bluuebunny/crossref_metadata_2025_split huggingface dataset:
Poly(ADP-Ribose) Polymerase Inhibition Synergizes with 5-Fluorodeoxyuridine but not 5-Fluorouracil in Ovarian Cancer Cells
Authors: Huehls Amelia M. , Wagner Jill M. , Huntoon Catherine J. , Geng Liyi , Erlichman Charles , Patel Anand G. , Kaufmann Scott H. , Karnitz Larry M. 
Published: May 2011

Abstract5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint signaling pathways and the base excision repair (BER) pathway. Here, we assessed which DNA damage response and repair processes influence 5-FU and FdUrd toxicity in ovarian cancer cells. These studies revealed that disabling the ATM, ATR, or BER pathways using small inhibitory RNAs did not affect 5-FU cytotoxicity. In stark contrast, ATR and a functional BER pathway protected FdUrd-treated cells. Consistent with a role for the BER pathway, the poly(ADP-ribose) polymerase (PARP) inhibitors ABT-888 (veliparib) and AZD2281 (olaparib) markedly synergized with FdUrd but not with 5-FU in ovarian cancer cell lines. Furthermore, ABT-888 synergized with FdUrd far more effectively than other agents commonly used to treat ovarian cancer. These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors. Cancer Res; 71(14); 4944–54. ©2011 AACR.
Berberine Suppresses Androgen Receptor Signaling in Prostate Cancer
Authors: Li Jing , Cao Bo , Liu Xichun , Fu Xueqi , Xiong Zhenggang , Chen Li , Sartor Oliver , Dong Yan , Zhang Haitao 
Published: May 2011

Abstract
The androgen receptor (AR) is critical in the normal development and function of the prostate, as well as in prostate carcinogenesis. Androgen deprivation therapy is the mainstay in the treatment of advanced prostate cancer; however, after an initial response, the disease inevitably progresses to castration-resistant prostate cancer (CRPC). Recent evidence suggests that continued AR activation, sometimes in a ligand-independent manner, is commonly associated with the development of CRPC. Thus, novel agents targeting the AR are urgently needed as a strategic step in developing new therapies for this disease state. In this study, we investigated the effect of berberine on AR signaling in prostate cancer. We report that berberine decreased the transcriptional activity of AR. Berberine did not affect AR mRNA expression, but induced AR protein degradation. Several ligand-binding, domain-truncated AR splice variants have been identified, and these variants are believed to promote the development of CRPC in patients. Interestingly, we found that these variants were more susceptible to berberine-induced degradation than the full-length AR. Furthermore, although the growth of LNCaP xenografts in nude mice was inhibited by berberine, and AR expression was reduced in the tumors, the morphology and AR expression in normal prostates were not affected. This study is the first to show that berberine suppresses AR signaling and suggests that berberine, or its derivatives, presents a promising agent for the prevention and/or treatment of prostate cancer. Mol Cancer Ther; 10(8); 1346–56. ©2011 AACR.
Functional mapping of factor VIII C2 domain
Authors: Pellequer Jean-Luc , Chen Shu-wen W. , Saboulard Didier , Delcourt Marc , Négrier Claude , Plantier Jean-Luc 
Published: May 2011

SummaryThe factor VIII (FVIII) is a cofactor of the coagulation cascade. The FVIII C2 domain is a critical domain that participates in the interactions with the von Willebrand factor and the phospholipidic surfaces. To assess the importance of each residue of this domain in the maintenance of the structure and the function of FVIII, a number (n=139) of mutants were generated by substituting the original residues, from Ser2173 to Gly2325, by an alanine. Mutants were built within a complete B domain- deleted FVIII and expressed in COS-1 cells. Mutant antigen levels and procoagulant activities were measured. Two in silico analyses, a sliding average procedure and an analysis of the mutation energy cost were conducted in parallel on the FVIII structure. Both results were in agreement with the functional data, and illustrated the benefit of using such strategies prior to targeting specific residues in the aim of generating active recombinant molecules. The functional assays identify the residues that are important to maintaining the structure of the C2 domain, mainly those forming β-sheet, and those that can afford substitution, establishing a detailed functional relation with the available crystallographic data. This study provided a comprehensive functional mapping of the FVIII C2 domain and discussed the implication of specific residues in respect to the maintenance in the activity and structure stability, the efficiency in secretion, the binding to phospholipids and the formation of epitope.
Myocardial infarction, ischaemic stroke and pulmonary embolism before and after breast cancer hospitalisation
Authors: Shantakumar Sumitra , Kamphuisen Pieter W. , Beest Fernie J. A. Penning-van , Herings Ron M. C. , Herk-Sukel Myrthe P. P. van 
Published: May 2011

