The effects of statins in patients with advanced-stage cancers - a systematic review and meta-analysis.

Background: Statin therapy has been shown to reduce mortality in a wide range of cancer types and overall stages. Still, there is uncertainty about its efficacy in increasing survival among advanced cancer patients. Methods: We conducted a meta-analysis with data from all studies that compared the hazard ratio of overall survival, cancer-specific survival, and progression-free survival in patients with advanced-stage cancer who receive statin therapy. Studies were selected from the PubMed, Embase, and Web of Science databases from their inception to December 31, 2022. Cancer types are limited to those rarely screened during the annual examination and more likely to develop into advanced stages, such as lung, pancreatic and ovarian cancers. This resulted in 27 studies eligible for meta-analysis. Results: Statin therapy was associated with a 26% decreased risk of overall survival (HR, 0.74; 95% CI, 0.67, 0.81), 26% decreased risk of cancer-specific survival (HR, 0.74; 95% CI, 0.61-0.88), and 24% decreased risk of progression-free survival (HR, 0.76; 95% CI, 0.65-0.87) for advanced-stage cancer patients. The associations were not attenuated or reinforced by study design, study regions, cancer types, or other medical care. Concomitant use of other anticancer medications did not result in confounding effects. Conclusions: Statin therapy produces significant benefits on overall survival and cancer-specific survival. Although the benefits might be lower than the approved immunotherapy medications, its cost-effectiveness could lead to dramatic health consequences. Concomitant use of statin drugs as cancer treatments is highly recommended in future clinical trials.

E-Cigarette Usage and Arthritis in the United States, a Nationwide Cross-Sectional Survey.

Aim: The prevalence of the use of electronic cigarettes (e-cigarettes) has grown rapidly in the past decade in the United States. While numerous studies have demonstrated combustible cigarette is closely associated with an increased risk of arthritis diseases, little is known about the effect of e-cigarette usage on inflammatory arthritis diseases. We aimed to determinate if e-cigarette usage is associated with an increased risk of inflammatory arthritis. Methods: Data were obtained from the Behavioral Risk Factor Surveillance System, which is the largest national telephone-based survey of randomly sampled adults in the United States. A total of 924,882 participants with information on e-cigarette usage and inflammatory arthritis were included. We used multivariable logistic regression to estimate the risk of arthritis associated with e-cigarette usage. Results: Of the 924,882 participants, there were 30,569 (3.3%) current e-cigarette users, and 314,190 (25.9%) reported to have inflammatory arthritis diseases. In the fully adjusted model, we observed that the odds ratio (OR) (95% confidence interval) of inflammatory arthritis diseases was 1.81 (95% CI, 1.70-1.93) for current e-cigarette users compared with never e-cigarette users. The ORs of inflammatory arthritis diseases were 1.31 (95% CI, 1.18-1.47), and 1.55 (95% CI, 1.42-1.69) among sole e-cigarette and dual users compared with never e-cigarette users, respectively. Conclusions: This is the first study to observe a cross-sectional association between e-cigarette usage and inflammatory arthritis diseases, and the findings were consistent in both sole-e-cigarette users and dual users. Our findings provide evidence that e-cigarette usage might be an important risk factor for arthritis diseases, which may have regulatory implications for e-cigarette control.

The Association Between E-Cigarette Use and Prediabetes: Results From the Behavioral Risk Factor Surveillance System, 2016-2018.

