bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Complex Mcl-1/Bim Regulates the Sensitivity of Human Myeloma Cells to Melphalan.
Authors: Gomez-Bougie Patricia , Oliver Lisa , Menoret Emmanuelle , Le Gouill Steven , Bataille Régis , Amiot Martine 
Published: October 2019

Abstract
Multiple myeloma is a fatal plasma-cell malignancy that evolves mainly in the bone marrow. Melphalan is widely used to treat patients with Multiple Myeloma, however its mechanism of action remains poorly documented. Thus, we studied the effect of this drug on the molecules of the Bcl-2 family. We showed that melphalan induces a drastic down-regulation of the anti-apoptotic proteins Mcl-1L and Bcl-xL and the pro-apoptotic BimEL in human melphalan-sensitive myeloma cells while the most potent pro-apoptotic Bim isoforms, L and S, are less affected. Interestingly, the disappearance of Mcl-1L and BimEL is associated with the generation of the respective cleaved forms, described as pro-apoptotic. We determined that the cleaved forms were generated by caspase cleavage since the addition of zVADfmk inhibited their formation. Indeed, we observed that caspase 3 activation occurred as early as Mcl-1 cleavage. Recently, we demonstrated that Mcl-1, the major anti-apoptotic molecule for myeloma cells, neutralizes the pro-apoptotic Bim molecule through endogenous complex formation and therefore, preventing the activation of death effectors. In this study, we demonstrate that melphalan disrupts the Mcl-1/Bim complex while the Bcl-2/Bim complex is not affected. In turn, the disappearance of full length Mcl-1 allows the release of Bim isoforms, particularly L and S, which can exert their pro-apoptotic function. In addition, we demonstrate both Bax activation and cytochrome c release, supporting the role of free Bim as a major initiator of the mitochondrial apoptotic cascade. Thus, we propose that in myeloma cells melphalan induces the disruption of Mcl-1/Bim complex resulting in the release of Bim from Mcl-1 sequestration and therefore leading to the initiation of the apoptotic process. Moreover, the cleaved 26kDa pro-apoptotic Mcl-1 and the 19kDa and 12kDa of Bim, generated during melphalan treatment could contribute to the amplification loop of apoptosis. MM remains a fatal disease which develops multi-drug resistance, including melphalan. A potential therapeutic approach could be the disruption of the Mcl-1/Bim complexes by the BH3 small molecules that might target those complexes leading to the release of sequestered Bim.
Mitochondrial Reactive Oxygen Species (ROS) Are Involved in Coated Platelet Formation and Platelet Procoagulant Activity.
Authors: Jobe Shawn , Lentz Steven R. , Di Paola Jorge 
Published: October 2019

Abstract
Increased vascular oxidative stress has been demonstrated in many pathological conditions associated with an increased predisposition for thrombotic events, including atherosclerosis, diabetes mellitus, and hypertension. We hypothesized that oxidative stress may promote thrombosis through increases in platelet procoagulant activity and coated platelet formation. Upon activation with convulxin (an agonist for the collagen receptor GPVI) and thrombin, approximately 70% of murine platelets acquired the coated platelet phenotype, characterized by increased alpha granule protein retention, decreased binding of the α2bβ3 activation-dependent antibody JON/A, and increased binding of annexin V. Dual stimulation with convulxin and thrombin also resulted in a 4-fold increase in platelet procoagulant activity (measured in a prothrombinase assay) together with rapid oxidation of the redox-sensitive dye, H2DCF. Only small increases in H2DCF oxidation were observed in platelets stimulated with thrombin or convulxin alone demonstrating a unique effect of dual agonist stimulation on platelet oxidant production. Formation of coated platelets and platelet procoagulant activity following stimulation with convulxin and thrombin were inhibited with the non-specific antioxidants, Tiron or Trolox. No inhibitory effect was observed using the NADPH oxidase inhibitor diphenylene iodonium or the NO synthase inhibitor L-NNA. The mitochondrial electron transport inhibitor, rotenone, effectively inhibited ROS production, coated platelet formation, and platelet procoagulant activity (53 ± 7%) (p<0.01) following dual agonist stimulation. We also found that hydrogen peroxide (H2O2) could effectively substitute for convulxin in mediating these dual-stimulated activities. Stimulation with H2O2 (100 mM) in the presence of thrombin (0.5 U/mL) resulted in a 4-fold increase in coated platelets and annexin V binding and a 3-fold increase in platelet procoagulant activity relative to platelets stimulated with thrombin alone (p<0.05). This response was dose-dependent, and no effect was observed with H2O2 in the absence of thrombin. Together these results suggest a central role for oxidant signaling and mitochondrial ROS production in platelet procoagulant activity and coated platelet production and point to a possible mechanism for thrombosis in pathological conditions associated with increased oxidative stress.
Improved Myocardial T2* in Transfusion Dependent Anemias Receiving ICL670 (Deferasirox).
Authors: Porter John B. , Tanner Mark A. , Pennell Dudley J. , Eleftheriou Perla 
Published: October 2019

