ELMO1 ameliorates intestinal epithelial cellular senescence via SIRT1/p65 signaling in inflammatory bowel disease-related fibrosis.

Background: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD), which still lacks of reliable markers and therapeutic options. Cellular senescence has been considered an important mechanism of intestinal fibrosis, but the underlying molecular link remains elusive. Methods: Tissues were stained using α-smooth muscle actin (α-SMA), fibronectin, and collagen I as markers of myofibroblastic differentiation. Cellular senescence was confirmed through Lamin B1 staining, senescence-associated ß-galactosidase staining, and the expression of senescence-associated secretory phenotype (SASP) factors. We explored the relationship between senescence of intestinal epithelial cells (IECs) and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. The effects of irisin on cellular senescence and fibrosis were determined. Results: Here, we identify engulfment and cell motility protein 1 (ELMO1) as a novel biomarker for intestinal cellular senescence and fibrosis. In fibrostrictured tissues from patients and murine models with IBD, significantly high levels of cellular senescence score and factors were noted, which positively correlated with the fibrotic regulator fibronectin. Senescent IECs, not fibroblast itself, released SASP factors to regulate fibroblast activation. Prolonging exposure to severe and persistent injurious stimuli decreased ELMO1 expression, which dampened SIRT1 deacetylase activity, enhanced NF-κB (p65) acetylation, and thereby accelerated cellular senescence. Deletion of ELMO1 led to senescent IECs accumulation and triggered premature fibrosis in murine colitis. Furthermore, irisin, inhibiting the degradation of ELMO1, could downregulate p65 acetylation, reduce IECs senescence, and prevent incipient intestinal fibrosis in murine colitis models. Conclusions: This study reveals ELMO1 downregulation is an early symbol of intestinal senescence and fibrosis, and the altered ELMO1-SIRT1-p65 pathway plays an important role in intestinal cellular senescence and IBD-related fibrosis.

The depth of perineural invasion is an independent prognostic factor for stage II colorectal cancer.

BACKGROUND: Perineural invasion (PNI) is the invasion of nerves by cancer cells and is associated with poor survival in stage II colorectal cancer. However, PNI can be further subdivided according to the depth of invasion, and the depth of PNI has not been clearly linked to prognosis. METHOD: This study aimed to assess the prognostic value of different depths of PNI in stage II colorectal cancer. We defined PNI in the submucosal plexus and myenteric plexus as superficial perineural invasion (sup-PNI) and PNI in the subserous plexus as deep perineural invasion (deep-PNI). Patients were divided into three groups based on the depth of PNI: sup-PNI, deep-PNI and non-PNI. Then, univariate and multivariate Cox regression analyses were conducted to evaluate the role of PNI in the prognosis of stage II colorectal cancer. RESULTS: This study enrolled 3508 patients with stage II colorectal cancer who underwent resection for primary colorectal lesions between January 2013 and September 2019. Clinicopathological features, including elevated carcinoembryonic antigen (CEA) levels, T4 stage, poor differentiation, deficient DNA mismatch repair (dMMR), and vascular invasion, were correlated with deep-PNI. Multivariate analyses revealed that deep-PNI was associated with worse overall survival (OS; hazard ratio [HR], 3.546; 95% confidence interval [CI], 2.307-5.449; P < 0.001) and disease-free survival (DFS; HR, 2.921; 95% CI, 2.032-4.198; P < 0.001), compared with non-PNI. Conversely, no significant difference in OS or DFS was observed between the sup-PNI and non-PNI groups in multivariate analyses. CONCLUSIONS: The study demonstrated that the depth of PNI was an independent prognostic factor for patients with stage II colorectal cancer, and patients with deep PNI had a worse prognosis. Thus, patients with PNI require further subdivision according to the depth of invasion.

Moisture chamber goggles for the treatment of postoperative dry eye in patients receiving SMILE and FS-LASIK surgery.

