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The transcription variation, leading to various forms of transcripts and protein diversity, remains largely unexplored in triple-negative breast cancers (TNBCs). Here, we presented a comprehensive analysis of RNA splicing in breast cancer to illustrate the biological function and clinical implications of tumor-specific transcripts (TSTs) arising from these splicing junctions. Aberrant RNA splicing or TSTs were frequently harbored in TNBC and were correlated with a poor outcome. We discovered a tumor-specific splicing variant of macrophage receptor with collagenous structure-TST (MARCO-TST), which was distinguished from myeloid cell-specific wild-type MARCO. MARCO-TST expression was associated with poor outcomes in TNBC patients and could promote tumor progression in vitro and in vivo. Mechanically, MARCO-TST interacted with PLOD2 and enhanced the stability of HIF-1α, which resulted in the metabolic dysregulation of TNBC to form a hypoxic tumor microenvironment. MARCO-TST was initiated from a de novo alternative transcription initiation site that was activated by a superenhancer. Tumors with MARCO-TST expression conferred greater sensitivity to bromodomain and extraterminal protein inhibitors. This treatment strategy was further validated in patient-derived organoids. In conclusion, our results revealed the transcription variation landscape of TNBC, highlighting MARCO-TST as a crucial oncogenic transcript and therapeutic target.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Carcinogênese/genética , Splicing de RNA , Proliferação de Células , Microambiente TumoralRESUMO
Developing ruthenium-based heterogeneous catalysts with an efficient and stable interface is essential for enhanced acidic oxygen evolution reaction (OER). Herein, we report a defect-rich ultrathin boron nitride nanosheet support with relatively independent electron donor and acceptor sites, which serves as an electron reservoir and receiving station for RuO2, realizing the rapid supply and reception of electrons. Through precisely controlling the reaction interface, a low OER overpotential of only 180â mV (at 10â mA cm-2) and long-term operational stability (350â h) are achieved, suggesting potential practical applications. Inâ situ characterization and theoretical calculations have validated the existence of a localized electronic recycling between RuO2 and ultrathin BN nanosheets (BNNS). The electron-rich Ru sites accelerate the adsorption of water molecules and the dissociation of intermediates, while the interconnection between the O-terminal and B-terminal edge establishes electronic back-donation, effectively suppressing the over-oxidation of lattice oxygen. This study provides a new perspective for constructing a stable and highly active catalytic interface.
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Semihydrogenation is a crucial industrial process. Noble metals such as Pd have been extensively studied in semihydrogenation reactions, owing to their unique catalytic activity toward hydrogen activation. However, the overhydrogenation of alkenes to alkanes often happens due to the rather strong adsorption of alkenes on Pd active phases. Herein, we demonstrate that the incorporation of Pd active phases as single-atom sites in perovskite lattices such as SrTiO3 can greatly alternate the electronic structure and coordination environment of Pd active phases to facilitate the desorption of alkenes rather than further hydrogenation. Furthermore, the incorporated Pd sites can be well stabilized without sintering by a strong host-guest interaction with SrTiO3 during the activation of H species in hydrogenation reactions. As a result, the Pd incorporated SrTiO3 (Pd-SrTiO3) exhibits an excellent time-independent selectivity (> 99.9 %) and robust durability for the photocatalytic semihydrogenation of phenylacetylene to styrene. This strategy based on incorporation of active phases in perovskite lattices will have broad implications in the development of high-performance photocatalysts for selective hydrogenation reactions.
