tbuckley/cabot-search huggingface dataset:
Endoplasmic reticulum Ca2+ depletion activates XBP1 and controls terminal differentiation in keratinocytes and epidermis
Authors: A. Celli, D.S. Mackenzie, D.S. Crumrine, C.L. Tu, M. Hupe, D.D. Bikle, P.M. Elias, T.M. Mauro
Journal: British Journal of Dermatology (2010)

Journal Article Endoplasmic reticulum Ca2+ depletion activates XBP1 and controls terminal differentiation in keratinocytes and epidermis Get access A. Celli, A. Celli Department of Dermatology, University of California, San Francisco Correspondence: Anna Celli. E‐mail: celli.anna@gmail.com Search for other works by this author on: Oxford Academic Google Scholar D.S. Mackenzie, D.S. Mackenzie Department of Dermatology, University of California, San Francisco Search for other works by this author on: Oxford Academic Google Scholar D.S. Crumrine, D.S. Crumrine San Francisco Veterans' Affairs Medical Center; 4150 Clement Street, San Francisco, CA 94121‐1545, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar C.L. Tu, C.L. Tu Department of Dermatology, University of California, San Francisco Search for other works by this author on: Oxford Academic Google Scholar M. Hupe, M. Hupe Department of Dermatology, University of California, San FranciscoSan Francisco Veterans' Affairs Medical Center; 4150 Clement Street, San Francisco, CA 94121‐1545, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar D.D. Bikle, D.D. Bikle Department of Dermatology, University of California, San Francisco Search for other works by this author on: Oxford Academic Google Scholar P.M. Elias, P.M. Elias San Francisco Veterans' Affairs Medical Center; 4150 Clement Street, San Francisco, CA 94121‐1545, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar T.M. Mauro T.M. Mauro Department of Dermatology, University of California, San FranciscoSan Francisco Veterans' Affairs Medical Center; 4150 Clement Street, San Francisco, CA 94121‐1545, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 164, Issue 1, 1 January 2011, Pages 16–25, https://doi.org/10.1111/j.1365-2133.2010.10046.x Published: 01 January 2011
Complex Histories of Genes Encoding 3-Hydroxy-3-methylglutaryl-CoenzymeA Reductase
Authors: Uri Gophna, Janelle R Thompson, Yan Boucher, W Ford Doolittle
Journal: Molecular Biology and Evolution (2005)

The mevalonate pathway for the synthesis of isoprenoids can be found in organisms from all domains of life. It has been previously demonstrated that the first gene specific to that pathway, which encodes the enzyme 3-hydroxy-3-methylglutaryl-CoenzymeA reductase (HMGR), has been transferred between domains by lateral gene transfer on several occasions. Here we look within the domain Bacteria at lateral acquisition of HMGR, whether as a single gene or as part of a mevalonate pathway cluster. We observe a complex history of multiple transfer events probably reflecting the fact that HMGR could be beneficial in a variety of physiological and genetic contexts. We demonstrate that even in Vibrio species, where HMGR is not clustered with other genes to form an operon or a metabolic cluster, it is under strong purifying selection.
Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression
Authors: Daniele Torella, Marcello Rota, Daria Nurzynska, Ezio Musso, Alyssa Monsen, Isao Shiraishi, Elias Zias, Kenneth Walsh, Anthony Rosenzweig, Mark A. Sussman, Konrad Urbanek, Bernardo Nadal-Ginard, Jan Kajstura, Piero Anversa, Annarosa Leri
Journal: Circulation Research (2004)

