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.

Structural basis for the inhibition of coronaviral main proteases by PF-00835231.

The main protease (M pro) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M pro. Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M pro and seven M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M pros. In addition, the crystal structures of SARS-CoV-2 M pro, SARS-CoV M pro, MERS-CoV M pro, and seven SARS-CoV-2 M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M pros. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M pro inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.

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.

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.

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.

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.

Integrative stemness characteristics associated with prognosis and the immune microenvironment in esophageal cancer.

BACKGROUND: Cancer stem cells (CSCs) induces tumor metastasis and recurrence. However, the role of CSCs in molding the tumor immune microenvironment (TIME) is largely inexplicit. This study aimed to comprehensively characterize the stemness of esophageal cancer (EC) and correlate the stemness patterns with TIME. METHODS: A trained stemness index model was used to score EC patients based on the one-class logistic regression (OCLR) machine-learning algorithm. Gene expression-based stemness index (mRNAsi) and DNA methylation-based stemness index (mDNAsi) were calculated for integrative analyses of EC stemness in the training cohort (n = 182) and validation cohort (n = 179). Intrinsic stemness patterns were estimated to determine its association with clinical features, biological pathways, prognosis, and potential inhibitors. Additionally, the dynamic interplay between EC stemness and TIME was integrally characterized. RESULTS: Analyses of EC stemness and clinical characteristics indicated that higher-stage and metastatic tumors featured more dedifferentiated phenotypically. Univariate and multivariate Cox regression analyses revealed that mRNAsi was significantly associated with overall survival (OS) of EC patients, whereas no relationship was observed between mDNAsi and OS. Notably, prolonged OS was observed with esophageal squamous cell carcinoma (ESCC) in low versus high mRNAsi groups, whereas the OS was equivalent between the two groups for esophageal adenocarcinoma (ESAD). The mRNAsi may thus recapitulate prognostic molecular subgroups of EC. The prognostic model comprising 14 stemness signatures was constructed using combined Cox and Lasso regression analyses which effectively distinguished individual survival of ESCC in two cohorts. Nevertheless, no significant differences in OS was observed when the same prognostic model of ESCC was applied to ESAD. Gene Set Enrichment Analysis (GSEA) of selected stemness signatures indicated that ESCC stemness is involved in immune-related pathways. Furthermore, ESCC stemness and stemness-related signatures were associated with tumor-infiltrating immune cells, immunoscore, and PD-L1 expression. Compounds specific to the selected stemness signatures were detected using the CMap database. CONCLUSION: This study determined integrated characteristics of EC stemness. The identified mRNAsi-based signatures conferred with the predictive ability of personalized ESCC prognosis and highlighted the potential targets for CSC-mediated immunotherapy. Analyses of the interface between ESCC stemness and TIME may help in predicting the efficacy of CSC-specific immunotherapy and provide insight into combinatorial therapy by targeting ESCC stem cells and TIME.

Prognostic Value of Site-Specific Metastases and Surgery in De Novo Stage IV Triple-Negative Breast Cancer: A Population-Based Analysis.

BACKGROUND This retrospective study aimed to evaluate the prognostic roles of distant metastatic patterns in de novo metastatic triple-negative breast cancer to explore the roles of surgery on the primary tumor and to characterize the prognostic factors of organ-specific metastasis. MATERIAL AND METHODS Data were obtained from the Surveillance, Epidemiology, and End Results program. Kaplan-Meier analyses and log-rank tests were employed to compare survival outcomes among variables. The Cox proportional hazards model was used to assess risk factors for survival. The key endpoints were overall survival and breast cancer-specific survival. RESULTS A total of 1888 patients were eligible. Distant metastatic site displayed a significant prognostic impact on survival. Using liver metastasis as the reference, overall survival was higher for bone (hazard ratio [HR] 0.770, 95% confidence interval [CI] 0.634-0.935, P=0.008) and lung (HR 0.747, 95% CI 0.612-0.911, P=0.004) metastases. Using patients with brain metastasis as the reference, patients with bone (HR 0.516, 95% CI 0.392-0.680, P<0.001), lung (HR 0.500, 95% CI 0.379-0.661, P<0.001) or liver (HR 0.670, 95% CI 0.496-0.905, P=0.009) metastases exhibited better overall survival. Single-site metastatic patients who received surgery for the primary tumor had more favorable overall survival (P<0.001) and breast cancer-specific survival (P<0.001) than those who did not. Additionally, age, insurance status, chemotherapy, and surgery affected overall survival for patients with isolated bone metastasis; chemotherapy, and surgery affected overall survival for patients with isolated lung metastasis; and insurance status, chemotherapy, and surgery affected overall survival for patients with isolated liver metastasis. CONCLUSIONS Our study verified the specific prognostic significance of distant metastatic site for metastatic triple-negative breast cancer at diagnosis. Surgery on the primary tumor significantly improved survival for patients with single distant metastasis. The identified prognostic factors contributed to evaluating the prognoses for distant metastatic triple-negative breast cancer patients.

Human hepatocytes express absent in melanoma 2 and respond to hepatitis B virus with interleukin-18 expression.

