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The organization of interphase chromosomes in a number of species is starting to emerge thanks to advances in a variety of experimental techniques. However, much less is known about the dynamics, especially in the functional states of chromatin. Some experiments have shown that the motility of individual loci in human interphase chromosome decreases during transcription and increases upon inhibiting transcription. This is a counterintuitive finding because it is thought that the active mechanical force (F) on the order of ten piconewtons, generated by RNA polymerase II (RNAPII) that is presumably transmitted to the gene-rich region of the chromatin, would render it more open, thus enhancing the mobility. We developed a minimal active copolymer model for interphase chromosomes to investigate how F affects the dynamical properties of chromatin. The movements of the loci in the gene-rich region are suppressed in an intermediate range of F and are enhanced at small F values, which has also been observed in experiments. In the intermediate F, the bond length between consecutive loci increases, becoming commensurate with the distance at the minimum of the attractive interaction between nonbonded loci. This results in a transient disorder-to-order transition, leading to a decreased mobility during transcription. Strikingly, the F-dependent change in the locus dynamics preserves the organization of the chromosome at [Formula: see text]. Transient ordering of the loci, which is not found in the polymers with random epigenetic profiles, in the gene-rich region might be a plausible mechanism for nucleating a dynamic network involving transcription factors, RNAPII, and chromatin.
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Cromatina , Cromossomos Humanos , Humanos , Cromatina/genética , Fatores de Transcrição/genética , Interfase/genética , RNA Polimerase II/genéticaRESUMO
Plasticity of the root system architecture (RSA) is essential in enabling plants to cope with various environmental stresses and is mainly controlled by the phytohormone auxin. Lateral root development is a major determinant of RSA. Abiotic stresses reduce auxin signaling output, inhibiting lateral root development; however, how abiotic stress translates into a lower auxin signaling output is not fully understood. Here, we show that the nucleo-cytoplasmic distribution of the negative regulators of auxin signaling AUXIN/INDOLE-3-ACETIC ACID INDUCIBLE 12 (AUX/IAA12 or IAA12) and IAA19 determines lateral root development under various abiotic stress conditions. The cytoplasmic localization of IAA12 and IAA19 in the root elongation zone enforces auxin signaling output, allowing lateral root development. Among components of the nuclear pore complex, we show that CONSTITUTIVE EXPRESSOR OF PATHOGENESIS-RELATED GENES 5 (CPR5) selectively mediates the cytoplasmic translocation of IAA12/19. Under abiotic stress conditions, CPR5 expression is strongly decreased, resulting in the accumulation of nucleus-localized IAA12/19 in the root elongation zone and the suppression of lateral root development, which is reiterated in the cpr5 mutant. This study reveals a regulatory mechanism for auxin signaling whereby the spatial distribution of AUX/IAA regulators is critical for lateral root development, especially in fluctuating environmental conditions.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Estresse Fisiológico , Raízes de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas Repressoras/metabolismo , Proteínas de Membrana/metabolismoRESUMO
The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 µg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis.
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Anti-Infecciosos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Animais , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Camundongos , Tuberculose/tratamento farmacológicoRESUMO
Alzheimer's Disease (AD) is complicated by pro-oxidant intraneuronal Fe(2+) elevation as well as extracellular Zn(2+) accumulation within amyloid plaque. We found that the AD ß-amyloid protein precursor (APP) possesses ferroxidase activity mediated by a conserved H-ferritin-like active site, which is inhibited specifically by Zn(2+). Like ceruloplasmin, APP catalytically oxidizes Fe(2+), loads Fe(3+) into transferrin, and has a major interaction with ferroportin in HEK293T cells (that lack ceruloplasmin) and in human cortical tissue. Ablation of APP in HEK293T cells and primary neurons induces marked iron retention, whereas increasing APP695 promotes iron export. Unlike normal mice, APP(-/-) mice are vulnerable to dietary iron exposure, which causes Fe(2+) accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD postmortem neocortex is inhibited by endogenous Zn(2+), which we demonstrate can originate from Zn(2+)-laden amyloid aggregates and correlates with Aß burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.
