RESUMEN
BACKGROUND: The aim of the study was to explore the role of recurrent TNM (rTNM) staging in predicting prognosis for ipsilateral breast tumor recurrence (IBTR) and determine the optimal treatment strategy for IBTR. METHOD: IBTR cases were identified from the Surveillance, Epidemiology, and End Results (SEER) database spanning the years 2000-2018. Cox proportional hazards analysis was performed to examine factors associated with overall survival (OS) and breast cancer-specific survival (BCSS). Propensity score matching (PSM) was employed to match IBTR with primary early breast cancer (EBC) based on clinicopathological characteristics. Investigations into the impact of different therapies were also included. RESULTS: Of the 4375 IBTR cases included in the study, the 5-year OS was 87.1%, 71.6% and 58.7% in rTNM stages I, II and III, respectively. After PSM, while IBTR patients had worse survival to primary EBC patients, prognosis of IBTR for different rTNM stage always closely aligned with the corresponding stage of primary EBC. Repeat breast-conserving surgery (BCS) with radiation therapy was equivalent to mastectomy with respect to OS and BCSS. Chemotherapy was favorable for OS and BCSS in estrogen receptor (ER)-negative IBTR or IBTR occurring within a 60-month interval. CONCLUSIONS: rTNM staging system has an outstanding prognostic value for survival outcome of patients with IBTR, and IBTR and primary EBC may have potentially analogous features in the context of TNM staging. BCS plus radiation therapy may be an alternative. IBTR cases who have experienced recurrence with short intervals and with ER-negative tumors might benefit from chemotherapy.
Asunto(s)
Neoplasias de la Mama , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Puntaje de Propensión , Programa de VERF , Humanos , Femenino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/mortalidad , Persona de Mediana Edad , Pronóstico , Anciano , Adulto , Mastectomía SegmentariaRESUMEN
Screening and prioritizing research on frequently detected mixture systems in the environment is of great significance, as conducting toxicity testing on all mixtures is impractical. Therefore, the frequent itemset mining (FIM) was introduced and applied in this paper to identify variables that commonly co-occur in a dataset. Based on the dataset of the quaternary ammonium compounds (QACs) in the water environment, the four frequent QAC mixture systems with detection rate ≥ 35â¯% were found, including [BDMM]+Cl--[BTMM]+Cl- (M1), [BDMM]+Cl--[BHMM]+Cl- (M2), [BTMM]+Cl- -[BHMM]+Cl- (M3), and [BDMM]+Cl--[BTMM]+Cl--[BHMM]+Cl- (M4). [BDMM]+Cl-, [BTMM]+Cl-, and [BHMM]+Cl- are benzyl dodecyl dimethyl ammonium chloride, benzyl tetradecyl dimethyl ammonium chloride, and benzyl hexadecyl dimethyl ammonium chloride, respectively. Then, the toxicity of the representative mixture rays and components for the four frequently detected mixture systems was tested using Vibrio qinghaiensis sp.-Q67 (Q67) as a luminescent indicator organism at 0.25 and 12â¯h. The toxicity of the mixtures was predicted using concentration addition (CA) and independent action (IA) models. It was shown that both the components and the representative mixture rays for the four frequently detected mixture systems exhibited obvious acute and chronic toxicity to Q67, and their median effective concentrations (EC50) were below 7â¯mg/L. Both CA and IA models predicted the toxicity of the four mixture systems well. However, the CA model had a better predictive ability for the toxicity of the M3 and M4 mixtures than IA at 12â¯h.
