tbuckley/cabot-search huggingface dataset:
Phase I Study of Oblimersen Sodium, an Antisense to Bcl-2, in Untreated Older Patients With Acute Myeloid Leukemia: Pharmacokinetics, Pharmacodynamics, and Clinical Activity
Authors: Guido Marcucci, Wendy Stock, Guowei Dai, Rebecca B. Klisovic, Shujun Liu, Marko I. Klisovic, William Blum, Cheryl Kefauver, Dorie A. Sher, Margaret Green, Mollie Moran, Kati Maharry, Steven Novick, Clara D. Bloomfield, James A. Zwiebel, Richard A. Larson, Michael R. Grever, Kenneth K. Chan, John C. Byrd
Journal: Journal of Clinical Oncology (2005)

Purposes Pharmacologic downregulation of Bcl-2, an antiapoptotic protein overexpressed in cancer, might increase chemosensitivity in acute myeloid leukemia (AML). Herein, we investigated the feasibility of this approach in untreated elderly AML patients by administering oblimersen sodium (G3139), an 18-mer phosphorothioate antisense to Bcl-2, during induction and consolidation treatments. Patients and Methods Untreated patients with primary or secondary AML (stratified to cohort 1 or 2, respectively) who were ≥ 60 years received induction with G3139, cytarabine, and daunorubicin at one of two different dose levels (45 and 60 mg/m 2 ) and, on achievement of complete remission (CR), consolidation with G3139 and high-dose cytarabine. An enzyme-linked immunosorbent assay (ELISA) –based assay was used to measure plasma and intracellular concentrations (IC) of G3139. Bcl-2 mRNA and protein levels were quantified by real-time reverse transcriptase polymerase chain reaction and ELISA, respectively, in bone marrow samples collected before induction treatment and after 72 hours of G3139 infusion, prior to initiation of chemotherapy. Results Of the 29 treated patients, 14 achieved CR. With a median follow-up of 12.6 months, seven patients had relapsed. Side effects of this combination were similar to those expected with chemotherapy alone and were not dose limiting at both dose levels. After 72-hour G3139 infusion, Bcl-2/ABL mRNA copies were decreased compared with baseline (P = .03) in CR patients and increased in nonresponders (NRs; P = .05). Changes in Bcl-2 protein showed a similar trend. Although plasma pharmacokinetics did not correlate with disease response, the median IC of the antisense was higher in the CR patients compared with NRs (17.0 v 4.4 pmol/mg protein, respectively; P = .05). Conclusion G3139 can be administered safely in combination with intensive chemotherapy, and the degree of Bcl-2 downmodulation may correlate with response to therapy.
Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation
Authors: Plinio Cirillo, Gaetano Calì, Paolo Golino, Paolo Calabrò, Lavinia Forte, Salvatore De Rosa, Mario Pacileo, Massimo Ragni, Francesco Scopacasa, Lucio Nitsch, Massimo Chiariello
Journal: Circulation (2004)

Tissue factor (TF) is the main initiator of coagulation in vivo. Recently, however, a role for TF as a cell receptor involved in signal transduction has been suggested. The aim of the present study was to assess whether activated factor VII (FVIIa) binding to TF could induce smooth muscle cell (SMC) proliferation and to clarify the possible intracellular mechanism(s) responsible for this proliferation.Cell proliferation was induced by FVIIa in a dose-dependent manner, as assessed by [3H]thymidine incorporation and direct cell counting, whereas no response was observed with active site-inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid of enzymatic activity. Similarly, no proliferation was observed when binding of FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by transient ERK phosphorylation in Western blots and by suppression of proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK phosphorylation was not observed with FVIIai or when cells were pretreated with AP-1.These data indicate a specific effect by which binding of FVIIa to TF on the surface of SMCs induces proliferation via a coagulation-independent mechanism and possibly indicate a new link between coagulation, inflammation, and atherosclerosis.
3′-UTR Poly(T/U) Tract Deletions and Altered Expression of <i>EWSR1</i> Are a Hallmark of Mismatch Repair–Deficient Cancers
Authors: Shivendra Kishore, Salvatore Piscuoglio, Michal B. Kovac, Annette Gylling, Friedel Wenzel, Francesca Trapani, Hans Joerg Altermatt, Valentina Mele, Giancarlo Marra, Päivi Peltomäki, Luigi Terracciano, Mihaela Zavolan, Karl Heinimann
Journal: Cancer Research (2013)

