bluuebunny/crossref_metadata_2025_split huggingface dataset:
Traits and characteristics of highly successful medical leaders
Authors: Sharma Shyam S 
Published: October 2019

Background Medicine attracts a broad range of personality traits but the inner thoughts of its leaders have rarely been studied. The BMJ has been asking perceived leaders in the field a set of structured questions on a weekly basis. Those responses have proved insightful into the characteristic traits of high profile doctors. Methods We analysed the responses of each medically qualified doctor interviewed weekly by BMJ Confidential following the use of a set of structured questions about their likes and dislikes. These structured questions allowed us to cross analyse responses. Results From 2013 to 2017, 134 medically qualified doctors were identified by the BMJ to be suitable for inclusion in their weekly BMJ Confidential series. These individuals were selected because they were deemed by the BMJ to be leaders in their clinical, medico-political or academic fields. Of the cohort, 91% were white and 69% male. Clinical mistakes by these individuals were not uncommon (28%) over the course of their careers. Conceit and arrogance were despised most (16%) whereas politics was of interest but not political correctness. The founder of the NHS Aneurin Bevan was identified as the best Secretary of State for Health while the worst was Andrew Lansley (26%) followed by the former health secretary Jeremy Hunt. Conclusion Medicine attracts a broad range of personalities, but the characteristics of its perceived leaders seem less diverse.
Does Size Matter? An Analysis of the Effect of Lumbar Disc Herniation Size on the Success of Nonoperative Treatment
Authors: Gupta Anmol , Upadhyaya Shivam , Yeung Caleb M. , Ostergaard Peter J. , Fogel Harold A. , Cha Thomas , Schwab Joseph , Bono Chris , Hershman Stuart 
Published: October 2019

Study Design: Retrospective study. Objective: In this study, we examined whether the size of a lumbar disc herniation (LDH) is predictive of the need for surgical intervention within 2 years after obtaining an initial magnetic resonance imaging (MRI) scan. We hypothesized that a fragment that occupied a larger percentage of the spinal canal would not predict which patients failed conservative management. Methods: Using the ICD-10 code M51.26, we identified patients at a single academic institution, across the 2-year period from 2015 to 2016, who received a diagnosis of primary lumbar radicular pain, had MRI showing a disc herniation, and underwent at least 6 weeks of nonoperative management. Patients experiencing symptoms suggesting cauda equina syndrome and those with progressive motor neurological deficits were excluded from analysis, as were patients exhibiting “hard” disc herniations. Within the axial view of an MRI, the following measurements were made on AGFA-IMPACS for a given disc herniation: the length of both the canal and the herniated disc along the anterior-posterior axis, the average width of the disc within the canal; the total canal area, and the area of the disc herniation. Data analysis was conducted in SPSS and a 2-tailed reliability analysis using Cronbach’s alpha as a measure of reliability was obtained. Results: A total of 368 patients met the inclusion and exclusion criteria for this study. Of these, 14 (3.8%) had L3-L4 herniations, 185 had L4-L5 herniations (50.3%), and 169 had L5-S1 herniations (45.9%). Overall, 336 (91.3%) patients did not undergo surgery within 1 year of the LDH diagnosis. Patients who did not receive surgery had an average herniation size that occupied 31.2% of the canal, whereas patients who received surgery had disc herniations that occupied 31.5% of the canal on average. A Cronbach’s alpha of .992 was observed overall across interobserver measurements. After controlling for age, race, gender, and location of herniation through a logistic regression, it was found that the size of the herniation and the percentage of the canal that was occupied had no predictive value with regard to failure of conservative management, generating an odds ratio for surgery of 1.00. Conclusions: The percentage of the spinal canal occupied by a herniated disc does not predict which patients will fail nonoperative treatment and require surgery within 2 years after undergoing a lumbar spine MRI scan.
