Dipeptidyl peptidase-4 disturbs adipocyte differentiation via the negative regulation of the glucagon-like peptide-1/adiponectin-cathepsin K axis in mice under chronic stress conditions.

Exposure to chronic psychosocial stress is a risk factor for metabolic disorders. Because dipeptidyl peptidase-4 (DPP4) and cysteinyl cathepsin K (CTSK) play important roles in human pathobiology, we investigated the role(s) of DPP4 in stress-related adipocyte differentiation, with a focus on the glucagon-like peptide-1 (GLP-1)/adiponectin-CTSK axis in vivo and in vitro. Plasma and inguinal adipose tissue from non-stress wild-type (DPP4+/+), DPP4-knockout (DPP4-/-) and CTSK-knockout (CTSK-/-) mice, and stressed DPP4+/+, DPP4-/-, CTSK-/-, and DPP4+/+ mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/or morphological alterations. On day 14 under chronic stress, stress decreased the weights of adipose tissue and resulted in harmful changes in the plasma levels of DPP4, GLP-1, CTSK, adiponectin, and tumor necrosis factor-α proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-α, GLP-1 receptor, peroxisome proliferator-activated receptor-γ, perilipin2, secreted frizzled-related protein-4, Wnt5α, Wnt11 and ß-catenin proteins and/or mRNAs as well as macrophage infiltration in adipose tissue; these changes were rectified by DPP4 deletion. GLP-1 receptor activation and CTSK deletion mimic the adipose benefits of DPP4 deficiency. In vitro, CTSK silencing and overexpression respectively prevented and facilitated stress serum and oxidative stress-induced adipocyte differentiation accompanied with changes in the levels of pref-1, C/EBP-α, and PPAR-γ in 3T3-L1 cells. Thus, these findings indicated that increased DPP4 plays an essential role in stress-related adipocyte differentiation, possibly through a negative regulation of GLP-1/adiponectin-CTSK axis activation in mice under chronic stress conditions.

A Dataset of apical periodontitis lesions in panoramic radiographs for deep-learning-based classification and detection.

Deep learning has been studied in recent years to identify periapical lesions- a significant indicator of periapical periodontitis in radiographs. An accurate dataset is essential for constructing an efficient learning model for detecting periapical lesions. In order to achieve this goal, we gathered and created a database of panoramic radiographs containing periapical lesions from the High-quality Dental Treatment Centre, School of Dentistry, Hanoi Medical University, between January 2016 and March 2021. Out of 16,519 radiographs, three experienced dentists identified 3,926 images of periapical lesions and annotated those lesions based on the Periapical Lesions Classification. By applying well-known data processing techniques (e.g. scaling, mirroring, and flipping), the amount of data is increased to 17,004 images through generating additional images for machine learning. The dataset has three folders: one for the original photos, one for the post-augmentation images, and the rest for the annotation of periapical lesions. The information could assist researchers in developing a predictive machine model for detecting periapical lesions in radiographs.

The efficacy of using a multiparametric magnetic resonance imaging-based radiomics model to distinguish glioma recurrence from pseudoprogression.

OBJECTIVE: The early differential diagnosis of the postoperative recurrence or pseudoprogression (psPD) of a glioma is of great guiding significance for individualized clinical treatment. This study aimed to evaluate the ability of a multiparametric magnetic resonance imaging (MRI)-based radiomics model to distinguish between the postoperative recurrence and psPD of a glioma early on and in a noninvasive manner. METHODS: A total of 52 patients with gliomas who attended the Hainan Provincial People's Hospital between 2000 and 2021 and met the inclusion criteria were selected for this study. 1137 and 1137 radiomic features were extracted from T1 enhanced and T2WI/FLAIR sequence images, respectively.After clearing some invalid information and LASSO screening, a total of 9 and 10 characteristic radiological features were extracted and randomly divided into the training set and the test set according to 7:3 ratio. Select-Kbest and minimum Absolute contraction and selection operator (LASSO) were used for feature selection. Support vector machine and logistic regression were used to form a multi-parameter model for training and prediction. The optimal sequence and classifier were selected according to the area under the curve (AUC) and accuracy. RESULTS: Radiomic models 1, 2 and 3 based on T1WI, T2FLAIR and T1WI + T2T2FLAIR sequences have better performance in the identification of postoperative recurrence and false progression of T1 glioma. The performance of model 2 is more stable, and the performance of support vector machine classifier is more stable. The multiparameter model based on CE-T1 + T2WI/FLAIR sequence showed the best performance (AUC:0.96, sensitivity: 0.87, specificity: 0.94, accuracy: 0.89,95% CI:0.93-1). CONCLUSION: The use of multiparametric MRI-based radiomics provides a noninvasive, stable, and accurate method for differentiating between the postoperative recurrence and psPD of a glioma, which allows for timely individualized clinical treatment.

