Predicting lymphovascular invasion in N0 stage non-small cell lung cancer: A nomogram based on Dual-energy CT imaging and clinical findings.

PURPOSE: To construct a nomogram for predicting lymphovascular invasion (LVI) in N0 stage non-small cell lung cancer (NSCLC) using dual-energy computed tomography (DECT) findings combined with clinical findings. METHODS: We retrospectively recruited 135 patients with N0 stage NSCLC from two hospitals underwent DECT before surgery and were divided into development cohort (n = 107) and validation cohort (n = 28). The clinical findings (baseline characteristics, biochemical markers, serum tumor markers and Immunohistochemical markers), DECT-derived parameters (iodine concentration [IC], effective atomic number [Eff-Z] and normalized iodine concentration [NIC], iodine enhancement [IE] and NIC ratio [NICr]) and Fractal dimension (FD) were collected and measured. A nomogram was constructed using significant findings to predict LVI in N0 stage NSCLC and was externally validated. RESULTS: Multivariable analysis revealed that lymphocyte count (LYMPH, odds ratio [OR]: 3.71, P=0.014), IC in arterial phase (ICa, OR: 1.25, P=0.021), NIC in venous phase (NICv, OR: 587.12, P=0.009) and FD (OR: 0.01, P=0.033) were independent significant factors for predicting LVI in N0 stage NSCLC, and were used to construct a nomogram. The nomogram exhibited robust predictive capabilities in both the development and validation cohort, with AUCs of 0.819 (95 % CI: 72.6-90.4) and 0.844 (95 % CI: 68.2-95.8), respectively. The calibration plots showed excellent agreement between the predicted probabilities and the actual rates of positive LVI, on external validation. CONCLUSIONS: Combination of clinical and DECT imaging findings could aid in predicting LVI in N0 stage NSCLC using significant findings of LYMPH, ICa, NICv and FD.

The Different Influence of Cutibacterium Acnes and Staphylococcus Epidermidis in the Lumbar Disc: An in Vivo Study in Rabbits.

STUDY DESIGN: Animal laboratory study. OBJECTIVE: This study investigated the effects of C. acnes and S. epidermidis on the lumbar discs of rabbits, as well as the outcomes of combined infection. SUMMARY OF BACKGROUND DATA: Many studies have indicated that bacterial infections are associated with lumbar disc degeneration (LDD). The most commonly cultured bacteria from disc tissues are Cutibacterium acne (C. acnes) and Staphylococcus epidermidis (S. epidermidis). METHODS: New Zealand white rabbits (n=40) were randomly divided into control, C. acnes, S. epidermidis, and C. acnes plus S. epidermidis (i.e., combined) groups. All groups except the control were injected with 25 µL of saline at L4-L5 and 25 µL of bacteria (1×107 CFU/mL) at L5-L6. All injections were performed under X-ray guidance. Weight measurements, haematological evaluations, and magnetic resonance imaging were performed after 4, 8, and 12 weeks. Histological examination and gene expression detection were performed 12 weeks after surgery. RESULTS: Inflammatory factors in the blood and weight did not differ among the groups after 4, 8, and 12 weeks (P >0.05). However, after 4 weeks, LDD occurred in the C. acnes group, and discitis occurred in the S. epidermidis and combined groups, all of which worsened after 8 weeks. After 12 weeks, the nucleus pulposus (NP) protruded and compressed the spinal cord in the C. acnes group, and tissue staining showed decreased NP tissue and cartilaginous endplate fracture. In the S. epidermidis and combined groups, the discitis was more confined, but tissue staining revealed a significant decrease in NP tissue, and loss of the normal disc structure. CONCLUSIONS: In the early stage of infection in rabbits, C. acnes caused LDD, and S. epidermidis caused discitis. Co-infection with C. acnes and S. epidermidis caused discitis but was more limited in scope than infection with S. epidermidis alone.

Assessment of the impact of resting heart rate on the risk of major adverse cardiovascular events after ischemic stroke: a retrospective observational study.

