Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

Radiomics signature for prediction of long-term survival and recurrence patterns in patients with gastric cancer after radical gastrectomy: A multicenter study.

Background: This study aimed to develop and validate a radiomics score to predict the long-term survival and patterns of recurrence of gastric cancer (GC). Methods: A total of 513 patients who underwent radical gastrectomy for GC after curative resection between 2008 and 2016 at two institutions were analyzed. A radiomics score was generated using the least absolute shrinkage and selection operator Cox regression model on 327 patients and was validated in 186 patients. A nomogram consisting of the radiomics score and clinicopathological factors was created and compared with the tumor-lymph node-metastasis (TNM) staging system. Model performance was assessed using calibration, discrimination, and clinical usefulness. Results: The radiomics score was established based on five selected features. A higher score was significantly associated with poorer recurrence-free survival (RFS) and overall survival (OS) rates, both in the training and validation cohorts (P < 0.05). Multivariate analysis demonstrated that the radiomics score was an independent prognostic factor for both RFS and OS (P < 0.05). A nomogram incorporating the radiomics score had a significantly better prognostic value than the TNM system alone. Moreover, a high score was significantly associated with an increased risk of distant recurrence, a medium score was significantly associated with an increased risk of peritoneal recurrence, and a low score was significantly associated with an increased risk of locoregional recurrence, in the entire cohort (P < 0.05). Conclusions: The newly proposed radiomics score may be a powerful predictor of long-term outcomes and recurrence patterns of GC. Further studies are warranted to confirm these findings.

Translation and validation of the Chinese version of the orthorexia nervosa assessment questionnaires among college students.

PURPOSE: The main objective of the study was to translate, validate, and compare the Chinese ORTO scales (ORTO-15 and ORTO-R). The secondary objective was to assess factors that may be related with risk of orthorexia nervosa (ON). METHODS: Two cross-sectional surveys were conducted on March-to-June 2021 for ORTO-15 and April 2022 for ORTO-R. ORTO questionnaires were translated into Chinese using the forward-backward-forward method. Exploratory factor analysis (EFA), discriminant validity and confirmatory factor analysis (CFA) were used to examine the construct validity of the questionnaires. The internal consistency was assessed using the Cronbach alpha coefficient and the test-retest reliability. Multivariate linear regression analysis was used to explore potential factors related with ON scores. RESULTS: Totally, 1289 and 1084 eligible participants were included for assessment of ORTO-15 and ORTO-R, with the mean age of 20.9 ± 2.0 years and 21.0 ± 2.3 years. The internal consistency of Chinese ORTO-15 scale and ORTO-R scale were both satisfactory (α = 0.79, ICC = 0.79; α = 0.77, ICC = 0.82). However, all ORTO-15 models showed a poor fit using CFA whereas the ORTO-R was characterized by acceptable goodness-of-fit. Multivariate linear regression indicated that physical activities and mental disorders were positively associated with ON risk assessed by both ORTO-R and ORTO-15. CONCLUSION: The Chinese ORTO-R scale was a more reliable tool to screen for ON tendencies than the Chinese version of ORTO-15. Mental disorders and physical activities might be associated with the increased ON risk. LEVEL OF EVIDENCE: Level V (descriptive cross-sectional study).

Efficacy and safety of intravenous combined with topical administration of tranexamic acid in reducing blood loss in opening wedge high tibial osteotomy procedure: A retrospective case-control study.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of intravenous combined with topical application of tranexamic acid (TXA) in reducing blood loss in opening wedge high tibial osteotomy (OWHTO). METHODS: A total of 60 patients who underwent unilateral OWHTO between May 2018 and May 2019 were retrospectively reviewed. All the patients were then divided into one of the two groups (30 per group): the TXA group, patients receiving intravenous combined with topical application of TXA, and the control group, patients receiving no TXA. Outcome measures were drain volume, total blood loss, hidden blood loss, transfusion requirements, and incidence of complications. RESULTS: The mean follow-up of TXA group was 14.2 2.3 months (range, 13-16 months) and the mean follow-up for the control group was 14.4 2.1 months (range, 13-17 months). No significant difference was found for the follow-up of two groups (P=0.829). Drainage volume (143.3 65.4 ml vs 307.8 51.4 mL, P < 0.001), hidden blood loss (156.7 63.8 mL vs 286.4 79.1 mL, P < 0.001) and knee swelling (3.2 0.9 vs 6.5 2.1, P < 0.001) in the TXA group was clearly less than that in the control group, and there was no statistical significance with regard to hospitalization time (P=0.746), transfusion requirements (P=1.000), wound complications (P=0.386), deep venous thrombosis (P=1.000), postoperative Lysholm knee score (P=0.681) and Knee Injury and Osteoarthritis Outcome subscales pain (P=0.752), symptoms (P=0.673), activities of daily living (P=0.871), sport/recreation function (P=0.816), and knee-related quality of life (P=0.576) at 6 months postoperatively. CONCLUSION: This study has shown that administration of intravenous combined with topical TXA in OWHTO can effectively reduce perioperative blood loss without increasing the incidence of postoperative complications. LEVEL OF EVIDENCE: Level III, Therapeutic Study.

FAM225A promotes sorafenib resistance in hepatocarcinoma cells through modulating miR-130a-5p-CCNG1 interaction network.