Residential mobility and liver cancer risk: findings from a prospective cohort study in Chinese women.

BACKGROUND: Residential mobility is believed to influence the occurrence and development of cancer; however, the results are inconclusive. Furthermore, limited studies have been conducted on Asian populations. This study aimed to evaluate the relationship between residential mobility and liver cancer risk among Chinese women. METHODS: We enrolled 72,818 women from urban Shanghai between 1996 and 2000, and then followed them until the end of 2016. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association between residential mobility and liver cancer risk. A linear trend test was conducted by ranking variables. A sensitivity analysis was also conducted, excluding participants with follow-up times of less than 2 years, to prevent potential bias. RESULTS: During the 1,269,765 person-years of follow-up, liver cancer was newly diagnosed in 259 patients. Domestic migration (HR = 1.47, 95% CI, 1.44-1.50), especially immigration to Shanghai (HR = 1.47, 95% CI, 1.44-1.50) was associated with an increased risk of liver cancer. In addition, migration frequency, age at initial migration and first immigration to Shanghai had linear trends with an increased liver cancer risk (Ptrend <0.001). The results were similar when excluding participants with less than two years of follow-up. CONCLUSIONS: The possible association between residential mobility and a higher risk of liver cancer in women could suggest the need for effective interventions to reduce adverse environmental exposures and enhance people's health.

A retrospective study of ovarian tissue cryopreservation in female patients with hematological diseases for fertility preservation.

PURPOSES: To investigate the effect and safety of ovarian tissue cryopreservation (OTC) for fertility preservation in female patients with hematological diseases. METHODS: We designed a retrospective study. The clinical data of patients with hematological diseases undergoing OTC admitted to Peking University People's Hospital from April 2017 to January 2023 were analyzed and summarized. RESULTS: A total of 24 patients were included in the study, including 19 patients with malignant hematological diseases and 5 patients with non-malignant hematological diseases. The former included 14 patients with acute leukemia, 1 patient with chronic leukemia, and 4 patients with myelodysplastic syndrome, while the latter 5 patients were aplastic anemia (AA). 16 patients had received chemotherapy before OTC. The average age of 24 patients was 22.80 ± 6.81 years. The average anti-Mullerian hormone (AMH) was 1.97 ± 2.12 ng/mL, and the average follicle-stimulating hormone (FSH) was 7.01 ± 4.24 IU/L in examination before OTC. FSH was greater than 10.0 IU/L in 4 cases. The pre-OTC laboratory tests showed that the average white blood cell (WBC) count was (3.33 ± 1.35) × 109/L, the average hemoglobin was 91.42 ± 22.84 g/L, and the average platelet was (147.38 ± 114.46) × 109/L. After injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF), blood transfusion, and iron supplementation in pre-OTC treatment, the average WBC count was (4.91 ± 3.07) × 109/L, the average hemoglobin was 98.67 ± 15.43 g/L, and the average platelet was (156.38 ± 103.22) × 109/L. Of the 24 patients, 22 underwent laparoscopic bilateral partial oophorectomy and oophoroplasty, and 2 underwent laparoscopic unilateral oophorectomy. The average duration of OTC was 59.54 ± 17.58 min, and the average blood loss was 32.1 ± 41.6 mL. The maximum blood loss was 200 mL. There was no significant difference in WBC count and hemoglobin concentration after OTC compared to pre-OTC period. Only the platelet count after OTC surgery was significantly different from that before surgery ([134.54 ± 80.84 vs. 156.38 ± 103.22] × 109/L, p < 0.05). None of the 24 patients had serious complications after OTC. 2 patients had mild infection symptoms, but both recovered well. 23 patients underwent hematopoietic stem cell transplantation (HSCT) after OTC. The median and interquartile range from OTC to the pretreatment of HSCT was 33 (57) days, and the median and interquartile range from OTC to HSCT was 41 (57) days. Seven of them began pretreatment of HSCT within 20 days and began HSCT within 30 days after OTC. All patients were followed up. Of the 23 patients who underwent HSCT after surgery, 22 presented with amenorrhea and 1 with scanty menstrual episodes. Seven patients underwent hormone replacement therapy (HRT) after HSCT. A patient with AA underwent ovarian tissue transplantation (OTT) 3 years after HSCT and resumed regular menstruation 6 months after OTT. CONCLUSIONS: Ovarian tissue cryopreservation has a promising future in fertility protection in patients with hematological diseases. However, patients with hematological malignancies often have received gonadotoxic therapy before OTC, which may be accompanied by myelosuppression while patients with non-malignant hematological diseases often present with severe hemocytopenia. So perioperative complete blood count of patients should be paid attention to. There was no significant difference in the WBC count and hemoglobin concentration in patients with hematological diseases before and after OTC surgery, and the platelet count decreased slightly within the normal range. Infection is the most common post-OTC complication, and HSCT pretreatment can be accepted as early as the 10th day after OTC. OTC has no adverse effects on patients with hematological diseases and does not delay HSCT treatment. For young patients with hematological diseases, OTC is an effective method of fertility preservation.

