tbuckley/cabot-search huggingface dataset:
Parallel Increase in Urinary Excretion Rates of Immunoglobulin G, Ceruloplasmin, Transferrin, and Orosomucoid in Normoalbuminuric Type 2 Diabetic Patients
Authors: Takuma Narita, Hiroshi Sasaki, Mihoko Hosoba, Takeshi Miura, Naomi Yoshioka, Tsukasa Morii, Takashi Shimotomai, Jun Koshimura, Hiroki Fujita, Masafumi Kakei, Seiki Ito
Journal: Diabetes Care (2004)

OBJECTIVE—Increased urinary excretions of several plasma proteins with different molecular radii &amp;lt;55 Å and different isoelectric points (pI), such as IgG, ceruloplasmin, transferrin, and orosomucoid, have been independently reported to precede the development of microalbuminuria in diabetic patients. We examined whether increases in urinary excretions of these proteins would be in parallel in the same patient. RESEARCH DESIGN AND METHODS—Urinary excretion rates of proteins mentioned above in timed overnight urine samples were evaluated in 61 normoalbuminuric type 2 diabetic patients (group D) aged 40–60 years and in 17 age-matched control subjects (group C). RESULTS—The excretion rates of these proteins were significantly higher in group D than in group C. These exhibited a strong linear correlation with each other and had a weak correlation with the excretion rate of N-acethylglucosaminidase. The excretion rate of α2-macroglobulin with large molecular radii of 88 Å was not different between groups C and D, nor did they have any correlations with the excretion rates of the other proteins. Creatinine clearance and blood pressure levels in group D were significantly higher than those in group C. CONCLUSIONS—In normoalbuminuric diabetic patients, excretion rates of plasma proteins with molecular radii &amp;lt;55 Å increased in parallel with each other. In view of our previous finding that urinary excretions of these plasma proteins selectively increased in parallel with enhanced glomerular filtration rate after acute protein loading, the present finding may be explained by renal hemodynamic changes, such as increased intraglomerular hydraulic pressure.
Lumbar intervertebral disk degeneration in Japanese male volleyball players belonging to the national team
Authors: M Hayashi, Y Hamu, Y Hashimoto, K Kaneoka, M Hangai, T Okuwak
Journal: British Journal of Sports Medicine (2011)

Background Lower back pain occurs more frequently among volleyball than other players and one of the main course affecting their performance on the court. Objective To identify the reason of the lower back pain, a detailed MRI analysis of disk degeneration (DD) and survey were conducted. Design, setting and participants There were 48 players from the 2009 and 2010 national teams; mean age, 25.1 years; mean height, 188.7 cm, mean weight, 81.9 kg; mean length of career as a volleyball player, 15.1 years. They practiced volleyball on 5.9 days of the week and for 4.1 h a day, on average. Intervention DD of each case was evaluated retrospectively based on the signal intensity (rated on a 5-grade scale: I through V) of five intervertebral disks (L1/2 to L5/S1) on MRI using Pfirrmann's classification. Results The DD grade was I-II in five players (10.4%) and III-V in 43 players (89.6%). It was 20.8% at L1/2, 22.9% at L2/3, 16.7% at L3/4, 45.8% at L4/5, and 75.0% at L5/S1. Of all the players, 95.8% had had lower back pain. Conclusions Hangai et al .1 reported a higher prevalence of DD among baseball players (59.7%) and swimmers (57.5%) than among non-athletes (31.4%). The prevalence of DD among the volleyball players was as high as 89.6% in this study. With an average of 200 jumps a day, a volleyball player will jump about one million times during a 15-year career. Factors possibly responsible for DD and lower back pain are: (1) shocks from jumping and landing associated with attacks, blocks, jump serves, etc., (2) body trunk twisting in the air at the time of attack, (3) flying receiving, etc. In summary, the prevalence of DD among Japanese male national volleyball players was 89.6%. DD was closely associated with volleyball tactics.
Comparative genomics of the social amoebae Dictyostelium discoideum and Dictyostelium purpureum
Authors: Richard Sucgang, Alan Kuo, Xiangjun Tian, William J Salerno, Anup Parikh, Christa L Feasley, Eileen Dalin, Hank Tu, Eryong Huang, Kerrie Barry, Erika A. Lindquist, Harris Shapiro, David G Bruce, Jeremy Schmutz, Asaf Salamov, Petra Fey, Pascale Gaudet, Christophe Anjard, M. Madan Babu, Siddhartha Basu, Yulia Bushmanova, Hanke van der Wel, Mariko Katoh-Kurasawa, Christopher Dinh, Pedro M Coutinho, Tamao Saito, Marek Eliáš, Pauline Schaap, Robert R. Kay, Bernard Henrissat, Ludwig Eichinger, Francisco Rivero, Nicholas H. Putnam, Christopher M West, William F Loomis, Rex L Chisholm, Gad Shaulsky, Joan E Strassmann, David C. Queller, Adam Kuspa, Igor V. Grigoriev
Journal: Genome biology (2011)

