Large Fermi surface in pristine kagome metal CsV3Sb5 and enhanced quasiparticle effective masses.

The kagome metal CsV[Formula: see text]Sb[Formula: see text] is an ideal platform to study the interplay between topology and electron correlation. To understand the fermiology of CsV[Formula: see text]Sb[Formula: see text], intensive quantum oscillation (QO) studies at ambient pressure have been conducted. However, due to the Fermi surface reconstruction by the complicated charge density wave (CDW) order, the QO spectrum is exceedingly complex, hindering a complete understanding of the fermiology. Here, we directly map the Fermi surface of the pristine CsV[Formula: see text]Sb[Formula: see text] by measuring Shubnikov-de Haas QOs up to 29 T under pressure, where the CDW order is completely suppressed. The QO spectrum of the pristine CsV[Formula: see text]Sb[Formula: see text] is significantly simpler than the one in the CDW phase, and the detected oscillation frequencies agree well with our density functional theory calculations. In particular, a frequency as large as 8,200 T is detected. Pressure-dependent QO studies further reveal a weak but noticeable enhancement of the quasiparticle effective masses on approaching the critical pressure where the CDW order disappears, hinting at the presence of quantum fluctuations. Our high-pressure QO results reveal the large, unreconstructed Fermi surface of CsV[Formula: see text]Sb[Formula: see text], paving the way to understanding the parent state of this intriguing metal in which the electrons can be organized into different ordered states.

Nomogram based on MRI and clinical features to predict progression-free survival in patients with stage IIIC1r cervical squamous cell carcinoma: A two-center study.

PURPOSE: To develop a nomogram based on MRI and clinical features to predict progression-free survival (PFS) of 2018 FIGO stage ⅢC1r cervical squamous cell carcinoma (CSCC). METHODS: 144 consecutive patients with stage ⅢC1r CSCC from two independent institutions were stratified into training cohort (from Institution 1, n=100) and independent validation cohort (from Institution 2, n=44). Univariate and multivariate Cox regression analyses of MRI and clinical features before treatment were performed to determine independent risk factors for PFS in training cohort. Nomogram was developed based on them. Concordance index (C-index), calibration curves, and receiver operating characteristic (ROC) analyses were performed to assess and validate the nomogram. RESULTS: In training cohort, 2009 FIGO stage, maximum length of the primary tumor, short diameter and roundness index of the maximum metastatic lymph node were independent risk factors of PFS in patients with stage IIIC1r CSCC (all P-values < 0.05). Nomogram based on them to predict 1- and 3-year PFS achieved C-indexes of 0.835 (95% confidence interval (CI): 0.809-0.862) and 0.789 (95%CI: 0.683-0.895) in the training and validation cohorts, respectively. Areas under ROC curves for the nomogram to predict 1- and 3-year PFS were 0.891 (95%CI: 0.829-0.954), 0.921 (95%CI: 0.861-0.981) in training cohort, and 0.902 (95%CI: 0.803-0.999), 0.885 (95%CI: 0.778-0.992) in validation cohort, respectively. Calibration curves indicated the nomogram predictions were in good agreement with actual observations. CONCLUSIONS: The nomogram based on MRI and clinical features has high accuracy and stability in predicting PFS of patients with stage IIIC1r CSCC.

HYPOXIA induces lncRNA HOTAIR for recruiting RELA in papillary thyroid cancer cells to upregulate miR-181a and promote angiogenesis.

BACKGROUND: Papillary thyroid carcinoma (PTC) is one of the most common subtypes of thyroid carcinoma. Exosomal miR-181a plays an important role in the development of PTC. This study examined the regulatory mechanism of miR-181a under conditions of hypoxia and its impact on angiogenesis. METHODS: A ribonucleoprotein immunoprecipitation (RIP) experiment was conducted to verify the interaction between HOTAIR and RELA. The relationship between RELA and the miR-181a promoter was detected by ChIP-qPCR. Short hairpin (sh) RNA was designed to knock down HOTAIR in TPC cells. The underlying mechanism of miR-181a was verified by use of dual-luciferase assays and rescue experiments. The regulatory effect of GATA6 on angiogenesis was studied using CCK8, EdU, Transwell, and western blot assays. RESULTS: A RIP assay showed that HOTAIR could bind to RELA under hypoxic conditions. ChIP-qPCR and dual luciferase assays showed RELA could interact with the miR181a promoter and upregulate miR-181a. Knockdown of HOTAIR downregulated miR-181a in TPC-1 cells, and the downregulation could be rescued by RELA overexpression. MiR-181a downregulated GATA6 in HUVEC cells. Overexpression of GATA6 inhibited HUVEC proliferation, migration, tube formation, and EGFR expression. Exosomal miR-181a promoted angiogenesis by downregulating GATA6 expression. CONCLUSION: HOTAIR activated RELA to upregulate miR-181a during hypoxia. Exosomal miR-181a promotes tumor angiogenesis by downregulating GATA6.

