tbuckley/cabot-search huggingface dataset:
Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation
Authors: Hirohisa Nakamae, Takahisa Yamane, Taro Hasegawa, Mika Nakamae, Yoshiki Terada, Kiyoyuki Hagihara, Kensuke Ohta, Masayuki Hino
Journal: American Journal of Hematology (2006)

Thrombotic microangiopathy (TMA) impairs long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). As the allogeneic HSCT procedure has developed, addressing risk factors for TMA has become more complicated. The aim of this study was to investigate the impact of transplant-associated factors on TMA incidence in patients who have undergone HSCT in various settings. One hundred twenty-three consecutive allogeneic HSCT patients with hematologic diseases receiving myeloablative and reduced-intensity conditioning were evaluated retrospectively. Of 123 patients, 22 (17.9%) developed TMA after HSCT. Multivariate analysis showed the significance of GVHD grade II–IV, and the use of FK506 and the use of high-dose busulfan (Bu) (16 mg/kg) persisted. The hazard ratios of the use of FK506, the use of high-dose Bu (16 mg/kg), and GVHD grade II–IV for TMA were 8.7 (95% CI 2.0–37), 5.7 (95% CI 1.5–21), and 3.4 (95% CI 1.3–9.1), respectively. In the present study, reduced-intensity conditioning did not have an advantage over myeloablative conditioning in decreasing the incidence of TMA after HSCT. Our results also showed that high-dose Bu (16 mg/kg) for the conditioning and FK506 for the prophylaxis of GVHD might contribute more significantly to TMA onset after HSCT than other agents. Am. J. Hematol. 81:525–531, 2006. © 2006 Wiley-Liss, Inc.
Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice
Authors: G OUDIT, Z KASSIRI, M PATEL, M CHAPPELL, J BUTANY, P BACKX, R TSUSHIMA, J SCHOLEY, R KHOKHA, J PENNINGER
Journal: Cardiovascular Research (2007)

The peptidase action of angiotensin converting enzyme 2 (ACE2) allows it to function as a negative regulator of the renin-angiotensin system. Current pharmacotherapies for human heart failure, such as ACE inhibitors and angiotensin and aldosterone receptor blockers, increase the activity of ACE2 in the heart. In this study, we investigate the mechanism for the age-dependent cardiomyopathy in ACE2 null mice.Ace2(-/y) mutant mice develop a progressive age-dependent dilated cardiomyopathy with increased oxidative stress, neutrophilic infiltration, inflammatory cytokine and collagenase levels, mitogen-activated protein kinase (MAPK) activation and pathological hypertrophy. The angiotensin II receptor-1 (AT1) blocker, irbesartan, prevented the dilated cardiomyopathy in aged Ace2(-/y) mutant mice, confirming a critical role of angiotensin II (Ang II)-mediated stimulation of AT1 receptors. Ang II activation of AT1 receptors triggers G-protein-coupled receptor (GPCR)-activated phosphoinositide 3-kinase gamma (PI3Kgamma) and its downstream pathways. We showed that p110gamma, the catalytic subunit of PI3Kgamma, is a key mediator of NADPH oxidase activation in response to Ang II. The double mutant mice (Ace2(-/y)/p110gamma(-/-)) exhibited marked reductions in oxidative stress, neutrophilic infiltration, and pathological hypertrophy resulting in myocardial protection, suggesting that PI3Kgamma plays a critical role in Ang II-mediated cardiomyopathy.Our findings demonstrate that the age-dependent cardiomyopathy in ACE2 null mice is related to increased Ang II-mediated oxidative stress and neutrophilic infiltration via AT1 receptors. Our combination of genetic and pharmacological approaches defines a critical role of ACE2 in the suppression of Ang II-mediated heart failure.
Mice Lacking the Vascular Endothelial Growth Factor-B Gene ( <i>Vegfb</i> ) Have Smaller Hearts, Dysfunctional Coronary Vasculature, and Impaired Recovery From Cardiac Ischemia
Authors: Daniela Bellomo, John P. Headrick, Ginters U. Silins, Carol A. Paterson, Penny S. Thomas, Michael Gartside, Arne Mould, Marian M. Cahill, Ian D. Tonks, Sean M. Grimmond, Steve Townson, Christine Wells, Melissa Little, Margaret C. Cummings, Nicholas K. Hayward, Graham F. Kay
Journal: Circulation Research (2000)

