tbuckley/cabot-search huggingface dataset:
Phylogenomics of Life-Or-Death Switches in Multicellular Animals: Bcl-2, BH3-Only, and BNip Families of Apoptotic Regulators
Authors: Abdel Aouacheria, Frédéric Brunet, Manolo Gouy
Journal: Molecular Biology and Evolution (2005)

In this report, we conducted a comprehensive survey of Bcl-2 family members, a divergent group of proteins that regulate programmed cell death by an evolutionarily conserved mechanism. Using comparative sequence analysis, we found novel sequences in mammals, nonmammalian vertebrates, and in a number of invertebrates. We then asked what conclusions could be drawn from phyletic distribution, intron/exon structures, sequence/structure relationships, and phylogenetic analyses within the updated Bcl-2 family. First, multidomain members having a sequence pattern consistent with the conservation of the Bcl-XL/Bax/Bid topology appear to be restricted to multicellular animals and may share a common ancestry. Next, BNip proteins, which were originally identified based on their ability to bind to E1B 19K/Bcl-2 proteins, form three independent monophyletic branches with different evolutionary history. Lastly, a set of Bcl-2 homology 3–only proteins with unrelated secondary structures seems to have evolved after the origin of Metazoa and exhibits diverse expansion after speciation during vertebrate evolution.
Short-course antibiotic treatment in acute exacerbations of chronic bronchitis and COPD: a meta-analysis of double-blind studies
Authors: R El Moussaoui, B M Roede, P Speelman, P Bresser, J M Prins, P M M Bossuyt
Journal: Thorax (2008)

A study was undertaken to determine whether a short course of antibiotic treatment (< or = 5 days) is as effective as the conventional longer treatment in acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease (COPD).MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched to July 2006. Studies considered eligible were double-blind randomised clinical trials including adult patients > or = 18 years of age with a clinical diagnosis of exacerbation of COPD or chronic bronchitis, no antimicrobial therapy at the time of diagnosis and random assignment to antibiotic treatment for < or = 5 days versus > 5 days. The primary outcome measure was clinical cure at early follow-up on an intention-to-treat basis.21 studies with a total of 10 698 patients were included. The average quality of the studies was high: the mean (SD) Jadad score was 3.9 (0.9). At early follow-up (< 25 days), the summary odds ratio (OR) for clinical cure with short treatment versus conventional treatment was 0.99 (95% CI 0.90 to 1.08). At late follow-up the summary OR was 1.0 (95% CI 0.91 to 1.10) and the summary OR for bacteriological cure was 1.05 (95% CI 0.87 to 1.26). Similar summary ORs were observed for early cure in trials with the same antibiotic in both arms and in studies grouped by the antibiotic class used in the short-course arm.A short course of antibiotic treatment is as effective as the traditional longer treatment in patients with mild to moderate exacerbations of chronic bronchitis and COPD.
Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a prospective placebo controlled double blind trial
Authors: S E Edmonds, P G Winyard, R Guo, B Kidd, P Merry, A Langrish-Smith, C Hansen, S Ramm, D R Blake
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> Vitamin E, the most potent naturally occurring lipid soluble antioxidant has been suggested to possess both anti-inflammatory and analgesic activity in humans. This double blind and randomised study used a broad spectrum of clinical and laboratory parameters to investigate whether there was any additional anti-inflammatory or analgesic effects, or both, of orally administered α-tocopherol in rheumatoid arthritis patients who were already receiving anti-rheumatic drugs. <h3>METHODS</h3> Forty two patients were enrolled and treated with α-tocopherol (n=20) at a dose of 600 mg twice a day (2 × 2 capsules) or with placebo (n=22) for 12 weeks. The following parameters were measured: (1) Three clinical indices of inflammation—the Ritchie articular index, the duration of morning stiffness, and the number of swollen joints; (2) three measures of pain—pain in the morning, pain in the evening, and pain after chosen activity; (3) haematological and biochemical measures of inflammatory activity; (4) assays for the oxidative modification of proteins and lipids. <h3>RESULTS</h3> All laboratory measures of inflammatory activity and oxidative modification were unchanged. Furthermore, the clinical indices of inflammation were not influenced by the treatment. However, the pain parameters were significantly decreased after vitamin E treatment when compared with placebo. <h3>CONCLUSION</h3> The results provide preliminary evidence that vitamin E may exert a small but significant analgesic activity independent of a peripheral anti-inflammatory effect, but which complements standard anti-inflammatory treatment.
Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations
Authors: Luciano G Martelotto, Charlotte KY Ng, Maria R De Filippo, Yan Zhang, Salvatore Piscuoglio, Raymond S Lim, Ronglai Shen, Larry Norton, Jorge S Reis-Filho, Britta Weigelt
Journal: Genome biology (2014)

