Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.086
Filtrar
1.
HLA ; 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34219402

RESUMO

The novel KIR3DL1*00702 allele differs from the closest allele KIR3DL1*00701 by a single silent mutation.

2.
Oxid Med Cell Longev ; 2021: 5590745, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34306310

RESUMO

Multi-infarct dementia (MID), a prominent subtype of vascular dementia (VD), is responsible for at least 15 to 20 percent of dementia in the elderly. Mitochondrial dysfunctions and glutamate neurotoxicity due to chronic hypoperfusion and oxidative stress were regarded as the major risk factors in the pathogenesis. Kaixin San (KXS), a classic prescription of Beiji Qianjin Yaofang, was applied to treatment for "amnesia" and has been demonstrated to alleviate the cognitive deficit in a variety of dementias, including MID. However, little is known whether mitochondria and glutamate are associated with the protection of KXS in MID treatment. The aim of this study was to investigate the role of KXS in improving the cognitive function of MID rats through strengthening mitochondrial functions and antagonizing glutamate neurotoxicity via the Shh/Ptch1 signaling pathway. Our data showed that KXS significantly ameliorated memory impairment and hippocampal neuron damage in MID rats. Moreover, KXS improved hippocampal mitochondrial functions by reducing the degree of mitochondrial swelling, increasing the mitochondrial membrane potential (MMP), and elevating the energy charge (EC) and ATP content in MID rats. As expected, the concentration of glutamate and the expression of p-NMDAR1 were significantly reduced by KXS in the brain tissue of MID rats. Furthermore, our results showed that KXS noticeably activated the Shh/Ptch1 signaling pathway which was demonstrated by remarkable elevations of Ptch1, Smo, and Gli1 protein levels in the brain tissue of MID rats. Intriguingly, the inhibition of the Shh signaling pathway with cyclopamine significantly inhibited the protective effects of KXS on glutamate-induced neurotoxicity in PC12 cells. To sum up, these findings suggested that KXS protected MID rats from memory loss by rescuing mitochondrial functions as well as against glutamate neurotoxicity through activating Shh/Ptch1 signaling pathway.

3.
J Environ Manage ; 296: 113165, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34252847

RESUMO

Carbon emission quota allocation plays a critical role in carbon emission reduction in an efficient and economic manner. However, the scientific assessment of carbon quota allocation schemes and thus making a reasonable decision depending on preference still confuses relevant decision makers. This study proposes a performance analysis framework for carbon quota allocation schemes by using a nonparametric frontier analysis approach from the perspectives of economic growth and energy conservation. Then, we apply this approach to evaluate the relative economic and energy conservation performances of 15 allocation schemes by reallocating the 2015 Chinese provincial carbon emission quotas, each of which is constructed via a combination of equity, grandfathering, efficiency and ability to pay principles. The results show that the proposed allocation scheme that integrates efficiency and the ability to pay principles is the best option, realizing approximately 6.78% outputs increase and 3.01% energy conservation relative to the actual 2015 emission scenario. We also show that the best scheme is linked to total quotas; the scheme considering only the equity principle is superior to others, while the total quotas are reduced by 10%. The study provides not only a theoretical tool, but also empirical evidence for the construction of China's carbon quota allocation scheme.

4.
J Transl Med ; 19(1): 317, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301274

RESUMO

BACKGROUND: Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood-brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-ß, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. RESULTS: Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood-brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-ß, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. CONCLUSIONS: Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