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WHAT IS KNOWN AND OBJECTIVES: Augmented renal clearance (ARC) is characterized by enhanced renal clearance, which leads to insufficient vancomycin exposure and treatment failure. In haematologic malignancy patients, determination of optimal vancomycin dosage is essential because of high stake of life-threatening bacterial infection and increased clearance. The aim of this study was to describe vancomycin pharmacokinetic parameters in haematologic malignancy with augmented renal clearance children and define the appropriate dosing regimen to achieve an AUC0-24h /MIC ≥400. METHODS: Hematologic malignancy with ARC children was enrolled in this retrospective study. The vancomycin PPK model was established by non-linear mixed-effects modelling programme. Goodness-of-fit (GOF) plots, non-parametric bootstrap, normalized prediction distribution error (NPDE) and visual predictive checks (VPCs) were carried out for internal evaluation of the final model. Monte Carlo simulation method was used to stimulate the optimal dosage regimens. RESULTS: Fifty-three patients with 106 samples were included. A one-compartment model with first-order elimination was developed, and the final model was as follows: CL (L/h) = 6.32×ï¼WT/70ï¼0.75 × e0.0467 ; V(L) = 39.6×(WT/70), where WT denotes weight (kg). The internal validation of the model showed a good prediction performance. Monte Carlo simulation results showed that when MIC was 0.5 mg/L or 1 mg/L, the recommended doses to achieve a target of AUC0-24h /MIC ≥400 were 25 to 40 and 50 to 75 mg/kg/d, respectively. With decreasing weight, the recommended dosage to achieve an AUC0-24h /MIC ≥400 increased. WHAT IS NEW AND CONCLUSION: A one-compartment vancomycin PPK model was established in haematologic malignancy with augmented renal clearance children with weight with allometric scaling as a significant covariate. When MIC was 1 mg/L, current recommended paediatric dosages were insufficient in haematologic malignancy with augmented renal clearance children and should be increased.
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Antibacterianos/administração & dosagem , Neoplasias Hematológicas/patologia , Modelos Biológicos , Vancomicina/administração & dosagem , Adolescente , Antibacterianos/farmacocinética , Área Sob a Curva , Infecções Bacterianas/tratamento farmacológico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Testes de Função Renal , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Estudos Retrospectivos , Vancomicina/farmacocinéticaRESUMO
BACKGROUND/PURPOSE: Chronic kidney disease (CKD) has become a worldwide health problem, leading to high morbidity and mortality, and non-alcoholic fatty liver disease (NAFLD) is considered a risk factor for CKD. The aim of this study was to explore the relationship between NAFLD fibrosis score (NFS) and the estimated glomerular filtration rate (eGFR), and identify possible risk factors related to the NFS among Taiwanese subjects. METHODS: Subjects were enrolled from the database of the Department of Preventive Medicine of Kaohsiung Municipal Hsiao-Kang Hospital. The eGFR was calculated according to the Taiwanese Modification of Diet in Renal Disease (TMDRD) equation, and the NFS was employed to evaluate the fibrotic level. RESULTS: In total, 11,376 subjects were enrolled in this study, with a mean age of 52.0 ± 6.81 years, including 4529 (39.8%) males. A fasting sugar level ≥100 mg/dL (OR = 1.70, 95% CI = 1.52-1.87) and an abnormal waist circumference (OR = 1.81, 95% CI = 1.65-1.99) were significant factors associated with NFS (p < 0.05). Trends of a decreasing TMDRD score and an increasing NFS with increasing age were noted (p < 0.05). The NFS was significantly negatively correlated with the TMDRD score (standard coefficients: -0.067, p < 0.001). CONCLUSION: A higher NFS is associated with an impaired eGFR in Taiwanese subjects. Controlling risk factors, especially fasting sugar level and waist circumference, may be useful in preventing NFS deterioration, which is negatively correlated with the eGFR.
