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Background: The impediment to ß-amyloid (Aß) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aß from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Sistema Glinfático , Camundongos Transgênicos , Ocitocina , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Ocitocina/farmacologia , Ocitocina/administração & dosagem , Ocitocina/metabolismo , Sistema Glinfático/metabolismo , Sistema Glinfático/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Administração Intranasal , Linfangiogênese/efeitos dos fármacos , Masculino , Aquaporina 4/metabolismo , Aquaporina 4/genética , Humanos , Imageamento por Ressonância Magnética , Meninges/metabolismo , Meninges/efeitos dos fármacos , Meninges/diagnóstico por imagemRESUMO
Background and Objectives: The success rate of Helicobacter pylori (H. pylori) eradication in China is declining. The aim of this study was to evaluate eradication outcomes in clinical practice and identifies factors contributing to treatment failure. Methods: A retrospective review was conducted on patients treated for H. pylori infection with 14-day bismuth-containing quadruple therapy at a Beijing medical center from January 2020 to December 2023. We analyzed demographic and clinical data, eradication rates across regimens, and performed multivariate analysis to pinpoint predictors of failure. Results: Out of 3340 participants, 2273 (68.1%) achieved eradication. Amoxicillin-based combinations (69.2%) outperformed other antibiotic regimens (58.9%, p < 0.001), with amoxicillin plus doxycycline reaching a 71.4% success rate. Esomeprazole-based regimens were more effective (73.6%) than other PPI regimens (65.2%, p = 0.001), notably, a rabeprazole, amoxicillin, doxycycline, and bismuth combination had an 80.0% success rate. Age, gender, and smoking and drinking were significant eradication failure predictors. Conclusion: In real-world settings, 14-day amoxicillin and esomeprazole-based quadruple regimens have been demonstrated to be more effective than other regimens. Age, gender, and lifestyle habits are identified as independent risk factors for eradication failure. Registration: This study was registered in the Chinese Clinical Trial Registry on 08/01/2024 (clinical trial registration number: ChiCTR2400079647).
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Endogenous opioid antinociception is a self-regulatory mechanism that reduces chronic pain, but its underlying circuit mechanism remains largely unknown. Here, we showed that endogenous opioid antinociception required the activation of mu-opioid receptors (MORs) in GABAergic neurons of the central amygdala nucleus (CEA) in a persistent-hyperalgesia mouse model. Pharmacogenetic suppression of these CEAMOR neurons, which mimics the effect of MOR activation, alleviated the persistent hyperalgesia. Furthermore, single-neuron projection analysis revealed multiple projectome-based subtypes of CEAMOR neurons, each innervating distinct target brain regions. We found that the suppression of axon branches projecting to the parabrachial nucleus (PB) of one subtype of CEAMOR neurons alleviated persistent hyperalgesia, indicating a subtype- and axonal-branch-specific mechanism of action. Further electrophysiological analysis revealed that suppression of a distinct CEA-PB disinhibitory circuit controlled endogenous opioid antinociception. Thus, this study identified the central neural circuit that underlies endogenous opioid antinociception, providing new insight into the endogenous pain modulatory mechanisms.
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BACKGROUND: The 8th edition American Joint Committee on Cancer staging system combined anatomic stage (AS) with receptor status and grade to create prognostic stage (PS). PS has been validated in single-institution and cancer registry studies; however, missing human epidermal growth factor receptor 2 (HER2) status and variable treatment and follow-up create limitations. OBJECTIVE: Our objective was to compare the relative prognostic ability of PS versus AS to predict survival using breast cancer clinical trial data. METHODS: Women with non-metastatic breast cancer enrolled in six Alliance for Clinical Trials in Oncology trials were included (enrollment years 1997-2010). AS and PS were constructed using pathological tumor size, nodal status, estrogen receptor (ER), progesterone receptor (PR), HER2 status, and grade. Unadjusted Cox proportional hazard models were estimated to predict overall survival within 5 years, with AS and PS as predictor variables. The relative predictive power of staging models was assessed by comparing Harrell concordance indices (C-indices). Kaplan-Meier-based mortality estimates were compared by stage. RESULTS: Overall, 6924 women were included (median age 53 years); 45.2% were diagnosed with ER+/PR+/HER2- tumors, 26.2% with HER2+ tumors, and 17.1% with ER-/PR-/HER2- tumors. Median follow-up time was 5 years (interquartile range 2.95-5.00). PS significantly improved predictive performance (C-index 0.721) for overall survival compared with AS (0.700) (p = 0.020). Kaplan-Meier hazard estimates suggested PS did not distinguish mortality risk between patients with IIB and IIIA or IB and IIA disease. CONCLUSIONS: PS has significantly improved predictive performance for OS compared with AS. As systemic therapies evolve, it will be important to re-evaluate the prognostic staging system, particularly for patients with intermediate-stage cancers. CLINICALTRIALS: gov Identifier: NCT02171078.