Absent in melanoma 2 (AIM2) is a recently recognized cytoplasmic receptor which could sense cytoplasmic double-stranded DNA (dsDNA). After AIM2 detects the presence of parasitic nucleic acids (dsDNA) derived from invasive bacteria or viral genomes (for example, vaccinia virus and cytomegalovirus) within infected cells, AIM2 inflammasome could be formed. The formed AIM2 inflammasome could induce innate immune response and increase expressions of IL-1ß and IL-18. Hepatitis B virus (HBV) is a hepatotropic, non-cytopathic double-stranded DNA virus. The immune response to viral antigens or virus is thought to be responsible for both liver damage and viral clearance in patients with HBV infection. However, there are no reports about whether AIM2 inflammasome exists in hepatocytes. In the present study, we investigated the presence and activity of AIM2 inflammasome in human hepatocytes. We found that AIM2 was expressed in cytoplasm of hepatocytes, and IL-18 expression was increased after AIM2 sensed HBV in hepatocytes in vitro. These results showed that AIM2 inflammasome was active in hepatocytes. We also found that hepatic AIM2 expression of chronic hepatitis B (CHB) patients was higher than that of controls. Hepatic AIM2 expression levels were positively correlated to the severity of liver inflammation. IL-18 is already considered to be associated with hepatic injury during HBV infection. In conclusion, we, therefore, believe that AIM2 inflammasome in hepatocytes might play an important role in the development and maintenance of HBV-related hepatitis.

Personalizing risk stratification by addition of PAK1 expression to TNM staging: improving the accuracy of clinical decision for gastroesophageal junction adenocarcinoma.

Gastroesophageal junction adenocarcinoma (GEJA) is an aggressive malignancy with an alarmingly rising incidence. TNM staging is widely used by oncologists to stratify prognosis as well as direct therapeutic strategies. However, inadequate lymphadenectomy is frequently encountered for GEJA and largely confounds prognosis resulting from TNM staging. Thus, a molecular biomarker, which can accurately forecast the risk of nodal metastasis in patients with inadequate lymphadenectomy, is required to guide precisely clinical decision. In this study, bioinformatics and pathological analysis identified that p21 protein-activated kinase 1 (PAK1) is associated with lymph nodal metastasis of GEJA. The PAK1 H-score was lower in the patients with negative lymph nodes than that in patients with positive (metastatic) lymph nodes (6.865 ± 3.376, 9.370 ± 2.530, respectively; p < 0.001). The PAK1 H-score in lymph nodes was positively correlated with that in primary tumors (PTs; p < 0.001; r = 0.475). PAK1 H-scores in PTs had the best performance based on its area under the receiver-operating characteristic (ROC) curve compared with PAK1 H-scores in lymph nodes, histological grade, lymph nodal metastasis status, tumor size, depth of tumor, TNM stage and number of resected lymph nodes. Multivariate Cox proportional hazard and Fine and Gray models showed that histological grade 3, Charlson comorbidity index > 7 and high PAK1 expression in PTs were associated with significantly increased risk of recurrence and cancer-related death. In conclusion, high PAK1 expression in PTs is predictive of node metastasis and can be easily integrated in the clinical decision process for personalized therapeutics of GEJA.

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.

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.

Crystal structures of the 3C proteases from Coxsackievirus B3 and B4.

Enteroviruses cause a wide range of disorders with varying presentations and severities, and some enteroviruses have emerged as serious public health concerns. These include Coxsackievirus B3 (CVB3), an active causative agent of viral myocarditis, and Coxsackievirus B4 (CVB4), which may accelerate the progression of type 1 diabetes. The 3C proteases from CVB3 and CVB4 play important roles in the propagation of these viruses. In this study, the 3C proteases from CVB3 and CVB4 were expressed in Escherichia coli and purified by affinity chromatography and gel-filtration chromatography. The crystals of the CVB3 and CVB4 3C proteases diffracted to 2.10 and 2.01 Šresolution, respectively. The crystal structures were solved by the molecular-replacement method and contained a typical chymotrypsin-like fold and a conserved His40-Glu71-Cys147 catalytic triad. Comparison with the structures of 3C proteases from other enteroviruses revealed high similarity with minor differences, which will guide the design of 3C-targeting inhibitors with broad-spectrum properties.

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.

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.

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.

[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.

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.

PTPRO promoter methylation is predictive of poorer outcome for HER2-positive breast cancer: indication for personalized therapy.

BACKGROUND: Protein Tyrosine Phosphatase Receptor-type O (PTPRO) has recently been in the spotlight as a tumor suppressor, whose encoding gene is frequently methylated in cancers. We examined the methylation status of the PTPRO gene promoter in breast cancer and evaluated the correlation between PTPRO promoter methylation and both clinicopathological parameters and prognosis of breast cancer patients. METHODS: Two hundred twenty-one formalin-fixed, paraffin-embedded (FFPE) tumor tissues, 20 FFPE normal adjacent tissues and 24 matched plasma samples, collected from primary breast cancer patients, were assessed for PTPRO gene promoter methylation using methylation-specific PCR. Associations of promoter methylation with clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect on survival. RESULTS: 175 samples gave identifiable PCR products, of which 130 cases (74.3%) had PTPRO gene promoter methylation. PTPRO methylation correlated with higher histological grade (P = 0.028), but not other clinical parameters. Multivariate analysis indicated that overall survival (OS) was significantly poorer in HER2-positive, but not ER-positive patients with methylated-PTPRO. Methylated-PTPRO was detectable in matched plasma samples and only observed in plasma from patients whose corresponding primary tumors were also methylated. CONCLUSIONS: PTPRO methylation is a common event in the primary breast cancer and can be reliably detected in peripheral blood samples. PTPRO methylation is associated with poor survival only in HER2-positive patients, suggesting use of PTPRO methylation as a prognostic factor for breast cancer and for optimizing individualized therapy for HER2-positive patients.

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.