tbuckley/cabot-search huggingface dataset:
Bromocriptine: a novel approach to the treatment of type 2 diabetes.
Authors: H Pijl, S Ohashi, M Matsuda, Y Miyazaki, A Mahankali, V Kumar, R Pipek, P Iozzo, J L Lancaster, A H Cincotta, R A DeFronzo
Journal: Diabetes Care (2000)

OBJECTIVE: In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: There were 22 obese subjects with type 2 diabetes randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study. Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements. Fasting plasma glucose concentration and HbA(1c) were measured at 2- to 4-week intervals during treatment. Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU x min(-1) x m(-2)) were measured before and after treatment. RESULTS: No changes in body weight or body composition occurred during the study in either placebo- or bromocriptine-treated subjects. Bromocriptine significantly reduced HbA(1c) (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA(1c) (delta = 1.2%, P = 0.01) and fasting glucose (delta = 54 mg/dl, P &amp;lt; 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant. The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine- or placebo-treated group. During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg x min(-1) kg(-1) fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg min(-1) x kg(-1) FFM (P &amp;lt; 0.05), whereas both of these variables deteriorated significantly (P &amp;lt; or = 0.02) in the placebo group. CONCLUSIONS: Bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.
Numbers of homicides and suicides among mentally ill patients have stopped rising
Authors: A. O'Dowd
Journal: BMJ (2010)

Numbers of homicides and suicides among people with mental health problems fell for the first time in the past few years after a previous steady rise, new figures show.

A report published on 8 July by the University of Manchester also found that it is likely that the previous rise in numbers of homicides by people with psychosis between 1997 and 2005 was due to the use of drugs, alcohol, or both.

The annual report of the national confidential inquiry into suicide and homicide by people with mental illness in England and Wales has been published by a team led …
The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease
Authors: Nibaldo C Inestrosa, Enrique M Toledo
Journal: Molecular Neurodegeneration (2008)

Recent evidence supports a neuroprotective role for Wnt signaling in neurodegenerative disorders such as Alzheimer's Disease (AD). In fact, a relationship between amyloid-beta-peptide (Abeta)-induced neurotoxicity and a decrease in the cytoplasmic levels of beta-catenin has been observed. Apparently Abeta binds to the extracellular cysteine-rich domain of the Frizzled receptor (Fz) inhibiting Wnt/beta-catenin signaling. Cross-talk with other signaling cascades that regulate Wnt/beta-catenin signaling, including the activation of M1 muscarinic receptor and PKC, the use of Ibuprofen-ChE bi-functional compounds, PPAR alpha, gamma agonists, nicotine and some antioxidants, results in neuroprotection against Abeta. These studies indicate that a sustained loss of Wnt signaling function may be involved in the Abeta-dependent neurodegeneration observed in Alzheimer's brain. In conclusion the activation of the Wnt signaling pathway could be proposed as a therapeutic target for the treatment of AD.
Migratory bronchiolitis obliterans organizing pneumonia after unilateral radiation therapy for breast carcinoma
Authors: B Crestani, M Kambouchner, P Soler, J Crequit, M Brauner, JP Battesti, D Valeyre
Journal: European Respiratory Journal (1995)

We report the case of a 59 year old woman who developed cough, dyspnoea and fever with patchy migratory airspace infiltrates, 2 months after right breast radiation therapy for breast carcinoma. Lung infiltrates were initially localized in the irradiated area and spread to the contralateral lung. Lung biopsy, performed in an unirradiated area of the contralateral lung 9 months after completion of radiotherapy, revealed a typical histological pattern of bronchiolitis obliterans organizing pneumonia. No cause of bronchiolitis obliterans organizing pneumonia other than radiation was found. Treatment with corticosteroids resulted in rapid clinical improvement and complete resolution of airspace opacities. This case suggests that localized lung irradiation might trigger the development of a bilateral lung disease, with a histological pattern of bronchiolitis obliterans organizing pneumonia.
Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer
Authors: Roberto Pili, Michael Häggman, Walter M. Stadler, Jeffrey R. Gingrich, Vasileios J. Assikis, Anders Björk, Örjan Nordle, Goran Forsberg, Michael A. Carducci, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2011)

