tbuckley/cabot-search huggingface dataset:
PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms
Authors: Franziska Briest, Patricia Grabowski
Journal: Theranostics (2014)

Gastroenteropancreatic neuroendocrine neoplasms are heterogeneous in their clinical behavior and require therapies specially tailored according to staging, grading, origin and expression of peptide receptors.Despite extensive scientific efforts, the therapy options are still not satisfactory.The main reasons are due to the lack of a broad mechanistic knowledge, an insufficient classification of specific diagnostic sub-groups, and predictive markers.GEP-NEN tumors evade early diagnosis because of slow asymptomatic growth behavior and are frequently not detected until metastasized.How signaling networks contribute to tumor progression and how these networks interact remains unclear in large parts.In this review we summarize the knowledge on the growth factor responsive non-angiogenetic pathways in sporadic GEP-NENs, highlight promising mechanistic research approaches, and describe important therapy targets.
Upregulation of Cardiac Angiotensin II AT <sub>1</sub> Receptors in Congenital Cardiomyopathic Hamsters
Authors: Chantal Lambert, Yolette Massillon, Sylvain Meloche
Journal: Circulation Research (1995)

Abstract Angiotensin II (Ang II) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in cardiac myocytes. To gain insight into the role of Ang II in cardiac hypertrophy, we examined the expression and subtype distribution of Ang II receptors in the ventricles of embryonic and of 25- to 350-day-old inbred control and cardiomyopathic (CHF 146) hamsters. Studies were also performed with heterozygous (cardiomyopathic×control) animals. Compared with the control hamsters, cardiomyopathic hamsters presented decreased body weights and increased ratios of ventricular weight to body weight in every adult group studied. Typical histological lesions appeared in the left ventricle of cardiomyopathic animals around 70 to 75 days, and their severity increased with time. Radioligand binding studies with cardiac ventricular membranes indicated that iodinated [Sar 1 ,Ile 8 ]Ang II (sarile) binds to a homogeneous population of sites in membranes derived from adult normal and cardiomyopathic animals. Competition curves using specific receptor subtype antagonists revealed that 125 I-sarile binding sites were exclusively of the AT 1 subtype in both groups of animals. Importantly, the density of AT 1 receptors was found to be significantly increased (90% augmentation at 70 to 75 days) in the ventricles of cardiomyopathic hamsters. This augmented expression was observed in all adult groups and was already present at 25 days, when no histological lesions were visible. The affinity of the receptor for losartan did not vary significantly between adult normal and cardiomyopathic animals (mean K d , 19.6 and 16.7 nmol/L, respectively). No significant differences were observed in the total expression of Ang II receptors and in the proportion of AT 1 and AT 2 subtypes between the two groups of embryonic hearts. Heterozygous animals expressed an intermediate level of AT 1 receptor binding activity in their ventricles. Together, these results suggest that Ang II acting through the AT 1 receptor may play a critical role in the development and/or maintenance of cardiac hypertrophy.
Fibroblasts from the inner granulation tissue of the pseudocapsule in hips at revision arthroplasty induce osteoclast differentiation, as do stromal cells
Authors: H Sakai
Journal: Annals of the Rheumatic Diseases (2002)

It has previously been shown that many osteoclast precursors are included in the granulation tissue within the pseudocapsule obtained at revision arthroplasty from hips with osteolysis. In vitro culture of only cells isolated from the granulation tissue has been previously shown to generate many mature osteoclasts.To investigate the presence or otherwise of supporting cells, similar to stromal cells, which differentiate osteoclasts within the granulation tissue.Cells isolated from the granulation tissue were cultured alone, and after four weeks fibroblast-like cells (granulation fibroblasts) remained. Rat non-adherent bone marrow cells (NA-BMCs) were co-cultured with the granulation fibroblasts with or without 1alpha,25(OH)2D3 (10(-8) M) or heat treated ROS 17/2.8 cell conditioned medium (ht ROSCM), or both. Multinucleated cells (MNCs), which formed, were assessed by biochemical and functional characterisation of osteoclasts. Receptor activator of NFkappaB ligand (RANKL) was investigated by immunohistochemistry.Co-culture of NA-BMCs and granulation fibroblasts caused the formation of tartrate resistant acid phosphatase (TRAP) positive MNCs, which had the calcitonin receptor (CTR), the Kat-1 antigen, which is specific to the surface of rat osteoclasts, and the ability to form pits in the presence of both 1alpha,25(OH)2D3 and ht ROSCM or in the presence of just ht ROSCM. RANKL was detected in fibroblast-like cells in the granulation tissue.These data suggest that granulation fibroblasts support osteoclast differentiation, as do osteoblasts/stromal cells, and may play a part in aseptic loosening.
Cardiac diacylglycerol accumulation in high fat-fed mice is associated with impaired insulin-stimulated glucose oxidation
Authors: Liyan Zhang, John R. Ussher, Tatsujiro Oka, Virgilio J.J. Cadete, Cory Wagg, Gary D. Lopaschuk
Journal: Cardiovascular Research (2010)

