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1.
J Adv Nurs ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009836

RESUMO

AIMS: To assess the overall relative risk of diabetes in individuals with prediabetes based on updated diagnostic criteria, as compared with individuals with normoglycaemia; and to identify the study characteristics associated with the heterogeneity between studies. DESIGN: Meta-analysis, meta-regression. DATA SOURCES: PubMed, CINAHL, British Nursing Index. Search time frame: December 1998-December 2018. REVIEW METHODS: The pooled relative risk of developing diabetes among individuals with prediabetes compared with those with normoglycaemia was calculated under a random effects model. Studies reported the natural progression from prediabetes to diabetes were included in this review. Sources of study heterogeneity were examined by a meta-regression. RESULTS: Fifty-nine eligible studies were systematically identified. The pooled relative risk for diabetes among individuals with prediabetes as compared with normoglycaemia was 5.88 (95% CI: 5.02-6.89). The annualized incidence rate (per 1,000 person-year) for diabetes among individuals with prediabetes defined by different criteria varied from 2.20-212.15, with high heterogeneity between studies (I2  = 96.64%, Q test: p < .001). In the multivariable meta-regression analysis, Asian population significantly increased RR compare to Caucasians. Besides, people with 'elevated glycated haemoglobin A1c or impaired fasting glucose' had highest relative risk compare to people with other types of prediabetes. CONCLUSION: Individuals with prediabetes had higher risk of developing diabetes than those with normoglycaemia. Races and diagnostic criteria of prediabetes were associated with the magnitude of the estimated risk. IMPACT: Prediabetes is a precursor of diabetes. To screen people with prediabetes as early as possible, practitioners could consider haemoglobin A1c test as an alternative to fasting plasma glucose test. Nurses should educate people especially Asians with prediabetes for the prevention of progression to diabetes.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33025078

RESUMO

PURPOSE: Laparoscopy-assisted gastrectomy (LAG) is proven by considerable studies as a safe procedure for early gastric cancer (EGC), but its long-term oncologic outcomes in advanced gastric cancer (AGC) have not been well-described. This study aimed at verifying the non-inferiority of LAG in the treatment of EGC and comparing the oncological feasibility of LAG and open gastrectomy (OG) for AGC. METHODS: A total of 209 consecutive patients who underwent LAG or OG with D2 lymph node dissection between December 2008 and November 2012 were included. The survival rate was estimated with the Kaplan-Meier method and the risk factors affecting the survival and recurrence were evaluated with Cox regression models. Subgroup analysis was performed in AGC patients receiving both distal and total gastrectomy. RESULTS: Of 209 patients, 194 (92.8%; mean age, 62.7 years; 56 [28.9%] women) eligible patients were finally enrolled in this study. No significant differences in the number of lymph nodes retrieved and postoperative complications were observed between patients receiving LAG and OG. During a mean follow-up of 58.3 ± 38.1 months (range 0-121 months), the 5-year overall survival and disease-free survival rates were 56.1% and 53.0% for LAG, and 57.7% and 50.9% for OG. In the subgroup analysis for AGC, laparoscopy-assisted distal gastrectomy and total gastrectomy did not result in inferior long-term outcomes, and recurrence was found in 49 patients (31.2%). Age more than 65 years and the advanced tumor stage were independent risk factors of survival. CONCLUSION: LAG is a feasible and safe treatment for gastric cancer, with good oncologic results.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33033904

