tbuckley/cabot-search huggingface dataset:
Effect of Genetic African Ancestry on eGFR and Kidney Disease
Authors: Miriam S. Udler, Girish N. Nadkarni, Gillian Belbin, Vaneet Lotay, Christina Wyatt, Omri Gottesman, Erwin P. Bottinger, Eimear E. Kenny, Inga Peter
Journal: Journal of the American Society of Nephrology (2014)

Self-reported ancestry, genetically determined ancestry, and APOL1 polymorphisms are associated with variation in kidney function and related disease risk, but the relative importance of these factors remains unclear. We estimated the global proportion of African ancestry for 9048 individuals at Mount Sinai Medical Center in Manhattan (3189 African Americans, 1721 European Americans, and 4138 Hispanic/Latino Americans by self-report) using genome-wide genotype data. CKD-EPI eGFR and genotypes of three APOL1 coding variants were available. In admixed African Americans and Hispanic/Latino Americans, serum creatinine values increased as African ancestry increased (per 10% increase in African ancestry, creatinine values increased 1% in African Americans and 0.9% in Hispanic/Latino Americans; P≤1x10−7). eGFR was likewise significantly associated with African genetic ancestry in both populations. In contrast, APOL1 risk haplotypes were significantly associated with CKD, eGFR<45 ml/min per 1.73 m2, and ESRD, with effects increasing with worsening disease states and the contribution of genetic African ancestry decreasing in parallel. Using genetic ancestry in the eGFR equation to reclassify patients as black on the basis of ≥50% African ancestry resulted in higher eGFR for 14.7% of Hispanic/Latino Americans and lower eGFR for 4.1% of African Americans, affecting CKD staging in 4.3% and 1% of participants, respectively. Reclassified individuals had electrolyte values consistent with their newly assigned CKD stage. In summary, proportion of African ancestry was significantly associated with normal-range creatinine and eGFR, whereas APOL1 risk haplotypes drove the associations with CKD. Recalculation of eGFR on the basis of genetic ancestry affected CKD staging and warrants additional investigation.
Bilaterian Phylogeny: A Broad Sampling of 13 Nuclear Genes Provides a New Lophotrochozoa Phylogeny and Supports a Paraphyletic Basal Acoelomorpha
Authors: J. Paps, J. Baguna, M. Riutort
Journal: Molecular Biology and Evolution (2009)

During the past decade, great progress has been made in clarifying the relationships among bilaterian animals. Studies based on a limited number of markers established new hypotheses such as the existence of three superclades (Deuterostomia, Ecdysozoa, and Lophotrochozoa) but left major questions unresolved. The data sets used to the present either bear few characters for many taxa (i.e., the ribosomal genes) or present many characters but lack many phyla (such as recent phylogenomic approaches) failing to provide definitive answers for all the regions of the bilaterian tree. We performed phylogenetic analyses using a molecular matrix with a high number of characters and bilaterian phyla. This data set is built from 13 genes (8,880 bp) belonging to 90 taxa from 27 bilaterian phyla. Probabilistic analyses robustly support the three superclades, the monophyly of Chordata, a spiralian clade including Brachiozoa, the basal position of a paraphyletic Acoelomorpha, and point to an ecdysozoan affiliation for Chaetognatha. This new phylogeny not only agrees with most classical molecular results but also provides new insights into the relationships between lophotrochozoans and challenges the results obtained using high-throughput strategies, highlighting the problems associated with the current trend to increase gene number rather than taxa.
Cancer risk in immune-mediated inflammatory diseases (IMID)
Authors: Rudi Beyaert, Laurent Beaugerie, Gert Van Assche, Lieve Brochez, Jean-Christophe Renauld, Manuelle Viguier, Veronique Cocquyt, Guy Jerusalem, Jean-Pascal Machiels, Hans Prenen, Pierre Masson, Edouard Louis, Filip De Keyser
Journal: Molecular Cancer (2013)

Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86.
NXY-059 for Acute Ischemic Stroke
Authors: Kennedy R. Lees, Justin A. Zivin, Tim Ashwood, Antonio Davalos, Stephen M. Davis, Hans-Christoph Diener, James Grotta, Patrick Lyden, Ashfaq Shuaib, Hans-Göran Hårdemark, Warren W. Wasiewski
Journal: New England Journal of Medicine (2006)

