tbuckley/cabot-search huggingface dataset:
P459Human fetal cardiac mesenchymal stromal cells on a novel spider silk 3D scaffold form vessel-like structures and deposit laminins
Authors: K Ljung, M Andersson, L Floderus, K Nordling, M Corbascio, J Johansson, K H Grinnemo, C Osterholm, A Rising
Journal: Cardiovascular Research (2018)

Materials and methods of research.The study included 19 patients with primary a STEMI the average age was 59 6 17 years.All patients underwent PCI with reperfusion of the infarctionrelated coronary artery.The mean recanalization time was 5 (4, 6) h.Using EchoCG, final systolic volume (CSR), terminal diastolic volume (BWW), LV ejection fraction (LVEF) was msured admission, 3rd, 7th and 21st day of STEMI.The CD133þ cells level was determined by flow cytometry of venous blood samples in the same periods.There was a control group of healthy volunteers (6 males) the average age was 41 6 9 years (absolutely healthy).Results: Carrying out an individual analysis of CD 133þ cells level circulating in patients with acute myocardial infarction, they found a multidirectional, nonlinear dynamics of their content by the 3rd day of MI.Due to this dynamics, all patients were divided into 2 subgroups: the 1st subgroup consisted of the patients with initially low level and it's further increasing on the 3rd day of MI, the 2nd subgroup -patients with a decrease level to a 3-m day of illness.Intragroup and intergroup differences were revealed on different days of the disease (p <0.05).A positive correlation was established between the relative amount of CD133þ cells in patients of the 2nd subgroup on the 7th day of MI and LVEF on the 21st day (R ¼ 0.7, p ¼ 0.02).Also, a relationship was found between the low absolute amount of CD 133þ cells in the first day of acute myocardial infarction and signs of chronic heart failure (CHF) after 6 months of the disease (p <0.05).Namely: in patients of the first subgroup, 6 months after of acute MI, minimal clinical manifestations of CHF were observed.This fact confirms that a high release of CD133þ cells into the peripheral channel is associated with a favorable course and disease prognosis. Conclusion:We showed the response of marrow to acute myocardial infarction, as release of CD133þ cells into the blood.It was found that the high mobilization of these cells both on the 1st day of MI and during the whole observation period was associated with a favorable course and disease prognosis, according to improvement of clinical and echocardiographic parameters.
Abstract 17136: MicroRNA-181b Inhibition Stabilises Abdominal Aortic Aneurysms by Promoting Collagen Accumulation and Elastin Deposition
Authors: Karina Di Gregoli, Nur Najmi Mohamad Anuar, Sarah J George, Jason L Johnson
Journal: Circulation (2015)