Asunto(s)
Compuestos de Amonio Cuaternario , Contaminantes Químicos del Agua , Compuestos de Amonio Cuaternario/toxicidad , Contaminantes Químicos del Agua/toxicidad , Monitoreo del Ambiente/métodos , Pruebas de Toxicidad/métodos , Minería de DatosRESUMEN
PURPOSE: Whether peripheral immune cell subsets can predict pathological complete response (pCR) in breast cancer patients remains to be elucidated. We aimed to dissect the relationship between peripheral immune cell subsets and pCR. METHODS: Two hundred and twenty-six eligible patients from two prospective clinical trials (SHPD001 and SHPD002) in China were randomly divided into a training cohort and a validation cohort. The breast cancer subtypes in this study included hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 95), HER2-positive (n = 100), and triple negative (n = 31) breast cancer. We defined the "Neo-Peripheral Adaptive Immune Score" for neoadjuvant chemotherapy (neoPAI Score) based on the percentages of CD4 + T cells, CD8 + T cells, B cells, and the CD4 + /CD8 + ratio in peripheral blood. We also evaluated the ability of the neoPAI Score derived from tumor-infiltrating immune cells (TIICs) to predict survival by employing The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) database. RESULTS: In the training cohort, multivariate analysis showed that HR status [odds ratio (OR) 0.325; 95% confidence interval (CI) 0.135-0.761; P = 0.010], HER2 status (OR 2.657; 95% CI 1.266-5.730; P = 0.011), Ki67 index (OR 3.191; 95% CI 1.509-6.956; P = 0.003), histological grade (OR 2.297; 95% CI 1.031-5.290; P = 0.045) and neoPAI Score (OR 4.451; 95% CI 1.608-13.068; P = 0.005) were independent predictors of pCR. In the validation cohort, histological grade (OR 3.779; 95% CI 3.793-1.136 × 103; P = 0.008) and neoPAI Score (OR 90.828; 95% CI 3.827-9.843 × 103; P = 0.019) were independent predictors of pCR. The Immune Model that integrated the neoPAI Score was more accurate in predicting pCR than the Clinical Model that exclusively contained clinicopathological parameters in both cohorts. In TCGA-BRCA database, the neoPAI Score constructed from TIICs can predict the progression-free interval (P = 0.048) of breast cancer. CONCLUSION: The neoPAI Score defined by the percentages of peripheral immune cell subsets could be used as a potential biomarker for neoadjuvant chemotherapy efficacy.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Estudios Prospectivos , Terapia Neoadyuvante , Supervivencia sin Enfermedad , Receptor ErbB-2/metabolismo , Inducción de Remisión , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Organophosphate flame retardants (OPFRs) are found in various environmental matrixes and human samples. Exposure to OPFRs during gestation may interfere with pregnancy, for example, inducing maternal oxidative stress and maternal hypertension during pregnancy, interfering maternal and fetal thyroid hormone secretion and fetal neurodevelopment, and causing fetal metabolic abnormalities. However, the consequences of OPFR exposure on pregnant women, impact on mother-to-child transmission of OPFRs, and harmful effects on fetal and pregnancy outcomes have not been evaluated. This review describes the exposure to OPFRs in pregnant women worldwide, based on metabolites of OPFRs (mOPs) in urine for prenatal exposure and OPFRs in breast milk for postnatal exposure. Predictors of maternal exposure to OPFRs and variability of mOPs in urine have been discussed. Mother-to-child transmission pathways of OPFRs have been scrutinized, considering the levels of OPFRs and their metabolites in amniotic fluid, placenta, deciduae, chorionic villi, and cord blood. The results showed that bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP) were the two predominant mOPs in urine, with detection frequencies of >90%. The estimated daily intake (EDIM) indicates low risk when infants are exposed to OPFRs from breast milk. Furthermore, higher exposure levels of OPFRs in pregnant women may increase the risk of adverse pregnancy outcomes and influence the developmental behavior of infants. This review summarizes the knowledge gaps of OPFRs in pregnant women and highlights the crucial steps for assessing health risks in susceptible populations, such as pregnant women and fetuses.
