The Role of Membrane-Tethered Mucins in Axial Epithelial Adhesion in Controlled Normal Stress Environments.

The collective adhesive behavior of epithelial cell layers mediated by complex macromolecular fluid environments plays a vital role in many biological processes. Mucins, a family of highly glycosylated proteins, are known to lubricate cell-on-cell contacts in the shear direction. However, the role of mucins mediating axial epithelial adhesion in the direction perpendicular to the plane of the cell sheet has received less attention. This article subjects cell-on-cell layers of live ocular epithelia that express mucins on their apical surfaces to compression/decompression cycles and tensile loading using a customized instrument. In addition to providing compressive moduli of native cell-on-cell layers, it is found that the mucin layer between the epithelia acts as a soft cushion between the epithelial cell layers. Decompression experiments reveal mucin layers act as soft, nonlinear springs in the axial direction. The cell-on-cell layers withstand decompression before fracturing by a cohesive failure within the mucin layer. When mucin deficiency is induced via a protease treatment, it is found that the axial adhesion between the cell layers is increased. The findings which correlate changes in biological factors with changes in mechanical properties might be of interest to challenges in ophthalmology, vision care, and mucus research.

Melatonin Protects Against Hyperoxia-Induced Apoptosis in Alveolar Epithelial type II Cells by Activating the MT2/PI3K/AKT/ETS1 Signaling Pathway.

PURPOSE: Hyperoxia-induced apoptosis in alveolar epithelial type II cells (AECIIs) plays a critical role in the development of bronchopulmonary dysplasia (BPD). Melatonin has been shown to improve BPD. However, the protective effect of melatonin on hyperoxia-induced apoptosis in AECIIs and the precise mechanisms involved remain unclear. METHODS: Human alveolar epithelial type II A549 cells were treated with hyperoxia as an in vitro model to investigate the antiapoptotic mechanism of melatonin. CCK-8 assays were performed to investigate the viability of A549 cells. Hoechst 33,258 staining was carried out to quantify apoptosis in A549 cells. The protein expression levels of E26 oncogene homolog 1 (ETS1), Bcl-2, Bax, Bim, Wnt, ß-catenin, AKT and phosphorylated AKT were measured by western blotting. LY294002, SC79 and the downregulation of ETS1, melatonin receptor 1 (MT1) and MT2 with specific siRNAs were used to investigate the role of the PI3K/AKT pathway, ETS1, MT1 and MT2 in hyperoxia-induced apoptosis in A549 cells. RESULTS: Melatonin prevented hyperoxia-induced apoptosis in A549 cells, and the upregulation of E26 oncogene homolog 1 (ETS1) contributed to the antiapoptotic effect of melatonin. Melatonin activated the PI3K/AKT axis, which led to ETS1 upregulation and inhibited apoptosis in hyperoxia-exposed A549 cells. Furthermore, melatonin-induced activation of the PI3K/AKT axis, upregulation of ETS1 and inhibition of apoptosis were reversed by melatonin receptor 2 (MT2) siRNA in hyperoxia-exposed A549 cells. CONCLUSION: Melatonin prevents hyperoxia-induced apoptosis by activating the MT2/PI3K/AKT/ETS1 axis in alveolar epithelial cells.

Identification of risk factors for attempted suicide by self-poisoning and a nomogram to predict self-poisoning suicide.

