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1.
Toxicol Appl Pharmacol ; 383: 114781, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618659

RESUMO

In recent years, anaplastic lymphoma kinase (ALK) rearrangement-positive anaplastic large cell lymphoma (ALCL) has rising morbidity and mortality. Unfortunately, no ALK inhibitor has been approved by the FDA for single treatment of ALK rearrangement-positive ALCL. In this study, we investigated the antitumor effect of ZYY, a novel ALK inhibitor, showing a strong growth inhibitory effect on Karpas299 cells in vitro and in vivo. Specifically, ZYY significantly reduced the mRNA and protein expression of ALK and its downstream signaling proteins in Karpas299 cells. Furthermore, ZYY induced G1 phase arrest and promoted apoptosis in Karpas299 cells. Furthermore, we demonstrated that ZYY-induced apoptosis was mainly related to the mitochondria-dependent endogenous pathway. In vitro studies further showed that ZYY induced autophagy in Karpas299 cells, along with increased levels of the autophagy-related proteins, including LC3II and Beclin-1. Moreover, knockdown Beclin-1 and application of autophagy inhibitor chloroquine potentiated ZYY-induced cytotoxicity and apoptosis in vitro, indicating that cytoprotective autophagy might be triggered by ZYY in Karpas299 cells. Taken together, the novel ALK inhibitor ZYY has tremendous potential for treating human ALCL, and a combination of autophagy and ALK inhibition could effectively elicit potent antitumor effects.

2.
J Cell Biochem ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31642107

RESUMO

Gastric cancer and cervical cancer are two major malignant tumors that threaten human health. The novel chemotherapeutic drugs are needed urgently to treat gastric cancer and cervical cancer with high anticancer activity and metabolic stability. Previously we have reported the synthesis, characterization and identification of a novel combretastatin A-4 analog, 3-(3-methoxyphenyl)-6-(3-amino-4- methoxyphenyl) -7H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine (XSD-7). In this study, we sought to investigate its anticancer mechanisms in a human gastric cancer cell line (SGC-7901 cells) and human cervical carcinoma cell line (HeLa cells). The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay showed that XSD-7 induced cytotoxicity in SGC-7901 and HeLa cells with inhibitory concentration 50 values of 0.11 ± 0.03 and 0.12 ± 0.05 µM, respectively. Immunofluorescence studies proved that XSD-7 inhibited microtubule polymerization during cell division in SGC-7901 and HeLa cells. Then, these cells were arrested at G2/M cell cycle and subsequently progressed into apoptosis. In further study, mitochondrial membrane potential analysis and Western blot analysis demonstrated that XSD-7 treatment-induced SGC-7901 cell apoptosis via both the mitochondria-mediated pathway and the death receptor-mediated pathway. In contrast, XSD-7 induced apoptosis in HeLa cells mainly via the mitochondria-mediated pathway. Hence, our data indicate that XSD-7 exerted antiproliferative activity by disrupting microtubule dynamics, leading to cell cycle arrest, and eventually inducing cell apoptosis. XSD-7 with novel structure has the potential to be developed for therapeutic treatment of gastric cancer and cervical cancer.

3.
Stat Methods Med Res ; : 962280219882043, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621503

RESUMO

Confidence interval (CI) methods for the ratio of two proportions in the presence of correlated bilateral binary data are constructed for comparative clinical trials with stratified design. Simulations are conducted to evaluate the performance of the presented CIs with respect to mean coverage probability (MCP), mean interval width (MIW), and the ratio of mesial non-coverage probability to the distal non-coverage probability (RMNCP). Based on the empirical results, we suggest the use of the proposed CI method based on the complete score statistics (CS) for general applications. An example from a rheumatology study is used to demonstrate the proposed methodologies.