[Effects of Rhodiola rosea injection on intrapulmonary shunt and blood IL-6 and TNF-α levels during single lung ventilation in patients undergoing radical resection of esophageal cancer].

OBJECTIVE: To explore the effects of Rhodiola rosea injection on pulmonary shunt and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels during single lung ventilation in patients undergoing radical resection of esophageal cancer. METHODS: Forty-six patients undergoing radical operation for esophageal cancer were randomized equally into control group and Rhodiola rosea injection group. In the Rhodiola group, 10 mL of Rhodiola rosea injection was added into 250 mL of normal saline or 5% glucose solution for slow intravenous infusion, and normal saline of the same volume was used in the control group after the patients entered the operation room. At T0, T1 and T3, PaO2 of the patient was recorded and 2 mL of deep venous blood was collected for determination of serum TNF-α and IL-6 levels. The incidence of postoperative atelectasis of the patients was recorded. RESULTS: Compared with those in the control group, the patients receiving Rhodiola rosea injection had significantly higher PaO2 and Qs/Qt at T1 and T2 (P<0.05) and lower serum IL-6 and TNF-α levels at T3 (P<0.05). No significant difference in the incidence of postoperative atelectasis was observed between the two groups (P>0.05). CONCLUSION: Rhodiola rosea injection before anesthesia induction can reduce intrapulmonary shunt during single lung ventilation, improve oxygenation, reduce serum IL-6 and TNF-α levels, and alleviate intraoperative lung injury in patients undergoing radical resection of esophageal cancer.

[Experimental study on the inhibition of the NLRP3 signaling pathway with Shengsan Jiedu Huayu decoction to alleviate inflammatory injury in rats with acute-on-chronic liver failure].

Objective: To observe the therapeutic effect of Shengsan Jiedu Huayu decoction in alleviating inflammatory liver injury in rats with acute-on-chronic liver failure (ACLF) and its effect on the activation intensity for the NLRP3 signaling pathway. Methods: 63 SD rats were randomly divided into a blank group, a model group, and low-, medium-, and high-dose groups of Shengsan Jiedu Huayu decoction (7.29 g/kg/d, 14.58 g/kg/d, and 29.16 g/kg/d). The ACLF rat model was replicated using carbon tetrachloride combined with d-galactosamine and lipopolysaccharide. Different dose gradients of the Shengsan Jiedu Huayu decoction were used for a five-day intervention treatment, and then rat serum and tissue samples were collected. A biochemical analyzer was used to detect the serum levels of ALT, AST, and TBIL in rats. ELISA was used to detect serum IL-18 and IL-1ß content. HE staining was used to observe histomorphological changes in liver tissue. Immunohistochemistry was used to detect GSDMD expression in liver tissue. Western blot and PCR were used to detect NLRP3, Caspase1, ASC, TLR4, IL-1ß, IL-18 protein, and mRNA expression levels.The groups were compared using analysis of variance and the rank-sum test. Results: Compared with the blank group, the model group's rat liver tissue was severely injured. Serum levels of ALT, AST, and TBIL, inflammatory factors IL-1ß and IL-18, and the GSDMD protein expression level, NLRP3 expression level, TLR4, caspase 1, ASC, IL-1ß, IL-18 protein, and mRNA (P<0.01) were all significantly increased in the model than the blank group (P<0.01). Additionally, compared with the model group, the low-, medium-, and high-dose groups of Shengsan Jiedu Huayu decoction had improved liver tissue injury in ACLF rats, while the serum levels of ALT, AST, TBIL, IL-1ß, IL-18, liver tissue GSDMD protein, NLRP3, TLR4, caspase 1, and ASC expressions were all lower in the different dose gradients of the Shengsan Jiedu Huayu decoction than the model group, with the most evident reduction in the high-dose group (P<0.01). Conclusion: Shengsan Jiedu Huayu decoction can weaken the activation intensity of the NLRP3 signaling pathway, alleviate liver tissue pathological injury, reduce inflammatory factor release, and alleviate inflammatory liver injury in ACLF rats.

Follow-up of women with cervical adenocarcinoma in situ treated by conization: A single centre clinical experience.

