Assuntos

Laparoscopia , Pancreatectomia , Peritônio , Grau de Desobstrução Vascular , Humanos , Laparoscopia/métodos , Pancreatectomia/métodos , Peritônio/cirurgia , Neoplasias Pancreáticas/cirurgia , Transplante Autólogo/métodos , Masculino , Feminino , Veia Porta/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Vasculares/métodos

RESUMO

Background: Personality has an impact on the health-related quality of life (HRQoL) of older adults. However, the relationship and mechanisms of the 2 variables are controversial, and few studies have been conducted on older adults. Objective: The aim of this study was to explore the relationship between personality and HRQoL and the mediating and moderating roles of sleep quality and place of residence in this relationship. Methods: A total of 4123 adults 60 years and older were from the Psychology and Behavior Investigation of Chinese Residents survey. Participants were asked to complete the Big Five Inventory, the Brief version of the Pittsburgh Sleep Quality Index, and EQ-5D-5L. A backpropagation neural network was used to explore the order of factors contributing to HRQoL. Path analysis was performed to evaluate the mediation hypothesis. Results: As of August 31, 2022, we enrolled 4123 older adults 60 years and older. Neuroticism and extraversion were strong influencing factors of HRQoL (normalized importance >50%). The results of the mediation analysis suggested that neuroticism and extraversion may enhance and diminish, respectively, HRQoL (index: ß=-.262, P<.001; visual analog scale: ß=-.193, P<.001) by increasing and decreasing brief version of the Pittsburgh Sleep Quality Index scores (neuroticism: ß=.17, P<.001; extraversion: ß=-.069, P<.001). The multigroup analysis suggested a significant moderating effect of the place of residence (EQ-5D-5L index: P<.001; EQ-5D-5L visual analog scale: P<.001). No significant direct effect was observed between extraversion and EQ-5D-5L index in urban older residents (ß=.037, P=.73). Conclusions: This study sheds light on the potential mechanisms of personality and HRQoL among older Chinese adults and can help health care providers and relevant departments take reasonable measures to promote healthy aging.

Assuntos

Personalidade , Qualidade de Vida , Humanos , Masculino , Estudos Transversais , Qualidade de Vida/psicologia , Feminino , Idoso , China/epidemiologia , Pessoa de Meia-Idade , Análise de Mediação , Idoso de 80 Anos ou mais , Inquéritos e Questionários , Qualidade do Sono , População do Leste Asiático

RESUMO

BACKGROUND: Lymphoma is the most common secondary cause of hemophagocytic lymphohistiocytosis (HLH) in adults. Lymphoma-associated HLH (LA-HLH) in the elderly population is not rare, however, little has been reported regarding clinicopathological characteristics, prognostic factors, and outcomes of LA-HLH in the elderly population. METHODS: We retrospectively analyzed a multicenter cohort of elderly patients with LA-HLH. Clinicopathological features and treatment information were collected. The impacts of baseline characteristics and treatments on survival outcomes were analyzed. RESULTS: A total of 173 elderly patients with LA-HLH were included. Compared with young patients, elderly patients showed different clinical and laboratory features. Regarding lymphoma subtypes, B-cell lymphoma was more common in elderly patients (elderly 61.3% vs. young 32.3%, p < 0.001) while T/NK-cell lymphoma was more common in young patients (65.3% vs. 35.3%, p < 0.001). The median survival of elderly patients with LA-HLH was only 92 days. The prior use of HLH therapy or etoposide-containing HLH therapy was not associated with improved overall survival. T/NK-cell subtype, a lower platelet count (≤53 × 109/L), a lower albumin level (≤32.1 g/L), a higher LDH level (>1407 U/L), and a higher creatinine level (>96.8 µmol/L) were independent predictors of decreased overall survival and 60-day survival. A prognostic index was established and demonstrated to be robust in predicting the overall survival and 60-day survival of elderly patients with LA-HLH. CONCLUSIONS: LA-HLH in elderly patients displayed heterogeneous clinicopathological features and survival outcomes. Treatments need to be optimized to improve the outcomes of elderly patients with LA-HLH.

