tbuckley/cabot-search huggingface dataset:
Short- and long-term determinants of baroreceptor function in aged normotensive and spontaneously hypertensive rats.
Authors: M C Andresen
Journal: Circulation Research (1984)

In a variety of animal models, baroreceptor resetting during chronic hypertension has been correlated to vessel wall hypertrophy and decreased distensibility. In one possible mechanism of chronic resetting, termed the splinting hypothesis here, it has been suggested that a stiffer vessel wall might increase the minimum pressure required for activation of these mechanoreceptors (pressure threshold) and decrease suprathreshold pressure sensitivity. Lower vessel distensibility would alter baroreceptor function by preventing equivalent pressures from producing equivalent vessel distensions and, thus, receptor distortions. Recent studies have also suggested that the pressure threshold is strongly influenced by the most recent (minutes) history of blood pressure exposure during a process termed rapid resetting. Hypertension and advanced aging are associated with distensibility changes. The present study examines pressure and equivalent mechanical response characteristics of aortic baroreceptors from aged normotensive Wistar-Kyoto and spontaneously hypertensive rats. An in vitro aortic arch-aortic nerve preparation was used to assess the discharge properties from a number of baroreceptors and the pressure-diameter relationship of each aorta. Both control and rapid resetting protocols were used to study the baroreceptor characteristics. Aged Wistar-Kyoto rats were normotensive and averaged 115 weeks of age. Aged spontaneously hypertensive rats had systolic tail pressures of 187 mm Hg and averaged 76 weeks of age. Although aortic distensibility of aged WKYs was much lower than previously found in younger animals, the pressure threshold was unchanged. Aged spontaneously hypertensive rat receptors were chronically reset in proportion to their blood pressure. Decreased distensibility did not alter the rapid resetting process. It is concluded that baroreceptor pressure sensitivity is more closely related to aortic distensibility under several conditions altering vessel stiffness, whereas, the pressure threshold may be regulated additionally by mechanisms independent of distensibility. The results are inconsistent with the splinting hypothesis.
Molecular Mechanisms and Treatment Options for Muscle Wasting Diseases
Authors: Markus A. Rüegg, David J. Glass
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Loss of muscle mass can be the consequence of pathological changes, as observed in muscular dystrophies; or it can be secondary to cachexia-inducing diseases that cause muscle atrophy, such as cancer, heart disease, or chronic obstructive pulmonary disease; or it can be a consequence of aging or simple disuse. Although muscular dystrophies are rare, muscle loss affects millions of people worldwide. We discuss the molecular mechanisms involved in muscular dystrophy and in muscle atrophy and present current strategies aimed at ameliorating these diseases. Finally, we discuss whether lessons learned from studying muscular dystrophies will also be helpful for halting muscle loss secondary to nondystrophic diseases and whether strategies to halt muscle atrophy have potential for the treatment of muscular dystrophies.
Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7
Authors: Charles L. Loprinzi, Ralph Levitt, Debra Barton, Jeff A. Sloan, Shaker R. Dakhil, Daniel A. Nikcevich, James D. Bearden, James A. Mailliard, Loren K. Tschetter, Tom R. Fitch, John W. Kugler
Journal: Journal of Clinical Oncology (2006)

Vasomotor hot flashes are a common problem in menopausal women. Given concerns regarding estrogen and/or combined hormonal therapy, other treatment options are desired. Prior trials have confirmed that progestational agents and newer antidepressants effectively reduce hot flashes. This current trial compared a single intramuscular dose of medroxyprogesterone acetate (MPA), depot preparation, versus daily oral venlafaxine as treatment for hot flashes.Women with bothersome hot flashes were entered onto this trial, were randomly assigned to treatment, and then had a baseline week where hot flash scores were recorded without treatment. They were then treated and observed for 6 weeks; daily diaries were used to measure hot flash frequencies and severities. There were 109 patients per each arm randomly assigned to receive MPA 400 mg intramuscularly for a single dose versus venlafaxine 37.5 mg per day for a week, then 75 mg per day.During the sixth week after random assignment, hot flash scores were reduced by 55% in the venlafaxine arm versus 79% in the MPA arm (P < .0001). In an intention-to-treat analysis, 46% of venlafaxine patients (50 of 109) compared with 74% of the MPA patients (81 of 109) had a decrease in hot flashes by more than 50% from baseline (P < .0001). Less toxicity was reported in the MPA arm.A single MPA dose seems to be well tolerated and more effectively reduces hot flashes than does venlafaxine.
Effect of a Free Prepared Meal and Incentivized Weight Loss Program on Weight Loss and Weight Loss Maintenance in Obese and Overweight Women
Authors: Cheryl L. Rock, Shirley W. Flatt, Nancy E. Sherwood, Njeri Karanja, Bilge Pakiz, Cynthia A. Thomson
Journal: JAMA (2010)