Abstract Background The social amoebae (Dictyostelia) are a diverse group of Amoebozoa that achieve multicellularity by aggregation and undergo morphogenesis into fruiting bodies with terminally differentiated spores and stalk cells. There are four groups of dictyostelids, with the most derived being a group that contains the model species Dictyostelium discoideum . Results We have produced a draft genome sequence of another group dictyostelid, Dictyostelium purpureum , and compare it to the D. discoideum genome. The assembly (8.41 × coverage) comprises 799 scaffolds totaling 33.0 Mb, comparable to the D. discoideum genome size. Sequence comparisons suggest that these two dictyostelids shared a common ancestor approximately 400 million years ago. In spite of this divergence, most orthologs reside in small clusters of conserved synteny. Comparative analyses revealed a core set of orthologous genes that illuminate dictyostelid physiology, as well as differences in gene family content. Interesting patterns of gene conservation and divergence are also evident, suggesting function differences; some protein families, such as the histidine kinases, have undergone little functional change, whereas others, such as the polyketide synthases, have undergone extensive diversification. The abundant amino acid homopolymers encoded in both genomes are generally not found in homologous positions within proteins, so they are unlikely to derive from ancestral DNA triplet repeats. Genes involved in the social stage evolved more rapidly than others, consistent with either relaxed selection or accelerated evolution due to social conflict. Conclusions The findings from this new genome sequence and comparative analysis shed light on the biology and evolution of the Dictyostelia.
Molecular Pathways: Aspirin and Wnt Signaling—A Molecularly Targeted Approach to Cancer Prevention and Treatment
Authors: Manish K. Gala, Andrew T. Chan
Journal: Clinical Cancer Research (2014)

The anti-inflammatory properties of aspirin have resulted in its widespread use as an analgesic, antipyretic, and cardioprotective agent. Beyond these applications, multiple observational studies and randomized controlled trials have demonstrated a chemopreventative role for aspirin, particularly in the development of colorectal neoplasia. Given the critical importance of Wnt dysregulation in colorectal carcinogenesis, the interplay between aspirin and canonical Wnt signaling has become a focus of investigation. These studies have illuminated our understanding of the anticancer mechanisms of aspirin, yielding the identification of potential biomarkers for which aspirin's chemopreventative efficacy can be safely optimized into routine clinical practice and providing leads into the discovery of novel preventive and therapeutic targets. In this review, we summarize key experimental and clinical studies of this interaction, as well as highlighting future strategies to advance their clinical translation.
Serotonin regulates amylase secretion and acinar cell damage during murine pancreatitis
Authors: Sabrina Sonda, Alberto B Silva, Kamile Grabliauskaite, Enrica Saponara, Achim Weber, Jae-Hwi Jang, Richard A Züllig, Martha Bain, Theresia Reding Graf, Adrian B Hehl, Rolf Graf
Journal: Gut (2012)

