PHYTOCHROME-INTERACTING FACTOR 7 and RELATIVE OF EARLY FLOWERING 6 act in shade avoidance memory in Arabidopsis.

Shade avoidance helps plants maximize their access to light for growth under crowding. It is unknown, however, whether a priming shade avoidance mechanism exists that allows plants to respond more effectively to successive shade conditions. Here, we show that the shade-intolerant plant Arabidopsis can remember a first experienced shade event and respond more efficiently to the next event on hypocotyl elongation. The transcriptional regulator PHYTOCHROME-INTERACTING FACTOR 7 (PIF7) and the histone H3K27-demethylase RELATIVE OF EARLY FLOWERING 6 (REF6) are identified as being required for this shade avoidance memory. RNA-sequencing analysis reveals that shade induction of shade-memory-related genes is impaired in the pif7 and ref6 mutants. Based on the analyses of enrichments of H3K27me3, REF6 and PIF7, we find that priming shade treatment induces PIF7 accumulation, which further recruits REF6 to demethylate H3K27me3 on the chromatin of certain shade-memory-related genes, leading to a state poised for their transcription. Upon a second shade treatment, enhanced shade-mediated inductions of these genes result in stronger hypocotyl growth responses. We conclude that the transcriptional memory mediated by epigenetic modification plays a key role in the ability of primed plants to remember previously experienced shade and acquire enhanced responses to recurring shade conditions.

Effectiveness of sarcopenia screening markers in predicting out-of-hospital death in the oldest (≥80 years) older.

OBJECTIVE: The goal of this investigation was to elucidate the correlation between sarcopenia screening indicators (aspartate transaminase/alanine transaminase (AST/ALT) and creatinine/cystatin C*100 (Cr/CysC*100)) and the risk of out-of-hospital (OFH) death among the very advanced age (≥80 years) population. METHODS: We conducted a retrospective cohort investigation, involving internal medicine inpatients aged ≥80 years of age, who sought treatment at a teaching hospital in western China. We obtained OFH mortality information from telephonic interviews. Subsequently, we employed Cox proportional hazards models to analyze the links between AST/ALT and Cr/CysC*100 and OFH all-cause mortality among the very advanced age (≥80 years old) population. RESULTS: In all, we recruited 398 subjects, among which 51.51% were male. The median age of OFH deceased male patients was 85 years, and the same for female patients was 87 years. The total quantity of OFH deaths was 164 (41.21%). Among the oldest male population, those who died OFH exhibited enhanced AST/ALT, relative to those who survived (death vs. survival: 1.5 vs 1.3, P=0.008). However, among the oldest female, there was no difference in AST/ALT between patients who expired OFH, and those who survived. Among the oldest elders (male and female), Cr/CysC*100 did not significantly differ between surviving and OFH deceased patients. Additional analysis involving the Cox proportional hazards model revealed that among the oldest male population, an enhanced AST/ALT denoted an augmented risk of OFH death (hazard ratios (HRs) =1.797, 95%CI: 1.2-2.691). However, Cr/CysC*100 was not correlated with OFH mortality risk. Among the oldest female population, neither AST/ALT nor Cr/CysC*100 was correlated with OFH mortality risk. CONCLUSIONS: Enhanced AST/ALT was correlated with an augmented OFH mortality risk among the oldest male, but not female population. Alternately, Cr/CysC*100 was not linked to OFH mortality risk among any population.

Effectiveness of the frailty index in predicting recurrent pneumonia and death in long-term hospitalized patients with vascular cognitive impairment.

