Non-small cell lung cancer cells with uncommon EGFR exon 19delins variants respond poorly to third-generation EGFR inhibitors.

BACKGROUND: This study compared the clinical efficacy of first-, second-, and third-generation tyrosine kinase inhibitors (TKIs) in previously untreated non-small cell lung cancer (NSCLC) patients harboring uncommon epidermal growth factor receptor (EGFR) exon 19delins variants. METHODS: We retrospectively analyzed the clinical outcomes of NSCLC patients with EGFR exon 19delins mutations who were treated with third- and first-generation EGFR TKIs. In vitro and in vivo studies were conducted to verify the sensitivity of these mutations to distinct generations of TKIs. Molecular simulation was used to investigate the structural characteristics of the EGFR mutant molecules. RESULTS: In a multicenter cohort of 1,526 patients, 37 (2.4 %) had uncommon EGFR 19delins mutations. Twenty-four patients were treated with first-generation EGFR TKIs, and third-generation TKIs were administered to ten patients as frontline therapy. Patients carrying EGFR exon 19delins mutations who were given third-generation TKIs exhibited comparatively shorter progression-free survival (PFS) and overall survival (OS) in relation to those who received first-generation EGFR inhibitors; median PFS: 6.9 months vs. 19.1 months (p < 0.001), Median OS: 19.1 months vs. 32.6 months (p < 0.001). In vivo and in vitro studies revealed that uncommon EGFR 19delins variants exhibit limited sensitivity to third-generation EGFR inhibitors in contrast to first- and second-generation EGFR inhibitors. The molecular binding affinity of third-generation EGFR TKIs toward uncommon EGFR 19delins mutations was less than that of first- and second-generation EGFR inhibitors. CONCLUSIONS: Uncommon EGFR 19delins variants respond poorly to third-generation EGFR inhibitors in NSCLC. Uncommon EGFR 19delins mutations may serve as an unfavorable predictive factor for the efficacy of third-generation EGFR TKI therapy, offering potential guidance for future clinical decision-making.

Oncostatin M/Oncostatin M Receptor Signal Induces Radiation-Induced Heart Fibrosis by Regulating SMAD4 in Fibroblast.

PURPOSE: Radiation-induced heart fibrosis (RIHF) is a severe consequence of radiation-induced heart damage (RIHD) leading to impaired cardiac function. The involvement of oncostatin M (OSM) and its receptor (OSMR) in RIHD remains unclear. This study aimed to investigate the specific mechanism of OSM/OSMR in RIHF/RIHD. METHODS AND MATERIALS: RNA sequencing was performed on heart tissues from a RIHD mouse model. OSM levels were assessed in serum samples obtained from patients receiving thoracic radiation therapy (RT), as well as in RIHF mouse heart tissues and serum using enzyme-linked immunosorbent assay. Fiber activation was evaluated through costimulation of primary cardiac fibroblasts and NIH3T3 cells with RT and OSM, using Western blotting, immunofluorescence, and quantitative Polymerase Chain Reaction (qPCR). Adeno-associated virus serotype 9-mediated overexpression or silencing of OSM specifically in the heart was performed in vivo to assess cardiac fibrosis levels by transthoracic echocardiography and pathologic examination. The regulatory mechanism of OSM on the transcription level of SMAD4 was further explored in vitro using mass spectrometric analysis, chromatin immunoprecipitation-qPCR, and DNA pull-down. RESULTS: OSM levels were elevated in the serum of patients after thoracic RT as well as in RIHF mouse cardiac endothelial cells and mouse serum. The OSM rate (post-RT/pre-RT) and the heart exposure dose in RT patients showed a positive correlation. Silencing OSMR in RIHF mice reduced fibrosis, while OSMR overexpression increased fibrotic responses. Furthermore, increased OSM promoted histone acetylation (H3K27ac) in the SMAD4 promoter region, influencing SMAD4 transcription and subsequently enhancing fibrotic response. CONCLUSIONS: The findings demonstrated that OSM/OSMR signaling promotes SMAD4 transcription in cardiac fibroblasts through H3K27 hyperacetylation, thereby promoting radiation-induced cardiac fibrosis and manifestations of RIHD.

Effect of virtual reality exercise on interventions for patients with Alzheimer's disease: A systematic review.