Mineralogical study of clays from Dobrodo, Serbia, for use in ceramics
Authors: Milošević Maja , Dabić Predrag , Kovač Sabina , Kaluđerović Lazar , Logar Mihovil 
Published: October 2019

AbstractThis study focuses on the mineralogical characterization of four raw clay samples from Dobrodo deposit, Serbia. Several analytical methods were applied to determine the chemical and mineralogical composition, morphology and physical properties (colour, plasticity, specific surface area, particle size and cation-exchange capacity) of the clay samples. Kaolinite, smectite and illite are the predominant phases in all of the samples studied that contain between 60.2 and 87.1 wt.% of clay. Quartz, feldspars, paragonite and Ti- and Fe-bearing phases were also identified. The relatively high SiO2/Al2O3 mass ratio indicates abundant quartz. The cation-exchange capacity of the samples varied between low and moderately charged clay minerals (12–52 mmol 100 g–1) with specific surface area values ranging from 94 to 410 m2 g–1. The plasticity index values (11–23%) suggest low to moderate plasticity. Preliminary results show that most of the raw clay from Dobrodo deposit might be suitable for use in ceramic applications.
A Novel Mechanism of Endothelial Protein C Receptor Release, in Microparticulate Form, by Activated Protein C.
Authors: Perez-Casal Margarita , Fukudome Kenji , Toh Cheng Hock 
Published: October 2019

Abstract
Activated protein C (APC) administration is now used for treating patients with severe sepsis. We investigated its effect on primary, physiologically relevant cells and demonstrate a novel mechanism of endothelial protein C receptor (EPCR) release from the cell surface. Exposure of human umbilical vein endothelial cells or monocytes to APC (from physiological levels of 0.5 up to 100nM) resulted in the increasing release of EPCR-containing microparticles (EPCR-MP), as demonstrated by confocal microscopy. Further characterisation through flow cytometry showed a concomitant fall in EPCR levels from the cell surface. This release of EPCR could not be inhibited by the metalloproteinase inhibitors 1, 10-phenanthroline or Ro31-9790, unlike soluble EPCR (sEPCR) that is metalloproteinase cleaved at the cell surface following thrombin or pro- inflammatory cytokine stimulation. Western blotting confirmed the molecular weight of EPCR-MP to be identical to the full-length membrane form (49 kD) and different from sEPCR (45 kDa). APC was also bound to EPCR-MP and could be quantified by ELISA using EPCR capture and APC detection by chromogenic substrate, S2366. Using an initial factor Va incubation step followed by a prothrombinase assay, the APC bound to EPCR-MP could significantly reduce thrombin generation. This was abrogated in the presence of excess α1-antitrypsin, an APC inhibitor. By contrast, APC bound to sEPCR could no longer inactivate factor Va. Further characterisation showed the APC induction of EPCR-MP to be time dependent with increasing release over 24 hours, as quantified by ELISA. The phenomenon also required the active site of APC. Neither protein C, heat-inactivated or D-Phe-Pro-Arg-chloromethylketone-blocked APC could induce EPCR-MP formation. Co-incubation with hirudin (6mM) did not alter the APC effect and excluded any role of contaminating thrombin. This novel observation provides new insights into the consequences of APC therapy in the septic patient as well as demonstrating for the first time that there can be 2 circulating forms of EPCR. Unlike sEPCR however, EPCR-MP can facilitate and potentially disseminate the anticoagulant activity of bound APC.
The Effect of Grp78 Inhibition on Tissue Factor Gene Expression, Procoagulant Activity, and Factor Xa Generation.
Authors: Bhattacharjee Gourab , Ahamed Jasimuddin , Pedersen Brian , El-Sheikh Amr , Liu Cheng , Mackman Nigel , Edgington Thomas S. 
