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PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.
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Neoplasias da Mama , Mastectomia , Terapia Neoadjuvante , Estadiamento de Neoplasias , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Adulto , Idoso , Estudos Retrospectivos , Radioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Metástase Linfática , Recidiva Local de Neoplasia/patologiaRESUMO
BACKGROUND AND AIMS: Alcohol-perturbed gut immune homeostasis is associated with the development of alcoholic liver disease (ALD). However, the role of intestinal dendritic cells (DCs) in ALD progression is still unknown. This study aimed to investigate the cellular and molecular mechanisms through which intestinal DCs respond to alcohol exposure and contribute to the pathogenesis of ALD. APPROACH AND RESULTS: After 8 weeks of alcohol consumption, the number of basic leucine zipper transcription factor ATF-like 3 ( Batf3 )-dependent conventional type 1 DCs (cDC1s) was dramatically decreased in the intestine but not the liver. cDC1 deficient Batf3 knockout mice along with wild-type mice were subjected to chronic-binge ethanol feeding to determine the role of intestinal cDC1s reduction in ALD. cDC1s deficiency exacerbated alcohol-induced gut barrier disruption, bacterial endotoxin translocation into the circulation, and liver injury. Adoptive transfer of cDC1s to alcohol-fed mice ameliorated alcohol-mediated gut barrier dysfunction and liver injury. Further studies revealed that intestinal cDC1s serve as a positive regulator of Akkermansia muciniphila ( A. muciniphila ). Oral administration of A. muciniphila markedly reversed alcoholic steatohepatitis in mice. Mechanistic studies revealed that cDC1s depletion exacerbated alcohol-downregulated intestinal antimicrobial peptides which play a crucial role in maintaining A. muciniphila abundance, by disrupting the IL-12-interferon gamma signaling pathway. Lastly, we identified that intestinal cDC1s were required for the protective role of Lactobacillus reuteri in alcoholic steatohepatitis. CONCLUSIONS: This study demonstrated that cDC1s protect alcohol-induced liver injury by maintaining A. muciniphila abundance in mice. Targeting cDC1s may serve as a promising therapeutic approach for treating ALD.
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Fígado Gorduroso Alcoólico , Hepatopatias Alcoólicas , Camundongos , Animais , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/patologia , Etanol , Verrucomicrobia , Células Dendríticas/metabolismo , Endotoxinas , Camundongos Endogâmicos C57BLRESUMO
BACKGROUNDS: Insulin resistance (IR) plays a vital role in the pathogenesis of the metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether triglyceride-glucose (TyG) related parameters, which serve as useful biomarkers to assess IR, have prognostic effects on mortality outcomes of MASLD. METHODS: Participants in the National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2018 years were included. TyG and its related parameters [TyG-waist circumference (TyG-WC) and TyG-waist to height ratio (TyG-WHtR)] were calculated. Kaplan-Meier curves, Cox regression analysis, and restricted cubic splines (RCS) were conducted to evaluate the association between TyG-related indices with the all-cause and cardiovascular mortality of adults with MASLD. The concordance index (C-index) was used to evaluate the prediction accuracy of TyG-related indices. RESULTS: A total of 8208 adults (4209 men and 3999 women, median age 49.00 years) with MASLD were included in this study. Multivariate-adjusted Cox regression analysis revealed that high quartile levels of TyG-related indices were significantly associated with the all-cause mortality of participants with MASLD [TyGadjusted hazard ratio (aHR) = 1.25, 95% confidence interval (CI) 1.05-1.50, P = 0.014; TyG-WCaHR for all-cause mortality = 1.28, 95% CI 1.07-1.52, P = 0.006; TyG-WHtRaHR for all-cause mortality = 1.50, 95% CI 1.25-1.80, P < 0.001; TyG-WCaHR for cardiovascular mortality = 1.81, 95% CI 1.28-2.55, P = 0.001; TyG-WHtRaHR for cardiovascular mortality = 2.22, 95% CI 1.55-3.17, P < 0.001]. The C-index of TyG-related indices for predicting all-cause mortality was 0.563 for the TyG index, 0.579 for the TyG-WC index, and 0.585 for the TyG-WHtR index, respectively. Regarding cardiovascular mortality, the C-index was 0.561 for the TyG index, 0.607 for the TyG-WC index, and 0.615 for the TyG-WHtR index, respectively. Nonlinear trends were observed between TyG and TyG-WC indices with all-cause mortality of MASLD (P < 0.001 and = 0.012, respectively). A non-linear relationship was observed between the TyG index and cardiovascular mortality of MASLD (P = 0.025). Subgroup analysis suggested that adults aged < 65 years old and those without comorbidities were more sensitive to the mortality prediction of TyG-related indices. CONCLUSION: Findings of this study highlight the predictive value of TyG-related indices, especially the TyG-WHtR index, in the mortality outcomes of adults with MASLD. TyG-related indices would be surrogate biomarkers for the clinical management of MASLD.
