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1.
Clin Cancer Res ; : OF1-OF13, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38592373

RESUMO

PURPOSE: TGFß signaling is implicated in the progression of most cancers, including esophageal adenocarcinoma (EAC). Emerging evidence indicates that TGFß signaling is a key factor in the development of resistance toward cancer therapy. EXPERIMENTAL DESIGN: In this study, we developed patient-derived organoids and patient-derived xenograft models of EAC and performed bioinformatics analysis combined with functional genetics to investigate the role of SMAD family member 3 (SMAD3) in EAC resistance to oxaliplatin. RESULTS: Chemotherapy nonresponding patients showed enrichment of SMAD3 gene expression when compared with responders. In a randomized patient-derived xenograft experiment, SMAD3 inhibition in combination with oxaliplatin effectively diminished tumor burden by impeding DNA repair. SMAD3 interacted directly with protein phosphatase 2A (PP2A), a key regulator of the DNA damage repair protein ataxia telangiectasia mutated (ATM). SMAD3 inhibition diminished ATM phosphorylation by enhancing the binding of PP2A to ATM, causing excessive levels of DNA damage. CONCLUSIONS: Our results identify SMAD3 as a promising therapeutic target for future combination strategies for the treatment of patients with EAC.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38525525

RESUMO

PURPOSE: The available data on the treatment strategy of pulsed field ablation (PFA) for patients with atrial fibrillation (AF) is limited. This study aims to provide a comparative analysis of the efficacy, safety, and procedural efficiency between PFA and cryoballoon ablation (CBA) for AF. METHODS: We conducted a comprehensive search of the EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov databases to identify trials comparing PFA with CBA for AF from their inception until December 2023. The odds ratio (OR) and mean difference (MD), along with a 95% confidence interval (CI), were utilized as measures of treatment effect. RESULTS: The analysis included 15 eligible trials with a total enrollment of 1880 patients. No significant differences were found in recurrent atrial arrhythmia (OR 0.83, 95% CI 0.64, 1.07) or periprocedural complications (OR 0.78, 95% CI 0.46, 1.30) between the two ablation techniques examined in this study. However, the PFA technique demonstrated a significantly shorter procedure time (MD -7.17, 95% CI -13.60, -0.73), but a longer fluoroscopy time (MD 2.53, 95% CI 0.87, 4.19). Similarly, PFA was found to be significantly associated with a decreased incidence of phrenic nerve palsy (OR 0.20, 95% CI 0.07, 0.59), but an increased incidence of cardiac tamponade (OR 4.07, 95% CI 1.15, 14.39). Moreover, there was a significantly higher release of troponin with PFA compared to CBA (MD 470.28, 95% CI 18.89, 921.67), while the increase in S100 protein and heart rate was significantly lower with PFA than with CBA (MD -64.41, 95% CI -105.46, -17.36), (MD -8.76, 95% CI -15.12, -2.40). CONCLUSION: The utilization of PFA provides a safer, time-saving, and tissue-specific procedure compared to CBA, while maintaining comparable success rates. This has the potential to enhance procedural efficiency and optimize resource utilization in clinical practice. These findings underscore the feasibility and promise of PFA as an alternative technique for PVI in patients with AF.

3.
Biol Trace Elem Res ; 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38367173

RESUMO

Pancreatic ß cell damage is the primary contributor to type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains nebulous. This study explored the role of ferroptosis in pancreatic ß cell damage and the protective effects of grape seed proanthocyanidin extract (GSPE). In T2DM model rats, the blood glucose, water intake, urine volume, HbA1c, and homeostasis model assessment-insulin resistance were significantly increased, while the body weight and the insulin level were significantly decreased, indicating the successful establishment of the T2DM model. MIN6 mouse insulinoma ß cells were cultured in high glucose and sodium palmitate conditions to obtain a glycolipid damage model, which was administered with GSPE, ferrostatin-1 (Fer-1), or nuclear factor erythroid 2-related factor 2 (Nrf2) small interfering (si) RNA. GSPE and Fer-1 treatment significantly improved pancreatic ß-cell dysfunction and protected against cell death. Both treatments increased the superoxide dismutase and glutathione activity, reduced the malondialdehyde and reactive oxygen species levels, and improved iron metabolism. Furthermore, the treatments reversed the expression of ferroptosis markers cysteine/glutamate transporter (XCT) and glutathione peroxidase 4 (GPX4) caused by glycolipid toxicity. GSPE treatments activated the expression of Nrf2 and related proteins. These effects were reversed when co-transfected with si-Nrf2. GSPE inhibits ferroptosis by activating the Nrf2 signaling pathway, thus reducing ß-cell damage and dysfunction in T2DM. Therefore, GSPE is a potential treatment strategy against T2DM.

