bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-Relapse Mortality Associated with Autologous Stem Cell Transplant (ASCT).
Authors: Stotler Christy , Kalaycio Matt , Dean Robert M. , Sobecks Ronald , Copelan Edward A. , Andresen Steven , Pohlman Brad , Sweetenham John William , Rybicki Lisa , Brown Stacey , Bell Kim , Cherni Kelly , Bernhard Laura , Ferraro Christina , Bolwell Brian J. 
Published: April 2020

Abstract
Advances in supportive care have reduced early treatment related mortality with ASCT to approximately 1%. Registry data has shown that relapse is the cause of treatment failure in approximately 80% of patients. However, non-relapse mortality (NRM), over time, affects 20% of transplant recipients. Delayed NRM is poorly studied. To characterize the factors associated with NRM, we reviewed 1573 consecutive autologous transplants performed at the Cleveland Clinic from 1/1992 through 12/2005. This analysis included only adult patients (pts) receiving peripheral stem cells, busulfan based preparative regimens, single transplants, and diagnoses of NHL, HD and MM (n = 856). The median age was 49, 62% were male, and 30% received prior radiation therapy. The most common number of prior chemotherapy regimens was 2 (48%); the primary diagnosis was NHL (67%), HD (18%), MM (15%); and 90% had sensitive disease at the time of transplant. 471 (55%) are alive and 385 (45%) have died. Relapse was the most common cause of death, occurring in 303 (79%) patients. Non-relapse mortality occurred in 82 patients (21% of deaths). The most common cause of NRM was pulmonary toxicity, occurring in 26 patients, followed by secondary malignancy in 19 pts, infection (12 pts), cardiac toxicity (7 pts), other organ failure (7 pts), and other causes (11 pts). Patients who died from secondary malignancy were significantly more likely to have received prior radiation therapy (p = 0.004), to require more days of pheresis to collect stem cells (p&lt;0.001) and had a longer time to platelet engraftment than did other patients (p&lt;0.001). 16/19 deaths due to secondary malignancy were from hematologic malignancies. Causes of death in the “other” category included accidents (n=3), homicide (n=1) and suicide (n=1). Liver toxicity was the most common organ affected in the “other organ failure” category. 46% of patients with NRM due to pulmonary toxicity had a prior exposure to radiation therapy, as did 43% of those with cardiac toxicity. The time to development of NRM is shown below:
Figure Figure
The substantial majority of NRM due to pulmonary toxicity, other organ failure or infection occurs within one year post-transplant. This suggests a need for more intensive surveillance of recipients of autologous transplantation for 12 months, possibly with regular visits to the transplanting institution. We have adopted more stringent follow up with promising early results at reducing 1 year NRM. The median time of NRM from secondary malignancy is 3.5 years, which suggests that surveillance of blood counts should continue well beyond one year post-transplant. Whether more aggressive surveillance will reduce NRM associated with ASCT requires further study.
Induction of GLUT1 during Erythropoiesis Triggers a Switch from Glucose to DHA Uptake in Vitamin C-Defective Mammals.
Authors: Montel-Hagen Amelie , Kinet Sandrina , Manel Nicolas , Mongellaz Cedric , Prohaska Rainer , Battini Jean-Luc , Delaunay Jean , Sitbon Marc , Taylor Naomi 
Published: April 2020