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Biomarcadores , Glicemia , Doenças Cardiovasculares , Causas de Morte , Resistência à Insulina , Inquéritos Nutricionais , Triglicerídeos , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Prognóstico , Medição de Risco , Biomarcadores/sangue , Estados Unidos/epidemiologia , Glicemia/metabolismo , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Adulto , Fatores de Tempo , Bases de Dados Factuais , Idoso , Fatores de Risco , Hepatopatia Gordurosa não Alcoólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Estudos Transversais , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: Triglyceride-glucose (TyG) index has been determined to play a role in the onset of metabolic syndrome (MetS). Whether the TyG index and TyG with the combination of obesity indicators are associated with the clinical outcomes of the MetS population remains unknown. METHOD: Participants were extracted from multiple cycles of the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018 years. Three indicators were constructed including TyG index, TyG combining with waist circumference (TyG-WC), and TyG combining with waist-to-height ratio (TyG-WHtR). The MetS was defined according to the National Cholesterol Education Program (NCPE) Adult Treatment Panel III. Kaplan-Meier (KM) curves, restricted cubic splines (RCS), and the Cox proportional hazard model were used to evaluate the associations between TyG-related indices and mortality of the MetS population. The sensitive analyses were performed to check the robustness of the main findings. RESULTS: There were 10,734 participants with MetS included in this study, with 5,570 females and 5,164 males. The median age of the study population was 59 years old. The multivariate Cox regression analyses showed high levels of TyG-related indices were significantly associated with the all-cause mortality of MetS population [TyG index: adjustedhazard ratio (aHR): 1.36, 95%confidence interval (CI): 1.18-1.56, p < 0.001; TyG-WHtR index: aHR = 1.29, 95%CI: 1.13-1.47, p < 0.001]. Meanwhile, the TyG-WC and TyG-WHtR index were associated with cardiovascular mortality of the MetS population (TyG-WC: aHR = 1.45, 95%CI: 1.13-1.85, p = 0.004; TyG-WHtR: aHR = 1.50 95%CI: 1.17-1.92, p = 0.002). Three TyG-related indices showed consistent significant correlations with diabetes mortality (TyG: aHR = 4.06, 95%CI: 2.81-5.87, p < 0.001; TyG-WC: aHR = 2.55, 95%CI: 1.82-3.58, p < 0.001; TyG-WHtR: aHR = 2.53 95%CI: 1.81-3.54, p < 0.001). The RCS curves showed a non-linear trend between TyG and TyG-WC indices with all-cause mortality (p for nonlinearity = 0.004 and 0.001, respectively). The sensitive analyses supported the positive correlations between TyG-related indices with mortality of the MetS population. CONCLUSION: Our study highlights the clinical value of TyG-related indices in predicting the survival of the MetS population. TyG-related indices would be the surrogate biomarkers for the follow-up of the MetS population.
