Development and validation of a simple and practical model for early detection of diabetic macular edema in patients with type 2 diabetes mellitus using easily accessible systemic variables.

OBJECTIVE: Diabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetes mellitus (DM). The goal of early detection has not yet achieved due to a lack of fast and convenient methods. Therefore, we aim to develop and validate a prediction model to identify DME in patients with type 2 diabetes mellitus (T2DM) using easily accessible systemic variables, which can be applied to an ophthalmologist-independent scenario. METHODS: In this four-center, observational study, a total of 1994 T2DM patients who underwent routine diabetic retinopathy screening were enrolled, and their information on ophthalmic and systemic conditions was collected. Forward stepwise multivariable logistic regression was performed to identify risk factors of DME. Machine learning and MLR (multivariable logistic regression) were both used to establish prediction models. The prediction models were trained with 1300 patients and prospectively validated with 104 patients from Guangdong Provincial People's Hospital (GDPH). A total of 175 patients from Zhujiang Hospital (ZJH), 115 patients from the First Affiliated Hospital of Kunming Medical University (FAHKMU), and 100 patients from People's Hospital of JiangMen (PHJM) were used as external validation sets. Area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity, and specificity were used to evaluate the performance in DME prediction. RESULTS: The risk of DME was significantly associated with duration of DM, diastolic blood pressure, hematocrit, glycosylated hemoglobin, and urine albumin-to-creatinine ratio stage. The MLR model using these five risk factors was selected as the final prediction model due to its better performance than the machine learning models using all variables. The AUC, ACC, sensitivity, and specificity were 0.80, 0.69, 0.80, and 0.67 in the internal validation, and 0.82, 0.54, 1.00, and 0.48 in prospective validation, respectively. In external validation, the AUC, ACC, sensitivity and specificity were 0.84, 0.68, 0.90 and 0.60 in ZJH, 0.89, 0.77, 1.00 and 0.72 in FAHKMU, and 0.80, 0.67, 0.75, and 0.65 in PHJM, respectively. CONCLUSION: The MLR model is a simple, rapid, and reliable tool for early detection of DME in individuals with T2DM without the needs of specialized ophthalmologic examinations.

Investigating Causality and Shared Genetic Architecture between Neurodegenerative Disorders and Inflammatory Bowel Disease.

Published observational studies have revealed the connection between neurodegenerative disorders and inflammatory bowel disease (IBD), whereas the causal association remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between neurodegenerative disorders and IBD. Two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], Parkinson's disease [PD], and multiple sclerosis [MS]). Shared genetic loci, functional interpretation, and transcriptomic profiles were further investigated in ALS and IBD. We identified that genetic predisposition to IBD was suggestively associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD was not genetically associated with an increased risk of AD, PD, or MS (and vice versa). Two shared genetic loci (rs6571361 and rs7154847) were derived, and SCFD1, G2E3, and HEATR5A were further identified as novel risk genes with enriched functions related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with ALS or IBD. Our study reveals the suggestively protective role of IBD on ALS, and does not support the causality of AD, PD, or MS on IBD (and vice versa). Our findings indicate possible shared genetic architecture and pathways between ALS and IBD. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.

EBD: an eye biomarker database.

MOTIVATION: Many ophthalmic disease biomarkers have been identified through comprehensive multiomics profiling, and hold significant potential in advancing the diagnosis, prognosis, and management of diseases. Meanwhile, the eye itself serves as a natural biomarker for several systemic diseases including neurological, renal, and cardiovascular systems. We aimed to collect and standardize this eye biomarkers information and construct the eye biomarker database (EBD) to provide ophthalmologists with a platform to search, analyze, and download these eye biomarker data. RESULTS: In this study, we present the EBD , a world-first online compilation comprising 889 biomarkers for 26 ocular diseases and 939 eye biomarkers for 181 systemic diseases. The EBD also includes the information of 78 "nonbiomarkers"-the objects that have been proven cannot be biomarkers. Biological function and network analysis were conducted for these ocular disease biomarkers, and several hub pathways and common network topology characteristics were newly identified, which may promote future ocular disease biomarker discovery and characterizes the landscape of biomarkers for eye diseases at the pathway and network level. The EBD is expected to yield broader utility among developmental biologists and clinical scientists in and outside of the eye field by assisting in the identification of biomarkers linked to eye disorders and related systemic diseases. AVAILABILITY AND IMPLEMENTATION: EBD is available at http://www.eyeseeworld.com/ebd/index.html.