Assuntos

Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Feminino , Idoso , Prognóstico , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Fatores Etários , Linfoma/mortalidade , Linfoma/complicações , Linfoma/patologia , Resultado do Tratamento

RESUMO

PURPOSE: The benefit of adjuvant therapy for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) remains unclear because of severely limited evidence. Although biologically distinct entities, adjuvant therapy practices for IPMN-derived PDAC are largely founded on pancreatic intraepithelial neoplasia-derived PDAC. We aimed to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC. METHODS: This international multicenter retrospective cohort study (2005-2018) was conceived at the Verona Evidence-Based Medicine meeting. Cox regressions were performed to identify risk-adjusted hazard ratios (HR) associated with overall survival (OS). Kaplan-Meier curves and log-rank tests were employed for survival analysis. Logistic regression was performed to identify factors motivating adjuvant chemotherapy administration. A decision tree was proposed and categorized patients into overtreated, undertreated, and optimally treated cohorts. RESULTS: In 1,031 patients from 16 centers, nodal disease (HR, 2.88, P < .001) and elevated (≥37 to <200 µ/mL, HR, 1.44, P = .006) or markedly elevated (≥200 µ/mL, HR, 2.53, P < .001) carbohydrate antigen 19-9 (CA19-9) were associated with worse OS. Node-positive patients with elevated CA19-9 had an associated 34.4-month improvement in median OS (P = .047) after adjuvant chemotherapy while those with positive nodes and markedly elevated CA19-9 had an associated 12.6-month survival benefit (P < .001). Node-negative patients, regardless of CA19-9, did not have an associated benefit from adjuvant chemotherapy (all P > .05). Based on this model, we observed undertreatment in 18.1% and overtreatment in 61.2% of patients. Factors associated with chemotherapy administration included younger age, R1-margin, poorer differentiation, and nodal disease. CONCLUSION: Almost half of patients with resected IPMN-derived PDAC may be overtreated or undertreated. In patients with node-negative disease or normal CA19-9, adjuvant chemotherapy is not associated with a survival benefit, whereas those with node-positive disease and elevated CA19-9 have an associated benefit from adjuvant chemotherapy. A decision tree was proposed. Randomized controlled trials are needed for validation.

RESUMO

BACKGROUND: The purpose of this study was to investigate the effects of caffeinated chewing gum on female softball pitching and hitting performance in trained female softball fielders and pitchers. METHODS: Twenty-four trained female softball players (10 pitchers and 14 fielders) were divided into a caffeine chewing gum trial (CAF) or a placebo trial (PLA) in a single-blind, randomized, crossover experimental design. Two pieces of gum containing 100 mg of caffeine (CAF) or without caffeine (PLA) were chewed for 10 minutes and then spit out, followed by a 15-minute warm-up. The physical tests included grip strength and countermovement jump (CMJ). The softball-specific tests included pitching or hitting. The two trials were separated by seven days. RESULTS: The CAF trial had significantly higher grip strength than the PAL trial in fielder (P=0.032, Cohen's d=0.29) and pitcher (P=0.016, Cohen's d=0.33). The height of CMJ in fielders was significantly higher in the CAF trial than in the PLA trial (P=0.015, Cohen's d=0.65) but not in pitchers (P=0.596, Cohen's d=0.15). The fielder's average and maximum batting exit speeds were significantly higher in the CAF trial than in the PLA trial (P<0.05). The average and max fastball speeds of the CAF trial were significantly higher than that of the PLA trial in pitchers (P<0.05). CONCLUSIONS: The study showed that chewing gum containing two pieces of gum containing 100 mg of caffeine effectively improved female softball fielder's batting performance and pitcher's pitching performance.