Assuntos
Biomarcadores , Glicemia , Causas de Morte , Síndrome Metabólica , Inquéritos Nutricionais , Triglicerídeos , Circunferência da Cintura , Humanos , Síndrome Metabólica/sangue , Síndrome Metabólica/mortalidade , Síndrome Metabólica/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Glicemia/metabolismo , Medição de Risco , Biomarcadores/sangue , Idoso , Prognóstico , Adulto , Fatores de Tempo , Estados Unidos/epidemiologia , Razão Cintura-Estatura , Valor Preditivo dos Testes , Fatores de Risco , Fatores de Risco Cardiometabólico , Estudos TransversaisRESUMO
BACKGROUND: Depression in late life has been associated with reduced quality of life and increased mortality. Whether the chronic fine particular matter (PM2.5) and its components exposure are contributed to the older depression symptoms remains unclear. METHOD: Middle-aged and older adults (>45 years) were selected from the China Health and Retirement Longitudinal Study during the four waves of interviews. The concentrations of PM2.5 and its major constituents were calculated using near real-time data at a spatial resolution of 10â¯km during the study period. The depressive symptom was evaluated by the Depression Center for Epidemiologic Studies Depression (CES-D)-10 score. The fix-effect model was applied to evaluate the association between PM2.5 and its major constituents with depressive symptoms. Three three-step methods were used to explore the modification role of sleep duration against the depressive symptoms caused by PM2.5 exposure. RESULTS: In our study, a total of 52,683 observations of 16,681 middle-aged and older adults were assessed. Each interquartile range (IQR) level of PM2.5 concentration exposure was longitudinally associated with a 2.6â¯% (95â¯% confidence interval [CI]: 1.3â¯%, 4.0â¯%) increase in the depression CES-D-10 score. Regarding the major components of PM2.5, OM, NO3-, and NH4+ showed the leading toxicity effects, which could increase the depression CES-D-10 score by 2.2â¯% (95â¯%CI: 1.0â¯%, 3.4â¯%), 2.2â¯% (0.6â¯%, 3.9â¯%), and 2.0â¯% (95â¯%CI: 0.6â¯%, 3.4â¯%) correspondingly. Besides, males were more susceptible to the worse depressive symptoms caused by PM2.5 and its major components exposure than female subpopulations. Shortened sleep duration might be the mediator of PM2.5-associated depressive symptoms. CONCLUSION: Our results suggest that long-term exposure to PM2.5 and its major components were associated with an increased risk for depressive symptoms in middle-aged and older adults. Reducing the leading components of PM2.5 may cost-effectively alleviate the disease burden of depression and promote healthy longevity in heavy pollutant countries.
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Poluentes Atmosféricos , Depressão , Exposição Ambiental , Material Particulado , Humanos , Material Particulado/análise , Masculino , Pessoa de Meia-Idade , Feminino , Depressão/epidemiologia , Depressão/psicologia , Idoso , China/epidemiologia , Poluentes Atmosféricos/análise , Estudos Longitudinais , Exposição Ambiental/estatística & dados numéricos , Estudos de Coortes , Poluição do Ar/efeitos adversos , Poluição do Ar/estatística & dados numéricosRESUMO
It is well known that exosomes could serve as anti-microbial immune factors in animals. However, despite growing evidences have shown that the homeostasis of the hemolymph microbiota was vital for immune regulation in crustaceans, the relationship between exosomes and hemolymph microbiota homeostasis during pathogenic bacteria infection has not been addressed. Here, we reported that exosomes released from Vibrio parahaemolyticus-infected mud crabs (Scylla paramamosain) could help to maintain the homeostasis of hemolymph microbiota and have a protective effect on the mortality of the host during the infection process. We further confirmed that miR-224 was densely packaged in these exosomes, resulting in the suppression of HSP70 and disruption of the HSP70-TRAF6 complex, then the released TRAF6 further interacted with Ecsit to regulate the production of mitochondrial ROS (mROS) and the expression of Anti-lipopolysaccharide factors (ALFs) in recipient hemocytes, which eventually affected hemolymph microbiota homeostasis in response to the pathogenic bacteria infection in mud crab. To the best of our knowledge, this is the first document that reports the role of exosome in the hemolymph microbiota homeostasis modulation during pathogen infection, which reveals the crosstalk between exosomal miRNAs and innate immune response in crustaceans.
