bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clostridium Difficile As a Risk Factor For Hospital-Acquired Venous Thrombosis In Medical Inpatients
Authors: Merrill Samuel A , Desarno Michael , Houghton Damon , Winters John P. , Huston Christopher , Callas Peter , Repp Allen B , Cushman Mary , Zakai Neil A 
Published: October 2019

Abstract

Introduction
The American College of Chest Physicians and government agencies recommend risk stratification and pharmacologic prophylaxis to prevent venous thromboembolism (VT) in hospitalized individuals. While risk factor assessment is often completed at admission, clinical changes during hospitalization may influence VT risk. Based on clinical observation of coincidence of C. difficile infection and VT, we sought to determine if C. diff or clinical suspicion of C. diff are risk factors for hospital acquired VT in medical inpatients.

Methods
Derivation and validation cohorts for the Medical Inpatient Venous Thrombosis Risk Assessment Score were used. Patients were admitted to the medical services at Fletcher Allen Health Care, a 500 bed teaching hospital for the University of Vermont. For derivation, all cases of hospital-acquired VT between 2002-2009 were identified using ICD-9 codes and verified by chart review; cases were matched by admission year and medical service to controls; VT risk factors and C. diff testing and Results were confirmed by chart review. For validation, hospital-acquired VT between 2009-2012 were captured by ICD-9 codes with confirmatory imaging; testing and Results for C. diff were ascertained from the microbiology lab database; VT risk factors were ascertained by ICD-9 codes, electronic problem lists, vital sign data, and lab values. Logistic regression, accounting for VT risk factors (Table), was used to determine whether 1) testing for C. diff or 2) a positive confirmation for C. diff was associated with hospital-acquired VT.

Results
In the derivation analysis 299 cases of hospital-acquired VT were identified from 64,334 medical admissions and matched to 601 controls. In the validation analysis 120 hospital-acquired VT were identified among 20,946 admissions. In the derivation cohort there were 4,793 tests for C. diff and 478 confirmed cases; and in the validation cohort there were 1,708 tests for C. diff and 260 confirmed cases. After accounting for other VT risk factors in the derivation cohort, testing for C. diff was associated with an OR of 2.14 (95% CI 1.28, 3.61) for VT, positive C. diff with an OR of 3.23 (95% CI 1.00, 10.45) for VT, and negative C. diff with an OR of 1.95 (95% CI 1.09-3.46) for VT. These associations were confirmed in the validation cohort (see Table).

Conclusions
Both testing for, and a diagnosis of C. diff were associated with hospital-acquired VT in medical inpatients. This relationship could be a surrogate of antimicrobial therapy indicating another active infection or a general marker for systemic illness, direct causation appears less likely. These data suggest that VT risk is dynamic during hospitalization and that further studies incorporating dynamic VT risk assessment are warranted in medical inpatients.

Disclosures:
No relevant conflicts of interest to declare.
Acute Myeloid Leukemia Survival In Elderly Patients In The United States
Authors: Shah Binay K. , Ghimire Krishna B 
Published: October 2019

Abstract

Background
Survival in Acute myeloid leukemia (AML) has improved in younger patients over the last decade. Though chemotherapy has not changed significantly, better patient care may have improved survival in AML patients. This study was conducted to evaluate the relative survival rates in older AML patients over two decades in the United States.

Methods
Newly diagnosed AML (first primary only) in older (age≥75 years) patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database. We analyzed SEER 18 registry database to evaluate relative survival rate in older (≥75 years) AML population diagnosed during 1992-2000. We selected AML patients from 13 SEER registries to compare RS during 1992-2000 and 2001-2009. The relative survival rates at 1 and 5 year were analyzed for various cohorts categorized by race (White, African-Americans (AA) & other), gender & age (≥75-84 and ≥85 years). The relative survival rates accompany standard error (SE). We used SEER-Stat, statistical software provided by NCI for statistical analysis.

