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1.
Blood ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-33024987

RESUMO

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted, oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

2.
Org Biomol Chem ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33016295

RESUMO

A simple and efficient synthetic protocol for the preparation of acridinium esters and amides through the cyclization and esterification or amidation of isatins with alcohols or amines as nucleophiles in the presence of CF3SO3H is established. A series of polycyclic acridine derivatives bearing large π-conjugated systems were obtained in high yields, including some key intermediates for the synthesis of biologically active molecules. The photophysical properties of these synthesized acridines were investigated, demonstrating that the sulfur heterocyclic acridine 9w was obtained in a high quantum yield.

3.
Antioxidants (Basel) ; 9(10)2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036258

RESUMO

Vascular calcification (VC) is highly prevalent in patients with atherosclerosis, chronic kidney disease, diabetes mellitus, and hypertension. In blood vessels, VC is associated with major adverse cardiovascular events. Xanthohumol (XN), a main prenylated chalcone found in hops, has antioxidant effects to inhibit VC. This study aimed to investigate whether XN attenuates VC through in vivo study. A rat VC model was established by four weeks oral administration of vitamin D3 plus nicotine in Sprague Dawley (SD) rats. In brief, 30 male SD rats were randomly divided into three groups: control, 25 mg/kg nicotine in 5 mL corn oil and 3 × 105 IU/kg vitamin D3 administration (VDN), and combination of VDN with 20 mg/L in 0.1% ethanol of XN (treatment group). Physiological variables such as body and heart weight and drinking consumption were weekly observed, and treatment with XN caused no differences among the groups. In comparison with the control group, calcium content and alkaline phosphatase (ALP) activity were increased in calcified arteries, and XN treatment reduced these levels. Dihydroethidium (DHE) and 2',7'-dichloroflurescin diacetate (DCFH-DA) staining to identify Superoxide and reactive oxygen species generation from aorta tissue showed increased production in VDN group compared with the control and treatment groups. Hematoxylin eosin (HE) and Alizarin Red S staining were determined to show medial vascular thickness and calcification of vessel wall. Administration of VDN resulted in VC, and XN treatment showed improvement in vascular structure. Moreover, overexpression of osteogenic transcription factors bone morphogenetic protein 2 (BMP-2) and runt-related transcription factor 2 (Runx2) were significantly suppressed by XN treatment in VC. Moreover, downregulation of vascular phenotypic markers alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) were increased by XN treatment in VC. Furthermore, XN treatment in VC upregulated nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expressions. Otherwise, Kelch-like ECH-associated protein 1 (Keap1) was alleviated by XN treatment in VC. In conclusion, our findings suggested that XN enhances antioxidant capacity to improve VC by regulating the Nrf2/Keap1/HO-1 pathway. Therefore, XN may have potential effects to decrease cardiovascular risk by reducing VC.

4.
Psychol Health Med ; : 1-10, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044837

RESUMO

The purpose of this study was to determine the effect of video-based nursing education on perioperative anxiety and depression. A total of 128 patients scheduled for minimally invasive gastrectomy were randomly divided into intervention (n = 64) and control (n = 64) group. The. The anxiety and depression scores, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were assessed before the intervention, 1 h before surgery and 24 h after surgery. And the cortisol levels were measured before the intervention and 1 h before surgery. No significant difference was observed in baseline anxiety score, depression score, vital signs and cortisol level (P > 0.05). The anxiety level, depression level, SBP, DBP and HR of patients in intervention group was significantly lower than that in control group at 1 h before surgery and 24 hs after surgery (P < 0.05). The serum cortisol in the intervention group was also significantly lower than that in the control group 1 h before surgery (p < 0.001). Video-based nursing education was effective in decreasing the perioperative anxiety and depression of patients undergoing minimally invasive gastrectomy. It could also keep vital signs and serum cortisol levels in normal limits.