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Proteínas de Artrópodes/metabolismo , Braquiúros/imunologia , Exossomos/genética , Hemolinfa/imunologia , Imunidade Inata/imunologia , MicroRNAs/genética , Vibrioses/imunologia , Animais , Proteínas de Artrópodes/genética , Braquiúros/microbiologia , Perfilação da Expressão Gênica , Hemócitos/imunologia , Hemócitos/metabolismo , Hemócitos/microbiologia , Hemolinfa/metabolismo , Hemolinfa/microbiologia , Homeostase , Microbiota , Filogenia , Vibrioses/microbiologia , Vibrio parahaemolyticus/fisiologiaRESUMO
Long-lived emissive nucleic acid probes are widely used in biochemical analysis due to their programmable structures, high signal-to-background ratio, and high sensitivity. Homogeneous detection based on long-lived emissive nucleic acid probes is often achieved through Förster resonance energy transfer (FRET), which suffers from the limitation of a narrow effective distance range. Herein, a new strategy of accessing nucleic acid hybridization-responsive luminescent probes is presented. The photoluminescence (PL) of a Lumi4-Tb complex internally modified with DNA is switched on by nucleic acid hybridization, after which the PL is increased up to 20 times. PL lifetime analysis revealed a possible mechanism of luminescence enhancement. Due to the flexibility of single-stranded nucleic acid chains, the bases and phosphate groups can coordinate with the Tb(III), which reduces the stability of the Tb complex and results in weak PL. After hybridization, the rigid double helix structure suppresses the coordination between Tb(III) and the bases or phosphate groups, causing luminescence enhancement. As the DNA sequence can be freely designed, an array of probes for different DNA or RNA targets can be created with the same Tb complex. Moreover, the novel probe design can afford pM detection limits of DNA or RNA without any nucleic acid amplification and exhibits great potential for nucleic acid detection in clinical diagnosis.
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Luminescência , Ácidos Nucleicos , RNA , Hibridização de Ácido Nucleico/métodos , DNA/química , Sondas de Ácido Nucleico , FosfatosRESUMO
BACKGROUND AND AIMS: Microbial dysbiosis is associated with alcohol-related hepatitis (AH), with the mechanisms yet to be elucidated. The present study aimed to determine the effects of alcohol and zinc deficiency on Paneth cell (PC) antimicrobial peptides, α-defensins, and to define the link between PC dysfunction and AH. APPROACH AND RESULTS: Translocation of pathogen-associated molecular patterns (PAMPs) was determined in patients with severe AH and in a mouse model of alcoholic steatohepatitis. Microbial composition and PC function were examined in mice. The link between α-defensin dysfunction and AH was investigated in α-defensin-deficient mice. Synthetic human α-defensin 5 (HD5) was orally given to alcohol-fed mice to test the therapeutic potential. The role of zinc deficiency in α-defensin was evaluated in acute and chronic mouse models of zinc deprivation. Hepatic inflammation was associated with PAMP translocation and lipocalin-2 (LCN2) and chemokine (C-X-C motif) ligand 1 (CXCL1) elevation in patients with AH. Antibiotic treatment, lipopolysaccharide injection to mice, and in vitro experiments showed that PAMPs, but not alcohol, directly induced LCN2 and CXCL1. Chronic alcohol feeding caused systemic dysbiosis and PC α-defensin reduction in mice. Knockout of functional α-defensins synergistically affected alcohol-perturbed bacterial composition and the gut barrier and exaggerated PAMP translocation and liver damage. Administration of HD5 effectively altered cecal microbial composition, especially increased Akkermansia muciniphila, and reversed the alcohol-induced deleterious effects. Zinc-regulated PC homeostasis and α-defensins function at multiple levels, and dietary zinc deficiency exaggerated the deleterious effect of alcohol on PC bactericidal activity. CONCLUSIONS: Taken together, the study suggests that alcohol-induced PC α-defensin dysfunction is mediated by zinc deficiency and involved in the pathogenesis of AH. HD5 administration may represent a promising therapeutic approach for treating AH.