Abstract
Glucose provides a key supply of energy and carbon and its transport is achieved via multimembrane-spanning glucose transporters (GLUTs). The human erythrocyte is the cell type expressing the highest level of the GLUT1 glucose transporter, harboring greater than 200,000 molecules per cell. We now demonstrate that GLUT1 transcripts increase by 3-logs during erythropoiesis and high GLUT1 surface expression is observed following passage through the basophilic erythroblast stage. Paradoxically though, glucose transport significantly decreases. As GLUT1 also transports L-dehydroascorbic acid (DHA), the oxidized form of ascorbic acid (AA), transport of this molecule was assessed and indeed, it increases dramatically during erythropoiesis. The switch from glucose to DHA transport is coupled to the physical association of GLUT1 with stomatin, an integral erythrocyte membrane protein. We find that stomatin inversely regulates the relative transports of glucose and DHA by GLUT1. Moreover, in a patient with overhydrated hereditary stomatocytosis, a rare genetic disorder of red cell membrane permeability wherein stomatin is absent, glucose uptake is significantly higher but there is a concomitant 50% reduction in DHA transport. Intriguingly, erythrocyte-specific DHA transport is not conserved amongst all mammalian species; we did not detect GLUT1 on mature murine erythrocytes where DHA uptake is minimal. Notably though, humans differ from the vast majority of the greater than 5,000 mammalian species in that they are unable to synthesize ascorbic acid from glucose. This trait is shared only with other higher primates, guinea pigs and and fruit bats. We have determined that erythrocyte GLUT1 expression and associated DHA transport are specific features of these diverse ascorbic acid-deficient mammals. Within the primate order, defective ascorbic acid synthesis is due to an inactivation of the L-gulonolactone oxidase (GLO) enzyme at the Haplorrhini-Strespsirrhini split. In accord with the data presented above, we find that erythrocyte GLUT1 expression and associated DHA transport are characteristic of erythrocytes from primates within the Haplorrhini suborder but not Strepsirrhini lemurs. Thus, the erythrocyte-specific co-expression of GLUT1 and stomatin constitutes a compensatory mechanism in mammals that are unable to synthesize the essential ascorbic acid metabolite.
Clinical and Haematologic Features of 300 Patients Affected by Hereditary Spherocytosis as a Function of the Type of the Membrane Protein Defect.
Authors: Barcellini Wilma , Mariani Mariagabriella , Vercellati Cristina , Marcello Anna P. , Fermo Elisa , Pedotti Paola , Boschetti Carla , Zanella Alberto 
Published: April 2020

Abstract
Hereditary Spherocytosis (HS) is caused by defects of red cell membrane proteins (spectrin, ankyrin, band 3 and band 4.2). The aim of this study is to analyse a large database of 300 HS patients grouped according to SDS-PAGE, 1) to ascertain whether the clinical/haematological features and response to splenectomy are related to the type of molecular defect, and 2) to compare the sensitivity of the most common laboratory screening tests for HS in the various subsets of patients. Three hundred consecutive patients were investigated; 41 patients had been splenectomised before the time of the study, and 21 thereafter. In not splenectomised subjects, anaemia was severe in 7% of cases, mild to moderate in 52% and compensated in the remaining cases. The median number of spherocytes at the peripheral blood smear examination was 7%. The most frequent protein abnormalities revealed by SDS-PAGE were band 3 (54%) and spectrin and/or ankyrin (34%) deficiency. The membrane protein defect was undetectable in 3% of splenectomised versus 11% of not splenectomised patients. In patients evaluated by SDS-PAGE before and after splenectomy surgery allowed the identification of the defect (one band 3 and seven spectrin/ankyrin deficiency) in all the 8 previously unclassified cases. No significant differences were observed among clinical and haematological parameters of patients grouped according to the type of biochemical defect, although the degree of anaemia, haemolysis markers and median spherocyte number were higher in spectrin deficient than in the other groups of patients. Splenectomy was clinically effective in correcting both anaemia and haemolysis, but splenectomised spectrin/ankyrin deficient patients showed after splenectomy a slightly lower median rise in haemoglobin, and a higher reticulocyte number and unconjugated bilirubin level than band 3 deficient patients. The red cell osmotic fragility tests’ sensitivity varies greatly and ranged from 48 to 95%. The sensitivity was similar in patients with band 3 and spectrin/ankyrin deficiency and also in patients without detectable membrane defect. Furthermore, the sensitivity of all the methods investigated increased in splenectomised cases. AGLT displayed the highest sensitivity, and the association of AGLT and NaCl test on incubated blood reached a sensitivity of 99%, enabling the diagnosis of the atypical HS cases, such as those with rare or no spherocytes in blood smears, normal MCHC and reticulocyte counts.
Bacterial Omptins Proteolytically Inactivate Tissue Factor Pathway Inhibitor (TFPI).
Authors: Yun Thomas H. , Cott Jessica , Tapping Richard I. , Slauch James M. , Morrissey James H. 
Published: April 2020