To determine whether cellular aging leads to a cardiomyopathy and heart failure, markers of cellular senescence, cell death, telomerase activity, telomere integrity, and cell regeneration were measured in myocytes of aging wild-type mice (WT). These parameters were similarly studied in insulin-like growth factor-1 (IGF-1) transgenic mice (TG) because IGF-1 promotes cell growth and survival and may delay cellular aging. Importantly, the consequences of aging on cardiac stem cell (CSC) growth and senescence were evaluated. Gene products implicated in growth arrest and senescence, such as p27 Kip1 , p53, p16 INK4a , and p19 ARF , were detected in myocytes of young WT mice, and their expression increased with age. IGF-1 attenuated the levels of these proteins at all ages. Telomerase activity decreased in aging WT myocytes but increased in TG, paralleling the changes in Akt phosphorylation. Reduction in nuclear phospho-Akt and telomerase resulted in telomere shortening and uncapping in WT myocytes. Senescence and death of CSCs increased with age in WT impairing the growth and turnover of cells in the heart. DNA damage and myocyte death exceeded cell formation in old WT, leading to a decreased number of myocytes and heart failure. This did not occur in TG in which CSC-mediated myocyte regeneration compensated for the extent of cell death preventing ventricular dysfunction. IGF-1 enhanced nuclear phospho-Akt and telomerase delaying cellular aging and death. The differential response of TG mice to chronological age may result from preservation of functional CSCs undergoing myocyte commitment. In conclusion, senescence of CSCs and myocytes conditions the development of an aging myopathy.
Heat-Solubilized Curcumin Should Be Considered in Clinical Trials for Increasing Bioavailability
Authors: Biji T. Kurien, R. Hal Scofield
Journal: Clinical Cancer Research (2009)

To the Editor: The recent article by Dhillon et al. (1) is of great interest to those working with curcumin. As the investigators suggest, the usefulness of curcumin could be minimized because of its poor oral bioavailability (2). Data from this study show that only 22 to 41 ng/mL were detectable in plasma even when 8 g curcumin/day was given orally (1). Curcumin levels in the microgram range have been shown to be necessary to show antiproliferative effects in in vitro studies (3).The solution to this problem would be to increase the solubility of curcumin before oral administration to patients. We have shown that we could increase the solubility of curcumin 12-fold by heating a solution of curcumin in water to boiling for 10 minutes (4). Matrix-assisted laser desorption ionization mass spectrometric and spectrophotometric profiling (400-700 nm) of the heat-extracted curcumin displays no heat-mediated disintegration of curcumin. With the use of an ELISA that used 4-hydroxy-2-nonenal modification of solid-phase antigen, the heat-solubilized curcumin was found to inhibit 4-hydroxy-2-nonenal-protein modification by 80% (5). We showed that mild alkali-solubilized curcumin also inhibited 4-hydroxy-2-nonenal protein modification significantly (6). Thus, inhibition of 4-hydroxy-2-nonenal modification of proteins may be a mechanism by which curcumin exerts its effect in many disorders (4, 5).As the full pharmacologic potential of curcumin is limited because of its extremely limited water solubility, heat-solubilized curcumin should be considered in clinical trials involving curcumin.No potential conflicts of interest were disclosed.
Anemia Management and the Delay of Chronic Renal Failure Progression
Authors: Jerome Rossert, Bruno Fouqueray, Jean Jacques Boffa
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Interstitial fibrosis plays a key role in the progression of chronic kidney diseases. Analysis of the biologic effects of erythropoietin and of the pathophysiology of interstitial fibrosis suggest that treatment with epoetin may slow the progression of chronic kidney disease, both by decreasing interstitial fibrosis and by protecting against its consequences. The results of two small prospective studies and of a retrospective one also suggest that treatment with epoetin may have such protective effects. E-mail: [email protected]
Mitogen-Activated Protein Kinases Inhibit the ROMK (Kir 1.1)-Like Small Conductance K Channels in the Cortical Collecting Duct
Authors: Elisa Babilonia, Dimin Li, Zhijian Wang, Peng Sun, Dao-Hong Lin, Yan Jin, Wen-Hui Wang
Journal: Journal of the American Society of Nephrology (2006)

