bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Utility of Immunophenotyping in Diffuse Large B-Cell and Follicular Lymphomas
Authors: Abdel-ghaffar Hasan A. , Degheidy Heba A. , Shamaa Sameh S. , Abd-El Aziz Sherin M. 
Published: April 2020

Abstract
Patients with Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphomas (FL) exhibit marked variability in survival, the international prognostic index (IPI) predicts the cure with chemotherapy as IPI is a well established predictor of outcome in DLBCL and FL. Biological prognostic markers including expression on of BCL2, BCL6, CD5, CD10, and HLA-DR have been described as IPI independent prognostic factors. The purpose of this study is to high light how these biomarkers might be incorporated into current risk – adjustment models for prognosis. Biological parameters were evaluated by flowcytometric immunophenotyping of 96 patients with DLBCL and FL.
In our study, Superior overall survival (OS) was associated with high expression of HLA-DR in DLBCL either do novo or on top of FL (p &lt; 0.001 for both group), and with low expression of CD 5 and BCL2 in de novo DLBCL (p &lt; 0.001 for both ) independently of the IPI. On the other hand Inferior overall survival was established with high expression of BCL6 in DLBCL. However Inferior progression free survival (PFS) was independently correlated with high expression of BCL2 (p = 0.007 and 0.018 ) and lower expression of HLA-DR ( p=0.003 and 0.03 ) in both de novo DLBCL and on top of follicular, but not in FL and with high expression of CD10 in de novo DLBCL only ( p&lt;0.001 ).
In 96 patients with DLBCL and FL treated with risk adapted therapy, low HLA-DR expression is associated with poor outcome in DLBCL either de novo or on top of follicular but not in a FL group. the time is right to begin to consider how these biomarkers should be incorporated into current prognostic models to move beyond the clinically based IPI.
Effects of Anti-Retroviral Drugs to Expression of Cell Surface Adhesion Molecules and Hypermutation of Immunoglobulin Heavy Chain Variable Gene of HIV-Related Lymphoma
Authors: Sasakawa Atsushi , Maeda Yasuhiro , Hirase Chikara , Kanamaru Akihisa 
Published: April 2020

Abstract
It has been known that non-Hodgkin’s lymphomas (NHL) are a major complication in human immunodeficiency virus (HIV) infection, and a major cause of death in HIV infected patients. Recently, it has been reported that highly active anti-retroviral therapy (HAART) declines the incidence of HIV-related lymphoma. In this study, we tried to make in vitro model of HIV-related lymphoma by Epstein-Barr virus transformation, and to examine the cellular and molecular characteristics of the HIV-related lymphoma cells derived from patients with HIV infection. PBMCs from 10 patients HIV infection and 10 HIV-negative normal individuals were obtained by Ficoll-Paque (Amersham Biosciences Corp. NJ) density gradient centrifugation. Lymphoblastoid cell lines (LCL) were obtained from each patient through transformation with Epstein-Barr virus (B95-8). Cells were cultured with RPMI 1640 medium (GIBCO, Grand Island, NY) supplemented with 10% fetal calf serum (FCS) (JRH Bioscences, Inc. Lenexa, Kansas), antibiotics, and L-glutamine and maintained at 37°C in an atmosphere containing 5% CO2. FACS analysis revealed the cells to be CD3−, CD4−, CD8−, CD5−, CD19+, CD20+, HLA-class I+, -class II+. After the establishment of LCLs, to obtain a highly purified population, CD19+LCLs were sorted on a FACS Vantage SE (Becton Dickinson, San Jose, CA). The purity of each CD19+LCLs population evaluated by FACS analysis was always higher than 98%. After growth advantage of LCLs, growth ability of the LCLs from HIV patients was examined by MTT assay. In results, there is no significant difference of growth ability between LCLs derived from HIV patients and those derived from normal individuals. Furthermore, the expression of cell adhesion molecules (CD11a, CD11b, CD18, CD50, and CD54) of LCLs was observed by FACS. The results showed that the expression of CD18 on LCLs derived from HIV patients was enhanced significantly in compared to those of normal LCLs. This phenomenon seems to be consistent with development of primary central nervous system (CNS) lymphoma. Furthermore, effects of anti-retroviral drugs to the expression of the adhesion molecules are examined. Somatic hypermutation of immunoglobulin heavy chain variable gene (IGHV) has been detected over 90% of HIV-related lymphoma. The effects of HAART to hypermuation of IGHV of LCL derived from HIV patients will be addressed.
Double Hematological Malignancy: An Unusual Presentation in Three Cases
Authors: Haddad Rami Y. , Attri Navneet , Kawar Yaser 
Published: April 2020

