Overexpression of TRPV1 activates autophagy in human lens epithelial cells under hyperosmotic stress through Ca2+-dependent AMPK/mTOR pathway.

AIM: To explore whether autophagy functions as a cellular adaptation mechanism in lens epithelial cells (LECs) under hyperosmotic stress. METHODS: LECs were treated with hyperosmotic stress at the concentration of 270, 300, 400, 500, or 600 mOsm for 6, 12, 18, 24h in vitro. Polymerase chain reaction (PCR) was employed for the mRNA expression of autophagy-related genes, while Western blotting detected the targeted protein expression. The transfection of stub-RFP-sens-GFP-LC3 autophagy-related double fluorescence lentivirus was conducted to detect the level of autophagy flux. Scanning electron microscopy was used to detect the existence of autolysosome. Short interfering RNA of autophagy-related gene (ATG) 7, transient receptor potential vanilloid (TRPV) 1 overexpression plasmid, related agonists and inhibitors were employed to their influence on autophagy related pathway. Flow cytometry was employed to test the apoptosis and intracellular Ca2+ level. Mitochondrial membrane potential was measured by JC-1 staining. The cell counting kit-8 assay was used to calculate the cellular viability. The wound healing assay was used to evaluate the wound closure rate. GraphPad 6.0 software was utilized to evaluate the data. RESULTS: The hyperosmotic stress activated autophagy in a pressure- and time-dependent manner in LECs. Beclin 1 protein expression and conversion of LC3B II to LC3B I increased, whereas sequestosome-1 (SQSTM1) protein expression decreased. Transient Ca2+ influx was stimulated caused by hyperosmotic stress, levels of mammalian target of rapamycin (mTOR) phosphorylation decreased, and the level of AMP-activated protein kinase (AMPK) phosphorylation increased in the early stage. Based on this evidence, autophagy activation through the Ca2+-dependent AMPK/mTOR pathway might represent an adaptation process in LECs under hyperosmotic stress. Hyperosmotic stress decreased cellular viability and accelerated apoptosis in LECs and cellular migration decreased. Inhibition of autophagy by ATG7 knockdown had similar results. TRPV1 overexpression increased autophagy and might be crucial in the occurrence of autophagy promoted by hyperosmotic stress. CONCLUSION: A combination of hyperosmotic stress and autophagy inhibition may be a promising approach to decrease the number of LECs in the capsular bag and pave the way for improving prevention of posterior capsular opacification and capsular fibrosis.

Effectiveness and safety of PD-1/PD-L1 inhibitors monotherapy in patients with endometrial cancer.

BACKGROUND: Studies evaluating the effectiveness of immune checkpoint inhibitors (ICI) for endometrial cancer (EC) are limited. This study aimed to assess the efficacy of PD-1/PD-L1 inhibitors as monotherapy for EC by conducting a meta-analysis. The predictive significance of MMR status, a biomarker for ICI response, also required further investigation. METHODS: A systematic literature search was conducted in English databases until September 2023. The analysis included objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and odds ratios (OR), along with their corresponding 95% confidence intervals (CI). RESULTS: There were twelve trials totaling 685 individuals. PD-1/PD-L1 inhibitor monotherapy resulted in an ORR for 34% (95% CI = 24-44%) of the pooled EC patients. Subgroup analysis revealed a significantly higher ORR in dMMR EC (45%) compared to pMMR EC (8%), with an OR of 6.36 (95% CI = 3.64-11.13). The overall DCR was 42%, with dMMR EC at 51% and pMMR EC at 30% (OR = 2.61, 95% CI = 1.69-4.05). Grade three or higher adverse events (AEs) occurred in 15% of cases (95% CI = 9-24%) of the pooled incidence of AEs, which was 68% (95% CI = 65-72%). CONCLUSIONS: This meta-analysis provides significant evidence for the effectiveness of PD-1/PD-L1 inhibitors as monotherapy for EC. Notably, dMMR EC patients demonstrated superior treatment efficacy with PD-1/PD-L1 inhibitor immunotherapy. Further research is required to explore subclassifications of EC based on dMMR molecular subtypes, enabling improved treatment strategies and outcomes for EC patients.

Perimenopausal syndrome and hypertension during perimenopause in South China: prevalence, relationships and risk factors.