SummaryWe studied the occurrence of myocardial infarction (MI), ischaemic stroke (IS) and pulmonary embolism (PE) before and after breast cancer hospitalisation compared with cancer-free controls. For this, women with a first breast cancer hospitalisation during 2000–2007 were selected from the PHARMO Record Linkage System, including drug use and hospitalisations of three million inhabitants in the Netherlands, and matched 1:10 by age to cancer-free women. The occurrence of MI, IS and PE were assessed in the 12 months before and after breast cancer hospitalisation. The study included 11,473 breast cancer patients, with a mean (± SD) age of 59 (± 14) years. Breast cancer patients were two to three times as likely as their cancer-free controls to have had a hospitalisation for PE, MI or IS in the 12 months before diagnosis, though prevalence was <1% in all groups. Breast cancer patients experienced an extreme high risk of PE in the first six months after diag- nosis (hazard ratio [HR] 23.5, 95% confidence interval [CI] 11.1–49.7 compared to controls), which declined gradually to a four times increased risk (HR 3.6, 95%CI 2.4–5.5) more than 12 months after breast cancer hospitalisation. However, incidence was low: less than five events per 1,000 person years during all time periods. For MI and IS we did not observe significant increased HRs after breast cancer hospitalisation compared to controls. Breast cancer patients seem to have a higher risk profile to develop MI and IS, and receive treatment that increases the risk of PE compared to cancer-free controls, although the frequency of hospitalisations was low.
Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy
Authors: Angiolillo Dominick J. , Capranzano Piera , Ferreiro Jose Luis , Ueno Masafumi , Capodanno Davide , Dharmashankar Kodlipet , Darlington Andrew , Sumner Sabrina , Desai Bhaloo , Charlton Ronald K. , Box Lyndon C. , Zenni Martin M. , Guzman Luis A. , Bass Theodore A. 
Published: May 2011

SummaryCilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post-randomisation, and 14 days post-cross-over. Functional testing to assess P2Y12 signalling included flow cytometric analysis of phosphorylation status of vasodilatorstimulated phosphoprotein measured by P2Y12 reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y12 signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding.
Knockout of Toll-Like Receptor-2 Attenuates Both the Proinflammatory State of Diabetes and Incipient Diabetic Nephropathy
Authors: Devaraj Sridevi , Tobias Peter , Kasinath Balakuntalam S. , Ramsamooj Rajendra , Afify Alaa , Jialal Ishwarlal 
Published: May 2011

Objective—
Type 1 diabetes (T1DM) is a proinflammatory state and confers an increased risk for vascular complications. Toll-like receptors (TLR) could participate in diabetic vasculopathies. Whether TLR activation contributes to the proinflammatory state of T1DM and the pathogenesis of diabetic nephropathy remains unknown.

Methods and Results—
We induced T1DM in TLR2 knockout mice (TLR2−/−) and wild-type littermates (C57BL/6J-WT) using streptozotocin (STZ). Fasting blood, peritoneal macrophages, and kidneys were obtained for flow cytometry, Western blot, microscopy, and cytokine assays at 6 and 14 weeks after induction of diabetes. Macrophage TLR2 expression and MyD88-dependent signaling were increased in diabetic mice (WT+STZ) compared with nondiabetic WT mice. These biomarkers were attenuated in diabetic TLR2−/− macrophages. WT+STZ mice showed increased kidney:body weight ratio due to cell hypertrophy, increased albuminuria, decreased kidney nephrin, podocin, and podocyte number and increased transforming growth factor-β and laminin compared with WT mice. Nephrin, podocin, and podocyte number and effacement were restored, and transforming growth factor-β and laminin levels were decreased in TLR2−/−+ STZ mice kidneys versus WT+STZ. Peritoneal and kidney macrophages were predominantly M1 phenotype in WT+STZ mice; this was attenuated in TLR2−/−+STZ mice.

