tbuckley/cabot-search huggingface dataset:
ADA Research Funding in 2009: Where Will We Be?
Authors: R. Paul Robertson
Journal: Diabetes Care (2008)

This decade has been disheartening to diabetes scientists, not because their scientific discovery and progress has slackened, but precisely the opposite. Scientific journals are replete with new basic and clinical research findings that fire imaginations about a better world for diabetic patients in the near future. Funding the research has been the big problem. Funds that are so critical to our progress on the road to preventing and curing diabetes have been drastically constrained in the past several years by the National Institutes of Health (NIH) and the American Diabetes Association (ADA) because of budget shortfalls (wars and economic downturns are expensive). The tragic irony is all too clear. In a time of unparalleled accumulation of important new knowledge and fresh scientific insights into prevention and reversal of diabetes complications, the financial resources to take full advantage of recent leaps in knowledge have been hard to come …
Determination of Interleukin 6 (IL-6) and Secretory Immunoglobulin A (Ig As) in Human Milk (Colostrum)
Authors: D.C. Rodríguez, D.M. Larrauri, J.L. Liporaci, E. Martinez, L.J. Feo, D. Fernandez, C. Rodriguez, M.A. Velasquez
Journal: Journal of Allergy and Clinical Immunology (2006)
Giardia induces proliferation and interferon γ production by intestinal lymphocytes
Authors: E C Ebert
Journal: Gut (1999)

BACKGROUND Murine intraepithelial lymphocytes kill Giardia lambia ; responses of human intestinal lymphocytes to this parasite are unknown. AIMS To examine giardia induced proliferation, interferon γ production, migration, and cytotoxicity by lymphocytes from the human intestine and peripheral blood. METHODS Giardia were added to intraepithelial lymphocytes, lamina propria lymphocytes, and peripheral blood lymphocytes, obtained from jejunal mucosa and blood of otherwise healthy patients undergoing gastric bypass surgery for morbid obesity. Proliferation was measured by 3 H-thymidine incorporation; frequency of proliferation precursors, by limiting dilution analysis; interferon γ production, by ELISA; cytotoxicity, by 51 Cr release of radiolabelled giardia and by release of serine esterases by effector lymphocytes that mediate cytotoxicity. RESULTS The CD4+ T lymphocytes from intestine and blood proliferated in response to giardia. The stimulus by the parasite was mitogenic rather than antigenic due to the fact that the peak response was on day 3 rather than day 6, and the large number of precursors was in the range of that for mitogens. CD4+ T lymphocytes from both sites produced interferon γ in response to giardia. Lymphocytes did not migrate towards or kill the parasite. CONCLUSIONS Giardia induced the same degree of proliferation and interferon γ production by CD4+ T lymphocytes in intestine and blood, but did not trigger cytotoxicity or migration.
Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients
Authors: M. C. Genovese, F. C. Breedveld, P. Emery, S. Cohen, E. Keystone, E. L. Matteson, Y. Baptiste, A. Chai, L. Burke, W. Reiss, M. Sweetser, T. M. Shaw
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objective:</h3> To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab. <h3>Methods:</h3> RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected. <h3>Results:</h3> Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred. <h3>Conclusions:</h3> In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.
Revisiting C.G. Moertel's Land of Small Tumors
Authors: Larry K. Kvols
Journal: Journal of Clinical Oncology (2008)

