tbuckley/cabot-search huggingface dataset:
Thiazolidinedione Treatment Decreases Bone Mineral Density in Type 2 Diabetic Men
Authors: Subhashini Yaturu, Barbara Bryant, Sushil K. Jain
Journal: Diabetes Care (2007)

Case-control studies of patients with fractures have found that subjects with diabetes have at least a twofold higher risk of fracture than subjects without diabetes (1), with an increased risk of hip, humerus, and foot fractures in elderly diabetic subjects (2–4). Risk factors that contribute to increased fracture in diabetic subjects include number of falls (5,6), insulin use (7,8), functional disability (9–11), diabetes duration (7,12), and poor vision (7). Recent studies report that older women and African Americans have higher incidence of osteoporotic fractures (13). In addition, lower bone strength (bone mineral density [BMD]) might be expected to increase risk for the development of osteoporosis and fracture.

Type 2 diabetic patients are widely prescribed drugs called thiazolidinediones, which increase insulin sensitivity via activation of peroxisome proliferator–activated receptor (PPAR)-γ receptors. However, it is not known whether thiazolidinedione use has any effect on bone mass and thereby increases risk of fracture in type 2 diabetic patients. In animal studies, thiazolidinedione treatment was associated with bone loss in a mouse model (14,15), which was explained by possible imbalance in bone from increased apoptotic death of osteogenic cells and diminished bone formation (15), and also in ovariectomized rats (16). Other investigators did not find bone loss in troglitazone-treated mice (17). There is limited information on the effect of …
Sensitization of Pancreatic Cancer to Chemoradiation by the Chk1 Inhibitor MK8776
Authors: Carl G. Engelke, Leslie A. Parsels, Yushen Qian, Qiang Zhang, David Karnak, Jordan R. Robertson, Daria M. Tanska, Dongping Wei, Mary A. Davis, Joshua D. Parsels, Lili Zhao, Joel K. Greenson, Theodore S. Lawrence, Jonathan Maybaum, Meredith A. Morgan
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Checkpoint kinase 1 (Chk1) inhibitor MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models. Experimental Design: We tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)–proficient and –deficient pancreatic cancer cells and assessed Rad51 focus formation. In vivo, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776. Results: We found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not -deficient (Capan-1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. In vivo, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose-limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an ex vivo platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer. Conclusions: Together, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer. Clin Cancer Res; 19(16); 4412–21. ©2013 AACR.
Remission of idiopathic nephrotic syndrome after treatment with cyclosporin A.
Authors: A Meyrier, P Simon, G Perret, M C Condamin-Meyrier
Journal: BMJ (1986)

Nephrotic syndrome in minimal change lipoid nephrosis and focal segmental glomerulosclerosis may be due to alteration of glomerular anionic sites by a lymphokine. Six adults with nephrotic syndrome who were resistant to treatment with corticosteroids and immunosuppressants were treated with cyclosporin A. In three patients with minimal change lipoid nephrosis who had been nephrotic for 3.5 to 23 years proteinuria resolved within 12 to 42 days. Subsequently, these patients became dependent on cyclosporin A. In three patients with focal segmental glomerulosclerosis who had been nephrotic for four to six years mean (SD) 24 hour urinary protein decreased from 14.7 (8.4) g to 3.6 (0.6) g within 20 to 25 days, serum albumin concentration rose, and oedema subsided. One patient died of myocardial infarction when still in partial remission after 11 weeks9 treatment. Two patients remained proteinuric despite continuing treatment with cyclosporin A, but control of sodium balance was easy and serum albumin concentrations remained higher than without cyclosporin A. In all patients renal function improved during treatment. These preliminary results show that cyclosporin A may be effective in the treatment of patients with nephrotic syndrome that resists every other form of treatment and especially in the treatment of those with minimal change lipoid nephrosis. The results are in keeping with a T lymphocyte mediated mechanism of minimal change lipoid nephrosis and focal segmental glomerulosclerosis, but they also suggest that minimal change lipoid nephrosis and focal segmental glomerulosclerosis are separate entities.
The synthetic genetic interaction spectrum of essential genes
Authors: Armaity P Davierwala, Jennifer Haynes, Zhijian Li, Renée L Brost, Mark D Robinson, Lisa Yu, Sanie Mnaimneh, Huiming Ding, Hongwei Zhu, Yiqun Chen, Xin Cheng, Grant W Brown, Charles Boone, Brenda J Andrews, Timothy R Hughes
Journal: Nature Genetics (2005)
Physical Activity/Exercise and Type 2 Diabetes
Authors: Ronald J. Sigal, Glen P. Kenny, David H. Wasserman, Carmen Castaneda-Sceppa, Russell D. White
Journal: Diabetes Care (2006)