The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene-specific effect in MMR-deficient cancers.
Alternative Splicing of cGMP-Dependent Protein Kinase I in Angiotensin-Hypertension
Authors: Volodymyr Gerzanich, Alexander Ivanov, Svetlana Ivanova, Jia Bi Yang, Hui Zhou, Yafeng Dong, J. Marc Simard
Journal: Circulation Research (2003)

Nitrate tolerance (NT) in hypertension is attributed to reduced activity of soluble guanylyl cyclase (sGC). We examined NT in basilar artery vascular smooth muscle cells (VSMCs) from control rats, rats infused with angiotensin II (Ang; 240 microg/kg per hour for 4 days), which were normotensive, and Ang-hypertensive rats (AHR; 240 microg/kg per hour for 28 days). Ca2+-activated K+ (Maxi-K) channels in VSMCs from AHR showed reduced activation by NO donor, consistent with NT. The concentration-response relationship for 8-Br-cGMP was shifted 2.5-fold to the right, indicating that abnormal sGC alone could not account for NT. Inside-out patches from AHR showed normal activation with exogenous cGMP-dependent protein kinase I (cGKI), suggesting no abnormality downstream of cGKI. We hypothesized that the reduction in apparent affinity of 8-Br-cGMP for cGKI in AHR might be due to a change in relative amounts of cGKIalpha versus cGKIbeta, since cGKIbeta is less sensitive to cGMP activators than cGKIalpha. This was substantiated by showing the following in AHR: (1) reduced effect of the cGKIalpha-selective activator 8-APT-cGMP; (2) reduced total cGKI protein (both isoforms), but an increase in cGKIbeta protein in quantitative immunofluorescence and Western blots; (3) similar changes in cGKI isoforms immunoisolated with Maxi-K channels; and (4) a large increase in cGKIbeta mRNA and a decrease in cGKIalpha mRNA in real-time PCR and Northern blots. Upregulation of cytosolic cGKIbeta was evident 4 days after Ang infusion, before development of hypertension. Our data identify a functional role for cGKIbeta in VSMCs previously ascribed exclusively to cGKIalpha. Ang-induced alternative splicing of cGKI represents a novel mechanism for reducing sensitivity to NO/cGMP.
cAMP Pulse During Preservation Inhibits the Late Development of Cardiac Isograft and Allograft Vasculopathy
Authors: Catherine Y. Wang, Isaak Aronson, Shin Takuma, Shunichi Homma, Yoshifumi Naka, Tarek Alshafie, Viktor Brovkovych, Tadeusz Malinski, Mehmet C. Oz, David J. Pinsky
Journal: Circulation Research (2000)

Abstract —The causes of transplant-associated coronary artery disease remain obscure, and there is no known treatment. Preservation injury of murine heterotopic vascularized cardiac isografts caused a small, albeit significant, increase in neointimal formation; preservation injury of allografts markedly increased both the incidence and severity of transplant-associated coronary artery disease. As cAMP is an important vascular homeostatic mediator the levels of which decline during organ preservation, buttressing cAMP levels solely during initial preservation both improved acute allograft function and reduced the severity of transplant-associated coronary artery disease in grafts examined 2 months later. Inhibiting the cAMP-dependent protein kinase abrogated these beneficial effects. cAMP treatment was associated with an early reduction in leukocyte infiltration and a reciprocal decrease in superoxide and increase in NO levels. These data indicate that alloantigen-independent injury to the graft, which occurs at the time of cardiac preservation, can set in motion pathological vascular events that are manifest months later. Furthermore, a cAMP pulse during cardiac preservation reduces the incidence and severity of transplant-associated coronary artery disease.
Single-feature polymorphism discovery in the barley transcriptome.
Authors: Nils Rostoks, Justin O Borevitz, Peter E Hedley, Joanne Russell, Sharon Mudie, Jenny Morris, Linda Cardle, David F Marshall, Robbie Waugh
Journal: Genome biology (2005)

