bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continuing Reduction in Level of Residual Disease after 4 Years in Patients with CML in Chronic Phase Responding to First-Line Imatinib (IM) in the IRIS Study.
Authors: Goldman John M. , Hughes Timothy , Radich Jerry , Branford Susan , Hochhaus Andreas , So Charlene , Gathmann Insa , Wehrle Elisabeth , Kaeda Jaspal 
Published: April 2020

Abstract
Background and methods: The IRIS study initiated in June 2000 compared treating newly diagnosed CML-CP pts with IM or interferon+ara-C. Pts who achieved a complete cytogenetic response (CCyR) had BCR-ABL transcript numbers in the blood measured serially by real-time quantitative PCR. Results were expressed as a log reduction from a standardized baseline value for untreated pts. We showed previously that by 1 year an estimated 40% of pts who started IM at 400 mg/day had achieved a major molecular response (MMR) defined as ≥3 log reduction in BCR-ABL levels. Of the 136 pts who achieved MMR at one year, all survived at 42 months without evidence of progression to advanced phase whereas 5% of the 94 pts who failed to achieve MMR at one year had progressed. Although routine PCR sampling was interrupted January 2003, (24 months after end of study recruitment), 6-monthly monitoring was resumed in August 2004 for all pts on study regardless of CCyR status. PCR data analyzed up to February 2005 are included here.
Objectives: To evaluate level of BCR-ABL transcripts after approximately 4 years on IM in pts who had transcript numbers measured in CCyR at 1 year. Of the 553 pts who started treatment with IM, this analysis is based on the 101 pts who had achieved CCyR within 1 year, who received first-line treatment at least for 24 months and who had blood collected for measuring transcript numbers at 1 year and 4 years after starting treatment.
Results: At 1 year BCR-ABL transcript levels had fallen by at least 3 log in 47 (46%) of the 101 pts. At the most recent measurement at or after 44 months from start of study (median 49 months, range 44 – 55), 76 (75%) pts showed a reduction of at least 3 logs. Of these 76 pts, 39 (51%) had already had a ≥3 log reduction at year one, whereas 37 (49%) had not. Conversely 8 of the 47 pts with ≥3 log reduction at 1 year had log reductions &lt;3 at 4 years (see table).
Table 1. BCR-ABL log reduction
For all pts the mean ± SD log reduction was 3.0 ± 1.0 at 1 year and 3.4 ± 1.1 at 4 years (p=0.0008, paired t-test). At the 1 and 4 year points 20 (20%) and 36 (36%) respectively of these pts had achieved ≥4 log reductions. In this subset responding well to IM, the majority of pts have BCR-ABL transcript levels that continue to decline with 35% falling more than 1 log and 18% falling 0.5–1 log between 1 and 4 years; however in 13% levels increased more than 1 log between the two time-points.
Summary:. Pts with CCyR and a moderate decline of their BCR-ABL transcript levels at 1 year still have a good chance of achieving an MMR at 4 years. The full analysis (data cut-off of 31-July-2005) will be presented together with the relationship of transcript levels to clinical outcomes.
Incidence, Timing of Onset and Severity of Post-Thrombotic Syndrome after Acute Symptomatic Deep Vein Thrombosis: Two-Year Results from a Canadian Multicenter Prospective Cohort Study (The VETO Study).
Authors: Kahn Susan R. , Ducruet Thierry , Arsenault Louise , Miron Marie Jose , Roussin Andre , Desmarais Sylvie , Joyal France , Kassis Jeannine , Solymoss Susan , Desjardins Louis , Johri Mira , Shrier Ian , Lamping Donna L. , Ginsberg Jeffrey S. 
Published: April 2020