Purpose: Suicide is a global concern, especially among young people. Suicide prediction models have the potential to make it easier to identify patients who are at a high risk of suicide, but they have very little predictive power when there is a positive value for suicide mortality. Therefore, the aim of the study is to uncover potential risk factors associated with suicide by self-poisoning and further to provide a trustworthy nomogram to predict self-poisoning suicide among poisoned patients. Methods: This study prospectively enrolled 237 patients who were treated for poisoning at the Fifth Medical Center of PLA General Hospital (Beijing) between May 2021 and May 2022. Patient's basic characteristics, daily activities, mental health status, and history of psychological illnesses were gathered to examine their predictive power for self-poisoning suicide. On developing a prediction model, patients were split 8:2 into a training (n = 196) group and a validation (n = 41) group at random via computer. The training group worked on model development, while the validation group worked on model validation. In this study, the Hosmer and Lemeshow test, accuracy, and area under the curve were the primary evaluation criteria. Shapley Additive exPlanations (SHAP) was determined to evaluate feature importance. To make the prediction model easy for researchers to utilize, it was presented in nomogram format. Two risk groups of patients were identified based on the ideal cut-off value. Results: Of all poisoned patients, 64.6% committed suicide by self-poisoning. With regard to self-poisoning attempted suicide, multivariate analysis demonstrated that female gender, smoking, generalized anxiety disorder-7 (GAD-7), and beck hopelessness scale-20 (BHS-20) were significant risk factors, whereas married status, relatively higher education level, a sedentary time of 1-3 h per day, higher sport frequency per week, higher monthly income were significant protective features. The nomogram contained each of the aforementioned nine features. In the training group, the area under curve (AUC) of the nomogram was up to 0.938 (0.904-0.972), whereas in the validation group, it reached a maximum of 0.974 (0.937-1.000). Corresponding accuracy rates were up to 0.883 and 0.927, respectively, and the P-values for the Hosmer and Lemeshow test were 0.178 and 0.346, respectively. SHAP demonstrated that the top three most important features were BHS-20, GAD-7, and marital status. Based on the best cut-off value of the nomogram (40%), patients in the high-risk group had a nearly six-time larger likelihood of committing suicide by self-poisoning than patients in the low-risk group (88.68 vs. 15.38%, P < 0.001). The dynamic nomogram was made available at the following address: https://xiaobo.shinyapps.io/Nomogramselfpoisoningsuicide/. Conclusions: This study proposes a prediction model to stratify patients at a high risk of suicide by self-poisoning and to guide individual preventive strategies. Patients in the high-risk group require further mental health counseling to alleviate anxiety and hopelessness, healthy lifestyle like quitting smoking and exercising more, and restriction of access to poison and psychiatric drugs.

A novel nomogram to stratify quality of life among advanced cancer patients with spinal metastatic disease after examining demographics, dietary habits, therapeutic interventions, and mental health status.

BACKGROUND: It would be very helpful to stratify patients and direct patient selection if risk factors for quality of life were identified in a particular population. Nonetheless, it is still challenging to forecast the health-related quality of life among individuals with spinal metastases. The goal of this study was to stratify patient's populations for whom the assessment of quality of life should be encouraged by developing and validating a nomogram to predict the quality of life among advanced cancer patients with spine metastases. METHODS: This study prospectively analyzed 208 advanced cancer patients with spine metastases, and collected their general characteristics, food preferences, addictions, comorbidities, therapeutic strategies, and mental health status. The functional assessment of cancer therapy-general (FACT-G) and hospital anxiety and depression scale (HADS) were used to assess quality of life and mental health, respectively. The complete cohort of patients was randomly divided into two groups: a training set and a validation set. Patients from the training set were conducted to train and develop a nomogram, while patients in the validation set were performed to internally validate the nomogram. The nomogram contained significant variables discovered using the least absolute shrinkage and selection operator (LASSO) approach in conjunction with 10-fold cross-validation. The nomogram's predictive ability was assessed utilizing discrimination, calibration, and clinical usefulness. Internal validation was also completed using the bootstrap method after applying 500 iterations of procedures. A web calculator was also developed to promote clinical practice. RESULTS: Advance cancer patients with spinal metastases had an extremely low quality of life, as indicated by the average FACT-G score of just 60.32 ± 20.41. According to the LASSO and 10-fold cross-validation, Eastern Cooperative Oncology Group (ECOG) score, having an uncompleted life goal, preference for eating vegetables, chemotherapy, anxiety status, and depression status were selected as nomogram predictors. In the training set, the area under the receiver operating characteristic curve (AUROC) was 0.90 (95% CI: 0.84-0.96), while in the validation set, it was 0.85 (95% CI: 0.78-0.93). They were 0.50 (95% CI: 0.41-0.58) and 0.44 (95% CI: 0.33-0.56), respectively, for the discrimination slopes. The nomogram had favorable capacity to calibrate and was clinically useful, according to the calibration curve and decision curve analysis. When compared to patients in the low-risk group, patients in the high-risk group were above four times more likely to experience a poor quality of life (82.18% vs. 21.50%, P < 0.001). In comparison to patients in the low-risk group, patients in the high-risk group also exhibited significant higher levels of anxiety and depression. The webpage for the web calculator was https://starshiny.shinyapps.io/DynNomapp-lys/ . CONCLUSIONS: This study suggests a nomogram that can be applied as a practical clinical tool to forecast and categorize the quality of life among patients with spine metastases. Additionally, patients with poor quality of life experience more severe anxiety and depression. Effective interventions should be carried out as soon as possible, especially for patients in the high-risk group, to improve their quality of life and mental health condition.

