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Information on the emission of coal combustion-sourced magnetite nanoparticles (MNPs) is lacking, which is critical for their health-related risks. In this study, MNPs in coal fly ashes (CFAs) from various coal-fired power plants (CFPPs) in China equipped with various dust removal devices were extracted and quantified using single particle ICP-MS. The number concentrations of MNPs in CFAs captured by dust removal increased with stage, while their size decreased. Among all the dust removal devices, electrostatic-fabric-integrated precipitators showed the best removal of MNPs. Furthermore, throughout all the coal combustion by-products in a typical CFPP, MNPs in EFA (fly ash escaped from the stack) showed the highest number concentration (1.2â¯×â¯107 particles/mg) and lowest size (78â¯nm). Although the mass of CFA escaping through the stack is extremely low, it still had an emission rate of 1.9â¯×â¯1015 particles/h, contributing 3.56â¯% of the total emissions of MNPs in number. In addition, the purity of MNPs and their associated toxic metals showed a size-dependent variation pattern. As the particle size of MNPs decreased, the proportion of Fe in MNPs increased from 43â¯% in bottom ash (BA) to 84â¯% in EFA, while the abundance of trace toxic metals in EFA was 3.3 times higher than that of BA. These MNPs with the highest purity can adsorb elevated concentrations of toxic metals, and can be discharged directly into the atmosphere, posing a risk of synergistic toxicity.
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T-cell immunoglobulin and mucin domain 3 (TIM3) is an immune checkpoint protein expressed on various types of immune cells in two forms, namely membrane TIM3 (mTIM3) and soluble TIM3 (sTIM3). mTIM3 and sTIM3 share the same ligands, but less is known about functions and mechanisms of sTIM3 compared to those of mTlM3. Abnormal levels of plasma sTIM3 have been observed in patients with many diseases including cancer. Current research mainly focuses on the potential of sTIM3 as a biomarker for the diagnosis and treatment of cancer. However, there are limited investigations on sTIM3 as a target for immunotherapy. This paper provides a literature review on the recent research progress of the production and biological functions of sTIM3 and its clinical significance in cancer immunotherapy.
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Receptor Celular 2 do Vírus da Hepatite A , Imunoterapia , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Imunoterapia/métodos , Animais , Biomarcadores Tumorais/imunologiaRESUMO
The utilization of Cobalt (Co) has surged due to it is critical role in renewable energy technologies and other high-tech applications. Concurrently, the potential health risks associated with Co exposure have raised concerns. Previous studies, including our own, have shown that Co can impair learn and memory functions as an epigenetic hazard, even at low concentrations. In this study, we explore the mechanisms of Co-induced ferroptosis in neurodegenerative damage both in vivo and in vitro, focusing on the epigenetic regulation by N6-methyladenosine (m6A) demethylase alkB homolog 5 (ALKBH5). We identify heme oxygenase-1 (HO-1) as a direct target gene of ALKBH5, playing a crucial role in mitigating Co-induced ferroptosis. ALKBH5 deficiency affects the post-transcriptional regulation of HO-1 through m6A modification, which in turn influences mRNA's stability, intracellular distribution, and alternative splicing, thereby enhancing susceptibility to Co-induced ferroptosis. Additionally, we discuss the potential involvement of heterogeneous nuclear ribonucleoprotein M (hnRNPM) in regulating alternative splicing of HO-1 mRNA, potentially mediated by m6A modifications. This study provides new epigenetic insights into the post-transcriptional regulatory mechanisms involved in Co-induced ferroptosis and highlights the broader implications of environmental hazards in neurodegenerative damage.
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Adenosina , Homólogo AlkB 5 da RNA Desmetilase , Cobalto , Ferroptose , Heme Oxigenase-1 , RNA Mensageiro , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Animais , Ferroptose/efeitos dos fármacos , Adenosina/análogos & derivados , Adenosina/metabolismo , Cobalto/toxicidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Camundongos , Humanos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/genética , Epigênese GenéticaRESUMO
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS: Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making. CLINICAL TRIAL NUMBER: NCT03267641 (Observational cohort).
