RESUMO
PURPOSE: Membrane associated ubiquitin ligase MARCH2 majorly involves in inflammation response and protein trafficking. However, its comprehensive role in hepatocellular carcinoma (HCC) is largely unknown. METHODS: Firstly, multiple bioinformatic analyses were applied to determine MARCH2 mRNA level, its expression comparison in diverse molecular and immune subtypes, and diagnostic value in HCC. Subsequently, RNA-seq, real-time quantitative PCR, immunohistochemistry and cell proliferation assay are used to explore the epithelial-mesenchymal transition (EMT) and proliferation by gene-silencing or overexpressing in cultured HCC cells or in vivo xenograft. Moreover, dual luciferase reporter assay and immunoblotting are delved into verify the transcription factor that activating MARCH2 promoter. RESULTS: Multiple bioinformatic analyses demonstrate that MARCH2 is upregulated in multiple cancer types and exhibits startling diagnostic value as well as distinct molecular and immune subtypes in HCC. RNA-seq analysis reveals MARCH2 may promote EMT, cell proliferation and migration in HepG2 cells. Furthermore, overexpression of MARCH2 triggers EMT and significantly enhances HCC cell migration, proliferation and colony formation in a ligase activity-dependent manner. Additionally, above observations are validated in the HepG2 mice xenografts. For up-stream mechanism, transcription factor KLF15 is highly expressed in HCC and activates MARCH2 expression. CONCLUSION: KLF15 activated MARCH2 triggers EMT and serves as a fascinating biomarker for precise diagnosis of HCC. Consequently, MARCH2 emerges as a promising candidate for target therapy in cancer management.
Assuntos
Carcinoma Hepatocelular , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like , Neoplasias Hepáticas , Ubiquitina-Proteína Ligases , Animais , Feminino , Humanos , Masculino , Camundongos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Células Hep G2 , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/diagnóstico , Camundongos Endogâmicos BALB C , Camundongos Nus , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
While linear ubiquitin plays critical roles in multiple cell signaling pathways, few substrates have been identified. Global profiling of linear ubiquitin substrates represents a significant challenge because of the low endogenous level of linear ubiquitination and the background interference arising from highly abundant ubiquitin linkages (e.g. K48- and K63-) and from the non-specific attachment of interfering proteins to the linear polyubiquitin chain. We developed a bio-orthogonal linear ubiquitin probe by site-specific encoding of a norbornene amino acid on ubiquitin (NAEK-Ub). This probe facilitates covalent labeling of linear ubiquitin substrates in live cells and enables selective enrichment and identification of linear ubiquitin-modified proteins. Given the fact that the frequent overexpression of the linear linkage-specific deubiquitinase OTULIN correlates with poor prognosis in glioblastoma, we demonstrated the feasibility of the NAEK-Ub strategy by identifying and validating substrates of linear ubiquitination in patient-derived glioblastoma stem-like cells (GSCs). We identified STAT3 as a bona fide substrate of linear ubiquitin, and showed that linear ubiquitination negatively regulates STAT3 activity by recruitment of the phosphatase TC-PTP to STAT3. Furthermore, we demonstrated that preferential expression of OTULIN in GSCs restricts linear ubiquitination on STAT3 and drives persistent STAT3 signaling, and thereby maintains the stemness and self-renewal of GSCs.
Assuntos
Glioblastoma , Fator de Transcrição STAT3 , Ubiquitina , Humanos , Poliubiquitina/genética , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. METHODS: Blood samples were available from haemangiomas patients undergoing hepatectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. RESULTS: Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6 h after 75 min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. CONCLUSIONS: The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target.