<h3>Objective</h3> Serotonin (5-hydroxytryptamine, 5-HT) is a potent bioactive molecule involved in a variety of physiological processes. In this study, the authors analysed whether 5-HT regulates zymogen secretion in pancreatic acinar cells and the development of pancreatic inflammation, a potentially lethal disease whose pathophysiology is not completely understood. <h3>Methods</h3> 5-HT regulation of zymogen secretion was analysed in pancreatic acini isolated from wild-type or tryptophan hydoxylase-1 knock-out (TPH1<sup>−/−</sup>) mice, which lack peripheral 5-HT, and in amylase-secreting pancreatic cell lines. Pancreatitis was induced by cerulein stimulation and biochemical and immunohistochemical methods were used to evaluate disease progression over 2 weeks. <h3>Results</h3> Absence and reduced intracellular levels of 5-HT inhibited the secretion of zymogen granules both ex vivo and in vitro and altered cytoskeleton dynamics. In addition, absence of 5-HT resulted in attenuated pro-inflammatory response after induction of pancreatitis. TPH1<sup>−/−</sup> mice showed limited zymogen release, reduced expression of the pro-inflammatory chemokine MCP-1 and minimal leucocyte infiltration compared with wild-type animals. Restoration of 5-HT levels in TPH1<sup>−/−</sup> mice recovered the blunted inflammatory processes observed during acute pancreatitis. However, cellular damage, inflammatory and fibrotic processes accelerated in TPH1<sup>−/−</sup> mice during disease progression. <h3>Conclusions</h3> These results identify a 5-HT-mediated regulation of zymogen secretion in pancreatic acinar cells. In addition, they demonstrate that 5-HT is required for the onset but not for the progression of pancreatic inflammation. These findings provide novel insights into the normal physiology of pancreatic acinar cells and into the pathophysiology of pancreatitis, with potential therapeutic implications.
Evidence for Sequenced Molecular Evolution of <i>IDH1</i> Mutant Glioblastoma From a Distinct Cell of Origin
Authors: Albert Lai, Samir Kharbanda, Whitney B. Pope, Anh Tran, Orestes E. Solis, Franklin Peale, William F. Forrest, Kanan Pujara, Jose A. Carrillo, Ajay Pandita, Benjamin M. Ellingson, Chauncey W. Bowers, Robert H. Soriano, Nils O. Schmidt, Sankar Mohan, William H. Yong, Somasekar Seshagiri, Zora Modrusan, Zhaoshi Jiang, Kenneth D. Aldape, Paul S. Mischel, Linda M. Liau, Cameron J. Escovedo, Weidong Chen, Phioanh Leia Nghiemphu, C. David James, Michael D. Prados, Manfred Westphal, Katrin Lamszus, Timothy Cloughesy, Heidi S. Phillips
Journal: Journal of Clinical Oncology (2011)

Purpose Mutation in isocitrate dehydrogenase 1 (IDH1) at R132 (IDH1 R132MUT ) is frequent in low-grade diffuse gliomas and, within glioblastoma (GBM), has been proposed as a marker for GBMs that arise by transformation from lower-grade gliomas, regardless of clinical history. To determine how GBMs arising with IDH1 R132MUT differ from other GBMs, we undertook a comprehensive comparison of patients presenting clinically with primary GBM as a function of IDH1 R132 mutation status. Patients and Methods In all, 618 treatment-naive primary GBMs and 235 lower-grade diffuse gliomas were sequenced for IDH1 R132 and analyzed for demographic, radiographic, anatomic, histologic, genomic, epigenetic, and transcriptional characteristics. Results Investigation revealed a constellation of features that distinguishes IDH1 R132MUT GBMs from other GBMs (including frontal location and lesser extent of contrast enhancement and necrosis), relates them to lower-grade IDH1 R132MUT gliomas, and supports the concept that IDH1 R132MUT gliomas arise from a neural precursor population that is spatially and temporally restricted in the brain. The observed patterns of DNA sequence, methylation, and copy number alterations support a model of ordered molecular evolution of IDH1 R132MUT GBM in which the appearance of mutant IDH1 protein is an initial event, followed by production of p53 mutant protein, and finally by copy number alterations of PTEN and EGFR. Conclusion Although histologically similar, GBMs arising with and without IDH1 R132MUT appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.
Bosentan for Sarcoidosis-associated Pulmonary Hypertension, Age-adjusted D-Dimer Levels in Pulmonary Embolism, and Mean Arterial Blood Pressure Targets in Septic Shock
Authors: Roger A. Alvarez, Ian J. Barbash, Jason J. Rose
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Pulmonary hypertension (PH) is present in a significant number of patients with advanced sarcoidosis, and is associated with increased mortality. Baughman and colleagues (1) performed a double-blind, randomized, placebo-controlled trial to determine whether bosentan is effective in treating sarcoidosis-associated PH. A total of 39 patients with sarcoidosis and pulmonary artery (PA) hypertension were randomized to receive either bosentan or placebo in a 2:1 ratio. Patients were excluded if they had severe exercise limitation (New York Heart Association class IV), severe airway obstruction, or significant heart failure. Right heart catheterization was performed before and after 16 weeks of therapy. Outcomes included the changes in mean PA pressure, 6-minute walk distance (6MWD), dyspnea, and quality of life as assessed by validated questionnaires. In the 30 patients with serial hemodynamic data, mean PA pressure decreased by 4 (66.6) mm Hg in the bosentan group (P , 0.02), and increased by 1 (63.7) mm Hg (P . 0.05) in the placebo group. There was no significant change in 6MWD, dyspnea, or quality of life scores in either group. Themajor limitation of this study is its emphasis on PA pressure. Changes in PA pressure correlate poorly with clinical outcomes. Contemporary studies of PH therapy generally emphasize functional outcomes, such as 6MWD (2). In this study, 6MWD decreased in the bosentan group (223 6 69.5 m; P . 0.05), whereas it increased in the placebo group (176 44.1; P. 0.05). Although not statistically significant, this difference, together with more frequent desaturation in the bosentan group, suggests that bosentan worsened gas exchange in some patients (3). In this study, 18 of 35 patients had fibrosis on chest radiograph, a forced vital capacity of less than 60%, or both. However, even a subgroup analysis of patients with forced vital capacity greater than 50% failed to demonstrate an increased 6MWD. Given the modest PH in this study (mean PA pressure, z35 mm Hg; mean right atrial pressure, 5 mm Hg), it is possible that patients with more severe PH (i.e., out of proportion to their fibrosis) would have experienced an increase in their exercise capacity. Until additional studies are performed, however, patients with sarcoidosis-associated PH should be referred to centers with expertise in PH and monitored closely for response to vasodilator therapy, if it is initiated (3). n
The Silent Revolution: RNA Interference as Basic Biology, Research Tool, and Therapeutic
Authors: Derek M. Dykxhoorn, Judy Lieberman
Journal: Annual Review of Medicine (2004)

RNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression. In primitive organisms, RNAi protects the genome from viruses and other insertable genetic elements and regulates gene expression during development. The antisense (guide) strand of short double-stranded RNAs is incorporated into an RNA-induced silencing complex that can either suppress protein expression or direct degradation of messenger RNAs that contain homologous sequence(s). The discovery that RNAi works in mammalian cells has sparked intense investigation into its role in normal mammalian cell function, its use as a tool to understand or screen for genes functioning in cellular pathways in healthy and diseased cells and animals, and its potential for therapeutic gene silencing. RNAi may provide an important new therapeutic modality for treating infection, cancer, neurodegenerative disease, and other illnesses, although in vivo delivery of small interfering RNAs into cells remains a significant obstacle.
GM-CSF in the Lung Protects against Lethal Influenza Infection
Authors: Fang-Fang Huang, Peter F. Barnes, Yan Feng, Ruben Donis, Zissis C. Chroneos, Steven Idell, Timothy Allen, Daniel R. Perez, Jeffrey A. Whitsett, Kyri Dunussi-Joannopoulos, Homayoun Shams
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Alveolar macrophages contribute to host defenses against influenza in animal models. Enhancing alveolar macrophage function may contribute to protection against influenza.To determine if increased expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the lung increases resistance to influenza.Wild-type mice and transgenic mice that expressed GM-CSF in the lung were infected with influenza virus, and lung pathology, weight loss, and mortality were measured. We also administered GM-CSF to the lungs of wild-type mice that were infected with influenza virus.Wild-type mice all died after infection with different strains of influenza virus, but all transgenic mice expressing GM-CSF in the lungs survived. The latter also had greatly reduced weight loss and lung injury, and showed histologic evidence of a rapid host inflammatory response that controlled infection. The resistance of transgenic mice to influenza was abrogated by elimination of alveolar phagocytes, but not by depletion of T cells, B cells, or neutrophils. Transgenic mice had far more alveolar macrophages than did wild-type mice, and they were more resistant to influenza-induced apoptosis. Delivery of intranasal GM-CSF to wild-type mice also conferred resistance to influenza.GM-CSF confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages. Pulmonary delivery of this cytokine has the potential to reduce the morbidity and mortality due to influenza virus.
Repeated stimulation of CD4 effector T cells can limit their protective function
Authors: Dawn M. Jelley-Gibbs, John P. Dibble, Svetlana Filipson, Laura Haynes, Roslyn A. Kemp, Susan L. Swain
Journal: The Journal of Experimental Medicine (2005)