Abstract
ICL670 (deferasirox) is an orally active iron chelator, intended as once daily mono-therapy for the treatment of transfusional iron overload, which has undergone extensive multi-centre Phase II and Phase III trials. Data from such studies suggest that 20mg/kg as a single daily dose will achieve iron balance in the majority of transfusionally dependent patients, whereas 30mg/kg/day typically achieves negative iron balance (Cappellini, Abstract 3619, ASH 2004) (Porter, Abstract 3193, ASH 2004). Patients with transfusion dependent anaemia and iron overload who were entered into these multi-centre studies at UCL Hospitals had myocardial T2* CMR performed at the Royal Brompton Hospital, as part of their routine monitoring, in line with previous clinical management at our centre. Study 108, a non-randomized study, included poorly chelated patients with -thalassemia and other iron overload conditions receiving regular blood transfusion: all patients received 10-30mg/kg/day of ICL670. Study 107 consisted exclusively of transfusion dependent -thalassemia patients, randomized to receive either 8–10h sc DFO (30–50mg/kg/day) or ICL670 (10–30mg/kg/day) with doses stratified for baseline liver iron concentration (LIC). We report here changes in cardiac T2*, LIC and serum ferritin, as well as LVEF in all patients on these two studies treated at UCLH for a mean of 13.1± 0.78 months, in whom CMR was obtained. In a total of 23 patients treated with ICL670, mean age 24.6y (range 9–50y), 18 with transfusion dependent -thalassaemia and 6 other iron overload conditions (2 Pyruvate kinase deficiency, 2 sideroblastic anemia, 2 Diamond Blackfan Anemia), myocardial T2* improved significantly from a pre-treatment geometric mean of 18.0ms to 23.1ms (p = 0.013, paired student t test). In the same patients, serum ferritin fell significantly from 3173 ±410 μg/L to 2451 ±242μg/L (p= 0.023, paired student t test) and LIC fell significantly from 18.3 ±2.2 mg/g dry wt to 10.0 ±1.49 (p= 0.0002, paired student t test). There was no significant change in LVEF before or after treatment over the same period. Patients treated in the DFO arm of study 107 (n=8) also showed a small non-significant increase in myocardial T2* from 18.1 ms to 21.1 ms (p= 0.11), These studies suggest that once daily mono-therapy with ICL670 will be effective at improving myocardial T2* and by inference myocardial iron loading in a wide range of patients with transfusional iron overload. Prospective randomised controlled studies in larger patient numbers are now indicated.
A Population of Small CXCR4+ SSEA-1+ Oct-4+ Embryonic-Like Stem Cells Identified in Adult Bone Marrow.
Authors: Kucia Magda , Reca Ryan , Ratajczak Janina , Ratajczak Mariusz Z. 
Published: October 2019

Abstract
We demonstrated that bone marrow (BM) stem cells are heterogenous and in addition to hematopoietic stem cells (HSC) BM also contains non-hematopoietic tissue committed stem cells (TCSC) for skeletal muscle, heart, neural tissue, epidermis and liver (Leukemia2004:18;29–40). In our follow up studies by employing multiparameter sorting we identified in murine BM a homogenous population of rare (~0.02% of BMMNC) Sca-1+ lin− CD45− cells that express by RQ-PCR and immunhistochemistry markers of pluripotent stem cells (PSC) such as SSEA-1, Oct-4, Nanog and Rex-1 and highly express Rif-1 telomerase protein. More important the direct electronmicroscopical analysis revealed that these cells display several features typical for primary embryonic stem cells such as i) small size (~3 μm in diameter), ii) poses large nuclei surrounded by a narrow rim of cytoplasm, and iii) contain open-type chromatin (euchromatin) that is typical for embryonic stem cells. Their number is highest in BM from young (1–2 month-old) mice and decreases with age. It is also significantly diminished in short living DBA/2J mice as compared to long living B6 mice. These cells in vitro respond strongly to several motomorphogens such as SDF-1, HGF and LIF and co-express the corresponding receptors such as CXCR4, c-met and LIF-R respectively on their surface. Interestingly, they adhere to fibronectin, and undergo emperipolesis in fibroblasts, thus they may be co-isolated with BM adherent cells. Furthermore, they are mobilized into peripheral blood during tissue/organ injuries (e.g., heart infarct, stroke). In in vitro cultures they differentiate into cells from different germ-layers (e.g., form neurospheres, grow cardiomyocytes). Thus, these findings support the theory of BM containing a reserve population of embryonic-like/pluripotent stem cells and it is also possible that several of the recently described BM-derived CD45− stem cell populations (e.g., MAPC, USSC or MIAMI cells) could in fact overlap with these rare non-hematopoietic CD45− stem cells identified by us, but due to the differences in the experimental approaches employed for their isolation and identification, were assigned different names. We postulate that this population of CD45− embryonic-like cells expressing pluripotent and tissue committed markers identified by us is an ideal source of cells for regeneration.
Specific Activation of Human beta-Globin Gene Expression by the Transcription Factor Ikaros.
Authors: Perkins Andrew C. , Papathanasiou Peter , Goodnow Christopher C. , Keys Janelle R. 
Published: October 2019

