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1.
Int J Mol Sci ; 25(14)2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39063050

RESUMO

Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice.


Assuntos
Biomarcadores , Proteína Glial Fibrilar Ácida , Proteínas de Neurofilamentos , Humanos , Adulto , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Feminino , Masculino , Proteína Glial Fibrilar Ácida/sangue , Idoso , Adolescente , Biomarcadores/sangue , Adulto Jovem , Estudos Transversais , Voluntários Saudáveis , Fatores Etários , Valores de Referência
2.
Small ; : e2402761, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953299

RESUMO

Flexible rechargeable Zn-air batteries (FZABs) exhibit high energy density, ultra-thin, lightweight, green, and safe features, and are considered as one of the ideal power sources for flexible wearable electronics. However, the slow and high overpotential oxygen reaction at the air cathode has become one of the key factors restricting the development of FZABs. The improvement of activity and stability of bifunctional catalysts has become a top priority. At the same time, FZABs should maintain the battery performance under different bending and twisting conditions, and the design of the overall structure of FZABs is also important. Based on the understanding of the three typical configurations and working principles of FZABs, this work highlights two common strategies for applying bifunctional catalysts to FZABs: 1) powder-based flexible air cathode and 2) flexible self-supported air cathode. It summarizes the recent advances in bifunctional oxygen electrocatalysts and explores the various types of catalyst structures as well as the related mechanistic understanding. Based on the latest catalyst research advances, this paper introduces and discusses various structure modulation strategies and expects to guide the synthesis and preparation of efficient bifunctional catalysts. Finally, the current status and challenges of bifunctional catalyst research in FZABs are summarized.

3.
Int J Public Health ; 69: 1606956, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948086

RESUMO

Objectives: We evaluated the long-term effects of air pollution controls on health and health inequity among Chinese >45 years of age. Methods: Data were derived from the China Health Aging and Retirement Longitudinal Survey and the China National Environmental Monitoring Centre. Decreases in PM2.5 and PM10 were scaled to measure air quality controls. We used a quasi-experimental design to estimate the impact of air quality controls on self-reported health and health inequity. Health disparities were estimated using the concentration index and the horizontal index. Results: Air pollution controls significantly improved self-reported health by 20% (OR 1.20, 95% CI, 1.02-1.42). The poorest group had a 40% (OR 1.41, 95% CI, 0.96-2.08) higher probability of having excellent self-reported health after air pollution controls. A pro-rich health inequity was observed, and the horizontal index decreased after air pollution controls. Conclusion: Air pollution controls have a long-term positive effect on health and health equity. The poorest population are the main beneficiaries of air pollution controls, which suggests policymakers should make efforts to reduce health inequity in air pollution controls.


Assuntos
Poluição do Ar , Disparidades nos Níveis de Saúde , Humanos , China , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Longitudinais , Material Particulado/análise , Fatores Socioeconômicos , Exposição Ambiental , População do Leste Asiático
4.
Am J Epidemiol ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38960670

RESUMO

We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between 1 September 2020 and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and otitis externa (NCO). The SCRI used a 60-day control window and dose-specific 28-day risk windows, stratified by vaccine brand and adjusted for calendar time. The QBA included two scenarios: (i) baseline probability of the confounder was higher in the control window and (ii) vice versa. The NCO was not associated with any of the COVID-19 vaccine types or doses except Moderna dose 1 (IRR = 1.09, 95%CI 1.01-1.09). The QBA suggested even the strongest literature-reported confounder (COVID-19; RRmyocarditis = 18.3) could only explain away part of the observed effect from IRR = 3 to IRR = 1.40. The SCRI seems robust to unmeasured confounding in the COVID-19 setting, although a strong unmeasured confounder could bias the observed effect upward. Replication of our findings for other safety signals would strengthen this conclusion.