Chemotherapy resistance is still a key hurdle in current hepatocellular carcinoma (HCC) treatment. Therefore, clarifying the molecular mechanisms contributing to this acquired resistance is urgent for the effective treatment of liver cancer. In this research, we observed that lncRNA FAM225A expression is dramatically upregulated not only in hepatocellular carcinoma tissues and cell lines but also in sorafenib-resistant HepG2/SOR cells. Moreover, FAM225A knockdown significantly weakened HepG2/SOR cells resistance to sorafenib treatment by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Similar results were obtained from the tumor xenograft model in mice. Further mechanistic researches revealed that the direct interaction between FAM225A and miR-130a-5p, while miR-130a-5p negatively modulated CCNG1 expression by targeting 3'UTR of CCNG1. MiR-130a-5p inhibition or CCNG1 overexpression could partially offset FAM225A knockdown-induced increased viability of HepG2/SOR cells in response to sorafenib challenge. Collectively, our findings provide evidence that FAM225A/miR-130a-5p/CCNG1 interaction network regulates the resistance of HCC cells to sorafenib treatment and could supply a possible strategy for restoring sorafenib sensitivity in HCC therapy.

Biomechanical Comparison of INTERTAN Nail and Gamma3 Nail for Intertrochanteric Fractures.

OBJECTIVE: To compare the biomechanical stabilities of Gamma3 nail and INTERTAN nail (ITN) for stable (AO/OTA 31A1.1) and unstable (AO/OTA 31A2.2) femoral intertrochanteric fracture. METHODS: Twenty-four synthetic femora were randomly divided into four groups. After internal fixation (Gamma3 nail or ITN) had been implanted, stable and unstable intertrochanteric fracture models were produced. A cyclic testing protocol with increasing loads was performed for both stable and unstable intertrochanteric fracture models, and then torsional test and axial compression failure test were conducted. Stiffness, failure load, torque, and fragment displacement were recorded. RESULTS: For stable fracture model: fragment displacement in ITN group were smaller than Gamma3 nail group (Gamma3 nail: 1.66 ± 0.13 mm; ITN: 1.55 ± 0.1 mm); stiffness (Gamma3 nail: 1142.6 ± 161.1 N/mm, ITN: 1159.3 ± 203.5 N/mm, P = 0.872) and failure load (Gamma3 nail: 5715.42 ± 616.34 N, ITN: 5690.27 ± 625.59 N, P = 0. 951) of the two nails were similar after cyclic test; torque of the ITN group was larger than the Gamma3 nail group. For unstable fracture model: fragment displacement in ITN group was significantly smaller than in the Gamma3 nail group when the axial load was larger than 800 N (Gamma3 nail: 3.59 ± 0.19 mm; ITN: 2.93 ± 0.28 mm); ITN group showed a significantly higher failure load than Gamma3 nail group (Gamma3 nail: 2942.77 ± 573.4 N, ITN: 3672.3 ± 790.5 N, P = 0. 011); torque was significantly higher for the ITN group compared to the Gamma3 nail group for three different angles. CONCLUSIONS: Both ITN and Gamma3 nail can maintain sufficient biomechanical stability for stable intertrochanteric fractures, but ITN was a better choice for unstable intertrochanteric fractures.

Preparation and characterization of layer-by-layer hypoglycemic nanoparticles with pH-sensitivity for oral insulin delivery.

New self-assembled layer-by-layer nanoparticles, based on hypoglycemic, mucoadhesive, epithelium-penetrating and pH-sensitive functional materials, have been synthesized. The confirmed hypoglycemic and negatively charged polygalacturonic acid, the well-known cell penetrating and positively charged chitosan, and the negatively charged, pH-sensitive polymer alginate were the components of these nanoparticles. The electrical attraction between the negatively charged PGLA and alginate and the positively charged chitosan motivated the assembly and supported the pH-sensitivity of the nanoparticles. The LBL4 and LBL4-Alg nanoparticles were characterized in vitro and in vivo. The pH-sensitivity of LBL4-Alg nanoparticles was greater, with the turning point near pH = 5. Moreover, according to the pharmacological and pharmacokinetic studies, the significant hypoglycemic effect was observed only 1 h after gavage with LBL4 and LBL4-Alg nanoparticles. Insulin was continually released for at least 6 h. These results show that the new self-assembled LBL4-Alg nanoparticles with pH-sensitivity have great potential for oral insulin delivery.

Risk Factors Comparison for Radial and Horizontal Tears.

Tears in posterior horn of medial meniscus mainly included horizontal tear, transversal tear, radial tear, complex tear, and bucket handle tear. We analyzed and compared the risk factors for radial tear and horizontal tear in the posterior horn of medial meniscus. A total of 407 consecutive cases who received arthroscopic treatment of medial meniscus tears were analyzed retrospectively. Among them, 103 cases were radial tear in posterior horn of medial meniscus and 107 were horizontal tear. Clinical data records included patients' age, gender, duration of symptoms, body mass index, trauma history, and slope angle of tibia, valgus angle of knee, and grading of cartilage (Outerbridge Grades) were collected and analyzed. In addition, multiple-factor nonconditional logistic regression was adopted to analyze the related risk factors in these two types of medial meniscus tears. The two groups have no difference in age, trauma history, slope angle of tibia, and duration of symptoms but have significant difference in gender, body mass index, and valgus angle of knee and grading of cartilage. Multiple factors analysis indicated that valgus angle, age, and grading of cartilage were risk factors in medial meniscus tears. Patients with posterior horn tear in medial meniscus have higher incidence among senile osteoarthritis, while radial tear was more likely to occur in elderly patients with knee-joint varus and serious cartilage degeneration.