4.
Environ Int ; 132: 105111, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31476640

RESUMO

The serious fine particle (PM2.5) pollution in China causes millions of premature deaths. Driven by swift economic growth and stringent control policies, air pollutant emissions in China have changed significantly in the last decade, but the change in the source contribution of PM2.5-related health impacts remains unclear. In this study, we develop a multi-pollutant emission inventory in China for 2005-2015, and combine chemical transport modeling, ambient/household exposure evaluation and health impact assessment to quantify the contribution of eight emission sectors to PM2.5 exposure and associated health risk. From 2005 to 2015, the mortality due to PM2.5 from ambient air pollution (AAP) decreases from 1.04 (95% confidence interval, 0.84-1.25) million to 0.87 (0.70-1.04) million. The agricultural sector contributes 25% and 32% to ambient PM2.5-attributed mortality in 2005 and 2015, respectively, representing the largest contributor during this period. The contribution of power plants drops monotonously from 13% to 6%. The percentage contribution of industrial process drops significantly while the contribution of industrial combustion stays the same level. The overall contribution of industry is still as large as 26% in 2015 in spite of strict control measures. For transportation, despite strict emission standards, its contribution increases remarkably due to the rapid growth of vehicle population. When both ambient and household PM2.5 exposures are taken into account, the mortality due to integrated population-weighted exposure to PM2.5 (IPWE) drops from 1.78 (1.46-2.09) million in 2005 to 1.28 (1.05-1.52) million in 2015. Most of the IPWE reduction comes from domestic combustion as a result of urbanization and improved income, whereas this sector remains the largest contributor (58%) to IPWE-related health risk in 2015. Our results suggest that the government should dynamically adjust the air pollution control strategy according to the change in source contributions. Domestic combustion and agriculture should be prioritized considering their predominant contributions to mortality and the lack of effective control policies. More stringent control measures for industry and transportation are necessary since the existing policies have not adequately reduced their health impacts. Electricity production is no longer the top priority of air pollution control policies given its lower health impact compared with that of other sources.

5.
Am J Perinatol ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382299

RESUMO

OBJECTIVE: To compare short-term respiratory outcomes of three steroids (dexamethasone, hydrocortisone, and methylprednisolone) to facilitate extubation by improving respiratory status in preterm infants. STUDY DESIGN: This is a retrospective, single-center, cohort study of 98 intubated preterm infants ≤346/7 weeks' gestation, admitted to a 64-bed, level III neonatal intensive care unit at the Women & Children's Hospital of Buffalo, Buffalo, NY, between 2006 and 2012, who received a short course of low-dose steroids for lung disease after first week of life. RESULTS: Study infants received dexamethasone (34%), hydrocortisone (44%), or methylprednisolone (22%) based on clinical team preference. By day 7 after initiation of steroids, extubation occurred in 59, 44, and 41%, respectively, in infants on dexamethasone, hydrocortisone, and methylprednisolone (p = 0.3). The mean respiratory severity score (RSS = fraction of inspired oxygen × mean airway pressure), a quantitative measure of respiratory status, decreased by 44% for all infants and by 59% in the dexamethasone group by day 7. CONCLUSION: Steroids improved short-term respiratory outcomes in all infants (RSS and extubation); by day 7, dexamethasone treatment was associated with the greatest decrease in RSS. Additional prospective, randomized trials of short-course low-dose steroids are warranted to substantiate these findings to guide clinical decision making and in evaluating differential steroid effects on long-term neurodevelopmental outcomes.

