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This study aims to explore: (1) the validity of post-exercise ultra-short-term heart rate variability (HRVust) after two different bouts of repeated sprint ability test (RSA), and (2) the relationship between HRVust measure and RSA performance. Twenty adolescent male futsal players voluntarily participated in this study (age: 17.65 ± 1.81 years, body height: 170.88 ± 4.98 cm, body weight: 61.78 ± 4.67 kg). The participants performed a standard RSA test (RSAstandard) and an RSA test with a 10% decrement of the best sprint time test (RSA10%decrement) on two separate occasions within a week. On both occasions, a 5-min resting electrocardiography was administered pre- and post-RSA exercise protocols. The first 30-s (HRVust30s), 60-s (HRVust60s), and 60-120-s (HRVust1-2min) were extracted and used to compare with the standard of 5-min HRV recording (HRVcriterion). The natural logarithm (ln) of the standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive normal-to-normal interval differences (RMSSD) HRV indices were utilised to establish intraclass correlation coefficient (ICC2,1), coefficient of variation (%CV), and Pearson product-moment correlation (r). Results revealed the ICC values of HRVust lnSDNN (RSAstandard = 0.77-0.88; RSA10%decrement = 0.41-0.71) and lnRMSSD (RSAstandard = 0.81-0.86; RSA10%decrement = 0.57-0.82). Furthermore, significantly positive correlations between best sprint time and post-exercise HRVust indices were found in lnSDNN (r = 0.47-0.62; p < 0.05) and lnRMSSD (r = 0.45; p < 0.05). Additionally, a large CV of lnSDNN (RSAstandard = 32%-45%; RSA10%decrement = 29%-39%), lnRMSSD (RSAstandard = 50%-66%; RSA10%decrement = 48%-52%), and ratio (RSAstandard = 45%-126%; RSA10%decrement = 27%-45%) was found after the RSA protocols. In conclusion, the number of bouts of RSA exercise potentially influences the agreement of post-exercise time-domain HRVust indices to standard HRV measure.
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Teste de Esforço , Frequência Cardíaca , Corrida , Humanos , Frequência Cardíaca/fisiologia , Masculino , Corrida/fisiologia , Adolescente , Teste de Esforço/métodos , Eletrocardiografia , Desempenho Atlético/fisiologia , Exercício Físico/fisiologiaRESUMO
High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.
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The tumor microenvironment (TME) is a highly heterogeneous ecosystem that plays critical roles in the initiation, progression, invasion, and metastasis of cancers. Extracellular vesicles (EVs), as emerging components of the host-tumor communication, are lipid-bilayer membrane structures that are secreted by most cell types into TEM and increasingly recognized as critical elements that regulate the interaction between tumor cells and their surroundings. They contain a variety of bioactive molecules, such as proteins, nucleic acids, and lipids, and participate in various pathophysiological processes while regulating intercellular communication. While many studies have focused on the EVs derived from different body fluids or cell culture supernatants, the direct isolation of tissue-derived EVs (Ti-EVs) has garnered more attention due to the advantages of tissue specificity and accurate reflection of tissue microenvironment. In this review, we summarize the protocol for isolating Ti-EVs from different tissue interstitium, discuss the role of tumor-derived and adipose tissue-derived Ti-EVs in regulating TME. In addition, we sum up the latest application of Ti-EVs as potential biomarkers for cancer diseases.