INTRODUCTION: Both E-cigarette use and the prevalence of prediabetes have risen dramatically in the past decade. It is crucial to understand whether E-cigarette use is associated with the risk of prediabetes. METHODS: Participants who completed the prediabetes and E-cigarette modules of the Behavioral Risk Factor Surveillance System survey (2016-2018) were included in this study. E-cigarette use information was collected by asking: Have you ever used an e-cigarette or other electronic "vaping" product, even just one time, in your entire life? We defined sole E-cigarette users as current E-cigarette users who are never combustible-cigarette users, and dual users were defined as both current E-cigarette and combustible-cigarette users. Participants with prediabetes were identified by asking: Ever been told by a doctor or other health professional that you have prediabetes or borderline diabetes? Multivariable logistic regression was used to determine the association between E-cigarette use and prediabetes. RESULTS: Among the 600,046 respondents, 28.6% of respondents were aged <35 years. The prevalence of prediabetes among current E-cigarette, sole E-cigarette users, and dual users was 9.0% (95% CI=8.6, 9.4), 5.9% (95% CI=5.3, 6.5), and 10.2% (95% CI=9.8, 10.7), respectively. In the fully adjusted model, the ORs for prediabetes were 1.22 (95% CI=1.10, 1.37) for current E-cigarette users and 1.12 (95% CI=1.05, 1.19) for former E-cigarette users compared with that of never E-cigarette users. The ORs for prediabetes were 1.54 (95% CI=1.17, 2.04) for sole E-cigarette users and 1.14 (95% CI=0.97, 1.34) for dual users. CONCLUSIONS: In this representative sample of U.S. adults, E-cigarette use was associated with greater odds of prediabetes. The results were consistent in sole E-cigarette users.

Phenolic Acids-Rich Fractions from Agaricus bitorguis (Quél.) Sacc. Chaidam ZJU-CDMA-12 Mycelia Modulate Hypoxic Stress on Hypoxia-Damaged PC12 Cells.

Hypoxia is a common pathological process in various clinical diseases. However, there is still a lack of effective anti-hypoxia active substances. Agaricus bitorguis (Quél.) Sacc Chaidam (ABSC) is a rare wild edible macrofungus that grows underground at high altitudes. Herein, intracellular phenolic acids-rich fractions (IPA) were extracted from ABSC ZJU-CDMA-12, and the structural characterization and anti-hypoxia activity of IPA on PC12 cells were elucidated as well. The results of HPLC-Q-TOF-MS illustrated that five kinds of IPA were isolated from ABSC, including (-)-epicatechin gallate, arabelline, yunnaneic acid D, 2'-O-p-hydroxybenzoyl-6'-O-trans-caffeoylgardoside,4'-O-methylgallocatechin-(4->8)-4'-O-methylepigallocatechin. IPA extracted from ABSC proved to show anti-hypoxia activity on hypoxia-damaged PC12 cells. Hypoxia enhanced reactive oxygen species (ROS) generation and reduced the mitochondrial membrane potential (ΔΨm) in PC12 cells, resulting in the inhibition of survival and induction of apoptosis in PC12 cells. Measurements of 100 µg/mL and 250 µg/mL IPA could significantly reduce hypoxia-induced damage in PC12 cells by decreasing overproduced intracellular ROS, improving ΔΨm, and reducing cell apoptosis rate. Our findings indicated that the IPA from ABSC potentially could be used as novel bioactive components applied to anti-hypoxia functional foods or medicines.

Chinese Yellow Rice Wine Processing with Reduced Ethyl Carbamate Formation by Deleting Transcriptional Regulator Dal80p in Saccharomyces cerevisiae.

Ethyl carbamate (EC) is a potential carcinogen that forms spontaneously during Chinese rice wine fermentation. The primary precursor for EC formation is urea, which originates from both external sources and arginine degradation. Urea degradation is suppressed by nitrogen catabolite repression (NCR) in Saccharomyces cerevisiae. The regulation of NCR is mediated by two positive regulators (Gln3p, Gat1p/Nil1p) and two negative regulators (Dal80p/Uga43p, Deh1p/Nil2p/GZF3p). DAL80 revealed higher transcriptional level when yeast cells were cultivated under nitrogen-limited conditions. In this study, when DAL80-deleted yeast cells were compared to wild-type BY4741 cells, less urea was accumulated, and genes involved in urea utilization were up-regulated. Furthermore, Chinese rice wine fermentation was conducted using dal80Δ cells; the concentrations of urea and EC were both reduced when compared to the BY4741 and traditional fermentation starter. The findings of this work indicated Dal80p is involved in EC formation possibly through regulating urea metabolism and may be used as the potential target for EC reduction.

Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects.