Abstract
Background and Objectives: The post thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). It is difficult to provide DVT patients with long-term prognostic information as there is little longitudinal data on the occurrence of PTS after DVT. We performed a prospective multicenter study of long-term outcomes after DVT (the Venous Thrombosis Outcomes [VETO] Study) to determine the incidence, timing of onset and severity of PTS.
Methods: Consecutive patients with objectively diagnosed acute DVT were recruited at 7 participating hospital centres from April 2001-July 2002. Patients attended study visits at Baseline, 4, 8, 12 and 24 months. Clinical data were recorded and standardized assessments for PTS (using Villalta scale) were performed by trained study personnel at each follow-up visit. Patients were classified as having developed PTS if the ipsilateral Villalta score was ≥ 5 on at least 2 visits or at the final follow-up visit, and having severe PTS if a score of &gt;14 or a venous ulcer was documented on any one occasion. The Kaplan-Meier survival method was used to estimate the cumulative probability of PTS and of severe PTS over time.
Results: The study cohort consisted of 359 patients. The mean age was 56 years, 50% were male, 2/3 were outpatients, 55% had proximal DVT and 20% had previous DVT. The Kaplan-Meier estimates of cumulative risk of PTS were 29% at 4 months, 33% at 8 months, 35% at 12 months and 37% at 24 months. Corresponding risks of severe PTS were 6.6%, 6.9%, 6.9% and 6.9%, respectively. When the analysis was stratified according to history of DVT, the cumulative incidence of PTS in patients without previous DVT was 25%, 28%, 30% and 31% at 4, 8, 12 and 24 months. Corresponding rates of PTS in patients with previous DVT were 45%, 51%, 53% and 57%.
Conclusions: More than one third of patients in our cohort developed PTS within 2 years of DVT, and of these, 1 in 6 was classified as severe. Most cases of PTS and of severe PTS were apparent by 4 months after DVT. Patients with previous DVT had a higher frequency of PTS and of late onset PTS. Our study provides longitudinal data on prognosis that is relevant both to patients with DVT and their treating physicians.
Factor XIII Val34Leu Polymorphism and the Risk of Myocardial Infarction: A Meta-Analysis.
Authors: Shafey Mona , Anderson Josdalyne L. , Scarvelis Dimitrios , Doucette Steve P. , Gagnon France , Wells Philip S. 
Published: April 2020

Abstract
Genetic factors involving blood coagulation are thought to contribute to the pathogenesis of myocardial infarction. A common polymorphism of Factor XIII, Factor XIII Val34Leu, may be protective against developing an acute myocardial infarction, but various studies show conflicting results. We performed a meta-analysis to determine whether the Factor XIII Val34Leu polymorphism is associated with a decreased risk of myocardial infarction. 93 articles were reviewed after a MEDLINE search of the literature (1966 through April Week 1 2005) and 12 case-control studies were selected. We included studies involving patients with objectively diagnosed myocardial infarctions (according to the WHO criteria) provided Factor XIII genotyping data were available. Inclusion decisions, quality assessment and data extraction were conducted by two reviewers. Hardy-Weinberg equilibrium was verified in all studies. Hypothesizing that the Leu allele was protective we performed 3 analyses with the Val/Val genotype as the reference group. Pooled odds ratios and their 95% confidence intervals were determined using the method of DerSimonian-Laird. Prior to pooling, heterogenity testing was performed using the I2 statistic. Funnel plots ruled out the possibility of publication bias. These studies included a total of 8743 patients, of which 3663 were MI patients and 5080 were healthy controls. Using the random effects methods, protective effects were seen with the Leu/Val genotype alone (OR for MI 0.79, 95% CI 0.68–0.93) and with Leu/Val and Leu/Leu genotypes (OR 0.79, 95% CI 0.68–0.93). There was also a protective effect with the Leu/Leu genotype alone, but this was not statistically significant (0.83, 95% CI 0.61–1.12) likley due to the low frequency of this genotype. Removing the first published study (Kohler 1998) due to potential publication bias assocaited with the first study evaluating a genotype did not significantly change the results. Our analysis found that the Factor XIII Leu allele confers a small but significant protective effect against myocardial infarction. The polymorphism may be useful in profiling an individual’s susceptibility for arterial thrombosis. It remains to be elucidated whether or not routine testing for the FXIII Val34Leu polymorphism will be clinically relevant.
The Thrombospondin-1 N700S Polymorphism Does Not Alter von Willebrand Factor Multimer Size in Patients Suffering an Acute Myocardial Infarction.
Authors: Zwicker Jeffrey , Peyvandi Flora , Palla Roberta , Lombardi Rosanna , Canciani Maria Teresa , Bauer Kenneth , Lawler Jack , Mannucci P.M. 
Published: April 2020

