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1.
Hum Mol Genet ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022708

RESUMO

Inguinal hernias are some of the most frequently diagnosed conditions in clinical practice and inguinal hernia repair is the most common procedure performed by general surgeons. Studies of inguinal hernias in non-European populations are lacking, though it is expected that such studies could identify novel loci. Further, the cumulative lifetime incidence of inguinal hernia is nine times greater in men than women, however it is not clear why this difference exists. We conducted a genome-wide association meta-analysis of inguinal hernia risk across 513 120 individuals (35 774 cases and 477 346 controls) of Hispanic/Latino, African, Asian, and European descent, with replication in 728 418 participants (33 491 cases and 694 927 controls) from the 23andMe, Inc dataset. We identified 63 genome-wide significant loci (P < 5x10-8), including 41 novel. Ancestry-specific analyses identified two loci (LYPLAL1-AS1/SLC30A10 and STXBP6-NOVA1) in African ancestry individuals. Sex-stratified analyses identified two loci (MYO1D and ZBTB7C) that are specific to women, and four (EBF2, EMX2/RAB11FIP2, VCL and FAM9A/FAM9B) that are specific to men. Functional experiments demonstrated that several of the associated regions (EFEMP1 and LYPLAL1-SLC30A10) function as enhancers and show differential activity between risk and reference alleles. Our study highlights the importance of large-scale genomic studies in ancestrally diverse populations for identifying ancestry-specific inguinal hernia susceptibility loci and provides novel biological insights into inguinal hernia etiology.

3.
Behav Brain Res ; 418: 113621, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34624424

RESUMO

Sleep is essential for important physiological functions. Impairment of learning and memory function caused by lack of sleep is a common physiological phenomenon of which underlying changes in synaptic plasticity in the hippocampus are not well understood. The possible different effects of sleep deprivation (SD) lasting for various durations on learning and memory function and hippocampal synaptic plasticity are still not completely clear. In this study, we used a modified multiple platform method (MMPM) to induce rapid eye movement SD (REM SD), lasting for 24 h, 48 h, and 72 h, separately. The novel place recognition (NPR) and novel object recognition (NOR) tasks were used to test the novelty-related object recognition memory (ORM) and object location memory (OLM) of mice. Then, hippocampal synaptic plasticity was evaluated after all behavioural experiments. The results showed that REM SD played a key role in OLM but not in ORM. Specifically, 24 h REM SD improved novelty-related OLM, accompanied by a significantly increased hippocampal synaptic plasticity, including gain of dendritic spines, increased expression of hippocampal GluA1, and enhanced long-term potentiation (LTP), whereas 48 h REM SD showed no effect on OLM or the hippocampal synaptic plasticity mentioned above; however, 72 h REM SD impaired novelty-related OLM and weakened hippocampal synaptic plasticity, including serious loss of dendritic spines, decreased expression of hippocampal GluA1, and significantly attenuated LTP. Our results suggest that REM SD of various durations has different effects on both novelty-related OLM and hippocampal synaptic plasticity.

4.
Front Genet ; 12: 728472, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868206

RESUMO

Uncovering the genetic architecture for grain yield (GY)-related traits is important for wheat breeding. To detect stable loci for GY-related traits, a genome-wide association study (GWAS) was conducted in a diverse panel, which included 251 elite spring wheat accessions mainly from the Northeast of China. In total, 52,503 single nucleotide polymorphisms (SNPs) from the wheat 55 K SNP arrays were used. Thirty-eight loci for GY-related traits were detected and each explained 6.5-16.7% of the phenotypic variations among which 12 are at similar locations with the known genes or quantitative trait loci and 26 are likely to be new. Furthermore, six genes possibly involved in cell division, signal transduction, and plant development are candidate genes for GY-related traits. This study provides new insights into the genetic architecture of GY and the significantly associated SNPs and accessions with a larger number of favorable alleles could be used to further enhance GY in breeding.

