bluuebunny/crossref_metadata_2025_split huggingface dataset:
Venous Thromboembolic Risk and Suboptimal Prophylaxis in the US Acute Hospital Care Setting: Findings from the ENDORSE Study.
Authors: Tapson Victor F. , Cohen Alexander T. , Bergmann Jean-Francois , Goldhaber Samuel , Kakkar Ajay K. , Anderson Frederick A. 
Published: April 2020

Abstract
Introduction Estimates for patients at risk of venous thromboembolism (VTE) in US acute care hospitals total approximately 4 million surgical and 8 million medical patients annually. However, limited data are available regarding practices in VTE prevention in the acute care setting. The ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk of Venous Thrombosis in the Acute Hospital Care Setting) study is a worldwide survey of inpatients in acute hospital care. We assessed data from US acute care hospitals to determine the prevalence of VTE risk and proportion of at-risk patients receiving prophylaxis in accordance with current ACCP guidelines.
Methods During the period August 2006 to January 2007, 9257 patients were enrolled from 81 randomly-selected US acute care hospitals. All medical patients ≥40 years, surgical patients ≥18 years, or patients ≥18 years admitted for non-surgical trauma were eligible for the study. Patients admitted to an ineligible ward, with missing data, or admitted solely for the treatment of VTE were excluded from the analysis. Patient charts were reviewed during a single day, pre-defined visit, with the evaluation criteria including medical history, admission and post-admission diagnoses, type of surgery, bleeding risks, and initiation and type of prophylaxis. The ACCP consensus guidelines were used to evaluate VTE risk and prophylaxis use in enrolled patients.
Results Of the 9257 study patients, 44% and 56% were surgical and medical, respectively. 78% and 52% of surgical and medical patients were judged at risk for VTE, respectively. Of these, 29% of surgical patients and 52% of medical patients failed to receive recommended types of prophylaxis (Table). Among at-risk patients who received recommended types of VTE prophylaxis, a majority received anticoagulants (90% surgical, 97% medical).
Table: VTE risk and prescription of recommended types of prophylaxis in US acute care hospitals US patients [X, range*] At-risk for VTE [X, range*] At-risk patients who received ACCP-recommended prophylaxis [X, range*] *Mean and range across all 81 US hospitals All (N=9257) 5885 [64%] 3536 [60%] Surgical (N=4061) [44%,13–94] 3165 [78%, 21–100] 2244 [71%, 0–100] Medical (N=5196) [56%, 6–87] 2720 [52%, 19–100] 1292 [48%, 0–100]
Conclusions These data from US acute care hospitals parallel the global ENDORSE study findings of the high prevalence of VTE risk and suboptimal provision of ACCP-recommended prophylaxis. Although a higher proportion of surgical patients were judged to be at risk of VTE, the absolute number of hospitalized medical patients was higher and half of these did not receive adequate VTE prophylaxis. Our data highlight the continued need for strategies to ensure that hospital patients at risk of VTE are identified and provided with adequate VTE prophylaxis.
Argatroban Associated Bleeding Complications.
Authors: Berz David , Colvin Gerald A. , Mital Priya , Quesenbery Peter J. 
Published: April 2020

Abstract
Background: Heparin induced thrombocytopenia (HIT) is a frequently observed side effect observed with heparin administration. Treatment for this condition includes direct thrombin inhibitor (DTI) therapy. Major hemorrhagic complications are considered rare events in this setting.
Methods: This is a case series of patients diagnosed with HIT in a tertiary medical referral center. The diagnosis of HIT was established on the base of clinical criteria. All included patients had positive HIT ELISA based antibody testing during the time interval from July 2006 to July 2007 and all patients were treated with argatroban. A systematic review for hemorrhagic and thrombotic complications of argatroban therapy was performed. Major hemorrhage was defined as clinically identified bleeding with the demand for transfusion therapy. Thrombotic complications were defined as thrombosis evidenced by imaging studies developing during argatorban therapy. We performed bivariate and multivariate logistic regression analysis to identify demographic and clinical factors that influence the development of complications of argatroban therapy as treatment for HIT. Examined covariates were gender, age, type of service the patient was admitted under (surgical versus medical), amount of comorbidities, preexisting history of gastrointestinal bleeding, documented thrombotic or thrombembolic event at the time point of HIT diagnosis and coexisting coexisting coagulopathy other than HIT.
Results: We identified 102 patients with the diagnosis of HIT. The median optical density (OD) of the ELISA HIT immunoassay was 1.23 (95% CI 0.93–1.43). We identified 11 (10.7%) major hemorrhagic events in patients on argatroban. Four patients (3.9%) died as a consequence of major hemorrhagic complications. No thrombotic events were identified in our study cohort. As statistically significant; predictors for clinically relevant hemorrhagic complications in our model remained male gender, preexisting GI bleeding history and being patient on a surgical service.
Conclusion: The incidence of major hemorrhagic episodes with agatroban therapy is significantly higher then generally reported and the mortality rate is very disturbing. These data suggest that alternatives to standard direct thrombin inhibitor therapy should be aggressively pursued.
Periostin Is a Previously Uncharacterised Vitamin K Dependent γ-Carboxyglutamic Acid (Gla) Containing Protein Expressed by Marrow-Derived Mesenchymal Stromal Cells.
Authors: Coutu Daniel L. , Wu Jian Wui , Rivard Georges-Etienne , Blostein Mark D. , Galipeau Jacques 
Published: April 2020

