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1.
Clin Transl Sci ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33142006

RESUMO

Only half of hypertensive patients respond to any given antihypertensive. Heterogeneity in pathophysiologic pathways underlying hypertension (HTN) is a major contributor. Personalizing antihypertensive therapy could improve blood pressure (BP) reduction. The objective of this study was to assess the effect of pragmatic implementation of a personalized plasma renin activity (PRA)-based smartphone app on improving BP reduction. Patients with untreated or treated but uncontrolled HTN were recruited. BP and PRA were measured at baseline with final BP measured at 6 months. Patient's information was entered into the app and treatment recommendations were returned. Clinicians were at liberty to follow or disregard the app recommendations. BP levels and percent BP control among patients whose clinicians did and did not follow the app recommendations were compared using independent t-test and Fisher's exact test, respectively. Twenty-nine European-American (EA) patients were included (38% women) with mean age of 52±9 years and median PRA of 1.3 ng/ml/hr (IQR 0.5-3.1 ng/ml/hr). Participants whose clinicians followed the app recommendations (n=16, 55%) as compared to those whose clinicians did not (n=13, 45%), had a greater reduction in 6-month systolic-BP (-15±21 vs. -3±21 mm Hg; adjusted-P=0.1) and diastolic-BP (-8±8 vs. -1±8 mm Hg; adjusted-P=0.04). BP control at 6 months tended to be greater among patients whose clinicians accepted the app recommendations versus those whose clinicians did not (63% vs. 23%, P=0.06). This pilot study demonstrates that acceptance of the app recommendations was associated with a greater BP reduction. Future studies to confirm these pilot findings are warranted.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33180731

RESUMO

A wireless and battery-less trimodal neural interface system-on-chip (SoC), capable of 16-ch neural recording, 8-ch electrical stimulation, and 16-ch optical stimulation, all integrated on a 53 mm2 chip fabricated in 0.35-m standard CMOS process. The trimodal SoC is designed to be inductively powered and communicated. The downlink data telemetry utilizes on-off keying pulse-position modulation (OOK-PPM) of the power carrier to deliver configuration and control commands at 50 kbps. The analog front-end (AFE) provides adjustable mid-band gain of 55-70 dB, low/high cut-off frequencies of 1-100 Hz/10 kHz, and input-referred noise of 3.46 Vrms within 1 Hz-50 kHz band. AFE outputs of every two-channel are digitized by a 50 kS/s 10-bit SAR-ADC, and multiplexed together to form a 6.78 Mbps data stream to be sent out by OOK modulating a 434 MHz RF carrier through a power amplifier (PA) and 6 cm monopole antenna, which form the uplink data telemetry. Optical stimulation has a switched-capacitor based stimulation (SCS) architecture, which can sequentially charge 4 storage capacitor banks up to 4 V and discharge them in selected LEDs at instantaneous current levels of up to 24.8 mA on demand. Electrical stimulation is supported by 4 independently driven stimulating sites at 5-bit controllable current levels in (25-775) A range, while active/passive charge balancing circuits ensure safety. In vivo testing was conducted on 4 anesthetized rats to verify the functionality of the trimodal SoC.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33060070

