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Cisplatin is widely employed in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rhTSG-6), or PBS through tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. hBM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen (BUN), tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, knockdown of TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviate cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.
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Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small-alpha helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterised the phenotypes induced by a genetic loss of function (LoF) and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human WT Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterised by Lamin B2 mis-localisation. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS+/-FTD patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.
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Genomic imprinting is an epigenetic regulation mechanism in mammals resulting in the parentally dependent monoallelic expression of genes. Imprinting disorders in humans are associated with several congenital syndromes and cancers and remain the focus of many medical studies. Cattle is a better model organism for investigating human embryo development than mice. Imprinted genes usually cluster on chromosomes and are regulated by different methylation regions (DMRs) located in imprinting control regions that control gene expression in cis. There is an imprinted locus on human chromosome 16q24.1 associated with congenital lethal developmental lung disease in newborns. However, genomic imprinting on bovine chromosome 18, which is homologous with human chromosome 16 has not been systematically studied. The aim of this study was to analyze the allelic expressions of eight genes (CDH13, ATP2C2, TLDC1, COTL1, CRISPLD2, ZDHHC7, KIAA0513, and GSE1) on bovine chromosome 18 and to search the DMRs associated gene allelic expression. Three transcript variants of the ZDHHC7 gene (X1, X2, and X5) showed maternal imprinting in bovine placentas. In addition, the monoallelic expression of X2 and X5 was tissue-specific. Five transcripts of the KIAA0513 gene showed tissue- and isoform-specific monoallelic expression. The CDH13, ATP2C2, and TLDC1 genes exhibited tissue-specific imprinting, however, COTL1, CRISLPLD2, and GSE1 escaped imprinting. Four DMRs, established after fertilization, were found in this region. Two DMRs were located between the ZDHHC7 and KIAA0513 genes, and two were in exon 1 of the CDH13 and ATP2C2 genes, respectively. The results from this study support future studies on the molecular mechanism to regulate the imprinting of candidate genes on bovine chromosome 18.
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Metilação de DNA , Epigênese Genética , Recém-Nascido , Gravidez , Feminino , Humanos , Bovinos/genética , Animais , Camundongos , Metilação de DNA/genética , Cromossomos Humanos Par 18 , Impressão Genômica/genética , Cromossomos , Mamíferos/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.
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Tumores do Estroma Gastrointestinal , Proteínas com Homeodomínio LIM , Proteínas Musculares , Proteínas Proto-Oncogênicas c-kit , Transdução de Sinais , Fatores de Transcrição , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Animais , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Humanos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mutação , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Mesilato de Imatinib/farmacologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/metabolismo , Linhagem Celular Tumoral , UbiquitinaçãoRESUMO
Triple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.
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BACKGROUND: Idiopathic membranous nephropathy (IMN) is a leading cause of end-stage renal disease (ESRD). The purpose of this study was to evaluate whether urinary albumin-to-creatinine ratio (UACR) diurnal variation rate calculated by spot urinary protein test predicts 1-year nephrotic outcomes as a biomarker of proteinuria severity in patients with IMN. METHODS: Patients' baseline demographics, blood and urinary biomarkers, and clinical and pathological characteristics were collected retrospectively. Urine samples were collected at 7:00 (before breakfast) and 19:00 (after dinner) to calculate the UACR diurnal variation rate. A prediction model for no remission (NR) was developed statistically based on differences between prognosis groups. Receiver operating characteristic curve (ROC) analysis was performed to evaluate prediction abilities and determine optimal cut-off points of the model and UACR diurnal variation rate alone. RESULTS: The formula for calculating the probability of NR was exp(L)/(1 + exp(L)), where the linear predictor L = - 22.038 + 0.134 × Age (years) + 0.457 × 24-h urinary protein + 0.511 × blood urea nitrogen (BUN) + 0.014 × serum uric acid (SUA) + 2.411 if glomerular sclerosis + 0.816 × fasting blood glucose (FBG)-0.039 × UACR diurnal variation rate (%). Optimal cut-off points for NR prediction by the final model and UACR diurnal variation rate alone were 0.331 and 58.5%, respectively. Sensitivity and specificity were 0.889 and 0.859 for the final model, and 0.926 and 0.676 for UACR diurnal variation rate alone. CONCLUSION: UACR diurnal variation using spot urinary protein is a simpler way to predict nephrotic outcomes and is a highly sensitive screening tool for identifying patients who should undergo further comprehensive risk assessment.