Asunto(s)
Retardadores de Llama , Organofosfatos , Lactante , Humanos , Femenino , Embarazo , Mujeres Embarazadas , Resultado del Embarazo/epidemiología , Transmisión Vertical de Enfermedad Infecciosa , FosfatosRESUMEN
INTRODUCTION: This study compares the perioperative results, aesthetic outcome and oncologic safety of single-port insufflation endoscopic nipple-sparing subcutaneous mastectomy combined with immediate reconstruction using prosthesis implantation (SIE-NSM-IRPI) with those of conventional open-nipple and areola-sparing subcutaneous mastectomy combined with immediate reconstruction using prosthesis implantation (C-NSM-IRPI). METHODS: In this retrospective cohort study, 64 early-stage breast cancer patients were divided into SIE-NSM-IRPI (n = 38) and C-NSM-IRPI (n = 26) groups. Perioperative results (operation time, intraoperative blood loss, incision length, drainage duration, and recent complications) were then compared between the two groups. Differences in satisfaction with the breasts, psychosocial well-being, physical well-being (chest) and sexual well-being were analyzed according to the BREAST-Q scale, and survival outcomes were also compared. RESULTS: The median follow-up time was 51.5 months. The incision length of SIE-NSM-IRPI was shorter than that of C-NSM-IRPI (P < 0.001). SIE-NSM-IRPI achieved the same detection rate and median number of sentinel lymph nodes as C-NSM-IRPI (3.00vs. 4.00, P = 0.780). The incidence of prosthesis removal due to infection or prosthesis exposure in the SIE-NSM-IRPI group was lower than that in the C-NSM-IRPI group (P = 0.015). Satisfaction with breasts (82.00vs.59.00, P < 0.001), psychosocial well-being (93.00vs.77.00, P = 0.001) and physical well-being (chest) (89.00vs.82.00, P < 0.001) scores were higher in the SIE-NSM-IRPI group. There were no significant differences between the two groups in disease-free survival (hazard ratio = 0.829, 95% confidence interval = 0.182-3.779) and overall survival (hazard ratio = 1.919, 95% confidence interval = 0.169-21.842). CONCLUSION: In this selected cohort of patients with early breast cancer, SIE-NSM-IRPI was comparable to C-NSM-IRPI, considering oncologic safety and detection of sentinel lymph nodes. It had a lower incidence of prosthesis removal, shorter incision length, and was associated with better patient satisfaction with the breasts. More random clinical trials of this novel approach in a larger cohort of Chinese patients with an extended follow-up period are needed in the future.
Asunto(s)
Neoplasias de la Mama , Mamoplastia , Mastectomía Subcutánea , Femenino , Humanos , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Mamoplastia/métodos , Mastectomía/métodos , Mastectomía Subcutánea/métodos , Pezones/patología , Pezones/cirugía , Estudios RetrospectivosRESUMEN
CYP2D6 gene polymorphism has a profound impact upon the effect of tamoxifen as adjuvant endocrine therapy in breast cancer. However, it had never been reported whether the adverse drug reactions vary by CYP2D6 metabolic status for patients treated with tamoxifen or toremifene. We conducted a retrospective study in breast cancer patients to investigate the impact of CYP2D6 metabolic status on liver dysfunction events, gynecological events and dyslipidemia events. According to CYP2D6*10 (100C â T) genotype, the enrolled patients were further categorized into four cohorts (extensive metabolizers taking tamoxifen [EM + TAM], extensive metabolizers taking toremifene [EM + TOR], intermediate metabolizers taking tamoxifen [IM + TAM], and intermediate metabolizers taking toremifene [IM + TOR]). A total of 192 patients were included in the study, with a median follow-up time of 26.2 months. In EM + TAM cohort, the risks of liver dysfunction events (P = .004) and gynecological events (P = .004) were significantly higher compared to EM + TOR cohort. In IM + TAM cohort, the risks of liver dysfunction events (P = .14) and gynecological events (P = .99) were not significantly different from IM + TOR cohort. A significant decrease of total cholesterol was observed in EM + TAM cohort around 1 year after taking tamoxifen (P < .001). Significant interactions between CYP2D6 metabolic status and endocrine agents were observed in terms of liver dysfunction events (P-interaction = .007) and gynecological events (P-interaction = .026). These findings suggested that CYP2D6 gene polymorphism played a significant role in predicting liver dysfunction, gynecological diseases and lipid metabolism changes among patients taking tamoxifen or toremifene.