4.
Qual Life Res ; 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38353890

RESUMO

PURPOSE: The high prevalence of multimorbidity in aging societies has posed tremendous challenges to the healthcare system. The aim of our study was to comprehensively assess the association of multimorbidity patterns and health-related quality of life (HRQOL) among rural Chinese older adults. METHODS: This was a cross-sectional study. Data from 4,579 community-dwelling older adults aged 60 years and above was collected by the clinical examination and questionnaire survey. Information on 10 chronic conditions was collected and the 3-Level EQ-5D (EQ-5D-3L) was adopted to measure the HRQOL of older adults. An exploratory factor analysis was performed to determine multimorbidity patterns. Regression models were fitted to explore the associations of multimorbidity patterns with specific health dimensions and overall HRQOL. RESULTS: A total of 2,503 (54.7%) participants suffered from multimorbidity, and they reported lower HRQOL compared to those without multimorbidity. Three kinds of multimorbidity patterns were identified including cardiovascular-metabolic diseases, psycho-cognitive diseases and organic diseases. The associations between psycho-cognitive diseases/organic diseases and overall HRQOL assessed by EQ-5D-3L index score were found to be significant (ß = - 0.097, 95% CI - 0.110, - 0.084; ß = - 0.030, 95% CI - 0.038, - 0.021, respectively), and psycho-cognitive diseases affected more health dimensions. The impact of cardiovascular-metabolic diseases on HRQOL was largely non-significant. CONCLUSION: Multimorbidity was negatively associated with HRQOL among older adults from rural China. The presence of the psycho-cognitive diseases pattern or the organic diseases pattern contributed to worse HRQOL. The remarkable negative impact of psycho-cognitive diseases on HRQOL necessiates more attention and relevant medical assistance to older rural adults.

5.
BMC Infect Dis ; 24(1): 137, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38287234

RESUMO

BACKGROUND: Dried blood spot (DBS) testing provides an alternative to phlebotomy and addresses barriers to accessing healthcare experienced by some key populations. Large-scale evaluations of DBS testing programs are needed to understand their feasibility. This study evaluated the implementation of a state-wide DBS HIV and hepatitis C virus (HCV) testing pilot. METHODS: The New South Wales (NSW) DBS Pilot is an interventional cohort study of people testing for HIV antibody and/or HCV RNA from DBS samples in NSW, Australia. Participants at risk of HIV/HCV participated in testing via: 1) self-registration online with a DBS collection kit delivered and returned by conventional postal service; or 2) assisted DBS sample collection at 36 community health sites (including drug treatment and harm-minimisation services) and prisons. Participants received results by text (HIV antibody/ HCV RNA not detected) or a healthcare provider (HIV antibody/ HCV RNA detected). The RE-AIM framework was used to evaluate reach, effectiveness, adoption, and implementation. RESULTS: Reach: Between November 2016 and December 2020, 7,392 individuals were tested for HIV and/or HCV (21% self-registration, 34% assisted in community, and 45% assisted in prison). EFFECTIVENESS: Of 6,922 people tested for HIV (19% men who have sex with men, 13% living outside major cities, 21% born outside Australia), 51% (3,521/6,922) had no HIV test in the past two years, 0.1% (10/6,922) were newly diagnosed with HIV, and 80% (8/10) initiated HIV treatment within six months. Of 5,960 people tested for HCV (24% women, 35% Aboriginal and/or Torres Strait Islander, 55% recently injected drugs), 15% had detectable HCV RNA (878/5,960), and 45% (393/878) initiated treatment within six months. Adoption: By the end of 2020, DBS via assisted registration was available at 36 community sites and 21 prisons. IMPLEMENTATION: 90% of DBS cards arriving at the laboratory had the three full spots required for testing; the proportion was higher in assisted (94%) compared to online (76%) registration. CONCLUSIONS: This study demonstrated the feasibility of DBS testing for HIV and HCV in key populations including Aboriginal and Torres Strait Islander peoples, men who have sex with men, people who inject drugs, and demonstrated the utility of DBS in the prison setting.


