tbuckley/cabot-search huggingface dataset:
Podocyte COX-2 Exacerbates Diabetic Nephropathy by Increasing Podocyte (Pro)renin Receptor Expression
Authors: Huifang Cheng, Xiaofeng Fan, Gilbert W. Moeckel, Raymond C. Harris
Journal: Journal of the American Society of Nephrology (2011)

Diabetic nephropathy (DN) increases podocyte cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition reduces proteinuria and glomerular injury in animal models of diabetes. To investigate the role of podocyte COX-2 in development of diabetic nephropathy, we employed a streptozotocin model of diabetic mellitus in wild-type and transgenic mice expressing COX-2 selectively in podocytes. Progressive albuminuria developed only in diabetic COX-2 transgenic mice despite hyperglycemia, BP, and GFR being similar to those in wild-type mice. Transgenic mice also manifested significant foot-process effacement, moderate mesangial expansion, and segmental thickening of the glomerular basement membrane. In cultured podocytes overexpressing COX-2, high glucose induced cell injury and increased both expression of the pro(renin) receptor and activation of the renin-angiotensin system. Downregulation of the (pro)renin receptor attenuated the injury induced by high glucose. In vivo, podocyte pro(renin) receptor expression increased in diabetic COX-2-transgenic mice, and treatment with a COX-2 inhibitor abrogated the upregulation of (pro)renin receptor and reduced albuminuria, foot-process effacement, and mesangial matrix expansion. In summary, these results demonstrate that increased expression of podocyte COX-2 predisposes to diabetic glomerular injury and that the (pro)renin receptor may be one mediator for this increased susceptibility to injury.
Dual-Targeted Proteins Tend to be More Evolutionarily Conserved
Authors: Irit Kisslov, Adi Naamati, Nitzan Shakarchy, Ophry Pines
Journal: Molecular Biology and Evolution (2014)

In eukaryotic cells, identical proteins can be located in more than a single subcellular compartment, a phenomenon termed dual targeting. We hypothesized that dual-targeted proteins should be more evolutionary conserved than exclusive mitochondrial proteins, due to separate selective pressures administered by the different compartments to maintain the functions associated with the protein sequences. We employed codon usage bias, propensity for gene loss, phylogenetic relationships, conservation analysis at the DNA level, and gene expression, to test our hypothesis. Our findings indicate that, indeed, dual-targeted proteins are significantly more conserved than their exclusively targeted counterparts. We then used this trait of gene conservation, together with previously identified traits of dual-targeted proteins (such as protein net charge and mitochondrial targeting sequence strength) to 1) create, for the first time (due to addition of conservation parameters), a tool for the prediction of dual-targeted mitochondrial proteins based on protein and mRNA sequences, and 2) show that molecular mechanisms involving one versus two translation products are not correlated with specific dual-targeting parameters. Finally, we discuss what evolutionary pressure maintains protein dual targeting in eukaryotes and deduce, as we initially hypothesized, that it is the discrete functions of these proteins in the different subcellular compartments, regardless of their dual-targeting mechanism.
HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A
Authors: Eva Juengel, Snigdha Nowaz, Jasmina Makarevi, Iyad Natsheh, Isabella Werner, Karen Nelson, Michael Reiter, Igor Tsaur, Jens Mani, Sebastian Harder, Georg Bartsch, Axel Haferkamp, Roman A Blaheta
Journal: Molecular Cancer (2014)

Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development. Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins. Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A. It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
Influence of Gynecologic Oncologists on the Survival of Patients With Endometrial Cancer
Authors: John K. Chan, Alexander E. Sherman, Daniel S. Kapp, Ruxi Zhang, Kathryn E. Osann, Larry Maxwell, Lee-May Chen, Harshal Deshmukh
Journal: Journal of Clinical Oncology (2011)

