tbuckley/cabot-search huggingface dataset:
Prognosis of Cerebral Embolism
Authors: A. B. Carter
Journal: BMJ (1958)

<h3>Background and objectives</h3> Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. <h3>Design, setting, participants, &amp; measurements</h3> The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6–17 years old with initial GFR of 10–60 ml/min per 1.73 m<sup>2</sup>. The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers. <h3>Results</h3> A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; <i>n</i>=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements &gt;95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level. <h3>Conclusions</h3> The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.
Analysis and reversal of formalin cross-links from fixed tissue for the molecular analysis of cancer biopsies
Authors: Alexandra Gorgevska, Louis J. Romano
Journal: Cancer Research (2005)

4834  Clinical and molecular medicines have and continue to undergo a revolution based on the accelerated advances in biotechnology. Unfortunately, many of these methods are not compatible with standard fixation methods used to preserve biopsy tissue. Fixation involves chemically modifying tissue proteins and constituents in order to stabilize the specimen for later analyses. Fixed and archived tissues are a very important resource of DNA, RNA, and proteins for molecular biological studies such as the diagnosis and study of cancer. New methods are needed for the fixation of tumor tissues from biopsies and for using biopsies from archived tissues that are compatible with molecular analysis. Neutral buffered formalin (NBF) is currently the most widely used chemical cross-linking fixative agent for preservation of tissue specimens prior to biochemical analysis of DNA and protein interactions. Formalin (aqueous formaldehyde) is highly reactive towards free amine groups located on proteins and possibly nucleic acids leading to the formation of stable covalent cross-links that are essentially irreversible without damaging the specimen under study. These covalent cross-linked structures have yet to be fully characterized. We have studied the reactions of formalin with DNA and find that formalin is unable to form cross-links between duplex or single-stranded DNA. But we have found that NBF is able to induce covalent cross-links between duplex DNA in close association with proteins, such as a DNA polymerase bound to a primer-template, producing both a stable monomeric and dimeric protein-DNA complexes. Our results show that these cross-linked complexes are quite stable under moderate heat, across a broad range of pHs, and even when exposed to various individual chemical denaturing agents. The covalent complexes can, however, be reversed when exposed to various chemical reversal cocktails. We have also found that small amine-containing compounds such as Tris-HCl buffer, spermine, and spermidine may play a role in the formation of these cross-links between DNA and proteins. In the absence of these small amines, formation of stable covalent cross-linked products is not seen. We are currently using several methods to detect the formation of covalent DNA-protein and protein-protein cross-links and to characterize the structures that form. The findings will hopefully lead to improved methods for tissue fixation and may allow the development of methods for successful reversal of formalin cross-links in archival tissues.
Type II Diabetes and Incidence of Estrogen Receptor Negative Breast Cancer in African American Women
Authors: Julie R. Palmer, Nelsy Castro-Webb, Kimberly Bertrand, Traci N. Bethea, Gerald V. Denis
Journal: Cancer Research (2017)

Abstract White women with type II diabetes (T2D) have an estimated 20% increased risk of developing breast cancer. Little is known about associations by breast cancer subtype or among African American (AA) women, who are disproportionately affected by T2D and estrogen receptor negative (ER−) breast cancer. We assessed the relation of T2D to incidence of ER− and ER+ breast cancer in data from the Black Women's Health Study, a prospective cohort of AA women enrolled in 1995 and followed biennially. During 847,934 person-years of follow-up, there were 1,851 incident invasive breast cancers, including 914 ER+ and 468 ER− cases. Multivariable Cox proportional hazards models were used to compute HRs for breast cancer incidence associated with T2D relative to no T2D, controlling for body mass index (BMI) and other potential confounders. The HR for T2D relative to no T2D was 1.18 [95% confidence interval (CI) 1.00–1.40] for overall breast cancer incidence, with the increase accounted for by ER− cancer: HRs were 1.02 (95% CI, 0.80–1.31) for ER+ and 1.43 (95% CI, 1.03–2.00) for ER− cancer. The HR for T2D and ER− breast cancer was highest among nonobese women (1.92; 95% CI, 1.22–3.04). The findings suggest that AA women with T2D are at increased risk of developing ER− breast cancer and that poor metabolic health may be more important than obesity for this subtype. Given the high prevalence of T2D in AA women, the observed association could, in part, explain racial disparities in incidence of ER− breast cancer. Cancer Res; 77(22); 6462–9. ©2017 AACR.
Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity
Authors: Jessica J. Chiang, Konstantin M. J. Sparrer, Michiel van Gent, Charlotte Lässig, Teng Huang, Nikolaus Osterrieder, Karl-Peter Hopfner, Michaela U. Gack
Journal: Nature Immunology (2017)
The UK DCD Risk Score: A new proposal to define futility in donation-after-circulatory-death liver transplantation
Authors: Andrea Schlegel, Marit Kalisvaart, Irene Scalera, Richard W. Laing, Hynek Mergental, Darius F. Mirza, Thamara Perera, John Isaac, Philipp Dutkowski, Paolo Muiesan
Journal: Journal of Hepatology (2017)
Abstract 16035: Impairment of Endothelial Function by Inhalation of Heat-Not-Burn Tobacco Aerosol
Authors: Pooneh Nabavizadeh, Jiangtao Liu, Sharina Ibrahim, Matthew L Springer
Journal: Circulation (2017)