5.
Front Oncol ; 11: 752642, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912709

RESUMO

Background: Glucose-6-phosphate isomerase (GPI) plays an important role in glycolysis and gluconeogenesis. However, the role of GPI in lung adenocarcinoma (LUAD) remains unclear. Methods: All original data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and integrated via R 3.2.2. GPI expression was explored with TCGA, GEO, and Oncomine databases. Immunohistochemistry staining was used to analyze GPI expression in clinical specimens. The correlations between GPI and cancer immune characteristics were analyzed via the TIMER and TISIDB databases. GPI-specific siRNAs were used to verify the role of GPI expression on cell proliferation and cell cycle distribution. Results: In general, GPI is predominantly overexpressed and has reference value in the diagnosis and prognostic estimation of LUAD. Upregulated GPI was associated with poorer overall survival, clinical stage, N stage, and primary therapy outcome in LUAD. Mechanistically, we identified a hub gene that included a total of 56 GPI-related genes, which were tightly associated with the cell cycle pathway in LUAD patients. Knockdown of GPI induced cell proliferation inhibition and cell cycle arrest. GPI expression was positively correlated with infiltrating levels of Th2 cells and regulatory T cells (Tregs); in contrast, GPI expression was negatively correlated with infiltrating levels of CD8+ T cells, central memory T cells, dendritic cells, macrophages, mast cells, and eosinophils. GPI was negatively correlated with the expression of immunostimulators, such as CD40L, IL6R, and TMEM173, in LUAD. Conclusion: GPI may play an important role in the cell cycle and can be used as a prognostic biomarker for determining the prognosis and immune infiltration in LUAD.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34921331

RESUMO

Recent technical advances regarding filamentous fungi have accelerated the engineering of fungal-based production and benefited basic science. However, challenges still remain and limit the speed of fungal applications. For example, high-throughput technologies tailored to filamentous fungi are not yet commonly available for genetic modification. The currently used fungal genetic manipulations are time-consuming and laborious. Here, we developed a flow cytometry-based plating-free system to directly screen and isolate the transformed protoplasts in industrial fungi Myceliophthora thermophila and Aspergillus niger. This system combines genetic engineering via the 2A peptide and the CRISPR-Cas9 system, strain screening by flow cytometry, and direct sorting of colonies for deep-well-plate incubation and phenotypic analysis while avoiding culturing transformed protoplasts in plates, colony picking, conidiation, and cultivation. As a proof of concept, we successfully applied this system to generate the glucoamylase-hyperproducing strains MtYM6 and AnLM3 in M. thermophila and A. niger, respectively. Notably, the protein secretion level and enzyme activities in MtYM6 were 17.3- and 25.1-fold higher than in the host strain. Overall, these findings suggest that the flow cytometry-based plating-free system can be a convenient and efficient tool for strain engineering in fungal biotechnology. We expect this system to facilitate improvements of filamentous fungal strains for industrial applications. KEY POINTS: • Development of a flow cytometry-based plating-free (FCPF) system is presented. • Application of FCPF system in M. thermophila and A. niger for glucoamylase platform. • Hyper-produced strains MtYM6 and AnLM3 for glucoamylase production are generated.

7.
Transl Oncol ; 15(1): 101287, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34808461

RESUMO

Cancer immunotherapy is a new therapeutic strategy for cancer treatment that targets tumors by improving or restoring immune system function. Therapies targeting immune checkpoint molecules have exerted potent anti-tumor effects and prolonged the overall survival rate of patients. However, only a small number of patients benefit from the treatment. Oncolytic viruses exert anti-tumor effects by regulating the tumor microenvironment and affecting multiple steps of tumor immune circulation. In this study, we engineered two oncolytic viruses that express mouse anti-PD-1 antibody (VT1093M) or mouse IL-12 (VT1092M). We found that both oncolytic viruses showed significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Importantly, the intratumoral combined injection with VT1092M and VT1093M inhibited growth of the primary tumor, prevented growth of the contralateral untreated tumor, produced a vaccine-like response, activated antigen-specific T cell responses and prolonged the overall survival rate of mice. These results indicate that combination therapy with the engineered oncolytic virus may represent a potent immunotherapy strategy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.