5.
Clin Cancer Res ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046514

RESUMO

PURPOSE: We investigated the value of circulating tumor DNA (ctDNA) in predicting tumor response to neoadjuvant chemoradiotherapy (nCRT), monitoring tumor burden, and prognosing survival in patients with locally advanced rectal cancer (LARC). EXPERIMENTAL DESIGN: This prospective multicenter trial recruited 106 LARC patients for treatment of nCRT followed by surgery. Serial ctDNA were analyzed by NGS at four time points: at baseline, during nCRT, pre-surgery and post-surgery. RESULTS: In total, 1098 mutations were identified in tumor tissues of the 104 patients being analyzed (median, 7 mutations per patient). ctDNA was detected in 75%, 15.6%, 10.5%, and 6.7% of cases at the four time points, respectively. None of the 29 patients with pathological complete response (ypCR) had preoperative ctDNA detected. Preoperative ctDNA positive rate was significantly lower in the well responded patients with pathological tumor regression grade of ypCAP 0-1 than ypCAP 2-3 group (P < 0.001), lower in ypCR than non-ypCR group (P = 0.02), and lower in ypT 0-2 than ypT 3-4 group (P = 0.002). With a median follow-up of 18.8 months, thirteen patients (12.5%) experienced distant metastasis. ctDNA positivity at all four time points was associated with a shorter metastasis-free survival (MFS) (P < 0.05). Multivariate analyses showed that the median VAF of mutations in baseline ctDNA was a strong independent predictor of MFS (HR=1.27, P < 0.001). CONCLUSIONS: We show that ctDNA is a real-time monitoring indicator that can accurately reflect the tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of MFS.

6.
Polymers (Basel) ; 12(10)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066612

RESUMO

Carboxyl-type boronic acid copolymers (CBACs) were synthesized by a radical polymerization method and used for the preparation of polyvinyl alcohol (PVA)-based composite membranes via a solution mixture method. The as-prepared composite membranes exhibited a water uptake (WR) of 122.6-150.0%, an ion exchange capacity (IEC) of 0.0147-0.0518 mmol g-1, and excellent mechanical (elongation at break (Eb) of 103.8-148.4%, tensile strength (TS) of 38.7-58.6 MPa) and thermal stability. The alkali resistances of the as-prepared membranes were tested by immersing the samples into 2 mol L-1 NaOH solutions at 25 °C for 60 h, and the results were encouraging: the mass loss and swelling degree of the as-prepared membranes were in the ranges of 1.9-5.9% and 222.6-241.9%, respectively. The separation performances of the as-prepared membranes were evaluated by the diffusion dialysis (DD) process with an NaOH/Na2WO4 mixture at room temperature. The results demonstrated that the dialysis coefficients of hydroxide (UOH) were in the range of 0.0147-0.0347 m h-1, and the separation factors (S) were in the range of 29.5-62.6. The introduced carboxyl groups from CBACs and the -OH groups from PVA were both deemed to play significant roles in the promotion of ion transport: the -COO- groups formed negatively charged transport channels for Na+ by electrostatic attraction, and the -OH groups promoted the transport of OH- via hydrogen bonding.

7.
Sci Rep ; 10(1): 17400, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060809

RESUMO

Smoking has been identified as a risk factor for atopic dermatitis and hand eczema, but less is known about the association of exposure to second-hand smoke (SHS) with hand eczema. The study aimed to investigate the association of SHS exposure with hand eczema and atopic dermatitis in a group of adolescents. We conducted a cross-sectional study among first-year college students. SHS exposure was measured by a self-administered questionnaire. Skin diseases were diagnosed by dermatologists in the field survey. Mixed models were used to estimate the associations. A total of 20,129 participants that underwent skin examination and a questionnaire survey were included in the analyses. The prevalence rates of atopic dermatitis and hand eczema were 3.86% and 3.35%, respectively. Crude and adjusted estimates consistently showed that exposure to SHS was significantly associated with atopic dermatitis and hand eczema in a dose-response manner. Attention deficit/hyperactivity disorder mediated minimal or no effect of SHS on hand eczema and atopic dermatitis. Subgroup analysis by type of hand eczema, and sensitivity analysis by excluding data with center effect showed consistent results. Exposure to SHS is an independent but modifiable risk factor for hand eczema and atopic dermatitis in adolescents.