Lack of Causal Associations of Inflammatory Bowel Disease with Parkinson's Disease and Other Neurodegenerative Disorders.

BACKGROUND: Observational studies have indicated associations between inflammatory bowel disease (IBD) and neurodegenerative diseases, including Parkinson's disease (PD). OBJECTIVE: To evaluate the causal associations of IBD with PD and other selected neurodegenerative disorders using updated data. METHODS: Bidirectional two-sample Mendelian randomization studies using genome-wide association studies summary statistics of IBD and PD. RESULTS: We found a lack of evidence for the causal association of IBD on PD (odds ratio [OR], 1.014; 95% confidence interval [CI], 0.967-1.063; P = 0.573). Reverse analysis also indicated no evidence of a causal effect for PD on IBD (OR, 0.978; 95% CI, 0.910-1.052; P = 0.549). The causality between IBD and Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis was unfounded (all P > 0.05). CONCLUSIONS: The updated analyses provide no clear evidence for causal associations of IBD with PD or the other three neurodegenerative diseases. Potential confounders might contribute to the previously observed associations, and further investigations are warranted. © 2023 International Parkinson and Movement Disorder Society.

Construction and analysis of evaluation model for medical students' innovation competency based on research-oriented biochemistry and molecular biology course in China.

Presently, a variety of policies and measures has implemented to enhance the scientific research and innovation ability of medical students, but in the process of practice, there are many problems, such as they lack of independent topic selection ability, weak scientific research skills, lack of autonomous learning ability, the research results are simple and ineffective, limited teacher guidance time and so on. This paper attempted to build an effective model for the promotion of medical students' scientific research and innovation ability, in order to establish an efficacy evaluation model of the "Medical students' Innovative Scientific Research Program." Undergraduates, graduate assistants, and tutors were interviewed with the Behavioral Event Interview technique, and a questionnaire of efficacy evaluation characteristics concluded from the interviews was formed. The questionnaire was conducted on medical students in the Medical students' Innovative Scientific Research Program, and the constructed model was analyzed using reliability analysis, validity analysis, and variation analysis. At the same time, the experimental teaching models are summarized and combed, and compared with other methods such as independent sample test. The results show the model could effectively evaluate the efficacy of the Medical students' Innovative Scientific Research Program and its teaching model is effective in cultivating medical students' learning and scientific research ability. It can provide theoretical support and practical reference for the evaluation and reform of the teaching modes related to the cultivation of scientific and innovative ability of medical students.

Corrigendum: Risk factors of falls in elderly patients with visual impairment.

[This corrects the article DOI: 10.3389/fpubh.2022.984199.].

Risk factors of falls in elderly patients with visual impairment.

Objective: To examine the risk factors for falls in elderly patients with visual impairment (VI) and assess the predictive performance of these factors. Methods: Between January 2019 and March 2021, a total of 251 elderly patients aged 65-92 years with VI were enrolled and then prospectively followed up for 12 months to evaluate outcomes of accidental falls via telephone interviews. Information of demographics and lifestyle, gait and balance deficits, and ophthalmic and systemic conditions were collected during baseline visits. Forward stepwise multivariable logistic regression analysis was performed to identify independent risk factors of falls in elderly patients with VI, and a derived nomogram was constructed. Results: A total of 143 falls were reported in 251 elderly patients during follow-up, with an incidence of 56.97%. The risk factors for falls in elderly patients with VI identified by multivariable logistic regression were women [odds ratio (OR), 95% confidence interval (CI): 2.71, 1.40-5.27], smoking (3.57, 1.34-9.48), outdoor activities/3 months (1.31, 1.08-1.59), waking up frequently during the night (2.08, 1.15-3.79), disorders of balance and gait (2.60, 1.29-5.24), glaucoma (3.12, 1.15-8.44), other retinal degenerations (3.31, 1.16-9.43) and best-corrected visual acuity (BCVA) of the better eye (1.79, 1.10-2.91). A nomogram was developed based on the abovementioned multivariate analysis results. The area under receiver operating characteristic curve of the predictive model was 0.779. Conclusions: Gender, smoking, outdoor activities, waking up at night, disorders of balance and gait, glaucoma, other retinal degeneration and BCVA of the better eye were independent risk factors for falls in elderly patients with VI. The predictive model and derived nomogram achieved a satisfying prediction of fall risk in these individuals.