BACKGROUND: Although elevated heart rate is a risk factor for cardiovascular morbidity and mortality in healthy people, the association between resting heart rate and major cardiovascular risk in patients after acute ischemic stroke remains debated. This study evaluated the association between heart rate and major adverse cardiovascular events after ischemic stroke. METHODS: We conducted a retrospective cohort study analyzing data from the Chang Gung Research Database for 21,655 patients with recent ischemic stroke enrolled between January 1, 2010, and September 30, 2018. Initial in-hospital heart rates were averaged and categorized into 10-beats per minute (bpm) increments. The primary outcome was the composite of hospitalization for recurrent ischemic stroke, myocardial infarction, or all-cause mortality. Secondary outcomes were hospitalization for recurrent ischemic stroke, myocardial infarction, and heart failure. Hazard ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, using the heart rate < 60 bpm subgroup as the reference. RESULTS: After a median follow-up of 3.2 years, the adjusted hazard ratios for the primary outcome were 1.13 (95% CI: 1.01 to 1.26) for heart rate 60-69 bpm, 1.35 (95% CI: 1.22 to 1.50) for heart rate 70-79 bpm, 1.64 (95% CI: 1.47 to 1.83) for heart rate 80-89 bpm, and 2.08 (95% CI: 1.85 to 2.34) for heart rate ≥ 90 bpm compared with the reference group. Heart rate ≥ 70 bpm was associated with increased risk of all secondary outcomes compared with the reference group except heart failure.  CONCLUSIONS: Heart rate is a simple measurement with important prognostic implications. In patients with ischemic stroke, initial in-hospital heart rate was associated with major adverse cardiovascular events.

Impact of Poly(Ester Amide) Structure on Properties and Drug Delivery for Prostate Cancer Therapy.

Objective: We aim to develop a polymer library consisting of phenylalanine-based poly(ester amide)s (Phe-PEAs) for cancer therapy and investigate the structure-property relationship of these polymers to understand their impact on the drug delivery efficiency of corresponding nanoparticles (NPs). Impact Statement: Our study provides insights into the structure-property relationship of polymers in NP-based drug delivery applications and offers a potential polymer library and NP platform for enhancing cancer therapy. Introduction: Polymer NP-based drug delivery systems have demonstrated substantial potential in cancer therapy by improving drug efficacy and minimizing systemic toxicity. However, successful design and optimization of these systems require a comprehensive understanding of the relationship between polymer structure and physicochemical properties, which directly influence the drug delivery efficiency of the corresponding NPs. Methods: A series of Phe-PEAs with tunable structures was synthesized by varying the length of the methylene group in the diol part of the polymers. Subsequently, Phe-PEAs were formulated into NPs for doxorubicin (DOX) delivery in prostate cancer therapy. Results: Small adjustments in polymer structure induced the changes in the hydrophobicity and thermal properties of the PEAs, consequently NP size, drug loading capacity, cellular uptake efficacy, and cytotoxicity. Additionally, DOX-loaded Phe-PEA NPs demonstrated enhanced tumor suppression and reduced side effects in prostate tumor-bearing mice. Conclusion: Phe-PEAs, with their finely tunable structures, show great promise as effective and customizable nanocarriers for cancer therapy.

Periodic Intermittent Adaptive Control with Saturation for Pinning Quasi-Consensus of Heterogeneous Multi-Agent Systems with External Disturbances.

A periodic intermittent adaptive control method with saturation is proposed to pin the quasi-consensus of nonlinear heterogeneous multi-agent systems with external disturbances in this paper. A new periodic intermittent adaptive control protocol with saturation is designed to control the internal coupling between the follower agents and the feedback gain between the leader and the follower. In particular, we use the saturation adaptive law: when the quasi-consensus error converges to a certain range, the adaptive coupling edge weight and the adaptive feedback gain will not be updated. Furthermore, we propose three saturated adaptive pinning control protocols. The quasi-consensus is achieved through its own pinning as long as the agents remain connected to each other. Using the Lyapunov function method and inequality technique, the convergence range of the quasi-consensus error of a heterogeneous multi-agent system is obtained. Finally, the rationality of the proposed control protocol is verified through numerical simulation. Theoretical derivation and simulation results show that the novel proposed periodic intermittent adaptive control method with saturation can successfully be used to achieve the pinning of quasi-consensus of nonlinear heterogeneous multi-agent systems.

Tuberculosis treatment delay and nosocomial exposure remain important risks for patients undergoing regular hemodialysis.

