Lenvatinib Suppresses Protein Kinase B Signaling and Induces Apoptosis in Osteosarcoma Cells.

BACKGROUND/AIM: Lenvatinib, an oral multikinase inhibitor, has demonstrated promising activity in patients with osteosarcoma (OS). Therefore, it is worth exploring the inhibitory efficacy and mechanism of action of lenvatinib in osteosarcoma. The primary goal of this study was to examine the inhibitory effectiveness and mechanism of lenvatinib on the growth and invasion of OS cells. MATERIALS AND METHODS: The effects of lenvatinib on cell viability, apoptosis, protein kinase B (AKT) activation, its downstream effector proteins involved in tumor progression, and invasion capability were assessed using MTT assay, flow cytometry, western blotting, and invasion/migration assay on U-2 OS and MG63 cells. RESULTS: Lenvatinib effectively induced cytotoxicity, apoptosis, as well as extrinsic and intrinsic apoptotic signaling in OS cells. Lenvatinib also significantly decreased the invasion/migration capability, AKT activation, and downstream effector proteins. CONCLUSION: The anti-OS effect of lenvatinib may be associated with the induction of apoptosis and the inactivation of AKT.

Let-7g Upregulation Attenuated the KRAS-PI3K-Rac1-Akt Axis-Mediated Bioenergetic Functions.

The aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experiments revealed that decreasing the interaction of kirsten rat sarcoma viral oncogene homolog (KRAS) with p110α in lipid rafts with the use of naringenin (NGN), a citrus flavonoid, causes lipid raft-associated phosphatidylinositol 3-kinase (PI3K)-GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)-protein kinase B (Akt)-regulated metabolic dysfunction of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), leading to apoptosis in human nasopharyngeal carcinoma (NPC) cells. The use of lethal-7g (let-7g) mimic and let-7g inhibitor confirmed that elevated let-7g resulted in a decrease in KRAS expression, which attenuated the PI3K-Rac1-Akt-BCL-2/BCL-xL-modulated mitochondrial energy metabolic functions. Increased let-7g depends on the suppression of the RNA-specificity of monocyte chemoattractant protein-induced protein-1 (MCPIP1) ribonuclease since NGN specifically blocks the degradation of pre-let-7g by NPC cell-derived immunoprecipitated MCPIP1. Converging lines of evidence indicate that the inhibition of MCPIP1 by NGN leads to let-7g upregulation, suppressing oncogenic KRAS-modulated PI3K-Rac1-Akt signaling and thereby impeding the metabolic activities of aerobic glycolysis and mitochondrial OXPHOS.

The Presence of Diabetes Mellitus or Pre-diabetes Mellitus Increases Mortality from Heart Disease in a Taiwanese Population: A 10-year Follow-Up Study.

BACKGROUND: We evaluated hyperglycemia-associated mortality in the Taiwanese population by conducting a 10-year retrospective cohort study. METHODS: From 2007 to 2017, all participants, regardless of their age or underlying diseases, were identified at a Health Screening Center in Taiwan. Overall, 114,534 participants were included in the analysis. They were classified into three subgroups according to glycemia and smoking status by combining survival for data analysis. RESULTS: The mean follow-up time, age, and body mass index (BMI) were 8.14 ± 2.22 years, 40.95 ± 12.14 years, and 23.24 ± 3.65 kg/m2, respectively. The cumulative death rate increased from 0.9% in the normal fasting blood glucose(FBG) subgroup to approximately 6% in the diabetes FBG subgroup. After adjusting for age, gender, BMI, high-density lipoprotein, triglycerides, waist circumference(WC), and smoking status, the hazard ratio (HR) for all-cause, cancer, and heart disease mortality in the diabetes mellitus(DM) subgroup was 1.560, 1.381, and 1.828, respectively.HR was 0.989 in all-cause, 0.940 in cancer, and 1.326 in heart disease in the pre-DM subgroup. CONCLUSION: Being tested for pre-DM is related to a higher risk of death from heart disease in the Taiwanese population at baseline. Therefore, cardiovascular risk must be actively measured among diabetes patients every visit.

Verifying the accuracy of self-reported smoking behavior in female volunteer soldiers.