Assuntos
Infecções por HIV , HIV-1 , Hepatite C , Minorias Sexuais e de Gênero , Masculino , Humanos , Feminino , New South Wales , Estudos de Coortes , Teste em Amostras de Sangue Seco/métodos , Homossexualidade Masculina , Sensibilidade e Especificidade , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepacivirus/genética , RNA Viral , Anticorpos Anti-HIV , HIV-1/genética , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico
6.
Sci Total Environ ; 915: 170000, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38242453

RESUMO

To address the challenge of increasing nitrogen retention in compost, this study investigated the effects of microbial communities on denitrification and ammonia assimilation during sludge composting by inoculating microbial inoculants. The results showed that the retention rates of total Kjeldahl nitrogen (TKN) and humic acid (HA) in MIs group (with microbial inoculants) were 4.94 % and 18.52 % higher than those in the control group (CK), respectively. Metagenomic analysis showed that Actinobacteria and Proteobacteria were identified as main microorganisms contributing to denitrification and ammonia assimilation. The addition of microbial agents altered the structure of the microbial community, which in turn stimulated the expression of functional genes. During cooling period, the ammonia assimilation genes glnA, gltB and gltD in MIs were 15.98 %, 24.84 % and 32.88 % higher than those in CK, respectively. Canonical correspondence analysis revealed a positive correlation between the dominant bacterial genera from the cooling stage to the maturity stage and the levels of NO3--N, NH4+-N, HA, and TKN contents. NH4+-N was positively correlated with HA, indicating NH4+-N might be incorporated into HA. Heat map and network analyses revealed NH4+-N as a key factor affecting functional genes of denitrification and ammonia assimilation, with Nitrospira identified as the core bacteria in the microbial network. Therefore, the addition of microbial agents could increase nitrogen retention and improve compost product quality.


Assuntos
Inoculantes Agrícolas , Compostagem , Esgotos/microbiologia , Inoculantes Agrícolas/metabolismo , Desnitrificação , Amônia/metabolismo , Nitrogênio/metabolismo , Bactérias/metabolismo , Solo
7.
Ann Thorac Cardiovasc Surg ; 30(1)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-37989281

RESUMO

PURPOSE: The conventional surgical treatment for postinfarction left ventricular aneurysm (LVA) is open-heart repair with cardiopulmonary bypass. However, the risk of the open-heart surgery under cardiopulmonary bypass may result in an unacceptable risk for many patients with multiple comorbidities. Here, we reported a new off-pump repair technique for postinfarction apical LVA. METHODS: A new off-pump repair technique, circular banding and occlusion technique, was applied to repair the postinfarction apical LVA in 12 patients. Clinical data of all those 12 patients were retrospectively reviewed. Patients were followed up prospectively by direct interviews and echocardiographic examination. RESULTS: The new repair technique was successfully performed in all these 12 patients. Acute reduction of the LVA mouth diameter, the left ventricular (LV) end-diastolic volume and end-systolic volume, and an increase in the LV ejection fraction (EF) were immediately obtained after the repair. Patients had an uneventful postoperative course. They were in New York Heart Association class 1-2, and the LV volume and EF detected by echocardiography remained unchanged during an average 28.4 ± 9.9 months (range 13 to 45 months) follow-up. CONCLUSIONS: Circular banding and occlusion is a simple, safe, and effective off-pump repair technique for postinfarction apical LVA. It can allow effective LV remodeling and improve heart function.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Aneurisma Cardíaco , Humanos , Estudos Retrospectivos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/cirurgia , Resultado do Tratamento , Aneurisma Cardíaco/diagnóstico por imagem , Aneurisma Cardíaco/etiologia , Aneurisma Cardíaco/cirurgia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Função Ventricular Esquerda , Volume Sistólico
8.
Nat Chem ; 16(1): 70-78, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37550391