Conclusion—
These data support a role for TLR2 in promoting inflammation and early changes of incipient diabetic nephropathy, in addition to albuminuria and podocyte loss.
Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells
Authors: Wang Xu-ping , Chen Yu-guo , Qin Wei-dong , Zhang Wei , Wei Shu-jian , Wang Juan , Liu Fu Qiang , Gong Lei , An Feng Shuang , Zhang Yun , Chen Zhe-Yu , Zhang Ming-Xiang 
Published: May 2011

Objective—
Inflammation plays an important role in atherosclerosis. Arginase I (Arg I) promotes the proliferation of vascular smooth muscle cells; however, the effect of Arg I on inflammation remains unknown. The present study investigated the role of Arg I in inflammation in vitro and in vivo.

Methods and Results—
Quantitative reverse transcription–polymerase chain reaction and Western blot analysis demonstrated that Arg I inhibited tumor necrosis factor-α production induced by lipopolysaccharide in human aortic smooth muscle cells. Inducible nitric oxide synthase substrate competition and nuclear factor-κB activation were main contributors to lipopolysaccharide-mediated inflammatory cytokine generation. However, Arg I could attenuate the function of inducible nitric oxide synthase and inhibit the subsequent nuclear factor-κB activation, leading to inhibition of tumor necrosis factor-α generation. Furthermore, upregulation of Arg I significantly decreased macrophage infiltration and inflammation in atherosclerotic plaque of rabbits, whereas downregulation of Arg I aggravated these adverse effects.

Conclusion—
The results indicate the antiinflammatory effects of Arg I and suggest an unexpected beneficial role of Arg I in inflammatory disease.
Community-Based Participatory Research
Authors: Skolarus Lesli E. , Zimmerman Marc A. , Murphy Jillian , Brown Devin L. , Kerber Kevin A. , Bailey Sarah , Fowlkes Sophronia , Morgenstern Lewis B. 
Published: May 2011

Background and Purpose—
Acute stroke treatments are underutilized primarily because of delayed hospital arrival. Using a community-based participatory research approach, we explored stroke self-efficacy, knowledge, and perceptions of stroke among a predominately African American population in Flint, Michigan.

Methods—
In March 2010, a survey was administered to youth and adults after religious services at 3 churches and during 1 church health day. The survey consisted of vignettes (12 stroke, 4 nonstroke) to assess knowledge of stroke warning signs and behavioral intent to call 911. The survey also assessed stroke self-efficacy, personal knowledge of someone who had experienced a stroke, personal history of stroke, and barriers to calling 911. Linear regression models explored the association of stroke self-efficacy with behavioral intent to call 911 among adults.

Results—

Two hundred forty-two adults and 90 youths completed the survey. Ninety-two percent of adults and 90% of youth respondents were African American. Responding to 12 stroke vignettes, adults would call 911 in 72% (SD, 0.26) of the vignettes, whereas youths would call 911 in 54% of vignettes (SD, 0.29;
P
<0.001). Adults correctly identified stroke in 51% (SD, 0.32) of the stroke vignettes and youth correctly identified stroke in 46% (SD, 0.28) of the stroke vignettes (
P
=0.28). Stroke self-efficacy predicted behavioral intent to call 911 (
P
=0.046).

