bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Incidence of Pelvic Deep Vein Thrombosis Detected by Magnetic Resonance Venograpy Post-Caesarean Section.
Authors: Rodger Marc , Avruch Leonard , Olivier Andre , Walker Mark 
Published: October 2019

Abstract
Background Venous thromboembolism (VTE) is the leading cause of maternal mortality in the developed world. The post-partum period is the highest risk period for pregnancy associated VTE and delivery by Caesarean section further increases this risk. The true incidence of deep vein thrombosis (DVT) post- Caesarean section is unknown but felt to be low. The limited number of screening studies conducted to date have not included systematic pelvic vein imaging.
Objectives To determine the incidence of DVT post-Caesarean section using Magnetic Resonance Venograpy (MRV) and bilateral compression ultrasounds.
Methods Prospective cohort study of moderate to high risk women (one or more VTE risk factors) post-Caesarean section. On the day of post-partum discharge we conducted systematic bilateral proximal leg vein compression ultrasound imaging to detect proximal leg DVT and pelvic vein imaging with magnetic resonance venography (MRV). MRVs were independently and blindly interpreted by two radiologists with disagreements resolved by consensus. MRVs were interpreted as demonstrating definite, probable, possible or no thrombosis. Two rater Kappa scores were calculated from initial interpretations (prior to consensus review). Incidence of DVT and 95% confidence interval were calculated.
Results Fifteen patients were recruited. At discharge, there were no proximal DVTs on bilateral leg compression ultrasounds. MRV results are shown in Table I.
Conclusions The incidence of pelvic vein DVT post- Caesarean section is much higher than anticipated (46%). The clinical significance of this finding remains to be determined. However, diagnoses such as septic pelvic vein thrombophlebitis, which depend on demonstrating the presence pelvic vein thrombosis in the setting of post-partum fever may be falsely overdiagnosed. Pelvic vein thrombosis may be a common (and normal) finding post-Caesarean section. MRV may also prove to be a useful surrogate outcome measure in post-partum VTE prophylaxis studies.
Table I: Pelvic Vein Imaging Results Post-C-Section
MRV Consensus Result n/N (%) 95% CI Two Rater Kappa 95% CI= 95% Confidence Interval Definite Thrombosis 7/15 (46%) 21–73% 0.5 Definite or Probable Thrombosis 8/15 (53%) 27–79% 0.6 Definite, Probable or Possible Thrombosis 10/15 (66%) 38–88% 1.0 No Thrombosis 5/15 (33%) 12–62% 1.0
Blood Outgrowth Endothelial Cells (BOEC) Contribute to Tumor Vascularization and Can Be Used for Delivery of Cancer Gene Therapy.
Authors: Dudek Arkadiusz Z. , Bodempudi Vidya , Nelson Curtis M. , Chang Liming , Hebbel Robert P. 
Published: October 2019

Abstract
Continuous and adequate levels of angiogenesis inhibitors at the site of tumor vasculature may be necessary to obtain optimal antitumor effect. Following recent observations that circulating in blood endothelial cells enhance tumor vasculogenesis we have designed grown from peripheral blood endothelial cells to deliver anti-angiogenic antitumor therapy. BOEC, after several-fold expansion, expressed endothelial markers: VE-cadherin, CD31, von Willebrand factor, and P1H12 and responded to functional endothelial assays: uptake of acetylated low-density lipoprotein, and vascular tube formation. BOEC were also found in functional vessels in vivo, when NOD-SCID mice implanted subcutaneously with Lewis lung carcinoma or H226 lung cancer, were injected via tail vein with 5x105 BOEC. Staining for CD31 on tumor sections of BOEC injected mice demonstrated increased blood vessel density (BOEC 1982±1281, sham 328±229 (P<0.001)). In FsaII tumor model, systemic BOEC injection resulted in increased tumor volumes and higher tumor oxygenation when compared with sham injected animals. Injected via tail vein BOEC distributed initially throughout organs with high vascularization, but in 72 hours remained only in tumor, liver, spleen, and bone marrow. Given the ability of BOEC to survive within tumor vasculature, we designed BOEC to deliver endostatin and soluble VEGFR-1 (sFlt1) genes to the tumor’s endothelium. A retroviral MSCV vector was constructed to contain green fluorescent protein (GFP) and human endostatin gene (hES) or sFlt1. The hES or sFlt1 containing BOEC were evaluated for vWF, CD31, and VE-cadherin, and found positive. Transduced with endostatin or sFlt1 gene BOEC had a slower growth rate in culture, produced detectable endostatin (1.84 ng/ml) or sFlt-1 (665 pg/ml), and were able to inhibit MVEC growth in co-culture condition. When endostatin transduced BOEC were injected to mice with tumor tumor vascularization was decreased (EBOEC 290±172 versus BOEC 1982±1281(p<0.001)). This resulted in tumor volume reduction in mice injected with EBOEC (0.364±0.227cm3 versus sham 0.802±0.431cm3 (p=0.102)). This early data suggest that BOEC have the potential for tumor-specific delivery of cancer gene therapy.
