Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells.

Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.

Wound infection and healing in minimally invasive plate osteosynthesis compared with intramedullary nail for distal tibial fractures: A meta-analysis.

To systematically explore the effects of minimally invasive plate osteosynthesis (MIPO) versus intramedullary nail (IMN) on wound infection and wound healing in patients with distal tibia fractures. A computerised search of PubMed, Web of Science, Cochrane Library, Embase, Wanfang, China Biomedical Literature Database (CBM) and China National Knowledge Infrastructure databases was performed, from their inception to October 2023, to identify relevant studies on the application of MIPO and IMN in patients with distal tibial fractures. The quality of the included literature was evaluated by two researchers based on inclusion and exclusion criteria, and basic information of the literature was collected, with wound infection, postoperative complications and wound healing time as the main indicators for analysis. Stata 17.0 software was applied for analysis. Overall, 23 papers and 2099 patients were included, including 1026 patients in the MIPO group and 1073 patients in the IMN group. The results revealed, when compared with IMN treatment, patients with distal tibia fractures who underwent MIPO treatment had a lower incidence of postoperative complications (OR = 0.33, 95% CI: 0.25-0.42, p < 0.001) and a shorter wound healing time (SMD = -1.00, 95% CI: -1.51 to -0.49, p < 0.001), but the incidence of postoperative wound infection was higher (OR = 2.01, 95% CI: 1.35-3.01, p = 0.001). Both MIPO and IMN are excellent treatments for distal tibia fractures. MIPO is effective in reducing the incidence of complications as well as shortening the time of wound healing time but increases the risk of wound infection. In clinical practice, surgeons can make individual choices based on the patient's wishes and proficiency in both techniques.

Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.

Exploring the role of PMEPA1 in gastric cancer.

Although there are several treatments available for gastric cancer (GC), the prognosis of the disease is still poor due to many factors, such as late diagnosis and tumor heterogeneity. To identify potential therapeutic targets, bioinformatics techniques and clinical sample validation were employed and prostate transmembrane protein androgen induced 1 (PMEPA1) was selected for further study. In the present study, we found that elevated PMEPA1 expression correlates with a worse prognosis and weaker anti-tumor immunity in GC patients. Moreover, our study showed that PMEPA1 not only influences cell proliferation, clone formation, invasion, and migration in vitro, but also plays an important role in GC progression in vivo. Mechanically, PMEPA1 exerts its oncogenic effects through activating the Wnt/ß-catenin signaling pathway. Therefore, PMEPA1 is a potential target for treating GC effectively.

PICH Activates Cyclin A1 Transcription to Drive S-Phase Progression and Chemoresistance in Gastric Cancer.

The chemotherapeutic agent 5-fluorouracil (5-FU) remains the backbone of postoperative adjuvant treatment for gastric cancer. However, fewer than half of patients with gastric cancer benefit from 5-FU-based chemotherapies owing to chemoresistance and limited clinical biomarkers. Here, we identified the SNF2 protein Polo-like kinase 1-interacting checkpoint helicase (PICH) as a predictor of 5-FU chemosensitivity and characterized a transcriptional function of PICH distinct from its role in chromosome separation. PICH formed a transcriptional complex with RNA polymerase II (Pol II) and ATF4 at the CCNA1 promoter in an ATPase-dependent manner. Binding of the PICH complex promoted cyclin A1 transcription and accelerated S-phase progression. Overexpressed PICH impaired 5-FU chemosensitivity in human organoids and patient-derived xenografts. Furthermore, elevated PICH expression was negatively correlated with survival in postoperative patients receiving 5-FU chemotherapy. Together, these findings reveal an ATPase-dependent transcriptional function of PICH that promotes cyclin A1 transcription to drive 5-FU chemoresistance, providing a potential predictive biomarker of 5-FU chemosensitivity for postoperative patients with gastric cancer and prompting further investigation into the transcriptional activity of PICH. SIGNIFICANCE: PICH binds Pol II and ATF4 in an ATPase-dependent manner to form a transcriptional complex that promotes cyclin A1 expression, accelerates S-phase progression, and impairs 5-FU chemosensitivity in gastric cancer.

HOXC13 promotes cell proliferation, metastasis and glycolysis in breast cancer by regulating DNMT3A.

