bluuebunny/crossref_metadata_2025_split huggingface dataset:
A GMCSF/Interleukin-15 Fusokine Leads to the Generation of a Novel Type of CD2/MHCII Immune Regulatory Cell with Potent Immune Suppressive Properties as Demonstrated in the EAE Mouse Model of Multiple Sclerosis.
Authors: Rafei Moutih , Hsieh Jeremy , Li Meng Yang , Zehntner Simone , Forner Kathy , Galipeau Jacques 
Published: October 2019

Abstract
Multiple sclerosis (MS) is an autoimmune disease characterised by the infiltration of autoreactive T-cell causing damages to the central nervous system. So far, interferon-β and glatiramer acetate are the only two immunomodulatory coumpounds that have been approved as non-curative disease managing strategies. Therefore, there is an urgent need for the development of novel efficient therapies that can be both safe and potent in inhibiting MS progression and promote reversal of disease state. We have recently published a report describing a novel synthetic GMCSF and IL15 Fusion Transgene (GIFT15) and have described its paradoxical and potent immune suppressive properties in vivo [Rafei et al., Blood (March 2007)]. Its mechanism of action relies on STAT3 hyperactivation arising from aberrant signalling taking place downstream of the IL15 receptor. We have now further studied the effect of GIFT15 on mouse spleen cells in vitro and here demonstrate that it leads to the conversion of murine T-cells to a novel suppressive regulatory cell type. Indeed, GIFT15-treated splenocytes (hereafter GIFT15 regs) shed their TCR and loose expression of CD3, CD4 and CD8, retain CD2 expression and acquire expression of MHC II. Distinct to classic T-regulatory cells, GIFT15 regs do not express CD25 or FOXP3. GIFT15 regs were able to suppress an in vitro two-way MLR by a contact-dependent mechanism as well as by the contemporaneous production of interleukin (IL)-10. Furthermore, GIFT15 regs were able to block antigen-specific activation of CD4-T-cells in response to autologous macrophage stimulation. As a proof-of-principle in vivo study, GIFT15 regs were injected intravenously in mice with pre-established experimental allergic encephalitis (EAE) and disease score was monitored over time. Interestingly, mice recovered significantly faster than controls following administration GIFT15 regs and a blockade in EAE progression was also noticed over time. In conclusion, our data suggests that GIFT15 can be used as a method to ex vivo generate suppressor cells of a new type which are distinct from classic Tregs or Tr1 cells. We propose that GIFT15 regs derived from autologous lymphocytes may be exploited for the treatment of autoimmune disease such as MS and may also be of use for other autoimmune ailments as well.
Development of Efficent Gene Therapy for the Treatment of Erythrocyte Pyruvate Kinase Deficiency.
Authors: Meza Nestor W. , Alonso Maria Eugenia , Navarro Susana , Guenechea Guillermo , Quintana-Bustamante Oscar , Garcia-Gomez Maria , Bueren Juan A. , Bautista Jose M. , Segovia Jose C. 
