Effect of Food, Crushing of Tablets, and Antacid Coadministration on Maribavir Pharmacokinetics in Healthy Adult Participants: Results From 2 Phase 1, Open-Label, Randomized, Crossover Studies.

The effect of food composition, tablet crushing, and antacid coadministration on maribavir pharmacokinetics was assessed in 2 Phase 1 studies in healthy adults. In the first, a single maribavir 400-mg dose was administered under fasting conditions, with a low-fat/low-calorie or a high-fat/high-calorie meal. In the second, a single maribavir 100-mg dose was administered under fasting conditions, as a crushed tablet, or as a whole tablet alone or with an antacid. The 90% confidence intervals of the geometric mean ratios were within 80%-125% for area under the concentration-time curve (AUC), but not for maximum plasma concentration (Cmax) for low-fat/low-calorie and high-fat/high-calorie meals versus fasting or for whole tablet with antacid versus whole tablet alone. The 90% confidence intervals of the geometric mean ratios for AUC and Cmax were within 80%-125% for crushed versus whole tablet. Maribavir median time to Cmax value in plasma under fed conditions was delayed versus fasting conditions, but there was no statistical difference for crushed versus whole tablet or with versus without antacid. As the antiviral efficacy of maribavir is driven by AUC but not Cmax, findings suggest that maribavir can be administered with food or antacids or as a crushed tablet.

Enumeration and Molecular Characterization of Circulating Tumor Cell Using an Epithelial Cell Adhesion Molecule/Vimentin/Epidermal Growth Factor Receptor Joint Capture System in Lung Cancer.

Background: Detection rate and isolation yield of circulating tumor cells (CTCs) are low in lung cancer with approaches due to CTC invasiveness and heterogeneity. In this study, on the basis of the epithelial cell adhesion molecule (EpCAM) phenotype, markers of vimentin and epidermal growth factor receptor (EGFR) phenotype were added to jointly construct a precise and efficient CTC capture system for capture of lung cancer CTCs. Methods: A CTC capture system combined with EpCAM lipid magnetic bead (Ep-LMB)/vimentin lipid magnetic bead (Vi-LMB)/EGFR lipid magnetic bead (EG-LMB) was constructed, and its performance was tested. The amount of CTC captured in the blood of patients with lung cancer was detected by immunofluorescence identification and analyzed for clinical relevance. Results: The constructed CTC capture system has low cytotoxicity. The capture efficiency of lung cancer cells in phosphate belanced solution (PBS) system was 95.48%. The capture efficiency in the blood simulation system is 94.55%. The average number of CTCs in the blood of patients with lung cancer was 9.73/2 mL. The quantity distribution of CTCs is significantly correlated with tumor staging and metastasis. The area under the curve (AUC) of CTCs for the diagnosis of lung cancer was 0.9994 (95% CI = 0.9981-1.000, P < .0001). The cutoff value was 4.5/2 mL. The sensitivity was 99.39%, and the specificity was 96.88%. Conclusion: The EpCAM/vimentin/EGFR combined capture system has feasibility and high sensitivity in the detection of lung cancer CTC typing, which can be used as an auxiliary diagnostic indicator for lung cancer and is expected to promote the clinical application of CTCs.

LncRNA PRKCA-AS1 promotes LUAD progression and function as a ceRNA to regulate S100A16 by sponging miR-508-5p.