BACKGROUND: The incidence of refractive surgery-related dry eye disease (DED) is rising due to the increasing popularity of corneal refractive surgery. The moisture chamber goggles (MCGs) have been shown to tear evaporation by increasing local humidity and minimizing airflow. The current study aims to evaluate the efficacy of moisture chamber goggles for refractive surgery-related DED. METHODS: In this nonrandomized open-label controlled study, 78 participants (156 eyes) receiving refractive surgery were enrolled between July 2021 and April 2022, and sequentially allocated to MGC and control groups. 39 participants were allocated to the MGC groups, of which 53.8% received small-incision lenticule extraction (SMILE) and 46.2% received femtosecond laser-assisted in situ keratomileusis (FS-LASIK), and were instructed to wear MCGs for the duration of 1 month postoperatively, in addition to the standard postoperative treatment received by the control groups (56.4% SMILE, 43.6% FS-LASIK). Participants underwent full ophthalmic examinations, including visual acuity, manifest refraction, DED evaluations, and higher-order aberrations (HOAs), both preoperatively and at routine follow-ups 1 day, 1 week, and 1 month after surgery. DED parameters included non-invasive tear film break-up time (NIBUT), tear meniscus height (TMH), conjunctival congestion, lipid layer thickness (LLT), and ocular surface disease index (OSDI) questionnaires. Student's t-test was used for comparisons between control and MCG groups, and between preoperative and postoperative parameters within groups. RESULTS: Postoperative NIBUT decreased in both SMILE and FS-LASIK control groups 1 day after the surgery (SMILE, P = 0.001; FS-LASIK, P = 0.008), but not in the corresponding MCG groups (SMILE, P = 0.097; FS-LASIK, P = 0.331). TMH in the MCG group was significantly higher at 1 week (P = 0.039) and 1 month (P = 0.015) in SMILE, and 1 day (P = 0.003) in FS-LASIK groups. In FS-LASIK participants, significantly lower HOAs and coma levels in the MCG group were observed 1 day (total HOAs, P = 0.023; coma, P = 0.004) and 1 week (total HOAs, P = 0.010, coma, P = 0.004) after surgery. No consistent statistically significant intergroup difference was observed between MCG and control groups in conjunctival congestion, LLT, and OSDI. CONCLUSIONS: MCGs effectively slowed tear evaporation, increased tear film stability, and improved HOAs in patients receiving SMILE and FS-LASIK surgeries. MCG is an effective adjuvant therapy in the comprehensive management of refractive surgery-related DED.

Combining perineural invasion with staging improve the prognostic accuracy in colorectal cancer: a retrospective cohort study.

BACKGROUND: Current guidelines only propose the importance of perineural invasion(PNI) on prognosis in stage II colon cancer. However, the prognostic value of PNI in other stages of colorectal cancer (CRC) is ambiguous. METHODS: This single-center retrospective cohort study included 3485 CRC patients who underwent primary colorectal resection between January 2013 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University. Associations of PNI with overall survival (OS) and disease-free survival (DFS) were evaluated using multivariable Cox proportional hazards regression models. In addition, interaction analyses were performed to explore the prognostic effects of PNI in different clinical subgroups. RESULTS: After median follow-up of 61.9 months, we found PNI was associated with poorer OS (adjusted hazard ratio [aHR], 1.290; 95% CI, 1.087-1.531) and DFS (aHR, 1.397; 95% CI, 1.207-1.617), irrespective of tumor stage. Interestingly, the weight of PNI was found second only to incomplete resection in the nomogram for risk factors of OS and DFS in stage II CRC patients. Moreover, OS and DFS were insignificantly different between stage II patients with PNI and stage III patients (both P > 0.05). PNI was found to be an independent prognostic factor of DFS in stage III CRC (aHR: 1.514; 95% CI, 1.211-1.892) as well. Finally, the adverse effect of PNI on OS was more significant in female, early-onset, and diabetes-negative patients than in their counterparts (interaction P = 0.0213, 0.0280, and 0.0186, respectively). CONCLUSION: PNI was an important prognostic factor in CRC, more than in stage II. The survival of patients with stage II combined with perineural invasion is similar with those with stage III. PNI in stage III CRC also suggests a worse survival.

Complement-mediated inflammation and mitochondrial energy metabolism in the proteomic profile of myopic human corneas.

Myopia is one of the most common causes of visual impairment worldwide. To identify proteins related to myopiagenesis, data-independent acquisition proteomic analysis was performed using corneal lenticules of myopic patients who underwent small incision lenticule extraction surgery. A total of 19 lenticules from 19 age and sex-matched patients were analyzed, 10 in high refractive error (HR, spherical equivalent over -6.00 D) group and 9 in low refractive error (LR, spherical equivalent between -3.00 and - 1.00 D) group. Differentially expressed proteins (DEPs) were identified by comparing the corneal proteome between the two groups. Functional analyses were performed to explore the biological pathways and interactions of the DEPs. 107 DEPs (67 upregulated and 40 downregulated in HR group, compared to LR) were identified from 2138 quantified proteins. Functional analyses indicated that upregulated proteins were primarily involved in the complement pathways and extracellular matrix (ECM) remodeling, while downregulated proteins were involved in mitochondrial energy metabolism. Western blot analysis confirmed increased complement C3a and apolipoprotein E in HR samples, further supporting the proteomics data. In conclusion, this proteomic study reveals that proteins associated with the complement system, ECM remodeling, and mitochondrial energy metabolism might be key effectors in myopiagenesis. SIGNIFICANCE: Myopia has become one of the most prevalent causes of visual impairment, especially in Asia. The underlying mechanism of myopia development is still up for debate. This study compares the proteomic profiles of high and low myopic corneas, identifying differentially expressed proteins associated with the complement system, ECM remodeling, and mitochondrial energy metabolism. The findings of this study could provide novel insights into the pathogenesis of myopia. The complement system and mitochondrial energy metabolism may provide potential therapeutic targets in the treatment and prevention of myopia.