Virtual reality (VR) interventions are increasingly being used in rehabilitating and treating patients with neurological disorders. This study aimed to explore the effects of VR exercise interventions for patients with Alzheimer's disease (AD). A systematic review of the published literature on randomized controlled trials of VR technology applied to patients with AD was conducted using the preferred reporting entry for systematic reviews and Meta-analysis guidelines. Descriptive analyses were performed to assess the quality of the studies in terms of the characteristics of the included studies, samples, diagnoses, types of VR technologies, subjective and objective levels of immersion, and quality of studies. Eight studies were included, including a pooled sample of 362 patients with AD. A systematic review showed that most studies focused on patients with AD's cognitive and physical functions. The main finding was that VR interventions could help improve cognitive and physical balance in patients with AD. However, future studies should emphasize design and use well-accepted assessment tools to validate the effects of VR interventions further.

Acetylation of Atp5f1c Mediates Cardiomyocyte Senescence via Metabolic Dysfunction in Radiation-Induced Heart Damage.

Objective: Ionizing radiation (IR) causes cardiac senescence, which eventually manifests as radiation-induced heart damage (RIHD). This study is aimed at exploring the mechanisms underlying IR-induced senescence using acetylation proteomics. Methods: Irradiated mouse hearts and H9C2 cells were harvested for senescence detection. Acetylation proteomics was used to investigate alterations in lysine acetylation. Atp5f1c acetylation after IR was verified using coimmunoprecipitation (Co-IP). Atp5f1c lysine 55 site acetylation (Atp5f1c K55-Ac) point mutation plasmids were used to evaluate the influence of Atp5f1c K55-Ac on energy metabolism and cellular senescence. Deacetylation inhibitors, plasmids, and siRNA transfection were used to determine the mechanism of Atp5f1c K55-Ac regulation. Results: The mice showed cardiomyocyte and cardiac aging phenotypes after IR. We identified 90 lysine acetylation sites from 70 protein alterations in the heart in response to IR. Hyperacetylated proteins are primarily involved in energy metabolism. Among them, Atp5f1c was hyperacetylated, as confirmed by Co-IP. Atp5f1c K55-Ac decreased ATP enzyme activity and synthesis. Atp5f1c K55 acetylation induced cardiomyocyte senescence, and Sirt4 and Sirt5 regulated Atp5f1c K55 deacetylation. Conclusion: Our findings reveal a mechanism of RIHD through which Atp5f1c K55-Ac leads to cardiac aging and Sirt4 or Sirt5 modulates Atp5f1c acetylation. Therefore, the regulation of Atp5f1c K55-Ac might be a potential target for the treatment of RIHD.

Constructing a novel prognostic signature of tumor driver genes for breast cancer.

OBJECTIVES: To systematically explore the function and prognostic ability of tumor-driver genes (TDGs) in breast carcinoma (BRCA). METHODS: Functional enrichment analysis of BRCA differentially expressed TDGs was assesed. We used univariate Cox, lasso, and multivariate Cox regression to identify the independent prognostic TDGs of BRCA. Then we constructed a prognostic signature and verified its predictive performance. Gene set enrichment analysis of the signal pathway revealed the differences between the prognostic signature high- and low-risk groups. Finally, a nomogram related to the prognostic model was established and verified. RESULTS: A total of 595 differentially expressed TDGs were identified, which are related to various molecular mechanisms of BRCA progression. We identified 8 independent prognostic TDGs for BRCA and validated their expression and prognosis with public data and clinical samples. The BRCA cohort was divided into training and validation cohorts, and prognostic signatures were constructed separately. The log-rank test showed that the survival rate of the high-risk group was significantly lower than that of the low-risk group in the prognostic signature (P<0.001); the AUC in the three cohorts were 0.805, 0.712, and 0.760, respectively; the nomogram also showed better predictive performance. Analyzing the difference between the two risk subtypes, the high-risk group is mainly enriched in angiogenesis, MTORC1, epithelial-mesenchymal transition and glycolysis, which means it is highly malignant. CONCLUSIONS: The prognostic signature and nomogram was confirmed to accurately predict the prognosis of patients with BRCA and we validated the hub genes, suggesting their potential as future therapeutic targets.

Preparation and mechanical properties analysis of porous structure for bone tissue engineering.

