacy, as monotherapy and combined with PI bortezomib, in relapsed/refractory (R/R) multiple myeloma (MM). We report preliminary data for VEN combined with second generation PI carfilzomib and dexamethasone (VENKd) in R/R MM. Methods: In this ongoing phase 2, dose escalation study (NCT02899052), pts with R/R MM received VENKd on 28-d cycles: VEN 400 mg/day + K 27 mg/m2 d1,2,8,9,15,16+ dex 40 mg d1,8,15,22 (Cohort 1), same regimen but with VEN 800 mg/day (Cohort 2), VEN 800 mg/day + K 70 mg/m2 d1,8,15 + dex 40 mg d1,8,15, 22 (Cohort 3/expansion cohort), or VEN 800 mg + K 56 mg/m2 d1,2,8,9,15,16 + dex 40 mg d1,2,8,9,15,16,22,23 (optional Cohort 4; no data available at cutoff). Treatment continued until progressive disease (PD) or unacceptable toxicity. Results: As of 01Dec2017, 26 pts were enrolled. Median age was 67.5 years (40 – 79), 68% had ISS II/III disease, and 23% had t(11;14). Pts received a median of 1 prior therapy (1 – 3); no pts had prior K exposure, 96% had received prior PI (54% refractory), 62% were IMiD refractory, and 35% double refractory. At data cut off, 23 pts were on therapy for 0.3 – 10 months and 3 pts discontinued the study for PD, physician decision, and death. 85% of pts had an AE, grade 3/4 AEs were neutropenia (15%), hypertension (12%), thrombocytopenia (8%), decreased white blood cells (8%), and nausea (4%). 7 serious AEs occurred, but no dose-limiting toxicities were reported. Maximum tolerated dose was not reached and Cohort 3 is being expanded. VEN pharmacokinetics with Kd were comparable to VEN plus bortezomib and dexamethasone. Of 17 pts evaluated after completing ≥2 cycles, 3 had complete response (CR), 2 very good partial response (VGPR), 3 partial response (PR), 3 stable disease, and 2 PD (awaiting response data for 4 pts). Median time to first response was 1 month. Of 5 evaluable pts with t(11;14) MM, 1 achieved CR, 1 VGPR, 3 PR. Conclusions: VENkd is well tolerated with promising preliminary efficacy that supports study in pts with R/R MM. Accrual continues with 34 pts enrolled to date. Updated safety and efficacy results will be available for presentation. Clinical trial information: NCT02899052.
A small molecule human PD-1/PD-L1 inhibitor promotes T cell immune activation and reduces tumor growth in a preclinical model
Authors: M. Vilalta Colomer, S. Punna, S. Li, V. Malathong, C. Lange, D. McMurtrie, J. Yang, H. Roth, J. McMahon, J.J. Campbell, L.S. Ertl, R. Ong, Y. Wang, N. Zhao, S. Yau, T. Dang, P. Zhang, T.J. Schall, R. Singh
Journal: Annals of Oncology (2018)

Background: In recent years, antibody-based therapies targeting the Programmed cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) immune checkpoint axis have gained tremendous success in cancer immunotherapy. We embarked on an effort to identify and develop small molecules capable of targeting this immune checkpoint, with an aim to provide new therapeutic options with improved anticancer immune responses, increased tumor penetration, shorter half-life to better managing immune related adverse events, and lower cost of goods. Methods: We developed a number of small molecule inhibitors based on the crystal structure of human PD-1/PD-L1 complex. Active compounds were first identified by an ELISA assay measuring inhibition of the PD-1/PD-L1 interaction, followed by functional cell-based reporter and mixed lymphocyte reaction (MLR) assays. Since these inhibitors specifically block human PD-1/PD-L1 interaction, we co-implanted A375 human melanoma cells along with human peripheral blood mononuclear cells (PBMCs) into immunodeficient NOD/SCID mice to test their efficacy in vivo. Results: We have obtained potent human PD-1/PD-L1 inhibitors with marked activities in both the cell-based reporter and MLR assays. Moreover, lead compound CCX4503 reduced tumor growth in vivo to a similar extent as the positive control anti-human PD-L1 antibody. Anti-tumor activity was completely dependent on the presence of human PBMCs. The tumor microenvironment analysis indicated that the anti-tumor activity of CCX4503 was accompanied by a significantly higher CD8+ T-Cell/CD4+ T-cell ratio. An X-ray structure of CCX4503 co-crystallized with PD-L1 provided information about the structural basis by which the compound disrupts the PD-1/PD-L1 immune checkpoint interaction. Conclusions: We have identified and advanced unique small molecule inhibitors of human PD-1/PD-L1 by rational design. Molecules resulting from these efforts, such as CCX4503, exhibited marked inhibition of the PD-1/PD-L1 interaction and signaling in vitro, and also clear anti-tumor effects in an animal model system in vivo. Legal entity responsible for the study: ChemoCentryx, Inc., Mountain View, CA. Funding: ChemoCentryx, Inc., Mountain View, CA. Disclosure: M. Vilalta Colomer, S. Li, V. Malathong, C. Lange, D. McMurtrie, J. Yang, H. Roth, J. McMahon, J.J. Campbell, L.S. Ertl, R. Ong, Y. Wang, N. Zhao, S. Yau, T. Dang, P. Zhang, T.J. Schall, R. Singh: Full-time employee of ChemoCentryx. S. Punna: Stock holder: ChemoCentryx.
Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy
Authors: Xiuxiu Jiao, Yuan Yu, Jianxia Meng, Mei He, Charles Jian Zhang, Wenqian Geng, Baoyue Ding, Zhuo Wang, Xueying Ding
Journal: Acta Pharmaceutica Sinica B (2018)

Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy (RT). However, there is no effective drug delivery system to effectively overcome the blood-brain barrier (BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles (ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed on brain capillary endothelial cells (BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2 (MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size (80-160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration (CMC) with positive surface charge, ranging from 15 to 40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
Abstract P335: Associations of Sleep Duration and Sleep Quality With Physical Performance in Older Adults --The Chicago Healthy Aging Study (CHAS)
Authors: ThanhHuyen T Vu, Kathryn J Reid, Martha L Daviglus, Daniel B Garside, Kiang Liu, Mercedes R Carnethon, Donald M Lloyd-Jones, Phyllis C Zee
Journal: Circulation (2018)

Background: Sleep duration (too short or too long) is associated with lower physical performance. However, the association of sleep duration and physical performance, taking into account the quality of sleep (e.g., sleep disturbance) in older populations, has not been thoroughly investigated. Methods: Using data from the Chicago Healthy Aging study conducted in 2007-10, we investigated a cross-sectional association of a combination of sleep duration and sleep disturbance with muscle strength (hand grip), and performance [4m gait speed and Short Physical Performance Battery (SPPB)]. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep duration [categorized as short (≤ 6 hours), normal (7-8 hours), and long (≥ 9 hours)] and sleep disturbance (defined as either cannot fall asleep within 30 minutes or waking up in the middle of the night or early morning three or more times per week). (See Table and Table Footnote for definitions of sleep duration and disturbance, and physical performance categories). Multivariable logistic regression analysis was used. Results: The study sample consists of 952 men and 350 women, ages 65-84 (mean age 71) in 2007-10; 9% were African American.12.6 % had SPPB score ≤ 8, 6.8 % had gait speed on 4 meter course &lt; 0.8 m/s, and 23.4 % had low sex-BMI specific handgrip strength. As compared to the group with normal sleep duration (7-8 hours) without sleep disturbance, adjusted odds (95% confidence interval) of low gait speed &lt;0.8 m/s in those with short sleep duration (≤ 6 hours) and sleep disturbance was much higher [2.00 (1.06-3.75)]. Similarly, the odds of low sex-BMI specific handgrip strength was about 2 times higher in those with long duration of sleep (≥ 9 hours), compared to those with normal sleep duration without sleep disturbance. No association was found for Short Physical Performance Battery (see Table). Conclusion: In older age, short sleep duration with poor quality as well as excessive sleep duration were associated with the greater likelihood of having low muscle strength and performance.
Abstract 15253: Ischemic Cerebrovascular Events Are Independent Predictors of Death in Patients With Chagas Disease: Time-Varying Covariate Analysis
Authors: Maria do Carmo P Nunes, Enrico A Colosimo, Fernanda Rodrigues Almeida, Paulo Cerqueira Santos-Junior, Maria Auxiliadora P Martins, Thiago Mendonça Nunes de Paula, Pedro Ferrari S Cunha, Rodrigo Citton Padilha Reis, Antonio Luiz Ribeiro, Manoel Otávio C Rocha
Journal: Circulation (2017)

Introduction: Chagas disease is an important cause of stroke in Latin America that results in major long-term disability. Ischemic cerebrovascular events (ICE) can occur at any stage of the disease...
Drak/STK17A Drives Neoplastic Glial Proliferation through Modulation of MRLC Signaling
Authors: Alexander S. Chen, Joanna Wardwell-Ozgo, Nilang N. Shah, Deidre Wright, Christina L. Appin, Krishanthan Vigneswaran, Daniel J. Brat, Harley I. Kornblum, Renee D. Read
Journal: Cancer Research (2018)

Glioblastoma (GBM) and lower grade gliomas (LGG) are the most common primary malignant brain tumors and are resistant to current therapies. Genomic analyses reveal that signature genetic lesions in GBM and LGG include copy gain and amplification of chromosome 7, amplification, mutation, and overexpression of receptor tyrosine kinases (RTK) such as EGFR, and activating mutations in components of the PI3K pathway. In Drosophila melanogaster, constitutive co-activation of RTK and PI3K signaling in glial progenitor cells recapitulates key features of human gliomas. Here we use this Drosophila glioma model to identify death-associated protein kinase (Drak), a cytoplasmic serine/threonine kinase orthologous to the human kinase STK17A, as a downstream effector of EGFR and PI3K signaling pathways. Drak was necessary for glial neoplasia, but not for normal glial proliferation and development, and Drak cooperated with EGFR to promote glial cell transformation. Drak phosphorylated Sqh, the Drosophila ortholog of nonmuscle myosin regulatory light chain (MRLC), which was necessary for transformation. Moreover, Anillin, which is a binding partner of phosphorylated Sqh, was upregulated in a Drak-dependent manner in mitotic cells and colocalized with phosphorylated Sqh in neoplastic cells undergoing mitosis and cytokinesis, consistent with their known roles in nonmuscle myosin-dependent cytokinesis. These functional relationships were conserved in human GBM. Our results indicate that Drak/STK17A, its substrate Sqh/MRLC, and the effector Anillin/ANLN regulate mitosis and cytokinesis in gliomas. This pathway may provide a new therapeutic target for gliomas.Significance: These findings reveal new insights into differential regulation of cell proliferation in malignant brain tumors, which will have a broader impact on research regarding mechanisms of oncogene cooperation and dependencies in cancer.See related commentary by Lathia, p. 1036.