Breast cancer (BC) is a life-threatening malignant tumor that affects females more commonly than males. The mechanisms underlying BC proliferation, metastasis and glycolysis require further investigation. Homeobox C13 (HOXC13) is highly expressed in BC; however, the specific mechanisms in BC are yet to be fully elucidated. Therefore, the aim of the present study was to investigate the role of HOXC13 in BC proliferation, migration, invasion and glycolysis. In the present study, the UALCAN database was used to predict the expression levels of HOXC13 in patients with BC. Western blot analysis and reverse transcription-quantitative PCR were used to determine the expression levels of HOXC13 in BC cell lines. Moreover, HOXC13 knockdown was induced using cell transfection, and the viability, proliferation and apoptosis of cells were detected using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining and flow cytometry. Migration, invasion and epithelial-mesenchymal transition (EMT) were measured using wound healing assay, Transwell assay and western blotting. In addition, XF96 extracellular flux analyzer and corresponding kits were used to detect glycolysis. The JASPAR database was used to predict promoter binding sites for the transcription factors HOXC13 and DNA methyltransferase 3α (DNMT3A). HOXC13 expression was silenced and DNMT3A was simultaneously overexpressed using cell transfection. The results of the present study revealed that HOXC13 expression was significantly elevated in BC tissues and cells. Following HOXC13 knockdown in BC cells, the viability, proliferation, glycolysis, migration, invasion and EMT were significantly decreased, and apoptosis was significantly increased. In addition, HOXC13 positively regulated the transcription of DNMT3A in BC cells, thus playing a regulatory role in the malignant progression of cells. In conclusion, HOXC13 promoted cell viability, proliferation, migration, invasion, EMT and glycolysis in BC by regulating DNMT3A.

Bioinformatics analysis to identify breast cancer-related potential targets and candidate small molecule drugs.

OBJECTIVE: The purpose of this study is to identify potential targets associated with breast cancer and screen potential small molecule drugs using bioinformatics analysis. METHODS: DEGs analysis of breast cancer tissues and normal breast tissues was performed using R language limma analysis on the GSE42568 and GSE205185 datasets. Functional enrichment analysis was conducted on the intersecting DEGs. The STRING analysis platform was used to construct a PPI network, and the top 10 core nodes were identified using Cytoscape software. QuartataWeb was utilized to build a target-drug interaction network and identify potential drugs. Cell survival and proliferation were assessed using CCK8 and colony formation assays. Cell cycle analysis was performed using flow cytometry. Western blot analysis was conducted to assess protein levels of PLK1, MELK, AURKA, and NEK2. RESULTS: A total of 54 genes were consistently upregulated in both datasets, which were functionally enriched in mitotic cell cycle and cell cycle-related pathways. The 226 downregulated genes were functionally enriched in pathways related to hormone level regulation and negative regulation of cell population proliferation. Ten key genes, namely CDK1, CCNB2, ASPM, AURKA, TPX2, TOP2A, BUB1B, MELK, RRM2, and NEK2 were identified. The potential drug Fostamatinib was predicted to target AURKA, MELK, CDK1, and NEK2. In vitro experiments demonstrated that Fostamatinib inhibited the proliferation of breast cancer cells, induced cell arrest in the G2/M phase, and down-regulated MELK, AURKA, and NEK2 proteins. CONCLUSION: In conclusion, Fostamatinib shows promise as a potential drug for the treatment of breast cancer by regulating the cell cycle and inhibiting the proliferation of breast cancer cells.

Individual exposure of ambient particulate matters and eosinophilic chronic rhinosinusitis with nasal Polyps: Dose-Response, mediation effects and recurrence prediction.

PURPOSE: We evaluated the association between ambient particulate matter (PM) exposure and eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), and predicted the CRSwNP recurrence risk using machine learning algorithms. METHODS: In total, 1,086 patients with CRSwNP were recruited from nine hospitals in China during 2014-2019. The average annual concentrations of ambient PMs before surgery were assessed using satellite-based daily concentrations of PM2.5 and PM10 for a 1 × 1-km2 area. Linear regression and logistic regression models were used to evaluate the associations of PM exposure with eosinophilia and risks of eosinophilic CRSwNPs. In addition, mediation effect analysis was used to validate the interrelationships of the aforementioned factors. Finally, machine learning algorithms were used to predict the recurrence risks of CRSwNPs. RESULTS: There was a significantly increased risk of eosinophilic CRSwNPs with each 10 µg/m3 increase in PMs, with odds ratios (ORs) of 1.039 (95% confidence interval [CI] = 1.007-1.073) for PM10 and 1.058 (95% CI = 1.007- 1.112) for PM2.5. Eosinophils had a significant mediation effect, which accounted for 52% and 35% of the relationships of CRSwNP recurrence with PM10 and PM2.5, respectively. Finally, we developed a naïve Bayesian model to predict the risk of CRSwNP recurrence based on PM exposure, inflammatory data, and patients' demographic factors. CONCLUSIONS: Increased PM exposure is associated with an increased risk of eosinophilic CRSwNP in China. Therefore, patients with eosinophilic CRSwNP should reduce PM exposure to mitigate its harmful impacts.