Abstract
An uncommon missense variant of thrombospondin-1 representing an asparagine (Asn-700) to serine substitution (Ser-700) has been identified as a potential genetic risk factor for myocardial infarction (MI). Thrombospondin-1 (TSP-1) is a glycoprotein stored in human platelet alpha granules and has been shown to regulate von Willebrand factor (VWF) multimer size. The TSP-1 domain responsible for VWF-reducing activity was localized to the calcium-binding C-terminal sequence at position Cys 974. Considering the proximity of the N700S TSP-1 polymorphism and the demonstration that the Ser-700 polymorphism alters the calcium binding affinity of this domain, we investigated whether altered VWF-reducing activity of Ser-700 polymorphism underlies the observed prothrombotic phenotype. Plasma samples were analyzed from a cohort of patients (N=31) who survived an acute myocardial infarction at age 45 or younger compared with age-matched controls (N=19). The relative percentage of high molecular weight VWF multimers did not differ significantly between individuals homozygous for either Ser-700 or Asn-700 (p=.20). Similarly, the relative percentage of high molecular weight multimers was 31.2% for the Ser-700 homozygous MI patients (N=21) versus 31.1% (p=.95) in the Asn-700 healthy controls (N=10). These findings were confirmed using the collagen binding assay to assess VWF activity relative to antigen concentrations. The mean ratio of CBA/Ag was .98 in the Ser-700 patients versus 1.0 in the Asn-700 control group (p=.22). Mean plasma thrombospondin-1 concentrations did not differ between the two groups. The VWF reducing capacity of TSP-1 was also assessed in vitro using recombinant TSP-1 N700S constructs containing the last EGF-like repeat, all type-3 repeats (calcium-binding domains), and C-terminal sequence. Incubation of Ser-700 peptide, Asn-700 peptide, or platelet purified full-length TSP-1 with ultra-large VWF (using either TTP plasma or recombinant ultra-large VWF) did not result in any significant reduction of VWF multimer size under static conditions. In conclusion, the association between coronary artery thrombosis and the TSP-1 Ser-700 polymorphism is not mediated through altered VWF reducing activity.
Mechanical Ventricular Assistance Rescues Endocardial Thrombomodulin Expression and May Restore Thromboresistance.
Authors: Kim Antony Y. , Favre Elizabeth , Tian Xiaojing , Paul Jonathan , Raman Jaishankar , Miller Jonathan L. 
Published: April 2020

Abstract
Heart failure is associated with a significant risk for thrombosis and an increased risk for thromboembolic events. Disturbance in blood flow, endothelial dysfunction or injury, and a hypercoagulable state are each present in heart failure and may contribute to the prothrombotic milieu. More recent evidence has linked heart failure with an active thrombogenic state, as demonstrated by elevated levels of thrombin-antithrombin complexes, prothrombin fragment F1+2, and fibrinopeptide A, all indices of thrombin activation. Thrombomodulin (TM), an integral membrane protein found on the endocardial endothelium (EE), is a potent thrombin inhibitor via activation of the protein C pathway. We hypothesized that the loss of thromboresistance on the ventricular endocardium, which has previously been described in cardiomyopathy, would be restored by placement of a temporary ventricular assistance device (VAD). Using left ventricular apical tissue obtained from heart failure subjects (CHF) undergoing a VAD as a bridge to heart transplant (n=4), and then from apical tissue of the same subjects at the time of explantation (post-VAD), we quantified TM protein expression using an anti-human TM antibody on EE by digital immunohistochemical analysis. TM expression levels were expressed as arbitrary units (AU) reaching signal intensity threshold per millimeter (mm) of left ventricular (LV) perimeter (AU/mm). Control TM staining of LV endocardial segments (n=2) obtained from the apex of normal hearts not used for transplantation after being excised from potential donors was 1482 and 1587 AU/mm (avg=1534 AU/mm). In CHF cardiac tissue obtained at the time of VAD placement (pre-VAD), TM protein expression on the ventricular EE of the LV apex was markedly decreased compared to control (275±67 AU/mm, p&lt;0.01 vs. control LV, using unpaired t-test). Endocardial TM protein expression returned to near baseline levels (1182±32 AU/mm) in post-VAD cardiac samples explanted at the time of transplant from the same subjects (following VAD placement of 1–4 months in all subjects). The post-VAD TM level represented a highly significant rise over pre-VAD TM level (p&lt;0.01 using paired t-test). Persistent staining of adjacent tissue sections in all cardiac samples for von Willebrand factor, an endothelial marker, provided clear evidence that endocardial integrity was maintained and endocardial cell loss was not responsible for the reduction of TM expression. The present study demonstrates that TM protein expression on the endocardial surface is reduced by greater than 80% in heart failure patients. Mechanical ventricular assistance restores endocardial TM levels up to 77% of control LV. The observable restoration of endocardial TM by mechanical ventricular assistance may rescue the loss of thromboresistance that is characteristic in heart failure.
Inducible Nitric Oxide Synthase Plays a Stimulatory Role in Platelet Activation.
Authors: Marjanovic Jasna A. , Stojanovic Aleksandra , Brovkovych Viktor , Skidgel Randal A. , Du Xiaoping 
Published: April 2020