8.
Immunol Lett ; 241: 15-22, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34774916

RESUMO

Tumors with a low level of pre-existing immune cell infiltration respond poorly to immune checkpoint therapies. Oncolytic viruses optimize immunotherapies by modulating the tumor microenvironment and affecting multiple steps in the cancer-immunity cycle, making them an attractive agent for combination strategies. We engineered an HSV-1-based oncolytic virus and investigated its antitumor effects in combination with the marketed PD-1 antibody Keytruda (pembrolizumab) in hPD-1 knock-in mice bearing non-immunogenic B16-F10 melanoma. Our results showed enhanced CD8+ and CD4+ T cell infiltration, IFN-γ secretion and PD-L1 expression in tumors, subsequently leading to the prolonged overall survival of mice. Systemic changes in lymphocyte cell proportions were also observed in the peripheral blood. In summary, these findings provide evidence that oncolytic viruses can be engineered as a potential platform for combination therapies, especially to treat tumors that are poorly responsive to immune checkpoint therapy.

9.
J Invest Dermatol ; 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34813871

RESUMO

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including with its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multi-trait analysis of GWAS (MTAG). We used bivariate LD-score regression to identify traits that are genetically correlated with clinically-confirmed cutaneous melanoma, and then used publicly available GWAS for these traits in a MTAG. MTAG allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci; 19 of them were not previously reported in the input cutaneous melanoma GWAS-meta-analysis. 55 of these loci were replicated (P < 0.05/74), Bonferroni corrected P -value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the new cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP, and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

10.
Natl Sci Rev ; 8(4): nwaa126, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34691608

RESUMO

The functionalization of otherwise unreactive C-H bonds adds a new dimension to synthetic chemistry, yielding useful molecules for a range of applications. Arylation has emerged as an increasingly viable strategy for functionalization of heteroarenes which constitute an important class of structural moieties for organic materials. However, direct bisarylation of heteroarenes to enable aryl-heteroaryl-aryl bond formation remains a formidable challenge, due to the strong coordination between heteroatom of N or S and transitional metals. Here we report Pd interstitial nanocatalysts supported on ordered mesoporous carbon as catalysts for a direct and highly efficient bisarylation method for five-membered heteroarenes that allows for green and mild reaction conditions. Notably, in the absence of any base, ligands and phase transfer agents, high activity (turn-over frequency, TOF, up to 107 h-1) and selectivity (>99%) for the 2,5-bisarylation of five-membered heteroarenes are achieved in water. A combination of characterization reveals that the remarkable catalytic reactivity here is attributable to the parallel adsorption of heteroarene over Pd clusters, which breaks the barrier to electron transfer in traditional homogenous catalysis and creates dual electrophilic sites for aryl radicals and adsorbate at C2 and C5 positions. The d-band filling at Pd sites shows a linear relationship with activation entropy and catalytic activity. The ordered mesopores facilitate the absence of a mass transfer effect. These findings suggest alternative synthesis pathways for the design, synthesis and understanding of a large number of organic chemicals by ordered mesoporous carbon supported palladium catalysts.

11.
JAMA Psychiatry ; 78(11): 1258-1269, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34586374

RESUMO

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires. Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (ß = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (ß = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (ß = -0.003, SE = 0.005, P = .53 for rs4656484 and ß = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

12.
Molecules ; 26(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34500807

RESUMO

A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson's disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.