Abstract
The zinc finger transcription factor Ikaros is recognized as a key regulator of lymphocyte differentiation. Recently generated dominant negative mutants have hinted at a broader role in haematopoietic stem cell generation. Most recently, a mouse strain, IkarosPlastic, with a point mutation in Ikaros that disrupts DNA binding but preserves efficient assembly of Ikaros protein complexes, is embryonically lethal due to severe defects in erythrocyte differentiation (Papathanasiou P, et al,. Immunity, 2003). (1). These mice display normal murine globin gene expression in the fetal liver. However in humans the globin locus is under alternative regulatory control, particularly with respect to the fetal-to-adult globin switch. Thus, to determine if Ikaros plays a role in human globin switching we crossed the IkarosPlastic mice with mice transgenic for a YAC containing the entire human b-globin locus, which show human fetal to adult globin gene switching from E12 to E17. Embryos were harvested from E12.5 to E15.5 and globin expression was determined in the fetal liver by real-time PCR (relative to actin). At all time points human gamma-globin gene expression was not significantly altered by the presence of the IkarosPlastic mutatation (relative expression Ikaroswt/wt 1±0.11, IkarosPlastic/Plastic 0.82±0.12). In contrast, human beta-globin gene expression was significantly down-regulated in IkarosPlastic fetal livers (relative expression Ikaroswt/wt 1±0.14, IkarosPlastic/Plastic 0.18±0.07). Interestingly, neither murine a- or b-globin gene expression was significantly different to wild type mice, which suggests that the transcription factor Ikaros plays a specific role in the transcriptional activation of the human b-globin gene during development. The mechanism by which this occurs remains to be elucidated, however it is intriguing to consider that Ikaros may act as a potentiator of transcription for erythroid specific transcription factors such as EKLF. Experiments to address this will be presented.
Recombinant Human Activated Protein C Suppresses Endotoxin Induced Hypotension in Mice Deficient of the Endothelial Protein C Receptor (EPCR).
Authors: Joyce David E. , Donahue Deborah L. , Liaw Patricia C. , Castellino Francis J. 
Published: October 2019