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RATIONALE: Leiomyoma is a benign smooth muscle tumor which is rarely found in urethra. We hereby report a case of a 44-year-old female who presented with complaints of dysuria. PATIENT CONCERNS: A 44-year-old female patient presented to the urology outpatient clinic with symptoms of dysuria. The patient described the presence of a protrusion from the urethra during urination. DIAGNOSIS: Urethral leiomyoma. INTERVENTIONS: Physical examination confirmed a solid urethral mass. CT scan and USG reports indicated that the mass originated from the mid-urethra with vascularity at the base. We performed a complete resection of the urethral mass. The patient was discharged after 3 days of observation. OUTCOME: During a follow-up after 1 month, the patient reported improved urinary flow and no occurrence of hematuria. The patient recovered well after discharge. LESSON: Urethral leiomyoma is a rare benign tumor that is often misdiagnosed in clinical practice. Diagnosis requires careful clinical examination. Surgical removal usually works well. It is important to remember that in some cases of acute urinary retention, it can be caused by a complete obstruction of a mass in the urethra. Urologists should be more cautious and experienced in handling such cases.
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Disuria , Leiomioma , Neoplasias Uretrais , Humanos , Feminino , Leiomioma/cirurgia , Leiomioma/diagnóstico , Leiomioma/complicações , Leiomioma/patologia , Leiomioma/diagnóstico por imagem , Adulto , Disuria/etiologia , Neoplasias Uretrais/diagnóstico , Neoplasias Uretrais/cirurgia , Neoplasias Uretrais/patologia , Tomografia Computadorizada por Raios XRESUMO
Polyvinyl chloride (PVC) foam, valued for its mechanical and thermal properties along with cost-effectiveness, is extensively utilized across diverse industries. However, its high volatile organic compound (VOC) emissions hinder its adoption in eco-friendly synthetic leather. This study proposes a solution by optimizing the formulation design and foaming processes and achieving mechanical property enhancement via carbon-fiber-reinforced PVC composite foam (CF/PVC). The aim is to reduce PVC usage via enhancing its intrinsic properties. Systematic investigations were carried out on the impact of foaming raw materials, foaming processes, fiber content, and fiber length on the foaming performance, mechanical properties, and VOC emissions. The material formulation and process parameters were successfully optimized. Further assessment of various indicators such as the density, mechanical properties, and tear resistance of synthetic leather samples confirmed that the innovative CF/PVC foam developed in this study meets the requirements for automotive interior applications. Notably, the tensile strength and tear resistance of CF/PVC composite synthetic leather increased by 50% and 29%, respectively, compared to pure PVC, while VOC emissions decreased by 28%. It is anticipated that a more pronounced reduction in VOC emissions will be achieved in practical automotive interior leather applications when further considering the reinforcing effect of fibers, which leads to a reduction in PVC usage. The findings present a technical reference for innovative applications, aiming to enhance PVC foam performance and minimize emissions.
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The pollution of heavy metals (HMs) in the environment is a significant global environmental issue, characterized by its extensive distribution, severe contamination, and profound ecological impacts. Excessive exposure to heavy metal pollutants can damage the nervous system. However, the mechanisms underlying the neurotoxicity of most heavy metals are not completely understood. Epigenetics is defined as a heritable change in gene function that can influence gene and subsequent protein expression levels without altering the DNA sequence. Growing evidence indicates that heavy metals can induce neurotoxic effects by triggering epigenetic changes and disrupting the epigenome. Compared with genetic changes, epigenetic alterations are more easily reversible. Epigenetic reprogramming techniques, drugs, and certain nutrients targeting specific epigenetic mechanisms involved in gene expression regulation are emerging as potential preventive or therapeutic tools for diseases. Therefore, this review provides a comprehensive overview of epigenetic modifications encompassing DNA/RNA methylation, histone modifications, and non-coding RNAs in the nervous system, elucidating their association with various heavy metal exposures. These primarily include manganese (Mn), mercury (Hg), lead (Pb), cobalt (Co), cadmium (Cd), nickel (Ni), sliver (Ag), toxic metalloids arsenic (As), and etc. The potential epigenetic mechanisms in the etiology, precision prevention, and target therapy of various neurodevelopmental disorders or different neurodegenerative diseases are emphasized. In addition, the current gaps in research and future areas of study are discussed. From a perspective on epigenetics, this review offers novel insights for prevention and treatment of neurotoxicity induced by heavy metal pollutants.