Assuntos
Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Estirenos/farmacologia , Sulfonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Células Cultivadas , Inflamação/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estirenos/síntese química , Estirenos/química , Sulfonas/síntese química , Sulfonas/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
J Vet Med Sci ; 83(10): 1608-1619, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34470981

RESUMO

A novel avian infectious bronchitis virus (IBV) variant, designated as GX-NN160421, was isolated from vaccinated chicken in Guangxi, China, in 2016. Based on analysis of the S1 gene sequence, GX-NN160421 belonged to the New-type 1 (GVI-1) strain. More importantly, three consecutive nucleotides (AAC) deletions were found in the highly conserved structure gene N. The serotype of GX-NN160421 was different from those of the commonly used vaccine strains. The mortality of the GX-NN160421 strain was 3.33%, which contrasted with 50% mortality in the clinical case, but high levels of virus shedding lasted at least 21 days. In conclusion, the first novel IBV variant with three-nucleotide-deletion in the N gene was identified, and this unique variant is low virulent but with a long time of virus shedding, indicating the continuing evolution of IBV and emphasizing the importance of limiting exposure to novel IBV strains as well as extensive monitoring of new IBVs.


Assuntos
Infecções por Coronavirus , Vírus da Bronquite Infecciosa , Doenças das Aves Domésticas , Animais , Galinhas , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/veterinária , Genótipo , Vírus da Bronquite Infecciosa/genética , Nucleocapsídeo , Nucleotídeos , Filogenia , Doenças das Aves Domésticas/epidemiologia
14.
Sci Total Environ ; 799: 149495, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371394

RESUMO

Agriculture is an important N2O emissions source. Water cycle and nitrogen cycles have important effects on N2O in farmland ecosystems. The changes in the groundwater table can lead to changes in farmland the water and nitrogen cycle processes. However, how this such changes will affect N2O emissions from farmland remains unclear. In this study, a two-year volume lysimeter experiment (2019-2020), including four controlled groundwater tables (i.e., 40, 70, 110, and 150 cm), was performed to monitor the variations in the NO3- and N2O concentrations in shallow groundwater as well as the direct N2O emissions due to surface soil and groundwater evaporation. Our results showed that N2O emissions during fertilization accounted for 80%-90% of the total N2O emissions throughout the maize growing period. Direct N2O emissions increase with the increase in the groundwater table. The total N2O emissions in 2020 were 96.44, 9.75, 6.46, and 6.22 kg ha-1 y-1 at a groundwater table of 40, 70, 110, and 150 cm, respectively. The high water-filled pore space (WFPS) value resulting from the elevated groundwater table increased the groundwater-atmosphere connectivity, leading to significantly increased N2O emissions after fertilization. Increased precipitation (454.90 mm in 2020 vs. 180.30 mm in 2019) accelerated the hydrological processes in agroecology, reducing the retention time of N2O (6 weeks in 2020 vs. 7.5 weeks in 2019) and NO3- (6.75 weeks in 2020 vs. 7.25 weeks in 2019) in shallow groundwater. Studying the influence of shallow groundwater tables on direct N2O emissions will provide insights into the interaction between the water and nitrogen cycles in agroecosystems. The results of this study suggest that direct N2O emissions can be effectively reduced by controlling the groundwater table in agricultural fields in the North China Plain.


Assuntos
Água Subterrânea , Zea mays , Agricultura , China , Ecossistema , Fertilizantes/análise , Nitrogênio , Óxido Nitroso/análise , Solo
15.
Redox Biol ; 46: 102089, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364220