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Neoplasias da Mama , Estadiamento de Neoplasias , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/mortalidade , Pessoa de Meia-Idade , Receptores de Estrogênio/metabolismo , Receptor ErbB-2/metabolismo , Prognóstico , Taxa de Sobrevida , Receptores de Progesterona/metabolismo , Seguimentos , Adulto , Idoso , Gradação de TumoresRESUMO
Transcriptional reprogramming is critical for plant immunity. Several calmodulin (CaM)-binding protein 60 (CBP60) family transcription factors (TFs) in Arabidopsis (Arabidopsis thaliana), including CBP60g, Systemic Acquired Resistance Deficient 1 (SARD1), CBP60a, and CBP60b, are critical for and show distinct roles in immunity. However, there are additional CBP60 members whose function is unclear. We report here that Arabidopsis CBP60c-f, four uncharacterized CBP60 members, play redundant roles with CBP60b in the transcriptional regulation of immunity responses, whose pCBP60b-driven expression compensates the loss of CBP60b. By contrast, neither CBP60g nor SARD1 is inter-changeable with CBP60b, suggesting clade-specific functionalization. We further show that function of CBP60b clade TFs relies on DNA-binding domains (DBDs) and CaM-binding domains, suggesting that they are downstream components of calcium signaling. Importantly, we demonstrate that CBP60s encoded in earliest land plant lineage Physcomitrium patens and Selaginella moellendorffii, are functionally homologous to Arabidopsis CBP60b, suggesting that the CBP60b clade contains the prototype TFs of the CBP60 family. Furthermore, tomato and cucumber CBP60b-like genes rescue the defects of Arabidopsis cbp60b and activate the expression of tomato and cucumber SALICYLIC ACID INDUCTION DEFICIIENT2 (SID2) and ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) genes, suggesting that immune response pathways centered on CBP60b are also evolutionarily conserved. Together, these findings suggest CBP60b clade transcription factors are functionally conserved in evolution and positively mediate immunity.
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The dorsal spinal cord is crucial for the transmission and modulation of multiple somatosensory modalities, such as itch, pain, and touch. Despite being essential for the well-being and survival of an individual, itch and pain, in their chronic forms, have increasingly been recognized as clinical problems. Although considerable progress has been made in our understanding of the neurochemical processing of nociceptive and chemical itch sensations, the neural substrate that is crucial for mechanical itch processing is still unclear. Here, using genetic and functional manipulation, we identified a population of spinal neurons expressing neuromedin U receptor 2 (Nmur2+) as critical elements for mechanical itch. We found that spinal Nmur2+ neurons are predominantly excitatory neurons, and are enriched in the superficial laminae of the dorsal horn. Pharmacogenetic activation of cervical spinal Nmur2+ neurons evoked scratching behavior. Conversely, the ablation of these neurons using a caspase-3-based method decreased von Frey filament-induced scratching behavior without affecting responses to other somatosensory modalities. Similarly, suppressing the excitability of cervical spinal Nmur2+ neurons via the overexpression of functional Kir2.1 potassium channels reduced scratching in response to innocuous mechanical stimuli, but not to pruritogen application. At the lumbar level, pharmacogenetic activation of these neurons evoked licking and lifting behaviors. However, ablating these neurons did not affect the behavior associated with acute pain. Thus, these results revealed the crucial role of spinal Nmur2+ neurons in mechanical itch. Our study provides important insights into the neural basis of mechanical itch, paving the way for developing novel therapies for chronic itch. PERSPECTIVE: Excitatory Nmur2+ neurons in the superficial dorsal spinal cord are essential for mechanical but not chemical itch information processing. These spinal Nmur2+ neurons represent a potential cellular target for future therapeutic interventions against chronic itch. Spinal and supraspinal Nmur2+ neurons may play different roles in pain signal processing.
