Technological Innovations in Surgical Approach for Thyroid Cancer

Over the last decade, surgeons have witnessed dramatic changes in surgical practice as a result of the introduction of new technological advancement. Some of these changes include refinement of techniques in thyroid cancer surgery. The development of various endoscopic thyroidectomy techniques, the addition of the da Vinci robot, and the use of operative adjuncts in thyroid surgery, such as intraoperative neuromonitoring and quick intraoperative parathyroid hormone, have made thyroid cancer surgery not only safer and better accepted by patients with thyroid cancer but also offer them more surgical treatment options

Modulation of Rat Hepatic S9-Dependent Mutagenesis, DNA Binding, and Metabolism of Aflatoxin B1 and Benzo[a]pyrene by Four Chinese Medicinal Herbs

Extracts of the herbs Oldenlandia diffusa (OD) and Scutellaria barbata (SB) have been used in traditional Chinese medicine for treating liver, lung and rectal tumors while extracts of Astragalus membranaceus (AM) and Ligustrum lucidum (LL) are often used as adjuncts in cancer therapy. In this study, we determined the effects of aqueous extracts of these four herbs on aflatoxin B1 (AFB1) benzo[a]pyrene (BaP), benzo[a]pyrene 7,8-dihydrodiol (BaP 7,8-DHD) and benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE)-induced mutagenesis, mediated by enzymes in rat hepatic 9000 x g supernatant (S9), in Salmonella typhimurium TA100. We also studied the effects of these four herbs on AFB1 and BaP binding to calf thymus DNA and the effects of OD and SB on BaP 7,8-DHD and BPDE binding to calf thymus DNA. After incubation with rat hepatic S9, organosoluble metabolites of AFB1, BaP, and BaP 7,8-DHD were analyzed by reverse phase high performance liquid chromatography (HPLC), and water-soluble conjugates of BaP, BaP 7,8-DHD and BPDE were analyzed by alumina column liquid chromatography. Water-soluble conjugates of AFB1 were determined by passing through C18-Sep-pak cartridge and analyzed by HPLC. Mutagenesis assays showed that aqueous extracts of the herbs we tested produced a concentration-dependent inhibition of histidine-independent revertant (His+) colonies induced by AFB1, BaP, BaP 7,8-DHD, and BPDE. LL, OD, and SB inhibited AFB1 metabolite binding to calf thymus DNA, formation of AFB1-DNA adducts and metabolism of AFB1. These three herbs also inhibited the binding of BaP metabolites to calf thymus DNA. LL and SB decreased BaP-DNA adduct formation and SB inhibited the metabolism of BaP. OD and SB significantly inhibited the metabolism of BaP 7,8-DHD and the formation of water-soluble conjugates of BaP 7,8-DHD and BPDE. Both OD and SB modified the distribution of conjugates within the water-soluble fraction. SB inhibited BaP 7,8- DHD and BPDE binding to DNA and decreased the formation of adducts. Our results therefore suggest that the Chinese medicinal herbs LL, OD and SB possess antimutagenic and anticarcinogenic properties. OD and SB may possess these properties because they are able to scavenge the reactive metabolites and thus prevent their interaction with DNA

Impact of Routine Unilateral Central Neck Dissection on Preablative and Postablative Stimulated Thyroglobulin Levels after Total Thyroidectomy in Papillary Thyroid Carcinoma

BACKGROUND: Prophylactic central neck dissection (CND) remains controversial in papillary thyroid carcinoma (PTC). Because postsurgical stimulated thyroglobulin (sTg) level is a good surrogate for recurrence, the study aimed to evaluate the impact of prophylactic CND on preablative and postablative sTg levels after total thyroidectomy. METHODS: Of the 185 patients retrospectively analyzed, 82 (44.3%) underwent a total thyroidectomy and prophylactic CND (CND-positive group) while 103 (55.7%) underwent total thyroidectomy only (CND-negative group). All patients had no preoperative or intraoperative evidence of lymph node metastases. Clinicopathological characteristics, postoperative outcomes, and preablative and postablative sTg levels were compared between the two groups. Preablative sTg level was taken at the time of radioiodine ablation, while postablative sTg level was taken 6 months after ablation. A multivariable analysis was conducted to identify factors for preablative athyroglobulinemia (sTg<0.5 mug/L). RESULTS: Relative to the CND-negative group, the CND-positive group had larger tumors (15 mm vs. 10 mm, P < 0.005), more extrathyroidal extension (26.8% vs. 14.6%, P<0.003), more tumor, node, metastasis system stage III disease (32.9% vs. 9.7%, P < 0.001), and more temporary hypoparathyroidism (18.3% vs. 8.7%, P=0.017). Fourteen patients (17.1%) in the CND-positive group were upstaged from stages I/II to III as a result of prophylactic CND. The CND-positive group experienced lower median preablative sTg (<0.5 mug/L vs. 6.7 mug/L, P < 0.001) and a higher rate of preablative athyroglobulinemia (51.2% vs. 22.3%, P = 0.024), but these differences were not observed 6 months after ablation. Prophylactic CND was the only independent factor for preablative athyroglobulinemia. CONCLUSIONS: Although performing prophylactic CND in total thyroidectomy may offer a more complete initial tumor resection than total thyroidectomy alone by minimizing any residual microscopic disease, such a difference becomes less noticeable 6 months after ablation.published_or_final_versionSpringer Open Choice, 21 Feb 201

Conformal deformations of the Ebin metric and a generalized Calabi metric on the space of Riemannian metrics