Conclusions—
In addition to knowledge of stroke warning signs, behavioral interventions to increase both stroke self-efficacy and behavioral intent may be useful for helping people make appropriate 911 calls for stroke. A community-based participatory research approach may be effective in reducing stroke disparities.
Nicotine restores morphine-induced memory deficit through the D1 and D2 dopamine receptor mechanisms in the nucleus accumbens
Authors: Azizbeigi Ronak , Ahmadi Shamseddin , Babapour Vahab , Rezayof Ameneh , Zarrindast Mohammad Reza 
Published: May 2011

Involvement of the dopamine D1 and D2 receptors in the nucleus accumbens (NAc) with interaction between morphine and nicotine on inhibitory avoidance (IA) memory was investigated. A step-through type of inhibitory avoidance tasks was used to assess memory in male Wistar rats. The results showed that subcutaneous (s.c.) administration of morphine (7.5 mg/kg) after training decreased retrieval of IA memory in the animals when tested 24 h later. Pre-test administration of the same dose of morphine significantly reversed the deficiency in retrieval. The results also showed that pre-test administration of nicotine (0.2 and 0.4 mg/kg, s.c.) by itself mimicked the effect of pre-test morphine, and lower doses of nicotine (0.1 and 0.2 mg/kg) also improved the effect of a low dose of morphine (2.5 mg/kg) on retrieval of IA memory. Pre-test intra-NAc administration of the dopamine D1 receptor antagonist, SCH 23390 (0.001 and 0.01 µg/rat), and the dopamine D2 receptor antagonist, sulpiride (0.5 and 1 µg/rat) caused no significant effects on IA memory by themselves, but both prevented reinstatement of the retrieval of IA memory by the effective dose of nicotine (0.4 mg/kg). It can be concluded that the dopaminergic mechanism(s) in the NAc is a crosslink for the effect of morphine and nicotine on reinstatement of retrieval of IA memory impaired by post-training administration of morphine.
Accuracy of Palpation-Guided and Ultrasound-Guided Needle Tip Placement Into the Deep and Superficial Posterior Leg Compartments
Authors: Peck Evan , Finnoff Jonathan T. , Smith Jay , Curtiss Heather , Muir Jeffery , Hollman John H. 
Published: May 2011

Background: Invasive leg compartment testing may be performed to diagnose chronic exertional compartment syndrome. No prior study has assessed the accuracy of leg compartment needle tip access. Purpose: This study was undertaken to describe and determine the accuracy of palpation-guided and ultrasound-guided techniques for needle tip placement into the deep and superficial posterior leg compartments by a less experienced clinician and a more experienced clinician using a cadaveric model. Study Design: Controlled laboratory study. Methods: Twenty unembalmed adult lower limb cadaveric specimens were used for the study. Two investigators, a sports medicine fellow with 10 months of musculoskeletal ultrasound experience and a staff physiatrist with 3 years of musculoskeletal ultrasound experience, each performed 1 palpation-guided and 1 ultrasound-guided colored latex dye injection into the deep and superficial posterior leg compartments of each cadaveric specimen. A blinded investigator dissected the specimens and graded them for accuracy. Results: The accuracy rates of palpation-guided (accuracy rate, 90%; 95% confidence interval [CI], 76%-97%) and ultrasound-guided (accuracy rate, 88%; 95% CI, 73%-95%) deep posterior compartment injections were statistically equivalent ( P = 1.000). All 80 injections performed into the superficial posterior compartment were accurate (accuracy rate, 100%; 95% CI, 89%-100%). The accuracy of the less experienced investigator (total injection accuracy rate, 88%; 95% CI, 73%-95%) and the more experienced investigator (total injection accuracy rate, 90%; 95% CI, 76%-97%) were not significantly different ( P = 1.000). Conclusion: Needle tip placement into the deep and superficial posterior leg compartments is relatively accurate with palpation guidance regardless of level of experience, and does not improve with the use of ultrasound guidance. Clinical Relevance: Ultrasound guidance does not appear to be indicated for routine deep or superficial posterior leg compartment pressure testing. However, this does not preclude the need for ultrasound guidance in selected clinical scenarios.
The relationship between relapse, impairment and disability in multiple sclerosis
Authors: Bennetto L , Burrow J , Sakai H , Cobby J , Robertson NP , Scolding N 
Published: May 2011

