bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome and Early Prognostic Indicators in Patients with Hematological Disorders Admitted to the Intensive Care Unit for a Life-Threatening Complication.
Authors: Cherif Honar , Hansen Jan , Kalin Mats , Prof Magnus Bjorkholm 
Published: April 2020

Abstract
Background: Appropriately aggressive treatment of haematological malignancies can be complicated by a variety of life threatening events. Despite high hospital mortality rates for such patients admitted to intensive care units (ICU) it is now generally considered to be appropriate to offer intensive care to selected cases, provided there is a reasonable prospect of cure or at least worthwhile palliation.
Aims and Methods: We conducted a retrospective observational study to assess outcome and prognostic indicators in consecutive patients with hematological diseases admitted to the ICU during a 6-year-period.
Results: From 1996 through 2001, a total of 95 patients with hematological diseases and a median age of 57 years (range 16–86) were admitted to the ICU. The median duration of ICU stay was 1 day (mean 4.2 days: range 1–67 days). The Mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 20 (± 9). The large majority of patients underwent active treatment of a hematological malignancy (90%) with acute leukaemia (27%), non-Hodgkin lymphoma (24%) and multiple myeloma (10%) dominating. Respiratory failure (46%), sepsis (24%), cardiovascular complications (9%) and bleeding disorders (7%) were the major reasons for ICU admission. A total of 49 patients (51%) had a microbiologically verified infection and 21 (22%) had bacteremia. Crude ICU, 4-week and 6-month mortality rates were 28%, 45%, and 57%, respectively. An APACHE II score &gt; 30 predicted a high short-term mortality rate (p= 0.0001). However, age &gt; 65 years, respiratory failure, bacteremia, and a diagnosis of acute leukemia were not significantly associated with a poor short-term survival (p&gt; 0.05). A total of 30 patients (31%) were alive after a minimum follow up of 3.5 years.
Conclusion: The lower mortality rate as compared with most other series is probably explained by a more liberal attitude towards ICU admission. Not withstanding this, for a substantial proportion of critically ill hematological patients a short time care at an ICU is life saving. Patients with life threatening complications of haematological disease should be offered intensive care unless or until it is clear that there is no prospect of recovery from the acute illness or that the underlying malignancy cannot be controlled.
CLL/SLL Is More Common Than Registry Incidence Suggests: A Population-Based Study in Manitoba, Canada.
Authors: Seftel Matthew D. , Hewitt Donna , Zhang Hui , Turner Donna , Gibson Spencer , Morales Carmen , Johnston James B. 
Published: April 2020

Abstract
Background: The exact incidence of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) is unknown. In the appropriate clinical setting, peripheral blood immunophenotyping is often sufficient for diagnosis. Cancer registries that rely only on histological or cytological reporting may inaccurately estimate the incidence of CLL/SLL. The province of Manitoba, with a population of 1.2 million people, has a centralized flow cytometry service as well as a provincial cancer registry. We thus had the opportunity to use these large databases to describe the demographic and clinical patterns of CLL/SLL. This has enabled us to test the hypothesis that registry data underestimates the incidence of this disease.
Methods: All patients diagnosed with CLL/SLL between January 1, 1998 and December 31, 2003 were obtained from the Manitoba cancer registry and the central flow cytometry database. Additional clinical characteristics were obtained from a chart review.
Results: 491 patients were diagnosed by flow cytometry. In contrast, cancer registry data reported 345 patients with CLL/SLL, 131 (38%) of which were diagnosed in tertiary care centres. Thus, 146 (30%) patients were not known to the provincial cancer registry. Median age of pts was 71 years (range, 24–97). Based on 2001 Canadian census data, the crude incidence of CLL/SLL in Manitoba is estimated to be 7 per 100 000 persons. Other demographic and clinical data of this population-based study will be presented.
Conclusion: By incorporating diagnostic immunophenotyping, the incidence of CLL/SLL appears to be higher than that reported by a large Canadian cancer registry. This observation may apply to other local and national jurisdictions, and should be studied further.
Age Significantly Influences Presentation and Patterns of Care in Patients with Newly Diagnosed Diffuse Large Cell Lymphoma (DLCL): Collective Data from 5 Centers Participating in the National Comprehensive Center Network (NCCN) NHL Outcomes Project.
Authors: Rodriguez Maria Alma , Czuczman Myron S. , Friedberg Jonathan W. , Kho Michelle E. , LaCasce Ann S. , Millenson Michael , Auayporn Nademanee , Niland Joyce , Veer Anna Ter , Zelenetz Andrew D. , Weeks Jane C. 
Published: April 2020