Abstract
Activation of the clotting system is an effector function of the immune response, resulting in extravascular fibrin deposition whose purpose appears to be to limit the spread of invasive microorganisms. Activation of the clotting cascade may also modulate inflammatory reactions. Some bacteria are known to counteract the host coagulant response by modulating specific components of the clotting system, thereby promoting fibrinolysis or inhibiting coagulation activation. Pla, a member of the omptin family of Gram-negative outer membrane proteases, is a known virulence factor for the plague agent, Yersinia pestis. Pla’s ability to activate plasminogen by limited proteolysis is thought to facilitate the organism’s escape from fibrin meshworks, promoting its dissemination through extravascular tissues. We now show that Pla, as well as its homologs OmpT in Escherichia coli and PgtE in Salmonella enterica serovar Typhimurium, abrogate the function of the endogenous anticoagulant, tissue factor pathway inhibitor (TFPI). Using gene deletions, we found that bacterial inactivation of TFPI required the expression of these omptins. Consistent with prior studies of other omptin substrates, cleavage of TFPI by the Salmonella omptin was demonstrable only in rough LPS backgrounds. Western blotting experiments showed that proteolysis of TFPI correlated with loss of TFPI anticoagulant activity in clotting assays. The specificity of the omptin/TFPI interaction is supported by the finding that both common and distinct TFPI cleavage fragments are generated by the omptins in these three bacterial species. Furthermore, TFPI inactivation proceeds even in plasma where an abundance of competing protein substrates would be expected to render TFPI proteolysis almost non-existent if the reaction were not specific. We hypothesize that the sensitivity of TFPI to inactivation by bacterial omptins is a novel host-pathogen interaction that potentiates the procoagulant immune response to bacterial infection. With the heavy bacterial loads present in the circulation during the late stages of severe septicemia, this interaction may contribute to the development of disseminated intravascular coagulation and end organ failure.
Thrombin-Releasable Protein Z-Dependent Protease Inhibitor Identified in Platelets and Is Likely Due to Uptake from Plasma.
Authors: Han Xin , Nguyen Martin H. , Fernandez Michael , Broze George J. , Bueso-Ramos Carlos E. 
Published: April 2020

Abstract
Protein Z (PZ) is a vitamin K-dependent protein, whereas PZ-dependent protease inhibitor (ZPI) is a member of the serine protease inhibitor superfamily. ZPI rapidly inhibits factor Xa in the presence of PZ, calcium, and phospholipids and inhibits factor XIa in a PZ-independent fashion (Blood2000; 96:3049–3055). PZ circulates as a complex with ZPI in plasma and deletion of either the PZ or the ZPI gene is associated with the prothrombotic phenotype in mice. In addition, W303X or R67X nonsense mutations in the ZPI gene are reportedly associated with deep venous thrombosis in certain human populations. Western blot analysis of platelets stimulated with thrombin (0–200 mU/mL) showed they contained and released ZPI (approximately 200 ng/109 platelets) with the same molecular weight as plasma ZPI (72 kDa). The majority of the ZPI was released within 1 min. by 25 mU/mL thrombin. PZ was not detected in platelets by western blot analysis. Immunohistochemical staining using a monoclonal anti-ZPI antibody demonstrated a cytoplasmic fine granular staining pattern in maturing megakaryocytes in bone marrow aspirates and in circulating platelets, suggesting that ZPI may be stored in alpha granules. ZPI mRNA, however, was not detected by reverse transcriptase polymerase chain reaction (RT-PCR) in platelets or bone marrow aspirates, but was detected in human liver cDNA. RT-PCR for platelet factor 4 and glyceraldehyde 3-phosphate dehydrogenase mRNA showed amplified products with expected sizes. In conclusion, thrombin-releasable ZPI, but not PZ, is present in platelets and is most likely derived from the uptake of ZPI from plasma. ZPI released from activated platelets may play a role in the regulation of local coagulation at a site of injury.
Genomic, Proteomic and Functional Screens Identify PAI-1 as an Important Factor Influencing Mesenchymal Stromal Cell Survival Post-Transplantation In Vivo.
Authors: Copland Ian B. , Cuerquis Jessica , Wang Eugenia , Galipeau Jacques 
Published: April 2020