<h3>Context</h3>The prevalence of overweight and obesity in the United States remains high. Commercial weight loss programs may contribute to efforts to reduce the prevalence of overweight and obesity, although few studies have examined their efficacy in controlled trials.<h3>Objective</h3>To test whether a free prepared meal and incentivized structured weight loss program promotes greater weight loss and weight loss maintenance at 2 years compared with usual care.<h3>Design, Setting, and Participants</h3>A randomized controlled trial of weight loss and weight loss maintenance in 442 overweight or obese women (body mass index, 25-40) aged 18 to 69 years (mean age, 44 years) conducted at US institutions over 2 years with follow-up between November 2007 and April 2010.<h3>Intervention</h3>The program, which involves in-person center-based or telephone-based one-to-one weight loss counseling, was available over a 2-year period. Behavioral goals were an energy-reduced, nutritionally adequate diet, facilitated by the inclusion of prepackaged food items in a planned menu during the initial weight loss phase, and increased physical activity. Participants assigned to usual care received 2 individualized weight loss counseling sessions with a dietetics professional and monthly contacts.<h3>Main Outcome Measures</h3>Weight loss and weight loss maintenance.<h3>Results</h3>Weight data were available at 24 months for 407 women (92.1% of the study sample). In an intent-to-treat analysis with baseline value substitution, mean weight loss was 7.4 kg (95% confidence interval [CI], 6.1-8.7 kg) or 7.9% (95% CI, 6.5%-9.3%) of initial weight at 24 months for the center-based group, 6.2 kg (95% CI, 4.9-7.6 kg) or 6.8% (95% CI, 5.2%-8.4%) for the telephone-based group, and 2.0 kg (95% CI, 0.6-3.3 kg) or 2.1% (95% CI, 0.7%-3.5%) for the usual care control group after 24 months (P &lt; .001 for intervention effect).<h3>Conclusion</h3>Compared with usual care, this structured weight loss program resulted in greater weight loss over 2 years.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00640900
Ancient Sex-Specific Extension of the Cytochrome c Oxidase II Gene in Bivalves and the Fidelity of Doubly-Uniparental Inheritance
Authors: Jason P. Curole, Thomas D. Kocher
Journal: Molecular Biology and Evolution (2002)

Bivalves of the families Mytilidae and Unionidae show a unique mode of mitochondrial DNA inheritance called doubly uniparental inheritance. In addition to receiving the maternally transmitted mtDNA lineage, males receive a separate mtDNA genome from their fathers. This system is sometimes compromised, in that female genomes are occasionally recruited into the male cycle of inheritance. These masculinization events are common in the Mytilidae but have not been reported in the Unionidae. In order to estimate the age of the male and the female lineages in the Unionidae and to look for evidence of masculinization, we sequenced the junction between the cytochrome c oxidase II gene and the cytochrome c oxidase I gene. The unionid male and female lineages diverged ∼450 MYA. There is no evidence for masculinization during this period, suggesting that there are taxon-specific differences in the rate of masculinization. Coincidentally, a 200-codon extension of the COII gene is present in the male genome of the Unionidae and may be responsible for the absence of masculinization.
p21ras couples the T cell antigen receptor to extracellular signal-regulated kinase 2 in T lymphocytes.
Authors: M Izquierdo, S J Leevers, C J Marshall, D Cantrell
Journal: The Journal of Experimental Medicine (1993)