It was demonstrated previously that low dietary potassium (K) intake stimulates Src family protein tyrosine kinase (PTK) expression via a superoxide-dependent signaling. This study explored the role of mitogen-activated protein kinase (MAPK) in mediating the effect of superoxide anions on PTK expression and ROMK (Kir 1.1) channel activity. Western blot analysis demonstrated that low K intake significantly increased the phosphorylation of P38 MAPK (P38) and extracellular signal–regulated kinase (ERK) but had no effect on phosphorylation of c-JUN N-terminus kinase in renal cortex and outer medulla. The stimulatory effect of low K intake on P38 and ERK was abolished by treatment of rats with tempol. The possibility that increases in superoxide and related products that are induced by low K intake were responsible for stimulating phosphorylation of P38 and ERK also was supported by the finding that application of H2O2 increased the phosphorylation of ERK and P38 in the cultured mouse collecting duct cells. Simultaneous blocking of ERK and P38 completely abolished the effect of H2O2 on c-Src expression in mouse collecting duct cells. For determination of the role of P38 and ERK in the regulation of ROMK-like small-conductance K (SK) channels, the patch-clamp technique was used to study the effect of inhibiting P38 and ERK on SK channels in the cortical collecting duct from rats that were on a control K diet (1.1%) and on a K-deficient diet for 1 d. Inhibition of ERK, c-JUN N-terminus kinase, or P38 alone had no effect on SK channels. In contrast, simultaneous inhibition of P38 and ERK significantly increased channel activity. The effect of inhibiting MAPK on SK channels was not affected in the presence of herbimycin A, a PTK inhibitor, and was larger in rats that were on a K-deficient diet than in rats that were on a normal-K diet. However, the stimulatory effect of inhibiting ERK and P38 on SK was absent in the cortical collecting duct that was treated with colchicine. It is concluded that low K intake–induced increases in superoxide levels are responsible for stimulation of P38 and ERK and that MAPK inhibit the SK channels by stimulating PTK expression and via a PTK-independent mechanism.
Dynamic reprogramming of chromatin accessibility during Drosophila embryo development
Authors: Sean Thomas, Xiao-Yong Li, Peter J Sabo, Richard Sandstrom, Robert E Thurman, Theresa K Canfield, Erika Giste, William Fisher, Ann Hammonds, Susan E Celniker, Mark D Biggin, John A Stamatoyannopoulos
Journal: Genome biology (2011)