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Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Ceruloplasmina/antagonistas & inibidores , Zinco/metabolismo , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Precursor de Proteína beta-Amiloide/química , Animais , Linhagem Celular , Ceruloplasmina/química , Ceruloplasmina/metabolismo , Humanos , Ferro/metabolismo , Camundongos , Alinhamento de SequênciaRESUMO
Inducible nitric oxide synthase (NOS2) produces high local concentrations of nitric oxide (NO), and its expression is associated with inflammation, cellular stress signals, and cellular transformation. Additionally, NOS2 expression results in aggressive cancer cell phenotypes and is correlated with poor outcomes in patients with breast cancer. DNA hypomethylation, especially of noncoding repeat elements, is an early event in carcinogenesis and is a common feature of cancer cells. In addition to altered gene expression, DNA hypomethylation results in genomic instability via retrotransposon activation. Here, we show that NOS2 expression and associated NO signaling results in substantial DNA hypomethylation in human cell lines by inducing the degradation of DNA (cytosine-5)methyltransferase 1 (DNMT1) protein. Similarly, NOS2 expression levels were correlated with decreased DNA methylation in human breast tumors. NOS2 expression and NO signaling also resulted in long interspersed noncoding element 1 (LINE-1) retrotransposon hypomethylation, expression, and DNA damage. DNMT1 degradation was mediated by an NO/p38-MAPK/lysine acetyltransferase 5dependent mechanism. Furthermore, we show that this mechanism is required for NO-mediated epithelial transformation. Therefore, we conclude that NOS2 and NO signaling results in DNA damage and malignant cellular transformation via an epigenetic mechanism.
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Metilação de DNA , Inflamação , S-Nitrosotióis , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Humanos , Inflamação/genética , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Retroelementos/genéticaRESUMO
Extensive research on medicinal herbs for bioactive compounds proposes that they could replace synthetic drugs, reducing side effects and economic burdens. Especially, interest in the synergistic benefits of natural products is increasing, implying that their combined use may enhance therapeutic effectiveness. This study aimed to explore the synergetic effects of turmeric (Curcuma longa L.) and black pepper (Piper nigrum L.) extract on lung normal (MRC-5) and cancer (A549 and NCI-H292) cell lines. The turmeric extract (TM) only affected the lung cancer cell lines, but it had no impact on the MRC-5 cell line. On the other hand, the black pepper extract (BP) did not cause any damage to either the lung normal or cancer cell lines, even at concentrations of up to 400 µg/mL. Response surface methodology was used to predict the ideal synergistic concentrations (EC50) of TM and BP, which were found to be 48.5 and 241.7 µg/mL, respectively. Notably, the selected condition resulted in higher cytotoxicity compared to the exposure to TM alone, indicating a potent synergetic effect. The rate of curcumin degradation under this combined treatment was significantly decreased to 49.72 ± 5.00 nmol/h/µg for A549 cells and 47.53 ± 4.78 nmol/h/µg for NCI-H292 cells, respectively, as compared to curcumin alone. Taken together, this study confirmed the potent synergistic effect of TM and BP on lung cancer cell lines. Further research is required to identify their specific synergetic mechanisms. Our findings provide crucial foundational data on the synergistic effects of TM and BP.
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Stress granule (SG) is a temporary cellular structure that plays a crucial role in the regulation of mRNA and protein sequestration during various cellular stress conditions. SG enables cells to cope with stress more effectively, conserving vital energy and resources. Focusing on the NTF2-like domain of G3BP1, a key protein in SG dynamics, we explore to identify and characterize novel small molecules involved in SG modulation without external stressors. Through in silico molecular docking approach to simulate the interaction between various compounds and the NTF2-like domain of G3BP1, we identified three compounds as potential candidates that could bind to the NTF2-like domain of G3BP1. Subsequent immunofluorescence experiments demonstrated that these compounds induce the formation of SG-like, G3BP1-positive granules. Importantly, the granule formation by these compounds occurs independent from the phosphorylation of eIF2α, a common mechanism in SG formation, suggesting that it might offer a new strategy for influencing SG dynamics implicated in various diseases.