Assuntos
Translocação Bacteriana , Fígado Gorduroso Alcoólico/microbiologia , Fígado Gorduroso Alcoólico/fisiopatologia , Microbiota/fisiologia , Celulas de Paneth/fisiologia , Zinco/deficiência , alfa-Defensinas/deficiência , Animais , Modelos Animais de Doenças , Disbiose/etiologia , Etanol/toxicidade , Fígado Gorduroso Alcoólico/complicações , Humanos , Metaloproteinase 7 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/efeitos dos fármacosRESUMO
Although alkaline earth metal cations play an important role in our daily life, little attention has been paid to the field of fast quantitative analysis of their content due to a lack of satisfactory precision and a fast and convenient means of detection. In this study, we have designed a set of molecular tweezers based on the calix[4]arene chemosensor L, which was found to exhibit high selectivity and sensitivity toward Ca2+, Sr2+, and Ba2+ (by UV-vis and fluorescence methods) with low detection limits of the order of 10-7 to 10-8 M and high association constants (of the order of 106). More significantly, sensor L not only can recognize Ca2+, Sr2+, and Ba2+ but also can further discriminate between these three cations via the differing red shifts in their UV-vis spectra (560 nm for L·Ca2+, 570 nm for L·Sr2+, and 580 nm for L·Ba2+ complex) which is attributed to their different atomic radii. A rare synergistic effect for the recognition mechanism has been demonstrated by 1H NMR spectroscopic titration. Sensor L constructed a high shielding field by the cooperation of Tris with alkaline earth metal ion after complex. Additionally, the presence of acetoxymethyl group in sensor L results in enhancement of cell permeability, and as a consequence, sensor L exhibited excellent sensing and imaging (in vivo) in living cells and in zebrafish.
Assuntos
Bário/análise , Cálcio/análise , Calixarenos/química , Metais Alcalinoterrosos/química , Imagem Óptica , Compostos Organometálicos/química , Fenóis/química , Estrôncio/análise , Animais , Sobrevivência Celular , Células HeLa , Humanos , Compostos Organometálicos/síntese química , Células Tumorais Cultivadas , Peixe-ZebraRESUMO
Clenbuterol (CLEN) is a sympathomimetic amine used as a decongestant and bronchodilator while treating breathing disorders. It is also used in food-producing animals as it improves the rate of red meat production. However, it is prohibited in many countries nowadays due to human health and safety concerns. Unfortunately, the illegal use of CLEN is still rampant. Thus, monitoring it in food and livestock is important. Here, we report a novel murine antibody and an open sandwich enzyme linked immunosorbent assay (OS-ELISA) to detect CLEN based on antigen-antibody reactions. The genes of antibody variable regions in mice immunized with CLEN conjugated with bovine serum albumin were cloned into a phagemid (pDong1/Fab) to construct a phage-display antibody library, from which a novel antibody, A12, was selected. Then, an OS-ELISA was developed to detect CLEN using separated variable regions of the A12 antibody. The limit of detection of the assay was found to be 8â¯ng/mL, which was useful for monitoring CLEN usage.
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Clembuterol/análise , Ensaio de Imunoadsorção Enzimática , Animais , Anticorpos , Humanos , Imunoensaio , Camundongos , Soroalbumina BovinaRESUMO
For achieving the power maximum transmission, the electrical impedance matching (EIM) for piezoelectric ultrasonic transducers is highly required. In this paper, the effect of EIM networks on the electromechanical characteristics of sandwiched piezoelectric ultrasonic transducers is investigated in time and frequency domains, based on the PSpice model of single sandwiched piezoelectric ultrasonic transducer. The above-mentioned EIM networks include, series capacitance and parallel inductance (I type) and series inductance and parallel capacitance (II type). It is shown that when I and II type EIM networks are used, the resonance and anti-resonance frequencies and the received signal tailing are decreased; II type makes the electro-acoustic power ratio and the signal tailing smaller whereas it makes the electro-acoustic gain ratio larger at resonance frequency. In addition, I type makes the effective electromechanical coupling coefficient increase and II type makes it decrease; II type make the power spectral density at resonance frequency more dramatically increased. Specially, the electro-acoustic power ratio has maximum value near anti-resonance frequency, while the electro-acoustic gain ratio has maximum value near resonance frequency. It can be found that the theoretically analyzed results have good consistency with the measured ones.