Abstract Background Massively parallel sequencing studies have led to the identification of a large number of mutations present in a minority of cancers of a given site. Hence, methods to identify the likely pathogenic mutations that are worth exploring experimentally and clinically are required. We sought to compare the performance of 15 mutation effect prediction algorithms and their agreement. As a hypothesis-generating aim, we sought to define whether combinations of prediction algorithms would improve the functional effect predictions of specific mutations. Results Literature and database mining of single nucleotide variants (SNVs) affecting 15 cancer genes was performed to identify mutations supported by functional evidence or hereditary disease association to be classified either as non-neutral (n = 849) or neutral (n = 140) with respect to their impact on protein function. These SNVs were employed to test the performance of 15 mutation effect prediction algorithms. The accuracy of the prediction algorithms varies considerably. Although all algorithms perform consistently well in terms of positive predictive value, their negative predictive value varies substantially. Cancer-specific mutation effect predictors display no-to-almost perfect agreement in their predictions of these SNVs, whereas the non-cancer-specific predictors showed no-to-moderate agreement. Combinations of predictors modestly improve accuracy and significantly improve negative predictive values. Conclusions The information provided by mutation effect predictors is not equivalent. No algorithm is able to predict sufficiently accurately SNVs that should be taken forward for experimental or clinical testing. Combining algorithms aggregates orthogonal information and may result in improvements in the negative predictive value of mutation effect predictions.
JIGSAW, GeneZilla, and GlimmerHMM: puzzling out the features of human genes in the ENCODE regions.
Authors: Jonathan E Allen, William H Majoros, Mihaela Pertea, Steven L Salzberg
Journal: Genome biology (2006)

Predicting complete protein-coding genes in human DNA remains a significant challenge. Though a number of promising approaches have been investigated, an ideal suite of tools has yet to emerge that can provide near perfect levels of sensitivity and specificity at the level of whole genes. As an incremental step in this direction, it is hoped that controlled gene finding experiments in the ENCODE regions will provide a more accurate view of the relative benefits of different strategies for modeling and predicting gene structures. Here we describe our general-purpose eukaryotic gene finding pipeline and its major components, as well as the methodological adaptations that we found necessary in accommodating human DNA in our pipeline, noting that a similar level of effort may be necessary by ourselves and others with similar pipelines whenever a new class of genomes is presented to the community for analysis. We also describe a number of controlled experiments involving the differential inclusion of various types of evidence and feature states into our models and the resulting impact these variations have had on predictive accuracy. While in the case of the non-comparative gene finders we found that adding model states to represent specific biological features did little to enhance predictive accuracy, for our evidence-based 'combiner' program the incorporation of additional evidence tracks tended to produce significant gains in accuracy for most evidence types, suggesting that improved modeling efforts at the hidden Markov model level are of relatively little value. We relate these findings to our current plans for future research.
US Medicare, Medicaid, and nurse practitioners all turn 50
Authors: Douglas Kamerow
Journal: BMJ (2015)

Much accomplished, much more to be done

This month marks the 50th anniversary of the creation of Medicare and Medicaid in the United States. In 1965, when President Lyndon Johnson signed the law that had been a dream of two of his predecessors, John F Kennedy and Harry S Truman, he handed the first two Medicare cards to the then 81 year old Truman and his wife. Truman had fought for a more comprehensive national health insurance system during his presidency, but political realities limited Johnson’s law to two separate programs that covered just elderly people (Medicare) and poor people (Medicaid).

Johnson was able to include coverage of poor people in the law only because conservative opponents to universal health insurance thought that including them initially would prevent later changes leading to a truly comprehensive program, what the critics called “socialized medicine.”1 And it did, for 45 years, until the passage of the Affordable Care Act in 2010.

Before Medicare older Americans were often medically destitute. Less than half had health insurance in 1962, compared with 2% today. Within a decade of the passage of Medicare, older people’s access to care had improved, with increases in rates of admission to hospital and physician contacts. The rate of cataract …
The Hormonal Regulation of Pyloric Sphincter Function
Authors: Robert S. Fisher, William Lipshutz, Sidney Cohen
Journal: Journal of Clinical Investigation (1973)