RESUMO

As a potent chemotherapeutic agent, doxorubicin (DOX) is widely used for the treatment of a variety of cancers However, its clinical utility is limited by dose-dependent cardiotoxicity, and pathogenesis has traditionally been attributed to the formation of reactive oxygen species (ROS). Accordingly, the prevention of DOX-induced cardiotoxicity is an indispensable goal to optimize therapeutic regimens and reduce morbidity. Acetylation is an emerging and important epigenetic modification regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). Despite extensive studies of the molecular basis and biological functions of acetylation, the application of acetylation as a therapeutic target for cardiotoxicity is in the initial stage, and further studies are required to clarify the complex acetylation network and improve the clinical management of cardiotoxicity. In this review, we summarize the pivotal functions of HDACs and HATs in DOX-induced oxidative stress, the underlying mechanisms, the contributions of noncoding RNAs (ncRNAs) and exercise-mediated deacetylases to cardiotoxicity. Furthermore, we describe research progress related to several important SIRT activators and HDAC inhibitors with potential clinical value for chemotherapy and cardiotoxicity. Collectively, a comprehensive understanding of specific roles and recent developments of acetylation in doxorubicin-induced cardiotoxicity will provide a basis for improved treatment outcomes in cancer and cardiovascular diseases.


Assuntos
Cardiotoxicidade , Miócitos Cardíacos , Acetilação , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Humanos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
16.
Commun Biol ; 4(1): 832, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215830

RESUMO

Sialyl-Lewis x (sLex, CD15s) is a tetra-saccharide on the surface of leukocytes required for E-selectin-mediated rolling, a prerequisite for leukocytes to migrate out of the blood vessels. Here we show using flow cytometry that sLex expression on basophils and mast cell progenitors depends on fucosyltransferase 6 (FUT6). Using genetic association data analysis and qPCR, the cell type-specific defect was associated with single nucleotide polymorphisms (SNPs) in the FUT6 gene region (tagged by rs17855739 and rs778798), affecting coding sequence and/or expression level of the mRNA. Heterozygous individuals with one functional FUT6 gene harbor a mixed population of sLex+ and sLex- basophils, a phenomenon caused by random monoallelic expression (RME). Microfluidic assay demonstrated FUT6-deficient basophils rolling on E-selectin is severely impaired. FUT6 null alleles carriers exhibit elevated blood basophil counts and a reduced itch sensitivity against insect bites. FUT6-deficiency thus dampens the basophil-mediated allergic response in the periphery, evident also in lower IgE titers and reduced eosinophil counts.


Assuntos
Basófilos/metabolismo , Fucosiltransferases/genética , Expressão Gênica , Antígeno Sialil Lewis X/biossíntese , Sequência de Bases , Basófilos/citologia , Células Cultivadas , Estudos de Coortes , Selectina E/metabolismo , Fucosiltransferases/deficiência , Perfilação da Expressão Gênica/métodos , Humanos , Contagem de Leucócitos , Migração e Rolagem de Leucócitos/genética , Migração e Rolagem de Leucócitos/fisiologia , Polimorfismo de Nucleotídeo Único , Homologia de Sequência do Ácido Nucleico
17.
Cancer Lett ; 518: 49-58, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34139284

RESUMO

Oncolytic viruses as cancer vaccines modulate the tumor microenvironment and act synergistically with immune checkpoint inhibitors to overcome resistance. Taking advantage of the loading capacity for exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-aPD-1, carrying a full-length humanized anti-PD-1 monoclonal antibody (anti-PD-1 mAb) that replicates and expresses anti-PD-1 mAbs in tumor cells in vitro and in vivo. Its anti-tumor effect was assessed in human PD-1 knock-in mice by analyzing tumor inhibition, cell populations and RNA expression in tumors, and serum cytokine levels. Enhanced anti-tumor immune responses and T-cell infiltration were induced by HSV-aPD-1 compared with unloaded virus or anti-PD-1 therapy in both MC38 and B16-F10 models, resulting in improved treatment efficacy in the latter. Moreover, compared with unloaded HSV-1 or HSV-1 loaded with GM-CSF/IL-2 combined with anti-PD-1 mAbs, HSV-aPD-1 displayed similar therapeutic control of tumor growth. Finally, tumor RNAseq analysis in the B16-F10 model showed upregulated IFN pathway and antigen processing and presentation genes, and downregulated angiogenesis and cell adhesion genes, which all contribute to tumor inhibition. These findings indicate the clinical potential of HSV-aPD-1 as monotherapy or combination therapy, especially in tumors resistant to immune checkpoint inhibitors.