HMGB1 regulates autophagy of placental trophoblast through ERK signaling pathway.

OBJECTIVE: The purpose of this study is to investigate the role of high mobility group protein B1 (HMGB1) in placental development and fetal growth. METHODS: We employed the Cre-loxP recombination system to establish a placenta-specific HMGB1 knockout mouse model. Breeding HMGB1flox/flox mice with Elf5-Cre mice facilitated the knockout, leveraging Elf5 expression in extra-embryonic ectoderm, ectoplacental cone, and trophoblast giant cells at 12.5 days of embryonic development. The primary goal of this model was to elucidate the molecular mechanism of HMGB1 in placental development, assessing parameters such as placental weight, fetal weight, and bone development. Additionally, we utilized lentiviral interference and overexpression of HMGB1 in human trophoblast cells to further investigate HMGB1's functional role. RESULTS: Our findings indicate that HMGB1flox/floxElf5cre/+ mouse display fetal growth restriction (FGR), characterized by decreased placental and fetal weight and impaired bone development. And the absence of HMGB1 inhibits autophagosome formation, impairs lysosomal degradation, and disrupts autophagic flux. Depletion of HMGB1 in human trophoblast cells also suppresses cell viability, proliferation, migration, and invasion by inhibiting the ERK signaling pathway. Overexpression of HMGB1 observed the opposite phenotypes. CONCLUSIONS: HMGB1 participates in the regulation of autophagy through the ERK signaling pathway and affects placental development.

Se Alleviated Pb-Caused Neurotoxicity in Chickens: SPS2-GPx1-GSH-IL-2/IL-17-NO Pathway, Selenoprotein Suppression, Oxidative Stress, and Inflammatory Injury.

Lead (Pb), a heavy metal environmental pollutant, poses a threat to the health of humans and birds. Inflammation is one of the most common pathological phenomena in the case of illness and poisoning. However, the underlying mechanisms of inflammation remain unclear. The cerebellum and the thalamus are important parts of the nervous system. To date, there have been no reports of Pb inducing inflammation in animal cerebellums or thalami. Selenium (Se) can relieve Pb poisoning. Therefore, we aimed to explore the mechanism by which Se alleviates Pb toxicity to the cerebellums and thalami of chickens by establishing a chicken Pb or/and Se treatment model. Our results demonstrated that exposure to Pb caused inflammatory damage in cerebellums and thalami, evidenced by the characteristics of inflammation, the decrease in anti-inflammatory factors (interleukin (IL)-2 and interferon-γ (INF-γ)), and the increase in pro-inflammatory factors (IL-4, IL-6, IL-12ß, IL-17, and nitric oxide (NO)). Moreover, we found that the IL-2/IL-17-NO pathway took part in Pb-caused inflammatory injury. The above findings were reversed by the supplementation of dietary Se, meaning that Se relieved inflammatory damage caused by Pb via the IL-2/IL-17-NO pathway. In addition, an up-regulated oxidative index malondialdehyde (MDA) and two down-regulated antioxidant indices (glutathione (GSH) and total antioxidant capacity (TAC)) were recorded after the chickens received Pb stimulation, indicating that excess Pb caused an oxidant/antioxidant imbalance and oxidative stress, and the oxidative stress mediated inflammatory damage via the GSH-IL-2 axis. Interestingly, exposure to Pb inhibited four glutathione peroxidase (GPx) family members (GPx1, GPx2, GPx3, and GPx4), three deiodinase (Dio) family members (Dio1, Dio2, and Dio3), and fifteen other selenoproteins (selenophosphate synthetase 2 (SPS2), selenoprotein (Sel)H, SelI, SelK, SelM, SelO, SelP1, SelPb, SelS, SelT, SelU, and selenoprotein (Sep)n1, Sepw1, Sepx1, and Sep15), suggesting that Pb reduced antioxidant capacity and resulted in oxidative stress involving the SPS2-GPx1-GSH pathway. Se supplementation, as expected, reversed the changes mentioned above, indicating that Se supplementation improved antioxidant capacity and mitigated oxidative stress in chickens. For the first time, we discovered that the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway is involved in the complex inflammatory damage mechanism caused by Pb in chickens. In conclusion, this study demonstrated that Se relieved Pb-induced oxidative stress and inflammatory damage via the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway in the chicken nervous system. This study offers novel insights into environmental pollutant-caused animal poisoning and provides a novel theoretical basis for the detoxification effect of Se against oxidative stress and inflammation caused by toxic pollutants.