Published: October 2019

Abstract
In vivo biopanning with phage displayed peptide libraries has generated a group of peptide probes which bind selectively to the surface of atherosclerotic plaque endothelium. The highest affinity peptide, EKO130, binds to the 78 kDa glucose regulated protein (Grp78). Grp78 has been demonstrated to play a role in numerous pathological processes as well as a possible role in the local cell surface regulation of the coagulation cascade. The goal of this study is to determine the role of Grp78 in coagulation including plasma clotting, factor Xa (Xa) generation, and tissue factor (TF) gene expression. siRNA mediated inhibition of Grp78 results in a marked increase in TF gene expression in bEND.3 endothelial cells and RAW macrophage-like cells. Antibody mediated inhibition of cell surface Grp78 results in increased TF procoagulant activity and TF-dependent Xa generation in both the endothelial and macrophage cell types. These studies are consistent with results from another laboratory demonstrating that Grp78 over-expression inhibits TF mediated initiation and support of the coagulation protease cascade. Thus, our work indicates that Grp78 suppresses TF at both the functional and molecular level by inhibiting both its thrombogenic potential and gene expression.
TAT/HDL Induces the Phospholylation of Cofilin in the Process of Platelet Production of Megakaryocytes.
Authors: Ishida Yoji , Kowata Syugo , Murai Kazunori , Oyake Tatsuo , Ito Shigeki 
Published: October 2019

Abstract
In the previous ASH Meetings, we have reported that thrombin/antithrombin complex in association with high density lipoprotein (TAT/HDL) directly stimulated proplatelet formation (PPF) of human or murine megakaryocytes. In this study, we investigated the signal transduction pathways responsible for platelet production from megakaryocytes using human megakaryoblastic cell line (MEG).
TAT/HDL stimulated MEGs to induce the many platelet-like particles (PP) around the cells in the serum free culture during 12~24 hrs (Fig. 1). The frequency of MEGs with PP increased with the increase of TAT/HDL in a dose dependent manner (0 μg/ml: 1.8±0.5%, 50 μg/ml: 30.8±4.5%, 100 μg/ml: 46.5±7.8%, 200 μg/ml: 57.8±8.3%, mean±SD, n=4). The frequency of MEGs with PP, expressed as a pecentage of the control, was significantly decreased after the incubation with TAT/HDL(150 μg/ml) and Y27632, a specific inhibitor for Rho kinase(ROCK), (Y27632 10 μM: 61.3±7.9% of the control (p<0.01), 100 μM: 12.5±5.9% of the control (p<0.01), mean±SD, n=4). MEGs were incubated with TAT/HDL (150 μg/ml) in serum free condition for 5, 10, 15, 30, 60, 90, 120, 150 and 180 min. MEGs were havested, washed twice and lysed by the lysis buffer (50mM Tris/HCl, 150 mM NaCl. 0.5% Nonidet P-40 pH 6.8 with protease inhibitors’ cocktail) for the Western blot analysis. Activated Rho (GTP-bound state Rho), measured by the Western blot using Rhotekin-Rho binding domain (RBD) beads and anti-Rho antibody, increased at 90, 120 and 150 min after the incubation. ROCK was co-precipitated with activated Rho using Rhotekin-RBD beads and detected by the Western blot analysis using anti-ROCK antibody at 90, 120 and 150 min. LIM kinase was immunoprecipitated with ROCK/anti-ROCK antibody and protein G sepharose. Western blot analysis using anti-phosphothreonine antibody revealed that LIM-kinase was phospholylated at 90, 120 and 150 min after the incubation. Phospholylated cofilin (Ser3) expression was detected by the Western blot using anti-phosphocofilin antibody at 60 min, peaked at 120 min and tapered at 150 min after the incubation (Fig.2). The intensity of the phospholylated cofilin (Ser3) band decreased in the incubation of MEGs with TAT/HDL and Y27632 (100 μM) at each time. These results strongly suggested the platelet-like particles production from MEGs, stimulated by TAT/HDL, was involved in the pathway from Rho activation, ROCK activation, LIM kinase phospholylation and cofilin phospholylation, based on the evidence that phospholylated cofilin showed the inhibition of actin depolymerization and the stabilization of actin filaments.
