tbuckley/cabot-search huggingface dataset:
Sensation and Psychiatry: Linking Age-Related Hearing Loss to Late-Life Depression and Cognitive Decline
Authors: Bret R. Rutherford, Katharine Brewster, Justin S. Golub, Ana H. Kim, Steven P. Roose
Journal: American Journal of Psychiatry (2017)

Recent research has linked age-related hearing loss to impaired performance across cognitive domains and increased risk for dementia diagnosis. The data linking hearing impairment to incident late-life depression are more mixed but suggest that diminished hearing does increase risk for depression. Behavioral mechanisms may explain these associations, such as the withdrawal of older adults from situations in which they may have difficulty hearing and communicating, which may contribute to the development of social isolation, loneliness, and consequent cognitive decline and depression. At a neural level, chronic hearing loss leads to reduced activation in central auditory pathways, resulting in compensatory increased activation in the cognitive control network, dysfunctional auditory-limbic connectivity, and deafferentation-induced atrophy in frontal brain regions. These pathologic changes decrease cognitive performance and increase depression risk by reducing cognitive reserve, increasing executive dysfunction, and disrupting normative emotion reactivity and regulation. Based on the available data and informed by this model, evidence-based suggestions are proposed for clinicians treating older adults, and a research agenda is advanced to facilitate the development of rationally designed and age-appropriate psychiatric treatments for older adults with age-related hearing loss. First and foremost, treating hearing loss should be investigated as a means of improving cognitive and depressive outcomes in well-designed studies incorporating comprehensive psychiatric assessments, randomization, objective documentation of compliance, and analyses of treatment mediators that will facilitate further therapeutic development. Multimodal neuroimaging studies integrating audiometric, neuropsychological, and clinical assessments also are needed to further evaluate the model proposed. [AJP at 175: Remembering Our Past As We Envision Our Future April 1995: Effect of Hearing Enhancement on Medical Status Ratings Twenty-one elderly psychiatric patients had lower levels of psychopathology when assessed while wearing hearing aids. (Am J Psychiatry 1995; 152:629-631 )].
Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients
Authors: Marie-Nicole Theodoraki, Saigopalakrishna S. Yerneni, Thomas K. Hoffmann, William E. Gooding, Theresa L. Whiteside
Journal: Clinical Cancer Research (2017)

Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCC) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated.Experimental Design: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFI) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients' clinicopathologic data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T cells ± PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients' plasma was tested for soluble PD-L1 (sPD-L1) by ELISA.Results: Levels of PD-L1 carried by exosomes correlated with patients' disease activity, the UICC stage and the lymph node status (P = 0.0008-0.013). In contrast, plasma levels of sPD-L1 or exosome PD-1 levels did not correlate with any clinicopathologic parameters. CD69 expression levels were inhibited (P < 0.03) by coincubation with PD-L1high but not by PD-L1low exosomes. Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression.Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients.Circulating PD-L1high exosomes in HNC patients' plasma but not soluble PD-L1 levels associate with disease progression. Clin Cancer Res; 24(4); 896-905. ©2017 AACR.
GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation
Authors: Christian Hinze, Janett Ruffert, Katharina Walentin, Nina Himmerkus, Elham Nikpey, Olav Tenstad, Helge Wiig, Kerim Mutig, Zeliha Yesim Yurtdas, Janet D. Klein, Jeff M. Sands, Federica Branchi, Michael Schumann, Sebastian Bachmann, Markus Bleich, Kai M. Schmidt-Ott
Journal: Journal of the American Society of Nephrology (2017)