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Albuminúria , Biomarcadores , Ritmo Circadiano , Creatinina , Glomerulonefrite Membranosa , Humanos , Glomerulonefrite Membranosa/urina , Masculino , Feminino , Pessoa de Meia-Idade , Creatinina/urina , Creatinina/sangue , Estudos Retrospectivos , Adulto , Albuminúria/urina , Albuminúria/etiologia , Biomarcadores/urina , Biomarcadores/sangue , Prognóstico , Curva ROC , Valor Preditivo dos Testes , Idoso , Proteinúria/urina , Proteinúria/etiologia , UrináliseRESUMO
Genomic imprinting is an epigenetic regulation in mammals in which a small subset of genes is monoallelically expressed dependent on their parental origin. A large imprinted domain, SGCE/PEG10 locus, is located on human chromosome 7q21s and mouse proximal chromosome 6. However, genomic imprinting of bovine SGCE/PEG10 cluster has not been systematically studied. In this study, we investigated allele expression of 14 genes of the SGCE/PEG10 locus in bovine somatic tissues and term placenta using a single nucleotide polymorphism (SNP)-based sequencing method. In addition to SGCE and PEG10, two conserved paternally expressed genes in human and mice, five other genes (TFPI2, GNG11, ASB4, PON1, and PON3) were paternally expressed. Three genes, BET1, COL1A2, and CASD1, exhibited tissue-specific monoallelic expression. CALCR showed monoallelic expression in tissues but biallelic expression in the placenta. Three genes, GNGT1, PPP1R9A, and PON2, showed biallelic expression in cattle. Five differentially methylated regions (DMRs) were found to be associated with the allelic expression of TFPI2, COL1A2, SGCE/PEG10, PON3, and ASB4 genes, respectively. The SGCE/PEG10 DMR is a maternally hypermethylated germline DMR, but TFPI2, COL1A2, PON3, and ASB4 DMRs are secondary DMRs. In summary, we identified five novel bovine imprinted genes (GNG11, BET1, COL1A2, CASD1, and PON1) and four secondary DMRs at the SGCE/PEG10 locus.
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Alelos , Metilação de DNA , Impressão Genômica , Animais , Bovinos/genética , Placenta/metabolismo , Feminino , Polimorfismo de Nucleotídeo Único , GravidezRESUMO
Gardeniae fructus (GF) is known for its various beneficial effects on cholestatic liver injury (CLI). However, the biological mechanisms through which GF regulates CLI have not been fully elucidated. This study aimed to explore the potential mechanisms of GF against α-naphthylisothiocyanate (ANIT)-induced CLI. First, HPLC technology was used to analyze the chemical profile of the GF extract. Second, the effects of GF on serum biochemical indicators and liver histopathology were examined. Lastly, metabolomics was utilized to study the changes in liver metabolites and clarify the associated metabolic pathways. In chemical analysis, 10 components were identified in the GF extract. GF treatment regulated serum biochemical indicators in ANIT-induced CLI model rats and alleviated liver histological damage. Metabolomics identified 26 endogenous metabolites as biomarkers of ANIT-induced CLI, with 23 biomarkers returning to normal levels, particularly involving primary bile acid biosynthesis, glycerophospholipid metabolism, tryptophan metabolism, and arachidonic acid metabolism. GF shows promise in alleviating ANIT-induced CLI by modulating multiple pathways.
