Evaluation of nintedanib efficacy: Attenuating the lens fibrosis in vitro and vivo.

PURPOSE: Organ fibrosis is a huge challenge in clinic. There are no drugs for fibrotic cataracts treatments in clinic. Nintedanib is approved by the FDA for pulmonary fibrosis treatments. This study aims to investigate the efficacy and mechanism of nintedanib on fibrotic cataracts. METHODS: Drug efficacy was validated through TGFß2-induced cell models and injury-induced anterior subcapsular cataract (ASC) mice. A slit lamp and the eosin staining technique were applied to access the degree of capsular fibrosis. The CCK-8 assay was used to evaluate the toxicity and anti-proliferation ability of the drug. The cell migration was determined by wound healing assay and transwell assay. The anti-epithelial mesenchymal transition (EMT) and anti-fibrosis efficacy were evaluated by qRT-PCR, immunoblot, and immunofluorescence. The inhibition of nintedanib to signaling pathways was certified by immunoblot. RESULTS: Nintedanib inhibited the migration and proliferation of TGFß2-induced cell models. Nintedanib can also repress the EMT and fibrosis of the lens epithelial cells. The intracameral injection of nintedanib can also allay the anterior subcapsular opacification in ASC mice. The TGFß2/ Smad and non-Smad signaling pathways can be blocked by nintedanib in vitro and in vivo. CONCLUSION: Nintedanib alleviates fibrotic cataracts by suppressing the TGFß2/ Smad and non-Smad signaling pathways. Nintedanib is a potential drug for lens fibrosis.

Inhibition of miR-29a-3p Alleviates Apoptosis of Lens Epithelial Cells via Upregulation of CAND1.

PURPOSE: Accumulated evidence has shown that microRNAs (miRNAs) are closely related to the pathogenesis and progression of senile cataracts. Here we investigate the effect of miR-29a-3p in cataractogenesis and determined the potential molecular mechanism involved. METHODS: In this study, we constructed a selenite cataract model in rats and obtained the miRNAs related to cataracts by whole transcriptome sequencing. To investigate the effect and mechanism of miR-29a-3p on cataracts, we performed several in vivo and in vitro experiments, including CCK8 assay, flow cytometry, luciferase reporter assay, Edu assay, and western blot analysis. RESULT: Sequencing data showed downregulation of miR-29a-3p in rats with selenite cataracts. Down-regulation of miR-29a-3p could promote lens epithelial cells (SRA01/04) proliferation and inhibit cell apoptosis, and miR-29a-3p silence could inhibit the development of cataracts. Additionally, CAND1 was a direct target gene for miR-29a-3p. CONCLUSION: These data demonstrate that miR-29a-3p inhibits apoptosis of lens epithelial cells by regulating CAND1, which may be a potential target for senile cataracts.

The burden of vision loss due to cataract in China: findings from the Global Burden of Disease Study 2019.

OBJECTIVE: To provide a reference for future policy and measure formulation by conducting a detailed analysis of the burden of vision loss due to cataract by year, age, and gender in China from 1990 to 2019. METHODS: Data on the prevalence and disability-adjusted life-years (DALYs) due to cataract in China and neighboring and other G20 countries were extracted from the 2019 Global Burden of Disease (GBD) study to observe the changing trends of vision loss. RESULTS: The number and rate of all-age prevalence and DALYs for cataract in China increased significantly from 1990 to 2019. The age-standardized DALYs rate witnessed a slowly declining trend by 10.16%. And the age-standardized prevalence increased by 14.35% over the 30-year period. Higher prevalence and DALYs were observed in female population from 1990 through 2019, with little improvement over the decades(all p < 0.001). The disease burden of cataract is higher in middle-aged and elderly people. Blindness accounted for the largest proportion of vision impairment burden caused by cataract in China. The age-standardized prevalence and DALY rate of cataract in China were lower than those in India and Pakistan, but higher than those in Russia, South Korea, North Korea, Singapore, and Japan. CONCLUSIONS: In the past 30 years, although the age-standardized DALYs rate has decreased slightly in China, the all-age prevalence and DALYs have both increased. This study highlights the importance of reducing cataract burden by providing timely and easily accessible quality care, especially in females and the elderly population.