Objective: This study aimed to elucidate the underlying mechanism of LncRNA PRKCA-AS1 in lung adenocarcinoma (LUAD). Methods: The expression of LncRNA PRKCA-AS1, miR-508-5p and S100A16, in LUAD tissues or cell lines (NCI-H520 and H1299) was analyzed with qRT-PCR. The clinical diagnostic value of LncRNA PRKCAAS1, miR-508-5p and S100A16 in LUAD were analyzed by receptor operating characteristic (ROC) curve. Then we knockdown or overexpression of PRKCAAS1 in NCI-H520 and H1299 cells, and the cell function test was applied to detect the activity and metastasis level of cells in different transfection groups. Then Pearson correlation analysis was used for the correlation between miR-508-5p and PRKCA-AS1. The dual-luciferase reporter experiment and CHIRP analysis was conducted to verify the target binding relationship of PRKCA-AS1, miR-508-5p or S100A16. FISH assay analyzed the colocalization of PRKCA-AS1 and miR-508-5p in NCI-H520 and H1299 cells. Rescue experiment and tumorigenesis experiment in nude mice further explore the regulatory mechanisms of LncRNA PRKCA-AS1, miR-508-5p and S100A16 on LUAD progression in vitro and in vivo. Results: From the results, PRKCA-AS1 and S100A16 were up-regulated in LUAD tissues, while miR-508-5p was downregulated compared with the adjacent tissues. And gain-of-function revealed that PRKCA-AS1 knock-down apparently suppressed the cell proliferation and metastasis, whereas miR-508-5p inhibitors or S100A16 overexpression showed a opposite effect. In addition, there is evidence that PRKCA-AS1, miR-508-5p and S100A16 have a targeted regulatory relationship. Moreover, rescue experiment and tumorigenesis experiment in nude mice further confirmed that LncRNA PRKCA-AS1 regulates S100A16 through sponging miR-508-5p to regulate LUAD progression in vitro and in vivo. Conclusion: These results demonstrated that LncRNA PRKCA-AS1 might regulate LUAD by acting as a ceRNA via sponging miR-508-5p and regulating S100A16 expression, indicating that manipulation of PRKCA-AS1 might be a potential therapeutic strategy in LUAD.

Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy for Refractory or Resistant Cytomegalovirus Infection in Transplant Recipients.

BACKGROUND: This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders). METHODS: Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27. RESULTS: At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n = 1) and UL97 F342Y (n = 3). Posttreatment, emergent maribavir resistance mutations were detected in 60 (26%) of those randomized to maribavir, including 49 (48%) of 103 nonresponders and 25 (86%) of the 29 nonresponders where viral DNA initially cleared then rebounded while on maribavir. The most common maribavir resistance mutations were UL97 T409M (n = 34), H411Y (n = 26), and C480F (n = 21), first detected 26 to 130 (median 56) days after starting maribavir. CONCLUSIONS: Baseline maribavir resistance was rare. Drug resistance to standard cytomegalovirus antivirals did not preclude treatment response to maribavir. Rebound in plasma cytomegalovirus DNA while on maribavir strongly suggests emerging drug resistance. CLINICAL TRIALS REGISTRATION: NCT02931539.

Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir.

BACKGROUND: Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir. METHODS: In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%). CONCLUSIONS: Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].

Pharmacokinetics and Safety Evaluation of Maribavir in Healthy Japanese and Matched White Participants: A Phase 1, Open-Label Study.

This phase I study compared pharmacokinetics and safety of maribavir in Japanese and White participants, and evaluated dose proportionality in Japanese participants. Under fasting conditions, 12 healthy adult participants of Japanese descent and 12 matched White participants received a single 400-mg dose of maribavir. Japanese participants received 2 further doses of maribavir: 200 mg and 800 mg, or 800 mg and 200 mg, separated by a ≥72-hour washout period. Serial blood samples were collected up to 24 hours after dosing for pharmacokinetic assessments. Following the 400-mg dose, the geometric mean ratios (90% confidence interval) of Japanese versus White participants were 110% (91.7%-133%) for maximum plasma concentration, 122% (96.8%-155%) for area under the plasma concentration-time curve (AUC) from time of dosing to the last measurable concentration, and 125% (98.0%-160%) for AUC extrapolated to infinity. In Japanese participants, maribavir AUC extrapolated to infinity and AUC from time of dosing to the last measurable concentration increased in a dose-proportional fashion over 200-800 mg; maximum plasma concentration increased less than dose proportionally. Seven participants reported treatment-emergent adverse events (TEAEs; Japanese participants, 400 mg: 2 [16.7%], 200 mg: 1 [8.3%]; White participants, 400 mg: 4 [33.3%]), all mild and most commonly dysgeusia. No serious TEAEs or TEAEs leading to discontinuation were reported. This study demonstrated higher maribavir systemic exposure in Japanese than White participants and similar safety outcomes. This difference in exposure is not considered clinically important and its significance remains to be determined.

miR-508-5p serves as an anti-oncogene by targeting S100A16 to regulate AKT signaling and epithelial-mesenchymal transition process in lung adenocarcinoma cells.