RESUMO

BACKGROUND: Cryoballoon (CB) has been widely utilized in the treatment of drug-refractory atrial fibrillation (AF), but the balance point between efficacy and safety has been unclear. The protocol based on the time-to-isolation (TTI) was expected to provide patients with individualized ablation strategies. METHODS: All studies up to June 2020 comparing the CB of TTI-based protocol (TTIP) and conventional protocol (ConP) in PubMed, Embase, and Cochrane Library databases were searched. The pooled OR or SMD with 95% CIs for each outcome were calculated with inverse-variance random effect model. The Egger method was used to evaluate the publication bias and the subgroup analysis was conducted according to the type of atrial fibrillation. RESULTS: Six studies enrolling a total of 1770 patients with drug-refractory AF were included. The pool real-time recording of pulmonary veins potential was 71% (95% CI: 61 ~ 81%, I2 = 97.9%) and a similar incidence of freedom from ATs after 1 year (OR: 1.12; 95% CI: 0.86 ~ 1.46, I2 = 0.0%, P = 0.481) was observed between two protocols. No difference was observed in complications (OR: 0.67; 95% CI: 0.43 ~ 1.04, I2 = 0.0%, P = 0.717) and phrenic nerve palsy (OR: 0.70; 95% CI: 0.37 ~ 1.35, I2 = 0.0%, P = 0.807). TTIP could significantly decrease the CB freezes per patient (SMD: - 2.44; 95% CI: - 4.46 to approximately - 0.41; I2 = 99.5%, P = 0.00) and shorten the cryotherapy application time (SMD: - 3.04; 95% CI: - 4.18 to approximately - 1.89; I2 = 97.4%, P = 0.00), procedure time (SMD: - 1.51; 95% CI: - 2.08 to approximately - 0.94; I2 = 95.4%, P = 0.00), and fluorescence time (SMD: - 0.70; 95% CI: - 1.25 to approximately - 0.15; I2 = 95.7%, P = 0.00). CONCLUSION: TTIP is safe and effective and it opens a new chapter in the field of individualized protocol of CB for patients with AF.

4.
Nat Med ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046868

RESUMO

Vα24-invariant natural killer T (NKT) cells have shown potent anti-tumor properties in murine tumor models and have been linked to favorable outcomes in patients with cancer. However, low numbers of these cells in humans have hindered their clinical applications. Here we report interim results from all three patients enrolled on dose level 1 in a phase 1 dose-escalation trial of autologous NKT cells engineered to co-express a GD2-specific chimeric antigen receptor (CAR) with interleukin-15 in children with relapsed or resistant neuroblastoma (NCT03294954). Primary and secondary objectives were to assess safety and anti-tumor responses, respectively, with immune response evaluation as an additional objective. We ex vivo expanded highly pure NKT cells (mean ± s.d., 94.7 ± 3.8%) and treated patients with 3 × 106 CAR-NKT cells per square meter of body surface area after lymphodepleting conditioning with cyclophosphamide/fludarabine (Cy/Flu). Cy/Flu conditioning was the probable cause for grade 3-4 hematologic adverse events, as they occurred before CAR-NKT cell infusion, and no dose-limiting toxicities were observed. CAR-NKT cells expanded in vivo, localized to tumors and, in one patient, induced an objective response with regression of bone metastatic lesions. These initial results suggest that CAR-NKT cells can be expanded to clinical scale and safely applied to treat patients with cancer.

5.
Cancer Med ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33047902

RESUMO

We performed a meta-analysis to determine cancer risks at multiple sites and their associations with tumor mutation burden (TMB), an index for immunogenicity, in heart or lung transplant recipients. A comprehensive search of PubMed, Web of Science, EMBASE, and Medline was conducted. Random effects models were used to calculate standardized incidence ratios (SIRs) versus the general population and to determine the risks of different cancers. Weighted linear regression (WLR) was used to analyze the associations between the SIRs and TMBs. (PROSPERO CRD42020159599). Data from 21 studies including 116,438 transplant recipients (51,173 heart transplant recipients and 65,265 lung transplant recipients) with a total follow-up of 601,330.7 person-years were analyzed. Compared with the general population, heart transplant recipients displayed a 3.13-fold higher cancer risk [SIR: 3.13; 95% confidence interval (CI): 2.38-4.13; p < 0.001]; lung transplant recipients displayed a 4.28-fold higher cancer risk [SIR: 4.28; 95% CI: 3.18-5.77; p < 0.001]. The correlation coefficients were 0.54 (p = 0.049) and 0.79 (p < 0.001) in heart and lung transplant recipients, respectively, indicating that 29% and 63% of the differences in the SIRs for cancer types might be explained by the TMBs. Our study demonstrated that both heart and lung transplant recipients displayed a higher risk of certain site-specific cancers. These findings can provide individualized guidance for clinicians for detection of cancer among heart or lung transplantation recipients. In addition, we provided evidence that increased risks of post-transplant cancers can be attributed to immunosuppression.