5.
Saudi J Ophthalmol ; 38(2): 152-156, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38988782

RESUMO

PURPOSE: The purpose of the study is to establish normative values of eye parameters such as lens thickness (LT), lens diameter (LD), and axial length (AXL) among wide age range of Saudis using Pentacam AXL and compare these values between gender, in addition to that, to find the correlation between the age and those parameters. METHODS: In this prospective cross-sectional study, we measured LT, LD, and AXL in 125 healthy Saudi controls aged between 8 and 60 years using OCULUS Pentacam AXL. The screening tests were performed for each subject to exclude any ocular abnormalities using slit lamp (Haag-Streit BQ 900), refractive error measured using auto refractometer (Topcon KR-1 Autorefractor/Keratometer), and subject who has spherical equivalent more than ± 4.00D and astigmatism more than 1.00DC was excluded from the study. The mean of three readings of LT, LD, and AXL was taken. All examination was applied on one eye (right eye). RESULTS: The overall mean and standard deviation of LT, LD, and AXL was 2.2 mm ± 0.5, 2.7 mm ± 0.6, and 23.8 mm ± 1.0, respectively. There was no statistically significant difference between males and females in these parameters in all age groups, except in Group 2 (age: 19-30 years), there was a statistically significant difference between males and females in AXL, mean difference (M = 0.48), and P = 0.015. The mean of LT and LD was negatively associated with age. However, there was no significant correlation between AXL and age. CONCLUSION: Normative values of LT, LD, and AXL have been established in wide age group of healthy Saudis; the findings of the present study can highlight not only the normal range of the different ocular parameters, namely LT, LD, and AXL, but also their variation with age and gender.

6.
Infection ; 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39017997

RESUMO

BACKGROUND: WHO postulates the application of adaptive design features in the global clinical trial ecosystem. However, the adaptive platform trial (APT) methodology has not been widely adopted in clinical research on vaccines. METHODS: The VACCELERATE Consortium organized a two-day workshop to discuss the applicability of APT methodology in vaccine trials under non-pandemic as well as pandemic conditions. Core aspects of the discussions are summarized in this article. RESULTS: An "ever-warm" APT appears ideally suited to improve efficiency and speed of vaccine research. Continuous learning based on accumulating APT trial data allows for pre-planned adaptations during its course. Given the relative design complexity, alignment of all stakeholders at all stages of an APT is central. Vaccine trial modelling is crucial, both before and in a pandemic emergency. Various inferential paradigms are possible (frequentist, likelihood, or Bayesian). The focus in the interpandemic interval may be on research gaps left by industry trials. For activation in emergency, template Disease X protocols of syndromal design for pathogens yet unknown need to be stockpiled and updated regularly. Governance of a vaccine APT should be fully integrated into supranational pandemic response mechanisms. DISCUSSION: A broad range of adaptive features can be applied in platform trials on vaccines. Faster knowledge generation comes with increased complexity of trial design. Design complexity should not preclude simple execution at trial sites. Continuously generated evidence represents a return on investment that will garner societal support for sustainable funding. Adaptive design features will naturally find their way into platform trials on vaccines.

7.
Med Res Arch ; 12(1)2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39026931

RESUMO

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

8.
Animals (Basel) ; 14(13)2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38998087

RESUMO

BACKGROUND: Even though the mental health of veterinarians has raised concerns, little is known about the wellbeing of official veterinarians ensuring animal welfare, food safety, and control of infectious diseases and performing other tasks for veterinary public health. Therefore, the aim of this study was to assess the psychosocial conditions of official German veterinarians and to compare them with those of other employees. METHODS: An online survey was conducted including 82 items of the Copenhagen Psychosocial Questionnaire (COPSOQ III) and additional questions on workplace and demographics. RESULTS: The answers of 838 respondents were analyzed, representing 26% of the target population. The average values for the dimensions Quantitative Demands, Emotional Demands, and Burnout Symptoms were substantially higher than those for German employees in other professions. Official veterinarians mainly working in animal welfare frequently experienced physical violence (6.7%) or threats of violence (53%). However, the profession also provides advantages: official veterinarians reported higher average values concerning the dimensions Control over Working Time and Influence at Work than other employees. Most participants stated that they experienced their work as meaningful, and the Job Insecurity dimension was low. CONCLUSIONS: Official veterinarians frequently experience offensive behavior and high-level demands. Therefore, measures to support and protect official veterinarians are needed. The positive aspects of this job should be emphasized to recruit and retain veterinarians in this field of the profession.