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Taxa de Filtração Glomerular , Cirrose Hepática/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adulto , Biomarcadores/sangue , Feminino , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Curva ROC , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Taiwan/epidemiologiaRESUMO
γ-Glutamyl transpeptidases (γ-GTs) are members of N-terminal nucleophile hydrolase superfamily. They are synthetized as single-chain precursors, which are then cleaved to form mature enzymes. Basic aspects of autocatalytic processing of these pro-enzymes are still unknown. Here we describe the X-ray structure of the precursor mimic of Bacillus licheniformis γ-GT (BlGT), obtained by mutating catalytically important threonine to alanine (T399A-BlGT), and report results of autoprocessing of mutants of His401, Thr415, Thr417, Glu419 and Arg571. Data suggest that Thr417 is in a competent position to activate the catalytic threonine (Thr399) for nucleophilic attack of the scissile peptide bond and that Thr415 plays a major role in assisting the process. On the basis of these new structural results, a possible mechanism of autoprocessing is proposed. This mechanism, which guesses the existence of a six-membered transition state involving one carbonyl and two hydroxyl groups, is in agreement with all the available experimental data collected on γ-GTs from different species and with our new Ala-scanning mutagenesis data.
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Sequência de Aminoácidos/genética , Bacillus/enzimologia , Conformação Proteica , gama-Glutamiltransferase/química , Alanina/química , Catálise , Cristalografia por Raios X , Cinética , Mutagênese Sítio-Dirigida , gama-Glutamiltransferase/genéticaRESUMO
γ-Glutamyltranspeptidases (γ-GTs) cleave the γ-glutamyl amide bond of glutathione and transfer the released γ-glutamyl group to water (hydrolysis) or acceptor amino acids (transpeptidation). These ubiquitous enzymes play a key role in the biosynthesis and degradation of glutathione, and in xenobiotic detoxification. Here we report the 3Šresolution crystal structure of Bacillus licheniformis γ-GT (BlGT) and that of its complex with l-Glu. X-ray structures confirm that BlGT belongs to the N-terminal nucleophilic hydrolase superfamily and reveal that the protein possesses an opened active site cleft similar to that reported for the homologous enzyme from Bacillus subtilis, but different from those observed for human γ-GT and for γ-GTs from other microorganisms. Data suggest that the binding of l-Glu induces a reordering of the C-terminal tail of BlGT large subunit and allow the identification of a cluster of acid residues that are potentially involved in the recognition of a metal ion. The role of these residues on the conformational stability of BlGT has been studied by characterizing the autoprocessing, enzymatic activity, chemical and thermal denaturation of four new Ala single mutants. The results show that replacement of Asp568 with an Ala affects both the autoprocessing and structural stability of the protein.
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Bacillus/química , Proteínas de Bactérias/química , Ácido Glutâmico/química , Magnésio/química , Subunidades Proteicas/química , gama-Glutamiltransferase/química , Alanina/química , Alanina/metabolismo , Substituição de Aminoácidos , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Bacillus/enzimologia , Bacillus subtilis/química , Bacillus subtilis/enzimologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Cátions Bivalentes , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Cinética , Magnésio/metabolismo , Mutagênese Sítio-Dirigida , Estabilidade Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , gama-Glutamiltransferase/genética , gama-Glutamiltransferase/metabolismoRESUMO
γ-Glutamyl transpeptidases (γ-GTs, EC 2.3.2.2) are a class of ubiquitous enzymes which initiate the cleavage of extracellular glutathione (γ-Glu-Cys-Gly, GSH) into its constituent glutamate, cysteine, and glycine and catalyze the transfer of its γ-glutamyl group to water (hydrolysis), amino acids or small peptides (transpeptidation). These proteins utilize a conserved Thr residue to process their chains into a large and a small subunit that then form the catalytically competent enzyme. Multiple sequence alignments have shown that some bacterial γ-GTs, including that from Bacillus licheniformis (BlGT), possess an extra sequence at the C-terminal tail of the large subunit, whose role is unknown. Here, autoprocessing, structure, catalytic activity and stability against both temperature and the chemical denaturant guanidinium hydrochloride of six BlGT extra-sequence deletion mutants have been characterized by SDS-PAGE, circular dichroism, intrinsic fluorescence and homology modeling. Data suggest that the extra sequence has a crucial role in enzyme activation and structural stability. Our results assist in the development of a structure-based interpretation of the autoprocessing reaction of γ-GTs and are helpful to unveil the molecular bases of their structural stability.
