bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms
Authors: Quintás-Cardama Alfonso , Vaddi Kris , Liu Phillip , Manshouri Taghi , Li Jun , Scherle Peggy A. , Caulder Eian , Wen Xiaoming , Li Yanlong , Waeltz Paul , Rupar Mark , Burn Timothy , Lo Yvonne , Kelley Jennifer , Covington Maryanne , Shepard Stacey , Rodgers James D. , Haley Patrick , Kantarjian Hagop , Fridman Jordan S. , Verstovsek Srdan 
Published: February 2010

AbstractConstitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC50] = 281nM), and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67nM) versus healthy donors (IC50 > 400nM). In a mouse model of JAK2V617F+ MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.
CNV Workshop: an integrated platform for high-throughput copy number variation discovery and clinical diagnostics
Authors: Gai Xiaowu , Perin Juan C , Murphy Kevin , O'Hara Ryan , D'arcy Monica , Wenocur Adam , Xie Hongbo M , Rappaport Eric F , Shaikh Tamim H , White Peter S 
Published: February 2010

Abstract

Background
Recent studies have shown that copy number variations (CNVs) are frequent in higher eukaryotes and associated with a substantial portion of inherited and acquired risk for various human diseases. The increasing availability of high-resolution genome surveillance platforms provides opportunity for rapidly assessing research and clinical samples for CNV content, as well as for determining the potential pathogenicity of identified variants. However, few informatics tools for accurate and efficient CNV detection and assessment currently exist.

Results
We developed a suite of software tools and resources (CNV Workshop) for automated, genome-wide CNV detection from a variety of SNP array platforms. CNV Workshop includes three major components: detection, annotation, and presentation of structural variants from genome array data. CNV detection utilizes a robust and genotype-specific extension of the Circular Binary Segmentation algorithm, and the use of additional detection algorithms is supported. Predicted CNVs are captured in a MySQL database that supports cohort-based projects and incorporates a secure user authentication layer and user/admin roles. To assist with determination of pathogenicity, detected CNVs are also annotated automatically for gene content, known disease loci, and gene-based literature references. Results are easily queried, sorted, filtered, and visualized via a web-based presentation layer that includes a GBrowse-based graphical representation of CNV content and relevant public data, integration with the UCSC Genome Browser, and tabular displays of genomic attributes for each CNV.

Conclusions
To our knowledge, CNV Workshop represents the first cohesive and convenient platform for detection, annotation, and assessment of the biological and clinical significance of structural variants. CNV Workshop has been successfully utilized for assessment of genomic variation in healthy individuals and disease cohorts and is an ideal platform for coordinating multiple associated projects.

Availability and Implementation
Available on the web at: http://sourceforge.net/projects/cnv
Cluster randomized trial in smoking cessation with intensive advice in diabetic patients in primary care. ITADI Study
Authors: Roig Lydia , Perez Santiago , Prieto Gemma , Martin Carlos , Advani Mamta , Armengol Angelina , Roura Pilar , Maria Manresa Josep , Briones Elena ,   ITADI Study Group
Published: February 2010

Abstract

Background
It is a priority to achieve smoking cessation in diabetic smokers, given that this is a group of patients with elevated cardiovascular risk. Furthermore, tobacco has a multiplying effect on micro and macro vascular complications. Smoking abstinence rates increase as the intensity of the intervention, length of the intervention and number and diversity of contacts with the healthcare professional during the intervention increases. However, there are few published studies about smoking cessation in diabetics in primary care, a level of healthcare that plays an essential role in these patients. Therefore, the aim of the present study is to evaluate the effectiveness of an intensive smoking cessation intervention in diabetic patients in primary care.

Methods/Design
Cluster randomized trial, controlled and multicentric. Randomization unit: Primary Care Team. Study population: 546 diabetic smokers older than 14 years of age whose disease is controlled by one of the primary care teams in the study. Outcome Measures: Continuous tobacco abstinence (a person who has not smoked for at least six months and with a CO level of less than 6 ppm measured by a cooximeter) , evolution in the Prochaska and DiClemente's Transtheoretical Model of Change, number of cigarettes/day, length of the visit. Point of assessment: one- year post- inclusion in the study. Intervention: Brief motivational interview for diabetic smokers at the pre-contemplation and contemplation stage, intensive motivational interview with pharmacotherapy for diabetic smokers in the preparation-action stage and reinforcing intevention in the maintenance stage. Statistical Analysis: A descriptive analysis of all variables will be done, as well as a multilevel logistic regression and a Poisson regression. All analyses will be done with an intention to treatment basis and will be fitted for potential confounding factors and variables of clinical importance. Statistical packages: SPSS15, STATA10 y HLM6.

