bluuebunny/crossref_metadata_2025_split huggingface dataset:
The BCL6 Proto-Oncogene Suppresses p53 Expression in Germinal-Center B Cells.
Authors: Phan Ryan T. , Niu Huifeng , Saito Masumichi , Basso Katia , Cattoretti Giorgio , Dalla-Favera Riccardo 
Published: October 2019

Abstract
The proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is necessary for germinal center (GC) formation and is implicated in the pathogenesis of B-cell lymphoma. In ~50% diffuse large cell lymphoma and 10% follicular lymphoma, BCL6 gene expression is deregulated by chromosomal translocations or mutations that affect its 5′ regulatory region. The precise function of BCL6 in GC development and lymphomagenesis is unclear since very few BCL6 direct target genes have been identified. We report that BCL6 suppresses p53-dependent and p53-indepenent growth arrest and apoptosis responses in GC B cells. BCL6 directly suppresses the transcription of the p53 gene, as demonstrated by (1) chromatin immunoprecipitation (ChIP) assays showing that BCL6 binds the p53 promoter region in vivo; and (2) transient transfection/reporter assays identifying within the p53 promoter region two BCL6-binding sites that mediate BCL6-mediated suppression of p53 transcription.
Accordingly, suppression of BCL6 expression via specific siRNA leads to increased expression of p53 both under basal condition and in response to DNA damage. Consistent with a physiological role for BCL6-mediated p53 suppression, immunohistochemical analysis shows that p53 expression is absent in GC B cells where BCL6 is highly expressed. In addition, our data reveal that BCL6 inhibits the p53-independent activation of the p21/WAF1 cell cycle arrest gene by binding to Miz-1, a transcription factor involved in p21 activation. Consistent with a role of BCL6 in inhibiting p53-related cell cycle arrest and apoptotic responses, constitutive expression of BCL6 suppresses p53 expression and p53-target genes (P21 and PUMA) and protects B cell lines from apoptosis induced by DNA damage. These results indicate that one function of BCL6 is to allow GC B cells (centroblasts) to constitutively proliferate and to sustain the physiologic DNA breaks required for immunoglobulin switch recombination and somatic hypermutation without inducing p53-related responses. These findings also imply that B cell lymphoma with deregulated BCL6 expression are functionally p53-negative and impaired in apoptotic responses.
Risk Factors for Outcomes of Family Haploidentical Allogeneic Stem Cell Transplantation for Adults with Acute Leukemias: A Survey on Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
Authors: Ciceri Fabio , Labopin Myriam , Rocha Vanderson , Rowe Jacob M. , Bunjes Donald , Di Bartolomeo Paolo , Frassoni Francesco , Martelli Massimo F. , Aversa Franco 
Published: October 2019

Abstract
Results of family haploidentical allogeneic stem cell transplantation (Haplo-SCT) have been reported from single-center studies as a curative treatment option for patients with high risk acute leukemias. We analysed 273 adult patients with de novo acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) receiving an Haplo-SCT transplanted from 1995 to 2002 in 75 EBMT centers. Overall, 170 AML patients underwent transplantation in CR1 (n=39), CR2 (n=34) or in advanced disease (n=97); median age was 38y (16–70). Overall, 103 ALL patients underwent transplantation in CR1 (n=31), CR2 (n=22) or in advanced disease (n=50); median age was 26y (16–56). Graft composition was based on CD34+ cell selection of PBSC, with median CD34+ cells x106/kg of 7.3 (1.1–45.5) in AML and 8.3 (1.14–30) in ALL. Conditioning regimen was TBI-based in 69% and 87% in AML and ALL respectively. Primary engraftment was documented in 87% AML and in 83% of ALL patients, with ANC 0.5 x109/L in a median of 13 days (8–35) and a 2y probability of PLT > 50 x109/L of 80+/− 5%. The use of TBI was significantly associated with engraftment (90% vs 71%) when adjusting for CD34 dose. The cumulative incidence of acute GvHD >=II was 16% in AML and 15% in ALL. With a median follow-up of 19 months (1–85), the estimated leukemia-free survival (LFS) at 2 years