Abstract —Vascular endothelial growth factor-B (VEGF-B) is closely related to VEGF-A, an effector of blood vessel growth during development and disease and a strong candidate for angiogenic therapies. To further study the in vivo function of VEGF-B, we have generated Vegfb knockout mice ( Vegfb −/− ). Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb −/− mice are healthy and fertile. Despite appearing overtly normal, Vegfb −/− hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia. These findings reveal a role for VEGF-B in the development or function of coronary vasculature and suggest potential clinical use in therapeutic angiogenesis. The full text of this article is available at http://www.circresaha.org.
[Ca2+]i transients in the cardiomyopathic hamster heart.
Authors: J Wikman-Coffelt, T Stefenelli, S T Wu, W W Parmley, G Jasmin
Journal: Circulation Research (1991)

Intracellular [Ca2+] transients were studied in isolated hearts of healthy and cardiomyopathic hamsters in late failure perfused with glucose or pyruvate. Hearts of healthy hamsters developed similar pressures when perfused with either glucose or pyruvate, and [Ca2+]i transients were comparable in amplitude when perfused with either substrate. On the other hand, hearts of cardiomyopathic hamsters in late failure developed normal pressure when perfused with pyruvate but developed depressed pressure (50%) when perfused with glucose. The amplitude of [Ca2+]i transients fell severely and was associated with a high diastolic [Ca2+]i in cardiomyopathic hamster hearts when the perfusate was switched from pyruvate to glucose. The high phosphomonoester sugars as evidenced by 31P nuclear magnetic resonance studies and the depressed oxygen consumption in the cardiomyopathic hamster hearts perfused with glucose reflect an inhibition in glycolysis and a subsequent decrease in mitochondrial activity. Without an adequate delivery of substrate to the mitochondria in the cardiomyopathic hamster, the myocardium is no longer capable of maintaining its [Ca2+]i homeostasis.
methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles
Authors: Altuna Akalin, Matthias Kormaksson, Sheng Li, Francine E Garrett-Bakelman, Maria E Figueroa, Ari Melnick, Christopher E Mason
Journal: Genome biology (2012)

DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit.
Estimation of Phylogenetic Inconsistencies in the Three Domains of Life
Authors: V. Soria-Carrasco, J. Castresana
Journal: Molecular Biology and Evolution (2008)

Discrepancies in phylogenetic trees of bacteria and archaea are often explained as lateral gene transfer events. However, such discrepancies may also be due to phylogenetic artifacts or orthology assignment problems. A first step that may help to resolve this dilemma is to estimate the extent of phylogenetic inconsistencies in trees of prokaryotes in comparison with those of higher eukaryotes, where no lateral gene transfer is expected. To test this, we used 21 proteomes each of eukaryotes (mainly opisthokonts), proteobacteria, and archaea that spanned equivalent levels of genetic divergence. In each domain of life, we defined a set of putative orthologous sequences using a phylogenetic-based orthology protocol and, as a reference topology, we used a tree constructed with concatenated genes of each domain. Our results show, for most of the tests performed, that the magnitude of topological inconsistencies with respect to the reference tree was very similar in the trees of proteobacteria and eukaryotes. When clade support was taken into account, prokaryotes showed some more inconsistencies, but then all values were very low. Discrepancies were only consistently higher in archaea but, as shown by simulation analysis, this is likely due to the particular tree of the archaeal species used here being more difficult to reconstruct, whereas the trees of proteobacteria and eukaryotes were of similar difficulty. Although these results are based on a relatively small number of genes, it seems that phylogenetic reconstruction problems, including orthology assignment problems, have a similar overall effect over prokaryotic and eukaryotic trees based on single genes. Consequently, lateral gene transfer between distant prokaryotic species may have been more rare than previously thought, which opens the way to obtain the tree of life of bacterial and archaeal species using genomic data and the concatenation of adequate genes, in the same way as it is usually done in eukaryotes.
GFP-FRNK Disrupts Focal Adhesions and Induces Anoikis in Neonatal Rat Ventricular Myocytes
Authors: Maria C. Heidkamp, Allison L. Bayer, Jared A. Kalina, Diane M. Eble, Allen M. Samarel
Journal: Circulation Research (2002)

Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase involved in adhesion-dependent signal transduction. FAK is highly expressed in cultured neonatal rat ventricular myocytes (NRVMs) and undergoes tyrosine autophosphorylation in response to cell adhesion, stretch, and growth factor stimulation. We previously showed that inhibition of FAK phosphorylation by adenovirally mediated overexpression of FRNK (the autonomously expressed C-terminal domain of FAK) prevented endothelin-1 (ET)-induced NRVM hypertrophy. One question raised by these studies was whether FRNK localized to focal adhesions and displaced FAK from sites required for downstream signaling. Therefore, we constructed a replication-defective adenovirus encoding a GFP-FRNK fusion protein (Adv-GFP-FRNK) and examined its effects on NRVM cytoarchitecture and signaling. Uninfected NRVMs contained small amounts of endogenous FRNK. NRVMs infected with Adv-GFP-FRNK expressed much larger amounts of a 66-/68-kDa protein that localized to costameres and focal adhesions. GFP-FRNK overexpression suppressed basal and ET-induced FAK phosphorylation and also inhibited ET-induced phosphorylation of PYK2, the other member of the FAK family of nonreceptor protein tyrosine kinases. In contrast, GFP-FRNK overexpression did not prevent ET-induced ERK, JNK, or p70S6K phosphorylation. Furthermore, GFP-FRNK resulted in the loss of detectable FAK and paxillin in focal adhesions, which was accompanied by reduced levels of total paxillin and, ultimately, cell detachment and apoptosis. We conclude that FRNK functions as a dominant-negative inhibitor of adhesion-dependent signaling by displacing FAK from focal adhesions and interfering with the anchorage of NRVMs that is necessary for cell survival, a process known as anoikis.
A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide: A North American Brain Tumor Consortium study
Authors: S. Clifford Schold, John G. Kuhn, Susan M. Chang, Michael E. Bosik, H. Ian Robins, Manesh P. Mehta, Alexander M. Spence, Dorcas Fulton, Karen L. Fink, Michael D. Prados
Journal: Neuro-Oncology (2000)

The North American Brain Tumor Consortium conducted a phase I trial of the combination 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide. Eligibility included a patient with a cancer type that was considered refractory to standard therapy. Prior nitrosourea treatments were not permitted. There were parallel dose escalations in two treatment schedules. Forty-five patients were enrolled during an 18-month period. The maximum tolerated doses (MTDs) when temozolomide followed BCNU (Arm A) were temozolomide at 550 mg/m2/p.o. and BCNU at 150 mg/m2/i.v.), whereas the MTD when temozolomide preceded BCNU (Arm B) was temozolomide at 400 mg/m2/p.o. and BCNU at 100 mg/m2/i.v. Toxicity was predominantly hematologic, although there were three instances of pulmonary toxicity, which in one case could have represented potentiation of nitrosourea-induced pulmonary fibrosis. The half-life of temozolomide was 1.86 (±0.31) h. There was a moderate relationship between dose and peak concentration and a strong relationship between dose and plasma concentration time curve. Pharmacokinetic parameters of temozolomide were unaffected by the treatment schedule, so the difference in MTD between the schedules is likely due to a biologic rather than a pharmacokinetic sequence interaction. There were 9 partial responses among 43 patients evaluable for response, including 5 of 25 with a histologic diagnosis of glioblastoma. The recommended dose and schedule for phase II trials of this regimen are BCNU 150 mg/m2/i.v. followed in 2 h by temozolomide 550 mg/m2/p.o. repeated every 6 weeks. We are also recommending screening and periodic pulmonary function testing during treatment to assess the possible potentiation of nitrosourea-induced pulmonary fibrosis.
Further observations on the folate-binding factor in some leukemic cells
Authors: Sheldon P. Rothenberg, Maria daCosta
Journal: Journal of Clinical Investigation (1971)

