Nurses' perspectives on professional self-concept and its influencing factors: A qualitative study.

BACKGROUND: Nurses with a strong professional self-concept tend to exhibit a positive mindset and strong work engagement, delivering high-quality patient care. Although numerous quantitative studies have examined the factors impacting professional self-concept, there remains a limited exploration of these factors from the perspective of nurses themselves. METHODS: This qualitative descriptive study uses the PERMA theory and Social Cognitive Theory as the theoretical framework. Semi-structured interviews were conducted with 15 nurses from six public hospitals in China. The data were analyzed thematically using a combination of inductive and deductive approaches. RESULTS: Nurses' understanding of professional self-concept could be divided into four categories: professional identity, competence, care, and knowledge. Factors influencing nurses' professional self-concept were categorized into eight subthemes in three domains: (1) personal factors, including psychological qualities and attitude towards the nursing profession; (2) occupational-related behavioral factors, including role-oriented behavior and knowledge-oriented behavior; and (3) work environment and external factors, including external evaluation and perceptions of nurses, time allocation, nursing work tasks, work atmosphere, school education, and perceived supports. CONCLUSIONS: This study found that, although nurses had different personal experiences, their perceptions of professional self-concept were similar. Nurses' professional self-concept is a multidimensional concept and involves various factors, such as personality, work-related characteristics, environment, and family. To thrive in a nursing career, nurses must discern the factors that can enhance or hinder their professional self-concept. By identifying and adjusting these factors, personalized support and positive interventions can be tailored to meet nurses' specific needs, which ultimately nurtures their professional development. TRIAL REGISTRATION: This study was registered on December 14, 2022, in the Chinese Clinical Trial Registry (ChiCTR2200066699) as part of our ongoing study.

Analysing a Group of Homologous BAHD Enzymes Provides Insights into the Evolutionary Transition of Rosmarinic Acid Synthases from Hydroxycinnamoyl-CoA:Shikimate/Quinate Hydroxycinnamoyl Transferases.

The interplay of various enzymes and compounds gives rise to the intricate secondary metabolic networks observed today. However, the current understanding of their formation and expansion remains limited. BAHD acyltransferases play important roles in the biosynthesis of numerous significant secondary metabolites. In plants, they are widely distributed and exhibit a diverse range of activities. Among them, rosmarinic acid synthase (RAS) and hydroxycinnamoyl-CoA:shikimate/quinate hydroxycinnamoyl transferase (HCT) have gained significant recognition and have been extensively investigated as prominent members of the BAHD acyltransferase family. Here, we conducted a comprehensive study on a unique group of RAS homologous enzymes in Mentha longifolia that display both catalytic activities and molecular features similar to HCT and Lamiaceae RAS. Subsequent phylogenetic and comparative genome analyses revealed their derivation from expansion events within the HCT gene family, indicating their potential as collateral branches along the evolutionary trajectory, leading to Lamiaceae RAS while still retaining certain ancestral vestiges. This discovery provides more detailed insights into the evolution from HCT to RAS. Our collective findings indicate that gene duplication is the driving force behind the observed evolutionary pattern in plant-specialized enzymes, which probably originated from ancestral enzyme promiscuity and were subsequently shaped by principles of biological adaptation.

Latent profiles of nurses' subjective well-being and its association with social support and professional self-concept.

AIM: To identify latent profiles of nurses' subjective well-being (SWB) and explore its association with social support and professional self-concept. DESIGN: This study used an online survey and cross-sectional latent profile analysis design. METHODS: A total of 1009 nurses from 30 hospitals in Guangdong Province, China, were selected using convenience sampling. An online questionnaire survey comprising the following scales was distributed: Index of Well-Being, Nurses' Professional Self-concept Questionnaire and Multidimensional Scale of Perceived Social Support. Nurses' SWB was examined and categorized into profiles using nine Index of Well-being items as explicit variables and ordinal logistic regression analysis was performed to explore factors related to the distinct categories. RESULTS: Nurses' SWB was divided into four latent profiles: extremely low, low, moderate and high. Regression analysis showed that social support and professional self-concept influenced SWB. There were statistically significant differences in age, title, working years, social support and professional self-concept among nurses in the different well-being categories. Ordered logistic regression analysis showed that social support and professional self-concept are associated with different SWB profiles.

The association of Life's Simple 7 and infertility among U.S. women.