Abstract
The modification of glutamic acid residues to g-carboxyglutamic acid (Gla) is a post-translational modification catalyzed by the vitamin K-dependent γ-glutamylcarboxylase enzyme. Despite ubiquitous expression of the γ-carboxylation machinery in mammalian tissues, only 12 Gla-containing proteins have so far been identified in humans. Because bone tissue is the second most abundant source of Gla-proteins after the liver, we sought to identify Gla proteins secreted by bone-marrow derived mesenchymal stromal cells (MSCs), a precursor to all non-hematopoietic cells in bones. We used a proteomics approach to screen the secretome of MSCs with a combination of 2D gel electrophoresis and tandem mass spectrometry. The most abundant Gla-protein secreted by MSCs was identified as periostin, a previously unrecognized γ-carboxylated protein. In silico aminoacid sequence analysis of periostin demonstrated the presence of four consensus γ-carboxylase recognition sites embedded within fasciclin-like protein domains. The carboxylation of periostin was confirmed by immunoprecipitation using anti-Gla antibodies and could be inhibited by warfarin in MSCs. In conclusion, periostin is a novel vitamin K-dependent γ-carboxylated protein distinguished from other Gla-proteins by the presence of multiple γ-carboxylase recognition sites and MSCs are an abundant source of periostin including its γ-carboxylated variant.
An Intron-Derived Insertion/Truncation Mutation in the BCR-ABL Kinase Domain in Three CML Patients Undergoing Kinase Inhibitor Therapy.
Authors: Laudadio Jennifer , Deininger Michael W.N. , Mauro Michael J. , Druker Brian J. , Press Richard D. 
Published: April 2020

Abstract
Although targeted inhibition of BCR-ABL with imatinib is an effective therapy for patients with chronic myeloid leukemia, a minority acquire mutations in the kinase domain (KD) that cause imatinib resistance. The spectrum of KD mutations thus far discovered, although quite heterogeneous, includes almost exclusively single nucleotide substitutions in key amino acids regulating drug binding or BCR-ABL function. Here, we describe a KD insertion/truncation mutation in 3 CML patients undergoing kinase inhibitor therapy. Two of these patients were being treated with imatinib (for 12 and 17 months), and one with dasatinib (for 13 months after a prior relapse while on imatinib). Suspected drug resistance was assessed by direct DNA sequencing of a BCR-ABL PCR product extending to the end of the kinase domain. Each of these 3 patients had 35 nucleotides from ABL intron 8 inserted at the normal exon 8–9 splice junction, after nucleotide 1423 (amino acid 475) of Genbank cDNA clone NM_005157. In all 3 cases, the mutation was co-expressed with wild type BCR-ABL sequence. The inserted sequence is derived from intron 8, beginning 1151 bp downstream from the normal splice donor site at the end of exon 8. This 35 bp intronic sequence is flanked by excellent consensus splice donor and acceptor sequences, suggesting alternative splicing as the likely mutational mechanism. The insertion creates a premature translational stop codon after 10 intron-encoded amino acids (figure), thus truncating 653 C-terminal amino acids including part of the KD and the entire last exon region - including a proline-rich domain, 3 nuclear localization signals, a DNA-binding domain, an actin-binding domain, and a nuclear export signal. These 3 insertion mutation cases were detected in our diagnostic clinical molecular pathology laboratory after sequencing 174 cases referred to us for suspected kinase inhibitor resistance, 78 of which contained a detectable mutation. The estimated prevalence of the exon 8/9 insertion/truncation mutation is then approximately 1.7% among patients with suspected drug resistance, and this mutation constitutes approximately 3.8% of all mutations.
Conclusion: Kinase domain insertions are an alternative (and not entirely uncommon) mutational mechanism in CML patients undergoing kinase inhibitor therapy. The functional significance in terms of kinase activity and drug resistance remains to be addressed.
Figure: Amino acid sequence of the C-terminus of the BCR-ABL kinase domain for the wild type and insertion/truncation mutant (with numbering as per GenBank cDNA clone NM_005157). Figure: Amino acid sequence of the C-terminus of the BCR-ABL kinase domain for the wild type and insertion/truncation mutant (with numbering as per GenBank cDNA clone NM_005157).
Dasatinib Resistance in CML Patients. Identification of Novel BCR-ABL Kinase Domain Mutation.
Authors: Krijanovski Yelena , Donato Nicholas , Quintas-Cardama Alfonso , Cortes Jorge , Talpaz Moshe 
Published: April 2020