Fig.1 (a) MEGs with no stimulation (b) MEGs with TAT/HDL (200 μg/ml) for 24h
Fig.2 Expression of phospholylated cofilin (Ser3).
Figure Figure Figure Figure
CHIR-12.12, an Antagonist Anti-CD40 Antibody, Exhibits Greater ADCC Than Rituximab Against a Variety of Malignant B Cells: Evaluation of FcγRIIIa Polymorphism and ADCC Response.
Authors: Luqman Mohammad , Tong Xia , Niu Xiaohong , Garcia Pablo , Faure Michel , Yabannavar Asha , Jallal Bahija 
Published: October 2019

Abstract
We have generated a novel, fully human IgG1 anti-CD40 antagonistic monoclonal antibody, CHIR-12.12, using XenoMouse® mice (Abgenix, Inc.) and have previously demonstrated that it inhibits normal human B cell proliferation and survival and has potent ADCC against primary CLL and NHL cells. CHIR-12.12 and the anti-CD20 monoclonal antibody rituximab were compared for their relative ADCC activity against a variety of malignant human B-cell lines expressing both CD40 and CD20 antigens, including two lymphoma cell lines (Daudi, Namalwa), two multiple myeloma cell lines (ARH77, IM-9), a B-ALL cell line (CCRF-SB), and a B-CLL cell line (EHEB). All cell lines expressed both CD20 and CD40 antigens, and the number of cell surface CD20 molecules per cell were 2.6- to 30.8-fold higher than CD40. For all target cell lines, despite the greater number of CD20 receptors, CHIR-12.12 showed greater maximum cell lysis and a lower ED50 than rituximab. ADCC activity of rituximab is known to correlate with the FcγRIIIa genotype of the effector cells. The homozygous valine (V/V) or heterozygous valine/phenylalanine (V/F) polymorphisms at aa158 are associated with greater cell lysis than is the homozygous F/F polymorphism. The role of the FcγRIIIa aa158 genotype as it relates to CHIR-12.12 activity was explored using Daudi lymphoma target cells and effector NK cells purified from human donors expressing the three polymorphisms. CHIR-12.12 induced potent ADCC with NK cells of all three genotypes (ED50s of 4, 2, and 0.4 pM for F/F, V/F, and V/V, respectively). The rituximab ED50s were 53, 21, and 9 pM for F/F, V/F, and V/V, respectively. Comparison of affinity of the FcγRIIIa F and V alleles for CHIR-12.12 and rituximab using Biacore® analysis showed that CHIR-12.12 bound the F allele with a 4.6-fold higher affinity than rituximab (2.8 μM versus 13 μM, respectively). These data demonstrate that CHIR-12.12 is a more potent ADCC mediator than rituximab, even with human NK cells of the aa158 F/F genotype. CHIR-12.12 is currently in Phase I clinical trials for B-cell malignancies.
Regulation of Exon 2′/2 of Protein 4.1R by Coordinated Transcription and Splicing.
Authors: Huang Shu-Ching , Norton Stephanie M. , Liu Eva S. , AnYu Zhou , Guang Yang , Benz Edward J. 