18.
World J Gastroenterol ; 27(21): 2895-2909, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34135560

RESUMO

BACKGROUND: Poorly differentiated gastric neuroendocrine neoplasms (PDGNENs) include gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma, which are highly malignant and rare tumors, and their incidence has increased over the past few decades. However, the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated. AIM: To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs. METHODS: The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively. RESULTS: Among the 232 patients with PDGNENs, 191 (82.3%) were male, with an average age of 62.83 ± 9.11 years. One hundred and thirteen (49.34%) of 229 patients had a stage III disease and 86 (37.55%) had stage IV disease. Three (1.58%) of 190 patients had no clinical symptoms, while 187 (98.42%) patients presented clinical symptoms. The tumors were mainly (89.17%) solitary and located in the upper third of the stomach (cardia and fundus of stomach: 115/215, 53.49%). Most lesions were ulcers (157/232, 67.67%), with an average diameter of 4.66 ± 2.77 cm. In terms of tumor invasion, the majority of tumors invaded the serosa (116/198, 58.58%). The median survival time of the 232 patients was 13.50 mo (7, 31 mo), and the overall 1-year, 3-year, and 5-year survival rates were 49%, 19%, and 5%, respectively. According to univariate analysis, tumor number, tumor diameter, gastric invasion status, American Joint Committee on Cancer (AJCC) stage, and distant metastasis status were prognostic factors for patients with PDGNENs. Multivariate analysis showed that tumor number, tumor diameter, AJCC stage, and distant metastasis status were independent prognostic factors for patients with PDGNENs. CONCLUSION: The overall prognosis of patients with PDGNENs is poor. The outcomes of patients with a tumor diameter > 5 cm, multiple tumors, and stage IV tumors are worse than those of other patients.


Assuntos
Tumores Neuroendócrinos , Neoplasias Gástricas , Idoso , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia
19.
Environ Pollut ; 284: 117405, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062430

RESUMO

River ecosystems are under increasing stress in the background of global change and ever-growing anthropogenic impacts in Central Asia. However, available water quality data in this region are insufficient for a reliable assessment of the current status, which come as no surprise that the limited knowledge of regulating processes for further prediction of solute variations hinders the development of sustainable management strategies. Here, we analyzed a dataset of various water quality variables from two sampling campaigns in 2019 in the catchments of two major rivers in Central Asia-the Amu Darya and Syr Darya Rivers. Our results suggested high spatial heterogeneity of salinity and major ion components along the longitudinal directions in both river catchments, pointing to an increasing influence of human activities toward downstream areas. We linked the modeling outputs from the global nutrient model (IMAGE-GNM) to riverine nutrients to elucidate the effect of different natural and anthropogenic sources in dictating the longitudinal variations of the riverine nutrient concentrations (N and P). Diffuse nutrient loadings dominated the export flux into the rivers, whereas leaching and surface runoff constituted the major fractions for N and P, respectively. Discharge of agricultural irrigation water into the rivers was the major cause of the increases in nutrients and salinity. Given that the conditions in Central Asia are highly susceptible to climate change, our findings call for more efforts to establish holistic management of water quality.


Assuntos
Ecossistema , Qualidade da Água , Ásia , Monitoramento Ambiental , Humanos , Rios
20.
J Med Primatol ; 50(4): 225-227, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34036592

RESUMO

This report aims to analyze the experimental monkey shortage generated by the COVID-19 lockdown. The supply capability of the monkey breeding farms is insufficient to meet demand, and the sales prices have skyrocketed since 2018. The contradiction will be further aggravated with import prohibition although the countermeasures suggested.


Assuntos
Cruzamento/estatística & dados numéricos , COVID-19 , Haplorrinos , Modelos Animais , Animais , China
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