Shared genetic architecture between the two neurodegenerative diseases: Alzheimer's disease and glaucoma.

Background: Considered as the representatives of neurodegenerative diseases, Alzheimer's disease (AD) and glaucoma are complex progressive neuropathies affected by both genetic and environmental risk factors and cause irreversible damages. Current research indicates that there are common features between AD and glaucoma in terms of epidemiology and pathophysiology. However, the understandings and explanations of their comorbidity and potential genetic overlaps are still limited and insufficient. Method: Genetic pleiotropy analysis was performed using large genome-wide association studies summary statistics of AD and glaucoma, with an independent cohort of glaucoma for replication. Conditional and conjunctional false discovery rate methods were applied to identify the shared loci. Biological function and network analysis, as well as the expression level analysis were performed to investigate the significance of the shared genes. Results: A significant positive genetic correlation between AD and glaucoma was identified, indicating that there were significant polygenetic overlaps. Forty-nine shared loci were identified and mapped to 11 shared protein-coding genes. Functional genomic analyses of the shared genes indicate their modulation of critical physiological processes in human cells, including those occurring in the mitochondria, nucleus, and cellular membranes. Most of the shared genes indicated a potential modulation of metabolic processes in human cells and tissues. Furthermore, human protein-protein interaction network analyses revealed that some of the shared genes, especially MTCH2, NDUFS3, and PTPMT1, as well as SPI1 and MYBPC3, may function concordantly. The modulation of their expressions may be related to metabolic dysfunction and pathogenic processes. Conclusion: Our study identified a shared genetic architecture between AD and glaucoma, which may explain their shared features in epidemiology and pathophysiology. The potential involvement of these shared genes in molecular and cellular processes reflects the "inter-organ crosstalk" between AD and glaucoma. These results may serve as a genetic basis for the development of innovative and effective therapeutics for AD, glaucoma, and other neurodegenerative diseases.

Neoadjuvant Therapy for Locally Advanced Esophageal Cancers.

Esophageal carcinoma is one of the most aggressive malignant diseases. At present, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy are regarded as the standard modalities for the treatments of locally advanced esophageal cancers based on several landmark trials. However, the optimal regimen, radiation dose, and surgical intervals are uncertain and the rate of recurrence after neoadjuvant therapy is high. Patients receiving neoadjuvant therapy and reaching a pathological complete response have been reported to have a better survival benefit and a fewer recurrence risk than those non-pathological complete responses. Nevertheless, less than half of patients will reach a pathological complete response after neoadjuvant therapy, and the methods to evaluate the efficacy after neoadjuvant therapy accurately are limited. Immune checkpoint inhibitors have been recommended for the treatments of advanced esophageal cancers. Recently, research has been beginning to evaluate the safety and efficacy of immunotherapy combined with neoadjuvant therapy. Here, we will review and discuss the development of the neoadjuvant therapy of locally advanced esophageal cancers and unsolved clinical problems.

Role of Rho guanine nucleotide exchange factors in non-small cell lung cancer.