Impact of Increased Body Weight on Acute Toxicity and Outcome of Autologous Stem Cell Transplantation for Non-Hodgkin’s Lymphoma: A Southwest Oncology Group Analysis.
Authors: Stiff Patrick , Unger Joseph , Forman Stephen , LeBlanc Michael , Miller Thomas , Press Oliver , Thompson John , Fisher Richard 
Published: October 2019

Abstract
Little is known about the optimal dosing of chemotherapy agents in patients significantly above their ideal body weight (IBW) who undergo high dose therapy with an autologous or allogeneic hematopoietic stem cell transplant. While dose attenuation is often advocated for overweight patients and appears to reduce acute toxicities, its effect on progression-free and overall survival (PFS/OS) is unknown. Due to a high relapse rate after autografts for relapsed/refractory NHL, SWOG has long investigated the use of augmented preparative regimens that utilize high-dose etoposide based on actual body weight (ABW) of 60 mg/kg, along with 12 Gy of TBI and cyclophosphamide (100 mg/kg) which is dosed on unadjusted IBW. We determined acute toxicities and PFS/OS using this approach in a recently completed study (S9438) of 358 patients undergoing autografts for relapsed/refractory NHL, comparing all grade 5 toxicities, grade 3–4 skin toxicities (known to be associated with high dose etoposide) and all other grade 4 toxicities in patients in this study based on % above IBW. The Devine formula for IBW with an adjustment for patients <5 feet was used. Patients at or below their IBW were dosed using their actual body weight. All patients received the preparative regimen as stated followed by autologous peripheral blood stem cells. Overall there were 31 patients with grade 5 toxicities. This group was a mean 42% above their IBW vs 24% for those surviving transplant (p=.001). Increasing % above IBW predicted grade 5 toxicity (p=.002). Even those at or 10% above their IBW had a higher toxic death rate (10.1 vs 3.6%; p=.04). While increasing weight above IBW did not predict for grade 4 lung, liver, cardiac toxicities or infections (p=.12), it did predict for grade 3/4 skin toxicities (p< .001). Skin toxicity, most commonly hand/foot syndrome was seen at rates up to 27.3% vs 7.3% for those ≥ 50 vs < 50% over IBW (p < .001). However, even those just ≥ 10% over IBW had nearly a 4 fold higher risk of skin toxicity (13.4 vs 3.6%; p=.005). While survival by % over IBW is confounded by comorbidities in overweight patients, we found no evidence of a different 2-year PFS or OS for overweight patients, even those ≥ 50% above IBW (PFS=42 vs 45%, p = .28; OS=52 vs 62%, p = .38). These multicenter trial data do establish a correlation of the ABW dosing of etoposide with significant skin toxicity. Without an apparent later PFS/OS benefit to the use of unadjusted etoposide dosing for overweight patients but higher acute skin toxicity and a higher early death rate, etoposide will be dosed using adjusted IBW [ IBW + .4 (ABW − IBW)] in subsequent studies of this regimen.