OBJECTIVE: The aim was to predict the effectiveness of using frailty, defined by the frailty index (FI), for predicting recurrent pneumonia and death in patients over 50 years and older with vascular cognitive impairment (VCI) during long-term hospitalization. MEASUREMENTS: This retrospective cohort study was conducted at a teaching hospital in western China and included VCI patients aged ≥50 years undergoing long-term hospitalization. The relevant data were collected from the electronic medical record system. The FI was based on 31 parameters and groups were defined using a cutoff value (0.2) as robust (FI < 0.2) and FRAIL (≥0.2). The definition of recurrent pneumonia was a minimum of two episodes within a year, with the symptoms, signs, and imaging results of pneumonia disappearing completely between episodes, and a minimum interval between episodes of seven days. Death was recorded by the hospital as the result of cardiac and respiratory arrest and survival was defined as the interval between hospital admission and confirmed death. Logistic regression models were used to assess the association between FI and recurrent pneumonia, while associations between FI and death were assessed by Cox proportional hazards models. RESULTS: A total of 252 long-term hospitalized VCI patients ≥50 years old were enrolled, of whom 115 were male (45.6 %). Ninety-seven patients (38.5 %) were defined as FRAIL. The median length of stay for hospitalized patients was 37 months. Overall, 215 patients developed pneumonia during hospitalization, which occurred an average of 14.5 months after admission, while 151 (59.9 %) had recurrent pneumonia, and 155 (61.5 %) died. Of these, 143 died in the hospital and 12 died after discharge. No significant differences were seen in the incidence of recurrent pneumonia between FRAIL and robust long-term hospitalized VCI patients (FRAIL vs. robust: 66.0 % vs. 56.1 %, P = 0.121) while FRAIL patients had a higher mortality rate than robust patients (FRAIL vs. robust: 71.1 % vs. 55.5 %, P = 0.013). After further Cox regression analysis and adjustment for possible confounders found to be significant in the univariate analysis (including age, sex, smoking history, and activities of daily living (ADL) score), FRAIL patients had a higher risk of death than healthy patients (HR = 1.595, 95 % CI: 1.149-2.213). In addition, based on Model 2, confounding variables that were not statistically significant in the univariate analysis but may have had an impact on the results (including marital status, educational level, drinking history, comorbidity and rehabilitation treatment) were incorporated into Model 3 for further correction. The result remained unchanged, namely, that compared with robust patients, FRAIL patients had a higher risk of death (HR = 1.771, 95 % CI: 1.228-2.554). CONCLUSIONS AND IMPLICATIONS: Frailty defined by the FI was effective for predicting the risk of mortality but not that of recurrent pneumonia in long-term hospitalized VCI patients aged 50 or older.

NDRG2 Deficiency Exacerbates UVB-Induced Skin Inflammation and Oxidative Stress Damage.

UVB radiation induces inflammatory and oxidative stress responses, contributing to skin damage, yet the underlying mechanisms are not fully understood. N-Myc downstream-regulated gene 2 (NDRG2), an emerging stress-associated gene, remains unexplored in UVB-induced skin injury. In this study, we detected skin NDRG2 expression after UVB irradiation for the first time and further used Ndrg2 knockout mice to clarify the role of NDRG2 in UVB-induced skin injury. Three-month-old male Ndrg2+/+ and Ndrg2-/- mice (16-18g) were exposed to UVB to induce acute skin damage, and then dorsal skin samples were collected for subsequent analyses. UVB-induced skin damage was scored. Western Blot Analysis, immunofluorescence (IF) double labeling, and immunohistochemistry (IHC) were employed to assess NDRG2 expression and/or distribution. The concentrations of TNF-α, IL-6, IL-1ß, MPO, MMP8, superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) were quantitatively assessed using enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (HE) staining were employed to determine pathological changes. RNA sequencing and analysis were performed to estimate transcript expression levels and analyze mRNA expression. DESeq2 software was employed to identify differentially expressed genes (DEGs). DEGs were visualized using volcanic and heat maps. Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed to identify primary biological functions, metabolic pathways, or signal transduction pathways associated with DEGs. UVB-challenged Ndrg2-/- mice exhibited significantly exacerbated skin damage (erythema, edema, and erosion), neutrophil infiltration, and apoptosis compared to Ndrg2+/+ mice. Furthermore, UVB-challenged Ndrg2-/- mice displayed significantly elevated pro-inflammatory cytokines, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP8), and reduced antioxidant expression. RNA sequencing identified 1091 significantly differentially expressed genes enriched in inflammation, immune response, and oxidative stress pathways. In conclusion, the deficiency of Ndrg2 markedly exacerbated UVB-induced skin damage by promoting inflammatory responses and inhibiting antioxidant responses. This suggests that stabilizing NDRG2 expression holds promise as a therapeutic strategy for protecting against UVB-induced skin damage.