Abstract Background The development of complex organisms is believed to involve progressive restrictions in cellular fate. Understanding the scope and features of chromatin dynamics during embryogenesis, and identifying regulatory elements important for directing developmental processes remain key goals of developmental biology. Results We used in vivo DNaseI sensitivity to map the locations of regulatory elements, and explore the changing chromatin landscape during the first 11 hours of Drosophila embryonic development. We identified thousands of conserved, developmentally dynamic, distal DNaseI hypersensitive sites associated with spatial and temporal expression patterning of linked genes and with large regions of chromatin plasticity. We observed a nearly uniform balance between developmentally up- and down-regulated DNaseI hypersensitive sites. Analysis of promoter chromatin architecture revealed a novel role for classical core promoter sequence elements in directing temporally regulated chromatin remodeling. Another unexpected feature of the chromatin landscape was the presence of localized accessibility over many protein-coding regions, subsets of which were developmentally regulated or associated with the transcription of genes with prominent maternal RNA contributions in the blastoderm. Conclusions Our results provide a global view of the rich and dynamic chromatin landscape of early animal development, as well as novel insights into the organization of developmentally regulated chromatin features.
Methylenetetrahydrofolate Reductase Genotype Affects Risk of Relapse after Hematopoietic Cell Transplantation for Chronic Myelogenous Leukemia
Authors: Kim Robien, Cornelia M. Ulrich, Jeannette Bigler, Yutaka Yasui, Ted Gooley, Barbara Bruemmer, John D. Potter, Jerald P. Radich
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Methylenetetrahydrofolate reductase (MTHFR) directs intracellular folate toward homocysteine metabolism and away from nucleotide synthesis. Two common MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association of these polymorphisms with risk of relapse and bcr-abl mRNA transcript detection among 336 Caucasian patients who underwent allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia. Experimental Design: Data on the transplant course and folate-related exposures were abstracted from medical records. MTHFR C677T and A1298C genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Qualitative bcr-abl mRNA testing was conducted using a two-step reverse transcription-polymerase chain reaction assay. Cox regression analysis was used to assess the association between MTHFR genotypes and time to relapse and bcr-abl mRNA detection. Results: A statistically significant decreased risk of relapse was observed in patients with the variant A1298C genotype [1298AC, hazard ratio (HR) = 0.48 and 95% confidence interval (CI) = 0.26–0.88; 1298CC, HR = 0.28 and 95% CI = 0.09–0.84; P-trend &amp;lt; 0.01). For the joint C677T/A1298C genotype, variant genotypes were associated with a decreased risk of relapse when compared with the wild-type 677CC/1298AA genotype. This risk was lowest for the 677CC/1298CC genotype (HR, 0.23; 95% CI, 0.08–0.72). MTHFR genotypes were not associated with bcr-abl transcript detection. Conclusions: These findings suggest that individuals with the 677CC/1298AA genotype are at higher risk of relapse after hematopoietic cell transplantation and that the balance of intracellular folate metabolites available for nucleotide synthesis (regulated by the relative activity of the MTHFR enzyme) may affect the progression from bcr-abl positivity to clinical relapse.
Minimal Residual Disease Quantification Is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial
Authors: Sebastian Böttcher, Matthias Ritgen, Kirsten Fischer, Stephan Stilgenbauer, Raymonde M. Busch, Günter Fingerle-Rowson, Anna Maria Fink, Andreas Bühler, Thorsten Zenz, Michael Karl Wenger, Myriam Mendila, Clemens-Martin Wendtner, Barbara F. Eichhorst, Hartmut Döhner, Michael J. Hallek, Michael Kneba
Journal: Journal of Clinical Oncology (2012)

Purpose To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial. Patients and Methods MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (&lt; 10 −4 ), intermediate- (≥ 10 −4 to &lt;10 −2 ), and high-level (≥ 10 −2 ) groups. Results Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P &lt; .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P &lt; .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC. Conclusion MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
Cystathionine Synthase Activity in Human Lymphocytes: Induction by Phytohemagglutinin
Authors: Joseph L. Goldstein, Barbara K. Campbell, Stanley M. Gartler
Journal: Journal of Clinical Investigation (1972)

Uncultured human leukocytes contain no detectable cystathionine synthase activity. A method is described in which the addition of phytohemagglutinin (PHA) to short-term lymphocyte cultures results in a significant induction of enzymatic activity. This PHA-stimulated activity has characteristics that resemble those previously described for cystathionine synthase of normal liver and cultured fibroblasts. Lymphocyte cystathionine synthase activity is completely dependent on the presence of homocysteine and is absent or severely deficient in extracts from individuals with the syndrome of homocystinuria. This system for induction of cystathionine synthase in lymphocytes thus provides a simple in vitro technique for (a) diagnosing homocystinuria, (b) studying the mechanism of enzyme regulation and differentiation, and (c) examining the nutritional and hormonal control of cystathionine synthase activity both in normal subjects and homocystinuric patients.
Bufale Spotting, part 10: assessing a journal
Authors: Tom Jefferson, Lucia Zarra
Journal: Journal of the Royal Society of Medicine (2008)