A probe-level model for analysis of GeneChip gene-expression data is presented which identified more than 10,000 single-feature polymorphisms (SFP) between two barley genotypes. The method has good sensitivity, as 67% of known single-nucleotide polymorphisms (SNP) were called as SFPs. This method is applicable to all oligonucleotide microarray data, accounts for SNP effects in gene-expression data and represents an efficient and versatile approach for highly parallel marker identification in large genomes.
Genetic variation in schlafen genes in a patient with a recapitulation of the murine Elektra phenotype
Authors: Mike Recher, Marja-Liisa Karjalainen-Lindsberg, Mikael Lindlöf, Maria Söderlund-Venermo, Gaetana Lanzi, Elina Väisänen, Arun Kumar, Mohammadreza Sadeghi, Christoph T. Berger, Tiina Alitalo, Pekka Anttila, Maija Kolehmainen, Rauli Franssila, Tingting Chen, Sanna Siitonen, Ottavia M. Delmonte, Jolan E. Walter, Itai Pessach, Christoph Hess, Michael A. Simpson, Alexander A. Navarini, Silvia Giliani, Klaus Hedman, Mikko Seppänen, Luigi D. Notarangelo
Journal: Journal of Allergy and Clinical Immunology (2013)
Anti-inflammatory Renoprotective Effect of Clopidogrel and Irbesartan in Chronic Renal Injury
Authors: Xiaowen Tu, Xiangmei Chen, Yuansheng Xie, Suozhu Shi, Jianzhong Wang, Yunshuang Chen, Jianjun Li
Journal: Journal of the American Society of Nephrology (2007)

Recent evidence suggests that platelet activation and angiotensin II may each contribute to glomerular inflammation and fibrosis. Clopidogrel inhibits platelet activation and may also reduce inflammation. This study investigated the anti-inflammatory and renoprotective effects of clopidogrel and irbesartan in the five-sixths nephrectomy rat model of chronic kidney disease. After 8 wk of treatment, 24-h proteinuria, serum creatinine, and histologic scores of glomerular sclerosis and tubulointerstitial damage were significantly lower in treated compared with untreated rats. Clopidogrel/irbesartan combination therapy had greater effects than either drug alone. Rats that underwent five-sixths nephrectomy had higher markers of platelet activation (plasma GMP-140 and renal cortical fibrin deposition) than sham-operated rats, and clopidogrel attenuated these effects. Clopidogrel and irbesartan similarly reduced the accumulation of ED-1-expressing macrophages in the cortical glomeruli and the interstitium. Combination therapy almost completely abolished macrophage infiltration and attenuated the expression of monocyte chemoattractant protein-1, intercellular adhesion molecule-1, TGF-beta(1), and connective tissue growth factor. In conclusion, combination treatment with clopidogrel and irbesartan, more so than either alone, decreases early renal injury induced by five-sixths nephrectomy by inhibiting renal inflammation.
Mediterranean and Low-Fat Diets Improve Endothelial Function in Hypercholesterolemic Men
Authors: Francisco Fuentes, José López-Miranda, Elias Sánchez, Francisco Sánchez, José Paez, Elier Paz-Rojas, Carmen Marín, Purificación Gómez, José Jimenez-Perepérez, José M. Ordovás, Francisco Pérez-Jiménez
Journal: Annals of Internal Medicine (2001)