6.
BMC Microbiol ; 20(1): 311, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054730

RESUMO

BACKGROUND: The symbiotic bacteria associated with edible fungi are valuable microbial resources worthy of in-depth exploration. It is important to analyze the community structure and succession of symbiotic bacteria in mushrooms. This can assist in the isolation of growth-promoting strains that have an essential relationship with the cultivation cycle as well as the agronomic traits and yields of fruiting bodies. RESULTS: In all of the samples from cultivation bags of Hypsizygus marmoreus, 34 bacterial phyla were detected. Firmicutes was the most abundant bacterial phylum (78.85%). The genus Serratia showed an exponential increase in abundance in samples collected from the cultivation bags in the mature period, reaching a peak abundance of 55.74% and the dominant symbiotic flora. The most predominant strain was Serratia odorifera HZSO-1, and its abundance increased with the amount of hyphae of H. marmoreus. Serratia odorifera HZSO-1 could reside in the hyphae of H. marmoreus, promote growth and development, shorten the fruiting cycle by 3-4 days, and further increase the fruiting body yield by 12%. CONCLUSIONS: This study is a pioneering demonstration of the community structure of the symbiotic microbiota and bacteria-mushroom interaction in the growth and development of edible fungi. This work lays a theoretical foundation to improve the industrial production of mushrooms with symbiotic bacteria as assisting agents.

7.
Environ Sci Technol ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33085459

RESUMO

Emissions of secondary products through reactions of oxidants, ozone (O3), and hydroxyl radical (·OH) with human skin lipids have become increasingly important in indoor environments. Here, we evaluate the secondary organic compounds formed through heterogeneous reactions of gaseous O3 with hand skin lipids by using a high-resolution quadrupole Orbitrap mass spectrometer coupled to a commercial secondary electrospray ionization (SESI) source. More than 600 ions were detected over a period of less than 40 min real-time measurements, among which 53 ions were characterized with a significant increasing trend in signal intensity at the presence of O3. Based on the detected ions, we suggest detailed reaction pathways initiated by ozone oxidation of squalene that results in primary and secondary ozonides; we noticed for the first time that these products may be further cleaved by direct reaction of nucleophilic ammonia (NH3), emitted from human skin. Finally, we estimate the fate of secondarily formed carbonyl compounds with respect to their gas-phase reactions with ·OH, O3, and NO3 and compared with their removal by air exchange rate (AER) with outdoors. The obtained results suggest that human presence is a source of an important number of organic compounds, which can significantly influence the air quality in indoor environments.

9.
Biotechnol Bioeng ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33022743

RESUMO

Yeast has been engineered for cost-effective organic acid production through metabolic engineering and synthetic biology techniques. However, cell growth assays in these processes were performed in bulk at the population level, thus obscuring the dynamics of rare single cells exhibiting beneficial traits. Here, we introduce the use of monodisperse picolitre droplets as bioreactors to cultivate yeast at the single-cell level. We investigated the effect of acid stress on growth and the effect of potassium ions on propionic acid tolerance for single yeast cells of different species, genotypes, and phenotypes. The results showed that the average growth of single yeast cells in microdroplets experiences the same trend to those of yeast populations grown in bulk, and microdroplet compartments do not significantly affect cell viability. This approach offers the prospect of detecting cell-to-cell variations in growth and physiology and is expected to be applied for the engineering of yeast to produce value-added bioproducts.

