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Single-cell Hi-C info evaluation: safety throughout amounts.
Primary aldosteronism (PA) is the most common cause of secondary hypertension with a high prevalence among patients with resistant hypertension. Despite the recent discovery of somatic variants in aldosterone-producing adenoma (APA)-associated PA, causes for PA due to bilateral aldosterone production (bilateral hyperaldosteronism; BHA) remain unknown. Herein, we identified rare gene variants in ATP2B4, in a cohort of patients with BHA. ATP2B4 belongs to the same family of Ca-ATPases as ATP2B3, which is involved in the pathogenesis of APA. Endogenous ATP2B4 expression was characterized in adrenal tissue, and the gene variants were functionally analyzed for effects on aldosterone synthase (CYP11B2) expression, steroid production in basal and agonist-stimulated conditions, and for changes in biophysical properties of channel properties. Go6976 Knockdown of ATP2B4 in HAC15 exhibited reduced angiotensin II stimulation in one of four shRNA clones. Stable HAC15 cell lines with doxycycline (dox) - inducible wild-type and variant forms of ATP2B4 - were generated, and dox-induced upregulation of ATP2B4 mRNA and protein was confirmed. However, ATP2B4 variants did not alter basal or agonist-stimulated CYP11B2 expression. Whole-cell recordings in HAC15 cells indicated robust endogenous ATP2B4 conductance in native cells but reduced conductance with overexpressed WT and variant ATP2B4. The previously defined PA-causing ATP2B3 variant served as a positive control and exhibited elevated CYP11B2 mRNA. In conclusion, while this study did not confirm a pathogenic role for ATP2B4 variants in BHA, we describe the sequencing analysis for familial and sporadic BHA and outline a template for the thorough in vitro characterization of gene variants.Due to an unfortunate mistake, an incorrect image appeared in Fig. 3 (Aspirin 24 h) of the original publication.Midkine (MK) is a heparin-binding growth factor, whose role as a biomarker of coronary artery disease, myocardial ischaemia and necrosis has not been well measured. This study quantified serial MK levels in patients undergoing coronary angiography (CA) and identified factors associated with MK. In this single-centre, parallel cohort study, forty patients undergoing CA had arterial samples collected prior, 10 and 20 min after heparin administration. Four groups were examined 1-stable coronary artery disease (CAD) without percutaneous coronary intervention (PCI); 2-stable CAD for elective PCI; 3-non-ST elevation myocardial infarction (NSTEMI) with or without PCI; 4-ST elevation myocardial infarction (STEMI) with primary PCI. Groups 1, 2 and 4 were heparin naïve, allowing assessment of the effects of myocardial necrosis between baseline levels; group 3 had received low-molecular-weight heparin. MK levels were analysed by ELISA. Median MK at baseline did not differ between groups, demonstrating that myocardial ischaemia or necrosis does not affect MK levels. Heparin administration had an immediate effect on median MK at 10 min, showing an average 500-fold increase that is dose-dependent (R2 = 0.35, p = 0.001). Median MK levels remained elevated at 20 min following heparin administration. Multivariate analysis showed that the estimated glomerular filtration rate (eGFR) was the only predictor of elevated baseline MK (p = 0.02). Baseline MK did not correlate with high-sensitivity troponin-I (HsTnI) taken just before CA (p = 0.97), or peak HsTnI during admission (p = 0.74). MK is not a reliable marker of myocardial ischaemia or necrosis. MK increased significantly in all patients following heparin administration in a dose-dependent manner.PURPOSE The phenotypic and genotypic landscapes in multifocal glioblastoma (MF GBM) cases can vary greatly among lesions. In a MF GBM patient, the rapid development of a secondary lesion was investigated to determine if a unique genetic signature could account for the apparent increased malignancy of this lesion. METHODS The primary (G52) and secondary (G53) tumours were resected to develop patient derived models followed by functional assays and multiplatform molecular profiling. RESULTS Molecular profiling revealed G52 was wild-type for TP53 while G53 presented with a TP53 missense mutation. Functional studies demonstrated increased proliferation, migration, invasion and colony formation in G53. CONCLUSION This data suggests that the TP53 mutation led to gain-of-function phenotypes and resulted in greater overall oncogenic potential of G53.The objective of this study is to report the first multicentric Brazilian series and learning curve of robotic radical cystectomy (RARC) with related intra- and postoperative outcomes. We retrospectively analyzed 37 RARC prospectively collected at four different centers in Brazil, from 2013 to 2019. We analyzed the patient's demographics, pathological tumor, and nodal status, as well as intra- and postoperative outcomes. Statistical analysis was performed with the IBM (SPSS version 25) software. Overall, 86% were male, and the median age was 69 years. 83% had muscle-invasive bladder cancer, and 17% a high-grade, recurrent non-muscle-invasive tumor. The median operative time was 420 min with 300 min as console time. Median blood loss was 350 ml and transfusion rate was 10%. In 68% of the cases, we performed an intracorporeal Bricker urinary diversion, 24% intracorporeal neobladder, and 8% ureterostomy. Six patients (16%) had a Clavien 1-2, 8% had Clavien 3, 2.5% had a Clavien 4, and 5% had Clavien 5. The median length of hospital stay was 7 days. The final pathological exam pointed out pT0 in 16%, pT1 in 8%, pT2 in 32%, ≥ pT3 in 27%, and 16% pTis. 95% had negative surgical margins. The survival at 30, 90, and 180 days was 98%, 95%, and 95%, respectively. To our knowledge, this is the first multicentric series of RARC reporting the learning curve in Brazil; even if still representing a challenging procedure, RARC could be safely and effectively faced by experienced surgeons at centers with high volumes of robotic surgery.In the developing cerebellum, the nascent white matter (WM) serves as an instructive niche for cerebellar cortical inhibitory interneurons. As their Pax2 expressing precursors transit the emerging WM, their laminar fate is programmed. The source(s) and nature of the signals involved remain unknown. Here, we used immunocytochemistry to follow the cellular maturation of the murine cerebellar WM during this critical period. During the first few days of postnatal development, when most Pax2 expressing cells are formed and many of them reach the cerebellar gray matter, only microglial cells can be identified in the territories through which Pax2 cells migrate. From p4 onward, cells expressing the oligodendrocytic or astrocyte markers, CNP-1, MBP or GFAP, started to appear in the nascent WM. Expression of macroglial markers increased with cerebellar differentiation, yet deep nuclei remained GFAP-negative at all ages. The progressive spread of maturing glia did not correlate with the exit of Pax2 cells from the WM, as indicated by the extensive mingling of these cells up to p15.
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