RESUMO

Sustained autocatalysis coupled to compartment growth and division is a key step in the origin of life, but an experimental demonstration of this phenomenon in an artificial system has previously proven elusive. We show that autocatalytic reactions within compartments-when autocatalysis, and reactant and solvent exchange outpace product exchange-drive osmosis and diffusion, resulting in compartment growth. We demonstrate, using the formose reaction compartmentalized in aqueous droplets in an emulsion, that compartment volume can more than double. Competition for a common reactant (formaldehyde) causes variation in droplet growth rate based on the composition of the surrounding droplets. These growth rate variations are partially transmitted after selective division of the largest droplets by shearing, which converts growth-rate differences into differences in droplet frequency. This shows how a combination of properties of living systems (growth, division, variation, competition, rudimentary heredity and selection) can arise from simple physical-chemical processes and may have paved the way for the emergence of evolution by natural selection.


Assuntos
Origem da Vida , Reprodução , Catálise , Difusão , Água
9.
Redox Biol ; 69: 102998, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38154380

RESUMO

Helicobacter pylori (H. pylori) is the leading risk factor for gastric carcinogenesis. Fibroblast growth factor receptor 4 (FGFR4) is a member of transmembrane tyrosine kinase receptors that are activated in cancer. We investigated the role of FGFR4 in regulating the cellular response to H. pylori infection in gastric cancer. High levels of oxidative stress signature and FGFR4 expression were detected in gastric cancer samples. Gene set enrichment analysis (GSEA) demonstrated enrichment of NRF2 signature in samples with high FGFR4 levels. H. pylori infection induced reactive oxygen species (ROS) with a cellular response manifested by an increase in FGFR4 with accumulation and nuclear localization NRF2. Knocking down FGFR4 significantly reduced NRF2 protein and transcription activity levels, leading to higher levels of ROS and DNA damage following H. pylori infection. We confirmed the induction of FGFR4 and NRF2 levels using mouse models following infection with a mouse-adapted H. pyloristrain. Pharmacologic inhibition of FGFR4 using H3B-6527, or its knockdown, remarkably reduced the level of NRF2 with a reduction in the size and number of gastric cancer spheroids. Mechanistically, we detected binding between FGFR4 and P62 proteins, competing with NRF2-KEAP1 interaction, allowing NRF2 to escape KEAP1-dependent degradation with subsequent accumulation and translocation to the nucleus. These findings demonstrate a novel functional role of FGFR4 in cellular homeostasis via regulating the NRF2 levels in response to H. pylori infection in gastric carcinogenesis, calling for testing the therapeutic efficacy of FGFR4 inhibitors in gastric cancer models.


Assuntos
Neoplasias Gástricas , Animais , Camundongos , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
10.
Environ Sci Pollut Res Int ; 31(5): 7514-7532, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38159188

RESUMO

Vegetation is an essential component of terrestrial ecosystems, influenced by climate change and human activities. Quantifying the relative contributions of climate change and human activities to vegetation dynamics is crucial for addressing global climate change. Sichuan Province is one of the essential ecological functional areas in the upper reaches of the Yangtze River, and its vegetation change is of great significance to the environmental function and ecological security of the Yangtze River Basin and southwest China. In this paper, the modified Carnegie-Ames-Stanford Approach(CASA) model was used to estimate the monthly NPP (Net Primary Productivity) of vegetation in Sichuan Province from 2000 to 2018, and the univariate linear regression analysis was used to analyze the temporal and spatial variation of vegetation NPP in Sichuan Province from 2000 to 2018. In addition, taking vegetation NPP as an index, Pearson correlation analysis, partial correlation analysis, and second-order partial correlation analysis were carried out to quantitatively analyze the contribution of climate change and human activities to vegetation NPP. Finally, the Hurst index and nonparametric Man-Kendall significance test were used to predict the future change trend of vegetation NPP in Sichuan Province. The results show that (1) from 2000 to 2018, the NPP of vegetation in Sichuan Province has a significant increasing trend (Slope = 6.09gC·m-2·a-1), with a multi-year average of 438.72 gC·m-2·a-1, showing a trend of low in the east and high in the middle. The response of vegetation NPP to altitude is different at different elevations; (2) the contribution rates of climate change and human activities to vegetation NPP change are 4.12gC·m-2·a-1 and 1.97gC·m-2·a-1, respectively. In contrast, the impact of human activities on NPP is more significant than climate change. Human activities are the main factors affecting vegetation restoration and degradation in Sichuan Province. However, the positive contribution to NPP change is less than climate change; (3) the future vegetation NPP change trend in Sichuan Province is mainly rising, and the same direction change trend is much larger than the reverse change trend. The areas with an increasing trend in the future account for 89.187% of the total area. This research helps understand the impact of climate change and human activities on vegetation change in Sichuan Province. It offers scientific bases for vegetation restoration and ecosystem management in Sichuan and the surrounding areas.