The lysates of peripheral cells as well as the serum from some patients with chronic myelogenous leukemia, contained a macromolecular factor which bound tritiated folic acid. Bound tracer folate filtered through Sephadex G-75 and G-100 columns with the early effluent and appeared with the inner volume through a Sephadex G-200 column. Bound tracer could not be extracted from solution by coated charcoal or the anion exchange resin Dowex 2-X8 and could not be reduced to tetrahydrofolate by folate reductase. The velocity of the binding reaction was very rapid and dissociation of bound tracer extremely slow. Binding decreased sharply below pH 5.0 and the binding factor as well as the folate-binder complex, resisted 56 degrees C for 30 min. The binding factor in the leukemic lysate could be separated from endogenous folate reductase by filtration through a G-75 Sephadex column. Competitive inhibition studies demonstrated little or no inhibition of binding of tritiated folic acid by formyltetrahydrofolate and methyltetrahydrofolate. Diopterin (pteroyldiglutamate), pteropterin (pteroyltriglutamate), methotrexate, and dihydrofolate inhibited binding of tracer folate but not as effectively as unlabeled folic acid. The function of this folate binder is unknown. However, that it reacts with dihydrofolate suggests some relationship (physiologic or pathologic) to DNA synthesis since this folate cofactor is essential for the de novo synthesis of thymidylate from deoxyuridylate. In addition, these findings also suggest that the binding of methotrexate may, like folate, inhibit its reaction with folate reductase, and thus be a mechanism by which leukemic cells become resistant to this drug.
Growth hormone and renal glutamine and glutamate handling.
Authors: T C Welbourne, K Horton, M J Cronin
Journal: Journal of the American Society of Nephrology (1992)

Growth hormone administration effects a positive nitrogen balance in part by recycling glutamine nitrogen as glutamate at the expense of ureagenesis. The study presented here focuses on the response of the isolated perfused hypophysectomized rat kidney to acute growth hormone administration during infusions of either glutamine or glutamate. Growth hormone at 50 nM acutely decreases the renal utilization of both glutamine and glutamate while enhancing reabsorption of the latter. During glutamine infusions of either 1,000 or 500 nmol/min, growth hormone markedly reduced net glutamine utilization by 55% at the high loads and reversed utilization to release at the lower load; associated with decreased glutamine utilization was reduced ammonium production and increased glutamate release. Although glutamine reabsorption was unchanged, glutamate reabsorption increased and NH4+ excretion decreased. During glutamate infusion of 180 nmol/min, growth hormone reduced glutamate utilization 66%, the residual utilization matching increased glutamate reabsorption was associated with enhanced bicarbonate reabsorption and a redistribution of NH4+ release into the urine; all three responses were eliminated by amiloride. These responses to growth hormone are consonant with reduced glutamate oxidation underlying decreased glutamine utilization and accelerated luminal Na+-H+ exchange mediating luminal transport, events that are conceivably interrelated.
Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer
Authors: Shahab Uddin, Rong Bu, Maqbool Ahmed, Jehad Abubaker, Fouad Al-Dayel, Prashant Bavi, Khawla S Al-Kuraya
Journal: Molecular Cancer (2009)