GATA-1 Forms Distinct Activating and Repressive Complexes in Erythroid Cells.
Authors: Strouboulis John , Rodriguez Patrick , Bonte Edgar , Krijgsveld Jeroen , Kolodziej Katarzyna , Guyot Boris , Vyas Paresh , de Boer Ernie , Grosveld Frank 
Published: October 2019

AbstractGATA-1 is a key transcription factor essential for the differentiation of the erythroid, megakaryocytic and eosinophilic lineages. GATA-1 functions in erythropoiesis involve lineage-specific gene activation and repression of early hematopoietic transcription programs. GATA-1 is known to interact with other transcription factors, such as FOG-1, TAL-1 and Sp1 and also with CBP/p300 and the SWI/SNF chromatin remodeling complex in vitro. Despite this information the molecular basis of its essential functions in erythropoiesis remains unclear. We show here that GATA-1 is mostly present in a high (> 670kDa) molecular weight complex that appears to be dynamic during erythroid differentiation. In order to characterize the GATA-1 complex(es) from erythroid cells, we employed an in vivo biotinylation tagging approach in mouse erythroleukemic (MEL) cells1. Briefly, this involved the fusion of a small (23aa) peptide tag to GATA-1 and its specific, efficient biotinylation by the bacterial BirA biotin ligase which is co-expressed with tagged GATA-1 in MEL cells. Nuclear extracts expressing biotinylated tagged GATA-1 were bound directly to streptavidin beads and co-purifying proteins were identified by mass spectrometry. In addition to the known GATA-1-interacting transcription factors FOG-1, TAL-1 and Ldb-1, we describe novel interactions with the essential hematopoietic transcription factor Gfi-1b and the chromatin remodeling complexes MeCP1 and ACF/WCRF. Significantly, GATA-1 interaction with the repressive MeCP1 complex requires FOG-1. We also show in erythroid cells that GATA-1, FOG-1 and MeCP1 are stably bound to repressed genes representing early hematopoietic (e.g. GATA-2) or alternative lineage-specific (e.g. eosinophilic) transcription programs, whereas the GATA-1/Gfi1b complex is bound to repressed genes involved in cell proliferation. In contrast, GATA-1 and TAL-1 are bound to the active erythroid-specific EKLF gene. Our findings on GATA-1 complexes provide novel insight as to the critical roles that GATA-1 plays in many aspects of erythropoiesis by revealing the GATA-1 partners in the execution of specific functions.
Correction of β Thalassemia by Homologous Recombination in Embryonic Stem Cells.
Authors: Ryan Thomas M. , Sun Chiao-Wang , Wu Li-Chen , Ren Jin-Xiang , Townes Tim M. 
Published: October 2019

Abstract
Genetic correction of patient-derived embryonic stem (ES) cells is a powerful strategy for the treatment of hemoglobinopathies such as β thalassemia and sickle cell disease. One genetic strategy for the correction of β thalassemia is to replace mutant or deleted β-globin alleles with a wild-type gene by homologous recombination in ES cells. Thalassemic mice that mimic the disorder have been generated by targeted gene deletion of the adult murine β-globin genes (PNAS 92: 9259–9263). We derived ES cells from our β-globin knockout mice and produced genetically identical mutant mice by injecting the ES cells into tetraploid embryos. These cloned β thalassemic mice have a severe microcytic anemia characterized by a marked reduction of the erythrocyte mean corpuscular volume (MCV), hemoglobin level (Hb), and hematocrit (Hct), and a marked increase in reticulocytes and red cell distribution width (RDW) compared to cloned wild-type control animals. In contrast to the normochromic, normocytic erythrocytes of wild-type clones, erythrocytes in peripheral blood smears of β thalassemic mice were hypochromic and exhibit extreme anisopoikilocytosis. A targeting construct containing 8.7 kb of mouse homology flanking a human γ- and β-globin gene cassette and a hygromycin marker gene was electroporated into the β thalassemic ES cells. After selection, DNA from 48 ES cell colonies was analyzed by PCR to identify homologous recombinants. Nineteen colonies (40%) had correctly integrated the human globin genes into the deleted mouse β-globin locus. Correctly targeted cells were injected into tetraploid blastocysts to produce mice that are derived solely from the corrected ES cells. These cloned mice synthesize high levels of human β-globin polypeptide that corrects the α- to β-globin chain imbalance, thereby eliminating the thalassemic erythrocyte morphology. The MCV, Hb, Hct, RDW, and reticulocyte levels in the blood of these mice are normal. These results demonstrate that a severe hemoglobinopathy can be cured after targeted gene replacement of a mutant gene(s) with a wild-type allele by homologous recombination in ES cells.