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Intoxicação por Arsênico , Poluentes Ambientais , Mercúrio , Metais Pesados , Humanos , Poluentes Ambientais/toxicidade , Poluentes Ambientais/análise , Metais Pesados/análise , Mercúrio/análise , Cádmio/análise , Epigênese Genética , Monitoramento Ambiental/métodos , Medição de RiscoRESUMO
OBJECTIVES: The implementation of outpatient training in primary care settings is an essential part of residency training for general practitioner (GP) residents. However, limited research exists on their experiences and perceptions of this training. This study aimed to explore the experiences and perceptions of GP residents regarding outpatient training in primary care settings in China and provide insights and recommendations to enhance training quality. DESIGN: A qualitative descriptive study employing in-depth interviews. SETTING: Two community healthcare centres (CHCs) that implement outpatient training programmes for GP residents in Zhejiang Province, China. PARTICIPANTS: In total, 20 GP residents affiliated with 14 CHCs and two hospitals across Zhejiang Province and Guizhou Province who had completed outpatient training in either CHC for over 1 month. RESULTS: Of the 20 participants in this study, 11 (55%) were women, and the mean age was 28 years. GP residents completed the process of consultation, physical examination and therapy independently; subsequently, the community preceptors provided feedback based on their clinical performance and modelled their clinical skills. The benefits perceived by GP residents included improved clinical skills and confidence in practice, and they learned approaches to maintaining good relationships with patients. They preferred dealing with complex cases, discussions with peers and the indirect supervision of community preceptors in the training session. Residents recommended that measures be taken to improve the training quality regarding patient selection and recruitment, clinical skills in the training session, and assessment of clinical performance. CONCLUSIONS: The outpatient training in primary care settings provides constructive opportunities for GP residents to improve their professional competencies. Although the current training sessions and the abilities of community preceptors largely satisfy the needs of GP residents, further research is needed to evaluate the effectiveness of training and explore approaches to improve its quality.
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Clínicos Gerais , Pacientes Ambulatoriais , Humanos , Feminino , Adulto , Masculino , Aprendizagem , China , Atenção Primária à SaúdeRESUMO
BACKGROUND: Painless gastroenteroscopy is a widely developed diagnostic and treatment technology in clinical practice. It is of great significance in the clinical diagnosis, treatment, follow-up review and other aspects of gastric cancer patients. The application of anesthesia techniques during manipulation can be effective in reducing patient fear and discomfort. In clinical work, the adverse drug reactions of anesthesia regimens and the risk of serious adverse drug reactions are increased with the increase in propofol application dose application dose; the application of opioid drugs often causes gastrointestinal reactions, such as nausea, vomiting and delayed gastrointestinal function recovery, after examination. These adverse effects can seriously affect the quality of life of patients. AIM: To observe the effect of modified ShengYangYiwei decoction on gastrointestinal function, related complications and immune function in patients with gastric cancer during and after painless gastroscopy. METHODS: A total of 106 patients with gastric cancer, who were selected from January 2022 to September 2022 in Xiamen Traditional Chinese Medicine Hospital for painless gastroscopy, were randomly divided into a treatment group (n = 56) and a control group (n = 50). Before the examination, all patients fasted for 8 h, provided their health education, and confirmed if there were contraindications to anesthesia and gastroscopy. During the examination, the patients were placed in the left decubitus position, the patients were given oxygen through a nasal catheter (6 L/min), the welling needle was opened for the venous channel, and a multifunction detector was connected for monitoring electrocardiogram, oxygen saturation, blood pressure, etc. Naporphl and propofol propofol protocols were used for routine anesthesia. Before anesthesia administration, the patients underwent several deep breathing exercises, received intravenous nalbuphine [0.nalbuphine (0.025 mg/kg)], followed by intravenous propofol [1.propofol (1.5 mg/kg)] until the palpebral reflex disappeared, and after no response, gastroscopy was performed. If palpebral reflex disappeared, and after no response, gastroscopy was performed. If any patient developed movement, frowning, or hemodynamic changes during the operation (heart rate changes during the operation (heart rate increased to > 20 beats/min, systolic blood pressure increased to > 20% of the base value), additional propofol [0.propofol (0.5 mg/kg)] was added until the patient was sedated again. The patients in the treatment group began to take the preventive intervention of Modified ShengYangYiwei