10.
Gynecol Endocrinol ; : 1-5, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084429

RESUMO

OBJECTIVE: To investigate the correlation between abdominal adipose tissue and lumbar bone mineral density (BMD) in different menopausal periods of Chinese women. METHODS: 230 women were included in this cross-sectional study. Subjects were divided into a perimenopausal and postmenopausal group. Lumbar BMD was measured by QCT to assess total adipose tissue (TAT), visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). The concomitant variables age, body mass index (BMI), and endocrine hormones were also considered. Multiple linear regression was used to assess the relationship between abdominal adipose tissue and BMD. RESULTS: In the perimenopausal group, Spearman correlation analysis showed that there was no significant association among TAT, SAT, VAT, and BMD (all p > .05). In the postmenopausal group, BMD was negatively correlated with TAT, SAT, and VAT. In both groups, after adjustment for age and BMI, multiple linear regression analysis showed that VAT was negatively correlated with BMD (p < .05). In contrast, there was no significant correlation with TAT, SAT, and BMD. CONCLUSIONS: High VAT volume is associated with low lumbar BMD in both perimenopausal and postmenopausal women. TAT and SAT have no significant correlation with lumbar trabecular BMD.

11.
Medicine (Baltimore) ; 99(40): e22511, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019452

RESUMO

RATIONALE: Granulosa cell tumors (GCTs) are rare, hormonally active sex cord-stromal tumors that generally present as solid unilateral ovarian lesions. It's quite uncommon that they present as pure bilateral ovarian cysts. Histopathology remains the gold standard for making a diagnosis of GCTs. However, as the differential diagnosis is difficult, cystic GCTs are frequently misdiagnosed as benign or other cystic tumors either prior to surgery or during pathologic diagnosis. Accordingly, herein, we describe a fairly rare case of bilateral ovarian cystic GCTs, along with a review of the related literature. PATIENT CONCERNS: A 43-year-old woman presented with abdominal distension and chronic pain since 1 day. The patient had a history of dysmenorrhea. DIAGNOSES: Physical examination revealed palpable bilateral adnexal tumors; ultrasonography revealed cystic and septate masses with a maximum diameter of 7.8 and 10.7 cm, respectively, in the bilateral ovaries. Hormonal analysis revealed that the blood estradiol levels were elevated. Postoperative pathological and immunohistochemical examinations of the surgical specimens revealed a final diagnosis of cystic adult GCTs of the ovaries. INTERVENTIONS: The patient first underwent laparoscopic bilateral ovarian cystectomy. On the basis of the final pathological diagnosis report, abdominal total hysterectomy, bilateral oophoro-salpingectomy, and partial omentectomy were then performed. Microscopic examination revealed that there were no residual CGT cells. The patient's federation international of gynecology and obstetrics (FIGO) Stage was IB period. OUTCOMES: The surgeries were successful. The tumor was a FIGO Stage IB tumor, and the patient did not require any additional treatment. The patient had been followed-up regularly for 2 years after surgery; she did not experience any complications and remained disease-free. LESSONS SUBSECTIONS: Cystic GCTs should be considered in the differential diagnosis if a female patient shows bilateral ovarian cysts. They are extremely rare ovarian malignant tumors that must be differentiated from other ovarian tumors, especially purely cystic tumors and benign cysts. Although pathological and immunohistochemical findings are important for making the diagnosis, the varying histopathological features on microscope make diagnosis difficult, including tumor cells with luteinization or free cell clusters. The current case highlights the importance of physicians being aware of and suspecting cystic CGTs in similar cases, along with knowing the characteristics of GCTs for the diagnosis and differential diagnosis.


Assuntos
Tumor de Células da Granulosa/patologia , Tumor de Células da Granulosa/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Adulto , Feminino , Humanos , Cistos Ovarianos/patologia , Cistos Ovarianos/cirurgia
12.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(5): 583-588, 2020 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-33085246

RESUMO

Epigenetics refers to a steady change in the level of gene expression caused by non-DNA sequence changes. Microbes can modulate host inflammation through epigenetic pathways to evade or expend immune responses. As an important part of human microbes, oral bacteria also have various epigenetic regulation mechanisms to affect host inflammatory responses. This article reviews the common pathways of epigenetic regulation in microbe infection and the regulation of host epigenetics by using oral microbes to provide a reference for the study of epigenetic-related mechanisms in oral diseases.