BACKGROUND: More than 2 billion women are experiencing the menopausal transition in China, and some of these women have hypertension. Limited studies has focused on perimenopausal syndrome and hypertension in a specific population, so we aimed to investigate the prevalence of perimenopausal syndrome and hypertension and to analyse their relationships and risk factors in perimenopausal women in South China. METHODS: This cross-sectional study included 3553 women aged 40 to 60 years from South China. We collected medical report, lifestyle, blood sample, general condition questionnaire, and modified Kupperman index (mKMI) data. Multivariate logistic regression analysis was performed to identify risk factors for perimenopausal syndrome and hypertension during perimenopause. RESULTS: The prevalence of hypertension in perimenopause patients was 16.58%, and the prevalence of perimenopausal syndrome was 9.9%. Compared with women without hypertension during perimenopause, women with HTN during perimenopause had an increased risk of perimenopausal syndrome (26.4% vs. 8.7%, P < 0.001). Lipid levels and urinary tract infections were risk factors for hypertension and perimenopausal syndrome, in addition to the presence of breast nodules, the intake of snacks at night, high-salt diets, red meat and sugar-sweetened beverages, and a history of smoking and drinking for perimenopausal syndrome and the presence of gestational hypertension and diabetes for hypertension. CONCLUSION: We concluded that perimenopausal syndrome and HTN are common in perimenopausal women in South China, and the associations between them are strong and positive. Perimenopausal syndrome shares some common risk factors with HTN during perimenopause, such as BMI and dyslipidaemia. Therefore, gynaecological endocrinologists in China should consider screening for perimenopausal syndrome in hypertensive perimenopausal women, and appropriate management of perimenopause is needed to alleviate these conditions.

A cross-sectional study on the potential drug-drug interaction risk of COVID-19 patients in hospital.

OBJECTIVE: To investigate the incidence of and risk factors for potential drug-drug interactions (DDIs) among elderly patients with corona virus disease 2019 (-COVID-19) in hospital and to explore management strategies to reduce the occurrence of potential DDIs and ensure patient medication safety. MATERIALS AND METHODS: This was a descriptive, retrospective cross-sectional study among patients aged 65 years and older who were hospitalized with COVID-19. Potential DDIs associated with prescriptions containing two or more medicines were analyzed with Lexicomp software, the incidence of DDIs was calculated, recommendations for medication adjustment were formulated, and the χ2-test and binary logistic regression were used to analyze related risk factors. RESULTS: A total of 772 prescriptions were analyzed, 527 (68.26) of which involved 5,732 potential DDIs. The results of this study showed that a total of 152 (28.84%) prescriptions had 270 X risk class potential DDIs (i.e., avoid combining), 313 (59.39%) prescriptions had 1,161 D risk class potential DDIs (i.e., consider therapy modification), and 476 (90.32%) prescriptions had 4,301 C risk class potential DDIs (i.e., monitor therapy). The study findings showed that the total number of drugs (p < 0.001), the length of hospital stay (p < 0.001), and the number of comorbidities (p < 0.001) were risk factors affecting the occurrence of potential DDIs. CONCLUSION: This study identified factors associated with potential DDIs, which can assist in changing medication strategies, preventing adverse drug reactions, and improving clinical efficacy.

Effects of yeast inoculation methods on caproic acid production and microbial community during anaerobic fermentation of Chinese cabbage waste.

To provide a sufficient supply of electron donors for the synthesis of caproic acid, yeast fermentation was employed to increase ethanol production in the anaerobic fermentation of Chinese cabbage waste (CCW). The results showed that the caproic acid yield of CCW with ethanol pre-fermentation was 7750.3 mg COD/L, accounting for 50.2% of the total volatile fatty acids (TVFAs), which was 32.5% higher than that of the CCW without yeast inoculation. The synchronous fermentation of yeast and seed sludge significantly promoted the growth of butyric acid consuming bacterium Bacteroides, resulting in low yields of butyric acid and caproic acid. With yeast inoculation, substrate competition for the efficient ethanol conversion in the early stage of acidogenic fermentation inhibited the hydrolysis and acidfication. Without yeast inoculation, the rapid accumulation of TVFAs severely inhibited the growth of Bacteroidetes. In the reactor with ethanol pre-fermentation, the key microorganism for caproic acid production, Clostridium_sensu_stricto_12, was selectively enriched.

Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.

The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.

