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2.
Lancet Microbe ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33495759

RESUMO

Background: Virological detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through RT-PCR has limitations for surveillance. Serological tests can be an important complementary approach. We aimed to assess the practical performance of RT-PCR-based surveillance protocols and determine the extent of undetected SARS-CoV-2 infection in Shenzhen, China. Methods: We did a cohort study in Shenzhen, China and attempted to recruit by telephone all RT-PCR-negative close contacts (defined as those who lived in the same residence as, or shared a meal, travelled, or socially interacted with, an index case within 2 days before symptom onset) of all RT-PCR-confirmed cases of SARS-CoV-2 detected since January, 2020, via contact tracing. We measured anti-SARS-CoV-2 antibodies in serum samples from RT-PCR-negative close contacts 2-15 weeks after initial virological testing by RT-PCR, using total antibody, IgG, and IgM ELISAs. In addition, we did a serosurvey of volunteers from neighbourhoods with no reported cases, and from neighbourhoods with reported cases. We assessed rates of infection undetected by RT-PCR, performance of RT-PCR over the course of infection, and characteristics of individuals who were seropositive on total antibody ELISA but RT-PCR negative. Findings: Between April 12 and May 4, 2020, we enrolled and collected serological samples from 2345 (53·0%) of 4422 RT-PCR-negative close contacts of cases of RT-PCR-confirmed SARS-CoV-2. 1175 (50·1%) of 2345 were close contacts of cases diagnosed in Shenzhen with contact tracing details, and of these, 880 (74·9%) had serum samples collected more than 2 weeks after exposure to an index case and were included in our analysis. 40 (4·5%) of 880 RT-PCR-negative close contacts were positive on total antibody ELISA. The seropositivity rate with total antibody ELISA among RT-PCR-negative close contacts, adjusted for assay performance, was 4·1% (95% CI 2·9-5·7), which was significantly higher than among individuals residing in neighbourhoods with no reported cases (0·0% [95% CI 0·0-1·1]). RT-PCR-positive individuals were 8·0 times (95% CI 5·3-12·7) more likely to report symptoms than those who were RT-PCR-negative but seropositive, but both groups had a similar distribution of sex, age, contact frequency, and mode of contact. RT-PCR did not detect 48 (36% [95% CI 28-44]) of 134 infected close contacts, and false-negative rates appeared to be associated with stage of infection. Interpretation: Even rigorous RT-PCR testing protocols might miss a substantial proportion of SARS-CoV-2 infections, perhaps in part due to difficulties in determining the timing of testing in asymptomatic individuals for optimal sensitivity. RT-PCR-based surveillance and control protocols that include rapid contact tracing, universal RT-PCR testing, and mandatory 2-week quarantine were, nevertheless, able to contain community spread in Shenzhen, China. Funding: The Bill & Melinda Gates Foundation, Special Foundation of Science and Technology Innovation Strategy of Guangdong Province, and Key Project of Shenzhen Science and Technology Innovation Commission.

3.
Aging (Albany NY) ; 122020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33288735

RESUMO

Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface receptor contributing to lymphocyte homing, adhesion and activation. The prognostic significance of the protein is unknown in diffuse large B-cell lymphoma (DLBCL) in post-rituximab era. We detected expression of ICAM-1 immunohistochemically in 102 DLBCL tissue samples. Overexpression of ICAM-1 was found in 28 (27.5%) cases. In patients with low ICAM-1 expression levels, the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy resulted in an improved overall response rate, progression-free survival (PFS) and overall survival (OS) (P=0.019, 0.01, 0.02). In pre-clinical models, we found that chronic exposure of cell lines to rituximab led to downregulation of ICAM-1 and acquirement of a rituximab resistant phenotype. In vitro exposure of rituximab resulted in rapid aggregation of B-cells regardless of the ICAM-1 expression levels. MTT assay showed knockdown of ICAM-1 could cause rituximab resistance. Neutralization of ICAM-1 did not affect rituximab activity in vitro and in vivo. Our data illustrated that in post-rituximab era, R-CHOP significantly improved the ORR, PFS and OS in ICAM-1 negative subset patients. Downregulation of ICAM-1 may contribute to rituximab resistance, and that rituximab, by promoting cell-cell aggregation, may sensitize cells to the cytotoxic effects of chemotherapy agents.