RESUMO
Sandwiched piezoelectric transducers are widely used, especially in high power applications. For more convenient analysis and design, a PSpice lossy model of sandwiched piezoelectric ultrasonic transducers in longitudinal vibration is proposed by means of the one-dimensional wave and transmission line theories. With the proposed model, the resonance and antiresonance frequencies are obtained, and it is shown that the simulations and measurements have good consistency. For the purpose of further verification the accuracy and application of the PSpice model, a pitch-catch setup and an experimental platform are built. They include two sandwiched piezoelectric ultrasonic transducers and two aluminum cylinders whose lengths are 20 mm and 100 mm respectively. Based on this pitch-catch setup, the impedance and transient analysis are performed. Compared with the measured results, it is shown that the simulated results have good consistency. In addition, the conclusion can be drawn that the optimal excitation frequency for the pitch-catch setup is not necessarily the resonance frequency of ultrasonic transducers, because the resonance frequency is obtained under no load. The proposed PSpice model of the sandwiched piezoelectric transducer is more conveniently applied to combine with other circuits such as driving circuits, filters, amplifiers, and so on.
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BACKGROUND: Few studies on cluster-based synthetic effects of multiple risk factors for birth defects have been reported. The present study aimed to identify maternal exposure clusters, explore the association between clusters of risk factors and birth defects, and further screen women with high risk for birth defects among expectant mothers. METHODS: Data were drawn from a large-scale, retrospective epidemiological survey of birth defects from 2006 to 2008 in six counties of Shanxi Province, China, using a three-level stratified random cluster sampling technique. Overall risk factors were extracted using eight synthetic variables summed and examined as a total risk factor score: maternal delivery age, genetic factors, medical history, nutrition and folic acid deficiency, maternal illness in pregnancy, drug use in pregnancy, environmental risk factors in pregnancy, and unhealthy maternal lifestyle in pregnancy. Latent class cluster analysis was used to identify maternal exposure clusters based on these synthetic variables. Adjusted odds ratios (AOR) were used to explore associations between clusters and birth defects, after adjusting for confounding variables using logistic regression. RESULTS: Three latent maternal exposure clusters were identified: a high-risk (6.15%), a moderate-risk (22.39%), and a low-risk (71.46%) cluster. The prevalence of birth defects was 14.08%, 0.85%, and 0.52% for the high-, middle- and low-risk clusters respectively. After adjusting for maternal demographic variables, women in the high-risk cluster were nearly 31 times (AOR: 30.61, 95% CI: [24.87, 37.67]) more likely to have an infant with birth defects than low-risk women. CONCLUSIONS: A high-risk group of mothers in an area with a high risk for birth defects were screened in our study. Targeted interventions should be conducted with women of reproductive age to improve neonatal birth outcomes in areas with a high risk of birth defects.
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Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Deficiência de Ácido Fólico , Idade Materna , Exposição Materna , Complicações na Gravidez , Adulto , China , Análise por Conglomerados , Feminino , Humanos , Lactente , Estilo de Vida , Modelos Logísticos , Programas de Rastreamento , Razão de Chances , Gravidez , Estudos Retrospectivos , Fatores de RiscoRESUMO
The discovery of induced pluripotent stem (iPS) cells provides not only new approaches for cell replacement therapy, but also new ways for drug screening. However, the undefined mechanism and relatively low efficiency of reprogramming have limited the application of iPS cells. In an attempt to further optimize the reprogramming condition, we unexpectedly observed that removing c-Myc from the Oct-4, Sox-2, Klf-4, and c-Myc (OSKM) combination greatly enhanced the generation of iPS cells. The iPS cells generated without c-Myc attained salient pluripotent characteristics and were capable of producing full-term mice through tetraploid complementation. We observed that forced expression of c-Myc induced the expression of many genes involved in cell cycle control and a hyperproliferation state of the mouse embryonic fibroblasts during the early stage of reprogramming. This enhanced proliferation of mouse embryonic fibroblasts correlated negatively to the overall reprogramming efficiency. By applying small molecule inhibitors of cell proliferation at the early stage of reprogramming, we were able to improve the efficiency of iPS cell generation mediated by OSKM. Our data demonstrated that the proliferation rate of the somatic cell plays critical roles in reprogramming. Slowing down the proliferation of the original cells might be beneficial to the induction of iPS cells.