Long Non-Coding RNA-Cardiac-Inducing RNA 6 Mediates Repair of Infarcted Hearts by Inducing Mesenchymal Stem Cell Differentiation into Cardiogenic Cells through Cyclin-Dependent Kinase 1.

This study aims to investigate the induction effect of LncRNA-CIR6 on MSC differentiation into cardiogenic cells in vitro and in vivo. In addition to pretreatment with Ro-3306 (a CDK1 inhibitor), LncRNA-CIR6 was transfected into BMSCs and hUCMSCs using jetPRIME. LncRNA-CIR6 was further transfected into the hearts of C57BL/6 mice via 100 µL of AAV9-cTnT-LncRNA-CIR6-ZsGreen intravenous injection. After three weeks of transfection followed by AMI surgery, hUCMSCs (5 × 105/100 µL) were injected intravenously one week later. Cardiac function was evaluated using VEVO 2100 and electric mapping nine days after cell injection. Immunofluorescence, Evans blue-TTC, Masson staining, FACS, and Western blotting were employed to determine relevant indicators. LncRNA-CIR6 induced a significant percentage of differentiation in BMSCs (83.00 ± 0.58)% and hUCMSCs (95.43 ± 2.13)% into cardiogenic cells, as determined by the expression of cTnT using immunofluorescence and FACS. High cTNT expression was observed in MSCs after transfection with LncRNA-CIR6 by Western blotting. Compared with the MI group, cardiac contraction and conduction function in MI hearts treated with LncRNA-CIR6 or combined with MSCs injection groups were significantly increased, and the areas of MI and fibrosis were significantly lower. The transcriptional expression region of LncRNA-CIR6 was on Chr17 from 80209290 to 80209536. The functional region of LncRNA-CIR6 was located at nucleotides 0-50/190-255 in the sequence. CDK1, a protein found to be related to the proliferation and differentiation of cardiomyocytes, was located in the functional region of the LncRNA-CIR6 secondary structure (from 0 to 17). Ro-3306 impeded the differentiation of MSCs into cardiogenic cells, while MSCs transfected with LncRNA-CIR6 showed a high expression of CDK1. LncRNA-CIR6 mediates the repair of infarcted hearts by inducing MSC differentiation into cardiogenic cells through CDK1.

Postmenopausal endometrial non-benign lesion risk classification through a clinical parameter-based machine learning model.

