GRIK3 deficiency promotes non-small cell lung cancer progression by the regulation of the UBE2C/CDK1/Wnt signaling pathway.

Glutamate ionotropic receptor kainate type subunit 3 (GRIK3) is a predominant excitatory neurotransmitter receptor in the mammalian brain. While it is known that GRIK3 is involved in normal neurophysiologic processes, its biological functions in tumor progression are still poorly understood due to limited investigation. In this study, we reported for the first time that GRIK3 expression was downregulated in non-small cell lung cancer (NSCLC) tissues as compared to paracarcinoma tissues. Additionally, we observed that GRIK3 expression was strongly correlated with the prognosis of NSCLC patients. We also noted that GRIK3 suppressed the cell proliferation and migration capability of NSCLC cells, thereby inhibiting xenografts growth and metastasis. Mechanistically, GRIK3 deficiency increased the expression of ubiquitin-conjugating enzyme E2 C (UBE2C) and cyclin-dependent kinase 1 (CDK1), which resulted in the activation of the Wnt signaling pathway and enhanced NSCLC progression. Our findings suggest that GRIK3 plays a role in regulating NSCLC progression and that its expression may serve as an independent prognostic indicator for NSCLC patients.

Genomic features of Chinese small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive disease with poor survival. Although molecular and clinical characteristics have been established for SCLC in western patients, limited investigation has been performed for Chinese SCLC patients. OBJECTIVE: In this study, we investigated the genomic features of Chinese SCLC patients. METHODS: A total of 75 SCLC patients were enrolled. Genomic alterations in 618 selected genes were analyzed by targeted next-generation sequencing. RESULTS: Here, we showed that TP53 (77.30%) and RB1 (30.70%) were the most prevalent genes alterations, followed by KMT2D, ALK, LRP1B, EGFR, NOTCH3, AR, CREBBP, ROS1, and BRCA2. And the most common genetic alterations were enriched in the cell cycle signaling pathway (84.00%) of Chinese SCLC patients. DNA damage repair (DDR) pathway analysis showed that the most frequently enriched DDR pathways were fanconi anaemia (FA, 29.41%) and homology recombination (HR, 21.57%). Notably, 9.33% SCLC patients in our cohort had pathogenic or likely pathogenic germline gene variants. Compared with the U Cologne cohort, a higher prevalence in EGFR, AR, BRCA2, TSC1, ATXN3, MET, MSH2, ERBB3 and FOXA1 were found in our cohort; while compared to the data from the Johns Hopkins cohort, a higher mutated frequency in TP53, KMT2D, ALK, and EGFR were found in our cohort. Moreover, a significant association was found between high tumor mutation burden (TMB) and mutations involved in TP53, CREBBP, EPHA3, KMT2D, ALK and RB1. Approximately 33.33% of patients with SCLC harbored at least one actionable alteration annotated by OncoKB, of which one patient had alterations of level 1; seventeen patients had level 3; fifteen patients possessed level 4. CONCLUSION: Our data might provide an insightful meaning in targeted therapy for Chinese SCLC patients.

Failure Analysis of Hat-Stringer-Stiffened Aircraft Composite Panels under Four-Point Bending Loading.

Hat-stringer-stiffened composite panels have been widely used in aircrafts. Accurate failure analysis of them is important for the safety and integrity of the fuselage. During the service period, these panels will bear not only the lateral force caused by the bending of fuselage, but also the radial pressure caused by the internal and external differential pressure during the take-off and landing of the aircraft. However, the latter case lacks investigation. Therefore, experimental and numerical studies for the static and fatigue failure of hat-stringer-stiffened composite panels under four-point bending loading have been performed in this work. To accurately predict the fatigue failure, a novel theoretical model has been proposed based on the fatigue damage theory. In addition, a user-defined subroutine USDFLD is developed for the implementation of the proposed theoretical model in Abaqus. Experimental results show that the main failure modes are the delamination of the skin and debonding between the girder flange and the skin. The experimental average value of the initial debonding load and displacement in static tests are 897.3 N and 10.8 mm, respectively. Predictions exhibit good agreement with experimental results with relative errors within 10%. Experimental average fatigue failure life of the specimens is 33,085 cycles, which is also close to the prediction with relative errors within 10%. This indicates the reliability and applicability of the established theoretical model and numerical method for predicting the failure of hat-shaped girder structures.

Using a mixed method to identify communication skills training priorities for Chinese general practitioners in diabetes care.