Quite simply, the 1983 article by Moertel on the treatment of the carcinoid tumor and the malignant carcinoid syndrome in the first volume of Journal of Clinical Oncology is brilliant. It is full of clinical pearls that ring as true today as when the article was written. I had the privilege and the pleasure of working with Dr Moertel for 18 years at the Mayo Clinic. This editorial will review the continuing evolution of oncology research in the field and highlight how the science has changed in the “land of small tumors” over the last 25 years.
1351 PREDICTION OF RELAPSE AFTER PEGINTERFERON ALFA-2B/RIBAVIRIN THERAPY IN CHRONIC HCV GENOTYPE 1 PATIENTS IS DEPENDENT ON MINIMAL RESIDUAL VIREMIA BUT NOT ON IL28B GENOTYPE
Authors: J. Wiegand, K. Neumann, S. Böhm, V. Weich, H. Klinker, B. Möller, J. Rasenack, H. Hinrichsen, T. Gerlach, U. Spengler, P. Buggisch, C. Sarrazin, T. Berg
Journal: Journal of Hepatology (2011)
Endoplasmic Reticulum Degradation–Enhancing α‐Mannosidase–like Protein 1 Targets Misfolded HLA–B27 Dimers for Endoplasmic Reticulum–Associated Degradation
Authors: David B. Guiliano, Helen Fussell, Izabela Lenart, Edward Tsao, Darren Nesbeth, Adam J. Fletcher, Elaine C. Campbell, Nasim Yousaf, Sarah Williams, Susana Santos, Amy Cameron, Greg J. Towers, Paul Kellam, Daniel N. Hebert, Keith G. Gould, Simon J. Powis, Antony N. Antoniou
Journal: Arthritis & Rheumatology (2014)

HLA-B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This study was undertaken to define the role of the UPR-induced ER-associated degradation (ERAD) pathway in the disposal of HLA-B27 dimeric conformers. HeLa cell lines expressing only 2 copies of a carboxy-terminally Sv5-tagged HLA-B27 were generated. The ER stress-induced protein ER degradation-enhancing α-mannosidase-like protein 1 (EDEM1) was overexpressed by transfection, and dimer levels were monitored by immunoblotting. EDEM1, the UPR-associated transcription factor X-box binding protein 1 (XBP-1), the E3 ubiquitin ligase hydroxymethylglutaryl-coenzyme A reductase degradation 1 (HRD1), and the degradation-associated proteins derlin 1 and derlin 2 were inhibited using either short hairpin RNA or dominant-negative mutants. The UPR-associated ERAD of HLA-B27 was confirmed using ER stress-inducing pharamacologic agents in kinetic and pulse chase assays. We demonstrated that UPR-induced machinery can target HLA-B27 dimers and that dimer formation can be controlled by alterations to expression levels of components of the UPR-induced ERAD pathway. HLA-B27 dimers and misfolded major histocompatibility complex class I monomeric molecules bound to EDEM1 were detected, and overexpression of EDEM1 led to inhibition of HLA-B27 dimer formation. EDEM1 inhibition resulted in up-regulation of HLA-B27 dimers, while UPR-induced ERAD of dimers was prevented in the absence of EDEM1. HLA-B27 dimer formation was also enhanced in the absence of XBP-1, HRD1, and derlins 1 and 2. The present findings indicate that the UPR ERAD pathway can dispose of HLA-B27 dimers, thus presenting a potential novel therapeutic target for modulation of HLA-B27-associated inflammatory disease.
Prevention of Cardiac Hypertrophy by Atorvastatin in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy
Authors: Vinitha Senthil, Suet N. Chen, Natalie Tsybouleva, Tripti Halder, Sherif F. Nagueh, James T. Willerson, Robert Roberts, A.J. Marian
Journal: Circulation Research (2005)