BACKGROUND AND OBJECTIVE: Studies have reported an increased tuberculosis (TB) incidence among patients with end-stage renal disease (ESRD). This nationwide nested Case-control study investigated the risk of active TB due to nosocomial exposure and its correlation with the delay in TB treatment in hemodialysis patients. METHODS: Adult (aged ≥20 years) patients with incident ESRD over 2000-2010 were identified from Taiwan National Health Insurance Research Database; 2331 patients with incident active TB (Case) were matched with 11,655 patients without TB (control) by age, sex, year of ESRD onset, Charlson comorbidity index, chronic obstructive pulmonary disease, and diabetes mellitus, at a 1:5 case-to-control ratio. RESULTS: Compared with the control group, the Case group had greater nosocomial exposure to index patients with pulmonary TB (2.36 vs. 0.11 month of exposure, p < 0.001). Nosocomial exposure increased active TB risk (adjusted odds ratio [OR; 95% confidence interval, CI]: 1.60 [1.55-1.66] per month of exposure), particularly when the exposure time was either within 6 months before the index case was diagnosed or 6-15 months before the ESRD patient became an incident active TB case. For patients with active TB, cough-related medication prescriptions (proxy for cough symptoms) exponentially increased over 6 months before TB treatment. CONCLUSION: Nosocomial exposure attributed to delay in the diagnosis of index pulmonary TB is important in TB transmission among patients undergoing regular hemodialysis. Additional studies investigating how TB can be diagnosed and treated early are warranted. SUMMARY AT A GLANCE: Our study revealed that nosocomial exposure, attributed to delay in pulmonary TB diagnosis, is important in TB transmission among patients undergoing regular hemodialysis. Strategies to diagnose and treat TB early are crucial to infection control, and they warrant further investigations.

MicroRNA-137 targets EZH2 to exert suppressive functions in uveal melanoma via regulation of Wnt/ß-catenin signaling and epithelial-to-mesenchymal transition.

PURPOSE: Uveal melanoma (UM) is one of the primary intraocular malignancies. Emerging studies have confirmed dysregulation of microRNA (miRNA/miR) in UM. The present study focused on the biofunctions of miR-137 in UM. METHODS: MiR-137 expressions in tissue samples were analyzed by qRT-PCR. MTT and transwell assays were applied to investigate the impacts of miR-137 on UM cell proliferation, invasion and migration. Luciferase assay was carried out to explore the downstream target of miR-137. Western blot was used to analyze the roles of miR-137 in UM cells, Wnt/ß-catenin pathway and epithelial-mesenchymal transition (EMT). RESULTS: qRT-PCR showed that miR-137 expressions were lower in UM tissue samples than para-carcinoma tissues, whereas EZH2 was simultaneously upregulated. MiR-137 overexpression evidently suppressed UM cell proliferation, invasion and migration. The findings also indicated that miR-137 restoration could block Wnt/ß-catenin pathway and EMT in UM cells thus resulting in downregulation of malignant behaviors. EZH2 was a downstream target of miR-137 as demonstrated by luciferase assay. CONCLUSION: The present study indicated that EZH2 participated in the anti-UM functions of miR-137. Taken together, the data in our study established miR-137/EZH2 axis in regulating UM progression, suggesting that miR-137 may function as a novel therapeutic biomarker for UM patients.

Effect of ß-Blocker in Treatment-Naïve Patients With Advanced Lung Adenocarcinoma Receiving First-Generation EGFR-TKIs.

BACKGROUND: Through activation of adrenergic receptors, chronic stress can trigger the secretion of neurotransmitters and hormones that enhance tumor growth, increase angiogenesis, and promote drug resistance. This study aimed to evaluate the effect of ß-blockers in patients receiving first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for lung adenocarcinoma. METHODS: This retrospective cohort study enrolled patients with advanced lung adenocarcinoma under first-line EGFR-TKIs between 2011 and 2014 in the National Health Insurance Research Database of Taiwan. The effects of ß-blockers use, defined as ≥60 defined daily doses within 180 days before initiation of EGFR-TKI therapy, on the 2-year time-to-discontinuation (TTD) of EGFR-TKIs and 4-year overall survival (OS) were investigated using Cox regression analyses with inverse propensity score weighting and sensitivity analysis in subgroup with either hypertension or ischemic heart diseases. RESULTS: Among 4988 enrolled patients, 552 (11.1%) were in the ß-blocker group. Patients in the ß-blocker group were more likely to be older than 75 and had diabetes mellitus and cardiovascular comorbidities. In Cox regression analysis, ß-blocker usage was associated with a longer TTD (hazard ratio, HR: 0.91 [0.86-0.96]) and OS (HR: 0.68 [0.64-0.72]). The results also favored ß-blocker group in sensitivity analysis. CONCLUSIONS: In treatment-naïve patients with advanced lung adenocarcinoma under first-line EGFR-TKIs, prior use of ß-blocker was associated with a better outcome. The findings encourage further prospective clinical study to validate the possibility of ß-blockers as adjuvant anticancer therapy.