Results
The relative survival rates improved significantly during 2001-2009 compared to 1992-2000 for all age groups, sex. For young elderly patients (≥75-84 years) RS increased from 13.1±0.8% to 17.4±0.9% at 1 year Z value=3.98, P<0.0001 and from 2.0±0.4 to 2.6±0.5%, Z value= 3.61, P<0.0005 at 5 years with improvement in median relative survival from 2.41 to 2.75 months.
Similarly, for very elderly (≥85 years) patients RS increased from 5.3±1.0% to 8.0±1.0%, Z value=3.03, P<0.005 at 1 year, 0.7±0.4% to 1.3±0.5% at 3 years Z value= 2.81, P=0.005, but no improvement seen at 5 years. There was significant improvement in RS from 1992-2000 to 2001-2009 in both sexes, caucasian and other races. There was no improvement in RS at 1 year and 5 year for older AA population. (Table)

Conclusion
The relative survival in elderly AML has increased significantly during 2001-2009 compared to 1992-2000. The RS improved both at 1 year and 5 years for young elderly patients. Improvement in RS was observed at 1 year and 3 years for very elderly (>85 years) AML patients.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Significance Of Systemic Inflammatory Factors In Patients With Diffuse Large B Cell Lymphoma Treated By R-CHOP
Authors: Yoh Kyung Ah , Lee Ho Sup , Park Lee Chun , Lee Eun Mi , Shin Seong Hoon , Ye Byeong Jin , Moon Joon Ho , Jo Jae-Cheol , Lee Won Sik , Shin Ho-Jin , Oh Sun Young , Kim Yang Soo 
Published: October 2019

Abstract

Background
Systemic inflammatory factors such as C-reactive protein (CRP), ¥â2-microglobulin (B2MG), and ferritin were documented an prognostic factor in patients with hematologic malignancies including lymphoma. The purpose of this study was to find the significance of systemic inflammatory factors for predicting survival outcome in patients with diffuse large B cell lymphoma (DLBCL).

Methods
A total of 188 patients who newly diagnosed DLBCL and received an rituximab combined chemotherapy at the South Korea between September 2004 and April 2012 were enrolled retrospectively in the current study. Pretreatment serum CRP, B2MG, and ferritin were measured within 4 weeks before the beginning of first line chemotherapy.

Results
The median age of patients was 58 years (range, 14-84 years) and the mean level of serum CRP, B2MG, and ferritin at pre-treatment were 2.37 mg/dL (range: 0.01 – 29.80), 2.64 mg/L (range: 0.71 – 24.01), and 285.01 ng/ml (range: 5.34-4872.40). Systemic inflammatory factors score were given 1 point if serum levels were more than normal range (CRP; 0.8 mg/dL, B2MG; 2.5 mg/L and ferritin; 220 ng/ml). Systemic inflammatory risk were divided into three groups according to systemic inflammatory factors scores ; low risk was 0 score, intermediate risk was 1 or 2 score, and high risk was 3 score respectively. 5-year progression free survival rates (PFS) were 66.9%, 65.0% and 10.6% in risk groups respectively (p < 0.001). 5-year overall survival rates (OS) were 74.4%, 48.8% and 19.8% in risk groups respectively (p < 0.001).

Conclusions
Systemic inflammatory factor (CRP, B2MG and ferritin) score were associated with survival outcomes in patients with DLBCL treated by R-CHOP. However, further studies are needed to confirm prognostic value of systemic factors such as CRP, B2MG and ferritin.
IPI, international prognostic index; LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group (ECOG) performance status; CRP, C-reactive protein; BM, bone marrow; ALC, absolute lymphocyte counts; CHOP-like (cyclophosphamide, adriamycin, vincristine, prednisolone); RCHOP (rituximab plus CHOP)
Systemic inflammatory factor (normal range); ¥â2-microglobulin (2.5mg/L), CRP (0.8mg/dL), ferritin (220 ng/mL)
Systemic inflammatory factor score : given 1 point if more than normal range
Low risk ; 0, Intermediate risk ; 1 or 2, High risk ; 3

Disclosures:
No relevant conflicts of interest to declare.
Intraperitoneal Administration Of Activated Protein C Prevents Post-Surgical Adhesion Band Formation
Authors: Dinarvand Peyman , Rezaie Alireza R. 
Published: October 2019

Abstract
Postoperative intraperitoneal adhesion bands are the most important causes of intestinal obstruction, pelvic pain and female infertility. Adhesion bands are induced by inflammatory responses elicited by injury following surgery. The objective of this study was to evaluate the effectiveness of activated protein C (APC), a natural anticoagulant and antiinflammatory serine protease in plasma, in preventing post-surgical intraperitoneal adhesion band formation. The protective effects of APC and the FDA approved agent, sodium hyaluronate/carboxymethylcellulose (HA/CMC, also called Seprafilm), were compared by administering the two drugs intraperitoneally into 30 male C57bl/6 mice. After 7 days, the pathological adhesion grades were scored by two scaling systems and the peritoneal fluid concentration of tissue plasminogen activator (tPA) as well as the concentrations of the proinflammatory cytokines, IL-1, IL-6, TNF-α, IFN-γ and TGF-β were evaluated. The inflammation scores of mice in all groups were also measured based on histological data obtained from peritoneal tissues. Relative to the HA/CMC group, intraperitoneal administration of APC led to a significantly higher reduction of adhesion band formation. Moreover, a markedly lower inflammation score was obtained in the adhesive tissues of the APC-treated group which correlated with significantly reduced peritoneal concentrations of IL-6, TNF-α, IFN-γ and TGF-β and elevated concentration of tPA in this group. These results suggest that in comparison to the FDA approved agent, Seprafilm, APC exhibits a markedly higher efficacy in preventing postoperative adhesion band formation. Thus, APC holds the potential to be therapeutically used as a novel anti-adhesive agent.