Abstract
The occurrence of more than one hematological malignancy in the same patient is an unusual pathologic condition and may pose a difficult challenge during decision to start various chemotherapy regimens. Cases of solid tumors of lung and gastrointestinal tract have been noted secondary to treatment of hematological malignancies but the occurrence of two hematological malignancies concomitantly is a rare presentation. We describe three cases of coexistent hematological malignancies at our institution.
First case describes a 77 yo male with synchronously occurring B cell Non Hodgkin Lymphoma: marginal zone lymphoma (main bone marrow population); Chronic Lymphocytic leukemia (Fluorescent-in–situ hybridization test positive for trisomy 12) and a Monoclonal Beta, elevated IgM, elevated B2. BM evaluation revealed involvement by both processes. The patient has been started on Rituximab recently. The second case is an 85 yo male with findings with peripheral blood flow cytometry consistent with chronic lymphocytic leukemia of B-cell immunophenotype and lymph node biopsy consistent with Follicular Lymphoma. He was found to be BCL2 + on BM and had a normal Karyotype: 46, XY. He was treated with Rituximab ×8 cycles. A follow up PET scan showed partial response. Our third case was an 83 yo man with simultaneous presentation of myelodysplastic syndrome (MDS) and multiple myeloma (MM). This patient had MDS (Refractory anemia with Ring sideroblasts RARS type) and smoldering Multiple myeloma (monoclonal plasma cells 10–15%) bone marrow infiltration which over a course of 3 years transformed into full blown Multiple Myeloma with bone marrow revealing 30–40% plasma cells and osteolytic lesions on skeletal survey. Cytogenetic were normal. He was treated with Lenalidomide (after failure of ESA) and became transfusion in dependent for one year (Hgb rose from baseline of 6–7 to 13 g/dL), after progression to active multiple myeloma he was treated with Thalidomide and Dexamthesone. He achieved a partial response on SPEP. Subsequently he was treated for MDS progression with Azacytidine for 5 cycles with minor hematological benefit (transfusion was less frequently), he recently succumbed to his disease, he was transfusion dependent and became acutely ill after an acute episode of diverticulitis. Patients with MM, MDS have been reported after chemotherapy but few cases documenting the coexistence of MDS and MM at diagnosis have been reported in the literature.
Conclusion: In this report, we describe a three cases of double hematological clonal processes or malignancy, all diagnosed at same time, without preceding hematological disorder or chemotherapy, and all required treatment.
Heparin Cofactor II (HCII) Levels and the Risk of Ischemic Stroke. No Deleterious Role of HCII Deficiency but Potential Protective Role of High Plasma Level
Authors: Toulon Pierre A. , Zuber Mathieu , Adda Raphael , Mas Jean-Louis 
Published: April 2020

Abstract
Background: Heparin cofactor II (HCII) is a thrombin inhibitor which activity is dramatically enhanced by heparin and more specifically by dermatan sulfate, another glycosaminoglycan. Its pathophysiological role remains unknown even if cases of HCII deficiency were reported in patients with a history of venous or arterial thrombosis. Recently, it was suggested that high plasma HCII level could play a protective role against atherosclerosis in elderly individuals and protect from restenosis after femoro-popliteal or coronary artery stenting. The aim of this case-control study was to investigate the significance of plasma HCII level in the development of ischemic stroke.
Methods: 81 cases (44 M and 37 F, mean age of 43 years, range: 22–63) and 80 age-and sex-matched healthy controls of the same ethnic origin. HCII activity was evaluated as antithrombin dermatan sulfate cofactor activity using a chromogenic assay. Test results were expressed in arbitrary unit per mL: 1 U/mL is the activity found in 1 mL of pooled normal human plasma.
Results: Plasma HCII activity was not significantly different in cases and in controls (1.04±0.17 vs. 1.00±0.23). The same applied after stratification in males and in females. The normal range for HCII, previously defined in a large cohort of healthy individuals, was between 0.60 and 1.40 U/mL. The frequency of HCII deficiency was not significantly different in cases and in controls [n=3/81 (3.7%) vs. n=2/80, (2.5%); p=1.00] and the same applied to the frequency of HCII level above 1.40 U/mL [n=0/81 (0%) vs. n=2/80 (2.5%); p=0.25]. Interestingly, HCII activity was found above 1.30 U/mL in 7 controls and in only 1 case (p&lt;0.05), none presenting with any of pathophysiological state usually associated with increased HCII levels such as pregnancy, oral contraceptive, inflammation, infection, or acute phase of illness.
Conclusions: These results suggest that HCII deficiency is not in itself a risk factor for the development of ischemic stroke. Even if the frequency of HCII level above the normal range was not statistically different in cases and in controls, the significance of a higher proportion of controls than cases presenting with a HCII level in the high end of the normal range deserves to be further evaluated in connection with a potential protective role against ischemic stroke.
Activated Akt Is Associated with Hyperglycemia and Platelet Hyperactivity in a Mouse Model of Diabetes
Authors: Lu Lin , Woulfe Donna 
Published: April 2020