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Vesículas Extracelulares , Neoplasias , Microambiente Tumoral , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Biomarcadores Tumorais/metabolismoRESUMO
Alcohol-Related Brain Damage (ARBD) manifests predominantly as cognitive impairment and brain atrophy with the hippocampus showing particular vulnerability. Fasudil, a Rho kinase (ROCK) inhibitor, has established neuroprotective properties; however, its impact on alcohol-induced cognitive dysfunction and hippocampal structural damage remains unelucidated. This study probes Fasudil's neuroprotective potential and identifies its mechanism of action in an in vivo context. Male C57BL/6â¯J mice were exposed to 30% (v/v, 6.0â¯g/kg) ethanol by intragastric administration for four weeks. Concurrently, these mice received a co-treatment with Fasudil through intraperitoneal injections at a dosage of 10â¯mg/kg/day. Fasudil was found to mitigate alcohol-induced spatial and recognition memory deficits, which were quantified using Y maze, Morris water maze, and novel object recognition tests. Concurrently, Fasudil attenuated hippocampal structural damage prompted by chronic alcohol exposure. Notably, Fasudil moderated alcohol-induced disassembly of the actin cytoskeleton and microtubules-mechanisms central to the maintenance of hippocampal synaptic integrity. Collectively, our findings indicate that Fasudil partially reverses alcohol-induced cognitive and morphological detriments by modulating cytoskeletal dynamics, offering insights into potential therapeutic strategies for ARBD.
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1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Disfunção Cognitiva , Etanol , Hipocampo , Camundongos Endogâmicos C57BL , Microtúbulos , Fármacos Neuroprotetores , Animais , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/metabolismo , Masculino , Camundongos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Etanol/farmacologia , Fármacos Neuroprotetores/farmacologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Modelos Animais de Doenças , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Positron emission tomography (PET), a cornerstone in cancer diagnosis and treatment monitoring, relies on the enhanced uptake of fluorodeoxyglucose ([18F]FDG) by cancer cells to highlight tumors and other malignancies. While instrumental in the clinical setting, the accuracy of [18F]FDG-PET is susceptible to metabolic changes introduced by radiation therapy. Specifically, radiation induces the formation of giant cells, whose metabolic characteristics and [18F]FDG uptake patterns are not fully understood. Through a novel single-cell gamma counting methodology, we characterized the [18F]FDG uptake of giant A549 and H1299 lung cancer cells that were induced by radiation, and found it to be considerably higher than that of their non-giant counterparts. This observation was further validated in tumor-bearing mice, which similarly demonstrated increased [18F]FDG uptake in radiation-induced giant cells. These findings underscore the metabolic implications of radiation-induced giant cells, as their enhanced [18F]FDG uptake could potentially obfuscate the interpretation of [18F]FDG-PET scans in patients who have recently undergone radiation therapy.
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BACKGROUND: Together with environmental factors, intrinsic capacity (the composite of all the physical and mental capacities of an individual) has been proposed as a marker of healthy ageing. However, whether intrinsic capacity predicts major clinical outcomes is unclear. We aimed to explore the association of intrinsic capacity with functional decline and mortality in older adults. METHODS: In this systematic review and meta-analysis, we conducted a systematic search in MEDLINE (via PubMed), Scopus, and Web of Science from database inception to Feb 14, 2024, of observational longitudinal studies conducted in older adults (age ≥60 years) assessing the association of intrinsic capacity with impairment in basic activities of daily living (BADL) or instrumental activities of daily living (IADL) or risk of mortality. Estimates were extracted by two reviewers (JLS-S and W-HL) and were pooled using three-level meta-analytic models. The quality of each study was independently assessed by two authors (JLS-S and PLV) using the Newcastle-Ottawa Scale for longitudinal studies. Heterogeneity was evaluated using the I2 indicator at two levels: within-study (level 2) and between-study (level 3) variation. For associations between intrinsic capacity and IADL and BADL, we transformed data (standardised ß coefficients and odds ratios [ORs]) into Pearson product moment correlation coefficients (r) using Pearson and Digby formulas to allow comparability across studies. For associations between intrinsic capacity and risk of mortality, hazard ratios (HRs) with 95% CIs were extracted from survival analyses. This study is registered with PROSPERO, CRD42023460482. FINDINGS: We included 37 studies (206â693 participants; average age range 65·3-85·9 years) in the systematic review, of which 31 were included in the meta-analysis on the association between intrinsic capacity and outcomes; three studies (2935 participants) were included in the meta-analysis on the association between intrinsic capacity trajectories and longitudinal changes in BADL or IADL. Intrinsic capacity was inversely associated with longitudinal impairments in BADL (Pearson's r -0·12 [95% CI -0·19 to -0·04]) and IADL (-0·24 [-0·35 to -0·13]), as well as with mortality risk (hazard ratio 0·57 [95% CI 0·51 to 0·63]). An association was also found between intrinsic capacity trajectories and impairment in IADL (but not in BADL), with maintained or improved intrinsic capacity over time associated with a lower impairment in IADL (odds ratio 0·37 [95% CI 0·19 to 0·71]). There was no evidence of publication bias (Egger's test p>0·05) and there was low between-study heterogeneity (I2=18·4%), though within-study (I2=63·2%) heterogeneity was substantial. INTERPRETATION: Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults. These findings could support the use of intrinsic capacity as a marker of healthy ageing, although further research is needed to refine the structure and operationalisation of this construct across settings and populations. FUNDING: None. TRANSLATIONS: For the Spanish and French translations of the abstract see Supplementary Materials section.