RESUMO

Racial and ethnic disparities persist in cancer survival rates across the United States, despite overall improvements. This comprehensive analysis examines trends in 5-year relative survival rates from 2002-2006 to 2015-2019 for major cancer types, elucidating differences among racial/ethnic groups to guide equitable healthcare strategies. Data from the SEER Program spanning 2000-2020 were analyzed, focusing on breast, colorectal, prostate, lung, pancreatic cancers, non-Hodgkin lymphoma, acute leukemia, and multiple myeloma. Age-standardized relative survival rates were calculated to assess racial (White, Black, American Indian/Alaska Native, Asian/Pacific Islander) and ethnic (Hispanic, Non-Hispanic) disparities, utilizing period analysis for recent estimates and excluding cases identified solely through autopsy or death certificates. While significant survival improvements were observed for most cancers, notable disparities persisted. Non-Hispanic Blacks exhibited the largest gain in breast cancer survival, with an increase of 5.2% points (from 77.6 to 82.8%); however, the survival rate remained lower than that of Non-Hispanic Whites (92.1%). Colorectal cancer survival declined overall (64.7-64.1%), marked by a 6.2% point drop for Non-Hispanic American Indian/Alaska Natives (66.3-60.1%). Prostate cancer survival declined across all races, with Non-Hispanic American Indian/Alaska Natives showing a decrease of 7.7% points (from 96.9 to 89.2%). Lung cancer, acute leukemia, and multiple myeloma showed notable increases across groups. Substantial racial/ethnic disparities in cancer survival underscore the notable need for tailored strategies ensuring equitable access to advanced treatments, particularly addressing significant trends in colorectal and pancreatic cancers among specific minority groups. Careful interpretation of statistical significance is warranted given the large dataset.

Assuntos

Neoplasias , Programa de SEER , Humanos , Neoplasias/mortalidade , Neoplasias/etnologia , Estados Unidos/epidemiologia , Masculino , Feminino , Taxa de Sobrevida , Etnicidade/estatística & dados numéricos , Grupos Raciais/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Pessoa de Meia-Idade , Idoso , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/tendências

RESUMO

OBJECTIVE: To determine the interobserver variability for complications of pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery (ISGPS) and others. SUMMARY BACKGROUND DATA: Good interobserver variability for the definitions of surgical complications is of major importance in comparing surgical outcomes between and within centers. However, data on interobserver variability for pancreatoduodenectomy-specific complications are lacking. METHODS: International cross-sectional multicenter study including 52 raters from 13 high-volume pancreatic centers in 8 countries on 3 continents. Per center, 4 experienced raters scored 30 randomly selected patients after pancreatoduodenectomy. In addition, all raters scored six standardized case vignettes. This variability and the 'within centers' variability were calculated for twofold scoring (no complication/grade A vs grade B/C) and threefold scoring (no complication/grade A vs grade B vs grade C) of postoperative pancreatic fistula (POPF), post-pancreatoduodenectomy hemorrhage (PPH), chyle leak (CL), bile leak (BL), and delayed gastric emptying (DGE). Interobserver variability is presented with Gwet's AC-1 measure for agreement. RESULTS: Overall, 390 patients after pancreatoduodenectomy were included. The overall agreement rate for the standardized cases vignettes for twofold scoring was 68% (95%-CI: 55%-81%, AC1 score: moderate agreement) and for threefold scoring 55% (49%-62%, AC1 score: fair agreement). The mean 'within centers' agreement for twofold scoring was 84% (80%-87%, AC1 score; substantial agreement). CONCLUSION: The interobserver variability for the ISGPS defined complications of pancreatoduodenectomy was too high even though the 'within centers' agreement was acceptable. Since these findings will decrease the quality and validity of clinical studies, ISGPS has started efforts aimed at reducing the interobserver variability.

RESUMO

With advancements in genomics and immunology, immunotherapy has emerged as a revolutionary strategy for tumor treatment. However, pancreatic ductal adenocarcinoma (PDAC), an immunologically "cold" tumor, exhibits limited responsiveness to immunotherapy. This study aimed to address the urgent need to uncover PDAC's immune microenvironment heterogeneity and identify the molecular mechanisms driving immune evasion. Using single-cell RNA sequencing datasets and spatial proteomics, we discovered LIM domain only 7 (LMO7) in PDAC cells as a previously unrecognized driver of immune evasion through Treg cell enrichment. LMO7 was positively correlated with infiltrating regulatory T cells (Tregs) and dysfunctional CD8+ T cells. A series of in vitro and in vivo experiments demonstrated LMO7's significant role in promoting Treg cell differentiation and chemotaxis while inhibiting CD8+ T cells and natural killer cell cytotoxicity. Mechanistically, LMO7, through its LIM domain, directly bound and promoted the ubiquitination and degradation of Foxp1. Foxp1 negatively regulated transforming growth factor-beta (TGF-ß) and C-C motif chemokine ligand 5 (CCL5) expression by binding to sites 2 and I/III, respectively. Elevated TGF-ß and CCL5 levels contribute to Treg cell enrichment, inducing immune evasion in PDAC. Combined treatment with TGF-ß/CCL5 antibodies, along with LMO7 inhibition, effectively reversed immune evasion in PDAC, activated the immune response, and prolonged mouse survival. Therefore, this study identified LMO7 as a novel facilitator in driving immune evasion by promoting Treg cell enrichment and inhibiting cytotoxic effector functions. Targeting the LMO7-Foxp1-TGF-ß/CCL5 axis holds promise as a therapeutic strategy for PDAC. Graphical abstract revealing LMO7 as a novel facilitator in driving immune evasion by promoting Tregs differentiation and chemotaxis, inducing CD8+ T/natural killer cells inhibition.