Mucin-Like Glycoproteins Modulate Interfacial Properties of a Mimetic Ocular Epithelial Surface.

Dry eye disease (DED) has high personal and societal costs, but its pathology remains elusive due to intertwined biophysical and biochemical processes at the ocular surface. Specifically, mucin deficiency is reported in a subset of DED patients, but its effects on ocular interfacial properties remain unclear. Herein a novel in vitro mucin-deficient mimetic ocular surface (Mu-DeMOS) with a controllable amount of membrane-tethered mucin molecules is developed to represent the diseased ocular surfaces. Contact angle goniometry on mimetic ocular surfaces reveals that high surface roughness, but not the presence of hydrophilic mucin molecules, delivers constant hydration over native ocular surface epithelia. Live-cell rheometry confirms that the presence of mucin-like glycoproteins on ocular epithelial cells reduces shear adhesive strength at cellular interfaces. Together, optimal surface roughness and surface chemistry facilitate sustainable lubrication for healthy ocular surfaces, while an imbalance between them contributes to lubrication-related dysfunction at diseased ocular epithelial surfaces. Furthermore, the restoration of low adhesive strength at Mu-DeMOS interfaces through a mucin-like glycoprotein, recombinant human lubricin, suggests that increased frictional damage at mucin-deficient cellular surfaces may be reversible. More broadly, these results demonstrate that Mu-DeMOS is a promising platform for drug screening assays and fundamental studies on ocular physiology.

Tuning corneal epithelial cell adhesive strength with varying crosslinker content in silicone hydrogel materials.

Purpose: To quantify the effect of silicone hydrogel crosslink density on the adhesion at corneal epithelial cells/silicone hydrogel contact lens interface. Methods: A custom-built rheometer, referred to as the live cell monolayer rheometer, was used to measure the adhesive strengths between corneal epithelial cell monolayers and silicone hydrogel lens surfaces. The resulting stress relaxations of senofilcon A-derived silicone hydrogel materials with varying crosslinking densities and delefilcon A were tested. Senofilcon A-like materials labeled L1, L2, L3, L4, and L5 contained crosslinker concentrations of 1.2, 1.35, 1.5, 1.65, and 1.8 wt%, respectively. The residual modulus measured from the live cell monolayer rheometer provided a direct indication of adhesive attachment. Results: Within the senofilcon-derived series, the adhesive strength shows a surprising minimum with respect to crosslink density. Specifically, L1 (1.20%) has the highest adhesive strength of 39.5 ± 11.2 Pa. The adhesive strength diminishes to a minimum of 11.2 ± 2.1 Pa for L3, whereafter it increases to 14.5 ± 2.5 Pa and 18.1 ± 5.1 Pa for L4 and L5, respectively. The delefilcon A lens exhibits a comparable adhesive strength of 27.8 ± 6.3 Pa to L1. Conclusions: These results demonstrated that increasing the crosslink density has a nonmonotonic influence on the adherence of lenses to mucin-expressing corneal epithelial cells, which suggests a competition mechanism at the cell/lens interface. Translational Relevance: Because the adhesiveness of contact lenses to ocular tissues may impact the comfort level for lens wearers and affect ease of removal, this study suggests that lens adhesion can be optimized through the control of crosslink density.

Perioperative safety analysis of transcatheter arterial chemoembolization for hepatocellular carcinoma patients with preprocedural leukopenia or thrombocytopenia.

Patients with hepatocellular carcinoma (HCC) exhibit a high incidence of concomitant cirrhosis with leukopenia and/or thrombocytopenia. In the present study, perioperative changes in the white blood cell (WBC) and platelet (PLT) counts and associated complications were investigated to assess the safety of transcatheter arterial chemoembolization (TACE) for HCC patients with preprocedural leukopenia or thrombocytopenia. The records of 1,461 HCC patients who received TACE between January 2012 and December 2013 were retrospectively reviewed. The incidence of complications during the perioperative period and changes in the WBC and PLT counts were recorded. A Chi-squared test was used to evaluate the associations between postoperative infection and preprocedural WBC count and between bleeding at the puncture site and preprocedural PLT count. The WBC count of the majority of the patients increased within 3 days and returned to the preprocedural level within 30 days after TACE. The PLT count decreased within 3 days and returned to the preprocedural level within 30 days after TACE. The major complications were liver decompensation (n=66), puncture site bleeding (n=45), infection (n=33), severe thrombocytopenia (n=8), upper gastrointestinal bleeding (n=6), tumor bleeding (n=4) and agranulocytosis (n=3). A Chi-squared test revealed that postoperative infection was not associated with preprocedural WBC count and puncture site bleeding was not associated with decreased PLT count due to hypersplenism. Therefore, TACE was found to be safe for HCC patients with preprocedural thrombocytopenia or leukopenia due to hypersplenism, with a low incidence of major complications during the perioperative period.