5.
Aging (Albany NY) ; 13(undefined)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34289449

RESUMO

This investigation attempted to discern whether formononetin restrained progression of triple-negative breast cancer (TNBC) by blocking lncRNA AFAP1-AS1-miR-195/miR-545 axis. We prepared TNBC cell lines (i.e. MDA-MB-231 and BT-549) and normal human mammary epithelial cell line (i.e. MCF-10A) in advance, and the TNBC cell lines were, respectively, transfected by pcDNA3.1-lncRNA AFAP1-AS1, si-lncRNA AFAP1-AS1, pcDNA6.2/GW/EmGFP-miR-545 or pcDNA6.2/GW/EmGFP-miR-195. Resistance of TNBC cells in response to 5-Fu, adriamycin, paclitaxel and cisplatin was evaluated through MTT assay, while potentials of TNBC cells in proliferation, migration and invasion were assessed via CCK8 assay and Transwell assay. Consequently, silencing of lncRNA AFAP1-AS1 impaired chemo-resistance, proliferation, migration and invasion of TNBC cells (P<0.05), and over-expression of miR-195 and miR-545, which were sponged and down-regulated by lncRNA AFAP1-AS1 (P<0.05), significantly reversed the promoting effect of pcDNA3.1-lncRNA AFAP1-AS1 on proliferation, migration, invasion and chemo-resistance of TNBC cells (P<0.05). Furthermore, CDK4 and Raf-1, essential biomarkers of TNBC progression, were, respectively, subjected to target and down-regulation of miR-545 and miR-195 (P<0.05), and they were promoted by pcDNA3.1-lncRNA AFAP1-AS1 at protein and mRNA levels (P<0.05). Additionally, formononetin significantly decreased expressions of lncRNA AFAP1-AS1, CDK4 and Raf-1, while raised miR-195 and miR-545 expressions in TNBC cells (P<0.05), and exposure to it dramatically contained malignant behaviors of TNBC cells (P<0.05). In conclusion, formononetin alleviated TNBC malignancy by suppressing lncRNA AFAP1-AS1-miR-195/miR-545 axis, suggesting that molecular targets combined with traditional Chinese medicine could yield significant clinical benefits in TNBC.

6.
J Genet Genomics ; 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34257044

RESUMO

Gut microbial dysbiosis has been linked to many noncommunicable diseases. However, little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection. Here, we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers, which have recently been identified as molecular signatures predicting the progression of the COVID-19. We demonstrate that in our cohort of 990 healthy individuals without infection, this proteomic risk score is positively associated with proinflammatory cytokines mainly among older, but not younger, individuals. We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals. Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation. Overall, our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals. These results may provide novel insights into the cross-talk between gut microbiota and host immune system.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34258990

RESUMO

To reach a carbon-neutral future, electrochemical CO2 reduction reaction (eCO2RR) has proven to be a strong candidate for the next-generation energy system. Among potential materials, single-atom catalysts (SACs) serve as a model to study the mechanism behind the reduction of CO2 to CO, given their well-defined active metal centers and structural simplicity. Moreover, using metal-organic frameworks (MOFs) as supports to anchor and stabilize central metal atoms, the common concern, metal aggregation, for SACs can be addressed well. Furthermore, with their turnability and designability, MOF-derived SACs can also extend the scope of research on SACs for the eCO2RR. Herein, we synthesize sulfurized MOF-derived Mn SACs to study effects of the S dopant on the eCO2RR. Using complementary characterization techniques, the metal moiety of the sulfurized MOF-derived Mn SACs (MnSA/SNC) is identified as MnN3S1. Compared with its non-sulfur-modified counterpart (MnSA/NC), the MnSA/SNC provides uniformly superior activity to produce CO. Specifically, a nearly 30% enhancement of Faradaic efficiency (F.E.) in CO production is observed, and the highest F.E. of approximately 70% is identified at -0.45 V. Through operando spectroscopic characterization, the probing results reveal that the overall enhancement of CO production on the MnSA/SNC is possibly caused by the S atom in the local MnN3S1 moiety, as the sulfur atom may induce the formation of S-O bonding to stabilize the critical intermediate, *COOH, for CO2-to-CO. Our results provide novel design insights into the field of SACs for the eCO2RR.