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DNA Helicases , RNA Helicases , DNA Helicases/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Simulação de Acoplamento Molecular , Grânulos Citoplasmáticos/metabolismoRESUMO
This paper introduces catheter-directed intravascular casting hydrogels for transarterial chemo/starvation/chemodynamic embolization (TACSCE) therapy of hepatocellular carcinoma (HCC). Comprising Mn ion-crosslinked hyaluronic acid-dopamine (HD) with glucose oxidase (for glucose decomposition to H2O2 in starvation therapy), doxorubicin (for chemotherapy), and iopamidol (for X-ray imaging), these hydrogels are fabricated for transarterial embolization therapy guided by X-ray fluoroscopy. Mn4+ (from MnO2) demonstrates strong coordination with the catechol group of HD, providing hypoxia relief through O2 generation and cellular glutathione (GSH) consumption, compared to the OH radical generation potential of Mn2+. The gelation time-controlled, catheter-injectable, and rheologically tuned multitherapeutic/embolic gel system effectively reaches distal arterioles, ensuring complete intravascular casting with fewer complications related to organic solvents. Glucose deprivation, cascade reactive oxygen species (ROS) generation, GSH depletion, and sustained release profiles of multiple drug cargos from the hydrogel system are also achieved. The combined chemo/starvation/chemodynamic efficacies of these designed hydrogel systems are confirmed in HCC cell cultures and HCC-bearing animal models. The developed radiopaque/injectable/embolic/sol-to-gel transformable systems for TACSCE therapy may offer enhanced therapeutic efficacies compared to typical transarterial embolization and transarterial chemoembolization procedures for HCC.
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MOTIVATION: Despite the success of recent machine learning algorithms' applications to survival analysis, their black-box nature hinders interpretability, which is arguably the most important aspect. Similarly, multi-omics data integration for survival analysis is often constrained by the underlying relationships and correlations that are rarely well understood. The goal of this work is to alleviate the interpretability problem in machine learning approaches for survival analysis and also demonstrate how multi-omics data integration improves survival analysis and pathway enrichment. We use meta-learning, a machine-learning algorithm that is trained on a variety of related datasets and allows quick adaptations to new tasks, to perform survival analysis and pathway enrichment on pan-cancer datasets. In recent machine learning research, meta-learning has been effectively used for knowledge transfer among multiple related datasets. RESULTS: We use meta-learning with Cox hazard loss to show that the integration of TCGA pan-cancer data increases the performance of survival analysis. We also apply advanced model interpretability method called DeepLIFT (Deep Learning Important FeaTures) to show different sets of enriched pathways for multi-omics and transcriptomics data. Our results show that multi-omics cancer survival analysis enhances performance compared with using transcriptomics or clinical data alone. Additionally, we show a correlation between variable importance assignment from DeepLIFT and gene coenrichment, suggesting that genes with higher and similar contribution scores are more likely to be enriched together in the same enrichment sets. AVAILABILITY AND IMPLEMENTATION: https://github.com/berkuva/TCGA-omics-integration.
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Multiômica , Neoplasias , Humanos , Algoritmos , Neoplasias/genética , Perfilação da Expressão Gênica , Aprendizado de MáquinaRESUMO
BACKGROUND: The exosome-mediated extracellular secretion of miRNAs occurs in many cancers, and RAB27A is a potent regulator of exosome secretion. For metastatic renal cell carcinoma (RCC), this study examines the mechanisms of cancer metastasis via the RAB27A-regulated secretion of specific miRNAs. METHODS: RAB27A knockdown (KD) and overexpressing (OE) RCC cells were used to examine cell migration and adhesion. The particle counts and sizes of exosomes in RAB27A OE cells were analyzed using Exoview, and those of intraluminal vesicles (ILV) and multivesicular bodies (MVB) were measured using an electron microscope. Analysis of RNA sequences, protein-protein interaction networks, and the competing endogenous RNA (ceRNA) network were used to identify representative downregulated miRNAs that are likely to undergo cargo-sorting into exosomes and subsequent secretion. A molecular beacon of miR-137-3p, one of the most representatively downregulated genes with a fold change of 339, was produced, and its secretion was analyzed using Exoview. RAB27A OE and control cells were incubated in an exosome-containing media to determine the uptake of tumor suppressor miRNAs that affect cancer cell metastasis. RESULTS: Migration and cell adhesion were higher in RAB27A OE cells than in RAB27A KD cells. Electron microscopy revealed that the numbers of multivesicular bodies and intraluminal vesicles per cell were higher in RAB27A OE cells than in control cells, suggesting their secretion. The finding revealed that miR-127-3p was sorted into exosomes and disposed of extracellularly. Protein-protein interaction analysis revealed MYCN to be the most significant hub for RAB27A-OE RCC cells. ceRNA network analysis revealed that MAPK4 interacted strongly with miR-127-3p. CONCLUSION: The disposal of miR-127-3p through exosome secretion in RAB27A overexpressing cells may not inhibit the MAPK pathway to gain metastatic potential by activating MYCN. The exosomes containing miRNAs are valuable therapeutic targets for cancer treatment.