Collecting ducts make up the distal-most tubular segments of the kidney, extending from the cortex, where they connect to the nephron proper, into the medulla, where they release urine into the renal pelvis. During water deprivation, body water preservation is ensured by the selective transepithelial reabsorption of water into the hypertonic medullary interstitium mediated by collecting ducts. The collecting duct epithelium forms tight junctions composed of barrier-enforcing claudins and exhibits a higher transepithelial resistance than other segments of the renal tubule exhibit. However, the functional relevance of this strong collecting duct epithelial barrier is unresolved. Here, we report that collecting duct-specific deletion of an epithelial transcription factor, grainyhead-like 2 (GRHL2), in mice led to reduced expression of tight junction-associated barrier components, reduced collecting duct transepithelial resistance, and defective renal medullary accumulation of sodium and other osmolytes. In vitro, Grhl2-deficient collecting duct cells displayed increased paracellular flux of sodium, chloride, and urea. Consistent with these effects, Grhl2-deficient mice had diabetes insipidus, produced dilute urine, and failed to adequately concentrate their urine after water restriction, resulting in susceptibility to prerenal azotemia. These data indicate a direct functional link between collecting duct epithelial barrier characteristics, which appear to prevent leakage of interstitial osmolytes into urine, and body water homeostasis.
Oncolytic virotherapy using the chimeric rhabdovirus VSV-GP: Tumor-selective induction of cell death and immune-activation
Authors: G. Wollmann, L-M Schreiber, Z. Banki, C Urbiola Rodriguez, I. Koske, M. Petersson, J. Kimpel, D. von Laer
Journal: Annals of Oncology (2017)
Four weeks of ledipasvir/sofosbuvir and ribavirin with or without pegylated interferon for chronic hepatitis C in non-cirrhotic people who inject drugs. A randomized trial
Authors: Anne L.H. Øvrehus, Henrik Krarup, Inge Birkemose, Dorte K. Holm, Belinda Mössner, Anja Ernst, Peer B. Christensen
Journal: Journal of Hepatology (2017)
Abstract 16886: Metabolomic Profiling of Alcohol Consumption in 10,000 Young Adults
Authors: Peter Wurtz, Sarah Cook, Qin Wang, Antti Kangas, Pasi Soininen, Veikko Salomaa, Marjo-Riitta Jarvelin, Olli Raitakari, David Leon, Mika Ala-Korpela
Journal: Circulation (2016)

Introduction:  High alcohol consumption is a major cause of morbidity, yet moderate alcohol intake is favorably associated with cardiovascular disease and many risk factors. We aimed to characterize the associations of regular alcohol consumption with a comprehensive systemic metabolic profile.   Methods:  86 circulating lipids, fatty acids and metabolites were quantified by high-throughput NMR metabolomics. Cross-sectional associations of alcohol intake with the metabolomic biomarkers were assessed for ≈10,000 individuals from three population-based cohorts from Finland aged 24-45 years. Metabolic changes associated with change in alcohol intake during 6-year follow-up were examined for 1466 individuals.   Results:  Increased alcohol intake was associated with circulating biomarkers across multiple metabolic pathways, including increased levels of monounsaturated fatty acids and decreased levels of omega-6 fatty acids, lower concentrations of glutamine and citrate as well as higher lipid concentrations in HDL subclasses and smaller LDL particle size (P   Conclusions:  Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk and may help to explain mediation of cardiovascular risk related to alcohol intake.
Exploring genetic alterations in human colorectal cancer through the combined use of array comparative genomic hybridization (aCGH), expression microarray, and tissue microarray technologies
Authors: Sarah L. Anzick, Sylvia Wong, Sean Davis, Lori Long, Jordan Winter, M A Choti, Paul Meltzer
Journal: Cancer Research (2006)

828  Small and large-scale chromosomal aberrations, including amplifications, deletions, and rearrangements, are commonly seen in solid tumors. In human colorectal cancer (CRC), amplification of chromosome regions 20q, 8q, 13q, 7p, 12p, and loss of 18q, 8p, 17p, 4p, and 15q are frequently observed. These regions harbor oncogenes, tumor suppressors, and DNA repair genes that are known to be involved in the etiology of the disease. A combined, high-resolution gene expression and DNA copy number approach has been applied to test the hypothesis that a more comprehensive measure of the genetic damage in CRC will reveal novel molecular targets. Here, microarrays consisting of ∼35,000 spotted oligonucleotides have been utilized to examine both gene expression and DNA copy number changes in primary colorectal tumors from patients with stage II-IV disease. A colorectal cancer tissue array containing approximately 100 CRC samples has been constructed for use in validation studies. To date, 50 primary CRC samples in which the site of metastasis and other clinical information is available have been profiled. For expression studies, an unsupervised, class-discovery algorithm was utilized to search for molecular signatures that are associated with the clinical data. A subset of samples characterized by genes involved in cell communication, signal transduction, and metabolism was identified; however, no correlation with the clinical data was found for this subset of tumors. Using class comparison and hierarchical clustering, a statistically significant set of genes discriminated between primary tumors located in the proximal (cecum, ascending colon, and transverse colon) colon from those isolated from the distal (descending, sigmoid, and rectal) colon, but no gene signatures were associated patient age, disease stage, or CEA levels. The same microarray platform was utilized for array comparative genomic hybridization (aCGH) studies. Analysis of the aCGH results revealed several chromosomal changes that have not been previously reported. A combined analysis of the aCGH and expression data, followed by validation on tumor tissue arrays, is being carried out to identify candidate genes associated with colorectal cancer.
Abstract 291: The Fibrin-Specific Streptokinase SKΔ59 Is A Potent Fibrinolytic Agent in vivo
Authors: Irina Y Sazonova, Rachel A McNamee, Aiilyan K Houng, Guy L Reed
Journal: Circulation (2006)