OBJECTIVE: Hysterectomy has been the historical gold standard final step in the treatment algorithm of adenocarcinoma in situ (AIS) recommended by most North American colposcopy guidelines. AIS disproportionately affects young childbearing age women, therefore a fertility sparing treatment option is desirable. Our study examines the impact of conservative treatment of AIS with conization followed by serial surveillance. METHODS: A retrospective chart review was completed of patients treated for AIS from 2006 to 2020. Charts were identified by pathologic diagnosis of AIS on cervical and uterine specimens. Charts were excluded if AIS was not treated with conization, if AIS was not confirmed on initial conization specimen, or if invasive disease was found at initial conization. RESULTS: 121 patient charts were analyzed. Median age of patients at first conization and hysterectomy was 34.8 and 40.9, respectively. First conization was by Cold Knife Cone in 58% of patients, and by Loop Electrosurgical Excisional Procedure in 42% of patients. Median follow-up period in our study was 609 days. 5% of patients had recurrence, with only one patient who recurred as cancer. One case of recurrence had a positive initial conization margin. Median time to recurrence was 700 days. 47% of patients underwent eventual hysterectomy. Residual AIS was found in 23% of hysterectomy specimens. Adenocarcinoma was diagnosed on hysterectomy specimen in four patients. CONCLUSION: Our study demonstrates the oncologic safety of treating AIS with conization and serial surveillance. Routine hysterectomy completed as a part of the AIS treatment algorithm, as in current clinical guidelines, is unnecessary.

Exploring Putative Causal Associations between Diet and Periodontal Disease Susceptibility.

INTRODUCTION: Dietary factors may play an important role in periodontal health. However, current evidence from observational studies remains inconclusive. OBJECTIVE: This study aimed to investigate the causal relationships between dietary exposures and periodontal disease risks using Mendelian randomization analysis. METHODS: Large-scale genome-wide association study summary statistics for 20 dietary factors were obtained from the MRC-IEU consortium. Multivariable and univariable 2-sample Mendelian randomization analyses were performed to assess the causal effects of each dietary exposure on 6 periodontal outcomes, including gingivitis and periodontitis. RESULTS: Genetically predicted higher dried fruit intake was significantly associated with reduced risks of acute gingivitis (odds ratio [OR]: 0.02; 95% confidence interval [CI]: 0.00-0.42; P = 0.01) and bleeding gums (OR: 0.96; 95% CI: 0.93-0.99; P = 0.01). Higher fresh fruit and water intake showed protective effects against chronic gingivitis (OR: 0.18; 95% CI: 0.04-0.91; P = 0.04 and OR: 0.15; 95% CI: 0.04-0.53; P = 0.00) and bleeding gums (OR: 0.95; 95% CI: 0.92-0.981; P = 0.00 and OR: 0.98; 95% CI: 0.96-0.99; P = 0.02). Alcohol intake frequency and processed meat intake were risk factors for bleeding gums (OR: 1.01; 95% CI: 1.00-1.02; P = 0.01 and OR: 1.05; 95% CI: 1.01-1.08; P = 0.00) and painful gums (OR: 1.01; 95% CI: 1.00-1.01; P = 0.00 and OR: 1.02; 95% CI: 1.01-1.03; P = 0.00). Most of the causal relationships between genetic predisposition to the specified dietary factors and periodontal diseases remained statistically significant (P < 0.05) after adjusting for genetic risks associated with dentures, smoking, and type 2 diabetes in multivariable Mendelian randomization models. CONCLUSIONS: The findings suggest potential protective effects of higher fruit and water intake against gingivitis and other periodontal problems, while alcohol and processed meat intake may increase the risks of periodontal disease. Our study provides preliminary causal evidence on the effects of diet on periodontal health and could inform prevention strategies targeting dietary habits to improve oral health. KNOWLEDGE TRANSFER STATEMENT: This study suggests that fruit and water intake may protect against periodontal disease, while alcohol and processed meats increase risk, informing dietary guidelines to improve oral health.

Beneficial Effects of High-Intensity Interval Training and Dietary Changes Intervention on Hepatic Fat Accumulation in HFD-Induced Obese Rats.

Lifestyle intervention encompassing nutrition and physical activity are effective strategies to prevent progressive lipid deposition in the liver. This study aimed to explore the effect of dietary change, and/or high-intensity interval training (HIIT) on hepatic lipid accumulation in high fat diet (HFD)-induced obese rats. We divided lean rats into lean control (LC) or HIIT groups (LH), and obese rats into obese normal chow diet (ND) control (ONC) or HIIT groups (ONH) and obese HFD control (OHC) or HIIT groups (OHH). We found that dietary or HIIT intervention significantly decreased body weight and the risk of dyslipidemia, prevented hepatic lipid accumulation. HIIT significantly improved mitochondrial fatty acid oxidation through upregulating mitochondrial enzyme activities, mitochondrial function and AMPK/PPARalpha/CPT1alpha pathway, as well as inhibiting hepatic de novo lipogenesis in obese HFD rats. These findings indicate that dietary alone or HIIT intervention powerfully improve intrahepatic storage of fat in diet induced obese rats. Keywords: Obesity, Exercise, Diet, Mitochondrial function, Lipid deposition.

