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Pulmonary hypertension (PH) is characterized by excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), in which inflammatory signaling caused by activation of the NF-κB pathway plays an important role. A20 is an important negative regulator of the NF-κB pathway, and zinc promotes the expression of A20 and exerts a protective effect against various diseases (e.g. COVID19) by inhibiting the inflammatory signaling. The role of A20 and intracellular zinc signaling in PH has been explored, but the extracellular zinc signaling is not well understood, and whether zinc has protective effects on PH is still elusive. Using inductively coupled plasma mass spectrometry (ICP-MS), we studied the alteration of trace elements during the progression of monocrotaline (MCT)-induced PH and found that serum zinc concentration was decreased with the onset of PH accompanied by abnormalities of other three elements, including copper, chromium, and magnesium. Zinc chloride injection with the dosage of 5 mg/kg intraperitoneally partially corrected this abnormality and inhibited the progression of PH. Zinc supplementation induced the expression of A20 in lung tissue and reduce the inflammatory responses. In vitro, zinc supplementation time-dependently upregulated the expression of A20 in PASMCs, therefore correcting the excessive proliferation and migration of cells caused by hypoxia. Using genetically encoded-FRET based zinc probe, we found that these effects of zinc ions are not achieved by entering cells, but most likely by activating cell surface zinc receptor (ZnR/GPR39). These results provide the first evidence of the effectiveness of zinc supplementation in the treatment of PH.
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Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.
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Antiinfecciosos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Adulto , Humanos , Niño , Farmacogenética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Antiinfecciosos/efectos adversosRESUMEN
Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.
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Genes myc , Simulación del Acoplamiento Molecular , Péptidos/farmacología , Tiazoles/farmacologíaRESUMEN
BACKGROUND: Poor nurse-patient relationship poses an obstacle to care delivery, jeopardizing patient experience and patient care outcomes. Measuring nurse-patient relationship is challenging given its multi-dimensional nature and a lack of well-established scales. PURPOSE: This study aimed to develop a multi-dimensional scale measuring nurse-patient relationship in China. METHODS: A preliminary scale was constructed based on the existing literature and Delphi consultations with 12 nursing experts. The face validity of the scale was tested through a survey of 45 clinical nurses. This was followed by a validation study on 620 clinical nurses. Cronbach's α, content validity and known-group validity of the scale were assessed. The study sample was further divided into two for Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA), respectively, to assess the construct validity of the scale. RESULTS: The Nurse-Patient Relationship Scale (NPRS) containing 23 items was developed and validated, measuring five dimensions: nursing behavior, nurse understanding and respect for patient, patient misunderstanding and mistrust in nurse, communication with patient, and interaction with patient. The Cronbach's α of the NPRS ranged from 0.725 to 0.932, indicating high internal consistency. The CFA showed excellent fitness of data into the five-factor structure: χ2/df = 2.431, GFI = 0.933, TLI = 0.923, CFI = 0.939, IFI = 0.923, RMSEA = 0.070. Good content and construct validity are demonstrated through expert consensus and psychometric tests. CONCLUSION: The NPRS is a valid tool measuring nurse-patient relationship in China.
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AIM: This study tested the mediating role of the nurse-patient relationship and self-rated health in the effect of emotional labour on turnover intention among nurses in China. BACKGROUND: The underlying mechanism behind the effect of emotional labour on turnover intention remains inadequately understood. INTRODUCTION: Nurses with a high level of emotional labour are predisposed to experiencing poor health and tension in their relationships with patients, which may increase turnover intention. METHODS: A cross-sectional survey of 527 nurses in a public tertiary hospital in Qiqihar, located in China's Heilongjiang province, was conducted. Emotional labour and turnover intention were assessed using existing validated scales containing multiple items, while the nurse-patient relationship and self-rated health were assessed using single items, respectively. Baron and Kenny's causal steps and the Karlson/Holm/Breen method were adopted to test the mediating effects of the nurse-patient relationship and self-rated health in the association between emotional labour and turnover intention after adjusting for variations in sociodemographic and job characteristics. RESULTS: Emotional labour was positively associated with turnover intention. Self-rated poor health and a disharmonious nurse-patient relationship partially mediated the positive effect of emotional labour on turnover intention. CONCLUSIONS: Emotional labour significantly affects the turnover intention of nurses working in public tertiary hospitals in China, and this effect is partially mediated by self-rated health and the nurse-patient relationship. IMPLICATIONS FOR NURSING PRACTICE AND NURSING POLICY: Giving more attention to nurses' negative emotions and work attitudes is crucial. Developing comprehensive strategies for enhancing nurses' emotional management ability, promoting their physical and psychological well-being, and improving nurse-patient relationship to reduce nurses' turnover.
