METTL16-SENP3-LTF axis confers ferroptosis resistance and facilitates tumorigenesis in hepatocellular carcinoma.

BACKGROUND: Ferroptosis, characterized by iron-dependent lipid peroxidation, emerges as a promising avenue for hepatocellular carcinoma (HCC) intervention due to its tumor susceptibility. RNA N6-methyladenosine (m6A) modification has been involved in several types of regulated cell death. However, the roles and molecular mechanisms of m6A-related regulators in HCC cell ferroptosis remain unclear. METHODS: By examining a series of m6A modification enzymes upon ferroptosis induction or inhibition, we identified METTL16 as a novel ferroptotic repressor in HCC cells. The roles of METTL16 on ferroptosis and HCC development were investigated in multiple cell lines, human HCC organoids, subcutaneous xenografts and MYC/Trp53-/- HCC model in hepatocyte-specific Mettl16 knockout and overexpression mice. The underlying mechanism was elucidated with MeRIP/RIP-qPCR, luciferase assay, Co-IP assay and Mass Spectrometry. The clinical significance and relevance were evaluated in human samples. RESULTS: High METTL16 expression confers ferroptosis resistance in HCC cells and mouse models, and promotes cell viability and tumor progression. Mechanistically, METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner, and the latter impedes the proteasome-mediated ubiquitination degradation of Lactotransferrin (LTF) via de-SUMOylation. Elevated LTF expression facilitates the chelation of free iron and reduces liable iron pool level. SENP3 and LTF are implicated in METTL16-mediated HCC progression and anti-ferroptotic effects both in vivo and in vitro. Clinically, METTL16 and SENP3 expression were positively correlated, and high METTL16 and SENP3 expression predicts poor prognosis in human HCC samples. CONCLUSIONS: Our study reveals a new METTL16-SENP3-LTF signaling axis regulating ferroptosis and driving HCC development. Targeting this axis is a promising strategy for sensitizing ferroptosis and against HCC.

Effect of patient position on the EEG bispectral index and entropy index under general anaesthesia.

BACKGROUND: Perioperative depth monitoring techniques, such as electroencephalography bispectral index (BIS), entropy index, and auditory evoked potential, are commonly used to assess anesthesia depth. However, the influence of patient positioning changes, particularly in gynecological surgeries where a head-down position is often required, on the accuracy of these monitoring indices remains unexplored. OBJECTIVE: The aim of the our study was to observe the impact of patient position changes on the monitoring value of entropy and BIS to identify a more sensitive method of anaesthesia depth monitoring for gynaecological surgery patients. METHODS: We conducted a study involving 40 women undergoing general anesthesia, during which routine monitoring of vital signs, including electrocardiogram (ECG), heart rate (HR), noninvasive arterial blood pressure (NIBP), oxyhemoglobin saturation (SpO2), and end-expiratory carbon dioxide (PetCO2), was initiated. Entropy and BIS devices were affixed to the patients' foreheads after alcohol sterilization to record brain activity. Tracheal intubation was performed following anesthesia induction. Throughout anesthesia maintenance, the value of BIS and response entropy (RE) were monitored and maintained between 40 and 50 by adjusting the infusion rate of propofol and remifentanil with Target Controlled Infusion (TCI, Mintopharmacokinetics model). Dosing for infusion control utilized corrected weight (height-105). Data were recorded before and after position changes, including tilting the operating table to head-down positions of 15 and 25 degrees, returning to a supine position, and elevating the head to 15 and 25-degree angles. BIS and entropy values at different time points were compared between the groups. RESULTS: Both BIS and entropy values increased from supine to head-down position and decreased from supine to head-up position, with entropy changes preceding those of BIS. Heart rate increased after head-up and decreased after head-down, while mean blood pressure (MBP) exhibited the opposite effect on heart rate. Significant correlations were found between heart rate and BIS (correlation coefficient: -0.43) and RE (correlation coefficient: -0.416), as well as between MBP and BIS (correlation coefficient: 0.346) and RE (correlation coefficient: 0.384). CONCLUSION: Changes in patient position can significantly affect the value of RE and BIS, as changes in entropy occur earlier than changes in the BIS.