RESUMO

OBJECTIVE: Glucose disposal by insulin-responsive tissues maintains the body glucose homeostasis and insulin resistance leads to a risk of developing type 2 diabetes (T2DM). Insulin stimulates the translocation of glucose transporter isoform 4 (GLUT4) vesicles from intracellular compartments to the plasma membrane to facilitate glucose uptake. However, the underlying mechanisms of GLUT4 vesicle translocation are not well defined. Here we show the role of huntingtin-associated protein 1 (HAP1) in GLUT4 translocation in adipocytes and the pathogenesis of T2DM. RESEARCH DESIGN AND METHODS: The parameters for glucose metabolism including body weight, glucose tolerance and insulin tolerance were assessed in wild-type (WT) and Hap1 +/- mice. HAP1 protein expression was verified in adipose tissue. Hap1 mRNA and protein expression was monitored in adipose tissue of high-fat diet (HFD)-induced diabetic mice. Insulin-stimulated GLUT4 vesicle translocation and glucose uptake were detected using immunofluorescence techniques and quantified in primary adipocytes from Hap1 -/- mice. The interaction between HAP1 and GLUT4 was assessed by immunofluorescence colocalization and co-immunoprecipitation in HEK293 cells and adipose tissue. The role of sortilin in HAP1 and GLUT4 interaction was approved by co-immunoprecipitation and RNA interference. RESULTS: The expression of Hap1 mRNA and protein was detected in WT mouse adipose tissue and downregulated in adipose tissue of HFD-induced diabetic mice. Hap1 +/- mice exhibited increased body weight, pronounced glucose tolerance and significant insulin intolerance compared with the WT mice. HAP1 colocalized with GLUT4 in mouse adipocytes and cotransfected HEK293 cells. Furthermore, the insulin-stimulated GLUT4 vesicle translocation and glucose uptake were defective in Hap1 -/- adipocytes. Finally, sortilin mediated the interaction of HAP1 and GLUT4. CONCLUSIONS: Our study showed that HAP1 formed a protein complex with GLUT4 and sortilin, and played a critical role in insulin-stimulated GLUT4 translocation in adipocytes. Its downregulation may contribute to the pathogenesis of diabetes.

4.
Cancer Med ; 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33098370

RESUMO

Lung adenocarcinoma (LUAD) is the most common and lethal cancer worldwide. Radiotherapy (RT) is widely used at all stages of LUAD, and the development of immunotherapy substantially enhances the survival of LUAD patients. Although the emerging treatments for LUAD have improved prognosis, only a small fraction of patients can benefit from clinical therapies. Thereby, approaches assessing responses to RT and immunotherapy in LUAD patients are essential. After integrating the analysis of RT, immunization, mRNA, and clinical information, we constructed a signature based on 308 tumor-infiltrating B lymphocyte-specific genes (TILBSig) using a machine learning method. TILBSig was composed of 6 B cell-specific genes (PARP15, BIRC3, RUBCNL, SP110, TLE1, and FADS3), which were highly associated with the overall survival as independent factors. TILBSig was able to differentiate better survival compared with worse survival among different patients, and served as an independent factor for clinical characteristics. The low-risk TILBSig group was correlated with more immune cell infiltration (especially B lineages) and lower cancer stem cell characteristics than the high-risk group. The patients with lower risk scores were more likely to respond to RT and immunotherapy. TILBSig served as an excellent predicator for prognosis and response to immunotherapy and RT in LUAD patients.

5.
Invest New Drugs ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052556

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

6.
Sci Rep ; 10(1): 18589, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122682

RESUMO

The stromal microenvironment has been shown to affect the infiltration of esophageal carcinoma (ESCA), which is linked to prognosis. However, the complicated mechanism of how infiltration is influenced by the stromal microenvironment is not well-defined. In this study, a stromal activation classifier was established with ridge cox regression to calculate stroma scores for training (n = 182) and validation cohorts (n = 227) based on the stroma-related 32 hub genes identified by sequential bioinformatics algorithms. Patients with high stromal activation were associated with high T stage and poor prognosis in both esophagus adenocarcinoma and esophagus squamous cell carcinoma. Besides, comprehensive multi-omics analysis was used to outline stromal characterizations of 2 distinct stromal groups. Patients with activated tumor stoma showed high stromal cell infiltration (fibroblasts, endothelial cells, and monocyte macrophages), epithelial-mesenchymal transition, tumor angiogenesis and M2 macrophage polarization (CD163 and CD206). Tumor mutation burden of differential stromal groups was also depicted. In addition, a total of 6 stromal activation markers in ESCA were defined and involved in the function of carcinoma-associated fibroblasts that were crucial in the differentiation of distinct stromal characterizations. Based on these studies, a practical classifier for the stromal microenvironment was successfully proposed to predict the prognosis of ESCA patients.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33067866

RESUMO

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.