6.
Sci Total Environ ; 689: 1293-1303, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31466166

RESUMO

Water-soluble inorganic ions (WSI), a major component of PM2.5, often increased rapidly during the haze event in Beijing. Sulfate (SO42-), Nitrate (NO3-), and Ammonium (NH4+) are three main components of WSI. Since year 2015, sulfate concentrations in PM2.5 has gradually decreased owing to the effective control of SO2 emissions. However, the contribution of nitrate to PM2.5 has significantly increased during haze events in Beijing at the same time. In this study, a highly time-resolved online analyzer (Monitor for Aerosols and Gases, MARGA) was employed to measure the WSI in PM2.5 in Beijing from 5 February to 15 November 2017. Three typical haze events during this sampling period were investigated. During heavy pollution episodes in winter, nitrate concentrations increased from 7.5 µg/m3 to 45.6 µg/m3 (45.0% of WSI), while sulfate increased from 4.2 µg/m3 to 20.1 µg/m3 (19.8% of WSI). This indicated that nitrate is more important than sulfate as a driver for the growth of PM2.5 during the period of heavy air pollution in winter. Nitrate also dominates the increase of WSI in the pollution episodes in autumn, with an average concentration of 52.5 µg/m3, and contributed up to 67% of WSI. The average concentration ratio of NH4+ to SO42- was higher in autumn (1.02) than that in summer (0.74) and close to that in winter (1.00). This is mainly because the emission control of coal combustion in Beijing and surrounding areas results in an NH3-rich and SO2-lean atmosphere, which promoted the formation of ammonium nitrate. Our study indicates that nitrate has become the most important component of WSI in PM2.5 and is driving the rapid growth of PM2.5 concentrations during heavy pollution episodes in Beijing. Therefore, more efforts shall be made to reduce the nitrogen oxide and ammonia emissions in Beijing and surrounding areas.

7.
Cancer Chemother Pharmacol ; 84(4): 679-688, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256210

RESUMO

The discovery of targetable mutations, which cause gene rearrangement, led to a major advancement in the treatment of patients with non-small cell lung cancer (NSCLC), and cancers with such mutations can be paired with drugs which specifically target them. c-ros oncogene (ROS1) positive NSCLC is one molecular subtype of NSCLC with a therapeutic target. Currently, different targeted therapies and ROS1 inhibitors have been discovered, but all are in different investigational phases, with only one (crizotinib) which is FDA approved. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) which was discovered to actively inhibit ALK, MET, and ROS1. Crizotinib has shown to be remarkably efficacious against ROS1 lung cancer, prompting ROS1 detection in lung cancer to be quite significant. Sadly, crizotinib resistance in ROS1 is a frequent occurrence which poses a major clinical challenge in the successful treatment of ROS1 lung cancer; hence, the discovery of the second and third generation ROS1 inhibitors is of utmost importance. In this review, we discuss the underlying mechanisms through which ROS1 tumor cells acquire resistance to crizotinib-the first-line drug for ROS1-positive NSCLC, and summarize various new potent drugs which can overcome this resistance and serve as viable alternatives.

8.
Cell Commun Signal ; 17(1): 63, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186051

RESUMO

Human telomerase reverse transcriptase (hTERT) is the core subunit of human telomerase and plays important roles in human cancers. Aberrant expression of hTERT is closely associated with tumorigenesis, cancer cell stemness maintaining, cell proliferation, apoptosis inhibition, senescence evasion and metastasis. The molecular basis of hTERT regulation is highly complicated and consists of various layers. A deep and full-scale comprehension of the regulatory mechanisms of hTERT is pivotal in understanding the pathogenesis and searching for therapeutic approaches. In this review, we summarize the recent advances regarding the diverse regulatory mechanisms of hTERT, including the transcriptional (promoter mutation, promoter region methylation and histone acetylation), post-transcriptional (mRNA alternative splicing and non-coding RNAs) and post-translational levels (phosphorylation and ubiquitination), which may provide novel perspectives for further translational diagnosis or therapeutic strategies targeting hTERT.