Introduction: “Heat-not-burn” (HNB) tobacco devices heat tobacco at temperatures that avoid combustion but cause the nicotine to aerosolize, leaving the leaf material intact but depleted of volatil...
Abstract 14424: mTORcise: Replicating Exercise Induced Remodeling of the Heart by targeted deletion of Tuberin.
Authors: Giovanni Davogustto, Rebecca Salazar, Hernan Vasquez, Patrick Guthrie, Heinrich Taegtmeyer
Journal: Circulation (2016)

Introduction:  When stressed, the heart remodels metabolically and structurally. Metabolically, the heart increases its reliance on carbohydrates for energy provision, while structurally, it hypertrophies. Whether both processes occur independently, or if they are interrelated is not known. In the heart, the activation of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway is closely tied to glucose metabolism and cellular growth, and is therefore a potential link between these two types of remodeling.   Objective:  We examined whether long-term, sustained mTORC1 activation results in metabolic and structural remodeling in the heart, with a focus on the time course of these events.   Methods:  We developed a mouse model of inducible, cardiac-specific deficiency of tuberin (TSC2), a key inhibitor of mTORC1. TSC2 gene recombination was induced between 5-7 weeks of age, and echocardiograms were performed at 4, 10 and 20 weeks after induction. Genomic DNA, total RNA and proteins were extracted from freeze-clamped hearts for PCR, real-time PCR and immunoblotting respectively. Glucose 6-phosphate (G6P) levels were measured by spectrophotometric enzymatic analysis. Histologic analysis using H/E and Masson’s Trichrome stains were used to determine cardiomyocyte area and interstitial fibrosis.   Results:  Immunoblotting of protein markers confirmed TSC2 knockout (KO) and activation of mTORC1 downstream targets as early as two weeks after induction. G6P was increased 4 weeks after induction, before any structural changes were detected. Serial echocardiograms revealed concentric remodeling 10 weeks after induction, which persisted at 20 weeks. Furthermore, the systolic function in the conditional KO animals was greater than the controls 20 weeks after induction. Cardiomyocytes hypertrophied at 20 weeks, without any evidence of increase in fibrosis.   Conclusions:  Inducible, sustained mTORC1 activation by TSC2 KO in the heart triggers physiologic remodeling, characterized by cardiomyocyte hypertrophy, concentric remodeling and improved systolic function. This phenotype is similar to the one induced by strength-training. Lastly, we show that metabolic remodeling precedes this type of structural remodeling.
Abstract 12646: Cellular Mechanisms Underlying Post-operative Atrial Fibrillation in Patients
Authors: Azinwi P Khan, Niels Voigt, Jordi Heijman, Ursula Ravens, Stanley Nattel, Dobromir Dobrev
Journal: Circulation (2016)