NXY-059 is a free-radical-trapping agent that is neuroprotective in animal models of stroke. We tested whether it would reduce disability in humans after acute ischemic stroke.We conducted a randomized, double-blind, placebo-controlled trial involving 1722 patients with acute ischemic stroke who were randomly assigned to receive a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours after the onset of the stroke. The primary outcome was disability at 90 days, as measured according to scores on the modified Rankin scale for disability (range, 0 to 5, with 0 indicating no residual symptoms and 5 indicating bedbound, requiring constant care).Among the 1699 subjects included in the efficacy analysis, NXY-059 significantly improved the overall distribution of scores on the modified Rankin scale, as compared with placebo (P=0.038 by the Cochran-Mantel-Haenszel test). The common odds ratio for improvement across all categories of the scale was 1.20 (95 percent confidence interval, 1.01 to 1.42). Mortality and rates of serious and nonserious adverse events were each similar in the two groups. NXY-059 did not improve neurologic functioning as measured according to the National Institutes of Health Stroke Scale (NIHSS): the difference between the two groups in the change from baseline scores was 0.1 point (95 percent confidence interval, -1.4 to 1.1; P=0.86). Likewise, no improvement was observed according to the Barthel index (P=0.14). In a post hoc analysis of patients who also received alteplase, NXY-059 was associated with a lower incidence of any hemorrhagic transformation (P=0.001) and symptomatic intracranial hemorrhage (P=0.036).The administration of NXY-059 within six hours after the onset of acute ischemic stroke significantly improved the primary outcome (reduced disability at 90 days), but it did not significantly improve other outcome measures, including neurologic functioning as measured by the NIHSS score. Additional research is needed to confirm whether NXY-059 is beneficial in ischemic stroke. (ClinicalTrials.gov number, NCT00119626.).
Increase in Cholesterol Predicts Survival Advantage in Renal Cell Carcinoma Patients Treated with Temsirolimus
Authors: Chee Khoon Lee, Ian C. Marschner, R. John Simes, Merryn Voysey, Brian Egleston, Gary Hudes, Paul de Souza
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Temsirolimus is an effective treatment for renal cell carcinoma. It is associated with increases in serum cholesterol, triglyceride, and glucose. We investigated whether changes of these biomarkers could predict its efficacy. Experimental Design: We examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to IFN or temsirolimus in the Global Advanced Renal Cell Carcinoma Trial. Using time-dependent proportional hazards models, we quantified the association between changes in these biomarkers from baseline with overall survival (OS) and progression-free survival (PFS). We also assess the extent to which changes of these biomarkers predict the effects of temsirolimus on survival. Results: Temsirolimus was associated with larger mean increases in cholesterol (1.02 mmol/L; P &amp;lt; 0.0001), triglycerides (0.32 mmol/L; P = 0.0008), and glucose (1.28 mmol/L; P &amp;lt; 0.0001) compared with IFN and improved survival rate (OS: HR = 0.76, P = 0.02; PFS: HR = 0.70, P = 0.001). Cholesterol increase during study was associated with longer survival (OS: HR = 0.77 per mmol/L, P &amp;lt; 0.0001; PFS: HR = 0.81 per mmol/L; P &amp;lt; 0.0001). Temsirolimus effect on cholesterol predicted its effect on survival with no additional survival advantage observed after adjusting for cholesterol change during study (OS: HR = 1.14, P = 0.37; PFS: HR = 0.88, P = 0.35). Temsirolimus effect on triglycerides or glucose did not predict its effect on survival, with survival advantage in favor of temsirolimus still observed after adjusting for these factors (P = 0.003 and P = 0.002). Conclusion: Cholesterol increase is a potential predictor for temsirolimus efficacy. Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol. Prospectively designed biomarker studies of temsirolimus or other mTOR inhibitors are recommended. Clin Cancer Res; 18(11); 3188–96. ©2012 AACR.
mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation
Authors: Oren Levy, Weian Zhao, Luke J. Mortensen, Sarah LeBlanc, Kyle Tsang, Moyu Fu, Joseph A. Phillips, Vinay Sagar, Priya Anandakumaran, Jessica Ngai, Cheryl H. Cui, Peter Eimon, Matthew Angel, Charles P. Lin, Mehmet Fatih Yanik, Jeffrey M. Karp
Journal: Blood (2013)
Enhancing drug delivery for boron neutron capture therapy of brain tumors with focused ultrasound
Authors: R. D. Alkins, P. M. Brodersen, R. N. S. Sodhi, K. Hynynen
Journal: Neuro-Oncology (2013)