Abstract
Background: Older patients with DLCL are underrepresented in clinical trials, and little is known about the impact of age on therapeutic decisions outside the clinical trial setting. Treatment for older individuals can be influenced by comorbidities, possibly limiting the use of proven aggressive therapies. We investigated the effects of age on patterns of presentation and treatment for patients with DLCL.
Methods: Data from the 5 centers participating in the NCCN NHL Outcomes Project were used for analysis. Patients with newly diagnosed DLCL, receiving some or all of their care at the NCCN institutions, with first presention between 7/01/2000 to 6/30/2004 were included. Independent variables evaluated were stage, International Prognostic Index (IPI), Charlson comorbidity score, NCCN center, and age (≤ 60 and &gt;60). Components of IPI were evaluated as separate independent variables. Fisher’s exact tests compared baseline characteristics between age groups. Univariate and multivariate logistic regression models were developed to identify factors associated with the receipt of anthracycline-based first-line therapy.
Results: Of 417 patients presenting with newly diagnosed DLCL, 376 were eligible for analysis. Older patients (&gt;60 years) accounted for 38% (142/376) of our cohort. The median age was 55.6 years; among older patients, over half were over 70. Older patients were significantly more likely to have HI/H IPI scores (52% vs. 27%, p=0.0001) and more than 2 major comorbidities (29% vs. 8%, p=0.0001). Overall, 18% (66/376) participated in first-line clinical trials, with no difference in participation by age (p=0.49). Among the 310 patients treated off protocol, 93% (289) received an anthracycline-containing first-line regimen. Older patients were less likely to receive anthracyclines [87% (105/120) vs. 97% (184/190)]. Among patients receiving anthracyclines, older patients were more likely to receive growth factor support [78% (82/105) vs.54% (100/184)]. In multivariable logistic regression adjusting for stage, comorbidity, and center, age was the only factor statistically significantly associated with treatment choice, with patients over 60 less likely to receive an anthracycline-based first-line regimen (OR=0.29; 95% CI=0.11 to 0.80 p=0.02).
Conclusions: In a large cohort of patients with newly diagnosed DLCL, we found that older patients (&gt;60 years) with DLCL had both higher risk disease, and more comorbidity at diagnosis. In our centers, there was no difference in clinical trail participation between older and younger patients; however, older patients were less likely to receive anthracyclines.
Autoantibodies Against the Fibrinolytic Receptor, Annexin 2, in Antiphospholipid Syndrome.
Authors: Cesarman Gabriela , Ríos-Luna Nina P. , Deora Arunkumar B. , del Carmen Cravioto Maria , Alarcón-Segovia Donato , Sánchez-Guerrero Jorge , Hajjar Katherine A. 
Published: April 2020

Abstract
The association of thrombosis, obstetric morbidity, and hemocytopenias with antiphospholipid antibodies is termed antiphospholipid syndrome. Annexin 2 is a profibrinolytic endothelial cell surface receptor that binds plasminogen, its tissue activator (tPA), and beta-2-glycoprotein-I, the main antigen for antiphospholipid antibodies. Here we evaluate annexin 2 as a target antigen in antiphospholipid syndrome. Serum samples from 434 individuals (206 patients with systemic lupus erythematosus without thrombosis, 62 with antiphospholipid syndrome, 21 with non-autoimmune thrombosis, and 145 healthy individuals) were analyzed by ELISA and immunoblotting for antiphospholipid and annexin 2 antibodies. IgG was purified and the effect of anti-annexin 2 antibodies on human umbilical vein endothelial cell activation and cell surface plasmin generation were evaluated. Anti-annexin 2 antibodies (titer &gt;3SD) were significantly more prevalent in patients with antiphospholipid syndrome (22.6%, venous 17.5%, arterial 34.3% and mixed thrombosis 40.4%), than in healthy individuals (2.1%, p&lt;0.001), patients with non-autoimmune thrombosis (0%, p=0.017) or patients with lupus without thrombosis (6.3%, p&lt;0.001). Anti-annexin 2 antibodies enhanced the expression of tissue factor, a procoagulant protein, on endothelial cells (6.4 fold ± 0.13 SE), and blocked the fibrinolytic cofactor activity of purified placental annexin 2 in a tissue plasminogen activator-dependent plasmin generation assay (19 – 71%), independently of beta-2-glycoprotein-I. Similarly, cell surface plasmin generation on human umbilical vein endothelial cells was inhibited by 34–83%. We conclude that antibodies against the fibrinolytic receptor annexin 2 are significantly associated with thrombosis in antiphospholipid syndrome, and that anti-annexin 2 antibodies activate endothelial cells and inhibit endothelial cell surface-localized plasmin generation. We propose that these mechanisms contribute to the prothrombotic tendency in antiphospholipid syndrome.
Ss Polymorphisms Carried on GPB in Brazilian Malaria Infected and Non-Infected Individuals.
Authors: Castilho Lilian , Lustigman Sara , Reid Marion , Cavasini Carlos E. , Rossit Andrea , Couto Alvaro , Costa Fernando F. , Machado Ricardo D. 
Published: April 2020