For decades, exercise has been considered a cornerstone of diabetes management, along with diet and medication. However, high-quality evidence on the importance of exercise and fitness in diabetes was lacking until recent years. The present document summarizes the most clinically relevant recent advances related to people with type 2 diabetes and the recommendations that follow from these. Our recently published technical review on physical activity/exercise and type 2 diabetes (1) includes greater detail on individual studies, on prevention of diabetes, and on the physiology of exercise.

The present statement focuses on type 2 diabetes. Issues primarily germane to type 1 diabetes will be covered in a subsequent technical review and ADA Statement. The levels of evidence used are defined by the ADA in ref. 2.

Two randomized trials each found that lifestyle interventions including ∼150 min/week of physical activity and diet-induced weight loss of 5–7% reduced the risk of progression from impaired glucose tolerance (IGT) to type 2 diabetes by 58% (3,4). A cluster-randomized trial found that diet alone, exercise alone, and combined diet and exercise were equally effective in reducting the progression from IGT to diabetes (5). Therefore, there is firm and consistent evidence that programs of increased physical activity and modest weight loss reduce the incidence of type 2 diabetes in individuals with IGT.

Boule et al. (6) undertook a systematic review and meta-analysis on the effects of structured exercise interventions in clinical trials of ≥8 weeks duration on HbA1c (A1C) and body mass in people with type 2 diabetes. Postintervention A1C was significantly lower in exercise than control groups (7.65 vs. 8.31%, weighted mean difference −0.66%; P < 0.001). In contrast, postintervention body weight did not differ between the exercise and control groups. Meta-regression confirmed that the beneficial effect of exercise on A1C …
Effect of carvedilol on major clinical events in patients with severe heart failure and an extremely depressed ejection fraction: results of the COPERNICUS study
Authors: Hugo A. Katus, Michal Tendera, Paul Mohacsi, Jean L. Rouleau, Michael B. Fowler, Andrew J. Coats, Henry Krum, Terry L. Holcslaw, Ellen B. Roecker, Milton Packer
Journal: Journal of the American College of Cardiology (2002)
Phagocytosis by Human Leucocytes. II. Relation of Nutritional Deficiency in Man to Phagocytosis1
Authors: Henry H. Balch, Margaret T. Spencer
Journal: Journal of Clinical Investigation (1954)