Efficacy of laparoscopic inguinal hernia in day surgery mode and inpatient surgery mode in China: A meta-analysis.

BACKGROUND: In China, laparoscopic inguinal hernia repair (LIHR) under the day surgery mode (DSM) has developed rapidly as an important surgical method for inguinal hernia repair, and it has unique advantages in many aspects. Compared with inpatient surgery mode (ISM), there are some differences in intraoperative and postoperative related indicators, hospitalization costs, and patient satisfaction. Many studies have shown that LIHR in DSM can significantly shorten hospital stay, effectively reduce hospitalization costs, and improve patient satisfaction. Accordingly, this study aimed to compare the differences in intraoperative and postoperative related indicators, hospitalization costs, and patient satisfaction of LIHR between DSM and ISM in China. METHODS: The PubMed/Medline, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wan Fang databases were searched for randomized controlled trials, cohort studies from the establishment of the database to July 1, 2022. Odds ratio (OR), mean difference, standardized mean difference (SMD), and 95% confidence interval were selected as the effect scale indices for the evaluation of the difference in hospitalization costs, hospital stay, operation time, recovery time, complications, and patient satisfaction. All of these were compared using RevMan 5.3 Software (The Cochrane Collaboration, Copenhagen, Denmark). RESULTS: Nine studies involving 1176 patients, 590 in the DSM group and 586 in the ISM group, were included. The hospital stay (d) (SMD = -7.27, 95% confidence interval, CI: -8.68 to -5.87, P  < .001), hospitalization costs (SMD = -7.89, 95% CI: -10.25 to -5.53, P  < .001) in DSM group were significantly lower than the ISM group. Additionally, the patient dissatisfaction (OR = 0.05, 95% CI: 0.01-0.17, P < .001) in DSM group was significantly lower than the ISM group. Nevertheless, no significant differences were found in the operation time (minute) (mean difference = -0.32, 95% CI: -1.78 to 1.14, P = .67), recovery time (h) (SMD = -3.27, 95% CI: -6.95 to 0.41, P  = .08), and postoperative complications (OR = 0.80, 95% CI: 0.47-1.36, P = .41) between the 2 groups. CONCLUSION: In China, compared with ISM, LIHR under DSM can significantly shorten hospital stay, greatly reduce hospitalization costs, and significantly improve patient satisfaction. There were no significant differences in operation time, recovery time and postoperative complications.

Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress.

BACKGROUND & AIMS: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. METHODS: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. RESULTS: Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. CONCLUSIONS: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

Reasonable Collocation of Two Different Functional 3D Laparoscopes May Improve the Efficiency of Transanal Total Mesorectal Excision Surgery Using a Synchronous Two-Team Approach?

Background: To investigate the effectiveness of two different functional three-dimensional (3D) laparoscopes in transanal total mesorectal excision (taTME). Methods: We retrospectively analyzed clinical data of 106 patients undergoing taTME of rectal cancer at the Affiliated Nanchong Central Hospital of North Sichuan Medical College between August 2017 and July 2020. Fifty-seven patients used the flexible 3D laparoscope (FTDL) and 49 patients used the rigid 3D laparoscope (RTDL). Results: Transabdominal operation duration in the FTDL group was shorter than in the RTDL group (125.5 ± 52.6 minutes versus 148.8 ± 59.3 minutes, P = .034). However, transanal operation duration in the FTDL group was longer than in the RTDL group (77.3 ± 26.8 minutes versus 104.6 ± 34.1 minutes, P = .000). There were no significant differences between the two groups in the number of harvested lymph nodes, total operation duration, postoperative complications, postoperative hospitalization, and quality of mesorectal specimen (P > .05). Conclusion: Synchronous two-team approach can be widely used in taTME. Making full use of the respective advantages of the two 3D laparoscopes is beneficial to improve the efficiency of taTME surgery. Clinical Trial Registration Number: NCT03416699.