Transcriptome sequencing and microRNA-mRNA regulatory network construction in the lens from a Na2SeO3-induced Sprague Dawley rat cataract model.

BACKGROUND: A sight-threatening, cataract is a common degenerative disease of the ocular lens. This study aimed to explore the regulatory mechanism of age-related cataract (ARC) formation and progression. METHODS: Cataracts in Sprague Dawley rats were induced by adopting the method that injected selenite subcutaneously in the nape. We performed high-throughput RNA sequencing technology to identify the mRNA and microRNA(miRNA) expression profiles of the capsular membrane of the lens from Na2SeO3-induced and saline-injected Sprague Dawley rats. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to forecast the regulatory and functional role of mRNAs in cataracts by DAVID and Metascape. The protein-protein interaction(PPI) network of differentially expressed mRNA(DEmRNAs) was built via the STRING. Target miRNAs of hub genes were predicted by miRBD and TargetScan. Furthermore, differentially expressed miRNA(DEmiRNAs) were selected as hub genes' targets, validated by quantitative real-time polymerase chain reaction(qRT-PCR), and a DEmiRNA-DEmRNA regulatory network was constructed via Cytoscape. RESULT: In total, 329 DEmRNAs including 40 upregulated and 289 downregulated genes were identified. Forty seven DEmiRNAs including 29 upregulated and 18 downregulated miRNAs were detected. The DEmRNAs are involved in lens development, visual perception, and aging-related biological processes. A protein-protein interaction network including 274 node genes was constructed to explore the interactions of DEmRNAs. Furthermore, a DEmiRNA-DEmRNA regulatory network related to cataracts was constructed, including 8 hub DEmRNAs, and 8 key DEmiRNAs which were confirmed by qRT-PCR analysis. CONCLUSION: We identified several differentially expressed genes and established a miRNA-mRNA-regulated network in a Na2SeO3-induced Sprague Dawley rat cataract model. These results may provide novel insights into the clinical treatment of cataracts, and the hub DEmRNAs and key DEmiRNAs could be potential therapeutic targets for ARC.

CircRNA 06209 inhibits cataract development by sponging miR-6848-5p and regulating ALOX15 expression.

Cataract is the leading cause of blindness in the world, and there is a lack of effective treatment drugs. CircRNA plays an important part in a variety of diseases, however, the role of circRNA in cataracts remains largely unknown. In this study, we constructed a cataract model of rats and obtained the circRNAs related to cataracts by whole transcriptome sequencing and circRNA-mRNA co-expression network. To investigate the effect and mechanism of circRNA 06209 on cataracts, we performed several in vivo and in vitro experiments, including CCK8 assay, flow cytometry, dual luciferase reporter assay, RIP assay, actinomycin D assay, and Western blot analysis. We identify that a necroptosis-related circRNA, circRNA 06209, is down-regulated in cataracts. Vitro experiments showed that up-regulation of circRNA 06209 could promote cell proliferation and inhibit cell apoptosis. Vivo experiments revealed that circRNA 06209 overexpression could inhibit the development of cataracts. Mechanistically, circRNA 06209 acts as a miRNA sponge and competitively binds to miR-6848-5p to curb the inhibitory effect of miR-6848-5p on ALOX15, thereby affecting cell viability and apoptosis. This study found that circRNA 06209 plays a critical part in inhibiting cataracts through the miR-6848-5p/ALOX15 pathway, suggesting that circRNA 06209 may be a promising therapeutic target for cataracts.

Targeted delivery of AZD5363 to T-cell acute lymphocytic leukemia by mSiO2-Au nanovehicles.