Short-Term Impact of Different Corneal Incision Positions on Postoperative Astigmatism and Visual Quality After SMILE Surgery.

INTRODUCTION: This study aimed to evaluate the short-term impact of different incision positions on astigmatism and visual quality after small incision lenticule extraction (SMILE) surgery. METHODS: This prospective study enrolled patients who decided to have SMILE to correct myopia. Patients were randomly allocated into three groups of different incision positions (group A, B, and C with incision position at 90°, 120°, and 150° respectively). Preoperative and postoperative visual acuity, spherical equivalent, and high-order aberrations (HOAs) were measured and compared among groups. Astigmatism was analyzed with the ASSORT Group Analysis Calculator based on the Alpins method. RESULTS: A total of 148 eyes were included for analysis (48 eyes in group A, 50 eyes in group B, and 50 eyes in group C). At 1 month postoperatively, the mean uncorrected distance visual acuity (UDVA) logMAR in group A, B, and C was - 0.03, - 0.03, and - 0.04, respectively. The mean corrected distance visual acuity (CDVA) logMAR in group A, B, and C was - 0.03, - 0.04, and - 0.04, respectively (P > 0.05). The mean postoperative spherical equivalent (SE) values were - 0.01 ± 0.38, - 0.07 ± 0.39, and - 0.16 ± 0.49 (D) in group A, B, and C, respectively (P > 0.05). There was no statistically significant difference in preoperative and postoperative magnitude of astigmatism among different groups (P > 0.05). Significant differences were found in the distribution of astigmatism axis among the three groups at 1 day (P = 0.02) and 1 week (P = 0.02) postoperatively. However, such differences were no longer significant at 1 month after surgery (P > 0.05). No significant differences were found in HOAs among different groups 1 month after surgery (P > 0.05). CONCLUSION: Different incision positions have no effect on postoperative astigmatism and visual quality 1 month after SMILE surgery, though differences were found in the distribution of the astigmatism axis within 1 week after the surgery.

CD51 Intracellular Domain Promotes Cancer Cell Neurotropism through Interacting with Transcription Factor NR4A3 in Colorectal Cancer.

The abundant nervous system in intestine provides the basis for perineural invasion (PNI) of colorectal cancer (CRC). PNI is defined as the invasion of the nerves by cancer cells. Although PNI is already known to be an independent prognostic factor in CRC, the molecular mechanism underlying PNI remains obscure. In this study, we first demonstrated that CD51 could promote the neurotropism of tumor cells through cleavage with γ-secretase to generate an intracellular domain (ICD). Mechanistically, ICD of CD51 could bind to the transcription factor NR4A3, and act as a coactivator to promote the expression of downstream effectors, such as NTRK1, NTRK3, and SEMA3E. Pharmacological inhibition of γ-secretase impedes PNI mediated by CD51 in CRC both in vitro and in vivo and may become a potential therapeutic target for PNI in CRC.

Nomogram for predicting overall survival time of patients with stage IV colorectal cancer.

Background: Prognosis varies among stage IV colorectal cancer (CRC). Our study aimed to build a robust prognostic nomogram for predicting overall survival (OS) of patients with stage IV CRC in order to provide evidence for individualized treatment. Method: We collected the information of 16,283 patients with stage IV CRC in the Surveillance, Epidemiology, and End Results (SEER) database and then randomized these patients in a ratio of 7:3 into a training cohort and an internal validation cohort. In addition, 501 patients in the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) database were selected and used as an external validation cohort. Univariate and multivariate Cox analyses were used to screen out significant variables for nomogram establishment. The nomogram model was assessed using time-dependent receiver-operating characteristic curve (time-dependent ROC), concordance index (C-index), calibration curve, and decision curve analysis. Survival curves were plotted using the Kaplan-Meier method. Result: The C-index of the nomogram for OS in the training, internal validation, and external validation cohorts were 0.737, 0.727, and 0.655, respectively. ROC analysis and calibration curves pronounced robust discriminative ability of the model. Further, we divided the patients into a high-risk group and a low-risk group according to the nomogram. Corresponding Kaplan-Meier curves showed that the prediction of the nomogram was consistent with the actual practice. Additionally, model comparisons and decision curve analysis proved that the nomogram for predicting prognosis was significantly superior to the tumor-node-metastasis (TNM) staging system. Conclusions: We constructed a nomogram to predict OS of the stage IV CRC and externally validate its generalization, which was superior to the TNM staging system.

