bluuebunny/crossref_metadata_2025_split huggingface dataset:
Citation Impact of Breakthrough Interventions for Malignant Blood Disorders.
Authors: Djulbegovic Benjamin , Soares Heloisa P. , Kumar Ambuj 
Published: April 2020

Abstract
Background: Citation count is a widely accepted measure of how much a study has drawn attention of other scientists and clinicians. The studies that have generated new, breakthrough interventions that potentially can affect the lives of many patients are expected to be widely disseminated. In this work, we test hypothesis if the breakthrough interventions as discovered in the NCI sponsored phase III hematological malignancies trials received high citation count. NCI trials account for almost 100% of publicly sponsored phase III trials in the US.
Methods: We evaluated all randomized controlled trials (RCTs) that have been conducted by six NCI sponsored cooperative oncology groups (COGs). We included all trials that were completed by 2002. Here, we focus on hematological malignancies trials. We arbitrarily defined as “breakthrough interventions” those interventions that were judged by the investigators highly preferred so they should become standard of care and/or had an effect size was so large that their log hazard ratio for survival or event-free survival was −1 or less. The study which received more than 1,000 citations is considered as highly-cited clinical research paper. (Ioannidis JPA, JAMA 2005)
Results: We evaluated 133 hematological-malignancy trials/comparisons. Ninety-two trials studied leukemias, 38 lymphomas and 3 either multiple myeloma or myelodysplastic syndrome. 26 (20%) interventions were found to meet the criteria for the “breaktrough interventions”. None of the papers met criteria for highly-cited research. Citation counts ranged from 4–311 (median: 62). The highest-cited paper reported the use of All-trans-retinoic acid for induction and maintanence of acute promyelocytic leukemia. This paper is currently cited in NCCN guidelines and the NCI PQD® treatment website.
Conclusions: The best clinical research in hematological malignancies has received relatively little scientific attention. Elucidating the factors that could explain these findings may help identify the barriers that prevent generation and dissemination of evidence of vital importance for improving outcomes of patients with malignant blood disorders.
Evaluation of Trends in Imatinib Dosing over Time: A Retrospective Cohort Study.
Authors: Hamdan Muhammad , Yood Marianne Ulcickas , Sanders Lynn M. , Hirji Ishan , Hoy Tracey , Oliveria Susan A. 
Published: April 2020

Abstract
Background: The recommended imatinib starting dose is 400mg/day for chronic myelogenous leukemia (CML) patients in chronic phase and 600mg/day for patients in accelerated phase or blast crisis. Some studies have reported improved response rates and progression-free survival in chronic phase patients receiving higher imatinib doses. However, little information is available regarding tolerability of higher doses and the actual initial dosing of imatinib dispensed in the clinical setting. To investigate initial imatinib dosing over time, we conducted a retrospective cohort study using the HealthCore Integrated Database. The data used for this analysis captured pharmacy and medical encounters for a base population of approximately 13 million covered lives.
Methods: We identified all patients with an ICD-9 coded diagnosis of CML (205.1) and at least one prescription for imatinib from January 1, 2001 through December 31, 2004. Using the pharmacy database, we identified the first imatinib prescription and calculated the daily dose of that first prescription (based on number of pills dispensed, dose per pill and prescription days supply).
Results: A total of 486 patients were exposed to imatinib (N=40 patients with starting dose &lt;400 mg/day; N=356 patients with starting dose 400 mg/day; N=5 patients with starting dose 500mg/day, N=52 patients with starting dose 600 mg/day; and N=33 patients with starting dose &gt;600 mg/day). Figure 1 presents initial dosing by calendar year for patients starting at 400mg/day and &gt;600 mg/day.
Imatinib Starting Dose by Year 2001–2004 Imatinib Starting Dose by Year 2001–2004
Among patients receiving imatinib &gt;600mg/day, 15% (95% confidence interval (CI) 5.8–30.4%) had a subsequent dose decrease (defined as a decrease of at least 100 mg/day). Among patients starting imatinib 600mg/day, 22.6% had a dose decrease (95% CI 12.9–35.3%), and 5.8% of the 361 patients receiving imatinib 400mg/day had a dose decrease (95% CI 3.7–8.6%).
Conclusions: These data indicate that a greater proportion of CML patients now receive high starting imatinib doses, potentially due to the fact that more aggressive dosing is used in chronic phase patients. Although phase of disease has not been verified at this point, medical record review is underway to determine imatinib indication and reasons for dose changes. Between 15–20% of patients receiving high starting doses of ≥ 600 mg/day underwent dose reduction of at least 100 mg/day.
Mortalin-2 (mthsp70/PBP74/Grp75), a Novel Mediator of Erythropoietin Signal.
Authors: Ohtsuka Rie , Abe Yasunobu , Fujii Tomomi , Nagasawa Eriko , Shimada Hirotoshi , Tachikawa Yoshimichi , Muta Koichiro 
Published: April 2020