Asunto(s)
Neoplasias de la Mama , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Estudios de Cohortes , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Femenino , Genotipo , Humanos , Estudios Retrospectivos , Tamoxifeno/efectos adversos , Toremifeno/efectos adversosRESUMEN
BACKGROUND: Telehealth has been widely adopted in providing Parkinson's disease care during the coronavirus disease 2019 pandemic. OBJECTIVE: The aim of this study was to survey people living with Parkinson's disease (PwPD) about their attitudes toward and utilization of telehealth services. METHODS: A survey was administered to PwPD via Parkinson's Foundation and Columbia University mailing lists. RESULTS: Of 1,163 responses, 944 complete responses were analyzed. Telehealth awareness was 90.2% (850/942), and utilization was 82.8% (780/942). More than 40% of PwPD were equally or more satisfied with telehealth compared with in-person visits in all types of services used. The highest satisfaction was observed in speech-language pathology appointments (78.8%, 52/66) followed by mental health services (69.2%, 95/137). CONCLUSIONS: In selected circumstances and indications, such as speech-language pathology and mental health services, telehealth may be a useful tool in the care of PwPD beyond the coronavirus disease 2019 pandemic. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
Asunto(s)
COVID-19 , Enfermedad de Parkinson , Telemedicina , Actitud , Humanos , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/terapia , Encuestas y CuestionariosRESUMEN
In the hazard assessment of mixtures, the mixture predicted no-effect concentration (mPNEC) is always derived by the concentration addition (CA) model (mPNECCA) to assess the risk of mixtures combined with exposure assessment. However, the independent action (IA) model, which is also widely used as the CA model in the prediction and evaluation of mixture toxicity, is always used to calculate the population fraction showing a predefined effect, not mPNEC, and this limits the application of IA model in the mixture risk assessment. In this study, we explored the process of mPNEC derived by the IA method (mPNECIA) based on the species sensitivity distribution (SSD) and compared mPNECIA with mPNECCA. Taking two common pesticides, dimethoate (DIM) and dichlorvos (DIC), exposed in the actual water environment as an example, their SSD models were constructed separately using nine distribution functions after toxicity data screening and quality testing. For both DIC and DIM, all different nine models had passed the Kolmogorov-Smirnov test. Then, the PNECs of two pesticides were derived based on SSD models. Finally, mPNECIA with different concentration ratios was derived and compared to mPNECCA based on 81 combinations of nine SSD models. Most mPNEC values derived by IA model were more conservative than those by CA. It is worth noting that the mPNECIA is more conservative than mPNECCA for the commonly used log-logit distribution (function 7), log-normal distribution (8), and log-Weibull distribution (9). This study provides a new direction for the application of IA in the risk assessment and enriches the framework of mixture risk assessment.
Asunto(s)
Plaguicidas , Diclorvos , Dimetoato , Plaguicidas/toxicidad , Medición de RiesgoRESUMEN
Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.
Asunto(s)
Diferenciación Celular , Colágeno Tipo III/metabolismo , Colágeno Tipo I/metabolismo , Dexmedetomidina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Lipopolisacáridos/farmacología , Miofibroblastos/citología , Receptores Adrenérgicos alfa 2/química , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Transducción de Señal , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína smad3/genética , Proteína smad3/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
With the rapid development of ultra high voltage alternating current (UHV AC) transmission, the intensity of environmental power frequency electric field (PFEF) near UHV AC transmission lines increased continuously, which has attracted considerable public attention on the potential health effects of PFEF. In this study, the effect of PFEF exposure on the kidney was explored. Institute of Cancer Research (ICR) mice were exposed to 35 kV/m PFEF (50 Hz). Two indicators relating to renal function (urea nitrogen and creatinine) were tested after the exposure of 7d, 14d, 21d, 35d and 49d. The pathological morphology and cellular ultrastructure of kidney were observed respectively by light microscopy and electron microscopy after the exposure of 25d and 52d. Results showed that compared with that of the control group, the concentration of urea nitrogen of 35 kV/m PFEF exposure group significantly increased on the 21st and 35th days, and the concentration of creatinine significantly increased on the 14th, 21st and 35th days. However, the concentrations of creatinine and urea nitrogen both returned to normal levels on the 49th day. Furthermore, an enlarged Bowman's space, the vacuolation of renal tubular epithelial cells and the foot process effacement of podocyte were found after 25d exposure, but no abnormality was observed after 52d exposure. Obviously, a short-term (35d) exposure of 35 kV/m PFEF could cause kidney injury, which could be recovered after a longer-term (52d) exposure. Based on this study and relevant literatures, one explanation for this two-way effect is as follows. Kidney injury was caused by the disequilibrium of mitochondrial dynamics under 35 kV/m PFEF exposure. PFEF could also activate Wnt/ß-catenin signal to promote the recovery of renal tubular epithelial cells and glomerular podocytes, so kidney injury could be repaired.