Discussion
The present study will try to describe the profile of a diabetic smoker who receives the most benefit from an intensive intervention in primary care. The results will be useful for primary care professionals in their usual clinical practice.

Trial Registration
Clinical Trials.gov Identifier: NCT00954967
Compliance with a three-day course of artesunate-mefloquine combination and baseline anti-malarial treatment in an area of Thailand with highly multidrug resistant falciparum malaria
Authors: Congpuong Kanungnit , Bualombai Pongwit , Banmairuroi Vick , Na-Bangchang Kesara 
Published: February 2010

Abstract

Background
Artemisinin-based combination therapy (ACT) is presently recommended by the World Health Organization as first-line treatment for uncomplicated Plasmodium falciparum malaria in several countries, as a mean of prolonging the effectiveness of first-line malaria treatment regimens. A three-day course of artesunate-mefloquine (4 mg/kg body weight once daily for three consecutive days, plus 15 and 10 mg/kg body weight mefloquine on the first and second days) has been adopted by Malaria Control Programme of Thailand as first-line treatment for uncomplicated falciparum malaria all over the country since 2008. The gametocytocydal anti-malarial drug primaquine is administered at the dose of 30 mg (0.6 mg/kg) on the last day. The aim of the present study was to assess patient compliance of this combination regimen when applied to field condition.

Methods
A total of 240 patients (196 males and 44 females) who were attending the malaria clinics in Mae-Sot, Tak Province and presenting with symptomatic acute uncomplicated falciparum malaria, with no reappearance of Plasmodium vivax parasitaemia during follow-up were included into the study. The first dose of the treatment was given to the patients under direct supervision. All patients were given the medication for self-treatment at home and were requested to come back for follow-up on day 3 of the initial treatment. Baseline (day 0) and day 3 whole blood mefloquine and plasma primaquine concentrations were determined by high performance liquid chromatography.

Results
Two patients had recrudescence on days 28 and 35. The Kaplan-Meier estimate of the 42-day efficacy rate of this combination regimen was 99.2% (238/240). Based on whole blood mefloquine and plasma primaquine concentrations on day 3 of the initial treatment, compliance with mefloquine and primaquine in this three-day artesunate-mefloquine combination regimen were 96.3% (207/215), and 98.5% (197/200), respectively. Baseline mefloquine and primaquine levels were observed in 24 and 16% of the patients.

Conclusion
The current first-line treatment and a three-day combination regimen of artesunate-mefloquine provides excellent patient compliance with good efficacy and tolerability in the treatment of highly multidrug resistance falciparum malaria. Previous treatment with mefloquine and primaquine were common in this area.
Unscheduled expression of CDC25B in S-phase leads to replicative stress and DNA damage
Authors: Bugler Béatrix , Schmitt Estelle , Aressy Bernadette , Ducommun Bernard 
Published: February 2010

AbstractBackgroundCDC25B phosphatase is a cell cycle regulator that plays a critical role in checkpoint control. Up-regulation of CDC25B expression has been documented in a variety of human cancers, however, the relationships with the alteration of the molecular mechanisms that lead to oncogenesis still remain unclear. To address this issue we have investigated, in model cell lines, the consequences of unscheduled and elevated CDC25B levels.ResultsWe report that increased CDC25B expression leads to DNA damage in the absence of genotoxic treatment. H2AX phosphorylation is detected in S-phase cells and requires active replication. We also report that CDC25B expression impairs DNA replication and results in an increased recruitment of the CDC45 replication factor onto chromatin. Finally, we observed chromosomal aberrations that are also enhanced upon CDC25B expression.ConclusionOverall, our results demonstrate that a moderate and unscheduled increase in CDC25B level, as observed in a number of human tumours, is sufficient to overcome the S-phase checkpoint efficiency thus leading to replicative stress and genomic instability.
Roles for common MLL/COMPASS subunits and the 19S proteasome in regulating CIITA pIV and MHC class II gene expression and promoter methylation
Authors: Koues Olivia I , Mehta Ninad T , Truax Agnieszka D , Dudley R Kyle , Brooks Jeanne K , Greer Susanna F 
Published: February 2010