T-cell acute lymphocytic leukemia (T-ALL) is the most common cancer in children, with a low survival rate because of drug resistance and a high recurrence rate. Targeted delivery of chemotherapy drugs can reduce their side effects and improve their efficacy. The abnormality of phosphatidylinositol-3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway plays a key role in T-ALL occurrence. AZD5363 is a selective Akt inhibitor with promising therapeutic potential for tumors encoded by the PI3K/Akt/mTOR pathway. However, the toxicity and side effects have limited its application in treating T-ALL. This study aimed to design a delivery system for targeting AZD5363 to T-ALL by sgc8c aptamer designed as mesoporous silica (mSiO2) decorated with Au nanoparticles. The cell-specific targeting and cytotoxicity of mSiO2-Au-AZD5363-Apt were investigated. The mSiO2-Au nanovehicles were found feasible for AZD5363 delivery, with high loading efficiency and pH-responsive release in the acidic lysosome. More importantly, mSiO2-Au-AZD5363-Apt nanovehicles could specifically recognize and enter T-ALL cells in vitro and in vivo, effectively inhibiting the proliferation of CCRF-CEM cells. In conclusion, mSiO2-Au-AZD5363-Apt provided an effective therapeutic method for the targeted treatment of T-ALL.

Case Report: A case of hepatocellular carcinoma with aberrant right hepatic artery treated with transarterial chemoembolization and infusion chemotherapy separately to bilobar lesion combining with systemic therapies and sequential hepatectomy.

Background: Hepatocellular carcinoma (HCC) with a dismal prognosis is the second most deadly malignancy globally. Surgery is believed to be a curative approach. Nevertheless, there is still a considerable probability of postoperative recurrence. Most patients present in advanced stages with a surgically and oncologically unresectable disease. Systemic medicines are increasingly important to downstage the disease and further improve survival. Case summary: A 67-year-old Chinese man with uncontrolled hepatitis B was discovered to have liver masses with abnormal serum vitamin K absence or antagonist-II (PIVKA-II) level during checkup for upper abdominal discomfort. Abdominal multiphase computerized tomography (CT) and gadoxetate disodium-enhanced magnetic resonance imaging (MRI) showed the bulky bilobar HCCs of Barcelona Clinic Liver Cancer stage B and China Liver Cancer Staging stage IIa. Furthermore, the aberrant right hepatic artery (RHA) originates from the superior mesenteric artery. Due to the location being adjacent to important vasculatures and massive size of the right-sided lesion, curative resection appears to be challenging. To achieve a favorable surgical margin, repeated hepatic arterial infusion chemotherapy (HAIC) was adopted through the variant RHA, while transarterial chemoembolization (TACE) was delivered to the left lobe to arrest tumor growth. Furthermore, sintilimab plus lenvatinib served as the sequential systemic therapy. After 5 months of conversion treatment, the partial response with a decreased serum PIVKA-II level was attained. The R0 hepatectomy was then performed without postoperative complications. The immunohistochemistry and next-generation sequencing results suggested that the two-side HCCs existing tumor heterogeneity were not completely consistent. The patient continues to be without evidence of disease. Conclusion: Our case highlights a favorable outcome in a man with bilobar bulky HCC after undergoing the comprehensive therapeutic schedule that includes personalized intervention and systemic drug therapy. In terms of conversion therapy, our case provides a secure and practical reference for managing unresectable bilobar HCC coexisting with the aberrant hepatic artery.

Preoperative incidence and risk factors of deep vein thrombosis in patients with an isolated patellar fracture.