Assuntos
Proteínas Proto-Oncogênicas c-myc/metabolismo , Células-Tronco/citologia , Fosfatase Alcalina/metabolismo , Animais , Ciclo Celular , Morte Celular , Proliferação de Células , Feminino , Fibroblastos/citologia , Teste de Complementação Genética , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fator 3 de Transcrição de Octâmero/metabolismo , Ploidias , Reação em Cadeia da Polimerase em Tempo Real/métodos , Retroviridae/genética , Fatores de Transcrição SOXB1/metabolismoRESUMO
We report the isolation and draft genome sequence of Ruoffia tabacinasalis, a novel member of the bovine nasal microbiota. The genome, which is estimated to be 90.5% complete, is composed of one contig comprising 2,363,349 bp with a GC content of 36.66%.
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BACKGROUND: Limited studies have explored the joint effect of physical activity (PA) and dietary quality (DQ) on the mortality outcomes of the cancer population. We aim to investigate the separate and joint prognostic effect of PA and DQ on the survival of US cancer survivors. METHODS: Data of cancer survivors (n=3,007, representing 22 million cancer survivors) were from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018. PA was assessed using the self-reported Global Physical Activity Questionnaire (GPAQ) and DQ was evaluated through the Health Eating Index-2015 (HEI-2015). Kaplan-Meier (KM) curves and the Cox proportional hazard model were used to evaluate the associations between separate and joint prognostic effects of PA and DQ with mortality outcomes among cancer survivors. RESULTS: In the joint analyses, cancer survivors with sufficiently active PA (≥600 MET-min/week) and qualified DQ (≥60) presented reduced risks of all-cause mortality (HR 0.45, 95% CI 0.35-0.59) as compared with each lifestyle intervention separately. Meanwhile, the joint effects of either insufficiently or sufficiently active PA (>0 MET-min/week) and qualified DQ (≥60) were associated with lower risks for cancer (HR 0.60, 95% CI 0.40-0.90) and non-cancer mortality (HR 0.43, 95% CI 0.32-0.59). CONCLUSIONS: Our study highlights the combination of active PA and qualified DQ was strongly associated with reduced mortality risk of cancer survivors. Our findings might help to refine the lifestyle intervention recommendations for this population.
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BACKGROUND: Treatment delays have frequently been observed in cancer patients. Whether the treatment delays would impair the survival of patients with nasopharyngeal carcinoma (NPC) is still unclear. METHODS: The data were derived from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Patients were divided into groups of timely treatment (<1 month), intermediate delay (1 and 2 months), and long delay (3-6 months). The influence of different treatment delay intervals on long-term survival was evaluated by multivariate Cox regression analysis. RESULTS: In total, 2,048 patients with NPC were included in our study. There were 551 patients in the early stage (I, II stage: 26.9 %) and 1,497 patients in the advanced stage (III, IV stage: 73.1 %). No significant difference in overall survival (OS) or cancer-specific survival (CSS) was observed among the groups with various treatment delay intervals (p = 0.48 in OS and p = 0.43 in CSS, respectively). However, upon adjusting for covariates, a significantly improved OS probability emerged in patients with intermediate treatment delays compared to those who received timely interventions in both the entire study population (adjustedHazard Ratio (aHR)=0.86, 95 % CI: 0.74-0.99, p = 0.043) and the subgroup with advanced stage (aHR=0.85, 95 % CI: 0.72-1.00, p = 0.049). Regarding the CSS probability, similar associations were also observed in the entire study population (aHR=0.84, 95 % CI: 0.71-0.98, p = 0.030) as well as the advanced-stage patients (aHR=0.83, 95 % CI: 0.70-0.99, p = 0.038). CONCLUSIONS: Our results revealed that treatment delays are not associated with worse survival of NPC patients. Tumor-specific characteristics and subsequent treatment modalities play more pivotal roles in the prognosis of NPC.
Assuntos
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/patologia , Estudos de Coortes , Estadiamento de Neoplasias , Prognóstico , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/terapiaRESUMO
BACKGROUND: Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. METHODS: BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. RESULTS: We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. CONCLUSIONS: Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.