Published: October 2019

Abstract
Human erythrocyte R-type pyruvate kinase deficiency (PKD) is an autosomal recessive disorder produced by mutations in the PKLR gene. Haemolytic anaemia is the major symptom of the disease. A severe deficiency in PKD causes ATP depletion in the RBC metabolism, which ultimately leads to haemolysis that may require periodical blood transfusion, splenectomy, and in some cases bone marrow transplantation. These clinical features make this disease a good candidate for gene therapy. With this aim, we have developed different gammaretroviral and lentiviral vectors expressing the human RPK and have characterized the functionality of the erythroid specific expression regulatory sequences of the human RPK gene in a lentiviral backbone. The transduction of mouse hematopoietic stem cells from a mouse strain deficient in the pklr gene [AcB55: pklr269A/269A mice], which mainly resembles the human RPK deficiency, with a retroviral vector expressing the human RPK, followed by the transplantation into irradiated syngenic recipients completely recovered the red cell parameters in peripheral blood, spleen and bone marrow. Also, intracellular values of ATP, plasmatic iron and circulating erythropoietin levels were recovered to normal values. After 100 days of transplantation, treated mice did not show any clinical symptom of the disease. Secondary pklr269A/269A recipients were also transplanted and their hematological symptoms were also reverted, demonstrating the stable therapeutic efficacy of the vector. To specifically express the RPK in the erythroid lineage, a lentiviral vector expressing the EGFP marker gene under the above RPK promoter (LVpRPKEG) was constructed to test its specificity. EGFP expression was detected in erythroid, but not in non-erythroid cell lines, transduced with this vector. Human CD34+ cells were also transduced with the LVpRPKEG vector and transplanted into NOD/SCID mice. Forty days post-transplantation human bone marrow cells were obtained and seeded in semisolid media. Significantly, only human erythroid colonies expressed the EGFP protein, demonstrating the efficacy of the RPK promoter to specifically express proteins in the erythroid lineage. Experiments using a lentiviral vector expressing the human RPK gene under the control of the human RPK promoter are now in progress. Overall, the transfer of lentiviral vectors harbouring the hRPK cDNA driven by its own promoter in PKLR mutated hematopoietic stem cells could represent an efficient therapeutic treatment of severe clinical cases of human erythrocyte PKD.
Cause-Specific Mortality and Second Cancer Incidence after Non-Hodgkin Lymphoma: A Report from the Childhood Cancer Survivor Study.
Authors: Bluhm Elizabeth C. , Ronckers Cecile , Hayashi Robert J. , Neglia Joseph P. , Mertens Ann C. , Meadows Anna T. , Mitby Pauline A. , Stovall Marilyn , Robison Leslie L. , Inskip Peter D. 
Published: October 2019

Abstract
Background: Second primary malignancies and premature death are a concern for patients surviving treatment for childhood lymphomas. Despite in-depth reports on second cancer risk after Hodgkin lymphoma, there is limited published information on clinical, demographic, and treatment risk factors for second malignant neoplasms (SMNs) or deaths after non-Hodgkin lymphoma (NHL).
Methods: We assessed mortality and SMNs among 1,082 five-year survivors of NHL in the Childhood Cancer Survivor Study, a multi-institutional North American retrospective cohort study of pediatric cancer survivors diagnosed between 1970 and 1986 before age 21. We searched the National Death Index for dates and causes of death and inquired about SMNs in periodic questionnaires, with confirmation of all reported SMNs by a study pathologist. We calculated standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) based on United States population rates. We calculated relative risks (RRs) for death and SMNs by demographic, clinical, and treatment characteristics using proportional hazards modeling. Medical physicists determined organ exposure to radiation therapy (RT) based on clinical RT records.
Results: There were 87 deaths among 5-year survivors (SMR=4.2, 95% confidence interval (CI): 1.8, 4.1). Leading causes of death were NHL (n=21), solid tumors (n=17), circulatory diseases (n=12), and leukemia (n=10). There were elevated rates of mortality due to NHL, solid tumor SMNs, leukemia, cardiac disease, and pneumonia. The mortality rate remained elevated beyond 20 years after NHL. Risk factors for death included NHL relapse (RR=8.5), doxorubicin (RR=1.8), bleomycin (RR=4.1), platinum agents (RR=4.0), and cardiac RT exposure (RR=1.8). There were 31 SMNs, including 27 solid tumor SMNs (SIR=3.9, 95%.CI: 2.6, 5.7), specifically SMNs of the breast (n=6, SIR=9.1), thyroid (n=6, SIR=9.4), oral cavity and pharynx (n=3), brain and nervous system (n=3), bone (n=2) and urinary bladder (n=2). Risk factors for solid tumor SMNs were female sex (RR=3.1), mediastinal NHL disease (RR=5.2), and breast RT exposure (RR=4.3). Overall cumulative incidence of solid tumor SMNs from 5 to 20 years after NHL diagnosis was 0.03 (95% CI: 0.02, 0.05).