The purpose of this study was to evaluate the hormonal control of pyloric sphincter function. Studies were performed on both pyloric circular muscle, in vitro, and the human pylorus, in vivo. Full dose-response curves to gastrin I, cholecystokinin, and secretin were constructed for the pyloric muscle of the opossum studied at its length of optimal tension development, Lo. Both cholecystokinin and secretin were potent agonists on the muscle but gastrin I gave no increase in muscle tension. The combination of cholecystokinin and secretin was additive at submaximal concentrations but potentiation of the maximal responses was not observed. Gastrin I produced a surmountable, competitive-like antagonism to the effect of cholecystokinin on the pyloric muscle. The octapeptide of cholecystokinin was a more potent agonist than the whole molecule of cholecystokinin on the pyloric muscle. In man, the pyloric pressure rose significantly during intravenous infusion of either cholecystokinin or secretin. The combination of maximal doses of both hormones did not show significant potentiation. Gastrin I did not significantly increase pyloric pressure but did antagonize the pyloric response to duodenal acidification. These studies suggest that: (a) Both secretin and cholecystokinin augment pyloric sphincter pressure while gastrin I is an antagonist inhibiting their effects. (b) The hormonal responses of pyloric sphincter circular muscle, in vitro, can be correlated with human sphincter function, in vivo.
Physiological effects of vibration in subjects with cystic fibrosis
Authors: B. McCarren, J. A. Alison
Journal: European Respiratory Journal (2006)

The physiological mechanisms by which vibration and other physiotherapy interventions may clear secretions in subjects with cystic fibrosis are unknown. The main aim of this study was to compare the expiratory flow rates and frequencies of airflow oscillation of vibration to those of Acapella®, Flutter®, positive expiratory pressure and percussion. Respiratory flow rates were measured during interventions, the order of which was randomised. The oscillation of the airflow of the interventions was determined by frequency spectral analysis. In 18 young adult subjects with cystic fibrosis, the mean peak expiratory flow rate of vibration was greater than Flutter®, percussion, Acapella® and positive expiratory pressure. The mean± sd of the oscillation of the airflow of vibration (8.4±0.4 Hz) was lower than Acapella® (13.5±1.7 Hz) and Flutter® (11.3±1.5 Hz) but similar to percussion (7.3±0.3 Hz). Theoretically, the higher peak expiratory flow rate of vibration compared to the other physiotherapy interventions may promote secretion clearance. In addition, the frequency of oscillation of vibration was within the range demonstrated to increase mucus transport. This study has provided some evidence for the physiological rationale for the use of vibration to aid secretion clearance.
Polyethylene flock-associated interstitial lung disease in a Spanish female
Authors: E. Barroso, M.D. Ibañez, F.I. Aranda, S. Romero
Journal: European Respiratory Journal (2002)

This case study presents a female aged 54 yrs with a 12 months history of progressive pulmonary impairment after a 7-yr period of occupational exposure to rotary-cut polyethylene. An open lung biopsy revealed the histopathology of follicular bronchiolitis that is viewed as a stereotypical feature for flock worker9s lung. It seems to be the first case of plastic flock-associated interstitial lung disease reported outside North America.
Romidepsin targets multiple survival signaling pathways in malignant T cells
Authors: B C Valdez, J E Brammer, Y Li, D Murray, Y Liu, C Hosing, Y Nieto, R E Champlin, B S Andersson
Journal: Blood Cancer Journal (2015)

Abstract Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 n m in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies.
Acute lymphoblastic leukemia in a patient with longstanding polycythemia vera: Cytogenetic analysis reveals two distinct abnormal clones
Authors: John Anastasi, Mark J. Pettenati, Michelle M. Le Beau, Hau C. Kwaan, Susan C. Weil
Journal: American Journal of Hematology (1988)

Abstract A 68‐year‐old female patient is described in whom acute lymphoblastic leukemia followed a long course of polycythemia vera. Chromosomal analysis of a peripheral blood specimen at the time of blastic transformation revealed two distinct clones: one characterized by a chromosomal abnormality frequently noted in polycythemia vera and the other by a rearrangement characteristically observed in lymphoid malignancies. These findings suggest the existence of two independent hematologic diseases: this phenomenon would not support the speculation from previous reports that lymphoproliferative disorders in patients with polycythemia vera arise from clonal evolution.
P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities.
Authors: A Moretta, M Vitale, C Bottino, A M Orengo, L Morelli, R Augugliaro, M Barbaresi, E Ciccone, L Moretta
Journal: The Journal of Experimental Medicine (1993)