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Liposomes are small spherical vesicles composed of phospholipid bilayers capable of encapsulating a variety of ingredients, including water- and oil-soluble compound, which are one of the most commonly used piggybacking and delivery techniques for many active ingredients and different compounds in biology, medicine and cosmetics. With the increasing number of active cosmetic ingredients, the concomitant challenge is to effectively protect, transport, and utilize these substances in a judicious manner. Many cosmetic ingredients are ineffective both topically and systemically when applied to the skin, thus changing the method of delivery and interaction with the skin of the active ingredients is a crucial step toward improving their effectiveness. Liposomes can improve the delivery of active ingredients to the skin, enhance their stability, and ultimately, improve the efficacy of cosmetics and and pharmaceuticals. In this review, we summarized the basic properties of liposomes and their recent advances of functionalities in cosmetics and and pharmaceuticals. Also, the current state of the art in the field is discussed and the prospects for future research areas are highlighted. We hope that this review will provide ideas and inspiration on the application and development of cosmetics and pharmaceuticals.
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BACKGROUND: More than half of patients with tuberous sclerosis complex (TSC) suffer from drug-resistant epilepsy (DRE), and resection surgery is the most effective way to control intractable epilepsy. Precise preoperative localization of epileptogenic tubers among all cortical tubers determines the surgical outcomes and patient prognosis. Models for preoperatively predicting epileptogenic tubers using 18F-FDG PET images are still lacking, however. We developed noninvasive predictive models for clinicians to predict the epileptogenic tubers and the outcome (seizure freedom or no seizure freedom) of cortical tubers based on 18F-FDG PET images. METHODS: Forty-three consecutive TSC patients with DRE were enrolled, and 235 cortical tubers were selected as the training set. Quantitative indices of cortical tubers on 18F-FDG PET were extracted, and logistic regression analysis was performed to select those with the most important predictive capacity. Machine learning models, including logistic regression (LR), linear discriminant analysis (LDA), and artificial neural network (ANN) models, were established based on the selected predictive indices to identify epileptogenic tubers from multiple cortical tubers. A discriminating nomogram was constructed and found to be clinically practical according to decision curve analysis (DCA) and clinical impact curve (CIC). Furthermore, testing sets were created based on new PET images of 32 tubers from 7 patients, and follow-up outcome data from the cortical tubers were collected 1, 3, and 5 years after the operation to verify the reliability of the predictive model. The predictive performance was determined by using receiver operating characteristic (ROC) analysis. RESULTS: PET quantitative indices including SUVmean, SUVmax, volume, total lesion glycolysis (TLG), third quartile, upper adjacent and standard added metabolism activity (SAM) were associated with the epileptogenic tubers. The SUVmean, SUVmax, volume and TLG values were different between epileptogenic and non-epileptogenic tubers and were associated with the clinical characteristics of epileptogenic tubers. The LR model achieved the better performance in predicting epileptogenic tubers (AUC = 0.7706; 95% CI 0.70-0.83) than the LDA (AUC = 0.7506; 95% CI 0.68-0.82) and ANN models (AUC = 0.7425; 95% CI 0.67-0.82) and also demonstrated good calibration (HosmerâLemeshow goodness-of-fit p value = 0.7). In addition, DCA and CIC confirmed the clinical utility of the nomogram constructed to predict epileptogenic tubers based on quantitative indices. Intriguingly, the LR model exhibited good performance in predicting epileptogenic tubers in the testing set (AUC = 0.8502; 95% CI 0.71-0.99) and the long-term outcomes of cortical tubers (1-year outcomes: AUC = 0.7805, 95% CI 0.71-0.85; 3-year outcomes: AUC = 0.8066, 95% CI 0.74-0.87; 5-year outcomes: AUC = 0.8172, 95% CI 0.75-0.87). CONCLUSIONS: The 18F-FDG PET image-based LR model can be used to noninvasively identify epileptogenic tubers and predict the long-term outcomes of cortical tubers in TSC patients.