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Planar monolayer microreactor arrays (PMMRAs) make droplet-based numerical measurements and statistical analysis cheap and easy. However, PMMRAs are typically produced in complex microfluidic devices and, moreover, still requires stringent control to reduce droplet loss during heating. In this paper, a simple, reliable, and flexible method for fabricating PMMRAs in a 96-well plate is described in detail by using simple materials and low-cost equipment. The partitioned droplets spontaneously assemble into PMMRAs in the plates, and this distribution is maintained even after incubation. This is advantageous for in situ analysis based on an individual droplet in droplet digital loop-mediated isothermal amplification (ddLAMP) and does not require the transfer of positive droplets. Precise and reproducible quantification of classical swine fever virus (CSFV) extracts was executed in these PMMRAs to verify its availability. Our results demonstrate that the proposed approach not only provides a flexible and controllable execution scheme for droplet-based nucleic acid quantification in resource-limited laboratories but also opens new perspectives for numerous analytical and biochemical applications using droplets as versatile plastic microreactors.
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Técnicas Analíticas Microfluídicas , Dispositivos Laboratorio en un Chip , Proyectos de InvestigaciónRESUMEN
BACKGROUND AND AIMS: The accuracy of model for end-stage liver disease (MELD) and MELD with sodium (MELD-Na) scores in reflecting the clinical outcomes of patients with cirrhosis and portal vein thrombosis (PVT) remains unclear. This study aimed to evaluate the performance of scores in predicting 90-day mortality in patients with cirrhosis and PVT. METHODS: Post hoc analysis was performed in two prospective cohorts (NCT02457637 and NCT03641872). The correlation between the MELD/MELD-Na score and 90-day liver transplantation (LT)-free mortality was investigated in patients with cirrhosis with and without PVT. RESULTS: In this study, 2826 patients with cirrhosis were included, and 255 (9.02%) had PVT. The cumulative incidence of 90-day LT-free mortality did not significantly differ between patients with and without PVT (log-rank P = 0.0854). MELD [area under the receiver operating curve (AUROC), 0.649 vs. 0.842; P = 0.0036] and MELD-Na scores (AUROC, 0.691 vs. 0.851; P = 0.0108) were compared in patients with and without PVT, regarding the prediction of 90-day LT-free mortality. In MELD < 15 and MELD-Na < 20 subgroups, patients with PVT had a higher 90-day LT-free mortality than those without PVT (7.91% vs. 2.64%, log-rank P = 0.0011; 7.14% vs. 3.43%, log-rank P = 0.0223), whereas in MELD ≥ 15 and MELD-Na ≥ 20 subgroups, no significant difference was observed between patients with and without PVT. CONCLUSIONS: The performance of MELD and MELD-Na scores in predicting 90-day LT-free mortality of patients with cirrhosis was compromised by PVT. MELD < 15 or MELD-Na < 20 may underestimate the 90-day LT-free mortality in patients with PVT.