Inulin alters gut microbiota to alleviate post-stroke depressive-like behavior associated with the IGF-1-mediated MAPK signaling pathway.

INTRODUCTION: Gut microbiota dysbiosis is a key factor of the pathogenesis of post-stroke depression (PSD). PSD is associated with increased hippocampal neuronal apoptosis and decreased synaptic connectivity. Inulin can be involved in hippocampal neuron protection through the microbiome-gut-brain axis. However, the neuroprotective effects of inulin in PSD are still to be further investigated. METHODS: By utilizing the GEO public database, we identify differentially expressed genes in the hippocampus following inulin intake. This can help us discover key signaling pathways through functional enrichment analysis. Furthermore, we validate the expression levels of signaling molecules in a rat model of PSD and examine the effects of inulin on behavioral changes and body weight. Additionally, conducting a microbiome analysis to identify significantly different microbial populations and perform correlation analysis. RESULTS: The intake of inulin significantly up-regulated mitogen-activated protein kinase signaling pathway in the hippocampus. Inulin changed in the gut microbiota structure, leading to an increase in the abundance of Lactobacillus and Clostridium_sensu_stricto_1 in the intestines of PSD rats, while decreasing the abundance of Ruminococcus UCG_005, Prevotella_9, Oscillospiraceae, and Clostridia UCG_014. Furthermore, the inulin diet elevated levels of insulin-like growth factor 1 in the serum, which showed a positive correlation with the abundance of Lactobacillus. Notably, the consumption of inulin-enriched diet increased activity levels and preference for sugar water in PSD rats, while also reducing body weight. CONCLUSION: These findings highlight the potential therapeutic benefits of inulin in the management of depression and emphasize the importance of maintaining a healthy gut microbiota for PSD.

SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway.

The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.

From biomaterials to biotherapy: cuttlefish ink with protoporphyrin IX nanoconjugates for synergistic sonodynamic-photothermal therapy.

Biologically produced nanomaterials capable of therapeutic purposes have received increasing interest in tumor therapy because of their intrinsic biocompatibility. In this study, we made cuttlefish ink (extracted from cuttlefish) and protoporphyrin IX (PpIX) nanoconjugates (CIPs) where PpIX was an endogenous organic compound. In the case of CIPs, PpIX could be triggered by ultrasound (US) for sonodynamic therapy (SDT), and the cuttlefish ink could be excited by a near-infrared laser for photothermal therapy (PTT). Thereafter, tumor growth was greatly inhibited through synergistic SDT-PTT in comparison to single SDT or PTT. In addition, in vivo administration of CIPs showed no noticeable side effects for mouse blood and chief organs, providing an effective strategy for developing biologically produced biomaterials and using them for biotherapy.

Accidental ingestion of multiple magnetic beads by children and their impact on the gastrointestinal tract: a single-center study.

OBJECTIVE: In this study, we aimed to enhance the treatment protocols and help understand the harm caused by the accidental ingestion of magnetic beads by children. METHODS: Data were collected from 72 children with multiple gastrointestinal perforations or gastrointestinal obstructions. The 72 pediatric patients were divided into a perforation and a non-perforation group. The data collected for the analysis included the gender, age, medical history, place of residence (rural or urban), and symptoms along with the educational background of the caregiver, the location and quantity of any foreign bodies discovered during the procedure, whether perforation was confirmed during the procedure, and the number of times magnetic beads had been accidentally ingested. RESULTS: The accuracy rate of preoperative gastrointestinal perforation diagnosis via ultrasound was 71%, while that of the upright abdominal X-ray method was only 46%. In terms of symptoms, the risk of perforation was 13.844 and 12.703 times greater in pediatric patients who experienced vomiting and abdominal pain with vomiting and abdominal distension, respectively, compared to patients in an asymptomatic state. There were no statistical differences between the perforation and the non-perforation groups in terms of age, gender, medical history, and the number of magnetic beads ingested (P > 0.05); however, there were statistical differences in terms of white blood cell count (P = 0.048) and c-reactive protein levels (P = 0.033). A total of 56% of cases underwent a laparotomy along with perforation repair and 19% underwent gastroscopy along with laparotomy. All pediatric patients recovered without complications following surgery. CONCLUSION: Abdominal ultrasonography and/or upright abdominal X-ray analyses should be carried out as soon as possible in case of suspicion of accidental ingestion of magnetic beads by children. In most cases, immediate surgical intervention is required. Given the serious consequences of ingesting this type of foreign body, it is essential to inform parents and/or caregivers about the importance of preventing young children from using such products.