RESUMO

Mammalian preimplantation development culminates in the formation of a blastocyst which undergoes extensive gene expression regulation to successfully implant into the maternal endometrium. Zinc-finger HIT domain-containing (ZNHIT) 1 and 2 are members of a highly conserved family, yet they have been identified as subunits of distinct complexes. Here we report that knockout of either Znhit1 or Znhit2 results in embryonic lethality during peri-implantation stages. Znhit1 and Znhit2 mutant embryos have overlapping phenotypes, including reduced proportion of SOX2-positive ICM cells, a lack of Fgf4 expression and aberrant expression of NANOG and SOX17. Furthermore, we find that the similar phenotypes are caused by distinct mechanisms. Specifically, embryos lacking ZNHIT1 likely fail to incorporate sufficient H2A.Z at the promoter region of Fgf4 and other genes involved in cell projection organization resulting in impaired invasion of trophoblast cells during implantation. In contrast, Znhit2 mutant embryos display a complete lack of nuclear EFTUD2, a key component of U5 spliceosome, indicating a global splicing deficiency. Our findings unveil the indispensable yet distinct roles of ZNHIT1 and ZNHIT2 in early mammalian embryonic development.

RESUMO

BACKGROUND: The relationships between 25-hydroxyvitamin D [25(OH)D] and calcium and age-related macular degeneration (AMD) are unclear. OBJECTIVES: This study aimed to investigate the causal role of 25(OH)D concentrations, calcium concentrations, and dietary supplements use of vitamin D and calcium on risk of AMD and its subtypes. METHODS: Independent genetic variants associated with 25(OH)D and calcium concentrations were used as instrumental variables in published genome-wide association studies (GWASs) of European ancestry. The bidirectional 2-sample Mendelian randomization (MR) analyses were performed using summary-level data from the UK Biobank and FinnGen datasets. Sensitivity analyses were conducted to ensure the robustness of the MR results. The meta-analyses were conducted using both fixed-effect and random-effect models to provide comprehensive and reliable estimates. RESULTS: A standard deviation increase in calcium concentrations was linked to a 14%, 17%, and 13% reduction in the likelihood of developing AMD (95% confidence interval [CI]: 0.77, 0.97), wet AMD (95% CI: 0.73, 0.95), and dry AMD (95% CI: 0.75, 1.00), respectively. No significant causal relationships were detected between genetically predicted 25(OH)D concentrations and AMD and its subtypes (all P > 0.05). The combined analyses showed that higher calcium concentrations were associated with a reduced risk of overall AMD, with an odds ratio of 0.89 (95% CI: 0.81, 0.98). CONCLUSIONS: This study provides evidence supporting the causal relationship between calcium concentrations and risk of AMD and its subtypes, which may have important implications for the prevention, monitoring, and treatment of AMD.