Abstract
Platelets generate nitric oxide (NO) in response to agonist stimulation. Previous reports have shown that the endothelial nitric oxide synthase (eNOS) plays a role in agonist-stimulated platelet NO production and in platelet activation. Here we show that platelets from eNOS knockout mice (eNOS−/−) showed only partial reduction in thrombin-induced NO production compared to wild type platelets (50% reduction), indicating the presence of another NOS isoform in platelets. More importantly, we show that resting platelets express functional inducible nitric oxide synthase (iNOS), which participates in platelet activation. Compared to wild type platelets, thrombin-induced NO production was reduced by 54% in platelets isolated from iNOS knockout mice (iNOS−/−), indicating an iNOS-dependent NO production in platelets induced by thrombin. Since thrombin-induced NO production occurs during the first 3 min of thrombin stimulation, our findings provide the first evidence for a short-term regulation of iNOS activity independent of transcription regulation. In contrast, previous description of iNOS activation was primarily at the transcriptional level and required much longer time of induction. To determine the role of iNOS in platelet activation, platelets from wild type and iNOS−/− mice were stimulated with low concentrations of agonists. iNOS−/− platelets exhibited lower aggregation and secretion response compared to wild type control, indicating that iNOS plays a stimulatory role in platelet activation. We also examined the effect of iNOS inhibitors on platelet activation. Human and mouse platelets preincubated with iNOS specific inhibitors, 1400W and aminoguanidine, exhibited a dose-dependent inhibition of platelet secretion and aggregation induced by either low-dose thrombin or collagen. Furthermore, the inhibitory effect of iNOS-specific inhibitors was only shown in wild type mouse platelets, but was lacking in iNOS−/− platelets. Thus, activation of both iNOS and eNOS is important in agonist-induced NO production which stimulates platelet secretion and aggregation.
AKT Mediates Platelet Activation by Stimulating Nitric Oxide Synthesis and cGMP Elevation.
Authors: Stojanovic Aleksandra , Marjanovic Jasna A. , Brokovych Viktor , Skidgel Randal A. , Hay Nissim , Du Xiaoping 
Published: April 2020

Abstract
Phosphoinositide 3-kinase (PI3-K) and Akt play important roles in platelet activation. However, the downstream mechanisms for their roles are unclear. We have recently shown that nitric oxide (NO) synthase 3 (NOS3) and cGMP-dependent protein kinase stimulate platelet secretion and aggregation. Here we show that PI3-K-mediated Akt activation plays a critical role in agonist-stimulated platelet NO synthesis and cGMP elevation. Agonist-induced elevation of NO and cGMP was inhibited by Akt inhibitors and reduced in Akt-1 knockout platelets. Akt-1 knockout or Akt inhibitor-treated platelets showed reduced platelet secretion and aggregation in response to low concentrations of agonists, which can be reversed by low concentrations of sodium nitroprusside (SNP) or cGMP analogs. Similarly, PI3-K inhibitors diminished elevation of cGMP and also inhibited platelet secretion and the second-wave platelet aggregation, which was also partially reversed by cGMP analogs and by SNP. These results indicate that the NO-cGMP pathway is an important downstream mechanism mediating PI3-K and Akt signals leading to platelet secretion and aggregation. Conversely, the PI3-K-Akt pathway is a major upstream mechanism responsible for activating the NO-cGMP pathway. Thus, this study delineates a novel platelet activation pathway involving sequential activation of PI3-K, Akt, NOS3, sGC, and cGMP-dependent protein kinase.
Inhibition of the Binding of von Willebrand Factor to the Platelet Glycoprotein Ib-IX with an Inhibitor of 14-3-3 and Glycoprotein Ib-IX Interaction.
Authors: Dai Kesheng , Bodnar Richard , Berndt Michael , Du Xiaoping 
Published: April 2020