Separation and Purification of Two Saponins from Paris polyphylla var. yunnanensis by a Macroporous Resin.

An effective method for separating and purifying critical saponins (polyphyllin II and polyphyllin VII) from a Paris polyphylla var. yunnanensis extract was developed in this study which was environmentally friendly and economical. Static adsorption kinetics, thermodynamics, and the dynamic adsorption-desorption of macroporous resins were investigated, and then the conditions of purification and separation were optimized by fitting with an adsorption thermodynamics equation and a kinetic equation. Effective NKA-9 resin from seven macroporous resins was screened out to separate and purify the two saponins. The static adsorption and dynamic adsorption were chemical and physical adsorption dual-processes on the NKA-9 resin. Under the optimum parameters, the contents of polyphyllin II and polyphyllin VII in the product were 17.3-fold and 28.6-fold those in plant extracts, respectively. The total yields of the two saponins were 93.16%. This research thus provides a theoretical foundation for the large-scale industrial production of the natural drugs polyphyllin II and polyphyllin VII.

Curative effect of different drainage methods on laparoscopic inguinal hernia repair: A meta-analysis.

BACKGROUND: Laparoscopic inguinal hernia repair has developed rapidly as an important surgical method for inguinal hernia repair; however, postoperative complications, especially postoperative seroma, are becoming an important factor hindering its development. Many studies have shown that placing a negative-pressure drainage tube in the preperitoneal space can effectively reduce postoperative seromas. Accordingly, this study aimed to compare differences in postoperative seroma between surgical procedures with drainage tubes (DRG) and those without drainage tubes (nonDRG). METHODS: PubMed/Medline, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from the establishment of the database to May 1, 2021. Odds ratio (OR), mean difference (MD), standardized mean difference (SMD), and 95% confidence interval (CI) were selected as the effect scale indices for the evaluation of the difference in seroma, operation time, hospital stay time, blood loss, and recovery time. All of these were compared using RevMan 5.3 Software. RESULTS: Sixteen studies involving 4369 patients, 2856 in the DRG group and 1513 in the nonDRG group, were included. The incidence of seroma in the DRG group was lower than that in the nonDRG group (OR = 0.16, 95% CI: 0.07-0.35, P < .001). Additionally, the operation time (min) in the DRG group was longer than that in the nonDRG group (MD = 3.67, 95% CI: 2.18-5.17, P < .001). Nevertheless, no significant differences were found in hospital stay (days) (SMD = 0.22, 95% CI: -0.10-0.54, P = .17), blood loss (mL) (MD = 0.28, 95% CI: -0.14-0.69, P = .19), and recovery time (h) (SMD = 0.54, 95% CI: -0.60-1.69, P = .35) between the 2 groups. CONCLUSION: Despite the slightly prolonged operation time, negative pressure drainage in the preperitoneal space during laparoscopic inguinal hernia repair can significantly reduce the occurrence of postoperative seroma without increasing blood loss, recovery, and hospital stay.

CdS QDs: Facile synthesis, design and application as an "on-off" sensor for sensitive and selective monitoring Cu2+, Hg2+ and Mg2+ in foods.

A new yellow CdS quantum dots (CdS QDs) with 59% quantum yield were synthesized successfully by one-pot method using thioglycolic acid as stabilizer, thiourea and sodium sulfide as double reducing agents. Based on CdS QDs, a novel "on-off" sensor for detecting Cu2+, Hg2+ and Mg2+ in foods has been constructed in the presence of glutathione (GSH). The fluorescence intensity of CdS QDs is improved about 1.5-fold by GSH, then quenched linearly by Cu2+, Hg2+ and Mg2+ owning to the electron transfer or ligand competition. Interestingly, without GSH, CdS QDs has no fluorescence response to Hg2+ at all, and with GSH, linear ranges of Cu2+ and Mg2+ is not only broader, but sensitivities are improved 16.9-fold for Cu2+ and 8.5-fold for Mg2+. GSH-CdS QDs sensor discloses a more sensitive, efficient and selective methodology for monitoring Cu2+, Hg2+ and Mg2+ in further heavy metal pollution and food safety.

Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.

The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.

GDC-0941 activates integrin linked kinase (ILK) expression to cause resistance to GDC-0941 in breast cancer by the tumor necrosis factor (TNF)-α signaling pathway.

Breast cancer is characterized by high morbidity and mortality. GDC-0941 is a PI3K inhibitor with oncogenic effects in breast cancer. However, certain breast cancer cells are insensitive to GDC-0941. Hence, the mechanism of GDC-0941 in breast cancer resistance was investigated in this study. Breast cancer cell lines BT-474, MCF7, Hs-578-T, MDA-MB-231, MDA-MB-453, and MDA-MB-468 were cultured in different medium and then treated with 100 or 500 nM GDC-0941, 100 nM OSU-T315, or TNF-α antibody. Moreover, ILK and shILK were transfected into cells. The half maximal inhibitory concentrations (IC50) for GDC-0941 were detected using CCK-8 assay. The levels of ILK, AKT, PDK1, S6, and p70S6K expression were detected using western blotting and qPCR. In addition, the mouse model of breast cancer was constructed to measure the tumor size, volume, and weight. The results showed that GDC-0941 decreased cell survival rate, downregulated the phosphorylation of AKT, S6, and p70S6K, and promoted the expression of ILK, while it had little effect on PDK1 expression. GDC-0941 inhibited the increases in p-AKT, p-S6, and p-p70S6K caused by ILK overexpression and promoted ILK knockdown-induced reduction of p-AKT, p-S6, and p-p70S6K. In addition, the combination of OSU-T315 and GDC-0941 decreased p-AKT, p-S6, and p-p70S6K level, tumor volume, and tumor weight. GDC-0941 promoted ILK expression by upregulating TNF-α level. Taken together, GDC-0941 increased ILK level by upregulating TNF-α, thus affecting AKT expression and the sensitivity of breast cancer cells to GDC-0941.

NCAPH regulates gastric cancer progression through DNA damage response.

Gastric cancer (GC) is one of the most common devastating and deadly malignancies of the gastrointestinal tract in the world. GLOBOCAN data analysis showed that GC accounted for approximately 1,033,000 new cases of cancer and 78,200 deaths in 2018. Nonstructural maintenance of chromosomes (non-SMC) condensin I complex subunit H (NCAPH) is a regulatory subunit that encodes the non-SMC condensin I complex. Previous studies have demonstrated that NCAPH is highly expressed in multiple cancers. This study aimed to explore the function and potential mechanism of NCAPH in GC. Our study showed that NCAPH expression was significantly upregulated in The Cancer Genome Atlas (TCGA) and Oncomine datasets. Quantitative real-time polymerase chain reaction and western blotting were used to detect NCAPH expression in GC and paracarcinoma tissues. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to examine cell proliferation. Cell scratch and Transwell invasion assays were performed to assess cell migration. In addition, western blotting was used to detect the expression of proteins related to the cell cycle, DNA damage repair, and epithelial-mesenchymal transition (EMT). Flow cytometry was applied for cell cycle and apoptosis detection. A xenograft model was employed to assess the effect of NCAPH in vivo. The results demonstrated that NCAPH expression was significantly increased in GC tissue samples and cell lines. Knockout of NCAPH notably inhibited cell proliferation, cell migration, cell invasion, cell cycle progression, and tumor growth in vitro and in vivo, and induced the G1-phase cell cycle arrest by regulating the DNA damage response. In addition, knockout of NCAPH promoted cell apoptosis and regulated the expression of EMT-related proteins. The results indicate that the knockout of NCAPH in GC cells inhibits proliferation and metastasis via the DNA damage response in vitro and in vivo. NCAPH plays an important role in GC and may be a potential therapeutic target for GC treatment.

ARHGAP11A Promotes the Malignant Progression of Gastric Cancer by Regulating the Stability of Actin Filaments through TPM1.