Assuntos
Epigênese Genética , Doenças da Boca , Bactérias , Expressão Gênica , Humanos , Inflamação/genética
13.
J Vasc Surg ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33091512

RESUMO

OBJECTIVE: To investigate the outcomes of endovascular repair for penetrating aortic ulcers (PAUs) with or without intramural hematoma (IMH). METHODS: Patients with PAUs who underwent thoracic endovascular aortic repair (TEVAR) or endovascular abdominal aortic repair (EVAR) in our center were enrolled. Patient demographics, presenting symptoms, and anatomic characteristics were collected and analyzed to investigate the TEVAR/EVAR indications, perioperative complications, and mortality. RESULTS: A total of 138 PAU patients were identified. Fifty-eight (42.0%) patients were associated with IMH. Compared to patients without IMH, patients with IMH showed significantly higher emergency admission rates (P <0.01), a larger aortic diameter (P =0.03), and stent-induced new entry (SINE) development incidence (P =0.02). There were no significant differences in mortality and free from reintervention between patients with PAUs with and without IMH during their follow-ups. However, cumulative survival rates calculated by Kaplan-Meier analysis of patients undergoing TEVAR/EVAR during their first hospitalization were significantly higher than those having delayed TEVAR/EVAR during their follow-up. CONCLUSIONS: TEVAR/EVAR was safe and effective with encouraging outcomes for patients with PAUs with or without IMH and can be used more aggressively in symptomatic patients. PAUs with IMH did not seem to adversely affect long-term mortality, but SINE was more likely to develop.

14.
J Biol Chem ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093178

RESUMO

NSun2 is an RNA methyltransferase introducing m5C into tRNAs, mRNAs and noncoding RNAs, thereby influencing the levels or function of these RNAs. Autotaxin (ATX) is a secreted glycoprotein and is recognized as a key factor in converting lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). The ATX-LPA axis exerts multiple biological effects in cell survival, migration, proliferation, and differentiation. Here, we show that NSun2 is involved in the regulation of cell migration through methylating ATX mRNA. In the human glioma cell line U87, knockdown of NSun2 decreased ATX protein levels, while overexpression of NSun2 elevated ATX protein levels. However, neither overexpression nor knockdown of NSun2 altered ATX mRNA levels. Further studies revealed that NSun2 methylated the 3'-untranslated region of ATX mRNA at cytosine 2756 in vitroand in vivo. Methylation by NSun2 enhanced ATX mRNA translation. In addition, NSun2-mediated m5C methylation promoted the export of ATX mRNA from nucleus to cytoplasm in an ALYREF-dependent manner. Knockdown of NSun2 suppressed the migration of U87 cells, which was rescued by the addition of LPA. In summary, we identify NSun2-mediated methylation of ATX mRNA as a novel mechanism in the regulation of ATX.