[Feasibility analysis of the application of programmed process endoscopic lateral neck dissection via chest-breast approach in papillary thyroid carcinoma surgery].

Objective: To explore the feasibility of endoscopic lymph node dissection(LND) with programmed breast approach for the treatment of papillary thyroid cancer. Methods: A case series study. The clinical data of 39 patients with papillary thyroid cancer who underwent endoscopic LND treatment with programmed breast approach in Shenzhen People's Hospital from January to November 2022 were retrospectively analyzed. There were 10 males and 29 females, aged (35.95±10.17) years. LND time, total surgical time, intraoperative bleeding volume, postoperative drainage volume, postoperative hospital stay and postoperative complications were analyzed. Results: Among 39 patients, there were 18 cases of unilateral thyroid cancer, 21 cases of bilateral thyroid cancer, 35 cases of unilateral LND, and 4 cases of bilateral LND. The maximum diameter of thyroid cancer lesions was (1.48±0.69) cm, and the maximum diameter of lymph node metastases was (1.63±0.58)cm. The operative time of unilateral neck dissection was (124.11±19.92) min (102-170 min), and the total operative time was (226.42±55.68) min (110-390 min). The number of lymph nodes cleaned was (32.40±10.44)(12-54), the number of metastasis and detection was 207/1 393. The postoperative drainage volume was (174.64±82.33) ml(41-350 ml). There were no neck hematomas, no skin burns or no shrugging disorders in the postoperative period. There were 7 cases of numbness and discomfort in neck skin sensation, which gradually relieved after half a year. Postoperative discharge time (4.77±1.94) d(3-15 d). Conclusion: It is safe and feasible to treat papillary thyroid cancer with endoscopic LND with programmed breast approach, which can improve surgical efficiency and clinical application value.

[Preparation of a dual-specific antibody targeting human CD123 and exploration of its anti-acute myeloid leukemia effects].

Objective: To construct a novel dual-specific antibody targeting human CD123 (CD123 DuAb) and study its effects in acute myeloid leukemia (AML) . Methods: Based on the variable region of the CD123 monoclonal antibody independently developed at our institution, the CD123 DuAb expression plasmid was constructed by molecular cloning and transfected into ExpiCHO-S cells to prepare the antibody protein. Through a series of in vitro experiments, its activation and proliferation effect on T cells, as well as the effect of promoting T-cell killing of AML cells, were verified. Results: ① A novel CD123 DuAb plasmid targeting CD123 was successfully constructed and expressed in the Expi-CHO eukaryotic system. ②The CD123 DuAb could bind both CD3 on T cells and CD123 on CD123(+) tumor cells. ③When T cells were co-cultured with MV4-11 cells with addition of the CD123 DuAb at a concentration of 1 nmol/L, the positive expression rates of CD69 and CD25 on T cells were 68.0% and 44.3%, respectively, which were significantly higher than those of the control group (P<0.05). ④Co-culture with CD123 DuAb at 1 nmol/L promoted T-cell proliferation, and the absolute T-cell count increased from 5×10(5)/ml to 3.2×10(6)/ml on day 9, and CFSE fluorescence intensity decreased significantly. ⑤ With the increase in CD123 DuAb concentration in the culture system, T-cell exhaustion and apoptosis increased. When the CD123 DuAb was added at a concentration of 1 nmol/L to the culture system, the proportion of CD8(+) PD-1(+) LAG-3(+) T cells was 10.90%, and the proportion of propidium iodide (PI) (-) Annexin Ⅴ(+) T cells and PI(+) Annexin Ⅴ(+) T cells was 18.27% and 11.43%, respectively, which were significantly higher than those in the control group (P<0.05). ⑥ The CD123 DuAb significantly activated T cells, and the activation intensity was positively correlated with its concentration. The expression rate of CD107a on T cells reached 16.05% with 1 nmol/L CD123 DuAb, which was significantly higher than that of the control group (P<0.05). ⑦The CD123 DuAb promoted cytokine secretion by T cells at a concentration of 1 nmol/L, and the concentration of IFN-γ and TNF-α in the supernatant of the co-culture system reached 193.8 pg/ml and 169.8 pg/ml, respectively, which was significantly higher than that of the control group (P<0.05). ⑧When CD123 DuAb was added at a concentration of 1 nmol/L to the co-culture system of T cells and CD123(+) tumor cells, the killing intensity of T cells significantly increased, and the residual rates of CD123(+) MV4-11 cells, CD123(+) Molm13 cells, and CD123(+) THP-1 cells were 7.4%, 6.7%, and 14.6% on day 3, respectively, which were significantly lower than those in the control group (P<0.05) . Conclusion: In this study, a novel CD123 DuAb was constructed and expressed. In vitro experiments verified that the DuAb binds to CD123(+) tumor cells and T cells simultaneously, promotes T-cell activation and proliferation, and facilitates their anti-leukemia effect, which provides a basis for further clinical research.