in AML was 39±9%, 33 ±10% and 4±3% and in ALL was 28±9%, 16±8, and 0% for CR1, CR2 and advanced patients respectively. Cumulative incidence using competing risks, for relapse (RI) at 2 y in AML was 8 ±8%, 9 ±9%, 25±8% for CR1, CR2 and advanced; RI in ALL was 27±16% and 41 ±20% in CR1 and CR2. The non-relapse mortality (NRM) at 2 y in AML was 52±18%, 56 ±19%, 69±8% for CR1, CR2 and advanced patients; NRM in ALL was 44±18% and 41±21% in CR1 and CR2. In a multivariate analysis for LFS, advanced disease status at transplant (RR 0.4), ALL (RR 0.5), recipient’s age >33 years (RR 0.4), and absence of TBI in conditioning (RR 0.6) were factors associated with lower LFS. Factors associated with higher transplant-mortality were advanced disease status (RR 2.01), absence of TBI (RR 1.6) and year of transplant<2000 (RR 1.42). Predictive factors for RI were diagnosis of ALL (RR 2.39) and advanced disease (RR 1.96). In conclusion, outcomes of allogeneic transplantation from haploidentical family donors in adults with high risk acute leukaemia are promising and should be considered in the algorithm treatment for patients with an indication of allogeneic SCT lacking an HLA identical donor. Status of the disease, age, type of leukemia and conditioning are some factors associated with outcomes after Haplo-SCT.
Distinct Functions of Erythropoietin and Stem Cell Factor Are Linked to Activation of p70S6/mTOR Kinase Signaling Pathway in Primary Erythroid Progenitors.
Authors: Wickrema Amittha , Shahab Uddin , Ah-Kang Jeong , Zhou Ying , van Besien Koen , Ulaszek Jodie 
Published: October 2019

Abstract
Erythropoietin (Epo) and stem cell factor (SCF) guide erythroid cell maturation by exerting their effects at various stages of differentiation. Distinct and overlapping functions of these two growth factors have been well characterized. However, signaling pathways responsible for the antiapoptotic function of Epo and the proliferative function of SCF has not been fully characterized. Especially activation of common upstream signaling elements PI3-kinase, Akt kinase and phosphorylation/inactivation of forkhead transcription factors by both Epo and SCF bring about distinct functional outcomes have not been understood. In the present study we examined the activation of p70S6/mTOR pathway by Epo and SCF in CD34-derived primary erythroid progenitors. Our results provide evidence for activation of p70S6 kinase and mTOR by SCF but not by Epo or IGF-1 (insulin-like growth factor-1). We also show that only SCF phosphorylates protein translational regulatory proteins, 4E-BP1 and S6 ribosomal protein suggesting its involvement in promoting protein translation. Furthermore, we demonstrate that inhibition of mTOR by rapamycin results in reduction in erythroid cell proliferation and colony-formation under steady state culture conditions demonstrating the involvement of downstream signaling elements in the PI3/Akt kinase pathway in cell proliferation apart from its antiapoptotic signal. The reduction of both BFU-E and CFU-GM colony formation indicated that rapamycin also affects early hematopoietic cells. Examination of a parallel pathway involving signaling element Mnk1 showed that both Mnk1 and its downstream target eIF4E are not phosphorylated in response to SCF or Epo. However, these protein were constitutively phosphorylated in primary erythroid progenitors. Interestingly, we also found that during the proliferative phase of erythroid differentiation mTOR is mostly detected in the cytoplasmic fraction of the cells whereas during terminal phase of differentiation mTOR is detected in the nuclear fraction. These results suggest that mTOR may have additional functions associated with chromatin remodeling in erythroid progenitors, which occur prior to enucleation. Taken together, our data provide a mechanism for how distinct functions of Epo and SCF are accomplished through selective use of a common signaling pathway explaining in part how functional diversity is acheived.
Factor XI Deficient Mice Have Reduced Platelet Accumulation and Fibrin Deposition after Laser Injury.
Authors: Regan Baird T. , Gailani David , Furie Bruce , Furie Barbara C. 