BACKGROUND: With the increasing aging of population, the incidence rate of diseases such as fracture and osteoporosis has been increasing. The demand for implant in Department of orthopedics has increased. The elastic modulus of the existing solid metal implant is much higher than that of human bone tissue, and it is easy to produce stress shielding effect after operation, which causes complications such as loosening of prosthesis and low fusion efficiency. OBJECTIVE: In order to solve the mismatch of elastic modulus between solid metal orthopedic implants and human bone tissue, metal structures with excellent mechanical properties were prepared. METHODS: The porous structure was designed by spatial dot matrix method, and the metal porous structure was prepared based on selective laser melting 3D printing technology. The residual stress in the preparation process was eliminated by vacuum annealing heat treatment, and the static compression experiment was carried out to study the effects of different pore shape and porosity parameters on the compressive yield strength and elastic modulus of porous structure. The performance changes of porous structure before and after heat treatment were compared, and the porous structure meeting the performance requirements of human bone tissue was selected. RESULTS: The porous structure prepared by selective laser melting technology met the requirements of human bone tissue. The elastic modulus was as low as 0.74 GPa and the compressive yield strength is 201.91 MPa; After annealing heat treatment, the compressive yield strength of porous structure decreased, the maximum change was 3.69%, the elastic modulus increased, and the maximum change was 8.69%. CONCLUSIONS: For the porous structure with the same pore shape, the lower the porosity, the better the mechanical properties of the porous structure. For the same porosity, the comprehensive mechanical properties of dodecahedral porous structure were the best and octahedral porous structure was the worst; the porous structure after annealing heat treatment was more conducive to meet the performance requirements of human bone tissue.

Potential benefit of osismertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer.

BACKGROUND: EGFR-mutant non-small cell lung cancer (NSCLC) is prone to leptomeningeal metastasis (LM) after Tyrosine kinase inhibitors (TKIs) treatment. Our previous study suggested that osimertinib plus bevacizumab was safe and effective in LM from EGFR-mutant NSCLC. This study aimed to compare the efficacy of osimertinib plus bevacizumab with osimertinib in EGFR-mutant NSCLC patients with LM. METHODS: We retrospectively reviewed the data from 27 LM patients with EGFR-mutant NSCLC who received osimertinib with or without bevacizumab at the Second Affiliated Hospital of Nanchang University. Next, we investigated the antitumor efficacy of osimertinib plus bevacizumab in an LM xenograft model using the H1975 (EGFR exon20 T790M and exon21 L858R) cell line. We examined the ability of osimertinib plus bevacizumab compared with osimertinib to penetrate the blood-brain barrier (BBB) and explored the potential mechanism. RESULTS: Our retrospective study observed the improved survival of LM patients in osimertinib plus bevacizumab group. The median overall survival (OS) of the patients who received osimertinib and bevacizumab (n = 16) compared with osimertinib group (n = 11) was 18.0 months versus 13.7 months (log-rank test, p = 0.046, HR = 2.867, 95% CI 1.007-8.162). The median intracranial Progression-free Survival (iPFS) was 10.6 months versus 5.5 months (log-rank test, p = 0.037, HR = 3.401, 95% CI 1.079-10.720). In the LM xenograft model with H1975 cells, the combined treatment significantly increased the effective intracranial concentration of osimertinib, modulated the level of E-cadherin and downregulated the levels of EGFR and downstream signaling pathways including p-AKT and reduced tumor microvessel density (TMD), indicated that combined osimertinib with bevacizumab may exhibit a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin. CONCLUSIONS: Our findings indicate the potential benefit of osimertinib plus bevacizumab in LM with EGFR-mutant NSCLC, and more larger sample size research are still needed.

Radiation­induced dysfunction of energy metabolism in the heart results in the fibrosis of cardiac tissues.

Thoracic radiotherapy increases the risk of radiation­induced heart damage (RIHD); however, the molecular mechanisms underlying these changes are not fully understood. The aim of the present study was to investigate the effects of radiation on the mouse heart using high­throughput proteomics. Male C57BL/6J mice were used to establish a model of RIHD by exposing the entire heart to 16 Gy high­energy X­rays, and cardiac injuries were verified using a cardiac echocardiogram, as well as by measuring serum brain natriuretic peptide levels and conducting H&E and Masson staining 5 months after irradiation. Proteomics experiments were performed using the heart apex of 5­month irradiated mice and control mice that underwent sham­irradiation. The most significantly differentially expressed proteins were enriched in 'cardiac fibrosis' and 'energy metabolism'. Next, the cardiac fibrosis and changes to energy metabolism were confirmed using immunohistochemistry staining and western blotting. Extracellular matrix proteins, such as collagen type 1 α 1 chain, collagen type III α 1 chain, vimentin and CCCTC­binding factor, along with metabolism­related proteins, such as fatty acid synthase and solute carrier family 25 member 1, exhibited upregulated expression following exposure to ionizing radiation. Additionally, the myocardial mitochondria inner membranes were injured, along with a decrease in ATP levels and the accumulation of lactic acid in the irradiated heart tissues. These results suggest that the high doses of ionizing radiation used lead to structural remodeling, functional injury and fibrotic alterations in the mouse heart. Radiation­induced mitochondrial damage and metabolic alterations of the cardiac tissue may thus be a pathogenic mechanism of RIHD.