8.
Sci Rep ; 10(1): 18769, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127971

RESUMO

Oxidative stress (OS) is associated with poor oocyte quality and in vitro fertilization and embryo transfer (IVF-ET) outcomes for patients with polycystic ovary syndrome (PCOS). Growth hormone (GH) can function to reduce OS in some types of cells. Therefore, this prospective randomized study investigated whether GH can significantly improve OS and oocyte quality in women with PCOS. This study enrolled 109 and 50 patients with and without PCOS (controls), respectively. The patients with PCOS were randomly assigned to receive treatment with GH (PCOS-T) or not (PCOS-C). The primary outcome included markers of OS in serum and FF, and secondary outcomes were mitochondrial function in granulosa cells (GCs) and IVF-ET outcomes. The PCOS groups showed higher basal serum total oxidant status (TOS) and OS index (OSI) levels. The follicle fluid (FF) TOS and OSI and GC apoptosis rate were significantly higher, whereas the GC mitochondrial membrane potential (MMP) was significantly lower in the PCOS-C group than in the PCOS-T and non-PCOS control groups (P < 0.05). Significantly more oocytes were fertilised and cleavage stage embryos were produced in the PCOS-T group than in the PCOS-C group (P < 0.05). GH also improved the rates of implantation and clinical pregnancy, but not significantly (P > 0.05). This study showed that GH alleviated the TOS and OSI level in FF and improved GC mitochondrial dysfunction and oocyte quality in patients with PCOS.Clinical Trial Registration Number: This project was prospectively registered on the Chinese Clinical Trial Registry on October 20, 2018. (ChiCTR1800019437) ( https://www.chictr.org.cn/edit.aspx?pid=28663&htm=4 ).

9.
Reprod Biol Endocrinol ; 18(1): 91, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891163

RESUMO

BACKGROUND: Oxidative stress (OS), defined as an imbalance between excessive reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) production and antioxidant insufficiency, has been suggested to be involved in the pathogenesis of poor ovarian response (POR). Growth hormone (GH) can reduce OS in some cell types. This study investigated whether GH can improve OS and the in vitro fertilization and embryo transfer (IVF-ET) outcomes of poor ovarian responders. METHODS: This study enrolled 105 patients with POR and 58 patients without POR (controls) who were diagnosed according to the Bologna criteria and underwent conventional IVF-ET. Poor ovarian responders were randomly assigned to two groups: the POR-GH group, which received pretreatment with GH 4 IU/d on day 2 of the previous menstrual cycle before IVF until the trigger day, and the POR-C group, which received no pretreatment. OS markers in follicular fluid (FF), ROS levels in granulosa cells (GCs), and the IVF outcomes of the groups were compared. RESULTS: Endometrial thickness on trigger day, the number of cleaved embryos, the number of higher-quality embryos, and the rates of embryo formation, higher-quality embryo formation, implantation and clinical pregnancy were significantly increased in the POR-GH group compared with the POR-C group (P < 0.05). Moreover, compared to those in the non-POR group, FF malondialdehyde (MDA), total oxidant status (TOS), oxidative stress index (OSI) and ROS levels in GCs were significantly higher, whereas superoxide dismutase (SOD) and the total antioxidant capacity (TAC) were significantly lower in the POR-C group (P < 0.05). Furthermore, compared with those in the POR-C group, the FF TAC was significantly increased in the POR-GH group, and TOS, OSI and intracellular ROS levels were significantly reduced (P < 0.05). CONCLUSIONS: Pretreatment with GH alleviates OS and improves oocyte quality and IVF outcomes of poor ovarian responders. TRIAL REGISTRATION: Chinese Clinical Trial Registry. ChiCTR1900021269 . Registered 8 February 2019, http://www.chictr.org.cn/edit.aspx?pid=35837&htm=4 .