Assuntos
Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos , Fígado , Camundongos Knockout , Traumatismo por Reperfusão , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Animais , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Humanos , Camundongos , Fígado/patologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Apoptose , Fígado Gorduroso/patologia , Fígado Gorduroso/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Camundongos Transgênicos , Feminino , HepatectomiaRESUMO
PURPOSE: Familial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Since the first functional and morphologic changes of the arterial wall occur in childhood, treatment should start early in childhood to mitigate the elevated risk of ASCVD. Pediatricians play an important role in the detection and care of children with FH. In this study, we aim to explore potential gaps in FH care amongst Dutch pediatricians, in order to enhance their knowledge and awareness of detecting and treating children with FH. METHODS: An anonymous online survey, deployed using Google Forms, including 26 closed and semi-closed questions on FH care in children was distributed by the Dutch Association of Pediatrics via a newsletter to which the majority of the practicing Dutch pediatricians subscribe. In addition, we requested that the pediatric departments of all Dutch hospitals in the Netherlands distribute this survey personally among their employed pediatricians. Respondents were instructed to answer the questions without any help or use of online resources. RESULTS: Between September 1st, 2023 and November 1st, 2023, 158 (an estimated 11% response rate) Dutch pediatricians completed the survey. They reported a median (IQR) of 15.0 (6.0-22.0) years of experience as a pediatrician, and 34 (21.5%) were working in academic hospitals. The majority (76.6%) of pediatricians correctly identified a typical FH lipid profile but 68 (43.0%) underestimated the true prevalence of FH (1:300). Underestimation and unawareness of the increased risk of FH patients for ASCVD were reported by 37.3% and 25.9% of pediatricians, respectively. Although 70.9% of the pediatricians correctly defined FH, only 67 (42.4%) selected statins and ezetimibe to treat severe hypercholesterolemia. CONCLUSIONS: The results of this study suggest significant gaps in knowledge and awareness of FH in children among Dutch pediatricians. FH care in children needs improvement through educational and training initiatives to mitigate the life-long risk of ASCVD from early life. WHAT IS KNOWN: ⢠Familial hypercholesterolemia (FH) leads to elevated LDL-cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). ⢠The process of atherosclerosis starts in childhood ⢠Pediatricians play an important role in the detection and treatment of children with FH. WHAT IS NEW: ⢠Our results highlight significant gaps in care for children with FH amongst pediatricians and this may lead to suboptimal detection and treatment. ⢠FH care in children needs improvement by educational initiatives to ultimately prevent ASCVD in adulthood.
Assuntos
Hiperlipoproteinemia Tipo II , Pediatras , Padrões de Prática Médica , Humanos , Países Baixos/epidemiologia , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pediatras/estatística & dados numéricos , Masculino , Padrões de Prática Médica/estatística & dados numéricos , Feminino , Criança , Inquéritos e Questionários , Adulto , Lacunas da Prática Profissional/estatística & dados numéricosRESUMO
BACKGROUND: Benzene and its metabolite hydroquinone (HQ) are widely used in daily life, and long-term exposure to benzene or HQ can induce acute myeloid leukemia (AML). Circular RNAs (circRNAs) are mostly produced by reverse splicing of gene exon mRNA precursors. The modulation of circRNA expression is connected to leukemia progression; however, the molecular mechanism is still unknown. MATERIALS AND METHODS: In this study, the cells were divided into four groups: PBS control group (PBS-TK6), TK6 malignantly transformed cells induced by 10.0 µmol/L HQ (HQ-TK6), and HQ-TK6 cells treated with 5 µmol/L 5-AzaC (DNA methyltransferase inhibitor) for 24 h (HQ + 5-AzaC). HQ-TK6 cells were treated with 200 nmol/L TSA (histone deacetylation inhibitor) for 24 h (HQ + TSA). qRT-PCR was used to identify the differential hsa_circ_401351 expression between the four groups. We further determined the hsa_circ_401351 promoter methylation level with methylation-specific PCR. DNMT1 and DNMT3b were knocked down by CRISPR/Cas9 to elucidate the specific molecular mechanism of hsa_circ_401351 in HQ-TK6 cells. CCK-8 and flow cytometry detected cell proliferation and apoptosis, respectively, after hsa_circ_401351 was overexpressed in HQ-TK6 cells. RESULTS: Compared with the PBS-TK6 group, the expression of hsa_circ_401351 was found to be lower in the HQ-TK6 group. Nevertheless, treatment with 5-AzaC or TSA increased hsa_circ_401351 expression, with the upregulation being more pronounced in the TSA group. The expression of hsa_circ_401351 in the DNMT1 knockdown group was dramatically increased by 50% compared to that in the control group, and the DNA methylation level of the hsa_circ_401351 promoter region was decreased. When hsa_circ_401351 was overexpressed, HQ-TK6 cell proliferation was significantly slowed after 48 h compared with the control group. Flow cytometry showed that cells were mainly arrested in G1 phase, and apoptosis was significantly enhanced. Similarly, qRT-PCR and Western blot data showed significant reductions in Caspase-3 mRNA and protein production, and Bcl-2 mRNA levels were also elevated. CONCLUSIONS: Overall, our research showed that elevated DNMT1 expression in HQ-TK6 cells increased methylation levels and decreased expression of the hsa_circ_401351 promoter region, limiting its ability to suppress HQ-TK6 cell growth and enhance apoptosis.