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Epilepsia , Esclerose Tuberosa , Humanos , Fluordesoxiglucose F18 , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/metabolismo , Reprodutibilidade dos Testes , Glicólise , Estudos RetrospectivosRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome characterized by the excessive accumulation of fat within liver cells, which can progress to end-stage liver disease in severe cases, posing a threat to life. Pyroptosis is a distinct, pro-inflammatory form of cell death, differing from traditional apoptosis. In recent years, there has been growing research interest in the association between pyroptosis and NAFLD, encompassing the mechanisms and functions of pyroptosis in the progression of NAFLD, as well as potential therapeutic targets. Controlled pyroptosis can activate immune cells, eliciting host immune responses to shield the body from harm. However, undue activation of pyroptosis may worsen inflammatory responses, induce cellular or tissue damage, disrupt immune responses, and potentially impact liver function. This review elucidates the involvement of pyroptosis and key molecular players, including NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome, gasdermin D (GSDMD), and the caspase family, in the pathogenesis and progression of NAFLD. It emphasizes the promising prospects of targeting pyroptosis as a therapeutic approach for NAFLD and offers valuable insights into future directions in the field of NAFLD treatment.
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The application of electrochemical hydrogen evolution reaction (HER) for renewable energy conversion contributes to the ultimate goal of a zero-carbon emission society. Metal phosphides have been considered as promising HER catalysts in the alkaline environment, which, unfortunately, is still limited owing to the weak adsorption of H* and easy dissolution during operation. Herein, a bimetallic NiCoP-2/NF phosphide is constructed on nickel foam (NF), requiring rather low overpotentials of 150 mV and 169 mV to meet the current densities of 500 and 1000 mA cm-2, respectively, and able to operate stably for 100 h without detectable activity decay. The excellent HER performance is obtained thanks to the synergetic catalytic effect between Ni and Co, among which Ni is introduced to enhance the intrinsic activity and Co increases the electrochemically active area. Meanwhile, the protection of the externally generated amorphous phosphorus oxide layer improves the stability of NiCoP/NF. An electrolyser using NiCoP-2/NF as both cathode and anode catalysts in an alkaline solution can produce hydrogen with low electric consumption (overpotential of 270 mV at 500 mA cm-2).
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OBJECTIVES: The economic implications of combining rezvilutamide with androgen deprivation therapy (ADT) remain uncertain, despite the observed survival advantages compared with bicalutamide plus ADT. Therefore, this study evaluates the cost-effectiveness of rezvilutamide plus ADT as the first-line treatment of metastatic hormone-sensitive prostate cancer (mHSPC) from the perspective of the Chinese healthcare system. DESIGN: A partitioned survival model was developed to assess the cost-effectiveness of rezvilutamide combined with ADT. Clinical data were obtained from the CHART trial. Costs and utility values were obtained from local estimate and published literature. Only direct medical costs were included in the model. INTERVENTIONS: Rezvilutamide was administered at 240 mg daily or bicalutamide at 50 mg daily until progression. OUTCOME MEASURES: The main outputs of the model included costs and quality-adjusted life years (QALYs), which were used to determine the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analysis (PSA) were used to explore model uncertainties. RESULTS: The rezvilutamide group showed an expected gain of 2.28 QALYs and an incremental cost of US$60 758.82 compared with the bicalutamide group. The ICER for rezvilutamide group versus bicalutamide group was US$26 656.94 per QALY. The variables with the greatest impact on the model results were the utility for progression-free survival state and the price of rezvilutamide. PSA revealed that rezvilutamide group had 100% probability of being cost-effective at a willingness-to-pay threshold of US$35707.5 per QALY. CONCLUSION: Rezvilutamide in combination with ADT is more cost-effective compared with bicalutamide plus ADT as the first-line treatment of mHSPC from the perspective of the Chinese healthcare system.