Novel Immunomodulatory Drugs (IMiDs®): A Potential, New Therapy for β-Hemoglobinopathies.
Authors: de Parseval Laure Moutouh , Brady Helen , Glezer Emila , Richard Normand , Muller George , Morris Christopher L. , Stirling Dave , Chan Kyle 
Published: October 2019

Abstract
Sickle cell anemia (SCA) and β-thalassemia constitute a public health problem worldwide and new therapies are needed 1. Inhibition of hemoglobin S (HbS) polymerization is a major target for therapeutic approaches in SCA. New experimental therapies including hydroxyurea (HU) have attempted to augment the synthesis of fetal hemoglobin (HbF) and improve upon current treatment 2. We examined whether immunomodulatory analogs of thalidomide (IMiDs®) which have effects on hematopoiesis and are currently under evaluation for the treatment of hematological cancers could stimulate erythropoiesis and hemoglobin synthesis 3. Clinical trial results have demonstrated that Thalidomide and Revlimid™ reduce or even eliminate the need for red blood cell transfusions in some anemic myelodysplastic patients 4,5. We demonstrate here that CC-4047 (Actimid™) and CC-5013 (Revlimid™) are potent inducers of HbF in vitro and synergize with hydroxyurea during erythroid differentiation of CD34 progenitors isolated from human donors. In addition, we show by gene microarray profiling of CD34 differentiated cells that IMiDs® regulate specific erythroid genes that participate in hemoglobin synthesis. These results support that IMiDs®, alone or in combination with current approved therapies, can be a new approach to augment HbF synthesis, and have the potential to provide an innovative therapy for the β-hemoglobinopathies and other anemias.
Induction of Gamma Globin and Erythrocyte Anion Exchane Protein in BFU-E Cultured in the Presence of Hydroxyurea.
Authors: Green Gloria A. , Braden Beau R. , Mba Obianuju , Chivira Stacy A. , Ramezani Laleh , Johnson Cage S. 
Published: October 2019

Abstract
Hydroxyurea (HU) an S-phase specific cytotoxic agent has been used for the treatment of patients with sickle cell hemoglobinopathy and beta-thalassemias. The clinical efficacy of HU is due primarily to increases in fetal hemoglobin (HbF) levels. HU increases the %HbF and the %F cells. The HU reactive mechanism(s) in erythroid cells, however, have not been clearly defined.
Patients receiving HU therapy develop subpopulations of macrocytic erythrocytes. Our previous studies demonstrate that sickle cell patients treated with HU develop subpopulations of RBCs that express greater relative levels of the erythrocyte anion exchange protein (AE1) per cell as compared with untreated individuals. We propose that part of the HU reactive mechanism will include the upmodulation of non-gamma globin erythroid proteins that contribute to the macrocytic structures. As part of our investigation of the development of RBCs expressing increased band 3 protein per cell, we have examined the possibility that HU induced AE1 synthesis can be detected in vitro using cultured erythroid progenitors.