9.
J Food Prot ; 87(9): 100332, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39029800

RESUMO

In-shell pecans are typically harvested after falling from trees to the ground, presenting a potential route of contamination of foodborne pathogens from soil contact. In-shell pecans are often subjected to various processing or washing steps prior to being shelled. This study determined Shiga toxin-producing Escherichia coli (STEC) reductions after treatment with antimicrobial washes on direct and soil-inoculated in-shell pecans and evaluated the cross-contamination potential of the spent pecan washes after treatment. Pecans were directly and soil-inoculated with an STEC cocktail (O157:H7, O157:NM, O121, O26). Direct inoculation was achieved by spraying the STEC cocktail on the pecans. For soil-inoculation pecans, autoclaved soil was sprayed with the STEC cocktail, homogenized for 2 min, and used to coat in-shell pecans. Inoculated pecans were washed in treatments of 2% lactic acid (LA), 1,000 ppm free chlorine (sodium hypochlorite; NaClO), hot water (HW; 85 ± 2 °C), or ambient water (C [control]; 18 ± 2 °C) for 2, 5, and 10 min and diluted to enumerate STEC populations. After treatments, 100 mL of the spent wash was vacuum filtered through a 0.45-µm membrane and plated on selective agar. HW significantly reduced STEC populations from pecans with and without soil regardless of treatment time (p < 0.05), NaClO reduced STEC populations more than the ambient control wash on directly inoculated pecans, but there were no significant differences between STEC reductions from ambient water (C), LA, and NaClO treatments on soil-inoculated pecans (p > 0.05). Larger STEC populations were enumerated from ambient water wash compared to the antimicrobial washes (p < 0.05). The HW, LA, and NaClO treatments were effective at maintaining the quality of the wash water, with STEC levels being generally at or below the detection limit (<1 CFU/100 mL), while HW was the most effective at reducing STEC from in-shell pecans with and without a soil coating (>5-log CFU/mL reductions).

10.
Front Pediatr ; 12: 1388673, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39026939

RESUMO

Background: Pediatric solid tumors are a common malignant disease in children, and more and more studies have proved that there is an inseparable relationship between adult tumors and intestinal microbiome, but the changes in the intestinal microbiota of pediatric solid tumor (PST) patients have been scarcely examined. This study aims to examine the differences in the intestinal microbiota features between patients diagnosed with PST and healthy controls (HCs). Methods: To elucidate the unique characteristics of the gut microbiota in pediatric patients with solid tumors, we recruited 23 PST patients and 20 HCs. A total of 43 stool samples were gathered, and then 16S rRNA sequencing was performed. Results: We noticed a noticeable pattern of elevated diversity in the gut microbiota within the PST groups. The differences in microbial communities among two groups were remarkable, regarding the analysis at the class level, the abundance of Bacilli was markedly increased in PST patients compared to HCs (P < 0.05), regarding the analysis at the genus level, The presence of Enterococcus was significantly higher in PST cases compared to HCs (P < 0.01), while Lachnospiraceae unclassified, Lachnospira, Haemophilus and Colidextribacter in PST cases, the abundance was significantly reduced. (P < 0.05), 6 genera, including Bacilli, Lactobacillales, Enterococcaceae and Morganella, showed a significant enrichment compared to healthy controls, while 10 genera, including Bilophila, Colidextribacter, Pasteurellales, Haemophilus, Lachnospiraceae unclassified, Lachnospira and Fusobacteriales, were significant reduction in the PST groups. Conclusion: Our research conducted the characterization analysis of the gut microbiota in PST patients for the first time. More importantly, there are some notable differences in the gut microbiota between PST patients and healthy controls, which we believe is an interesting finding.