[Value of peripheral blood rare cell EGFR gene amplification detection in the evaluation of benign and malignant pulmonary nodules].

Objective: To explore the value of detection of epidermal growth factor receptor (EGFR) gene amplification in peripheral blood rare cells in the assessment of benign and malignant pulmonary nodules. Methods: A total of 262 patients with pulmonary nodules were selected as the retrospectively study subjects from the Second Affiliated Hospital of Army Military Medical University and Peking Union Medical College Hospital from July 2022 to August 2023. There were 98 males and 164 females, with the age range from 16 to 79 (52.1±12.1) years. The EGFR gene amplification testing was performed on the rare cells enriched from patients' peripheral blood, and the clinical manifestations, CT imaging features, histopathological and/or pathological cytological confirmed results of patients were collected. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of the method of detection of EGFR gene amplification in peripheral blood rare cells, and its diagnostic efficacy was evaluated. Results: Among the 262 patients, 143 were malignant pulmonary nodules and 119 were benign pulmonary nodules. The differences between malignant pulmonary nodules and benign pulmonary nodules in nodule diameter and nodule density were statistically significant (both P<0.001), while the differences in age, gender and nodule number were not statistically significant (all P>0.05). The number [M (Q1, Q3)] of EGFR gene amplification positive rare cells in patients with malignant pulmonary nodule was 8 (6, 11), which was higher than that in patients with benign pulmonary nodule [2 (1, 4), P<0.001]. The ROC curve results showed that when the optimal cut-off value was 5 (that was, the number of EGFR gene amplification positive rare cells was>5), the area under the curve (AUC) of the detection of EGFR gene amplification in peripheral blood rare cells for discrimination of benign and malignant pulmonary lesions was 0.816 (95%CI: 0.761-0.870), with a sensitivity of 83.2%, a specificity of 80.7%, and an accuracy of 82.1%. Based on the analysis of the diameter of the nodules, the AUC for distinguishing between benign and malignant pulmonary nodules with diameter 5-9 mm and 10-30 mm was 0.797 (95%CI: 0.707-0.887) and 0.809 (95%CI: 0.669-0.949), respectively, with sensitivity, specificity and accuracy reached 75% or above. Based on the analysis of nodule density, the AUC for distinguishing between benign and malignant solid nodule and subsolid nodule was 0.845 (95%CI: 0.751-0.939) and 0.790 (95%CI: 0.701-0.880), respectively, with sensitivity, specificity and accuracy reached 75% or above. Based on the analysis of nodule number, the AUC for distinguishing between benign and malignant solitary pulmonary nodule and multiple pulmonary nodule was 0.830 (95%CI: 0.696-0.965) and 0.817 (95%CI: 0.758-0.877), respectively, with sensitivity, specificity and accuracy reached 80% or above. Conclusion: The detection of EGFR gene amplification in peripheral blood rare cells contributes to the evaluation of benign and malignant pulmonary nodules, and can be used in the auxiliary diagnosis of benign and malignant pulmonary nodules.

[The influence of knocking down the expression of low-density lipoprotein receptor associated proteins on the vascular abnormalities in hepatocellular carcinoma and its mechanisms].