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Enfermedad Hepática en Estado Terminal , Trombosis de la Vena , Humanos , Enfermedad Hepática en Estado Terminal/etiología , Cirrosis Hepática/patología , Vena Porta/patología , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Sodio , Trombosis de la Vena/complicacionesRESUMEN
BACKGROUND: Local environmental factors are associated with health and healthcare-seeking behaviors. However, there is a paucity in the literature documenting the link between air pollution and healthcare-seeking behaviors. This study aimed to address the gap in the literature through a cross-sectional study of domestic migrants in China. METHODS: Data were extracted from the 2017 China Migrants Dynamic Survey (n = 10,051) and linked to the official air pollution indicators measured by particulate matter (PM2.5 and PM10) and air quality index (AQI) in the residential municipalities (n = 310) of the study participants over the survey period. Probit regression models were established to determine the association between air pollution and refraining from visiting health facilities after adjustment for variations in the predisposing, enabling and needs factors. Thermal inversion intensity was adopted as an instrumental variable to overcome potential endogeneity. RESULTS: One unit (µg/m3) increase in monthly average PM2.5 was associated with 1.8% increase in the probability of refraining from visiting health facilities. The direction and significance of the link remained unchanged when PM2.5 was replaced by AQI or PM10. Higher probability of refraining from visiting health facilities was also associated with overwork (ß = 0.066, p = 0.041) and good self-related health (ß = 0.171, p = 0.006); whereas, lower probability of refraining from visiting health facilities was associated with short-distance (inter-county) migration (ß=-0.085, p = 0.048), exposure to health education (ß=-0.142, p < 0.001), a high sense of local belonging (ß=-0.082, p = 0.018), and having hypertension/diabetes (ß=-0.169, p = 0.005). CONCLUSION: Air pollution is a significant predictor of refraining from visiting health facilities in domestic migrants in China.
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Contaminantes Atmosféricos , Contaminación del Aire , Migrantes , Humanos , Estudios Transversales , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , China/epidemiología , Instituciones de Salud , Exposición a Riesgos Ambientales/análisisRESUMEN
The objective of our overview of systematic reviews was to critically analyze the evidence from existing systematic reviews investigating the effectiveness and safety of low-level laser therapy (LLLT) in patients with breast cancer-related lymphedema (BCRL). In addition, an updated and comprehensive systematic review was conducted, which aimed to provide updated evidence about this topic. PubMed, EMBASE, and Cochrane Library databases were systematically searched for systematic reviews and randomized controlled trials (RCTs) investigating the effectiveness and safety of LLLT in patients with BCRL. The methodological quality for each of included systematic reviews or RCTs was assessed using the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2) tool or Cochrane risk of bias tool, respectively. The updated systematic review separately compared the effectiveness of LLLT to each of active or negative interventions. Data were pooled with random-effects models for each outcome per comparison. The evidence quality of outcomes was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) or GRADE-Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) for quantitative studies and qualitative studies, respectively. Seven systematic reviews and ten RCTs met the eligibility criteria. Conflicting results regarding the effectiveness of LLLT were presented by the overview of systematic reviews. The AMSTAR 2 showed that the methodological quality of included systematic reviews was low or critically low quality due to one or more critical weaknesses. The GRADE and GRADE-CERQual showed that the evidence quality was low to very low for most outcomes. The updated systematic review showed that LLLT may offer additional benefits as compared to compression therapies (pneumatic compression or compression bandage), placebo laser, or no treatment for patients with BCRL. However, when compared to other types of active interventions, LLLT did not improve outcomes significantly. None of the treatment-related adverse event was reported. Many trials had a high or unclear risk of bias for two or more items, and our updated systematic review showed low quality of evidence per outcome using GRADE approach. Due to insufficient data and poor quality of evidence, there is uncertain to reach these conclusions that LLLT is superior to another active or negative intervention and is safe. More RCTs of high methodological quality, with large sample sizes and long-term follow-up, are needed to inform clinical guidelines and routine practice.