Abstract
MSCs have robust reparative properties through their ability to limit apoptosis, enhance angiogenesis and direct positive tissue remodelling. However, a major limitation on the widespread application of MSC transplantation is that transplanted cells have low survival rates in vivo. Thus, enhancing MSCs survival post-transplantation is critical for the successful implementation of cellular therapy. One explanation for their low survival is that MSCs are often transplanted into ischemic tissue - such as infarcted myocardium - where there is poor blood supply and low oxygen tension. How these factors influence MSC survival is still unclear, therefore the objective of this project was to better understand how hypoxia under low nutrient conditions affects the behaviour and survival of MSCs. To answer this question, we performed the following series of experiments:
Isolate and immunophenotype murine MSCs. Assess impact of in vitro ischemic conditions (hypoxia and serum deprivation) on MSCs by microarray analysis and ITRAQ proteomics for secreted proteins. Confirm changes of specific factors in vitro. Isolate and immunophenotype MSCs from knock-out mice for specific factors. Determine whether knock-out MSCs have altered survival in vitro and in vivo.
As confirmed by PCR and Western blotting, microarray and proteomic screens, identified plasminogen activator inhibitor-1 (PAI-1) as one factor consistently upregulated in hypoxia (3% oxygen) treated MSCs. In vitro migration studies demonstrated that PAI-1 blocks migration of MSCs towards a chemotactic gradient, while isolation of PAI-1 knock-out MSCs, revealed an enhanced survival of PAI-1null MSCs over wild-type MSCs. In vivo subcutaneous transplantation of beta-galactosidase engineered wild-type and PAI-1null MSCs, recapitulated our in vitro results, such that 14 days post-implantation PAI-1null MSCs had a five fold increase in survival compared to wild-type MSCs. In conclusion, PAI-1 is a multifunctional protein. As an inhibitor, PAI-1 acts as ‘bait’ regulating the conversion of plasminogen to plasmin thus functioning as a major control point in the regulation of systemic fibrinolysis and local growth factor availability. In addition, PAI-1 can also act as a ligand for vitronectin to influence cellular migration/adhesion. Up-regulation of PAI-1 by MSCs after transplantation impacts MSC survival. Determining how to block PAI-1 following transplantation of MSCs is currently under investigation.
AML1-ETO9a Correlated with C-KIT Overexpression/Mutation and Indicated Poor Disease Outcome in t(8;21) Acute Myeloid Leukemia.
Authors: Liang Yang , Jiao Bo , Wu Chuan-Feng , Xiong Shu-Min , Gu Long-Jun , Chen Zhu , Chen Sai-Juan 
Published: April 2020

Abstract
AML1-ETO fusion gene is generated from chromosome translocation t(8;21) in acute myeloid leukemia (AML). It is recently reported that its spliced variant AML1-ETO9a induced leukemia rapidly in murine model. Here we detected AML1-ETO9a expression in 58 of 71 (81.7%) patients with t(8;21) AML by using qualitative RT-PCR. Quantitative RT-PCR revealed significantly higher C-KIT levels in the AML1-ETO9a positive group than in the negative group (P=0.0001). Among 29 cases harbored C-KIT mutations, 28 (96.6%) expressed AML1-ETO9a. Clinically, patients expressing AML1-ETO9a exhibited significantly elevated white blood cell counts and a short overall survival time (P=0.0455 and 0.0039, respectively). Morphologically, although there is no difference of leukemic blasts percentage between AML1-ETO9a positive and negative cases (P=0.1169), the latter possessed more aberrant myelocytes (P=0.0462). Taken together, AML1-ETO9a correlated with C-KIT overexpression/mutation and indicated poor disease outcome in t(8;21) AML.
Thromboprophylaxis for Catheter-Related Thrombosis in Patients with Cancer: A Systematic Review.
Authors: Carrier Marc , Tay Jason , Fergusson Dean , Well Philip S. 
Published: April 2020