Survival After Treatable Hepatocellular Carcinoma Recurrence in Liver Recipients: A Nationwide Cohort Analysis.

BACKGROUND: Survival after post-transplant recurrence of HCC is dismal, and almost all treatments for recurrent HCC are off-labeled, without an extensive large-scale analysis. We aimed to delineate their post-recurrence courses and define benchmarks for comparing future treatment effectiveness. METHODS: Three national databases, including health insurance, catastrophic illness, and the cause of death, were linked for cohort establishment and data collection during the period from 2005 to 2016. Patients with HCC recurrence ≥6 months after transplant surgery and under treatment were recruited for survival analysis. Selection of treatment strategies for HCC recurrence after liver transplant was based on the same criteria for those without liver transplant. RESULTS: Of 2,123 liver transplant recipients, 349 developed HCC recurrence ≥6 months after liver transplant, and the median recurrence time was 17.8 months post-transplant. Within 2 years of treatment, 61% patients showed recurrence (early recurrence group), and survival in these patients was poorer than in the late recurrence group. According to a multivariable analysis, the transplant era before 2008 and radiofrequency ablation were associated with good prognosis, whereas receiving sorafenib and radiotherapy was associated with poor prognosis. The effect of transplant era became insignificant after stratification by recently receiving pretransplant transarterial chemoembolization. CONCLUSION: Timing of recurrence and interventions used were associated with the outcomes of patients with post-transplant HCC recurrence. These data provide the benchmark and indicate the critical period and high-risk factors for further therapeutic trial consideration.

Cysteine-based redox-responsive nanoparticles for small-molecule agent delivery.

As a significant part of molecular-targeted therapies, small-molecule agents (SMAs) have been increasingly used for cancer treatment. Nevertheless, most SMAs are currently administered orally due to their poor solubility, resulting in a low bioavailability and unavoidable side effects. Herein, we proposed a promising SMA delivery strategy using a biocompatible and redox-responsive nanoparticle (NP) delivery system to improve their bioavailability, alleviate side effects and enhance therapeutic performance. To demonstrate the feasibility of this strategy, a type of cysteine-based hydrophobic polymer was employed to construct a redox-sensitive nanoplatform for the delivery of various hydrophobic oral SMAs. These SMA-loaded nanoparticles (SMA-NPs) all have a small particle size and good drug-loading capacity. Particularly, lapatinib-loaded nanoparticles (LAP-NPs) with a minimal particle size (79.71 nm) and an optimal drug-loading capacity (12.5%) were utilized as a model to systemically explore the in vitro and in vivo anticancer potential of SMA-NPs. As expected, the LAP-NPs exhibited rapid redox-responsive drug release, enhanced in vitro cytotoxicity and cell apoptosis, and demonstrated notable anti-metastasis ability and desirable intracellular localization. Additionally, the in vivo results demonstrated the preferential accumulation of LAP-NPs in tumor tissues and the significant suppression of tumor growth. Therefore, the generated SMA-NP delivery system shows great SMA delivery potential for advanced molecular-targeted therapies.

Use of Antiplatelet Agents and Survival of Tuberculosis Patients: A Population-Based Cohort Study.