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Neoplasias de la Mama , Terapia por Luz de Baja Intensidad , Linfedema , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/radioterapia , Femenino , Humanos , Terapia por Luz de Baja Intensidad/efectos adversos , Revisiones Sistemáticas como AsuntoRESUMEN
A dual-mode immunoassay strategy based on CdS nanoparticles as signal probes with both of photoluminescent (PL) and multi-phonon resonance Raman scattering (MRRS) properties was developed. Simplified structural design and preparation were achieved due to the intrinsic integration of PL and MRRS dual signals in the single-unit CdS nanoprobes. Human immunoglobulin G (HIgG) was sensitively and specifically detected using the proposed PL-MRRS dual-mode strategy. The linear relationship between the HIgG concentration and the intensity of 707 nm PL peaks/300 cm-1 MRRS peaks under the excitation of 488 nm laser was established. The limit of detection was 0.93 fg mL-1 for PL and 1.10 fg mL-1 for MRRS. In comparison with previous IgG detection methods, the proposed method exhibited prominent advantages in detection sensitivity and working range with good stability and repeatability. An internal self-calibration was realized which ensured the accuracy and reliability of detection results. Both results of specificity experiments and serum sample analysis further confirmed the feasibility of the designed immunoassay strategy in practical serological detection.
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Nanopartículas del Metal , Espectrometría Raman , Humanos , Espectrometría Raman/métodos , Fonones , Oro/química , Reproducibilidad de los Resultados , Inmunoensayo/métodos , Inmunoglobulina G , Nanopartículas del Metal/químicaRESUMEN
Nitrogen (N) is a major limiting factor for plant growth and crop production. The use of N fertilizer in forestry production is increasing each year, but the loss is substantial. Mastering the regulatory mechanisms of N uptake and transport is a key way to improve plant nitrogen use efficiency (NUE). However, this has rarely been studied in pecans. In this study, 10 AMT and 69 NRT gene family members were identified and systematically analyzed from the whole pecan genome using a bioinformatics approach, and the expression patterns of AMT and NRT genes and the uptake characteristics of NH4+ and NO3- in pecan were analyzed by aeroponic cultivation at varying NH4+/NO3- ratios (0/0, 0/100,25/75, 50/50, 75/25,100/0 as CK, T1, T2, T3, T4, and T5). The results showed that gene duplication was the main reason for the amplification of the AMT and NRT gene families in pecan, both of which experienced purifying selection. Based on qRT-PCR results, CiAMTs were primarily expressed in roots, and CiNRTs were majorly expressed in leaves, which were consistent with the distribution of pecan NH4+ and NO3- concentrations in the organs. The expression levels of CiAMTs and CiNRTs were mainly significantly upregulated under N deficiency and T4 treatment. Meanwhile, T4 treatment significantly increased the NH4+, NO3-, and NO2- concentrations as well as the Vmax and Km values of NH4+ and NO3- in pecans, and Vmax/Km indicated that pecan seedlings preferred to absorb NH4+. In summary, considering the single N source of T5, we suggested that the NH4+/NO3- ratio of 75:25 was more beneficial to improve the NUE of pecan, thus increasing pecan yield, which provides a theoretical basis for promoting the scale development of pecan and provides a basis for further identification of the functions of AMT and NRT genes in the N uptake and transport process of pecan.
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Carya , Plantones , Plantones/metabolismo , Carya/genética , Nitrógeno/metabolismo , Raíces de Plantas/metabolismo , Hojas de la Planta/metabolismo , Nitratos/metabolismoRESUMEN
Mitogen-activated protein kinases consist of three kinase modules composed of MPKs, MKKs, and MPKKKs. As members of the protein kinase (PK) superfamily, they are involved in various processes, such as developmental programs, cell division, hormonal progression, and signaling responses to biotic and abiotic stresses. In this study, a total of 18 MPKs and 10 MKKs were annotated on the pecan genome, all of which could be classified into four subgroups, respectively. The gene structures and conserved sequences of family members in the same branch were relatively similar. All MPK proteins had a conserved motif TxY, and D(L/I/V)K and VGTxxYMSPER existed in all MKK proteins. Duplication events contributed largely to the expansion of the pecan MPK and MKK gene families. Phylogenetic analysis of protein sequences from six plants indicated that species evolution occurred in pecan. Organ-specific expression profiles of MPK and MKK showed functional diversity. Ka/Ks values indicated that all genes with duplicated events underwent strong negative selection. Seven CiPawMPK and four CiPawMKK genes with high expression levels were screened by transcriptomic data from different organs, and these candidates were validated by qRT-PCR analysis of hormone-treated and stressed samples.