Automated medical literature screening using artificial intelligence: a systematic review and meta-analysis.

OBJECTIVE: We aim to investigate the application and accuracy of artificial intelligence (AI) methods for automated medical literature screening for systematic reviews. MATERIALS AND METHODS: We systematically searched PubMed, Embase, and IEEE Xplore Digital Library to identify potentially relevant studies. We included studies in automated literature screening that reported study question, source of dataset, and developed algorithm models for literature screening. The literature screening results by human investigators were considered to be the reference standard. Quantitative synthesis of the accuracy was conducted using a bivariate model. RESULTS: Eighty-six studies were included in our systematic review and 17 studies were further included for meta-analysis. The combined recall, specificity, and precision were 0.928 [95% confidence interval (CI), 0.878-0.958], 0.647 (95% CI, 0.442-0.809), and 0.200 (95% CI, 0.135-0.287) when achieving maximized recall, but were 0.708 (95% CI, 0.570-0.816), 0.921 (95% CI, 0.824-0.967), and 0.461 (95% CI, 0.375-0.549) when achieving maximized precision in the AI models. No significant difference was found in recall among subgroup analyses including the algorithms, the number of screened literatures, and the fraction of included literatures. DISCUSSION AND CONCLUSION: This systematic review and meta-analysis study showed that the recall is more important than the specificity or precision in literature screening, and a recall over 0.95 should be prioritized. We recommend to report the effectiveness indices of automatic algorithms separately. At the current stage manual literature screening is still indispensable for medical systematic reviews.

Increased risk of colorectal neoplasia in inflammatory bowel disease patients with post-inflammatory polyps: A systematic review and meta-analysis.

BACKGROUND: Inflammatory bowel disease (IBD) patients with post-inflammatory polyps (PIPs) may carry an increased risk of colorectal neoplasia (CRN) including dysplasia and cancer. Current guidelines recommend active colonoscopy follow-up for these patients. However, the evidence for guidelines is still poor. In addition, some recent high-quality reports present a different view, which challenges the current guidelines. We hypothesize that IBD patients with PIPs are at increased risk of CRN. AIM: To evaluate the risk of CRN in IBD patients with and without PIPs. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was performed to identify studies that compared the risk of CRN in IBD patients with and without PIPs. In addition, we screened the reference lists and citation indices of the included studies. Quality assessment was performed using the Newcastle-Ottawa Scale. Pooled odds ratio (OR) was calculated using the random-effects model to explore the final pooled effect size of the included studies and determine whether PIPs increase the risk of CRN. Sensitivity analysis, subgroup analysis, and assessment of publication bias were performed to examine the sources of heterogeneity. RESULTS: Twelve studies with 5819 IBD patients, including 1281 (22.01%) with PIPs, were considered eligible for this meta-analysis. We found that IBD patients with PIPs were at an increased risk of CRN as compared to those without PIPs [OR 2.01; 95% confidence interval (CI): 1.43-2.83]. The results were similar when colorectal cancer was used as the study endpoint (OR 2.57; 95%CI: 1.69-3.91). Furthermore, the risk of CRN was still increased (OR 1.80; 95%CI: 1.12-2.91) when restricted to ulcerative colitis patients. Heterogeneity was high among the included studies (I² = 75%). Subgroup analysis revealed that the high heterogeneity was due to the study design. Sensitivity analysis showed that the main statistical outcomes did not essentially change after excluding any one of the included studies. No significant publication bias was found in the funnel plots. CONCLUSION: IBD patients with PIPs have an increased risk of CRN as compared with those without PIPs, which support the current guidelines. However, a high-quality randomized controlled trial is warranted.

Case Report: Bilateral Corneal Ectasia Developed during Pregnancy after Small-incision Lenticule Extraction.