Abstract
Dasatinib is a dual specific SRC-ABL kinase inhibitor which has been increasingly used in treatment of CML and Ph + ALL patients. Although it has excellent activity, a proportion of patients, particularly those with advanced disease had developed evidence of dasatinib resistance. In order to assess the reasons for resistance we have analyzed BCR-ABL kinase domain utilizing single step PCR reaction followed by amplification of ABL kinase domain with subsequent subcloning (≥10 clones) from 23 CML patients who demonstrated clinical evidence of dasatinib failure. We have found mutations in the BCR-ABL domain in 19 out of 23 patients. 14 were mapped to ATP “binding pocket”, of those, seven had pan-resistant T315I and five had F317L with one F317I mutation. In addition, three of 19 patients had V299L mutation. All of these mutations were previously reported in association with dasatinib resistance. We also observed that one of 8 patients in chronic phase and three of 15 patients in advanced phase had two different mutations in separate clones§. Interestingly, four of 19 patients were found to have novel V304D mutation, which is located outside of dasatinib binding site in β 4–5 loop structure and may not be directly involved in dasatinib resistance. It appears that BCR-ABL mutations in advanced phase CML are more common, but occur at lower frequency in dasatinib resistant patients in chronic phase, 93% vs. 62%. In conclusion, our clinical sample suggests that selection for T315I and F317L mutations occurs frequently in dasatinib resistant patients which was predicted from preclinical study. Both mutations were proposed to directly and indirectly affect dasatinib binding. Two additional mutations have been identified with incidence that exceeds random occurrence. The significance of these mutations (V299L, D304D) will be further studied.
Table 1. Mutations status at different phases of CML chronic phase advanced phase mutations yes 5 § no 3 yes 14§ no 1 1 patient in chronic phase group have subcloning results pending. T315I 2 7 F317L 1 4 F317I 0 1 V299L 1 2 V304D 1 3
Incidence and Clinical Outcome of Intestinal Thrombotic MicroAngiopathy (TMA) in Patients Suspected to Clinical Graft Versus Host Disease (GVHD).
Authors: Park Gyeongsin , Moon Yeonsook , Eom Ki-Seong , Lee Kyungji , Lee Youn-Soo , Kim Yoo-Jin , Kim Yonggoo , Cho Bin , Cho Seok-Goo , Kang Chang-Suk , Lee Kyo-Young 
Published: April 2020