Conclusions: We identified a four-fold risk of mortality and three-fold risk of SMNs in a large cohort of pediatric NHL survivors relative to the general U.S. population. Survivors of childhood NHL, particularly those treated with chest RT, may be at continued increased risk of early mortality and solid tumor SMNs. Health care providers responsible for this population should remain alert to second cancers and other severe late health outcomes.
Comparison between Intravenous Iron and Oral Iron Preparations for the Treatment of Anemia of Chronic Kidney Disease - A Systematic Review and Meta-Analysis
Authors: Gafter-Gvili Anat , Rozen-Zvi Benaya , Paul Mical , Leibovici Leonard , Uzi Gafter , Shpilberg Ofer 
Published: October 2019

Abstract
Background: There is confounding data regarding the best method of iron supplementation in chronic kidney disease (CKD), without a consistent approach in clinical practice. Objectives: To evaluate the efficacy and safety of intravenous (IV) iron versus oral iron in patients treated for anemia of CKD.
Methods: Systematic review and meta-analysis of randomized controlled trials comparing IV iron preparation with oral iron preparation for the treatment of anemia in patients with CKD (stage III, IV and V). The Cochrane Library, MEDLINE, conference proceedings and references were searched until 2007. Primary outcomes: absolute hemoglobin (Hb) level or change in Hb level from baseline at two months or at end of study; all-cause mortality. Secondary outcomes: need for renal replacement therapy (RRT) in predialysis patient and adverse events. Weighted mean differences (WMD) for outcomes with continuous variables and relative risks (RR) for dichotomous outcomes with 95% confidence intervals (CI) were estimated and pooled.
Results: Our search yielded 11 trials which compared IV iron preparations (iron sucrose, iron gluconate or iron dextran) to oral iron. Compared to oral iron, there was a significant rise in Hb level in the IV iron treated hemodialysis patients (WMD 1.17; 95%CI 0.19–2.15, fig). Significant heterogeneity was observed due to different baseline Hb values and baseline iron status, different dosages of oral iron, and different dosages of erythropoiesis stimulating agents (ESA). For predialysis patients, there was a small but significant difference in the Hb level favoring the IV iron group (WMD 0.28; 95% CI 0.15–0.4, fig). For both groups effect estimates were not influenced by ESA administration. In predialysis patients, there was no significant difference in the risk for requiring RRT during the trial between the different groups (RR 0.63; 95%CI 0.25–1.65). Data on all-cause mortality were sparse (RR 0.54; 95%CI 0.09–3.13, 3 trials) and there was no difference in adverse events (RR 0.9; 95%CI 0.65–1.24) between the IV and oral treated patients. However, discontinuations of treatment were more common (RR 3.27; 95%CI 1.15–9.26) for the IV iron treated patients.
Conclusions: Our review demonstrates that dialysis patients treated with IV iron have better Hb response than patients treated with oral iron. For predialysis patients, this effect is very small. IV iron should be preferred in the treatment of anemia in dialysis patients. In predialysis patients the slight advantage in Hb response should be weighed against the inconvenience and cost of IV iron treatment.
Proteomics Analysis of Naturally Occurring CD4+/CD25+ Regulatory T Cells.
Authors: Garin Marina I. , Chu Cheri C. , Wait Robin , Bueren Juan A. , Lechler Robert I. 