Purpose Despite a lack of evidence for survival benefit, the American College of Obstetrics and Gynecology has recommendations for referral to gynecologic oncologists for the treatment of endometrial cancer. Therefore, we propose to determine the influence of gynecologic oncologists on the treatment and survival of patients with endometrial cancer. Patients and Methods Data were obtained from Medicare and Surveillance, Epidemiology, and End Results (SEER) databases from 1988 to 2005. Kaplan-Meier and Cox proportional hazard methods were used for analyses. Results Of 18,338 women, 21.4% received care from gynecologic oncologists (group A) while 78.6% were treated by others (group B). Women in group A were older (age &gt; 71 years: 49.6% v 44%; P &lt; .001), had more lymph nodes (&gt; 16) removed (22% v 17%; P &lt; .001), presented with more advanced (stages III to IV) cancers (21.9% v 14.6%; P &lt; .001), had higher-grade tumors (P &lt; .001), and were more likely to receive chemotherapy for advanced disease (22.6% v 12.4%; P &lt; .001). In those with stages II to IV disease, the 5-year disease-specific survival (DSS) of group A was 79% versus 73% in group B (P = .001). Moreover, in advanced-stage (III to IV) disease, group A had 5-year DSS of 72% versus 64% in group B (P &lt; .001). However, no association with DSS was identified in stage I cancers. On multivariable analysis, younger age, early stage, lower grade, and treatment by gynecologic oncologists were independent prognostic factors for improved survival. Conclusion Patients with endometrial cancer treated by gynecologic oncologists were more likely to undergo staging surgery and receive adjuvant chemotherapy for advanced disease. Care provided by gynecologic oncologists improved the survival of those with high-risk cancers.
Combination Chemotherapy of Advanced Murine Myeloma and Subsequent Resistance to Tumor Cell Challenge 2
Authors: Morris N. Teller, Matthew Bowie, Isabel M. Mountain, C. Chester Stock
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article Combination Chemotherapy of Advanced Murine Myeloma and Subsequent Resistance to Tumor Cell Challenge Get access Morris N. Teller, Morris N. Teller Search for other works by this author on: Oxford Academic PubMed Google Scholar Matthew Bowie, Matthew Bowie Search for other works by this author on: Oxford Academic PubMed Google Scholar Isabel M. Mountain, Isabel M. Mountain Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Chester Stock C. Chester Stock 3Memorial Sloan-Kettering Cancer Center, New York, N.Y. 10021. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 52, Issue 3, March 1974, Pages 667–671, https://doi.org/10.1093/jnci/52.3.667 Published: 01 March 1974 Article history Received: 23 August 1973 Accepted: 16 November 1973 Published: 01 March 1974
Mechanisms of development of multimorbidity in the elderly
Authors: Peter J. Barnes
Journal: European Respiratory Journal (2015)

In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular senescence with telomere shortening, activation of PI3K–AKT–mTOR signalling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and low grade chronic inflammation (“inflammaging”). Many of these pathways are driven by chronic oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerates the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs have already been developed that may slow the ageing process, as well as lifestyle interventions, such as diet and physical activity. This indicates that in the future new treatment approaches may target the common pathways involved in multimorbidity and this area of research should be given high priority. Thus, COPD should be considered as a component of multimorbidity and common disease pathways, particularly accelerated ageing, should be targeted.
Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle
Authors: Romain Barrès, Jie Yan, Brendan Egan, Jonas Thue Treebak, Morten Rasmussen, Tomas Fritz, Kenneth Caidahl, Anna Krook, Donal J. O'Gorman, Juleen R. Zierath
Journal: Cell Metabolism (2012)
Meta-Analysis of the Symptom Structure of Obsessive-Compulsive Disorder
Authors: Michael H. Bloch, Angeli Landeros-Weisenberger, Maria C. Rosario, Christopher Pittenger, James F. Leckman
Journal: American Journal of Psychiatry (2008)