Abstract
Intestinal TMA, a upcoming and serious problem after HSCT, usually manifests diarrhea, vomiting, GI bleeding and abdominal pain as initial clinical presentations similar to those of intestinal GVHD. But intestinal TMA should be distinguished from GVHD, because they needed to be treated in absolutely different way. Here we investigated the incidence of intestinal TMA and evaluated their clinical progressions in HSCT patients. We retrospectively reviewed 243 gastrointestinal mucosal biopsy slides obtained from HSCT patients having suffered from GI problems in the Catholic University Hospital, from 2000 to 2004. The collected cases were reviewed by two pathologists blindly and classified into TMA; showing microthrombi formation in the lumina of microvasculatures, GVHD; showing epithelial apoptosis and/or loss of glands, TMA+GVHD and non-specific inflammation. And next, their incidence and clinical outcomes were analyzed. On histopathological examination, 15 out of 243 cases (6.2%) showed luminal thrombi of microvasculature compatible with TMA, 58 cases (23.9%) showed findings compatible with GVHD, 3 cases (1.2%) showed both TMA and GVHD, and 173 cases (71.2%) showed nonspecific gastroenteritis. On peripheral blood smear examination, all 15 TMA cases showed less than 1% of fragmented RBC at the time of biopsy. But 2 out of 15 cases (13.3%) showed increase to 8% and 10% of fragmented RBC in follow-up, and they had been aggravated clinically and improved only after treatments including discontinuing immunosuppressant and plasma exchange. Among 58 GVHDs, 34 patients (75.9%) were improved with steroid pulse therapy, but 14 patients (24.1%) failed. These results show that intestinal TMA is not infrequent in HSCT patients and can be combined with intestinal GVHD. In conclusion, intestinal TMA should be recognized in pathological diagnosis of HSCT patients. It is important to differentiate intestinal TMA from GVHD in patients suffering from severe and refractory diarrhea after HSCT.
Elevated CD56dimCD16neg NK Cells on Day 28 after HCT: Role in Immunity Against Viral Infections or Residual Tumor Cells?.
Authors: Khan Faisal , Storek Jan 
Published: April 2020

Abstract
Natural killer (NK) cells represent a lymphocyte subset important in the immune surveillance against virus infected and malignant cells. In humans, two major NK cell subsets have been defined by CD56 and CD16 staining:
Regulatory NK cells (CD56 high CD16 neg), which are potent cytokine (IFNg) producers; and Cytolytic NK cells (CD56 dim CD16 pos) that are involved in target cell lysis.
Functions of other NK cell subset are unknown. One of such subset, CD56 dimCD16 neg NK cells have recently been reported to represent cytolytic cells, degranulated after contact with target cells. NK cells are the first lymphocyte subset recovering to normal quantity and function after an allogeneic or autologous HCT, typically by 4 weeks post HCT. In the present investigation, we attempted to determine percentages of following NK cell subsets (Regulatory NK cells, Cytolytic NK cells, CD56dimCD16 neg, CD56 highCD16 pos and CD56neg CD16 high NK cells) at multiple time points (day 28, 56, 84, 180 and 365) after allogeneic (n= 32) and autologous (n= 25) HCT and compared with that of healthy individuals (n=14). Whole blood specimen was incubated with fluorochrome-conjugated monoclonal antibodies (CD3-ECD, CD14-PE, CD56-FITC and CD16-PC5) and analyzed by four color flowcytometry. NK cells were defined as mononuclear cells expressing CD16 or CD56 and not expressing CD3 or CD14. The most striking finding was that of significant increase in percentage of CD56dimCD16−ve cells (among NK cells) on day 28. This was true for both autologous HCT recipient (n=24; median = 1.02% of total NK cells) and allogeneic HCT recipient (n=26; median = 1.1% of total NK cells) in comparison to the healthy individuals (n=14; median = 0.56% of total NK cells). We speculate the rise in CD56dimCD16−ve NK cells at 1 month post HCT may be due to increased degranulation of cytolytic NK cells in response to viral infections or residual malignancy.
BMP and Wnt Induce Embryonic Blood Fate by Activation of the Cdx-Hox Pathway.
Authors: Lengerke Claudia , Schmitt Sabine , Bowman Teresa , Maouche-Chretien Leila , McKinney-Freeman Shannon L. , Jang Il Ho , Davidson Alan J. , Hammerschmidt Matthias , Rentzsch Fabian , Green Jeremy B. , Zon Leonard I. , Daley George Q. 
Published: April 2020