Asunto(s)
Electricidad , Exposición a Riesgos Ambientales , Riñón/fisiología , Animales , Riñón/patología , Masculino , Ratones , Electricidad EstáticaRESUMEN
Background and Purpose- We used a decision analysis approach to analyze triage strategies for patients with acute stroke symptoms while accounting for prehospital large vessel occlusion (LVO) screening methods and key time metrics. Methods- Our decision analysis compared anticipated functional outcomes for patients within the IV-tPA (intravenous tissue-type plasminogen activator) treatment window in the mothership and drip-and-ship frameworks. Key branches of the model included IV-tPA eligibility, presence of an LVO, and endovascular therapy eligibility. Our decision analysis evaluated 2 prehospital LVO screening approaches: (1) no formal screening and (2) the use of clinical LVO screening scales. An excellent outcome was defined as modified Rankin Scale scores 0-1. Probabilities and workflow times were guideline-based or imputed from published studies. In sensitivity analyses, we individually and jointly varied transport time to the nearest primary stroke center, additional time required to transport directly to a comprehensive stroke center, and LVO screening scale predictive probabilities. We evaluated 2 separate scenarios: one in which ideal time metrics were achieved and one under current real-world metrics. Results- In the ideal metrics scenario, the drip-and-ship strategy was almost always favored in the absence of formal LVO screening. For patients screened positive for an LVO, mothership was favored if the additional transport time to the comprehensive stroke center was <3 to 23 minutes. Under real-world conditions, in which primary stroke center workflow is slower than ideal, the mothership strategy was favored in more scenarios, regardless of formal LVO screening. For example, mothership was favored with an additional transport time to the comprehensive stroke center of <32 to 99 minutes for patients screened positive for an LVO and <28 to 39 minutes in the absence of screening. Conclusions- Joint consideration of LVO probability, screening, workflow times, and transport times may improve prehospital stroke triage. Drip-and-ship was more favorable when more ideal primary stroke center workflow times were modeled.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Técnicas de Apoyo para la Decisión , Fibrinolíticos/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Activador de Tejido Plasminógeno/uso terapéutico , Triaje , Servicios Médicos de Urgencia , Procedimientos Endovasculares , Humanos , Modelos Teóricos , Terapia Trombolítica , Tiempo de TratamientoRESUMEN
Previous studies demonstrated long-term stimulation of some commercial personal care products (PCPs) on freshwater luminescent bacteria Vibrio qinghaiensis sp.-Q67 (Q67). However, whether a certain component can affect mixture's hormetic effect is still unknown. In this paper, two of ingredients in PCPs, 2-phenoxyethanol (PhE) and polyethylene glycol 400 (PEG400), were selected as object compounds to explore the relationship between concentration-response (CR) of mixtures and that of a single component. It was found that PEG400 has monotonic CR (MCR) on Q67 both at the short-term (0.25â¯h) and long-term (12â¯h) exposures while PhE has MCR at 0.25â¯h and hormetic CR (HCR) at 12â¯h. Here, the concentration-response curves (CRCs) of PEG400 at 0.25 and 12â¯h are overlapped each other and the CRCs of PEG400 are on the right of PhE. If the pEC50 is taken as a toxic index, the toxicities of PEG400 at two times are basically the same, and those of PhE are the same, too, but PhE is twice as toxic as PEG400. For the mixtures of PEG400 and PhE, all rays except R1 have MCRs at 0.25â¯h while all rays have HCRs at 12â¯h where the higher the mixture ratio of PhE is, the more negative the maximum stimulation effect is. More importantly, the Emin values of all rays are more negative (1.79-3.17-fold) than that of PhE worked alone, which implies that the introduction of PEG400 significantly enhances stimulative effect of PhE. At 0.25â¯h, all binary mixture rays but R1 produce a low-concentration additive action and high-concentration synergism. At 12â¯h, all rays display additive action, antagonism, additive action, and synergism in turn when the concentration changes from low to high. The overall findings suggested toxicological interactions should be considered in the risk assessment of PCPs and their potential impacts on ecological balances.
Asunto(s)
Glicoles de Etileno/toxicidad , Polietilenglicoles/toxicidad , Vibrio/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Cosméticos/química , Interacciones Farmacológicas , Hormesis , Luminiscencia , Factores de Tiempo , Pruebas de ToxicidadRESUMEN
The biological effects related to personal care products (PCPs) are almost induced by some active ingredients in the PCPs rather than the PCP itself. In this study, 23 common and widely used toner, skin water, and make-up water (TSM) commodities were directly taken as mixture samples, and Vibrio qinghaiensis sp.-Q67 (Q67) was used as the test organism. The toxicities of the TSMs to Q67 were determined via microplate toxicity analysis at 0.25â¯h and 12â¯h. Each TSM commodity can be regarded as a complicated mixture (relative concentration is 1). It was shown that the concentration-response curves (CRCs) of 23 TSMs are monotonic sigmoid-shaped (S-shaped) at 0.25â¯h, the CRCs of six TSMs are also S-shaped but the other 17 TSMs are non-monotonic hormetic or J-shaped at 12â¯h. In addition, to effectively characterize the nature of the stimulation and inhibition phases, it is suggested that five parameters such as the ECL (the median stimulation effective concentration (left)), Emin (the maximum stimulation effect), ECmin (the maximum stimulation effective concentration), ZEP (zero effect point where the effect is 0 and the concentration is ZEP), and EC50 can depict the non-monotonic CRC. To the best of our knowledge, this is the first study about the hormetic CRCs of commercial PCP mixtures.