Assuntos
Mudança Climática , Ecossistema , Humanos , Modelos Teóricos , Atividades Humanas , China
11.
J Transl Med ; 21(1): 793, 2023 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-37940996

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine characterized by a compromised intestinal epithelial barrier. Mucin glycans are crucial in preserving barrier function during bacterial infections, although the underlying mechanisms remain largely unexplored. METHODS: A cohort comprising 15 patients diagnosed with UC and 15 healthy individuals was recruited. Stool samples were collected to perform 16S rRNA gene sequencing, while biopsy samples were subjected to nanocapillary liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) to assess O-glycosylation. Gene expression was evaluated through qPCR analysis and Western blotting. Furthermore, animal experiments were conducted to investigate the effects of Escherichia coli and/or O-glycan inhibitor benzyl-α-GalNAc on the development of colitis in mice. RESULTS: Our findings revealed that the mucus barrier was disrupted during the early stages of UC, while the MUC2 protein content remained unaltered. Additionally, a noteworthy reduction in the O-glycosylation of MUC2 was observed, along with significant changes in the intestinal microbiota during the early stages of UC. These changes included a decrease in intestinal species richness and an increase in the abundance of Escherichia coli (E. coli). Moreover, subsequent to the administration of galactose or O-glycan inhibitor to intestinal epithelial cells, it was observed that the cell culture supernatant had the ability to modify the proliferation and adhesive capacity of E. coli. Furthermore, when pathogenic E. coli or commensal E. coli were cocultured with intestinal epithelium, both strains elicited activation of the NF-KB signaling pathway in epithelial cells and facilitated the expression of serine protease in comparison to the untreated control. Consistently, the inhibition of O-glycans has been observed to enhance the pathogenicity of E. coli in vivo. Furthermore, a correlation has been established between the level of O-glycans and the development of ulcerative colitis. Specifically, a reduction in the O-glycan content of MUC2 cells has been found to increase the virulence of E. coli, thereby compromising the integrity of the intestinal epithelial barrier. CONCLUSIONS: Together, there exist complex interactions between the intestinal epithelium, O-glycans, and the intestinal microbiota, which may inform the development of novel therapeutic strategies for the treatment of ulcerative colitis.


Assuntos
Colite Ulcerativa , Colite , Escherichia coli Enteropatogênica , Humanos , Camundongos , Animais , Colite Ulcerativa/patologia , Mucinas/metabolismo , NF-kappa B/metabolismo , Escherichia coli Enteropatogênica/metabolismo , Glicosilação , RNA Ribossômico 16S/metabolismo , Espectrometria de Massas em Tandem , Colite/patologia , Mucosa Intestinal/patologia , Polissacarídeos/metabolismo , Transdução de Sinais , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Colo/patologia
12.
Anal Chem ; 95(48): 17622-17628, 2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-37997359

RESUMO

Short-chain fatty acids (SCFAs), as the main metabolites of gut microbiota, are recognized as crucial players in the host's inflammatory response and metabolic disease. Imaging the spatial distributions and calculating the accurate contents of SCFAs in the heterogeneous intestinal tissue are critical to reveal their biological functions. Here, we develop an isotope-coded on-tissue derivatization method combined with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to map the spatial expressions of SCFAs in the colon tissue based on pair-labeled N,N,N-trimethyl-2-(piperazin-1-yl)ethan-1-aminium iodide (TMPA) and D3-TMPA. A noticeable increase in the MALDI-MSI sensitivity of SCFAs was achieved after on-tissue derivatization, which enables the visualization of acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, hydroxy acetic acid, and hydroxy propionic acid in the colon tissue. Moreover, the introduction of D3-TMPA-tagged SCFAs as internal standards can significantly reduce quantitation deviation from the matrix effects, ensuring the quantitative MALDI-MSI of SCFAs. We further used this method to characterize the spatial alterations of SCFAs in the colon tissues of mice with enterocolitis. The development of this strategy provides a reliable approach to image the spatial expressions of SCFAs in tissues and paves an insight way to study the roles of SCFAs in the gut microbiota and disease.