OBJECTIVE: This study aimed to develop and evaluate a machine learning model utilizing non-invasive clinical parameters for the classification of endometrial non-benign lesions, specifically atypical hyperplasia (AH) and endometrioid carcinoma (EC), in postmenopausal women. METHODS: Our study collected clinical parameters from a cohort of 999 patients with postmenopausal endometrial lesions and conducted preprocessing to identify 57 relevant characteristics from these irregular clinical data. To predict the presence of postmenopausal endometrial non-benign lesions, including atypical hyperplasia and endometrial cancer, we employed various models such as eXtreme Gradient Boosting (XGBoost), Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), Back Propagation Neural Network (BPNN), as well as two ensemble models. Additionally, a test set was performed on an independent dataset consisting of 152 patients. The performance evaluation of all models was based on metrics including the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision, and F1 score. RESULTS: The RF model demonstrated superior recognition capabilities for patients with non-benign lesions compared to other models. In the test set, it attained a sensitivity of 88.1% and an AUC of 0.93, surpassing all alternative models evaluated in this study. Furthermore, we have integrated this model into our hospital's Clinical Decision Support System (CDSS) and implemented it within the outpatient electronic medical record system to continuously validate and optimize its performance. CONCLUSIONS: We have trained a model and deployed a system with high discriminatory power that may provide a novel approach to identify patients at higher risk of postmenopausal endometrial non-benign lesions who may benefit from more tailored screening and clinical intervention.

Sporisorium reilianum polysaccharides improve DSS-induced ulcerative colitis by regulating intestinal barrier function and metabolites.

This study investigated the regulatory effects of Sporisorium reilianum polysaccharides (SRPS) on metabolism and the intestinal barrier in mice with colitis induced by dextran sulfate sodium (DSS). SRPS were resistant to the digestion of saliva, gastric juices, and intestinal fluid. SRPS significantly reduced the disease activity index and inhibited DSS-induced colon shortening. The expression of proinflammatory cytokines in the colon was normal (P < 0.05). Acetic acid, propionic acid, butyric acid, isobutyric acid, and isovaleric acid contents increased. Moreover, 64 biomarker metabolites were affected, including 42 abnormal decreases and 22 abnormal increases caused by DSS, which targeted amino acid biosynthesis; tryptophan metabolism; protein digestion and absorption; aminoacyl-tRNA biosynthesis; and glycine, serine, and threonine metabolism. In addition, SRPS reduced goblet cell loss and increased mucin secretion. The short-chain fatty acid receptor GPR41 was activated, and zonula occludens-1 and occludin expression levels were upregulated. Epithelial cell apoptosis was inhibited by increased Bcl-2 and decreased Bax expression NLRP3, ASC, and caspase-1 protein levels decreased. Intestinal barrier damage improved, and colon inflammation was reduced. Thus, our preliminary findings reveal that SRPS regulates metabolism and has the potential to protect the intestinal barrier in ulcerative colitis mice.

CHinese Acute Tissue-Based Imaging Selection for Lysis In Stroke Tenecteplase II (CHABLIS-T II): rationale and design.

BACKGROUND AND PURPOSE: Tenecteplase (TNK) has demonstrated non-inferiority to alteplase in patients who had an acute ischaemic stroke presenting within 4.5 hours from symptom onset. The trial is aimed to explore the efficacy and safety of TNK in Chinese patients who had an acute ischaemic stroke with large/medium vessel occlusion in an extended time window. METHODS AND DESIGN: Chinese Acute Tissue-Based Imaging Selection for Lysis In Stroke Tenecteplase II (CHABLIS-T II) is a multicentre, prospective, block-randomised, open-label, blinded-endpoint, phase IIb study. Eligible patients are 1:1 randomised into two groups: 0.25 mg/kg TNK versus best medical management (excluding TNK). The safety and efficacy of 0.25 mg/kg TNK are assessed through reperfusion status and presence of symptomatic intracranial haemorrhage (sICH). STUDY OUTCOMES: The primary outcome is major reperfusion without sICH at 24-48 hours after randomisation. Major reperfusion is defined as restoration of blood flow to greater than 50% of the involved ischaemic territory assessed by catheter angiography or repeated perfusion imaging. Secondary outcomes include post-thrombolytic recanalisation, neurological improvements, change in the National Institutes of Health Stroke Scale score, haemorrhagic transformation at 24-48 hours, systematic bleeding at discharge, modified Rankin Scale (mRS) 0-1, mRS 0-2, mRS 5-6, mRS distribution and Barthel index at 90 days. DISCUSSION: CHABLIS-T II will provide important evidence of intravenous thrombolysis with TNK for patients who had an acute stroke in an extended time window.

[Morphological and biochemical characterization during seed development of Notopterygium incisum].