11.
Brain Commun ; 6(3): fcae127, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38887702

RESUMO

Cerebral microbleeds are frequent incidental findings on brain MRI and have previously been shown to occur in Coronavirus Disease 2019 (COVID-19) cohorts of critically ill patients. We aimed to determine the risk of having microbleeds on medically indicated brain MRI and compare non-hospitalized COVID-19-infected patients with non-infected controls. In this retrospective case-control study, we included patients over 18 years of age, having an MRI with a susceptibility-weighted sequence, between 1 January 2019 and 1 July 2021. Cases were identified based on a positive reverse transcriptase polymerase chain reaction test for SARS-CoV-2 and matched with three non-exposed controls, based on age, sex, body mass index and comorbidities. The number of cerebral microbleeds on each scan was determined using artificial intelligence. We included 73 cases and 219 matched non-exposed controls. COVID-19 was associated with significantly greater odds of having cerebral microbleeds on MRI [odds ratio 2.66 (1.23-5.76, 95% confidence interval)], increasingly so when patients with dementia and hospitalized patients were excluded. Our findings indicate that cerebral microbleeds may be associated with COVID-19 infections. This finding may add to the pathophysiological considerations of cerebral microbleeds and help explain cases of incidental cerebral microbleeds in patients with previous COVID-19.

13.
Appl Microbiol Biotechnol ; 108(1): 367, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38850297

RESUMO

Recent microbiome research has incorporated a higher number of samples through more participants in a study, longitudinal studies, and metanalysis between studies. Physical limitations in a sequencing machine can result in samples spread across sequencing runs. Here we present the results of sequencing nearly 1000 16S rRNA gene sequences in fecal (stabilized and swab) and oral (swab) samples from multiple human microbiome studies and positive controls that were conducted with identical standard operating procedures. Sequencing was performed in the same center across 18 different runs. The simplified mock community showed limitations in accuracy, while precision (e.g., technical variation) was robust for the mock community and actual human positive control samples. Technical variation was the lowest for stabilized fecal samples, followed by fecal swab samples, and then oral swab samples. The order of technical variation stability was inverse of DNA concentrations (e.g., highest in stabilized fecal samples), highlighting the importance of DNA concentration in reproducibility and urging caution when analyzing low biomass samples. Coefficients of variation at the genus level also followed the same trend for lower variation with higher DNA concentrations. Technical variation across both sample types and the two human sampling locations was significantly less than the observed biological variation. Overall, this research providing comparisons between technical and biological variation, highlights the importance of using positive controls, and provides semi-quantified data to better understand variation introduced by sequencing runs. KEY POINTS: • Mock community and positive control accuracy were lower than precision. • Samples with lower DNA concentration had increased technical variation across sequencing runs. • Biological variation was significantly higher than technical variation due to sequencing runs.


Assuntos
DNA Bacteriano , Fezes , Microbiota , RNA Ribossômico 16S , Análise de Sequência de DNA , Humanos , RNA Ribossômico 16S/genética , Fezes/microbiologia , Microbiota/genética , Análise de Sequência de DNA/métodos , DNA Bacteriano/genética , Bactérias/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Reprodutibilidade dos Testes , Boca/microbiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos
14.
Epilepsia Open ; 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38861254

RESUMO

OBJECTIVE: In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal-onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real-world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult-to-treat epilepsies. Our aim was to investigate the efficacy of add-on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add-on lacosamide, perampanel, and brivaracetam therapy. METHODS: Patients were enrolled from the CENKORK study, which is a prospective, non-interventional, open-label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure-free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. RESULTS: Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow-up, leaving 150 cases for the 1-year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6-month and 1-year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6-month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001). SIGNIFICANCE: Add-on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs. PLAIN LANGUAGE SUMMARY: This observational study was carried out in 172 adult patients with difficult-to-treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