4.
Chin Clin Oncol ; 9(5): 68, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33161724

RESUMO

BACKGROUND: The goal of this study was to evaluate aprepitant usage in the context of routine clinical practice with dose/regimens at the discretion of prescribers for chemotherapy-induced nausea and vomiting (CINV) treatments. METHODS: In this single arm, multicenter prospective study 1,000 patients with solid malignancies were enrolled across 21 centers in China. The primary endpoint was the rate of adverse events (AEs), including drug related AEs and serious AEs (SAEs). Secondary efficacy endpoints included the proportion of patients achieving complete response (CR; no vomiting, no nausea, and no use of rescue medication) within 120 h after highly emetogenic chemotherapy, the rates of no nausea and no vomiting, as well as quality of life (QoL). Multivariable logistic regression analysis was carried out to determine factors associated with the overall (0-120 h), acute (0-24 h) and delayed (25-120 h) CR. RESULTS: Of the 1,000 highly emetogenic chemotherapy treated patients enrolled in the study ≥1 AE, ≥1 drug related AE, ≥1 SAE and drug related SAE rates in 998 patients were 45.9%, 2.5%, 4.0% and 0.1%, respectively. Approximately half of the patients (455/990, 46.0%) received aprepitant as part of a 3-drug anti-CINV regimen consistent with prescribing guidelines. The overall CR (0 to 120 h) for anti-emetic drug use was 41.0%, with an acute CR of 66.0% and a delayed CR of 46.5%. The rates of no vomiting and no nausea after solely aprepitant anti-emetic therapy from 0 to 120 h were 70.9% and 43.0%, for dual anti-emetic therapy 86.9% and 64.6%, and for triple therapy 86.4% and 69.5%, respectively. Multivariate regression analysis revealed that triple anti-emetic therapy (P=0.038), male gender (P<0.001) and a history of chemotherapy (P=0.016) were significantly associated with the overall acute CR. CONCLUSIONS: Especially as a combination treatment, aprepitant is safe and efficient for preventing CINV in patients receiving highly emetogenic chemotherapy.

5.
Org Lett ; 22(23): 9371-9375, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33179502

RESUMO

A ligand-controlled system has been disclosed for the regioselective palladium-catalyzed diamination of unactivated alkenes, which provides an easy access to a variety of amino-functionalized piperidines and pyrrolidines. The steric hindrance of ligands controlled the regioselectivtities of products. 6-Endo diamination occurred with less sterically hindered quinox ligand to afford 3-aminopiperidines, while 5-exo diamination occurred with sterically bulky pyox ligand to give amino-substituted pyrrolidines.

6.
J Biomed Res ; 34(6): 446-457, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33100275

RESUMO

We compared subgroup differences in COVID-19 case and mortality and investigated factors associated with case and mortality rate (MR) measured at the county level in Mississippi. Findings were based on data published by the Mississippi State Department of Health between March 11 and July 16, 2020. The COVID-19 case rate and case fatality rate (CFR) differed by gender and race, while MR only differed by race. Residents aged 80 years or older and those who live in a non-metro area had a higher case rate, CFR, and MR. After controlling for selected factors, researchers found that the percent of residents who are obese, low income, or with certain chronic conditions were associated with the county COVID-19 case rate, CFR, and/or MR, though some were negatively related. The findings may help the state to identify counties with higher COVID-19 case rate, CFR, and MR based on county demographics and the degree of its chronic conditions.