Conventionally, Rho guanine nucleotide exchange factors (GEFs) are known activators of Rho guanosine triphosphatases (GTPases) that promote tumorigenesis. However, the role of Rho GEFs in non-small cell lung cancer (NSCLC) remains largely unknown. Through the screening of 81 Rho GEFs for their expression profiles and correlations with survival, four of them were identified with strong significance for predicting the prognosis of NSCLC patients. The four Rho GEFs, namely ABR, PREX1, DOCK2 and DOCK4, were downregulated in NSCLC tissues compared to normal tissues. The downregulation of ABR, PREX1, DOCK2 and DOCK4, which can be attributfed to promoter methylation, is correlated with poor prognosis. The underexpression of the four key Rho GEFs might be related to the upregulation of MYC signaling and DNA repair pathways, leading to carcinogenesis and poor prognosis. Moreover, overexpression of ABR was shown to have a tumor-suppressive effect in PC9 and H1703 cells. In conclusion, the data reveal the unprecedented role of ABR as tumor suppressor in NSCLC. The previously unnoticed functions of Rho GEFs in NSCLC will inspire researchers to investigate the distinct roles of Rho GEFs in cancers, in order to provide critical strategies in clinical practice.

Online health information-seeking behaviors and skills of Chinese college students.

BACKGROUND: Seeking online health information (OHI) has become a common practice globally. The information seekers could face health risks if they are not proficient in OHI literacy. The OHI-seeking behaviors and skills of Chinese college students, the largest proportion of college students in the world, are understudied. This study was aimed to describe OHI-seeking behaviors and skills of college students in Guangdong, China. METHODS: College students in the Guangdong province with OHI-seeking experience were invited via WeChat, QQ, and Sina Weibo using QR code posters and flyers for participation in this online anonymized questionnaire-based study. Data on demographics, OHI literacy, information resources, search approaches, and behaviors were collected. The relationship between perceived OHI literacy and high-risk behaviors was investigated by bivariate logistic regression analysis. RESULTS: Respondents were 1203 college students with a mean age of 20.6 years, females (60.2%), and undergraduates (97.2%). They sought health information via websites (20.3%), WeChat (2.6%), or both (77.1%). Baidu was the main search engine, and baike.baidu.com (80.3%), Zhihu.com (48.4%), and Zhidao.baidu.com (35.8%) were top three among 20 searched websites for information about self-care (80.7%), general health (79.5%), disease prevention (77.7%), self-medication (61.2%), family treatment (40.9%), drugs (37.7%), western medications (26.6%), hospitals (22.7%), physicians (21.4%), and Traditional Chinese Medicine (15.6%). Despite most respondents (78%) lacked confidence in the evidence quality and satisfaction with the results, only 32.4% further consulted doctors. Many (> 50%) would recommend the retrieved information to others. About 20% experienced hacking/Internet fraud. Cronbach's alpha for the internal consistency of OHI literacy was 0.786. Bivariate logistic regression analysis showed that students who believed they can judge the evidence level of OHI were more likely to self-diagnose (OR = 2.2, 95%CI, 1.6-3.1) and look for drug usage (OR = 3.1, 95%CI, 1.9-5.0). CONCLUSIONS: This study reveals Chinese college students' heavy reliance on OHI to manage their own and others' health without sufficient knowledge/skills to identify misinformation and disinformation. The apparent risky information-seeking behaviors of Chinese college students warrant the provision of regulated, accurate, and actionable health information; assurance of cybersecurity; and health information literacy promotion in colleges by concerned authorities.

The Early Diagnostic Value of Serum Interleukin-8 in Esophagogastric Junction Adenocarcinoma.