Published: October 2019

Abstract
Recently, a naturally occurring regulatory T cell population (Tregs) has been identified and shown to actively suppress immune responses of self-reactive T cells. The molecular basis for the function of Tregs remains unclear. We are interested in identifying molecules specifically expressed in human Tregs that are candidates for mediating suppression by comparative proteomic and transcriptomic analysis of human CD4+/CD25+ and CD4+/CD25- T cells using two-dimensional electrophoresis (2-DE) followed by electrospray tandem MS on the Micromass Q-Tof (HPLC-MS/MS) and high-density cDNA microarray technology, respectively. Thus far, the most revealing results of the 2-DE analysis are the detection of an upregulation in the expression of a protein kinase inhibitor and FUSE binding protein (FBP), a regulator of c-Myc expression. The gene expression pattern of the Tregs was overall very similar compared to CD4+/CD25- T cells despite their major functional differences. We have identified several sets of genes differentially expressed in the Tregs. Of special interest are adhesion molecules and chemokine receptors that could reveal distinct trafficking patterns. We are in the process of validating and screening at the protein level several of these candidate genes that could lead to the identification of specific molecular events in the Tregs. The upregulation of the PKC inhibitor is especially interesting, as the reduction of IL-2 production may explain the hypoproliferative status of Tregs. The increase in FBP and a resulting increase in c-Myc transcription may promote the survival of Tregs, thereby contributing to the prevention of autoimmunity.
Von Willebrand Disease in Taiwan: A Clinical and Laboratory Studies of 52 Patients.
Authors: Chen Yeu-Chin , Chao Tsu-Yi , Cheng Shin-Nan 
Published: October 2019

Abstract
Von Willebrand disease (VWD) has been found to be the most common inherited bleeding disorder in Caucasian with a prevalence of around 1%, yet it has not been well recognized in Taiwan and Asian countries. Only a small number of patients have been identified and reported. The aim of this retrospective study was to identify patients with VWD by clinical manifestation and laboratory tests in Taiwan. VWD was detected by a panel of laboratory tests, including bleeding time, aPTT, factor VIII activity assay, Von Willebrand antigen (VWF: Ag) and ristocetin cofactor activity (VWF: RCo), and platelet function analyzer (PFA) test using both Collagen/ADP and Collagen/Epinephrine (CEPI). VWF multimer analysis was performed by western blot to confirm the disease subtype. From October, 2003 to April, 2007, 52 of 494 (9.5%) patients, from 44 families, were identified to have VWD, including 16 men and 36 women. Their median age was 29 with a range of 4∼69 years of age. The most frequently encountered reasons for VWD detection was menorrhagia accounting for 19.2%. The others included inherited detection because of affected family (11.5%), prolonged aPTT (11.5%), excessive bleeding after dental procedures (9.6%) and excessive bleeding after surgery or invasive procedure (9.6%). By laboratory tests, the mean value of VWF: Ag and VWF: RCo was 46.9 ± 18.4% and 32.3 ± 17.4%, respectively. The most sensitive test was VWF: RCo with 90.3%, followed by CEPI with 83.8%. Of 37 patients with VWF multimer analysis, 34(92%) were revealed to have type I VWD, 1 had type IIA, and 2 from the same family had type III VWD. In conclusion, our study demonstrated that VWD was not an uncommon inherited bleeding disease in Taiwan. Menorrhagia was the most common reason for VWD determination, and VWF: RCo and PFA test CEPI were the more sensitive tests for the VWD identification.
D-DImer Dosing for Risk Prediction of Central Venous Catheter Thrombosis (The DIReCT Trial).