15.
Ital J Food Saf ; 13(2): 12241, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38846046

RESUMO

The internet and digital technologies pose new, specific challenges to competent authorities, whose activity fields are limited to their own jurisdictions. Consequently, these authorities must operate a system of controls adapted to online sites and e-sales, and official control must be strengthened. To address these challenges and protect consumers from misleading practices that can lead to the consumption of unsafe food, it is necessary to adapt official controls to new distance-selling techniques. The food inspection scheme as conceived in the European legal system cannot be easily applied to online food sales. To this purpose, the competent authorities need to equip themselves to guarantee effective control and compliance with the European Union laws regarding food sold online. It emerged that there are different levels of non-compliance with online food: the non-registration of the food business operator (registrant) and the non-compliance with the obligations as the law prescribes (obligations on food hygiene, electronic commerce, and information to consumers about the food). The focus of this survey on the distance sale of dairy products in the Modena Local Competent Authority territory is on the pattern suggested by the Food Standards Agency in 2016. This analysis is based on two different phases. The first one is the study of the websites, and the second one is the physical visit to the address of the online food business. This survey shows how to collect the first phase's data and organize the official controls.

16.
Artigo em Inglês | MEDLINE | ID: mdl-38934089

RESUMO

The study of sensitive and specific biomarkers, such as blood inflammatory cytokines, could provide an answer to the challenges faced in the differential diagnosis of patients with systemic inflammation. Limited data exist on the impact of age on serum levels of inflammatory cytokines. We collected serum samples of 42 healthy children and young adults (1 month to 21 years). Serum levels of interleukin 1 receptor antagonist (IL-1Ra), IL-1ß, IL-6, IL-18, tumor necrosis factor-alpha (TNF-α), CXCL9, and CXCL10 were measured. Data were analyzed for three different age groups (<6, 6-17, and 18-21 years). IL-18, TNF-α, and CXCL9 values varied significantly according to age group. Median values of IL-18 and TNF-α decline with age, whereas CXCL9 and CXCL10 are lowest at 6-17 years. IL-1Ra is stable among age groups. In the majority of cases, IL-1ß and IL-6 are not measurable above the lower limit of quantification. A scoping literature review revealed highly variable data on IL-1Ra, IL-18, TNF-α, and CXCL10. For CXCL9, pediatric reference data are scarce. In conclusion, we report an age-dependent signature of multiple inflammatory cytokines measured in the serum of healthy children and young adults, suggesting the need to use age-specific reference values in future pediatric studies.

17.
Int J Drug Policy ; : 104500, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38945754

RESUMO

Inspired by Giommoni's assessment of the Cunningham precursor control scholarship, we propose two concepts to help drug policy scholars think through the mechanisms that operate when market participants are faced with a change in precursor availability. The first is the concept of restrictive deterrence, that emphasizes risks mitigation strategies such as looking into changes in the frequency, methods, markets that may occur after different types of interventions. While restrictive deterrence is an improvement over current approaches in thinking through adaptations, it falls short in its narrower focus on the individual, rather than organizations or the market as a collective. The concept of resilience is then proposed as alternative that allows scholars to elaborate specific hypotheses and assess both organizations and markets based on their capacity to anticipate, cope, adapt and ultimately recover from disruptions. We finish by providing a reading of the Cunningham and colleagues precursor control papers with the resilience framework in mind, showing that many of the elements were already present in their work.

18.
Am J Epidemiol ; 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38918020

RESUMO

Development of new therapeutics for a rare disease such as cystic fibrosis (CF) is hindered by challenges in accruing enough patients for clinical trials. Using external controls from well-matched historical trials can reduce prospective trial sizes, and this approach has supported regulatory approval of new interventions for other rare diseases. We consider three statistical methods that incorporate external controls into a hypothetical clinical trial of a new treatment to reduce pulmonary exacerbations in CF patients: 1) inverse probability weighting, 2) Bayesian modeling with propensity score-based power priors, and 3) hierarchical Bayesian modeling with commensurate priors. We compare the methods via simulation study and in a real clinical trial data setting. Simulations showed that bias in the treatment effect was <4% using any of the methods, with type 1 error (or in the Bayesian cases, posterior probability of the null hypothesis) usually <5%. Inverse probability weighting was sensitive to similarity in prevalence of the covariates between historical and prospective trial populations. The commensurate prior method performed best with real clinical trial data. Using external controls to reduce trial size in future clinical trials holds promise and can advance the therapeutic pipeline for rare diseases.