8.
World J Gastroenterol ; 27(24): 3595-3608, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34239272

RESUMO

BACKGROUND: The drug resistance rate of clinical Helicobacter pylori (H. pylori) isolates has increased. However, the mechanism of drug resistance remains unclear. In this study, drug-resistant H. pylori strains were isolated from different areas and different populations of Chinese for genomic analysis. AIM: To investigate drug-resistant genes in H. pylori and find the genes for the early diagnosis of clarithromycin resistance. METHODS: Three drug-resistant H. pylori strains were isolated from patients with gastritis in Bama County, China. Minimal inhibitory concentrations of clarithromycin, metronidazole, and levofloxacin were determined and complete genome sequencing was performed with annotation. Hp1181 and hp1184 genes were found in these strains and then detected by reverse transcription polymerase chain reaction. The relationships between hp1181 or hp1184 and clarithromycin resistance were ascertained with gene mutant and drug-resistant strains. The homology of the strains with hp26695 was assessed through complete genome detection and identification. Differences in genome sequences, gene quantity, and gene characteristics were detected amongst the three strains. Prediction and analysis of the function of drug-resistant genes indicated that the RNA expression of hp1181 and hp1184 increased in the three strains, which was the same in the artificially induced clarithromycin-resistant bacteria. After gene knockout, the drug sensitivity of the strains was assessed. RESULTS: The strains showing a high degree of homology with hp26695, hp1181, and hp1184 genes were found in these strains; the expression of the genes hp1184 and hp1181 was associated with clarithromycin resistance. CONCLUSION: Hp1181 and hp1184 mutations may be the earliest and most persistent response to clarithromycin resistance, and they may be the potential target genes for the diagnosis, prevention, and treatment of clarithromycin resistance.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , China/epidemiologia , Claritromicina/farmacologia , Farmacorresistência Bacteriana/genética , Diagnóstico Precoce , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/genética , Humanos , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , RNA Ribossômico 23S
9.
Nat Mater ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239084

RESUMO

The antagonism between strength and resistance to hydrogen embrittlement in metallic materials is an intrinsic obstacle to the design of lightweight yet reliable structural components operated in hydrogen-containing environments. Economical and scalable microstructural solutions to this challenge must be found. Here, we introduce a counterintuitive strategy to exploit the typically undesired chemical heterogeneity within the material's microstructure that enables local enhancement of crack resistance and local hydrogen trapping. We use this approach in a manganese-containing high-strength steel and produce a high dispersion of manganese-rich zones within the microstructure. These solute-rich buffer regions allow for local micro-tuning of the phase stability, arresting hydrogen-induced microcracks and thus interrupting the percolation of hydrogen-assisted damage. This results in a superior hydrogen embrittlement resistance (better by a factor of two) without sacrificing the material's strength and ductility. The strategy of exploiting chemical heterogeneities, rather than avoiding them, broadens the horizon for microstructure engineering via advanced thermomechanical processing.

10.
Environ Entomol ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34240131

RESUMO

Holotrichia oblita (Faldermann) (Coleoptera: Scarabaeidae) is a major soil insect pest that damages forest trees, crops, and lawns. Adults of H. oblita fly, forage, and mate at night but remain underground during the day. We studied the effect of photoperiod on H. oblita reproduction. H. oblita females laid more eggs at 8:16 (L:D) h and 0:24 (L:D) h than other photoperiods. As the scotophase increased, the preoviposition period decreased and the oviposition period increased. Female longevity exceeded that of males at all photoperiods, and both males and females at 0:24 (L:D) h had the shortest longevity. The number of eggs laid per female increased with increasing food consumption. Females at 8:16 (L:D) h had the greatest food consumption and laid the most eggs, while females at 24:0 (L:D) h had the lowest food consumption and laid few eggs. The food intake of adults increased gradually and decreased slowly after reaching a peak. Females began to lay eggs when their food consumption reached a maximum. These results indicate that a scotophase is necessary for the reproduction of H. oblita. A long scotophase promotes greater oviposition. The effect of photoperiod on reproduction is affected by food intake.

11.
J Acoust Soc Am ; 149(5): 3106, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34241102

RESUMO

A decentralized method is proposed to estimate the two-dimensional horizontal ocean current field using the underwater acoustic sensor networks (UASNs), termed the "UASN-decentralized" method, which integrates the state-of-the-art ocean current field estimation techniques for UASNs: triangle-division-based travel time difference tomography and a spatiotemporal autoregressive model of ocean current dynamics. Moreover, the UASN-decentralized method employs a single-time scale consensus+innovations distributed estimator, called the "distributed information Kalman filter," to perform decentralized estimation and tracking. Given the redundancy of travel time differences when using UASN-based tomography, sensor nodes are classified into two types (i.e., type I and type II) to perform different tasks to reduce computations. A shortest-path-based consensus weight matrix is designed to accommodate fast-varying ocean dynamics. More communication rounds after each sensing are studied as an extension of the adopted single-time scale distributed estimator. Synthetic data are used to verify the decentralized method. Monte Carlo simulations show the feasibility of the proposed method and its robustness to measurement error related problems. With an increased number of communication rounds, the proposed method can also work well for fast-varying dynamics or a lowered sensor measurement rate.