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Atividades Cotidianas , Mortalidade , Humanos , Idoso , Estudos Longitudinais , Atividades Cotidianas/psicologia , Mortalidade/tendências , Avaliação Geriátrica/métodos , Idoso de 80 Anos ou mais , Feminino , MasculinoRESUMO
OBJECTIVE: After traumatic injury in pregnant women, providing timely and appropriate management for high-risk patients is crucial for both pregnant women and fetuses. This study aimed to identify risk factors that predict adverse pregnancy outcomes after traumatic injury. METHODS: A retrospective cohort study including 317 pregnant patients who experienced trauma was conducted. The collected data included general demographics, injury mechanisms and adverse pregnancy outcomes. Patients were divided into two subgroups based on the absence or presence of trauma-related adverse pregnancy outcomes. Univariate and multivariate logistic regressions were conducted to estimate the associations between clinical variables and adverse pregnancy outcomes. RESULTS: A total of 41 (12.93%) patients experienced adverse pregnancy outcomes within the first 24 h post-trauma. This study revealed that age >35 years (OR=14.995, 95% CI: 5.024-44.755, P<0.001), third trimester trauma (OR=3.878, 95% CI: 1.343-11.204, P=0.012), abdominal pain (OR=3.032, 95% CI: 1.221-7.527, P=0.017), vaginal bleeding (OR=3.226, 95% CI: 1.093-9.523, P=0.034), positive scan in focused assessment with sonography for trauma (FAST) positive (OR=8.496, 95% CI: 2.825-25.555, P<0.001), 9≤ injury severity score (ISS) <16 (OR=3.039, 95% CI: 1.046-8.835, P=0.041) and ISS≥16 (OR=5.553, 95% CI: 1.387-22.225, P=0.015) increased the probability of posttraumatic adverse pregnancy outcomes. Maternal age, gestational age at delivery, vaginal bleeding and positive FAST results were risk factors for abnormal delivery. CONCLUSION: Advanced maternal age, third trimester, and positive FAST results should alert multidisciplinary trauma teams to closely monitor patients to prevent adverse pregnancy outcomes.
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Resultado da Gravidez , Ferimentos e Lesões , Humanos , Gravidez , Feminino , Adulto , Estudos Retrospectivos , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/complicações , Fatores de Risco , Complicações na Gravidez/epidemiologiaRESUMO
BACKGROUND: Alcohol abuse, a prevalent global health issue, is associated with the onset of cognitive impairment and neurodegeneration. Actin filaments (F-actin) and microtubules (MTs) polymerized from monomeric globular actin (G-actin) and tubulin form the structural basis of the neuronal cytoskeleton. Precise regulation of the assembly and disassembly of these cytoskeletal proteins, and their dynamic balance, play a pivotal role in regulating neuronal morphology and function. Nevertheless, the effect of prolonged alcohol exposure on cytoskeleton dynamics is not fully understood. This study investigates the chronic effects of alcohol on cognitive ability, neuronal morphology and cytoskeleton dynamics in the mouse hippocampus. METHODS: Mice were provided ad libitum access to 5% (v/v) alcohol in drinking water and were intragastrically administered 30% (v/v, 6.0 g/kg/day) alcohol for six weeks during adulthood. Cognitive functions were then evaluated using the Y maze, novel object recognition and Morris water maze tests. Hippocampal histomorphology was assessed through hematoxylin-eosin (HE) and Nissl staining. The polymerized and depolymerized states of actin cytoskeleton and microtubules were separated using two commercial assay kits and quantified by Western blot analysis. RESULTS: Mice chronically exposed to alcohol exhibited significant deficits in spatial and recognition memory as evidenced by behavioral tests. Histological analysis revealed notable hippocampal damage and neuronal loss. Decreased ratios of F-actin/G-actin and MT/tubulin, along with reduced levels of polymerized F-actin and MTs, were found in the hippocampus of alcohol-treated mice. CONCLUSIONS: Our findings suggest that chronic alcohol consumption disrupted the assembly of the actin cytoskeleton and MTs in the hippocampus, potentially contributing to the cognitive deficits and pathological injury induced by chronic alcohol intoxication.