decoction one week before the examination, while the patients in the control group received routine gastrointestinal endoscopy. The patients in the two groups were examined by conventional painless gastroscopy, and the characteristics of the painless gastroscopies of the patients in the two groups were recorded and compared. These characteristics included the total dosage of propofol during the examination, the incidence of complications during the operation, the time of patients' awakening, the time of independent activities, and the gastrointestinal function of the patients after examination, such as the incidence of reactions such as malignant vomiting, abdominal distension and abdominal pain, as well as the differences in the levels of various immunological indicators and inflammatory factors before anesthesia induction (T0), after conscious extubation (T1) and 24 h after surgery (T2). RESULTS: There was no difference in the patients' general information, American Society of Anesthesiologist classification or operation time between the two groups before treatment. In terms of painless gastroscopy, the total dosage of propofol in the treatment group was lower than that in the control group (P < 0.05), and the time of awakening and autonomous activity was significantly faster than that in the control group (P < 0.05). During the examination, the incidence of hypoxemia, hypotension and hiccups in the treatment group was significantly lower than that in the control group (P < 0.01). In terms of gastrointestinal function, the incidences of nausea, vomiting, abdominal distension and abdominal pain in the treatment group after examination were significantly lower than those in the control group (P < 0.01). In terms of immune function, in both groups, the number of CD4+ and CD8+ cells decreased significantly (P < 0.05), and the number of natural killer cells increased significantly (P < 0.05) at T1 and T2, compared with T0. The number of CD4+ and CD8+ cells in the treatment group at the T1 and T2 time points was higher than that in the control group (P < 0.05), while the number of natural killer cells was lower than that in the control group (P < 0.05). In terms of inflammatory factors, compared with T0, the levels of interleukin (IL) -6 and tumor necrosis factor-alpha in patients in the two groups at T1 and T2 increased significantly and then decreased (P < 0.05). The level of IL-6 at T1 and T2 in the treatment group was lower than that in the control group (P < 0.05). CONCLUSION: The preoperative use of modified ShengYangYiwei decoction can optimize the anesthesia program during painless gastroscopy, improve the gastrointestinal function of patients after the operation, reduce the occurrence of examination-related complications.
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Background & Aims: Lifestyle and environmental-related exposures are important risk factors for hepatocellular carcinoma (HCC), suggesting that epigenetic dysregulation significantly underpins HCC. We profiled 30 surgically resected tumours and the matched adjacent normal tissues to understand the aberrant epigenetic events associated with HCC. Methods: We identified tumour differential enhancers and the associated genes by analysing H3K27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) and Hi-C/HiChIP data from the resected tumour samples of 30 patients with early-stage HCC. This epigenome dataset was analysed with previously reported genome and transcriptome data of the overlapping group of patients from the same cohort. We performed patient-specific differential expression testing using multiregion sequencing data to identify genes that undergo both enhancer and gene expression changes. Based on the genes selected, we identified two patient groups and performed a recurrence-free survival analysis. Results: We observed large-scale changes in the enhancer distribution between HCC tumours and the adjacent normal samples. Many of the gain-in-tumour enhancers showed corresponding upregulation of the associated genes and vice versa, but much of the enhancer and gene expression changes were patient-specific. A subset of the upregulated genes was activated in a subgroup of patients' tumours. Recurrence-free survival analysis revealed that the patients with a more robust upregulation of those genes showed a worse prognosis. Conclusions: We report the genomic enhancer signature associated with differential prognosis in HCC. Findings that cohere with oncofoetal reprogramming in HCC were underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC. Impact and Implications: Lifestyle and environmental-related exposures are the important risk factors of hepatocellular carcinoma (HCC), suggesting that tumour-associated epigenetic dysregulations may significantly underpin HCC. We profiled tumour tissues and their matched normal from 30 patients with early-stage HCC to study the dysregulated epigenetic changes associated with HCC. By also analysing the patients' RNA-seq and clinical data, we found the signature genes - with epigenetic and transcriptomic dysregulation - associated with worse prognosis. Our findings suggest that systemic approaches are needed to consider the surrounding cellular environmental and epigenetic changes in HCC tumours.