12.
J Med Internet Res ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34280115

RESUMO

BACKGROUND: The control of vaccine hesitancy and the promotion of vaccination are key protective measures against COVID-19. OBJECTIVE: This study assesses the prevalence of vaccine hesitancy and the vaccination rate and examines the association between factors of the health belief model and vaccination. METHODS: A convenience sample of 2,531 valid participants from 31 provinces and autonomous regions of mainland China was enrolled in this online survey study from January 1st to 24th, 2021. Multivariable logistic regression was used to identify the associations of the vaccination rate and health belief model factors with the prevalence of vaccine hesitancy after other covariates were controlled. RESULTS: The prevalence of vaccine hesitancy was 44.3% (95% CI: 42.3%-46.2%), and the vaccination rate was 10.4% (9.2%-11.6%). The direct promoting factors of vaccination behaviour were a lack of vaccine hesitancy (OR=7.75, 95% CI: 5.03-11.93), agreement with recommendations from friends/family for vaccination (OR=3.11, 95% CI: 1.75-5.52) and absence of perceived barriers to COVID-19 vaccination (OR=0.51, 95% CI: 0.35-0.75). The direct factors associated with a higher vaccine hesitancy rate were a high level of perceived barriers (OR=1.63, 95% CI: 1.36-1.95), and perceived benefits (OR=0.51, 95% CI: 0.32-0.79). A mediating effect of self-efficacy, influenced by perceived barriers (SSC = -0.71, p < 0.001), perceived benefits (SSC = 0.58, p < 0.001), agreement with recommendations from authorities (SSC = 0.27, p < 0.001), and agreement with recommendations from friends/family (SSC = 0.31, p < 0.001), was negatively associated with vaccination (SSC = -0.45, p < 0.001), via vaccine hesitancy (SSC = -0.32, p < 0.001). CONCLUSIONS: It may be beneficial to increase the vaccination rate by reducing vaccine hesitancy and perceived barriers to vaccination and encouraging volunteers to advocate vaccination to their friends and family members. It is also important to reduce vaccine hesitancy by enhancing self-efficacy for vaccination due to its crucial mediating function.

13.
Sci Total Environ ; 796: 148819, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34265615

RESUMO

The global spatiotemporal pattern of the COPD burden attributable to ambient PM2.5 is unknown in the context of the continuing increase in exposure to ambient PM2.5. Data on COPD burden attributable to ambient PM2.5 from 1990 to 2019 were retrieved from the Global Burden of Disease Study 2019. Cases and age-standardized rates of COPD mortality (ASMR) and disability-adjusted life years (ASDR) were estimated by age, sex, region, and country. The estimated annual percentage change (EAPC) was calculated to quantify the secular trends of ASMR and ASDR from 1990 to 2019. Globally, the number of COPD deaths and DALYs attributable to ambient PM2.5 both increased by over 90% from 1990 to 2019, but ASMR and ASDR both slightly decreased, with EAPC of -0.58 (95% CI: -0.72, -0.44) and -0.40 (95% CI: -0.51, -0.29), respectively. Most COPD deaths and DALYs attributable to PM2.5 occurred in the middle sociodemographic index (SDI) region, but the fastest growth of ASMR and ASDR occurred in the low SDI region, with EAPCs of 2.41 (95% CI: 2.23, 2.59) and 2.34 (95% CI: 2.16, 2.52), respectively. East Asia and South Asia were the high-risk areas of COPD deaths and DALYs attributable to PM2.5, among which China and India were the countries with the heaviest burden. COPD deaths and DALYs attributable to PM2.5 mainly occurred in individuals 70-89 years old and 60-84 years old, respectively. The age-specific rates of mortality and DALYs had a rapid increase in low and low-middle SDI regions from 1990 to 2019. The ASMR or ASDR had a reverse V-shaped relationship with SDI. In summary, the ambient PM2.5-attributable COPD burden is socioeconomic- and age-dependent, and it mediates the heterogeneity of spatial and temporal distribution. Low- and middle-income countries endure the highest ambient PM2.5-attributable COPD burden due to the high exposure to PM2.5 and poor availability and affordability of medicines and diagnostic tests.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34284072