10.
Artigo em Inglês | MEDLINE | ID: mdl-32951360

RESUMO

Recent clinical guidelines recommend lower blood pressure (BP) goals for most patients, and recent trends have favored use of automated unattended BP measurements in the office setting to minimize observer error and white-coat effects. Patients attending a routinely scheduled CVD clinic visit were prospectively randomized to BP measured using an attended, followed by an unattended method, or vice versa, after a controlled rest period. All study BP measurements were obtained in triplicate using the automated Omron HEM-907XL BP monitor, and averaged. The outcome was difference in SBP. Routinely measured clinic BP from the same visit was extracted from the medical record, and compared with attended and unattended BP. A total of 102 patients were randomized, and mean age was 63 years, 52% female and 75% Caucasian. Attended and unattended SBP was 125.4 ± 20.4 and 122.6 ± 21.0 mm Hg, mean ± SD, respectively. Routine clinic SBP was 130.6 ± 23.6 mm Hg. Attended SBP was 2.7 mm Hg higher than the unattended measurement (95% CI 1.3-4.1; P = .0002). Routine clinic SBP was 5.2 mm Hg higher than attended SBP (95% CI 2.4-8.0; P = .0003) and 8.0 mm Hg higher than unattended SBP (95% CI 5.4-10.5; P < .0001). Attended measurement of BP is significantly higher than unattended measurement and the difference is physiologically meaningful, even in a CVD cohort with generally well-controlled hypertension. Furthermore, routine clinic SBP substantially overestimates both attended and unattended automated SBP, with important implications for treatment decisions like dose and/or drug escalation.

11.
J Bone Miner Res ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967053

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse drug reaction. Our previous whole-exome sequencing study found SIRT1 intronic region single-nucleotide polymorphism (SNP) rs7896005 to be associated with MRONJ in cancer patients treated with intravenous (iv) bisphosphonates (BPs). This study aimed to identify causal variants for this association. In silico analyses identified three SNPs (rs3758391, rs932658, and rs2394443) in the SIRT1 promoter region that are in high linkage disequilibrium (r2 > 0.8) with rs7896005. To validate the association between these SNPs and MRONJ, we genotyped these three SNPs on the germline DNA from 104 cancer patients of European ancestry treated with iv BPs (46 cases and 58 controls). Multivariable logistic regression analysis showed the minor alleles of these three SNPs were associated with lower odds for MRONJ. The odds ratios (95% confidence interval) and p values were 0.351 (0.164-0.751; p = 0.007) for rs3758391, 0.351 (0.164-0.751; p = 0.007) for rs932658, and 0.331 (0.157-0.697; p = 0.0036) for rs2394443, respectively. In the reporter gene assays, constructs containing rs932658 with variant allele A had higher luciferase activity than the reference allele, whereas constructs containing SNP rs3758391 and/or rs2394443 did not significantly affect activity. These results indicate that the promoter SNP rs932658 regulates the expression of SIRT1 and presumably lowers the risk of MRONJ by increasing SIRT1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

12.
Clin Pharmacol Ther ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32897581

RESUMO

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.

13.
Curr Biol ; 30(22): 4467-4475.e4, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32946753

RESUMO

Multicellular development depends on generating and precisely positioning distinct cell types within tissues. During leaf development, pores in the epidermis called stomata are spaced at least one cell apart for optimal gas exchange. This pattern is primarily driven by iterative asymmetric cell divisions (ACDs) in stomatal progenitors, which generate most of the cells in the tissue. A plasma membrane-associated polarity crescent defined by BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL) and BREVIS RADIX family (BRXf) proteins is required for asymmetric divisions and proper stomatal pattern, but the cellular mechanisms that orient ACDs remain unclear. Here, utilizing long-term, quantitative time-lapse microscopy, we identified two oppositely oriented nuclear migrations that precede and succeed ACD during epidermal patterning. The pre- and post-division migrations are dependent on microtubules and actin, respectively, and the polarity crescent is the unifying landmark that is both necessary and sufficient to orient both nuclear migrations. We identified a specific and essential role for MYOXI-I in controlling post-ACD nuclear migration. Loss of MYOXI-I decreases stomatal density, owing to an inability to accurately orient a specific subset of ACDs. Taken together, our analyses revealed successive and polarity-driven nuclear migrations that regulate ACD orientation in the Arabidopsis stomatal lineage.