7.
Insect Sci ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33037856

RESUMO

Chitin deacetylases (CDAs, including CDA1 and CDA2) are considered key enzymes for body cuticle formation and tracheal morphogenesis in various insect species. However, their functions in the formation of the cuticular intima of the foregut and hindgut are unclear. Here, we investigated the roles of their respective genes LmCDA1 and LmCDA2 in this process, in the hemimetabolous insect Locusta migratoria. Transcripts of LmCDA1 and LmCDA2 were highly expressed both before and after molting in the foregut. In the hindgut, their expression was high only before molting. In both the foregut and hindgut, LmCDA1 protein was localized in the basal half of the chitin matrix (procuticle), whereas LmCDA2 was detected in the upper half of the procuticle. Knockdown of LmCDA1 by RNA interference (RNAi) in 5th-instar nymphs caused no visible defects of the hindgut cuticle. By contrast, the chitinous lamellae of the cuticular intima in the foregut of knockdown animals were less compact than in control animals. RNAi against LmCDA2 led to thickening of both the foregut and hindgut cuticles, with a greater number of thinner laminae than in the respective control cuticles. Taken together, our results show that LmCDA1 and LmCDA2 have distinct, but overlapping, functions in chitin organization in the foregut cuticle. However, in the hindgut, this process seems independent of LmCDA1 activity but requires LmCDA2 function. Thus, the CDAs reflect tissue-specific differences in cuticular organization and function, which need further detailed molecular and histological analyses for full comprehension.

8.
Oncol Lett ; 20(3): 2711-2720, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32782587

RESUMO

C-X-C motif chemokine ligand 17 (CXCL17) is a mucous chemokine and its expression is highly correlated with that of G protein-coupled receptor 35 (GPR35), which has been confirmed as its receptor and named C-X-C motif chemokine receptor 8 (CXCR8). CXCL17 is upregulated in several types of cancer. However, the biological role of this chemokine in colon cancer remains unknown. In the present study, the expression levels of CXCL17 and CXCR8 were examined using immunohistochemistry in 101 colon cancer tissues and 79 healthy tumour-adjacent tissues. CXCL17 and CXCR8 expression levels were increased in the colon cancer samples compared with tumour-adjacent samples. Patients with high CXCL17 expression had longer overall survival (OS) compared with patients with low expression of CXCL17 (log-rank test; P=0.027). However, CXCR8 expression, but not CXCL17, was an independent prognostic factor for OS in patients with colon cancer. The expression of CXCR8 correlated positively with that of CXCL17 in colon cancer samples (ρ=0.295; P=0.003). Furthermore, the combined high expression of CXCL17 and CXCR8 was a significant independent prognostic factor for OS in patients with colon cancer (P=0.001). In subgroups with a TNM stage of I-II, the patients with combined high expression of CXCL17 and CXCR8 had a longer survival compared with those without combined high expression (P=0.001). However, this difference was not observed in subgroups with a TNM stage of III-IV. Collectively, these findings suggest that CXCL17/CXCR8 signalling may be involved in colon cancer and contribute to improved patient outcomes.

9.
iScience ; 23(9): 101446, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32829287

RESUMO

Identification of safe and effective compounds to increase or activate UCP1 expression in brown or white adipocytes remains a potent therapeutic strategy to combat obesity. Here we reported that, glyburide, one of the FDA-approved drugs currently used to treat type 2 diabetes, can significantly enhance UCP1 expression in both brown and white adipocytes. Glyburide-fed mice exhibited a clear resistance to high-fat diet-induced obesity, reduced blood triglyceride level, and increased UCP1 expression in brown adipose tissue. Moreover, in situ injection of glyburide to inguinal white adipose tissue remarkably enhanced UCP1 expression and increased thermogenesis. Further mechanistic studies indicated that the glyburide effect in UCP1 expression in adipocytes was KATP channel independent but may involve the regulation of the Ca2+-Calcineurin-NFAT signal pathway. Overall, our findings revealed the significant effects of glyburide in regulating UCP1 expression and thermogenesis in adipocytes, which can be potentially repurposed to treat obesity.