The activity of the novel antitumor agent tasquinimod (TASQ) with S100A9 as a molecular target was investigated in men with metastatic castration-resistant prostate cancer (CRPC) and minimal symptoms.We conducted a randomized, double-blind, placebo-controlled phase II trial in men assigned (at a ratio of two to one) to either oral once-daily TASQ 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, defined by Response Evaluation Criteria in Solid Tumors Group, Prostate Cancer Working Group (PCWG2), or pain criteria, excluding prostate-specific antigen.Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively (P < .001), and median progression-free survival (PFS) was 7.6 versus 3.3 months (P = .0042). In PCWG2 CRPC clinical subgroups, PFS in months was as follows: nodal metastases, 6.1 versus 3.1; bone metastases, 8.8 versus 3.4; and visceral metastases, 6.0 versus 3.0 for patients receiving TASQ versus placebo, respectively. Bone alkaline phosphatase levels were stabilized in the TASQ group, whereas the impact on PSA kinetics was less pronounced. Adverse events (AEs) occurring more frequently in the TASQ arm included GI disorders, fatigue, musculoskeletal pains, and elevations of pancreatic and inflammatory biomarkers. Grade 3 to 4 AEs, including asymptomatic elevations of laboratory parameters, were reported in 40% of patients receiving TASQ versus 10% receiving placebo; deep vein thrombosis (4% v 0%) was more common in the TASQ arm.TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.
Enhancing Therapeutic Effects of Docetaxel-Loaded Dendritic Copolymer Nanoparticles by Co-Treatment with Autophagy Inhibitor on Breast Cancer
Authors: Xudong Zhang, Ying Yang, Xin Liang, Xiaowei Zeng, Zhigang Liu, Wei Tao, Xiaojun Xiao, Hongbo Chen, Laiqiang Huang, Lin Mei
Journal: Theranostics (2014)

Dendrimers are synthetic nanocarriers that comprise a highly branched spherical polymer as new, efficient tools for drug delivery.However, the fate of nanocarriers after being internalized into cells has seldom been studied.Docetaxel loaded dendritic copolymer H40-poly(D,L-lactide) nanoparticles, referred to as "DTX-H40-PLA NPs", were prepared and used as a model to evaluate whether the NPs were sequestered by autophagy and fused with lysosomes.Besides being degraded through the endolysosomal pathway, the DTX-loaded H40-PLA NPs were also sequestered by autophagosomes and degraded through the autolysosomal pathway.DTX-loaded H40-PLA NPs may stop exerting beneficial effects after inducing autophagy of human MCF-7 cancer cells.Co-delivery of autophagy inhibitor such as chloroquine and chemotherapeutic drug DTX by dendritic copolymer NPs greatly enhanced cancer cell killing in vitro, and decreased both the volume and weight of the tumors in severe combined immunodeficient mice.These findings provide valuable evidence for development of nanomedicine such as dendritic copolymer NPs for clinical application.
A toll for T cell costimulation
Authors: F Y Liew
Journal: Annals of the Rheumatic Diseases (2004)

Toll was originally found in Drosophila as a pattern recognition receptor associated with defence against fungal and bacterial infections.1,2 Subsequently, toll was found in mammals and named toll-like receptor (TLR). At least 10 distinct TLRs have now been identified in humans.3–9 TLRs are activated by pathogen associated molecular patterns (PAMPs) with target selectivity. PAMPs are integral structural components of pathogens that are thus thought to be essential for survival of infectious organisms and considered to be conserved among a range of pathogens including viruses, bacteria, and fungi.