While evidence is accumulating that platelets contribute to tissue destruction in tuberculosis (TB) disease, it is still not known whether antiplatelet agents are beneficial to TB patients. We performed this retrospective cohort study and identified incident TB cases in the Taiwan National Tuberculosis Registry from 2008 to 2014. These cases were further classified into antiplatelet users and non-users according to the use of antiplatelet agents prior to the TB diagnosis, and the cohorts were matched using propensity scores (PSs). The primary outcome was survival after a TB diagnosis. In total, 74,753 incident TB cases were recruited; 9497 (12.7%) were antiplatelet users, and 7764 (10.4%) were aspirin (ASA) users. A 1:1 PS-matched cohort with 8864 antiplatelet agent users and 8864 non-users was created. After PS matching, antiplatelet use remained associated with a longer survival (adjusted hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.88-0.95, p < 0.0001). The risk of major bleeding was not elevated in antiplatelet users compared to non-users (p = 0.604). This study shows that use of antiplatelet agents has been associated with improved survival in TB patients. The immunomodulatory and anti-inflammatory effects of antiplatelet agents in TB disease warrant further investigation. Antiplatelets are promising as an adjunct anti-TB therapy.

Association of Metformin Use With End-Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay-for-Performance Program.

Animal studies have demonstrated that metformin exerts a renoprotective effect. Human studies of patients with diabetes mellitus (DM) regarding the association of metformin use with end-stage renal disease (ESRD) are lacking. Patients with type 2 DM and without a history of kidney disease who were enrolled under the pay-for-performance program of the National Health Insurance in Taiwan were identified. Those who received ≥90 cumulative defined daily doses of metformin within 1 year were selected (metformin users) and compared with a 1:1 propensity score-matched metformin nonuser cohort. Primary and secondary outcomes were development of ESRD and chronic kidney disease (CKD), respectively. Independent predictors were investigated using Cox regression analysis. A total of 24 158 pairs of metformin users and nonusers were enrolled, with an incidence of ESRD of 1908 and 1723 and CKD of 1095 and 1056 cases per 100 000 person-years, respectively. Metformin use was independently associated with increased risks of ESRD (adjusted hazard ratio, 1.22; 95% confidence interval, 1.12-1.32) and CKD (adjusted hazard ratio, 1.25; 95% confidence interval, 1.12-1.40) in a dose-response relationship. Patients with hypertension plus nonuse of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers potentiated kidney damage by metformin. In patients with DM, use of metformin may increase the risk of ESRD and CKD. Health care professionals should be alert and closely monitor renal function when prescribing metformin.

Nanoparticle Therapy for Prostate Cancer: Overview and Perspectives.

Traditional prostate cancer therapy and especially chemotherapy has faced many challenges. Low accumulation levels, rapid clearance or drug resistance at the tumor site have been central to why the effect of chemotherapy drugs has declined. Applications of nanotechnology to biomedicine have enabled the development of nanoparticle therapeutic carriers suited for the delivery of chemotherapeutics in cancer therapy. This review describes the current nature of nanoparticle therapeutic carriers for prostate cancer. It describes typical nanocarriers commonly used for the delivery of chemotherapy or for imaging examination. Targeting strategies and related influencing factors are investigated to find ways of enhancing treatment effects of nanoparticles. The overall purpose of this review is to further understanding and to offer recommendations on the design and development of therapeutic nanoparticles for prostate cancer.

Risk of cardiotoxicity induced by adjuvant anthracycline-based chemotherapy and radiotherapy in young and old Asian women with breast cancer.

PURPOSE: The risk of cardiotoxicity induced by adjuvant anthracycline-based chemotherapy (CT) and radiotherapy (RT) is yet to be investigated in a large-scale randomized controlled trial with an adequate sample size of young and old women with breast cancer. PATIENTS AND METHODS: To compare the occurrence of major heart events (heart failure and coronary artery disease) in patients with breast cancer, 3489 women who underwent surgical resection of the breast tumor were retrospectively selected from the Taiwan National Health Insurance Research Database. The patients were categorized into the following groups based on their treatment modalities: group 1 (n = 1113), no treatment; group 2 (n = 646), adjuvant RT alone; group 3 (n = 705), adjuvant anthracycline-based CT alone; and group 4 (n = 1025), combined adjuvant RT and anthracycline-based CT. RESULTS: The mean patient age was 50.35 years. Subsequent coronary artery disease and heart failure were identified in 244 (7.0%) and 206 (5.9%) patients, respectively. All three adjuvant therapies were significant independent prognostic factors of major heart events (adjusted hazard ratio [95% confidence interval]: 1.47 [1.24-1.73]; 1.48 [1.25-1.75], and 1.92 [1.65-2.23] in groups 2, 3, and 4, respectively). In patients aged ≥50 years with breast cancer who underwent surgery, the log-rank p values of groups 2 and 3 after adjustment were 0.537 and 0.001, respectively. CONCLUSION: Adjuvant RT can increase cardiotoxicity in patients with breast cancer, particularly when used in combination with anthracycline-based CT. Therefore, it should be offered with optimal heart-sparing techniques, particularly in younger patients with good prognosis and long life expectancy.