OCD is a clinically heterogeneous condition. This heterogeneity has the potential to reduce power in genetic, neuroimaging, and clinical trials. Despite a mounting number of studies, there remains debate regarding the exact factor structure of OCD symptoms. The authors conducted a meta-analysis to determine the factor structure of the Yale-Brown Obsessive Compulsive Scale Symptom Checklist.Studies were included if they involved subjects with OCD and included an exploratory factor analysis of the 13 Yale-Brown Obsessive Compulsive Scale Symptom Checklist categories or the items therein. A varimax-rotation was conducted in SAS 9.1 using the PROC FACTOR CORR to extract factors from sample-size weighted co-occurrence matrices. Stratified meta-analysis was conducted to determine the factor structure of OCD in studies involving children and adults separately.Twenty-one studies involving 5,124 participants were included. The four factors generated were 1) symmetry: symmetry obsessions and repeating, ordering, and counting compulsions; 2) forbidden thoughts: aggression, sexual, religious, and somatic obsessions and checking compulsions, 3) cleaning: cleaning and contamination, and 4) hoarding: hoarding obsessions and compulsions. Factor analysis of studies including adults yielded an identical factor structure compared to the overall meta-analysis. Factor analysis of child-only studies differed in that checking loaded highest on the symmetry factor and somatic obsessions, on the cleaning factor.A four-factor structure explained a large proportion of the heterogeneity in the clinical symptoms of OCD. Further item-level factor analyses are needed to determine the appropriate placement of miscellaneous somatic and checking OCD symptoms.
Elevated Serum Cytokines Correlated with Altered Behavior, Serum Cortisol Rhythm, and Dampened 24-Hour Rest-Activity Patterns in Patients with Metastatic Colorectal Cancer
Authors: Tyvin Rich, Pasquale F. Innominato, Julie Boerner, M. Christine Mormont, Stefano Iacobelli, Benoit Baron, Claude Jasmin, Francis Lévi
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Incapacitating symptom burden in cancer patients contributes to poor quality of life (QOL) and can influence treatment outcomes because of poor tolerance to therapy. In this study, the role of circulating cytokines in the production symptoms in cancer patients is evaluated. Experimental Design: Eighty patients with metastatic colorectal cancer with either normal (group I, n = 40) or dampened (group II, n = 40) 24-hour rest/activity patterns measured by actigraphy were identified. Actigraphy patterns were correlated with QOL indices, serum cortisol obtained at 8:00 a.m. and 4:00 p.m. and with serum levels of transforming growth factor-α, tumor necrosis factor-α, and interleukin 6 (IL-6) obtained at 8:00 a.m. and analyzed in duplicate by ELISA. Cytokine levels and survival were also correlated. Results: Group II patients had significantly higher pre treatment levels of all three cytokines, displayed significantly poorer emotional and social functioning, had higher fatigue, more appetite loss, and poorer performance status compared with group I patients. Transforming growth factor-α (TGF-α) and IL-6 were significantly increased in the patients with WHO performance status &amp;gt;1 and in those with appetite loss. Fatigue was significantly associated with elevated TGF-α only. IL-6 was increased in those patients with extensive liver involvement and multiple organ replacement, and it was significantly correlated with dampened cortisol rhythm. In a multivariate analysis, IL-6 was correlated with poor treatment outcome. Conclusions: Significant correlations were found between serum levels of TGF-α and IL-6, circadian patterns in wrist activity and serum cortisol and tumor-related symptoms in patients with metastatic colorectal cancer. These data support the hypothesis that some cancer patient's symptoms of fatigue, poor QOL, and treatment outcome are related to tumor or host generated cytokines and could reflect cytokine effects on the circadian timing system. This interplay between cytokine signaling pathways, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and efferent pathways of the suprachiasmatic nucleus that control circadian physiology, opens the way to new rational interventions for symptom management in cancer patients.
Induction of Ouabain-resistant Mutation and Sister Chromatid Exchanges in Chinese Hamster Cells with Chemical Carcinogens Mediated by Human Pulmonary Macrophages
Authors: Ih Chang Hsu, Curtis C. Harris, Maria Yamaguchi, Benjamin F. Trump, Paul W. Schafer
Journal: Journal of Clinical Investigation (1979)

Pulmonary macrophages (PAM) metabolically activated benzo[a]pyrene [B(a)P] and its proximate carcinogenic metabolite, (+/-)trans 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (7,8-diol), to ultimate mutagens that were detected in cocultivated Chinese hamster V79 cells. Increases in the frequency of ouabainresistant (O(r)) mutations and sister chromatid exchanges were found in V79 cells only when they were cocultivated with both PAM and the chemical procarcinogens. 7,8-Diol caused higher frequencies of both O(r) mutations and sister chromatid exchanges than did the parent compound, B(a)P. When metabolically activated by PAM the mean O(r) mutation frequency caused by B(a)P was 9 O(r) mutants/10(6) surviving V79 cells per 10(6) PAM and a 10-fold interindividual variation (range, 2-21) was found. The mean O(r) mutation frequency caused by 7,8-diol was 64 and a ninefold interindividual variation (range, 14-120) was found. In the absence of PAM, the O(r) mutation frequency in V79 cells was one or less O(r) mutant per 10(6) survivors. 7,8-Benzoflavone, an inhibitor of mixed function oxidases, reduced the frequencies of O(r) mutations and of sister chromatid exchanges in V79 cells caused by 7,8-diol and B(a)P. As expected 7,8-benzoflavone did not influence the frequency of O(r) mutations caused by one of the ultimate mutagens derived from B(a)P and 7,8-diol, (+/-)7beta, 8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. These data are consistant with the hypothesis that PAM may play a role in the activation of environmental chemical procarcinogens.
A Hypermutation Phenotype and Somatic <i>MSH6</i> Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy
Authors: Chris Hunter, Raffaella Smith, Daniel P. Cahill, Philip Stephens, Claire Stevens, Jon Teague, Chris Greenman, Sarah Edkins, Graham Bignell, Helen Davies, Sarah O'Meara, Adrian Parker, Tim Avis, Syd Barthorpe, Lisa Brackenbury, Gemma Buck, Adam Butler, Jody Clements, Jennifer Cole, Ed Dicks, Simon Forbes, Matthew Gorton, Kristian Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Jonathon Hinton, Andy Jenkinson, David Jones, Vivienne Kosmidou, Ross Laman, Richard Lugg, Andrew Menzies, Janet Perry, Robert Petty, Keiran Raine, David Richardson, Rebecca Shepherd, Alexandra Small, Helen Solomon, Calli Tofts, Jennifer Varian, Sofie West, Sara Widaa, Andy Yates, Douglas F. Easton, Gregory Riggins, Jennifer E. Roy, Kymberly K. Levine, Wolf Mueller, Tracy T. Batchelor, David N. Louis, Michael R. Stratton, P. Andrew Futreal, Richard Wooster
Journal: Cancer Research (2006)