Background: The regulatory function of the endothelium is altered in hypercholesterolemia, and the subsequent endothelial dysfunction plays a central role in the development of atherosclerosis. Objective: To determine whether endothelial function in hypercholesterolemic patients is affected by replacing a saturated fat–enriched diet with a low-fat, low–saturated fat diet (the U.S. National Cholesterol Education Program stage 1 [NCEP-1] diet) or a diet rich in monounsaturated fat (such as that common in Mediterranean countries). Design: Intervention dietary study with a baseline phase and two randomized crossover dietary periods. Setting: Hospital Universitario Reina Sofía, Córdoba, Spain. Patients: 22 hypercholesterolemic men. Intervention: Patients followed a diet high in saturated fat, then were assigned in a crossover design to the NCEP-1 diet or a Mediterranean diet. Each dietary period lasted 28 days. Measurements: Plasma P-selectin levels, lipid concentrations, and endothelial function. Results: Compared with the saturated fat diet, flow-mediated dilatation increased during the Mediterranean diet but not during the NCEP-1 diet. In addition, levels of plasma cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and P-selectin decreased during the NCEP-1 and Mediterranean diets. Conclusion: In hypercholesterolemic men, diets low in fat (especially saturated fat) and diets rich in monounsaturated fats improve endothelial function.
Blood group A sub-groups and serum cholesterol
Authors: E. J. WAKLEY, M. J. S. LANGMAN, P. C. ELWOOD
Journal: Cardiovascular Research (1973)

A1, A2, B, O, and Lewis blood groups and serum total cholesterol concentrations were determined in a randomly selected population sample of 959 men and women in South Wales and in 767 university students. Mean serum cholesterol concentrations were higher for individuals of group A than for those of groups O, B, and AB combined, except in the women studied in South Wales, and this exception was only in part due to the chance occurrence of a higher average age in the women of blood group O than in those of group A. In the South Wales population sample, mean serum cholesterol levels were significantly higher in both sub-group A1 than in sub-group A2, and in those who were Lewis (a positive) than in those who were Lewis (a negative).
Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon -2b therapy
Authors: H J Flink
Journal: Gut (2005)

Flares are a well known phenomenon during antiviral treatment for chronic hepatitis B. Little is known about the effect of flares on response. We investigated the timing and characteristics of flares, in relation to treatment response (hepatitis B e antigen loss).A total of 266 patients, participating in a global randomised controlled study, were assigned to 52 weeks of 100 mug pegylated (Peg)-interferon alpha-2b weekly, combined with either daily lamivudine 100 mg or placebo.Sixty seven patients (25%) exhibited 75 flares, with 38 (51%) flares in the combination therapy and 37 (49%) in the monotherapy groups. Overall, 30% of patients with and 38% of patients without a flare responded to therapy (p = 0.25). In 24 patients (36%) the flare was followed by a decrease in hepatitis B virus (HBV) DNA (host induced flare). In 25 (38%) patients the flare was preceded by an increase in HBV DNA (virus induced flare). In 17 (26%) patients the flare did not meet one of these criteria (indeterminate flare). Of patients with host induced flare, 58% responded whereas only 20% of patients with virus induced flares responded (p = 0.008). Hepatitis B surface antigen loss (n = 8) was exclusively seen in patients experiencing a host induced flare. Multivariate logistic analysis showed that host induced flares was an independent predictor of response (p = 0.043).Flares are not more common in responders than in non-responders to Peg-interferon alpha-2b therapy. Virus induced flares, which occur after an increase in HBV DNA level, and most probably are indicative for increased expression of viral antigens, did not lead to treatment response. In contrast, host induced flares which were followed by a HBV DNA decrease were highly associated with treatment response.
In situ detection of lipid peroxidation by-products in chronic liver diseases
Authors: V Paradis
Journal: Hepatology (1997)