8.
Int J Med Sci ; 17(16): 2594-2602, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029102

RESUMO

Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

9.
J Phys Chem Lett ; : 9110-9116, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33049137

RESUMO

State coupling certainly determines the topologic features of the molecular potential energy surface (PES) and potentially diversifies chemical reaction pathways. Here we report the new PESs of BrCN- in the low-lying electronic states that are distinctly different from the previous predictions in the short Br-CN bond region but validated by the high-resolution ion velocity imaging measurements of low-energy dissociative electron attachment (DEA) to BrCN. Besides the vibrating CN- ions produced in the fast Br-CN bond stretching motions, we confirm that the ro-vibrating CN- ions with a nearly isotropic angular distribution are produced by receiving a torque in the combinational motion of Br-CN bond bending and stretching. The latter process is closely related to the potential well of BrCN- at the first excited state A2Π3/2 that arises from the Π-Σ state couplings. Our findings not only suggest that the PESs of other anionic cyanogen halides are in dire need of reexamination but also show that ion velocity imaging of the DEA process is a powerful experimental method for evaluating the theoretical PESs of molecular anions.

10.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020469

RESUMO

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.

11.
PLoS One ; 15(10): e0240331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031392

RESUMO

OBJECTIVE: Melanoma is rare but dangerous skin cancer, and it can spread rather quickly in the advanced stages of the tumor. Abundant evidence suggests the relationship between tumor development and progression and the immune system. A robust gene risk model could provide an accurate prediction of clinical outcomes. The present study aimed to explore a robust signature of immune-related gene pairs (IRGPs) for estimating overall survival (OS) in malignant melanoma. METHODS: Clinical and genetic data of skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) was performed as a training dataset to identify candidate IRGPs for the prognosis of melanoma. Two independent datasets from the Gene Expression Omnibus (GEO) database (GSE65904) and TCGA dataset (TCGA-UVM) were selected for external validation. Univariate and multivariate Cox regression analyses were then performed to explore the prognostic power of the IRGPs signature and other clinical factors. CIBERSORTx was applied to estimate the fractions of infiltrated immune cells in bulk tumor tissues. RESULTS: A signature consisted of 33 IRGPs was established which was significantly associated with patients' survival in the TCGA-SKCM dataset (P = 2.0×10-16, Hazard Ratio (HR) = 4.220 (2.909 to 6.122)). We found the IRGPs signature exhibited an independent prognostic factor in all the three independent cohorts in both the univariate and multivariate Cox analysis (P<0.01). The prognostic efficacy of the signature remained unaffected regardless of whether BRAF or NRAS was mutated. As expected, the results were verified in the GSE65904 dataset and the TCGA-UVM dataset. We found an apparent shorter OS in patients of the high-risk group in the GSE65904 dataset (P = 2.1×10-3; HR = 1.988 (1.309 to 3.020)). The trend in the results of the survival analysis in TCGA-UVM was as we expected, but the result was not statistically significant (P = 0.117, HR = 4.263 (1.407 to 12.91)). CD8 T cells, activated dendritic cells (DCs), regulatory T cells (Tregs), and activated CD4 memory T cells presented a significantly lower fraction in the high-risk group in the TCGA-SKCM dataset(P <0.01). CONCLUSION: The results of the present study support the IRGPs signature as a promising marker for prognosis prediction in melanoma.