9.
J Dermatolog Treat ; : 1-5, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31084382

RESUMO

Background: Vitiligo is an acquired depigmentation skin disorder mainly caused by the destruction of melanocytes. There are many therapeutic options available for vitiligo, but the options are not uniformly effective. Objectives: This study aimed to explore the clinical effect of the autologous non-cultured epidermal cell suspension (NCES) technique in the treatment of patients with stable vitiligo. Methods: A retrospective study of before-after comparisons was undertaken with 41 patients with stable vitiligo who received treatment with the NCES technique. The percentage of repigmentation area was evaluated using image analysis of the appearance before and 6-9 months after operation. Results: A total of 41 patients (18 males and 23 females) with a duration of clinical stability for ranging from 1 to 10 years (mean 1.6 ± 1.9) were included. The mean age was 20.2 years (range, 8-50) and 4 (9.8%) were children under the age of 14 years. After 6-9 months of follow-up, 80.5% (33/41) of the patients showed good response; among these patients, 17.1% (7/41) showed complete or almost complete repigmentation. Interestingly, all 4 children showed very good response (more than 76% repigmentation). There were no significant differences in the efficacy of treatment between the different transplantation areas of the facial neck, trunk, and distal limbs and there were no adverse effects such as infection or scar formation. Limitation: This study included only a single center with a small sample size. Conclusions: Our study shows that the NCES technique has a high therapeutic effect, is safe for patients with stable vitiligo, and may be a very promising potential option for treating children.

10.
Small ; 15(48): e1901494, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31074934

RESUMO

The rapid development of lightweight and wearable devices requires electronic circuits possessing compact, high-efficiency, and long lifetime in very limited space. Alternating current (AC) line filters are usually tools for manipulating the surplus AC ripples for the operation of most common electronic devices. So far, only aluminum electrolytic capacitors (AECs) can be utilized for this target. However, the bulky volume in the electronic circuits and limited capacitances have long hindered the development of miniaturized and flexible electronics. In this work, a facile laser-assisted fabrication approach toward an in-plane micro-supercapacitor for AC line filtering based on graphene and conventional charge transfer salt heterostructure is reported. Specifically, the devices reach a phase angle of 73.2° at 120 Hz, a specific capacitance of 151 µF cm-2 , and relaxation time constant of 0.32 ms at the characteristic frequency of 3056 Hz. Furthermore, the scan rate can reach up to 1000 V s-1 . Moreover, the flexibility and stability of the micro-supercapacitors are tested in gel electrolyte H2 SO4 /PVA, and the capacitance of micro-supercapacitors retain a stability over 98% after 10 000 cycles. Thus, such micro-supercapacitors with excellent electrochemical performance can be almost compared with the AECs and will be the next-generation capacitors for AC line filters.

11.
Chemosphere ; 226: 825-833, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30974375

RESUMO

A sulfur cycle-driven bioprocess was developed for co-treatment wet flue gas desulfurization wastes with municipal sewage, as a result of sludge minimization. In this process, organics removal (one of the main objectives in sewage treatment) is closely associated with biological sulfate/sulfite reduction (BSR). In the previous studies, both the pros and corns of sulfite (SO32-) in microbial activities were demonstrated. In this study, we are motivated to unveil the detailed role of SO32- in organic compound removal in the sulfur conversion-associated process. In addition, the effect of internal recirculation (IR) of UASB reactor was also explored. The results demonstrated that sulfite does inhibit the organic removal rate via depressing the acetate oxidation to inorganic carbon. And the inhibition is reversible when influent sulfite concentration decreased from 400 to 132 mg S/L, corresponding to the relative sulfate/sulfite-reducing genera increased from 18.66 to 38.62%. And the fermenting-related bacteria significantly decreased when an internal recirculation was employed for the UASB reactor. The results of this study could shed light on the understanding of the roles of sulfite and IR in organic compound removal performance and microbial community structures in BSR, which could be in turn beneficial to optimize the organic removal capacity of the sulfur bionconversion-concerning sewage treatment technology.


Assuntos
Biodegradação Ambiental , Compostos Orgânicos/isolamento & purificação , Sulfitos/farmacologia , Enxofre/química , Águas Residuárias/química , Purificação da Água/métodos , Bactérias/metabolismo , Reatores Biológicos/microbiologia , Microbiota , Oxirredução , Esgotos/química , Sulfitos/química
12.
J Biopharm Stat ; : 1-16, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30831053

RESUMO

In ophthalmological and otolaryngology studies, measurements obtained from both organs (e.g., eyes or ears) of an individual are often highly correlated. Ignoring the intraclass correlation between paired measurements may yield biased inferences. In this article, four different confidence interval (CI) construction methods (maximum likelihood estimates based Wald-type CI, profile likelihood CI, asymptotic score CI and an existing method adjusted for correlated bilateral data) are applied to this type of correlated bilateral data to construct CI for proportion ratio, taking the intraclass correlation into consideration. The coverage probabilities and widths of the resulting CIs are compared with each other in a Monte Carlo simulation study to evaluate their performances. A real dataset from an ophthalmologic study is used to illustrate our methodology.