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Fast-scan cyclic voltammetry (FSCV) is a widely used technique for detecting neurotransmitters. However, electrode fouling can negatively impact its accuracy and sensitivity. Fouling refers to the accumulation of unwanted materials on the electrode surface, which can alter its electrochemical properties and reduce its sensitivity and selectivity. Fouling mechanisms can be broad and may include biofouling, the accumulation of biomolecules on the electrode surface, and chemical fouling, the deposition of unwanted chemical species. Despite individual studies discussing fouling effects on either the working electrode or the reference electrode, no comprehensive study has been conducted to compare the overall fouling effects on both electrodes in the context of FSCV. Here, we examined the effects of biofouling and chemical fouling on the carbon fiber micro-electrode (CFME) as the working electrode and the Ag/AgCl reference electrode with FSCV. Both fouling mechanisms significantly decreased the sensitivity and caused peak voltage shifts in the FSCV signal with the CFME, but not with the Ag/AgCl reference electrode. Interestingly, previous studies have reported peak voltage shifts in FSCV signals due to the fouling of Ag/AgCl electrodes after implantation in the brain. We noticed in a previous study that energy-dispersive spectroscopy (EDS) spectra showed increased sulfide ion concentration after implantation. We hypothesized that sulfide ions may be responsible for the peak voltage shift. To test this hypothesis, we added sulfide ions to the buffer solution, which decreased the open circuit potential of the Ag/AgCl electrode and caused a peak voltage shift in the FSCV voltammograms. Also, EDS analysis showed that sulfide ion concentration increased on the surface of the Ag/AgCl electrodes after 3 weeks of chronic implantation, necessitating consideration of sulfide ions as the fouling agent for the reference electrodes. Overall, our study provides important insights into the mechanisms of electrode fouling and its impact on FSCV measurements. These findings could inform the design of FSCV experiments, with the development of new strategies for improving the accuracy and reliability of FSCV measurements in vivo.
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Incrustação Biológica , Técnicas Eletroquímicas , Neurotransmissores , Neurotransmissores/análise , Incrustação Biológica/prevenção & controle , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Animais , Compostos de Prata/química , Fibra de Carbono/química , Microeletrodos , Sulfetos/química , EletrodosRESUMO
This study aimed to investigate the diverse clinical manifestations and simple early biomarkers predicting mortality of COVID-19 patients admitted to the emergency department (ED). A total of 710 patients with COVID-19 were enrolled from 6,896 patients presenting to the ED between January 2022 and March 2022. During the study period, a total of 478 patients tested positive for COVID-19, among whom 222 (46.4%) presented with extrapulmonary manifestations of COVID-19; 49 (10.3%) patients displayed gastrointestinal manifestations, followed by neurological (n = 41; 8.6%) and cardiac manifestations (n = 31; 6.5%). In total, 54 (11.3%) patients died. A Cox proportional hazards model revealed that old age, acute kidney injury at presentation, increased total leukocyte counts, low platelet counts, decreased albumin levels, and increased LDH levels were the independent predictors of mortality. The albumin levels exhibited the highest area under the curve in receiver operating characteristic analysis, with a value of 0.860 (95% confidence interval, 0.796-0.875). The study showed the diverse clinical presentations and simple-to-measure prognostic markers in COVID-19 patients presenting to the ED. Serum albumin levels can serve as a novel and simple early biomarker to identify COVID-19 patients at high risk of death.
