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RIG-I (retinoic acid inducible gene-I) can sense subtle differences between endogenous and viral RNA in the cytoplasm, triggering an anti-viral immune response through induction of type I interferons (IFN) and other inflammatory mediators. Multiple crystal and cryo-EM structures of RIG-I suggested a mechanism in which the C-terminal domain (CTD) is responsible for the recognition of viral RNA with a 5'-triphoshate modification, while the CARD domains serve as a trigger for downstream signaling, leading to the induction of type I IFN. However, to date contradicting conclusions have been reached around the role of ATP in the mechanism of the CARD domains ejection from RIG-I's autoinhibited state. Here we present an application of NMR spectroscopy to investigate changes induced by the binding of 5'-triphosphate and 5'-OH dsRNA, both in the presence and absence of nucleotides, to full length RIG-I with all its methionine residues selectively labeled (Met-[ϵ-13CH3]). With this approach we were able to identify residues on the CTD, helicase domain, and CARDs that served as probes to sense RNA-induced conformational changes in those respective regions. Our results were analyzed in the context of either agonistic or antagonistic RNAs, by and large supporting a mechanism proposed by the Pyle Lab in which CARD release is primarily dependent on the RNA binding event.
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Transativadores , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Interferon Tipo I/genética , Estrutura Terciária de Proteína , RNA de Cadeia Dupla , RNA Viral/genética , RNA Viral/metabolismo , Transdução de Sinais , Transativadores/metabolismoRESUMO
BACKGROUND: Acupuncture may improve degenerative lumbar spinal stenosis (DLSS), but evidence is insufficient. OBJECTIVE: To investigate the effect of acupuncture for DLSS. DESIGN: Multicenter randomized clinical trial. (ClinicalTrials.gov: NCT03784729). SETTING: 5 hospitals in China. PARTICIPANTS: Patients with DLSS and predominantly neurogenic claudication pain symptoms. INTERVENTION: 18 sessions of acupuncture or sham acupuncture (SA) over 6 weeks, with 24-week follow-up after treatment. MEASUREMENTS: The primary outcome was change from baseline in the modified Roland-Morris Disability Questionnaire ([RMDQ] score range, 0 to 24; minimal clinically important difference [MCID], 2 to 3). Secondary outcomes were the proportion of participants achieving minimal (30% reduction from baseline) and substantial (50% reduction from baseline) clinically meaningful improvement per the modified RMDQ. RESULTS: A total of 196 participants (98 in each group) were enrolled. The mean modified RMDQ score was 12.6 (95% CI, 11.8 to 13.4) in the acupuncture group and 12.7 (CI, 12.0 to 13.3) in the SA group at baseline, and decreased to 8.1 (CI, 7.1 to 9.1) and 9.5 (CI, 8.6 to 10.4) at 6 weeks, with an adjusted difference in mean change of -1.3 (CI, -2.6 to -0.03; P = 0.044), indicating a 43.3% greater improvement compared with SA. The between-group difference in the proportion of participants achieving minimal and substantial clinically meaningful improvement was 16.0% (CI, 1.6% to 30.4%) and 12.6% (CI, -1.0% to 26.2%) at 6 weeks. Three cases of treatment-related adverse events were reported in the acupuncture group, and 3 were reported in the SA group. All events were mild and transient. LIMITATION: The SA could produce physiologic effects. CONCLUSION: Acupuncture may relieve pain-specific disability among patients with DLSS and predominantly neurogenic claudication pain symptoms, although the difference with SA did not reach MCID. The effects may last 24 weeks after 6-week treatment. PRIMARY FUNDING SOURCE: 2019 National Administration of Traditional Chinese Medicine "Project of building evidence-based practice capacity for TCM-Project BEBPC-TCM" (NO. 2019XZZX-ZJ).