Background: The Life's Simple 7 (LS7) metric is a comprehensive measure of cardiovascular health (CVH) that encompasses seven distinct risk factors and behaviors associated with cardiovascular disease (CVD). Some studies have shown an association between infertility and CVD. The present study aimed to explore the potential association between the LS7 factors and infertility. Methods: A cross-sectional study was conducted on a sample of 3537 women aged 18-44 years from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2013-2018. The LS7 metrics encompassed various factors including physical activity, smoking habits, body mass index, blood pressure levels, dietary patterns, blood glucose levels, and total cholesterol levels. We computed a 14-point LS7 score based on participants' baseline data, classifying them as "inadequate" (3-6), "average" (7-10), or "ideal" (11-14). Infertility is defined as an affirmative answer to either of two questions on the NHANES questionnaire: "Have you tried to conceive for at least one year without success?" and "Have you sought medical help for your inability to conceive?" Logistic regression was utilized to estimate odds ratios (O.R.s) and 95% confidence intervals (C.I.s). Results: In total, 17.66% of participants were classified as individuals who reported experiencing infertility. In the continuous analysis, each one-unit increase in LS7 score was associated with a significantly decreased odds of infertility (OR=0.88 [0.77-0.89]). Analyzing the categorical representation of LS7 score, compared to individuals with poor scores, those with ideal scores exhibited a substantial 58% reduction in the odds of infertility (OR=0.42 [0.26-0.69]). Additionally, the observed interaction suggested that the influence of age on the relationship between LS7 and infertility is not consistent across different age groups (P for interaction < 0.001). Among individuals aged 35 or younger, each unit increase in LS7 score was associated with a substantial 18% (OR=0.82 [0.76-0.89]) decrease in the odds of infertility. However, in the older age group (>35), the association was attenuated and non-significant. Conclusions: Our research suggests a significant inverse association between LS7 scores and infertility. Age demonstrated a varying impact on this relationship, with a more pronounced impact observed among individuals aged 35 or younger.

Structural Basis for Coronaviral Main Proteases Inhibition by the 3CLpro Inhibitor GC376.

The main protease (Mpro) of coronaviruses participates in viral replication, serving as a hot target for drug design. GC376 is able to effectively inhibit the activity of Mpro, which is due to nucleophilic addition of GC376 by binding covalently with Cys145 in Mpro active site. Here, we used fluorescence resonance energy transfer (FRET) assay to analyze the IC50 values of GC376 against Mpros from six different coronaviruses (SARS-CoV-2, HCoV-229E, HCoV-HUK1, MERS-CoV, SARS-CoV, HCoV-NL63) and five Mpro mutants (G15S, M49I, K90R, P132H, S46F) from SARS-CoV-2 variants. The results showed that GC376 displays effective inhibition to various coronaviral Mpros and SARS-CoV-2 Mpro mutants. In addition, the crystal structures of SARS-CoV-2 Mpro (wide type)-GC376, SARS-CoV Mpro-GC376, MERS-CoV Mpro-GC376, and SARS-CoV-2 Mpro mutants (G15S, M49I, S46F, K90R, and P132H)-GC376 complexes were solved. We found that GC376 is able to fit into the active site of Mpros from different coronaviruses and different SARS-CoV-2 variants properly. Detailed structural analysis revealed key molecular determinants necessary for inhibition and illustrated the binding patterns of GC376 to these different Mpros. In conclusion, we not only proved the inhibitory activity of GC376 against different Mpros including SARS-CoV-2 Mpro mutants, but also revealed the molecular mechanism of inhibition by GC376, which will provide scientific guidance for the development of broad-spectrum drugs against SARS-CoV-2 as well as other coronaviruses.

PRMT5-PAK1 Signaling Participates in Metastasis and Is Associated With Poor Prognosis in Human Esophageal Carcinoma.