Adherence to ACSM exercise guidelines and its influence on Fibromyalgia treatment outcomes: a meta-analysis of randomized controlled trials.

Background: The Fibromyalgia Syndrome (FMS) is a multifaceted chronic pain disorder that exerts a substantial impact on the overall state of health and quality of life of patients. Purpose: Investigate the effects of exercise therapy and adherence to the American College of Sports Medicine (ACSM) guidelines on treatment outcomes in FMS patients. Methods: The literature search, which concluded in October 2023, encompassed studies investigating the impact of exercise interventions on patients diagnosed with FMS and providing adequate data for calculating standardized mean difference (SMD). The primary outcome measures encompassed the Fibromyalgia Impact Questionnaire (FIQ) and Health Assessment Questionnaire (HAQ), while secondary outcome measures comprised pain levels, sleep quality, fatigue, and mental health. Results: Among 4,008 records, 19 studies (patients = 857) were eligible for qualitative synthesis. The meta-analysis revealed that the SMD for overall state of health impact was -0.94 (95%CI -1.26, -0.63), and the pooled SMD for the subgroup with high adherence to ACSM guidelines was -1.17 (95%CI -1.65, -0.69). The SMD for the subgroup with low or uncertain adherence was -0.73 (95%CI -1.12, -0.34). The overall effects included a -1.21 (95%CI -1.62, -0.79) SMD for pain relief, with high adherence achieving a -1.32 (95%CI -2.00, -0.64) SMD and low adherence a -1.06 (95%CI -1.55, -0.57) SMD. Mental health improvements showed a -0.95 (95%CI -1.32, -0.57) overall SMD, with high and low adherence subgroups at -0.96 (95%CI -1.62, -0.30) and -0.94 (95%CI -1.29, -0.60), respectively. Sleep quality impact was -1.59 (95%CI -2.31, -0.87) overall, with high adherence at -1.71 (95%CI -2.58, -0.83) and low adherence at -1.11 (95%CI -1.88, -0.33). Fatigue impact had a -1.55 (95%CI -2.26, -0.85) overall SMD, with -1.77 (95%CI -3.18, -0.36) for high adherence and -1.35 (95%CI -2.03, -0.66) for low adherence. Conclusion: Exercise therapy can improve the overall state of health, pain, sleep, and fatigue of FMS patients, particularly when adhering to ACSM guidelines. However, adherence levels do not affect mental health gains, indicating a need for future research on psychological impact. Systematic Review Registration: https://inplasy.com/inplasy-2024-3-0106/, identifier INPLASY202430106.

Ophthalmic Artery Morphology and Hemodynamics Associated with White Matter Hyperintensity.

Purpose: To investigate morphological and hemodynamic characteristics of the ophthalmic artery (OA) in patients with white matter hyperintensity (WMH), and the association of the presence and severity of WMH with OA characteristics. Methods: This cross-sectional study included 44 eyes of 25 patients with WMH and 38 eyes of 19 controls. The Fazekas scale was adopted as criteria for evaluating the severity of white matter hyperintensities. The morphological characteristics of the OA were measured on the basis of three-dimensional reconstruction. The hemodynamic parameters of the OA were calculated using computational fluid dynamics simulations. Results: Compared with the control group, the diameter (16.0±0.27 mm vs. 1.71±0.18 mm, P=0.029), median blood flow velocity (0.12 m/s vs. 0.22 m/s, P<0.001), mass flow ratio (2.16% vs. 3.94%, P=0.012) and wall shear stress (2.65 Pa vs. 9.31 Pa, P<0.001) of the OA in patients with WMH were significantly decreased. After adjusting for confounding factors, the diameter, blood flow velocity, wall shear stress, and mass flow ratio of the OA were significantly associated with the presence of WMH. Male sex and high low-density protein level were associated with moderate-to-severe total WMH, and smoking was associated with the moderate-to-severe periventricular WMH. Conclusions: The diameter, blood flow velocity, mass flow ratio, and wall shear stress of the OA were independently associated with the presence of WMH. Atherosclerosis might be involved in the common mechanism of the occurrence of WMH and the OA changes.