Increased matrix metalloproteinase (MMP) activity, and related collagen and elastin degradation as a result of macrophage accumulation, are key characteristics of abdominal aortic aneurysm (AAA) progression and rupture. Accordingly targeting MMPs or promoting expression of the endogenous tissue inhibitor of metalloproteinases (TIMPs), may represent novel therapeutic strategies to prevent AAA progression and rupture. To closely mimic human AAA, we used an angiotensin II (AngII)-infused, high fat-fed apolipoprotein E knockout mouse model. Sudden death due to aortic dissection/rupture, was significantly increased (30%, p&lt;0.001, n=20) in TIMP3 KO mice compared to wild-type controls, supporting a protective role for TIMP3 in AAA progression. Moreover Q-PCR revealed that microRNA (miR)-181b, a validated repressor of TIMP3 protein expression, was up-regulated 22-fold (n=6, p&lt;0.001) in human AAA compared to non-aneurysmal sites. In vitro, miR181b inhibition increased macrophage TIMP3 protein expression 3-fold (n=4, p&lt;0.05), highlighting miR181b inhibition as a potential approach to retard AAA progression. Indeed using a miR181b inhibitor, AAA development and inflammation was retarded in AngII-infused high fat-fed ApoE KO mice. This effect was characterised by a 56% reduction in macrophage content (n=5, p&lt;0.05), augmented collagen content 1.9-fold (n=5, p&lt;0.05) and collagen fibre thickness (+24%, p&lt;0.05) in AAAs compared to scrambled-miR control animals. AAA elastin content was also increased (1.5-fold, n=5, p&lt;0.05) in miR181b inhibitor treated mice versus controls. Collagen accumulation was TIMP-3 dependent as miR-181b inhibition did not affect collagen levels in TIMP-3 KO mice. However elastin content remained elevated in miR-181b inhibitor treated TIMP3 KO mice (2-fold, n=6, p=0.001), suggesting a TIMP-3 independent mechanism. In vitro miR181b inhibition in smooth muscle cells revealed a 2.5-fold increase in elastin production (n=3, p&lt;0.05), supporting a direct role for miR-181b in elastin regulation. Collectively our data show that miR181b inhibition stabilises AAA through a dual beneficial effect, by promoting collagen preservation via TIMP3 modulation, and through directly increasing elastin production and deposition.
Host Nitric Oxide Disrupts Microbial Cell-to-Cell Communication to Inhibit Staphylococcal Virulence
Authors: Rodolfo Urbano, Joyce E. Karlinsey, Stephen J. Libby, Paschalis-Thomas Doulias, Harry Ischiropoulos, Helen I. Warheit-Niemi, Denny H. Liggitt, Alexander R. Horswill, Ferric C. Fang
Journal: Cell Host & Microbe (2018)
Night shifts: chronotype and social jetlag
Authors: Chika E Uzoigwe, Luis Carlos Sanchez Franco
Journal: BMJ (2018)

McKenna and Wilkes’s review on optimising sleep for night shifts is insightful and useful.1 Chronotypes and social jetlag are important relevant factors.2345

Chronotype is an individual’s circadian sleeping pattern when they have no commitments influencing waking and sleeping.2 At one extreme of the chronotype spectrum are “larks,” whose circadian rhythm dictates that they go to bed early and rise early. …
Heritability of Heart Rate Variability
Authors: Jagmeet P. Singh, Martin G. Larson, Christopher J. O’Donnell, Hisako Tsuji, Jane C. Evans, Daniel Levy
Journal: Circulation (1999)

There is evolving evidence that heart rate (HR) is genetically determined. Heart rate variability (HRV) measured by power spectral analysis provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HR and HRV only partially explain their variability in the population. The purpose of this study was to assess the heritability of HR and HRV and estimate the contribution of genetic factors to their variance.Subjects who underwent ambulatory recordings at a routine examination were eligible; subjects with congestive heart failure, coronary artery disease, diabetes mellitus, and those taking cardioactive medications were excluded. We analyzed high-frequency power, low-frequency power, very low-frequency power, total power, low-frequency/high-frequency ratio, and the standard deviation of normal R-R intervals from 2-hour continuous ECG recordings. Heritability analysis was done by studying correlations between siblings (n=682, in 291 sibships, 517 pairs) and between spouse pairs (n=206 pairs) after adjusting for important covariates. Results from separate models were combined to estimate the components of variance attributable to measured covariates, additive genetic effects (heritability), and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21 to 0.26) compared with spouses (0.01 to 0.19). The measured covariates in general accounted for 13% to 40% of the total phenotypic variance, whereas genetic factors accounted for 13% to 23% of the variation among HR and HRV measures.Heritable factors may explain a substantial proportion of the variance in HR and HRV. These results highlight the contribution of genetic versus environmental factors to autonomic nervous system activity.
Systems Immunology: Learning the Rules of the Immune System
Authors: Alexandra-Chloé Villani, Siranush Sarkizova, Nir Hacohen
Journal: Annual Review of Immunology (2018)