BACKGROUND: Esophagogastric junction adenocarcinoma (EJA) is one of the most common malignant tumors of digestive tract with high mortality worldwide. Given a lack of early diagnosis biomarkers, the prognosis of EJA is poor. Non-invasive biomarkers for early-stage EJA are urgently required. OBJECTIVE: We aimed at evaluating the early diagnostic value of serum interleukin-8 (IL-8) level in EJA patients. METHODS: The IL-8 mRNA expression data were analyzed based on the stomach cardia adenocarcinoma samples of The Cancer Genome Atlas (TCGA) database. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of serum IL-8 in 95 EJA patients and 95 normal controls enrolled from 2 different cancer hospitals. The diagnostic accuracy of serum IL-8 was evaluated by applying Mann-Whitney U test and receiver operating characteristic (ROC) curve. RESULTS: The mRNA expression levels and serum levels of IL-8 in EJA group were significantly higher than those in the normal group (all P < 0.001). The areas under the ROC curve (AUC) were 0.661 (95% CI, 0.583-0.740) and 0.745 (95% CI, 0.606-0.885), with the sensitivities of 43.2% (95% CI, 33.2%-53.7%) and 66.7% (95% CI, 46.0%-82.8%) and the specificities of 87.4% (95% CI, 78.6%-93.1%) in EJA group and early-EJA group, respectively, when the optimal cutoff value was 109.086 pg/mL. The clinical data analysis showed there were significant correlations between patient genders, depth of invasion, lymph node metastasis, TNM stage and the serum level of IL-8 (all P < 0.05). CONCLUSIONS: Serum IL-8 represents a potential diagnostic biomarker to identify early-stage EJA.

Role of Small GTPase RhoA in DNA Damage Response.

Accumulating evidence has suggested a role of the small GTPase Ras homolog gene family member A (RhoA) in DNA damage response (DDR) in addition to its traditional function of regulating cell morphology. In DDR, 2 key components of DNA repair, ataxia telangiectasia-mutated (ATM) and flap structure-specific endonuclease 1 (FEN1), along with intracellular reactive oxygen species (ROS) have been shown to regulate RhoA activation. In addition, Rho-specific guanine exchange factors (GEFs), neuroepithelial transforming gene 1 (Net1) and epithelial cell transforming sequence 2 (Ect2), have specific functions in DDR, and they also participate in Ras-related C3 botulinum toxin substrate 1 (Rac1)/RhoA interaction, a process which is largely unappreciated yet possibly of significance in DDR. Downstream of RhoA, current evidence has highlighted its role in mediating cell cycle arrest, which is an important step in DNA repair. Unraveling the mechanism by which RhoA modulates DDR may provide more insight into DDR itself and may aid in the future development of cancer therapies.

Rho GTPases in cancer radiotherapy and metastasis.

Despite treatment advances, radioresistance and metastasis markedly impair the benefits of radiotherapy to patients with malignancies. Functioning as molecular switches, Rho guanosine triphosphatases (GTPases) have well-recognized roles in regulating various downstream signaling pathways in a wide range of cancers. In recent years, accumulating evidence indicates the involvement of Rho GTPases in cancer radiotherapeutic efficacy and metastasis, as well as radiation-induced metastasis. The functions of Rho GTPases in radiotherapeutic efficacy are divergent and context-dependent; thereby, a comprehensive integration of their roles and correlated mechanisms is urgently needed. This review integrates current evidence supporting the roles of Rho GTPases in mediating radiotherapeutic efficacy and the underlying mechanisms. In addition, their correlations with metastasis and radiation-induced metastasis are discussed. Under the prudent application of Rho GTPase inhibitors based on critical evaluations of biological contexts, targeting Rho GTPases can be a promising strategy in overcoming radioresistance and simultaneously reducing the metastatic potential of tumor cells.

Serum interleukin-8 as a potential diagnostic biomarker in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has poor prognosis mainly due to the difficulty of making early diagnosis. Therefore, novel biomarkers are critically needed. OBJECTIVE: We aimed to investigate the diagnostic value of serum interleukin-8 (IL-8) in ESCC. METHODS: Data mining of TCGA was used to analyze expression level of IL-8 mRNA in esophageal carcinoma. Serum levels of IL-8 were measured in 103 ESCC patients and 86 normal controls by ELISA. Receiver operating characteristic (ROC) curve was used to evaluate its diagnostic accuracy. RESULTS: IL-8 mRNA expression level and serum IL-8 concentration were both statistically higher in patients than normal controls (P< 0.001). ROC curve demonstrated that the optimum diagnostic cut-off for serum IL-8 was 80.082 pg/mL, providing an area under the curve (AUC) of 0.694 (95% CI: 0.620-0.768), with specificity of 86.0% and sensitivity of 42.7%. The AUC for early-stage ESCC was 0.618 (95% CI: 0.499-0.737), with sensitivity of 35.3% and specificity of 86.0%. Kaplan-Meier analysis and the log-rank test indicated that IL-8 may not be a prognostic predictor for ESCC. CONCLUSIONS: Serum IL-8 was highly expressed in ESCC patients and may be a potential marker for early diagnosis of ESCC.