Assuntos
Metilação de DNA , MicroRNAs , Hidroquinonas/toxicidade , Benzeno , Proliferação de Células , RNA Mensageiro/metabolismo , MicroRNAs/genética , Apoptose/genéticaRESUMO
Chemical investigation of Penicillium sp. GDGJ-N37, a Sophora tonkinensis-associated fungus, yielded two new azaphilone derivatives, N-isoamylsclerotiorinamine (1) and 7-methoxyl-N-isoamylsclerotiorinamine (2), and four known azaphilones (3-6), together with two new chromone derivatives, penithochromones X and Y (7 and 8). Their structures were elucidated based on spectroscopic data, CD spectrum, and semi-synthesis. Sclerotioramine (3) showed significant antibacterial activities against B. subtilis and S. dysentery, and it also showed most potent anti-plant pathogenic fungi activities against P. theae, C. miyabeanus, and E. turcicum.
Assuntos
Anti-Infecciosos , Penicillium , Sophora , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , FungosRESUMO
BACKGROUND: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands. METHODS: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom. RESULTS: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score >â¯4 on a 1-7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions. CONCLUSION: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts.
RESUMO
Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy.
Assuntos
Cardiomiopatias , Mitocôndrias , Humanos , Fosforilação , Mitocôndrias/genética , Mitocôndrias/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/metabolismoRESUMO
PURPOSE OF REVIEW: Describe the application of implementation science to improve the detection and management of familial hypercholesterolaemia. RECENT FINDINGS: Gaps between evidence and practice, such as underutilization of genetic testing, family cascade testing, failure to achieve LDL-cholesterol goals and low levels of knowledge and awareness, have been identified through clinical registry analyses and clinician surveys. Implementation science theories, models and frameworks have been applied to assess barriers and enablers in the literature specific to local contextual factors (e.g. stages of life). The effect of implementation strategies to overcome these factors has been evaluated; for example, automated identification of individuals with FH or training and education to improve statin adherence. Clinical registries were identified as a key infrastructure to monitor, evaluate and sustain improvements in care. The expansion in evidence supporting the care of familial hypercholesterolaemia requires a similar expansion of efforts to translate new knowledge into clinical practice.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Humanos , Ciência da Implementação , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , LDL-Colesterol , Testes Genéticos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêuticoRESUMO
Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.
Assuntos
Vesículas Extracelulares , Neoplasias Gástricas , Histona Desmetilases/genética , Humanos , Lisina , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genéticaRESUMO
Achieving long-term stable deep desulfurization at room temperature and recovering high value-added sulfone products is a challenge at present. Herein, a series of catalysts [Cnmim]5VW12O40Br (CnVW12, 1-alkyl-3-methylimidazolium bromide tungstovanadate, n = 4, 8, 16) were presented for the room temperature catalytic oxidation of dibenzothiophene (DBT) and its derivatives. Factors affecting the reaction process, such as the amount of catalyst, oxidant, and temperature, were systematically discussed. C16VW12 showed higher catalytic performance, and 100% conversion and selectivity could be achieved in 50 min with only 10 mg. The mechanism study showed that the hydroxyl radical was the active radical in the reaction. Benefiting from the "polarity strategy", the sulfone product accumulated after 23 cycles in a C16VW12 system, and the yield and purity were about 84% and 100%, respectively.