Abstract Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers. (Cancer Res 2006; 66(8): 3987-91)
Magnetic stimulation for the measurement of respiratory and skeletal muscle function
Authors: W.D-C. Man, J. Moxham, M.I. Polkey
Journal: European Respiratory Journal (2004)

Respiratory and skeletal muscle function is of interest in many areas of pulmonary and critical care medicine. The capacity of the respiratory muscle pump to respond to the load imposed by disease is the basis of an understanding of ventilatory failure. Over the last four decades, considerable progress has been made in quantifying the capacity of the respiratory muscles, in terms of strength, endurance and fatigue. With the development of magnetic stimulation, it has recently become possible to nonvolitionally assess the respiratory muscles in a clinically acceptable way. This is of particular interest in the investigation of patients receiving critical care, those with neuromuscular disease, and in children where volitional efforts are either not possible or likely to be sub-maximal. Furthermore, the adaptation of these techniques to quantify the strength of peripheral muscles, such as the quadriceps, has allowed the effects of muscle training or rehabilitation, uninfluenced by learning effect, to be assessed. This article focuses on the physiological basis of magnetic nerve stimulation, and reviews how the technique has been applied to measure muscle strength and fatigue, with particular emphasis upon the diaphragm. The translation of magnetic stimulation into a clinical tool is described, and how it may be of diagnostic, prognostic and therapeutic value in several areas of pulmonary medicine. In particular, the use of magnetic stimulation in neuromuscular disease, the intensive care setting, chronic obstructive pulmonary disease and paediatrics will be discussed.
Model for Bangalore helped disseminate information to doctors in India
Authors: C B Sridhar
Journal: BMJ (2003)

EDITOR—In their editorial last year Langer and Villar described the promotion of evidence based practice in maternal care.1 Recon Healthcare's model for Bangalore was developed to disseminate knowledge from the World Health Organization's reproductive healthcare library to doctors caring for women's health in India.

The information is stored in electronic form and updated annually and is available free of …
Anti-outer membrane of porin C and anti-I2 antibodies in indeterminate colitis
Authors: S Joossens, J-F Colombel, C Landers, D Poulain, K Geboes, X Bossuyt, S Targan, P Rutgeerts, W Reinisch
Journal: Gut (2006)

In a previous prospective study on the diagnostic value of serological markers in patients with indeterminate colitis (IC), we demonstrated that those who remained classified as IC during prospective follow up were more often negative for anti- Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) compared with patients with an eventual diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC).1 New antibodies directed against luminal bacterial components have been reported in inflammatory bowel disease. Anti-OmpC IgA (directed against outer membrane porin C of E coli ) and anti-I2 (directed against Pseudomonas fluorescens ) have both been found in approximately 50% of CD patients2–4 and are both associated with ileal disease, increasing disease duration, and more severe disease that requires small bowel surgery.5,6

We investigated if anti-OmpC and anti-I2 were additive to ASCA and pANCA in the definitive diagnosis of patients who were included in our initial cohort of …
Electrocardiographic Studies of Cardiac Orthotopic Allotransplantation: 1. The Normal Puppy
Authors: J. Cabasson, H. A. Joos
Journal: Cardiovascular Research (1969)

Nine lead electrocardiograms were recorded from 50 healthy 3–4 month old puppies under standardized conditions. Mean values and variability of basic parameters are presented. Pronounced spontaneous QRS voltage variation was noted. Oesophageal and intracavitary leads localized the sinus node. The effects of vagal stimulation and neostigmine administration are described.
HAIR GROWTH AS AN INDEX OF PROTEIN SYNTHESIS
Authors: R. T. Sims
Journal: British Journal of Dermatology (1968)

Journal Article HAIR GROWTH AS AN INDEX OF PROTEIN SYNTHESIS Get access R. T. Sims R. T. Sims Department of Anatomy University of Cambridge Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 80, Issue 5, 1 May 1968, Pages 337–339, https://doi.org/10.1111/j.1365-2133.1968.tb12308.x Published: 01 May 1968