BACKGROUND/AIM: Protein arginine methyltransferase 5 (PRMT5), a member of the arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical posttranslational modifications (PTMs). Phosphorylated P21-activated kinase 1 (p-PAK1), a serine/threonine protein kinase family member, is a cytoskeletal protein that plays a critical role in metastasis. We examined the expression of PRMT5 and PAK1 in esophageal squamous cell carcinoma (ESCC) and evaluated the correlation between PRMT5/p-PAK1 and both clinicopathological parameters and prognosis of ESCC patients. MATERIALS AND METHODS: 106 tumor tissues collected from ESCC patients were assessed for PRMT5 and PAK1 expression using immunohistochemistry. Pearson's correlation and Kaplan-Meier analysis were used to estimate the correlation with the clinicopathological parameters and effect on patient survival. Western blot analysis was used to determine the PRMT5/p-PAK1 protein expression. The wound healing assay was performed to assess the effect of PRMT5 on the migration of ESCC cells. RESULTS: PRMT5 is upregulated in ESCC and the level of PRMT5 is correlated with metastasis and can serve as an independent prognostic factor for overall survival (OS). PRMT5 knockdown remarkably inhibited ESCC cell migration with concomitantly reduced levels of phosphorylated PAK1 (p-PAK1) but not total PAK1. Kaplan-Meier analysis showed that the OS of the subgroup of patients with PRMT5high/p-PAK1high is remarkably shorter than those of other subgroups (i.e., PRMT5high/p-PAK1low, PRMT5low/p-PAK1low and PRMT5low/p-PAK1high). CONCLUSION: PRMT5-PAK1 signaling participates in ESCC metastasis and can predict patients' outcomes.

[New research direction of organ dysfunction caused by hemorrhagic shock: mechanisms of mitochondrial quality control].

Hemorrhagic shock (HS) is one of the leading causes of death among young adults worldwide. Multiple organ dysfunction in HS is caused by an imbalance between tissue oxygen supply and demand, which is closely related to the poor prognosis of patient. Mitochondrial dysfunction is one of the key mechanisms contributing to multiple organ dysfunction in HS, while mitochondrial quality control regulates mitochondrial function through a series of processes, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial-derived vesicles, and mitochondrial protein homeostasis. Modulating mitochondrial quality control can improve organ dysfunction. This review aims to summarize the effects of mitochondrial dysfunction on organ function in HS and discuss the potential mechanisms of mitochondrial quality control, providing insights into the injury mechanisms underlying HS and guiding clinical management.

Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress.

Chemoresistance poses a significant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-activated kinase 4 (PAK4) has been implicated in NSCLC progression by invasion and migration. However, the involvement of PAK4 in cisplatin resistance is not clear. Here, we presented a comprehensive investigation into the involvement of PAK4 in cisplatin resistance within NSCLC. Our study revealed enhanced PAK4 expression in both cisplatin-resistant NSCLC tumors and cell lines. Notably, PAK4 silencing led to a remarkable enhancement in the chemosensitivity of cisplatin-resistant NSCLC cells. Cisplatin evoked endoplasmic reticulum stress in NSCLC. Furthermore, inhibition of PAK4 demonstrated the potential to sensitize resistant tumor cells through modulating endoplasmic reticulum stress. Mechanistically, we unveiled that the suppression of the MEK1-GRP78 signaling pathway results in the sensitization of NSCLC cells to cisplatin after PAK4 knockdown. Our findings establish PAK4 as a promising therapeutic target for addressing chemoresistance in NSCLC, potentially opening new avenues for enhancing treatment efficacy and patient outcomes.

Crystal structure of SARS-CoV-2 main protease (Mpro) mutants in complex with the non-covalent inhibitor CCF0058981.

SARS-CoV-2 constantly circulates and evolves worldwide, generating many variants and posing a menace to global health. It is urgently needed to discover effective medicines to treat the disease caused by SARS-CoV-2 and its variants. An established target for anti-SARS-CoV-2 drug discovery is the main protease (Mpro), since it exerts an irreplaceable action in viral life cycle. CCF0058981, derived from ML300, is a non-covalent inhibitor that exhibits low nanomolar potency against SARS-CoV-2 Mpro and submicromolar anti-SARS-CoV-2 activity, thereby providing a valuable starting point for drug design. However, structural basis underlying inhibition of SARS-CoV-2 Mpro by CCF0058981 remains undetermined. In this study, the crystal structures of CCF0058981 in complex with two SARS-CoV-2 Mpro mutants (M49I and V186F), which have been identified in the recently emerged Omicron subvariants, were solved. Structural analysis defined the pivotal molecular factors responsible for the interactions between CCF0058981 and these two Mpro mutants, and revealed the binding modes of CCF0058981 to Mpro M49I and V186F mutants. These data not only provide structural insights for SARS-CoV-2 Mpro inhibition by CCF0058981, but also add to develop effective broad-spectrum drugs against SARS-CoV-2 as well as its variants.