Prognostic insights, immune infiltration, and therapeutic response: Cytoplasmic poly(A) tail regulators in hepatocellular carcinoma.

The presence of a poly(A) tail is indispensable for the post-transcriptional regulation of gene expression in cancer. This dynamic and modifiable feature of transcripts is under the control of various nuclear and cytoplasmic proteins. This study aimed to develop a novel cytoplasmic poly(A)-related signature for predicting prognosis, clinical attributes, tumor immune microenvironment (TIME), and treatment response in hepatocellular carcinoma (HCC). Utilizing RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA), non-negative matrix factorization (NMF), and principal-component analysis (PCA) were employed to categorize HCC patients into three clusters, thus demonstrating the pivotal prognostic role of cytoplasmic poly(A) tail regulators. Furthermore, machine learning algorithms such as least absolute shrinkage and selection operator (LASSO), survival analysis, and Cox proportional hazards modeling were able to distinguish distinct cytoplasmic poly(A) subtypes. As a result, a 5-gene signature derived from TCGA was developed and validated using International Cancer Genome Consortium (ICGC) HCC datasets. This novel classification based on cytoplasmic poly(A) regulators has the potential to improve prognostic predictions and provide guidance for chemotherapy, immunotherapy, and transarterial chemoembolization (TACE) in HCC.

Phospholipid-Anchored Ligand Conjugation on Extracellular Vesicles for Enhanced Cancer Targeting.

Extracellular vesicles (EVs) are recognized as potential candidates for next-generation drug delivery systems. However, the inherent cancer-targeting efficiency is unsatisfactory, necessitating surface modification to attach cell-binding ligands. By utilizing phospholipase D from Streptomyces in combination with maleimide-containing primary alcohol, the authors successfully anchored ligands onto milk-derived EVs (mEVs), overcoming the issues of ligand leakage or functional alteration seen in traditional methods. Quantitative nano-flow cytometry demonstrated that over 90% of mEVs are effectively modified with hundreds to thousands of ligands. The resulting mEV formulations exhibited remarkable long-term stability in conjugation proportion, ligand number, size distribution, and particle concentration, even after months of storage. It is further shown that conjugating transferrin onto mEVs significantly enhanced cellular uptake and induced pronounced cytotoxic effects when loaded with paclitaxel. Overall, this study presents a highly efficient, stable, cost-effective, and scalable ligand conjugation approach, offering a promising strategy for targeted drug delivery of EVs.

PUMC-MB1 is a novel group 3 medulloblastoma preclinical model, sensitive to PI3K/mTOR dual inhibitor.

PURPOSE: Medulloblastoma (MB), a common and heterogeneous posterior fossa tumor in pediatric patients, presents diverse prognostic outcomes. To advance our understanding of MB's intricate biology, the development of novel patient tumor-derived culture MB models with necessary data is still an essential requirement. METHODS: We continuously passaged PUMC-MB1 in vitro in order to establish a continuous cell line. We examined the in vitro growth using Cell Counting Kit-8 (CCK-8) and in vivo growth with subcutaneous and intracranial xenograft models. The xenografts were investigated histopathologically with Hematoxylin and Eosin (HE) staining and immunohistochemistry (IHC). Concurrently, we explored its molecular features using Whole Genome Sequencing (WGS), targeted sequencing, and RNA sequecing. Guided by bioinformatics analysis, we validated PUMC-MB1's drug sensitivity in vitro and in vivo. RESULTS: PUMC-MB1, derived from a high-risk MB patient, displayed a population doubling time (PDT) of 48.18 h and achieved 100% tumor growth in SCID mice within 20 days. HE and Immunohistochemical examination of the original tumor and xenografts confirmed the classification of PUMC-MB1 as a classic MB. Genomic analysis via WGS revealed concurrent MYC and OTX2 amplifications. The RNA-seq data classified it within the Group 3 MB subgroup, while according to the WHO classification, it fell under the Non-WNT/Non-SHH MB. Comparative analysis with D283 and D341med identified 4065 differentially expressed genes, with notable enrichment in the PI3K-AKT pathway. Cisplatin, 4-hydroperoxy cyclophosphamide/cyclophosphamide, vincristine, and dactolisib (a selective PI3K/mTOR dual inhibitor) significantly inhibited PUMC-MB1 proliferation in vitro and in vivo. CONCLUSIONS: PUMC-MB1, a novel Group 3 (Non-WNT/Non-SHH) MB cell line, is comprehensively characterized for its growth, pathology, and molecular characteristics. Notably, dactolisib demonstrated potent anti-proliferative effects with minimal toxicity, promising a potential therapeutic avenue. PUMC-MB1 could serve as a valuable tool for unraveling MB mechanisms and innovative treatment strategies.

Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

Metabolites, Healthy Lifestyle, and Polygenic Risk Score Associated with Upper Gastrointestinal Cancer: Findings from the UK Biobank Study.

Previous metabolomics studies have highlighted the predictive value of metabolites on upper gastrointestinal (UGI) cancer, while most of them ignored the potential effects of lifestyle and genetic risk on plasma metabolites. This study aimed to evaluate the role of lifestyle and genetic risk in the metabolic mechanism of UGI cancer. Differential metabolites of UGI cancer were identified using partial least-squares discriminant analysis and the Wilcoxon test. Then, we calculated the healthy lifestyle index (HLI) score and polygenic risk score (PRS) and divided them into three groups, respectively. A total of 15 metabolites were identified as UGI-cancer-related differential metabolites. The metabolite model (AUC = 0.699) exhibited superior discrimination ability compared to those of the HLI model (AUC = 0.615) and the PRS model (AUC = 0.593). Moreover, subgroup analysis revealed that the metabolite model showed higher discrimination ability for individuals with unhealthy lifestyles compared to that with healthy individuals (AUC = 0.783 vs 0.684). Furthermore, in the genetic risk subgroup analysis, individuals with a genetic predisposition to UGI cancer exhibited the best discriminative performance in the metabolite model (AUC = 0.770). These findings demonstrated the clinical significance of metabolic biomarkers in UGI cancer discrimination, especially in individuals with unhealthy lifestyles and a high genetic risk.

Purine salvage-associated metabolites as biomarkers for early diagnosis of esophageal squamous cell carcinoma: a diagnostic model-based study.

Esophageal squamous cell carcinoma (ESCC) remains an important health concern in developing countries. Patients with advanced ESCC have a poor prognosis and survival rate, and achieving early diagnosis remains a challenge. Metabolic biomarkers are gradually gaining attention as early diagnostic biomarkers. Hence, this multicenter study comprehensively evaluated metabolism dysregulation in ESCC through an integrated research strategy to identify key metabolite biomarkers of ESCC. First, the metabolic profiles were examined in tissue and serum samples from the discovery cohort (n = 162; ESCC patients, n = 81; healthy volunteers, n = 81), and ESCC tissue-induced metabolite alterations were observed in the serum. Afterward, RNA sequencing of tissue samples (n = 46) was performed, followed by an integrated analysis of metabolomics and transcriptomics. The potential biomarkers for ESCC were further identified by censoring gene-metabolite regulatory networks. The diagnostic value of the identified biomarkers was validated in a validation cohort (n = 220), and the biological function was verified. A total of 457 dysregulated metabolites were identified in the serum, of which 36 were induced by tumor tissues. The integrated analyses revealed significant alterations in the purine salvage pathway, wherein the abundance of hypoxanthine/xanthine exhibited a positive correlation with HPRT1 expression and tumor size. A diagnostic model was developed using two purine salvage-associated metabolites. This model could accurately discriminate patients with ESCC from normal individuals, with an area under the curve (AUC) (95% confidence interval (CI): 0.680-0.843) of 0.765 in the external cohort. Hypoxanthine and HPRT1 exerted a synergistic effect in terms of promoting ESCC progression. These findings are anticipated to provide valuable support in developing novel diagnostic approaches for early ESCC and enhance our comprehension of the metabolic mechanisms underlying this disease.