To investigate HU induced protein synthesis as a function of HU concentration, erythroid progenitors were cultured in semisolid media containing different concentrations of HU [0–40 micromolar] then assayed for AE1(band 3) and gamma globin. BFU-E were scored and harvested after 15 days in culture, then assayed. The change in the frequency of cells positive for band 3 protein was determined by flow cytometry, these cells were then assessed by laser scanning confocal microscopy. Results show that the frequency of cells positive for band 3 protein was greater in colonies grown in hydroxyurea as compared to controls. The band-3 upmodulation appears to plateau at 12.5 micromolar HU. These cells were assessed for dual and single stains by laser scanning confocal microscopy. Both band-3 protein and spectrin were detected. Laser scanning confocal microscopy revealed spectrin in the majority of cells; both band 3 and spectrin were detected in forty percent of the cells cultured in 12.5 micromolar HU. Band 3 protein detected by Western blots was increased [1–1.5 fold] over untreated control BFU-E harvested during the same time period.
Secondly, the presence of band 3 protein and gamma globin in BFU-E was detected using two-color flow cytometry. BFU-E were cultured in increasing concentrations of HU. Colonies were permeabilized, and then labeled with tricolor-conjugated-anti-gamma globin. These cells were subsequently labeled with monoclonal anti-band 3 and PE-labeled anti-mouse antibody. Results show 2–3 fold increase in the % band 3 plus gamma globin positive cells over untreated cells. Collectively, these results suggest that part of the mechanism of HU action in erythroid cells involves the induction of erythroid structural proteins concordant with the induction of gamma globin.
Serum Ferritin a Predictor of Iron Overload in Patients with Thalassemia and Sickle Cell Disease?.
Authors: Pakbaz Zahra , Fischer Roland , Gamino Richard , Fung Ellen B. , Harmatz Paul , Vichinsky Elliott 
Published: October 2019

Abstract
Introduction: Monitoring iron overload by serum ferritin in patients with hemosiderosis is still a routine practice although its limitations are widely studied and well known. Using non-invasive liver iron assessment by quantitative MRI or by biomagnetic liver susceptometry (BLS) with SQUID biomagnetometers would be the better alternative, however, these methods are available at only a few centers worldwide.
Objective: To determine the relationship between serum ferritin (SF) and liver iron concentration (LIC), measured by BLS at CHRCO, in patients with different types of hemosiderosis.
Methods and Patients: A total of 97 patients with thalassemia (TM: 3 to 52 y, 54% females) and 39 patients with sickle cell disease (SCD: 5 to 49 y, 60% female) were prospectively assessed for LIC and SF. Both tests were performed within 2 weeks of each other. Most patients with TM and SCD were chronically transfused, while 10 b-thalassemia intermedia (TI), 5 HbE/β-thalassemia (HbE), and 5 SCD patients were not on transfusion programs. LIC was measured by LTc SQUID biosusceptometer system (Ferritometer®, Model 5700, Tristan Technologies, San Diego, USA) under the standardized Hamburg-Torino-Oakland protocol. A non-parametric test (U-test) was utilized to analyze differences between SF and LIC data.
Results: In chronically transfused TM and SCD patients, the median SF and LIC were very similar (Table I). In TI&HbE patients, ferritin results were disproportionately low with respect to LIC. In order to improve prediction of iron stores by SF, the SF/LIC ratio was calculated. There was a significant difference between the median ratios of the two groups of transfused and non- transfused thalassemia patients, 0.82 vs. 0.32 [μg/l]/[μg/gliver], respectively (p < 0.01). In SCD patients the ratio is significantly (p < 0.01) higher.
Conclusion: Present data confirm ferritin to be a poor predictor of liver iron stores both in sickle cell disease and thalassemia. Relying only on ferritin to monitor iron overload in patients with hemosiderosis can be misleading, especially, in sickle cell disease and non-transfused thalassemia patients. Taking into account disease specific ferritin-LIC relations, could improve the prediction of iron stores. However, assessment of liver iron stores is the ultimate method to initiate and adjust chelation treatment in order to avoid progressive organ injury.