TLRs act as primary sensors of microbial products and activate signalling pathways that lead to the induction of immune and inflammatory genes.10 They belong to a broader family of proteins, which includes receptors for the proinflammatory cytokines interleukin (IL)-1, IL-18 and the orphan receptor T1/ST2.11 All members of this superfamily signal inflammation in a very similar manner. This is due to the presence of a conserved protein sequence in the cytosolic domain called the Toll/IL-1 receptor domain, which activates common signalling pathways, most notably those leading to the activation of the transcription factor NF-κB and stress activated protein kinases.11

Most investigations of TLRs have focused on cells of the innate immune system. This is because TLRs are closely associated with the innate response. However, although innate immunity may constitute the primary function of TLRs, there is no a priori reason why TLRs may not have a direct role in adaptive immunity. We investigated the expression and functions of TLRs on T cells and found that TLR2 is expressed on the surface of activated and memory T cells. Furthermore, it functions as a costimulator receptor molecule for T cell activation and helps to maintain T cell memory. These data suggest a novel role for TLR2 and may …
Stromal fibroblasts from basal cell carcinoma affect phenotype of normal keratinocytes
Authors: L. Lacina, K. Smetana, B. Dvořánková, R. Pytlík, L. Kideryová, L. Kučerová, Z. Plzáková, J. Štork, H-J. Gabius, S. André
Journal: British Journal of Dermatology (2007)

Epithelial-mesenchymal interactions are important not only to direct the course of prenatal development of skin and its appendages but also to influence the behaviour of transformed epithelial cells.Evaluation of the role of stromal fibroblasts on the phenotype of epithelial cells of basal cell carcinoma (BCC).The phenotype of human BCC was compared with the in vitro model where the growth and phenotypic pattern of normal human keratinocytes were monitored in co-culture with fibroblasts prepared from stroma of BCC (BCCFs), with normal dermal fibroblasts or with two established fibroblast lines. We visualized the expression of a panel of keratins, three types of endogenous lectin [galectin (Gal)-1, Gal-3 and Gal-7], binding sites for Gal-1 and Gal-3, a proliferation marker Ki67, nucleolar protein nucleostemin (NuclS) and membrane protein Ber-EP4. A phenotype and karyotype of BCCFs were also monitored. BCCFs were also grafted to NOD/LtSz-Rag1(null) mice to evaluate their malignant potential.Prolonged cultivation of BCCFs has led to morphological changes, loss of contact inhibition, loss of fibroblast surface antigens and progressive aneuploidity. However, a fully malignant phenotype did not develop as these cells did not form tumours in immunodeficient mice. Co-culture of BCCFs with normal keratinocytes in vitro led to their phenotypical changes resembling those in BCC, namely, expression of keratin 19. These keratinocytes also strongly express nuclear binding sites for Gal-1 and NuclS. This phenotype was not observed when normal keratinocytes were cultured with nontumour-originated fibroblasts.These observations indicate that BCCFs may differ from normal fibroblasts and may play a regulatory role in BCC biology.
Gene Expression in Gastrointestinal Stromal Tumors Is Distinguished by <b> <i>KIT</i> </b> Genotype and Anatomic Site
Authors: Cristina R. Antonescu, Agnes Viale, Lisa Sarran, Sylvia J. Tschernyavsky, Mithat Gonen, Neil H. Segal, Robert G. Maki, Nicholas D. Socci, Ronald P. DeMatteo, Peter Besmer
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Gastrointestinal stromal tumors (GISTs) are specific KIT expressing and KIT-signaling driven mesenchymal tumors of the human digestive tract, many of which have KIT-activating mutations. Previous studies have found a relatively homogeneous gene expression profile in GIST, as compared with other histological types of sarcomas. Transcriptional heterogeneity within clinically or molecularly defined subsets of GISTs has not been previously reported. We tested the hypothesis that the gene expression profile in GISTs might be related to KIT genotype and possibly to other clinicopathological factors. Experimental Design: An HG-U133A Affymetrix chip (22,000 genes) platform was used to determine the variability of gene expression in 28 KIT-expressing GIST samples from 24 patients. A control group of six intra-abdominal leiomyosarcomas was also included for comparison. Statistical analyses (t tests) were performed to identify discriminatory gene lists among various GIST subgroups. The levels of expression of various GIST subsets were also linked to a modified version of the growth factor/KIT signaling pathway to analyze differences at various steps in signal transduction. Results: Genes involved in KIT signaling were differentially expressed among wild-type and mutant GISTs. High gene expression of potential drug targets, such as VEGF, MCSF, and BCL2 in the wild-type group, and Mesothelin in exon 9 GISTs were found. There was a striking difference in gene expression between stomach and small bowel GISTs. This finding was validated in four separate tumors, two gastric and two intestinal, from a patient with familial GIST with a germ-line KIT W557R substitution. Conclusions: GISTs have heterogeneous gene expression depending on KIT genotype and tumor location, which is seen at both the genomic level and the KIT signaling pathway in particular. These findings may explain their variable clinical behavior and response to therapy.
VITAMIN B12Co60 DISTRIBUTION IN DOG TISSUES DURING MANY MONTHS
Authors: W. D. Woods, W. B. Hawkins, G. H. Whipple
Journal: The Journal of Experimental Medicine (1958)