PURPOSE: This study aimed to investigate the incidence, location, and related factors of preoperative deep venous thrombosis (DVT) in patients with isolated patellar fractures. METHODS: Patients with an isolated patellar fracture, admitted between January 2013 and December 2019 at our institution, were retrospectively analyzed. Upon admission, patients underwent routine Doppler ultrasound scanning (DUS) of the bilateral lower extremities to detect DVT; those with DVT were assigned to the case group and those without DVT to the control group. Patients in both groups did not perform preoperative off-bed weight-bearing exercises. Data on demographics, comorbidities, and laboratory test results upon admission were extracted. Variables were evaluated between the two groups using univariate analyses, and independent risk factors associated with DVT were identified by logistic regression analysis. RESULTS: During the study period, 827 patients were included, of whom 5.8% (48/827) were found to have preoperative DVT. In DVT patients, 85.4%(41/48) were injured, 8.3%(4/48) were not injured, and 6.3%(3/48) were lower limbs. Multivariate analysis showed that male (male vs. female, odds ratio, OR = 2.25), delayed from injury to DUS (in each day, OR = 1.29), and elevated plasma D-dimer level (> 0.5 µg/mL, OR = 2.47) were independent risk factors associated with DVT. CONCLUSIONS: Despite the low prevalence of DVT after an isolated patellar fracture, this study underscores the importance of identifying those with a high risk of DVT, especially those with multiple identifiable factors, and encourage the early targeted use of anti-thromboembolic agents to reduce DVT occurrence.

Incidence and risk factors associated with preoperative deep venous thrombosis in the young and middle-aged patients after hip fracture.

OBJECTIVE: This study aims to investigate the incidence, occurrence timing and locations of preoperative DVT and identify the associated factors in this group. METHODS: A retrospective analysis of collected data in young and middle-aged (18-59 years) patients who presented with hip fracture between October 2015 and December 2018 was conducted. Before operation, patients were routinely examined for DVT by Duplex ultrasonography (DUS). Electronic medical records were retrieved to collect the data, involving demographics, comorbidities, injury and laboratory biomarkers after admission. Multivariate logistic regression analysis was performed to identify factors that were independently associated with DVT. RESULTS: Eight hundred and fifty-seven patients were included, and 51 (6.0%) were diagnosed with preoperative DVT, with 2.5% for proximal DVT. The average age of patients with DVT is 48.7 ± 9.4 year, while that of patients without DVT is 45.0 ± 10.9 year. The mean time from injury to diagnosis of DVT was 6.8 ± 5.5 days, 43.1% cases occurring at day 2-4 after injury. Among 51 patients with DVT, 97 thrombi were found. Most patients had thrombi at injured extremity (72.5%), 19.6% at uninjured and 7.8% at bilateral extremities. There are significantly difference between patients with DVT and patients without DVT in term of prevalence of total protein (41.2% vs 24.4%, P = 0.008), albumin (54.9% vs 25.6%, P = 0.001), low lactate dehydrogenase (51.0% vs 30.3%, P = 0.002), lower serum sodium concentration (60.8% vs 29.9%, P = 0.001), lower RBC count (68.6% vs 37.0%, P = 0.001), lower HGB (51.0% vs 35.1%, P = 0.022), higher HCT (86.3% vs 35.1%, P = 0.022) and higher platelet count (37.3% vs 11.3%, P = 0.001). The multivariate analyses showed increasing age in year (OR 1.04, 95% CI; P = 0.020), delay to DUS (OR, 1.26; P = 0.001), abnormal LDH (OR, 1.45; P = 0.026), lower serum sodium concentration (OR, 2.56; P = 0.007), and higher HCT level (OR, 4.11; P = 0.003) were independently associated with DVT. CONCLUSION: These findings could be beneficial in informed preventive of DVT and optimized management of hip fracture in specific group of young and mid-aged patients.

Surgeon volume and the risk of deep surgical site infection following open reduction and internal fixation of closed tibial plateau fracture.