Screening of pH-responsive long-circulating polysaccharide-drug conjugate nanocarriers for antitumor applications.

For the treatment of malignant tumors, drug nanocarriers with long blood circulation time and ability to target the tumor microenvironment are promising therapeutic abilities. In this work, to systematically investigate the roles and functions of polysaccharides as drug nanocarriers targeting the tumor microenvironment, different types of polysaccharides (alginic acid (Alg), hyaluronic acid (HA), and dextran (Dex)) were covalently bonded with doxorubicin (DOX) through a Schiff base reaction to form a pH-sensitive polysaccharide-DOX prodrug having an acid-sensitive imine bond. After screening, Dex-DOX exhibited high drug loading content and good stability, while Alg-DOX and HA-DOX may have disadvantages such as low degree of oxidation, limited drug loading capacity, or instability in physiological conditions. Dex-DOX prodrugs were able to self-assemble into stable nanoparticles in phosphate buffered saline (PBS). Then, Dex6k-DOX and Dex150k-DOX were selected for further comparisons since they had similar drug-binding rates and long circulation time. When compared with Dex6k-DOX, the longer main-chain Dex150k-DOX showed a higher drug release rate under simulated acidic conditions in vitro, which significantly inhibited cell proliferation. Further in vivo experiments showed that Dex150k-DOX could more effectively improve the antitumor efficiency and survival rate while reducing side-effects. Overall, the screening and comparisons provided detailed and systematical information about the polysaccharide-DOX prodrug platform as potential antitumor drugs.

Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study.

BACKGROUND: Research has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated. METHODS: From 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders. RESULTS: Among the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81-1.16) and 0.96 (0.80-1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46-14.1). CONCLUSION: Compared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe.

Association of doublecortin-like kinase 1 with tumor aggressiveness and poor biochemical recurrence-free survival in prostate cancer.

BACKGROUND: Doublecortin-like kinase 1 (DCLK1) has been proven to be involved in numerous tumors, while its role in prostate cancer (PCa) is still unclear. This study aimed at investigating the expression pattern and prognostic value of DCLK1 in PCa. PATIENTS AND METHODS: Real-time polymerase chain reaction and Western blot were employed to determine DCLK1 mRNA and protein levels in 25 paired fresh samples of PCa and benign prostatic hyperplasia (BPH) as well as in PCa cell lines. Immunohistochemistry (IHC) was also performed in 125 PCa and 65 BPH tissues to assess DCLK1 expression. Then, the association of DCLK1 expression with clinicopathological parameters and biochemical recurrence (BCR) after radical prostatectomy was statistically analyzed. In addition, the role of DCLK1 in PCa cell proliferation, migration, and invasion was evaluated by using MTT and transwell assays. RESULTS: The mRNA and protein levels of DCLK1 were markedly higher in the fresh samples of PCa than that in BPH. Consistently, IHC revealed increased expression of DCLK1 in PCa paraffin-embedded tissues compared with BPH. Moreover, increased DCLK1 expression was significantly associated with postoperative Gleason grading (P=0.012), pathological T stage (P=0.001), seminal vesicle invasion (P=0.026), and lymph node involvement (P=0.017), respectively. The Kaplan-Meier curve analysis demonstrated that high DCLK1 expression was associated with lower postoperative BCR-free survival (bRFS). Furthermore, multivariate Cox analysis showed that postoperative Gleason grading (P=0.018), pathological T stage (P<0.001), seminal vesicle invasion (P=0.012), lymph node involvement (P=0.014), and DCLK1 expression (P=0.014) were independent predictors of BCR. In vitro, the overexpression and knockdown of DCLK1 in PCa cell lines indicated that DCLK1 could promote cell proliferation, migration, and invasion. CONCLUSION: Increased DCLK1 expression is associated with PCa aggressiveness and may independently predict poor bRFS in patients with PCa.