Background: Post-operative atrial fibrillation (poAF) after cardiac surgery is a common condition. Although usually self-limiting, poAF increases length of hospital stay and can cause debilitating strokes. A multifactorial pathophysiology involving triggered activity has been hypothesized, but the underlying cellular and molecular mechanisms are unknown and were the subject of this study. Methods: Multicellular action potentials (APs) were recorded with sharp microelectrodes in right atrial trabeculae obtained from sinus-rhythm patients during open-heart surgery and correlated with subsequent non-poAF (Ctl) or poAF status. Membrane currents (whole-cell voltage clamp) and [Ca 2+ ] i (Fluo-3) were also measured in right atrial cardiomyocytes isolated from Ctl and poAF patient samples. Protein expression was quantified by immunoblot. Results: In poAF, AP duration at 90% repolarization (APD 90 ) was slightly prolonged (Fig A), whereas AP amplitude, upstroke velocity, APD 20 , APD 50, and resting membrane potential (RMP) were unchanged. I Ca,L -triggered [Ca 2+ ] i transient (CaT) amplitude was 37% lower in poAF despite greater Ca 2+ influx via L-type Ca 2+ current (integral I Ca,L ), pointing to sarcoplasmic reticulum (SR) dysfunction (Fig B). Na + -Ca 2+ exchange (NCX) activity was similar in both groups (Fig C). SR Ca 2+ content calculated by integrating NCX current (I NCX ) during caffeine-induced SR Ca 2+ release was decreased by 50% in poAF (Fig C), likely because of smaller expression of SR Ca 2+ -ATPase-2a (SERCA2a) and decreased Ser16-phosphorylation (stronger SERCA2a inhibition) of the SERCA2a regulator phospholamban (PLB, Fig D). Expression of cardiac SR ryanodine receptor (RyR2) was reduced by 56% (Fig D), consistent with the reduced CaT amplitude. Conclusions: PoAF is associated with prolonged APD and impaired SR function. These abnormalities likely result in the Ca 2+ mishandling that predisposes patients to triggered activity underlying poAF.
Phase (Ph) I/II study of investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Updated ph II results in patients (pts) with small cell lung cancer (SCLC), non-SCLC (NSCLC), breast cancer (BrC), head and neck squamous cell carcinoma (HNSCC), and gastroesophageal cancer (GE).
Authors: Bohuslav Melichar, Antoine Adenis, Libor Havel, Albert C. Lockhart, Jaafar Bennouna, Claudia Schusterbauer, Claudio Dansky Ullmann, Bin Zhang, Ely Benaim, Elizabeth Claire Dees
Journal: Journal of Clinical Oncology (2013)

605 Background: MLN8237 is an investigational oral AAK inhibitor being evaluated in pts with hematologic (Ph III) and non-hematologic malignancies. We report here Ph II results from a, 5-arm study of single agent MLN8237 in pts with advanced, predominantly refractory, solid tumors (NCT01045421; closed for enrolment). Methods: Pts ≥18 years with relapsed/refractory disease measurable by RECIST, ECOG PS 0–1, and ≤2 prior (≤4 for BrC pts) cytotoxic chemotherapy regimens were enrolled. Pts with stable brain metastases were eligible. Pts were treated at the recommended Ph II dose; 50 mg BID for 7 d in 21-d cycles. For each cohort, a Simon’s 2-stage design was employed for Ph II, with ≥2 responses required in the first 20 response-evaluable pts to proceed to stage 2. The primary endpoint was overall response rate (ORR) by RECIST v1.1; safety and progression-free survival (PFS) were key secondary endpoints. Results: As of Dec 2012, 47 SCLC, 23 NSCLC, 49 BrC, 45 HNSCC and 47 GE pts in Ph II were response-evaluable (median age, 61 yrs [range 30–88]). NSCLC did not proceed to stage 2. ORR was 9%, 6%, and 4% in HNSCC, GE, and NSCLC pts, respectively; median PFS was 2.7, 1.5 and 3.1 months. BrC and SCLC data are shown in the Table. 92% of pts had a drug-related adverse event (DRAE). 57% of pts had Gr ≥3 DRAEs; including neutropenia (38%), anemia (10%), stomatitis (8%), and thrombocytopenia (6%). 22 pts died during the study; none were study-drug related. Conclusions: Single-agent activity of MLN8237 was evaluated across a range of solid tumors with a manageable toxicity profile. Encouraging Ph2 data in BrC and SCLC pts suggest that MLN8237 warrants further evaluation in these tumor types. Clinical trial information: NCT01045421. [Table: see text]
A Bacterial Type III Effector Targets the Master Regulator of Salicylic Acid Signaling, NPR1, to Subvert Plant Immunity
Authors: Huan Chen, Jian Chen, Min Li, Ming Chang, Kaimei Xu, Zhenhua Shang, Yi Zhao, Ian Palmer, Yuqiang Zhang, Jon McGill, James R. Alfano, Marc T. Nishimura, Fengquan Liu, Zheng Qing Fu
Journal: Cell Host & Microbe (2017)
Building machines that learn and think for themselves
Authors: Matthew Botvinick, David G. T. Barrett, Peter Battaglia, Nando de Freitas, Darshan Kumaran, Joel Z Leibo, Timothy Lillicrap, Joseph Modayil, Shakir Mohamed, Neil C. Rabinowitz, Danilo J. Rezende, Adam Santoro, Tom Schaul, Christopher Summerfield, Greg Wayne, Theophane Weber, Daan Wierstra, Shane Legg, Demis Hassabis
Journal: Behavioral and Brain Sciences (2017)