Abstract
Platelet hyperactivation has been reported in patients with both Type I and Type II diabetes mellitus and likely contributes to the increased prevalence of thrombotic complications in diabetic patients. However, the mechanisms leading to platelet hyperactivity in diabetes are not fully understood. Our previous studies showed that the Akt signaling pathway positively regulates platelet activity. Here, we evaluate the effect of hyperglycemia on Akt phosphorylation and platelet activation using a Type I diabetic mouse model. Hyperglycemia was induced by intraperitoneal injection of streptozotocin (STZ 50mg/kg for 5 days) in C57BL/6 mice. Blood glucose levels were elevated in 12 mice 4 weeks after STZ injection (mean ± SD: 410 ± 70 mg/ml) compared with 11 mice without STZ injection (212 ± 50 mg/ml). Platelets from hyperglycemic mice showed enhanced agonist-dependent aggregation (max % aggregation: 58% ± 10% in hyperglycemia versus 0% in normoglycemia at 0.6mM AYPGKF, n=3 each), fibrinogen binding (62.2% fibrinogen-bound cells ± 5.4% in hyperglycemic conditions versus 46.1% ± 16.3% in normoglycemia at 2mM AYPGKF) and P-selectin binding (42.1% cells with surface P-selectin ± 3.7% in hyperglycemic platelets, 25.3% ± 5.9% in normoglycemia at 2mM AYPGKF) compared with platelets from mice with normal glucose levels. The blood glucose levels were directly correlated with Alexafluor-fibrinogen binding (r=0.65, p=0.042) when platelets were stimulated with thrombin receptor agonist peptide AYPGKF (1.5mM), and also directly correlated with P-selectin surface exposure (r=0.95, p=0.003) after platelets were stimulated with 1.5mM AYPGKF. To determine whether the Akt pathway is involved in enhanced platelet activation in diabetes, we tested phosphorylation of Akt ser473 by immunoblotting. Akt phosphorylation of this residue was increased (35% ± 4%) in platelets from hyperglycemic mice compared with platelets from nondiabetic mice. In conclusion, platelets from hyperglycemic mice are more sensitive to PAR4 agonist-induced fibrinogen binding and P-selectin exposure compared with nondiabetic platelets. Enhanced activation of Akt in platelets under hyperglycemic conditions may play a role in platelet hyperactivation in diabetes.
Palmitoylation Augments the Association of Tetraspanin CD63 with the αIIbβ3-CD9 Complex and the Actin Cytoskeleton in Thrombin-Activated Platelets
Authors: Israels Sara J. , McMillan-Ward Eileen M. 
Published: April 2020