Cardiac hypertrophy, a major determinant of morbidity and mortality in hypertrophic cardiomyopathy (HCM), is considered a secondary phenotype and potentially preventable. To test this hypothesis, we screened 30 5- to 6-month-old β-myosin heavy chain Q403 transgenic rabbits by echocardiography and selected 26 without cardiac hypertrophy. We randomized the transgenic rabbits to treatment with atorvastatin (2.5 mg/Kg/d), known to block hypertrophic signaling or a placebo. We included 15 nontransgenic rabbits as controls. Cardiac phenotype was analyzed serially before, 6 and 12 months after randomization. Serum total cholesterol levels were reduced by 49% with atorvastatin administration. Left-ventricular mass, wall thickness; myocyte size, myocardial levels of molecular markers of hypertrophy, lipid peroxides, and oxidized mitochondrial DNA; and the number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive myocytes were increased significantly in the placebo but not in the atorvastatin group. Myocardium catalase mRNA levels were decreased by 5-fold in the placebo but were normal in the atorvastatin group. Catalase protein level and activity were not significantly changed. Levels of membrane-bound Ras and phospho-p44/42 mitogen-activated-protein kinase (MAPK) were increased in the placebo group (≈2.5 fold) but were reduced in the atorvastatin group. Levels of GTP- and membrane-bound RhoA and Rac1, phospho-p38, and phospho-c-Jun NH2-terminal kinases were unchanged. Thus, atorvastatin prevented development of cardiac hypertrophy; determined at organ, cellular, and molecular levels, partly through reducing active Ras and p44/42 MAPK. The results indicate potential beneficial effects of atorvastatin in prevention of cardiac hypertrophy, a major determinant of morbidity in all forms of cardiovascular diseases, and beckon clinical studies in humans with HCM.
Plasma androgens in acne vulgaris
Authors: L.S. LIM, V.H.T. JAMES
Journal: British Journal of Dermatology (1974)

In a group of patients with acne, the levels of plasma 17β-hydroxysteroids (a group of naturally occurring androgens), their diurnal variation and their binding to plasma proteins were investigated. No clear abnormality of plasma 17β-hydroxysteroid levels was present in the patients and neither was any consistent pattern of change seen through the 24 h. Basal (10,00 h) levels of total plasma 17β-hydroxysteroids were found to be elevated in four out of eighteen female patients with acne. These women were clinically indistinguishable from other female patients. The mean level of free 17β-hydroxysteroids was significantly higher in the female patients with acne than in controls (P<0.01). However, in male patients neither the mean basal level of plasma 17β-hydroxysteroids nor that of the free fraction was significantly different from controls. Indirect estimation of testosterone-binding globulin concentration also showed no differences either in the range, or in the mean level between patients and controls of both sexes. It is possible that the elevated level of free 17β-hydroxysteroids found in a few female patients contributed to the pathology of their disorder.
A retrospective study of kidney transplant recipients from living unrelated donors.
Authors: R Sesso, M A Josephson, M S Anção, S A Draibe, D Sigulem
Journal: Journal of the American Society of Nephrology (1998)

Due to the shortage of cadaveric organs, kidneys from living unrelated donors (LUD) are increasingly being used for transplantation. The long-term outcome for LUD recipients is not completely known. This study was undertaken to evaluate the long-term graft survival in LUD recipients and compare it with that of cadaver donor allograft recipients. Three hundred and sixty-four LUD and 3881 cadaveric kidney recipients were evaluated using data obtained through the Brazilian Renal Transplant Registry. Transplants performed between January 1, 1987, and June 30, 1996, were eligible for analysis. Graft and patient survival were estimated by the Kaplan-Meier method. Sixty percent of the LUD were from spouses. The median duration of follow-up was 23.8 mo (0 to 117.2 mo). Patient survival rates were not significantly different for LUD and cadaveric kidney recipients (69% [95% confidence interval (CI), 61.9 to 76.1%] versus 73.2% [71 to 75.4%] at 5 yr; 69% [61.9 to 76.1%] versus 60.6% [55.1 to 66.1%] at 9.6 yr). Graft survival rates for recipients of LUD allografts were similar to those for cadaveric kidneys at 5 yr (50.1% [43.2 to 57%] versus 50.4% [48.1 to 52.8%]) and higher, although not significantly, at 9.6 yr (45.7% [37.7 to 53.7%] versus 32.7% [26.4 to 39%], respectively, P = 0.14). In a multivariate analysis using the Cox proportional hazards regression model, after adjusting for recipient age, race, history of previous transplantation, and year of transplantation, the risk of graft failure was 16% (95% CI, -3% to 31%) lower for LUD than cadaveric recipients. We conclude that LUD are an excellent alternative to cadaveric kidney donors. The long-term patient and graft survival rates for recipients of LUD allografts are at least as good as those for recipients of cadaveric kidneys.
Low frequency of H3.3 mutations and upregulated DAXX expression in MDS
Authors: Youmna Attieh, Qi-Rong Geng, Courtney D. DiNardo, Hong Zheng, Yu Jia, Zhi-Hong Fang, Irene Gañán-Gómez, Hui Yang, Yue Wei, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2013)
Cardiac protection takes off
Authors: H. M. Piper, D. Garcia-Dorado
Journal: Cardiovascular Research (2009)