Abstract
Erythropoietin (EPO) stimulates erythroid growth by enhancing the proliferation, maturation and survival of late stage erythroid progenitor cells. Intracellular signaling molecules such as Janus kinase 2 (JAK2) and phosphoinositide-3 kinase (PI-3K)/Akt are considered mediators of the EPO signal, however the entire process of EPO stimulation remains undetermined. To further clarify the intracellular mechanism by which EPO affects the growth of erythroid progenitor cells, we analyzed protein obtained from purified human erythroid colony forming cells (ECFCs) cultured with, or without EPO, by 2-dimensional gel electrophoresis. Five protein spots were apparently related to EPO stimuli, and these proteins were then examined by peptide mass fingerprinting. One of the 5 was identified as mortalin-2, which is a member of the heat shock protein 70 family of chaperones. Mortalin-2 is thought to perform multiple functions relevant to stress response, intracellular trafficking, antigen processing, control of cell proliferation and differentiation. When the expression of mortalin-2 was confirmed by Western blotting, the amount of mortalin-2 was found to be greater in ECFCs cultured with EPO. The amount of mortalin-2 mRNA was then analyzed by quantitative real time PCR. In the presence of EPO, the amount of mortalin-2 mRNA gradually increased during erythroid maturation, peaked on day 6, and then decreased in the terminal stage of maturation. When day 6 ECFCs were incubated with different concentrations of EPO, the amount of mortalin-2 mRNA increased in a dose-dependent manner. Next, we designed a small interfering RNA (siRNA) to RNA encoding mortalin-2, and used this in a transient transfection assay. When the siRNA was transfected into day 6 ECFCs, the expression of mortalin-2 mRNA was suppressed to 40–60% of that seen in the control culture. In the presence of different concentrations of EPO (0–1.0 u/ml), the effect of the siRNA on ECFC growth was determined by MTT assay. The siRNA significantly suppressed the growth of ECFCs in the presence of relatively low concentrations of EPO (0.5 u/ml). These data suggest that mortalin-2 mediates the EPO signal to stimulate the growth of erythroid progenitor cells.
Regulation of the Anti-Apoptotic Protein, Bcl-xL, during Differentiation of Megakaryocytes from Stem Cells.
Authors: Kojima Hiroshi , Kozuma Yukinori , Nagasawa Toshiro 
Published: April 2020

Abstract
This study was conducted to elucidate the anti-apoptotic mechanism operating during differentiation of megakaryocytes (Mgks) from hematopoietic stem cells. As previous reports have indicated the relevance of Bcl-xL for maintaining primitive hematopoietic cells, we focused on Bcl-xL among various anti-apoptotic proteins. Expression of Bcl-xL, which is relatively low in stem cells, increased gradually within 2–3 days of the culture of c-kit+/Lineage- stem cells in the presence of TPO. Expression of Bcl-xL temporally correlated well with that of GATA-1. Inhibition of GATA-1 expression in TPO-independent Meg-O1 megakaryocytic cells by using siRNA resulted in the decrease in Bcl-xL expression, suggesting that expression of Bcl-xL is directly or indirectly regulated by the GATA-1 transcription factor. On the other hand, when TPO was withdrawn from TPO-dependent UT-7 megakaryocytic cells, expression of Bcl-xL protein decreased dramatically within 48 hours despite the stable expression of Bcl-xL mRNA, indicating the post-transcriptional regulation of Bcl-xL after TPO depletion. As a broad caspase inhibitor z-VAD-fmk significantly reduced the decrease in Bcl-xL expression, we considered that proteolysis of Bcl-xL by a caspase might be responsible for down regulation of Bcl-xL. Indeed, corresponding with the time course of decrease in Bcl-xL protein after TPO depletion, activation of caspase-3 was recognized by immunostaining. As these results suggest that TPO-mediated signaling maintains caspase-3 inactive, we cultured UT-7 cells in the presence of a PI3K inhibitor or a MAPK inhibitor in search of the signaling molecule involved in this process. As PI3K inhibitor, wortmannin, induced the activation of caspase-3 even in the presence of TPO, we concluded that PI3K, in the downstream signaling pathway of c-Mpl, maintains caspase-3 inactive, which prevents cleavage of Bcl-xL by caspase-3. Withdrawal of TPO from primary culture of megakaryocytes similarly resulted in the activation of caspase-3 and decreased expression of Bcl-xL protein. Taken together, we conclude that expression of Bcl-xL protein is regulated transcriptionally by GATA-1 and post-transcriptionally by caspase-3 whose activation is prevented by TPO-mediated PI3K activation.
Receptor Specificity in the Self-Renewal, Survival and Differentiation of Hematopoietic Stem and Progenitor Cells In Vitro and In Vivo.
Authors: Lintmaer Ingrid , Weinreich Michael A. , Wang Linlin , Liggitt Denny , Harkey Michael , Blau C. Anthony 
Published: April 2020