Asunto(s)
Cosméticos/toxicidad , Hormesis , Vibrio/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidadRESUMEN
Uric acid (UA) is a natural antioxidant and iron scavenger in the human body, which has been hypothesized to exert an anti-oxidative effect in Parkinson's disease (PD). This study aimed to investigate the relationship between serum UA levels and freezing of gait (FOG) in PD. A total of 321 Chinese PD patients with fasting serum UA evaluated were included in the cross-sectional study. Demographics, clinical features, and therapeutic regimen were collected. The Unified PD Rating Scale (UPDRS) III and Hoehn and Yahr (H and Y) stage were used to evaluate the severity of disease, and the Frontal Assessment Battery (FAB) and Montreal Cognitive Assessment (MoCA) scales were used to assess the cognitive function. Patients with FOG showed lower proportion of male, longer disease duration, lower body mass index, lower concentrations of serum UA, higher total levodopa equivalent daily dosage, higher UPDRS III score, greater median H and Y stage, lower scores of FAB and MoCA, and higher frequencies of motor fluctuation, dyskinesia, falls, and festination compared to patients without FOG (P < 0.05). The binary logistic regression model indicated that high UPDRS III score (OR = 1.049, P < 0.001), fluctuation (OR = 2.677, P = 0.035), dyskinesia (OR = 6.294, P = 0.003), festination (OR = 3.948, P < 0.001), falls (OR = 7.528, P < 0.001), and low serum UA levels (OR = 0.990, P < 0.001) were associated with FOG. Our study suggests that low serum UA concentration is associated with the occurrence of FOG in PD.
Asunto(s)
Marcha , Enfermedad de Parkinson/fisiopatología , Ácido Úrico/sangre , Antiparkinsonianos/uso terapéutico , Biomarcadores/sangre , Índice de Masa Corporal , Cognición , Estudios Transversales , Progresión de la Enfermedad , Ayuno , Femenino , Marcha/fisiología , Humanos , Modelos Logísticos , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
The risk assessment of an expanding array of emerging contaminants in aquatic ecosystems and the establishment of water quality criteria rely on species sensitivity distribution (SSD), necessitating ample multi-trophic toxicity data. Computational methods, such as quantitative structure-activity relationship (QSAR), enable the prediction of specific toxicity data, thus mitigating the need for costly experimental testing and exposure risk assessment. In this study, robust QSAR models for four aquatic species (Rana pipiens, Crassostrea virginica, Asellus aquaticus, and Lepomis macrochirus) were developed using leave-one-out (LOO) screening variables and the partial least squares algorithm to predict toxicity data for paraquat, bisphenol A, and carbamazepine. These predicted data can be integrated with experimental data to construct SSD models and derive hazardous concentration for 5 % of species (HC5) for the criterion maximum concentration. The chronic water quality criterion for paraquat, bisphenol A, and carbamazepine were determined at 6.7, 11.1, and 3.5 µg/L, respectively. The QSAR-SSD approach presents a viable and cost-effective method for deriving water quality criteria for other emerging contaminants.