Regulation of hydraulic retention time on caproic acid production via two-phase anaerobic fermentation of Chinese cabbage waste with autopoietic electron donors.

The effects of hydraulic retention time (HRT) on the performance of two-phase anaerobic fermentation for caproic acid production from Chinese cabbage waste (CCW) were investigated. In the electron donor phase, yeast was inoculated to achieve efficient autopoietic ethanol, providing electron donors for the chain elongation process. Shorter HRT led to drastic fluctuations in microorganisms, thus resulting in lower acid yields at HRT of 6 days. At HRT of 10 days, the balanced collaboration of various key bacteria avoided the accumulation of intermediate by-products, and the caproic acid production reached 4660 mg COD/L, which was 119.5% and 154.8% higher than that at HRTs of 6 and 14 days, respectively. At HRT of 14 days, the low ethanol loading rate resulted in ethanol excessive-oxidation to acetic acid. Acetic acid accounted for 41.5% of the total product, while the selectivity of caproic acid was only 15.3%. The main contributor to the production process of caproic acid was Caproiciproducens, while the Ruminalococcaceae also played a role in the process. This study provided a theoretical basis for the efficient production of caproic acid through continuous fermentation with autopoietic electron donors.

LATS2 condensates organize signalosomes for Hippo pathway signal transduction.

Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

Exploration of pathogenic microorganism within the small intestine of necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common severe gastrointestinal emergency in neonates. We designed this study to identify the pathogenic microorganisms of NEC in the microbiota of the small intestine of neonates. METHODS: Using the 16S ribosomal DNA (rDNA) sequencing method, we compared and analyzed the structure and diversity of microbiotas in the intestinal feces of different groups of neonates: patients undergoing jejunostomy to treat NEC (NP group), neonates undergoing jejunostomy to treat other conditions (NN group), and neonates with NEC undergoing conservative treatment (NC group). We took intestinal feces and saliva samples from patients at different time points. RESULTS: The beta diversities of the NP, NN, and NC groups were all similar. When comparing the beta diversities between different time points in the NP group, we found similar beta diversities at time points E1 to E3 but significant differences between the E2-E3 and E4 time points: the abundances of Klebsiella and Enterococcus (Proteobacteria) were higher at the E1-E3 time points; the abundance of Escherichia-Shigella (Proteobacteria) increased at the E2 time point, and the abundance of Klebsiella decreased significantly, whereas that of Streptococcus increased significantly at the E4 time point. CONCLUSIONS: Our results suggest that the pathological changes of intestinal necrosis in the small intestine of infants with NEC are not directly caused by excessive proliferation of pathogenic bacteria in the small intestine. The sources of microbiota in the small intestine of neonates, especially in premature infants, may be affected by multiple factors.

The Psychometric Properties of the Chinese version of the Interoceptive Awareness Questionnaire (IAQ) among PATIENTS WITH Cardiovascular Disease.

BACKGROUND: Interoceptive awareness (perception of body conditions and processes) and heart rate variability are connected physiologically in cardiovascular disease (CVD) patients. At present, there is no specific evaluation model for the perception of the physical state and processes of CVD patients in China. OBJECTIVES: The objective of this study is to examine the reliability and validity of the Chinese Interoceptive Awareness Questionnaire (C-IAQ) for Chinese CVD patients. METHODS: 160 CVD patients were recruited from a hospital in Hubei province using a convenient sampling method. A standard "forward-backward" translation method was applied to convert the C-IAQ into Mandarin. Split-half reliability and internal consistency were conducted by using reliability tests. Validity testing was conducted on the content, structure, and criterion-related validity. Criterion-related validity was assessed by using the Anxiety Sensitivity Index-III (ASI-III). RESULTS: The research results indicate that the dual factor structure of the original C-IAQ has 19 items, including attention to unpleasant sensations (9 items) and awareness of neutral body sensations (10 items). Moreover, C-IAQ is positively correlated with ASI-III (r = 0.48, P<0.01). The entire scale has a Cronbach's α value of 0.85 and split-half dependability of 0.77. CONCLUSION: The C-IAQ has favorable psychometric feature. Hence, it can be used to measure the interoceptive awareness of CVD patients.

Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer.

Ovarian cancer is a highly malignant gynecological cancer influenced by the immune microenvironment, metabolic reprogramming, and cellular senescence. This review provides a comprehensive overview of these characteristics. Metabolic reprogramming affects immune cell function and tumor growth signals. Cellular senescence in immune and tumor cells impacts anti-tumor responses and therapy resistance. Targeting immune cell metabolism and inducing tumor cell senescence offer potential therapeutic strategies. However, challenges remain in identifying specific targets and biomarkers. Understanding the interplay of these characteristics can lead to innovative therapeutic approaches. Further research is needed to elucidate mechanisms, validate strategies, and improve patient outcomes in ovarian cancer.

Comparison of perventricular and percutaneous ultrasound-guided device closure of perimembranous ventricular septal defects.

Background: Ultrasound-guided percutaneous device closure of perimembranous ventricular septal defects (PmVSD) is a minimally invasive recent treatment approach. Perventricular PmVSD device closure is an emerging radiation-free intervention, yet it comes with certain limitations. No studies compared both of these treatment approaches. Methods: We performed a retrospective institutional data comparison of percutaneous (PCP Group, n = 138) and perventricular (PVP Group, n = 67) ultrasound-guided device closure procedures in 205 patients with PmVSD between March 2017 and December 2022. Results: Patients of the PCP and PVP groups had a median age of 4.9 years (IQR, 3.1-14.0) and 5.3 years (IQR, 3.4-13.1) respectively. The median PmVSD diameter in the PCP Group was 4.0 mm (IQR, 3.3-5.3) and 5.2 mm (IQR, 4.0-7.0) in the PVP Group (p = 0.001). There was no significant difference in success rates between the PCP and PVP Groups (intention-to-treat population, 88.4% vs. 92.5%, p = 0.36; as-treated population, 88.4% vs. 89.3%, p = 0.84). 5/8 failed percutaneous cases that were shifted to the perventricular approach were successful. Compared to the PVP Group, patients of the PCP group experienced a significant decrease in ventilation time, drainage volume, and postoperative hospital stay (p < 0.001). The median follow-up period was 24 months (IQR, 6-42) for the PCP group and 61 months (IQR, 53-65) for the PVP group. The overall severe adverse event rate was 0% in the PCP group and 3.0% in the PVP group. Conclusions: Perventricular and percutaneous ultrasound-guided device closure of PmVSD are both effective and safe treatment options. The percutaneous approach offers less trauma and faster recovery and may be the preferred approach in selected patients.

Hot spots and trends in PCI prognostic research: A bibliometric analysis with CiteSpace.

BACKGROUND: The number of patients undergoing percutaneous coronary intervention (PCI) procedures is increasing along with the number of studies involving guidelines, prognostic assessments, and cardiac rehabilitation related to PCI strategies. However, fewer studies have reported the mapping of knowledge structure and hotspot analysis in this field. Our goal was to discuss and analyze the current status, hot spots and developmental trends associated with research into the prognosis of patients undergoing PCI, and to provide reference for PCI-related research. METHODS: The Web of Science Core Collection and China Knowledge Network were searched for relevant literature from January 2003 to October 2022, and CiteSpace 6.1. R3 software was used to analyze the co-occurrence, clustering, and emerging authors, institutions, and keywords. RESULTS: A total of 2666 English and 2010 Chinese publications were included. The number of publications showed a growing trend. The author with the maximum number of articles was Xu Bo. The institutions with high productivity were Peking Union Medical College and Capital Medical University. Although the number of Chinese articles was high, the cooperation between institutions was low and the impact was small. The results of the analysis suggest a shift in the focus of keywords from coronary artery disease and PCI to studies involving the assessment and intervention of risk factors associated with poor prognosis of PCI. Traditional Chinese Medicine and anxiety represent the emerging direction of PCI prognosis. The assessment of major adverse cardiovascular events and cardiac rehabilitation require careful analysis in post-PCI research. CONCLUSION: The findings of this bibliometric study present a comprehensive and systematic overview of the PCI prognosis, based on the analysis of the current status and trends in research, which may facilitate the identification of hot topics and new directions for future research.

Speckle-Tracking Echocardiography Predicts Adverse Left Ventricular Remodeling After Valve Replacement in Rheumatic Mitral Stenosis.