13.
Curr Drug Targets ; 20(10): 1018-1028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827236

RESUMO

HACE1 belongs to the family of HECT domain-containing E3 ligases, which plays an important role in the occurrence, invasion and metastatic process in many human malignancies. HACE1 is a tumor suppressor gene that is reduced in most cancer tissues compared to adjacent normal tissue. The loss or knocking out of HACE1 leads to enhanced tumor growth, invasion, and metastasis; in contrast, the overexpression of HACE1 can inhibit the development of tumors. Hypermethylation reduces the expression of HACE1, thereby promoting tumor development. HACE1 can inhibit the development of inflammation or tumors via the ubiquitination pathway. Therefore, HACE1 may be a potential therapeutic target, providing new strategies for disease prevention and treatment.

14.
Oxid Med Cell Longev ; 2019: 2593742, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728884

RESUMO

Excessive drinking can damage brain tissue and cause cognitive dysfunction. Studies have found that the early stage of neurodegenerative disease is closely related to heavy drinking. Acetaldehyde (ADE) is the main toxic metabolite of alcohol. However, the exact mechanisms of ADE-induced neurotoxicity are not fully clear. In this article, we studied the cytotoxic effect of ADE in HT22 cells and primary cultured cortical neuronal cells. We found that ADE exhibited cytotoxicities against HT22 cells and primary cultured cortical neuronal cells in dose-dependent manners. Furthermore, ADE induced apoptosis of HT22 cells by upregulating the expression of caspase family proapoptotic proteins. Moreover, ADE treatment could significantly increase the intracellular Ca2+ and reactive oxygen species (ROS) levels and activate endoplasmic reticulum stress (ERS) in HT22 cells. ADE upregulated ERS-related CHOP expression dose-dependently in primary cultured cortical neuronal cells. In addition, inhibition of ROS with antioxidant N-acetyl-L-cysteine (NAC) reduced the accumulation of ROS and reversed ADE-induced increase of ERS-related protein and apoptosis-related protein levels. Mitigation of ERS with ERS inhibitor 4-PBA obviously suppressed ADE-induced apoptosis and the expression of ERS-related proteins. Therefore, ADE induces neurotoxicity of HT22 cells via oxidative stress- and Ca2+ imbalance-mediated ERS.


Assuntos
Acetaldeído/efeitos adversos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo/fisiologia , Animais , Humanos , Camundongos , Síndromes Neurotóxicas/patologia , Ratos
15.
Sci Total Environ ; 660: 1191-1200, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30743914

RESUMO

Regional transport plays an important role in the serious PM2.5 pollutions in the Beijing-Tianjin-Hebei (BTH) region, China. Practical regional joint emission control strategies require quantitative assessments of the transport contribution among cities and regions. The Community Multiscale Air Quality model equipped with the Integrated Source Apportionment Model is used to simulate the contributions from 5 major emission sectors in 13 cities of the BTH region, and 4 surrounding provinces outside BTH for the year 2014. Annual averaged local contribution ranges from 32% to 63% for the 13 cities in the BTH region, where secondary components contributing more than primary components. Regional contribution ratio becomes larger and the transport distance longer in July and October than in January and March. For Beijing, local contributions are 62% and 69% in January and March respectively, and the regional transports are mainly from nearby cities such as Zhangjiakou, Baoding and Langfang. In July and October, local contributions in Beijing are only 33% and 38% respectively, and a large range of regions in the south have substantial contributions, where Shandong Province and Henan Province contribute 3.6-5.3 µg/m3. Analysis of daily contributions suggests that regional transport is stronger under higher PM2.5 concentrations. During heavy pollution, local emissions in Beijing contribute 61%, 49%, 23% and 25% in January, march, July and October respectively, while during the clean days, the ratios are 88%, 88%, 76% and 57% respectively. Southerly regional transport during the rising phase of "saw tooth" pattern might be enhanced by weak cold high pressure and its easterly, northerly moving path. Among the major emission sectors, in winter, local domestic combustion is the most important source for Beijing, Tianjin and Shijiazhuang. In summer, transportation and domestic combustion are two important local sources for Beijing, while joint control in other cities should focus on industry.