Disclosures:
No relevant conflicts of interest to declare.
Reversal Of Dabigatran Anticoagulation By a 4-Factor Prothrombin Complex Concentrate: Correlation Between Effects On Parameters Of Thrombin Generation and Hemostatic Effect In Vivo
Authors: Hoffman Maureane , Volovyk Zoya , Monroe Dougald 
Published: October 2019

Abstract
Dabigatran etexilate (Pradaxa®) is a prodrug that is metabolized to a small molecule direct thrombin inhibitor. It has the drawback that it is not readily reversible. Several studies have suggested that prothrombin complex concentrates (PCCs) might reverse the effects of dabigatran on laboratory assays. However, the effects of PCCs on laboratory assays do not seem to correlate well with their effects on hemostatic function in several animal models. We have previously reported the effects of a 4-factor PCC (KCentra®, CSL-Behring) on parameters of thrombin generation in a cell-based assay of thrombin generation (cell-based Calibrated Automated Thrombogram Assay, CAT®). This model allowed us to use varying levels of dabigatran and varying levels of PCC in the presence of freshly isolated platelets, a cell-associated source of tissue factor (TF) and plasma levels of coagulation factors. We found that dabigatran lengthens the lag, and reduces the total and peak levels of active thrombin in this model. KCentra can normalize the peak, rate and total amount of thrombin generated in the presence of dabigatran, but does not normalize the lag time. These effects were seen at all levels of dabigatran tested. A level of 1 U/mL KCentra® (equivalent to an dose of 50 U/kg in vivo) was able to restore the rate and peak levels of thrombin generation, as well as the area-under-the-curve, to normal levels. A level of 0.5 U/mL KCentra did not completely normalize the rate, peak and AUC.
We compared results in the cell-based CAT assay to results in a novel mouse saphenous vein bleeding model (Pastoft, et al, A sensitive venous bleeding model in haemophilia A mice: effects of two recombinant FVIII products (N8 and Advate) 2012). We found that an i.v. dose of 15 ug/kg dabigatran doubled the time to hemostasis from 80 sec + 9 in controls to 173 sec + 24. A dose of 25 U/kg KCentra partially corrected hemostasis and a dose of 50 U/kg completely corrected hemostasis in this model. These results are completely consistent with the results of the cell-based CAT assay.
While many workers report the peak or the area under the thrombin generation curve (AUC or ETP) as the key parameter in thrombin generation assays, it is not known which parameters reflect hemostatic function in vivo. Because the parameters of thrombin generation are not independent, it is very difficult to determine which of them are most closely related the hemostasis. However, our current data suggest that a 4-factor PCC is able to completely correct the time to hemostasis is a reproducible mouse model, even though it does not the lag time in an assay of thrombin generation

Disclosures:
Hoffman: Novo Nordisk: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Boehringer Ingelheim: Research Funding. Monroe:CSL-Behring: Research Funding.
Circulatory Glycan-Modifying Enzymes As Systemic Regulators In Blood Cell Development
Authors: Lau Joseph 
Published: October 2019