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Biomarcadores , COVID-19 , Serviço Hospitalar de Emergência , Humanos , COVID-19/mortalidade , COVID-19/sangue , COVID-19/diagnóstico , Serviço Hospitalar de Emergência/estatística & dados numéricos , Masculino , Feminino , Biomarcadores/sangue , Pessoa de Meia-Idade , Idoso , Adulto , SARS-CoV-2 , Prognóstico , Idoso de 80 Anos ou mais , Albumina Sérica/análise , Estudos Retrospectivos , Modelos de Riscos ProporcionaisRESUMO
The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56 years (interquartile range [IQR], 45-62), and the median follow-up time was 3.9 years (IQR 2.0-5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09-0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19-0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.
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Corticosteroides , Everolimo , Rejeição de Enxerto , Transplante de Coração , Imunossupressores , Sistema de Registros , Humanos , Everolimo/administração & dosagem , Everolimo/uso terapêutico , Transplante de Coração/efeitos adversos , Pessoa de Meia-Idade , Masculino , Feminino , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , República da Coreia/epidemiologia , Rejeição de Enxerto/prevenção & controle , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Resultado do Tratamento , Sobrevivência de Enxerto , Estudos RetrospectivosRESUMO
A consensus regarding subsequent therapeutic strategies for patients with platinum- and poly (ADP-ribose) polymerase inhibitor (PARPi)-resistant ovarian cancer is lacking. These patients typically receive non-platinum-based chemotherapy; however, survival outcomes remain poor. Compared with chemotherapy alone, combination therapy with novel target agents can provide additional benefits to these patients. Oregovomab, an investigational murine monoclonal antibody against CA-125, has shown promising efficacy in a phase II study in patients with recurrent ovarian cancer. Herein, we described the rationale and design of OPERA/KGOG 3065/APGOT-OV6, a multicenter, investigator-initiated, two-cohort, single-arm phase II trial, aimed at examining the efficacy of oregovomab plus non-platinum-based chemotherapy in patients with PARPi/platinum-resistant ovarian cancer. The primary end point was the objective response rate, according to RECIST 1.1.Clinical Trial Registration: NCT05407584 (ClinicalTrials.gov).
OPERA/KGOG 3065/APGOT-OV6 is a promising phase II studies that test new drug (oregovomab) on the patients with poly (ADP-ribose) polymerase inhibitor (PARPi)/platinum-resistant epithelial ovarian cancer. PARPis have changed the treatment landscape of ovarian cancer in a relatively short time. PARPi/platinum-resistant epithelial ovarian cancer refer to a subtype of recurrent epithelial cancer of ovarian, tubal or peritoneal origin who experienced disease progression despite treatment with a PARPi or platinum-based chemotherapy drugs. Although various new drugs have been tested to improve the treatment response in resistant patients, a consensus regarding the international standard of treatment is yet to be established, despite the poor survival outcomes of these patients. OPERA/KGOG 3065/APGOT-OV6 has been designed to add oregovomab, a murine monoclonal antibody to cancer antigen-125 (CA-125), to non-platinum chemotherapy (pegylated liposomal doxorubicin or paclitaxel) for patients with ovarian cancer determined as PARPi/platinum-resistant and ineligible for bevacizumab treatment. The results of this study will aid in developing effective treatment strategies for patients with PARPi/platinum-resistant ovarian cancer.
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BACKGROUND: Although two recent phase III randomized controlled trials showed survival benefits of undergoing secondary cytoreductive surgery for an initial relapse of ovarian cancer, patients who received a poly-ADP ribose polymerase inhibitor (PARPi) as the first-line maintenance treatment, which is currently the standard treatment for advanced ovarian cancer, were not included in those trials. Therefore, determining an optimal treatment strategy, including secondary cytoreductive surgery, in patients whose cancer progresses even with PARPi treatment, is needed. PRIMARY OBJECTIVE: To determine whether secondary cytoreductive surgery is beneficial in patients who have progressed on PARPi maintenance treatment. STUDY HYPOTHESIS: Secondary cytoreductive surgery followed by chemotherapy is superior to chemotherapy alone for patients who have progressed on PARPi maintenance treatment. TRIAL DESIGN: The SOCCER-P study is a multicenter randomized phase II clinical trial. Patients who meet the eligibility criteria will be randomized to either undergo secondary cytoreductive surgery and subsequent platinum-based chemotherapy plus or minus bevacizumab, or to receive platinum-based chemotherapy plus or minus bevacizumab alone. Patients randomly allocated to the surgery group will undergo secondary cytoreductive surgery followed by six cycles of a physician's choice of platinum-based chemotherapy once they have recovered from surgery. MAJOR INCLUSION/EXCLUSION CRITERIA: The major inclusion criteria are as follows: first recurrence of disease with treatment-free interval from last platinum dose (TFIp) ≥6 months and progression during PARPi maintenance or treatment-free interval from last PARPi therapy (TFIPARPi) <3 months. The major exclusion criteria are as follows: >1 line of prior chemotherapy, TFIp <6 months, and radiological signs suggesting metastases not accessible to surgical removal (complete resection is deemed not possible). PRIMARY ENDPOINT: Progression-free survival. SAMPLE SIZE: 124 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual completion approximately the end of 2026 and the results are expected after 2 years of follow-up in 2029. TRIAL REGISTRATION: NCT05704621.