Authors: Doucet Stephane , Miron Marie-Jose , Denis Soulieres , Karl Belanger , Marie Florescu , Jean-Pierre Ayoub , Louise Yelle , Olney Harold J. , Blais Normand 
Published: October 2019

Abstract
Cancer patients receiving chemotherapy often need central venous catheters (CVC). There is no laboratory marker to identify patients at high risk of thrombosis who may benefit from thromboprophylaxis. D-Dimer dosing is a well studied test that may correlate with thrombosis risk. The aim of this study is to determine if d-dimer levels are a predictor of CVC thrombosis. Adult cancer patients needing a new CVC for more than 1 month and without an ongoing indication for anticoagulation were included. D-dimer dosing was done before (0–3 days), 24–48h after and 7 days after insertion of CVC. Duplex ultrasonography (US) was performed approximately 30 days after installation. We planned to look at quantitative d-dimer variation in patients to establish its prognostic value in relationship with eventual thrombosis occurrence. Thirty five patients are included in this analysis. There were 63% males and 37% females and the median age was 57. Eighty nine percent had solid tumors (64% gastrointestinal, 23% head and neck, 13% breast) and 11% had an hematologic malignancy. Fifty one percent received concomitant radiotherapy. Seventy nine percent had continuous infusion chemotherapy. Twenty two patients underwent US and 27 patients had at least 2 out of three planned d-dimer values. The incidence of venous thrombosis in the whole cohort was 31% (5 symptomatic, 6 asymptomatic) whereas 24 patients were considered free of thrombosis (11 confirmed by duplex, 13 clinically asymptomatic). In patients with available US results, baseline d-dimer level was similar for those with or without thrombosis (924 and 902). For these patients, the absolute increase of d-dimer was not significantly different in the two groups (194 vs 115 at day 1–2; 421 vs 63 at day 7) as well as relative increase (51% vs 31% at day 1–2; 145% vs 40% at day 7). Baseline d-dimer level was similar for the five patients with symptomatic thrombosis compared to the other 30 patients (1038 and 859), but higher at day 7 (1616 vs 905 p=0,048). Different strategies were analysed to try to define a high and a low risk group and two were selected. First, the population with a cutoff value of d-dimer levels at day 7 of > 1100 had a 40% risk of symptomatic thrombosis vs 0% for those below 1100. Second, an absolute increase in d-dimer values at day 1–2 of more than 500 was associated with a 66,7% risk of symptomatic thrombosis vs 0% for the others. Although numbers are small, patients with symptomatic thrombosis were more frequently receiving G-CSF, red cell transfusions, platelets transfusions and were less likely to be receiving continuous infusion chemotherapy. Our pilot study suggests that d-dimer testing after CVC insertion might permit risk stratification for thrombotic complications. If confirmed by larger trials, this strategy might be useful to plan more effective prophylaxis studies in these populations.
Non Hodgkin’s Lymphoma (NHL) and Deep Vein Thrombosis (DVT): A Dangerous Liaison Still Unexplored.
Authors: Giordano Giulio , Piano Silvia , Marra Roberto , De Stefano Valerio , Hohaus Stefan , Iacoviello Licia , Leone Giuseppe , Donati Maria Benedetta , Storti Sergio 
Published: October 2019

Abstract
Introduction DVT incidence ranges from 3 to 15% in cancer patient. Nevertheless there are only few data about DVT in lymphoma. Aim of our study is to define the real DVT risk and incidence in lymphoma patients.
Patients and Methods Our study is a retrospective study including patients of two haematology centers. We considered the age of the patients, sex, histological type of lymphoma (indolent -IL- vs aggressive -AL), localization over or under diaphragm, extranodal localizations, vascular compression, stage of disease, IPI, LDH level, chemotherapy type and timing of administration (weekly vs every 2wks or 3 weeks), the use of chemotherapy regimen containing methotrexate as potential risk factors in DVT onset. Data regarding 567 NHL patients, observed from 2001 to 2006, were collected. 400 patients had indolent NHL (IL) and 167 Aggressive NHL (AL). Median age was 59 years (R 13–94), M/F ratio was 300/267. DVT was diagnosed by ultrasound or CT scan. The statistical analysis was conducted with Yates corrected chi square test, Odds Ratio (OR), Log-rank test (to compare Kaplan-Meier curves).