The mechanism underlying the poor prognosis of gastric cancer, including its high degree of malignancy, invasion, and metastasis, is extremely complicated. Rho GTPases are involved in the occurrence and development of a variety of malignant tumors. ARHGAP11A, in the Rho GTPase activating protein family, is highly expressed in gastric cancer, but its function and mechanism have not yet been explored. In this study, the effect of ARHGAP11A on the occurrence and development of gastric cancer and the mechanism related to this effect were studied. The expression of ARHGAP11A was increased in gastric cancer cells and tissues, and high ARHGAP11A expression in tissues was related to the degree of tumor differentiation and poor prognosis. Moreover, ARHGAP11A knockout significantly inhibited cell proliferation, cell migration, and invasion in vitro and significantly inhibited the tumorigenic ability of gastric cancer cells in nude mice in vivo. Further studies revealed that ARHGAP11A promotes the malignant progression of gastric cancer cells by interacting with TPM1 to affect cell migration and invasion and the stability of actin filaments. These results suggest that ARHGAP11A plays an important role in gastric cancer and may become a useful prognostic biomarker and therapeutic target for gastric cancer patients.

Anti-inflammatory effects of miR-150 are associated with the downregulation of STAT1 in macrophages following lipopolysaccharide treatment.

Sepsis is a condition that is associated with high rates of mortality. It is characterized by serious systemic inflammatory responses induced by pathogenic invasion. Although microRNA-150 (miR-150) has been previously reported to be involved in the modulation of sepsis, the underlying molecular mechanism in sepsis remains poorly understood. In the present study, the human monocytic cell line THP-1 was treated with LPS to mimic sepsis in vitro, following which miR-150 and STAT1 expression were measured using reverse transcription-quantitative PCR or western blotting. Secretion of inflammatory cytokines interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α) into the medium were measured by ELISA. The potential relationship between STAT1 and miR-150 was determined using dual-luciferase reporter and RNA immunoprecipitation assays. miR-150 expression was found to be was downregulated by LPS treatment in THP-1 cells in both dose- and time-dependent manners. LPS treatment also induced IL-1ß, IL-6 and TNF-α secretion in a manner that could be inhibited by miR-150 overexpression and enhanced by transfection with the miR-150 inhibitor. miR-150 was revealed to directly target STAT1 by negatively regulating its expression. In addition, STAT1 expression was demonstrated to be upregulated by LPS treatment. STAT1 overexpression reversed the inhibitory effects of miR-150 overexpression on IL-1ß, IL-6 and TNF-α secretion whilst STAT1 knockdown attenuated IL-1ß, IL-6 and TNF-α secretion induced by miR-150 inhibitor transfection. In conclusion, the present study suggested that miR-150 regulates the inflammatory response in macrophages following LPS challenge by regulating the expression of STAT1.

Caspase-1-Inhibitor AC-YVAD-CMK Inhibits Pyroptosis and Ameliorates Acute Kidney Injury in a Model of Sepsis.

OBJECTIVE: To observe the protective effect of AC-YVAD-CMK on sepsis-induced acute kidney injury in mice and to explore its possible mechanisms primarily. METHODS: Eighteen male C57BL/6 mice were randomly divided into sham-operated group (Control), cecal ligation and puncture group (CLP), and CLP model treated with AC-YVAD-CMK group (AC-YVAD-CMK) (n = 6 in each group). Mice were sacrificed at 24 h after operation, and blood and kidney tissue samples were collected for analyses. Histologic changes were determined microscopically following HE staining. The expression of Ly-6B and CD68 was investigated using immunohistochemistry. Serum concentrations of creatinine (sCR) and blood urea nitrogen (BUN) were measured. Serum levels of interleukin-1ß (IL-1ß), interleukin-18 (IL-18), TNF-α, and interleukin-6 (IL-6) were determined by ELISA. The expressions of Caspas-1, NLRP-1, IL-1ß, and IL-18 in renal tissues were investigated using Western blot. Immunofluorescence staining was used to detect the expression of GSDMD protein in renal tissues. RESULTS: AC-YVAD-CMK treatment significantly alleviates sepsis-induced acute kidney injury, with decreased histological injury in renal tissues, suppresses the accumulation of neutrophils and macrophages in renal tissues, and decreased sCR and BUN level (P < 0.05). Attenuation of sepsis-induced acute kidney injury was due to the prohibited production of inflammatory cytokines and decrease expression of Caspas-1, NLRP-1, IL-1ß, and IL-18 in renal tissues. In addition, AC-YVAD-CMK treatment significantly reduced the expression of GSDMD in renal tissues compared to those observed in controls (P < 0.05). CONCLUSIONS: We demonstrated a marked renoprotective effect of caspase-1-inhibitor AC-YVAD-CMK in a rat model of sepsis by inhibition of pyroptosis.