10.
Cancer Manag Res ; 12: 5041-5048, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612391

RESUMO

Background: Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a common subtype of extranodal non-Hodgkin lymphoma (NHL), with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as the commonly used treatment regimen. However, full cycles of standard R-CHOP present the risk of severe bleeding or perforation, even leading to emergency surgery, especially for those with deep lesions in their first 1-2 cycles of treatment. This study aims to explore the safety and efficacy of fractioned R-CHOP (rituximab d0, 50% dose of CHOP d1 and d5) followed by standard R-CHOP cycles in PG-DLBCL patients guided by endoscopic ultrasonography (EUS). Patients and Methods: Thirty-one PG-DLBCL patients were analyzed in this retrospective study. All patients had lesions infiltrated to at least the 3rd layer of the stomach under EUS at baseline. Patients switched to standard R-CHOP if they showed the reduced infiltrated layers and restricted lesions after fractioned R-CHOP cycles. Results: The overall response rate, 5-year progression-free survival (PFS) and overall survival (OS) of patients in our study were 93.5%, 75% and 84%, respectively. No treatment delay or dosage reduction from gastric adverse event was observed. None of the patients in our study suffered from severe bleeding or perforation during the treatment. Kaplan-Meier analyses showed that PG-DLBCL patients characterized by multiple localization, lesions ≥3cm, having B symptoms, lower serum albumin level, and elevated LDH level were associated with worse PFS and OS. Conclusion: Our data indicate that it might be an effective approach in treating deeply infiltrated PG-DLBCL patients by switching fractioned R-CHOP to standard R-CHOP cycles guided by EUS.

11.
Nat Metab ; 2(5): 447-460, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32694659

RESUMO

The rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. The Rev-erbα-HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes; however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15, which is encoded by the mortality factor on chromosome 4 (MORF4)-related gene on chromosome 15, displays a significant diurnal rhythm and activates lipid genes in the mouse liver. RNA polymerase II (Pol II) recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. MRG15 interacts with the nuclear receptor LRH-1, rather than with known core clock proteins, and is recruited to genomic loci near lipid genes via LRH-1. Blocking of MRG15 by CRISPR targeting or by the FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in the rhythmic regulation of hepatic lipid metabolism.

12.
Geospat Health ; 15(1)2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32575968

RESUMO

As a leading cause of morbidity and premature mortality, obesity has become a major global public health problem. It is therefore important to investigate the spatial variation of obesity prevalence and its associations with environmental and behavioral factors (e.g., food environment, physical activity), to optimize the targeting of scarce public health resources. In this study, the geographic clustering of obesity in the Netherlands was explored by analyzing the local spatial autocorrelation of municipal-level prevalence rates of adulthood obesity (aged ≥19 years) in 2016. The potential influential factors that may be associated with obesity prevalence were first selected from five categories of healthrelated factors through binary and Least Absolute Shrinkage and Selection Operator (LASSO) regressions. Geographically Weighted Regression (GWR) was then used to investigate the spatial variations of the associations between those selected factors and obesity prevalence. The results revealed marked geographic variations in obesity prevalence, with four clusters of high prevalence in the north, south, east, and west, and three clusters of low prevalence in the north and south of the Netherlands. Lack of sports participation, risk of anxiety, falling short of physical activity guidelines, and the number of restaurants around homes were found to be associated with obesity prevalence across municipalities. Our findings show that effective, region-specific strategies are needed to tackle the increasing obesity in the Netherlands.

13.
Cancer Med ; 9(15): 5400-5405, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32519518

RESUMO

BACKGROUND: The optimal treatment strategies for extranodal natural killer/ T-cell lymphoma (ENKTL) have not been defined. We conducted this prospective, open-label, phase II, single-center study aimed to explore the efficacy and safety of radiotherapy followed by DICEP (Dexamethasone, ifosfamide, cisplatin, etoposide, and pegaspargase) regimen in the treatment of patients with untreated, stage IE/IIE, extranodal NK/T-cell lymphoma. METHODS: Thirty eligible patients were enrolled in this study, receiving radiotherapy of 50Gy/25fx, and followed by chemotherapy with DICEP regimen for 3 cycles if tolerated. Median follow-up time of this study was 70.8 months. We constructed Kaplan-Meier survival curves for survival analyses. RESULTS: The most common manifestations at the onset of disease were nasal obstruction (80%), with or without fever, and pharyngalgia (20%). The overall response rate (ORR) was 96.7% (29/30). Four patients (13.3%) had progression of the disease (PD), the estimated 5-year progression-free survival (PFS) rate was 86%. Four patients (13.3%) died of disease, and the estimated 5-year cumulative overall survival (OS) was 87%. The most common hematological toxicity was grade 3 or grade 4 neutropenia, which could be successfully managed via using growth-stimulating factors or dose modifications. Hypoalbuminemia and decreased fibrinogen are the top two nonhematologic toxicities. No treatment-related death occurred in this study. CONCLUSIONS: Our present study showed that radiotherapy followed by DICEP chemotherapy could be an effective and tolerable treatment modality for newly diagnosed, stage IE/IIE ENKTL patients. Adverse events were predictable and manageable. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01667302. Registered: 1 July 2012.