Assuntos

Estudo de Associação Genômica Ampla , Degeneração Macular , Análise da Randomização Mendeliana , Vitamina D , Humanos , Vitamina D/análogos & derivados , Vitamina D/sangue , Degeneração Macular/genética , Degeneração Macular/sangue , Degeneração Macular/epidemiologia , Cálcio/sangue , Cálcio da Dieta/administração & dosagem , Suplementos Nutricionais , Fatores de Risco , Polimorfismo de Nucleotídeo Único , Feminino , Idoso

RESUMO

OBJECTIVE: The ISGPS aims to develop a universally accepted complexity and experience grading system to guide the safe implementation of robotic and laparoscopic minimally-invasive pancreatoduodenectomy (MIPD). BACKGROUND: Despite the perceived advantages of MIPD, its global adoption has been slow due to the inherent complexity of the procedure and challenges to acquiring surgical experience. Its wider adoption must be undertaken with an emphasis towards appropriate patient selection according to adequate surgeon and center experience. METHODS: The ISGPS developed a complexity and experience grading system to guide patient selection for MIPD based on an evidence-based review and a series of discussions. RESULTS: The ISGPS complexity and experience grading system for MIPD is subclassified into patient-related risk factors and provider experience-related variables. The patient-related risk factors include anatomical (main pancreatic and common bile duct diameters), tumor-specific (vascular contact), and conditional (obesity and previous complicated upper abdominal surgery/disease) factors, all incorporated in an A-B-C classification, graded as no, a single, and multiple risk factors. The surgeon and center experience-related variables include surgeon total MIPD experience (cut-offs 40 and 80) and center annual MIPD volume (cut-offs 10 and 30), all also incorporated in an A-B-C classification. CONCLUSION: This ISGPS complexity and experience grading system for robotic and laparoscopic MIPD may enable surgeons to optimally select patients after duly considering specific risk factors known to influence the complexity of the procedure. This grading system will likely allow for a thoughtful and stepwise implementation of MIPD and facilitate a fair comparison of outcome between centers and countries.

RESUMO

The role of the bronchoalveolar lavage fluid (BALF) microbiome in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) remains unclear. The advent of the metagenomic next-generation sequencing (mNGS) has made it possible to reveal the complex microbiome composition of the respiratory tract. This study aimed to explore whether there are differences in the BALF microbiome of AECOPD patients with different lung functions. We enrolled 55 AECOPD patients and divided them into a mild group (n = 31) and a severe group (n = 24) according to their lung function. We collected BALF and submitted it to mNGS and bioinformatics analysis. At the species level, mNGS identified 264 bacteria, 13 fungi and 12 viruses in the mild group, and 174 bacteria, 6 fungi and 6 viruses in the severe group. Mixed bacterial and viral infection occurred in both groups. At the genus level, Rothia and Veillonella were more abundant in the mild group, while Pseudomonas and Staphylococcus were more abundant in the severe group. At the species level, compared with the mild group, the relative abundance of Haemophilus influenzae and Pseudomonas aeruginosa was increased in the severe group. Besides, the BALF microbiome composition was similar between the two groups, and there was no significant difference in α and ß diversity. Forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) (%) showed no significant correlation with the Shannon or Simpson index. The microbiome abundance was different between the mild and severe groups; however, microbiome diversity was similar between the two groups. Based on our findings, Haemophilus influenzae and Pseudomonas aeruginosa may be the pathogenic bacteria that cause the difference in lung function in patients with AECOPD.

RESUMO

Although the strigolactone (SL) signaling pathway and SL-mediated anthocyanin biosynthesis have been reported, the molecular association between SL signaling and anthocyanin biosynthesis remains unclear. In this study, we identified the SL signal transduction pathway associated with anthocyanin biosynthesis and the crosstalk between gibberellin (GA) and SL signaling in apple (Malus × domestica). ELONGATED HYPOCOTYL5 (HY5) acts as a key node integrating SL signaling and anthocyanin biosynthesis, and the SL response factor AGAMOUS-LIKE MADS-BOX9 (AGL9) promotes anthocyanin biosynthesis by activating HY5 transcription. The SL signaling repressor SUPPRESSOR OF MAX2 1-LIKE8 (SMXL8) interacts with AGL9 to form a complex that inhibits anthocyanin biosynthesis by downregulating HY5 expression. Moreover, the E3 ubiquitin ligase PROTEOLYSIS1 (PRT1) mediates the ubiquitination-mediated degradation of SMXL8, which is a key part of the SL signal transduction pathway associated with anthocyanin biosynthesis. In addition, the GA signaling repressor REPRESSOR-of-ga1-3-LIKE2a (RGL2a) mediates the crosstalk between GA and SL by disrupting the SMXL8-AGL9 interaction that represses HY5 transcription. Taken together, our study reveals the regulatory mechanism of SL-mediated anthocyanin biosynthesis and uncovers the role of SL-GA crosstalk in regulating anthocyanin biosynthesis in apple.