Knockdown of Long Noncoding RNA (lncRNA) Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Inhibits Proliferation, Migration, and Invasion and Promotes Apoptosis by Targeting miR-124 in Retinoblastoma.

Evidence suggests that the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is upregulated in cancer tissues, and its elevated expression is associated with hyperproliferation. However, the underlying mechanisms regarding the role of MALAT1 in retinoblastoma (RB) remain unclear. This study aimed to explore the functional role of MALAT1 in RB by targeting miR-124. The results showed that the expression of MALAT1 was significantly higher in the Y79 cell line than in the ARPE-19 cell line (p < 0.01). Moreover, MALAT1 silence inhibited cell viability, migration, and invasion and promoted apoptosis in Y79 cells (p < 0.05, p < 0.01, or p < 0.001). miR-124 was upregulated by MALAT1 silence and hence was identified as a target of MALAT1 (p < 0.05 or p < 0.001). In addition, miR-124 suppression inhibited cell apoptosis and remarkably abolished the inhibitory effects of MALAT1 silence on cell viability, migration, and invasion (p < 0.05, p < 0.01, or p < 0.001). In addition, Slug was a target of miR-124 and regulated cell viability, migration, invasion, and apoptosis in Y79 cells (p < 0.05, p < 0.01, or p < 0.001). Further, Slug silence abolished miR-124 suppression-induced inactivation of the ERK/MAPK and Wnt/ß-catenin pathways. Taken together, our data highlight the pivotal role of MALAT1 in RB. Moreover, the present study elucidated the MALAT1-miR-124-ERK/MAPK and Wnt/ß-catenin signaling pathways in RB, which might provide a new approach for the treatment of RB.

Effects of insulin-like growth factor 2 and its receptor expressions on corneal repair.

Limbal stem cell (LSC) on the basal layer of cornea plays an important role in the epithelial repair after corneal injury as it can proliferate, differentiate and migrate into injury sites under the direction of cytokines. This study explored the signaling pathway and cellular mechanism between corneal epithelial cells LSC, on a mouse model with mechanic corneal injury. Ipsilateral corneal mechanic injury model was prepared on mice using the contralateral eye as the control. Tissues from both central and peripheral regions of cornea were collected, cultured and quantified for expression of various cytokines including epidermal growth factor (EGF), fibroblast growth factor-ß (FGF-ß), heparin-like growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-ß1 (TGF-ß1), IGF-1 and IGF-2. The effects of these factors on the differentiation of LSC and fibroblasts were also studied. Most of those cytokines had elevated gene expressions after the corneal injury. Among those IGF-2 had significantly increased expression, along with the high expression of IGF-2 receptor in corneal peripheral cells. IGF-2 also induced the differentiation of LSC into keratin-12-positive cells. Further studies showed the prominent expression of α-actin in injured tissues, suggesting the potential transformation of fibroblasts into myofibroblasts. Both IGF-2 and its receptor had elevated expressions after corneal injury. They may facilitate the transformation of LSC into epithelial cells, in addition to the role in transformation from fibroblasts to myofibroblasts.

Efficient capillary electrophoresis separation and determination of free amino acids in beer samples.

Simultaneous detection of various o-phthalaldehyde (OPA)-labeled amino acids (AAs) in food samples was reported based on CE separation. Ionic liquid was used for the first time for CE analysis of AAs with in-capillary derivatization. Several other additives, including SDS, α/ß-CD, and ACN, as well as key parameters for CE separation (buffer pH value, separation voltage), were also investigated. Our results show that the multiple additive strategy exhibits good stable and repeatable character for CE analysis of OPA-labeled AAs, for either in-capillary derivatization or CE separation, and allows simultaneous quantification of different OPA-labeled AAs in a large concentration range of 50 µM to 3.0 mM with LOD down to 10 µM. Seventeen OPA-labeled AAs, except for two pairs of AAs (His/Gln and Phe/Leu), which were separated with resolutions of 1.1 and 1.2, respectively, were baseline separated and identified within 23 min using the present multiple additive strategy. The method was successfully applied for simultaneous analysis of AAs in seven beer samples and as many as eleven trace-amount AAs were detected and quantified, indicating the valuable potential application of the present method for food analysis.