Abstract
In Clinical sepsis and human endotoxin studies, administration of the recombinant human form of the anticoagulant activated protein C (rhaPC) demonstrates benefit in parameters of coagulation, inflammation, shock, and sepsis survival. Utilizing transgenic mice deficient in the endothelial protein C receptor, (EPCR), we investigated whether provision of rhaPC improved the hypotensive response and survival subsequent to administration of a lethal dose of endotoxin (LPS). A novel central venous infusion protocol for rhaPC was developed using low expressing EPCR mice (EPCRδ/δ surface expression &lt;10% of WT EPCR) which were generated in our center. WT C57Bl/6 (&gt;F8) mice were used as controls. An aortic arch continuous blood pressure (B.P.) monitor and right internal jugular vein catheter were placed. The continuous infusion dosing of rhaPC (Eli Lilly) was approximately 1.8 μg/g/hr for 20 hr through the central venous catheter (N=3 per group). The control group received saline. Bolus LPS (10 μg/g i.p.) was administered concomitant to rhaPC. Continuous B.P. measurements were obtained until death or for up to 72 hr. RhaPC kinetic parameters (N=4 per group) collected from WT citrate-benzamidine plasma samples were determined by monoclonal antibody capture assays. In initial kinetic studies plasma levels of rhaPC in WT mice given LPS achieved steady state concentrations (90 ng/mL at 4 hr) similar to that found in human studies (45 ng/mL at 2hr). RhaPC dosing produced no allergic reaction or overt bleeding. The subsequent 72 hour B.P. study achieved the goal of suppressing endotoxin-induced hypotension in both WT and EPCRδ/δ mice. The two LPS/rhaPC-treated groups were able to overcome the hypotensive stress and survive longer than the two LPS-only treated groups. RhaPC treated EPCRδ/δ mice were able to recover blood pressure to the same or greater degree than the rhaPC treated WT mice, suggesting either enhanced cell signaling potential by less cell surface EPCR or an alternate aPC receptor. The administered volume of 30 μL/hr (0.6 mL over 20 hr) did not appear to counter the onset of hypotension in EPCRδ/δ mice, and the rhaPC B.P. effect persisted beyond the 20 hr infusion. The expected sequence of LPS-induced mortalitv, viz., EPCRδ/δ &gt; WT &gt; WT/rhaPC &gt; EPCRδ/δ/rhaPC was demonstrated in this study. These transgenic murine studies implicate the protein C pathway as linking coagulation, inflammation and hypotension. By reducing the burden of hypotension in WT and EPCR deficient mice with rhaPC treatment in endotoxin-induced sepsis, this infusion model provides a valuable approach to study effects of aPC in vascular inflammation and hypotension.
New Reference Ranges in Haematology for Healthy Adults Using the Modern Sysmex XE-2100 Automated Analyser.
Authors: Wakeman Lisa , Munro Roger , Russell Chris , Benton Ann , Hartnell Sally , Al-Ismail Saad 
Published: October 2019

Abstract
Establishing clearly defined, accurate reference ranges facilitates good interpretation and effective discrimination between health and disease. These can be used to obviate the need for unnecessary follow-up medical examinations thereby reducing costs. Our data represent findings from one of the most comprehensive studies ever undertaken with the XE-2100 to establish reference ranges (RRs) in healthy adults. Early morning venous samples were collected into Greiner EDTA Vacuettes (Ref: 454286) from 221 healthy laboratory personnel (F= 159;M = 62) aged 20–63 yrs for both gender. Age groups were equally represented. Samples were processed on a Sysmex XE-2100 analyser within 1 hour of collection. NCCLS guidelines (C28-A and H3-A4) were followed throughout. Outliers were excluded, data examined for normal distribution from histograms, Q-Q normality plots, skewness and kurtosis and significance levels calculated from the Kolmogorov-Smirnov and Shapiro-Wilk tests of normality. RRs for near normally distributed parameters were calculated using means ± 2SDs. RRs for non-normally distributed parameters were calculated using the log natural transformation and the antilog of the 2.5- and 97.5- percentiles. Bold parameters shown below have near-normal distribution. Non emboldened values are non-normally distributed. P values are derived from Mann-Whitney U test for differences between males and females.
New Limits Historical Limits Test of M&F diff. (P value) *=sig. diff. Haemoglobin (g/dL) M 13.7–17.2 13.0–17.5 <0.05* F 12.0–15.2 11.7–15.7 RBC (x1012/L) M 4.5–5.6 4.5–5.9 <0.05* F 3.9–5.1 3.8–5.9 Hct (L/L) M 0.40–0.50 0.40–0.52 <0.05* F 0.37–0.46 0.37–0.47 MCV (fL) M 83–98 80–100 0.090 F 85–98 80–100 MCH (pg) M 28–33 27–32 0.391 F 28–33 26–31 MCHC (g/dL) M 32–36 30–36 <0.05* F 32–35 30–36 RDW (%) M 11.6–14.1 11.0–15.0 0.067 F 12.0–14.7 11.0–15.0 Reticulocytes (x109/L) M 27–93 25–85 0.138 F 22–76 25–85 Platelets ( (x109/L) M 140–320 140–450 <0.05* F 180–380 140–450 MPV (fL) M 9.4–12.2 6.3–10.1 0.426 F 9.2–12.9 6.3–10.1 Leucocytes (x109/L) 3.6–9.2 4.0–11.0 0.854 Neutrophils (x109/L) 1.7–6.2 2.0–7.5 0.760 Lymphoctes (x109/L) 1.0–3.4 1.0–4.0 0.854 Monocytes(x109/L) 0.2–0.8 0.2–0.8 0.073 Eosinophils(x109/L) 0.00–0.4 0.04–0.4 0.847 Basophils(x109/L) 0.00–0.1 0.00–0.1 0.279
Reference limits determined for total leucocytes and neutrophils are significantly lower than historical ranges. However, leucocyte counts are at their lowest in the early morning. Our findings are in general agreement with previously published data from more limited trials undertaken in other countries.
Hematological Damage in Systemic Lupus Erythematosus (SLE) and It’s Relationship with Immunological Paramerters.
Authors: Zhao Xiaoying , Zhang Ping , Huang Liansheng 
Published: October 2019