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Carya , Filogenia , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Secuencia de AminoácidosRESUMEN
BACKGROUND: Polyphenol oxidase (PPO) is considered to have a key role in the food industry because it initiates enzymatic browning in the processing and storage of fruit and vegetables. Increasing numbers of benzoic and cinnamic acid derivatives have been found to be efficient inhibitors of polyphenol oxidase, but a comparison study on activity and action mechanism is lacking. In this study, 18 benzoic acid and cinnamic acid hydroxy derivatives were selected and investigated. RESULTS: Three substrates, four activators and 11 inhibitors were identified from benzoic and cinnamic acid derivatives. 2,4-Dihydroxycinnamic acid and benzoic acid showed the strongest inhibitory effect on PPO, with IC50 of 0.092 and1.425 mmol L-1 , respectively. Benzoic acid reversibly inhibited PPO in a competitive manner, while 2,4-dihydroxycinnamic acid showed a mixed-type inhibition. Both of them showed that static-type fluorescence quenching and electrostatic interaction were the main driving force in the bonding process. Compared with benzoic acid, 2,4-dihydroxycinnamic acid more easily formed hydrogen bonds in the active site of PPO, making the interaction more stable. CONCLUSION: Comparative analysis showed that the inhibition effect of cinnamic acid hydroxyl derivatives on PPO was stronger than that of benzoic acid derivatives. Benzoic acid and 2,4-dihydroxycinnamic acid were the strongest inhibitors. PPO inhibitors identified from benzoic and cinnamic acid derivatives are expected to be promising inhibitors for controlling fruit and vegetable browning. © 2021 Society of Chemical Industry.
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Ácido Benzoico , Catecol Oxidasa , Ácido Benzoico/farmacología , Catecol Oxidasa/química , Cinamatos/farmacología , Simulación del Acoplamiento Molecular , VerdurasRESUMEN
In this study, we constructed two pandemic anxiety indexes based on an assumption that people's emotions fluctuate with the COVID-19 reported cases and deaths, to examine the dynamic co-movements between these anxiety indexes and the stock markets in the BRICS and G7 countries. We found that the anxiety indexes are volatile over time but have an overall downtown trend. The correlations between stock market returns and the epidemic anxiety indexes are time varying. We found a common feature across the countries studied, namely that the correlation becomes weaker and has smaller fluctuations after the announcement of the mRNA-based COVID-19 vaccine.
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OBJECTIVE: The main aim of this study was to ascertain the effectiveness of ultrasound-guided fine needle aspiration cytology (US-FNAC) in the diagnosis of para-aortic lymph node (PALN) metastasis in uterine cervical cancer and to establish its potential impact on clinical therapeutic decision making. METHODS: We retrospectively reviewed clinical data from 92 patients diagnosed with cervical cancer with PALN enlargement between 2010 and 2018. Cytological results obtained with US-FNAC were classified by the same experienced cellular pathologists. Diagnostic indicators were determined on the basis of biopsy, imaging and clinical follow-up results. Univariate and multivariate analyses were used to assess the differences of influencing factors. The effect of US-FNAC on clinical decision making was evaluated. RESULTS: Cytological results of US-FNAC were categorized as malignancy (n = 62; 67.4%), suspicious malignancy (n = 11; 12.0%), undetermined (n = 5; 5.4%), benign (n = 10; 10.9%), and inadequate (n = 4; 4.3%). Satisfactory biopsy samples were obtained from 95.7% of PALNs sampled (88/92). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of FNAC in distinguishing benign from malignant cases were 90.1% (95% CI: 0.809-0.953), 100% (95% CI: 0.561-1), 100% (95% CI: 0.938-1), 46.7% (95% CI: 0.223-0.726) and 90.9% (95% CI: 0.848-0.970), respectively. Univariate analysis indicated significant differences in experience of puncture physicians (radiologists) between the correct and wrong diagnosis groups (P < 0.05), which was further confirmed as an independent predictor of diagnostic accuracy in multivariate analysis (p = 0.031, OR = 0.077, 95% CI: 0.354-0.919). All patients tolerated the US-FNAC procedure well and only nine presented slight abdominal discomfort. The therapeutic strategies for 74 patients (80.4%) were influenced by US-FNAC findings. CONCLUSIONS: US-FNAC was a relatively safe and effective technique for examination of enlarged para-aortic lymph nodes and may therefore serve as a routine diagnostic tool to guide clinical decision making for management of cervical cancer.
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Toma de Decisiones Clínicas , Citodiagnóstico/métodos , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Biopsia del Ganglio Linfático Centinela/métodos , Ultrasonografía/métodos , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Fina , Femenino , Estudios de Seguimiento , Humanos , Biopsia Guiada por Imagen/métodos , Metástasis Linfática/diagnóstico por imagen , Persona de Mediana Edad , Pronóstico , Curva ROC , Estudios Retrospectivos , Neoplasias del Cuello Uterino/diagnóstico por imagenRESUMEN
BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive carcinoma located in pleural cavity. Due to lack of effective diagnostic biomarkers and therapeutic targets in MPM, the prognosis is extremely poor. Because of difficulties in sample extraction, and the high rate of misdiagnosis, MPM is rarely studied. Therefore, novel modeling methodology is crucially needed to facilitate MPM research. METHODS: A novel patient-derived xenograft (PDX) modeling strategy was designed, which included preliminary screening of patients with pleural thickening using computerized tomography (CT) scan, further reviewing history of disease and imaging by a senior sonographer as well as histopathological analysis by a senior pathologist, and PDX model construction using ultrasound-guided pleural biopsy from MPM patients. Gas chromatography-mass spectrometry-based metabolomics was further utilized for investigating circulating metabolic features of the PDX models. Univariate and multivariate analysis, and pathway analysis were performed to explore the differential metabolites, enriched metabolism pathways and potential metabolic targets. RESULTS: After screening using our strategy, 5 out of 116 patients were confirmed to be MPM, and their specimens were used for modeling. Two PDX models were established successfully. Metabolomics analysis revealed significant metabolic shifts in PDX models, such as dysregulations in amino acid metabolism, TCA cycle and glycolysis, and nucleotide metabolism. CONCLUSIONS: To sum up, we suggested a novel modeling strategy that may facilitate specimen availability for MM research, and by applying metabolomics in this model, several metabolic features were identified, whereas future studies with large sample size are needed.