Published: October 2019

Abstract
Alternative splicing events altering the 5′ end of the red blood cell protein 4.1 (4.1R) mRNA are critical for modulating the expression of both the 135 kD and 80 kD isoforms. Three mutually exclusive 5′ exons, 1A, 1B, and 1C, are transcribed from their respective promoter and exhibit differential splicing to exon 2′/2 splice acceptor sites. Exon 1A splices to the distal 3′ splice site (3′ ss) excluding exon 2′ and encoding for the 80 kD isoform. Exons 1B and 1C splice to the proximal 3′ ss, including exon 2′ in mature mRNA and encoding for the 135 kD form. We investigated the regulatory mechanism involved in the selection of the alternative 3′ ss, using 1A, 1B, and 1C minigene constructs containing intronic sequences downstream of each exon joined with intronic sequences upstream of exon 2′. We positioned either CMV or the respective native promoter upstream of the minigene and analyzed the spliced products for exon 2′ expression in mouse (MELC or C2C12) or human (HeLa or RD) cells. When under the control of the CMV promoter, all 1A, 1B, and 1C minigenes resulted in the inclusion of exon 2′. However, when under the control of its respective promoter, the minigene mimicked its endogenous splicing pattern, suggesting that promoter identity influences the alternative exon 2′ splicing decision. To confirm this hypothesis, we switched 1A and 1B promoters in their respective minigene constructs. Replacement of the 1A promoter by the 1B promoter resulted in the inclusion of exon 2′ in the 1A minigene. Conversely, replacement of the 1B promoter by the 1A promoter caused increased exclusion of exon 2′ in the 1B minigene, confirming that alternative splicing of exon 2′ is sensitive to the type of promoter. The current model on the modulation of alternative splicing by promoters suggests that the promoter might control alternative splicing via the regulation of polymerase II (pol II) elongation or processivity. To test whether the same mechanism applies to exon 2′/2 splicing, we treated 1A and 1B minigene-transfected cells with transcription elongation inhibitor 5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB). Inhibition of transcription elongation did not affect splicing of the 1B minigene, but it enhanced exon 2′ inclusion in the 1A minigene. The distal 3′ ss is a stronger splice site than the proximal 3′ ss. A highly processive elongating pol II favors the simultaneous presentation of both sites to the splicing machinery, a situation in which the distal 3′ ss out-competes the proximal 3′ ss, resulting in exon 2′ exclusion. Conversely, a slow pol II processivity on the 1B promoter favors the selection of the proximal 3′ ss and inclusion of exon 2′. Taken together, our results show that the alternative splicing of exon 2′/2 is tightly coupled to promoter architecture. Inclusion or exclusion of exon 2′ is achieved through a coordinated action of transcription and splicing.
Identification of New Megakaryocytic Subpopulations in Mouse Bone Marrow.
Authors: Sogo Shinji , Matsumura-Takeda Kuniko , Isakari Yoshimasa , Harada Yasuo , Nishioka Kinue , Kawakami Takuma , Ono Toshihide , Taki Takao 
Published: October 2019

Abstract
Platelets (PLT) are produced from megakaryocytes (Mks) via proplatelet formation (PPF). However, the molecular mechanisms from Mks to PPF are not clearly elucidated, because the maturational steps of the Mks in bone marrow (BM) are not analyzed in detail. Until now, mouse Mks have been only isolated as acetylcholinesterase (AchE) positive cells and they are understood as well maturated population. In this study, we found the presence of different megakaryocytic subpopulations in BM by flowcytometry. To isolate the Mks, first we depleted lineage marker (CD4, CD8a, CD11b, B220, CD71, CD90, TER119, Gr-1, F4/80, 7/4) positive cells from BM cells of BALB/c mice. The analysis of the expression-pattern of CD41, CD45 and CD61 in the lineage negative (Lin−) cells showed the presence of two types of megakaryocytic subpopulations. By sorting, they were identified as Lin−CD41+/45+/61+ cells (AchE negative) and Lin−CD41++/45+/61++ cells (partially AchE positive), respectively. To assess the maturational stages of the subpopulations, each population was cultured with 10ng/mL of TPO followed by counting of PPF and PLT production. Both PPF and PLT production were observed in Lin−CD41+/45+/61+ cells later than those in Lin−CD41++/45+/61++ cells. On the other hand, CFU-Mk was scarcely detected in each subpopulation. The results indicate that both populations are the committed megakaryocytes and Lin−CD41+/45+/61+ cells are more immature population than Lin−CD41++/45+/61++ cells. Then to characterize these subpopulations in detail, gene expression profiling was performed against four-megakaryocytic lineage-populations, Lin−CD41−Thy1lowc-kit+ cells as stem/progenitor, Lin−CD41+/45+/61+ cells, Lin−CD41++/45+/61++ cells and PLT using GeneChipU74 or RT-PCR. These analyses revealed that many PLT-specific genes including gpIb/IX, P-selectin, thrombin-R and ADP-R were already expressed on Lin−CD41+/45+/61+ cells but less than Lin−CD41++/45+/61++ cells. Especially, beta-1 tubulin that is necessary for PPF was only expressed on Lin−CD41++/45+/61++ cells. On the contrary, the expression of c-kit gene was gradually decreasing from stem/progenitor fraction to PLT. In conclusion, we succeeded in the isolation of new subpopulations distinguishable between immature Mks and more matured Mks beginning to prepare PLT. The present finding can contribute to elucidate the molecular mechanisms during terminal maturation.