15.
Zhongguo Zhen Jiu ; 40(10): 1027-33, 2020 Oct 12.
Artigo em Chinês | MEDLINE | ID: mdl-33068341

RESUMO

OBJECTIVE: To establish and promote the non-contact doctor-patient interactive diagnosis and treatment mode based on mobile internet for the treatment of coronavirus disease 2019 (COVID-19) with moxibustion therapy, and to observe the feasibility and effectiveness of the model in the pandemic. METHODS: A total of 43 first-line medical staff and 149 suspected and confirmed cases with COVID-19 [18 cases in medical observation period, 17 cases of mild type (cold dampness and stagnation in the lung), 24 cases of ordinary type (cold-dampness accumulated in the lung) and 90 cases in recovery period (qi deficiency of spleen and lung)] were included. A non-contact doctor-patient interactive diagnosis and treatment platform was established for the treatment of COVID-19 with indirect moxibustion plaster based on mobile internet. By the platform, the patients were instructed to use indirect moxibustion plaster in treatment. For the first-line medical staff and patients in the medical observation period, Zusanli (ST 36), Qihai (CV 6) and Zhongwan (CV 12) were selected. For the mild cases (cold dampness and stagnation in the lung) and the cases of ordinary type (cold-dampness accumulated in the lung), Hegu (LI 4), Taichong (LR 3), Zusanli (ST 36) and Guanyuan (CV 4) were selected. In the recovery period (qi deficiency of spleen and lung), Dazhui (GV 14), Feishu (BL 13), Geshu (BL 17), Zusanli (ST 36) and Kongzui (LU 6) were used. The treatment was given once daily for 40 min each time. The intervention lasted for 10 days. After intervention, the infection rate and the improvement in the symptoms and psychological status of COVID-19 were observed in clinical first-line medical staff and COVID-19 patients. RESULTS: In 10 days of intervention with indirect moxibustion plaster, there was "zero" infection among medical staff. Of 43 first-line physicians and nurses, 33 cases had some physical symptoms and psychological discomforts, mainly as low back pain, poor sleep and anxiety. After treatment, regarding the improvements in the symptoms and psychological discomforts, the effective rate was 78.8% (26/33) and the curative rate was 36.4% (12/33). Regarding the improvements in psychological discomforts, the effective rate was 58.3% (14/24) and the curative rate was 37.5 (9/24). Of 149 patients, 133 cases had the symptoms and psychological discomforts. After treatment, regarding the improvements in the symptoms and psychological discomforts, the effective rate was 81.2% (108/133) and the curative rate was 34.6% (46/133). Regarding the improvements in psychological discomforts, the effective rate was 76.5% (52/68) and the curative rate was 57.4 % (39/68). CONCLUSION: It is feasible to apply the indirect moxibustion plaster technique based on mobile internet to the treatment COVID-19. This mode not only relieves the symptoms such as cough and fatigue, improves psychological state, but also possibly prevents the first-line medical staff from COVID-19.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33070260

RESUMO

Combining chemotherapy with immunotherapy improves the therapeutic outcome for first-line (1L) patients with advance nonsmall-cell lung cancer (NSCLC). Two cohorts of a phase 1b study (NCT02937116) aimed to evaluate the safety and efficacy of sintilimab, a PD-1 inhibitor, plus chemotherapy in 1L patients with nonsquamous and squamous NSCLC (nsqNSCLC/sqNSCLC); and to identify potential biomarkers for treatment response. Treatment-naïve patients with nsqNSCLC were enrolled and intravenously given sintilimab (200 mg), pemetrexed (500 mg/m2), and cisplatin (75 mg/m2), every 3 weeks (Q3W) for 4 cycles in cohort D. Treatment-naïve patients with sqNSCLC were enrolled and intravenously given sintilimab (200 mg), gemcitabine (1250 mg/m2), and cisplatin (75 mg/m2), Q3W, for 6 cycles in cohort E. The primary objective was to evaluate the safety and efficacy of the treatment. The additional objective was to explore biomarkers for the treatment efficacy. Twenty-one patients with nsqNSCLC, and 20 patients with sqNSCLC were enrolled in cohort D and cohort E, respectively. By the data cutoff (April 17, 2019), 8 (38.1%) patients in cohort D and 17 (85.0%) patients in cohort E experienced grade 3-4 adverse events. The median follow-up duration was 16.4 months (14.8-23.0) in cohort D and 15.9 months (11.7-17.7) in cohort E. The objective response rate was 68.4% (95% CI 43.4%, 87.4%) in cohort D and 64.7% (95% CI 38.3%, 85.8%) in cohort E. Neither PD-L1 expression nor tumor mutation burden value was significantly associated with an improved treatment response. Sintilimab plus chemotherapy exhibited manageable toxicity and an encouraging antitumor activity in patients with nsqNSCLC and sqNSCLC.