12.
Environ Pollut ; 268(Pt B): 115702, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-33007653

RESUMO

Anthropogenic activities have increased lead (Pb) emissions and impacted their spatiotemporal distributions in coastal seas. To quantify the increasing variability of Pb and identify the specific origins and their corresponding magnitudes, Pb and Pb isotopes are investigated in a well-placed sediment core covering the period of 1928-2008 in the Central Yellow Sea Mud (CYSM). The concentration of Pb varied from 27.17 µg/g to 37.30 µg/g upwardly along the core, with pronounced anthropogenic disturbance since the late 1960s. The Pb input history of the CYSM experienced five stages according to industrialization levels and Pb contamination, with relative pristine stages from 1928 to 1969 and human activity-impacted stages from 1969 to 2008. The 206Pb/207Pb ratio demonstrated an overall decreasing profile while the 208Pb/206Pb ratio displayed the reverse trend upwardly along the core, possibly due to the atmospheric delivery of anthropogenic Pb emissions from northern China. Furthermore, 208Pb/206Pb vs. 206Pb/207Pb shows certain linearity between natural sediment sources and anthropogenic emissions of Pb (atmospheric deposition); thus, atmospheric inputs account for 34-43% of the Pb in the sediment since Pb enrichment using the two-endmember mixing model. Moreover, the steep decrease in 206Pb/207Pb and rapid increase in 208Pb/206Pb since the 1970s suggest the introduction of leaded gasoline and the increasing proportionate consumption of gasoline relative to total energy consumption. The continuously decreasing 206Pb/207Pb ratio and increasing 208Pb/206Pb ratio since 2000 are the combined results of coal consumption, nonferrous smelting, and residual Pb contamination from leaded gasoline, which is quite distinctive from cases in North America and Europe. The relatively high 206Pb/207Pb and low 208Pb/206Pb ratios before 1969 represent the natural Pb isotopic signatures. Hence, Pb input is significantly affected by regional energy consumption and restructuring, and the Pb isotopic ratios may be a potential proxy for the shift in energy consumption.

13.
Phys Chem Chem Phys ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073282

RESUMO

Present work systematically investigates the kinetic role played by H2 molecules during Ni surface diffusion and deposition to generate branched Ni nanostructures by employing Density Functional Theory (DFT) calculations and ab initio molecule dynamic (AIMD) simulations, respectively. The Ni surface diffusion results unravel that in comparison to the scenarios of Ni(110) and Ni(100), both the subsurface and surface H hinder the Ni surface diffusion over Ni(111) especially under the surface H coverage of 1.5 ML displaying the lowest Ds values, which greatly favors the trapping of the adatom Ni and subsequent overgrowth along the 111 direction. The Ni deposition simulations by AIMD further suggest that both the H2 molecule (in solution) and surface dissociatively adsorbed atomic H can promote Ni depositions onto Ni(111) and Ni(110) facets in a liquid solution. Moreover, a cooperation effect between H2 molecules and surface atomic H can be clearly observed, which greatly favors Ni depositions. Additionally, in addition to working as the solvent, the liquid C2H5OH can also interact with the Ni(111) surface to produce the surface atomic H, which then favored the Ni deposition. Finally, the Ni deposition rate predicted using the deposition constant (Ddep) was found to be much higher than its surface diffusion rate predicted using Ds for Ni(111) and Ni(110), which quantitatively verified the overgrowth along the 111 and 110 directions to produce the branched Ni nanostructures.

14.
Asian J Endosc Surg ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33073502

RESUMO

Transdiaphragmatic duplication of digestive tract in infants is very rare. Open surgery is the main surgical treatment. We report the clinical data of a child with gastrointestinal duplication across the diaphragm who underwent thoraco-laparoscopic surgery at 12 days were retrospectively analyzed, and to explore the experience of thoraco-laparoscopic surgery in the treatment of alimentary tract duplication across the diaphragm in children, we believe minimally invasive surgical resection using thoracolaparoscopy is safe, effective and clinically feasible, focusing on the skilled use of the technique to achieve the ideal surgical effect and appearance.