Given the many cell types and molecular components of the human immune system, along with vast variations across individuals, how should we go about developing causal and predictive explanations of immunity? A central strategy in human studies is to leverage natural variation to find relationships among variables, including DNA variants, epigenetic states, immune phenotypes, clinical descriptors, and others. Here, we focus on how natural variation is used to find patterns, infer principles, and develop predictive models for two areas: (a) immune cell activation—how single-cell profiling boosts our ability to discover immune cell types and states—and (b) antigen presentation and recognition—how models can be generated to predict presentation of antigens on MHC molecules and their detection by T cell receptors. These are two examples of a shift in how we find the drivers and targets of immunity, especially in the human system in the context of health and disease.
Integrated infectious toxicity analysis of the BTK inhibitor ibrutinib.
Authors: James Michael Pauff, Benjamin Forrest Tillman, Mahsa Talbott, Gowri Satyanarayana, Jeremy Warner
Journal: Journal of Clinical Oncology (2016)

e19025 Background: Ibrutinib is an oral therapeutic inhibitor of Bruton’s tyrosine kinase (BTK) with efficacy in the treatment of multiple B cell malignancies. Ibrutinib also inhibits interleukin-2-inducible kinase (ITK), found in CD4+ Th2 cells, and thereby modulates T-cell signaling and effector pathways (Dubovsky JA Blood 2013). We conducted a systematic review of infectious toxicities reported with published clinical trial evaluations of ibrutinib, and note a case in our hospital of an opportunistic infection (OI), cryptococcalpneumonia, in a treated patient with normal CD4+ subsets. Methods: A review of the published literature and conference abstracts was conducted using PubMed, Google Scholar and HemOnc.org. Rates of infection and pneumonia were collated as reported to determine overall rates of CTCAE grades 1-2, 3-4, and 5 infectious toxicities. Results: Infectious complications were noted in nearly all reviewed clinical studies and trials (see Table). Most appeared to be mild, but infections were the most common grade 5 adverse event, including reports of grade 5 infection due to OI such as Pneumocystis and Histoplasma. Some infectious AEs develop with prolonged use of the drug as noted in long-term follow-up studies, independent of specific doses. Conclusions: Ibrutinib has shown tremendous efficacy in treating hematologic malignancies, but requires significant considerations as to the impacts on the humoral and cellular immune system. It is notable that trials of acalabrutinib (ACP-196), a more selective BTK inhibitor, have also reported substantial rates of infection, including one grade 5 pneumonia. Interestingly, congenital mutations of BTK are associated with a severe phenotype, X-linked hypogammaglobulinemia; OI such as C. neoformans and P. jirovecii are common despite normal CD4+ counts. Further investigation into the link between BTK inhibition and OI is warranted. CLL (%) Other (%) No. of trials included 9 6 No. of patients 785 319 CTCAE toxicities Grade 1-2 infection (any) 233 (29) 51 (16) Grade 1-2 pneumonia 26 (3.3) 8 (2.5) Grade 3-4 infection (any) 109 (14) 46 (14) Grade 3-4 pneumonia 53 (6.8) 10 (3.1) Grade 5 (any) 25 (3.2) 7 (2.2) Grade 5 infection (any) 17 (2.2) 4 (1.3) Grade 5 pneumonia 11 (1.4) 3 (0.9)
TCTAP A-012 Comparison of Short-term Outcomes of Percutaneous Coronary Intervention Between Young Male and Female Patients with Acute Coronary Syndrome
Authors: Fathima Aaysha Cader, Afzalur Rahman, Mohammad Arifur Rahman, M Maksumul Haq, Sahela Nasrin, Mohammad Golam Azam, Md Minhaj Arefin, Md Saqif Shahriar
Journal: Journal of the American College of Cardiology (2018)
Progress toward hepatitis C virus elimination through provision of care and treatment services, Georgia, 2015–2017
Authors: D. Sergeenko, A. Gamkrelidze, T. Tsertsvadze, G. Kamkamidze, D. Metreveli, L. Sharvadze, M. Tsereteli, A. Aslanikashvili, E. Adamia, L. Gvinjilia, M. Nasrullah, T. Kuchuloria, F. Averhoff
Journal: Journal of Hepatology (2018)
Use of Vitamins and Dietary Supplements by Patients With Multiple Sclerosis
Authors: Emily Evans, Laura Piccio, Anne H. Cross
Journal: JAMA Neurology (2018)

Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues.Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studies may help guide clinical recommendations.At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation.
Hydrophobic Patterning‐Based 3D Microfluidic Cell Culture Assay
Authors: Sewoon Han, Junghyun Kim, Rui Li, Alice Ma, Vincent Kwan, Kevin Luong, Lydia L. Sohn
Journal: Advanced Healthcare Materials (2018)

Abstract Engineering physiologically relevant in vitro models of human organs remains a fundamental challenge. Despite significant strides made within the field, many promising organ‐on‐a‐chip models fall short in recapitulating cellular interactions with neighboring cell types, surrounding extracellular matrix (ECM), and exposure to soluble cues due, in part, to the formation of artificial structures that obstruct &gt;50% of the surface area of the ECM. Here, a 3D cell culture platform based upon hydrophobic patterning of hydrogels that is capable of precisely generating a 3D ECM within a microfluidic channel with an interaction area &gt;95% is reported. In this study, for demonstrative purposes, type I collagen (COL1), Matrigel (MAT), COL1/MAT mixture, hyaluronic acid, and cell‐laden MAT are formed in the device. Three potential applications are demonstrated, including creating a 3D endothelium model, studying the interstitial migration of cancer cells, and analyzing stem cell differentiation in a 3D environment. The hydrophobic patterned‐based 3D cell culture device provides the ease‐of‐fabrication and flexibility necessary for broad potential applications in organ‐on‐a‐chip platforms.
P558The role of plasma membrane calcium ATPase 1 in angiogenesis
Authors: A Njegic, D Page, H Shiels, E J Cartwright
Journal: Cardiovascular Research (2018)

Background: -Angiogenesis is an essential process required to generate, refine and retune a healthy vascular network.However, in certain pathological conditions, such as after a myocardial infarction, blood vessels can be damaged and/or destroyed.Therefore stimulating angiogenesis could be therapeutically advantageous.Plasma membrane calcium ATPases (PMCA) are a family of calcium extrusion pumps which can also mediate intracellular signalling processes.PMCA1, 2 and 4 are expressed in human endothelial cells, and recently PMCA4 has been established as a mediator of angiogenesis through its role in endothelial cell migration and tubule formation.Purpose: -Previous data indicates PMCA4 negatively impacts blood vessel development through modulation of pro-angiogeneic endothelial cell characteristics, therefore we aim to investigate the role of PMCA1 in angiogenesis.Methods: -Transient knockdown of PMCA1 was achieved in HUVECs using siRNA (si-PMCA1) and confirmed with qPCR.HUVEC viability, migration, proliferation and apoptosis was assessed over a period of 6 days-post transfection using the MTT assay, wound healing 'scratch test' assay, Ki-67 immunofluorescence and Caspase-Glo 3/7 assay respectively.Live-cell imaging over a period of 24 hours was performed to further evaluate cytotoxicity, cell death and migration.Fluorescent activated cell sorting using DAPI was performed to evaluate cell cycle distribution.Furthermore, the expression of both zebrafish isoforms of PMCA1 (PMCA1a and PMCA1b) was characterised in whole zebrafish embryos and zebrafish endothelial cells.In the zebrafish, transient knockdown of PMCA1a and PMCA1b, was achieved using splice-site morpholino's.Results: -Transient knockdown of PMCA1 in HUVECs resulted in an 85% reduction in PMCA1 gene expression.Phenotypically, 3 and 6 days post-knockdown, loss of PMCA1 decreased HUVEC viability, but also reduced apoptosis.Additionally, there was no difference in the number of Ki-67 positive nuclei between si-PMCA1 HUVECs and control HUVECs, but si-PMCA1 HUVECs had a reduction in total cell number.FACs-mediated cell cycle analysis revealed si-PMCA1 HUVECs had a larger proportion of cells in S-phase and a smaller proportion of cells in G2/M-phase compared to control HUVECs after serum starvation.Furthermore, loss of PMCA1 impairs migration of HUVECs into the 'wound' 24 hours after the scratch assay was performed.In the zebrafish embryo, both zebrafish isoforms of PMCA1 are detectable in whole embryos and in endothelial cells from 3 days post-fertilisation.Conclusion: -Overall, loss of PMCA1 may be detrimental for HUVEC viability, which could be due to altered cell cycle kinetics.Furthermore, si-PMCA1 targeted HUVECs show impaired migration, although further work is required to establish the pumps direct role in vessel formation.
Michael Gelder: pioneered behavioural therapies in psychotherapy
Authors: Anne Taylor
Journal: BMJ (2018)