The relationship between low and asymmetric handgrip strength and low muscle mass: results of a cross-sectional study on health and aging trends in western China.

OBJECTIVE: The aim was to determine the relationship between low handgrip strength (HGS) only, asymmetric HGS only, and low HGS combined with asymmetric HGS and low muscle mass in the West China Health and Aging Trends Study (WCHAT) data. STUDY DESIGN: Individuals aged at least 50 years old were included in this cross-sectional study using WCHAT data. Demographic characteristics, such as age, marital status, education level, ethnicity, and drinking and smoking history, as well as chronic diseases, were recorded for all participants. The HGS of both hands was tested three times using a grip dynanometer with the participant in a standing position with arms extended, before recording the maximum value for both hands. The maximum value referred to values < 28 kg and < 18 kg for males and females, respectively. HGS ratios (non-dominant HGS/dominant HGS) of < 0.90 or > 1.10 suggest asymmetric HGS. The subjects were then allocated to the low HGS, asymmetrical HGS, and combined low and asymmetrical HGS (BOTH group) groups, and those with neither low nor asymmetric HGS (the normal group). The InBody 770 instrument was used for the analysis of muscle mass, with low muscle mass defined as a skeletal muscle mass index (SMI) of < 7.0 kg/m2 or < 5.7 kg/m2 for males and females, respectively. The associations between the different HGS groups and low muscle mass were assessed by logistic regression analysis. RESULTS: The study included 1748 subjects, of whom 1272 (72.77%) were over the age of 60 years. The numbers of Han, Tibetan, and Qiang were 885 (50.63%), 217 (12.41%), and 579 (33.12%), respectively. A total of 465 individuals (26.60%) were classified as having low muscle mass, while 228 (13.04%), 536 (30.66%), and 125 (7.15%) participants were allocated to the low HGS, asymmetric HGS, and BOTH groups, respectively. The average SMI differed significantly between the normal group and the other groups (normal group vs. asymmetric HGS group vs. low HGS group vs. BOTH group: 6.627 kg/m2 vs. 6.633 kg/m2 vs. 6.492 kg/m2 vs. 5.995 kg/m2, respectively, P < 0.05). In addition, the prevalence of low muscle mass in the normal, asymmetric HGS, low HGS, and BOTH groups increased sequentially, with significant differences (normal group vs. asymmetric HGS group vs. low HGS group vs. BOTH group: 21.5% vs. 22.4% vs. 39.5% vs. 56%, respectively, P = 0.001). Further logistic regression analysis showed that the presence of low HGS (OR = 1.7, 95%CI: 1.203-2.402) and both low and asymmetric HGS (OR = 3.378, 95%CI: 2.173-5.252) were predictive of low muscle mass, with the chance being higher for the latter condition. CONCLUSION: The findings suggest that although asymmetrical HGS itself does not increase the chances of low muscle mass. When low HGS and a combination of both features (low HGS combined with asymmetric HGS) is present in subjects, the chance of low muscle mass increases.

SARC-F, SARC-CalF, and SARC-F+EBM as practical predictive tools for the risk of pneumonia in patients with stable schizophrenia-a prospective study.