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Ozone pollution is still considered a severe environmental problem in China despite the fact that great efforts have been devoted to monitoring and alleviating its impact by the Chinese government including the establishment of numerous observational networks. One of the issues most relevant to the design of emission reduction policies is to distinguish the O3 chemical regime. Here a method of quantifying the fraction of the radical loss versus NOx chemistry was applied to identify the O3 chemical regime inferred from the weekly pattern of atmospheric O3, CO, NOx, and PM10, which were monitored by Ministry of Ecology and Environment of China (MEEC). During spring and autumn, O3 and the total odd oxygen (Ox, Ox = O3 + NO2) weekend afternoon concentrations are both higher than the weekday values during 2015-2019 except in 2016, while CO and NOx weekend morning concentrations were generally both smaller than weekday values except 2017. Results from the calculated values of fraction of the radical loss by NOx chemistry relative to total radical loss (Ln/Q) suggested a volatile organic compound (VOC)-limited regime at this site in the spring of 2015-2019, as expected from the decreasing trend in NOx concentration and essentially constant CO after 2017. With respect to autumn, a shift from a transition regime during 2015-2017 to a VOC-limited regime in 2018 was found, which rapidly took place to a NOx-limited regime in 2019. No significant differences were detected in the Ln/Q values under different assumptions on photolysis frequencies both in spring and autumn mostly from 2015 to 2019, giving the same conclusion of determining the O3 sensitivity regime. This study develops a new method in determining the O3 sensitivity regime in the typical season in China and provides insight into efficient O3 control strategies in different seasons.
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Cobalt exposure, even at low concentrations, induces neurodegenerative damage, such as Alzheimer's disease (AD). The specific underlying mechanisms remain unclear. Our previous study demonstrated that m6A methylation alteration is involved in cobalt-induced neurodegenerative damage, such as in AD. However, the role of m6A RNA methylation and its underlying mechanisms are poorly understood. In this study, both epidemiological and laboratory studies showed that cobalt exposure could downregulate the expression of the m6A demethylase ALKBH5, suggesting a key role for ALKBH5. Moreover, Methylated RNA immunoprecipitation and sequencing (MeRIP-seq) analysis revealed that ALKBH5 deficiency is associated with neurodegenerative diseases. KEGG pathway and Gene ontology analyses further revealed that the differentially m6A-modified genes resulting from ALKBH5 downregulation and cobalt exposure were aggregated in the pathways of proliferation, apoptosis, and autophagy. Subsequently, ALKBH5 deficiency was shown to exacerbate cell viability decline, motivate cell apoptosis and attenuate cell autophagy induced by cobalt with experimental techniques of gene overexpression/inhibition. In addition, morphological changes in neurons and the expression of AD-related proteins, such as APP, P-Tau, and Tau, in the cerebral hippocampus of wild-type and ALKBH5 knockout mice after chronic cobalt exposure were also investigated. Both in vitro and in vivo results showed that lower expression of ALKBH5 aggravated cobalt-induced neurodegenerative damage. These results suggest that ALKBH5, as an epigenetic regulator, could be a potential target for alleviating cobalt-induced neurodegenerative damage. In addition, we propose a novel strategy for the prevention and treatment of environmental toxicant-related neurodegeneration from an epigenetic perspective.
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Cobalto , RNA , Camundongos , Animais , Cobalto/toxicidade , MetilaçãoRESUMO
BACKGROUND: Painless gastroscopy is a widely used diagnostic and therapeutic technology in clinical practice. Propofol combined with opioids is a common drug for painless endoscopic sedation and anaesthesia. In clinical work, adverse drug reactions of anaesthesia schemes are often one of the important areas of concern for doctors and patients. With the increase in propofol dosage, the risk of serious adverse drug reactions, such as respiratory depression and hypotension, increases significantly; the use of opioids often causes gastrointestinal reactions in patients after examination, such as nausea, vomiting, delayed recovery of gastrointestinal function and other complications, which seriously affect their quality of life. AIM: To observe the effect of wrist-ankle acupuncture therapy on the anaesthesia regimen and anaesthesia-related complications during and after painless gastroscopy examination. METHODS: Two hundred patients were selected and randomly divided into a treatment group (n = 100) and a control group (n = 100). Both groups were routinely anaesthetized with the nalbuphine and propofol regimen, gastroscopy began after the patient lost consciousness, and given supportive treatment and vital sign monitoring. If the patient interrupted the surgery due to intraoperative torsion, intravenous propofol was used to relieve his or her discomfort. The treatment group received wrist-ankle acupuncture on this basis. RESULTS: The general data before treatment, American Society of Anesthesiologist (ASA) grade and operation time between the two groups was no significant difference. The Wakeup time, and the Self-ambulation time in the treatment group was significantly faster than that in the control group (P < 0.05). The total dose of propofol in the treatment group was 109 ± 8.17 mg, significantly lower than that in the control group (P < 0.05). The incidence of respiratory depression and hypotension was not significantly different, but the incidence of hiccups was significantly lower than that in the control group (P < 0.05). After the examination, the incidence of nausea, vomiting, abdominal distension, and abdominal pain was 11%, 8%, 6%, and 5%, respectively, which was significantly lower than that in the control group (P < 0.05). In addition, both the operators and the patients were more satisfied with this examination, with no significant difference between the groups (P > 0.05). CONCLUSION: Wrist-ankle acupuncture treatment can optimize the painless gastroscopy and anaesthesia scheme, reduces propofol total dose; shortens patient Wakeup time and Self-ambulation time, improves patient compliance and tolerance, is beneficial to clinical application.