Hydroxyurea Treated Sickle Disorders Demonstrate Decreased Plasma Hb, Red Cell Vesicles and Thrombolysis.
Authors: Westerman Maxwell P. , Pizzey Arnold , Hirshman Jocelyn , Cerino Mario , Eze Ada , Lawrie Andrew , Purdie Gordon , Mackie Ian , Porter John 
Published: October 2019

Abstract
Free plasma Hb has been recently implicated in the genesis of pulmonary hypertension in sickle cell disorders (SCD) through a putative NO scavenging mechanism. We have recently reported that free plasma Hb is correlated with increased plasma red cell derived vesicles (RBVes) in sickle cell and thalassemia disorders (Westerman, Blood2004; 104:1671). Since high levels of HbF have been associated with decreased elevation of RBVes in children with SCD (Setty Blood2000;96:1119–1124), we hypothesized that patients treated with hydroxyurea (HU) might show a similar normalisation of RBVes. Given our finding of an association between RBVes and free plasma Hb, such treatment might also be predicted to correct increments in free plasma Hb. In this study we have examined whether sickle cell patients treated with HU show evidence of a decrease in free plasma Hb and RBVes compared to untreated SCD patients. RBVes, free plasma Hb, and markers of activation of thrombolysis were quantitated. 35 adult SCD patients, 27 in steady state, untransfused and not receiving HU and 7 patients on long term HU at a dose of 10–30 mg/kg/day. These parameters were also measured in 27 healthy control subjects without SCD. RBVes were significantly higher in untreated SCD (15.59±3.07 x 103/μL of blood) than in control subjects (2.13 ± 0.5)(p=0.001). In HU-treated SCD patients, vesicles were significantly lower (3.97±0.83)(p=0.0371). than in untreated patients and approached levels found in healthy controls. Free plasma Hb was significaly increased in untreated SCD (16.74±3.87) compared with healthy controls (1.77±0.2)(p=0.001); these levels were also corrected in HU treated SCD patients (13.42±4.48). The proportion of RBVes expressing phosphatadyl serine was also lower in HU-treated SCD (37.25± 9.79) than in untreated SCD (52.52±4.74). This was paralleled by a decrease in red cells expressing PS in HU treated patients (11.83± 3.95) compared with untreated patients (42.71±8.45)(p=0.011). This decrease in both RBVes and RBCs expressing PS in HU-treated patients might in principle decrease activation of coagulation. Indeed, plasma Ddimers, which are increased in untreated SCD (480 ±60.14) compared with healthy controls (117.43±38)(p=0.018). are normalised in HU treated patients (190±28.69). These data provide evidence of a link between RBVes and plasma Hb and suggest that PS expression on RBVes and red cells plays a role in the prothrombotic state seen in SCD. As HU treatment appears to correct plasma Hb, long term treatment may be associated with a decreased scavenging of NO and hence the risk of pulmonary hypertension. The correction of the prothrombotic tendency may also be beneficial in this regard. Prospective trials are indicated to confirm whether HU treated patients have evidence of decreased risk of pulmonary hypertension.