BACKGROUND: Our aim was to expose the effect of miR-508-5p on the developmental and biological behaviour of lung adenocarcinoma (LUAC). METHODS: The KM plotter was used to analyze the survival significance of miR-508-5p and S100A16 expression in LUAC patients. qRT-PCR was performed to detect the expression of miR-508-5p and S100A16 in LUAC tissue and LUAC cell lines. CCK8, colony formation and Transwell were performed to evaluate the effects of miR-508-5p and S100A16 on cell proliferation and metastasis. Dual luciferase reporter assay was used to verify that S100A16 were targets of miR-508-5p. Western blot analysis was performed to analyze protein expression. RESULTS: Results showed that low miR-508-5p expression in LUAC tissues indicated poorer overall survival of LUAC patients and miR-508-5p was downregulated in LUAC cell lines compared to the normal human lung epithelial cell line. miR-508-5p mimics could inhibit A549 cell proliferation and metastasis abilities, while miR-508-5p Antagomir showed the opposite effect. We identified S100A16 as one direct target of miR-508-5p, and rescuing S100A16 expression could reverse the effect of miR-508-5p mimics on A549 cell proliferation and metastasis. miR-508-5p could involve the coordination of AKT signaling and epithelial-mesenchymal transition (EMT) progress using western-blot assays and rescuing S100A16 expression could reverse the inhibited AKT signaling and EMT progress induced by miR-508-5p mimics. CONCLUSIONS: We found that miR-508-5p targeted S100A16 to regulate AKT signaling and EMT progress in A549 cells, resulting in impaired cell proliferation and metastasis activity, suggesting that miR-508-5p might be a promising therapeutic target and an important diagnostic and prognostic marker for improved LUAC therapeutic schedule.

Maribavir Pharmacokinetics and Safety in Participants With Moderate Hepatic Impairment: A Phase 1, Open-Label, Single-Dose, Parallel Group Study.

Maribavir, an orally bioavailable antiviral, has shown superior activity against posttransplant cytomegalovirus infection compared with conventional antivirals. It is primarily metabolized in the liver. This open-label, single-center study evaluated the effect of hepatic impairment on the pharmacokinetics of maribavir in nontransplant participants. A single 200-mg dose of maribavir was administered orally under fasting conditions to participants with moderate hepatic impairment (Child-Pugh class B) (n = 10) and healthy controls (n = 10) matched for age, weight, sex, and smoking status. Compared with participants with normal hepatic function, maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 to infinity values for maribavir in participants with moderate hepatic impairment were 1.346-fold (90%CI of geometric mean ratio, 1.091-1.660) and 1.261-fold (0.889-1.787) higher, respectively. However, Cmax and AUC values for unbound maribavir were comparable. For VP 44469, the main metabolite of maribavir, the Cmax and AUC from time 0 to infinity values were 1.190-fold (0.836-1.693) and 1.309-fold (1.007-1.702) higher, respectively, in participants with moderate hepatic impairment. In total, 7 mild treatment-emergent adverse events were reported, all in the moderate hepatic impairment group. Dysgeusia was the most frequently reported treatment-emergent adverse event, at a frequency of 50%. These results indicated that total maribavir concentrations were mildly increased in participants with moderate hepatic impairment, while unbound concentrations were unaffected. Similar maribavir pharmacokinetics in participants with moderate hepatic impairment and normal hepatic function suggest that dose adjustment may not be required for patients with moderate hepatic impairment.