Chronic infections often result in CD8 T-cell deletion or functional nonresponsiveness. However, to date no definitive studies have attempted to determine the impact of repeated T cell receptor stimulation on CD4 effector T cell generation. We have determined that when antigen presentation is limited to 2 d, optimum in vitro CD4 effector generation is achieved. Alternatively, repeated stimulation results in decreased CD4 effector expansion, decreased cytokine production, and altered migration. Similarly, functionally impaired effectors develop in vivo when antigen-pulsed antigen-presenting cells are replenished every 24 h during a primary immune response. CD4 effectors that are generated with repeated stimulation provide no protection during influenza infection, and have an impaired ability to provide cognate help to B cells. These results suggest that duration of antigen presentation dictates CD4 effector function, and repeated T cell receptor stimulation in vitro and in vivo that exceeds an optimal threshold results in effectors with impaired function.
In vitro induction of myeloid surface markers in a rare case of acute leukemia
Authors: Hans G. Drexler, Elaine Coustan‐Smith, Suzanne M. Gignac, Harsha Jani, A. Victor Hoffbrand
Journal: American Journal of Hematology (1987)

Abstract The phenotypic marker profile of a case of acute leukemia is described; its immunophenotype is unique in that the blast cells were initially negative for a wide panel of monoclonal antibodies (McAbs) to surface and intracytoplasmic antigens and for the nuclear enzyme terminal deoxynucleotidyl transferase. Morphological and cytochemical examination suggested an acute myeloid leukemia (AML), but the cells were unreactive with anti‐myeloid McAbs. Treatment with the phorbol ester 12‐0‐tetradecanoylphorbol 13‐acetate (TPA) induced the cells to differentiate morphologically to macrophage‐like cells and led to the expression of surface antigens that could be detected by antimyeloid McAbs. It is not clear whether these cells represent a rare subclass of leukemic cells that are void of any characteristic surface markers but have the potential to differentiate along the myeloid axis, or whether the antigens were masked by an unknown process.
Telaprevir with Peginterferon and Ribavirin for Chronic HCV Genotype 1 Infection
Authors: John G. McHutchison, Gregory T. Everson, Stuart C. Gordon, Ira M. Jacobson, Mark Sulkowski, Robert Kauffman, Lindsay McNair, John Alam, Andrew J. Muir
Journal: New England Journal of Medicine (2009)

Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies.
Replicators, lineages, and interactors
Authors: Daniel J. Taylor, Joanna J. Bryson
Journal: Behavioral and Brain Sciences (2014)

Abstract The target article argues that whole groups can act as interactors in an evolutionary process. We believe that Smaldino's discussion would be advanced by a more thorough analysis of the appropriate replicators and lineages for this model. We show that cultural evolution is necessarily a separate process from cultural group selection, and we also illustrate that the two processes may influence each other as demonstrated by an agent-based model of communicating food-processing skills.
Regional Variation in the Association Between Advance Directives and End-of-Life Medicare Expenditures
Authors: Lauren Hersch Nicholas, Kenneth M. Langa, Theodore J. Iwashyna, David R. Weir
Journal: JAMA (2011)

<h3>Context</h3>It is unclear if advance directives (living wills) are associated with end-of-life expenditures and treatments.<h3>Objective</h3>To examine regional variation in the associations between treatment-limiting advance directive use, end-of-life Medicare expenditures, and use of palliative and intensive treatments.<h3>Design, Setting, and Patients</h3>Prospectively collected survey data from the Health and Retirement Study for 3302 Medicare beneficiaries who died between 1998 and 2007 linked to Medicare claims and the National Death Index. Multivariable regression models examined associations between advance directives, end-of-life Medicare expenditures, and treatments by level of Medicare spending in the decedent's hospital referral region.<h3>Main Outcome Measures</h3>Medicare expenditures, life-sustaining treatments, hospice care, and in-hospital death over the last 6 months of life.<h3>Results</h3>Advance directives specifying limits in care were associated with lower spending in hospital referral regions with high average levels of end-of-life expenditures (−$5585 per decedent; 95% CI, −$10 903 to −$267), but there was no difference in spending in hospital referral regions with low or medium levels of end-of-life expenditures. Directives were associated with lower adjusted probabilities of in-hospital death in high- and medium-spending regions (−9.8%; 95% CI, −16% to −3% in high-spending regions; −5.3%; 95% CI, −10% to −0.4% in medium-spending regions). Advance directives were associated with higher adjusted probabilities of hospice use in high- and medium-spending regions (17%; 95% CI, 11% to 23% in high-spending regions, 11%; 95% CI, 6% to 16% in medium-spending regions), but not in low-spending regions.<h3>Conclusion</h3>Advance directives specifying limitations in end-of-life care were associated with significantly lower levels of Medicare spending, lower likelihood of in-hospital death, and higher use of hospice care in regions characterized by higher levels of end-of-life spending.