Abstract We agree with Lake and colleagues on their list of “key ingredients” for building human-like intelligence, including the idea that model-based reasoning is essential. However, we favor an approach that centers on one additional ingredient: autonomy. In particular, we aim toward agents that can both build and exploit their own internal models, with minimal human hand engineering. We believe an approach centered on autonomous learning has the greatest chance of success as we scale toward real-world complexity, tackling domains for which ready-made formal models are not available. Here, we survey several important examples of the progress that has been made toward building autonomous agents with human-like abilities, and highlight some outstanding challenges.
Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study
Authors: Ariane L Herrick, Sebastien Peytrignet, Mark Lunt, Xiaoyan Pan, Roger Hesselstrand, Luc Mouthon, Alan J Silman, Graham Dinsdale, Edith Brown, László Czirják, Jörg H W Distler, Oliver Distler, Kim Fligelstone, William J Gregory, Rachel Ochiel, Madelon C Vonk, Codrina Ancuţa, Voon H Ong, Dominique Farge, Marie Hudson, Marco Matucci-Cerinic, Alexandra Balbir-Gurman, Øyvind Midtvedt, Paresh Jobanputra, Alison C Jordan, Wendy Stevens, Pia Moinzadeh, Frances C Hall, Christian Agard, Marina E Anderson, Elisabeth Diot, Rajan Madhok, Mohammed Akil, Maya H Buch, Lorinda Chung, Nemanja S Damjanov, Harsha Gunawardena, Peter Lanyon, Yasmeen Ahmad, Kuntal Chakravarty, Søren Jacobsen, Alexander J MacGregor, Neil McHugh, Ulf Müller-Ladner, Gabriela Riemekasten, Michael Becker, Janet Roddy, Patricia E Carreira, Anne Laure Fauchais, Eric Hachulla, Jennifer Hamilton, Murat İnanç, John S McLaren, Jacob M van Laar, Sanjay Pathare, Susanna M Proudman, Anna Rudin, Joanne Sahhar, Brigitte Coppere, Christine Serratrice, Tom Sheeran, Douglas J Veale, Claire Grange, Georges-Selim Trad, Christopher P Denton
Journal: Annals of the Rheumatic Diseases (2018)

Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs).
Abstract 296: Loss of Trpc6 Function in Cardiomyocytes Improves Survival and Attenuates Progression of Cardiac Dysfunction After Mi
Authors: Polina Gross, Xiaoxiao Zhang, Tao Wang, Amir Toib, Markus Wallner, Timothy Starosta, Daohai Yu, Xiongwen Chen, Steven Houser
Journal: Circulation Research (2016)