Smoking rates in the military are evaluated through questionnaire surveying. Because the accurate identification of smokers facilitates the provision of smoking cessation services, this study conducted urine cotinine concentration testing to verify the accuracy of self-reported smoking behavior by female volunteer soldiers and analyzed the effects of second-hand smoking on urine cotinine concentrations. This study is a cross-sectional study conducted using purposive sampling on female volunteer soldiers receiving training at the Taichung Recruit Training Center in May 2014. This study simultaneously collected questionnaires and urine samples, and urine samples were analyzed with an enzyme-linked immunosorbent assay. The self-reported smoking rate of female volunteer soldiers was 19.3%, whereas the smoking rate as determined by urine cotinine concentration testing was 26.3%, indicating an overall underestimation of 7.0%. Chi-square (χ2) goodness of fit test results indicated that the distribution of self-reported smoking behaviors and that verified from urine cotinine concentration testing were significantly different. The sensitivity of self-reported smoking behavior was 66.7% with a specificity of 97.6%. There was no significant association between second-hand smoking and urine cotinine concentrations. Questionnaire survey self-reporting methods could underestimate the smoking behavior of female volunteer soldiers and routine testing with biochemical verification is necessary.

The Association between Serum Testosterone and Hyperuricemia in Males.

Gout is a common systemic inflammatory disease with a male predominance. This study aimed to determine the relationship between serum total testosterone level and hyperuricemia. Data on 1899 men, collected from 2007 to 2017, were included in the analysis. Serum testosterone and urate (SU) were measured on enrolment. The primary endpoints were SU levels ≥ 7 mg/dL and ≥9 mg/dL. On enrolment, participants had a mean age of 45.6 years and mean total testosterone and SU levels of 510 ng/dL and 6.6 mg/dL, respectively. The mean total testosterone levels were 533 and 470 ng/dL in patients with SU levels < 7 mg/dL and ≥7 mg/dL, respectively (p < 0.001); and 515 and 425 ng/dL in patients with SU levels < 9 mg/dL and ≥9 mg/dL, respectively (p < 0.001). After adjusting for age, body mass index, creatinine, serum lipid, fasting blood glucose, systolic blood pressure, and diastolic blood pressure, low testosterone level (<400 ng/dL) was significantly associated with an SU level ≥ 7 mg/dL (hazard ratio: 1.182, 95% confidence interval: 1.005−1.39) and ≥9 mg/dL (hazard ratio: 1.905, 95% confidence interval: 1.239−2.928). In men, a low testosterone level may be associated with an increased risk of hyperuricemia.

Anti-Oxidative Effect of Pu-erh Tea in Animals Trails: A Systematic Review and Meta-Analysis.

This study adopted systematic literature review and meta-analysis methodology to explored anti-oxidative effect of pu-erh tea. Study authors have systemically searched seven databases up until 21 February 2020. In performing the literature search on the above-mentioned databases, the authors used keywords of pu-erh AND (superoxide dismutase OR glutathione peroxidase OR malondialdehyde). Results derived from meta-analyses showed statistically significant effects of pu-erh tea on reducing serum MDA levels (SMD, −4.19; 95% CI, −5.22 to −3.15; p < 0.001; I2 = 93.67%); increasing serum SOD levels (SMD, 2.41; 95% CI, 1.61 to 3.20; p < 0.001; I2 = 91.36%); and increasing serum GSH-Px levels (SMD, 4.23; 95% CI, 3.10 to 5.36; p < 0.001; I2 = 93.69%). Results from systematic review and meta-analyses validated that various ingredients found in pu-erh tea extracts had anti-oxidation effects, a long-held conventional wisdom with limited supporting evidence.

Overexpression of Cell-Surface Marker SLC16A1 Shortened Survival in Human High-Grade Gliomas.

Solute carrier family 16 member 1 (SLC16A1) is a crucial transcription factor in modifying cancer progression and metastasis. However, its character in defining the clinical prognosis of human gliomas has not been illuminated. In our analysis from PREdiction of Clinical Outcomes from Genomic Profiles (PRECOG), The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA), we found that SLC16A1 mRNA expression level was significantly increased in high-grade gliomas in contrast to low-grade gliomas and non-tumor controls (P < 0.05). Kaplan-Meier analysis of four independent cohort studies from the Gene Expression Omnibus (GEO) profile, TCGA, and CGGA which consistently presented patients with high SLC16A1 mRNA expression displayed poor overall survival in high-grade glioma patients (P < 0.05 by log-rank test). Based on the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), the protein-protein interaction analysis of SLC16A1-regulated oncogenesis showed SLC16A1 as a potential hub protein. Immunohistochemical staining exhibited that SLC16A1 protein overexpressed in high-grade gliomas compared with low-grade clinical glioma samples. All these findings suggest that SLC16A1 expression has a positive correlation with WHO pathological grading and poor survival. SLC16A1 might be a potential biomarker of prognosis in human gliomas.