Glioblastoma is a notoriously difficult tumor to treat because of its relative sanctuary in the brain and infiltrative behavior. Therapies need to penetrate the CNS but avoid collateral tissue injury. Boron neutron capture therapy (BNCT) is a treatment whereby a (10)B-containing drug preferentially accumulates in malignant cells and causes highly localized damage when exposed to epithermal neutron irradiation. Studies have suggested that (10)B-enriched L-4-boronophenylalanine-fructose (BPA-f) complex uptake can be improved by enhancing the permeability of the cerebrovasculature with osmotic agents. We investigated the use of MRI-guided focused ultrasound, in combination with injectable microbubbles, to noninvasively and focally augment the uptake of BPA-f.With the use of a 9L gliosarcoma tumor model in Fisher 344 rats, the blood-brain and blood-tumor barriers were disrupted with pulsed ultrasound using a 558 kHz transducer and Definity microbubbles, and BPA-f (250 mg/kg) was delivered intravenously over 2 h. (10)B concentrations were estimated with imaging mass spectrometry and inductively coupled plasma atomic emission spectroscopy.The tumor to brain ratio of (10)B was 6.7 ± 0.5 with focused ultrasound and only 4.1 ± 0.4 in the control group (P < .01), corresponding to a mean tumor [(10)B] of 123 ± 25 ppm and 85 ± 29 ppm, respectively. (10)B uptake in infiltrating clusters treated with ultrasound was 0.86 ± 0.10 times the main tumor concentration, compared with only 0.29 ± 0.08 in controls.Ultrasound increases the accumulation of (10)B in the main tumor and infiltrating cells. These findings, in combination with the expanding clinical use of focused ultrasound, may offer improvements in BNCT and the treatment of glioblastoma.
Fitness testing of tennis players: How valuable is it?
Authors: Jaime Fernandez-Fernandez, Alexander Ulbricht, Alexander Ferrauti
Journal: British Journal of Sports Medicine (2014)

In tennis, sport-specific technical skills are predominant factors, although a complex profile of physical performance factors is also required. The fitness test batteries assist in examining tennis players’ capabilities for performance at different levels in the laboratory as well as in the field, in the junior or elite level. While laboratory tests can be, and are, used to evaluate basic performance characteristics of athletes in most individual sports, in a more specific approach, field-based methods are better suited to the demands of complex intermittent sports like tennis. A regular test battery performed at different periods of the year allows to obtain an individual's performance profile, as well as the ability to prescribe individual training interventions. Thus, the aim of the present review was to describe and evaluate the different physical tests recommended and used by practitioners, sports scientists and institutions (national tennis federations).
Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors
Authors: Suzane Kioko Ono-Nita, Naoya Kato, Yasushi Shiratori, Keng-Hsin Lan, Hideo Yoshida, Flair José Carrilho, Masao Omata
Journal: Journal of Clinical Investigation (1999)

The emergence of resistant hepatitis B virus (HBV), with mutations in the YMDD motif of the polymerase gene after treatment with lamivudine, is becoming an important clinical problem. In this study, susceptibility of wild-type and lamivudine-resistant HBV M552I, M552V, and L528M/M552V mutants to other reverse transcriptase inhibitors was investigated by transient transfection of full-length HBV DNA into human hepatoma cells. HBV DNA replication was monitored by Southern blot hybridization, which showed the presence of a single-stranded band (representative of the HBV replicative intermediates) in the drug-free, wild-type HBV-transfected cells. This band was diminished in the samples of wild-type HBV DNA treated with either lamivudine, adefovir, or lobucavir. The band intensities from the lamivudine-resistant mutants were not decreased by treatment with lamivudine, but were decreased by the treatments with adefovir or lobucavir. In contrast, penciclovir and nevirapine did not diminish the intensity of the single-stranded band of wild-type HBV or the lamivudine-resistant mutants. These results demonstrate that lamivudine-resistant HBV is susceptible to adefovir and lobucavir. Lamivudine-resistant HBV should be treated with adefovir or lobucavir, and combination therapy with lamivudine and adefovir/lobucavir may prevent the emergence of lamivudine-resistant HBV.
Synthetic Retinoid Am80 Suppresses Smooth Muscle Phenotypic Modulation and In-Stent Neointima Formation by Inhibiting KLF5
Authors: Katsuhito Fujiu, Ichiro Manabe, Atsushi Ishihara, Yumiko Oishi, Hiroshi Iwata, Go Nishimura, Takayuki Shindo, Koji Maemura, Hiroyuki Kagechika, Koichi Shudo, Ryozo Nagai
Journal: Circulation Research (2005)