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In this study, we synthesized water-soluble hyperbranched poly(amido acid)s (HBPAAs) featuring multiple terminal CO2H units and internal tertiary amino and amido moieties and then used them in conjunction with an in situ Fe2+/Fe3+ co-precipitation process to prepare organic/magnetic nanocarriers comprising uniformly small magnetic iron oxide nanoparticles (NP) incorporated within the globular HBPAAs. Transmission electron microscopy revealed that the HBPAA-γ-Fe2O3 NPs had dimensions of 6-11 nm, significantly smaller than those of the pristine γ-Fe2O3 (20-30 nm). Subsequently, we covalently immobilized a bacterial γ-glutamyltranspeptidase (BlGGT) upon the HBPAA-γ-Fe2O3 nanocarriers through the formation of amide linkages in the presence of a coupling agent. Magnetization curves of the HBPAA-γ-Fe2O3/BlGGT composites measured at 300 K suggested superparamagnetic characteristics, with a saturation magnetization of 52 emu g⻹. The loading capacity of BlGGT on the HBPAA-γ-Fe2O3 nanocarriers was 16 mg g⻹ support; this sample provided a 48% recovery of the initial activity. The immobilized enzyme could be recycled 10 times with 32% retention of the initial activity; it had stability comparable with that of the free enzyme during a storage period of 63 days. The covalent immobilization and stability of the enzyme and the magnetization provided by the HBPAA-γ-Fe2O3 NPs suggests that this approach could be an economical means of depositing bioactive enzymes upon nanocarriers for BlGGT-mediated bio-catalysis.
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Proteínas de Bactérias/química , Enzimas Imobilizadas/química , Compostos Férricos/química , Nanopartículas de Magnetita/química , Nylons/química , gama-Glutamiltransferase/química , Estabilidade Enzimática , Reutilização de Equipamento , Escherichia coli/química , Escherichia coli/enzimologia , Escherichia coli/genética , Concentração de Íons de Hidrogênio , Cinética , Tamanho da Partícula , Proteínas Recombinantes/química , TemperaturaRESUMO
BACKGROUND: Though previous studies have documented various clinical outcomes after cervical arthroplasty for degenerative cervical disc disease, none of them reported the impact of cervical arthroplasty on severe cervical disc degeneration (CDD). METHODS: This retrospective cohort study included severe 40 CDD (C3-C7) patients who underwent single-level cervical arthroplasty using ProDisc-C between January 2017 and December 2019. After surgical intervention, the range of motion (ROM) was determined, whereas clinical outcomes were measured in terms of the Visual Analogue Scale (VAS) and Neck Disability Index (NDI) to evaluate neck pain and disability, respectively. RESULTS: Compared to the mean preoperative ROM (6.57 ± 4.85°), the cervical dynamic ROM was increased 3 months after cervical arthroplasty, and the increment was maintained for at least 1 year. The increased ROM is attributed to the extension and not flexion components. The mean preoperative ROM of 6.57 ± 4.85° significantly increased to 11.67 ± 4.98° (P = 0.0005), 10.05 ± 5.18° (P = 0.0426) and 10.46 ± 4.73° (P = 0.0247) after 3 months, 6 months and 1 year, respectively. The extension ROM also revealed a similar trend. VAS for neck and arm decreased from 7.4 and 6.6 to 1.4 and 1.2, respectively. Consistently, the preoperative mean Neck Disability Index (NDI) score of 27.6 decreased to 14.6. We recorded a case of device subsidence, but without extrusion. CONCLUSIONS: Cervical arthroplasty can improve clinical outcomes and restore ROM in severe CDD patients.