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BACKGROUND: Neoadjuvant chemo-immunotherapy combination has shown remarkable advances in the management of esophageal squamous cell carcinoma (ESCC). However, the identification of a reliable biomarker for predicting the response to this chemo-immunotherapy regimen remains elusive. While computed tomography (CT) is widely utilized for response evaluation, its inherent limitations in terms of accuracy are well recognized. Therefore, in this study, we present a novel technique to predict the response of ESCC patients before receiving chemo-immunotherapy by testing volatile organic compounds (VOCs) in exhaled breath. METHODS: This study employed a prospective-specimen-collection, retrospective-blinded-evaluation design. Patients' baseline breath samples were collected and analyzed using high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). Subsequently, patients were categorized as responders or non-responders based on the evaluation of therapeutic response using pathology (for patients who underwent surgery) or CT images (for patients who did not receive surgery). RESULTS: A total of 133 patients were included in this study, with 91 responders who achieved either a complete response (CR) or a partial response (PR), and 42 non-responders who had stable disease (SD) or progressive disease (PD). Among 83 participants who underwent both evaluations with CT and pathology, the paired t-test revealed significant differences between the two methods (p < 0.05). For the breath test prediction model using breath test data from all participants, the validation set demonstrated mean area under the curve (AUC) of 0.86 ± 0.06. For 83 patients with pathological reports, the breath test achieved mean AUC of 0.845 ± 0.123. CONCLUSIONS: Since CT has inherent weakness in hollow organ assessment and no other ideal biomarker has been found, our study provided a noninvasive, feasible, and inexpensive tool that could precisely predict ESCC patients' response to neoadjuvant chemo-immunotherapy combination using breath test based on HPPI-TOFMS.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/terapia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Terapia Neoadjuvante , Testes Respiratórios/métodos , BiomarcadoresRESUMO
Antiretroviral therapy (ART) is an effective treatment for people living with HIV (PLHIVs), requiring an extended period to achieve immune reconstitution. Metabolic alterations induced by ART are crucial for predicting long-term therapeutic responses, yet comprehensive investigation through large-scale clinical studies is still lacking. Here, we collected plasma samples from 108 PLHIVs to the untargeted plasma metabolomics study, based on the longitudinal metabolomics design. Cross-sectional analyzes were performed at pre- and post-ART to explore the metabolic transformation induced by the therapy. Subsequently, delta values between pre- and post-ART measurements were calculated to quantify metabolic alterations. Then, the optimal set of metabolic traits and clinical signatures were further identified and applied to construct random forest model for predicting the future therapeutic responses to ART. We found distinct ART-induced metabolic transformation among PLHIVs. After confounder-adjustments, five metabolites exhibited significant associations with future immune response: tetracosatetraenoic acid (24:4n-6) (pre-ART) (odds ratio [OR]: 0.978, 95% confidence interval [CI]: 0.955~0.997), 1-(3,4-dihydroxyphenyl)-5-hydroxy-3-decanone (pre-ART) (OR: 1.298, 95% CI: 1.061~1.727), beta-PC-M6 (change) (OR: 0.967, 95% CI: 0.938~0.993), d-Galactaro-1,4-lactone (change) (OR: 1.032, 95% CI: 1.007~1.063), Annuionone C (change) (OR: 1.100, 95% CI: 1.030~1.190). The addition of plasma metabolites to clinical markers accurately predicted immune response to ART with an area under curve of 0.91. Notably, most disrupted metabolites were significantly correlated with blood lipids, suggesting that metabolic transformation might contribute to dyslipidemia among PLHIVs. This study highlights the distinct metabolic transformation post-ART among PLHIVs and reveals the potential role of metabolic transformation as key determinants of ART efficacy.