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0301461.].

RESUMO

Local anesthetic (LA) cardiotoxicity is one of the main health problems in anesthesiology and pain management. This study reviewed the reported LA-induced cardiac toxicity types, risk factors, management, and mechanisms, with attention to the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in heart toxicity research. Important scientific databases were searched to find relevant articles. We briefly assessed the reported cardiotoxic effects of different types of LA drugs, including ester- and amide-linked LA agents. Furthermore, cardiotoxic effects and clinical manifestations, strategies for preventing and managing LA-induced cardiotoxic effects, pharmacokinetics, pharmacodynamics, and sodium channel dynamics regarding individual variability and genetic influences were discussed in this review. The applications and importance of hiPSC-CMs cellular model for evaluating the cardiotoxic effects of LA drugs were discussed in detail. This review also explored hiPSC-CMs' potential in risk assessment, drug screening, and developing targeted therapies. The main mechanisms underlying LA-induced cardiotoxicity included perturbation in sodium channels, ROS production, and disorders in the immune system response due to the presence of LA drugs. Furthermore, drug-specific characteristics including pharmacokinetics and pharmacodynamics are important determinants after LA drug injection. In addition, individual patient factors such as age, comorbidities, and genetic variability emphasize the need for a personalized approach to mitigate risks and enhance patient safety. The strategies outlined for the prevention and management of LA cardiotoxicity underscore the importance of careful dosing, continuous monitoring, and the immediate availability of resuscitation equipment. This comprehensive review can be used to guide future investigations into better understanding LA cardiac toxicities and improving patient safety.

Assuntos

Anestésicos Locais , Cardiotoxicidade , Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Anestésicos Locais/efeitos adversos , Anestésicos Locais/toxicidade , Cardiotoxicidade/etiologia , Animais

RESUMO

Emerging evidence highlights the regulatory role of paired-like (PRD-like) homeobox transcription factors (TFs) in embryonic genome activation (EGA). However, the majority of PRD-like genes are lost in rodents, thus prompting an investigation into PRD-like TFs in other mammals. Here, we showed that PRD-like TFs were transiently expressed during EGA in human, monkey, and porcine fertilized embryos, yet they exhibited inadequate expression in their cloned embryos. This study, using pig as the research model, identified LEUTX as a key PRD-like activator of porcine EGA through genomic profiling and found that LEUTX overexpression restored EGA failure and improved preimplantation development and cloning efficiency in porcine cloned embryos. Mechanistically, LEUTX opened EGA-related genomic regions and established histone acetylation via recruiting acetyltransferases p300 and KAT2A. These findings reveal the regulatory mechanism of LEUTX to govern EGA in pigs, which may provide valuable insights into the study of early embryo development for other non-rodent mammals.

Assuntos

Genoma , Técnicas de Transferência Nuclear , Animais , Suínos , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Desenvolvimento Embrionário/genética , Embrião de Mamíferos/metabolismo , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Acetilação , Clonagem de Organismos/métodos , Histonas/metabolismo , Blastocisto/metabolismo

RESUMO

Genetic differences between pluripotent stem cell lines cause variable activity of extracellular signaling pathways, limiting reproducibility of directed differentiation protocols. Here we used human embryonic stem cells (hESCs) to interrogate how exogenous factors modulate endogenous signaling events during specification of foregut endoderm lineages. We find that transforming growth factor ß1 (TGF-ß1) activates a putative human OTX2/LHX1 gene regulatory network which promotes anterior fate by antagonizing endogenous Wnt signaling. In contrast to Porcupine inhibition, TGF-ß1 effects cannot be reversed by exogenous Wnt ligands, suggesting that induction of SHISA proteins and intracellular accumulation of Fzd receptors render TGF-ß1-treated cells refractory to Wnt signaling. Subsequently, TGF-ß1-mediated inhibition of BMP and Wnt signaling suppresses liver fate and promotes pancreas fate. Furthermore, combined TGF-ß1 treatment and Wnt inhibition during pancreatic specification reproducibly and robustly enhance INSULIN+ cell yield across hESC lines. This modification of widely used differentiation protocols will enhance pancreatic ß cell yield for cell-based therapeutic applications.