BACKGROUND: In China diabetes care is gradually shifting from secondary to primary care with great infrastructure investment and GP training. However, most GPs in China lack communication skills training, which is a huge obstacle in communication with their patients in primary care. In this study we seek to identify training priorities that is evidence-based, appropriate for the context of primary care in China, and that meet the real needs of both GPs and people with diabetes. METHODS: A mixed method approach was used. A conceptual framework was designed based on the MRC framework, action research and adult learning theories. Through a systematic review of the literature and qualitative research with GPs and patients with diabetes, a list of communication skills training components was developed by the research team. A modified nominal group technique (NGT) with GPs was used to evaluate these contents. Purposive sampling was used to recruit a variation of participants (age, work area, practice years and education background) from general practices in Guangzhou city, China. Eight structured nominal groups were facilitated to elicit the views of group members, and participants rated the 9-point Likert scale of importance and feasibility of the training items independently, before and after focus groups. The ranking of each item was calculated, based on the mean Likert score ratings from all participants. Video recordings of four NGT group discussions were thematically analysed using the Framework Method to explore reasons for any differences in rating items. RESULTS: 29 males and 29 female GPs from 28 general practices participated in NGT group discussions, with a mean age of 38.5 years and mean 12.3 years of practice experience. Based on the mean scores of importance and feasibility rating scores, the top 3 ranked priorities for communication training were 'health education' (importance 8.39, feasibility 7.67), 'discussing and explaining blood glucose monitoring' (8.31, 7.46), and 'diabetes complications and cardiovascular disease risk communication' (8.36, 7.12). Five main themes were identified from focus group discussions through qualitative analysis: 'impact on diabetes patients', 'GP attitudes towards communication skills', 'patient-related factors influencing the application of communication skills by GPs, 'local contextual factors', and 'training implementation'. CONCLUSIONS: Priorities for communication skills training for Chinese GPs in diabetes care were identified. These are set in the context of GPs' current experience of communication with patients in China who have diabetes, which is often unsatisfactory. This study describes the baseline from which better primary care for diabetes in China needs to be developed. Based on suggestions from GPs themselves, it identifies an agenda for improvement in communication as a key component of diabetes care in China.

A Two-Dimensional Model for Pin-Load Distribution and Failure Analysis of Composite Bolted Joints.

Multibolt composite joints are widely used in aircraft structures. The determination of the pin-load distribution among the bolts is a critical step in the failure prediction of bolted joints. In this paper, a two-dimensional model of the multibolt composite structure is established for the pin-load distribution analysis. Its accuracy is validated by experimental results and the results from a 3D finite element model. Based on the determined pin-load distribution, FE models for a laminated plate with three-row fastener joints are built for failure prediction. Hashin stress criteria and the degradation guidelines of the material stiffness with respect to the different failure modes proposed by Tserpes are applied for the failure evaluation and the material degradation, respectively. The failure location and ultimate load are well predicted, which further validates the effectiveness and applicability of the proposed model for the pin-load distribution analysis.

[Diagnostic values of the clinical characteristics of chronic cough].

OBJECTIVE: To evaluate whether the clinical characteristics of chronic cough were helpful in determining its specific causes. METHODS: Patients with chronic cough were evaluated by a validated systematic diagnostic protocol. The patients with identified single cause were divided into 4 groups accordingly: cough-variant asthma (CVA), upper airway cough syndrome (UACS) or post-nasal drip syndrome (PNDS), eosinophilic bronchitis (EB), gastroesophageal reflux related cough (GERC), and the characteristics of the timing, character, onset and associated manifestations of chronic cough in different causes were compared. RESULTS: A total of 196 patients met the inclusion criteria, including 55 with EB, 45 with UACS, 50 with CVA and 46 with GERC. No significant difference was found in age, gender and course among EB, UACS, CVA and GERC. The incidence of nocturnal cough in CVA was 26.0% (13/44), significantly higher than in EB (9.1% (5/55), chi2 = 5.272, P<0.05), UACS (2.2% (1/45), chi2 = 10.657, P<0.01) and GERC (0% (0/46), chi2 = 13.833, P<0.01). The specificity of nocturnal cough for CVA was 95.9%. The sensitivity and specificity of cough associated with meals in GERC was 52.2% (24/46) and 83.3%, and regurgitation associated symptom in GERC were 69.6% (32/46) and 80.0%, which were significantly higher than other groups. The incidence of postnasal drip, rhinitis associated symptom and case history of nasal diseases in UACS were 66.7% (30/45), 88.9% (40/45) and 82.2% (37/45), and the specificity of them were 89.4%, 65.6% and 63.6% respectively. CONCLUSION: The timing character and some associated symptoms of chronic cough are useful in predicting a single cause.