C1QTNF6 regulated by miR-29a-3p promotes proliferation and migration in stage I lung adenocarcinoma.

OBJECTIVE: C1QTNF6 has been implicated as an essential component in multiple cellular and molecular preliminary event, including inflammation, glucose metabolism, endothelial cell modulation and carcinogenesis. However, the biological process and potential mechanism of C1QTNF6 in lung adenocarcinoma (LUAD) are indefinite and remain to be elucidated. Therefore, we investigated the interaction among the traits of C1QTNF6 and LUAD pathologic process. METHODS: RT-qPCR and western blot were conducted to determine the expression levels of C1QTNF6. RNA interference and overexpression of C1QTNF6 were constructed to identify the biological function of C1QTNF6 in cellular proliferative, migratory and invasive potentials in vitro. Dual-luciferase reporter assay was applied to identify the possible interaction between C1QTNF6 and miR-29a-3p. Moreover, RNA sequencing analysis of C1QTNF6 knockdown was performed to identify the potential regulatory pathways. RESULTS: C1QTNF6 was upregulated in stage I LUAD tissues compared with adjacent non-cancerous tissues. Concurrently, C1QTNF6 knockdown could remarkably inhibit cell proliferation, migratory and invasive abilities, while overexpression of C1QTNF6 presented opposite results. Additionally, miR-29a-3p may serve as an upstream regulator of C1QTNF6 and reduce the expression of C1QTNF6. Subsequent experiments showed that miR-29a-3p could decrease the cell mobility and proliferation positive cell rates, as well as reduce the migratory and invasive possibilities in LUAD cells via downregulating C1QTNF6. Moreover, RNA sequencing analysis demonstrated that the cytokine-cytokine receptor interaction pathway may participate in the process of C1QTNF6 regulating tumor progression. CONCLUSION: Our study first demonstrated that downregulation of C1QTNF6 could inhibit tumorigenesis and progression in LUAD cells negatively regulated by miR-29a-3p. These consequences could reinforce our awareness and understanding of the underlying mechanism and provide a promising therapeutic target for LUAD.

A targeted siRNA-loaded PDL1-exosome and functional evaluation against lung cancer.

BACKGROUND: As an endocytic nanosicle involved in intercellular communication, an exosome can efficiently deliver drugs from one cell to another and deliver therapeutic short interfering RNA (siRNA) to target cells. This is conducive to gene therapy for cancers. In this study, an exosome was used as the siRNA-loaded substrate to prepare a targeted siRNA-loaded PD-L1 exosome and evaluate its function against lung cancer. METHODS: The optimal preparation process and binding ratio of the targeted nanovesicle/siRNA complex was determined by detecting the particle size, potential, and other physical parameters in combination with cell binding and uptake capacity of exosome complexes. The biological cell behavior of targeted exosome nanosicles was evaluated through cytotoxicity, apoptosis, and the cell uptake capacity. RESULTS: A targeted exosome nanovesicle capable of loading siRNA and characterized with low toxicity, high loading rate, and the ability to be used for targeted tumor cell gene therapy was constructed. CONCLUSION: The PD-L1 targeting exosome can be used as an efficient siRNA delivery carrier, which is an efficient and safe nanocarrier for tumor targeted gene therapy.

Identification of a ZC3H12D-regulated competing endogenous RNA network for prognosis of lung adenocarcinoma at single-cell level.