Assuntos

Proteínas Morfogenéticas Ósseas , Diferenciação Celular , Endoderma , Células-Tronco Embrionárias Humanas , Via de Sinalização Wnt , Humanos , Endoderma/citologia , Endoderma/metabolismo , Diferenciação Celular/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Proteínas Morfogenéticas Ósseas/metabolismo , Linhagem da Célula/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia

RESUMO

PURPOSE: To examine the association between ambient air pollution and dry eye symptoms (DES) during the COVID-19 pandemic and explore whether air pollution had increased the risk of DES to a greater extent than other risk factors. METHODS: A nationwide cross-sectional survey was conducted from June 20, 2022 to August 31, 2022. The Ocular Surface Disease Index-6 (OSDI-6) questionnaire was used to assess the presence of DES. Logistic regression models were employed to analyze the associations between DES and air pollution variables, including air quality index (AQI), fine particulate matter (PM2.5), PM10, sulfur dioxide (SO2), carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3) and residing near industrial zones. We explored the interactions of air pollutants and other risk factors in the additive models by calculating the synergy index (SI). Standardized regression coefficients were calculated to compare the relative importance of risk factors for DES. RESULTS: A total of 21,909 participants were included in the analysis. Residing near industrial zones was significantly correlated with a higher risk of DES (Odds ratio (OR): 1.57, 95 % confidence interval (CI): 1.38-1.79). No significant associations were found between DES and air pollutants except SO2 (OR: 1.05, 95 % CI: 1.02-1.09, per standard deviation increment in SO2 concentration). The restricted cubic spline analyses revealed a linear concentration-response relationship between SO2 and DES. The interaction analyses suggested synergetic interactions of SO2 with depression and problematic internet use. Among the risk factors, depression, anxiety and problematic Internet use contributed more to the increased risk of DES. CONCLUSION: The association between ambient air pollutants and DES may have been mitigated during the pandemic due to increased time spent indoors. Despite this, our findings support the deleterious health impact of air pollutants. Future urban planning should plan industrial zones further away from residential areas.

Assuntos

Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Síndromes do Olho Seco , Material Particulado , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , China/epidemiologia , COVID-19/epidemiologia , Estudos Transversais , Síndromes do Olho Seco/epidemiologia , Síndromes do Olho Seco/induzido quimicamente , População do Leste Asiático , Exposição Ambiental/estatística & dados numéricos , Pandemias , Material Particulado/análise , Fatores de Risco , Dióxido de Enxofre/análise

RESUMO

BACKGROUND: Ovarian cancer (OC) is a malignancy among female globally. Circular RNAs (circRNAs) are a family of circular endogenous RNAs generated from selective splicing, which take part in many traits. Former investigation suggested that circ-TFRC was abnormally expressed in breast cancer (BC). Further, the role of circ-TFRC to the progress of OC remains unclear. So, the aim of this study was to reveal the regulatory mechanism of circ-TFRC. METHODS: Our team made the luciferase reporter assay to validate circ-TFRC downstream target. Transwell migration assay, 5-ethynyl-20-deoxyuridine, and cell counting kit-8 were applied to investigate both proliferation and migration. In vivo tumorigenesis and metastasis assays were performed to investigate the circ-TFRC role in OC. RESULTS: The outputs elucidated that circ-TFRC expression incremented in OC cells and tissues. circ-TFRC downregulation inhibited OC cell proliferation as well as migration in in vivo and in vitro experiments. The luciferase results validated that miR-615-3p and IGF2 were circ-TFRC downstream targets. IGF2 overexpression or miR-615-3p inhibition reversed OC cell migration after circ-TFRC silencing. Also, IGF2 overexpression reversed OC cell migration and proliferation post miR-615-3p upregulation. CONCLUSION: Results demonstrate that circ-TFRC downregulation inhibits OC progression and metastasis via IGF2 expression regulation and miR-615-3psponging.