It has previously been shown in T cells that stimulation of protein kinase C (PKC) or the T cell antigen receptor (TCR) induces the rapid accumulation of the active guanosine triphosphate-bound form of p21ras. These stimuli also induce the activation of extracellular signal-regulated kinase 2 (ERK2), a serine/threonine kinase that is rapidly activated via a kinase cascade in response to a variety of growth factors in many cell types. In this study, we show that p21ras is a component of the TCR signaling pathway that controls ERK2 activation. In the human Jurkat T cell line, transient expression of constitutively active p21ras induces ERK2 activation, measured as an increase in the ability of an ERK2-tag reporter protein to phosphorylate myelin basic protein. Thus, constitutively active p21ras bypasses the requirement for PKC activation or TCR triggering to induce ERK2 activation. In addition, activation of PKC or the TCR produces signals that cooperate with activated p21ras to stimulate ERK2. Conversely, expression of a dominant negative mutant of ras, Ha-ras N17, blocks ERK2 activation after TCR stimulation, indicating that endogenous p21ras function is necessary for the TCR-stimulated ERK2 activation. Taken together, these results demonstrate that the activation of p21ras is both necessary and sufficient to induce ERK2 activation in T cells.
The rarity of gene shuffling in conserved genes.
Authors: Gavin C Conant, Andreas Wagner
Journal: Genome biology (2005)

Abstract Background Among three sources of evolutionary innovation in gene function - point mutations, gene duplications, and gene shuffling (recombination between dissimilar genes) - gene shuffling is the most potent one. However, surprisingly little is known about its incidence on a genome-wide scale. Results We have studied shuffling in genes that are conserved between distantly related species. Specifically, we estimated the incidence of gene shuffling in ten organisms from the three domains of life: eukaryotes, eubacteria, and archaea, considering only genes showing significant sequence similarity in pairwise genome comparisons. We found that successful gene shuffling is very rare among such conserved genes. For example, we could detect only 48 successful gene-shuffling events in the genome of the fruit fly Drosophila melanogaster which have occurred since its common ancestor with the worm Caenorhabditis elegans more than half a billion years ago. Conclusion The incidence of gene shuffling is roughly an order of magnitude smaller than the incidence of single-gene duplication in eukaryotes, but it can approach or even exceed the gene-duplication rate in prokaryotes. If true in general, this pattern suggests that gene shuffling may not be a major force in reshaping the core genomes of eukaryotes. Our results also cast doubt on the notion that introns facilitate gene shuffling, both because prokaryotes show an appreciable incidence of gene shuffling despite their lack of introns and because we find no statistical association between exon-intron boundaries and recombined domains in the two multicellular genomes we studied.
PTU-143 Should We Investigate Mesenteric Panniculitis?: Uk Experience Of 58 Patients
Authors: C Ford, P Patel, K Burney, C Fernandez, R Fisher, P Youd
Journal: Gut (2014)