Abstract
Regulating blood cell production is crucial to meeting physiologic demands and to maintaining hematopoietic equilibrium. Elucidating the systemic factors and how they contribute to the interaction of hematopoietic progenitors with their bone marrow microenvironments is crucial to the mechanistic understanding of hematopoietic regulation and development of novel therapeutic strategies. Glycosyltransferases are enzymes that normally reside within the intracellular secretory apparatus to assemble glycans on nascent proteins and lipids in transit, but they are also present in abundance in the extracellular spaces, especially in systemic circulation. One such blood-borne enzyme is the ST6Gal-1 sialyltransferase that mediates the attachment of sialic acids in a6-linkages to glycoproteins. By virtue of their presence on cell surfaces, sialyl-glycans, which are conserved structures in mammals, occupy the critical interphase between cells and their external environment. We hypothesize that remodeling of these cell surface glycans can drastically modulate the communication of systemic cues among marrow hematopoietic cells. A mouse model genetically modified for low circulating ST6Gal-1 has increased numbers of hematopoietic progenitors, increased ability to produce inflammatory cells upon acute challenge, and faster recovery from cyclophosphamide-induced myelosuppression. In ex vivo cultures, addition of ST6Gal-1 strikingly delays expansion and differentiation of murine LSK (Linneg sca-1pos cKitpos) and human CD34pos cells. We developed a subcutaneously implantable B16-F10 model genetically modified to overexpress circulatory ST6Gal-1 (B16st6gal1). Mice bearing B16st6gal1 had >10-fold elevation in circulating ST6Gal-1 levels, accompanied by >50% reduction in marrow granulocyte and B cell populations. B16st6gal1 bearing mice also had 2-fold increase in the number of Linneg cells, suggesting a blockade in development of progenitors into end-effector cells. Murine LSK cell surfaces are decorated with a6-sialic acids but they do not endogenously express ST6Gal-1. Bone chimeras show that the a6-sialic acids on LSK surfaces require the distally synthesized ST6Gal-1 enzyme in circulation. Taken together, our data indicates the glycan-modifying enzyme, the ST6Gal-1 in circulation, is a potent systemic regulator of hematopoiesis by remodeling of cell surface glycan architecture of marrow hematopoietic stem and progenitors. (Funded by NIH Program of Excellence in Glycosciences award P01HL107146 and NIH R01AI56082)

Disclosures:
No relevant conflicts of interest to declare.
LFA-1-Mediated Adhesion Of Human Hematopoietic Progenitors To Bone Marrow Stromal Cells Enhances B-Lineage Differentiation Toward CD19+ ProB Cells, While The Generation Of CD7+CD56-CD45RA+ Multipotent Lymphoid and CD10+CD19- B-Biased Progenitors Is Supported By Soluble Factors Produced From Stromal Cells
Authors: Minami Hirohito , Ohishi Kohshi , Nakamori Yoshiki , Masuya Masahiro , Katayama Naoyuki 
Published: October 2019

Abstract
The regulatory mechanism of human lymphoid differentiation remains less defined. Here we examined how bone marrow stromal cells regulate human early lymphoid differentiation, using human telomerized bone marrow stromal cells that support the generation of CD7+CD56- early T and CD10+CD19+ proB cells from human hematopoietic progenitors. To examine the role of direct contact between hematopoietic progenitors and stromal cells in lymphopoiesis, cultures were performed by inhibiting the cell-cell contact with microporous insert or by incubating hematopoietic progenitors with conditioned medium collected from stromal cell cultures. The separation suppressed B-lineage differentiation to CD10+CD19+ cells, while the generation of CD7+ cells was not significantly influenced. The CD7+ cells generated with or without direct contact with stromal cells similarly had multipotent differentiation capacity for T, B, NK, granulocytic, and monocytic cells but not for erythroid cells in various culture conditions. On the other hand, even CD10+CD19- immature cells had more limited differentiation capacity for T, B, and monocytic cells in various culture conditions, and mostly differentiated toward CD10+CD19+ proB cells on the stromal cells. By time course analysis after coculture on the stromal cells, CD7+CD10- followed by CD10+CD19- and then CD10+CD19+ cells were developed. Some portion of CD7+CD10- and most of CD7-CD10+CD19- cells, upon recultured on stromal cells, differentiated toward CD10+CD19+ cells, but such B-lineage differentiation on the stromal cells was diminished by reculture with conditioned medium. ICAM-1 was expressed on the telomerized stromal cells. Coculture on stromal cells in the presence of LFA-1 neutralizing antibody that blocks the binding to ICAM-1 inhibited the differentiation to CD19+ proB cells. Our findings show that stromal cells support the generation of CD7+ multipotent lymphoid and CD10+ B-biased progenitors by producing soluble factors, but enhances B-lineage differentiation toward CD19+ proB cells in part via LFA-1-mediated direct cell-cell contact.