Objectives: To investigate the effect of the expression of low-density lipoprotein receptor associated protein (LDLR) on the vascular abnormalities in hepatocellular carcinoma (HCC) and its mechanisms. Methods: Based on the information of Oncomine Cancer GeneChip database, we analyzed the correlation between the expression level of LDLR and the expression level of carcinoembryonic antigen (CEA) and CD31 in hepatocellular carcinoma tissues. Lentiviral transfection of short hairpin RNA target genes was used to construct LDLR-knockdown MHCC-97H and HLE hepatocellular carcinoma cells. The differential genes and their expression level changes in LDLR-knockdown hepatocellular carcinoma cells were detected by transcriptome sequencing, real-time fluorescence quantitative polymerase chain reaction, and protein immunoblotting. The gene-related signaling pathways that involve LDLR were clarified by enrichment analysis. The effect of LDLR on CEA was assessed by the detection of CEA content in conditioned medium of hepatocellular carcinoma cells. Angiogenesis assay was used to detect the effect of LDLR on the angiogenic capacity of human umbilical vein endothelial cells, as well as the role of CEA in the regulation of angiogenesis by LDLR. Immunohistochemical staining was used to detect the expression levels of LDLR in 176 hepatocellular carcinoma tissues, and CEA and CD31 in 146 hepatocellular carcinoma tissues, and analyze the correlations between the expression levels of LDLR, CEA, and CD31 in the tissues, serum CEA, and alanine transaminase (ALT). Results: Oncomine database analysis showed that the expressions of LDLR and CEA in the tissues of hepatocellular carcinoma patients with portal vein metastasis were negatively correlated (r=-0.64, P=0.001), whereas the expressions of CEA and CD31 in these tissues were positively correlated ( r=0.46, P=0.010). The transcriptome sequencing results showed that there were a total of 1 032 differentially expressed genes in the LDLR-knockdown group and the control group of MHCC-97H cells, of which 517 genes were up-regulated and 515 genes were down-regulated. The transcript expression level of CEACAM5 was significantly up-regulated in the cells of the LDLR-knockdown group. The Gene Ontology (GO) function enrichment analysis showed that the differential genes were most obviously enriched in the angiogenesis function. The Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis showed that the relevant pathways involved mainly included the cellular adhesion patch, the extracellular matrix receptor interactions, and the interactions with the extracellular matrix receptors. The CEA content in the conditioned medium of the LDLR-knockdown group was 43.75±8.43, which was higher than that of the control group (1.15±0.14, P＜0.001). The results of angiogenesis experiments showed that at 5 h, the number of main junctions, the number of main segments, and the total area of the lattice formed by HUVEC cells cultured with the conditioned medium of MHCC-97H cells in the LDLR-knockdown group were 295.3±26.4, 552.5±63.8, and 2 239 781.0±13 8211.9 square pixels, which were higher than those of the control group (113.3±23.5, 194.8±36.5, and 660 621.0±280 328.3 square pixels, respectively, all P＜0.01).The number of vascular major junctions, the number of major segments, and the total area of the lattice formed by HUVEC cells cultured in conditioned medium with HLE cells in the LDLR-knockdown group were 245.3±42.4, 257.5±20.4, and 2 535 754.5±249 094.2 square pixels, respectively, which were all higher than those of the control group (113.3±23.5, 114.3±12.2, and 1 565 456.5±219 259.7 square pixels, respectively, all P＜0.01). In the conditioned medium for the control group of MHCC-97H cells,the number of main junctions, the number of main segments, and the total area of the lattice formed by the addition of CEA to cultured HUVEC cells were 178.9±12.0, 286.9±12.3, and 1 966 990.0±126 249.5 spixels, which were higher than those in the control group (119.7±22.1, 202.7±33.7, and 1 421 191.0±189 837.8 square pixels, respectively). The expression of LDLR in hepatocellular carcinoma tissues was not correlated with the expression of CEA, but was negatively correlated with the expression of CD31 (r=-0.167, P=0.044), the level of serum CEA (r=-0.061, P=0.032), and the level of serum ALT(r=-0.147,P=0.05). The expression of CEA in hepatocellular carcinoma tissues was positively correlated with the expression of CD31 (r=0.192, P=0.020). The level of serum CEA was positively correlated with the level of serum ALT (r=0.164, P=0.029). Conclusion: Knocking down LDLR can promote vascular abnormalities in HCC by releasing CEA.

ELABELA-APJ Axis Enhances Mesenchymal Stem Cell Proliferation and Migration via the METTL3/PI3K/AKT Pathway.

Mesenchymal stem cells (MSCs) possess a strong therapeutic potential in regenerative medicine. ELABELA (ELA) is a 32 amino acid peptide that binds to the apelin peptide jejunum receptor (APJ) to regulate cell proliferation and migration. The aim of this study was to investigate the function of ELA vis-a-vis the MSC proliferation and migration, and further explore the underlying mechanism. We demonstrated that the exogenous supplement of ELA boosts the proliferation and migration ability of MSCs, alongside improved in vitro cell viability. These capabilities were rendered moot upon APJ knockdown. In addition, ELA (5-20 µM) was shown to upregulate the expression of METTL3 in a concentrationdependent pattern, a capacity which was suppressed by APJ reduction, whereas the downregulation of METTL3 expression blocked the beneficial effects induced by ELA. ELA was also observed to upregulate the phosphorylation level of AKT. This ELA-induced activation of the PI3K/AKT pathway, however, is inhibited with knockdown of METTL3. Our data indicate that ELA could act as a promoter of MSC proliferation and migration in vitro through the APJ receptor, something which might be attributed to the activation of the METTL3/PI3K/AKT signaling pathway. Therefore, ELA is a candidate for optimizing MSC-based cell therapy, while METTL3 is a potential target for its promoting action on MSCs.