Effect of tea polyphenols on intestinal barrier and immune function in weaned lambs.

Introduction: The purpose of this study was to explore the effects of tea polyphenols on growth performance, cytokine content, intestinal antioxidant status and intestinal barrier function of lambs, in order to provide reference for intestinal health of ruminants. Methods: Thirty weaned lambs (average initial weight 9.32 ± 1.72 kg) were randomly divided into five groups with six lambs in each group. The control group did not add anything but the basic diet mainly composed of Pennisetum and Corn, and the other four groups added 2, 4, 6 g/kg tea polyphenols and 50 mg/kg chlortetracycline to the basic diet, respectively. The experiment lasted for 42 days. Results: Dietary tea polyphenols improved the growth and stress response and reduced intestinal permeability of lambs (p > 0.05), while CTC did not affect the final lamb weight (p > 0.05). Both tea phenols and CTC significantly reduced inflammatory factors and enhanced the immune system (p > 0.05). Dietary tea polyphenols increased villus height, villus height/crypt depth, secretory immunoglobulin A (p > 0.05), and antioxidant enzymes, while decreasing MDA and apoptosis in the intestine (p > 0.05). However, compared with other groups, the content of T-AOC in jejunum did not change significantly (p > 0.05). Tea polyphenols also increased claudin-1 levels in the duodenum, jejunum, and ileum more than CTC (p > 0.05). CTC had a limited effect on the mRNA expression of Occludin and ZO-1, while tea polyphenols increased these in both the duodenum and ileum (p > 0.05). Conclusion: This study demonstrated that tea polyphenols can effectively improve the intestinal barrier of weaned lambs, and that they have anti-inflammatory and antioxidant effects similar to those of antibiotics. Thus, tea polyphenols could be used to replace antibiotics in ensuring safety of livestock products and in achieving the sustainable development of modern animal husbandry.

Associations between metabolic profiles and incident CKD in the Chinese population aged 45-85 years.

PURPOSE: The roles of metabolic indices in predicting chronic kidney disease (CKD) were lacking. This study aimed to examine the concomitant impact of metabolic and novel anthropometric indices on incident CKD in the Chinese populations. METHODS: This prospective cohort study included 1825 males and 2218 females aged between 45 and 85 years, derived from the ongoing prospectively cohort of China Health and Retirement Longitudinal Study (CHARLS), from 2011 to 2015. The outcome was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. RESULTS: During the 5-years follow-up period, 3.0% (55/1825) of males and 4.1% (90/2218) of the females developed CKD. After multivariable adjustment, elevated triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), serum uric acid (sUA), elevated visceral fat index (VFI), elevated body shape index (BSI) and elevated body roundness index (BRI) in males, and sUA, and BRI in females were the independent predictors for CKD. Composite scores, composed of sUA, history of cardiovascular disease (CVD), waist circumstance (WC), HDL-C, and BRI in males and sUA, hypertension, and BRI in females were constructed that could accurately predict CKD. CONCLUSION: Our study found that elevated levels of TG, sUA, BSI, BRI, and diminished HDL in males and elevated levels of sUA, and BRI in females, are indicative of the incident CKD. The composite score, integrating a history of disease, metabolic indices, and noval anthropometric indices, could accurately differentiate individuals with and without incident CKD, proving useful for CKD care and management.

Diverse roles of UBE2S in cancer and therapy resistance: Biological functions and mechanisms.

The Ubiquitin Conjugating Enzyme E2 S (UBE2S), was initially identified as a crucial member in controlling substrate ubiquitination during the late promotion of the complex's function. In recent years, UBE2S has emerged as a significant epigenetic modification in various diseases, including myocardial ischemia, viral hepatitis, and notably, cancer. Mounting evidence suggests that UBE2S plays a pivotal role in several human malignancies including breast cancer, lung cancer, hepatocellular carcinoma and etc. However, a comprehensive review of UBE2S in human tumor research remains absent. Therefore, this paper aims to fill this gap. This review provides a comprehensive analysis of the structural characteristics of UBE2S and its potential utility as a biomarker in diverse cancer types. Additionally, the role of UBE2S in conferring resistance to tumor treatment is examined. The findings suggest that UBE2S holds promise as a diagnostic and therapeutic target in multiple malignancies, thereby offering novel avenues for cancer therapy.