AbstractBackgroundStudies indicate that the 19S proteasome contributes to chromatin reorganization, independent of the role the proteasome plays in protein degradation. We have previously shown that components of the 19S proteasome are crucial for regulating inducible histone activation events in mammalian cells. The 19S ATPase Sug1 binds to histone-remodeling enzymes, and in the absence of Sug1, a subset of activating epigenetic modifications including histone H3 acetylation, H3 lysine 4 trimethylation and H3 arginine 17 dimethylation are inhibited at cytokine-inducible major histocompatibilty complex (MHC)-II and class II transactivator (CIITA) promoters, implicating Sug1 in events required to initiate mammalian transcription.ResultsOur previous studies indicate that H3 lysine 4 trimethylation at cytokine-inducible MHC-II and CIITA promoters is dependent on proteolytic-independent functions of 19S ATPases. In this report, we show that multiple common subunits of the mixed lineage leukemia (MLL)/complex of proteins associated with Set I (COMPASS) complexes bind to the inducible MHC-II and CIITA promoters; that overexpressing a single common MLL/COMPASS subunit significantly enhances promoter activity and MHC-IIHLA-DRAexpression; and that these common subunits are important for H3 lysine 4 trimethylation at MHC-II and CIITA promoters. In addition, we show that H3 lysine 27 trimethylation, which is inversely correlated with H3 lysine 4 trimethylation, is significantly elevated in the presence of diminished 19S ATPase Sug1.ConclusionTaken together, these experiments suggest that the 19S proteasome plays a crucial role in the initial reorganization of events enabling the relaxation of the repressive chromatin structure surrounding inducible promoters.
Insulin-treated diabetes is not associated with increased mortality in critically ill patients
Authors: Vincent Jean-Louis , Preiser Jean-Charles , Sprung Charles L , Moreno Rui , Sakr Yasser 
Published: February 2010

Abstract
Introduction
This was a planned substudy from the European observational Sepsis Occurrence in Acutely ill Patients (SOAP) study to investigate the possible impact of insulin-treated diabetes on morbidity and mortality in ICU patients.

Methods
The SOAP study was a cohort, multicenter, observational study which included data from all adult patients admitted to one of 198 participating ICUs from 24 European countries during the study period. For this substudy, patients were classified according to whether or not they had a known diagnosis of insulin-treated diabetes mellitus. Outcome measures included the degree of organ dysfunction/failure as assessed by the sequential organ failure assessment (SOFA) score, the occurrence of sepsis syndromes and organ failure in the ICU, hospital and ICU length of stay, and all cause hospital and ICU mortality.

Results
Of the 3147 patients included in the SOAP study, 226 (7.2%) had previously diagnosed insulin-treated diabetes mellitus. On admission, patients with insulin-treated diabetes were older, sicker, as reflected by higher simplified acute physiology system II (SAPS II) and SOFA scores, and more likely to be receiving hemodialysis than the other patients. During the ICU stay, more patients with insulin-treated diabetes required renal replacement therapy (hemodialysis or hemofiltration) than other patients. There were no significant differences in ICU or hospital lengths of stay or in ICU or hospital mortality between patients with or without insulin-treated diabetes. Using a Cox proportional hazards regression analysis with hospital mortality censored at 28-days as the dependent factor, insulin-treated diabetes was not an independent predictor of mortality.

Conclusions
Even though patients with a history of insulin-treated diabetes are more severely ill and more likely to have renal failure, insulin-treated diabetes is not associated with increased mortality in ICU patients.
HIV DNA in circulating monocytes as a mechanism to dementia and other HIV complications
Authors: Valcour Victor G , Shiramizu Bruce T , Shikuma Cecilia M 
Published: February 2010

Abstract
Failure of potent antiretroviral therapy to eradicate this HIV reservoir may be responsible for the continued occurence of dementia in HIV-infected individuals.
It is broadly accepted that HIV DNA in lymphoid and myeloid cells persists despite combination antiretroviral therapy. Recognized as the Achilles heel to HIV eradication, the role of these peripheral reservoirs in HIV morbidity is less well developed. The burden of HIV DNA in peripheral mononuclear cells is linked to HIV disease outcomes such as time to AIDS diagnosis, survival, and CD4 T-lymphocyte counts. Monocytes are a minor HIV DNA reservoir, and the burden of HIV DNA in these cells appears to be linked to dementia, suggesting that residual infection in this subset is linked to tissue-related HIV complications. Since monocytes are likely involved in trafficking virus to the brain, there is a strong mechanistic link underlying this discovery. Herein, we summarize our current understanding of monocyte HIV DNA and central nervous system dysfunction in humans. We present a model to understand these relationships and suggest possible treatment approaches to be tested.
The prophylactic effects of platelet-leucocyte gel in osteomyelitis
Authors: Jia W.-T. , Zhang C.-Q. , Wang J.-Q. , Feng Y. , Ai Z.-S. 
Published: February 2010