Published: October 2019

Abstract
Tissue factor exposure at sites of vascular injury results in the generation of factor Xa and thrombin. A current model of blood coagulation suggests that the amount of thrombin generated through this pathway is limited by the inhibition of the factor VIIa-tissue factor complex by tissue factor pathway inhibitor in the presence of factor Xa. The initial thrombin activates a number of hemostatic proteins including factor XI. Factor XIa then activates factor IX leading to generation of the tenase complex to maintain the thrombin flux. While in vitro studies support this hypothesis the importance of factor XI for thrombus formation in vivo remains unclear. We have examined thrombus formation upon laser injury to the arterioles (30–50 μm diameter) of the cremaster muscle in living mice lacking factor XI using digital multi-channel fluorescence intravital microscopy. Platelets were labeled with Alexa 488 conjugated murine CD41 Fab fragments by systemic infusion of the antibody. Maximum platelet accumulation in factor XI null mice (median of 35 thrombi in 4 mice) is only 25% of that of wild type mice (median of 40 thrombi in 4 mice) after injury (p<0.03). The time course of platelet accumulation is similar between both genotypes. Maximum platelet accumulation occurs in approximately 90 seconds (p<0.2). Fibrin deposition was observed simultaneously using an Alexa 660 conjugated anti-fibrin antibody that does not recognize fibrinogen. Maximum fibrin deposition in factor XI null mice is 50% that of wild type mice (p<0.001) and the rate of fibrin generation is slower in factor XI null mice. However, the time to achieve half maximal fibrin deposition is approximately the same in factor XI null mice (77 sec) compared to wild type mice (63.5 sec, p<0.09). These data suggest that the primary difference in response to laser induced injury between the factor XI null mice and wild type mice is the level of thrombin generated and supports the hypothesis that factor XI participates in maintaining thrombin flux after inhibition of the factor VII-tissue factor. The model above postulates a single source of tissue factor, the vessel wall, and further, that the tissue factor-factor VIIa complex formed from the exposed tissue factor is rapidly inactivated by tissue factor pathway inhibitor after the appearance of the initial factor Xa formed. In addition it has been suggested that a rapidly growing thrombus blocks access to vascular wall tissue factor. However we have recently observed that there is a P-selectin and P-selectin glycoprotein ligand 1 dependent pathway of blood coagulation that recruits blood borne tissue factor into a growing thrombus at sites of laser-induced vessel injury. Both vessel wall and blood borne tissue factor are required for normal thrombus formation. Our data suggest that although tissue factor is continuously recruited to the growing thrombus, factor XIa plays a significant role in thrombin generation.
Thromboembolism in Hospitalized Neutropenic Cancer Patients.
Authors: Khorana Alok A. , Francis Charles W. , Culakova Eva , Fisher Richard I. , Kuderer Nicole , Lyman Gary H. 
Published: October 2019

Abstract
Background: Cancer is associated with thrombosis, but the frequency of thromboembolism in hospitalized cancer patients receiving contemporary chemotherapy regimens is not known. We investigated the frequency of arterial and venous thromboembolism in hospitalized cancer patients receiving active therapy (as identified by the presence of neutropenia) and characterized its association with in-hospital mortality.
Methods: We conducted a retrospective cohort study using the discharge database of the University HealthSystem Consortium. This included 66,106 adult neutropenic cancer patients with 88,074 hospitalizations between 1995 and 2002 at 115 academic medical centers. Patients were identified using ICD-9-CM codes that contained at least one diagnosis of malignant disease and agranulocytosis. Patients with thromboembolism were identified using codes for venous thrombosis, pulmonary embolism, arterial embolism, acute cerebrovascular disease, and acute coronary arterial disease. The association of VTE with clinical variables was studied in univariate analysis and in a multivariate logistic regression model. The chi-square test was used to compare categorical variables, and Cochran-Armitage test to determine trend.