The ability of streptokinase (SK) to activate plasminogen (Pg) in plasma at sites distant from thrombi appears to limit its therapeutic efficiency. We examined the relative potency and specificity of recombinant SKΔ59 whose activity was engineered to be restricted to the fibrin thrombus. In standard assays of the fibrinolytic activity of Pg activators (fibrin-plate and turbidometric assays) we found that SKΔ59 displayed unique properties when compared to SK and t-PA.  In vitro  doses of SKΔ59 that were equivalent to t-PA and SK in fibrin plate assays were markedly more potent than t-PA and SK in plasma clot lysis assays. At doses where SKΔ59 gave equivalent fibrinolysis to t-PA and SK, SKΔ59 showed less plasma Pg degradation than t-PA (5±5% versus 20±10%) or SK (96±2%). Thrombolysis of human clots  in vivo  was studied in a humanized mouse model of thromboembolism where Pg −/ −  mice were supplemented by physiologic levels (2 μM) of human Pg.  In vivo  dose response studies demonstrated that 0.19 mg/kg of SKΔ59 (n=4) was slightly better than 0.3 mg/kg of t-PA (n=4) (92±6% lysis versus 64±19%) and caused less degradation of Pg in plasma (8±14% versus 24±37%). SKΔ59 also showed markedly less Pg consumption than equivalent doses of SK (97±2%, n=3). We conclude that the engineering of fibrin-dependency into the SK molecule creates a Pg activator with unique properties of specificity and potency that are comparable to or better than t-PA.
WNT Signaling in Cardiac and Vascular Disease
Authors: Sébastien Foulquier, Evangelos P. Daskalopoulos, Gentian Lluri, Kevin C. M. Hermans, Arjun Deb, W. Matthijs Blankesteijn
Journal: Pharmacological Reviews (2017)

WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-<i>β</i> and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context.
Bone Tissue Engineering: Biomimetic Materials and Fabrication Approaches for Bone Tissue Engineering (Adv. Healthcare Mater. 23/2017)
Authors: Hwan D. Kim, Sivashanmugam Amirthalingam, Seunghyun L. Kim, Seunghun S. Lee, Jayakumar Rangasamy, Nathaniel S. Hwang
Journal: Advanced Healthcare Materials (2017)

Hwan D. Kim and co-workers describe bone tissue engineering strategies based on biomimetic materials. In particular, latest findings on the role of biomimetic inorganic materials for phenotypically stable bone tissue formation and osteogenic differentiation are presented in article number 1700612. Furthermore, fabricated scaffold designs and compositions that provide an osteo-friendly environment for the osteogenic commitment of stem cells are important for successful bone tissue regeneration. This Progress Report revisits various strategies to engineer three-dimensional porous structures for stem cell infiltration, vascularization, and nutrient differentiation.
Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation
Authors: Lorenzo Gallon, James M. Mathew, Sai Vineela Bontha, Catherine I. Dumur, Pranav Dalal, Lakshmi Nadimpalli, Daniel G. Maluf, Aneesha A. Shetty, Suzanne T. Ildstad, Joseph R. Leventhal, Valeria R. Mas
Journal: Journal of the American Society of Nephrology (2017)

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.
Abstract 17905: Aetiological Role of Folate Deficiency in Congenital Cardiovascular Malformation: Evidence From “Mendelian Randomisation” and Meta-Analysis
Authors: Chrysovalanto Mamasoula, Darroch Hall, Tomasz Pierscionek, Ana Topf, Julian Palomino-Doza, Thahira Rahman, Huay Tan, Jamie Bentham, Shoumo Bhattacharya, Catherine Cosgrove, David Brook, Javier Granados Riveron, Frances Bu'Lock, John O'Sullivan, Graham Stuart, Judith Goodship, Heather Cordell, Bernard Keavney
Journal: Circulation (2011)