China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI) to Prevent Cognitive Decline: Study Design and Progress.

BACKGROUND: Alzheimer's disease (AD), the most common type of irreversible dementia, is predicted to affect 152 million people by 2050. Evidence from large-scale preventive randomized controlled trials (RCTs) on modifiable risk variables in Europe has shown that multi-domain lifestyle treatments for older persons at high risk of dementia may be practical and effective. Given the substantial differences between the Chinese and European populations in terms of demographics and living conditions, direct adoption of the European program in China remains unfeasible. Although a RCT has been conducted in China previously, its participants were mainly from rural areas in northern China and, thus, are not representative of the entire nation.There is an urgent need to establish cohorts that represent different economic, cultural, and geographical situations in order to explore implementation strategies and evaluate the effects of early multi-domain interventions more comprehensively and accurately. MEDTODS: We developed an integrated intervention procedure implemented in urban neighborhood settings, namely China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI). CHINA-IN-MUDI is a 2-year multicenter open-label cluster-randomised controlled trial centered around a Chinese-style multi-domain intervention to prevent cognitive decline. Participants aged 60-80 years were recruited from a nationally representative study, i.e. China Healthy Aging and Dementia Study cohort. An external harmonization process was carried out to preserve the original FINGER design. Subsequently, we standardized a series of Chinese-style intervention programs to align with cultural and socioeconomic status. Additionally, we expanded the secondary outcome list to include genomic and proteomic analyses. To enhance adherence and facilitate implementation, we leveraged an e-health application. RESULTS: Screening commenced in July 2022. Currently, 1,965 participants have been randomized into lifestyle intervention (n = 772) and control groups (n = 1,193). Both the intervention and control groups exhibited similar baseline characteristics. Several lifestyle and vascular risk factors were present, indicating a potential window of opportunity for intervention. The intervention will be completed by 2025. CONCLUSIONS: This project will contribute to the evaluation of the effectiveness and safety of intervention strategies in controlling AD risk and reducing clinical events, providing a basis for public health decision-making in China.

[Treatment status of tyrosine kinase inhibitor for newly-diagnosed chronic myeloid leukemia: a domestic multi-centre retrospective real-world study].

Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

MECP2 directly interacts with RNA polymerase II to modulate transcription in human neurons.

Mutations in the methyl-DNA-binding protein MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). How MECP2 contributes to transcriptional regulation in normal and disease states is unresolved; it has been reported to be an activator and a repressor. We describe here the first integrated CUT&Tag, transcriptome, and proteome analyses using human neurons with wild-type (WT) and mutant MECP2 molecules. MECP2 occupies CpG-rich promoter-proximal regions in over four thousand genes in human neurons, including a plethora of autism risk genes, together with RNA polymerase II (RNA Pol II). MECP2 directly interacts with RNA Pol II, and genes occupied by both proteins showed reduced expression in neurons with MECP2 patient mutations. We conclude that MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due, in part, to the loss of gene activity of these genes in neurons.

[A case of Takayasu arteritis complicated with cavernous sinus syndrome presenting as unilateral optic nerve DWI hyperintensity].

A 47-year-old male patient with a history of Takayasu arteritis presented with prominent symptoms of left eyeball fixation, protrusion, and visual loss. Orbital magnetic resonance imaging revealed hyperintensity on diffusion-weighted imaging of the left optic nerve, with corresponding low signal on apparent diffusion coefficient maps, suggestive of acute infarction of the left optic nerve. Combined with the patient's cranial magnetic resonance imaging findings, the diagnosis of cavernous sinus syndrome was established.

[Comparison of the latest cancer statistics, cancer epidemic trends and determinants between China and the United States].