Objectives: Individuals diagnosed with schizophrenia have a high incidence and fatality rates due to pneumonia. Sarcopenia is a contributing factor to the development of pneumonia in patients with schizophrenia. In this study, we examine the effectiveness of three simple screening questionnaires, namely SARC-F, SARC-CalF, and SARC-F + EBM, in predicting the occurrence of pneumonia in stable patients with schizophrenia who are experiencing sarcopenia. Design: A prospective study. Setting: Patients with stable schizophrenia patients aged ≥50 years in two psychiatric hospitals in western China. Methods: Medical data from patients were collected from September 1 to September 30, 2020. Data specifically from patients diagnosed with pneumonia were collected for a period of one year, from October 2020 to October 2021. Three hundred thirty-five stable schizophrenia patients, among whom 229 were males (68.36 %.), were enrolled in the prospective study. The risk of sarcopenia was evaluated using the SARC-F, SARC-CalF, and SARC-F + EBM scores, with values of ≥4, 11, and 12 indicating an elevated risk of sarcopenia. The collected data were analyzed using logistic regression analysis to establish the association between the scores of these screening tools and the risk of pneumonia in individuals with stable schizophrenia. Results: The rate of pneumonia in stable schizophrenia individuals was 24.48 %. Among the included stable schizophrenia patients, the incidence of pneumonia in individuals with SARC-CalF scores ≥11 was higher than in those with SARC-CalF scores less than 11 (29.91 % vs 14.88 %, P = 0.002). In individuals with SARC-F + EBM scores ≥12, the pneumonia occurrence was higher than that in those with SARC-F + EBM scores less than 12 (37.33 % vs 20.77 %, P = 0.003). However, this pattern was not found in patients with stable schizophrenia who had SARC-F scores of 4 or above and less than 4. Following the implementation of logistic regression data analysis, it has been discovered that persons with SARC-CalF scores greater than or equal to 11 were at a significantly increased risk of having pneumonia compared to patients with SARC-CalF scores less than 11 (OR = 2.441, 95 % CI: 1.367-4.36). After adjusting the possible confounders, patients with SARC-CalF scores ≥11 had a greater danger of pneumonia (OR = 2.518, 95%CI: 1.36-4.665). As a result, it was found that individuals with SACR-F+EBM scores ≥12 were more likely to acquire pneumonia (OR = 2.273, 95%CI: 1.304-3.961) when compared to those with scores <12 (OR = 2.273, 95%CI: 1.304-3.961). The results of this study, which controlled for potential confounders, indicated that patients with SARC-F + EBM scores ≥12 were more inclined to acquire pneumonia (OR = 2.181, 95%CI: 1.182-4.026). However, in stable schizophrenia patients with SARC-F scores ≥4 and < 4, this study has not yet observed a similar pattern for pneumonia risk. Conclusions and implications: These results demonstrate, in stable adults with schizophrenia, a relationship between pneumonia risk and SARC-F + EBM and SARC-CalF scores. It is, therefore, advised to use these scores to determine whether these patients have pneumonia, especially in hospitals that cannot diagnose sarcopenia.

Identification of Dwarfing Candidate Genes in Brassica napus L. LSW2018 through BSA-Seq and Genetic Mapping.

Plant height, as a crucial component of plant architecture, exerts a significant influence on rapeseed (Brassica napus L.) lodging resistance, photosynthetic efficiency, yield, and mechanized harvest level. A previous study identified dwarf rapeseed LSW2018. In this study, LSW2018 (dwarf parent (PD)) was crossed with 389 (high parent (PH)) to establish the F2 population, and 30 extremely dwarf (bulk-D) and high (bulk-H) plants in the F2 population were respectively selected to construct two bulked DNA pools. Whole-genome sequencing and variation analysis (BSA-seq) were performed on these four DNA pools (PD, PH, bulk-D, and bulk-H). The BSA-seq results revealed that the genomic region responsible for the dwarf trait spanned from 19.30 to 22.19 Mb on chromosome A03, with a length of 2.89 Mb. After fine mapping with simple sequence repeat (SSR) markers, the gene was narrowed to a 0.71 Mb interval. Within this region, a total of 113 genes were identified, 42 of which contained large-effect variants. According to reference genome annotation and qRT-PCR analysis, there are 17 differentially expressed genes in this region between high and dwarf individuals. This study preliminarily reveals the genetic basis of LSW2018 dwarfing and provides a theoretical foundation for the molecular marker-assisted breeding of dwarf rapeseed.