Michael Gelder (b 1929; q University College Hospital, London, 1953, MA, DM Oxon, FRCP, FRCPsych (Hon), FMedSci, DPM), died from prostate cancer on 30 March 2018. Eminent psychiatrist Michael Gelder was a manifestation of the oft cited quote: “It’s amazing what you can accomplish if you don’t mind who gets the credit.” He was recognised as the father of behavioural therapy for the treatment of anxiety disorders, and his groundbreaking work formed the foundation for a transformation of the modern psychotherapeutic treatment landscape.



Gelder established, and for 27 years led, a world class research and teaching department of psychiatry at the University of Oxford, attracting talented clinicians and scientists to work with him. Many of his students became leaders in the psychiatric and research communities responsible for national policy and treatment protocols. Thanks to Gelder’s research legacy it is recognised that cognitive behaviour therapy (CBT) is an effective alternative to drugs in a wide range of anxiety disorders. CBT interventions have now benefited enormous numbers of people across the globe.

With his extensive knowledge and formal persona—he always dressed in a grey suit and tie, even …
A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening
Authors: Michael L. Beshiri, Caitlin M. Tice, Crystal Tran, Holly M. Nguyen, Adam G. Sowalsky, Supreet Agarwal, Keith H. Jansson, Qi Yang, Kerry M. McGowen, JuanJuan Yin, Aian Neil Alilin, Fatima H. Karzai, William L. Dahut, Eva Corey, Kathleen Kelly
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis. Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested &amp;gt;20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin. Results: All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2−/− organoids, similar to responses observed in patients. Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC. Clin Cancer Res; 24(17); 4332–45. ©2018 AACR.
Abstract 17550: Predictors of High DFT in Single and Dual Coil Leads: Is There Still a Role for DFT Testing in Current Practice?
Authors: Jeffrey J Senfield, James Smith, Frank Cuoco, J. L Sturdivant, Robert Leman, Anil George, Geoffrey Lewis, Michael R Gold
Journal: Circulation (2015)

Background: Two recent changes in implantable cardioverter defibrillator (ICD) practice are the increased use of single coil leads and less frequent defibrillation threshold (DFT) testing at implantation. Single coil leads have higher mean DFTs which is of unclear clinical significance. Such leads were used in only a minority of subjects in SIMPLE, which showed no benefit of DFT testing. Hypothesis: Clinical characteristics can be used to predict patients at increased risk of an inadequate defibrillation safety margin with single coil leads. Methods: This analysis included 174 consecutive patients undergoing de novo left pectoral, single coil ICD implantation. A standardized modified step down testing algorithm at implantation was used to determine the delivered energy DFT. Logistic regression was used to assess predictors of DFT and of a high DFT (&gt; 25 J). Results: The patient population was 71.3 percent male and 35 percent African American (AA). The mean age was 60.8 ± 14.3 years and ejection fraction was 34.3 ± 15.6 percent. Of twelve clinical factors assessed, the univariate predictors of DFT were age (p &lt; 0.001), male sex (p &lt; 0.001) and AA race (p &lt; 0.001). After covariate adjustment, race, age and ejection fraction were found to be associated with a high DFT. The mean DFT (J) among AA was 16.1 ± 8.8 compared with 13.3 ± 6.5 for the rest of the cohort (p &lt; 0.05). Moreover, 13.1% of AAs had a high DFT compared with 1.7% for the rest of the cohort (p &lt; 0.005). Conclusions: Age, race and sex predict DFTs with single coil leads. AA are at increased risk for a high DFT and thus an inadequate defibrillation safety margin (&lt; 10 J) and should be considered for dual coil leads and/or defibrillation testing at implantation.