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Antagonistas de Androgênios , Anilidas , Análise Custo-Benefício , Nitrilas , Neoplasias da Próstata , Anos de Vida Ajustados por Qualidade de Vida , Compostos de Tosil , Humanos , Masculino , Compostos de Tosil/uso terapêutico , Compostos de Tosil/economia , Anilidas/economia , Anilidas/uso terapêutico , Nitrilas/uso terapêutico , Nitrilas/economia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/economia , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/economia , Antagonistas de Androgênios/uso terapêutico , Idoso , China , Pessoa de Meia-Idade , Análise de Custo-EfetividadeRESUMO
Curcumin, extracted from Zingiberaceae and Araceae rhizomes, is clinically used for its anti-inflammatory, antibacterial, antioxidant, and anti-cancer properties. Its safety and potential make it a promising base for designing enhanced derivatives. The focus now is on optimizing curcumin and synthesizing more potent 1,4-pentadien-3-ones, which have anti-cancer activities. In the realm of triple-negative breast cancer (TNBC), an aggressive and invasive form with high metastatic potential, the need for innovative treatments is acute. The challenges posed by chemotherapy resistance, recurrence, and TNBC's heterogeneity have emphasized the necessity for novel therapeutic approaches. Our strategy involved the integration of a quinoxaline ring into 1,4-pentadien-3-one, followed by subsequent modifications. In this study, N17 demonstrated the ability to induce cell death and effectively suppress cell proliferation in breast cancer cells. These observed anti-cancer effects were attributed to the inhibition of p-AKT(S473), a key regulator implicated in both cell apoptosis and the modulation of epithelial-mesenchymal transition process in breast cancer cells. Furthermore, our investigation indicated N17 achieves its inhibitory effects on p-AKT(S473) by specifically targeting the CSNK1G3 protein. Remarkably, N17 not only impedes the EMT process but also triggers apoptosis through the CSNK1G3/AKT signaling axis. These findings provide the critical role of CSNK1G3 as an anti-cancer regulator in TNBC, establishing N17 as a pharmacological intervention with immense promise for treating cancer metastasis.
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BACKGROUND: Interstitial lung abnormalities (ILA) are associated with further disease progression, increased mortality risk, and decline in lung function in the elderly, which deserves enough attention. OBJECTIVE: The objective of this study was to quantify the extent of interstitial lung abnormalities (ILA) in a non-smoking asymptomatic urban cohort in China using low-dose CT (LDCT) and to analyze the age-related pathological changes. METHODS: We retrospectively analyzed clinical data and chest LDCT images from a cohort of 733 subjects who were categorized into 3 groups: 18-39, 40-59, and ≥60 years old according to age. Furthermore, we selected 40 cases of wax-embedded lung tissue blocks archived after pulmonary bullectomy and the same age groups were categorized. Four representative CT signs of ILA, including interlobular septal thickening (ILST), intralobular interstitial thickening (ILIT), ground-glass opacity (GGO), and reticular shadow (RS), were semi-quantified based on the percentage of the affected area. The scores and distribution of four CT signs of ILA were compared between different sex and age groups. The age-related pathological changes were analyzed. RESULTS: The ILA findings were found predominantly in the lower lobes and the subpleural region. The semi-quantitative scores of four CT signs in all subjects under 40 were 0. However, in subjects over 40 years old, the scores gradually increased with age, although most of them remained low. The size of the alveoli increased, the number of alveoli decreased, the alveolar septum became thinner, and the number of ATII cells increased with age. A statistically significant difference was observed among the different age groups (χ2=50.624, P=0.033; χ2=80.000, P=0.043; χ2=33.833, P=0.000; χ2=13.525, P=0.031). The macrophage population and the percentage of collagen fibers in the alveolar septum increased, while the percentage of elastic fibers decreased with age. There was no significant difference among the different age groups (χ2=19.817, P=0.506; χ2=52.419, P=0. 682; χ2=54.868, P=0.518). CONCLUSION: When the four CT signs mentioned above are in the upper central area, and the score has a medium or high score, it is crucial to determine the underlying pathological causes. ILA may be the result of chronic lung injury.