Risk Factors and Prediction Nomogram of Cognitive Frailty with Diabetes in the Elderly.

Purpose: Diabetes is a well-recognized risk factor for cognitive frailty. This study aimed to investigate the influencing factors of cognitive frailty in elderly patients with diabetes and develop a nomogram for its assessment. Methods: We collected the clinical data of diabetic patients aged 60 years or older and the patients were divided into training and validation cohorts at a ratio of 7:3. In the training cohort, logistic regression was used to screen out the influencing factors of cognitive frailty in elderly diabetic patients, and a risk prediction model and nomogram were constructed and verified in the validation cohort. The performance of the model was evaluated using various measures, including the area under the receiver operating characteristic curve, calibration curve, Hosmer-Lemeshow test and decision curve analysis. Results: A total of 315 elderly diabetic patients were included, of which 87 (27.6%) patients had cognitive frailty. Age, albumin levels, calf circumference, duration of diabetes, intellectual activity, and depressive state were identified as independent risk factors for cognitive frailty in older patients with diabetes (P < 0.05). The training cohort and validation cohort demonstrated area under curve (AUC) values of 0.866 and 0.821, respectively. Conclusion: Older patients with diabetes have a higher prevalence of cognitive frailty. The nomogram model exhibited satisfactory calibration and identification, providing a reliable tool for assessing the risk of cognitive frailty in individuals with diabetes.

Chinese cross-cultural adaptation and validation of the Well-being Numerical Rating Scales.

Introduction: Well-being is a multi-domain concept that involves measuring physical, psychological, social, and spiritual domains. However, there are currently few multi-domain and comprehensive well-being instruments available. In addition, measures that do exist customarily contain a vast number of items that may lead to boredom or fatigue in participants. The Well-being Numerical Rating Scales (WB-NRSs) offer a concise, multi-domain well-being scale. This study aimed to perform the translation, adaptation, and validation of the Chinese version of WB-NRSs (WBNRSs-CV). Methods: A total of 639 clinical participants and 542 community participants completed the WB-NRSs-CV, the Single-item Self-report Subjective Well-being Scale (SISRSWBS), the World Health Organization Five-item Well-Being Index (WHO-5), the 10-item Perceived Stress Scale (PSS-10), and the Kessler Psychological Distress Scale (K10). Results: High internal consistency and test-retest reliability were obtained for both samples. Additionally, WB-NRSs-CV was positively associated with SISRSWBS and WHO-5 and negatively associated with PSS-10 and K10. In the item response theory analysis, the model fit was adequate with the discrimination parameters ranging from 2.73 to 3.56. The diffculty parameters ranged from -3.40 to 1.71 and were evenly spaced along the trait, attesting to the appropriateness of the response categories. The invariance tests demonstrated that there was no difference in WB-NRSs-CV across groups by gender or age. Discussion: The WB-NRSs-CV was translated appropriately and cross-culturally adapted in China. It can be used as a rapid and relevant instrument to assess well-being in both clinical and non-clinical settings, with its utility for well-being measurement and management among the Chinese people.

Bioinformatics Analysis and Screening of Potential Target Genes Related to the Lung Cancer Prognosis.

OBJECTIVE: Several genes have been validated as molecular targets for gene therapy in lung cancer. We screened target genes that affect survival of patients with lung cancer. METHODS: Data on gene expression in normal lung tissues/lung adenocarcinoma (LUAD) samples were acquired from Genotype-Tissue Expression (GTEx)/The Cancer Genome Atlas (TCGA) databases and merged to expand the sample size, followed by differential analysis of the merged expression data and acquisition of differentially expressed genes. Survival and simple Cox analyses were used to screen for genes affecting LUAD survival. Protein-protein interaction/multivariable Cox analyses were utilized, and a risk model was established. Candidate genes expression levels in cancer/paracancerous tissues of lung cancer patients, and BEAS-2B/A549/HCC95 cells were measured by RT-qPCR/Western blot. Survival analysis of candidate genes was conducted in LUAD samples collected from TCGA. RESULTS: Among 947 genes differentially expressed in LUAD, 151 were correlated with patient survival, and 116 might act as risk factors for LUAD. The 7 identified candidate genes (TOP2A, TK1, KIF4A, ANLN, KIF2C, ASF1B, CCNB1) were high-risk genes playing possible roles in LUAD. These genes were differentially expressed in lung cancer and were associated with TNM stages (III - IV)/differentiation grade/lymph node metastasis/distant metastasis, which affected lung cancer patient survival. CONCLUSION: P2A, TK1, KIF4A, ANLN, KIF2C, ASF1B and CCNB1 were highly-expressed in LUAD/lung squamous cell carcinoma (LUSC) and correlated with LUAD patient survival. This study contributes to better understanding of the prognostic regulation mechanism in LUAD and the screening of target genes for clinical treatment.