RESUMO
BACKGROUND: Leptospirosis is an infectious disease caused by pathogenic Leptospira spp., which could result in severe illnesses. Indirect contact with these pathogens is more common. Individuals could contract this disease through contact with contaminated water or during floods. In this case, we present the details of a 40-year-old male pig farmer who suffered from severe pulmonary hemorrhagic leptospirosis and multiple organ failure. The diagnosis of leptospirosis was confirmed through metagenomics next-generation sequencing (mNGS) while the patient received extracorporeal membrane oxygenation (ECMO) support, and antibiotic treatment was adjusted accordingly. The patient underwent comprehensive treatment and rehabilitation in the intensive care unit. CONCLUSION: This case illustrates the importance of early diagnosis and treatment of leptospirosis. While obtaining the epidemiological history, second-generation metagenomics sequencing was utilized to confirm the etiology. The prompt initiation of ECMO therapy provided a crucial window of opportunity for addressing the underlying cause. This case report offers valuable insights for diagnosing patients with similar symptoms.
Assuntos
Oxigenação por Membrana Extracorpórea , Leptospira , Leptospirose , Masculino , Humanos , Animais , Suínos , Adulto , Leptospira/genética , Sequenciamento de Nucleotídeos em Larga Escala , Leptospirose/diagnóstico , Leptospirose/terapia , CogniçãoRESUMO
BACKGROUND: Lipoprotein(a) (Lp[a]) is a risk factor for cardiovascular disease. The burden of thrombus in ST-segment elevation myocardial infarction (STEMI) has implications on treatment and outcomes. However, the association between Lp(a) and atherothrombosis in STEMI remains unclear. OBJECTIVES: The aim of the study was to determine the association between Lp(a) and culprit artery thrombus burden in younger patients with STEMI. METHODS: This was a single-center study of 83 patients aged <65 years with STEMI between 2016-2018 who underwent percutaneous coronary intervention and measurement of Lp(a); those receiving thrombolytic therapy were excluded. Thrombus burden in the culprit artery was determined angiographically using the Thrombolysis In Myocardial Infarction score and classified as absent-to-small, moderate, or large. Elevated Lp(a) was defined as plasma mass concentration >30 mg/dL. Multivariate analysis was performed adjusting for cardiovascular risk factors. RESULTS: The mean age was 48.0 ± 8.4 years, and 78.3% were male. Thirteen (16%), 9 (11%), and 61 (73%) patients had small, moderate, or large thrombus burden, respectively, and 34 (41%) had elevated Lp(a). Elevated Lp(a) was associated with greater thrombus burden compared to normal Lp(a) (large burden 85% vs. 65%; p = 0.024). Elevated Lp(a) was associated with moderate or large thrombus in univariate (OR 10.70 [95% CI 1.32-86.82]; p = 0.026) and multivariate analysis (OR 10.33 [95% CI 1.19-89.52]; p = 0.034). Lp(a) was not associated with culprit artery or stenosis location according to culprit artery. CONCLUSIONS: Elevated Lp(a) is associated with greater thrombus burden in younger patients with STEMI. The finding of this observational study accords with the thrombotic and anti-fibrinolytic properties of Lp(a). A causal relationship requires verification.
Assuntos
Trombose Coronária , Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Trombose Coronária/complicações , Trombose Coronária/diagnóstico por imagem , Lipoproteína(a) , Angiografia Coronária , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Artérias , Resultado do TratamentoRESUMO
Nearly 80% of the approved human therapeutic antibodies are produced by Chinese Hamster Ovary (CHO) cells. To achieve better cell growth and high-yield recombinant protein, fed-batch culture is typically used for recombinant protein production in CHO cells. According to the demand of nutrients consumption, feed medium containing multiple components in cell culture can affect the characteristics of cell growth and improve the yield and quality of recombinant protein. Fed-batch optimization should have a connection with comprehensive factors such as culture environmental parameters, feed composition, and feeding strategy. At present, process intensification (PI) is explored to maintain production flexible and meet forthcoming demands of biotherapeutics process. Here, CHO cell culture, feed composition in fed-batch culture, fed-batch culture environmental parameters, feeding strategies, metabolic byproducts in fed-batch culture, chemostat cultivation, and the intensified fed-batch are reviewed. KEY POINTS: ⢠Fed-batch culture in CHO cells is reviewed. ⢠Fed-batch has become a common technology for recombinant protein production. ⢠Fed batch culture promotes recombinant protein production in CHO cells.