Abstract
CD63 and CD9 are members of the tetraspanin superfamily of integral membrane proteins that function as organizers of multi-molecular signaling complexes involved in cell morphology, motility and proliferation. In resting platelets, CD63 is located in the membranes of lysosomes and dense granules, and CD9 complexes with the αIIbβ3 integrin on the platelet surface. Following platelet activation and granule exocytosis, CD63 translocates to the plasma membrane, where it co-localizes with the αIIbβ3-CD9 complex and is incorporated in the Triton-insoluble actin cytoskeleton. Tetraspanin complexes cluster dynamically in unique cholesterol-rich membrane microdomains (tetraspanin-enriched microdomains, TEMs) that differ from prototypic lipid rafts. The assembly and maintenance of TEMs depends on the palmitoylation of both tetraspanins and some of their partner proteins. Protein palmitoylation most commonly involves the thioester linkage of palmitate to a cysteine residue and, because the process is reversible, can regulate cellular functions. In cell lines, palmitoylation of tetraspanin juxta-membrane cysteine residues affects subcellular distribution, complex stability, cellular signaling and motility. Recently we demonstrated that tetraspanins and their partner proteins form TEMs in platelets, however the role of palmitoylation in platelet TEMs assembly and maintenance has not been studied. 3[H]-palmitate-labeled, washed human platelets were studied at rest, or following activation with thrombin (0.1U/ml). CD63 and CD9 were isolated by immunoprecipitation, separated by density gradient centrifugation, and 3[H]-palmitate quantitated. Palmitate levels increased in all fractions however the relative inter-fraction distribution did not change, consistent with previous results showing that the distribution of CD63 and CD9 does not change following platelet activation. 2-bromopalmitate (2- BP), which blocked palmitoylation as demonstrated by decreased 3[H]-palmitate-labeling of platelets, inhibited both thrombin-induced platelet aggregation and platelet spreading on immobilized fibrinogen, in a dose and time-dependent manner. 2-BP also inhibited the activation-dependent association of CD63 with CD9 and the incorporation of CD63 into the Triton-insoluble actin cytoskeleton in thrombin-activated platelets. In contrast 2-BP had minimal effect on either the integrity of the α IIb β3-CD9 complex or its agonist-induced association with the cytoskeleton. In summary, inhibition of palmitoylation blocked the activation-dependent association of CD63 with the αIIbβ3-CD9 complex and with the actin cytoskeleton but did not alter the tetraspanin-integrin association present in resting platelets. The effect of 2-BP on platelet spreading on fibrinogen mirrored that previously seen with anti-CD63 MoAbs, and supports the hypothesis that the association of CD63 with αIIbβ3-CD9 modulates outside-in signaling in adherent platelets.
UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis
Authors: Elorza Alvaro A , Hyde Brigham B , Mikkola Hanna , Collins Sheila , Shirihai Orian S 
Published: April 2020

Abstract
UCP2, an inner membrane mitochondrial protein, has been implicated in bioenergetics and Reactive Oxygen Species (ROS) modulation. UCP2 has been previously hypothesized to function as a facilitator of heme synthesis and iron metabolism by reducing ROS production. While UCP2 has been found to be induced by GATA1 during erythroid differentiation its role in erythropoiesis in vivo or in vitro has not been reported thus far. Here we report on the study of UCP2 role in erythropoiesis and the hematologic phenotype of UCP2 deficient mouse. In vivo we found that UCP2 protein peaks at early stages of erythroid maturation when cells are not fully committed in heme synthesis and then becomes undetectable at the reticulocyte stage. Iron incorporation into heme was unaltered in erythroid cells from UCP2 deficient mice. While heme synthesis was not influenced by UCP2 deficiency, mice lacking UCP2 had a delayed recovery from chemically induced hemolytic anemia. Analysis of the erythroid lineage from bone marrow and fetal liver revealed that in the UCP2 deficient mice the R3 (CD71high/Ter119high) population was reduced by 24%. The count of BFU-E and CFU-E colonies, scored in an erythroid colony assay, was unaffected, indicating an equivalent number of early erythroid progenitor cells in both UCP2 deficient and control cells. Ex-vivo differentiation assay revealed that UCP2 deficient c-kit+ progenitor cells expansion was overall reduced by 14% with population analysis determining that the main effect is at the R3 stage. No increased rate of apoptosis was found indicating that expansion rather than cell death is being compromised. Reduced expansion of c-kit+ cells was accompanied by 30% reduction in the phosphorylated form of ERK, a ROS dependent cytosolic regulator of cell proliferation. Analysis of ROS in UCP2 null erythroid progenitors revealed altered distribution of ROS resulting in 14% decrease in cytosolic and 32% increase in mitochondrial ROS. Restoration of the cytosolic oxidative state of erythroid progenitor cells by the pro-oxidant Paraquat reversed the effect of UCP2 deficiency on cell proliferation in in vitro differentiation assays. Together, these results indicate that UCP2 is a regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.
Rational Anemia Diagnostics and Therapy Control of Pediatric Patients Employing the Novel Hemaplot and Thomasplot
Authors: Weimann Andreas , Lun Andreas , Gaedicke Gerhard 
Published: April 2020