16.
J Transl Med ; 17(1): 46, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30767763

RESUMO

BACKGROUND: Although previous prevalence studies of DED were reported from some countries worldwide, national data are unavailable in China. We aimed to conduct an up-to-date national survey on the prevalence of DED in China and find out the potential risk factors including air pollutant. METHODS: 23,922 eligible outpatients were recruited from ophthalmic clinics of 32 cities in China in 2013 by registration orders. The patients' demographic characteristics, history of keratorefractive surgery, diseases and medication history were collected and the daily air pollutant data in 2013. Multivariate logistic analysis was performed to identify the potential risk factors associated with DED. The association between related factors and dry eye diseases subtypes evaluated as p value and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Among 23,922 outpatients, the prevalence of DED was 61.57%, and that of the male patients was 57.64% and of the female was 65.32% (P < 0.0001). Multivariate logistic regression suggested that the possible risk factors for DED included: female, older age, history of keratorefractive surgery, presence of arthritis, thyroid diseases, and antihistamine, diuretic, duodenal ulcer drugs, diazepam. Air pollutants including O3, PM2.5, and SO2 were also identified as the risk factors. CONCLUSION: The prevalence of DED among ophthalmic outpatients in China was considerably high. Age, gender, history of keratorefractive surgery, diseases, medication history, and air pollutants were associated with DED prevalence.

17.
Sci Total Environ ; 661: 375-385, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30677683

RESUMO

A direct and quantitative linkage of air pollution-related health effects to emissions from different sources is critically important for decision-making. While a number of studies have attributed the PM2.5-related health impacts to emission sources, they have seldom examined the complicated nonlinear relationships between them. Here we investigate the nonlinear relationships between PM2.5-related premature mortality in the Beijing-Tianjin-Hebei (BTH) region, one of the most polluted regions in the world, and emissions of different pollutants from multiple sectors and regions, through a combination of chemical transport model (CTM), extended response surface model (ERSM), and concentration-response functions (CRFs). The mortalities due to both long-term and short-term exposures to PM2.5 are most sensitive to the emission reductions of primary PM2.5, followed by NH3, nonmethane volatile organic compounds and intermediate volatility organic compounds (NMVOC+IVOC). The sensitivities of long-term mortality to emissions of primary organic aerosol (POA), NMVOC+IVOC and SO2 do not change much with reduction ratio, whereas the sensitivities to primary inorganic PM2.5 (defined as all chemical components of primary PM2.5 other than POA), NH3 and NOx increase significantly with the increase of reduction ratio. The emissions of primary PM2.5, especially those from the residential and commercial sectors, contribute a larger fraction of mortality in winter (57-70%) than in other seasons (28-42%). When emissions of multiple pollutants or those from both local and regional emissions are controlled simultaneously, the overall sensitivity of long-term mortality is much larger than the arithmetic sum of the sensitivities to emissions of individual pollutants or from individual regions. This implies that a multi-pollutant, multi-sector and regional joint control strategy should be implemented to maximize the marginal health benefits. For NOx emissions, we suggest a nationwide control strategy which significantly enhances the effectiveness for reducing mortality by avoiding possible side effects when only the emissions within the BTH region are reduced.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Ambiental/efeitos adversos , Mortalidade Prematura , Material Particulado/efeitos adversos , China/epidemiologia , Humanos , Dinâmica não Linear , Tamanho da Partícula
18.
Cancer Biol Ther ; : 1-11, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514153