Protecting the heart from ischaemia- and reperfusion-induced injury represents the greatest challenge of cardiology, since myocardial infarction is the major cause of mortality in industrialized countries. Research on cardiac protection has a long history in the discovery of new principles of protection, replete with triumphs but also broken dreams with respect to their clinical application. Treatment of acute myocardial infarction nowadays commences with a rapid opening of the occluded coronary vessel by percutaneous coronary intervention (PCI). When recanalization is achieved, ischaemia is followed by reperfusion. Even though reperfusion restores blood flow, oxygen, and nutrient supply to the cardiac muscle, it does not simply put an end to the cellular disturbance and injury elicited by the period of ischaemic malsupply of the affected myocardium; reperfusion may also aggravate damage to the myocardium beyond that occurring during the preceding period of ischaemia. Therefore, cardiac malfunction and manifest tissue damage after ischaemia–reperfusion may be due to events during ischaemia as well as additional ones during reperfusion, and different routes of protection need to be considered for the (pre)ischaemic or post-ischaemic period. The known mechanisms of protection include targets … 

*Corresponding author. Tel: +49 641 9947 241; fax: +49 641 9947 239; E-mail address : cvr{at}physiologie.med.uni-giessen.de
Phase II Study of Everolimus and Letrozole in Patients With Recurrent Endometrial Carcinoma
Authors: Brian M. Slomovitz, Yunyun Jiang, Melinda S. Yates, Pamela T. Soliman, Taren Johnston, Maureen Nowakowski, Charles Levenback, Qian Zhang, Kari Ring, Mark F. Munsell, David M. Gershenson, Karen H. Lu, Robert L. Coleman
Journal: Journal of Clinical Oncology (2015)

Purpose The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC. Patients and Methods Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response. Results Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. Conclusion Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way.
Differences in bronchodilating potency of salbutamol in Turbuhaler as compared with a pressurized metered-dose inhaler formulation in patients with reversible airway obstruction
Authors: CG Lofdahl, L Andersson, E Bondesson, LG Carlsson, K Friberg, J Hedner, Y Hornblad, P Jemsby, A Kallen, A Ullman, S Werner, N Svedmyr
Journal: European Respiratory Journal (1997)

Two studies are presented, with the aim of establishing the dose potency ratio for salbutamol given via Turbuhaler and via a pressurized metered-dose inhaler (pMDI). Both studies were of a double-blind, randomized design. Outpatients with mild-to-moderate chronic reversible airway obstruction were given single doses of salbutamol administered via Turbuhaler and via pMDI. Efficacy and safety variables were measured before and during 6 h after each dose. The first study was a four-way crossover study including 12 patients. The salbutamol doses given were: 50, 100 and 2x100 microg via Turbuhaler and 2x100 microg via pMDI (Ventolin). The study showed that 2x100 microg of salbutamol inhaled via Turbuhaler is more potent than 2x100 microg salbutamol inhaled via a pMDI, and that 100 microg salbutamol via Turbuhaler is at least as potent as 2x100 microg salbutamol inhaled via a pMDI. The second study including 50 patients was a placebo-controlled five-way crossover, study. Two doses of salbutamol via Turbuhaler, 50 and 2x100 microg, and via pMDI, 100 and 2x200 microg, were given. There was a dose-dependent response in forced expiratory volume in one second (FEV1) for both inhalers. Adjusted for differences in baseline FEV1 values, the estimated relative dose potency for Turbuhaler versus pMDI was 1.98:1 (95% confidence interval 12-3.2). These studies showed that the same bronchodilating effect can be achieved when half the dose of salbutamol given via a conventional pressurized metered-dose inhaler is given via Turbuhaler.
Renal Structural and Functional Repair in a Mouse Model of Reversal of Ureteral Obstruction
Authors: Anita L. Cochrane, Michelle M. Kett, Chrishan S. Samuel, Naomi V. Campanale, Warwick P. Anderson, David A. Hume, Melissa H. Little, John F. Bertram, Sharon D. Ricardo
Journal: Journal of the American Society of Nephrology (2005)