The feasibility of family-centred early intervention for children with disabilities in mainland China: Practitioners' perceptions.

BACKGROUND: Family-centred practice (FCP) has become a recommended practice for early intervention services for children with disabilities in many countries. However, its feasibility in Chinese context has been unclear. This study is the first to explore the perceptions of early intervention service practitioners about the implementation of FCP in mainland China. METHODS: Focus groups were employed to collect data from 37 early intervention practitioners who attended a workshop about FCP in Wuhan, China and two officers from the provincial disabled persons' federation. The data were analysed thematically. RESULTS: Four themes were identified: (a) family-centred early intervention is possible, (b) traditional concepts are not friendly towards FCP, (c) parents do not collaborate and (d) financing and personal resources are not sufficient to implement FCP. Chinese practitioners agreed with the philosophies of FCP; however, there was concern that widespread implementation may meet conceptual and practical challenges. CONCLUSIONS: The results highlighted practitioners were optimistic and keen for FCP implementation in the Chinese context, but to do so across China may still be some way in the future.

Psychometric Properties of the Exercise Orientation Questionnaire: A Confirmatory Study on Chinese University Students.

The Exercise Orientation Questionnaire (EOQ) is a method for evaluating individuals' exercise attitudes and behaviors associated with exercise motivation. A lack of exercise motivation can affect physical activity attitudes, behavior, and action among university students. Physical inactivity may lead to health risks. The purpose of this study was to assess the measurement of psychological properties in the EOQ and to determine the reliability and validity of the EOQ when applied to Chinese university students. A total of 368 university students (male 48.8%) aged between 17 and 23 years (M = 19.60, SD = 1.18) participated in the current study. Confirmatory factor analysis (CFA) and exploratory structural equation modeling (ESEM) were used to verify the factorial validity of the EOQ. The internal consistency coefficient (Cronbach's alpha and McDonald's omega) was used to determine reliability. Multiple regression analysis was used to test concurrent validity. The International Physical Activity Questionnaire (IPAQ) was used to determine the participants' level of physical activity. The range of the subscale coefficient was 0.80-0.89, and the total scale was 0.95, which indicated that the reliability of the EOQ was excellent. The research showed that the initial CFA model of the EOQ had poorly fitting indices. The corrected model after seven residual correlations achieved the setting standard, but the correlation coefficient between some factors exceeded the standard threshold, which indicated that the CFA fitting model was not ideal. ESEM is a combination of exploratory and verifiable analytical techniques. Using ESEM and abbreviated version CFA to analyze the data indicated that the model fitted well [ESEM: TLI = 0.97 > 0.90, CFI = 0.96 > 0.90, SRMR = 0.02 < 0.08, and RMSEA = 0.045 < 0.08 (90% CI 0.033-0.055); CFA: TLI = 0.92 > 0.90, CFI = 0.91 > 0.90, SRMR = 0.08, and RMSEA = 0.06 < 0.08 (90% CI 0.055-0.067)]. The results of multiple regression analysis suggested that the ESEM model was effective in distinguishing the differences between individuals with different levels of physical activity (PAL) and body mass index (BMI). Overall, the Chinese abbreviated version of the EOQ (EOQ-CA) was fond to be a reliable tool for monitoring the exercise attitudes and behaviors of Chinese University students.

Development and Validation of a Short Version Sport Orientation Questionnaire for Chinese Adolescents (SOQ-CA).

A noted decrease in adolescent physical activity in the past decade has resulted in an increase in health risks. Sport orientation correlates closely with physical activity. A sufficient assessment scale that measures an individual's sport orientation is important to measure an adolescent's physical inactivity. The purpose of this study was to develop and validate a short version of the Sport Orientation Questionnaire for Chinese Adolescents (SOQ-CA). Based on Gill's SOQ and previous literature, an initial 30-item questionnaire was developed to create the original SOQ-CA. A five-point Likert scale was used to measure by self-report. In this study, three surveys were conducted. Volunteer participants completed 1,235 valid questionnaires. The data of the first collection sample (n = 486) were split randomly into two groups, sample 1 (n = 150) used for exploratory factor analysis (EFA) and sample 2 (n = 336) for confirmatory factor analysis (CFA). The data of the second (n = 377) and third (n = 372) collection samples were used to perform test-retest reliability, internal consistency, and CFA of the SOQ-CA. The SOQ-CA obtained good reliability and validity through both EFA and CFA. The development of the SOQ-CA provides an opportunity to develop further theories and practices regarding the assessment of both sport motivation and individual achievement orientation. The application of the SOQ-CA in China would be significant for monitoring the development of adolescent physical activity and aiding in the implementation of policies.