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Infecções por HIV , Metabolômica , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/sangue , Masculino , Feminino , Adulto , Estudos Transversais , Pessoa de Meia-Idade , Metaboloma/efeitos dos fármacos , Fármacos Anti-HIV/uso terapêutico , Estudos Longitudinais , Plasma/química , Antirretrovirais/uso terapêutico , Biomarcadores/sangue , Terapia Antirretroviral de Alta AtividadeRESUMO
Tissue regeneration technology has been rapidly developed and widely applied in tissue engineering and repair. Compared with traditional approaches like surgical treatment, the rising gene therapy is able to have a durable effect on tissue regeneration, such as impaired bone regeneration, articular cartilage repair and cancer-resected tissue repair. Gene therapy can also facilitate the production of in situ therapeutic factors, thus minimizing the diffusion or loss of gene complexes and enabling spatiotemporally controlled release of gene products for tissue regeneration. Among different gene delivery vectors and supportive gene-activated matrices, advanced gene/drug nanocarriers attract exceptional attraction due to their tunable physiochemical properties, as well as excellent adaptive performance in gene therapy for tissue regeneration, such as bone, cartilage, blood vessel, nerve and cancer-resected tissue repair. This paper reviews the recent advances on nonviral-mediated gene delivery systems with an emphasis on the important role of advanced nanocarriers in gene therapy and tissue regeneration.
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Técnicas de Transferência de Genes , Terapia Genética , Regeneração , Engenharia Tecidual , Alicerces Teciduais , Humanos , Animais , Terapia Genética/métodos , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Nanopartículas/química , Portadores de Fármacos/química , Vetores GenéticosRESUMO
Cytochrome P450 (P450)-mediated bioactivation, which can lead to the hepatotoxicity through the formation of reactive metabolites (RMs), has been regarded as the major problem of drug failures. Herein, we purposed to establish machine learning models to predict the bioactivation of P450. On the basis of the literature-derived bioactivation dataset, models for Benzene ring, Nitrogen heterocycle and Sulfur heterocycle were developed with machine learning methods, i.e., Random Forest, Random Subspace, SVM and Naïve Bayes. The models were assessed by metrics like "Precision", "Recall", "F-Measure", "AUC" (Area Under the Curve), etc. Random Forest algorithms illustrated the best predictability, with nice AUC values of 0.949, 0.973 and 0.958 for the test sets of Benzene ring, Nitrogen heterocycle and Sulfur heterocycle models, respectively. 2D descriptors like topological indices, 2D autocorrelations and Burden eigenvalues, etc. contributed most to the models. Furthermore, the models were applied to predict the occurrence of bioactivation of an external verification set. Drugs like selpercatinib, glafenine, encorafenib, etc. were predicted to undergo bioactivation into toxic RMs. In vitro, IC50 shift experiment was performed to assess the potential of bioactivation to validate the prediction. Encorafenib and tirbanibulin were observed of bioactivation potential with shifts of 3-6 folds or so. Overall, this study provided a reliable and robust strategy to predict the P450-mediated bioactivation, which will be helpful to the assessment of adverse drug reactions (ADRs) in clinic and the design of new candidates with lower toxicities.
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Benzeno , Carbamatos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Sulfonamidas , Humanos , Teorema de Bayes , Sistema Enzimático do Citocromo P-450/metabolismo , Aprendizado de Máquina , Enxofre , NitrogênioRESUMO
The incorporation of real-world data (RWD) into medical product development and evaluation has exhibited consistent growth. However, there is no universally adopted method of how much information to borrow from external data. This paper proposes a study design methodology called Tree-based Monte Carlo (TMC) that dynamically integrates patients from various RWD sources to calculate the treatment effect based on the similarity between clinical trial and RWD. Initially, a propensity score is developed to gauge the resemblance between clinical trial data and each real-world dataset. Utilizing this similarity metric, we construct a hierarchical clustering tree that delineates varying degrees of similarity between each RWD source and the clinical trial data. Ultimately, a Gaussian process methodology is employed across this hierarchical clustering framework to synthesize the projected treatment effects of the external group. Simulation result shows that our clustering tree could successfully identify similarity. Data sources exhibiting greater similarity with clinical trial are accorded higher weights in treatment estimation process, while less congruent sources receive comparatively lower emphasis. Compared with another Bayesian method, meta-analytic predictive prior (MAP), our proposed method's estimator is closer to the true value and has smaller bias.
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Biliary-enteric anastomotic stenosis is one of the main long-term complications after pancreaticoduodenectomy, with an incidence of 2%-8%. Although the relevant reports and studies are relatively few, the consequences such as biliary obstruction and refractory cholangitis seriously affect the quality of life of patients. In this case, the patient is not willing to receive conventional surgery again. This paper provides a bridge technique of EUS-guided Biliary Drainage (EUS-BD) to treat biliary-enteric anastomotic stenosis and solve the problem of obstructive jaundice in the patient.
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Chronic pancreatitis in children is an irreversible inflammatory disease, which can cause intractable abdominal pain and abnormal internal and external secretion function of the pancreas, seriously affecting the growth and development of children and the quality of life. ERCP has become the first choice because of its good effect and less trauma. However, the severe stenosis of pancreatic duct caused by chronic pancreatitis may make ERCP more difficult. Here we used the rendezvous technique to assist ERCP to complete the treatment of severe pancreatic duct stenosis and abdominal pain.
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Pancreatic cutaneous fistula is a complex condition, making it challenging to achieve favorable outcomes with conservative medical treatment. Surgical interventions often entail surgical risks and postoperative complications. Here, we present a case involving endoscopically guided stent placement between the stomach and the fistula. By internalizing the fistula, patients can potentially remove the external drainage tube, offering a novel endoscopic treatment approach for such cases.
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PURPOSE: To investigate the balance between post-treatment effect and continued nature growth after maxillary protraction treatment in patients with skeletal class III malocclusion. METHODS: 31 patients aged 8.79 ± 1.65 years with skeletal Class III malocclusion had been treated with maxillary protraction and the treatment lasted an average of 1.16 years. The average observation duration after treatment in the maxillary protraction group was 2.05 ± 0.39 years. In the control groups, a sample of 22 patients (9.64 ± 2.53 years) with untreated skeletal class III malocclusion and 24 patients (9.28 ± 0.96 years) with skeletal class I malocclusion were matched to the treatment group according to age, sex and observation period. The mean observation interval of the control groups was 2.39 ± 1.29 years in the class III group and 1.97 ± 0.49 years in the class I group. RESULTS: The active orthopedic treatment effect showed a opposite trend to the natural craniomaxillofacial growth effect after treatment in many aspects. In the observation duration of treatment group, decrease in ANB, Wits appraisal and BAr-AAr were statistically significant compared to class I control group (p < 0.001), and there was a significant increase in NA-FH (P < 0.001) which was contrary to class III control group. Treatment group presented a significant increase in Gn-Co (P < 0.01) and Co-Go (P < 0.001), except for changes in the extent of the mandibular base (Pog-Go, P = 0.149) compared to class I control group. The vertical maxillomandibular skeletal variables (Gonial; MP-SN; MP-FH; Y-axis) in treatment group decreased significantly compared to those in class III control group (P < 0.01). U1-SN and L1-MP showed a significant increase, which was similar to the class I group (P > 0.05), and overjet decreased significantly relative to both of the two control groups (P < 0.05). CONCLUSION: Maxillary protraction therapy led to stable outcomes in approximately 77.42% of children with Class III malocclusion approximately 2 years after treatment. Unfavorable skeletal changes were mainly due to the greater protrusion of the mandible but maxillary protraction did have a certain degree of postimpact on the mandibular base. Protraction therapy does not fundamentally change the mode of maxillary growth in Class III subjects except for the advancement of the maxilla. Craniomaxillofacial region tend to restabilize after treatment and lead to skeletal growth rotation and more dentoalveolar compensation.
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Má Oclusão Classe III de Angle , Má Oclusão , Criança , Humanos , Maxila , Estudos Retrospectivos , Grupos Controle , Cefalometria , Má Oclusão Classe III de Angle/terapia , MandíbulaRESUMO
cGMP-dependent protein kinase (PKG) represents a compelling drug target for treatment of cardiovascular diseases. PKG1 is the major effector of beneficial cGMP signaling which is involved in smooth muscle relaxation and vascular tone, inhibition of platelet aggregation and signaling that leads to cardioprotection. In this study, a novel piperidine series of activators previously identified from an ultrahigh-throughput screen were validated to directly bind partially activated PKG1α and subsequently enhance its kinase activity in a concentration-dependent manner. Compounds from initial optimization efforts showed an ability to activate PKG1α independent of the endogenous activator, cGMP. We demonstrate these small molecule activators mimic the effect of cGMP on the kinetic parameters of PKG1α by positively modulating the KM of the peptide substrate and negatively modulating the apparent KM for ATP with increase in catalytic efficiency, kcat. In addition, these compounds also allosterically modulate the binding affinity of cGMP for PKG1α by increasing the affinity of cGMP for the high-affinity binding site (CNB-A) and decreasing the affinity of cGMP for the low-affinity binding site (CNB-B). We show the mode of action of these activators involves binding to an allosteric site within the regulatory domain, near the CNB-B binding site. To the best of our knowledge, these are the first reported non-cGMP mimetic small molecules shown to directly activate PKG1α. Insights into the mechanism of action of these compounds will enable future development of cardioprotective compounds that function through novel modes of action for the treatment of cardiovascular diseases.
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Doenças Cardiovasculares , Proteína Quinase Dependente de GMP Cíclico Tipo I , GMP Cíclico , Piperidinas , Trifosfato de Adenosina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/enzimologia , GMP Cíclico/metabolismo , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Humanos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
KEY MESSAGE: We proposed a working model of BR to promote leaf size through cell expansion. In the BR signaling pathway, GhBES1 affects cotton leaf size by binding to and activating the expression of the E-box element in the GhEXO2 promoter region. Brassinosteroid (BR) is an essential phytohormone that controls plant growth. However, the mechanisms of BR regulation of leaf size remain to be determined. Here, we found that the BR deficient cotton mutant pagoda1 (pag1) had a smaller leaf size than wild-type CRI24. The expression of EXORDIUM (GhEXO2) gene, was significantly downregulated in pag1. Silencing of BRI1-EMS-SUPPRESSOR 1 (GhBES1), inhibited leaf cell expansion and reduced leaf size. Overexpression of GhBES1.4 promoted leaf cell expansion and enlarged leaf size. Expression analysis showed GhEXO2 expression positively correlated with GhBES1 expression. In plants, altered expression of GhEXO2 promoted leaf cell expansion affecting leaf size. Furthermore, GhBES1.4 specifically binds to the E-box elements in the GhEXO2 promoter, inducing its expression. RNA-seq data revealed many down-regulated genes related to cell expansion in GhEXO2 silenced plants. In summary, we discovered a novel mechanism of BR regulation of leaf size through GhBES1 directly activating the expression of GhEXO2.
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Brassinosteroides , Gossypium , Gossypium/metabolismo , Brassinosteroides/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Regiões Promotoras Genéticas/genética , Folhas de Planta/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Manganese-based Na superionic conductors (NASICONs) Na4 MnCr(PO4 )3 with three-electron reaction are attractive cathode materials for sodium-ion batteries. However, the irreversible distortion of Mn local structure leads to sluggish electrode kinetics, voltage hysteresis, and poor cycling stability. Here, SiO4 is introduced to substitute PO4 to modulate the local environment of Mn to activate the redox activity and stabilize the reversibility of Na4 MnCr(PO4 )2.9 (SiO4 )0.1 (NMCP-Si). A combined experimental and theoretical investigation have been undertaken to reveal the evolution of electronic structures and Na storage properties associated with SiO4 substitution. The NMCP-Si exhibits much-enhanced rate capability and cycling stability, being attributed to the unique Jahn-Teller distortion (Mn3+ ) that facilitates sodium de/insertion kinetics by optimizing the Na ion diffusion channels. This work addresses the challenge of stabilizing the structure of Mn-based NASICONs and represents a breakthrough in understanding how to improve the Na+ conductivity by regulating local structure.
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Heat stress causes many pathophysiological responses in the brain, including neuroinflammation and cognitive deficits. ß-Hydroxybutyric acid (BHBA) has been shown to have neuroprotective effects against inflammation induced by lipopolysaccharide. The aim of the present study was to evaluate the effects of BHBA on neuroinflammation induced by heat stress, as well as the underlying mechanisms. Mice were pretreated with vehicle, BHBA or minocycline (positive control group) and followed by heat exposure (43°C) for 15 min for 14 days. In mice subjected to heat stress, we found that treatment with BHBA or minocycline significantly decreased the level of serum cortisol, the expressions of heat shock protein 70 (HSP70), and the density of c-Fos+ cells in the hippocampus. Surprisingly, the ethological tests revealed that heat stress led to cognitive dysfunctions and could be alleviated by BHBA and minocycline administration. Further investigation showed that BHBA and minocycline significantly attenuated the activation of microglia and astrocyte induced by heat stress. Pro-inflammatory cytokines were attenuated in the hippocampus by BHBA and minocycline treatment. Importantly, compared with the heat stress group, mice in the BHBA treatment group and positive control group experienced a decrease in the expressions of toll-like receptor 4 (TLR4), phospho-p38 (p-p38), and nuclear factor kappa B (NF-κB). Our results elucidated that BHBA inhibits neuroinflammation induced by heat stress by suppressing the activation of microglia and astrocyte, and modulating TLR4/p38 MAPK and NF-κB pathways. This study provides new evidence that BHBA is a potential strategy for protecting animals from heat stress.
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NF-kappa B , Receptor 4 Toll-Like , Ácido 3-Hidroxibutírico/metabolismo , Animais , Resposta ao Choque Térmico , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Microglia/metabolismo , Minociclina/metabolismo , Minociclina/farmacologia , NF-kappa B/metabolismo , Doenças Neuroinflamatórias , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Single-crystal-to-single-crystal (SCSC) transformations provide more possibilities for phase transitions, which have attracted great attention in crystal engineering. In this paper, we report a series of reversible SCSC transformations between nanoscale two-dimensional layered double hydroxide (LDH) crystals and three-dimensional metal-organic framework crystals. They can proceed not only in solution systems but also on the surface of solid-state polyacrylonitrile films and fibers. Specifically, reversible SCSC transformations can be carried out between nanoscale ZIF-67 and Co-LDH. The Co-LDH nanomaterials displayed excellent oxygen evolution reaction performance. This work has good universality and scalability, which provides a novel avenue for the synthesis of crystal materials and is of great significance for the recycling of resources.