Asunto(s)
Compuestos de Bencidrilo , Carbamazepina , Paraquat , Fenoles , Relación Estructura-Actividad Cuantitativa , Contaminantes Químicos del Agua , Calidad del Agua , Fenoles/toxicidad , Compuestos de Bencidrilo/toxicidad , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisis , Carbamazepina/toxicidad , Paraquat/toxicidad , Animales , Medición de Riesgo , Copépodos/efectos de los fármacosRESUMEN
Mounting evidence suggests that environmental pollutants may affect reproductive health, potentially leading to adverse outcomes like pregnancy loss. However, it remains unclear whether exposure to synthetic phenolic antioxidants (SPAs) correlates with early pregnancy loss (EPL). This study explores SPA exposure's link to EPL and its potential molecular mechanisms. From 2021 to 2022, 265 early pregnant women (136 serum and 129 villus samples) with and without EPL were enrolled. We quantified 17 SPAs in serum and chorionic villus, with AO1010, AO3114, BHT, AO2246, and BHT-Q frequently being detected, suggesting their ability to cross the placental barrier. AO1135 showed a positive relationship with EPL in sera, indicating a significant monotonic dose-response relationship (p-trend <0.001). BHT-Q exhibited a similar relationship with EPL in villi. Inhibitory effects of BHT-Q on estradiol (E2) were observed. Molecular docking revealed SPA-protein interactions involved in E2 synthesis. SPA-induced EPL might occur with specific serum levels of AO1135 and certain villus levels of AO1010, BHT-Q, and AO2246. BHT-Q emerges as a potential biomarker for assessing EPL risk. This study provides insights into understanding of the exposure to SPAs and potential adverse outcomes in pregnant women.
Asunto(s)
Aborto Espontáneo , Antioxidantes , Fenoles , Femenino , Humanos , Embarazo , Aborto Espontáneo/inducido químicamente , Adulto , Simulación del Acoplamiento Molecular , Contaminantes AmbientalesRESUMEN
Cardiomyopathy is a common complication and significantly increases the risk of death in septic patients. Our previous study demonstrated that post-treatment with dexmedetomidine (DEX) aggravates septic cardiomyopathy. However, the mechanisms for the side effect of DEX post-treatment on septic cardiomyopathy are not well-defined. Here we employed a cecal ligation and puncture (CLP) model and α2A-adrenoceptor deficient (Adra2a-/-) mice to observe the effects of DEX post-treatment on myocardial metabolic disturbances in sepsis. CLP mice displayed significant cardiac dysfunction, altered mitochondrial dynamics, reduced cardiac lipid and glucose uptake, impaired fatty acid and glucose oxidation, enhanced glycolysis and decreased ATP production in the myocardium, almost all of which were dramatically enhanced by DEX post-treatment in septic mice. In Adra2a-/- mice, DEX post-treatment did not affect cardiac dysfunction and metabolic disruptions in CLP-induced sepsis. Additionally, Adra2a-/- mice exhibited impaired cardiac function, damaged myocardial mitochondrial structures, and disturbed fatty acid metabolism and glucose oxidation. In sum, DEX post-treatment exacerbates metabolic disturbances in septic cardiomyopathy in a α2A-adrenoceptor dependent manner.
Asunto(s)
Cardiomiopatías , Dexmedetomidina , Cardiopatías , Sepsis , Humanos , Ratones , Animales , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Cardiopatías/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Glucosa/uso terapéutico , Ácidos GrasosRESUMEN
Global sensitivity analysis combined with quantitative high-throughput screening (GSA-qHTS) uses random starting points of the trajectories in mixture design, which may lead to potential contingency and a lack of representativeness. Moreover, a scenario in which all factor levels were at stimulatory effects was not considered, thereby hindering a comprehensive understanding of GSA-qHTS. Accordingly, this study innovatively introduced an optimised experimental design, uniform design (UD), to generate non-random and representative sample points with smaller uniformity deviation as starting points of multiple trajectories. By combining UD with the previously optimised one-factor-at-a-time (OAT) method, a novel mixture design method was developed (UD-OAT). The single toxicity tests showed that three pyridinium and five imidazolium ionic liquids (ILs) exerted stimulatory effects on Vibrio qinghaiensis sp.-Q67; thus, four stimulatory effective concentrations of each IL were selected as factor levels. The UD-OAT generated 108 mixture samples with equal frequency and without repetition. High-throughput microplate toxicity analysis revealed that all 108 mixtures exhibited inhibitory effects. Among these, type B mixtures exhibited increasing toxicities that subsequently decreased, unlike type C mixtures, which consistently increased over time. GSA successfully identified three of the eight ILs as important factors influencing the toxicities of the mixtures. When individual ILs produced stimulatory effects, mixtures containing two to three ILs exhibited either stimulatory effects or none. In contrast, mixtures containing five to eight ILs exhibited inhibitory effects, while those containing four ILs showed a transition from stimulatory to inhibitory effects. This study provides a novel mixture design method for studying mixture toxicity and fills the application gap of GSA-qHTS. The phenomenon of individuals being beneficial while mixtures can be harmful challenges traditional mixture risk assessments.