We consider geometries on the space of Riemannian metrics conformally equivalent to the widely studied Ebin L^2 metric. Among these we characterize a distinguished metric that can be regarded as a generalization of Calabi's metric on the space of K\"ahler metrics to the space of Riemannian metrics, and we study its geometry in detail. Unlike the Ebin metric, the geodesic equation involves non-local terms, and we solve it explicitly by using a constant of the motion. We then determine its completion, which gives the first example of a metric on the space of Riemannian metrics whose completion is strictly smaller than that of the Ebin metric.Comment: 28 page

Potential Biomarkers for Physical Exercise-Induced Brain Health

Physical exercise has long been recognized as an effective and economic strategy to promote brain health in humans. The cellular and structural changes in the brains of exercised animals, including enhancements of neurogenesis and synaptogenesis, dendritic remodeling, and synaptic plasticity, have been considered as the key biological alterations accounting for exercise-elicited benefits to brain health. However, what transduces body movements into the above-mentioned changes remains largely unknown. Emerging theories indicate that physical activity triggers the release of various factors into the circulation from skeletal muscle (neurotrophins, myokines, and cytokines) and/or adipose tissue (adipokines). In this chapter, we review several of these molecules that are potentially implicated in this process, including neurotrophic factors (BDNF, IGF-1, and VEGF), adipokines (adiponectin and irisin), and myokines/cytokines (IL-15). The relationship, either causal or concomitant, between levels of these molecules (particularly in the blood) and brain function after exercise may help to identify biomarkers that can serve as objective indicators to evaluate exercise therapy on diseased or ageing brain. In addition, unmasking biomarkers may be instrumental in elucidating the mechanisms mediating exercise-induced brain health, thereby contributing to novel drug discovery for treatments to maintain brain health

Contribution of Endogenous Glucocorticoids and Their Intravascular Metabolism by 11β-HSDs to Postangioplasty Neointimal Proliferation in Mice

Exogenous glucocorticoids inhibit neointimal proliferation in animals. We aime to test the hypothesis that endogenous glucocorticoids influence neointimal proliferation; this may be mediated by effects on systemic risk factors or locally in vessels, and modulated either by adrenal secretion or by enzymes expressed in vessels which mediate local inactivation (11β-HSD2 in endothelium) or regeneration (11β-HSD1 in smooth muscle) of glucocorticoids. Femoral artery wire-angioplasty was conducted in C57Bl/6J, Apo-E(−/−), 11β-HSD1(−/−), Apo-E, 11β-HSD1(−/−) (double knockout) and 11β-HSD2(−/−) mice following glucocorticoid administration, adrenalectomy, glucocorticoid or mineralocorticoid receptor antagonism, or selective 11β-HSD1 inhibition. In C57Bl/6J mice, neointimal proliferation was reduced by systemic or local glucocorticoid administration, unaffected by adrenalectomy, reduced by the mineralocorticoid receptor antagonist eplerenone, and increased by the glucocorticoid receptor antagonist RU38486. 11β-HSD2 deletion had no effect on neointimal proliferation, with or without eplerenone. 11β-HSD1 inhibition or deletion had no effect in chow-fed C57Bl/6J mice, but reduced neointimal proliferation in Apo-E(−/−) mice on Western diet. Reductions in neointimal size were accompanied by reduced macrophage and increased collagen content. We conclude that pharmacological administration of glucocorticoid receptor agonists or of mineralocorticoid receptor antagonists may be useful in reducing neointimal proliferation. Endogenous corticosteroids induce beneficial glucocorticoid receptor activation and adverse mineralocorticoid receptor activation. However, manipulation of glucocorticoid metabolism has beneficial effects only in mice with exaggerated systemic risk factors, suggesting effects mediated primarily in liver and adipose rather than intra-vascular glucocorticoid signalling. Reducing glucocorticoid action with 11β-HSD1 inhibitors that are being developed for type 2 diabetes appears not to risk enhanced neointimal proliferation

Cognitive and disease-modifying effects of 11ß-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer's disease

Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia

Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by the overexpansion of cytosine-guanine-guanine (CGG) trinucleotide in Fmr1 gene, resulting in complete loss of the fragile X mental retardation protein (FMRP). Previous studies using Fmr1 knockout (Fmr1 KO) mice have suggested that a N-methyl-D-aspartate receptors (NMDAR) hypofunction in the hippocampal dentate gyrus may partly contribute to cognitive impairments in FXS. Since activation of NMDAR plays an important role in dendritic arborization during neuronal development, we examined whether deficits in NMDAR function are associated with alterations in dendritic complexity in the hippocampal dentate region. The dentate granule cell layer (GCL) presents active postnatal neurogenesis, and consists of a heterogenous neuronal population with gradient ages from the superficial to its deep layer. Here, we show that neurons with multiple primary dendrites that reside in the outer GCL of Fmr1 KO mice display significantly smaller NMDAR excitatory post-synaptic currents (EPSCs) and a higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA ratio in comparison to their wild-type counterparts. These deficits were associated with a significant decrease in dendritic complexity, with both dendritic length and number of intersections being significantly reduced. In contrast, although neurons with a single primary dendrite resided in the inner GCL of Fmr1 KO mice had a trend toward a reduction in NMDAR EPSCs and a higher AMPA/NMDA ratio, no alterations were found in dendritic complexity at this developmental stage. Our data indicate that the loss of FMRP causes NMDAR deficits and reduced dendritic complexity in granule neurons with multiple primary dendrites which are thought to be more mature in the GCL

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P &lt; .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice

AbstractHigh glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design.Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals