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PURPOSE: To investigate the potential factors related to variability of alignment in childhood concomitant strabismus. DESIGN: Prospective inter-examiner (test-retest) reliability analysis. METHODS: In total, 197 children with concomitant strabismus (57 esotropia, 140 exotropia) underwent repeat prism and alternate cover test (PACT) by two orthoptists who were certified by the study, and sensory tests were all performed once. We defined the alignment measurement as stable if the absolute value of the measurement difference between two orthoptists was within 10 prism diopters (PD), and unstable if the difference was 10 PD or greater. We analyzed the relationship between the measurement variability and sensory results, patient age, and angle of deviations. RESULTS: The mean age of the esotropia and exotropia patients was 68.5 ± 26.3 months (range, 36-164 months) and 96.0 ± 33.7 months (range, 22-200 months), respectively, and there was a significant difference in suppression related variability of alignment, both at distance (Pâ¯=â¯0.004) and at near (Pâ¯=â¯0.046). Anisometropia also showed a significant difference at distance (Pâ¯=â¯0.035) for variability of alignment, and there was no significant statistical effect of age on measurement variability in our study. Variability of alignment is positively associated with the angle of deviation, especially at distance (Pâ¯=â¯0.021 for exotropia, Pâ¯=â¯0.002 for esotropia) with more variability between observers with larger angles of misalignment. CONCLUSION: Suppression is an important factor for variability of alignment in childhood concomitant strabismus. Other factors, such as anisometropia and a large angle of strabismus should be taken into account when evaluating binocular alignment.
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Background: Previous studies have typically explored daily lagged relationships among pertussis and meteorology, with little assessment of effect and interaction among pollutants mixtures. Methods: Our researchers collected pertussis cases data from 2017-2022 as well as meteorological and contaminative factors for the Jining region. First, we reported the application of the Moving Epidemic Method (MEM) to estimate epidemic threshold and intensity level. Then we developed a Weighted Quantile Sum (WQS) regression and Bayesian Kernel Machine Regression (BKMR) model to assess single, multiple effects and interaction of meteorological and pollution factors on pertussis cases for different sex, delayed and epidemic threshold groups. Results: There has been a yearly upward trend in the incidence of pertussis in Jining regions. High prevalence threshold years were in 2018-2019, the epidemic peak was mainly concentrated in 32 weeks. Totally, pertussis infections disease was separately 2.1% (95% confidence Interval (CI) = 1.3, 2.8) and 1.1% (95% CI = 0.3, 1.9) higher per decile increase in temperature and sulphur dioxide (SO2). And pertussis infections disease was 1.1% lower per decile increase in humidity. In the different stratified analyses, air pressure was a strong negative effect in males and in the lagged 11-20 days group, with 7.3 and 14.7%, respectively. Sulphur dioxide had a relatively weak positive effect in males, females and the group after 20 days lag, ranging from 0.5 to 0.6%. The main positive effectors affecting the onset of disease at low and high threshold levels were ozone (O3) and SO2, respectively, while the negative effectors were SO2 and carbon monoxide (CO), respectively. Conclusions: This is the first mathematically based study of seasonal threshold of pertussis in China, which allows accurate estimation of epidemic level. Our findings support that short-term exposure to pollutants is the risk factor for pertussis. We should concentrate on pollutants monitoring and effect modeling.
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Poluição do Ar , Conceitos Meteorológicos , Coqueluche , Humanos , Coqueluche/epidemiologia , Feminino , China/epidemiologia , Masculino , Poluição do Ar/efeitos adversos , Pré-Escolar , Lactente , Criança , Incidência , Exposição Ambiental/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Adolescente , Teorema de Bayes , Adulto , Dióxido de Enxofre/análise , Dióxido de Enxofre/efeitos adversosRESUMO
BACKGROUND: Tissue mimicking optical phantoms are commonly used to calibrate or validate the performance of near-infrared spectroscopy or tomography. Human tissue is not only irregular in shape, but also exhibits dynamic behaviour, which can cause changes in optical properties. However, existing phantoms lack complex structures and/or continuously varying optical properties. AIM: The project aimed to design, fabricate and characterise a novel phantom system for testing near-infrared imaging devices. MATERIAL AND METHODS: We designed a dynamic tissue-mimicking phantom platform which features arbitrary internal shapes and variable optical properties. The solid part of phantom was made of silicone material with absorbing and scattering properties similar to the brain. We printed a semi-ellipsoidal sphere (a major axis = 20 mm and a minor axis = the third axis = 12 mm) using a water-soluble material polyvinyl alcohol (PVA). The shape was placed at the depth of 5 mm in the silicone bulk. The desired internal hollow structure was formed after curing and submerging the phantom in water. The liquid part contained dyes and Intralipid. The optical properties within the internal shape were adjusted by injecting the liquid solutions of varying dye concentrations with a syringe pump at a constant rate. The phantom was measured by a frequency domain near-infrared spectroscopy (FD NIRS) and imaged by a time domain near-infrared optical tomography (TD NIROT). RESULTS AND DISCUSSION: A dynamic phantom system with a complex internal structure and varying optical properties was created. Changes in light intensity were detected by the FD NIRS. The internal structure of this phantom was accurately recovered by NIROT image reconstruction. CONCLUSION: We successfully developed a novel phantom system with an internal complex shape and continuously adjustable optical properties. This phantom was accurately imaged using NIROT, and the changing light intensity was detected by NIRS. It is a valuable tool for validating optical technologies.
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Imagens de Fantasmas , Espectroscopia de Luz Próxima ao Infravermelho , Humanos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Silicones/química , Imagem Óptica/métodos , Imagem Óptica/instrumentação , Álcool de Polivinil/química , Desenho de Equipamento , Tomografia Óptica/métodos , Tomografia Óptica/instrumentaçãoRESUMO
BACKGROUND AND AIM: The occurrence of brain lesions in preterm infants is common and can result in lasting disabilities. To prevent these and to safeguard the brain through therapeutic measures or neuroprotective treatments, it is important to identify cerebral ischaemia/hypoxia and haemorrhage at an early stage. For this purpose, we have successfully developed a cutting-edge time-domain near-infrared optical tomography (TD-NIROT) system, which offers diagnostic imaging for neonatal brain oxygenation. Our objective is to validate the effectiveness of the TD-NIROT in detecting deep ischaemia/hypoxia and haemorrhages through phantom experiments. METHODS: Spherical silicone phantoms were fabricated to replicate the head of preterm infant. To simulate the lesions, we made two head phantoms and embedded small inclusions mimicking ischaemia and haemorrhage at the depth of 30 mm. Additionally, a spherical interface was constructed to connect the spherical phantom to the imaging system, allowing us to collect time-domain data. Following the data acquisition, we proceeded with image reconstruction. Dice similarity was used as an indicator of the accuracy and similarity between the reconstructed images and the ground truth. RESULTS AND DISCUSSION: The resulting images exhibited an accurate location of haemorrhage and detected the ischaemia with a slightly shifted position with Dice similarity of 0.47 and 0.27. CONCLUSION: Our experiment validates the capability of our TD-NIROT system in successfully detecting deep haemorrhages and ischaemia within the phantom model. The achieved results suggest a promising level of accuracy in the imaging process. These findings are encouraging to continue this work to ultimately achieve clinical application of the TD-NIROT system in diagnosing and monitoring neonatal brain injuries.
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Recém-Nascido Prematuro , Imagens de Fantasmas , Tomografia Óptica , Humanos , Recém-Nascido , Tomografia Óptica/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Isquemia Encefálica/diagnóstico por imagem , Cabeça/irrigação sanguínea , Cabeça/diagnóstico por imagem , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Hemorragia Cerebral/diagnóstico por imagemRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by myofibroblast proliferation and extracellular matrix (ECM) deposition. However, current treatments are not satisfactory. Therefore, more effective therapies need to be explored. Cepharanthine (CEP) is a naturally occurring alkaloid that has recently been reported to have multiple pharmacological effects, particularly in chronic inflammation. METHODS: For in vivo experiments, first, a pulmonary fibrosis murine model was generated via tracheal injection of bleomycin (BLM). Second, the clinical manifestations and histopathological changes of the mice were used to verify that treatment with CEP might significantly reduce BLM-induced fibrosis. Furthermore, flow cytometric analysis was used to analyze the changes in the number of M2 macrophages in the lung tissues before and after treatment with CEP to explore the relationship between macrophage M2 polarization and pulmonary fibrosis. In vitro, we constructed two co-culture systems (THP-1 and MRC5 cells, RAW264.7 and NIH 3T3 cells), and measured the expression of fibrosis-related proteins to explore whether CEP could reduce pulmonary fibrosis by regulating macrophage M2 polarization and fibroblast activation. RESULTS: The results showed that the intranasal treatment of CEP significantly attenuated the symptoms of pulmonary fibrosis induced by BLM in a murine model. Our findings also indicated that CEP treatment markedly reduced the expression of fibrosis markers, including TGF-ß1, collagen I, fibronectin and α-SMA, in the mouse lung. Furthermore, in vitro studies demonstrated that CEP attenuated pulmonary fibrosis by inhibiting fibroblast activation through modulating macrophage M2 polarization and reducing TGF-ß1 expression. CONCLUSIONS: This study demonstrated the potential and efficacy of CEP in the treatment of pulmonary fibrosis. In particular, this study revealed a novel mechanism of CEP in inhibiting fibroblast activation by regulating macrophage M2 polarization and reducing the expression of fibrosis-associated factors. Our findings open a new direction for future research into the treatment of pulmonary fibrosis.
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Benzilisoquinolinas , Bleomicina , Modelos Animais de Doenças , Macrófagos , Animais , Benzilisoquinolinas/farmacologia , Camundongos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/tratamento farmacológico , Pulmão/patologia , Pulmão/efeitos dos fármacos , Humanos , Células RAW 264.7 , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Fator de Crescimento Transformador beta1/metabolismo , Células NIH 3T3 , BenzodioxóisRESUMO
BACKGROUND: Lumbar disc herniation (LDH) has become a serious public health and socioeconomic problem. Tuina is a Chinese medicine treatment method based on meridian acupuncture theory and modern anatomy. Tuina can relieve pain and muscle tension and improve functional disorders; this massage is performed by pressing, kneading, pushing, pulling, and shaking the skin, muscles, and bones. However, the mechanism of action and the effect of Tuina as an external treatment on the activities of the central nervous system to relieve LDH pain is unclear. Therefore, we performed functional magnetic resonance imaging (fMRI), which is widely used in pain-related research, as it can detect the effects of different types of pain on brain activity. OBJECTIVE: Our randomized controlled parallel-group trial aims to compare the effects of Tuina with those of transcutaneous electrical nerve stimulation (TENS) with traction in patients with LDH. METHODS: This trial will be conducted between May 2024 and April 2025 in the Rehabilitation Hospital affiliated to Fujian University of Traditional Chinese Medicine. Seventy-six participants with LDH will be enrolled for this trial and randomly assigned to 2 groups: Tuina intervention group and TENS with traction intervention group. Participants in both groups will receive treatment for 14 days. fMRI will be performed for the main pain measurements by assessing the effect of the intervention on brain activity before and after the end of the intervention. Short-Form McGill Pain Questionnaire, pressure pain thresholds, and the Oswestry disability index will be used to reflect the degree of pain and lumbar dysfunction, and the results will be used as secondary outcome measurements. RESULTS: The study protocol has been approved by the ethics review committee of The Rehabilitation Hospital affiliated to Fujian University of Traditional Chinese Medicine. This study was registered on May 1, 2024, with the Chinese Clinical Trial Registry. Data collection began on May 2024 and is expected to end on April 2025. Currently, data from this trial are in the collection phase, and no data analysis has been performed. As of July 1, 2024, we have collected data from 21 patients. The results of this trial are expected to be submitted for publication in September 2025. CONCLUSIONS: This clinical trial will compare the effectiveness of Tuina with that of TENS with traction in the treatment of patients with LDH and will show the cerebral mechanism of Tuina in LDH treatment by using fMRI. The results of our trial will be helpful in clarifying the cerebral mechanism of Tuina in the treatment of LDH and provide a solid foundation for Tuina therapy research. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083784; https://www.chictr.org.cn/showproj.html?proj=225157. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/63852.
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Deslocamento do Disco Intervertebral , Imageamento por Ressonância Magnética , Humanos , Deslocamento do Disco Intervertebral/terapia , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Massagem/métodos , Medicina Tradicional Chinesa/métodos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Neuropathic pain (NP) remains one of the world's most difficult problems, and people suffering from NP have their quality of life affected to a great extent and constantly suffer from pain. Sensitization of injurious receptors, ectopic firing of afferent nerves after nerve injury, and coupling between sympathetic and sensory neurons are involved in the onset or development of NP, but the pathogenesis of NP is still not well understood. We found that the ubiquitin system is involved in the pathogenesis of NP and has a crucial role in it. The ubiquitin system can be involved in the onset or reversal of NP by affecting ion channels, cellular signal transduction, glial cells, and the regulation of non-coding RNAs. This provides new ideas for the treatment of NP. The ubiquitin system may be a new effective target for the treatment of NP. A continued, in-depth understanding of the mechanisms of the ubiquitin system involved in NP could further refine the study of analgesic targets and improve pharmacological studies.
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Neuralgia , Ubiquitina , Neuralgia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Humanos , Ubiquitina/metabolismo , Animais , Transdução de SinaisRESUMO
BACKGROUND: Gestational diabetes mellitus is a common complication during pregnancy, and its prevalence rates have increased dramatically in recent years. Treatment of gestational diabetes requires the active self-management, however, this can be challenging. Understanding the barriers and facilitators of adherence to self-management recommendations is essential for designing effective interventions. AIM: To identify and synthesize barriers and facilitators to self-management of gestational diabetes reported by pregnant women. METHODS: This was a mixed-methods systematic review, including qualitative, quantitative, and mixed-methods studies. A literature search was conducted in four databases (PubMed, Embase, CINAHL, and the Web of Science). Eligible studies explored the barriers and/or facilitators, experiences and/or perceptions to engage in self-management in women with gestational diabetes. The Capability, Opportunity, Motivation, Behaviour model was used to classify barriers and facilitators affecting self-management. RESULTS: Thirty-six studies (23 qualitative, 11 quantitative, and 2 mixed-methods) met the inclusion criteria. We identified barriers and facilitators relating to capability (e.g., physical discomforts and constraints; lack of knowledge of GDM and self-management behaviours; forgetfulness), opportunity (e.g., limited education and resources; social support from family, friends, and peer groups; conflict with existing lifestyles or cultural norms), and motivation (e.g., perceived negative consequence of self-management behaviours or not perceived benefits; negative emotion; concern the health of the baby). CONCLUSION: In this study, we identified the barriers and facilitators of self-management in women with gestational diabetes, which were explained by relevant theoretical models. Interventions should be developed with full consideration of these findings to ensure that pregnant women have the correct knowledge and confidence to self-manage their complications.
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Diabetes Gestacional , Autogestão , Feminino , Humanos , Gravidez , Diabetes Gestacional/psicologia , Diabetes Gestacional/terapia , Gestantes/psicologia , Pesquisa Qualitativa , Autogestão/métodos , Autogestão/psicologiaRESUMO
Emission trading schemes (ETS) are increasingly becoming a popular policy instrument to balance carbon abatement and economic growth. As a globally unified carbon pricing system has not yet been established, whether regionally operated ETSs cause carbon leakage remains a major concern. Taking China's regional pilot ETSs as a quasi-natural experiment, the study uses the spatial difference-in-differences method to examine how regional ETSs affect carbon emissions in and outside cities of policy implementation. Our analysis finds that China's regional ETS policy contributes to a 6.1% reduction in urban CO2 emissions and a 6.6% decline in emissions intensity in regulated cities, causing carbon leakages that increase CO2 emissions in neighboring cities by 1.7% on average. Our finding further suggests that regional ETSs mitigate local CO2 emissions through outsourcing production, improving energy efficiency and decarbonizing energy structure, whereas the outsourcing of industrial production drives up CO2 emissions in adjacent cities. Moreover, the performances of regional ETSs vary largely by socioeconomic context and mechanism design. China's regional ETSs reduce CO2 emissions more effectively in central and industrial cities but with more severe carbon leakage, while rigorous compliance mechanisms and active market trading help deepen carbon abatement and alleviate carbon leakage.
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Dióxido de Carbono , Carbono , China , CidadesRESUMO
Left bundle branch pacing (LBBP) has proven to be an alternative method for delivering physiological pacing to achieve electrical synchrony of the left ventricle (LV), especially in patients with atrioventricular block and left bundle branch block (LBBB). However, it is unclear whether it still achieved in patients whose left bundle branch (LBB) has had surgery-induced damage. The Morrow operation (Morrow septal myectomy) is regarded as one of the most effective treatments for hypertrophic obstructive cardiomyopathy (HOCM). The surgery resects small sections of muscle tissue in the proximal ventricular septum nearby or contains the LBB, which means that physical damage to the LBB is almost inevitable. Approximately 2%-12% of patients may need pacemaker implanted after Morrow surgery. LBBP is a feasible and effective method for achieving electric resynchronization of LBBB compared to right ventricular pacing (RVB). Nevertheless, there is a dearth of data on LBBP in third-degree atrioventricular block (AVB) following Morrow surgery. We report a case of successful LBBP in those patients.
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The oxygen reduction reaction (ORR) catalyzed by efficient and economical catalysts is critical for sustainable energy devices. Although the newly-emerging atomically dispersed platinum catalysts are highly attractive for maximizing atomic utilization, their catalytic selectivity and durability are severely limited by the inflexible valence transformation between Pt and supports. Here, we present a structure by anchoring Pt atoms onto valence-adjustable CuOx/Cu hybrid nanoparticle supports (Pt1-CuOx/Cu), in which the high-valence Cu (+2) in CuOx combined with zero-valent Cu (0) serves as a wide-range valence electron reservoir (0â2e) to dynamically adjust the Pt 5d valence states during the ORR. In situ spectroscopic characterizations demonstrate that the dynamic evolution of the Pt 5d valence electron configurations could optimize the adsorption strength of *OOH intermediate and further accelerate the dissociation of O = O bonds for the four-electron ORR. As a result, the Pt1-CuOx/Cu catalysts deliver superior ORR performance with a significantly enhanced four-electron selectivity of over 97% and long-term durability.
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Pheochromocytomas and paragangliomas (PPGLs) represent the highest degree of heritability of any known tumor types in humans. Previous studies have characterized a dramatic difference between Chinese and European Caucasians with regards to both genetics and clinical features of PPGLs. The proportion of PGLs in Chinese patients was higher than in Caucasians, and the prevalence of metastasis was much lower in Chinese patients. Compared with Caucasians, there were more pathogenic variants (PVs) found in HRAS and FGFR1, but less in NF1 and SDHB. There were less germline PVs found in Chinese patients. Importantly, in Chinese patients, there was a large proportion of PGLs with PVs found in HRAS and FGFR1, mostly with epinephrine-producing capacity. This finding provided solid evidence that genetics (cluster 1 vs. 2), rather than location (PCC vs. PGL), determines the catecholamine-producing phenotype. Besides, the lower prevalence of SDHB partially explained lower occurrence of metastatic lesions in Chinese patients. These findings underscore the importance of considering ethnic differences when evaluating PPGLs and patient outcomes.
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BACKGROUND: Perioperative management to maintain intraoperative haemodynamic stability is crucial during surgical treatment of pheochromocytomas and paragangliomas (PPGLs). Although approximately 70% of PPGLs carry pathogenic variants (PVs) in susceptibility genes, whether intraoperative haemodynamic instability (IHI) is associated with genetic background remains unclear. This study aimed to analyse IHI in patients with PPGL due to PVs in different genes. MATERIALS AND METHODS: This retrospective study recruited 756 patients with abdominal PPGL from two tertiary care centres. Clinical information including sex, age, catecholamine-associated signs and symptoms (CAS), tumour location and size, biochemistry, and perioperative characteristics were collected. Genetic mutations were investigated using next-generation sequencing. RESULTS: Among the 671 patients included in the analysis, 61.8% (415/671) had IHI. IHI was significantly associated with genetic background in patients with PPGL. Most (80.9%, 89/110) patients with PPGL due to PVs in HRAS suffered IHI. In contrast, only half (31/62) of patients with PPGL due to PVs in VHL had IHI. In the multivariate regression analysis, compared to those with negative genetic testing results, patients with PPGL due to PVs in HRAS (OR 3.82, 95% CI 2.187-6.679, P<0.001), the other cluster 2 genes (OR 1.95, 95% CI 1.287-2. 569, P< 0.05), and cluster 1 genes other than VHL (OR 2.35, 95% CI 1.338-4.111, P<0.05) were independent risk factors for IHI, while PVs in VHL was not independent risk factor (OR 1.09, 95% CI 0.605-1.953, P>=0.05). In addition, age at diagnosis of primary tumour, presenting of CAS, and tumour size were identified as independent factors for IHI. The nomogram illustrated that genetic background as sharing the largest contribution to IHI, followed by tumour size, age, and presenting of CAS. CONCLUSION: IHI is associated with the genetic background in patients with PPGL. The perioperative management of patients with PPGL can be personalized according to their genetic backgrounds, tumour size, age, and presenting of CAS.
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The dose-response of intravenous lidocaine in preventing postoperative vomiting (POV) in children remains unclear. This study investigated whether intravenous lidocaine dose-dependently decreased POV risk within 24 h postoperatively in children undergoing tonsillectomy (with or without adenoidectomy) without severe complications. Patients aged 3-12 years (American Society of Anesthesiologists grade I-II) scheduled for elective tonsillectomy (with or without adenoidectomy) were enroled from December 2021 to March 2022. They were randomly grouped according to the lidocaine dose (A [0 mg kg-1], B [1 mg kg-1], C [1.5 mg kg-1], and D [2 mg kg-1]) and were administered the same induction protocol (sufentanil, propofol, and suxamethonium chloride). Anaesthesia was maintained with sevoflurane. The incidence of POV within 24 h postoperatively was 46, 40, 36, and 20% in groups A, B, C, and D, respectively, with significant differences between groups D and A. Postoperative analgesic rescues in groups A, B, C, and D were 62, 36, 34, and 16%, respectively, with significant differences between groups D and B, C and A, and D and A. No severe adverse events were reported. Intravenous lidocaine has a dose-dependent effect on reducing the risk of POV in children undergoing tonsillectomy (with or without adenoidectomy) without serious adverse events.Trial registration: Chinese Clinical Trial Registry, ChiCTR2100053006.
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Lidocaína , Náusea e Vômito Pós-Operatórios , Tonsilectomia , Humanos , Tonsilectomia/efeitos adversos , Lidocaína/administração & dosagem , Lidocaína/uso terapêutico , Lidocaína/efeitos adversos , Criança , Masculino , Pré-Escolar , Feminino , Náusea e Vômito Pós-Operatórios/prevenção & controle , Adenoidectomia/efeitos adversos , Relação Dose-Resposta a Droga , Anestésicos Locais/administração & dosagem , Anestésicos Locais/uso terapêuticoRESUMO
Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.
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Ferroptose , Infarto da Artéria Cerebral Média , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Estresse Oxidativo , Traumatismo por Reperfusão , Tionas , Tiofenos , Animais , Ferroptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Tionas/farmacologia , Tionas/uso terapêutico , Células PC12 , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Ratos , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Modelos Animais de Doenças , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , PirazinasRESUMO
BACKGROUND: Gliomas are highly invasive brain tumors that evade accurate geographic assessment by conventional MRI due to microscopic invasion along white matter (WM) tracts. Advanced diffusion MRI techniques are needed to assess occult WM involvement. PURPOSE: To evaluate peak width of skeletonized mean diffusivity (PSMD) and peak width of skeletonized free water (PSFW), and axonal water fraction (AWF) for assessing glioma-induced alterations in normal-appearing WM and their relationship with isocitrate dehydrogenase 1 (IDH1) mutation. STUDY TYPE: Retrospective. POPULATION: One hundred five glioma patients (46 ± 13 years), 53 healthy controls (HCs) (46 ± 9 years). FIELD STRENGTH/SEQUENCE: 3.0 T, T1WI, T1-CE, T2WI, T2FLAIR, and DKI. ASSESSMENT: PSMD and PSFW were compared between lesion and contralateral sides in glioma patients and between patients and HCs. The associations between these metrics and clinical variables, including IDH1 mutation, was assessed. Corpus callosum (CC) injury, quantified by the AWF, was evaluated for its mediated effect of IDH1 mutation on contralesional PSMD and PSFW. STATISTICAL TESTS: Paired-t tests, ANCOVA, univariate and multivariate linear regression, and mediation analysis with significance set at P < 0.05. RESULTS: Contralateral PSMD and PSFW were significantly higher in left-sided gliomas (PSMD: 0.206 ± 0.027 vs. 0.193 ± 0.023; PSFW: 0.119 ± 0.019 vs. 0.106 ± 0.020) than in HCs, with similar increases in right-sided gliomas (PSMD: 0.219 ± 0.036 vs. 0.195 ± 0.023; PSFW: 0.129 ± 0.031 vs. 0.109 ± 0.020). IDH1 wild-type gliomas were associated with higher contralateral PSMD and PSFW (ß = -0.302 and -0.412). AWF of CC mediated the impact of IDH1 mutations on contralesional PSMD and PSFW (mediated proportion: 42.7% and 53.7%). DATA CONCLUSION: PSMD and PSFW are effective biomarkers for assessing WM integrity in gliomas, significantly associated with IDH1 mutation status. AWF of CC mediates the relationship between IDH1 mutation and contralesional PSMD and PSFW. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.
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Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.
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BACKGROUND: Colorectal cancer (CRC) prognosis prediction is currently a major challenge. Epigenetic regulation has been widely reported for its role in cancer development. AIM: To construct a robust prognostic signature, we used developed and validated across datasets. METHODS: After constructing the signature, the prognostic value of the signature was evaluated in the TCGA cohort and six independent datasets (GSE17526, GSE17537, GSE33113, GSE37892, GSE39048 and GSE39582). The clinical, genomic and transcriptomic features related to the signature were identified. The correlations of the signature score with immune cell infiltration and cell-cell interactions were analyzed. The correlations between the signature score and the sensitivity to different drugs were also predicted. RESULTS: In the TCGA cohort, patients in the low-risk group according to the signature score had longer survival than those in the high-risk group, and this finding was validated in the validation datasets. The signature was a prognostic factor independent of age and sex and was correlated with stage and PD-1/PD-L1 expression. Area under the receiving operating characteristic curve was 0.72. Genomic association analyses revealed that samples from high-risk patients exhibited chromosomal instability. Transcriptomic analyses revealed that the signature score was significantly associated with multiple cellular pathways. Bulk RNA-seq and single-cell sequencing data revealed that the signature reflected differences in infiltrating immune cell-tumor cell interactions, especially for macrophages. The signature also predicted the putative drug sensitivity of CRC samples. CONCLUSION: The signature is a valuable biomarker for predicting CRC prognosis and reflects multiple features of CRC, especially macrophage infiltration in the microenvironment.
RESUMO
Current KRASG12C (OFF) inhibitors that target inactive GDP-bound KRASG12C cause responses in less than half of patients and these responses are not durable. A class of RASG12C (ON) inhibitors that targets active GTP-bound KRASG12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRASG12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRASG12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRASG12C-dependent lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Sinergismo Farmacológico , Neoplasias Pulmonares , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas Proto-Oncogênicas p21(ras) , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Animais , Linhagem Celular Tumoral , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais/efeitos dos fármacos , Ciclina D1/metabolismo , Ciclina D1/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Feminino , Proteína 11 Semelhante a Bcl-2/metabolismo , Proteína 11 Semelhante a Bcl-2/genéticaRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC), a globally common cancer, often presents late and shows high resistance to chemotherapy, resulting in suboptimal treatment efficacy. Components from traditional Chinese medicines have been recognized for their anti-cancer properties. OBJECTIVE: Exploring the mechanism of Schisandra chinensis lignans and acteoside in suppressing Epithelial-Mesenchymal Transition (EMT) in hepatoma cells through the Extracellular signal-Regulated Kinases (ERK)1/2 pathway and identifying biomarkers, molecular subtypes, and targets via multi-omics for precision oncology. METHODS: Proliferation was assessed using cell counting kit-8 (CCK-8) assays, with scratch and transwell assays for evaluating invasion and migration. Flow cytometry quantified apoptosis rates. Expression levels of CCL20, p-ERK1/2, c-Myc, Vimentin, and E-cadherin/N-cadherin were analyzed by real-time PCR and Western blot. Tumor volume was calculated with a specific formula, and growth. RESULTS: The Schisandra chinensis lignans and acteoside combination decreased CCL20 expression, inhibited hepatoma proliferation and migration, and enhanced apoptosis in a dose- and time-dependent manner. Molecular analysis revealed increased E-cadherin and decreased N-cadherin, p-ERK1/2, c-Myc, and Vimentin expression, indicating ERK1/2 pathway modulation. In vivo, treated nude mice showed significantly reduced tumor growth and volume. CONCLUSION: Schisandra chinensis lignans and acteoside potentially counteract CCL20-induced EMT, invasion, and migration in hepatocellular carcinoma cells via the ERK1/2 pathway, enhancing apoptosis. Multi-omics analysis further aids in pinpointing novel biomarkers for precision cancer therapy.