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Degeneração do Disco Intervertebral , Humanos , Seguimentos , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , ArtroplastiaRESUMO
Chitosan acts as a versatile carrier in polymeric nanoparticle (NP) for diverse drug administration routes. Delivery of antioxidants, such as quercetin (Qu) showcases potent antioxidant and anti-inflammatory properties for reduction of various cardiovascular diseases, but low water solubility limits uptake. To address this, we developed a novel layer-by-layer zein/gamma-polyglutamic acid (γPGA)/low-molecular-weight chitosan (LC)/fucoidan NP for encapsulating Qu and targeting inflamed vessel endothelial cells. We used zein (Z) and γPGA (r) to encapsulate Qu (Qu-Zr NP) exhibited notably higher encapsulation efficiency compared to zein alone. Qu-Zr NP coated with LC (Qu-ZrLC2 NP) shows a lower particle size (193.2 ± 2.9 nm), and a higher zeta potential value (35.2 ± 0.4 mV) by zeta potential and transmission electron microscopy analysis. After coating Qu-ZrLC2 NP with fucoidan, Qu-ZrLC2Fa NP presented particle size (225.16 ± 0.92 nm), zeta potential (-25.66 ± 0.51 mV) and maintained antioxidant activity. Further analysis revealed that Qu-ZrLC2Fa NP were targeted and taken up by HUVEC cells and EA.hy926 endothelial cells. Notably, we observed Qu-ZrLC2Fa NP targeting zebrafish vessels and isoproterenol-induced inflamed vessels of rat. Our layer-by-layer formulated zein/γPGA/LC/fucoidan NP show promise as a targeted delivery system for water-insoluble drugs. Qu-ZrLC2Fa NP exhibit potential as an anti-inflammatory therapeutic for blood vessels.
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Antioxidantes , Quitosana , Nanopartículas em Multicamadas , Ácido Poliglutâmico , Polissacarídeos , Quercetina , Peixe-Zebra , Zeína , Animais , Humanos , Masculino , Ratos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Antioxidantes/farmacologia , Antioxidantes/química , Vasos Sanguíneos/efeitos dos fármacos , Quitosana/química , Portadores de Fármacos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Nanopartículas em Multicamadas/química , Peso Molecular , Tamanho da Partícula , Ácido Poliglutâmico/química , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Quercetina/farmacologia , Quercetina/química , Zeína/químicaRESUMO
BACKGROUND AND AIMS: Fatty liver disease (FLD) is associated with several metabolic derangements. We conducted a retrospective cross-sectional and longitudinal study to evaluate the role of FL severity in the risk of new-onset and co-existing hypertension (HTN) and diabetes mellitus (DM). METHODS: The cross-sectional cohort consisted of 41,888 adults who received health checkups in a tertiary hospital of Taiwan from 1999 to 2013. Of them, 34,865 without HTN and/or DM at baseline and within 1 year after enrollment were included as a longitudinal cohort (mean, 6.45 years for HTN; 6.75 years for DM). FL severity based on the degree of hepatic steatosis was assessed by ultrasound sonography. RESULTS: In cross-sectional cohort, 22,852 (54.6%) subjects had FL (18,203 [43.46%] mild FL and 4,649 [11.10%] moderate/severe FL); 13.5% (n = 5668) had HTN; and 3.4% (n = 1411) had DM. Moderate/severe FL and mild FL had significantly higher risks of existing HTN (adjusted odds ratio/95% confidence interval [CI] 1.59/1.43-1.77 and 1.22/1.13-1.32, respectively). In longitudinal cohort, 3,209 and 822 subjects developed new-onset HTN and DM, respectively (annual incidence, 14.3 and 3.5 per 1000 person-years; 10-year cumulative incidence, 14.35% and 3.89%, respectively). Moderate/severe and mild FL had significantly higher risks of new-onset HTN (adjusted hazard ratio [aHR]/CI 1.54/1.34-1.77 and 1.26/1.16-1.37, respectively) and DM (aHR/CI 5.88/4.44-7.81 and 3.22/2.56-4.07, respectively). Resolved FL during follow-up decreased the risk of HTN and/or DM. CONCLUSIONS: Patients with FL are at high risk of prevalent and incident HTN and/or DM. The risk increases with the severity of FL.