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Neurônios , Prurido , Medula Espinal , Prurido/fisiopatologia , Prurido/metabolismo , Animais , Medula Espinal/metabolismo , Camundongos , Neurônios/metabolismo , Neurônios/fisiologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
Ferroptosis is a vital driver of pathophysiological consequences of Alzheimer's disease (AD). High-efficiency pharmacological inhibition of ferroptosis requires comprehensive coordination of diverse abnormal intracellular events, which is an urgent problem and great challenge for its application in AD treatment. Herein, a triphenylphosphonium-modified quercetin-derived smart nanomedicine (TQCN) is developed for multipronged anti-ferroptosis therapy in AD. Taking advantage of the favorable brain-targeting and mitochondria-locating properties, TQCN can efficiently chelate iron through phytopolyphenol-mediated spontaneous coordination and self-assemble into metal-phenolic nanocomplexes in situ, exerting escalating exogenous offensive effects to attenuate iron overload and its induced free radical burst. Meanwhile, the Nrf2 signaling-mediated endogenous defensive system is reconstituted to restore iron metabolism homeostasis represented by iron export and storage and enhance cytoprotective antioxidant cascades represented by lipid peroxidation detoxification. Benefiting from the multifaceted regulation of pathogenic processes triggering ferroptosis, TQCN treatment can ameliorate various neurodegenerative manifestations associated with brain iron deposition and rescue severe cognitive decline in AD mice. This work displays great promise of in situ self-assembled phytopolyphenol-coordinated intelligent nanotherapeutics as advanced candidates against ferroptosis-driven AD progression.
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Doença de Alzheimer , Ferroptose , Compostos Organofosforados , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Antioxidantes , FerroRESUMO
Soil organic carbon (SOC) is the core component of terrestrial carbon (C) sink. Exploring the transformation and stabilization mechanism of SOC is key to understand the function of terrestrial C sink which copes with climate change. The traditional perspective is that plant residues are the initial source of SOC. The new concept of "soil microbial C pump" emphasizes that the synthesized products of soil microbial assimilation are important contributors to the stable SOC. This provides a new insight to the sequestration mechanism of SOC. Due to the complex and variable decomposition process of plant residues and the high heterogeneity of microbial residues, the transformation and stabilization mechanism of plant residues and microbial residues into SOC is still unclear. We reviewed research progress in plant and microbial residues, and introduced the characterization methods of quantification and transformation of plant residues and microbial residues, and also summarized the new findings on the transformation of plant and microbial residues into SOC. We further discussed the contribution and driving factors of microbial and plant-derived C to SOC. Finally, we prospected the future development direction and research focus in this field. This review would provide the scientific reference for the research of soil C sequestration in terrestrial ecosystem.
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Ecossistema , Solo , Solo/química , Carbono , Sequestro de Carbono , Celulose , Plantas , Microbiologia do SoloRESUMO
Objective: This study aimed to analyze the effect of modular nursing model for typical issues on enteral nutrition status, immune function, and quality of life in patients with colon cancer. Methods: The clinical data of 106 colorectal cancer patients who came to our hospital from January 2020 to January 2022 were retrospectively analyzed. The patients were randomized into the control and observation group based on the different nursing models, with 53 cases in each group. The patients in the control group received a simple enteral nutrition nursing model, while these in the observation group were administrated with a modular nursing model for typical issues on the basis of the control group. The differences in enteral nutrition status, immune function, and quality of life indicators of patients before and after nursing were counted and compared between the two groups. Results: After the nursing, the contents of albumin, serum albumin, and transferrin were all elevated in both two groups compared with these before the nursing (P < 0.001), and these contents in observation group was markedly higher than these in the control group after the nursing (P < 0.001). The expressions of immune function indicators, including CD3+, CD4+, CD4+/CD8+, and SIgA of the two groups after the nursing, were much higher than these before the nursing (P < 0.05), while the contents of CD8+ and IgG were sharply decreased in comparison with these before the nursing (P < 0.05). The improvement of immune indicators in the observation group after the nursing was strongly better than that in the control (P < 0.01). The proportion of the total nursing satisfaction was significantly higher in the observation group than that in the control (P < 0.05). After the nursing, the life quality scores of two groups were both strongly elevated (P < 0.05), and the improvement of life quality scores were memorably better in the observation group after nursing than these in the control (P < 0.01). Conclusion: For patients undergoing radical colon cancer resection, modular nursing model for typical issues in the early postoperative period is not only safe, but also improves enteral nutrition, can better maintain immune function in the early postoperative period, improve nursing satisfaction, improve patient prognosis, and promote the improvement of the condition, which is worthy of popularization and application.