RESUMO

This study reviewed the midterm outcomes of supravalvular aortic stenosis (SVAS) repair and determined the risk factors associated with postoperative aortic or pulmonary stenosis. We retrospectively reviewed 225 patients who underwent surgical correction of SVAS from 2010 to 2019. 178 (79.1%), 44 (19.6%) and 3 (1.3%) patients underwent McGoon, Doty, and Brom repair, respectively. The median age at surgery was 2.2 years (interquartile range, 1.2-4.4). The median follow-up time was 3.7 years (interquartile range, 1.9-5.7). Early and late mortality rates were 3.1% and 1.4%, respectively. The overall 5-year survival rate was 97.9%. Eleven patients received reintervention, including 6 (2.8%) reoperations and 5 (2.3%) balloon dilatations. Higher preoperative pressure gradient at the distal ascending aorta or aortic arch was a risk factor for reintervention (p = 0.04). Rates of mortality and complications were not related to the surgical technique. Eleven patients (5.2%) developed sinotubular junction (STJ) stenosis. Freedom from postoperative distal artery stenosis (DAS) of type II SVAS was significantly lower than that of type I (p < 0.01). Higher preoperative pressure gradient at the STJ (p < 0.01) and concomitant bilateral or peripheral pulmonary artery (PA) stenosis (p < 0.01) were risk factors for postoperative DAS. Postoperative PA stenosis occurred more frequently in patients who received bilateral pulmonary arterioplasty (p < 0.01). Postoperative prognosis of the aortic root after SVAS repair was satisfactory. DAS and PA stenosis were common. The results of bilateral pulmonary arterioplasty were unsatisfactory. The surgical timing and technique for PA stenosis should be carefully considered.

15.
Anal Chem ; 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284572

RESUMO

Retinal dopamine is believed to be involved in the development of myopia, which is projected to affect almost half of the world population's visual health by 2050. Direct visualization of dopamine in the retina with high spatial precision is essential for understanding the biochemical mechanism during the development of myopia. However, there are very few approaches for the direct detection of dopamine in the visual system, particularly in the retina. Here, we report surface-enhanced Raman scattering (SERS)-based dopamine imaging in cells and retinal tissues with high spatial precision. The surface of gold nanoparticles is modified with N-butylboronic acid-2-mercaptoethylamine and 3,3'-dithiodipropionic acid di(N-hydroxysuccinimide ester), which shows excellent specific reaction with dopamine. The existence of dopamine triggers the aggregation of gold nanoparticles that subsequently form plasmonic hot spots to dramatically increase the Raman signal of dopamine. The as-synthesized SERS nanoprobes have been evaluated and applied for dopamine imaging in living cells and retinal tissues in form-deprivation (FD) myopia guinea pigs, followed by further investigation on localized dopamine levels in the FD-treated mice. The results suggest a declined dopamine level in mice retina after 2-week FD treatment, which is associated with the development of myopia. Our approach will greatly contribute to better understanding the localized dopamine level associated with myopia and its possible treatments. Furthermore, the imaging platform can be utilized to sensing other important small molecules within the biological samples.

16.
J Phys Chem Lett ; : 7010-7018, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34286998

RESUMO

Two-dimensional (2D) organic-inorganic hybrid perovskites (OIHPs) with superior nonlinear optical (NLO) properties show great versatility in frequency upconversion applications. Optical anisotropy plays an indispensable role in interpreting the interactions between incoming photons and crystal structure. Recently, the in-plane anisotropic NLO properties of 2D OIHPs have been reported and attracted much attention. However, the structure-related NLO anisotropy of the 2D OIHP framework is not well-established. Here, NLO properties of (C6H5(CH2)2NH3)2PbI4 (PEPI), (C6H11NH3)2PbI4 (C6H11), and (C4H9NH3)2PbI4 (C4PI) were systematically studied to interrogate the correlation between the in-plane anisotropic NLO responses and its lattice structure. In-plane nonparametric NLO responses, e.g., two-photon photoluminescence (2PPL) and three-photon photoluminescence (3PPL), manifest similar anisotropy configurations for PEPI, C6H11, and C4PI regardless of aromatic, cyclic, or linear organic molecules; however, the anisotropies of THG signals are strongly dependent on the specific crystal structures of the individual flakes, and they are much higher than that of the multiphoton excited photoluminescence.