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Citoesqueleto de Actina , Etanol , Hipocampo , Microtúbulos , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Masculino , Etanol/farmacologia , Etanol/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Depressores do Sistema Nervoso Central/farmacologia , Depressores do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacosRESUMO
Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.
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Artrite Reumatoide , Isomerases de Dissulfetos de Proteínas , Fator de Transcrição STAT1 , Isomerases de Dissulfetos de Proteínas/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Humanos , Artrite Reumatoide/metabolismo , Camundongos , Animais , Fator de Transcrição STAT1/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Transporte Ativo do Núcleo Celular , Proteínas de Transporte/metabolismo , Transdução de Sinais , Proteínas de Ligação a Hormônio da Tireoide , Fatores de Transcrição NFATC/metabolismo , Ativação Linfocitária , Hormônios Tireóideos/metabolismo , Regulação da Expressão Gênica , Células Th17/metabolismo , Células Th17/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Modelos Animais de Doenças , Piruvato QuinaseRESUMO
Arterial pulse wave velocity (PWV) is recognized as a convenient method to assess peripheral vascular stiffness. This study explored the clinical characteristics of hand PWV (hPWV) and hand pulse transit time (hPTT) in healthy adults (sixty males = 42.4 ± 13.9 yrs; sixty-four females = 42.8 ± 13.9 yrs) voluntarily participated in this study. The arterial pulse waveform and the anatomical distance from the radial styloid process to the tip of the middle finger of both hands were recorded in the sitting position. The hPWV was calculated as the traversed distance divided by hPTT between those two points. Male subjects showed significantly greater hPWV, systolic blood pressure, and pulse pressure than age-matched female subjects, while the hPTT was not significantly different between genders. Multiple linear regression analysis showed that gender is a common determinant of hPWV and hPTT, and that age and heart rate (HR) were negatively correlated with hPWV and hPTT, respectively. We conclude that male subjects have greater hPWV than female subjects. Ageing is associated with decreased hPWV, while increased HR is associated with a smaller hPTT. The hPWV and hPTT might be used as non-invasive indices to characterise the ageing and arterial stiffness of peripheral blood vessels.