Objective: To provide supports for the cancer prevention and control strategies in China by comparing the disease burden, epidemic trends, 5-year relative survival rate and major determinants of common cancers between China and the United States. Methods: A descriptive secondary analysis was conducted using data extracted from the GLOBOCAN database, the Surveillance, Epidemiology, and End Results database, Global Burden of disease 2019 database, and previous studies. The main indicators included the cases of malignant tumors in different sites, the cases of deaths, the age-standardized incidence (world standard incidence) and mortality (world standard mortality), the 5-year relative survival rate, and population attributable fraction (PAF). Results: In 2022, an estimated 4.825 million new cases and 2.574 million deaths of malignant neoplasms in China. The world standard incidence rate (201.6/100 000) in China was lower than that in the United States (367.0/100 000), and the world standard mortality rate (96.5/100 000) was higher than that in the United States (82.3/100 000). Lung cancer ranked first in the disease burden of malignant tumors in China, the new cases and deaths accounted for 22.0% and 28.5% of all malignant tumors, respectively. The top three malignant tumors in China were breast cancer (11.5%), prostate cancer (9.7%) and lung cancer (9.5%), which were also among the top five causes of death. However, the second to fifth leading causes of death from malignant tumors in China were digestive system tumors (liver cancer 12.3%, stomach cancer 10.1%, colorectal cancer 9.3%, and esophageal cancer 7.3%). From 2000 to 2018, the world standard incidence of malignant tumors showed an increasing trend and the world standard mortality of malignant tumors showed a decreasing trend in China, while the world standard incidence and mortality of malignant tumors in the United States showed a significant decreasing trend after 2000. The incidence of breast cancer, colorectal cancer and thyroid cancer increased rapidly in China, while the incidence and mortality of stomach cancer, liver cancer and esophageal cancer decreased, but they still had a heavy disease burden. From 2003 to 2015, the overall 5-year relative survival rate of malignant tumors increased from 30.9% to 40.5% in China. However, with the exception of esophageal cancer, the 5-year relative survival rates of other major malignant tumors were lower than those in the United States. In 2019, the PAF of malignant tumors death attributable to potential modifiable risk factors was 48.3% in China, which was similar to the United States (49.8%). Of these, smoking was the most important attributable risk factor, and the PAF was more than 30% both in China and the United States. In addition, about 18.8% of malignant tumors were caused by preventable chronic infections, such as hepatitis B virus and Helicobacter pylori, while less than 4% of malignant tumors in the United States were caused by infection. Conclusions: China has made great progress in the prevention and treatment of malignant tumors, but it still faces a serious disease burden. The cancer spectrum is changing from developing countries to developed countries. We should pay attention to modifiable factors, take comprehensive measures, and prevent cancer scientifically.

[Clinical characteristics and prognosis analysis of pulmonary sarcomatoid carcinoma].

Objective: To summarize the clinical characteristics, treatment, and outcomes of patients with pulmonary sarcomatoid carcinoma (PSC) in order to improve clinicians' understanding of this disease. Methods: The clinical data of patients diagnosed with PSC in our hospital from January 1, 2015 to November 30, 2023 were retrospectively analyzed. According to whether radical resection was performed, the patients were divided into resectable group and unresectable group. The characteristics and treatments of PSC in different groups were compared. The survival curves were drawn by Kaplan-Meier method to compare the prognosis of different groups of patients. Results: A total of 43 PSC patients were included, including 32 males, with an average age of (62.79±9.59) years, and 31 smokers. Peripheral-type tumors were more common, with imaging showing predominantly solid soft tissue masses, and the maximum diameter of the tumor was more than 5 cm in 14 patients. Among the 23 patients who underwent NGS gene testing, the KRAS mutation rate was 43.5%, the TP53 mutation rate was 30.4%, and the MET mutation rate was 8.7%, all of which were MET-14 exon skipping mutations. PD-L1 expression was detected in 13 patients, 10 of whom showed high expression. The median overall survival (mOS) of the 43 patients with PSC was 24.6 months (13.0-52.7 months). Among them, 22 patients underwent radical lobectomy plus mediastinal lymph node dissection, 13 patients had postoperative recurrence, and 7 patients died during follow-up. The median disease-free survival (mDFS) was 12.3 months, the mOS was not achieved and the 1-year OS rate was 77.3 %. Twenty-one patients had unresectable locally advanced or advanced stage, and 15 patients died. The mDFS was 2.5 months, the mOS was 6.2 months, and the 1-year OS rate was 42.9 %. Seventeen patients received immunotherapy, and 1 patient received targeted therapy with the MET inhibitor glumetinib. Conclusions: PSC has a higher incidence in the elderly, smokers, and males, is highly malignant and has a poor prognosis. Based on its molecular biological characteristics, PD-L1 expression and tumor molecular detection can be performed to guide treatment options.

IGSF8 is an innate immune checkpoint and cancer immunotherapy target.

Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.