Abstract
“Anemia” is one of the most frequent diagnoses during childhood. For the choice of the right therapy an exact diagnosis is a prerequisite. Due to numerous and rather diverse pathophysiological etiologies of anemia and different mechanisms of compensation of the organism, establishing the correct diagnosis might turn out to be rather difficult for the general practioner as well as for the hospital doctor. Within a prospective study the routine blood counts of 100 anemic pediatric patients were measured at ten time points per patient with SYSMEX XE-2100 blood analyzer including the parameters Hb, MCV, MCH, Ret-Hb, delta-Hb and RPI. Plasma samples were checked for transferrin, iron binding capacity, sTfR, Ferritin and CRP levels. The EXPERTviewer was used for transmitting the numerical and graphical data to the clinician. The “Hemaplot” (Ret-Hb versus delta-Hb) as well as the “Thomasplot” (Ret-Hb versus Ferritin-Index) and all regular scatterplots and histograms were conveyed. Preliminary data show that the Thomasplot and Hemaplot help to distinguish hyperregenerative anemias and nutritive or deficiency types. The plots also proved to be helpful in identifiying hyporegenerative as well as congenital and aquired forms of anemia. Thomasplot and Hemaplot might help to better understand pathophysiology of anemias and thus to make rational therapeutic decisions easier and more efficient.
Rituximab Therapy for Treatment of Chronic Warm Autoimmune Hemolytic Anemia
Authors: Sreenivasappa Shylendra B , Telfer Margaret Clare 
Published: April 2020

Abstract
Autoimmune hemolytic anemia (AIHA) is a disorder in which auto antibodies are directed against red blood cells resulting in severe anemia. It is a relatively uncommon disorder with an estimated incidence of 1–3 cases per 100,000 persons per year. These disorders are classified as either warm AIHA or cold AIHA depending on the temperature at which the auto antibodies show maximal binding. First line therapy for patients (pts) with warm AIHA is corticosteroids, 20% achieve complete remission most patients require maintenance treatment. Splenectomy is the usual second line treatment. Cytotoxic and immunosuppressive medications can be tried. Rituximab a monoclonal antibody against CD 20 has also shown efficacy in pt with chronic AIHA.
In this study we retrospectively studied 2 cases of chronic warm AIHA. Case 1 was a female diagnosed with AIHA at the age of 15 years with a history of vasculitis. AIHA had a relapsing and a remitting course. She was treated with steroids, splenectomy, cytotoxic therapy with cyclophosphamide and immunosuppressive therapy with azathioprine with no long-term remission. At 36 yr of age she had a relapse, steroids induced a minimal response, cyclophosphamide induced a partial response. She developed hemorrhagic cystitis hence cyclophosphamide was discontinued. Rituximab was administered at 375mg/m2 weekly for 3 doses with minimal response. After 4 weeks she was given 3 more doses of weekly rituximab with minimal response. 2 weeks after the last Rituximab dose, pt developed pancytopenia, gram-negative sepsis and died.
Case 2 was also a female who was diagnosed with AIHA at the age of 21 years, etiology was considered idiopathic. She had a relapsing remitting course as well. She had been treated with steroids, splenectomy, cytotoxic therapy and immunosuppressive therapy. At 41 years of age she relapsed, this episode was, not responsive to steroids, Rituximab 375mg/m2 was infused weekly for 3 weeks with minimal improvement, after 6 weeks, 3 more doses of Rituximab were infused. She had a gradual improvement of her hemoglobin over 4 months and pt has been in remission since. She has had a sustained response for over 24 months.
There have been a few case series published about the effects of Rituximab in pt with warm AIHA, with an estimated complete response ranging from 40 – 100%. The toxicities of this therapy in this pt population has been not been well documented. We conclude that Rituximab must be used cautiously in pt with AIHA. Prospective Randomized clinical trails are needed to assess the efficacy of Rituximab in pt with warm AIHA.