Ischemic heart disease (IHD) commonly culminates in myocardial infarction (MI), which causes cardiac myocyte death and depressed cardiac pump function. Surviving myocytes can usually maintain pump function by increasing Ca 2+ influx and contractility. However, elevated intracellular Ca 2+ also can activate pathological hypertrophic signaling that promotes cardiac dysfunction and progression into heart failure. Ca 2+ influx through Canonical Transient Receptor Potential (TRPC) channels has been classified as a potential source of hypertrophic signaling. Specifically, TRPC6 gene expression and biological activity is significantly upregulated in cardiac myocytes after MI. Our aim was to determine if TRPC6 loss of function is cardioprotective in MI mouse model. We performed an MI study on cardiac specific dominant negative (dn) TRPC6 transgenic mice that express 3 mutated amino acids (L678A-W680A) in the pore region, which disables TRPC6 channel function. In the course of 6 weeks post MI, dnTRPC6 mice had significantly greater survival (69.2%) than wild-type (WT) mice (47.5%). Cardiac function at 2 weeks post MI was decreased to the same extent in WT and dnTRPC6 mice. Ejection fraction (EF) in WT group was 30.6% vs. 57.1% and in dnTRPC6 EF was 31% vs. 61% (MI vs. sham, respectively). The EF in dnTRPC6 mice 6 weeks post MI suggested attenuation of heart failure progression compared to WT mice (32.5% vs. 26.5%, *P=0.05). Mice in the WT group demonstrated significant elevation in end diastolic and end systolic volumes (EDV and ESV) 6 weeks post MI, while dnTRPC6 had reduced end diastolic and end systolic volumes (116μL vs. 88μL and 106μL vs. 76μL, WT vs. dnTRPC6, EDV and ESV, respectively. ***P&lt;0.0001). Hypertrophy measures of heart weight to body weight ratio and heart weight to tibia length ratio were significantly reduced in dnTRPC6 mice 6 weeks post MI as opposed to WT mice (8.4 vs. 7.3 and 13.4 vs. 11.7, respectively *P&lt;0.05). Hypertrophic markers of ANP, BNP and βMHC followed similar downregulation trend in the dnTRPC6 mice. In conclusion, loss of TRPC6 function slows the progression of cardiac dysfunction and cardiac remodeling in the post MI heart.
Local sympathetic denervation attenuates myocardial inflammation and improves cardiac function after myocardial infarction in mice
Authors: Karin A Ziegler, Andrea Ahles, Timo Wille, Julia Kerler, Deepak Ramanujam, Stefan Engelhardt
Journal: Cardiovascular Research (2017)

Abstract Aims Cardiac inflammation has been suggested to be regulated by the sympathetic nervous system (SNS). However, due to the lack of methodology to surgically eliminate the myocardial SNS in mice, neuronal control of cardiac inflammation remains ill-defined. Here, we report a procedure for local cardiac sympathetic denervation in mice and tested its effect in a mouse model of heart failure post-myocardial infarction. Methods and results Upon preparation of the carotid bifurcation, the right and the left superior cervical ganglia were localized and their pre- and postganglionic branches dissected before removal of the ganglion. Ganglionectomy led to an almost entire loss of myocardial sympathetic innervation in the left ventricular anterior wall. When applied at the time of myocardial infarction (MI), cardiac sympathetic denervation did not affect acute myocardial damage and infarct size. In contrast, cardiac sympathetic denervation significantly attenuated chronic consequences of MI, including myocardial inflammation, myocyte hypertrophy, and overall cardiac dysfunction. Conclusion These data suggest a critical role for local sympathetic control of cardiac inflammation. Our model of myocardial sympathetic denervation in mice should prove useful to further dissect the molecular mechanisms underlying cardiac neural control.
Mesenchymal stromal cells in treatment of acute‐on‐chronic liver failure
Authors: Lin Wang
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: We read with great interest the recent article by Lin et al., which sheds new light on the treatment of acute‐on‐chronic liver failure (ACLF).1 However, we would like to raise the following concerns. This article reported that the number of deaths due to severe infection and multiple organ failure in the mesenchymal stromal cell (MSC) treatment group was much lower than that in the control group. As shown in Table 1 of this article, most patients in both groups had infection at baseline. Regretfully the severity of infection was not addressed, so it is not known whether the difference in mortality was caused by an uneven distribution of severe infection. Furthermore, the pretreatment grade of ACLF in the two groups was not also evaluated, which was a determinant of the clinical outcomes of patients with ACLF.2 This point had been implicated in previous studies on the use of MSCs to treat end‐stage liver disease. A study by Peng et al. found that MSC transplantation improved liver function of patients with liver failure (including decompensated cirrhosis and ACLF),3 but a randomized study by Mohamadnejad et al. revealed that MSCs had no beneficial effect for patients with decompensated cirrhosis.4 One explanation for this discrepancy would be that the first study excluded patients with infection and other serious complications. Similarly, the efficacy of granulocyte colony‐stimulating factor for ACLF treatment was also compromised in patients with severe infection at baseline.5 In summary, it would be more convincing if the authors had evaluated the baseline severity of sepsis (such as serum lactate and Sequential Organ Failure Assessment score)7 and the pretreatment proportion of different grades of ACLF in the two groups.