Comparison of short-term outcomes of laparoscopic surgery, robot-assisted laparoscopic surgery, and open surgery for lateral lymph-node dissection for rectal cancer: a network meta-analysis.

This study attempted to compare short-term outcomes of laparoscopic surgery (LS), robot-assisted laparoscopic surgery (RS), and open surgery (OS) for lateral lymph-node dissection (LLND) in treatment of rectal cancer through network meta-analysis. Embase, Web of Science, PubMed, and The Cochrane Library databases were searched to collect cohort studies on outcomes of LS, RS, and OS for LLND for rectal cancer. Newcastle-Ottawa Scale (NOS) was utilized to evaluate the quality of cohort studies. Primary outcomes should at least include one of the following clinical outcome measures: operative time, blood loss, total lymph-node harvest, positive resection margin rate, postoperative complications, and postoperative hospital stay. A network meta-analysis was conducted using STATA software. Fourteen cohort studies including 8612 patients were eligible for inclusion. The network meta-analysis results showed that, in terms of intraoperative outcomes, the RS group had the longest operative time, while the OS group had the shortest; the LS and RS groups had significantly less blood loss than the OS group. In terms of histological outcomes, there were no significant differences in the total number of lymph nodes harvested and the positive margin rate among the LS, RS, and OS groups (P > 0.05). Regarding postoperative outcomes, the OS group had the highest probability of postoperative complications and the longest hospital stay, followed by the LS group, with the RS group being the lowest. RS was the best method in blood loss, postoperative complication rate, and postoperative hospital stay, followed by LS. OS had the shortest operative time and the highest blood loss.

Advancing skeletal health and disease research with single-cell RNA sequencing.

Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.

Quadrotors' double-loop controller design with tensor product model transformation and partial fully actuated method.

In the existing work of tensor product (TP) model transformation, the TP model transformation-based work on the quadrotor's control system design is scarce, the direct TP model transformation control strategy that applied to the quadrotor fails due to the calculation complexity, infeasibility of the huge amount of linear matrix inequalities, and the complexity of solving the linear matrix inequalities. To solve this problem, a partial TP model transformation-based double loop fuzzy controller has been studied in this work, the double-loop hybrid control scheme combines the fully actuated control method and the TP model transformation, while the fully actuated control method is used to the position subsystem control loop, and the TP model transformation based fuzzy controller is applied to the attitude control of the quadrotor. Moreover, for comparison purpose, a varying-input method based on TP model transformation is extended to the quadrotor's system control. The double-loop hybrid control scheme could also be extended with other TP model transformation based tensor sampling methods, such as, uniform sampling method and varying-input method. At last, the proposed algorithms are evaluated and compared on Parrot Mambo Minidrone, MFP450 and CUAV V5+ based hexarotor.

Radiating blood flow signal: A new ultrasound feature of thyroid carcinoma.

OBJECTIVE: To summary radiating blood flow signals and evaluate their diagnostic value in differentiating benign and malignant thyroid nodules. MATERIALS AND METHODS: We retrospectively recruited consecutive patients undergoing US at 4 hospitals from 2018 to 2022. In a training dataset, the correlations of US features with malignant thyroid nodules were assessed by multivariate logistic analysis. Multivariate logistic regression models involving the ACR TI-RADS score, radiating blood flow signals and their combination were built and validated internally and externally. The AUC with 95% asymptotic normal confidence interval as well as sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) with 95% exact binomial confidence intervals were calculated. RESULTS: Among 2475 patients (1818 women, age: 42.47 ± 11.57; 657 men, age: 42.16 ± 11.69), there were 3187 nodules (2342 malignant nodules and 845 benign nodules). Radiating blood flow signals were an independent risk factor for diagnosing thyroid carcinoma. In the training set, the AUC of the model using the combination of radiating blood flow signals and the ACR TI-RADS score (0.95 95 % CI: [0.94, 0.97]; P < 0.001) was significantly higher than that of the ACR TI-RADS model (0.91 [0.89, 0.93]). In the two internal validation sets and the external validation set, the AUCs of the combination model were 0.97 [0.96, 0.98], 0.92 [0.88, 0.96], and 0.91 [0.86, 0.95], respectively, and were all significantly higher than that of the ACR TI-RADS score (0.92 [0.90, 0.95], 0.86 [0.81, 0.91], 0.84 [0.79, 0.89]; P < 0.001). CONCLUSION: Radiating blood flow is a new US feature of thyroid carcinomas that can significantly improve the diagnostic performance vs. the ACR TI-RADS score.