Inhibitory effects of pu-erh tea on alpha glucosidase and alpha amylase: a systemic review.

OBJECTIVE: Pu-erh tea was presumed to have anti-hyperglycemic effects via inhibition on alpha-amylase and alpha-glucosidase. However, no integerated literatures were published to substantiate such presumption. METHODS: Current study adopted systemic review method to validate inhibitory effects on alpha amylase and alpha-glucosidase. Five English databases (PubMed, EBSCO, SCOPUS, Cochrane Library, Web of Science) and three Chinese ones (Airti Library, CNKI Library, and Google Scholar) were searched up to 22 March 2018 for eligible literatures, using keywords of Pu-erh, Pu'er, alpha-amylase or alpha-glucosidase. RESULTS: Six studies exploring inhibitory effects on alpha-glucosidase and seven on alpha-amylase were included for systemic review. Though results showed pu-erh tea has significant inhibitory effects on alpha-amylase and alpha-glucosidase, high heterogeneity was detected among studies included. CONCLUSIONS: High heterogeneity may be due to complex alterations of chemicals under different degrees of fermentation. More future studies are required to further identify principal bioactive component(s) at work.

Citrate-Induced p85α⁻PTEN Complex Formation Causes G2/M Phase Arrest in Human Pharyngeal Squamous Carcinoma Cell Lines.

Citrate is a key intermediate of the tricarboxylic acid cycle and acts as an allosteric signal to regulate the production of cellular ATP. An elevated cytosolic citrate concentration inhibits growth in several types of human cancer cells; however, the underlying mechanism by which citrate induces the growth arrest of cancer cells remains unclear. The results of this study showed that treatment of human pharyngeal squamous carcinoma (PSC) cells with a growth-suppressive concentration of citrate caused cell cycle arrest at the G2/M phase. A coimmunoprecipitation study demonstrated that citrate-induced cell cycle arrest in the G2/M phase was associated with stabilizing the formation of cyclin B1-phospho (p)-cyclin-dependent kinase 1 (CDK1) (Thr 161) complexes. The citrate-induced increased levels of cyclin B1 and G2/M phase arrest were suppressed by the caspase-3 inhibitor Ac-DEVD-CMK and caspase-3 cleavage of mutant p21 (D112N). Ectopic expression of the constitutively active form of protein kinase B (Akt1) could overcome the induction of p21 cleavage, cyclin B1-p-CDK1 (Thr 161) complexes, and G2/M phase arrest by citrate. p85α-phosphatase and tensin homolog deleted from chromosome 10 (PTEN) complex-mediated inactivation of Akt was required for citrate-induced G2/M phase cell cycle arrest because PTEN short hairpin RNA or a PTEN inhibitor (SF1670) blocked the suppression of Akt Ser 473 phosphorylation and the induction of cyclin B1-p-CDK1 (Thr 161) complexes and G2/M phase arrest by citrate. In conclusion, citrate induces G2/M phase arrest in PSC cells by inducing the formation of p85α-PTEN complexes to attenuate Akt-mediated signaling, thereby causing the formation of cyclin B1-p-CDK1 (Thr 161) complexes.

Suppression of Akt-mediated HDAC3 expression and CDK2 T39 phosphorylation by a bichalcone analog contributes to S phase retardation of cancer cells.