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BACKGROUND: Early cervical spondylotic myelopathy (CSM) is challenging to diagnose and easily missed. Diffusion MRI (dMRI) has the potential to identify early CSM. METHODS: Using diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI), a 1:1 matched case-control study was conducted to evaluate the potential of dMRI in identifying early CSM and assessing uncompressed segments of CSM patients. CSM patients and volunteers were matched by age and spinal location. The differences in dMRI parameters between groups were assessed by the paired t-test, the multicollinearity of the dMRI parameters was evaluated by the variance inflation factor (VIF), and the value of dMRI parameters in distinguishing controls from CSM patients was determined by logistic regression. The univariate t-test was used to analyse differences between CSM patients and volunteers in adjacent uncompressed areas. RESULTS: In total, 56 CSM patients and 56 control volunteers were included. Paired t-tests revealed significant differences in nine dMRI parameters between groups. Multicollinearity calculated through VIF and combined with logistic regression showed that the orientation division index (ODI) was significantly positively correlated (r = 2.12, p = 0.035), and the anisotropic water fraction (AWF) was significantly negatively correlated (r = -0.98, p = 0.015). The fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), isotropic volume fraction (ISOVF), ODI, and AWF were significantly different in the upper and lower uncompressed areas at all ages. CONCLUSION: dMRI can noninvasively identify early CSM patients and potentially identify the extent of CSM lesions involving the cervical spinal cord. CRITICAL RELEVANCE STATEMENT: Diffusion MRI (dMRI) can identify early cervical spondylotic myelopathy (CSM) and has the potential to help determine the extent of CSM involvement. The application of dMRI can help screen for early CSM and develop clinical surgical and rehabilitation treatment plans. KEY POINTS: ⢠Diffusion MRI can differentiate between normal and early-stage cervical spondylotic myelopathy patients. ⢠Diffusion MRI has the ability to identify the extent of spinal cord involvement in cervical spondylotic myelopathy. ⢠Diffusion MRI enables the early screening of cervical spondylotic myelopathy and helps guide clinical treatment.
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The electrocatalytic methanol oxidation reaction (MOR) is a viable approach for realizing high value-added formate transformation from biomass byproducts. However, usually it is restricted by the excess adsorption of intermediates (COad) and overoxidation of catalysts, which results in low product selectivity and inactivation of the active sites. Herein, a novel Cu-O-Ni electron-transfer channel was constructed by loading NiCuO x on nickel foam (NF) to inhibit the overoxidation of Ni and enhance the formate selectivity of the MOR. The optimized NiCuO x -2/NF demonstrated excellent MOR catalytic performance at industrial current density (E 500 = 1.42 V) and high faradaic efficiency of â¼100%, as well as durable formate generation up to 600 h at â¼500 mA cm-2. The directional electron transfer from Cu to Ni and enhanced lattice stability could alleviate the overoxidation of Ni(iii) active sites to guarantee reversible Ni(ii)/Ni(iii) cycles and endow NiCuO x -2/NF with high stability under increased current density, respectively. An established electrolytic cell created by coupling the MOR with the hydrogen evolution reaction could produce H2 with low electric consumption (230 mV lower voltage at 400 mA cm-2) and concurrently generated the high value-added product of formate at the anode.
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GATA-binding protein 4 (GATA4) is recognized for its significant roles in embryogenesis and various cancers. Through bioinformatics and clinical data, it appears that GATA4 plays a role in breast cancer development. Yet, the specific roles and mechanisms of GATA4 in breast cancer progression remain elusive. In this study, we identify GATA4 as a tumor suppressor in the invasion and migration of breast cancer. Functionally, GATA4 significantly reduces the transcription of MMP9. On a mechanistic level, GATA4 diminishes MMP9 transcription by interacting with p65 at the NF-κB binding site on the MMP9 promoter. Additionally, GATA4 promotes the recruitment of HDAC1, amplifying the bond between p65 and HDAC1. This leads to decreased acetylation of p65, thus inhibiting p65's transcriptional activity on the MMP9 promoter. Moreover, GATA4 hampers the metastasis of breast cancer in vivo mouse model. In summary, our research unveils a novel mechanism wherein GATA4 curtails breast cancer cell metastasis by downregulating MMP9 expression, suggesting a potential therapeutic avenue for breast cancer metastasis.