14.
Commun Biol ; 3(1): 509, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929169

RESUMO

Rhinoceroses have been considered to have originated from tapiroids in the middle Eocene; however, the transition remains controversial, and the first unequivocal rhinocerotoids appeared about 4 Ma later than the earliest tapiroids of the Early Eocene. Here we describe 5 genera and 6 new species of rhinoceroses recently discovered from the early Eocene to the early middle Eocene deposits of the Erlian Basin of Inner Mongolia, China. These new materials represent the earliest members of rhinocerotoids, forstercooperiids, and/or hyrachyids, and bridge the evolutionary gap between the early Eocene ceratomorphs and middle Eocene rhinocerotoids. The phylogenetic analyses using parsimony and Bayesian inference methods support their affinities with rhinocerotoids, and also illuminate the phylogenetic relationships and biogeography of Ceratomorpha, although some discrepancies are present between the two criteria. The nearly contemporary occurrence of various rhinocerotoids indicates that the divergence of different rhinocerotoid groups occurred no later than the late early Eocene, which is soon after the split between the rhinocerotoids and the tapiroids in the early early Eocene. However, the Bayesian tip-dating estimate suggests that the divergence of different ceratomorph groups occurred in the middle Paleocene.

15.
Thorac Cancer ; 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32841514

RESUMO

BACKGROUND: Exosomes have significant implications in cancer progression via transferring various modulatory molecules. Long non-coding RNAs (lncRNAs) play essential biological roles in lung cancer. In this report, we unlock the functional mechanism of tumor protein P73 antisense RNA 1 (TP73-AS1) in lung cancer. METHODS: The expression analyses of TP73-AS1, microRNA-216a-5p (miR-216a-5p) and Cullin 4B (CUL4B) were performed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell migration and invasion were assessed using wound healing and transwell assays. Flow cytometry was applied to determine cell apoptosis. Colony formation assay was performed for cell survival to evaluate the effect on radiosensitivity. The intergenic interaction was analyzed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Western blot was used for associated protein determination. An in vivo experiment was conducted by establishing xenograft models in mice. RESULTS: TP73-AS1 was conspicuously overexpressed in lung cancer tissues and cells. Silencing TP73-AS1 restrained cell migration and invasion while it enhanced apoptosis and radiosensitivity of lung cancer. TP73-AS1 could bind to miR-216a-5p as well as miR-216a-5p and CUL4B. The function of TP73-AS1 downregulation in lung cancer was achieved by miR-216a-5p/CUL4B axis. Inhibition of TP73-AS1 also exerted an inhibitory effect on tumor growth and radioresistance in vivo potentially via regulating miR-216a-5p/CUL4B axis. Moreover, exosomes from lung cancer cells downregulated TP73-AS1 could repress tumor evolution and radioresistance. CONCLUSIONS: Collectively, TP73-AS1 acted as a sponge of miR-216a-5p to regulate CUL4B in order to promote tumor progression and radioresistance in lung cancer cells with the implication of exosomes, which presents a novel mechanism of tumor action and radioresistance in lung cancer. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: TP73-AS1 silence inhibits migration and invasion while elevates apoptosis and radiosensitivity in lung cancer cells TP73-AS1 targets miR-216a-5p and miR-216a-5p targets CUL4B WHAT THIS STUDY ADDS: Downregulation of TP73-AS1 reduces tumor growth and radioresistance in vivo via the miR-216a-5p/CUL4B axis Exosomes from si-TP73-AS1-transfected cells inhibits lung cancer progression and radioresistance.

16.
Clin Transl Sci ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770710

RESUMO

Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long-term complications. Cancer treatment-related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio-Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline-induced cardiotoxicity (AIC), which can lead to heart failure. Early-onset cardiotoxicity appears within a year of treatment, whereas late-onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.