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BACKGROUND: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC). METHODS: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples. RESULTS: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate. DISCUSSION/CONCLUSION: Our results highlight the importance of identifying patient-specific DE genes, with its potential to provide clinically valuable insights into patient subgroups for applications in precision medicine.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Regulação Neoplásica da Expressão GênicaRESUMO
Objectives: This study was performed to explore the preventive and therapeutic effects of Lactobacillus plantarum ZFM4 on H. pylori infections of the stomach tissue in C57BL/6 mice. Methods: In this study, 40 specific-pathogen-free female C57BL/6 mice were randomly divided into five groups, namely, the control, ZFM4 pretreatment) ZFM4 pretreatment before H. pylori infected), model (H. pylori infected), triple therapy (H. pylori infected and treated with triple therapy), and ZFM4 treatment groups (H. pylori infected and treated with ZFM4). The preventive and therapeutic effects of Lactobacillus plantarum ZFM4 were evaluated in H. pylori-infected C57BL/6 mice by assessing gastric tissue morphology, inflammatory cytokine levels, microbial composition, and microbial diversity. Results: Lactobacillus plantarum ZFM4 was able to survive in low gastric pH and play a role in preventing H. pylori infection. This was evident from a reduction in both, the gastric inflammatory response and expression of inflammatory factors caused by H. pylori infection. Lactobacillus plantarum ZFM4 could also inhibit the growth of H. pylori via its beneficial impact on the gastric microbiota. Conclusion: Our findings suggest that Lactobacillus plantarum ZFM4 offers superior preventive effects against H. pylori infections when used alone. However, the therapeutic effect on established infections is weaker. Further clinical trials are needed to confirm the specific dosage, duration, and other aspects of administration.
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Infecções por Helicobacter , Helicobacter pylori , Lactobacillus plantarum , Probióticos , Camundongos , Animais , Feminino , Lactobacillus plantarum/fisiologia , Camundongos Endogâmicos C57BL , Estômago , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/prevenção & controle , Probióticos/uso terapêutico , Mucosa GástricaRESUMO
Previous studies have suggested that Helicobacter pylori (H. pylori) infection is associated with nonalcoholic fatty liver disease (NAFLD). The purpose of the present study was to investigate the effect of H. pylori eradication treatment on NAFLD patients. Two hundred NAFLD patients who tested positive for H. pylori infection were randomized into the H. pylori eradication treatment group or the control group. Metabolic and inflammatory parameters and FibroScan were measured in all subjects at baseline and 1 year after treatment. At 1 year after treatment, the decrease in metabolic indicators, such as fasting blood glucose, glycosylated haemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, body mass index and controlled attenuation parameter values, were more obvious in the treatment group. Moreover, the inflammatory indicators white blood count and high-sensitivity C-reactive protein (hs-CRP) and the inflammatory factors interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were also significantly decreased. H. pylori eradication can further reduce the metabolic indices of NAFLD and the degree of liver steatosis. H. pylori infection may participate in the occurrence and development of NAFLD through its influence on inflammatory factors. Thus, checking for the presence of H. pylori infection in patients at risk of NAFLD may be beneficial.
