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Atypical Demonstration regarding Idiopathic Retroperitoneal Fibrosis Effectively Helped by Colchicine Right after Lymphoma Misdiagnosis.
Applying the DTF model to predict missing entries in our drug-cell line tensor, we identified novel synergistic drug combinations for 10 cell lines from the 5 cancer types. A literature survey showed that some of these predicted drug synergies have been identified in vivo or in vitro. Thus, the DTF model could be a valuable in silico tool for prioritizing novel synergistic drug combinations. AVAILABILITY Source code and data is available at https//github.com/ZexuanSun/DTF-Drug-Synergy. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online. © The Author(s) (2020). Published by Oxford University Press. All rights reserved. For Permissions, please email [email protected] Invasive meningococcal disease clusters occur amongst university students and may reflect higher carriage prevalence amongst this population. We aimed to measure meningococcal carriage prevalence, acquisition and risk factors amongst first-year university students in South Africa, a middle-income country. METHODS In summer to autumn 2017, after consenting to participate, we collected oropharyngeal swabs and questionnaires on carriage risk factors and tested students for HIV infection at two universities, during registration week (survey one) and 6-8 weeks later (survey two). Meningococci were detected by culture and polymerase chain reaction. RESULTS We enrolled 2120 students at registration. Mean age was 18.5 years, 59% (1252/2120) were female and 0.8% (16/1984) were HIV-infected. Seventy-eight percent of students returned for survey two (1655/2120).Amongst the cohort, carriage prevalence was 4.7% (77/1655) at registration; increasing to 7.9% (130/1655) at survey two 5.0% (83) acquired new carriage, 2.8% (47) had persistent carriage, 1.8% (30) cleared the initial carriage and 90.3% (1495) remained carriage-free. At both surveys, non-genogroupable meningococci predominated, followed by genogroups Y, B, W and C. On multinomial analysis risk factors for carriage acquisition included attending nightclubs (adjusted relative risk ratio (aRRR) 2.1 (95%CI=1.1-4.0)), having intimate kissing partners (aRRR 1.8 (95%CI=1.1-2.9)) and being HIV-infected (aRRR 5.0 (95%CI=1.1-24.4)). CONCLUSION Meningococcal carriage amongst first-year university students increased after two months. Social-behavioural risk factors were associated with increased carriage for all analyses. HIV-infection was associated with carriage acquisition. Until vaccination programmes become mandatory in South African universities, data suggest that HIV-infected students could benefit most from meningococcal vaccination. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.The bispecific antibody Emicizumab is increasingly used for hemophilia A-treatment. However, its specificity for human factors IX and X (FIX, FX) has limited its in vivo functional analysis to primate models of acquired hemophilia. Here we describe a novel mouse model allowing to examine Emicizumab function. Briefly, FVIII-deficient mice receive Emicizumab intravenously 24h before performing a tail clip-bleeding model. A second infusion with human FIX and FX is administered 5 min before bleeding. This approach generates consistent levels of Emicizumab (0.7-19 mg/dL for 0.5-10 mg/kg dose) and of both FIX and FX (85 and 101 U/dL respectively, after dosing 100 U/kg). Plasmas from these mice display FVIII-like activity in a diluted aPTT and in thrombin generation assays, similar to human samples containing Emicizumab. Emicizumab doses of 1.5 mg/kg and higher significantly reduced blood loss in a tail clip-bleeding model using FVIII-deficient mice. However, reduction was incomplete compared to mice treated with human FVIII concentrate, and no difference in efficacy between doses was observed. From this model, we deducted a FVIII-like activity of Emicizumab that corresponds to a dose of 4.5 U FVIII/kg (i.e. 9.0 U/dL). Interestingly, combined with a low FVIII dose (5 U/kg), Emicizumab provided additive activity to allow a complete bleeding arrest. This model could be useful for further in vivo analysis of Emicizumab. Copyright © 2020 American Society of Hematology.The platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases allows cells to communicate with the environment to regulate diverse cellular activities. Here, we highlight recent data investigating the structural makeup of individual PDGFRs upon activation, revealing the importance of the whole receptor in the propagation of extracellular ligand binding and dimerization. Furthermore, we review ongoing research demonstrating the significance of receptor internalization and signal attenuation in the regulation of PDGFR activity. Interactions with internalization machinery, signaling from endosomes, receptor degradation and receptor recycling are physiological means by which cells fine-tune PDGFR responses to growth factor stimulation. In this review, we discuss the biophysical, structural, in silico and biochemical data that have provided evidence for these mechanisms. We further highlight the commonalities and differences between PDGFRα and PDGFRβ signaling, revealing critical gaps in knowledge. In total, this review provides a conclusive summary on the state of the PDGFR field and underscores the need for novel techniques to fully elucidate the mechanisms of PDGFR activation, internalization and signal attenuation. MSC2530818 © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.This review discusses recent advances in single-particle cryo-EM and single-molecule approaches used to visualise eukaryotic DNA replication reactions reconstituted in vitro. We comment on the new challenges facing structural biologists, as they turn to describing the dynamic cascade of events that lead to replication origin activation and fork progression. © 2020 The Author(s).BACKGROUND Type 2 diabetes (T2D) and resistant hypertension (rHT) often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676). METHODS Overall, 7020 patients received empagliflozin 10mg, 25mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ≥3 classes of antihypertensive drugs including a diuretic and uncontrolled BP (SBP≥140 and/or diastolic BP [DBP]≥90 mmHg), or ≥4 classes of antihypertensive, including a diuretic, and controlled BP. We explored the effect of empagliflozin on CV death, heart failure hospitalization (HHF), 3-point major adverse cardiac events (3P-MACE), all-cause death, and incident/worsening nephropathy by Cox regression and BP over time by a mixed-repeated-measures-model analysis. RESULTS 1579 (22.5%) patients had prHT. The mean difference in change in SBP from baseline to week 12 versus placebo was -4.
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