17.
Sensors (Basel) ; 20(19)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003284

RESUMO

Biosensors are widely used in production and life, and can be used in medicine, industrial production, and scientific research. Among them, the detection of pH has always received extensive attention. In this study, we demonstrate the use of a one-step hydrothermal method to prepare Co-FeS2/CoS2 nanomaterials as pH sensor (pH vs. overpotential) for the first time. The proposed pH sensor exhibits outstanding performance in KOH solutions via electrochemical methods with good stability. Overall, the results of this study not only add to the non-noble transition metal electrocatalysis research, but also identify important sensing characteristics for electrocatalysts.

18.
Future Med Chem ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030058

RESUMO

Background: Abuse of analgesic and sedative drugs often leads to severe respiratory depression and sometimes death. Approximately 69,000 people worldwide die annually from opioid overdoses. Purpose: This work aimed to investigate whether CX1739 can be used for emergency treatment of acute respiratory depression due to drug abuse. Results: First, the results clarify that CX1739 is a low-impact ampakine that can safely activate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors without causing excito-neurotoxicity. Second, CX1739 rapidly crossed the blood-brain barrier (Tmax = 2 min), which meets the requirement of rapid onset of action in vivo. Our work provides preliminarily confirmation that high-dose intravenous administration of CX1739 can immediately reverse respiratory depression in animal models of respiratory depression caused by opioid agonist 030418, pentobarbital sodium and ethanol.

19.
Inorg Chem ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32877185

RESUMO

We report the synthesis and reactivity of heterometallic Mg-Ni complexes with bridging hydrides. Treatment of magnesium monoalkyl complexes, which are supported by a tridentate ß-diketiminato ligand bearing a pendent phosphine group, with nickel(0) reagent Ni(COD)2 (COD: 1,5-cyclooctadiene) at a molar ratio of 2:1 resulted in the formation of a heterotrimetallic hydride-bridged [Mg-Ni-Mg] complex via facile elimination of the corresponding alkenes. A heterobimetallic hydride-bridged [Mg-Ni] complex served as an intermediate species for the formation of the [Mg-Ni-Mg] complex. Computational studies revealed that the reaction was initiated by coordination of nickel to magnesium followed by an alkyl group transfer. ß-H elimination at the nickel center subsequently occurred to give the heterometallic hydride-bridged complex. Density functional theory analysis also highlighted a three-center two-electron interaction for the Mg-H-Ni unit. The hydride-bridged [Mg-Ni-Mg] complex showed diverse reactivity toward unsaturated small molecules. For instance, reactions with isocyanides provided heterometallic species by coordination of isocyanides to the nickel center, with no subsequent reduction detected. Isocyanides could also be dissociated at 80 °C. In contrast, hydromagnesiation occurred upon treatment of the heterotrimetallic hydride with carbodiimides, affording C3-symmetric complexes with three heteroleptic magnesium mixed ß-diketiminate/amidinate moieties. The hydride-bridged heterotrimetallic complex underwent dehydrogenation reaction with phenyl acetylene to produce an acetylide-bridged [Mg-Ni-Mg] complex.

20.
Nat Microbiol ; 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868923

RESUMO

Fluoxazolevir is an aryloxazole-based entry inhibitor of hepatitis C virus (HCV). We show that fluoxazolevir inhibits fusion of HCV with hepatic cells by binding HCV envelope protein 1 to prevent fusion. Nine of ten fluoxazolevir resistance-associated substitutions are in envelope protein 1, and four are in a putative fusion peptide. Pharmacokinetic studies in mice, rats and dogs revealed that fluoxazolevir localizes to the liver. A 4-week intraperitoneal regimen of fluoxazolevir in humanized chimeric mice infected with HCV genotypes 1b, 2a or 3 resulted in a 2-log reduction in viraemia, without evidence of drug resistance. In comparison, daclatasvir, an approved HCV drug, suppressed more than 3 log of viraemia but is associated with the emergence of resistance-associated substitutions in mice. Combination therapy using fluoxazolevir and daclatasvir cleared HCV genotypes 1b and 3 in mice. Fluoxazolevir combined with glecaprevir and pibrentasvir was also effective in clearing multidrug-resistant HCV replication in mice. Fluoxazolevir may be promising as the next generation of combination drug cocktails for HCV treatment.

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