Lipid peroxidation is an autocatalytic mechanism leading to oxidative destruction of cellular membranes. The deleterious consequences of this mechanism are related in part to the formation of reactive aldehydic products that bind to intra- or extracellular molecules to form adducts. Specific antibodies directed against malondialdehyde (MDA) and 4-hydroxynonenal (HNE) adducts, major aldehydic metabolites of lipid peroxidation, allowed us to investigate in situ, with an immunohistochemical procedure, the occurrence of lipid peroxidation in a panel of different chronic liver diseases. Intracellular HNE and MDA adducts were detected respectively in 24 of 39 cases (62%) and in 12 of 34 cases investigated (35%). They were localized mainly in the cytoplasm of hepatocytes, with the strongest staining observed in hemochromatosis, Wilson's disease, and in areas of acute alcoholic hepatitis in cases of alcoholic liver diseases. A peculiar pattern of immunostaining was observed in primary biliary cirrhosis where biliary cells of destroyed but also intact bile ducts strongly expressed HNE adducts. The liver extracellular matrix also displayed MDA adducts (30 of 34 cases, 88%) and HNE adducts (23 of 39 cases, 59%). While HNE adducts were specifically localized on large bundles of collagen fibers, MDA adducts were detected in a thin reticular network and in sinusoidal cells around portal tracts or fibrous septa. In conclusion, lipid peroxidation by-products are detectable in chronic liver diseases. Immunohistochemical results suggest that this mechanism is implicated very early in the pathogenesis of some of these diseases.
Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis
Authors: Shizhen Zhu, Jeong-Soo Lee, Feng Guo, Jimann Shin, Antonio R. Perez-Atayde, Jeffery L. Kutok, Scott J. Rodig, Donna S. Neuberg, Daniel Helman, Hui Feng, Rodney A. Stewart, Wenchao Wang, Rani E. George, John P. Kanki, A. Thomas Look
Journal: Cancer Cell (2012)
The Evolution of Transcription-Initiation Sites
Authors: M. Lynch
Journal: Molecular Biology and Evolution (2005)

Unlike the situation in prokaryotes, most eukaryotic messenger RNAs contain a moderately long 5′ untranslated region (UTR). Such leader sequences impose a burden on eukaryotic genes by providing substrate for the mutational origin of premature translation-initiation codons, which generally result in defective proteins. To gain an insight into the expansion of 5′ UTRs in eukaryotic genomes, we present a simple null model in which the evolution of transcription-initiation sites is entirely driven by the stochastic mutational flux of core-promoter sequences and premature translation-initiation codons. This model yields results consistent with a variety of heretofore disconnected observations, including the form of length distributions of 5′ UTRs, the relatively low variance in UTR features among distantly related eukaryotes, the universal reliance on relatively simple core-promoter sequences, and the elevated density of introns in the 5′ UTR. We suggest that the reduced effective population sizes of most eukaryotes impose a population-genetic environment conducive to the movement of core promoters to random positions, subject to the constraint imposed by the upstream accumulation of premature translation-initiation codons. If this hypothesis is correct, then selection for gene-specific regulatory features need not be invoked to explain either the origin of lengthy eukaryotic 5′ UTRs or the 1,000-fold range of 5′-UTR lengths among genes within species. Nevertheless, once permanently established, expanded 5′ UTRs may have provided a novel substrate for the evolution of mechanisms for posttranscriptional regulation of eukaryotic gene expression. These results provide a further example of how an increase in the power of random genetic drift can passively promote the evolution of forms of gene architecture that ultimately facilitate the evolution of organismal complexity.
Local steroid therapy and bacterial skin flora in atopic dermatitis
Authors: J.F. STALDER, M. FLEURY, M. SOURISSE, M. ROSTIN, F. PHELINE, P. LITOUX
Journal: British Journal of Dermatology (2006)

A double-blind, randomized trial was conducted to determine the influence of topical steroid therapy on atopic skin flora. The bacteriological and clinical effects of desonide (Locapred®), compared with those of its excipient, were studied in 40 children. Clinical scoring and bacteriological sampling were performed before the start of the trial and after 7 days of once-daily topical treatment. Before treatment, no differences in clinical score or Staphylococcus aureus colonization were noted between the two groups. After treatment, the clinical score improved (P<0.001) in the desonide group, and S. aureus density decreased dramatically (P<0.001). In the excipient group, no significant differences in clinical score or S. aureus density were noted. A comparison of the two groups demonstrated statistically significant differences with regard to clinical score (P<0.001) and S. aureus density (P<0.05). These results show the efficacy of topical corticosteroid treatment alone on S. aureus colonization in atopic skin, and confirm the critical role of inflammation in bacterial colonization.