The construction, validation and promotion of the nomogram prognosis prediction model of UCEC, and the experimental verification of the expression and knockdown of the key gene GPX4.

Background: Adequate prognostic prediction of Uterine Corpus Endometrial Carcinoma (UCEC) is crucial for informing clinical decision-making. However, there is a scarcity of research on the utilization of a nomogram prognostic evaluation model that incorporates pyroptosis-related genes (PRGs) in UCEC. Methods: By analyzing data from UCEC patients in the TCGA database, four PRGs associated with prognosis were identified. Subsequently, a "risk score" was developed using these four PRGs and LASSO. Ordinary and web-based dynamic nomogram prognosis prediction models were constructed. The discrimination, calibration, clinical benefit, and promotional value of the selected GPX4 were validated. The expression level of GPX4 in UCEC cell lines was subsequently verified. The effects of GPX4 knock-down on the malignant biological behavior of UCEC cells were assessed. Results: Four key PRGs and a "risk score" were identified, with the "risk score" calculated as (-0.4323) * GPX4 + (0.2385) * GSDME + (0.0525) * NLRP2 + (-0.3299) * NOD2. The nomogram prognosis prediction model, incorporating the "risk score," "age," and "FIGO stage," demonstrated moderate predictive performance (AUC >0.7), good calibration, and clinical significance for 1, 3, and 5-year survival. The web-based dynamic nomogram demonstrated significant promotional value (https://shibaolu.shinyapps.io/DynamicNomogramForUCEC/). UCEC cells exhibited abnormally elevated expression of GPX4, and the knockdown of GPX4 effectively suppressed malignant biological activities, including proliferation and migration, while inducing apoptosis. The findings from tumorigenic experiments conducted on nude mice further validated the results obtained from cellular experiments. Conclusion: Following validation, the nomogram prognosis prediction model, which relies on four pivotal PRGs, demonstrated a high degree of accuracy in forecasting the precise probability of prognosis for patients with UCEC. Additionally, the web-based dynamic nomogram exhibited considerable potential for promotion. Notably, the key gene GPX4 exhibited characteristics of a potential oncogene in UCEC, as it facilitated malignant biological behavior and impeded apoptosis.

Association between cancer health literacy and cancer-related behavior of residents in Shandong, China.

Health literacy is closely related to the incidence of major chronic diseases and its related behaviors such as cancer-related behaviors. This study explored how the cancer health literacy level affects cancer-related behaviors. About one to two villages from six cities of Shandong province were selected as sample areas. Professionals conducted face-to-face interviews with the participants. Finally, 1200 residents completed 1085 effective questionnaires. Data were analysed from a cross-sectional survey in 2019, which included 1085 residents in six cities/counties of Shandong province, China. The result showed that residents with high cancer health literacy were more likely to eat fruits and vegetables frequently, avoid eating moldy food and take exercise. Besides, they were more likely to engage in health education and have a higher willingness to pay for cancer screenings. Most residents in Shandong province have a basic level of cancer health literacy. Improving the cancer health literacy of the population can be an effective strategy to promote a healthier lifestyle, thereby reducing the incidence rates related to cancers.

Artesunate improves glucose and lipid metabolism in db/db mice by regulating the metabolic profile and the MAPK/PI3K/Akt signalling pathway.