Cancer cells display novel characteristics which can be exploited for therapeutic advantage. Isolated studies have shown that 1) the mevalonate pathway and 2) increased macropinocytosis are important in tumorigenesis, but a connection between these two observations has not been envisioned. A library screen for compounds that selectively killed Dictyostelium pten- cells identified pitavastatin. Pitavastatin also killed human breast epithelial MCF10A cells lacking PTEN or expressing K-RasG12V, as well as mouse tumor organoids. The selective killing of cells with oncogenic defects was traced to GGPP (geranylgeranyl diphosphate) depletion. Disruption of GGPP synthase in Dictyostelium revealed that GGPP is needed for pseudopod extension and macropinocytosis. Fluid-phase uptake through macropinocytosis is lower in PTEN-deleted cells and, as reported previously, higher in cells expressing activated Ras. Nevertheless, uptake was more sensitive to pitavastatin in cells with either of these oncogenic mutations than in wild-type cells. Loading the residual macropinosomes after pitavastatin with high concentrations of protein mitigated the cell death, indicating that defective macropinocytosis leads to amino acid starvation. Our studies suggest that the dependence of cancer cells on the mevalonate pathway is due to the role of GGPP in macropinocytosis and the reliance of these cells on macropinocytosis for nutrient uptake. Thus, inhibition of the networks mediating these processes is likely to be effective in cancer intervention.

Lidocaine inhibits melanoma cell proliferation by regulating ERK phosphorylation.

The melanoma is responsible for the majority of all skin cancer-related deaths worldwide. Evidence suggests that local anesthetics provide some benefit in the treatment of cancer via inhibition of cellular proliferation, invasion and migration. However, the potential antiproliferative effects of local anesthetics in the treatment of melanoma remain to be elucidated. In this study, we investigated the antiproliferative effects and underlying mechanism of the commonly used local anesthetic (lidocaine) on melanoma cells. A375 melanoma cells were treated by lidocaine or vemurafenib. Cell Counting Kit-8, histological staining, flow cytometric analysis, immunohistochemical staining, and Western blot analyses were carried out to test the effects of lidocaine and vemurafenib on A375 cells. BALB/C-nu/nu mice intraperitoneally injected with A375 cells were treated by lidocaine, and then tumor volume and weight were calculated. Lidocaine exhibited vemurafenib-like effects totally. Lidocaine inhibited A375 melanoma cell proliferation in a dose- and time-dependent manner and colony formation also showed a dose-dependent inhibition. Lidocaine treatment resulted in the arrest of cell-cycle progression in the G1 phase and inhibited Ki-67 expression in a dose-dependent manner. This effect was associated with inhibited extracellular signal-regulated kinase (ERK) phosphorylation. In vivo experiments revealed that intravenous injections of lidocaine suppressed tumor volume and weight. Lidocaine inhibits melanoma cell proliferation in a dose- and time-dependent manner via a mechanism that may involve inhibition of the ERK signaling pathway. Thus, lidocaine may provide some benefit for the treatment of melanoma.

In Vitro Antioxidant Activities and in Vivo Anti-Hypoxic Activity of the Edible Mushroom Agaricus bisporus (Lange) Sing. Chaidam.

With the rising awareness of a healthy lifestyle, natural functional foods have gained much interest as promising alternatives to synthetic functional drugs. Recently, wild Agaricus bisporus (Lange) Sing. Chaidam has been found and artificially cultivated for its thick fresh body and excellent taste, with its antioxidant and anti-hypoxic abilities unknown. In this work, the antioxidant potential of its methanolic, 55% ethanolic, aqueous extracts and crude polysaccharide was evaluated in different systems. The results showed that polysaccharide was the most effective in scavenging ability on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radicals, metal chelating activity and reducing power, with EC50 values of 0.02, 2.79, 1.29, and 1.82 mg/mL, respectively. Therefore, we further studied the anti-hypoxic activity of crude polysaccharide. The results turned out that polysaccharide (300 mg/kg) prolonged the survival time, decreased the blood urea nitrogen and lactic acid content as well as increased the liver glycogen significantly, compared with the blank control and the commercialized product Hongjingtian (p < 0.05). With such excellent activities, we purified the polysaccharide and analyzed its molecular weight (120 kDa) as well as monosaccharide components (glucose, fructose and mannose). This study indicated that wild Agaricus bisporus (Lange) Sing. Chaidam had strong potential to be exploited as an effective natural functional food to relieve oxidative and hypoxia stresses.