Fibroblasts and endothelial cells interplay drives hypertrophic scar formation: Insights from in vitro and in vivo models.

Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co-culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF-ß. Additionally, a suspended co-culture multicellular spheroid model revealed molecular-level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro-angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF-ß, IL-17, Wnt, Notch, PI3K-Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts-endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.

Assessment of sarcopenic obesity as a predictor of pneumonia in patients with stable schizophrenia-A prospective study.

OBJECTIVE: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) recently released the first international consensus on the diagnostic criteria for Sarcopenic obesity (SO). The present study aimed to explore the ability of SO to predict the risk of pneumonia in patients with stable schizophrenia. METHODS: This was a prospective study involving hospitalized patients with schizophrenia aged ≥50 years from two mental health centers in western China. Baseline patient data were collected from September 1 to September 30, 2020. Follow-up data on pneumonia were collected from October 2020 to October 2022. The diagnosis of SO was based on the ESPEN/EASO criteria. Patients were assessed for handgrip strength (HGS), skeletal muscle mass/weight (SMM/W), and fat mass percentage (FM%). Logistic regression analysis was used to explore the effect of SO on the risk of pneumonia in patients with stable schizophrenia. RESULTS: A total of 320 patients with stable schizophrenia were included. Of these, 74 (23.13%) were diagnosed with SO, while 117 (36.56%) developed pneumonia. Compared with patients in the non-low HGS, non-low HGS + non-low SMM/W (or non-low HGS + low SMM/W or low HGS + non-low SMM/W) and non-SO groups, the proportions of patients with pneumonia in the low HGS (42.3% vs. 25.9%, p = 0.004), low HGS + low SMM/W (45.3% vs. 33.3%, p = 0.048), and SO (47.3% vs. 33.3%, p = 0.029) groups, respectively, were higher. However, there was no difference in the proportion of patients with pneumonia in the low SMM/W group and the obese group compared with the non-low SMM/W and non-obese groups. Further logistic regression analysis after adjustment for potential influencing factors showed that compared with the non-low HGS group, patients in the low HGS group had a higher risk of pneumonia (OR = 1.892, 95%CI: 1.096-3.264). CONCLUSION: SO defined according to the ESPEN/EASO criteria was not found to be significantly associated with the development of pneumonia in patients with stable schizophrenia. Further verification of these results is needed with larger sample sizes and the establishment of a cutoff value for this population.

A prospective phase II single-arm study and predictive factor analysis of irinotecan as third-line treatment in patients with metastatic gastric cancer.