Abstract
Background: The present study was carried out to compare the Ss blood group polymorphisms carried on GPB in patients infected by malaria (n=51–100) with blood donors (n=100–170) living under the same conditions in a malaria endemic region of the Brazilian Amazon (Macapá, Belém, Porto Velho and Rio Branco). The blood donors had no clinical signs for malaria, their thick blood film exam was negative and they reported during the interview that they had no prior episodes of malaria.
Methods: Blood donors and individuals having only P. falciparum infected were identified and their blood was used for Ss phenotyping in gel cards (DiaMed-AG) and to prepare DNA for Ss genotyping and associations studies. The Ss polymorphisms were genotyped by allele-specific (AS)-PCR.
Results: Comparison between the frequencies of the Ss phenotypes/genotypes in the two studied groups in each endemic area showed a significant correlation between the frequency of individual carrying the S+s+ or S+s- phenotypes/genotypes and incidence of malaria infection in three regions of the study; Rio Branco, Porto Velho and Belem. The presence of the S antigen was significantly more frequent in malaria patients when compared with the blood donors in three regions of the study; Rio Branco (60.8 vs. 38%), Porto Velho (53.1 vs. 38%) and Belem (62 vs. 50%). As a confirmation, we also found that the S-s+ phenotype in the three regions was contributing to resistance to infection with malaria, as it was significantly more frequent in the donor population than in infected individuals. Importantly, there are approximately 1.5 times more copies of GPB in S+s- than in S-s+ RBCs. S+s+ RBCs have an intermediate amount of GPB. When we combined the results from the four regions and analyzed the 64 P. falciparum (Pf) positive individuals vs. the total 63 blood donors, 46 P. falciparum positive individuals (71.8%) carried the S+ phenotype on the GPB whereas in normal donor population only 30 individuals (47.6%) carried the S antigen.. In this analysis, the presence of the S antigen was significantly more frequent in the P. falciparum patients when compared with the blood donors (P = 0.006). Conversely, the S-s+ phenotype in the four regions was contributing to resistance to P. falciparum infection, as it was significantly more frequent in the donor population (52.3%) than in infected individuals (28.1%).
Conclusion: These results support the hypothesis that the expression of the S antigen on GPB is associated not only with incidence of malaria infection, but more importantly, with incidence of P. falciparum infection. These preliminary results open up the opportunity to study the utilization of the GPB invasion pathway, in particular via a domain that contains the S antigen, by the P. falciparum field isolates of Brazil.
Marked Improvement in Detecting the Number of Involved Nodal Areas in Lymphoma, Using 18 F- FDG - PET and CT Scan.
Authors: Chalapud Juan , Sobrevilla-Calvo Pedro , Rivas-Vera Silvia , Altamirano-Levy Javier 
Published: April 2020