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The objectives of this study were to evaluate the difference of selective attention efficiency between children with low and high socioeconomic status (SES) and the promotional effect of attention network training (an attention network test was used as the training task) on selective attention in children with the low SES. A total of 139 10- to 12-year-old children participated in two experiments (71 in Experiment 1 and 68 in Experiment 2). The results suggest that selective attention and switch ability of children with high SES are better than those of children with low SES. After attention network training, selective attention, switch ability, and working memory of low-SES children improved significantly. The findings provide evidence that attention network training could enhance selective attention in low-SES children and that the beneficial training effect could also transfer to switch ability and working memory. The research may provide a promising method to compensate cognitive delay of low-SES children.
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Baixo Nível Socioeconômico , Classe Social , Criança , Humanos , Memória de Curto Prazo , Eletroencefalografia , AtençãoRESUMO
OBJECTIVES: Thyroid cancer incidence increased over 200% from 1992 to 2018, whereas mortality rates had not increased proportionately. The increased incidence has been attributed primarily to the detection of subclinical disease, raising important questions related to thyroid cancer control. We developed the Papillary Thyroid Carcinoma Microsimulation model (PATCAM) to answer them, including the impact of overdiagnosis on thyroid cancer incidence. METHODS: PATCAM simulates individuals from age 15 until death in birth cohorts starting from 1975 using 4 inter-related components, including natural history, detection, post-diagnosis, and other-cause mortality. PATCAM was built using high-quality data and calibrated against observed age-, sex-, and stage-specific incidence in the United States as reported by the Surveillance, Epidemiology, and End Results database. PATCAM was validated against US thyroid cancer mortality and 3 active surveillance studies, including the largest and longest running thyroid cancer active surveillance cohort in the world (from Japan) and 2 from the United States. RESULTS: PATCAM successfully replicated age- and stage-specific papillary thyroid cancers (PTC) incidence and mean tumor size at diagnosis and PTC mortality in the United States between 1975 and 2015. PATCAM accurately predicted the proportion of tumors that grew more than 3 mm and 5 mm in 5 years and 10 years, aligning with the 95% confidence intervals of the reported rates from active surveillance studies in most cases. CONCLUSIONS: PATCAM successfully reproduced observed US thyroid cancer incidence and mortality over time and was externally validated. PATCAM can be used to identify factors that influence the detection of subclinical PTCs.
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Carcinoma Papilar , Carcinoma , Neoplasias da Glândula Tireoide , Humanos , Estados Unidos/epidemiologia , Adolescente , Câncer Papilífero da Tireoide/epidemiologia , Carcinoma/diagnóstico , Carcinoma/patologia , Carcinoma Papilar/epidemiologia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , IncidênciaRESUMO
BACKGROUND: Due to multiple factors, left-behind children in rural areas suffer from neurodevelopment delay and their caregivers suffer from depressive symptoms. This study aimed to analyze the effect of caregivers' depressive symptoms on left-behind children's neurodevelopment, with early stimulation and responsive care mediating. METHODS: We conducted a cross-sectional survey in five counties in China. A total of 904 left-behind children aged 0-3 and their primary caregivers were enrolled. The Zung Self-rating Depression Scale (ZSDS) was used to measure caregivers' depressive symptoms. The Ages and Stages questionnaires-third edition (ASQ-3), which contains five domains: communication (CM), gross motor (GM), fine motor (FM), problem-solving (CG), and personal social (PS), was used to screen children for suspected developmental delay (SDD). RESULTS: 31.4 % of left-behind children suffered from SDD, while 39.7 % of left-behind children's caregivers experienced depressive symptoms. Caregivers' ZSDS scores were positively correlated with the SDD on four domains (FM, GM, CG, and PS), while Early stimulation and responsive care was negatively correlated with the SDD on four domains (CM, FM, CG, and PS). LIMITATIONS: The cross-sectional design limited the ability to ascertain causal relations. Besides, the findings may not be generalized to all regions of China due to the heterogeneity of the study population. CONCLUSIONS: Left-behind children under three years old in rural China were at high risk of SDD, while a substantial proportion of their caregivers had depressive symptoms. Caregivers' depressive symptoms may negatively affect the SDD of left-behind children through caregivers providing less early stimulation and responsive care.