(1) Inclusion in library lists: as subscription costs rocket you only go for the best (2) Indexing (NLM, ISI): basking in reflected prestige of the indexing body (3) Citations: your colleagues will cite what they read and like (4) Not throwaway: a study has shown that throwaway journals present lower quality information (but use better language) (5) Not publishing single drug company-sponsored supplements: bias galore (6) Indexes of scrutiny: more authors, but also more editors, equal more scrutiny and better quality (7) Indexes of competition: higher number of submissions with space limits mean a more desirable journal (8) Proportion of articles doomed by their design: rise in RCTs (considered the most DECLARATIONS
COPD and cancer mortality: the influence of statins
Authors: Y R B M van Gestel, S E Hoeks, D D Sin, V Huzeir, H Stam, F W Mertens, R T van Domburg, J J Bax, D Poldermans
Journal: Thorax (2009)

Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of lung cancer, independently of smoking. However, the relationship between COPD and total cancer mortality is less certain. A study was undertaken to investigate the association between COPD and total cancer mortality and to determine whether the use of statins, which have been associated with cancer risk in other settings, modified this relationship.The study included 3371 patients with peripheral arterial disease who underwent vascular surgery between 1990 and 2006; 1310 (39%) had COPD and the rest did not. The primary end point was cancer mortality (lung and extrapulmonary) over a median follow-up of 5 years.COPD was associated with an increased risk of both lung cancer mortality (hazard ratio (HR) 2.06; 95% CI 1.32 to 3.20) and extrapulmonary cancer mortality (HR 1.43; 95% CI 1.06 to 1.94). The excess risk was mostly driven by patients with moderate and severe COPD. There was a trend towards a lower risk of cancer mortality among patients with COPD who used statins compared with patients with COPD who did not use statins (HR 0.57; 95% CI 0.32 to 1.01). Interestingly, the risk of extrapulmonary cancer mortality was lower among statin users with COPD (HR 0.49; 95% CI 0.24 to 0.99).COPD was associated with increased lung and extrapulmonary cancer mortality in this large cohort of patients with peripheral arterial disease undergoing vascular surgery. The risk of lung cancer mortality increased with progression of COPD. Statins were associated with a reduced risk of extrapulmonary cancer mortality in patients with COPD.
The pruritus of cholestasis: Facts
Authors: Nora V. Bergasa
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. To the Editor: Lipophosphatidic acid (LPA) may contribute to the pathogenesis of the pruritus of cholestasis; however, there is no evidence to support the assertion that LPA is the putative pruritogen, as stated in the review by Beuers et al.1 Specifically: (1) A pruritogenic effect of LPA and/or autotoxin (ATX) in human beings, including patients with cholestasis, has not been documented, (2) the scratching behavior reported in mice after the injection of LPA is not relevant in the study of the pruritus of cholestasis, because this is not a model of the human condition, and (3) the variation in serum activity of ATX in relation to the severity of this symptom in some patients with liver disease could have been a result of changes in the degree of cholestasis from interventions to which the patients were submitted, including nasobiliary drainage, and albumin dialysis,2 and does not demonstrate any connection between the reported amelioration of the symptom and the decrease in enzyme activity. Drugs with opioid receptor agonist activity increase opioidergic tone and cause pruritus. Increased opioidergic tone contributes to the pathogenesis of cholestasis and the mediation of the associated pruritus,3 as supported by the opiate withdrawal‐like reaction precipitated by opiate antagonists in patients with cholestasis, and by the amelioration of the pruritus by this type of drugs, as demonstrated in several clinical trials of variable rigor,2 including a double‐blind, randomized, placebo‐controlled study of naloxone infusions4 that provided type IA evidence in support of opiate antagonists for the treatment of this type of pruritus. It is emphasized that the role of the endogenous opioid system in the mediation of the pruritus of cholestasis is independent from plasma concentrations of endogenous opioids and/or opioid activity; however, in primates, the microinjection of plasma extracts from patients with cholestasis and pruritus, and not from patients with cholestasis without pruritus, into the medullary dorsal horn, not spinally administered, as stated in the review,1 induced facial scratching that was abolished and prevented by naloxone, suggesting that plasma from patients with cholestasis and pruritus contains a factor that could induce pruritus by a central opioid receptor‐mediated mechanism.5