Objective: To describe the spatial relationship between relapse and disability in multiple sclerosis (MS). Methods: 141 relapse onset MS patients were studied. For each patient an examination was performed and a relapse history obtained. Multivariate logistic regression examined whether there was an association between localizing clinical signs and a history of relevant relapse in order to explore the spatial relationship between relapse and subsequent disability. Results: The presence of impaired vision or sensation was independently associated with a history of one or more anatomically related relapses. The presence of weakness or cerebellar ataxia in a limb was not associated with a single relevant relapse but was associated with multiple relevant relapses. A history of multiple episodes of weakness or ataxia in the same limb was uncommon. Conclusions: Our data suggest that motor pathways are relatively resistant to chronic impairment from acute relapse, whereas afferent pathways are more susceptible. This, in combination with prominent usage of the Expanded Disability Status Scale, which is dependent on mobility and motor function at higher scores, may explain the paradox between natural history studies that suggest relapses are irrelevant to long-term disability and shorter studies at lower disability levels suggesting relapses are responsible for disability accumulation.
Toso regulates the balance between apoptotic and nonapoptotic death receptor signaling by facilitating RIP1 ubiquitination
Authors: Nguyen Xuan-Hung , Lang Philipp A. , Lang Karl S. , Adam Dieter , Fattakhova Gulnar , Föger Niko , Kamal Mohammad Azhar , Prilla Patricia , Mathieu Sabine , Wagner Christina , Mak Tak , Chan Andrew C. , Lee Kyeong-Hee 
Published: May 2011

Abstract
The regulation of cellular survival and apoptosis is of critical importance for the immune system to maintain immune homeostasis and to establish tolerance. Here, we demonstrate that the immune specific cell surface molecule Toso exhibits antiapoptotic effects on death receptor signaling by a novel regulatory mechanism involving the adaptor kinase RIP1. The antiapoptotic function of Toso depends on RIP1 ubiquitination and involves the recruitment of the death adaptor FADD to a Toso/RIP1 protein complex. In response to CD95L and TNFα, Toso promotes the activation of MAPK and NF-κB signaling pathways. Because of this relative augmentation of survival versus apoptotic signals, Toso raises the threshold for death receptor–mediated apoptosis. Our analysis of Toso-deficient mice revealed that Toso is essential for TNFα-mediated liver damage. Furthermore, the antiapoptotic function of Toso could be blocked by a Toso-specific monoclonal antibody, opening up new therapeutic prospects for the treatment of immune disorders and hematologic malignancies.
Inhibitory receptors specific for MHC class I educate murine NK cells but not CD8αα intestinal intraepithelial T lymphocytes
Authors: Taveirne Sylvie , Filtjens Jessica , Van Ammel Els , De Colvenaer Veerle , Kerre Tessa , Taghon Tom , Vandekerckhove Bart , Plum Jean , Held Werner , Leclercq Georges 
Published: May 2011

AbstractThe engagement of inhibitory receptors specific for major histocompatibility complex class I (MHC-I) molecules educates natural killer (NK) cells, meaning the improvement of the response of activation receptors to subsequent stimulation. It is not known whether inhibitory MHC-I receptors educate only NK cells or whether they improve the responsiveness of all cell types, which express them. To address this issue, we analyzed the expression of inhibitory MHC-I receptors on intestinal intraepithelial lymphocytes (iIELs) and show that T-cell receptor (TCR)-αβ CD8αα iIELs express multiple inhibitory receptors specific for MHC-I molecules, including CD94/NKG2A, Ly49A, and Ly49G2. However, the presence of MHC-I ligand for these receptors did not improve the response of iIELs to activation via the TCR. The absence of iIEL education by MHC-I receptors was not related to a lack of inhibitory function of these receptors in iIELs and a failure of these receptors to couple to the TCR. Thus, unlike NK cells, iIELs do not undergo an MHC-I–guided education process. These data suggest that education is an NK cell–specific function of inhibitory MHC-I receptors.