14.
Yonsei Med J ; 61(6): 471-481, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32469171

RESUMO

PURPOSE: Gastric cancer (GC) has a very poor prognosis when diagnosed at a late stage. Acyl-CoA thioesterase 7 (ACOT7) is a major isoform of the acyl coenzyme family that catalyzes the hydrolysis of fatty acyl-CoAs into unesterified free fatty acid and coenzyme A. The purpose of this study was to investigate the expression levels of ACOT7 in GC and mechanisms related therewith. MATERIALS AND METHODS: Screening of systematic biology studies revealed ACOT7 as a key gene in GC, as well as involvement of the long non-coding RNA NMRAL2P in ACOT7 expression. In this study, GC tissues and adjacent tissue samples were obtained from 10 GC patients at the Department of Gastrointestinal Surgery. GES1 and SGC-7901 cells were collected and treated to silence ACOT7 and overexpress NMRAL2P. The expressions of ACOT7 and NMRAL2P were detected by real-time quantitative PCR and Western blot. Additionally, cell proliferation, apoptosis, migration, and invasion were examined. RESULTS: ACOT7 was upregulated in gastric tumor tissues and GC cell lines. ACOT7 gene silencing induced a less malignant phenotype and was closely correlated to reduced cell proliferation and migration, altered cell cycle, and increased apoptosis. Furthermore, NMRAL2P was downregulated in tumor tissues and GC cell lines. NMRAL2P overexpression induced a more malignant phenotype and significantly inhibited the expression of ACOT7. Importantly, NMRAL2P indirectly methylated ACOT7 by binding to DNMT3b, thereby suppressing ACOT7 expression. CONCLUSION: NMRAL2P activation suppresses ACOT7 expression in GC. Thus, ACOT7 could be a promising target for the treatment of GC.


Assuntos
Metilação de DNA/genética , Progressão da Doença , Palmitoil-CoA Hidrolase/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Invasividade Neoplásica , Palmitoil-CoA Hidrolase/genética , RNA Longo não Codificante/genética , Regulação para Cima
15.
Lancet Infect Dis ; 20(8): 911-919, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32353347

RESUMO

BACKGROUND: Rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, prompted heightened surveillance in Shenzhen, China. The resulting data provide a rare opportunity to measure key metrics of disease course, transmission, and the impact of control measures. METHODS: From Jan 14 to Feb 12, 2020, the Shenzhen Center for Disease Control and Prevention identified 391 SARS-CoV-2 cases and 1286 close contacts. We compared cases identified through symptomatic surveillance and contact tracing, and estimated the time from symptom onset to confirmation, isolation, and admission to hospital. We estimated metrics of disease transmission and analysed factors influencing transmission risk. FINDINGS: Cases were older than the general population (mean age 45 years) and balanced between males (n=187) and females (n=204). 356 (91%) of 391 cases had mild or moderate clinical severity at initial assessment. As of Feb 22, 2020, three cases had died and 225 had recovered (median time to recovery 21 days; 95% CI 20-22). Cases were isolated on average 4·6 days (95% CI 4·1-5·0) after developing symptoms; contact tracing reduced this by 1·9 days (95% CI 1·1-2·7). Household contacts and those travelling with a case were at higher risk of infection (odds ratio 6·27 [95% CI 1·49-26·33] for household contacts and 7·06 [1·43-34·91] for those travelling with a case) than other close contacts. The household secondary attack rate was 11·2% (95% CI 9·1-13·8), and children were as likely to be infected as adults (infection rate 7·4% in children <10 years vs population average of 6·6%). The observed reproductive number (R) was 0·4 (95% CI 0·3-0·5), with a mean serial interval of 6·3 days (95% CI 5·2-7·6). INTERPRETATION: Our data on cases as well as their infected and uninfected close contacts provide key insights into the epidemiology of SARS-CoV-2. This analysis shows that isolation and contact tracing reduce the time during which cases are infectious in the community, thereby reducing the R. The overall impact of isolation and contact tracing, however, is uncertain and highly dependent on the number of asymptomatic cases. Moreover, children are at a similar risk of infection to the general population, although less likely to have severe symptoms; hence they should be considered in analyses of transmission and control. FUNDING: Emergency Response Program of Harbin Institute of Technology, Emergency Response Program of Peng Cheng Laboratory, US Centers for Disease Control and Prevention.