BACKGROUND: Emerging evidences supported that the surgeon case volume significantly affected post-operative complications or outcomes following a range of elective or non-elective orthopaedic surgery; no data has been available for surgically treated tibial plateau fractures. We aimed to investigate the relationship between surgeon volume and the risk of deep surgical site infection (DSSI) following open reduction and internal fixation (ORIF) of closed tibial plateau fracture. METHODS: This was a further analysis of the prospectively collected data. Adult patients undergoing ORIF procedure for closed tibial plateau fracture between January 2016 and December 2019 were included. Surgeon volume was defined as the number of surgically treated tibial fractures in the preceding 12 months and dichotomized on the basis of the optimal cut-off value determined by the receiver operating characteristic (ROC) curve. The outcome was DSSI within one year post-operatively. Multiple multivariate logistic models were constructed for "drilling down" adjustment of confounders. Sensitivity and subgroup analyses were performed to assess the robustness of outcome and identify the "optimal" subgroups. RESULTS: Among 742 patients, 20 (2.7%) had a DSSI and 17 experienced re-operations. The optimal cut-off value for case volume was nine, and the low-volume surgeon was independently associated with 2.9-fold (OR, 2.9; 95%CI, 1.1 to 7.5) increased risk of DSSI in the totally adjusted multivariate model. The sensitivity analyses restricted to patients with original BMI data or those operated within 14 days after injury did not alter the outcomes (OR, 2.937, and 95%CI, 1.133 to 7.615; OR, 2.658, and 95%CI, 1.018 to 7.959, respectively). The subgroup analyses showed a trend to higher risk of DSSI for type I-IV fractures (OR, 4.6; 95%CI, 0.9 to 27.8) classified as Schatzker classification and substantially higher risk in patients with concurrent fractures (OR, 6.1; 95%CI, 1.0 to 36.5). CONCLUSION: The surgeon volume is independently associated with the rate of DSSI, and a number of ≥ nine cases/year are necessarily kept for reducing DSSIs; patients with concurrent fractures should be preferentially operated on by high-volume surgeons.

Plasma lncRNA FEZF1-AS1 as a potential biomarker for diagnosis of non-small-cell lung carcinoma.

Diagnosis of numerous cancers has been closely linked to the expression of certain long non-coding RNAs. This study aimed to evaluate levels of plasma FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) relative to non-small-cell lung carcinoma (NSCLC) diagnosis.The level of FEZF1-AS1 in the blood plasma of 126 NSCLC patients and 62 healthy controls was examined by quantitative real-time polymerase chain reaction.Plasma FEZF1-AS1 of the NSCLC group was increased compared with that in the control group (P < .0001). Plasma FEZF1-AS1 could distinguish patients with NSCLC from healthy individuals via the area under the ROC curve (AUC) of 0.855 (95% CI = 0.800-0.909; P = .000). FEZF1-AS1 combined with neuron-specific enolase increased the area under the (ROC) curve to 0.932 (95% CI = 0.897-0.968; P = .018). A high expression level of plasma FEZF1-AS1 was associated with some clinical features of NSCLC. Increased expression of FEZF1-AS1 greatly improved the risk of NSCLC (adjusted OR = 2.42; 95% CI = 1.23-4.76). A significant concentration-dependent relationship was noted between risk of NSCLC and higher FEZF1-AS1 expression (P for trend <.001).Plasma FEZF1-AS1 could potentially be used as a biomarker for NSCLC diagnosis.

Focal shift in metasurface based lenses.

In this paper, the focal shift issues of squared metasurface lenses are investigated. Axial intensity distribution formula of the squared planar lens model is obtained by utilizing traditional diffraction theories combining with the Fresnel approximation method. Fresnel integral and Cornu spiral are adopted to obtain the relations between the relative focal shift and Fresnel number, which can be used to predict the shift for different Fresnel numbers. In the far infrared region (at 10.6µm), a group of C-shaped nanoantennas are designed to cover the phase shift from 0 to 2π and simulations also performed by using finite-difference time-domain (FDTD) method. Several lenses are arranged by those resonators, and simulation results of focusing performance are in good agreement with the theoretical prediction. It's expected that this work will provide a better solution for the design of lens in the infrared integrated optical systems.