It is generally believed that malnourished patients are more prone to bacterial infection than normal healthy individuals. Increased susceptibility to infection has been attributed to an impaired capacity to produce specific antibodies against the infectious agent (1) or possibly to decreased phagocytic activity resulting from nutritional deficiency (2). Quantitative data have already been presented (3) showing that emaciated patients produce antibody as well as or better than healthy control subjects so that such proneness to develop infection is probably not often related to lack of antibody production. In the present communication studies are reported on the second possibility, namely, that decreased phagocytosis in malnourished patients predisposes them to infection.
Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17 -Estradiol
Authors: R X Song, G Mor, F Naftolin, R A McPherson, J Song, Z Zhang, W Yue, J Wang, R J Santen
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: High doses of estrogen can promote tumor regression in postmenopausal women with hormone-dependent breast cancer, but the mechanism is unknown. We investigated the molecular basis of this process by using LTED cells, which were derived by growing MCF-7 breast cancer cells under long-term (6–24 months) estrogen-deprived conditions. Methods: We treated LTED and MCF-7 cells with various concentrations of 17β-estradiol (estradiol) and assayed their growth by counting the cells and measured apoptosis by annexin V staining and DNA fragmentation. Using western blot analysis, we also examined the expression of the apoptosis-inducing system of the Fas death receptor protein and its ligand, FasL, in these cells. To assess the involvement of Fas and FasL in the induction of apoptosis in LTED cells, we used activating anti-Fas antibodies and the universal caspase inhibitor Z-VAD. Finally, we examined the expression of Fas protein in E8CASS and BSK3 cells, two other cell lines derived by depriving MCF-7 cells of estrogen long term, and the responses of these cells to high-dose estradiol. All statistical tests were two-sided. Results: High concentrations of estradiol (≥0.1 nM) resulted in a statistically significant, 60% reduction in the growth of LTED cells (P<.001) and in a sevenfold increase in apoptosis (P<.001) as compared with levels in vehicle-treated cells. Both LTED and MCF-7 cells expressed FasL, but only LTED cells expressed Fas. Treatment of LTED cells with 0.1 nM estradiol increased the expression of FasL. Activating anti-Fas antibodies increased apoptosis of LTED cells, which was further stimulated by estradiol. Z-VAD blocked estradiol-induced apoptosis. E8CASS cells, which express Fas protein, but not BSK3 cells, which do not, also responded to 0.1 nM estradiol by increasing apoptosis. Conclusion: Tumor regression induced by high-dose estrogen therapy in postmenopausal woman may result from estrogen activation of Fas-mediated apoptosis.
Up-Regulation of Functional Chemokine Receptor CCR3 in Human Renal Cell Carcinoma
Authors: Karin Jöhrer, Claudia Zelle-Rieser, Alexander Perathoner, Patrizia Moser, Martina Hager, Reinhold Ramoner, Hubert Gander, Lorenz Höltl, Georg Bartsch, Richard Greil, Martin Thurnher
Journal: Clinical Cancer Research (2005)

Abstract There is increasing evidence that chemokines and chemokine receptors are causally involved in tumorigenesis by facilitating tumor proliferation and metastasis. Little is known about the possible function of chemokine receptors in the development and progression of renal cell carcinoma (RCC). We, therefore, analyzed the expression of chemokine receptors in tumor specimens and adjacent healthy kidney tissues [normal kidney cell (NKC)] from 10 RCC patients. We also characterized the permanent RCC cell line A-498. CCR6, CXCR2, and CXCR3 were consistently expressed by both malignant cells and NKCs. A-498 displayed additional expression of CXCR4. Importantly, the expression of CCR3 was almost absent on NKCs but clearly enhanced in a substantial proportion of RCC specimens. The primary CCR3 ligand, eotaxin-1/CCL11, induced intracellular Ca2+ mobilization, receptor internalization, and proliferation in A-498 cells confirming signaling competence of RCC-associated CCR3. In addition, we screened tumor tissue sections of 219 patients and found that 28% (62 of 219) expressed the CCR3 receptor. The presence of CCR3 in tumor samples seemed to correlate with the grade of malignancy. Previous work has established that eotaxin-1 expression is induced by tumor necrosis factor-α, a cytokine known to be present in RCC tissue. Our data, therefore, supports a scenario in which eotaxin-1 as part of tumor-associated inflammation promotes progression and dissemination of CCR3-positive RCC.
Vulnerability of the mildly ischemic ventricle to cathodal, anodal, and bipolar stimulation.
Authors: R Mehra, S Furman, J F Crump
Journal: Circulation Research (1977)

We studied the difference between myocardial vulnerability to arrhythmias caused by cathodal, anodal, and bipolar stimulation in 29 dogs with partial right coronary artery occlusion. We used 2-msec duration stimuli of up to 8 mA to determine the ventricular vulnerable periods, their relationship to the refractory periods, and the fibrillation or multiple response thresholds for unipolar anodal and cathodal stimulation after two premature ventricular contractions. The vulnerable period for arrhythmias began at the end of the respective refractory periods and terminated at a specific time within the cardiac cycle. Within this period the arrhythmia and excitation thresholds were equal. Because shorter refractory periods were obtained with anodal stimulation than cathodal, the vulnerable periods for anodal stimulation were longer. This indicated that the vulnerable periods for bipolar stimulation also would be longer than for unipolar cathodal stimulation since bipolar and anodal refractory periods are equal when the cathode and anode are of similar surface area. Results from seven of the experiments showed that a dual focus of excitation, which can only occur with bipolar stimulation, did not make the ventricle more vulnerable to arrhythmias than did unifocal stimulation. These results indicate that the difference between the arrhythmia vulnerability to unipolar cathodal, anodal, and bipolar stimulation is dependent on the relationship between their excitability characteristics, i.e., their strength-interval curves.
Two Is Better Than One: Combining IGF1R and MEK Blockade as a Promising Novel Treatment Strategy Against <i>KRAS</i>-Mutant Lung Cancer
Authors: Ron Chen, E. Alejandro Sweet-Cordero
Journal: Cancer Discovery (2013)