Assuntos
Ácidos e Sais Biliares , Resina de Colestiramina , Hepatopatias Alcoólicas , Camundongos Endogâmicos C57BL , Animais , Camundongos , Resina de Colestiramina/farmacologia , Resina de Colestiramina/uso terapêutico , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Ácidos e Sais Biliares/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Autofagia/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
Campylobacteriosis outbreaks have previously been linked to dairy foods. While the genetic diversity of Campylobacter is well understood in high-income countries, it is largely unknown in low-income countries, such as Ethiopia. This study therefore aimed to conduct the first genomic characterization of Campylobacter isolates from the Ethiopian dairy supply chain to aid in future epidemiological studies. Fourteen C. jejuni and four C. coli isolates were whole genome sequenced using an Illumina platform. Sequences were analyzed using the bioinformatics tools in the GalaxyTrakr platform to identify MLST types, and single nucleotide polymorphisms, and infer phylogenetic relationships among the studied isolates. Assembled genomes were further screened to detect antimicrobial resistance and virulence gene sequences. Among 14 C. jejuni, ST 2084 and ST 51, which belong to the clonal complexes ST-353 and ST-443, respectively, were identified. Among the 4 sequenced C. coli isolates, two isolates belonged to ST 1628 and two to ST 830 from the clonal complex ST-828. The isolates of C. jejuni ST 2084 and ST 51 carried ß-lactam resistance gene blaOXA-605, a fluoroquinolone resistance-associated mutation T86I in the gryA gene, and a macrolide resistance-associated mutation A103V in 50S L22. Only ST 2084 isolates carried the tetracycline resistance gene tetO. Conversely, all four C. coli ST 830 and ST 1628 isolates carried tetO, but only ST 1628 isolates also carried blaOXA-605. Lastly, C. jejuni ST 2084 isolates carried a total of 89 virulence genes, and ST 51 isolates carried up to 88 virulence genes. Among C. coli, ST 830 isolates carried 71 genes involved in virulence, whereas two ST 1628 isolates carried up to 82 genes involved in virulence. Isolates from all identified STs have previously been isolated from human clinical cases, demonstrating a potential food safety concern. This finding warrants further monitoring of Campylobacter in dairy foods in Ethiopia to better understand and manage the risks associated with Campylobacter contamination and transmission.
Assuntos
Campylobacter coli , Campylobacter jejuni , Variação Genética , Filogenia , Campylobacter coli/genética , Campylobacter coli/isolamento & purificação , Campylobacter coli/efeitos dos fármacos , Campylobacter coli/patogenicidade , Campylobacter jejuni/genética , Campylobacter jejuni/isolamento & purificação , Campylobacter jejuni/patogenicidade , Etiópia/epidemiologia , Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/epidemiologia , Laticínios/microbiologia , Genoma Bacteriano/genética , Sequenciamento Completo do Genoma , Polimorfismo de Nucleotídeo Único , Microbiologia de Alimentos , Antibacterianos/farmacologia , Humanos , Tipagem de Sequências Multilocus , Virulência/genética , Farmacorresistência Bacteriana/genética , AnimaisRESUMO
Listeriosis caused by Listeria monocytogenes often poses a significant threat to vulnerable populations. Dairy products have been implicated in outbreaks of listeriosis worldwide. In Ethiopia, studies have identified Listeria spp. and L. monocytogenes in various dairy products, but the genetic diversity and phylogenetic relationships of these bacteria remain largely unknown in the low- and middle-income countries. Therefore, we conducted whole-genome sequencing on 15 L. monocytogenes and 55 L. innocua isolates obtained from different levels of the dairy supply chains across three regions in Ethiopia. Genomes were assembled and used for MLST genotyping and single nucleotide polymorphism (SNP) analysis to infer phylogenetic relationships. We identified a total of 3 L. monocytogenes (i.e., 2, 145, and 18) and 12 L. innocua (i.e., 1489, 1619, 603, 537, 1010, 3186, 492, 3007, 1087, 474, 1008, and 637) MLST sequence types among the studied isolates. Some of these sequence types showed region-specific occurrence, while others were broadly distributed across regions. Through high-quality SNP analysis, we found that among 13 L. monocytogenes identified as ST 2, 11 of them were highly similar with low genetic variation, differing by only 1 to 10 SNPs, suggesting potential selection in the dairy food supply chain. The L. innocua isolates also exhibited low intra-ST genetic variation with only 0-10 SNP differences, except for the ST 1619, which displayed a greater diversity.