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Pressão Sanguínea , Mãos , Frequência Cardíaca , Análise de Onda de Pulso , Rigidez Vascular , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Mãos/fisiologia , Rigidez Vascular/fisiologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Voluntários SaudáveisRESUMO
BACKGROUND: Sarcopenia and intrinsic capacity (IC) declines pose significant challenges to healthy aging, particularly in the rapidly growing octogenarian population. This study aimed to elucidate the relationship between sarcopenia and declines in IC across multiple cohorts of community-dwelling older adults. METHODS: Data from four Taiwanese cohorts were analyzed. Sarcopenia was diagnosed based on the Asian Working Group for Sarcopenia (AWGS) 2019 criteria (algorithm 1: categorized as either having possible sarcopenia or not (robust); algorithm 2: categorized as robust, possible sarcopenia or sarcopenia). IC was operationalized using the World Health Organization's Integrated Care for Older People (ICOPE) framework (step 1 and step 2), encompassing six domains: locomotion, vitality, vision, hearing, cognition, and psychological well-being. Multivariable logistic regression models were adopted to assess the association between sarcopenia and IC decline. RESULTS: Among 599 octogenarians (median age 82.2 years, 54.8% male), the prevalence of possible sarcopenia (algorithm 1) was 64.6%. When adopting algorithm 2, the prevalence of possible sarcopenia and sarcopenia was 46,2% and 32.1%, respectively. After adjusting for covariates, participants with possible sarcopenia or sarcopenia (algorithm 2) were more likely to exhibit declines in vitality (ICOPE Step 1: possible sarcopenia aOR 3.65, sarcopenia aOR 4.74; ICOPE Step 2: possible sarcopenia aOR 5.11, sarcopenia aOR 14.77) and cognition (ICOPE Step 1: possible sarcopenia aOR 2.40, sarcopenia aOR 2.12; ICOPE Step 2: possible sarcopenia aOR 2.02, sarcopenia aOR 2.51) compared to robust individuals. CONCLUSIONS: This study underscores the robust association between sarcopenia and declines in vitality and cognition among octogenarians, highlighting the importance of sarcopenia screening and management in promoting healthy longevity in this vulnerable population.
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Cognição , Sarcopenia , Humanos , Sarcopenia/epidemiologia , Masculino , Feminino , Idoso de 80 Anos ou mais , Cognição/fisiologia , Taiwan/epidemiologia , Estudos de Coortes , Prevalência , Avaliação Geriátrica/métodos , Vida IndependenteRESUMO
AIMS: Pre-emptive prediction to avoid myelosuppression and harmful sequelae is difficult given the complex interplay among patients, drugs and treatment protocols. This study aimed to model plasma and bone marrow concentrations and the likelihood of myelotoxicity following administration of 5-fluorouracil (5-FU) by diverse intravenous (IV) bolus or continuous infusion (cIF) regimens. METHODS: Using physicochemical, in vitro and clinical data obtained from the literature consisting of various regimens and patient cohorts, a 5-FU physiologically based pharmacokinetic (PBPK) model was developed. The predicted and observed PK values were compared to assess model performance prior to examining myelotoxicity potential of IV bolus vs. cIF and DPYD wild type vs. genetic variant. RESULTS: The established model was verified by utilizing 5-FU concentration-time profiles of adequate heterogeneity contributed by 36 regimens from 15 studies. The study provided corroborative evidence to explain why cIF (vs. IV bolus) had lower myelotoxicity risk despite much higher total doses. The PBPK model was used to estimate the optimal dosage in patients heterozygous for the DPYD c.1905 + 1G > A allele and suggested that a dose reduction of at least 25% was needed (compared to the dose in wild-type subjects). CONCLUSION: A verified PBPK model was used to explain the lower myelotoxicity risk of cIF vs. IV bolus administration of 5-FU and to estimate the dose reduction needed in carriers of a DPYD variant. With appropriate data, expertise and resources, PBPK models have many potential uses in precision medicine application of oncology drugs.