Abstract
Positron emission tomography (PET) imaging with 18-fluoro-2-deoxiglucose (FDG) is used increasingly for the initial evaluation and staging of patients with Hodgkin’s lymphoma (HL) and non- Hodgkin’s lymphoma (NHL). However, the degree of concordance of PET and TAC scanning for each nodal and extra nodal site are not well defined. The number of nodal areas involved is a new prognostic factor in follicular lymphomas as was demonstrated in the Follicular Lymphoma (FL) International prognostic index (FLIPI), and their use may be useful for the LNH and HL. In this study, we examined the performance of CT versus FDG-PET scanning, comparing each one of the nodal and extra nodal areas, as it is described in the FLIPI, in a retrospective cohort of lymphoma patients (pts) with HL and NHL. We reviewed the charts of 56 patients with diagnosis of HL and NHL in the initial and relapse staging, in a single tertiary care center. All patients had FDG-PET imaging study, clinical examination and CT scans. The Ann Arbor stage, each nodal site (cervical, mediastinal, axillary, mesenteric, para aortic, inguinal), and extra nodal sites were evaluated on the basis of FDG-PET scanning and were compared with the findings derived from CT. Bone marrow biopsy results were excluded from this initial analysis. The histopathological diagnoses included diffuse large B-cell Lymphomas in 20/56 pts (36%), HL 15/56 pts (27%), anaplastic large cell lymphoma 8/56 pts (14%), FL 5/56 pts (9%), peripheral T-cell Lymphoma 4/56 (7%) and others 7%. Among the 56 pts, 22 (39%) had discordant results between FDG-PET scanning and CT scanning, that lead to a change in stage assignment. Among the discordant cases FDG-PET resulted in upstaging in 18/56 pts (32%), and down staging in 4/56 pts (7%). Forty for pts (79%) had discordant results in the number of nodal areas, among the discordant cases FDG-PET detected more nodal areas in 36/56 pts (64%) and CT in 8/56 pts (14%). The discordant cases were distributed as it is shown in the table.
In conclusion Pet and CT in combination detects more involved nodal areas than each method by itself.
Summary of PET/CT correlation with nodal areas Nodal areas Cervical(n) Axillar (n) Mediastinal(n) Paraaortic(n) Inguinal (n) positive total 40 26 26 24 17 Only Positive FDG-PET 16 12 13 7 11 Only Positive CT 7 3 2 2 1 Positive FGD-PET + CT 17 11 11 15 5
Enhancing Neutrophil Differentiation - A Novel Role for the Death-Associated Protein Kinase 2 (DAPK2).
Authors: Rizzi Mattia , Britschgi Christian , Tschan Mario P. , Grob Tobias J. , Huegli Barbara , Leupin Nicolas , Mueller Beatrice U. , Ziemiecki Andrew , Torbett Bruce E. , Fey Martin F. , Tobler Andreas 
Published: April 2020

Abstract
DAPK2 is a 42-kDa Ca2+/Calmodulin-regulated serine/threonine kinase involved in apoptosis. In gene expression profiles derived from in vitro differentiated myeloid leukemic NB4 cells treated with all-trans retinoid acid (ATRA), we found that DAPK2 was decisively induced during differentiation towards neutrophils. DAPK1, a close relative of DAPK2, is inactivated in a number of hematopoietic malignancies (AML, lymphoma, myeloma), and it may play a role during normal and leukemic myeloid cell differentiation. We therefore investigated DAPK2 for its possible role in both normal and leukemic myelopoiesis. Real time quantitative RT-PCR (RQ-PCR) and Western blot analysis of DAPK2 gene expression in primary myeloid cells revealed significantly higher DAPK2 expression in granulocytes (G; n=9) compared with monocytes/macrophages (M; n=8) and CD34+ progenitor cells (CD34+; n=6) (Δ, p&lt; 0.001; figure, left panel). Moreover, significantly increased DAPK2 mRNA levels were also seen when cord blood CD34+ progenitor cells were induced to differentiate towards neutrophils with human recombinant G-CSF (hrG-CSF). In addition, ATRA-induced neutrophil differentiation of two leukemic cell lines, NB4 and U937, showed significantly higher DAPK2 mRNA expression paralleled by DAPK2 protein induction. However, during differentiation of CD34+ cells (with hrM-CSF) and U937 cells (with PMA) towards monocytes/macrophages, DAPK2 mRNA levels remained low. DAPK2 expression in primary leukemic cells revealed significantly lower DAPK2 expression levels in AML blasts (AML; n=100) than in samples from chronic myeloid leukemia patients in chronic phase (CML-CP; n=9) (ΔΔ, p&lt; 0.001; figure, right panel).
Figure Figure
Stable lentiviral-mediated expression of wild-type DAPK2 enhanced ATRA-induced granulocytic differentiation of NB4 cells as shown by morphology and by increased CD11b expression. Furthermore, upregulation of mRNA levels of key regulator genes for terminal differentiation, such as C/EBPe, the G-CSF receptor and the secondary granule protein lactoferrin, was also enhanced. Expression of a kinase-inactive DAPK2 mutant did not show these effects, a finding consistent with a role of DAPK2 in granulopoiesis.
Conclusion: we demonstrate for the first time, that DAPK2 expression levels correlate with the degree of granulocytic differentiation, and that DAPK2 upregulation is restricted to granulopoiesis. Furthermore lentiviral-mediated DAPK2 expression enhances granulocytic differentiation. The finding that DAPK2 expression is low in AML and high in CML-CP patients suggests that suppressed DAPK2 expression may contribute to the differentiation block in AML.
CD8+/TCR− Graft Facilitating Cells Enhance HSC Engraftment and Survival Via TNF-α Mediated Prevention of Apoptosis.
Authors: Ildstad Suzanne T. , Rezzoug Francine , Huang Yiming , Wysoczynski Marcin , Schanie Carrie L. , Ratajczak Mariusz Z. , Fugier-Vivier Isabelle J. 
Published: April 2020