<h3>Introduction</h3> Mesenteric panniculitis (MP) is an inflammatory condition of the bowel mesentery with characteristic features on CT (computer tomography). Studies suggest MP is associated with malignant pathology, previous abdominal surgery, inflammatory and autoimmune diseases. There is a lack of consensus on the clinical significance of MP and its further investigation. <h3>Methods</h3> A retrospective analysis of medical records, imaging, endoscopy reports and histology. <h3>Results</h3> 58 patients were identified with mesenteric panniculitis by CT criteria during the study period. 8 patients (13.8%) had undergone previous abdominal surgery. 12 patients (20.7%) had a previous history of malignancy; lymphoma 3, prostate 2, bladder 2, both lymphoma/bladder 1, leukaemia 1, endometrial 1, carcinoid 1, and bronchial 1. Following index CT a new malignancy was identified in 5 patients (8.6%) and recurrence of a previous cancer in 1 (1.7%). 1 patient was diagnosed with lymphoma, 1 gastric carcinoma, 1 malignant myeloma, 1 bronchial carcinoma and 1 bladder cancer. 1 patient was diagnosed with a recurrence of a previously treated lymphoma. Of these 6 patients, 2 underwent endoscopic investigation; gastric carcinoma/lymphoma was suspected on index CT and endoscopy performed for histological confirmation. Of the remaining 52 patients with MP on index CT (and no new or recurrent malignancy) 18 (34.6%) underwent further endoscopic investigation. None of these patients were diagnosed with a new malignancy at the time of endoscopy; a new diagnosis of ulcerative colitis was made in 2 (3.8%). 15 patients (36.8%) underwent a follow up CT scan within an 18 month period. None were diagnosed with a new malignancy at the time of follow up CT. <h3>Conclusion</h3> This study suggests a high prevalence of malignancy amongst patients with MP on index CT. The diagnosis of MP on CT should alert the physician to the possibility of an undiagnosed malignancy. MP is poorly understood and inconsistently followed up. Its diagnosis can lead to investigation with poor clinical yield and patient/cost implications. This study suggests a diagnostic strategy for underlying malignancy should focus on close evaluation and scrutiny of index CT prior to consideration of further investigation. A larger study is required to identify the prevalence of associated organ specific malignancies, define the diagnostic yield of further investigation and inform an evidence-based diagnostic approach. <h3>Disclosure of Interest</h3> None Declared.
Short- and long-term outcome of linear morphoea in children
Authors: M. Piram, C.C. McCuaig, C. Saint-Cyr, D. Marcoux, A. Hatami, E. Haddad, J. Powell
Journal: British Journal of Dermatology (2013)

Linear morphoea (LM) is a rare fibrosing disorder of the limbs or the face that may cause functional disability and severe aesthetic sequelae. Despite a wide range of therapeutics reported for LM, there is currently a lack of consensus on the optimal therapy. Little is known about the long-term outcome of this disease.To describe the short- and long-term outcome of a large series of patients with LM acquired in childhood.A retrospective chart review of 52 paediatric patients with LM seen in our centre during a 20-year span (1990-2010) and a telephone survey in 2011 to assess the long-term outcome of these patients.Limbs were affected twice as often as the face, with a higher proportion of female patients. Stabilization was obtained after a mean disease duration of 5·4 years. Patients sometimes experienced long stretches of disease quiescence followed by reactivation; 31% of patients reported active disease after 10 years. All but one patient had aesthetic sequelae, and 38% had functional limitations. The effectiveness of methotrexate and systemic corticosteroids was apparent in the short term.LM needs prolonged monitoring as the disease can have very long periods of quiescence followed by reactivation. The combination of methotrexate and systemic corticosteroids was effective in the early stages of the disease but did not seem to prevent long-standing active disease or relapse in the long term.
A pathway sensor for genome-wide screens of intracellular proteolytic cleavage
Authors: Robin Ketteler, Zairen Sun, Karl F Kovacs, Wei-Wu He, Brian Seed
Journal: Genome biology (2008)

Abstract Protein cleavage is a central event in many regulated biological processes. We describe a system for detecting intracellular proteolysis based on non-conventional secretion of Gaussia luciferase (GLUC). GLUC exits the cell without benefit of a secretory leader peptide, but can be anchored in the cell by fusion to β-actin. By including protease cleavage sites between GLUC and β-actin, proteolytic cleavage can be detected. Using this assay, we have identified regulators of autophagy, apoptosis and β-actin cleavage.
Inflamed target tissue provides a specific niche for highly expanded T-cell clones in early human autoimmune disease
Authors: P L Klarenbeek, M J H de Hair, M E Doorenspleet, B D C van Schaik, R E E Esveldt, M G H van de Sande, T Cantaert, D M Gerlag, D Baeten, A H C van Kampen, F Baas, P P Tak, N de Vries
Journal: Annals of the Rheumatic Diseases (2012)