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Alzheimer's disease is strongly linked to metabolic abnormalities. We aimed to distinguish amyloid-positive people who progressed to cognitive decline from those who remained cognitively intact. We performed untargeted metabolomics of blood samples from amyloid-positive individuals, before any sign of cognitive decline, to distinguish individuals who progressed to cognitive decline from those who remained cognitively intact. A plasma-derived metabolite signature was developed from Supercritical Fluid chromatography coupled with high-resolution mass spectrometry (SFC-HRMS) and nuclear magnetic resonance (NMR) metabolomics. The 2 metabolomics data sets were analyzed by Data Integration Analysis for Biomarker discovery using Latent approaches for Omics studies (DIABLO), to identify a minimum set of metabolites that could describe cognitive decline status. NMR or SFC-HRMS data alone cannot predict cognitive decline. However, among the 320 metabolites identified, a statistical method that integrated the 2 data sets enabled the identification of a minimal signature of 9 metabolites (3-hydroxybutyrate, citrate, succinate, acetone, methionine, glucose, serine, sphingomyelin d18:1/C26:0 and triglyceride C48:3) with a statistically significant ability to predict cognitive decline more than 3 years before decline. This metabolic fingerprint obtained during this exploratory study may help to predict amyloid-positive individuals who will develop cognitive decline. Due to the high prevalence of brain amyloid-positivity in older adults, identifying adults who will have cognitive decline will enable the development of personalized and early interventions.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Vida Independente , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Disfunção Cognitiva/metabolismo , Encéfalo/metabolismo , Metabolômica , Proteínas Amiloidogênicas , Peptídeos beta-Amiloides/metabolismo , BiomarcadoresRESUMO
Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Mutações Sintéticas Letais , Glicólise , CarnitinaRESUMO
Robertsonian translocations (ROBs) are the most common structural chromosomal abnormalities in the general population, with an estimated incidence rate of 1/1000 births. In this study, we retrospectively analyzed the cases of ROBs from September 2015 to August 2022 and totally identified ROB carriers from 84,569 specimens karyotyped in a single accredited laboratory in China, including 189 cases of balanced ROBs and 3 of mosaic ROBs. Microsoft Excel and descriptive statistics were used to record and analyze the collected data. The male/female ratio of ROBs is 1/1.29, with der(13;14) and der(14;21) being the main karyotypes. Among the 192 patients, 7 were lost to follow-up, 82 had given birth, and 103 were childless (such as miscarriage, fetal chromosomal abnormalities, in vitro fertilization (IVF) failure, or divorce). A total of 44 amniocenteses were performed in 42 couples; ROB cases with natural pregnancies showed that the normal karyotype and balanced ROBs of fetal accounted for 66.67% (16/24), while the results of assisted pregnancies showed 90.00% (18/20). This study represents the largest collections of ROBs in Jiangxi population and reminder that the ROB carriers can achieve the ideal outcome for pregnancy with the appropriate genetic guidance and assisted reproductive technologies (ART).
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Aborto Espontâneo , Transtornos Cromossômicos , Gravidez , Humanos , Masculino , Feminino , Estudos Retrospectivos , Translocação Genética , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/genéticaRESUMO
BACKGROUND: Individuals with X chromosomal translocations, variable phenotypes, and a high risk of live birth defects are of interest for scientific study. These characteristics are related to differential breakpoints and various types of chromosomal abnormalities. To investigate the effects of X chromosome translocation on clinical phenotype, a retrospective analysis of clinical data for patients with X chromosome translocation was conducted. Karyotype analysis plus endocrine evaluation was utilized for all the patients. Additional semen analysis and Y chromosome microdeletions were assessed in male patients. RESULTS: X chromosome translocations were detected in ten cases, including seven females and three males. Infantile uterus and no ovaries were detected in case 1 (FSH: 114 IU/L, LH: 30.90 mIU/mL, E2: < 5.00 pg/ml), and the karyotype was confirmed as 46,X,t(X;22)(q25;q11.2) in case 1. Infantile uterus and small ovaries were both visible in two cases (FSH: 34.80 IU/L, LH: 17.06 mIU/mL, E2: 15.37 pg/ml in case 2; FISH: 6.60 IU/L, LH: 1.69 mIU/mL, E2: 23.70 pg/ml in case 3). The karyotype was detected as 46,X,t(X;8)(q13;q11.2) in case 2 and 46,X,der(X)t(X;5)(q21;q31) in case 3. Normal reproductive hormone levels and fertility abilities were found for cases 4, 6 and 7. The karyotype were detected as 46,X,t(X;5)(p22.3;q22) in case 4 and 46,X,der(X)t(X;Y)(p22.3;q11.2) in cases 6 and 7. These patients exhibited unremarkable clinical manifestations but experienced a history of abnormal chromosomal pregnancy. Normal phenotype and a complex reciprocal translocation as 46,X,t(X;14;4)(q24;q22;q33) were observed in case 5 with a history of spontaneous abortions. In the three male patients, multiple semen analyses confirmed the absence of sperm. Y chromosome microdeletion and hormonal analyses were normal. The karyotypes were detected as 46,Y,t(X;8)(q26;q22), 46,Y,t(X;1)(q26;q23), 46,Y,t(X;3)(q26;p24), respectively. CONCLUSIONS: Our study provides insights into individuals with X chromosome translocations. The clinical phenotypes are variable and unpredictable due to differences in breakpoints and X chromosome inactivation (XCI) patterns. Our results suggest that physicians should focus on the characteristics of the X chromosome translocations and provide personalized clinical evaluations in genetic counselling.