Abstract
Objective To investigate the incidence of hematological damage in systemic lupus erythematosus (SLE) and it’s relationship with disease state of SLE and immunological paramerters.
Methods 155 inpatients with SLE were enrolled in this retrospective study in our hospital from Jan. 2002 to May 2005. All patients fulfiled the criteria of SLE which drawn up by American rheumatism association (ARA) in 1982. Fasting blood samples were obtained and routine of blood, liver and renal function, immunological paramerters (ANA, ENA, Anti -dsDNA,Anti-RNP,Anti-Sm,Anti-SSA,Anti-SSB and C3,C4 constituents of complement)were determined. Acording to SLE Disease activity Index(SLEDAI),disease stata were evaluated in 155 patients and their correlotion with hematological damage and immunological paramerters were analyzed.
Results 67.74% of patients existed hematological disorder. Single cell line damage were in 32.90% of patients while 34.84% of patients were involved several cell lines. The detectable rate of Anti-Sm (43.81%) and Anti-RNP(63.81%) in patients with hematological disorder. were were higher than those in patients without hematological disorder, Anti-Sm in 26.00%, Anti-RNP in 46.00%.The positive rate of Anti-RNP were 68.97% in patients with red cell line damage while only 46.00% in patient without hematological disorder(p<0.05). There were no significant difference in Anti-RNP between patients without hematological disorder and patients with leucocytopenia or thrombocytopenia. 49 patients were in progressive stage and 106 were in stationary stage among 155 patients. hematological damage occurred in approximately 75.51% of patients in progressive stage while it occurred in 64.15% of patients in stationary stage. The prevalence of Anti-dsDNA,Anti-RNP,Anti-Sm were significantly higher in patients with progressive stage than those in patient with stationary stage. single cell line damage and renal damage were early sign of progressive stage of SLE.
Conclusions Hematological system were easily damaged in patients with SLE and Which was related to disease state. Anti-RNP could reflected red cell line damage.
Case Report of Priapism in a Patient with Thalassemia Minor.
Authors: Mankan Nagender , Samavedi Venkata , Mazumder Sudipta , Razaq Mohammad , Gloria Fernandez , Maini Archana 
Published: October 2019

Abstract
Background - Priapism is a urologic emergency caused by hematological problems in about 35% of cases. Its occurrence in sickle cell anemia, leukemia /other malignancies and primary thrombocythemias is well established. A very few case reports of priapism occurring in Thalassemia Intermedia especially after splenectomy have been documented in literature. Veno-occlusive priapism (low flow priapism) beyond 4hours is a compartment syndrome requiring emergent medical intervention. The most important late complication of priapism is fibrosis and impotence and their incidence is related to the duration and aggressiveness of treatment of priapism. We report a case of priapism in a patient of Thalassemia minor.
Case report- A 42 year Asian male was referred from urology service for a hematologic work-up for recurrent episodes of priapism. He was admitted with a 24 hours-long episode of priapism. The history of priapism dates back to 1998, a few months after marriage, when he was admitted for the first episode of priapism and had a decompressive procedure. Since then, for 6 years, he had intermittent, 15 minutes to 1 hour episodes of penile erection. These episodes usually occur after midnight and were unrelated to sexual activity. He did not have any other medical problems and was not on any medications. He was not on any pro-erectile medications. He denied any history of masturbation. He denied any history of alcohol or illicit drug use. He was unaware of any family history of anemia. On physical examination, he did not have pallor, icterus, lymphadenopathy, skin ulcers or hepatosplenomegaly. The penis was circumcised without any trauma or necrosis. His hemoglobin was 10.5 g/dl, hematocrit 34%, MCV 65fl, RDW14.5 %, reticulocyte count 1.3%, platelets 274k/μl, and WBC 6.9k/μl. Peripheral smear showed poikilocytosis, hypochromia and microcytosis without any sickle cells or nucleated RBCs. Hemoglobin electrophoresis showed Hb A of 94%, Hb A2 of 5.6% and Hb F of 0.4%. His clinical picture, blood count, peripheral smear and electrophoresis were consistent with Thalassemia minor. He was managed by removal of inspissated blood and injection of phenylephrine into the corpora cavernosa. This was repeated a few times and the priapism was relieved and patient discharged.
Conclusion- This is the first reported case of priapism in a patient with Thalassemia minor.