Background: Rheumatic mitral stenosis(RMS) may leads to left ventricular remodeling (LVR), which can persist even after valve surgery. Identifying markers for early structure and function in patients with rheumatic heart disease who are at risk for adverse LVR after surgery can help determine the optimal timing of intervention. This study aimed to investigate whether preoperative parameters of global left ventricular long-axis strain (LVGLS) and mechanical discretization (MD) could predict postoperative adverse LVR. Methods: A total of 109 adult patients with RMS and 50 healthy controls were enrolled in this study. Baseline clinical features, conventional echocardiography results, LVGLS, and MD were compared between the two groups. Pre- and post-surgery echocardiography measurements were collected, and adverse LVR was defined as a>15% increase in left ventricular end-diastolic volume or >10% decrease in left ventricular ejection fraction. Binary regression analysis was used to determine independent predictors of poor left ventricular remodeling. Results: The variables associated with adverse LVR in this study were LVGLS (P<0.001, odds ratio: 1.996, 95% CI: 1.394-2.856) and MD (P=0.011, odds ratio: 1.031, 95% CI: 1.007-1.055). The poorly reconstructed group had lower absolute values of LVGLS and higher MD than the healthy control group and the non-poorly reconstructed group. A LVGLS cutoff of -15.0% was the best predictor for patients with poorly reconstructed LVR (sensitivity: 75.7%; specificity: 100.0%; AUC: 0.93), and a MD cutoff of 63.8ms was the best predictor (sensitivity: 63.8%; specificity: 98.6%; AUC: 0.88). Conclusion: Speckle tracking echocardiography has potential value for predicting the progression of adverse LVR and for identifying non-responders among patients with RMS undergoing surgery.

Targeting LGSN restores sensitivity to chemotherapy in gastric cancer stem cells by triggering pyroptosis.

Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gastric cancer stem cells (GCSCs) remains largely unknown. Here, we present evidence that lengsin, lens protein with glutamine synthetase domain (LGSN), a vital cell fate determinant, is overexpressed in GCSCs and is highly correlated with malignant progression and poor survival in GC patients. Ectopic overexpression of LGSN in GCSC-derived differentiated cells facilitated their dedifferentiation and treatment resistance by interacting with vimentin and inducing an epithelial-to-mesenchymal transition. Notably, genetic interference of LGSN effectively suppressed tumor formation by inhibiting GCSC stemness maintenance and provoking gasdermin-D-mediated pyroptosis through vimentin degradation/NLRP3 signaling. Depletion of LGSN combined with the chemo-drugs 5-fluorouracil and oxaliplatin could offer a unique and promising approach to synergistically rendering this deadly cancer eradicable in vivo. Our data place focus on the role of LGSN in GCSC regeneration and emphasize the critical importance of pyroptosis in battling GCSC.

Albumin pre-opsonized membrane-active iPep nanomedicine potentiates chemo to immunotherapy of cancer.

Chemotherapy-conjugated immunotherapy in clinical oncology conceptually resembles the combined effects of cytoreduction and immunostimulation in membrane targeted cell killings mediated by pore-forming proteins or host defense peptides. Of the similar concept, targeting cancer cell membrane using membrane active peptides is a hopeful therapeutic modality but had long been hindered from in vivo application. Here we report an enabling strategy of pre-opsonizing a membrane penetrating Ir-complexed octa-arginine peptide (iPep) with serum albumin via intrinsic amphipathicity-driven bimodal interactions into nanoparticles (NP). We found that NP triggered stress-mediated 4T1 cell oncosis which induced potent immunological activation, surpassing several well-known immunogenic medicines. Vested with albumin-enhanced in vivo tumor targeting specificity and pharmacokinetic properties, NP showed combined chemo to immunotherapies of s. c. tumors in mice, with decreased percentages of MDSC, Treg, M2-like macrophage and improved infiltration of CTLs in tumor site, caused complete regression of 4T1 and CT26 tumors, outperforming clinical medicines. In a challenging orthotopic breast cancer model, boost i. v. injections of NP acted as in situ tumor vaccine that drastically enhanced 4T1-specific cellular and humoral immunities to reverse disease progression. Thus, with combined effects of direct cytoreduction, immune activation and tumor vaccine, iPep-NP presents the promise and potential of a new modality of cancer medicine.