Abstract
Hematopoietic growth factors have had many applications in clinical medicine. However the entry of new growth factors into the clinic has been hampered by the ability of many ligands to affect non-targeted tissues, or to activate more than one receptor type in the targeted tissue. Here we test whether receptors, rather than ligands, can be used to differentially regulate hematopoiesis in vitro and in vivo. Using modified receptors whose activity is solely dependent on a synthetic ligand, called a chemical inducer of dimerization (CID), we compared a conditional derivative of fibroblast growth factor receptor -1 (F36VFGFR1) with an analogous derivative of the thrombopoietin receptor (F36VMpl) in the transduced bone marrow cells of mice. While both receptors allowed for the sustained expansion of transduced marrow cells in culture, only F36VFGFR1 allowed for the expansion of short term repopulating HSCs, and the survival of long term repopulating HSCs, in culture. Both receptors supported the CID dependent expansion of erythroid cells in vivo, however F36VFGFR1 was much more potent, and also induced a marked CID-dependent expansion of platelets and granulocytes, lineages in which F36VMpl had little effect. Cultures in the presence of inhibitors of cell signaling showed a surprising amount of overlap, with both receptors exhibiting equal susceptibility to Jak2 inhibition, whereas F36VFGFR1 was relatively more sensitive to inhibitors of src kinases and phospholipase Cgamma.
Prevalence of Pulmonary Hypertension and Renal Dysfunction by Systemic Blood Pressure Categories in Sickle Cell Disease.
Authors: Gordeuk Victor R. , Gladwin Mark T. , Kato Gregory , Castro Oswaldo 
Published: April 2020

Abstract
In an emerging paradigm of sickle cell disease (SCD) vasculopathy, the risk for pulmonary and systemic hypertension, renal dysfunction, proteinuria, stroke and early death may be related to the degree of hemolysis, nitric oxide scavenging and resultant damage to the vasculature (JAMA2005;293:1653). The systemic blood pressure (BP) in sickle cell anemia (SS) is lower than in normal subjects. Yet, the concept of relative systemic hypertension has been proposed because SS pts. Have higher BP than subjects with other forms of congenital anemias (Am J Med Sci 1993). Furthermore, apparently minor BP increases in SS are associated with stroke risk (Am J Med Sci1993;305:150, Am J Med1997;102:171).
We hypothesized that in contrast to otherwise healthy individuals without SCD, systolic blood pressures (sBP) of 120 to 139 mm Hg define relative hypertension in SCD and identify patients at increased risk for vasculopathy and its complications. We analyzed entry data from 195 adult patients enrolled in the prospective Sickle Cell Pulmonary Hypertension Screening Study (NEJM2004;350:886), and stratified their ECHO-determined tricuspid regurgitant jet velocity (TRV) and serum creatinine concentration according to sBP categories.
As shown in Figure 1, among Hb SS and S beta thal patients, the prevalence of pulmonary hypertension (PHTN, TRV 2.5 m/sec or greater) was 26% with sBP &lt;120 mm Hg, 36% with sBP 120–139 mm Hg and 89% with sBP 140 mm Hg or higher (P &lt;0.0005 for trend). Similarly, the prevalence of a serum creatinine concentration of 1.0 mg/dL or higher was 7% with sBP &lt;120 mm Hg, 13% with sBP 120–139 mm Hg and 30% with sBP 140 mm Hg or higher (P = 0.002 for trend, Figure 2). The increasing prevalences of PHTN and renal dysfunction with the three progressively higher sBP categories are consistent with our hypothesis that sBP 120–139 represents relative hypertension and increased risk for vascular complications in patients with SCD. Whether treatment of relative hypertension in sickle patients would improve vasculopathy and lower their risk for PHTN, renal impairment or other complications such as stroke, is unknown. Consideration should be given to clinical trials to answer this important question.
Figure Figure Figure Figure
Matched Sibling Donor Hematopoietic Cell Transplantation for Sickle Cell Disease Using a Reduced Intensity Conditioning Regimen Can Lead To Stable Long Term Engraftment.
Authors: Krishnamurti Lakshmanan , Wu Catherine , Baker K. Scott , Wagner John E. 
Published: April 2020