This study aimed to examine the morphological, physiological, and biochemical alterations occurring in Notopterygium incisum seeds throughout their developmental stages, with the objective of establishing a theoretical foundation for the cultivation of superior quality seeds. The experimental materials utilized in this study were the seeds of N. incisum at various stages of development following anthesis. Through the employment of morphological observation and plant physiology techniques, the external morphology, nutrients, enzyme activity, and endogenous hormones of the seeds were assessed. The results revealed a transition in seed coat color from light green to brown during the growth and development of N. incisum seeds. Additionally, as the seeds matured, a decrease in water content was observed. Conversely, starch content exhibited a progressive increase, while sucrose content displayed fluctuations. At 7 days after anthesis, the soluble sugar content attained its highest level of 4.52 mg·g~(-1), whereas the soluble protein content reached its maximum of 6.00 mg·g~(-1) at 14 days after anthesis and its minimum of 4.94 mg·g~(-1) at 42 days after anthesis. The activity of superoxide dismutase(SOD) exhibited an initial increase, followed by a decrease, and eventually reached a stable state. Conversely, the activities of catalase(CAT) and peroxidase(POD) demonstrated a decrease initially, followed by an increase, and then another decrease. The levels of the four endogenous hormones, namely gibberellin(GA_3), zeatin riboside(ZR), auxin(IAA), and abscisic acid(ABA), in the seeds displayed significant variations, with IAA and ABA exhibiting considerably higher levels compared to the other hormones. The levels of plant growth-promoting hormones, represented by IAA, generally displayed a pattern of initial increase followed by a subsequent decrease during seed development, while the plant growth-inhibiting hormone ABA showed the opposite trend. The findings indicate that the alterations in nutrient composition, antioxidant enzyme activity, and endogenous hormone levels vary throughout the maturation process of N. incisum seeds. These observations hold relevance for the cultivation of N. incisum seeds.

Prediagnostic plasma metabolite concentrations and liver cancer risk: a population-based study of Chinese men.

BACKGROUND: Previous metabolic profiling of liver cancer has mostly used untargeted metabolomic approaches and was unable to quantitate the absolute concentrations of metabolites. In this study, we examined the association between the concentrations of 186 targeted metabolites and liver cancer risk using prediagnostic plasma samples collected up to 14 years prior to the clinical diagnosis of liver cancer. METHODS: We conducted a nested case-control study (n = 322 liver cancer cases, n = 322 matched controls) within the Shanghai Men's Health Study. Conditional logistic regression models adjusted for demographics, lifestyle factors, dietary habits, and related medical histories were used to estimate the odds ratios. Restricted cubic spline functions were used to characterise the dose-response relationships between metabolite concentrations and liver cancer risk. FINDINGS: After adjusting for potential confounders and correcting for multiple testing, 28 metabolites were associated with liver cancer risk. Significant non-linear relationships were observed for 22 metabolites. The primary bile acid biosynthesis and phenylalanine, tyrosine and tryptophan biosynthesis were found to be important pathways involved in the aetiology of liver cancer. A metabolic score consisting of 10 metabolites significantly improved the predictive ability of traditional epidemiological risk factors for liver cancer, with an optimism-corrected AUC increased from 0.84 (95% CI: 0.81-0.87) to 0.89 (95% CI: 0.86-0.91). INTERPRETATION: This study characterised the dose-response relationships between metabolites and liver cancer risk, providing insights into the complex metabolic perturbations prior to the clinical diagnosis of liver cancer. The metabolic score may serve as a candidate risk predictor for liver cancer. FUNDING: National Key Project of Research and Development Program of China [2021YFC2500404, 2021YFC2500405]; US National Institutes of Health [subcontract of UM1 CA173640].

Sex-specific impact of dietary patterns on liver cancer incidence: updated results from two population-based cohort studies in China.