The molecular processes leading to cardiac insulin resistance induced via a high-fat diet (HFD) remain unclear. We examined the changes in cardiac insulin sensitivity and the potential mechanism(s) involved following HFD in mice. C57BL/6 mice were fed either a low-fat diet (LFD, 4% kcal fat) or a HFD (60% kcal fat) for 3 or 10 weeks. Insulin-stimulated glucose oxidation in isolated working hearts was decreased at 10 weeks of HFD compared with mice on LFD (249 ± 19 to 399 ± 46 vs. 551 ± 97 to 1464 ± 243 nmol/g dry wt/min; P < 0.05). The accumulation of myocardial diacylglycerol (DAG; 479 ± 174 vs. 266 ± 29 µmol/g wet wt; P < 0.05), but not long-chain acyl CoA, ceramide, or triacylglycerol, correlated with the development of insulin resistance. The accumulation of DAG occurred concomitantly with an increase in glycerol phosphate acyltransferase activity, a decrease in DAG acyltransferase activity, as well as an increase in the translocation of protein kinase C-α (PKCα) and phosphorylation of p70s6k. Neither HFD-induced accumulation of cardiac DAG nor up-regulation of phosphorylated p70s6k occurred in mice lacking malonyl CoA decarboxylase which are resistant to the development of HFD-induced insulin resistance. The activation of myocardial p70s6k and PKCα is closely associated with cardiac insulin resistance in which the accumulation of intra-myocardial DAG could be responsible.
Sports insurance and national governing bodies.
Authors: L Jones, M McCabe
Journal: British Journal of Sports Medicine (1991)

A postal survey was conducted of the attitudes and advice of Welsh governing bodies of amateur sports and their Cardiff-based clubs towards personal sports insurance. Information on 36 of the 39 sports surveyed (92%) was sufficient for analysis. Twenty-two of these 36 sports (61%) organized insurance at a national level, one at club level (3%) and 13 (36%) provided no insurance advice. Only 12 sports (33%) insisted on mandatory insurance cover. Many sportsmen and women are left to search for an appropriate insurance cover themselves or remain uninsured. Owing the lack of advice in 36% of cases it was decided to survey Cardiff-based insurance brokers to establish what type of policy they would recommend. Only 41% of the brokers were able to offer a suitable policy. Club policies recommended by the Central Council for Physical Recreation provide individuals with the same sports cover (but at a lower premium) as is available from a personal accident policy. However, cover is somewhat inadequate and may provide a false sense of security. Sports with mandatory sports insurance are not necessarily those with the highest risk of disabling injury.
British Thoracic Society Study on cryptogenic fibrosing alveolitis: response to treatment and survival
Authors: R. M Rudd, R. J Prescott, J C Chalmers, I. D A Johnston
Journal: Thorax (2006)

The initial results of a survey of 588 patients with a clinical presentation of cryptogenic fibrosing alveolitis (CFA) also known as idiopathic pulmonary fibrosis, have been published. This article reports further results pertaining to response to treatment and survival.
Princess Takamatsu Symposium on DNA Repair and Human Cancers
Authors: Lawrence A. Loeb, Susumu Nishimura
Journal: Cancer Research (2010)