Assuntos
Betacoronavirus/isolamento & purificação , Controle de Doenças Transmissíveis/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Transmissão de Doença Infecciosa/prevenção & controle , Transmissão de Doença Infecciosa/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Número Básico de Reprodução , Criança , Pré-Escolar , China/epidemiologia , Controle de Doenças Transmissíveis/organização & administração , Busca de Comunicante , Infecções por Coronavirus/prevenção & controle , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Estudos Retrospectivos , Medição de Risco , Adulto Jovem
16.
Pest Manag Sci ; 76(9): 2907-2917, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32358831

RESUMO

BACKGROUND: Knickkopf (Knk) proteins play crucial roles in the formation of insect cuticle. Recent studies in the holometabolous insect red flour beetle (Tribolium castaneum) have shown that three Knk genes encoding TcKnk, TcKnk2 and TcKnk3 play different but essential roles at different developmental stages and in different tissues. However, the functions of Knk genes had not been fully explored in hemimetabolous insects such as the migratory locust Locusta migratoria. RESULTS: We identified three transcripts of LmKnk-like genes LmKnk2 and LmKnk3 with the full-length cDNA sequences, which were named as LmKnk2, LmKnk3-FL and LmKnk3-5'. These three transcripts were highly expressed before molting and mainly expressed in the integument. Among these genes, silencing only LmKnk3-5' by RNA interference (RNAi) caused molting defects and high mortality of the locusts. Injection of dsLmKnk3-5' dramatically decreased chitin content, but did not affect cuticle laminar ultra-structures in the integument. After the knockdown of LmKnk3-5' transcript, lipid deposition on the cuticle surface was impeded, and locusts exhibited increased susceptibility to each of four insecticides in three different classes. However, no visible phenotypic changes were observed after LmKnk2 or LmKnk3-FL was silenced by RNAi. CONCLUSION: We demonstrate that LmKnk3-5' is essential for cuticle formation in L. migratoria. This contrasts the findings that the cognate protein in T. castaneum TcKnk3-5' is dispensable for cuticle formation and survival. Hence, we provide some evidence that the function of Knk-type proteins may be species-specific. We therefore think that LmKnk3-5' may be a good target for the application of RNAi-based technologies for species-specific insect pest management. © 2020 Society of Chemical Industry.

17.
J Cancer ; 11(12): 3476-3482, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32284743

RESUMO

The prognosis of acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations is poor. Some studies, including our previous study, have indicated that arsenic trioxide (ATO) exhibited significant anti-carcinogenic activity in FLT3-ITD AML cells and explored the possibility of targeting the FLT3-ITD protein for degradation as a therapy. Autophagy is a critical mechanism of the anti-leukemic effects of ATO. In this study, we explored the therapeutic efficacy of ATO treatment in a mouse model bearing FLT3-ITD AML and found that ATO significantly reduced the leukemic burden in bone marrow and spleen. We also found that autophagy was responsible for, at least in part, the degradation of the FLT3-ITD protein by ATO. After ATO treatment, MV4-11 cells showed complete autophagic flux. The autophagy inhibitor bafilomycin A or down-regulation of the key autophagy genes Atg5 and Atg7 reversed the FLT3 degradation induced by ATO. We also found that p62/SQSTM1 delivered FLT3-ITD proteins to the lysosome, where they were subsequently degraded. These results indicate that ATO can induce autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD AML.