Crystal structures of main protease (Mpro) mutants of SARS-CoV-2 variants bound to PF-07304814.

There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease (Mpro) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 Mpro with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 Mpro. However, the binding modes of PF-07304814 with Mpros from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six Mpro mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to Mpro mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant Mpros. Patterns for PF-07304814 to bind with these investigated Mpro mutants and the wild-type Mpro are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of Mpro mutants when bound to an inhibitor.

Crystal structures of main proteases of SARS-CoV-2 variants bound to a benzothiazole-based inhibitor.

Main protease (M pro) serves as an indispensable factor in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as its constantly emerging variants and is therefore considered an attractive target for antiviral drug development. Benzothiazole-based inhibitors targeting M pro have recently been investigated by several groups and proven to be promising leads for coronaviral drug development. In the present study, we determine the crystal structures of a benzothiazole-based inhibitor, YH-53, bound to M pro mutants from SARS-CoV-2 variants of concern (VOCs) or variants of interest (VOIs), including K90R (Beta, B.1.351), G15S (Lambda, C.37), Y54C (Delta, AY.4), M49I (Omicron, BA.5) and P132H (Omicron, B.1.1.529). The structures show that the benzothiazole group in YH-53 forms a C-S covalent bond with the sulfur atom of catalytic residue Cys145 in SARS-CoV-2 M pro mutants. Structural analysis reveals the key molecular determinants necessary for interaction and illustrates the binding mode of YH-53 to these mutant M pros. In conclusion, structural insights from this study offer more information to develop benzothiazole-based drugs that are broader spectrum, more effective and safer.

Evaluation of the Inhibition Potency of Nirmatrelvir against Main Protease Mutants of SARS-CoV-2 Variants.

SARS-CoV-2 continues to pose a threat to public health. Main protease (Mpro) is one of the most lucrative drug targets for developing specific antivirals against SARS-CoV-2 infection. By targeting Mpro, peptidomimetic nirmatrelvir is able to inhibit viral replication of SARS-CoV-2 and reduce the risk for progression to severe COVID-19. However, multiple mutations in the gene encoding Mpro of emerging SARS-CoV-2 variants raise a concern of drug resistance. In the present study, we expressed 16 previously reported SARS-CoV-2 Mpro mutants (G15S, T25I, T45I, S46F, S46P, D48N, M49I, L50F, L89F, K90R, P132H, N142S, V186F, R188K, T190I, and A191V). We evaluated the inhibition potency of nirmatrelvir against these Mpro mutants and solved the crystal structures of representative Mpro mutants of SARS-CoV-2 bound to nirmatrelvir. Enzymatic inhibition assays revealed that these Mpro variants remain susceptible to nirmatrelvir as the wildtype. Detailed analysis and structural comparison provided the inhibition mechanism of Mpro mutants by nirmatrelvir. These results informed the ongoing genomic surveillance of drug resistance of emerging SARS-CoV-2 variants to nirmatrelvir and facilitate the development of next-generation anticoronavirus drugs.