The 40th International Symposium of the Princess Takamatsu Cancer Research Fund, entitled "DNA Repair and Human Cancers," was held on November 10-12, 2009 at Hotel Grand Palace, Tokyo, Japan. The meeting focused on the role of DNA repair in preventing mutations by endogenous and exogenous DNA damage and increasing the efficacy of chemotherapeutic agents by interfering with DNA repair. The 14 presentations by the speakers from the United States, four from the United Kingdom, one each from Italy, The Netherlands, and France, and 13 from Japan, covered most aspects of DNA repair, spanning DNA damage, molecular structures of repair enzymes, and clinical studies on inhibition of DNA repair processes. Extensive time was reserved for discussions with the active participation of the 150 invited Japanese scientists. The choice of a symposium on DNA repair in human cancers resulted in part from the excellent basic and clinical studies that have been carried out for many years in Japan, and the general lack of recognition versus the importance of DNA repair in understanding carcinogenesis.
High-Value, Cost-Conscious Health Care: Concepts for Clinicians to Evaluate the Benefits, Harms, and Costs of Medical Interventions
Authors: Douglas K. Owens
Journal: Annals of Internal Medicine (2011)

Health care costs in the United States are increasing unsustainably, and further efforts to control costs are inevitable and essential. Efforts to control expenditures should focus on the value, in addition to the costs, of health care interventions. Whether an intervention provides high value depends on assessing whether its health benefits justify its costs. High-cost interventions may provide good value because they are highly beneficial; conversely, low-cost interventions may have little or no value if they provide little benefit. Thus, the challenge becomes determining how to slow the rate of increase in costs while preserving high-value, high-quality care. A first step is to decrease or eliminate care that provides no benefit and may even be harmful. A second step is to provide medical interventions that provide good value: medical benefits that are commensurate with their costs. This article discusses 3 key concepts for understanding how to assess the value of health care interventions. First, assessing the benefits, harms, and costs of an intervention is essential to understand whether it provides good value. Second, assessing the cost of an intervention should include not only the cost of the intervention itself but also any downstream costs that occur because the intervention was performed. Third, the incremental cost-effectiveness ratio estimates the additional cost required to obtain additional health benefits and provides a key measure of the value of a health care intervention.
Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106.
Authors: P S Gaynon, P G Steinherz, W A Bleyer, A R Ablin, V C Albo, J Z Finklestein, N J Grossman, L J Novak, A F Pyesmany, G H Reaman
Journal: Journal of Clinical Oncology (1993)

PURPOSE On past Childrens Cancer Group (CCG) trials, children with acute lymphoblastic leukemia and unfavorable presenting features had obtained an event-free survival (EFS) rate of no better than 50%. Following promising pilot experience, this study was conducted to determine the benefit and morbidity of two intensive experimental regimens, Reg A, based on the Berlin-Frankfurt-Münster (BFM) 1976 regimen, and Reg B, the New York regimen. PATIENTS AND METHODS Between February 1983 and November 1984, 217 eligible children with acute lymphoblastic leukemia and unfavorable presenting features were entered and randomly assigned to receive Reg A, Reg B, or Reg C, the control regimen. Assignment to Reg C was halted in November 1984 after interim analyses showed an inferior outcome. Subsequently, between November 1984 and March 1987, an additional 328 patients were randomly allocated to receive Reg A or Reg B. RESULTS The 7-year EFS rate was 63% (+/- 6%, 1 SD) for Reg A, 61% (+/- 6%) for Reg B, and 40% (+/- 6%) for Reg C (P &lt; .006). The difference between Reg A or Reg B and Reg C remained greater than 20 percentage points for EFS at 7 years and 15 percentage points for survival. Relative to Reg C, patients on Reg A accrued 16.3 additional days of hospitalization on average and, on Reg B, 20.2 days. EFS and survival were similar on Reg A and Reg B, but Reg B required more days of parenteral therapy and greater exposure to anthracyclines and alkylating agents. CONCLUSION Both Reg A and Reg B provided a better outcome than Reg C for children with acute lymphoblastic leukemia and unfavorable presenting features. Outcomes on Reg A and Reg B were similar. Use of the more effective but more toxic regimens resulted in 78 additional hospital days per relapse prevented on Reg A and 101 days on Reg B. The current CCG trial for this population builds on Reg A.
Angiogenesis, vascular endothelial growth factor and the endometrium
Authors: S. Smith
Journal: Human Reproduction Update (1998)