Human CD3-16+56+ natural killer (NK) cells have been shown to display a clonally distributed ability to recognize major histocompatibility complex (MHC) class I alleles. Opposite to T lymphocytes, in NK cells, specific recognition of MHC class I molecules appears to induce inhibition of cytolytic activity and, thus, to protect target cells. Since a precise correlation has been established between the expression of the NK-specific GL183 and EB6 surface molecules (belonging to the novel p58 molecular family) and the specificity of NK clones, we analyzed whether p58 molecules could function as receptors for MHC in human NK cells. NK clones displaying the previously defined "specificity 2" and characterized by the GL183+EB6+ phenotype, specifically recognize the Cw3 allele and thus fail to lyse the Fc gamma R+ P815 target cells transfected with Cw3. On the other hand, NK clones displaying "specificity 1" and expressing the GL183-EB6+ phenotype failed to lyse Cw4+ target cells. Addition of the F(ab')2 fragments of either GL183 or EB6 mAb as well as the XA141 mAb of IgM isotype (specific for the EB6 molecules) completely restored the lysis of Cw3-transfected P815 cells by the Cw3-specific NK clones EX2 and EX4. Similarly, both the entire EB6 mAb, its F(ab')2 fragment and the XA141 mAb reconstituted the lysis of C1R, a Fc gamma R- target cell expressing Cw4 as the only serologically detected class I antigen. Thus, it appears that masking of different members of p58 molecules prevents recognition of "protective" MHC class I alleles and thus the delivering of inhibitory signals. Further support to the concept that p58 molecules represent a NK receptor delivering a negative signal was provided by experiments in which the entire anti-p58 mAbs (of IgG isotype) could inhibit the lysis of unprotected Fc gamma R+ P815 target cells, thus mimicking the inhibitory effect of MHC class I molecules.
Minimally modified low density lipoprotein stimulates monocyte endothelial interactions.
Authors: J A Berliner, M C Territo, A Sevanian, S Ramin, J A Kim, B Bamshad, M Esterson, A M Fogelman
Journal: Journal of Clinical Investigation (1990)

The effect of minimally modified LDL (MM-LDL) on the ability of large vessel endothelial cells (EC) to interact with monocytes and neutrophils was examined. These LDL preparations, obtained by storage or by mild iron oxidation, were indistinguishable from native LDL to the LDL receptor and were not recognized by the scavenger receptor. Treatment of EC with as little as 0.12 micrograms/ml MM-LDL caused a significant increase in the production of chemotactic factor for monocytes (sevenfold) and increased monocyte binding (three- to fivefold). Monocyte binding was maximal after 4 h of EC exposure to MM-LDL, persisted for 48 h, and was inhibited by cycloheximide. In contrast, neutrophil binding was not increased after 1-24 h of exposure. Activity in the MM-LDL preparations was found primarily in the polar lipid fraction. MM-LDL was toxic for EC from one rabbit but not toxic for the cells from another rabbit or any human umbilical vein EC. The resistant cells became sensitive when incubated with lipoprotein in the presence of cycloheximide, whereas the sensitive strain became resistant when preincubated with sublethal concentrations of MM-LDL. We conclude that exposure of EC to sublethal levels of MM-LDL enhances monocyte endothelial interactions and induces resistance to the toxic effects of MM-LDL.
Adult-onset Still's disease with an associated severe restrictive pulmonary defect: a case report.
Authors: A J Corbett, T M Zizic, M B Stevens
Journal: Annals of the Rheumatic Diseases (1983)

A 21-year-old black female with an 18-month history of adult Still9s disease developed symptoms and objective findings of restrictive lung disease. The pulmonary function abnormalities persisted unchanged for an additional 18 months despite moderate doses of prednisone. This complication has not been previously described in association with adult Still9s disease.
Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia
Authors: Jaime G. Maldonado-Avilés, Allison A. Curley, Takanori Hashimoto, A. Leslie Morrow, Amy J. Ramsey, Patricio O’Donnell, David W. Volk, David A. Lewis
Journal: American Journal of Psychiatry (2009)

Cognitive impairments in schizophrenia are associated with lower expression of markers of gamma-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA(A) receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA(A) receptor alpha4 and delta subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia.
The role of Raf-1 in the regulation of extracellular signal-regulated kinase 2 by the T cell antigen receptor.
Authors: M Izquierdo, S Bowden, D Cantrell
Journal: The Journal of Experimental Medicine (1994)

Triggering of the T cell antigen receptor (TCR) complex activates the serine/threonine kinase Raf-1 whose function is necessary for TCR induction of the interleukin 2 gene. Raf-1 has been identified as a candidate mitogen-activated protein (MAP) kinase kinase kinase (MKKK) and thus has the potential to couple the TCR to the activation of the MAP kinases such as ERK2. In the present study, the role of Raf-1 in ERK2 regulation of ERK2 in T cells has been explored. A constitutively active Raf-1 kinase, v-raf, or a dominant inhibitory Raf-1 mutant were expressed transiently from the pEF BOS vector in Jurkat cells and the effects of these Raf-1 mutants on a coexpressed ERK2 reporter was assessed. The action of the constitutively active Raf-1 was to stimulate the ERK2 kinase, whereas the dominant negative version of Raf-1 inhibited the ERK2 activation induced by triggering of the TCR. These data indicate a role for Raf-1 in the regulation of ERK2 in T cells.