The cross talk between cGMP signal pathway and PKC in pulmonary endothelial cell angiogenesis.

Angiogenic proliferation of vascular endothelial cells is believed to play an important role in pulmonary vascular remodeling in pulmonary arterial hypertension. In the present study, we found that c-GMP (cyclic guanosine monophosphate) inhibited the proliferation and tube formation of pulmonary vascular endothelial cells induced by TGF-ß1, and that this process was reversed by PKG (protein kinase G) inhibitor and PKC (protein kinase C) inhibitor. In addition, small interfering RNA (siRNA) targeting ERK also reduced cellular proliferation. Furthermore, western blotting showed that cGMP down-regulated the phosphorylation level of ERK1/2, which was reversed not only by PKG inhibitor but also by PKC inhibitor. Silencing different PKC isoforms showed that PKCΔ, PKCγ and PKCα were involved in ERK phosphorylation, suggesting that PKC kinases have a permissive action. Three subtypes, PKCΔ, PKCγ and PKCα are likely to be involved the phosphorylation suppression of ERK included cGMP. Taken together, these data suggest that ERK phosphorylation mediates the proliferation of pulmonary vascular endothelial cells, and PKC kinases have a permissive action in this process.

Ethyl Carbamate in Fermented Beverages: Presence, Analytical Chemistry, Formation Mechanism, and Mitigation Proposals.

Ethyl carbamate (EC) commonly found in fermented beverages has been verified to be a multisite carcinogen in experimental animals. EC was upgraded to Group 2A by the Intl. Agency for Research on Cancer (IARC) in 2007, which indicates that EC is a probable carcinogen to humans. Because of its threat to human safety, the presence of EC may be a big challenge in the alcoholic beverage industry. During the past few years, thorough and systematic research has been carried out in terms of the generation of EC in order to meet the allowed limitation levels in fermented beverages. Previous studies have indicated that EC primarily results from the reaction of ethanol and compounds containing carbamyl groups. These main EC precursors are commonly generated from arginine metabolism by Saccharomyces cerevisiae or lactic acid bacteria accompanied by the fermentation process. This review comprehensively summarizes the genotoxicity, analytical methods, formation pathways, and removal strategies of EC in various beverages. The article also presents the metabolic mechanism of EC precursors and pertinent metabolites, such as urea, citrulline, and arginine.

Optimal effective concentration of ropivacaine for postoperative analgesia by single-shot femoral-sciatic nerve block in outpatient knee arthroscopy.

OBJECTIVE: To compare analgesic and mobility effects of different ropivacaine concentrations in femoral-sciatic nerve block, for postoperative analgesia in knee arthroscopy. METHODS: Outpatients (American Society of Anesthesiologists physical classification status of I or II), scheduled for elective knee arthroscopy, were randomly allocated to one of seven groups, prospectively investigating different concentrations of ropivacaine (0.12%; 0.14%; 0.16%; 0.18%; 0.20%; 0.22% or 0.50%), for ultrasound-guided femoral-sciatic nerve block procedures for postoperative analgesia. Visual analogue scale (VAS) pain scores and motor block evaluation scales were observed at 4, 8, 16 and 24 h postsurgery. RESULTS: In total, 105 patients were enrolled; results were analysed for 103. VAS scores for the 0.12%, 0.14% and 0.16% groups were significantly different from the 0.50% group. There were no significant differences between the 0.18%, 0.20%, 0.22% and 0.50% groups: half maximal effective concentrations and 95% maximal effective concentrations of ropivacaine were 0.158 (95% confidence intervals [CI] 0.149, 0.167) and 0.198 (95% CI 0.186, 0.221), respectively. Rates of motor blockade (Bromage score or hip motor function scale > 0) were significantly different between the 0.50% group and all other ropivacaine doses. CONCLUSION: The 0.20% ropivacaine dose for femoral-sciatic nerve block in knee arthroscopy provided satisfactory postoperative analgesia, while preserving ability of motion.