Results: Thromboembolism was reported in 5,272 patients (8%), with 5.4% patients developing venous and 1.5% arterial thromboembolism during the first hospitalization. There was a significant association between the occurrence of venous and arterial thromboembolism (OR 1.73, 95%CI, 1.38–2.16). Venous thromboembolism was more frequent in patients with metastatic disease (OR, 1.23, 95% CI 1.13–1.34), but arterial thromboembolism was not (OR, 0.59, 95% CI, 0.51–0.69). In-hospital mortality was significantly greater in patients with venous (OR 2.01, 95% CI 1.83– 2.22) or arterial thromboembolism (OR 5.04, 95% CI, 4.38–5.79), even in patients without metastatic disease. Patients with lymphoma or leukemia accounted for one-third of venous events and one-half of arterial events. Clinical variables most frequently associated with thromboembolism in a multivariate logistic regression analysis were age ≥ 65 years, primary sites of cancer including lung, gastrointestinal, gynecologic and brain, length of stay ≥ 10 days, and comorbidities including infection, pulmonary and renal disease, and obesity. From 1995 to 2002, there was a 36% increase in venous and a 124 % increase in arterial events (P for trend <0.0001) (see Figure).
Conclusions: The incidence of thromboembolism is high across all cancer subgroups including patients with hematologic malignancies and with non-metastatic disease, commonly perceived to be at lower risk for thromboembolism. Of particular concern is the increasing frequency of venous and arterial thromboembolism. Prospective studies are necessary to characterize the risks and benefits of thromboprophylaxis in this patient population.
Figure Figure
Unreliability of Point of Care Devices for INR Monitoring of Oral Anticoagulant Therapy. A Re-Evaluation.
Authors: Sands Caryn O. , Padilla Vilma , Naraine Khrishan , Rand Jacob , Fox Amy S. 
Published: October 2019

Abstract
Oral anticoagulant treatment with vitamin K antagonists has been encumbered by the need for interval monitoring of INRs to adjust dosage. Point of Care (POC) testing of capillary blood has come into widespread use because of the advantages of rapid analysis and dose adjustment. To assess the reliability of this procedure, we compared INR results from 2 POC devices from different manufacturers - POC1 and POC2 - and compared these results to standard assays on venous samples with a BCS automated analyzer.
78 patients on warfarin for at least 3 months were studied. Results of 56 patients with POC2 and 76 patients with POC1 were compared to the BCS. Capillary blood samples were taken within 30 minutes of the venous draw. The therapeutic INR range was considered to be 2.0–3.5.
The bias plots for the 2 POC methods compared to the reference INR are shown in the 2 Figs, below. Within the therapeutic range, 71% and 85% of the results correlated with BCS for POC1 and the POC2, respectively. Both instruments showed the greatest variation from the reference measurement at INR values greater than 2.5 Both POC methods demonstrated clinically relevant overestimates of INR(see table).
Figure Figure Figure Figure
Agreement % of Reference INR Values to POC INR
Reference INR* POC1-subtherapeutic POC1-therapeutic POC1-supratherapeutic POC2-subtherapeutic POC2-therapeutic * INR = 2.0–3.5 BCS-subtherapeutic 77% 23% - 63% 37% BCS-therapeutic 4% 71% 25% 5% 85% BCS-supratherapeutic - - 100% - 33%
Conclusion: This study raises a significant question rearding the accuracy of POC methods for INR determinations. Despite ease of use and immediacy of results, the lack of correlation, even under study conditions, and the potentials for under-and overdosing makes relying on these devices problematic.
Development and Pilot testing of a Disease-Specific Quality of Life Questionnaire for Adult Patients with Haemophilia (Haem-A-QoL).
Authors: Mackensen Sylvia v. , Gringeri Alessandro ,   Haem-A-QoL Study Group
Published: October 2019

Abstract
Background: Haemophilia and its treatment influence the every-day-life of patients and impact on their quality of life. For the adequate assessment of quality of life validated instruments are necessary. While haemophilia-specific questionnaires for children are existing (v. Mackensen et al., 2004; Young et al., 2004), up to now no validated instrument for adults is available. Currently some developmental works are on-going in order to develop such an instrument as well for adults. In a multi-centre validation study a health-related quality of life questionnaire for adults with haemophilia was developed and pilot tested in Italy.
Aim: This study was designed to develop and validate a haemophilia-specific quality of life measurement for adults (Haem-A-QoL) in Italy.
Methods: The study consisted of three phases: a) a qualitative study including focus groups (with patients and physicians), item formulation and expert ratings of a catalogue of items by patients and physicians, b) a psychometric study including cognitive debriefing, and feasibility testing and c) data analysis. The qualitative study has been performed by the University of Hamburg in cooperation with the University of Milan.