Abstract
Hematopoietic Cell Transplantation (HCT) from sibling donors has been demonstrated to cure sickle cell disease. Concerns about high regimen related toxicity particularly in older patients and in those with advanced organ damage and the potential for late sequelae such as chronic graft-versus-host disease (GVHD) and infertility have limited the applicability of HCT. HCT following a reduced intensity conditioning (RIC) regimen has the potential for reducing toxicity and making this curative therapy more acceptable and applicable to this group of patients. We report preliminary results on the first five patients enrolled on a pilot study to evaluate the safety and efficacy of HCT following a RIC regimen for patients with high risk sickle cell disease. All patients received bone marrow from a matched sibling donor. The conditioning regimen consisted of Busulfan 2 mg/kg orally q12 hr x 2 days (0.8mg/kg IV q 6 hr x 2 days for patient#3, 4, 5), Fludarabine 35 mg/m2/dose IV daily x 5 days, anti-thymocyte globulin 30 mg/kg/dose IV daily x 5 days and total lymphoid irradiation 500 cGy with shielding of the liver, lungs, heart, and gonads. GVHD prophylaxis consisted of cyclosporine A and Mycophenolate mofetil. Clinical characteristics, outcomes and donor chimerism in peripheral blood genomic DNA and of subjects are summarized in the Table.1 The preparative regimen was well tolerated with no serious infections or mucositis in any patient. No patient has had recurrence of previous sickle cell related symptoms. Lineage-specific chimerism analysis (patients # 3, 4, 5), reveal predominance of donor erythropoiesis (Table 2). These findings indicate that HCT for sickle cell disease following a RIC regimen is well tolerated and can lead to stable long term engraftment.
Clinical Characteristics of patients with sickle cell disease undergoing HCT from a matched sibling donor following a reduced intensity conditioning regimen PIN. Age, Indication Follow-up (days) Regimen Related Toxicity ANC&lt;500(days) GVHD Acute or Chronic % Engraftment Day 100 % Engraftment Day180 % Engraftment Day 365 1. 8 yrs. Stroke, allosensitization 2100 None 7 None 89 100 100 2. 8 yrs. Repeated ACS 1800 None 8 Grad II Skin 75 81 81 3. 6yrs. Repeated ACS 750 None 9 None 75 85 81 4. 8 years Repeated ACS 295 None 14 None 79 71 - 5.18 yrs. Stroke, allosensitization 288 Mild 13 None 100 100 - Lineage Specific Chimerism PIN, Genotype Donor Genotype % donor erythroid day 100 % donor erythroid day 180 % Donor Lymphoid day 100 % Donor Lymphoid day 180 % Hemoglobin S Day 100 % Hemoglobin S Day 180 3. Hb SS Sickle trait 100 100 30 35 30 34 4. HbS/β Thalassemia β Thalassemia trait 100 81 33 58 4 3 5. HbSS Sickle trait 100 100 100 100 32 34
Framingham Score in Congenital Hemophilia Patients (HP) with Cardiovascular Disease (CVD).
Authors: Parameswaran Rekha , Greist Anne , Miller-Rice Lorrie , Roberson Chris , Murry Renee , Sulkin Matthew , Lynn Henry , Shapiro Amy 
Published: April 2020