Assuntos
Ácidos Graxos Voláteis , Propionatos , Camundongos , Animais , Ácidos Graxos Voláteis/análise , Ácido Acético , Isótopos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ácido Butírico
13.
Open Forum Infect Dis ; 10(11): ofad517, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38023551

RESUMO

Background: Dried blood spot (DBS) testing for hepatitis C virus (HCV) RNA provides a sampling option that avoids venepuncture and can be carried out in a nonclinical setting. Large-scale evaluations are needed to understand how DBS testing can reduce HCV burden. This study estimated prevalence of, and factors associated with, HCV RNA and treatment initiation among people enrolled in a state-wide pilot of people testing in the NSW DBS Pilot in New South Wales, Australia. Methods: People at risk of HIV/HCV could participate via (1) self-registration online with a DBS collection kit delivered and returned by conventional postal service; or (2) assisted DBS sample collection at a community site or prison. Logistic regression was used to identify factors associated with detectable HCV RNA and treatment initiation within 6 months of testing. Results: Between September 2017 and December 2020, 5960 people were tested for HCV (76% men, 35% Aboriginal and/or Torres Strait Islander, 55% recently injected drugs): 21% online self-registration, 34% assisted registration in the community, 45% assisted registration in prison. Fifteen percent had detectable HCV RNA (878/5960). Overall, 44% (n = 386/878) of people with current HCV initiated treatment within 6 months (13% online self-registration, 27% assisted registration in the community, 61% assisted registration in prison). Testing in prison compared with the community (adjusted odds ratio [aOR], 4.28; 95% CI, 3.04-6.03) was associated with increased odds of treatment initiation. Being a woman compared with a man (aOR, 0.68; 95% CI, 0.47-0.97) was associated with reduced treatment initiation. Conclusions: The NSW DBS Pilot demonstrates the feasibility of using DBS to promote HCV testing and treatment in community and prison settings.

14.
Appl Opt ; 62(28): 7455-7462, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37855514

RESUMO

In long-distance oil pipelines, the abnormal flow state of the fluid in the pipeline can cause continuous water hammer effects, which can damage the pipeline and even cause leakage or collapse. Based on this phenomenon, this paper proposes a new, to the best of our knowledge, detection method based on sensing optical fiber and phase-sensitive optical time-domain reflectometry (φ-OTDR) system to solve the problem of continuous water hammer detection in long-distance pipelines. The method uses a non-invasive, low-cost, real-time approach to monitor pipeline wall deformation characteristics and assess flow-induced vibration (FIV) intensity by statistically distinguishing water hammer signals from normal vibration signals and calculating the peak-to-average ratio (PAR) of these signals. Experimental results show that the FIV status of different types of pipelines can be effectively monitored by calculating the PAR of water hammer signals and vibration signals. The measured PAR based on the φ-OTDR system has high consistency with the PAR variation trend of simulation results, the distributed fiber optic sensor is less affected by environmental factors, and its detection distance and anti-interference ability are better than those of high-precision commercial triaxial acceleration sensors.

15.
Mol Psychiatry ; 28(9): 3739-3750, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37848710

RESUMO

Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years. However, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost prohibit a wide use of them in preclinical studies. Canine model is an appealing alternative because of its complex and effective dog-human social interactions. In contrast to non-human primates, dog has comparable drug metabolism as humans and a high reproduction rate. In this study, we aimed to model ASD in experimental dogs by manipulating the Shank3 gene as SHANK3 mutations are one of most replicated genetic defects identified from ASD patients. Using CRISPR/Cas9 gene editing, we successfully generated and characterized multiple lines of Beagle Shank3 (bShank3) mutants that have been propagated for a few generations. We developed and validated a battery of behavioral assays that can be used in controlled experimental setting for mutant dogs. bShank3 mutants exhibited distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings (n = 27 for wild-type controls and n = 44 for mutants). We demonstrate the feasibility of producing a large number of mutant animals in a reasonable time frame. The robust and unique behavioral findings support the validity and value of a canine model to investigate the pathophysiology and develop treatments for ASD and potentially other psychiatric disorders.