Platelet-leucocyte gel (PLG), a new biotechnological blood product, has hitherto been used primarily to treat chronic ulcers and to promote soft-tissue and bone regeneration in a wide range of medical fields. In this study, the antimicrobial efficacy of PLG against Staphylococcus aureus (ATCC 25923) was investigated in a rabbit model of osteomyelitis. Autologous PLG was injected into the tibial canal after inoculation with Staph. aureus. The prophylactic efficacy of PLG was evaluated by microbiological, radiological and histological examination. Animal groups included a treatment group that received systemic cefazolin and a control group that received no treatment.Treatment with PLG or cefazolin significantly reduced radiological and histological severity scores compared to the control group. This result was confirmed by a significant reduction in the infection rate and the number of viable bacteria. Although not comparable to cefazolin, PLG exhibited antimicrobial efficacy in vivo and therefore represents a novel strategy to prevent bone infection in humans.
Metal-backed acetabular components with conventional polyethylene
Authors: Hallan G. , Dybvik E. , Furnes O. , Havelin L. I. 
Published: February 2010

The Norwegian Arthroplasty Register has shown that several designs of uncemented femoral stems give good or excellent survivorship. The overall findings for uncemented total hip replacement however, have been disappointing because of poor results with the use of metal-backed acetabular components. In this study, we exclusively investigated the medium-to long-term performance of primary uncemented metal-backed acetabular components. A total of 9113 primary uncemented acetabular components were implanted in 7937 patients between 1987 and 2007. These were included in a prospective, population-based observational study. All the implants were modular and metal-backed with ultra-high-molecular-weight polyethylene liners. The femoral heads were made of stainless steel, cobalt-chrome (CoCr) alloy or alumina ceramic. In all, seven different designs of acetabular component were evaluated by the Kaplan-Meier survivorship method and Cox regression analysis. Most acetabular components performed well up to seven years. When the endpoint was revision of the acetabular component because of aseptic loosening, the survival ranged between 87% and 100% at ten years. However, when the endpoint was revision for any reason, the survival estimates were 81% to 92% for the same implants at ten years. Aseptic loosening, wear, osteolysis and dislocation were the main reasons for the relatively poor overall performance of the acetabular components. Prostheses with alumina heads performed slightly better than those with stainless steel or CoCr alloy in subgroups. Whereas most acetabular components performed well at seven years, the survivorship declined with longer follow-up. Fixation was generally good. None of the metal-backed uncemented acetabular components with ultra-high-molecular-weight polyethylene liners in our study had satisfactory long-term results because of high rates of wear, osteolysis, aseptic loosening and dislocation.
Lack of a central role for osteoprogenitor cells from the femoral canal in heterotopic ossification of the hip
Authors: Toom A. , Suutre S. , Märtson A. , Haviko T. , Selstam G. , Arend A. 
Published: February 2010

We have developed an animal model to examine the formation of heterotopic ossification using standardised muscular damage and implantation of a beta-tricalcium phosphate block into a hip capsulotomy wound in Wistar rats. The aim was to investigate how cells originating from drilled femoral canals and damaged muscles influence the formation of heterotopic bone. The femoral canal was either drilled or left untouched and a tricalcium phosphate block, immersed either in saline or a rhBMP-2 solution, was implanted. These implants were removed at three and 21 days after the operation and examined histologically, histomorphometrically and immunohistochemically. Bone formation was seen in all implants in rhBMP-2-immersed, whereas in those immersed in saline the process was minimal, irrespective of drilling of the femoral canals. Bone mineralisation was somewhat greater in the absence of drilling with a mean mineralised volume to mean total volume of 18.2% (sd 4.5) versus 12.7% (sd 2.9, p < 0.019), respectively. Our findings suggest that osteoinductive signalling is an early event in the formation of ectopic bone. If applicable to man the results indicate that careful tissue handling is more important than the prevention of the dissemination of bone cells in order to avoid heterotopic ossification.
The Durom Large Diameter Head acetabular component
Authors: Berton C. , Girard J. , Krantz N. , Migaud H. 
Published: February 2010

Implantation of a large-diameter femoral head prosthesis with a metal-on-metal bearing surface reduces the risk of dislocation, increases the range of movement, minimises the risk of impingement and, in theory, results in little wear. Between February 2004 and March 2007 we implanted 100 consecutive total hip replacements with a metal-on-metal bearing and a large femoral head into 92 patients. There were 51 men and 41 women with a mean age of 50 years (18 to 70) at the time of surgery. Outcome was assessed using the Western Ontario McMaster University osteoarthritis index and the Harris hip score as well as the Devane activity score. These all improved significantly (p < 0.0001). At the last follow-up there were no cases of dislocation, no impingement, a good range of movement and no osteolysis, but seven revisions, two for infection and five for aseptic loosening. The probability of groin pain increased if the other acetabular component inclination exceeded 50° (p = 0.0007). At 4.8 years of follow-up, the projected survival of the Durom acetabular component, with revision for any reason, was 92.4% (sd 2.8) (95% confidence interval 89.6 to 95.2). The design of the component made it difficult both to orientate and seat, which when combined with a poor porous coating, produced unpredictable fixation and a low survival at five years.