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Using a three-wave longitudinal sample of 108 Chinese American parent-adolescent dyads (Mparent-ageW1 = 45.44 years, 17% fathers; Madolescent-ageW1 = 13.34 years, 50% boys), this study examined the effects of parents' COVID-19-related racial discrimination experiences on adolescents' ethnic identity exploration and anxiety as mediated by parents' awareness of discrimination (AOD) socialization and moderated by parents' anxiety and racial socialization competency (RSC). Parents' racial discrimination experiences in 2020 predicted adolescents' greater ethnic identity exploration or greater anxiety in 2022 via parents' greater use of AOD in 2021, depending on the levels of parents' anxiety and RSC. These findings highlighted individual and contextual factors impacting racial socialization processes in Chinese American families.
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COVID-19 , Racismo , Masculino , Humanos , Adolescente , Feminino , Socialização , Asiático , PaisRESUMO
Excessive vascular endothelial growth factor-A (VEGF-A) signaling induces vascular leakage and angiogenesis in diseases. VEGFR2 trafficking to the cell surface, mediated by kinesin-3 family protein KIF13B, is essential to respond to VEGF-A when inducing angiogenesis. However, the precise mechanism of how KIF13B regulates VEGF-induced signaling and its effects on endothelial permeability is largely unknown. Here we show that KIF13B-mediated recycling of internalized VEGFR2 through Rab11-positive recycling vesicle regulates endothelial permeability. Phosphorylated VEGFR2 at the cell-cell junction was internalized and associated with KIF13B in Rab5-positive early endosomes. KIF13B mediated VEGFR2 recycling through Rab11-positive recycling vesicle. Inhibition of the function of KIF13B attenuated phosphorylation of VEGFR2 at Y951, SRC at Y416, and VE-cadherin at Y685, which are necessary for endothelial permeability. Failure of VEGFR2 trafficking to the cell surface induced accumulation and degradation of VEGFR2 in lysosomes. Furthermore, in the animal model of the blinding eye disease wet age-related macular degeneration (AMD), inhibition of KIF13B-mediated VEGFR2 trafficking also mitigated vascular leakage. Thus, the present results identify the fundamental role of VEGFR2 recycling to the cell surface in mediating vascular permeability, which suggests a promising strategy for mitigating vascular leakage associated with inflammatory diseases.
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Permeabilidade Capilar , Cinesinas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Permeabilidade Capilar/genética , Permeabilidade Capilar/fisiologia , Membrana Celular/metabolismo , Cinesinas/metabolismo , Fosforilação , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: To elucidate the association between phase angle (PA) and a composite adverse outcome in patients requiring off-pump coronary artery bypass grafting (OPCAB). DESIGN: A prospective observational study. SETTING: High-volume single center. PARTICIPANTS: A total of 229 adult patients who underwent OPCAB from May 2019 to October 2020. INTERVENTIONS: Each patient underwent bioelectrical impedance analysis, including PA assessment before surgery (PApre), immediately postoperatively (PApost), and 1 day postoperatively (PAPOD1), using an Inbody S10. Frailty index and nutritional assessments also were obtained before surgery. MEASUREMENTS AND MAIN RESULTS: Patient outcomes were assessed using a composite adverse outcome comprising death, myocardial infarction, revascularization, new-onset atrial fibrillation, acute kidney injury, stroke, postoperative pulmonary complications, wound complications, sepsis, reoperation, and/or delirium occurring during hospitalization and over the following year. Patients for whom composite adverse outcomes were reported had lower PApre than those without complications (5.4 ± 0.9 v 6.0 ± 0.9, p < 0.001). The PA was significantly associated with in-hospital and 1-year composite postoperative outcomes. The odds ratios (OR, [95% confidence interval]) for PApre by time were in-hospital complications (0.435 [0.314, 0.604], p < 0.001; 1-year complications: 0.459 [0.330, 0.638], p < 0.001) and PAPOD1 (OR, in-hospital complications: 0.400 [0.277, 0.576], 1-year complications: 0.429 [0.298, 0.619], p < 0.001). The PApre was significantly associated with days alive and out of hospital until 1 year. The cut-off value of PApre for optimal prediction of in-hospital complications was 6.0 (area under the curve: 0.691 [0.623-0.758], p < 0.001). CONCLUSION: Low PA as an indicator of frailty is associated with adverse postoperative outcomes after OPCAB. Low PA may be employed as a noninvasive and practical tool for the prediction of prognosis in patients with coronary artery disease.