Assuntos
Técnicas de Cultura Celular por Lotes , Reatores Biológicos , Cricetinae , Animais , Humanos , Cricetulus , Células CHO , Proteínas Recombinantes/metabolismo , ImunoglobulinasRESUMO
Cancer immunotherapy is a rapidly developing and effective method for the treatment of a variety of malignancies in recent years. As a significant immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play the most significant role in cancer immune escape and cancer immunotherapy. Though PD-L1 have become an important target for drug development and there have been various approved drugs and clinic trials targeting it, and various clinical response rate and adverse reactions prevent many patients from benefiting from it. In recent years, combination trials have become the main direction of PD-1/PD-L1 antibodies development. Here, we summarized PD-L1 biofunctions and key roles in various cancers along with the development of PD-L1 inhibitors. The regulators that are involved in controlling PD-L1 expression including post-translational modification, mRNA level regulation as well as degradation and exosome secretory pathway of PD-L1 were focused. This systematic summary may provide comprehensive understanding of different regulations on PD-L1 as well as a broad prospect for the search of the important regulator of PD-L1. The regulatory factors of PD-L1 can be potential targets for immunotherapy and increase strategies of immunotherapy in combination.
Assuntos
Antígeno B7-H1 , Neoplasias , Antígeno B7-H1/metabolismo , Humanos , Imunoterapia/métodos , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
BACKGROUND: The World Health Organization (WHO) has proposed healthy aging framework, supposing that intrinsic capacity (IC), environment and their interaction may have influence on functional ability (FA). It was still unclear how the IC level and age-friendly living environment impact on FA. This study aims to confirm the relationship between the IC level and age-friendly living environment with FA, especially in older adults with low IC. METHODS: Four hundred eighty-five community-dwelling residents aged ≥ 60 years were enrolled. IC constructed by locomotion, cognition, psychological, vitality, and sensory domains was assessed using full assessment tools recommended by WHO. Age-friendly living environment was measured with 12 questions adapted from the spatial indicators framework of age-friendly cities. FA was assessed using activities of daily living (ADL) and one question about mobile payment ability. Multivariate logistic regression was used to explore the association between IC, environment and FA. The influence of the environment on electronic payment and ADL under the IC layer was assessed. RESULTS: Of 485 respondents, 89 (18.4%) had ADL impairment, and 166 (34.2%) had mobile payment function impairment. Limited IC (odds ratio [OR] = 0.783, 95% confidence interval [CI] = 0.621-0.988) and poor environment (OR = 0.839, 95% CI = 0.733-0.960) were associated with mobile payment ability impairment. Our results suggested that a supportive age-friendly living environment influenced FA was more prominent in older adults with poor IC (OR = 0.650, 95% CI = 0.491-0.861). CONCLUSIONS: Our results confirmed IC and the environment had an impact on mobile payment ability. The relationship between environment and FA showed differences according to IC level. These findings suggest that an age-friendly living environment is important to maintain and enhance elders' FA, especially in those with poor IC.
Assuntos
Atividades Cotidianas , Envelhecimento Saudável , Humanos , Idoso , Vida Independente , Estudos Transversais , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
Perfluoroalkyl substances (PFASs) are a classic environmental endocrine disruptor with carcinogenic risk. Epidemiological studies have shown that PFASs contamination is associated with breast cancer development, but the mechanism remains largely unknown. This study first obtained complex biological information about PFASs-induced breast cancer through the comparative toxicogenomics database (CTD). The Protein-Protein Interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were utilized to investigate molecular pathways. The ESR1 and GPER expression levels at different pathological stages and the prognosis of Breast Cancer patients were confirmed using the Cancer Genome Atlas (TCGA) database. Furthermore, we verified this by cellular experiments and the results showed breast cancer cell migration and invasion were promoted by PFOA. Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression.