The end point of immune and nonimmune renal injury typically involves glomerular and tubulointerstitial fibrosis. Although numerous studies have focused on the events that lead to renal fibrosis, less is known about the mechanisms that promote cellular repair and tissue remodeling. Described is a model of renal injury and repair after the reversal of unilateral ureteral obstruction (UUO) in male C57bl/6J mice. Male mice (20 to 25 g) underwent 10 d of UUO with or without 1, 2, 4, or 6 wk of reversal of UUO (R-UUO). UUO resulted in cortical tubular cell atrophy and tubular dilation in conjunction with an almost complete ablation of the outer medulla. This was associated with interstitial macrophage infiltration; increased hydroxyproline content; and upregulated type I, III, IV, and V collagen expression. The volume density of kidney occupied by renal tubules that exhibited a brush border was measured as an assessment of the degree of repair after R-UUO. After 6 wk of R-UUO, there was an increase in the area of kidney occupied by repaired tubules (83.7 ± 5.9%), compared with 10 d UUO kidneys (32.6 ± 7.3%). This coincided with reduced macrophage numbers, decreased hydroxyproline content, and reduced collagen accumulation and interstitial matrix expansion, compared with obstructed kidneys from UUO mice. GFR in the 6-wk R-UUO kidneys was restored to 43 to 88% of the GFR in the contralateral unobstructed kidneys. This study describes the regenerative potential of the kidney after the established interstitial matrix expansion and medullary ablation associated with UUO in the adult mouse.
T-786C Polymorphism of the Endothelial Nitric Oxide Synthase Gene Is Associated with Albuminuria in the Diabetes Heart Study
Authors: Yongmei Liu, Kathryn P Burdon, Carl D Langefeld, Stephanie R Beck, Lynne E Wagenknecht, Stephen S Rich, Donald W Bowden, Barry I Freedman
Journal: Journal of the American Society of Nephrology (2005)

Albuminuria demonstrates significant heritability in multiply affected hypertensive and diabetic families. The role of endothelial nitric oxide synthase (eNOS) gene variants as risk factors for albuminuria was investigated in 590 European American siblings from 230 families in the Diabetes Heart Study. Two polymorphisms in the eNOS gene (T-786C in the promoter region and Glu298Asp in exon 7) were genotyped. Albuminuria was defined as an albumin:creatinine ratio (ACR) >/=17 mg/g in men and >/=25 mg/g in women. Tests of association were based on generalized estimating equations, and tests of linkage disequilibrium were based on the quantitative pedigree disequilibrium test. A total of 83% of participants had type 2 diabetes. The median ACR was 10.7 mg/g (interquartile range, 5.1 to 32.8), and 34% (202 of 590) of participants had an elevated ACR. The eNOS -786C allele but not the Glu298Asp was associated with increased ACR (31% increase in absolute level of ACR for each additional copy of the -786C allele; P < 0.0001) and a higher risk for albuminuria (odds ratio, 1.55 for each additional copy of the -786C allele; P = 0.0005). Adjustment for the nongenetic determinants of ACR had no significant effect on the results; neither did stratification by gender, presence of diabetes, and the Glu298Asp genotype. Results were confirmed by quantitative pedigree disequilibrium test analysis and were consistent with haplotype analysis. The -786C eNOS variant was positively correlated with a higher prevalence and a greater degree of albuminuria in European American families in both diabetic and nondiabetic family members.