BACKGROUND: To identify hub genes from the competing endogenous RNA (ceRNA) network of lung adenocarcinoma (LUAD) and to explore their potential functions on prognosis of patients from a single-cell perspective. METHODS: We performed RNA-sequencing of LUAD to construct ceRNA regulatory network, integrating with public databases to identify the vital pathways related to patients' prognosis and to reveal the expression level of hub genes under different conditions, the functional enrichment of co-expressed genes and their potential immune-related mechanisms. RESULTS: ZC3H12D-hsa-miR-4443-ENST00000630242 axis was found to be related with LUAD. Lower ZC3H12D expression was significantly associated with shorter overall survival (OS) of patients (HR = 2.007, P < 0.05), and its expression was higher in early-stage patients, including T1 (P < 0.05) and N0 (P < 0.05). Additionally, ZC3H12D expression was higher in immune cells displayed by single-cell RNA-sequencing data, especially in Treg cells of lung cancer and CD8 T cells, B cells and CD4 T cells of LUAD. The functional enrichment analysis showed that the co-expressed genes mainly played a role in lymphocyte activation and cytokine-cytokine receptor interaction. In addition, ZC3H12D was associated with multiple immune cells and immune molecules, including immune checkpoints CTLA4, CD96 and TIGIT. CONCLUSION: ZC3H12D-hsa-miR-4443-ENST00000630242 ceRNA network was identified in LUAD. ZC3H12D could affect prognosis of patients by regulating mRNA, miRNA, lncRNA, immune cells and immune molecules. Therefore, it may serve as a vital predictive marker and could be regarded as a potential therapeutic target for LUAD in the future.

Drug Resistance Mutations and Associated Phenotypes Detected in Clinical Trials of Maribavir for Treatment of Cytomegalovirus Infection.

BACKGROUND: In separate phase 2 trials, 120 patients received maribavir for cytomegalovirus (CMV) infection failing conventional therapy (trial 202) and 119 received maribavir for asymptomatic infection (trial 203). Overall, 172 cleared their CMV infection (CMV DNA <200 copies/mL) within 6 weeks. METHODS: Baseline and posttreatment plasma samples were tested for mutations in viral genes UL97, UL54, and/or UL27. Selected viral mutants were phenotyped for drug susceptibility. RESULTS: Baseline samples revealed UL54 mutations newly phenotyped as conferring resistance to standard DNA polymerase inhibitor(s), including K493N, P497S, K513T, L565V, V823A, A987V, and E989D. Of 29 patients (including 25 from trial 202) who cleared but later experienced recurrent CMV infection while on maribavir, 23 had available UL97 genotyping data; 17 had known resistance mutations (T409M or H411Y) and 5 additional had UL97 C480F alone. The newly phenotyped mutation C480F conferred high-grade maribavir resistance and low-grade ganciclovir resistance. Among 25 who did not respond to >14 days of therapy, 9 showed T409M or H411Y and 4 others showed C480F alone. CONCLUSIONS: After maribavir therapy (400-1200 mg twice daily), UL97 mutations T409M, H411Y, or C480F emerge to confer maribavir resistance in patients with recurrent CMV infection while on therapy or no response to therapy. CLINICAL TRIALS REGISTRATION: NCT01611974 and EudraCT 2010-024247-32.

Global Incidence, Progression, and Risk Factors of Age-Related Macular Degeneration and Projection of Disease Statistics in 30 Years: A Modeling Study.

OBJECTIVE: Age-related macular degeneration(AMD) has become a major cause of visual impairment worldwide, especially in the elderly. Estimates of incidence, progression rates, and risk factors of AMD vary among studies, complicating the understanding of its epidemiology. METHODS: For this systematic review and meta-analysis, literature published up to March 1, 2021, was searched in both English and Chinese databases. Hierarchical Bayesian approaches were used to estimate pooled incidence, progression, and 95% credible intervals (CrIs). RESULTS: Thirty studies were included. The pooled annual early and late AMD incidence rates were 1.59 (95% CrI: 1.18-2.11) and 0.23 (95% CrI: 0.14-0.34) per 100 person-years, respectively. The annual progression rate of AMD was 5.5 (95% CrI: 2.3-8.8) per 100 person-years. Smoking was an independent risk factor for both early and late AMD, whereas age, high-density lipoprotein cholesterol, and alcohol consumption were risk factors for early AMD incidence only. The projected number of new cases of early and late AMD in 2050 would be 39.05 million (95% CrI: 23.12-63.57) and 6.41 million (95% CrI: 3.37-13.22), respectively. CONCLUSION: The prediction the number of new cases of AMD is not equal across the globe. Our findings indicate the need for more rigorous control and prevention measures in AMD focus on its risk factors for early intervention. The epidemiological estimates reported in this study could inform to identify effective strategies for preventing AMD worldwide.

Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial.

BACKGROUND: Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase. METHODS: In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16. RESULTS: 352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs. CONCLUSIONS: Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).

The Triglyceride-Glucose Index is Associated with Diabetic Retinopathy in Chinese Patients with Type 2 Diabetes: A Hospital-Based, Nested, Case-Control Study.

BACKGROUND: This study aimed to investigate the association between the triglyceride-glucose (TyG) index and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes. METHODS: In this nested case-control study, all diabetic participants were registered hospitalizations during 2012-2018, including 596 with DR as cases and three matching controls per case. DR was assessed using Early Treatment Diabetic Retinopathy Study criteria. The TyG index was calculated: Ln (fasting blood glucose [mg/dL] × fasting triglycerides [mg/dL] ÷ 2). Multivariate logistic regression, a receiver-operating characteristic (ROC) curve, linear regression models, and mediation analysis were used to explore associations. RESULTS: The TyG index was lower in DR and decreased as its severity advanced among 2,112 subjects (P=0.005). After confounders (sex, duration of diabetes, use of antidiabetic agents, heart rate, systolic blood pressure, pulse pressure, height, weight, body-mass index, and glycated hemoglobin) had been accounted for, there were significant associations between the TyG index and any-severity DR (OR 0.83, 95% CI 0.73-0.95; P=0.006), as well as vision-threatening DR (VTDR; OR 0.53, 95% CI 0.36-0.76; P=0.001). ROC analysis indicated that the TyG index showed significant discriminatory ability in any-severity DR (area under curve [AUC] 0.534, P=0.015) and VTDR (AUC 0.624, P=0.001). CONCLUSION: The TyG index was associated with the presence and severity of DR. Our findings suggest that the TyG index may become a useful biomarker in evaluating and following the presence of DR and VTDR.

LncRNA WT1-AS/miR-494-3p Regulates Cell Proliferation, Apoptosis, Migration and Invasion via PTEN/PI3K/AKT Signaling Pathway in Non-Small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most common malignancies with the highest morbidity and mortality worldwide. Long non-coding RNAs (lncRNAs) are recently recognized as noteworthy regulators of different tumors, counting NSCLC. However, the biological functions and regulatory mechanism of lncRNA WT1-AS in NSCLC progression still stay uninvestigated. METHODS: WT1-AS and miR-494-3p levels in NSCLC cell lines were detected by real-time quantitative polymerase chain reaction (RT-qPCR). In the current study, the regulatory effects of WT1-AS/miR-494-3p axis on cellular behaviors of NSCLC cell lines (A549 and NCI-H1975) were evaluated by a variety of methods. Cell counting kit-8 (CCK-8) and EDU assays were adopted to assess NSCLC cell proliferation. Tunnel staining and flow cytometry assay were applied to determine cell apoptosis and cell cycle distribution. Besides, cell migration and invasion abilities were analyzed by performing wound healing and transwell assays. Meanwhile, the levels of key proteins related to NSCLC cell apoptosis and PTEN/PI3K/AKT pathway were examined using Western blot assay. In addition, luciferase reporter assays were used to determine the interaction between WT1-AS and miR-494-3p or miR-494-3p and PTEN. RESULTS: Visibly downregulated WT1-AS in NSCLC cell lines was obtained from Broad Institute Cancer Cell Line Encyclopedia (CCLE) database and further verified by performing RT-qPCR. Besides, miR-494-3p was the downstream target gene of WT1-AS and obviously upregulated miR-494-3p in NSCLC cell lines was confirmed. WT1-AS overexpression suppressed cell proliferation, migration and invasion abilities while enhanced cell apoptosis of A549 and NCI-H1975 cells. Furthermore, upregulation of miR-494-3p distinctly reversed these inhibitory effects of WT1-AS overexpression on the tumorigenesis and progression of NSCLC. In addition, WT1-AS promoted PTEN expression and thereby inhibited activation of PI3K/AKT pathway by sponging miR-494-3p. CONCLUSION: To conclude, lncRNA WT1-AS impeded cell proliferation, migration, invasion but accelerated cell apoptosis via negatively regulating miR-494-3p to mediate PTEN/PI3K/AKT pathway in NSCLC.