Modulation of smooth muscle cell (SMC) phenotype plays a central role in neointima formation. We recently demonstrated that Am80, a synthetic retinoic acid receptor alpha-specific agonist, inhibits the activity of the transcription factor KLF5, which is essential for neointima formation after vascular injury. In the present study, we aimed to further analyze the mechanism by which Am80 inhibits KLF5 and the effects of inhibiting KLF5 on SMCs and vascular lesion formation, as well as to evaluate potential of Am80 for use in the prevention of in-stent neointima formation. We found that Am80 inhibited both the expression and transcriptional function of KLF5. Of particular interest was our finding that KLF5 forms a transcriptionally active complex with unliganded RAR/RXR heterodimer on the PDGF-A promoter; Am80 disrupts this complex, thereby inhibiting KLF5-dependent transcriptional activation. Knocking down KLF5 using small interfering RNA suppressed serum-induced downregulation of SMC differentiation marker gene expression in cultured SMCs, and haploinsufficiency of KLF5 in mice attenuated phenotypic modulation of SMCs after vascular injury, indicating that KLF5 plays a key role in the control of SMC phenotype. Am80 augmented expression of the SMC differentiation marker genes in culture and within the vessel walls, and oral administration of Am80 significantly inhibited in-stent neointima formation in a rabbit stent-placement model. Taken together, these results demonstrate that KLF5 plays an important role in the control of SMC phenotype after vascular injury and suggest the feasibility of using Am80, delivered systemically and/or with a drug eluting stent, to prevent in-stent neointima formation.
Novel agents for anti-platelet therapy
Authors: Xuebin Ji, Ming Hou
Journal: Journal of Hematology & Oncology (2011)

Anti-platelet therapy plays an important role in the treatment of patients with thrombotic diseases. The most commonly used anti-platelet drugs, namely, aspirin, ticlopidine, and clopidogrel, are effective in the prevention and treatment of cardio-cerebrovascular diseases. Glycoprotein IIb/IIIa antagonists (e.g., abciximab, eptifibatide and tirofiban) have demonstrated good clinical benefits and safety profiles in decreasing ischemic events in acute coronary syndrome. However, adverse events related to thrombosis or bleeding have been reported in cases of therapy with glycoprotein IIb/IIIa antagonists. Cilostazol is an anti-platelet agent used in the treatment of patients with peripheral ischemia, such as intermittent claudication. Presently, platelet adenosine diphosphate P2Y(12) receptor antagonists (e.g., clopidogrel, prasugrel, cangrelor, and ticagrelor) are being used in clinical settings for their pronounced protective effects. The new protease-activated receptor antagonists, vorapaxar and atopaxar, potentially decrease the risk of ischemic events without significantly increasing the rate of bleeding. Some other new anti-platelet drugs undergoing clinical trials have also been introduced. Indeed, the number of new anti-platelet drugs is increasing. Consequently, the efficacy of these anti-platelet agents in actual patients warrants scrutiny, especially in terms of the hemorrhagic risks. Hopefully, new selective platelet inhibitors with high anti-thrombotic efficiencies and low hemorrhagic side effects can be developed.
Postoperative Nomogram Predicting Risk of Recurrence After Radical Cystectomy for Bladder Cancer
Authors: Bernard H Bochner, Michael W Kattan, Kinjal C Vora
Journal: Journal of Clinical Oncology (2006)

Radical cystectomy and pelvic lymphadenectomy (PLND) remains the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy.Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9,000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability.The final nomogram included information on patient age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P < .001) or standard pathologic subgroupings (concordance index, 0.62; P < .001).We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.
Email consultations in health care: 1—scope and effectiveness
Authors: Josip Car, Aziz Sheikh
Journal: BMJ (2004)

<h3>Abstract</h3> Bacterial decomposition of organic matter in soils is generally believed to be mainly controlled by the accessibility of bacteria to their substrate. The influence of bacterial metabolic traits on this control has however received little attention in highly heterogeneous spatial conditions under advective-dispersive transport of bacteria and substrates. Here, we develop a biochemical transport model to screen the interactive impacts of dispersion and metabolic traits on mineralization. We compare the model results with two sets of previously performed cm-scale soil-core experiments in which the mineralization of the pesticide 2,4-D was measured under well-controlled initial distributions and transport conditions. Bacterial dispersion away from the source of substrate induced a significant increase in 2,4-D mineralization, revealing the existence of a control of decomposition by the bacterial density, in addition to the accessibility to the substrate. This regulation of degradation by density becomes dominant for bacteria with an efficient uptake of substrate at low substrate concentrations (i.e. oligotrophs). The model output suggests that the distance between bacteria adapted to oligotrophic environments is a stronger regulator of degradation than the distance between substrate source and these bacteria. Such oligotrophs, commonly found in soils, compete with each other for substrate even under remarkably low population densities. The ratio-dependent Contois growth model, which includes a density regulation in the expression of the uptake efficiency, appears more versatile and accurate than the substrate-dependent Monod model. In view of their strong interactions, biochemical and transport processes cannot be handled independently but should be integrated, in particular when biochemical processes of interest are carried out by oligotrophs. <h3>Highlights</h3> –Biodegradation in soils results from strong biochemical and transport couplings –Biodegradation depends on bacterial density, in addition to substrate accessibility –Bacterial density regulation counterbalances substrate accessibility regulation –Density regulation is enhanced for oligotrophic bacteria –The ratio-dependent Contois model is relevant to represent this double regulation