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Multitargeted kinase inhibitors (MKIs) including sorafenib and lenvatinib, are applied for first-line treatment for inoperable hepatocellular carcinoma (HCC) patients, but the therapeutic effect is limited because of drug resistance. Therefore, we sought potential biomarkers to indicate sorafenib and lenvatinib resistance in HCC. In this article, we report a novel long non-coding RNA (lncRNA), AC026401.3, in promoting sorafenib and lenvatinib resistance of HCC cells. AC026401.3 is upregulated in HCC tissues and is positively relevant to HCC patients with large tumor size, cancer recurrence, advanced TNM stage, and poor prognosis. AC026401.3 knockdown or knockout enhances the sensitivity of HCC cells to sorafenib and lenvatinib, respectively. Moreover, AC026401.3 upregulates the expression of the transcription factor E2F2. Mechanistically, AC026401.3 interacts with OCT1 and promotes the recruitment of OCT1 to the promoter region of E2F2, intensifying sorafenib and lenvatinib resistance in HCC by activating the transcription of E2F2. In conclusion, our results reveal that lncRNA AC026401.3 is a risk factor for HCC patients by enhancing sorafenib and lenvatinib resistance of HCC cells, and targeting the AC026401.3-OCT1-E2F2 signaling axis would be a promising strategy for HCC therapeutics.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Fator 1 de Transcrição de Octâmero/metabolismo , RNA Longo não Codificante , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Quinolinas , RNA Longo não Codificante/genética , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Fatores de TranscriçãoRESUMO
BACKGROUND AND OBJECTIVE: The major contributing risk factors to airflow obstruction (AO) in China remain largely unknown. We examined the environmental and lifestyle risk factors of unrecognized AO in the baseline of a population-based cohort drawn from 115 urban and rural communities across 12 provinces in China. METHODS: Amongst 46,285 adults recruited from 2005 to 2009, 3686 were identified with AO on spirometry (defined by the ratio of forced expiratory volume in the first second to forced vital capacity <0.7) and without known chronic lung disease. These cases were age- and sex-matched to 11,129 controls with normal spirometry and no chronic lung disease from the same community. Conditional multivariable adjusted OR and population attributable fraction (PAF) were calculated for each identified risk factor and their combined effect. RESULTS: Compared to controls, smoking initiation age <20 years (OR 1.22 [95% CI 1.01-1.48]), smoking duration ≥40 years (OR 1.82 [1.50-2.22]), low vegetables (OR 1.86 [1.67-2.07]) and fruits (OR 1.14 [1.02-1.29]) intake, cooking with biomass fuels (OR 2.54 [2.32-2.78]) and poor kitchen ventilation (OR 1.37 [1.19-1.58]) were significantly associated with elevated risks of unrecognized AO. The combined effect of these lifestyle factors significantly elevated the odds by 25 fold (18.6-34.3). The addition of prior tuberculosis and low socioeconomic status further increased the odds to 40.1 (28.2-57.0) and the PAF to 66.7% (51.1-78.1). CONCLUSION: Smoking, unhealthy diet, biomass cooking fuels and low socioeconomic status are strongly associated with AO. Addressing these risk factors could substantially reduce the burden of AO in China.
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Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Adulto Jovem , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Estudos de Casos e Controles , Prevalência , Volume Expiratório Forçado , Capacidade Vital , Espirometria , Culinária , Fumar/efeitos adversos , Fumar/epidemiologia , China/epidemiologia , Fatores de Risco , Dieta/efeitos adversosRESUMO
Patients with inflammatory bowel disease (IBD) always suffer from severe abdominal pain and appear to be at high risk for colorectal cancer. Recently, the co-delivery of targeted drugs and gut microbiota has developed into an attractive strategy. A new strategy using gut microbiota fermentation to overcome the interspace diffuse resistance from the mucus layer to control drug release in inflammatory bowel sites (IBS sites) has not yet been available. Here, we designed an alginate hydrogel microsphere encapsulating bifidobacterium (Bac) and drug-modified nanoscale dietary fibers (NDFs). The hydrogel microsphere is responsible for protecting drugs from acidic and multi-enzymatic environments and delivering drugs to the colorectum. Subsequently, the fermentation of Bac by digesting NDFs and proteins as carbon and nitrogen sources can promote drug release and play a probiotic role in the gut microbiota. In vitro evidence indicated that small-sized NDF (NDF-1) could significantly promote short-chain fatty acid (SCFA) expression. Notably, NDF-1 hydrogel microspheres showed a boost release of 5-ASA in the IBS sites, resulting in the amelioration of gut inflammation and remodeling of gut microbiota in chronic colitis mice. This study developed a controlled release system based on microbial fermentation for the treatment of IBD.
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Doenças Inflamatórias Intestinais , Síndrome do Intestino Irritável , Humanos , Animais , Camundongos , Microesferas , Fermentação , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mesalamina , Alginatos , Fibras na DietaRESUMO
BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.