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Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/patología , Metabolómica/métodos , Pleura/patología , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , Anciano de 80 o más Años , Aminoácidos/metabolismo , Análisis de Varianza , Animales , Investigación Biomédica/métodos , China , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Femenino , Cromatografía de Gases y Espectrometría de Masas , Glucólisis , Xenoinjertos , Humanos , Inmunohistoquímica , Masculino , Mesotelioma Maligno/diagnóstico , Ratones , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Nucleótidos/metabolismo , Pleura/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND AND AIM: Globally, China has the highest chronic hepatitis C (CHC) burden, but its real-world direct-acting antiviral (DAA) data are limited. Our aim is to investigate the real-world outcome of China Food and Drug Administration-approved DAA therapies across mainland China including those with genotype (GT) 3. METHODS: The REAL-C is a multinational real-world interferon-free DAA-treated CHC registry of several mainland China and other Asian centers. We evaluated the sustained virological response rate 12 weeks after end of treatment (SVR12), adverse events, and treatment effect on liver function and fibrosis (fibrosis-4 index). RESULTS: We analyzed 859 DAA-treated CHC patients (6/1/2017-5/30/2019) from 12 mainland China centers (three municipalities and nine provinces): median age 52, 49.9% male, 33.1% cirrhosis, 95% treatment naïve, and 2.5% HBsAg+ . The most common GT was GT1b (523, 62.2%), followed by GT2a (156, 18.5%), GT3b (74, 8.8%), GT3a (41, 4.9%), and GT6 (37, 4.4%). SVR12 rates were 98.0% overall (95% confidence interval 96.9-98.8%), 98.1% for GT1b, 96.8% GT2a, 100% GT3a, 97.3% GT3b, and 100% GT6. Baseline cirrhosis and male sex but not prior treatment history, renal dysfunction, age, and GTs were associated with SVR12. For both cirrhotic and non-cirrhotic patients, there were significant improvement in liver function tests, alpha fetoprotein, and fibrosis-4 index with SVR12. Serious adverse events were rare (1.1%) with only nine patients discontinuing therapy prematurely and anemia being the most common adverse event (13.1%, mostly with ribavirin). CONCLUSIONS: In real-world Chinese patients with diverse GTs, Chinese Food and Drug Administration-approved interferon-free DAAs were well tolerated, provided high cure rates (98.0% overall) including GT3a/3b, and led to improvement of liver function.
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Antivirales/uso terapéutico , Estudios de Asociación Genética , Genotipo , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Anemia/inducido químicamente , Antivirales/efectos adversos , Pueblo Asiatico/genética , China , Femenino , Hepatitis C Crónica/fisiopatología , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self-renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue-specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non-proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell toward stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.
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Células Madre NeoplásicasRESUMEN
Pulmonary senescence and fibrosis occur with deoxyribonucleic acid (DNA) damage response in the lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that pulmonary alveolar epithelial type 2 cells (AEC2) (alveolar stem cells) undergo not only replicative senescence, but also apoptosis and differentiation in association with increased innate immune natural killer (NK) cells in telomerase knockout (KO) mice. Telomerase ribonucleic acid (RNA) component (TERC) deficiency results in increased senescence-associated heterochromatin foci marker HP1γ, p21, p16 and apoptosis-associated cleaved caspase-3 in AEC2. However, p53 deficiency in the Trp53-/- allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated alveolar epithelial type 1 cells [AEC1]) in AEC2 of the late generation of TERC KO mice. Collectively, our findings suggest that pulmonary senescence takes place in deficiency of telomerase RNA component with the alveolar stem cells undergoing p53-dependent senescence and apoptosis as well as p53-independent differentiation.
Asunto(s)
Telomerasa , Células Epiteliales Alveolares , Animales , Ratones , Proteína p53 Supresora de TumorRESUMEN
Hypoxia-induced epithelial-mesenchymal transition (EMT) involves the interplay between chromatin modifiers histone deacetylase 3 (HDAC3) and WDR5. The histone mark histone 3 lysine 4 acetylation (H3K4Ac) is observed in the promoter regions of various EMT marker genes (eg, CDH1 and VIM). To further define the genome-wide location of H3K4Ac, a chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) analysis was performed using a head and neck squamous cell carcinoma (HNSCC) FaDu cell line under normoxia and hypoxia. H3K4Ac was found to be located mainly around the transcription start site. Coupled with analysis of gene expression by RNA sequencing and using a HDAC3 knockdown cell line, 10 new genes (BMI1, GLI1, SMO, FOXF1, SIRT2, etc) that were labeled by H3K4Ac and regulated by HDAC3 were identified. Overexpression or knockdown of GLI1/SMO increased or repressed the in vitro migration and invasion activity in OECM-1/FaDu cells, respectively. In HNSCC patients, coexpression of GLI1 and SMO in primary tumors correlated with metastasis. Our results identify new EMT marker genes that may play a significant role in hypoxia-induced EMT and metastasis and further provide diagnostic and prognostic implications.