Abstract
CVD risk factors of age, hypertension, high cholesterol (HC), smoking, diabetes are expressed in the Framingham coronary risk score. Previous data suggest that hemophilia may protect against CVD. However, CVD risk factors may place HP at risk as they age. HIV infected patients are a rapidly developing group with CVD. No data address the effect of established risk factors on CVD prevalence in HP. We report an extensive analysis of a single hemophilia treatment center (HTC) database for CVD risk factors and prevalence in HP. Framingham coronary risk scores were calculated for HP patients with documented CVD events, using age at time of event to calculate risk. HTC population ≥40 yrs, used as denominator, comprised 156 with FVIII deficiency (63 severe, 16 moderate, 77 mild);109 with FIX deficiency (24 severe, 53 moderate, 31 mild). Forty-eight HP had HIV infection, 113 had hepatitis C, and 25 had HIV/hepatitis C coinfection. Twenty-one HP, 10 with viral infection, ranging 49 to75 years, experienced 23 CVD events. They included 11 FVIII (0 severe, 1 moderate, 10 mild),10 FIX (2 severe,6 moderate, 2 mild). CVD events included 13 myocardial infarction (MI); 5 cerebrovascular accidents (CVA); 1 patient with carotid stenosis and 4 HP with coronary artery disease on catheterization. Two patients each had both MI and CVA. Four patients underwent coronary artery bypass graft surgery. Of 8 patients on antiplatelet therapy, 2 had major bleeds (CNS and GI bleed); one had a minor bleed (epistaxis). Of these 21 HP with CVD, one patient had HIV disease; 8 had hepatitis C, 1 had co-infection with HIV and hepatitis C. One patient was on Vioxx® at the time of his CVD event.Six are deceased, all due to CVD. Overall, CVD affected 7.9% of HP aged &gt;40 years in this population. Of all HP with viral infection in this HTC population, 40% experienced CVD. Ten-year CVD risk per Framingham model at time of event ranged from 10% to 37% (mean 20.1%; median 16%). All HP patients with CVD met the definition of high coronary risk per AHA guidelines with 10-year risk of CVD&gt;10%. Management of established CVD in HP is difficult due to need for invasive procedures and bleeding risk with antiplatelet therapy. Primary prevention of CVD is thus crucial. Aggressive risk factor modification is indicated in all HP with 10-year risk score &gt;10% for primary prevention of CVD. To our knowledge, this is the first application of the well validated Framingham score in the HP population.We conclude that the easily calculable Framingham score should be assessed in all HP over age 40, especially those with viral infections, and incorporated into the comprehensive care model.
Microarray Analysis of Non- Classical Haemophilia A Patients.
Authors: Cutler Jacky , Mitchell Mike , Savidge Geoffrey F. 
Published: April 2020

Abstract
Haemophilia A is classically due to a defect in the factor 8 gene. Mutations are heterogeneous, and located throughout the gene. Other than the IVS 22 inversion mutation, causative of approximately 46% of severe haemophilias, there are few mutation hot spots. It has been established that approximately 2% of patients with confirmed Haemophilia A have no detectable genetic abnormality in the factor 8 gene. Genetic analysis at the RNA level has generally failed to identify mutations not seen at the genomic level. Splicing abnormalities appear to be restricted to the splice junctions as no cryptic splice sites have yet been identified deep within introns.
One possible approach in the investigation of these non-F8 associated Haemophilia patients, is to look at up/down regulation of other genes via genome wide gene expression analysis. To this end we have subjected a small number of confirmed Haemophilia A patients with no identifiable mutation to microarray analysis, utilising an Affymetrix GeneChip® array system comprising 54676 genes. Their gene expression pattern was then compared to that of patients with similar phenotype in whom mutations have been defined. Initially, data analysis has focussed on the X chromosome, as the sex distribution in this group of patients does not appear to differ from classical F8-associated Haemophilia.
Preliminary results suggest a significant down regulation of ARHGAP6, a Rho GTPase activating protein. This gene is located at Xp22, comprises 14 exons, and encodes a 974 amino acid protein, with multiple splice variants. Interestingly, ARHGAP shares with factor 8 the possession of an embedded gene within a large intron. The F8A gene located within intron 22 of F8 is involved in the recombination event which results in the IVS22 inversion mutation. Intron 1of the ARHGAP gene spans more than 280kb and contains the amelogenin gene (AMELX). Like F8A, AMELX is transcribed from the opposite strand to the ’host gene’. This unusual phenomenon has only been reported in a very small number of human genes.
ARHGAP6 is known to have two independent functions, one as a GTPase-activating protein (GAP) involved in signal transduction, and another as a GTPase activator, regulating the interaction of signalling molecules with the actin cytoskeleton. It is possible that such interactions affect the secretion of the factor VIII protein from hepatocytes.
The genetic basis of Haemophilia A becomes more complex as the patient base investigated increases. It is likely that the number of genes that have an affect on plasma FVIII levels will continue to grow. ARHGAP6, and other GTPase activating proteins, may be worthy of closer examination in the search for genetic modifiers of FVIII levels.