17.
Micromachines (Basel) ; 11(9)2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32858951

RESUMO

Reliable packaging for implantable neural prosthetic devices in body fluids is a long-standing challenge for devices' chronic applications. This work studied the stability of Parylene C (PA), SiO2, and Si3N4 packages and coating strategies on tungsten wires using accelerated, reactive aging tests in three solutions: pH 7.4 phosphate-buffered saline (PBS), PBS + 30 mM H2O2, and PBS + 150 mM H2O2. Different combinations of coating thicknesses and deposition methods were studied at various testing temperatures. Analysis of the preliminary data shows that the pinholes/defects, cracks, and interface delamination are the main attributes of metal erosion and degradation in reactive aging solutions. Failure at the interface of package and metal is the dominating factor in the wire samples with open tips.

18.
Ecol Evol ; 10(13): 6636-6645, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32724538

RESUMO

Aridity and salinity have a key role in driving physiological and ecological processes in desert ecosystems. However, how community-scale foliar nutrients respond to aridity and salinity, and how these responses might vary with community composition along aridity and salinity gradients is unclear. We hypothesize that the response will be a shift in community stoichiometric values resulting from nutrient variability of shared species and unique species (site-specific species), but little research has addressed the relative contribution of either component.We analyzed the community-scale stoichiometric response of a desert community of perennial plants along an aridity and salinity transect by focusing on foliar nitrogen (N) and phosphorous (P) concentrations and N:P ratios. After evaluating the shared and unique species variability, we determined their relative contribution to the community stoichiometric response to aridity and salinity, reflected by changes in nonweighted and weighted community-average values.Community-scale stoichiometry decreased significantly under aridity and salinity, with significantly consistent changes in nonweighted and weighted community-average stoichiometry for most shared and unique species measurements. The relative contribution of unique species shifts to the changes in community stoichiometry was greater (15%-77%) than the relative contribution of shared species shifts (7%-45%), excluding the change in weighted P concentration under aridity. Thus, the shifts of unique species amplified the community stoichiometric response to environmental changes. Synthesis. These results highlighted the need for a more in-depth consideration of shared and unique species variability to understand and predict the effects of environmental change on the stoichiometry of plant communities. Although variation in community stoichiometry can be expected under extreme aridity and salinity conditions, changes of unique species could be a more important driver of the stoichiometric response of plant communities.

19.
Circulation ; 142(6): 546-555, 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32654539

RESUMO

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

20.
Int J Biol Sci ; 16(12): 2145-2158, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32549761

RESUMO

Background: Recent advances in nanomedicine provided promising alternatives for tumor treatment to improve the survival and life quality of cancer patients. This study was designed to explore the insight mechanisms of the anti-tumor effects of the novel nanocomposites (NCs) MFP-FePt-GO with non-small cell lung cancer (NSCLC). Methods: A chemical co-reduction method was applied to the synthesis process of MFP-FePt-GO NCs. The chemical synthesis efficiency and morphology of the NCs were measured with spectroscope and transmission electron microscope. Colony formation assay and cell apoptosis were conducted to assess the radiosensitivity effect of NCs with radiation. Then, we detected cell mitochondrial membrane potential and reactive oxygen species (ROS) level by flow cytometry to further explore the cause of cell death. Immunofluorescence staining and Confocal were carried out to determine the DNA damage repair. A Lewis lung carcinoma animal model was used to measure safety and anti-tumor efficiency in vivo. Results: The novel NCs MFP-FePt-GO designed on a lamellar-structure magnetic graphene oxide and polyethylene glycol drug delivery system was synthesized and functionalized for co-delivery of metronidazole and 5-fluorouracil. While no severe allergies, liver and kidney damage, or drug-related deaths were observed, MFP-FePt-GO NCs promoted radiosensitivity of NSCLC cells both in vivo and in vitro. It improved the effects of radiation via activating intrinsic mitochondrial-mediated apoptosis and impairing DNA damage repair. This NCs also induced a ROS burst, which suppressed the antioxidant protein expression and induced cell apoptosis. Furthermore, MFP-FePt-GO NCs prevented NSCLC cell migration and invasion. Conclusion: MFP-FePt-GO NCs showed a synergistic anti-tumor effect with radiation to eliminate tumors. With good safety and efficacy, this novel NCs could be a potential radiosensitive agent for NSCLC patients.

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