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Cuidadores , Depressão , Humanos , Criança , Pré-Escolar , Estudos Transversais , China , ComunicaçãoRESUMO
Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer's disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and 18F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.
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Doença de Alzheimer , Microglia , Camundongos , Animais , Microglia/metabolismo , Microglia/patologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologia , Transdução de Sinais , Glucose/metabolismoRESUMO
The pathogenesis of colon cancer, a common gastrointestinal tumour, involves complicated factors, especially a series of cell cycle-related genes. E2F transcription factors during the cell cycle play an essential role in the occurrence of colon cancer. It is meaningful to establish an efficient prognostic model of colon cancer targeting cellular E2F-associated genes. This has not been reported previously. The authors first aimed to explore the links of E2F genes with the clinical outcomes of colon cancer patients by integrating data from the TCGA-COAD (n = 521), GSE17536 (n = 177) and GSE39582 (n = 585) cohorts. The Cox regression and Lasso modelling approach to identify a novel colon cancer prognostic model involving several hub genes (CDKN2A, GSPT1, PNN, POLD3, PPP1R8, PTTG1 and RFC1) were utilised. Moreover, an E2F-related nomogram that efficiently predicted the survival rates of colon cancer patients was created. Additionally, the authors first identified two E2F tumour clusters, which showed distinct prognostic features. Interestingly, the potential links of E2F-based classification and 'protein secretion' issues of multiorgans and tumour infiltration of 'T-cell regulatory (Tregs)' and 'CD56dim natural killer cell' were detected. The authors' findings are of potential clinical significance for the prognosis assessment and mechanistic exploration of colon cancer.
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Neoplasias do Colo , Humanos , Prognóstico , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Relevância Clínica , Fatores de Transcrição E2F , Endorribonucleases , Fosfoproteínas Fosfatases , Proteínas de Ligação a RNARESUMO
Introduction: Air pollution imposes a significant burden on public health. Compared with the popular air quality index (AQI), the air quality health index (AQHI) provides a more comprehensive approach to measuring mixtures of air pollutants and is suitable for overall assessments of the short-term health effects of such mixtures. Methods: We established an AQHI and cumulative risk index (CRI)-AQHI for Tianjin using single-and multi-pollutant models, respectively, as well as environmental, meteorological, and daily mortality data of residents in Tianjin between 2018 and 2020. Results and discussion: Compared with the AQI, the AQHI and CRI-AQHI established herein correlated more closely with the exposure-response relationships of the total mortality effects on residents. For each increase in the interquartile range of the AQHI, CRI-AQHI and AQI, the total daily mortality rates increased by 2.06, 1.69 and 0.62%, respectively. The AQHI and CRI-AQHI predicted daily mortality rate of residents more effectively than the AQI, and the correlations of AQHI and CRI-AQHI with health were similar. Our AQHI of Tianjin was used to establish specific (S)-AQHIs for different disease groups. The results showed that all measured air pollutants had the greatest impact on the health of persons with chronic respiratory diseases, followed by lung cancer, and cardiovascular and cerebrovascular diseases. The AQHI of Tianjin established in this study was accurate and dependable for assessing short-term health risks of air pollution in Tianjin, and the established S-AQHI can be used to separately assess health risks among different disease groups.