BACKGROUND: Diabetes is a metabolic disorder characterized by chronic hyperglycaemia. Chronic metabolic abnormalities and long-term hyperglycaemia may result in a wide range of acute and chronic consequences. Previous studies have demonstrated that artesunate(ART) has antidiabetic, anti-inflammatory, antiatherosclerotic, and other beneficial effects, but the specific regulatory mechanism is not completely clear. AIM: This study investigated the effects of ART on metabolic disorders in type 2 diabetes mellitus (T2DM) model db/db mice and explored the underlying mechanisms involved. METHODS: C57BL/KsJ-db/db mice were used to identify the targets and molecular mechanism of ART. Metabolomic methods were used to evaluate the efficacy of ART in improving T2DM-related metabolic disorders. Network pharmacology and transcriptomic sequencing were used to analyse the targets and pathways of ART in T2DM. Finally, molecular biology experiments were performed to verify the key targets and pathways selected by network pharmacology and transcriptomic analyses. RESULTS: After a 7-week ART intervention (160 mg/kg), the glucose and lipid metabolism levels of the db/db mice improved. Additionally, the oxidative stress indices, namely, the MDA and SOD levels, significantly improved (p<0.01). Linoleic acid and glycerophospholipid metabolism, amino acid metabolism, bile acid synthesis, and purine metabolism disorders in db/db mice were partially corrected after ART treatment. Network pharmacology analysis identified important targets of ART for the treatment of metabolic disorders in T2DM . These targets are involved in key signalling pathways, including the highest scores observed for the PI3K/Akt signalling pathway. Transcriptomic analysis revealed that ART could activate the MAPK signalling pathway and two key gene targets, HGK and GADD45. Immunoblotting revealed that ART increases p-PI3K, p-AKT, Glut2, and IRS1 protein expression and suppresses the phosphorylation of p38, ERK1/2, and JNK, returning HGK and GADD45 to their preartesunate levels. CONCLUSION: Treatment of db/db mice with 160 mg/kg ART for 7 weeks significantly reduced fasting blood glucose and lipid levels. It also improved metabolic imbalances in amino acids, lipids, purines, and bile acids, thereby improving metabolic disorders. These effects are achieved by activating the PI3K/AKT pathway and inhibiting the MAPK pathway, thus demonstrating the efficacy of the drug.

Single-cell transcriptomic analysis reveals tumor cell heterogeneity and immune microenvironment features of pituitary neuroendocrine tumors.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are one of the most common types of intracranial tumors. Currently, the cellular characteristics of normal pituitary and various other types of PitNETs are still not completely understood. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on 4 normal samples and 24 PitNET samples for comprehensive bioinformatics analysis. Findings regarding the function of PBK in the aggressive tumor cells were validated by siRNA knockdown, overexpression, and transwell experiments. RESULTS: We first constructed a reference cell atlas of the human pituitary. Subsequent scRNA-seq analysis of PitNET samples, representing major tumor subtypes, shed light on the intrinsic cellular heterogeneities of the tumor cells and tumor microenvironment (TME). We found that the expression of hormone-encoding genes defined the major variations of the PIT1-lineage tumor cell transcriptomic heterogeneities. A sub-population of TPIT-lineage tumor cells highly expressing GZMK suggested a novel subtype of corticotroph tumors. In immune cells, we found two clusters of tumor-associated macrophages, which were both highly enriched in PitNETs but with distinct functional characteristics. In PitNETs, the stress response pathway was significantly activated in T cells. While a majority of these tumors are benign, our study unveils a common existence of aggressive tumor cells in the studied samples, which highly express a set of malignant signature genes. The following functional experiments confirmed the oncogenic role of selected up-regulated genes. The over-expression of PBK could promote both tumor cell proliferation and migration, and it was also significantly associated with poor prognosis in PitNET patients. CONCLUSIONS: Our data and analysis manifested the basic cell types in the normal pituitary and inherent heterogeneity of PitNETs, identified several features of the tumor immune microenvironments, and found a novel epithelial cell sub-population with aggressive signatures across all the studied cases.

Prolyl isomerase Pin1 sculpts the immune microenvironment of colorectal cancer.