SIGNIFICANCE: This case highlights that hormonal changes during pregnancy could affect the biomechanical stability of the cornea and lead to corneal ectasia during pregnancy after corneal refractive surgery. PURPOSE: We report an unusual case of bilateral corneal ectasia after small-incision lenticule extraction that developed during pregnancy. CASE REPORT: A 27-year-old woman experienced post-small-incision lenticule extraction corneal ectasia. Her pre-operative corneal topography was normal, with a minimum central corneal thickness of 538 µm in the right eye and 530 µm in the left eye. The manifest refraction was -7.75 -0.25 × 180 and -7.50 -0.75 × 10, and the lenticule thickness was 140 and 139 µm in the right and left eyes, respectively. After 11 months, in her first trimester, the patient began to experience gradually deteriorating blurred vision. Two years post-operatively, corneal ectasia was diagnosed based on topographic data. The automatic optometer examination was -7.25 -2.50 × 42 in the right eye and -11.00 -5.00 × 140 in the left eye. Later, the patient underwent corneal collagen cross-linking to control further progression and was recommended to wear rigid gas-permeable contact lenses. CONCLUSIONS: Surgeons should be alert for cornea ectasia after refractive surgery in pregnant patients, as hormonal changes during pregnancy may affect corneal biomechanical stability.

Impact of conventional lipid-lowering therapy on circulating levels of PCSK9: protocol for a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: Conventional lipid-lowering agents, including statins, ezetimibe, fibrates, bile acid sequestrants, nicotinic acid, bempedoic acid and Omega-3, are essential to the management of dyslipidaemia. However, these agents have been shown to increase the level of plasma proprotein convertase subtilisin/kexin 9 (PCSK9), a serine protease associated with increased cardiovascular risk. This review aims to investigate the impact of commonly available conventional lipid-lowering agents on circulating PCSK9 levels and lipid profiles. METHODS AND ANALYSIS: This protocol is conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. A systematic search will be conducted in the following databases: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, SCOPUS and ScienceDirect. Additional information will be retrieved from clinical trial registries or from reference list searches. Published and peer-reviewed randomised controlled trials with adults receiving statin, ezetimibe, fibrate, bile acid sequestrant, nicotinic acid, bempedoic acid or Omega-3 monotherapy or in combination for at least 2 weeks, with availability of plasma PCSK9 at the beginning and end of treatment or the net changes in values, will be included. Study selection, data extraction and assessment of the risk of bias will be independently conducted by two investigators. Continuous data will be presented as a standardised mean difference with 95% confidence interval (CI) and dichotomous data as risk ratios with 95% CI. Subgroup analysis and sensitivity analysis will be performed when sufficient studies are included. Publication bias will be assessed with a funnel plot and Egger's test. ETHICS AND DISSEMINATION: Ethics approval is not required as this review will only include data from published sources. The results will be published in a peer-reviewed journal. PATIENT AND PUBLIC INVOLVEMENT: No patient or members of the general public are involved. PROSPERO REGISTRATION NUMBER: CRD42022297942.

Risk factors and incidence of suction loss during small incision lenticule extraction (SMILE) in 8493 eyes.

BACKGROUND: To report the incidence and risk factors of suction loss during small incision lenticule extraction (SMILE). METHODS: This retrospective comparative case control study included 8493 eyes of 4261 patients. Patients underwent SMILE surgery between January 2014 and September 2019 were included. Videos of suction loss were reviewed, and the direct causes of suction loss were noted. An independent samples t-test was used for comparisons between the suction loss group and the control group. A binary logistic regression model was used to determine the possible significant risk factors that might increase the likelihood of suction loss during SMILE surgery. RESULTS: Suction loss occurred in 31 (0.37%) eyes of 30 patients; 23 (74.2%) cases occurred in the right eye (the first operative eye) and 8 (25.8%) cases occurred in the left eye. Among the 30 patients, 23 (76.7%) were male and 7 (23.3%) were female. The incidence in the six consecutive years were 0, 2.13, 0.34, 0.24, 0.22, and 0.25%. Head and eye movements during surgery caused suction loss in 16 (51.6%) and 15 (48.4%) eyes, respectively. Comparison between the suction loss group and the control group showed that the first operative eye and male sex are at a significantly high risk for suction loss (p < 0.05). CONCLUSIONS: The risk factors of suction loss were first operative eye and male sex. Head and eye movements due to patient anxiety are the most common direct causes of suction loss. Surgeon's experience may help to reduce the incidence of suction loss. Preoperative education and better communication during surgery needs to be emphasized. TRIAL REGISTRATION: Retrospectively registered. ChiCTR-ORC-17011040 . Registered 1 April 2017. Name of registry: The observation of clinical results after corneal refractive surgery. Data of enrolment of the first participant to the trial: 1 January 2014.