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Virus-like particles (VLPs) have natural structural antigens similar to those found in viruses, making them valuable in vaccine immunization. Furthermore, VLPs have demonstrated significant potential in drug delivery, and emerged as promising vectors for transporting chemical drug, genetic drug, peptide/protein, and even nanoparticle drug. With virus-like permeability and strong retention, they can effectively target specific organs, tissues or cells, facilitating efficient intracellular drug release. Further modifications allow VLPs to transfer across various physiological barriers, thus acting the purpose of efficient drug delivery and accurate therapy. This article provides an overview of VLPs, covering their structural classifications, deliverable drugs, potential physiological barriers in drug delivery, strategies for overcoming these barriers, and future prospects.
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Vacinas de Partículas Semelhantes a Vírus , Vírus , Humanos , Preparações Farmacêuticas , Sistemas de Liberação de Medicamentos , AntígenosRESUMO
The existence of intrinsic capacity (IC) subtypes and their distinct impacts on age-related outcomes remain unexplored. This study sought to investigate IC impairment trajectories across domains and their associations with the risk of age-related outcomes, including falls, functional limitations, reduced quality of life (QoL) and mortality at 4- and 8-year follow-ups. The study sample comprised 1,782 older adults residing in the community from the Taiwan Longitudinal Study on Ageing (TLSA). Utilizing group-based multitrajectory modeling, distinct subtypes of IC decline trajectories across various domains were identified. Cox proportional hazard models and multivariable logistic regression analyses were employed to assess the associations between the identified subtypes and age-related outcomes. We identified four subtypes of IC decline: robust with mild decline (n=902), hearing loss with cognitive decline (n=197), physio-cognitive decline (PCD) with depression (n=373), and severe IC decline (n=310). Over the 4-year study period, compared to the robust with mild decline group, hearing loss with cognitive decline group exhibited a significantly higher risk of diminished QoL (OR=2.53 [1.66-3.86], p>0.01), whereas those in the PCD with depression group experienced an elevated risk of falls (OR=1.62 [1.18-2.23], p>0.01), as well as functional limitation (OR=2.61 [1.81-3.75], p>.01). Individuals in the severe IC decline group faced a substantially increased risk of all outcomes of interest. Distinct subtypes of IC decline across different domains have varying impacts on age-related outcomes, highlighting the need for a personalized approach to promote healthy ageing at the population level, while further investigation into specific pathophysiological mechanisms is warranted as well.
RESUMO
Intrinsic capacity (IC), a function-centered construct, is defined as the composite of all physical and mental capacities of an individual. IC and surrounding environmental factors determine an individual's functional ability to do what they want or feel valued. Current literature lacks evidence on how IC varies throughout adulthood. In this study, we demonstrated a method to establish age-specific and sex-specific reference centiles for IC using the Human Translational Research Cohort of the INSPIRE Platform (975 adults, aged 20-102 years, living in the southwest France, Toulouse area). IC was operationalized as the mean score of the five key domains (cognition, locomotion, psychology, sensory and vitality) and the factor score from a bifactor model, respectively. Both IC operationalizations showed higher IC levels in young and middle age and markedly lower levels after age 65 years, with greater inter-individual variation in old age than in youth. Individuals with IC ≤10th percentile tended to have high comorbidity, prefrailty/frailty, difficulties in basic and instrumental activities of daily living and falls than individuals with IC >90th percentile. These findings suggest that IC reference centiles can help monitor the functional capacity of individuals during aging, similar to tracking children's development with growth charts.