17.
Cancer Med ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34288562

RESUMO

BACKGROUND: Primary tumor resection (PTR) as a treatment option for patients with stage IV pancreatic cancer (PC) is controversial. PATIENTS AND METHODS: Stage IV PC patients, with treatment data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER), were screened. The main outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS: We enrolled 15,836 stage IV PC patients in this study. Propensity score-matched analyses revealed improved OS and CSS of patients receiving chemotherapy plus PTR versus chemotherapy (median survival time [MSTOS ]: 13 vs. 9 months, p = 0.024; MSTCSS : 14 vs. 10 months, p = 0.035), and chemoradiotherapy plus PTR versus chemoradiotherapy (MSTOS : 14 vs. 7 months, p = 0.044; MSTCSS : 14 vs. 7 months, p = 0.066). Multivariate adjusted analyses further confirmed these results. Stratified with different metastatic modalities, multivariate analyses suggested that PTR significantly improved the OS and CSS among patients with ≤1 metastatic organ, and that patients with brain metastasis might not benefit from chemotherapy treatment. CONCLUSION: PTR improves the OS and CSS of stage IV PC patients on the basis of chemotherapy or chemoradiotherapy, provided that the metastases involve ≤1 organ. Chemotherapy, however, should be carefully considered in patients with metastases involving the brain.

18.
J Med Chem ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34279934

RESUMO

Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention.

19.
Dev Comp Immunol ; 124: 104203, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252476

RESUMO

As the executor of pyroptosis known to date, gasdermins (GSDMs), consists of GSDMA, GSDMB, GSDMC, GSDMD, GSDME and pejvakin, might play critical roles in anti-bacterial infection as well as inflammatory diseases. However, zebrafish only harbors a pair of Gsdme (Gsdmea/b), and their activation mechanisms remain largely unknown. Herein, we investigate the activation mechanism of Gsdmea/b cleaved by inflammatory and apoptotic caspases in zebrafish,and found that Gsdmea/b are equally cleaved by Caspase 19b, a sister of Caspy2, but not Caspy. Moreover, the zebrafish apoptotic effector caspases, including Caspase 3a/b and Caspase 7, also can cleave Gsdmea/b at the same sites as inflammatory caspases recognized. Importantly, our results reveal that Caspase 8a/b can cleave Gsdmeb, but only Caspase 8a can cleave Gsdmea. Taken together, these findings suggest that zebrafish Gsdmea/b can concurrently function as GSDMD and GSDME in mammals, which will contribute to better understanding the mechanism of pyroptosis activation in teleost, as well as provide a clue for drug screening model against inflammatory diseases.

20.
Sci Rep ; 11(1): 14774, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285244

RESUMO

The WMI and WLI inbred rats were generated from the stress-prone, and not yet fully inbred, Wistar Kyoto (WKY) strain. These were selected using bi-directional selection for immobility in the forced swim test and were then sib-mated for over 38 generations. Despite the low level of genetic diversity among WKY progenitors, the WMI substrain is significantly more vulnerable to stress relative to the counter-selected WLI strain. Here we quantify numbers and classes of genomic sequence variants distinguishing these substrains with the long term goal of uncovering functional and behavioral polymorphism that modulate sensitivity to stress and depression-like phenotypes. DNA from WLI and WMI was sequenced using Illumina xTen, IonTorrent, and 10X Chromium linked-read platforms to obtain a combined coverage of ~ 100X for each strain. We identified 4,296 high quality homozygous SNPs and indels between the WMI and WLI. We detected high impact variants in genes previously implicated in depression (e.g. Gnat2), depression-like behavior (e.g. Prlr, Nlrp1a), other psychiatric disease (e.g. Pou6f2, Kdm5a, Reep3, Wdfy3), and responses to psychological stressors (e.g. Pigr). High coverage sequencing data confirm that the two substrains are nearly coisogenic. Nonetheless, the small number of sequence variants contributes to numerous well characterized differences including depression-like behavior, stress reactivity, and addiction related phenotypes. These selected substrains are an ideal resource for forward and reverse genetic studies using a reduced complexity cross.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...