Pin1, a peptide prolyl cis-trans isomerase, is overexpressed and/or overactivated in many human malignancies. However, whether Pin1 regulates the immunosuppressive TME has not been well defined. In this study, we detected the effect of Pin1 on immune cells and immune checkpoint PD-L1 in the TME of CRC and explored the anti-tumor efficacy of Pin1 inhibitor ATRA combined with PD-1 antibody. We found that Pin1 facilitated the immunosuppressive TME by raising the proportion of myeloid-derived suppressor cells (MDSCs) and declining the percentage of CD8+ T cells and CD4+ T cells. Pin1 restrained PD-L1 protein expression in CRC cells and the effect was tempered by endoplasmic reticulum (ER) stress inducers. Mechanically, Pin1 overexpression decreased the stability of PD-L1 and promoted its degradation by mitigating ER stress. Silencing or inhibiting Pin1 promoted PD-L1 protein expression by inducing ER stress. Hence, Pin1 inhibitor ATRA enhanced the anti-tumor efficacy of PD-1 antibody in the CRC allograft by upregulating PD-L1. Our results reveal the critical and pleiotropic effects of Pin1 on managing the immune cells and immune checkpoint PD-L1 in the TME of CRC, providing a new promising candidate for combination with immunotherapy.

Classification of high-risk depressed mood groups in cancer patients based on Health Ecology Model.

BACKGROUND: Depressed mood affects a significant number of patients with cancer, and can impair their quality of life and interfere with successful treatment. Our study aims to create a predictive model for identifying high-risk groups of depressed mood in cancer patients, offering a theoretical support for preventing depressed mood in these individuals. METHODS: The China Health and Retirement Longitudinal Study (CHARLS) provided the data for this research, which used CES-D as a tool to identify individuals with depressed mood. Influencing factors of depressed mood in cancer patients was analyzed using a binary logistic regression model. Using the Harvard Cancer Index, we classified the high-risk patients for depressed mood. RESULTS: In present study, 52.96 % of cancer patients met criteria for depressed mood based on the CES-D. Significant correlations were found between depressed mood and factors such as gender, self-rated health, sleep duration, exercise, satisfaction with family, residence, education, life satisfaction, and medical insurance. Utilizing the Harvard Cancer Index, we classified patients into five risk levels for depressed mood, revealing a significant variation in the number of depressive patients across these levels (x2=99.82, P < 0.05). Notably, the incidence of depressed mood increased with the risk level among cancer patients (x2=103.40, P < 0.05). LIMITATIONS: Lack of data on tumor typing and subgroups makes it unlikely to explore the specifics of depressed mood in patients with various types of cancer. CONCLUSION: The determinants of depressed mood in cancer patients are multi-dimensional. The Harvard Cancer Index may be helpful in identifying high-risk populations.

Assessment of the prevalence and related factors of financial toxicity in cancer patients based on the COST scale: A systematic review and meta-analysis.

PURPOSE: The high cost of cancer treatment exposes patients to financial toxicity during treatment; however, no study has comprehensively analyzed the incidence of financial toxicity using a validated assessment tool. In this study, the objective was to ascertain the incidence of financial toxicity in cancer patients and the factors influencing it. METHODS: Nine electronic databases were retrieved to collect cross-sectional studies reporting financial toxicity in cancer patients. A random effects meta-analysis was applied to yield the overall prevalence of financial toxicity. Subgroup analyses were conducted depending on the factors affecting financial toxicity. RESULTS: In total, 30 studies met our inclusion criteria. The pooled prevalence of financial toxicity in cancer patients was 48% (95%CI:38%-58%, I2 = 99.4%, p < 0.001). In the subgroup analysis, a higher prevalence of financial toxicity in patients aged <67 years (47%, 95%CI: 28%-66%, I2 = 97.5%, p < 0.001), female (46%, 95%CI:39%-53%, I2 = 94.9%,p < 0.001), lung cancer(57%, 95%CI:38%-75%, I2 = 96.9%, p < 0.001), developing countries (64%, 95%CI:55%-72%, I2 = 98.1%, p < 0.001), time of investigation following COVID-19 (53%, 95%CI:37%-69%, I2 = 99.4%, p < 0.001). CONCLUSION: Financial toxicity is prevalent in cancer patients and is increasingly evident after COVID-19. Furthermore, the odds of financial toxicity are higher in patients who are female, younger, whose cancer type is lung cancer, and from developing countries. These findings emphasize the significance of evaluating financial toxicity in cancer patients after COVID-19, especially in developing countries. This may play a pivotal role in helping patients cope with financial toxicity.