Abstract Summary: A small-molecule inhibitor screen on a panel of human lung cancer cell lines has uncovered an unexpected sensitivity of cells expressing oncogenic KRAS toward insulin-like growth factor 1 receptor (IGF1R) inhibition. Combining IGF1R and MAP-ERK kinase blockade led to significant effects on viability in human non–small cell lung cancer (NSCLC) cell lines and in 2 mouse models of oncogenic KRAS-driven lung cancer. The mechanistic basis for this effect seems to be an increased baseline activation of IGF1R–mediated activation of AKT in cells that express oncogenic KRAS. The studies thus point to a novel approach for treatment of KRAS-driven NSCLC, a particularly difficult subset of patients to treat with existing approaches. Cancer Discov; 3(5); 491–3. ©2013 AACR. See related article by Molina-Arcas et al., p. 548
Risk Factors for Hearing Impairment Among U.S. Adults With Diabetes
Authors: Kathleen E. Bainbridge, Howard J. Hoffman, Catherine C. Cowie
Journal: Diabetes Care (2011)

OBJECTIVE The objective of this study was to examine the risk factors of low/mid-frequency and high-frequency hearing impairment among a nationally representative sample of diabetic adults. RESEARCH DESIGN AND METHODS Data came from 536 participants, aged 20–69 years, with diagnosed or undiagnosed diabetes who completed audiometric testing during 1999–2004 in the National Health and Nutrition Examination Survey (NHANES). We defined hearing impairment as the pure-tone average &amp;gt;25 dB hearing level of pure-tone thresholds at low/mid-frequencies (500; 1,000; and 2,000 Hz) and high frequencies (3,000; 4,000; 6,000; and 8,000 Hz) and identified independent risk factors using logistic regression. RESULTS Controlling for age, race/ethnicity, and marital status, odds ratios for associations with low/mid-frequency hearing impairment were 2.20 (95% CI 1.28–3.79) for HDL &amp;lt;40 mg/dL and 3.55 (1.57–8.03) for poor health. Controlling for age, race/ethnicity, sex, and income-to-poverty ratio, odds ratios for associations with high-frequency hearing impairment were 4.39 (1.26–15.26) for history of coronary heart disease and 4.42 (1.26–15.45) for peripheral neuropathy. CONCLUSIONS Low HDL, coronary heart disease, peripheral neuropathy, and having poor health are potentially preventable correlates of hearing impairment for people with diabetes. Glycemic control, years since diagnosis, and type of glycemic medication were not associated with hearing impairment.
Muscle Expression of Mutant Androgen Receptor Accounts for Systemic and Motor Neuron Disease Phenotypes in Spinal and Bulbar Muscular Atrophy
Authors: Constanza J. Cortes, Shuo-Chien Ling, Ling T. Guo, Gene Hung, Taiji Tsunemi, Linda Ly, Seiya Tokunaga, Edith Lopez, Bryce L. Sopher, C. Frank Bennett, G. Diane Shelton, Don W. Cleveland, Albert R. La Spada
Journal: Neuron (2014)
Cardiomyocyte Degeneration With Calpain Deficiency Reveals a Critical Role in Protein Homeostasis
Authors: Anita S. Galvez, Abhinav Diwan, Amy M. Odley, Harvey S. Hahn, Hanna Osinska, Jaime G. Melendez, Jeffrey Robbins, Roy A. Lynch, Yehia Marreez, Gerald W. Dorn
Journal: Circulation Research (2007)