Experiments dealing with the distribution of B(12)Co(60) in the dog indicate that with time (9 months after administration) there is a shift in the distribution of the vitamin as compared to the short term experiments, as well as prolonged retention of the vitamin within various dog tissues. The heart, gastric mucosa, liver, spleen, and brain show high concentrations of the isotope in long term experiments. This distribution, in the heart for example, does not fit with an hypothetical breakdown of B(12)Co(60) complex and storage of a physiologically inactive fraction. Repeated periods of anemia produced by phenylhydrazine make it possible to demonstrate radioactive material in red cell stroma of dogs that have previously received vitamin B(12)Co(60). This radioactive material must have come from other body stores, such as liver and stomach. The high concentration of B(12)Co(60) in the gastric mucosa suggests a relationship between it and the intrinsic factor as described by Castle.
Elevated level of anterior gradient-2 in pancreatic juice from patients with pre-malignant pancreatic neoplasia
Authors: Ru Chen, Sheng Pan, Xiaobo Duan, Brad H Nelson, Rob A Sahota, Sarah de Rham, Richard A Kozarek, Martin McIntosh, Teresa A Brentnall
Journal: Molecular Cancer (2010)

Pancreatic intraepithelial neoplasias (PanINs) are precursors of malignant pancreatic cancer, an ideal stage for early cancer detection. We applied quantitative proteomics to identify aberrantly elevated proteins in pancreatic juice samples derived from patients with PanIN3. Twenty proteins were found elevated in all three PanIN juices by at least two-fold. Among these proteins, anterior gradient-2 (AGR2) was found to be 2-10 fold elevated in PanIN3 juice samples analyzed by quantitative proteomics. An ELISA assay was developed to evaluate AGR2 levels in 51 pancreatic juice samples and 23 serum samples from patients with pancreatic cancer, pre-malignant lesions (including PanIN3, PanIN2, Intraductal Papillary Mucinous Neoplasms (IPMNs)) and benign disease controls (including chronic pancreatitis). AGR2 levels in the pancreatic juice samples were found significantly elevated in patients with pre-malignant conditions (PanINs and IPMNs) as well as pancreatic cancer compared to control samples (p ≤ 0.03). By ROC analysis, the AGR2 ELISA achieved 67% sensitivity at 90% specificity in predicting PanIN3 juice samples from the benign disease controls. These results suggest that elevation of AGR2 levels in pancreatic juice occurs in early pancreatic cancer progression and could be further investigated as a potential candidate juice biomarker for early detection of pancreatic cancer.
Intervals Longer Than 20 Weeks From Breast-Conserving Surgery to Radiation Therapy Are Associated With Inferior Outcome for Women With Early-Stage Breast Cancer Who Are Not Receiving Chemotherapy
Authors: Ivo A. Olivotto, Mary L. Lesperance, Pauline T. Truong, Alan Nichol, Tanya Berrang, Scott Tyldesley, François Germain, Caroline Speers, Elaine Wai, Caroline Holloway, Winkle Kwan, Hagen Kennecke
Journal: Journal of Clinical Oncology (2008)