PURPOSE: The associations between dietary patterns and liver cancer risk have received much attention, but evidence among the Chinese population is scarce. This study aims to update the results of two cohort studies and provide the sex-specific associations in the Chinese population. METHODS: This study was based on two cohorts from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). Diet information was collected by validated food frequency questionnaires. Dietary patterns were derived by factor analysis. Cox regression model was utilized to estimate the hazard ratio (HR) and 95% confidence interval (CI) for associations between dietary patterns and liver cancer risk. RESULTS: During median follow-up years of 11.2 (male) and 17.1 (female) years, 427 males and 252 females were identified as incident primary liver cancer cases. In males, vegetable-based dietary pattern was inversely associated with liver cancer (HRQ4-Q1: 0.67, 95%CI 0.51-0.88, Ptrend < 0.001). Interaction analysis indicated that in males lower vegetable-based dietary pattern score and older age/medical history of chronic hepatitis combined increase the hazard of liver cancer more than the sum of them, with a 114% and 1061% higher risk, respectively. In females, the fruit-based dietary pattern was associated with a reduced risk of liver cancer (HRQ4-Q1: 0.63, 95%CI 0.42-0.95, Ptrend = 0.03). In both males and females, null associations were observed between the meat-based dietary pattern and the risk of liver cancer. CONCLUSION: A vegetable-based dietary pattern in males and a fruit-based dietary pattern in females tended to have a protective role on liver cancer risk. This study provided updated information that might be applied to guide public health action for the primary prevention of liver cancer.

Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection: the umbrella phase IIa CHABLIS-T randomised clinical trial.

BACKGROUND: The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/medium vessel occlusion beyond 4.5-hour time window. METHODS: The CHinese Acute tissue-Based imaging selection for Lysis In Stroke-Tenecteplase was an investigator-initiated, umbrella phase IIa, open-label, blinded-endpoint, Simon's two-stage randomised clinical trial in 13 centres across mainland China. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis. RESULTS: A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon's two-stage design. DISCUSSION: Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04086147, https://clinicaltrials.gov/ct2/show/NCT04086147).

A diet-wide association study for liver cancer risk: findings from a prospective cohort study in Chinese men.

Dietary factors have been extensively investigated as possible risk factors for liver cancer, but the evidence is inconclusive. Our study systematically assessed the association between 142 foods and nutrients and liver cancer risk in a Chinese population using a diet-wide association study. Based on data from 59,844 men in the Shanghai Men's Health Study (SMHS), we assessed the diet intake by dietary questionnaires. Cox regression was used to quantify the association between each food and nutrient and liver cancer risk. A false discovery rate (FDR) of 0.05 was used to select the foods and nutrients for validation. In the cohort, 431 liver cancer cases were identified during 712,373 person-years of follow-up. Retinol (HR per 1 SD increment = 1.09, 95% CI: 1.03-1.14) was associated with a higher risk of liver cancer, whereas onions (HR per 1 SD increment = 0.67, 95% CI: 0.54-0.84) and manganese (HR per 1 SD increment = 0.85, 95% CI: 0.78-0.94) were inversely associated with liver cancer risk. In the replication analysis, estimates for these foods and nutrients were similar in magnitude and direction. Our findings confirm that retinol, onions and manganese were associated with liver cancer risk, which provides reliable evidence between diet and liver cancer development.

The benefit of favorable venous outflow profile is mediated through reduced microvascular dysfunction in acute ischemic stroke.

INTRODUCTIONS: Venous outflow (VO) is emerging as a marker of microvascular integrity in acute ischemic stroke. Using hemorrhagic transformation (HT) and infarct growth as mediators, we tested whether a favorable VO profile benefited functional outcome by reducing consequences of microvascular dysfunction. PATIENTS AND METHODS: Patients receiving thrombectomy in three comprehensive stroke centers due to acute anterior circulation occlusion were included. VO was assessed semi-quantitatively by the opacification of ipsilateral vein of Labbé, Trolard and superficial middle cerebral vein. HT was graded on follow-up CT. Infarct growth volume (IGV) was the difference of final infarct volume and baseline core volume. The association of VO and functional independence (90-day modified Rankin Scale ⩽ 2) was examined by logistic regression. Mediation analysis was performed among VO, HT or IGV, and functional outcome in patients with or without recanalization, respectively. RESULTS: In 242 patients analyzed, VO was strongly correlated with functional independence and VO ⩾ 4 was defined favorable. In 175 patients recanalized, favorable VO was associated with a reduced risk of HT (OR = 0.82, 95% CI 0.71-0.95, p = 0.008), which accounted for 13.1% of the association between VO and favorable outcome. In 67 patients without recanalization, favorable VO was associated with decreased IGV (ß = -0.07, 95% CI -0.11 to -0.02, p = 0.007). The association of favorable VO and functional independence was no longer significant (aOR = 4.84, 95% CI 0.87-38.87, p = 0.089) after including IGV in the model, suggesting a complete mediation. DISCUSSION AND CONCLUSION: In patients with acute anterior large vessel occlusion, the clinical benefit of VO may be mediated through reduced microvascular dysfunction.