Regulating the balance between synthesis and proteasomal degradation of cellular proteins is essential for tissue growth and maintenance, but the critical pathways regulating protein ubiquitination and degradation are incompletely defined. Although participation of calpain calcium-activated proteases in post-necrotic myocardial autolysis is well characterized, their importance in homeostatic turnover of normal cardiac tissue is controversial. Hence, we evaluated the consequences of physiologic calpain (calcium-activated protease) activity in cultured cardiomyocytes and unstressed mouse hearts. Comparison of in vitro proteolytic activities of cardiac-expressed calpains 1 and 2 revealed calpain 1, but not calpain 2, activity at physiological calcium concentrations. Physiological calpain 1 activation was evident in adenoviral transfected cultured cardiomyocytes as proteolysis of specific substrates, generally increased protein ubiquitination, and accelerated protein turnover, that were each inhibited by coexpression of the inhibitor protein calpastatin. Conditional forced expression of calpain 1, but not calpain 2, in mouse hearts demonstrated substrate-specific proteolytic activity under basal conditions, with hyperubiquitination of cardiac proteins and increased 26S proteasome activity. Loss of myocardial calpain activity by forced expression of calpastatin diminished ubiquitination of 1 or more specific myocardial proteins, without affecting overall ubiquitination or proteasome activity, and resulted in a progressive dilated cardiomyopathy characterized by accumulation of intracellular protein aggregates, formation of autophagosomes, and degeneration of sarcomeres. Thus, calpain 1 is upstream of, and necessary for, ubiquitination and proteasomal degradation of a subset of myocardial proteins whose abnormal accumulation produces autophagosomes and degeneration of cardiomyocytes with functional decompensation.
Insights Into the Pathogenicity of Rare Missense <i>GCK</i> Variants From the Identification and Functional Characterization of Compound Heterozygous and Double Mutations Inherited in <i>Cis</i>
Authors: Nicola L. Beer, Kara K. Osbak, Martijn van de Bunt, Nicholas D. Tribble, Anna M. Steele, Kirsty J. Wensley, Emma L. Edghill, Kevin Colcough, Amy Barrett, Lucia Valentínová, Jana K. Rundle, Anne Raimondo, Joseph Grimsby, Sian Ellard, Anna L. Gloyn
Journal: Diabetes Care (2012)

To demonstrate the importance of using a combined genetic and functional approach to correctly interpret a genetic test for monogenic diabetes.
P-Cadherin Is Up-Regulated by the Antiestrogen ICI 182,780 and Promotes Invasion of Human Breast Cancer Cells
Authors: Joana Paredes, Christophe Stove, Veronique Stove, Fernanda Milanezi, Veerle Van Marck, Lara Derycke, Marc Mareel, Marc Bracke, Fernando Schmitt
Journal: Cancer Research (2004)

Abstract P-cadherin expression in breast carcinomas has been associated with tumors of high histologic grade and lacking estrogen receptor-α, suggesting a link between these proteins. In the MCF-7/AZ breast cancer cell line, blocking estrogen receptor-α signaling with the antiestrogen ICI 182,780 induced an increase of P-cadherin, which coincided with induction of in vitro invasion. Retroviral transduction of MCF-7/AZ cells, as well as HEK 293T cells, showed the proinvasive activity of P-cadherin, which requires the juxtamembrane domain of its cytoplasmic tail. This study establishes a direct link between P-cadherin expression and the lack of estrogen receptor-α signaling in breast cancer cells and suggests a role for P-cadherin in invasion, through its interaction with proteins bound to the juxtamembrane domain.
THE PROLONGED COEXISTENCE OF VACCINIA VIRUS IN HIGH TITRE AND LIVING CELLS IN ROLLER TUBE CULTURES OF CHICK EMBRYONIC TISSUES
Authors: A. E. Feller, John F. Enders, T. H. Weller
Journal: The Journal of Experimental Medicine (1940)

1. The virus of vaccinia in so called roller tube cultures of mixed embryonic chick tissue rapidly increases to maximal titre. 2. Under these conditions the quantity of virus in the tissue remains at or near the maximum for at least 9 weeks and considerable amounts are present in the fluids removed each day. 3. The same results are obtained when only fragments of embryonic chick heart are employed. 4. Many, though not necessarily all, of the cells in infected cultures remain alive and retain the capacity to proliferate. The presence of these living cells is essential for the persistence of the virus. 5. No apparent differences in the rate or amount of growth of cells in infected as contrasted with non-infected cultures can be discerned in the gross. 6. It is suggested, but not proved, that virus is continually being produced rather than simply preserved throughout the period.