Recent epidemiological studies have suggested that obesity is associated with ovarian cancer. Obesity hormone leptin and its receptor (Ob-R) contribute to tumor development by enhancing cell growth and survival. This study was design to investigate the prevalence of leptin and Ob-R in Middle Eastern epithelial ovarian cancer (EOC) and to analyze the role of leptin and the mechanisms under its action in EOC tissue sample and cell lines.The expression of leptin and Ob-R was examined by immunohistochemistry in a tissue microarray of 156 EOC samples. Proliferation of EOC cells in response to leptin was assessed by MTT assays, and its anti-apoptotic effects were determined by flow cytometry. Effect of leptin on PI3K/AKT signaling pathway was further determined by western blotting.In clinical samples, Ob-R overexpression was seen in 59.2% EOCs and was significantly associated with poor progression free survival (p = 0.0032). Furthermore, Ob-R expression was associated with anti apoptotic proteins Bcl-XL (p = 0.0035) and XIAP (p = 0.0001). In vitro analysis using EOC cell lines showed that leptin stimulated cell proliferation and inhibits apoptosis via activation of PI3K/AKT signaling pathway. Inhibition of PI3K activity by LY294002, a specific inhibitor of PI3-kinase abrogated leptin mediated PI3K/AKT signaling. Gene silencing of Ob-R with Ob-R siRNA in EOC cells resulted in down regulation of phospho-AKT and its down stream targets.Our findings have potential clinical implication for EOC development and progression.
Cardiac fatty acid uptake and transport in health and disease
Authors: G van der Vusse
Journal: Cardiovascular Research (2000)

Fatty acids are important energy donors for the healthy heart. These substrates are supplied to the myocardium bound to albumin to overcome their low solubility in aqueous solutions such as blood plasma. Transport from the microvascular compartment to the mitochondria inside the cardiomyocytes is most likely a combination of passive and protein-mediated diffusion. Alterations in tissue content of fatty acid-transport proteins may contribute to myocardial diseases such as the diabetic heart, and cardiac hypertrophy and failure.
Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management
Authors: Kei Hayashida, Motoaki Sano, Naomi Kamimura, Takashi Yokota, Masaru Suzuki, Shigeo Ohta, Keiichi Fukuda, Shingo Hori
Journal: Circulation (2014)

We have previously shown that hydrogen (H2) inhalation, begun at the start of hyperoxic cardiopulmonary resuscitation, significantly improves brain and cardiac function in a rat model of cardiac arrest. Here, we examine the effectiveness of this therapeutic approach when H2 inhalation is begun on the return of spontaneous circulation (ROSC) under normoxic conditions, either alone or in combination with targeted temperature management (TTM).Rats were subjected to 6 minutes of ventricular fibrillation cardiac arrest followed by cardiopulmonary resuscitation. Five minutes after achieving ROSC, post-cardiac arrest rats were randomized into 4 groups: mechanically ventilated with 26% O2 and normothermia (control); mechanically ventilated with 26% O2, 1.3% H2, and normothermia (H2); mechanically ventilated with 26% O2 and TTM (TTM); and mechanically ventilated with 26% O2, 1.3% H2, and TTM (TTM+H2). Animal survival rate at 7 days after ROSC was 38.4% in the control group, 71.4% in the H2 and TTM groups, and 85.7% in the TTM+H2 group. Combined therapy of TTM and H2 inhalation was superior to TTM alone in terms of neurological deficit scores at 24, 48, and 72 hours after ROSC, and motor activity at 7 days after ROSC. Neuronal degeneration and microglial activation in a vulnerable brain region was suppressed by both TTM alone and H2 inhalation alone, with the combined therapy of TTM and H2 inhalation being most effective.H2 inhalation was beneficial when begun after ROSC, even when delivered in the absence of hyperoxia. Combined TTM and H2 inhalation was more effective than TTM alone.
RESPONSE: Re: Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde Industries
Authors: M. Hauptmann, J. H. Lubin, P. A. Stewart, R. B. Hayes, A. Blair
Journal: JNCI Journal of the National Cancer Institute (2004)

Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde IndustriesThe study described in the article by Hauptmann et al.(1) has several strengths, including large size, long follow-up, and attempts to control for potentially important confounding factors.However, the study does not provide conclusive evidence of a causal association between formaldehyde exposure and leukemia for several reasons.In particular, the large relative risks (RRs) reported for the internal comparison stratified by exposure category need to be reconciled with the external compari-
Efficacy of 6-Mercaptopurine as Second-Line Treatment for Patients With Autoimmune Hepatitis and Azathioprine Intolerance
Authors: Sina Hübener, Ye Htun Oo, Nwe Ni Than, Peter Hübener, Christina Weiler-Normann, Ansgar W. Lohse, Christoph Schramm
Journal: Clinical Gastroenterology and Hepatology (2015)