METTL3-mediated lncRNA HOXD-AS1 stability regulates inflammation, and the migration and invasion of trophoblast cells via the miR-135a/ ß-TRCP axis.

Background: Preeclampsia (PE) is a serious pregnancy-specific syndrome associated with the inadequate invasion of trophoblast cells and inflammation of the uterus. A previous study found that lncRNA HOXD-AS1 promotes PE. However, its regulatory network requires additional exploration. Methods: HOXD-AS1-targeted miRNAs and genes were predicted by different databases in a bioinformatics analysis. The expression HOXD-AS1 and its potential m6A methylase (METTL3) were detected in placentas from healthy female patients with PE. The targeting relationship and role of the HOXD-AS1/miR-135a/ß-TRCP axis in trophoblast cells were demonstrated by overexpression/knockdown assays. The levels of ß-TRCP downstream pathway proteins IκBα, NF-κB, and p65 were measured. The levels of inflammatory factors in cell supernatants were detected by ELISA. To verify the molecular mechanism of ß-TRCP in PE, IκBα was co-overexpressed in ß-TRCP in trophoblast cells. Results: The levels of METTL3, HOXD-AS1, and ß-TRCP were elevated in PE placental tissues, while miR-135a levels were reduced. MiR-135a was found to be targeted by HOXD-AS1, and HOXD-AS1 expression was maintained at a high level by METTL3-mediated m6A methylation. Overexpression of METTL3, HOXD-AS1, and ß-TRCP, and knockdown of miR-135a in HTR-8/SVneo cells all inhibited cell invasion and migration, and promoted apoptosis and the secretion of inflammatory factors. Knockdown of METTL3, HOXD-AS1, and ß-TRCP, and overexpression of miR-135a had the opposite effects. Furthermore, IκBα expression was negatively associated with ß-TRCP expression, and the levels of NF-κB, p65, and NLRP3 were positively regulated by ß-TRCP. A high level of ß-TRCP expression attenuated the effect of HOXD-AS1 knockdown in trophoblast cells. Conclusion: METTL3 functioned to maintain a high level of HOXD-AS1 expression in PE, which influenced inflammation and the migration and invasion of trophoblast cells via the miR-135a/ß-TRCP axis and NF-κB pathway.

Leptin secreted by adipocytes promotes EMT transition and endometrial cancer progression via the JAK2/STAT3 signalling pathway.

BACKGROUND: Endometrial cancer is a malignant tumour with a high incidence and mortality rate, and obesity is one of the most significant risk factors for the disease. However, it remains unclear whether leptin affects cell activity, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). MATERIALS AND METHODS: Samples of endometrial cancer tissue were obtained from clinical patients and nude mice Enzyme-linked immunosorbent assays (ELISAs) were performed to assess leptin levels. Western blotting, immunohistochemical (IHC) and immunofluorescence (IF) analyses were conducted to detect EMT, JAK2/STAT3 signalling pathway proteins, and cell proliferation biomarkers. Cell Counting Kit-8 (CCK-8) assays, 5-ethynyl-2'-deoxyuridine (EdU) staining, and Transwell assays were used to evaluate cell activity, proliferation, migration, and invasion, respectively. RESULTS: ELISA, western blot and immunohistochemistry (IHC) analyses showed that leptin was highly expressed, and the JAK2/STAT3 signalling pathway was activated in endometrial cancer patients. Cell-based experiments showed that adipocytes secreted leptin, which increased the levels of leptin, and also promoted cell migration and invasion, EMT transition, and cell activity and proliferation. Leptin accelerated cell progression and promoted EMT via the JAK2/STAT3 signalling pathway in a dose-dependent manner. The tumour-promoting effect of leptin on endometrial cancer cells was further verified by in vivo experiments, in which leptin promoted tumour growth and activated the JAK2/STAT3 signalling pathway. CONCLUSION: Leptin secreted by adipocytes promotes EMT transition and endometrial cancer progression via the JAK2/STAT3 signalling pathway in a dose-dependent manner.Highlights Endometrial cancer patients have high levels of leptinLeptin promotes EMT transition via the JAK2/STAT3 signalling pathwayLeptin promotes endometrial cancer progression via the JAK2/STAT3 signalling pathwayLeptin promotes endometrial cancer in a dose-dependent manner.