RESUMO

2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ), a novel synthesized combretastatin A-4(CA-4) analogue, is identified as a microtubule inhibitor and has been shown to exert anticancer activity in breast cancer cells. Here, we found that SQ reversed epidermal growth factor (EGF)-induced motility and invasion in breast cancer cell lines by the in vitro Wound healing and Transwell assay. Further studies showed that SQ treatment resulted in inhibitory alteration of EGF-stimulated epithelial-to-mesenchymal transition (EMT) and MMP-2 activity. What is more, SQ significantly inhibited the EGF-induced mouse double minute 2- (MDM2) expression and transcription factor Twist1 expression. In addition, compared with the control cells, MDM2 overexpression up-regulated Twist1 expression and dramatically promoted cell migration and invasion, MDM2 under-expression also down-regulated Twist1 expression and suppressed cell motility and invasion. Taken together, our findings suggest that the inhibitory effects of SQ on migration and invasion were related to the suppression of MDM2 and Twist1 signal axis.

19.
J Biol Chem ; 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30404921

RESUMO

High-throughput sequencing has revealed a tremendous complexity of cellular transcriptomes, which is partly due to the generation of multiple alternative transcripts from a single gene locus. Because alternative transcripts often have low abundance in bulk cells, the functions of most of these transcripts and their relationship to their canonical counterparts remain unclear. Here, we applied single-cell RNA-Seq to analyze the transcriptome complexity of in vitro-differentiated, murine type 2 T helper (Th2) cells. We found that cytokine gene transcripts contribute most of the intercellular heterogeneity, with a group of universal cytokines, including interleukins 1a, 2, 3, and 16, being bimodally expressed. At the single-cell level, usage of alternative promoters prevalently generated alternative transcripts. For instance, although undetectable in bulk cells, a noncoding RNA isoform of IL-4 (IL4nc), which was driven by an intronic promoter in the IL-4 locus, was predominantly expressed in a subset of the Th2 cells. IL4nc displayed distinct temporal expression patterns compared with the canonical IL-4 mRNA and post-transcriptionally promoted the production of IL-4 protein in the Th2 cells. In conclusion, our findings reveal a mechanism whereby minor noncanonical transcripts post-transcriptionally regulate expression of their cognate canonical genes.

20.
Am J Gastroenterol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429592

RESUMO

BACKGROUND: There is a need for safe and effective IBS treatments that provide immediate and sustained improvement of IBS symptoms, particularly among more severe patients. The aim was to assess long-term clinical response of cognitive behavioral therapy (CBT) with reference to IBS education. METHODS: A total of 436 Rome III-diagnosed IBS patients (80% F, M age = 41 years) were randomized to: 4 session home-based CBT (minimal contact (MC-CBT)), 10 session clinic-based CBT (standard (S-CBT)), or 4 session IBS education (EDU). Follow-up occurred at 2 weeks and 3, 6, 9, and 12 months following treatment completion. Treatment response was based a priori on the Clinical Global Improvement Scale (global IBS symptom improvement) and IBS Symptom Severity Scale (IBS-SSS). RESULTS: Post-treatment CGI gains were generally maintained by MC-CBT patients at quarterly intervals through 12-month follow-up with negligible decay. For MC-CBT and S-CBT, 39 and 33% of respondents maintained treatment response at every follow-up assessment. The corresponding percent for EDU was 19%, which was significantly lower (p < 0.05) than for the CBT groups. On the IBS-SSS, therapeutic gains also showed a pattern of maintenance with trends towards increased efficacy over time in all conditions, with the mean unit reductions between baseline and follows-up being approximately -76 at immediate and approximately -94 at 12 months (-50 = clinically significant). CONCLUSION: For treatment-refractory IBS patients, home- and clinic-based CBT resulted in substantial and enduring relief of multiple IBS symptoms that generally extended to 12-month post treatment.

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