Targeting cell cycle regulators has been a suggested mechanism for therapeutic cancer strategies. We report here that the bichalcone analog TSWU-CD4 induces S phase arrest of human cancer cells by inhibiting the formation of cyclin A-phospho (p)-cyclin-dependent kinase 2 (CDK2, threonine [Thr] 39) complexes, independent of mutant p53 expression. Ectopic expression of CDK2 (T39E), which mimics phosphorylation of the Thr 39 residue of CDK2, partially rescues the cells from TSWU-CD4-induced S phase arrest, whereas phosphorylation-deficient CDK2 (T39A) expression regulates cell growth with significant S phase arrest and enhances TSWU-CD4-triggered S phase arrest. Decreased histone deacetylase 3 (HDAC3) expression after TSWU-CD4 treatment was demonstrated, and TSWU-CD4 induced S phase arrest and inhibitory effects on cyclin A expression and CDK2 Thr 39 phosphorylation, while cyclin A-p-CDK2 (Thr 39) complex formation was suppressed by ectopic wild-type HDAC3 expression. The co-transfection of CDK2 (T39E) along with HDAC3 completely restored cyclin A expression, Thr 39-phosphorylated CDK2, cyclin A-p-CDK2 (Thr 39) complex formation, and the S phase population to normal levels. Protein kinase B (Akt) inactivation was required for TSWU-CD4-induced S phase cell cycle arrest, because constitutively active Akt1 blocks the induction of S phase arrest and the suppression of cyclin A and HDAC3 expression, CDK2 Thr 39 phosphorylation, and cyclin A-p-CDK2 (Thr 39) complex formation by TSWU-CD4. Taken together, our results indicate that TSWU-CD4 induces S phase arrest by inhibiting Akt-mediated HDAC3 expression and CDK2 Thr 39 phosphorylation to suppress the formation of cyclin A-p-CDK2 (Thr 39) complexes.

Global trend in articles related to stereotactic published in science citation index-expanded.

BACKGROUND: This is the first article using bibliometrics to study the field of stereotactic related research. This study aims to evaluate the global scientific production of simulation research in the category of "stereotactic" during 1993-2008 and to provide insights on the characteristics of the stereotactic related research patterns, tendencies, and methods that might exist in the papers, as well as in leading countries and institutes. METHODS: In this study, "stereotactic*" was used as the keyword to search titles, abstracts, and keywords in the database of the Science Citation Index Expanded. All the articles referring to stereotactic during the studied years, were assessed by the following aspects: document type of publication, characteristics of publication outputs, distribution of outputs in journals, publication outputs of source country, source institute, and analysis of words cluster in title, author keywords, and KeyWords Plus. RESULTS: Eleven document types were found in the total 10 015 publications during 1993-2008. Clinical neurology was the most common category in stereotactic-related research. Neurosurgery listed in categories of clinical neurology and surgery, ranked first. The most productive country and institute were USA and University of Pittsburgh respectively. Words cluster analysis was elaborated regarding the issues of movement disorders, radiosurgery, tumor, and vascular/stroke, it revealed the sharp rise of articles from 1995 until the end of the period covered in "movement disorders" category. CONCLUSIONS: The results analyzed by this bibliometric method can show the research performance, significant events and major inventors, those attributed to stereotactic neurosurgery, and trend of stereotactic related research.

Traumatic subdural hematoma in the lumbar spine.

Traumatic spinal subdural hematoma is rare and its mechanism remains unclear. This intervention describes a patient with mental retardation who was suffering from back pain and progressive weakness of the lower limbs following a traffic accident. Magnetic resonance imaging of the spine revealed a lumbar subdural lesion. Hematoma was identified in the spinal subdural space during an operation. The muscle power of both lower limbs recovered to normal after surgery. The isolated traumatic spinal subdural hematoma was not associated with intracranial subdural hemorrhage. A spinal subdural hematoma should be considered in the differential diagnosis of spinal cord compression, especially for patients who have sustained spinal trauma. Emergency surgical decompression is usually the optimal treatment for a spinal subdural hematoma with acute deterioration and severe neurological deficits.

Spinal arteriovenous fistulae with a concomitant cauda equina schwannoma.

BACKGROUND: Perimedullary spinal arteriovenous malformations or direct spinal arteriovenous fistulaes (AVFs) may be associated with other vascular abnormalities, such as arteriovenous malformations, venous ectasis, and aneurysms, but rarely have been reported with intraspinal intradural tumors. PURPOSE: The authors present an interesting case of type IV-A spinal AVF concomitant with a cauda equina schwannoma. STUDY DESIGN: The diagnostic procedures and surgical outcome were described. METHODS: The patient underwent surgery, the vessel feeding the AVFs was identified and cauterized, and the spinal tumor was removed. The fistula was small and located inside the tumor. The pathology revealed AVF and schwannoma, respectively. RESULTS: After surgery, the patient's symptoms began to improve and subside. Two years after surgery, follow-up magnetic resonance imaging showed no vascular lesion and tumor in the spinal canal. CONCLUSIONS: The association of spinal AVFs and cauda equina schwannoma has not been reported previously in any literature. The patient presents the symptoms of myelopathy associated with a spinal vascular lesion; it has to be noted that a concomitant and related intradural spinal tumor may exist.