The genomic characteristics of RET fusion positive tumors in Chinese non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Approximately 1-2% of non-small cell lung cancer (NSCLC) patients harbor RET (rearranged during transfection) fusions. The oncogenic RET fusions could lead to constitutive kinase activation and oncogenesis. METHODS: 1746 Chinese NSCLC patients were analyzed in this study. Tumor tissues were collected, and were formalin fixed, paraffin-embedded (FFPE) and archived. Peripheral blood (PB) samples were also collected from each patient as control. In addition, we selected 17 of them for cfDNA NGS testing and 14 tumor samples for immunohistochemistry testing using PD-L1 rabbit monoclonal antibody, clones 28-8 (Abcam, Cambridge, UK). RESULTS: Of the 1746 NSCLC cases, RET rearrangements were identified in 25 cases (1.43%) with locally advanced or metastatic NSCLC, of which 20 (80%) were female. We found that 14 out of 25 patients had an KIF5B-RET fusion, with KIF5B exon15-RET exon12, KIF5B exon23-RET exon12, and KIF5B exon24-RET exon11 detected in 14, 3, and 1 patients, respectively. We also identified one novel RET fusion partner PLCE1 and 4 intergenic-breakpoint fusions. CONCLUSION: In this study, using the hybrid capture based next generation sequencing (NGS) techniques, we revealed the genomic profiling for the patients with RET fusion-positive NSCLC. To the best of our knowledge, this is the first study that exhibited the detailed breakpoints of Chinese NSCLC patients with RET rearrangement, and we found a novel new partner PLCE1. The results provided genomic information for patients with RET fusion which is significant for personalized clinical management in the era of precision medicine.

Clinical Significance and Immune Landscape of Recurrence-Associated Ferroptosis Signature in Early-Stage Lung Adenocarcinoma.

BACKGROUND: The prevalence of patients newly diagnosed with early-stage lung adenocarcinoma (LUAD) is growing alongside significant advances in screening approaches. This study aimed to construct ferroptosis-related gene score (FRGscore) for predicting recurrence, explore immune-molecular characteristics, and determine the benefit of immunotherapy in distinct ferroptosis-based patterns and FRGscore-defined subgroups. METHODS: A total of 1,085 early-stage LUAD patients from four independent cohorts were included. Consensus clustering analysis was performed using 217 co-expressed FRGs to explore different ferroptosis-mediated patterns. An FRG scoring system was established to predict relapse, quantify ferroptosis-mediated patterns, and evaluate the response to immunotherapy in individual patients based on Lasso-penalized and stepwise Cox regression analyses. Immune landscape involving multiple parameters was further evaluated, stratified by cluster subtypes and FRGscore subgroups. RESULTS: Two ferroptosis-mediated patterns were identified and verified, which were characterized by significantly distinct prognosis and immune profiles. Analyses of immune characteristics showed that identified ferroptosis patterns were characterized as immune-inflamed phenotype and immune-exhausted phenotype. The FRG scoring model based on 11 FRG-derived signatures panel classified patients into the FRGscore-high and FRGscore-low subgroups. Significantly longer recurrence-free survival (RFS) and overall survival (OS) were observed in the FRGscore-low subgroup. FRGscore-low patients were characterized by higher tumor mutational burden (TMB), immunoscore, immunophenoscore, and PD-L1 expression level and were associated with lower Tumor Immune Dysfunction and Exclusion (TIDE) score, whereas the opposite was observed in FRGscore-high patients. Immune-active pathways were remarkably enriched in the FRGscore-low subgroup. This scoring model remained highly predictive of prognosis across different clinical, molecular, and immune subgroups. Further analysis indicated that FRGscore-low patients exhibited higher response to anti-PD-1/PD-L1 immunotherapy and better clinical benefits based on two independent immunotherapy cohorts. CONCLUSION: The proposed FRGscore could highly distinguish the recurrence patterns and molecular and immune characteristics and could predict immunotherapy prognosis, potentially representing a powerful prognostic tool for further optimization of individuated treatment and management strategies in early-stage LUAD.

Simulated aeromedical evacuation exacerbates burn induced lung injury: targeting mitochondrial DNA for reversal.