Angiogenesis is an essential component of endometrial renewal. The formation of new vessels depends on interactions between various hormones and growth factors, and this review focuses on the expression of angiogenic growth factors in the human endometrium. Peptide and non-peptide angiogenic factors interact during endometrial renewal, including epidermal growth factor (EGF), transforming growth factors (e.g. TGF-β), platelet-derived endothelial growth factor/thymidine phosphorylase (PD-ECGF/TP), tumour necrosis growth factors and vascular endothelial growth factor (VEGF). Their role in the proliferation and migration of endothelial cells from pre-existing vessels is described, concentrating on VEGF and its receptors (VEG-R1 and -R2), and the fibroblast growth factor (FGF) family. The actions of the products of the VEGF gene are outlined, and the hormonal and non-hormonal control of their localization in the human endometrium and biological actions on vasculature and coagulation are described. Finally, the role of VEGF in menorrhagia is assessed. Keywords:angiogenesis/endometrium/human/menorrhagia/vascular endothelial growth factor
Protocolized Anemia Management with Erythropoietin in Hemodialysis Patients
Authors: K. Scott Brimble, Christian G. Rabbat, Pat McKenna, Kim Lambert, Euan J. Carlisle
Journal: Journal of the American Society of Nephrology (2003)

Treatment of the anemia of chronic renal failure with exogenous recombinant human erythropoietin (rHuEpo) is well established. The objective of this randomized clinical trial was to evaluate an anemia management team protocol in hemodialysis patients, using subcutaneous rHuEpo and intravenous iron. A total of 215 patients were randomized to either usual care or the protocol. The primary outcome was the proportion of patient hemoglobin (Hgb) values between 11.0 and 12.5 g/dl over the final 8 wk. The study was halted after 240 d because of an institutional change to intravenous rHuEpo. The proportion of Hgb values in the target range increased from 47.4% to 62.8% overall (P = 0.001); there was no difference between treatment groups. The proportion of baseline Hgb values between 11.0 and 12.5 g/dl increased from 44.6% in patients who had enrolled within the first 3 mo of study inception to 75.0% in those who started later (P = 0.017), suggesting a Hawthorne effect. A nonsignificant decrease in rHuEpo dose was observed in the protocol group; subgroup analysis in patients who were enrolled for at least 5 mo demonstrated a reduction in the rHuEpo dose of 2788 units/wk in the protocol group (P < 0.05), independent of intravenous iron dose. Multivariate analysis demonstrated that a higher transferrin saturation and albumin and protocol group assignment were associated with a lower final rHuEpo dose. This study demonstrated that a protocolized approach to anemia management in hemodialysis patients results in comparable Hgb levels and may reduce rHuEpo requirements, independent of iron use.
Chronobiological Patterns of Acute Aortic Dissection
Authors: Rajendra H. Mehta, Roberto Manfredini, Fauziya Hassan, Udo Sechtem, Eduardo Bossone, Jae K. Oh, Jeanna V. Cooper, Dean E. Smith, Francesco Portaluppi, Marc Penn, Stuart Hutchison, Christoph A. Nienaber, Eric M. Isselbacher, Kim A. Eagle
Journal: Circulation (2002)

Chronobiological rhythms have been shown to influence the occurrence of a variety of cardiovascular disorders. However, the effects of the time of the day, the day of the week, or monthly/seasonal changes on acute aortic dissection (AAD) have not been well studied.Accordingly, we evaluated 957 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2000 (mean age 62+/-14 years, type A 61%). A chi2 test for goodness of fit and partial Fourier analysis were used to evaluate nonuniformity and rhythmicity of AAD during circadian, weekly, and monthly periods. A significantly higher frequency of AAD occurred from 6:00 AM to 12:00 noon compared with other time periods (12:00 noon to 6:00 PM, 6:00 PM to 12:00 midnight, and 12:00 midnight to 6:00 AM; P<0.001 by chi2 test). Fourier analysis showed a highly significant circadian variation (P<0.001) with a peak between 8:00 AM and 9:00 AM. Although no significant variation was found for the day of the week, the frequency of AAD was significantly higher during winter (P=0.008 versus other seasons by chi2 test). Fourier analysis confirmed this monthly variation with a peak in January (P<0.001). Subgroup analysis identified a significant association for all subgroups with circadian rhythmicity. However, seasonal/monthly variations were observed only among patients aged <70 years, those with type B AAD, and those without hypertension or diabetes.Similar to other cardiovascular conditions, AAD exhibits significant circadian and seasonal/monthly variations. Our findings may have important implications for the prevention of AAD by tailoring treatment strategies to ensure maximal benefits during the vulnerable periods.
Proliferative and metabolic markers in incompletely excised pediatric pilocytic astrocytomas--an assessment of 3 new variables in predicting clinical outcome
Authors: L. R. Margraf, L. Gargan, Y. Butt, N. Raghunathan, D. C. Bowers
Journal: Neuro-Oncology (2011)