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Diabetes Mellitus , Hipertensão , Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Estudos Longitudinais , Estudos Retrospectivos , Estudos Transversais , Fatores de Risco , Diabetes Mellitus/epidemiologia , Hipertensão/epidemiologia , Estudos de Coortes , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/complicaçõesRESUMO
This work presents the synthesis and use of surface-modified iron oxide nanoparticles for the covalent immobilization of Bacillus licheniformis γ-glutamyl transpeptidase (BlGGT). Magnetic nanoparticles were prepared by an alkaline solution of divalent and trivalent iron ions, and they were subsequently treated with 3-aminopropyltriethoxysilane (APES) to obtain the aminosilane-coated nanoparticles. The functional group on the particle surface and the amino group of BlGGT was then cross-linked using glutaraldehyde as the coupling reagent. The loading capacity of the prepared nanoparticles for BlGGT was 34.2 mg/g support, corresponding to 52.4% recovery of the initial activity. Monographs of transmission electron microscopy revealed that the synthesized nanoparticles had a mean diameter of 15.1 ± 3.7 nm, and the covalent cross-linking of the enzyme did not significantly change their particle size. Fourier transform infrared spectroscopy confirmed the immobilization of BlGGT on the magnetic nanoparticles. The chemical and kinetic behaviors of immobilized BlGGT are mostly consistent with those of the free enzyme. The immobilized enzyme could be recycled ten times with 36.2% retention of the initial activity and had a comparable stability respective to free enzyme during the storage period of 30 days. Collectively, the straightforward synthesis of aldehyde-functionalized nanoparticles and the efficiency of enzyme immobilization offer wide perspectives for the practical use of surface-bound BlGGT.
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Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA-seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Transcriptoma/genética , Metástase Linfática/genética , Metástase Linfática/patologia , Glicólise/genética , LinfonodosRESUMO
The controlled attenuation parameter (CAP) measurement obtained from FibroScan® is a low-risk method of assessing fatty liver. This study investigated the association between the FibroScan® CAP values and nine anthropometric indicators, including the abdominal volume index (AVI), body fat percentage (BFP), body mass index (BMI), conicity index (CI), ponderal index (PI), relative fat mass (RFM), waist circumference (WC), waist-hip ratio (WHR), and waist-to-height ratio (WHtR), and risk of non-alcoholic fatty liver disease (fatty liver). We analyzed the medical records of adult patients who had FibroScan® CAP results. CAP values <238 dB/m were coded as 0 (non- fatty liver) and ≥238 dB/m as 1 (fatty liver). An individual is considered to have class 1 obesity when their body mass index (BMI) ranges from 30 kg/m2 to 34.9 kg/m2. Class 2 obesity is defined by a BMI ranging from 35 kg/m2 to 39.9 kg/m2, while class 3 obesity is designated by a BMI of 40 kg/m2 or higher. Out of 1763 subjects, 908 (51.5%) had fatty liver. The BMI, WHtR, and PI were found to be more strongly correlated with the CAP by the cluster dendrogram with correlation coefficients of 0.58, 0.54, and 0.54, respectively (all p < 0.0001). We found that 28.3% of the individuals without obesity had fatty liver, and 28.2% of the individuals with obesity did not have fatty liver. The BMI, CI, and PI were significant predictors of fatty liver. The BMI, PI, and WHtR demonstrated better predictive ability, indicated by AUC values of 0.72, 0.68, and 0.68, respectively, a finding that was echoed in our cluster group analysis that showed interconnected clustering with the CAP. Therefore, of the nine anthropometric indicators we studied, the BMI, CI, PI, and WHtR were found to be more effective in predicting the CAP score, i.e., fatty liver.