Abstract
The hematopoietic morphogen BMP4 has been implicated in early blood development, however the precise role and the underlying genetic pathways that link BMP action to blood fate specification remain poorly understood. In this study, we have employed the in vitro system of murine embryonic stem (mES) cell differentiating into embryoid bodies (EBs) as a model to explore mesoderm induction and hematopoietic specification during mammalian embryogenesis. We show that BMP plays a role in blood fate specification in two sequential phases: initially, BMP acts as a dorsoventral patterning agent, inducing ventroposterior mesoderm; at a later phase, BMP is required for hematopoietic fate specification from mesoderm. In dissecting this second specification phase, we discovered a previously unsuspected coordination between BMP4 and Wnt3a signaling, and linked these morphogens directly to Cdx and Hox genes. Using chromatin immunoprecipitation assays performed on EB-derived cells, we detected the association of the Wnt signaling effector LEF1 with the proximal Cdx1 promoter. This association was modulated by BMP signaling. In promoter reporter assays both BMP4 and Wnt3a activated the Cdx1 promoter while Wnt inhibitors or point mutations in the LEF1 responsive elements of the Cdx1 promoter abrogated this response. Together, these results suggest that BMP4 activates the Cdx1 promoter via LEF1 and the Wnt pathway. In functional assays, inhibition of Wnt signaling strongly suppressed the formation of hematopoietic colony initiating cells, suggesting that activation of the Wnt-Cdx-Hox pathway is a central downstream component of the BMP dependent blood fate specification program. Using ES cell lines engineered for conditonal Cdx1 or Cdx4 gene overexpression, we demonstrate that ectopic activation of Cdx genes is sufficient to establish hematopoietic fate decisions in the absence of BMP signaling during mesoderm specification to blood. Finally, to explore the relevance of our findings in vivo, we studied the effects of conditional BMP overexpression on cdx4 expression and embryonic blood formation during zebrafish embryogenesis. Matching our results with EBs, we find that overexpression of bmp2b at midgastrulation expands the cdx4 expression domain and strongly enhances blood formation. Taken together our results reveal an interaction between the BMP and Wnt signaling pathways, upstream of the Cdx genes, that is critical for the induction of the embryonic blood cell program. Given the evolutionary conservation of the BMP-Wnt-Cdx-Hox effect on blood formation from fish to mice, we anticipate that similar pathways can be exploited to direct the differentiation of human ES cells into blood.
Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan: The Impact of Methotrexate on the Clinical Outcome.
Authors: Kato Koji , Yoshimi Ayami , Ito Etsuro , Oki Kentaro , Hara Jun , Nagatoshi Yoshihisa , Kikuchi Akira , Kobayashi Ryoji , Nagamura-Inoue Tokiko , Kai Shunro , Azuma Hiroshi , Takanashi Minoko , Isoyama Keiichi , Kato Shunichi 
Published: April 2020

Abstract
Cord blood transplantation (CBT) became one of the important alternatives in allogeneic stem cell transplantation for children with hematological malignancies. We have analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified risk factors of transplant outcome, when they had no prior transplant. From 1997 to 2006, total 332 children with ALL have undergone CBT from unrelated donor and 270 of them had no prior transplant. They are 0–15 yrs (median 5) and 4 to 60kg of body weight (median 18). Serological disparities of HLA for graft-versus-host disease (GVHD) direction were 0(n=54), 1(n=168) and 2(n=47), and disease status at transplant were 1st complete remission (CR) (n=120), 2nd CR (n=71), and more advanced stages (n=75). The median number of nucleated cells in cord blood unit was 4.93×107/kg (1.35–24.9), and that of CD34+ cells was 1.53×105/kg (0.17–15.0). As preconditioning, total body irradiation (TBI) was given in 194 patients and methotrexate (MTX) was given as GVHD prophylaxis in 159 patients. The neutrophil engraftment was achieved in 88.5% (95%CI: 84.1–91.8%) of patients and platelet engraftment (&gt;50k) was obtained in 72.6% (95%CI: 66.8–77.7). The incidence of grade II–IV and III–IV acute GVHD was 45.6% (95%CI: 39.5–51.4) and 20.4% (95%CI: 15.8–25.4) respectively. Non-relapse mortality was observed in 22.6% (95%CI: 17.7–27.8) and 35.2% (95%CI: 29.2–41.3) of patients relapsed after CBT. The five year event free survival (EFS) of all patients was 38.1% (95%CI: 34.9–41.3); 47.4%(95%CI: 42.4–52.4) in 1st CR, 45.5%(95%CI: 38.9–52.1) in 2nd CR and 15.2%(95%CI: 10.8–38.9) in more advanced stages, respectively. The multivariate analysis revealed that the larger number of CD34+ cells (p&lt;0.01) and administration of granulocyte colony stimulating factor after CBT (p&lt;0.01) were associated with earlier neutrophil engraftment. Preconditioning with TBI (p&lt;0.01) and absence of MTX (p=0.037) significantly affected the development of grade II-IV acute GVHD. Advanced disease at transplant was the most predominant factor for leukemic relapse (p&lt;0.01). GVHD prophylaxis with MTX (p=0.042), less allele mismatches (p=0.013) and disease status of 1st and 2nd CR at transplant (p&lt;0.01) were significantly associated with better EFS. Our results showed the favorable effect of MTX for the development of acute GVHD and EFS. In conclusion, GVHD prophylaxis including MTX is important in CBT for children with ALL.