15.
Med Sci Monit ; 26: e922316, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32890392

RESUMO

BACKGROUND Oligoasthenospermia is one of the major reasons for male infertility in clinical practice. Nevertheless, some patients with oligoasthenospermia show normal fertility. Currently, there is a lack of an effective method to distinguish patients with oligoasthenospermia showing normal fertility from those who lack natural fertility and should participate in in vitro fertilization and assisted reproduction. MATERIAL AND METHODS In this study, we collected semen and blood samples from 153 males of Shui nationality at reproductive age in Guizhou Province, southwest China. We measured the routine parameters for semen and some serological indicators. A clinical diagnosis model was then constructed to evaluate the fertility potential of oligoasthenospermia patients using a logistic stepwise regression method, which was then visualized with a nomogram. RESULTS Our results showed that this model could effectively assess the natural pregnancy potential of patients with oligoasthenospermia, and its sensitivity and specificity were superior to those of a traditional model that used only sperm motility and count to assess male fertility potential (area under the curve=0.7626 vs. 0.6677). Additionally, we evaluated the clinical net benefit for patients with oligoasthenospermia at different risk scores in our model using decision curve analysis. The results showed that the net benefit was obtained at scores ranging from 0.1 to 0.6. CONCLUSIONS This comprehensive clinical prediction model can be used to determine whether infertile oligoasthenospermia patients lack natural fertility.

16.
Brain Behav ; : e01818, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32869541

RESUMO

OBJECTIVE: As a result of the pandemic of COVID-19, the public have been experiencing psychological distress. However, the prevalence of psychological distress during the COVID-19 pandemic remains unknown. Our objective was to evaluate the prevalence of psychological distress during COVID-19 outbreak and their risk factors, especially their internal paths and causality. METHODS: A nationwide cross-sectional survey of the prevalence of mental disorders was conducted. We used Hospital Anxiety and Depression Scale (HADS) to estimate the prevalence of anxiety and depression. The internal paths and the causality of the psychological health were analyzed using a structural equation modeling (SEM) approach. RESULTS: A total of 24,789 respondents completed the survey. We found that the overall prevalence of anxiety, depression, combination of anxiety, and depression were 51.6% (95% CI: 51.0-52.2), 47.5% (95% CI: 46.9-48.1), and 24.5% (95% CI: 24.0-25.0), respectively. The risk of psychological disorders in men was higher than that in women. The status of psychological health was different across different age groups, education levels, occupations, and income levels. The SEM analysis revealed that inadequate material supplies, low income, low education, lack of knowledge or confidence of the epidemic, and lack of exercise are major risk factors for psychological distress. CONCLUSIONS: The evidence from this survey poses serious challenges related to the high prevalence of psychological distress, but also offers strategies to deal with the mental health problems caused by the COVID-19 pandemic.

17.
Neurotherapeutics ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32959271

RESUMO

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32900700

RESUMO

INTRODUCTION: Determinants and correlates of a novel index of adipose tissue insulin resistance (AT-IR) (the product of fasting insulin and free fatty acid concentrations) were investigated in Japanese women without diabetes and obesity. RESEARCH DESIGN AND METHODS: Cross-sectional associations of AT-IR with fat mass and distribution, and IR-related cardiometabolic variables were examined in 210 young and 148 middle-aged women whose average body mass index (BMI) was <23 kg/m2 and waist was <80 cm. Multivariate linear regression analyses were used to identify most important determinants of AT-IR. RESULTS: Young and middle-aged women did not differ in AT-IR (3.5±2.7 and 3.2±2.1, respectively). In both young and middle-aged women, AT-IR was positively associated with trunk/leg fat ratio, a sophisticated measure of abdominal fat accumulation, fasting plasma glucose (FPG), fasting triglycerides (FTG), serum alanine aminotransferase and γ-glutamyl-transpeptidase (all p<0.05). Furthermore, in middle-aged but not in young women, AT-IR showed positive associations with BMI, waist, fat mass index, low-density lipoprotein cholesterol, apolipoprotein B and systolic and diastolic blood pressure (BP) (all p<0.05). AT-IR showed no association with hemoglobin A1c, high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 in two groups of women. On multivariate analysis including waist, FPG, FTG, HDL cholesterol and systolic BP as independent variables, FPG, FTG and HDL cholesterol emerged as independent determinants of AT-IR in young women (cumulative R2=0.141) and waist in middle-aged women (cumulative R2=0.056). In a model which included trunk/leg fat ratio instead of waist, trunk/leg fat ratio and systolic BP were determinants of AT-IR in middle-aged women (cumulative R2=0.093). Results did not alter in young women. CONCLUSIONS: AT-IR may be a simple and useful surrogate index of adipose tissue insulin resistance even in populations without diabetes and obesity.