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Neoplasias da Mama , Movimento Celular , Fator de Transcrição GATA4 , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1 , Metaloproteinase 9 da Matriz , Invasividade Neoplásica , Humanos , Fator de Transcrição GATA4/metabolismo , Fator de Transcrição GATA4/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Feminino , Movimento Celular/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilase 1/genética , Animais , Acetilação , Linhagem Celular Tumoral , Camundongos , Fator de Transcrição RelA/metabolismo , Transcrição Gênica , Regiões Promotoras Genéticas/genética , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have reported that immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity. However, the efficacy of this combination as a later-line therapy in patients with ECOG PS 2 is unclear. This study evaluated the effectiveness and safety of this combination strategy as third- or further-line therapy in stage IV non-small cell lung cancer (NSCLC) patients with ECOG PS 2. METHODS: In this retrospective study, patients treated with camrelizumab plus antiangiogenic therapy (bevacizumab, anlotinib, or recombinant human endostatin) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), quality of life (QOL) assessed by ECOG PS, and safety were analyzed. RESULTS: Between January 10, 2019, and February 28, 2024, a total of 59 patients were included. The ORR was 35.6% (21/59) and the DCR was 86.4%. With a median follow-up of 10.5 months (range: 0.7-23.7), the median PFS was 5.5 months (95% confidence interval [CI]: 3.8-7.3) and the median OS was 10.5 months (95% CI: 11.2-13.6). QOL was improved (≥1 reduction in ECOG PS) in 39 patients (66.1%). The most common Grade 3-4 treatment-related adverse events were hepatic dysfunction (6 [10%]), hypertension (5 [8%]), and hypothyroidism (3 [5%]). There were no treatment-related deaths. CONCLUSIONS: Third- or further-line immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity in stage IV NSCLC patients with ECOG PS 2. Future large-scale prospective studies are required to confirm the clinical benefits of this combination therapy.
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Inibidores da Angiogênese , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Endostatinas , Imunoterapia , Neoplasias Pulmonares , Estadiamento de Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Endostatinas/uso terapêutico , Endostatinas/administração & dosagem , Imunoterapia/métodos , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Qualidade de Vida , Quinolinas/uso terapêutico , Estudos RetrospectivosRESUMO
OBJECTIVES: We aimed to evaluate and compare the risk of hematological adverse events (AEs) associated with CDK4/6 inhibitors using data from randomized controlled trials (RCTs) and Food and Drug Adverse Event Reporting System (FAERS) database. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for RCTs related to abemaciclib, palbociclib, and ribociclib. A network meta-analysis (NMA) was conducted to compare the risks of hematological AEs, and a disproportionality analysis was performed to detect signals of hematological AEs. RESULTS: 16 RCTs comprising 16,350 breast cancer patients were included. Palbociclib and ribociclib had similar risks for hematological AEs, except a higher risk of grade 3-4 leukopenia observed with palbociclib (risk ratio [RR]: 7.84, 95% confidence interval [95%CI]: 1.33-41.28). Abemaciclib had a higher risk of anemia than both ribociclib (grade 1-4: RR: 2.23, 95% CI: 1.25 - 3.96; grade 3-4: RR: 3.52, 95% CI: 1.59 - 8.11) and palbociclib (grade 1-4: RR: 1.65, 95%CI: 1.03 - 2.59), but a lower risk of grade 3-4 of both leukopenia (RR: 0.12, 95%CI: 0.02 - 0.49) and neutropenia (RR: 0.15, 95%CI: 0.04 - 0.52) compared with palbociclib. Signals indicating occurrence of leukopenia, neutropenia, anemia, and thrombocytopenia were identified for three CDK4/6 inhibitors. CONCLUSION: Abemaciclib, palbociclib, and ribociclib showed significant but inconsistent hematological toxicity risks.