Acquired amegakaryocytic thrombocytopenic purpura induced by percutaneous ethanol injection during treatment of hepatocellular carcinoma: A case report.

Percutaneous ethanol injection is an important localized treatment method for patients presenting with hepatocellular carcinoma (HCC). Among the advantages of percutaneous ethanol injection are its minimal invasiveness, simplicity, low cost and low risk of complications. However, the increasing popularity of percutaneous ethanol injection has resulted in serious adverse effects attributed to individual variations. The present study describes the case of a patient who exhibited acquired amegakaryocytic thrombocytopenic purpura, caused by percutaneous ethanol injection treatment for HCC. This complication was promptly identified, and platelet transfusion and injection of recombinant human interleukin-11 resulted in a rapid recovery of the patient's platelet count. Attention should be given to this rare complication in patients administered percutaneous ethanol injection treatment for HCC.

Enhanced therapeutic efficacy of combined use of sorafenib and transcatheter arterial chemoembolization for treatment of advanced hepatocellular carcinoma.

OBJECTIVE: Clinical trials suggest that combining transcatheter arterial chemoembolization with sorafenib in patients with advanced hepatocellular carcinoma shows a superior safety and tolerability profile. Our study aimed to retrospectively analyze the utility and prognostic factors of this combined therapy in these patients. METHODS: Patients with advanced hepatocellular carcinoma, treated by transcatheter arterial chemoembolization and sorafenib subsequently, between February 2010 and September 2012 in our hospital, were retrospectively analyzed. After sorafenib treatment for 12 weeks, abdominal enhanced computed tomography or magnetic resonance imaging was used to evaluate short-term outcomes and clinical benefit rate. Overall survival and adverse events were recorded during follow-up. Univariate and multivariate analyses were used to identify relationships between baseline characteristics and overall survival. RESULTS: Fifty-one advanced hepatocellular carcinoma patients were included. Common adverse events for sorafenib were hand-foot skin reaction, alopecia, diarrhea, anorexia and fatigue. The clinical benefit rate was 64% and the median survival time was 7.5 months. Median survival of patients with and without portal vein tumor thrombi was 6.0 months and 10.3 months (P < 0.001), respectively. Median survival of patients with cholinesterase ≥5000 U/l and < 5000 U/l was 10.6 months and 6.1 months (P < 0.001), respectively. Multivariate analysis identified the presence of portal vein tumor thrombi and low cholinesterase level as independent negative predictors of survival. CONCLUSIONS: Combining sorafenib and transcatheter arterial chemoembolization was safe and effective for advanced hepatocellular carcinoma patients with extrahepatic spread but without portal vein tumor thrombi. Portal vein tumor thrombi and cholinesterase level are independent predictors of prognosis following this combined therapy.

The efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization for primary hepatocellular carcinoma in a cohort of 487 patients.

Although diagnostic methods, surgical techniques, and perioperative care have undergone significant advancement over the past decades, the prognosis of primary hepatocellular carcinoma (HCC) remains discouraged because of the high postoperative recurrence rate and high cancer mortality. Radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) is a recently developed means for the treatment of HCC. In this study, we analyzed the efficacy of RFA plus TACE in 487 cases of HCC in our institution. We observed that the 1-, 2-, 3-, 4- and 5-year rates of overall survival rates after RFA and TACE treatment were 97.5% (475/487), 89.4% (277/310), 84.2% (181/215), 80.4% (150/186) and 78.7% (141/177), respectively. We did not find that age or tumor location (the caudate group or non-caudate group) plays a role in this cohort. However, we have identified that tumor recurrent status, the number of tumors, albumin (ALB), prothrombin time (PT) and platelet count (PLT) were significantly associated with poor overall survival in HCC patients receiving RFA combined with TACE. Interestingly, tumor size did not significantly impact overall survival, indicating that RFA combined with TACE for HCC treatment has the same efficiency for different sizes of tumors. Our results provide evidence for the rationale for using combined RFA and TACE in the treatment of primary HCC.