Table I. Median values and ranges ( − ) of serum ferritin (SF) and liver iron concentration (LIC) in transfused (Tx) and non-transfused (non-Tx) hemosiderosis patients.
Patient group n SF μg/l] LIC [mg/gliver ] SF:LIC Thalassemia Tx 82 1721 (209–8867) 3424 (364–7570) 0.82 (0.3–1.8) TI &HbE non-Tx 15 766 (52–2681) 2174 (226–5498) 0.32 (0.1–1.4) SCD Tx 34 2757 (400–9138) 1941 (518–6670) 1.2 (0.6–3.3)
Acute Hyperglycaemia Enhances Platelet Activation: Involvement of Multiple Mechanisms.
Authors: Li Nailin , Sudic Dzana , Forslund Mikael , Razmara Masoud 
Published: October 2019

Abstract
Diabetes mellitus is associated with platelet dysfunction, and hypoglycemic treatments may counteract this diabetic alteration. We thus studied how acute hyperglycemia influences platelet function. Fast blood (n=20) was incubated with different levels of glucose (5, 15, and 30 mM) for 5 min, and without or with in vitro stimuli. Platelet activation was monitored by whole blood flow cytometry, while platelet aggregation was also measured using impedance aggregometry. Blood glucose levels had little influence on unstimulated platelets. Hyperglycemia enhanced ADP- and TRAP-induced platelet P-selectin expression. Hyperglycemia also increased TRAP-induced platelet fibrinogen binding. High glucose levels mildly increased ADP- and TRAP-induced platelet-leukocyte aggregation. The blockade of protein kinase C (PKC) slightly attenuated ADP-induced, and markedly inhibited TRAP-induced platelet activation. PKC blockade had, however, little effect on hyperglycemia effect. Platelet P-selectin expression induced by the direct PKC activator phorbol 12-myristate 13-acetate (PMA) was not augmented by hyperglycemia. Superoxide anion scavenging by superoxide dismutase (SOD) reduced, whistle cyclo-oxygenase (COX) inhibition by naproxen did not reduced the enhancing effect of platelet activation by hyperglycemia. In conclusion, acute hyperglycemia enhances platelet activation in whole blood. Superoxide anions contribute importantly to hyperglycemia-enhanced platelet activation, while other mechanisms not identified presently also contribute to hyperglycemic effects.
Cyclosporin A as Immunosuppressive Treatment Option for Patients with Refractory Auto-Immune Thrombocytopenic Purpura.
Authors: Zver Samo , Zupan Irena P. , Andoljsek Dusan , Cernelc Peter 
Published: October 2019

Abstract
The treatment of auto-immune thrombocytopenic purpura (AITP) remains unsatisfactory in patients refractory to first-line management such as corticosteroids and/or splenectomy. Those patients usually require unacceptably high doses of corticosteroids to maintain a safe platelet count and thus have refractory AITP. Relativelly new immunosupressive treatment modality is cyclosporin A (CsA) and no large studies involving these drug have been conducted. We treated 7 refractory AITP patients with CsA. Their platelet count were without any therapy below 20x109/L and mostly they had signs of subcutaneous and mucosal bleeding. In 6/7 patients splenectomy was performed earlier. In order to maintain »safe« platelet count, they all needed methylprednisolon (MP), at least 32 mg/daily. So at the time treatment with CsA began, all patients were on MP. During next months MP dosage was tapered or withdrew, according to patients platelet count and treatment efficacy. At the endpoint, in 4/7 patients complete remission (CR) was achieved and later CsA was slowly ceased. 3/7 patients are currently in partial remission (PR) of the disease. Also one of them who has more than 30 years history of the disease is in stable PR, on low dose CsA and low dose MP maintanance therapy. Her platelet count is well above 20x109/L. Among CsA treatment related side effects painful lower limb edema was most frequent.
Based on our experience we suggest, that CsA should be recommended in refractory (chronic) AITP patients, because it shows long-term efficacy and good safety profile and is able to sustain remission at low doses or even after CsA discontinuation.