Assuntos
Neoplasias da Mama , Fluorocarbonos , Humanos , Feminino , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células , Estrogênios/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Fluorocarbonos/toxicidade , Linhagem Celular TumoralRESUMO
AIMS: The aim of this study was to assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolaemia (FH). METHODS AND RESULTS: We designed a decision analytic Markov model to compare the current standard of care for heterozygous FH diagnosis in Australia (opportunistic cholesterol screening and genetic cascade testing) with the alternate strategy of population genomic screening of adults aged 18-40 years to detect pathogenic variants in the LDLR/APOB/PCSK9 genes. We used a validated cost-adaptation method to adapt findings to eight high-income countries. The model captured coronary heart disease (CHD) morbidity/mortality over a lifetime horizon, from healthcare and societal perspectives. Risk of CHD, treatment effects, prevalence, and healthcare costs were estimated from published studies. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER), discounted 5% annually. Sensitivity analyses were undertaken to explore the impact of key input parameters on the robustness of the model. Over the lifetime of the population (4 167 768 men; 4 129 961 women), the model estimated a gain of 33 488years of life lived and 51 790 QALYs due to CHD prevention. Population genomic screening for FH would be cost-effective from a healthcare perspective if the per-test cost was ≤AU$250, yielding an ICER of Assuntos
Doença das Coronárias
, Hiperlipoproteinemia Tipo II
, Análise Custo-Benefício
, Feminino
, Humanos
, Hiperlipoproteinemia Tipo II/diagnóstico
, Hiperlipoproteinemia Tipo II/epidemiologia
, Hiperlipoproteinemia Tipo II/genética
, Masculino
, Metagenômica
, Pró-Proteína Convertase 9
, Anos de Vida Ajustados por Qualidade de Vida
, Adulto Jovem
RESUMO
BACKGROUND: Familial hypercholesterolaemia (FH) is associated with a significant increase in the risk of premature coronary artery disease. Pregnancy is likely a vulnerable time for atherosclerosis progression, with a physiological rise in low-density lipoprotein cholesterol (LDL-C) further exaggerated by the discontinuation of cholesterol-lowering therapy. MATERIALS AND METHODS: A retrospective review was undertaken of 13 women with familial hypercholesterolemia who were managed during pregnancy between 2007 and 2021 by a multidisciplinary team following individualised risk assessment. RESULTS: Overall, pregnancy outcomes were good, with no maternal or fetal complications, including congenital abnormalities, maternal cardiac events or hypertensive complications. Loss of statin treatment time ranged between 12 months and 3.5 years resulting from the accumulation of the preconception, pregnancy and lactation periods and was magnified in women having more than one pregnancy. Of seven women treated with cholestyramine, one developed abnormal liver function with an elevated international normalisation ratio which was corrected with vitamin K. CONCLUSION: Pregnancy is associated with prolonged cessation of cholesterol-lowering therapy, a concern with respect to the risk of coronary artery disease in FH. Continuation of statin therapy up to conception and even during pregnancy in patients at higher risk of cardiovascular disease may be justified, especially with increasing evidence supporting the safety of statin therapy during pregnancy. However, more long-term maternal and fetal data are required for the routine use of statins during pregnancy. Guideline-informed models of care covering family planning and pregnancy should be implemented for all women with FH.
Assuntos
Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Feminino , Humanos , Gravidez , Austrália/epidemiologia , Colesterol , Doença da Artéria Coronariana/etiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/tratamento farmacológicoRESUMO
BACKGROUND: Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature cardiovascular morbidity and mortality. High-level evidence and clinical practice guidelines support preventative care for people with FH. However, it is estimated that less than 10% of people at risk of FH have been detected using any approach across Australian health settings. The aim of this study was to identify the implementation barriers to and facilitators of the detection of FH in Australia. METHODS: Four, 2-hour virtual focus groups were facilitated by implementation scientists and a clinicians as part of the 2021 Australasian FH Summit. Template analysis was used to identify themes. RESULTS: There were 28 workshop attendees across four groups (n=6-8 each), yielding 13 barriers and 10 facilitators across three themes: (1) patient related, (2) provider related, and (3) system related. A "lack of care pathways" and "upskilling clinicians in identifying and diagnosing FH" were the most interconnected barriers and facilitators for the detection of FH. CONCLUSIONS: The relationships between barriers and facilitators across the patient, provider, and system themes indicates that a comprehensive implementation strategy is needed to address these different levels. Future research is underway to develop a model for implementing the Australian FH guidelines into practice.