19.
Eur J Med Res ; 29(1): 293, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38773551

RESUMO

Artesunate (ART), an effective antimalarial semisynthetic derivative of artemisinin, exhibits antitumour properties, but the mechanism(s) involved remain elusive. In this study, we investigated the antitumour effects of ART on human oesophageal squamous cell carcinoma (ESCC) cell lines. Treatment of ESCC cell lines with ART resulted in the production of excessive reactive oxygen species (ROS) that induced DNA damage, reduced cell proliferation and inhibited clonogenicity via G1-S cell cycle arrest and/or apoptosis in vitro. The administration of ART to nude mice with ESCC cell xenografts inhibited tumour formation in vivo. However, the cytotoxicity of ART strongly differed among the ESCC cell lines tested. Transcriptomic profiling revealed that although the expression of large numbers of genes in ESCC cell lines was affected by ART treatment, these genes could be functionally clustered into pathways involved in regulating cell cycle progression, DNA metabolism and apoptosis. We revealed that p53 and Cdk4/6-p16-Rb cell cycle checkpoint controls were critical determinants required for mediating ART cytotoxicity in ESCC cell lines. Specifically, KYSE30 cells with p53Mut/p16Mut were the most sensitive to ART, KYSE150 and KYSE180 cells with p53Mut/p16Nor exhibited intermediate responses to ART, and Eca109 cells with p53Nor/p16Nor exhibited the most resistance to ATR. Consistently, perturbation of p53 expression using RNA interference (RNAi) and/or Cdk4/6 activity using the inhibitor palbociclib altered ART cytotoxicity in KYSE30 cells. Given that the p53 and Cdk4/6-cyclin D1-p16-Rb genes are commonly mutated in ESCC, our results potentially shed new light on neoadjuvant chemotherapy strategies for ESCC.


Assuntos
Apoptose , Artesunato , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Artesunato/farmacologia , Artesunato/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Animais , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Camundongos , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos Nus , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Dano ao DNA/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-38702572

RESUMO

BACKGROUND: The functional-cognitive impact of first-episode psychosis (FEP) is extremely relevant and implies dysfunction from early life stages like adolescence and youth. Like other illnesses, FEP incidence is also influenced by environmental factors. It is necessary to attend to this age group with early interventions and to act on the environmental factors that the literature correlates with increased FEP incidence: socio-economic aspects, social adversity, bullying at school or cannabis use. In this context, identifying the areas of cities where FEP patients concentrate is important to perform early interventions. The spatial analysis of patient distribution in a whole city is one way to identify the most vulnerable areas and to propose psycho-social interventions for the possible prevention and/or early detection of FEP by improving urban mental health. METHODS: An epidemiological study of point patterns to determine the areas of a city with a higher incidence of patients with FEP. To do so, the addresses of FEP cases were georeferenced from 1 January 2016 to 31 October 2022, and 109 FEP patients were analysed. Data from a random sample of 383 controls, comprising their addresses, age, and sex, were randomly obtained from the official city council database. By GIS, the areas with higher FEP incidence were analysed to see if they coincided with the zones where inhabitants with lower incomes lived. RESULTS: The risk ratio of the FEP patients was compatible with the constant risk ratio in Albacete (p = 0.22). When performing the process separately with cases and controls only in men and women, the results were not significant for both distributions (p value: 0.12 and 0.57, respectively). Nonetheless, areas within the city had a significantly higher risk. These groups of cases coincided with those who had lower income and more inequality for women, but this pattern was not clear for men. CONCLUSIONS: Classifying city areas per income can help to determine the zones at higher risk of FEP, which would allow early healthcare and preventive measures for these zones.

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