Background: Currently, there is no recommended standard third-line chemotherapy for metastatic gastric cancer. Objectives: In this study, we aimed to evaluate irinotecan's efficacy and safety in treating metastatic gastric cancer after the failure of first- and second-line chemotherapy. Design: Prospective single-arm, two-center, phase II trial. Methods: Patients were aged 18-70 years, with histologically confirmed gastric adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0-1, progressed during or within 3 months following the last administration of second-line chemotherapy and had no other severe hematologic, cardiac, pulmonary, hepatic, or renal functional abnormalities or immunodeficiency diseases. Eligible patients received 28-day cycles of irinotecan (180 mg/m2 intravenously, days 1 and 15) and were assessed according to the RECIST 1.1 criteria every two cycles. Patients who discontinued treatment for any reason were followed up every 2 months until death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity. Results: A total of 98 eligible patients were enrolled in this study. In the intention-to-treat population, the median OS was 7.17 months, the median PFS was 3.47 months, and the ORR and DCR were 4.08% and 47.96%, respectively. In the per-protocol population, the median OS was 7.77 months, the median PFS was 3.47 months, and the ORR and DCR were 4.82% and 50.60%, respectively. The incidence of grade 3 or 4 hematological and non-hematological toxicities was 19.4%, and none of the patients died owing to adverse events. Cox regression analysis revealed neutropenia and baseline thrombocyte levels were independently correlated with PFS and OS. Conclusion: Irinotecan monotherapy is an efficient, well-tolerated, and economical third-line treatment for patients with metastatic gastric cancer as a third-line treatment. Trial registration: ClinicalTrials.gov identifier: NCT02662959.

Mitochondrial tRNASer(UCN) mutations associated non-syndromic sensorineural hearing loss in Chinese families.

Mitochondrial transfer RNA mutation is one of the most important causes of hereditary hearing loss in humans. Mitochondrial transfer RNASer (UCN) gene is another hot spot for mutations associated with non-syndromic hearing loss, besides the 12S ribosomal RNA gene. In this study, we assessed the clinical phenotype and the molecular characteristics of two Chinese families with non-syndromic hearing loss. Mutational analysis revealed that 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene were the molecular etiology of Family 1 and Family 2, respectively. However, the clinical and genetic characteristics of the two families carrying the above mutations in the transfer RNASer (UCN) gene exhibited a variable expression of hearing loss and an incomplete penetrance. Sequencing analysis of the complete mitochondrial genome showed the presence of transfer RNATrp 5568A > G and NADH-ubiquinone oxidoreductase chain 4 11696G > A mutations in Family 1. The mitochondrial haplotype analysis showed that the two families belonged to Asian D4 and M80'D haplotypes, respectively, and no pathogenic variations were found in the nuclear genes. To our knowledge, our study is the first to report 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene, in multi-generation non-syndromic hearing loss pedigrees from China. Our study suggests that 5568A > G and 11696G > A mutations may enhance the penetrance of hearing loss in Chinese Family 1, while mitochondrial haplotypes and known nuclear genes may not be modifiers for the phenotypic expression of 7445A > G and 7510T > C mutations in these Chinese families.

Water extract of moschus alleviates erastin-induced ferroptosis by regulating the Keap1/Nrf2 pathway in HT22 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Moschus, first described in the Shennong's Classic of the Materia medicine, is a scarce and precious animal medicine. Modern pharmacological researches have suggested that Moschus has neuroprotective actions, and its mechanism is related to anti-inflammatory, antioxidant, and anti-apoptosis effects. Ferroptosis is one of the major pathologies of Alzheimer's disease (AD) and is widely implicated in the pathogenesis and progression of AD. Although previous studies have suggested that Moschus possesses neuroprotective effect, whether Moschus could mitigate neuronal damages by inhibiting the onset of ferroptosis is unknown in model cells of AD. AIM OF THE STUDY: The aim of study was to explore the water extract of Moschus (WEM) on ferroptosis caused by erastin and the potential mechanism. MATERIALS AND METHODS: Erastin was used to stimulate HT22 cells to form ferroptosis model to evaluate the anti-ferroptosis effect of WEM by cell counting kit-8 and lactic dehydrogenase (LDH) tests. The malondialdehyde (MDA) and glutathione (GSH) kits are used for detection of MDA and GSH levels, and 2',7'-dichlorofluorescein diacetate and C11 BODIPY 581/591 fluorescence probe are used for evaluation of reactive oxygen species (ROS) and lipid peroxide (LOOH) levels. And Western blot was used to test nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), and ferroptosis associated proteins including glutathione peroxidase 4 (GPX4), cystine/glutamate antiporter subunit (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin1 (FPN1), transferrin receptor (TFRC). In addition, the Nrf2 inhibitor ML385 was applied to verify whether WEM prevents erastin-induced ferroptosis by activating the Keap1/Nrf2 pathway. RESULTS: After WEM treatment, erastin-induced HT22 cell survival was significantly elevated, the accumulation of intracellular MDA, ROS, and LOOH were significantly reduced, the level of GSH and expressions of ferroptosis inhibitors GPX4 and SLC7A11 were significantly increased, and iron metabolism-related proteins TFRC, FPN1, and FTH1 were regulated. These effects of WEM are implemented by activating the Keap1/Nrf2 pathway. CONCLUSIONS: This study demonstrated that WEM could perform neuroprotective effects by alleviating ferroptosis, verified that WEM treatment of AD can be mediated by the Keap1/Nrf2 pathway, and provided theoretical support for the application of WEM in the treatment of AD.