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After the mass vaccination project in Taiwan, the prevalence of the hepatitis B virus (HBV) infection for the college-aged population of 18 to 21 years is uncertain. We aimed to investigate the prevalence of hepatitis B markers in different birth cohorts. A total of 38,075 students in universities in Kaohsiung area undergoing entrance examinations between July 2006 to September 2020 were included. Seroprevalence of the hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) status and laboratory data were collected. The seropositive rate of HBsAg was less than 1% for students born after 1991. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly higher, and body mass index (BMI) was significantly lower in HBV carriers compared to those who were not carriers (all p < 0.001). Multivariate logistic regression showed that age, male, higher BMI, and positive HBsAg were risk factors of abnormal ALT value. A decrease in the positive rate of anti-HBs which was significantly higher in the cohort of plasma-derived vaccines than recombinant vaccines was found. We concluded that there were decreasing trends in seropositive rates of HBsAg and anti-HBs for students of the college-aged population in the Kaohsiung area. The status of HBsAg was a predictive factor of abnormal ALT levels. The period effect on anti-HBs seropositivity for DNA recombinant vaccine somehow existed.
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Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR+/HER2- breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR+/HER2- breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Receptores de Progesterona/uso terapêutico , Prognóstico , Biomarcadores Tumorais/genéticaRESUMO
Heavy metals, including arsenic and lead, may lead to cellular oxidative damage that is linked to hypertension. Manganese superoxide dismutase (MnSOD) is a scavenger of reactive oxygen species, and 8-oxoguanine DNA glycosylase (OGG1) is the major glycosylase that repairs DNA lesions. Interestingly, whether there is an elevated risk of hypertension with arsenic or lead exposure in individuals with genetic variations in MnSOD or OGG1 has not yet been investigated. Questionnaires were administered to 240 Taiwanese rural residents. Blood pressure and biochemical indicators were assessed in each subject. Urinary levels of arsenic and lead were measured with atomic absorption spectrometry; and MnSOD and OGG1 genotypes were identified via polymerase chain reaction. There was a dose-response relationship between urinary arsenic levels and risk of hypertension (P = 0.021, test for trend). However, there was no association between urinary lead levels and hypertension risk. Individuals with high urinary arsenic levels and the MnSOD Val-Ala/Ala-Ala genotypes had a greater risk of hypertension than those with low urinary arsenic levels and the MnSOD Val-Val genotype (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 1.7-10.3). Subjects with a high urinary arsenic level and the OGG1 Cys-Cys genotype also had a greater risk of hypertension than those with a low urinary arsenic level and the OGG1 Ser-Ser/Ser-Cys genotypes (OR = 3.4, 95% CI = 1.1-10.7). Thus, both MnSOD and OGG1 genotypes may be prone to an increased risk of hypertension associated with arsenic exposure.
Assuntos
Arsênio/toxicidade , DNA Glicosilases/genética , Hipertensão/induzido quimicamente , Hipertensão/genética , Polimorfismo Genético , População Rural/estatística & dados numéricos , Superóxido Dismutase/genética , Adulto , Idoso , Arsênio/urina , Estudos Transversais , Relação Dose-Resposta a Droga , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Hipertensão/epidemiologia , Hipertensão/urina , Chumbo/toxicidade , Chumbo/urina , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/estatística & dados numéricos , Estresse Oxidativo/genética , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Bi-manual therapy (BT), mirror therapy (MT), and robot-assisted rehabilitation have been conducted in hand training in a wide range of stages in stroke patients; however, the mechanisms of action during training remain unclear. In the present study, participants performed hand tasks under different intervention conditions to study bilateral sensorimotor cortical communication, and EEG was recorded. A multifactorial design of the experiment was used with the factors of manipulating objects (O), robot-assisted bimanual training (RT), and MT. The sum of spectral coherence was applied to analyze the C3 and C4 signals to measure the level of bilateral corticocortical communication. We included stroke patients with onset <6 months (n = 6), between 6 months and 1 year (n = 14), and onset >1 year (n = 20), and their Brunnstrom recovery stage ranged from 2 to 4. The results showed that stroke duration might influence the effects of hand rehabilitation in bilateral cortical corticocortical communication with significant main effects under different conditions in the alpha and beta bands. Therefore, stroke duration may influence the effects of hand rehabilitation on interhemispheric coherence.