Background: The existence of a causal relationship between lower levels of plasma folate and congenital cardiovascular malformation (CVM) remains contentious. We undertook a genetic approach using the principles of “Mendelian randomization” to determine the causality of folate in CVM risk. Methods and Findings: We compared genotype frequencies at the methylene tetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP) in 1186 CVM cases and 4168 controls. The TT genotype at MTHFR C677T is associated with lower plasma folate. Thus, if lower plasma folate had a causal effect on CVM risk, a higher frequency of TT genotype among CVM cases than among healthy controls would be anticipated. We placed our results in the context of a meta-analysis of all previously published studies of this question, which included a further 1883 cases and 3069 controls in 25 studies. We used random-effects models to meta-analyse the data. We conducted sensitivity analyses to examine folate fortification of flour as a potential source of heterogeneity. The primary genotyping data in 1186 cases and 4168 controls revealed a trend towards increased risk with the TT genotype, but this did not reach statistical significance (OR 1.15 [95% CI 0.94-1.40]). Combination of our primary data with previous studies, however, showed association in the complete dataset (OR 1.45 [95% CI 1.12-1.89]; p=0.005) comprising a total of 3069 CVM cases and 7271 controls. Studies conducted in countries without mandatory folate fortification showed an effect of C677T genotype on CVM risk (OR 1.63 [95% CI 1.19 - 2.25]) whereas studies conducted in countries with mandatory fortification did not (OR 0.96 [95% CI 0.64-1.44]). These odds ratios were significantly different from each other (p=0.032). Conclusions: We demonstrate genetic evidence in favour of a causal relationship between lower levels of plasma folate and CVM. Moreover, our results suggest that folate fortification abrogates the risk of CVM attributable to folate deficiency.
Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer
Authors: Laura P. Stabile, Mariya Farooqui, Beatriz Kanterewicz, Shira Abberbock, Brenda F. Kurland, Brenda Diergaarde, Jill M. Siegfried
Journal: Journal of Thoracic Oncology (2017)
Brote de Salmonella Enteritidis lisotipo 21 en Austria, 2005
Authors: D Schmid, S Schandl, A M Pichler, C. Kornschober, C Berghold, A Beranek, G Neubauer, M Neuhold-Wassermann, W Schwender, A Klauber, A Deutz, P Pless, F Allerberger
Journal: Eurosurveillance (2006)

El articulo siguiente describe un brote de gastroenteritis debido a Salmonella Enteritidis PT 21 asociado a la participacion, el 4 mayo de 2005, a la fiesta anual tradicional de un pueblo de Austria. El brote duro del 4 al 8 mayo. Se llevaron a cabo investigaciones epidemiologicas descriptivas y analiticas para determinar la amplitud del brote e identificar los factores de riesgo. De las 115 personas que habian participado en la fiesta, 85 respondian al criterio de caso epidemico (tasa de ataque=73,9%). Las muestras de heces de 52 pacientes, incluyendo dos empleados de las cocinas, fueron analizadas para salmonella: Salmonella Enteritidis PT 21 estaba presente en 21 muestras. El estudio de cohorte mostro que el brote fue probablemente debido al consumo de ensalada mixta con patatas cocidas (RR: 10,4, 95% CI 2,8 – 39,1; P=l0.001). El agente responsable del brote fue aislado por cultivo en los huevos utilizados para la fiesta, en tres muestras de heces, y en una muestra de polvo del gallinero del cual provenian los huevos. El subtipaje molecular por electroforesis en campo pulsado del ADN genomico tras la digestion por XbaI demostro que los aislamientos provenientes de los huevos, de los casos y del gallinero eran identicos. Nuestra hipotesis es que se produjo una contaminacion cruzada en la cocina entre los huevos y las patatas cocidas, cuando los habitantes del pueblo prepararon una salsa vienesa tradicional con huevos crudos. Es posible que la proliferacion bacteriana fuera facilitada por el hecho de las patatas peladas no estuvieran refrigeradas. Los huevos procedentes de pequenas granjas avicolas, conservados de modo “natural” tradicional no deberian ser considerados como libres de salmonelas.