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Poluentes Atmosféricos , Poluição do Ar , Poluentes Ambientais , Material Particulado/análise , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , China/epidemiologiaRESUMO
With the pandemic of COVID-19, the application of quaternary ammonium compounds (QACs), which can be used in SARS-CoV-2 disinfection products, has increased substantially. QACs cumulated in sewer system are ultimately deposited and enriched in sludge. QACs in the environment can adversely affect human health and the environment. In this study, a liquid chromatography-mass spectrometry method was established for the simultaneous determination of 25 QACs in sludge samples. Ultrasonic extraction and filtration of the samples was performed using a 50 mM hydrochloric acid-methanol solution. The samples were separated by liquid chromatography and detected in multiple reaction monitoring mode. The matrix effects of the sludge on the 25 QACs ranged from - 25.5% to 7.2%. All substances showed good linearity in the range of 0.5-100 ng/mL, with all determination coefficients (R2) greater than 0.999. The method detection limits (MDLs) were 9.0 ng/g for alkyltrimethylammonium chloride (ATMAC), 3.0 ng/g for benzylalkyldimethylammonium chloride (BAC), and 3.0 ng/g for dialkyldimethylammonium chloride (DADMAC). The spiked recovery rates were in the range of 74-107%, while the relative standard deviations were in the range of 0.8-20.6%. Considering its sensitivity, accuracy, and easy operation, the proposed method in this study was used to determine 22 sludge samples collected from a comprehensive wastewater treatment plant. The results showed that the concentrations of ΣATMACs, ΣBACs, and ΣDADMACs were 19.684, 3.199, and 8.344 µg/g, respectively. The main components included ATMAC-C16, ATMAC-C18, ATMAC-C20, ATMAC-C22, BAC-C12, and DADMAC-C18:C18, with concentrations exceeding 1.0 µg/g. The concentration relationships of different components in the congeners showed that some components were of similar origin.
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COVID-19 , Compostos de Amônio Quaternário , Humanos , Compostos de Amônio Quaternário/análise , Esgotos/química , Cloretos , SARS-CoV-2 , Cromatografia Líquida , Espectrometria de Massas , Cromatografia Líquida de Alta Pressão/métodos , Extração em Fase SólidaRESUMO
BACKGROUND: Risk-stratified follow-up guidelines that account for the absolute risk and timing of recurrence may improve the quality and efficiency of breast cancer follow-up. The objective of this study was to assess the relationship of anatomic stage and receptor status with timing of the first recurrence for patients with local-regional breast cancer and generate risk-stratified follow-up recommendations. METHODS: The authors conducted a secondary analysis of 8007 patients with stage I-III breast cancer who enrolled in nine Alliance legacy clinical trials from 1997 to 2013 (ClinicalTrials.gov identifier NCT02171078). Patients who received standard-of-care therapy were included. Patients who were missing stage or receptor status were excluded. The primary outcome was days from the earliest treatment start date to the date of first recurrence. The primary explanatory variable was anatomic stage. The analysis was stratified by receptor type. Cox proportional-hazards regression models produced cumulative probabilities of recurrence. A dynamic programming algorithm approach was used to optimize the timing of follow-up intervals based on the timing of recurrence events. RESULTS: The time to first recurrence varied significantly between receptor types (p < .0001). Within each receptor type, stage influenced the time to recurrence (p < .0001). The risk of recurrence was highest and occurred earliest for estrogen receptor (ER)-negative/progesterone receptor (PR)-negative/Her2neu-negative tumors (stage III; 5-year probability of recurrence, 45.5%). The risk of recurrence was lower for ER-positive/PR-positive/Her2neu-positive tumors (stage III; 5-year probability of recurrence, 15.3%), with recurrences distributed over time. Model-generated follow-up recommendations by stage and receptor type were created. CONCLUSIONS: This study supports considering both anatomic stage and receptor status in follow-up recommendations. The implementation of risk-stratified guidelines based on these data has the potential to improve the quality and efficiency of follow-up.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Receptor ErbB-2 , Receptores de Estrogênio , Recidiva Local de Neoplasia/patologia , Receptores de ProgesteronaRESUMO
Immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain, leading to neurodegeneration in Alzheimer's disease (AD). Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses, but is very challenging. Herein, an engineered macrophage-biomimetic versatile nanoantidote (OT-Lipo@M) is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression. Coating macrophage membranes can not only endow OT-Lipo@M with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain, but also efficiently reduce neurotoxin levels to prevent them from activating microglia. The loaded oxytocin (OT) can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4 (TLR4) on microglia, inhibiting TLR4-mediated pro-inflammatory signalling cascade. Benefiting from this two-pronged immunosuppressive strategy, OT-Lipo@M exhibits outstanding therapeutic effects on ameliorating cognitive deficits, inhibiting neuronal apoptosis, and enhancing synaptic plasticity in AD mice, accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo 9.4T MR imaging. This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.