Objective To profile quantitatively the T-cell repertoire in multiple joints and peripheral blood of patients with recent onset (early) or established rheumatoid arthritis (RA) using a novel next-generation sequencing protocol to identify potential autoreactive clones. Methods Synovium of patients with recent onset (early) RA (<6 months) (n=6) or established RA (>18 months) (n=6) was screened for T-cell clones by sequencing over 10 000 T-cell receptors (TCR) per sample. T cells from paired blood samples were analysed for comparison. From two patients synovial T cells were obtained from multiple inflamed joints. The degree of expansion of each individual clone was based on its unique CDR3 sequence frequency within a sample. Clones with a frequency of over 0.5% were considered to be highly expanded clones (HEC). Results In early RA synovium, the T-cell repertoire was dominated by 35 HEC (median, range 2–70) accounting for 56% of the TCR sequenced. The clonal dominance in the synovium was patient specific and significantly greater than in established RA (median of 11 HEC (range 5–24) in established RA synovium accounting for 9.8% of T cells; p<0.01). 34% (range 28–40%) of the most expanded T-cell clones were shared between different joints in the same patients, compared with only 4% (range 0–8%) between synovium and blood (p=0.01). Conclusions In RA, a systemic autoimmune disease, the inflamed synovium forms a niche for specific expanded T-cell clones, especially in early disease. This suggests that, at least in RA, autoreactive T cells should be addressed specifically in the inflamed tissue, preferably in the early phase of the disease.
Immunotherapy of distant metastatic disease
Authors: D. Schadendorf, S.M. Algarra, L. Bastholt, G. Cinat, B. Dreno, A.M.M. Eggermont, E. Espinosa, J. Guo, A. Hauschild, T. Petrella, J. Schachter, P. Hersey
Journal: Annals of Oncology (2009)

Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed.
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells
Authors: Loise M. Francisco, Victor H. Salinas, Keturah E. Brown, Vijay K. Vanguri, Gordon J. Freeman, Vijay K. Kuchroo, Arlene H. Sharpe
Journal: The Journal of Experimental Medicine (2009)

Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1−/− antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1–coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1−/−PD-L2−/− Rag−/− recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.
Epigenetic regulation of glial fibrillary acidic protein by DNA methylation in human malignant gliomas
Authors: A. Restrepo, C. A. Smith, S. Agnihotri, M. Shekarforoush, P. N. Kongkham, H. J. Seol, P. Northcott, J. T. Rutka
Journal: Neuro-Oncology (2010)

Glial fibrillary acidic protein (GFAP) is an intermediate filament expressed in glial cells that stabilizes and maintains the cytoskeleton of normal astrocytes. In glial tumors, GFAP expression is frequently lost with increasing grade of malignancy, suggesting that GFAP is important for maintaining glial cell morphology or regulating astrocytoma cell growth. Most permanent human glioma cell lines are GFAP negative by immunocytochemistry. Given that the GFAP gene is not mutated in human glioma specimens or glioma cell lines, we considered epigenetic mechanisms, such as promoter methylation, as a cause of silencing of GFAP in these tumors. In this study, we treated known GFAP-negative glioma cell lines with 5-aza-2′-deoxycytidine to examine GFAP promoter hypermethylation. Additionally, we performed bisulfite sequencing on primary glioma samples and glioma cell lines and showed an inverse relationship between GFAP promoter methylation status and GFAP expression. Using a gene reporter assay with the GFAP promoter cloned upstream of a luciferase gene, we showed that methylation of the GFAP promoter downregulates the expression of the luciferase gene. Our results suggest that epigenetic silencing of the GFAP gene through DNA methylation of its promoter region may be one mechanism by which GFAP is downregulated in human gliomas and glioma cell lines.
CASTANOSPERMINE AND OTHER PLANT ALKALOID INHIBITORS OF GLUCOSIDASE ACTIVITY BLOCK THE GROWTH OF HIV
Authors: A.S. Tyms, E.M. Berrie, T.A. Ryder, R.J. Nash, M.P. Hegarty, D.L. Taylor, M.A. Mobberley, J.M. Davis, E.A. Bell, D.J. Jeffries, D. Taylor-Robinson, L.E. Fellows
Journal: The Lancet (1987)