Abstract
Platelet adhesion and activation are essential for thrombosis and hemostasis. In arteries and capillaries where blood flow shear rate is high, initial platelet adhesion is dependent on the binding of von Willebrand factor (VWF) to its platelet receptor, the glycoprotein (GP) Ib-IX-V complex (GPIb-IX), which consists of four subunits, GPIbα, GPIbβ, GPIX and GPV. We have shown previously that a phosphoserine-dependent intracellular signaling molecule, 14-3-3, interacts with the C-terminal SIRYSGHSL610 sequence in the cytoplasmic domain of GPIbα, and this interaction is dependent upon phosphorylation at Serine 609 of GPIbα. Here we show that a short cell-permeable myristoylated phospho-peptide corresponding to the 14-3-3 binding sequence of GPIbα inhibits VWF binding to platelets and VWF-mediated platelet adhesion. This peptide also specifically inhibits VWF-dependent platelet agglutination induced by ristocetin but has no significant effect on platelet aggregation induced by platelet agonists such as ADP and collagen. Furthermore, intravenous injection of this phospho-peptide caused significantly prolonged bleeding time in mice. Thus, 14-3-3 interaction with GPIbα plays critical roles in VWF binding function of GPIb-IX and hemostatic function of platelets. These results also suggest a new type of anti-platelet drugs that may potentially be useful in treating thrombosis.
Human Mesenchymal Stem Cells (MSC) Home at Injured Sites after Local Irradiation and Contribute To Reduce Radiation-Induced Intestinal Lesion.
Authors: Chapel Alain , Semont Alexandra , Francois Sabine , Mouiseddine Moubarack , Thierry Dominique 
Published: April 2020

Abstract
Some patients who undergo radiotherapy may develop side effects that can be life threatening. Tissue complications can result in functional alterations of organs caused by radiation-induced stem cell depletion. Stem cell therapy is a promising approach to improve radiotherapy-enhanced tissue complications. The multipotential of Mesenchymal Stem Cells (MSC), their easy isolation and high ex vivo expansive capacity make these cells good candidates for replenishment of the depleted stem cell compartment during radiotherapy. In this study, we make the assumption that radiation-induced normal tissue injuries might play a role in the recruitment of MSC for tissue repair. We isolated MSC from the human bone marrow (hMSC) and transplanted them via the systemic route into immunotolerent NOD/SCID mice. Using two models of radiation-induced lesion (total body irradiation: TBI, total abdominal irradiation: TAI), we have studied the link between tissue damage and hMSC implantation. Tissue alterations were studied by histological analysis. hMSC in tissues of transplant was quantified by real-time PCR assay 14 days after their injection. In unirradiated NOD/SCID mice, hMSC homed significantly in lung (0.06% of total lung cells), muscle (0.07%) and bone marrow (0.14%). Following TBI of NOD/SCID mice at a sublethal dose (3.2 Gy), we observed an increase of engraftment in brain (0.07%), heart (0.05%), liver (0.11%), muscle (0.12%) and bone marrow (0.37%) compared to unirradiated mice. TAI (8 Gy) induced a significant increase of hMSC engraftment levels in kidney (0.10%), stomach (0.12%), liver (0.44%), spleen (0.94%), and small intestine (0.17%) compared to TBI mice. Histological study show that MSC reduce radiation-induced intestinal lesion: following AI, MSC accelerate the renewal of small intestine in participating to their regenerative process. From 3 days after radiation exposure, when hMSC are injected, the integrity of small intestine is already regained. The villus length is significantly increased (1.7 fold compared with control). We also observe many proliferating zone). 15 days after irradiation, the villus length remains elevated and is significantly increased in comparison with uninjected or unirradiated group. We then demonstrated that hMSC could accelerate and favour small intestinal regeneration after radiation-induced their damages. We conclude that mainly MSC implantation takes place in radiation-injured organs of exposed areas. We demonstrate the capacity of hMSC to improve the spontaneous renewal of NOD/SCID mice small intestine. The characterization of the capacity of MSC in intestinal functional recover is under progress in our laboratory.