To determine the interval from breast-conserving surgery (BCS) to radiation therapy (RT) that affects local control or survival.The 10-year Kaplan-Meier (KM) local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) were computed for 6,428 women who had T1 to 2, N0 to 1, M0 breast cancer that was diagnosed in British Columbia between 1989 and 2003, and who were treated with BCS and RT without chemotherapy. Intervals from BCS to RT were grouped by weeks as follows: < or = 4 (n = 83), greater than 4 to 8 (n = 2,288; reference group); greater than 8 to 12 (n = 2,606); greater than 12 to 16 (n = 961); greater than 16 to 20 (n = 358); and greater than 20 weeks (n = 132). Cox proportional hazards models and matching were used to control for confounding variables.The median follow-up time was 7.5 years. The 10-year KM outcomes were as follows: LRFS, 95.4%; DRFS, 90.5%; and BCSS, 92.5%. Compared with the greater than 4 to 8 weeks group, hazard ratios (HR) were not significantly different for any outcome among patients who were treated up to 20 weeks after BCS. However, LRFS (hazard ratio [HR], 2.00; P = .15), DRFS (HR, 1.86; P = .02) and BCSS (HR, 2.15; P = .009) were inferior for women with BCS-to-RT intervals greater than 20 weeks compared with those greater than 4 to 8 weeks. The matched analysis yielded similar results.Outcomes were statistically similar for BCS-to-RT intervals up to 20 weeks, but they were inferior for intervals beyond 20 weeks. Time can be reasonably allowed for the breast to heal and for patients to consider treatment options, but RT should start within 20 weeks of BCS.
THE INFLUENCE OF CERTAIN FACTORS, ESPECIALLY EMOTIONAL DISTURBANCES, ON THE EPINEPHRIN CONTENT OF THE ADRENALS
Authors: G. N. Stewart, J. M. Rogoff
Journal: The Journal of Experimental Medicine (1916)

1. No evidence has been obtained that in cats and dogs with the nerves of one adrenal cut, emotional disturbances cause depletion of the epinephrin store of the normally innervated adrenal as compared with its fellow. 2. The depletion of the epinephrin store in cats under morphine is not dependent upon so called morphine fright, since a similar depletion is found in dogs in which, as is known, morphine produces symptoms the reverse of those of fright. 3. The signs of morphine fright can all be elicited by administering morphine to a cat in which one adrenal has been removed and the nerve supply of the other cut, and in which accordingly no detectable liberation of epinephrin takes place. 4. The reactions of the denervated iris elicited by emotional disturbance, asphyxia, or etherization in a cat, one of whose adrenals has been removed and the nerves of the other cut, do not differ from these reactions in cats whose adrenals have not been interfered with. 5. The influence of postoperative edema of the adrenal in diminishing the epinephrin load, and the recuperation of the load after a time, have been studied in rabbits. 6. The diminution in the epinephrin store of the adrenals which follows operations on animals (postoperative depletion) has been studied. It is only in part associated with the anesthesia, since it may be as marked 6 or 8 hours after an operation lasting less than 1 hour as after 6 or 8 hours' anesthesia without operation. 7. One adrenal was removed in rabbits and the epinephrin content of the remaining gland assayed at varying periods of time after removal of the first, the periods being longer than the time necessary for recovery from the postoperative depletion. In general, the second adrenal contained more epinephrin than the first, sometimes double the amount. 8. Marked depletion of the epinephrin store of innervated adrenals as compared with the corresponding denervated glands was seen in animals dead of infections of various kinds. 9. As shown by Elliott, diminution of the stock of epinephrin in the adrenal through electrical stimulation of the splanchnics is not easy to demonstrate, despite the fact that the liberation of epinephrin into the blood is notably increased by the stimulation. With short periods of stimulation, however, repeated over a long time at intervals just long enough to prevent fatigue, it has proved possible to demonstrate a distinct depletion.