BACKGROUND: Aeromedical evacuation of patients with burn trauma is an important transport method in times of peace and war, during which patients are exposed to prolonged periods of hypobaric hypoxia; however, the effects of such exposure on burn injuries, particularly on burn-induced lung injuries, are largely unexplored. This study aimed to determine the effects of hypobaric hypoxia on burn-induced lung injuries and to investigate the underlying mechanism using a rat burn model. METHODS: A total of 40 male Wistar rats were randomly divided into four groups (10 in each group): sham burn (SB) group, burn in normoxia condition (BN) group, burn in hypoxia condition (BH) group, and burn in hypoxia condition with treatment intervention (BHD) group. Rats with 30% total body surface area burns were exposed to hypobaric hypoxia (2000 m altitude simulation) or normoxia conditions for 4 h. Deoxyribonuclease I (DNase I) was administered systemically as a treatment intervention. Systemic inflammatory mediator and mitochondrial deoxyribonucleic acid (mtDNA) levels were determined. A histopathological evaluation was performed and the acute lung injury (ALI) score was determined. Malonaldehyde (MDA) content, myeloperoxidase (MPO) activity, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome level were determined in lung tissues. Data among groups were compared using analysis of variance followed by Tukey's test post hoc analysis. RESULTS: Burns resulted in a remarkably higher level of systemic inflammatory cytokines and mtDNA release, which was further heightened by hypobaric hypoxia exposure (P < 0.01). Moreover, hypobaric hypoxia exposure gave rise to increased NLRP3 inflammasome expression, MDA content, and MPO activity in the lung (P < 0.05 or P < 0.01). Burn-induced lung injuries were exacerbated, as shown by the histopathological evaluation and ALI score (P < 0.01). Administration of DNase I markedly reduced mtDNA release and systemic inflammatory cytokine production. Furthermore, the NLRP3 inflammasome level in lung tissues was decreased and burn-induced lung injury was ameliorated (P < 0.01). CONCLUSIONS: Our results suggested that simulated aeromedical evacuation further increased burn-induced mtDNA release and exacerbated burn-induced inflammation and lung injury. DNase I reduced the release of mtDNA, limited mtDNA-induced systemic inflammation, and ameliorated burn-induced ALI. The intervening mtDNA level is thus a potential target to protect from burn-induced lung injury during aeromedical conditions and provides safer air evacuations for severely burned patients.

Apatinib Combined with Irinotecan in the Treatment of Advanced Small-Cell Esophageal Carcinoma: A Case Report.

Chemotherapy is the mainstay of treatment for advanced small cell esophageal carcinoma (SCEC) characterized by poor prognosis. Preclinical studies demonstrated that apatinib has the potential to enhance the efficacy of conventional chemotherapeutic drugs and reverse multidrug resistance (MDR). This report described the application of apatinib combined with irinotecan as the third-line treatment for advanced SCEC in a 54-year-old male patient. His symptoms of upper abdominal pain and distension were ameliorated notably after the combination therapy. Computed tomography (CT) examination revealed the treatment efficacy was partial response (PR). The progression-free survival (PFS) and overall survival (OS) were 12.5 months and 28 months, respectively. The treatment-related toxicity was manageable. Apatinib combined with chemotherapy may serve as a new treatment choice for advanced SCEC patients. However, further studies should be conducted to confirm the therapeutic value of this combination regimen in advanced SCEC.

Long non-coding RNA H19 promotes the proliferation, migration and invasion while inhibits apoptosis of hypertrophic scarring fibroblasts by targeting miR-3187-3p/GAB1 axis.

BACKGROUND: It had been reported that long non-coding RNA (lncRNA) H19 was associated with the proliferation of fibroblasts. However, the regulatory mechanism of H19 remains unclear. Thus, the study was designed to explore the underlying mechanism of H19 in the process of Hypertrophic scarring (HS). METHODS: The expression levels of H19, miR-3187-3p, and growth factor receptor binding 2-associated binding protein 1 (GAB1) in HS tissues and HS fibroblasts were measured by real-time quantitative polymerase chain reaction (RT-qPCR) assay. The biological behaviors of HS fibroblasts, such as cell proliferation, apoptosis, migration, and invasion were assessed by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT), colony formation, flow cytometry, and transwell assays, respectively. The protein expression level was quantified by western blot assay. The interaction association between miR-3187-3p and H19 or GAB1 was predicted by Starbase database analysis and confirmed by dual-luciferase reporter assay, respectively. RESULTS: H19 was significantly increased in HS tissues and HS fibroblasts. Loss-of-functional experiments revealed that knockdown of H19 inhibited the development of HS. Moreover, silencing of H19 impeded the proliferation, migration, and invasion, while enhanced apoptosis of HS fibroblasts by increasing miR-3187-3p expression. In addition, overexpression of GAB1 could abolish miR-3187-3p overexpression-induced effects on cell proliferation, apoptosis, migration, and invasion of HS fibroblasts. Mechanistically, H19 could act as a sponge of miR-3187-3p to upregulate the expression of GAB1 in HS fibroblasts. CONCLUSION: Collectively, our results revealed that H19 promoted the proliferation, migration, and invasion, while impeded apoptosis of HS fibroblasts by targeting miR-3187-3p/GAB1 axis.