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Infecções por Helicobacter , Helicobacter pylori , Hepatopatia Gordurosa não Alcoólica , Humanos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/complicações , Hemoglobinas Glicadas , Interleucina-6RESUMO
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide. Immune escape is considered to be a reason for immunotherapy failure in PDAC. In this study, we explored the correlation between immune escape-related genes and the prognosis of PDAC patients. Methods: 1163 PDAC patients from four public databases, including The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Array-express, and Gene Expression Omnibus (GEO), were included in our study. Cox regression analysis was used to identify the 182 immune genes which were significantly associated with overall survival (OS). And then we established an immune escape-related gene prognosis index (IEGPI) score using several datasets as the training cohort and validated it using the validation cohort. Kaplan-Meier (KM) and Cox regression analysis were used to detect the relationship of IEGPI score with OS. We further explored the relationship between the IEGPI and immune indexes. And the prediction value of response for immunotherapy in Tumor Immune Dysfunction and Exclusion (TIDE) dataset. Results: We establish an IEGPI score based on 27 immune escape genes which were significantly related to the prognosis of OS in PDAC patients. Patients in the high-IEGPI group had a significantly worse overall survival rate compared with that in the low-IEGPI groups by KM curves and cox-regression. 5 of the 32 cancer types in TCGA could be significantly distinguished in survival rates through the low- and high-IEGPI groups. Moreover, the correlation between the IEGPI score was negatively correlated with an immune score in several datasets. And higher IEGPI better recurrence-free survival (RFS) and OS in the patients after patients were treated with both PD-1 and CTLA4 in the public datasets (P<0.05). Intriguingly, by using RT-PCR, we verified that the gene of PTPN2, CEP55, and JAK2 were all higher in the BxPC-3 and PANC-1 than HPDE5 cells. Lastly, we found that the IEGPI score was higher in K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cre (KPC) mice model with anti-PD-L1 than that without anti-PD-L1. Conclusion: Using the immune escape-related genes, our study established and validated an IEGPI score in PDAC patients from the public dataset. IEGPI score has the potential to serve as a prognostic marker and as a tool for selecting tumor patients suitable for immunotherapy in clinical practice.
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L-tryptophan (Trp) is an essential amino acid for humans and plays crucial roles in many metabolic functions. Trp levels can be used for diagnosing different kinds of metabolic disorders and the symptoms associated with those diseases. Herein, a novel, simple and sensitive sensor based on 3D peony-like bimetallic conductive MOFs (Co-Ni-MOFs) was fabricated for the electrochemical determination of Trp. The bimetallic conductive MOFs were synthesized by a facile one-pot hydrothermal process. On account of the synergy between the Ni2+ and Co2+ ions, the bimetallic Co-Ni-MOFs showed excellent electrochemical performance, including good conductivity, large effective surface areas, and high electrocatalytic reactivity toward the oxidation of Trp. Consequently, the Co-Ni-MOFs-modified electrodes obtained a wide linear range from 10 nmol L-1 to 300 µmol L-1 and a low detection limit of 8.7 nmol L-1 (S/N = 3) for Trp. Additionally, the prepared sensor also displayed high selectivity, long-term stability and reproducibility. Moreover, the proposed sensor was successfully applied to determine the levels of Trp in the plasma of mice after cadmium intoxication.
Assuntos
Técnicas Eletroquímicas , Triptofano , Animais , Eletrodos , Limite de Detecção , Camundongos , Reprodutibilidade dos Testes , Triptofano/químicaRESUMO
Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.
RESUMO
Air pollution in China is complex, and the formation mechanism of chemical components in particulate matter is still unclear. This study selected three consecutive heavy haze pollution episodes (HPEs) during winter in Beijing for continuous field observation, including an episode with heavy air pollution under red alert. Clean days during the observation period were selected for comparison. The HPE characteristics of Beijing in winter were: under the influence of adverse meteorological conditions such as high relative humidity, temperature inversion and low wind speed; and strengthening of secondary transformation reactions, which further intensified the accumulation of secondary aerosols and other pollutants, promoting the explosive growth of PM2.5. PM2.5/CO values, as indicators of the contribution of secondary transformation in PM2.5, were approximately 2 times higher in the HPEs than the average PM2.5/CO during the clean period. The secondary inorganic aerosols (sulfate nitrate and ammonium salt) were significantly enhanced during the HPEs, and the conversion coefficients were remarkably improved. In addition, it is interesting to observe that the production of sulfate tended to exceed that of nitrate in the late stage of all three HPEs. The existence of aqueous phase reactions led to the explosive growth sulfur oxidation ratio (SOR) and rapid generation of sulfate under high relative humidity (RH>70%).