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Ponte de Artéria Coronária , Fragilidade , Humanos , Ponte de Artéria Coronária/efeitos adversos , Vasos Coronários , Fragilidade/diagnóstico , Resultado do Tratamento , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , BiomarcadoresRESUMO
INTRODUCTION: Bladder cancer, with a greater incidence in males than in females, requires frequent cystoscopies. We aimed to evaluate the effect of music played through noise-canceling headphones on male bladder cancer patients during follow-up cystoscopy. METHODS: A total of 160 male bladder cancer patients undergoing follow-up flexible cystoscopy were randomly divided into the noise-canceling headphones without music group and the noise-canceling headphones with music group (groups 1 and 2, respectively; n = 80 per group). The patients' clinical characteristics were examined, and objective and subjective measurements were compared before and after cystoscopy. The primary outcomes that were evaluated included the visual analog scale (VAS, 0-10) and the state-trait anxiety inventory (STAI, 20-80). Other outcomes, including vital signs and scores for assessing satisfaction and the willingness to repeat the procedure, were also examined. RESULTS: The characteristics of the patients in groups 1 and 2, and their pre-cystoscopy status, did not differ significantly. Although post-cystoscopy vital signs for the objective parameters and VAS pain scores were similar between the groups, subjective parameters were not. When compared with group 1, post-cystoscopy STAI-state scores were significantly lower in group 2, whereas patients' satisfaction scores and the willingness to repeat the procedure were significantly higher in group 2 (p = 0.002, 0.001, and 0.001, respectively). Additionally, in group 2, STAI-state scores changed significantly after the procedure when compared with before the procedure (p = 0.002). CONCLUSION: Providing music to male bladder cancer patients through noise-canceling headphones was found to reduce anxiety during cystoscopy and to improve patient satisfaction and willingness to undergo repeat cystoscopy.
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OBJECTIVE: The objective of this randomized controlled trial is to compare the effect of bowel preparation using only oral polyethylene glycol electrolyte (PEG) solution vs. oral polyethylene glycol electrolyte solution (PEG) combined with mechanical sodium phosphate (NaP) enema on the surgical field visualization in patients undergoing robot-assisted laparoscopic gynecologic procedures. METHODS: Participants were randomized to either a single oral PEG solution or an oral PEG solution combined by mechanical NaP enema. The intraoperative visualization of the surgical field, the ease of manipulation of the bowels and overall difficulty level of the surgery were evaluated by the surgeon using a self-administered questionnaire. After the surgery, the patients completed a survey assessing postoperative gastrointestinal discomfort. RESULTS: 114 women were enrolled and randomized to oral PEG solution only group (n=48), and oral PEG plus mechanical NaP enema group (n=66). 42 women in oral PEG only group and 59 oral PEG plus NaP enema group completed the study. There was no difference in intraoperative visualization, or overall difficulty of the operation between the two groups, and bowel manipulation was easier in the oral PEG only group. Also, there was no difference in operating time between the groups. The patients' level of gastrointestinal discomfort after the surgery was not significantly different between the two groups. CONCLUSION: Routine use of mechanical NaP enema before robot-assisted laparoscopic gynecologic surgery is not recommended, because it has no additional benefit regarding intraoperative visualization or the surgical level of difficulty over oral bowel preparation methods.