Survival outcomes for patients with four treatments in stages I-III esophageal squamous cell carcinoma: a SEER analysis.

BACKGROUND: Esophageal cancer (EC) is globally acknowledged as one of the most common malignancies among all gastrointestinal cancers. Furthermore, in Eastern Asia, squamous cell carcinoma is the main pathological type of EC. There are different treatments for esophageal squamous cell carcinoma (ESCC), but there is still a lack of large-sample analysis of prognosis among different treatments, especially for different tumor stages. The analysis of the prognosis of ESCC patients with different treatments may be helpful to choose the treatment methods for different stages ESCC. METHODS: A total of 3,346 patients with pathological ESCC between 1976 and 2016 were derived from the Surveillance, Epidemiology, and End Results (SEER) database. All clinical factors associated with prognosis were collected and analyzed to achieve the difference of prognosis among different treatments in ESCC patients, such as ages, sex, race, tumor grade, anatomic location and so on. Kaplan-Meier and Cox proportional hazard analysis were used to compare survival of different treatments in ESCC patients with stage I-III. RESULTS: The overall survival (OS) in all ESCC patients who had received surgery and surgery plus radiation therapy or/and chemotherapy are superior than that had not received any treatments and radiation therapy or/and chemotherapy. The OS in ESCC patients with stage I who had received surgery and surgery plus radiation therapy or/and chemotherapy are superior than that had not received any treatments and radiation therapy or/and chemotherapy. The OS in ESCC patients with stage II/III who had received surgery and surgery plus radiation therapy or/and chemotherapy are superior than that in other groups. Age, race and grade as an independent predictive factor for survival (P<0.05). A nomogram model was constructed to show surgery group had better 1-, 3- and 5-year OS than radiation therapy or/and chemotherapy group (OS: 78.5% vs. 59.2%, 37.9% vs. 18.4%, 16.9% vs. 6.1%). CONCLUSIONS: Surgery is still the first choice for all ESCC patients with stage I-III. Radiotherapy and chemotherapy could improve the survival rate in ESCC patients with stage II-III who have received surgery.

Cardiovascular Safety of Anagrelide Hydrochloride versus Hydroxyurea in Essential Thrombocythaemia.

Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac safety, efficacy and tolerability of first-line treatment with anagrelide or hydroxyurea in high-risk ET patients for up to 3 years. Eligible patients aged ≥ 18 years with a diagnosis of high-risk ET confirmed by bone marrow biopsy within 6 months of randomisation received anagrelide (n = 75) or hydroxyurea (n = 74), administered twice daily. Treatment dose for either compound was titrated to the lowest dose needed to achieve a response. Planned primary outcome measures were change in left ventricular ejection fraction from baseline over time and platelet count at Month 6. Planned secondary outcome measures were platelet count change from baseline at Months 3 and 36; percentage of patients with complete or partial response; time to complete or partial response; number of patients with thrombohaemorrhagic events; and changes in white blood cell count or red blood cell count over time. Neither treatment altered cardiac function. There were no significant differences in adverse events between treatment groups, and no reports of malignant transformation. The incidence of disease-related thrombotic or haemorrhagic events was numerically higher in anagrelide-treated patients. Both treatments controlled platelet counts at 6 months, with the majority of patients experiencing complete or partial responses. In conclusion, these results suggest that long-term treatment with anagrelide is not associated with adverse effects on cardiac function. This is one of the few studies using left ventricular ejection fraction assessment and central biopsy reading to confirm the diagnosis of ET.Trial registration number: Clinicaltrials.gov NCT00202644.