Disclosures:
No relevant conflicts of interest to declare.
Primitive Erythropoiesis and Osteogenesis Are Differentially Impaired In Rpl5 and Rps19 Mutant Murine Embryonic Stem Cell Models Of Diamond Blackfan Anemia
Authors: Dulmovits Brian M. , Singh Sharon A. , Goldberg Tracie , Didier Sebastien , Lipton Jeffrey M. , Blanc Lionel , Liu Johnson M. 
Published: October 2019

Abstract

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by red blood cell hypoplasia, congenital anomalies and cancer predisposition. In addition, short stature and poor skeletal growth are found in a subset of DBA patients, suggesting similar developmental abnormalities in erythropoiesis and osteogenesis in that subset. Furthermore it has been shown recently that osteoblasts secrete erythropoietin, linking the marrow niche to the modulation of erythropoiesis. DBA has been shown in the majority of cases to result from haploinsufficiency of large or small ribosomal subunit proteins. The p53 pathway, known to be activated by abortive ribosome assembly, contributes to the erythroid failure of DBA. We studied two DBA genotypes in vitro using murine embryonic stem (ES) cell lines harboring gene trap mutations in ribosomal proteins RPS19 and RPL5, respectively. Both mutants had decreased embryoid body (EB) formation, decreased definitive erythroid colony formation and similar p53-dependent primitive erythroid differentiation defects (see Figure A). Cell cycle analyses were normal in the Rps19 mutant ES cells, but there was a significant G2/M arrest in the Rpl5 mutant ES cells, which was unaffected by p53 knockdown. In addition, the Rpl5 mutant cells had a more pronounced growth defect in culture compared to the Rps19 mutant cells (Figure B). ES cells were differentiated, in vitro, to osteoblasts using established culture conditions, and confirmed both by morphology and molecular characterization (e.g. RUNX2 and Osteopontin). Following 14 days of osteogenic differentiation, bone mineralization was confirmed via Alizarin Red staining. A marked reduction in Alizarin Red staining was seen in the Rpl5 mutant cells while there was only a slight diminution of staining in the Rps19 mutant ES cultures (see Figure C). Therefore the erythroid differentiation defect appears similar in both the Rps19 and Rpl5 mutant ES cells. However the Rpl5 mutant appears to have a more severe phenotype at the ES stage, as evidenced by a pronounced p53-independent G2/M arrest and slower growth rate and subsequently during osteogenic differentiation. These data suggest an explanation for the more severe non-erythroid phenotype seen in a subset of DBA patients.

Disclosures:
No relevant conflicts of interest to declare.
AML1-ETO Represses Multiple Transcription Factor Induced CTSG Activation by Reducing H3 Acetylation
Authors: Tan Yun , Jin Wen , Wu Kang , Wang Kankan 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is often accompanied with the aberrant expression of transcription factors. In t(8;21) AML, the AML1-ETO fusion protein executes its critical role in leukemogenesis through the interference with hematopoietic transcription factors (TFs) including AML1, C/EBPα, PU.1 and c-Myb. These transcription factors cooperate to modulate hematopoiesis by regulating their differentiation-related target genes. In our previous work, we have identified that AML1-ETO suppresses the AML1-dependent transactivation of the gene encoding the neutrophil granule protease, cathepsin G (CTSG). However, the detailed mechanisms of AML1-ETO mediated transrepression, especially coordinated regulation of hematopoietic transcription factors, have not been characterized yet. To investigate the regulatory pattern of CTSG by hematopoietic specific transcription factors, we constructed a luciferase reporter containing the CTSG promoter and co-transfect it with AML1, c-Myb, C/EBPα or PU.1 to 293T cells. The results of luciferase assays showed that these TFs individually activated the CTSG promoter, and synergistic transactivation occurred between AML1 and c-Myb, C/EBPα and PU.1, and PU.1 and c-Myb on the CTSG promoter. Furthermore, AML1/ETO effectively suppressed the transcription factor-dependent transactivation and synergistic transactivation of the CTSG promoter. Chromatin immunoprecipitation assays further demonstrated that AML1-ETO coexisted with these TFs on the CTSG promoter in AML1/ETO-positive Kasumi-1 cell line, indicating AML1-ETO was tethered to the chromatin bound by these TFs. The data suggested that AML1-ETO might act as a negative regulator by interfering the normal function of hematopoietic TFs instead of competing for their binding. In addition, to reveal the underlying mechanism of AML1/ETO-mediated transcription repression at the epigenetic level, we examined the epigenetic status of the CTSG promoter in AML1-ETO negative and positive cells, and found the level of histone H3 Lys9 acetylation on the CTSG promoter was obviously lower in AML1-ETO positive cells than that in AML1-ETO negative cells. The data suggested that AML1-ETO might repress the gene transcription by changing the H3 acetylation status of its target gene. Collectively, our findings demonstrate that AML1-ETO represses the transactivation of the CTSG promoter mediated by multiple hematopoietic transcription factors through a decrease of H3 acetylation.

Disclosures:
No relevant conflicts of interest to declare.