RESUMEN
BACKGROUND: Angiogenesis is an effective method for promoting neurological function recovery after cerebral ischemia (CI). Buyang Huanwu decoction (BHD) is a traditional Chinese medicinal recipe that is frequently employed for CI treatment. Previous investigations have validated that it promotes angiogenesis following CI. Nevertheless, the precise mechanism by which it does this has yet to be completely understood. OBJECTIVE: This study aims to examine the underlying mechanism through which BHD facilitates angiogenesis following CI by regulating the exosomal MALAT1/YAP1/HIF-1α signaling axis, specifically via the involvement of caveolin-1 (Cav1), an endocytosis-associated protein. METHODS: A CI model was created using middle cerebral artery occlusion (MCAO). Following the administration of multiple doses of BHD, various parameters, including the neurobehavioral score, pathological damage, and angiogenesis, were assessed in each group of mice to identify the optimal dosage of BHD for treating CI. The molecular processes underlying the angiogenic implications of BHD following CI were investigated exhaustively by employing single-cell sequencing. Finally, the involvement of Cav1 was confirmed in Cav1 knockout mice and Cav1-silenced stably transfected strains to validate the mechanism by which BHD increases angiogenesis following CI. RESULTS: BHD could promote angiogenesis after CI. Single-cell sequencing results suggested that its potential mechanism of action might be connected with Cav1 and the exosomal MALAT1/YAP1/HIF-1α signaling axis. BHD could promote angiogenesis after CI by regulating the exosomal MALAT1/YAP1/HIF-1α axis through Cav1, as validated in vivo and in vitro experiments. Accordingly, Cav1 may be a key target of BHD in promoting angiogenesis after CI. CONCLUSION: This investigation represents the initial attempt to comprehensively ascertain the underlying mechanism of action of BHD in treating CI using single-cell sequencing, gene-knockout mice, and stable transfected cell lines, potentially associated with the modulation of the exosomal MALAT1/YAP1/HIF-1α axis by Cav1. Our findings offer novel empirical evidence for unraveling the regulatory pathways through which Cav1 participates in angiogenesis following CI and shed light on the potential mechanisms of BHD.
Asunto(s)
Isquemia Encefálica , Caveolina 1 , Medicamentos Herbarios Chinos , Exosomas , Subunidad alfa del Factor 1 Inducible por Hipoxia , ARN Largo no Codificante , Proteínas Señalizadoras YAP , Animales , ARN Largo no Codificante/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Medicamentos Herbarios Chinos/farmacología , Caveolina 1/metabolismo , Ratones , Masculino , Exosomas/metabolismo , Exosomas/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Humanos , AngiogénesisRESUMEN
Background: Circulating tumor DNA (ctDNA) is a potential biomarker not only capable of monitoring the treatment response during neoadjuvant therapy (NAT) or rescue therapy, but also identifying minimal residual disease (MRD) and detecting early relapses after primary treatment. However, it remains uncertain whether the detection of ctDNA at diagnosis, before any treatment, can predict the prognosis for patients with early breast cancer. The objective of our study was to evaluate the predictive value of baseline ctDNA for prognosis in patients with early breast cancer. Methods: A total of 90 patients with early breast cancer and 24 healthy women were recruited between August 2016 and October 2016. Peripheral blood samples were collected from patients at diagnosis, before any treatment. Blood samples were processed and subjected to targeted deep sequencing with a next-generation sequencing (NGS) panel of 1,021 cancer-related genes. The recurrence-free survival (RFS) and invasive disease-free survival (iDFS) were reported. Results: The 90 patients with breast cancer included 6 patients with ductal carcinoma in situ (DCIS) and 84 patients with invasive breast cancer. Within the cohort of patients with invasive breast cancer, ctDNA were detected in 57 patients, with a ctDNA detection rate of 67.9%. Meanwhile, no ctDNA was detected in DCIS patients. Among 84 patients with invasive breast cancer, patients with high-level ctDNA had a significantly lower RFS compared to patients with low-level ctDNA (log-rank P=0.0036). Conclusions: Our study suggested that ctDNA at diagnosis, before any treatment, could potentially serve as a biomarker to predict the prognosis for patients with early breast cancer. However, further follow-up and more studies with large sample sizes are required to confirm these findings.