Assuntos
Transtorno do Espectro Autista , Animais , Cães , Humanos , Transtorno do Espectro Autista/genética , Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Edição de Genes , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
16.
Nanoscale ; 15(42): 17036-17044, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37846513

RESUMO

The electronic contact between two-dimensional (2D) transition metal dichalcogenide (TMD) semiconductors and metal electrodes is a formidable challenge due to the undesired Schottky barrier, which severely limits the electrical performance of TMD devices and impedes the exploration of their unconventional physical properties and potential electronic applications. In this study, we report a two-step chemical vapor deposition (CVD) growth of 2D TaSe2-WSe2 metal-semiconductor heterostructures. Raman mapping confirms the precise spatial modulation of the as-grown 2D TaSe2-WSe2 heterostructures. Transmission electron microscopy (TEM) characterization reveals that this two-step method provides a high-quality and clean interface of the 2D TaSe2-WSe2 heterostructures. Meanwhile, the upper 1T-TaSe2 is formed heteroepitaxially on/around the pre-synthesized 2H-WSe2 monolayers, exhibiting an epitaxial relationship of (20-20)TaSe2//(20-20)WSe2 and [0001]TaSe2//[0001]WSe2. Furthermore, characterization studies using a Kelvin probe force microscope (KPFM) and electrical transport measurements present compelling evidence that the 2D metal-semiconductor heterostructures under investigation can improve the performance of electrical devices. These results bear substantial significance in augmenting the properties of field-effect transistors (FETs), leading to notable improvements in FET mobility and on/off ratio. Our study not only broadens the horizons of direct growth of high-quality 2D metal-semiconductor heterostructures but also sheds light on potential applications in future high-performance integrated circuits.

17.
Cancers (Basel) ; 15(19)2023 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-37835513

RESUMO

The incidence of esophageal adenocarcinoma (EAC) has risen rapidly during the past four decades, making it the most common type of esophageal cancer in the USA and Western countries. The NEK (Never in mitosis A (NIMA) related kinase) gene family is a group of serine/threonine kinases with 11 members. Aberrant expression of NEKs has been recently found in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEKs in EAC and its precancerous condition (Barrett's esophagus, BE) has not been investigated. In the present study, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which 8 contain EAC and 6 contain BE) using bioinformatic approaches for NEKs expression in EAC and BE. We identified that several NEK members, such as NEK2 (7/8), NEK3 (6/8), and NEK6 (6/8), were significantly upregulated in EAC as compared to normal esophagus samples. Alternatively, NEK1 was downregulated in EAC as compared to the normal esophagus. On the contrary, genomic alterations of these NEKs are not frequent in EAC. We validated the above findings using qRT-PCR and the protein expression of NEKs in EAC cell lines using Western blotting and in primary EAC tissues using immunohistochemistry and immunofluorescence. Our data suggest that frequent upregulation of NEK2, NEK3, and NEK7 may be important in EAC.

18.
Medicine (Baltimore) ; 102(39): e34559, 2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37773874

RESUMO

Coronavirus disease 2019 (COVID-19) is still rampant and uncontrolled across the globe. China's strict epidemic prevention measures have had an impact on the treatment in patients with non-small cell lung cancer (NSCLC). The aim of this study is to explore the impact of the COVID-19 outbreak on the uninfected NSCLC patients. The chemotherapeutic efficacy and survival of 89 uninfected advanced NSCLC patients were retrospectively analyzed. The endpoints were overall survival (OS), progression-free survival (PFS), and response rate. Forty and forty-nine patients with advanced NSCLC received chemotherapy during the COVID-19 outbreak and nonoutbreak periods, respectively. Mean delay time was 12.8 months for COVID-19 outbreak stage versus 5.68 months for nonoutbreak stage (P = .003). There was no significant difference in the rates of chemotherapy delay and discontinuation between the 2 groups (P = .055 and .239). Significant difference was not detected in median OS (15.8 months) for COVID-19 outbreak stage versus 16.0 months for nonoutbreak stage (adjusted hazard ratio, 1.058; 95% confidence interval, 0.593-1.888; P = .849); Median PFS was 7.9 months for COVID-19 outbreak stage versus 10.3 months for nonoutbreak stage (adjusted hazard ratio, 0.878; 95% confidence interval 0.513-1.503; P = .634). There was also no statistical difference in the disease control rate between the 2 groups (P = .137). The earliest COVID-19 outbreak had no significant impact on the PFS and OS in uninfected advanced NSCLC patients receiving chemotherapy. However, the mean delay time of receiving chemotherapy was prolonged during the COVID-19 outbreak.