Although pilocytic astrocytoma (PA) is the most common brain tumor diagnosed in children, few prognostic variables have been delineated that stratify the risk of clinical progression in patients with this tumor. In this study, the MIB-1 labeling index was compared with 2 other immunohistochemical markers of cell proliferation, phospho-histone H3 (PHH3) and mini-chromosomal maintenance protein 2 (MCM2) in 80 incompletely resected PAs to see which was best able to identify patients at risk for tumor progression. 0(6)-Methylguanine-DNA methyltransferase (MGMT) protein expression, which has been predictive of progression-free survival (PFS) in high-grade gliomas in children, was also evaluated in these cases. The mean follow-up period was 7.81 ± 3.9 years, and 42.8% of tumors have shown progression at the time of censoring. A MIB-1 labeling index ≥2.0 was associated with shortened PFS as a grouped variable by log-ranked analysis (P = .03) and by Cox regression analysis as a continuous variable (P = .007). None of the other potential biomarkers was significantly predictive of PFS. Although the amount of MCM2 staining correlated with the MIB-1 labeling index (P < .001), MCM2 reactivity was not independently associated with outcome. We conclude that MIB-1 labeling remains the best predictor of PFS in pediatric PAs.
First-Trimester C-Reactive Protein and Subsequent Gestational Diabetes
Authors: Myles Wolf, Laura Sandler, Karen Hsu, Karen Vossen-Smirnakis, Jeffrey L. Ecker, Ravi Thadhani
Journal: Diabetes Care (2003)

Systemic inflammation is associated with the development of type 2 diabetes. We tested the hypothesis that increased inflammation, measured early in pregnancy, is associated with the subsequent development of gestational diabetes mellitus (GDM), a precursor of type 2 diabetes.We conducted a prospective nested case-control study in a pregnancy cohort. First-trimester C-reactive protein (CRP) levels were measured using a high-resolution assay in 43 women who subsequently developed GDM and in a random sample of 94 women who remained euglycemic throughout pregnancy. Median CRP levels were compared using Wilcoxon's rank-sum test. Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among CRP tertiles.First-trimester CRP levels were significantly increased among women who subsequently developed GDM compared with control subjects (3.1 vs. 2.1 mg/l, P < 0.01). The risk of developing GDM among women in the highest CRP tertile compared with the lowest tertile was 3.2 (95% CI 1.2-8.8). After adjusting for age, race/ethnicity, smoking, parity, blood pressure, and gestational age at CRP sampling, the risk of developing GDM among women in the highest compared with the lowest tertile was 3.6 (95% CI 1.2-11.4). When BMI was included in the model, however, the association between increased CRP and GDM was attenuated (odds ratio for the highest compared with lowest tertile 1.5 [95% CI 0.4-5.5]).In women who develop GDM, there is evidence of increased inflammation during the first trimester. This association is mediated in part by increased BMI. Larger studies are needed to verify these results.
Use of oral glycopyrronium bromide in hyperhidrosis
Authors: V. Bajaj, J.A.A. Langtry
Journal: British Journal of Dermatology (2007)

Idiopathic hyperhidrosis may be a disabling condition causing emotional stress and negative impact on a patient's quality of life. Oral anticholinergics are one of the treatments available. There are few published data on the use of the anticholinergic drug glycopyrronium bromide (glycopyrrolate) given orally in the treatment of hyperhidrosis.To report a retrospective analysis describing the treatment responses, doses and side-effects of oral glycopyrrolate in the treatment of idiopathic hyperhidrosis.Review of case notes in a series of 24 patients, nine with generalized and 15 with localized hyperhidrosis.Fifteen of 19 evaluable patients (79%) responded to oral glycopyrrolate. However, treatment was limited by side-effects in around one third of patients.A prospective clinical study to compare the efficacy and side-effects of oral anticholinergics is warranted.