Results: Focus groups with semi-structured interviews were performed in 32 patients from 6 Italian haemophilia centres (Milan, Perugia, Genova, Bari, Castelfranco, Parma). 14 physicians and 8 nurses were asked the same questions. Patients and physicians/nurses consider similar dimensions important for quality of life. But the order of importance is different for patients (physical health, social interaction, dependence, future, work) and physicians/nurses (dependence, work, social interaction, treatment, physical health). Based on the focus group results a draft version of the questionnaire was formulated and given to patients and physicians in order to evaluate the items concerning importance for haemophilia and comprehensibility. The draft version consisted of 159 items. After expert evaluation the questionnaire was revised: several items could be eliminated and some were reworded. The revised version of the Haem-A-QoL consisting of 50 items and was psychometrically tested in 10 Italian centres. The pilot testing showed excellent psychometric characteristics in terms of reliability and validity (convergent, discriminant).
Conclusions: The development of a disease-specific quality of life instrument requires multiple steps and the involvement of different experts (patients, physicians, nurses) in order to have a standardised and valid questionnaire. The Haem-A-QoL is well-accepted by adult haemophiliacs and proved to be a valid and reliable disease-specific self-report measurement for the assessment of quality of life in haemophiliacs. In a next step the Haem-A-QoL will be applied in clinical trials to evaluate patient perceptions of different treatment regimens in haemophilia.
Targeted Pre-Emptive Anti-Aspergillus Therapy in Neutropenic Patients Not Receiving Empirical Antifungal Therapy.
Authors: Maertens Johan A. , Theunissen Koen , Verhoef Gregor , Verschaekelen Johnny , Lagrou Katrien , Verbeken Eric , Verhaegen Jan , Meersseman Wouter , Wilmer Alexander , Boogaerts Marc , Van Eldere Johan 
Published: October 2019

Abstract
Background. For several decades, empirical antifungal therapy has been the standard of care for the early treatment of invasive aspergillosis (IA) in neutropenic cancer patients. However, this approach results in the undue exposure to potentially toxic drugs, may select for resistant strains, and jeopardizes the hospital budget. We conducted a prospective study to evaluate the feasibility and safety of a targeted pre-emptive approach (while avoiding empirical therapy), based on the incorporation of sensitive, non-invasive diagnostic tests.
Methods. A total of 136 treatment episodes at high risk for IA (41 % ≥40 years of age; 26 % relapsed leukemia; 30 % high dose cytarabine; mean duration of neutropenia: 21.5 days; mean duration of broad-spectrum antibiotics: 15.9 days) were screened daily for circulating galactomannan by the Platelia (Bio-Rad) enzyme immunoassay (EIA) while receiving fluconazole prophylaxis. An index of ≥0.5 was considered positive if confirmed by the subsequent sample. In addition, well-defined clinical, radiological, and microbiological criteria triggered a diagnostics work-up for invasive fungal infection, including thoracic computed tomography scanning and bronchoscopy with bronchoalveolar lavage. Antifungal therapy (AmBisome 5 mg/kg/day) was withheld unless the patient became EIA-positive or had a positive culture or microscopy for molds with supportive radiological findings.
Results A total of 4170 serum samples (mean 30.6/episode) was analyzed. The combined EIA-CT-scan approach identified 19 episodes (14 percent) of IA. Less than one quarter of the episode that qualified for empirical therapy (unexplained persisting or relapsing fever) received antifungal therapy (6.6 percent versus 30 percent). Conversely, early antifungal therapy was started in 10 episodes (7.3 percent) not otherwise suspected for IA due to treatment with corticosteroids or due to the presence of confounding co-factors/co-infections. Undetected cases of IA were not found at autopsy. Unexpectedly, autopsy identified one patient with disseminated zymogycosis. At 12 weeks, a 77 percent survival rate was noted in case patients with controlled underlying hematological disease (versus 30 percent for patients with refractory underlying disease)
Conclusions. Replacing empirical therapy by a targeted, pre-emptive therapy offered effective antifungal control and spared patients from exposure to potentially toxic and expensive drugs without negative impact on mortality. This strategy should further be explored in a multicenter, randomized setting.