Abstract
Background Patients with malignancy have an overall 4-fold increased relative risk of developing a venous thrombosis. Central venous catheters are commonly used in patients with cancer (chemotherapy, blood products, parenteral nutrition, etc) and further increase the absolute risk of thrombosis in this population. Thromboprophylaxis to prevent catheter-related thrombosis in patients with cancer is controversial. Both low-molecular-weight-heparin (LMWH) and low dose warfarin have been studied in adults. We sought to summarize and quantify the clinical effects of LMWH and low dose warfarin to prevent catheter-related thrombosis in patients with cancer.
Methods A systematic literature search strategy was used to identify potential trials on MEDLINE (1950 to January week 4 2007), EMBASE (1980 to 2007 week 5), the Cochrane Register of Controlled Trials (1st quarter 2007) and all EBM Reviews (4th quarter of 2006) using an OVID interface. RCTs were evaluated using a previously validated scale (Jadad scale) and assessed for allocation concealment. The primary outcome measure was symptomatic catheter-related thrombosis. Secondary outcome measures included: clinically significant catheter-related thrombosis, death and bleeding episodes. Relative risk (RR) was used as the primary measurement with 95% confidence intervals (CIs). Pooled measurements were calculated for randomized clinical trials using a random-effects model.
Results In total, 510 records were identified and 16 records (14 articles and 2 abstracts) were deemed potentially eligible. 6 articles and one abstract met our inclusion criteria; 3 investigated LMWH and 4 low dose warfarin. Three studies were double-blinded and 2 reported on allocation concealment. The pooled RR of symptomatic catheter-related thrombosis for LMWH thromboprophylaxis was 0.43 (95% CI: 0.12–1.56). The pooled RR of symptomatic catheter-related thrombosis for low-dose warfarin thromboprophylaxis was 0.82 (95% CI: 0.46–1.47). All RCTs also reported the proportion of clinically significant catheter-related thrombosis. The pooled RR was 0.42 (95% CI: 0.12–1.42) and 0.74 (95% CI: 0.41–1.32) for LMWH and warfarin respectively. Very few studies reported any adverse events (death, major and minor bleeding).
Conclusions Based on the available data, we cannot recommend routine thromboprophylaxis for patients with cancer receiving a central venous catheter. Further studies with a greater number of enrolled patients are required before we can draw firmer conclusions regarding its utility.
The Impact of Histological Subtypes on Outcome in Patients with Mantle Cell Lymphoma Treated with or without Autologous Stem Cell Transplant.
Authors: Zulfiqar Muhammad I. , Weisenburger Dennis D. , Loberiza Fausto R. , Vose Julie M. , Bierman Philip J. , Bociek R. Gregory , Armitage James O. 
Published: April 2020

Abstract
Mantle cell lymphoma (MCL) accounts for 7% of all non-Hodgkin’s lymphomas, with median overall survival in most series of 3–4 years. MCL has been classified into three histological subtypes which include diffuse MCL, nodular MCL, and blastic MCL. A relatively small number of studies have examined the prognostic importance of histology in MCL. The aim of this study was to determine if the progression free survival (PFS) and overall survival (OS) rates in mantle cell lymphoma differ among histological subtypes. A total of 102 patients with MCL, treated by the Nebraska Lymphoma Study Group between January 1986 and June 2006, with a median age of 60 years (range 32–89 years) were available for study. Patients were treated with HyperCVAD or a CHOP like regimen with or without rituximab and autologous hematopoetic stem cell transplant (ASCT). All cases were confirmed using cyclin D1 staining. Regardless of treatment, our study failed to show a significant difference in PFS (p=0.26) or OS (P=0.06) among histological subtypes. There was a trend for better survival in patients with nodular MCL. However, in patients receiving ASCT, there was a significantly higher PFS (P=0.0001) and OS (p=0.0005) compared to patients not receiving ASCT. The 3 year PFS for patients receiving HyperCVAD followed by ASCT was 64% compared to the 3 year PFS for HyperCVAD alone of 0 (p=0.008). In conclusion, we failed to show association between histological subtypes of MCL with outcomes regardless of treatment. However, the use of ASCT improved survival.