18.
PLoS Negl Trop Dis ; 14(3): e0008085, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32196496

RESUMO

BACKGROUND: The epidemic of hand, foot, and mouth disease (HFMD) has become a severe public health problem in the world and has also brought a high economic and health burden. Furthermore, the prevalence of HFMD varies significantly among different locations. However, there have been few investigations of the effects of socioeconomic factors and air pollution factors on the incidence of HFMD. METHODS: This study collected data on HFMD in Shenzhen, China, from 2012 to 2015. We selected eleven factors as potential risk factors for HFMD. A Bayesian spatiotemporal model was used to quantify the influence of the factors on HFMD and to identify the relative risks in different districts. RESULTS: The risk factors of HFMD were the population, population density, concentration of SO2, and concentration of NO2. The relative risks (RRs) were 1.00473 (95% CI: 1.00059-1.00761), 1.00010 (95% CI: 1.00002-1.00016), 1.00215 (95% CI: 1.00170-1.00232) and 1.00058 (95% CI: 1.00028-1.00078), respectively. The protective factors against HFMD were the per capita GDP, the number of public kindergartens, the concentration of PM10, and the concentration of O3. The RRs were 0.98840 (95% CI: 0.98660-0.99026), 0.97686 (95% CI: 0.96946-0.98403), 0.99108 (95% CI: 0.98551-0.99840) and 0.99587 (95% CI: 0.99534-0.99610), respectively. The risk of incidence in Longgang district and Pingshan district decreased, while the risk of incidence in Baoan district increased. CONCLUSIONS: Studies have confirmed that socioeconomic factors and air pollution factors have an impact on the incidence of HFMD in Shenzhen, China. The results will be of great practical significance to local authorities, which is conducive to accurate prevention and can be used to formulate HFMD early warning systems.


Assuntos
Doença de Mão, Pé e Boca/epidemiologia , Poluição do Ar , Teorema de Bayes , Criança , Pré-Escolar , China/epidemiologia , Exposição Ambiental , Feminino , Humanos , Incidência , Lactente , Masculino , Medição de Risco , Fatores Socioeconômicos , Análise Espaço-Temporal
19.
Cell Death Dis ; 11(1): 39, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959745

RESUMO

Ginsenosides exhibit a large variety of biological activities in maintaining physical health; however, the molecule underpinnings underlining these biological activities remain to be defined. Here, we took a cellular condition that compound K (CK) induces autophagic cell death in HeLa cells, and setup a high-throughput genetic screening using CRISPR technology. We have identified a number of CK-resistant and CK-sensitive genes, and further validated PMAIP1 as a CK-resistant gene and WASH1 as a CK-sensitive gene. Compound K treatment reduces the expression of WASH1, which further accelerates the autophagic cell death, highlighting WASH1 as an interesting downstream mediator of CK effects. Overall, our study offers an easy-to-adopt platform to study the functional mediators of ginsenosides, and provides a candidate list of genes that are potential targets of CK.

20.
Cell Biochem Funct ; 38(3): 242-248, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31709594

RESUMO

Classical Hodgkin lymphoma (cHL) is a particular kind of malignant tumour that originates from the B cells. The malignant phenotype of cHL is, at least in part, maintained by epigenetic aberrations, which primarily consist of abnormal histone methylation and acetylation. Progress has been made in clinical trials concerning the histone deacetylases inhibitors (HDACis) in cHL. Also, some demethylation regimens could serve the purpose of preventing and treating tumours. Programmed death-ligand receptor 1 (PD-L1, CD274) inhibitors or apoptosis receptor 1 (PD-1, CD279) inhibitors are used in treating patients with relapsed cHL in recent years. Academic researches indicated that PD-1/PD-L1 inhibitors, including nivolumab and pembrolizumab, demonstrate remarkable activity in relapsed cHL. In addition, in recent years, a close association between epigenetic aberrations and immune escape has been explored in cHL. DNA methyltransferase (DNMT) inhibitors, HDACis, and immune checkpoint blockade exhibit synergistic effects. Thus, this review aims to provide an overview on the epigenetic abnormalities of cHL and its effect on immune escape, in order to explore the optimal combination approach to treat the disease. SIGNIFICANCE OF THE STUDY: Cancer Statistics 2018 reported that more than 8000 new cases of Hodgkin lymphoma were diagnosed. In recent years, PD-1/PD-L1 inhibitors for cHL have been utilized, and the therapeutic strategies of HDACis combined with PD-1/PD-L1 inhibitors have been raised. It is critical for improving the efficacy and decreasing the toxicity in treating the patients with cHL.

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