Association of Patient Age With Progression of Low-risk Papillary Thyroid Carcinoma Under Active Surveillance: A Systematic Review and Meta-analysis.

Importance: Active surveillance is sometimes considered as a disease management option for individuals with small, low-risk papillary thyroid carcinoma. Objective: To assess whether patient age is associated with progression of low-risk papillary thyroid carcinoma (tumor growth or incident metastatic disease) in adults under active surveillance. Evidence Review: Eight electronic databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Emcare, PsycINFO, Web of Science, and ClincalTrials.gov) were searched from inception to March 2019, supplemented with a hand search. Two investigators independently screened citations, reviewed full-text articles, and abstracted data. Additional data were sought from authors. Random-effects meta-analyses were performed using incidence data (statistically adjusted for confounders and crude rates). Findings: A total of 1658 unique citations were screened, and 62 full-text articles were reviewed, including 5 studies. Three studies included exclusively microcarcinomas and 2 included tumors up to 2 cm in maximal diameter. The mean age of participants was 51.0 to 55.2 years in 4 studies reporting this value. The mean or median follow-up was 5 years or more in 3 studies and approximately 2 years in 2 studies. The pooled risk ratio for tumor growth of 3 mm or more in maximal diameter in individuals aged 40 to 50 years compared with younger individuals was 0.51 when adjusted for confounders (95% CI, 0.29-0.89; 1619 patients, 2 studies), and the unadjusted risk ratio of this outcome for individuals 40 years or older was 0.55 (95% CI, 0.36-0.82; 2097 patients, 4 studies). In adults aged 40 to 45 years, the unadjusted risk ratio for any tumor volume increase compared with younger individuals was 0.65 (95% CI, 0.51-0.83; 1232 patients, 4 studies). The pooled risk ratio for incident nodal metastases in individuals 40 years or older was 0.22 (95% CI, 0.10-0.47; 1806 patients, 3 studies); however, in a secondary analysis, the risk difference was not significantly different. There was no statistically significant heterogeneity in any of the meta-analyses. There were no thyroid cancer-related deaths nor incident distant metastases. Conclusions and Relevance: This study suggests that older age may be associated with a reduced risk of primary papillary thyroid carcinoma tumor growth under active surveillance. Incident metastatic disease is uncommon during active surveillance.

Effects of Vitamin D3 in Long-Term Ovariectomized Rats Subjected to Chronic Unpredictable Mild Stress: BDNF, NT-3, and NT-4 Implications.

The purpose of this study was to explore the antidepressant-like effects of vitamin D3 at different doses (1.0, 2.5, and 5.0 mg/kg sc) on a model of depression produced by chronic unpredictable mild stress (CUMS) for 28 days in long-term (3 months) ovariectomized (OVX) adult rats. Sucrose preference (SPT), forced swimming (FST) and open-field (OFT) tests were conducted to examine the depression-like state. Serum corticosterone/adrenocorticotrophic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3/NT-4 expressions by ELISA kits and/or western blotting were determined to assess the possible mechanisms of the vitamin D3 effects on the depression-like profile in long-term OVX rats subjected to CUMS. The results showed that vitamin D3 (5.0 mg/kg), as well as fluoxetine treatment, considerably reversed the depression-like state in the SPT and FST, decreased serum corticosterone/ACTH levels, and increased BDNF and NT-3/NT-4 levels in the hippocampus of long-term OVX rats compared to OVX rats with CUMS (p < 0.05). Thus, a high dose of vitamin D3 (5.0 mg/kg sc) could improve the depression-like profile in long-term OVX adult female rats subjected to the CUMS procedure, which might be mediated by the regulation of BDNF and the NT-3/NT-4 signaling pathways in the hippocampus, as well as the corticosterone/ACTH levels of the blood serum.

Rac-1 superactivation triggers insulin-independent glucose transporter 4 (GLUT4) translocation that bypasses signaling defects exerted by c-Jun N-terminal kinase (JNK)- and ceramide-induced insulin resistance.

Insulin activates a cascade of signaling molecules, including Rac-1, Akt, and AS160, to promote the net gain of glucose transporter 4 (GLUT4) at the plasma membrane of muscle cells. Interestingly, constitutively active Rac-1 expression results in a hormone-independent increase in surface GLUT4; however, the molecular mechanism and significance behind this effect remain unresolved. Using L6 myoblasts stably expressing myc-tagged GLUT4, we found that overexpression of constitutively active but not wild-type Rac-1 sufficed to drive GLUT4 translocation to the membrane of comparable magnitude with that elicited by insulin. Stimulation of endogenous Rac-1 by Tiam1 overexpression elicited a similar hormone-independent gain in surface GLUT4. This effect on GLUT4 traffic could also be reproduced by acutely activating a Rac-1 construct via rapamycin-mediated heterodimerization. Strategies triggering Rac-1 "superactivation" (i.e. to levels above those attained by insulin alone) produced a modest gain in plasma membrane phosphatidylinositol 3,4,5-trisphosphate, moderate Akt activation, and substantial AS160 phosphorylation, which translated into GLUT4 translocation and negated the requirement for IRS-1. This unique signaling capacity exerted by Rac-1 superactivation bypassed the defects imposed by JNK- and ceramide-induced insulin resistance and allowed full and partial restoration of the GLUT4 translocation response, respectively. We propose that potent elevation of Rac-1 activation alone suffices to drive insulin-independent GLUT4 translocation in muscle cells, and such a strategy might be exploited to bypass signaling defects during insulin resistance.

Direct and macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells.

Obesity is associated with insulin resistance and increased risk for developing type 2 diabetes. Enlarged adipocytes develop resistance to the anti-lipolytic action of insulin. Elevated levels of fatty acids in the plasma and interstitial fluids lead to whole-body insulin resistance by disrupting normal insulin-regulated glucose uptake and glycogen storage in skeletal muscle. A new understanding has been cultivated in the past 5 to 10 years that adipocytes and macrophages (resident or bone marrow-derived) in adipose tissue of obese animals and humans are activated in a pro-inflammatory capacity and secrete insulin resistance-inducing factors. However, only recently have fatty acids themselves been identified as agents that engage toll-like receptors of the innate immunity systems of macrophages, adipocytes and muscle cells to trigger pro-inflammatory responses. This review summarizes our observations that fatty acids evoke the release of pro-inflammatory factors from macrophages that consequently induce insulin resistance in muscle cells.