© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open-label, multicenter study to investigate an intrapatient nilotinib dose-escalation strategy for patients with newly diagnosed chronic-phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty-three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. https://www.selleckchem.com/products/pyridostatin-trifluoroacetate-salt.html An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207-736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5 . The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non-AE related reasons. Four of these patients achieved MR4.5 . The MR4.5 rate by 24 months was 45.7%. The progression-free, overall and event-free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML-CP. © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.AIMS Although serum uric acid (SUA) level is correlated with oxidative stress and serves as a marker of poor prognosis in heart failure patients, its possible association with subclinical left ventricular (LV) dysfunction has not been evaluated. This study aimed to investigate the association between SUA and subclinical LV dysfunction in a sample of a general population without overt cardiac disease. METHODS AND RESULTS We examined 1175 participants who underwent extensive cardiovascular health check-up including laboratory tests and speckle-tracking echocardiography to assess LV global longitudinal strain (GLS). The association of SUA concentration, as a continuous variable and a categorical variable using quartiles, with the presence of abnormal LVGLS was assessed. Mean age was 62 ± 12 years, and 656 (56%) were male participants. Mean SUA was 5.6 ± 1.3 mg/dL (25th-75th percentile, 4.6-6.5 mg/dL). The prevalence of abnormal LVGLS (greater than -18.6%) was greatest in the upper quartile of SUA. In multivariable analysis, SUA as a continuous variable was significantly associated with abnormal LVGLS [adjusted odds ratio (OR), 1.26 per 1 mg/dL; P = 0.008] independent of traditional cardiovascular risk factors, pertinent laboratory parameters and echocardiographic measures, and medications. In the categorical analysis, the upper quartile of SUA was independently associated with abnormal LVGLS in a fully adjusted model (adjusted OR, 2.28 vs. lowest quartile; P = 0.020). CONCLUSIONS In a sample of the general population, an elevated SUA was independently associated with subclinical LV dysfunction. Assessment of LVGLS may add important prognostic information in individuals with elevated SUA, even in the absence of overt cardiac disease. © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.BACKGROUND Polysyndactyly (PSD) is an autosomal dominant genetic limb malformation caused by mutations. METHODS Whole exome sequencing and Sanger sequencing were used to determine the mutations in PSD patients. Luciferase reporter assay was performed to determine the effect of GLI3 mutation on its transcriptional activity. RESULTS In this study, we investigated the gene mutations of three affected individuals across three generations. The frameshift mutations of GLI3 (NM_000168c.4659del, NP_000159.3 p.Ser1553del), ANKUB1 (NM_001144960c.1385del, NP_001138432.1 p.Pro462del), and TAS2R3 (NM_016943c.128_131del, NP_058639.1 p.Leu43del) were identified in the three affected individuals, but not in three unaffected members by whole exome sequencing and sanger sequencing. Luciferase reporter assay demonstrated that GLI3 mutation reduced the transcriptional activity of GLI3. The results from SMART analysis showed that the frameshift mutation of TAS2R3 altered most protein sequence, which probably destroyed protein function. Although the frameshift mutation of ANKUB1 did not locate in ankyrin repeat domain and ubiquitin domain, it might influence the interaction between ANKUB1 and other proteins, and further affected the ubiquitinylation. CONCLUSION These results indicated that the frameshift mutations of GLI3, ANKUB1, and TAS2R3 might alter the functions of these proteins, and accelerated PSD progression. © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.PURPOSE The behavior of implant-crowns fabricated from recently introduced CAD-CAM zirconia-reinforced lithium silicate ceramic (ZLS) or a hybrid ceramic containing resin-reinforced glass network (HC) for strains around the implant platform is not well-known. A force absorption capacity of the latter has been claimed by the manufacturer. The aim of this study was to measure and compare recently introduced ZLS and HC with commonly used CAD-CAM implant crown materials for strain distribution around the implant platform. METHODS Four implants (Legacy 1; Implant Direct) were placed into a resin block. Zirconia abutments (Straight contoured stock abutment; Implant Direct) were torqued into the implant fixtures to support crowns that were milled from a virtual design using four different CAD-CAM materials (Vita Suprinity PC (ZLS), Vita Enamix (HC), IPS Emax, ZirCAD Zirkonzahn) (N = 20). The crowns were cemented with a resin cement, loaded and strain values were recorded. Three-dimensional digital image correlation (3D-DIC) was used to measure compressive and tensile strains around the implant platforms. The tensile and compressive strains were recorded for each test and first analyzed for equality of variance using Levene's test, and further tested using a 2-way ANOVA repeated measures analysis of variance (α = .05). RESULTS The data analysis showed no statistically significant effect of crown material on the generated strains (P > .05). Compressive strains were significantly higher than the tensile strains (P  less then  .05). One of the HC crowns fractured during loading. CONCLUSIONS Strains generated around implant platform when new generation CAD-CAM crown materials were used was similar to strains observed when CAD-CAM zirconia and lithium disilicate crowns were used. New generation crown materials did not have a significant load absorption effect to change or minimize the strains generated around the implant platform. © 2020 Wiley Periodicals LLC.