Rho GTPases: Promising candidates for overcoming chemotherapeutic resistance.

Despite therapeutic advances, resistance to chemotherapy remains a major challenge to patients with malignancies. Rho GTPases are essential for the development and progression of various diseases including cancer, and a vast number of studies have linked Rho GTPases to chemoresistance. Therefore, understanding the underlying mechanisms can expound the effects of Rho GTPases towards chemotherapeutic agents, and targeting Rho GTPases is a promising strategy to downregulate the chemo-protective pathways and overcome chemoresistance. Importantly, exceptions in certain biological conditions and interactions among the members of Rho GTPases should be noted. In this review, we focus on the role of Rho GTPases, particularly Rac1, in regulating chemoresistance and provide an overview of their related mechanisms and available inhibitors, which may offer novel options for future targeted cancer therapy.

Computational Prediction of Hot Spots and Binding Site of Inhibitor NSC23766 on Rac1 Binding With Tiam1.

Rac1 is a small signaling protein, which belongs to the Rho subfamily of Ras superfamily. It is activated by binding GTP and inactivated by exchanging GDP for GTP. The ability of nucleotide exchange depends on guanine nucleotide exchange factors (GEFs) family proteins. T-lymphoma invasion and metastasis factor 1 (Tiam1) is a member of GEFs. Rac1 participates in multiple signaling pathways and regulates various cellular events by interacting with GEFs. Particularly, it is involved in the development and progression of various kinds of tumors. In this paper, we have studied the detailed interaction between Rac1 and Tiam1. Seven residues on Rac1 are predicted to be important for the interaction with Tiam1, i.e. E31, Y32, D38, N39, Y64, D65 and W56. All these residues are located on the switch 1 and 2 domains which are the interface between Rac1 and Tiam1, except W56. In addition, we analyzed how inhibitor NSC23766 interacts with Rac1. Our docking results show that NSC23766 binds to the same region as Tiam1. Several residues, i.e. F37, D38, N39, W56, Y64, L67, L70 and S71, contribute much to binding free energy. These findings are very useful for the structure-based design of inhibitors toward Rac1.

RAC1 inhibition reverses cisplatin resistance in esophageal squamous cell carcinoma and induces downregulation of glycolytic enzymes.

Development of chemoresistance remains a major challenge in treating esophageal squamous cell carcinoma (ESCC) patients despite treatment advances. However, the role of RAC1 in chemoresistance of ESCC and the underlying mechanisms remain largely unknown. In this study, we found that higher levels of RAC1 expression were associated with poorer prognosis in ESCC patients. Enhanced RAC1 expression increased cell proliferation, migration, and chemoresistance in vitro. Combination therapy using RAC1 inhibitor EHop-016 and cisplatin significantly promoted cell viability inhibition, G2/M phase cycle arrest, and apoptosis when compared to each monotherapy. Mechanistically, glycolysis was significantly downregulated in the RAC1 inhibitor monotherapy group and the combination group via inhibiting AKT/FOXO3a signaling when compared to the control group. Moreover, the silencing of RAC1 inhibited AKT/FOXO3a signaling and cell glycolysis while the upregulation of RAC1 produced an opposite effect. In murine xenograft models, the tumor volume and the expression of glycolytic enzymes were significantly reduced in combination therapy when compared to each monotherapy group. Overall, our study demonstrates that targeting RAC1 with an inhibitor overcomes cisplatin resistance in ESCC by suppressing glycolytic enzymes, which provides a promising strategy for treatment of ESCC in clinical practice.