Assuntos
COVID-19 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Intervalo Livre de Doença , Surtos de Doenças , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
19.
Gut ; 73(1): 47-62, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-37734913

RESUMO

OBJECTIVE: Chronic gastro-oesophageal reflux disease, where acidic bile salts (ABS) reflux into the oesophagus, is the leading risk factor for oesophageal adenocarcinoma (EAC). We investigated the role of ABS in promoting epithelial-mesenchymal transition (EMT) in EAC. DESIGN: RNA sequencing data and public databases were analysed for the EMT pathway enrichment and patients' relapse-free survival. Cell models, pL2-IL1ß transgenic mice, deidentified EAC patients' derived xenografts (PDXs) and tissues were used to investigate EMT in EAC. RESULTS: Analysis of public databases and RNA-sequencing data demonstrated significant enrichment and activation of EMT signalling in EAC. ABS induced multiple characteristics of the EMT process, such as downregulation of E-cadherin, upregulation of vimentin and activation of ß-catenin signalling and EMT-transcription factors. These were associated with morphological changes and enhancement of cell migration and invasion capabilities. Mechanistically, ABS induced E-cadherin cleavage via an MMP14-dependent proteolytic cascade. Apurinic/apyrimidinic endonuclease (APE1), also known as redox factor 1, is an essential multifunctional protein. APE1 silencing, or its redox-specific inhibitor (E3330), downregulated MMP14 and abrogated the ABS-induced EMT. APE1 and MMP14 coexpression levels were inversely correlated with E-cadherin expression in human EAC tissues and the squamocolumnar junctions of the L2-IL1ß transgenic mouse model of EAC. EAC patients with APE1high and EMThigh signatures had worse relapse-free survival than those with low levels. In addition, treatment of PDXs with E3330 restrained EMT characteristics and suppressed tumour invasion. CONCLUSION: Reflux conditions promote EMT via APE1 redox-dependent E-cadherin cleavage. APE1-redox function inhibitors can have a therapeutic role in EAC.


Assuntos
Adenocarcinoma , Refluxo Gastroesofágico , Humanos , Animais , Camundongos , Metaloproteinase 14 da Matriz/metabolismo , Adenocarcinoma/patologia , Oxirredução , Transição Epitelial-Mesenquimal , Caderinas/metabolismo , Linhagem Celular Tumoral
20.
Mol Ther Oncolytics ; 30: 286-300, 2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37732296

RESUMO

Esophageal adenocarcinoma (EAC) patients have poor clinical outcomes, with an overall 5-year survival rate of 20%. Smoking is a significant risk factor for EAC. The role of WEE1, a nuclear kinase that negatively regulates the cell cycle in normal conditions, in EAC tumorigenesis and drug resistance is not fully understood. Immunohistochemistry staining shows significant WEE1 overexpression in human EAC tissues. Nicotine, nicotine-derived nitrosamine ketone, or 2% cigarette smoke extract treatment induces WEE1 protein expression in EAC, detected by western blot and immunofluorescence staining. qRT-PCR and reporter assay indicates that smoking induces WEE1 expression through miR-195-5p downregulation in EAC. ATP-Glo cell viability and clonogenic assay confirmed that WEE1 inhibition sensitizes EAC cells to docetaxel treatment in vitro. A TE-10 smoking machine with EAC patient-derived xenograft mouse model demonstrated that smoking induces WEE1 protein expression and resistance to docetaxel in vivo. MK-1775 and docetaxel combined treatment improves EAC patient-derived xenograft mouse survival in vivo. Our findings demonstrate, for the first time, that smoking-induced WEE1 overexpression through miRNA dysregulation in EAC plays an essential role in EAC drug resistance. WEE1 inhibition is a promising therapeutic method to overcome drug resistance and target treatment refractory cancer cells.

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