Abstract
The use of accessory cells to enhance hematopoietic stem cell (HSC) engraftment could have a significant therapeutic impact, especially when stem cell numbers are limited. The bone marrow (BM) microenvironment is involved in regulation of HSC, allowing production of mature blood cells while maintaining HSC self renewal. To date, the precise identity of specific cells in the microenvironment that exert this regulatory effect on HSC has not been defined. We recently reported that CD8+/TCR− facilitating cells (FC), a subpopulation of BM cells containing predominantly B220+/CD11c+/CD11b− tolerogenic precursor-plasmacytoid dendritic cells, enhance HSC engraftment in allogeneic recipients. Additionally, FC significantly enhance engraftment of limiting numbers of HSC in syngeneic recipients. In the present studies, we investigated the mechanism of FC-mediated enhancement of HSC engraftment. We show for the first time that FC significantly increase HSC survival in vitro and exert an anti-apoptotic effect on HSC via TNF-α. Co-culture of FC with HSC induces production of physiologically relevant low levels of TNF-α by FC. FC from TNF-α−/− mice are impaired in function in vitro and in facilitating HSC engraftment in vivo. Furthermore, neutralization of TNF-α on FC using anti-TNF antibody results in loss of FC function in vitro, confirming a major role for TNF-α in FC function. Notably, co-culture of FC with HSC prevents HSC apoptosis and is associated with significant upregulation of the anti-apoptotic I-κB family member Bcl-3 in HSC. Blocking of TNF-α on FC abrogates the anti-apoptotic effect of FC on HSC and prevents upregulation of Bc1-3 in HSC. Taken together, these findings demonstrate that TNF-α-induced in FC affects highly primitive HSC and identify Bcl-3 as a possible pathway for TNF-α in regulating HSC survival.
Reaction of Fibrinogen with Homocysteine Thiolactone Mimics the Dysfibrinogenemia Produced by Hyperhomocysteinemia.
Authors: Sauls Derrick L. , Lockhart Evelyn , Hoffman Maureane 
Published: April 2020

Abstract
Elevated plasma homocysteine (HCys) is associated with atherosclerosis and thrombosis. We have previously found that clots from plasma, whole blood and purified fibrinogen from homocysteinemic rabbits are composed of thin, tightly-packed fibers and are resistant to fibrinolysis. HCys thiolactone is a metabolite of Hcys that can react with lysine residues under physiologic conditions. This reaction introduces a new free sulfhydryl group into the protein. The current study was designed to test the hypothesis that HCys thiolactone modifies key lysines in fibrinogen, thereby causing the alterations in fibrin structure and susceptibility to fibrinolysis that characterize the homocysteine-induced dysfibrinogenemia. We examined the effect of incubation of HCys thiolactone with purified human fibrinogen. The control and homocysteine thiolactone treated fibrinogen (HCys-fibrinogen) samples were added to fibrinogen-deficient plasma, which was then clotted by addition of thrombin and calcium in the presence of tissue plasminogen activator (tPA). Clots from HCys-fibrinogen lysed more slowly than control clots and the magnitude of this effect depended on the concentration of HCys thiolactone used. At 300 μM Hcys thiolactone, the fibrinogen formed clots with characteristics similar to fibrinogen from hyperhomocysteinemic rabbits. These clots 1) had thinner fibers than controls; 2) the reduced fiber thickness could be partially corrected by increasing calcium and 3) were more resistant to fibrinolysis than controls. In addition, the HCys-fibrinogen formed disulfide-stabilized high molecular weight forms, which are also found in the plasma of hyperhomocysteinemic rabbits. Mass spectrometric analysis of Hcys-fibrinogen revealed 12 different HCys-modified lysines - primarily in the D- and alpha-C-domains. Some of these are close to sites of tPA and plasminogen binding and/or plasmin cleavage. Two of them are very close to sites of naturally-occurring prothrombotic mutations that introduce a new cysteine into the alpha-C-domain. A new Cys at these sites mediates mixed disulfide formation with albumin in the plasma - a structural modification that is thought to underlie their prothrombotic effects. Similarly, we find that HCys-fibrinogen forms mixed disulfides with human albumin. Our data suggest that homocysteinylation of fibrinogen could lead to abnormal resistance of fibrin clots to lysis and thus might contribute to the increased risk of cardiovascular disease in hyperhomocysteinemia.