19.
Adv Healthc Mater ; : e2001101, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32940013

RESUMO

Sequential mineralization enables the integration of minerals within the 3D structure of hydrogels. Hydrolyzed collagen-based hydrogels are sequentially mineralized over 10 cycles. One cycle is defined as an incubation period in calcium chloride dihydrate followed by incubation in sodium phosphate dibasic dihydrate. Separate cycles are completed at 30-minute and 24-hour intervals. For the gels mineralized for 30 min and 24 h, the compressive moduli increases from 4.25 to 87.57 kPa and from 4.25 to 125.47 kPa, respectively, as the cycle number increases from 0 to 10. As indicated by X-ray diffraction (XRD) and Fourier transform infrared analysis (FTIR) analyses, the minerals in the scaffolds are mainly hydroxyapatite. In vitro experiments, which measure mechanical properties, porous structure, mineral content, and gene expression are performed to evaluate the physical properties and osteoinductivity of the scaffolds. Real time-quantitative polymerase chain reaction (RT-qPCR) demonstrates 4-10 fold increase in the expression of BMP-7 and osteocalcin. The in vivo subcutaneous implantation demonstrates that the scaffolds are biocompatible and 90% biodegradable. The critical size cranial defects in vivo exhibit nearly complete bone regeneration. Cycle 10 hydrogels mineralized for 24 h have a volume of 59.86 mm3 and a density of 1946.45 HU. These results demonstrate the suitability of sequentially mineralized hydrogel scaffolds for bone repair and regeneration.

20.
J Med Econ ; : 1-10, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-32991222

RESUMO

AIMS: For children aged 1-5 years with persistent asthma, double low-dose inhaled corticosteroids (ICS) are recommended as the preferred Step 3 treatment and low-dose ICS plus leukotriene receptor antagonists (LTRA) as an alternative. Budesonide inhalation suspension (0.5 mg daily) and montelukast (4.0 mg daily) are commonly used low-dose ICS and LTRA, respectively, among children in China. This study compared the cost-effectiveness of double low-dose budesonide vs. low-dose budesonide plus montelukast from a Chinese healthcare payer's perspective. METHODS: A Markov model was constructed with four health states (i.e. no exacerbation, mild exacerbation, moderate-to-severe exacerbation, and death). Transition probabilities were estimated based on exacerbation rates, case-fatality of hospitalized patients due to exacerbation, and natural mortality. Treatment adherence was considered and assumed to impact both drug costs and exacerbation rates. Costs (in 2019 Chinese Yuan [¥]) included drug costs and exacerbation management costs. Cost inputs and utilities for each health state were obtained from a public database and the literature. In-depth interviews were conducted with a health economics expert to validate the model, and a clinical expert to verify inputs and assumptions related to clinical practice. Costs and quality-adjusted life-years (QALYs) were estimated over a year. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Compared with low-dose budesonide plus montelukast, double low-dose budesonide was associated with lower costs (¥1,534 vs. ¥2,327), fewer exacerbation events (0.43 vs. 1.67) and slightly better QALYs (0.98 vs. 0.97). Sensitivity analyses supported the robustness of the results and the generalizability of findings across geographic regions in China. CONCLUSION: The cost-effectiveness analysis suggests that double low-dose budesonide is a dominant Step 3 treatment strategy compared with low-dose budesonide plus montelukast for patients aged 1-5 years with persistent asthma in China.

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