Results 87 patients (15%) showed DVT. Of these, 37(43%) were localized at legs and 19(22%) involved abdominal veins (especially iliac veins, 10% of total). DVT onset median time was 3 months from NHL diagnosis (Range 0–156 months). Sex, histological type of lymphoma (IL vs AL), localization over or under diaphragm, extranodal localization, stage of disease, IPI, LDH level, and use of chemotherapy regimen containing methotrexate were not related to an increased risk to develop DVT. Vascular compression was the most significant risk factor for DVT development with OR 3.1 (CI95%:1.9–5), Chi Square22.7(p< 0.0001). Patients receiving weekly chemotherapy showed an increased risk to develop DVT (OR 1.8; CI95%:1.1–2.8), Chi Square5.1, p0.024. Patients aged ≥60 presented increased risk of DVT with OR 1.7(CI95%: 1–2.7), Chi Square 4.28 (p 0.04). Patients with DVT within 3 months from NHL diagnosis had an higher risk of disease relapse or non response at first line chemotherapy: OR 3.7 (CI95%: 1.8–7.3), Chi Square 13.4 (p < 0.0001), positive predictive value 0.71(CI95%: 0.57–0.82), specificity 0.95(CI95%: 0.93–0.97). However DVT had no impact on mortality and survival, also in the subgroup of patients with DLBCL. Discussion In our study vascular compression by enlarged lymphonodes, patient age ≥60 y.o., and weekly administration of chemotherapy seem to be the main risk factors to develop DVT in NHL patients. Further studies, concerning genetic conditions and other disease-related parameters, are ongoing to individuate other risk factors for thrombosis in NHL patients. The DVT development within 3 months from NHL diagnosis seems to be a risk factor for non response/relapse. An antithrombotic prophylaxis could be considered in the patients with higher thrombotic risk.
Massive Transfusion in Wartime: Experience from Northern Israel, Summer 2006.
Authors: Dann Eldad J. , Dally Najib , Chezar Judith , Michaelson Moshe , Barzelay Mirit , Braester Andrei , Hoffman Ron , Bonstein Lilach 
Published: October 2019

Abstract
In July 2006 hostilities erupted in Israel/Lebanon. Reported here is the experience of three medical centers in Northern Israel during 33 days of the warfare; the Rambam Health Care Campus in Haifa - a level I trauma center, the Rebecca Sieff Hospital in Safed and the Western Galilee Hospital in Nahariah - both secondary trauma centers. 504, 1138 and 868 wounded were presented to the three medical centers and 281, 415 and 195, respectively, required hospitalization. Sixty, 32 and 15 hospitalized patients were concomitantly transfused in each corresponding center, representing 20%, 7% and 7%, respectively, of admitted patients. Patients with an injury severity score of ≥16 had a higher need for blood products than those less severely injured, with a mean packed red blood cell (PRBC) transfusion of 7 versus 4 units (p=0.03) and FFP transfusion of 13 versus 1.5 units (p=0.002), respectively. Twenty four soldiers and one civilian had massive transfusions and twenty three of these patients survived. The median ratio between transfused fresh frozen plasma (FFP) and packed red blood cells (PRBC) was 0.8, ranging from a ratio of 0.25 to 1.3. Among 25 massively transfused patients 21 received cryoprecipitate and 19 - platelets. The median prothrombin time (INR) and partial thromboplastin time (PTT) increased during the first 2 hours after admission from 1.29 to 1.51 and from 33.6 seconds to 39 seconds, respectively. In the cohort of massively transfused patients 3 individuals additionally received 3 g of tranexamic acid, while another 2 patients were treated with recombinant factor VII. In conclusion, massively transfused patients with wartime penetrating injuries have an ongoing coagulopathy despite vigorous replacement therapy, which needs to be continued until the patients are stabilized. Early intervention and consultation in the Emergency Room by transfusion-service specialists is essential to the overall management of critically and massively wounded patients in wartime.
Wounded (hospitalized) Transfused patients Packed RBC units FFP units Cryo units Platelet units Massive transfusion (patients) Rambam 504 (281) 60 463 413 266 258 21 Rebecca Sieff 1138 (415) 32 134 34 50 30 4 Western Galilee 868 (195) 15 71 68 51 10 1