General Strategy to Prepare Nondoped Circularly Polarized Luminescent Liquid Crystal Materials with Tunable Performance.

Chiral luminescent liquid crystals have attracted widespread attention from researchers due to their unique advantages in constructing circularly polarized luminescent (CPL) materials with large luminescent asymmetry factor (glum) values. However, how to effectively prepare nondoped CPL chiral liquid crystals remains a challenge. In this article, we developed an effective and universal method to prepare nondoped CPL chiral liquid crystal materials. To achieve our strategy, we copolymerized chiral monomer M0Mt with α-cyanostilbene-based luminescent monomers MmPVPCN (m = 6, 8, 10) bearing different flexible spacer lengths to obtain a series of CPL chiral liquid crystal copolymers poly(MmPVPCN(x)-co-M0Mt(y)). Under the induction of the chiral component, the α-cyanostilbene component assembles to form chiral liquid crystals. Meanwhile, α-cyanostilbene also exhibits aggregation-induced emission enhancement characteristics. Therefore, with the help of the selective reflection effect of chiral liquid crystals, the copolymer films can emit efficient CPL. For poly(M8PVPCN(0.85)-co-M0Mt(0.15)), the glum and solid luminescence quantum yield can achieve -2.61 × 10-2 and 25.04%, respectively. In addition, by altering the chemical structure of the copolymers, the phase structure of the copolymers can be effectively controlled, thereby regulating their CPL properties.

Versatile dopamine-functionalized hyaluronic acid-recombinant human collagen hydrogel promoting diabetic wound healing via inflammation control and vascularization tissue regeneration.

The management of chronic wounds in diabetes remains challenging due to the complexity of impaired wound healing, delayed healing, susceptibility to infection, and elevated risk of reopening, highlighting the need for effective chronic wound management with innovative approaches such as multifunctional hydrogels. Here, we have produced HA-DA@rhCol hydrogels consisting of dopamine-modified hyaluronic acid and recombinant human collagen type-III (rhCol) by oxidative coupling of the catechol group using the H2O2/HRP catalytic system. The post-reactive hydrogel has a good porous structure, swelling rate, reasonable degradation, rheological and mechanical properties, and the catechol group and dopamine impart to the hydrogel tissue adhesiveness, antioxidant capacity, and excellent photothermal effects leading to superior in vitro antimicrobial activity. In addition, the ability of rhCol to confer hydrogels to promote angiogenesis and wound repair has also been investigated. Cytotoxicity and hemolysis tests demonstrated the good biocompatibility of the hydrogel. Wound closure, collagen deposition and immunohistochemical examination confirmed the ability of the hydrogel to promote diabetic wound healing. In summary, the adhesive hemostatic antioxidative hydrogel with rhCol to promote wound healing in diabetic rat is an excellent chronic wound dressing.

Better than being aPARt: S. aureus itches to get close to sensory neurons.

In a recent issue of Cell, Deng et al. show that S. aureus serine protease V8 triggers itch, independent of inflammation, by activating sensory neurons through PAR1. This study presents mechanistic insights into pruritogenic bacteria and their interactions with sensory neurons while providing a possible approach for treating itch-related diseases.