Predicting malignancy in thyroid nodules: molecular advances

Over the last several years, a clearer understanding has developed of the genetic alterations underlying thyroid carcinogenesis. This knowledge can be used to tackle 1 of the challenges facing thyroidologists: management of the indeterminate thyroid nodule. Despite the accuracy of fine-needle aspiration cytology, many patients undergo surgery to diagnose malignancy and better diagnostic tools are required. A number of biomarkers have recently been studied and show promise in this setting. In particular, BRAF, RAS, PAX8-PPARγ, microRNAs, and loss of heterozygosity have each been demonstrated as useful molecular tools for predicting malignancy and can potentially guide decisions regarding surgical management of nodular thyroid disease. This review summarizes the current literature surrounding each of these markers, highlights our institution's prospective analysis of these markers, and describes the subsequent incorporation of molecular markers into a management algorithm for thyroid nodules.     

Cyclic strain delays the expression of tissue factor induced by thrombin in human umbilical vein endothelial cells

Most studies of tissue factor (TF) expression in endothelial cells (EC) are performed under stationary culture conditions. The purpose of this study was to determine the influence of mechanical stimuli such as cyclic strain (CS) on the expression of TF in EC exposed to thrombin (Thr). Human umbilical vein endothelial cells (HUVEC) were exposed to 4 U·mL⁻¹ Thr in the presence or absence of 10% average CS at 60 cycles·min⁻¹ and then TF expression was measured. TF messenger RNA (mRNA) expression peaked at 2 hours in HUVEC exposed to Thr, but at 4 hours in HUVEC exposed to both Thr + CS. TF expression was inhibited by p38 and extracellular signal-regulated protein kinase (ERK) inhibitors. For both Thr or Thr + CS stimuli, p38 and ERK activity peaked at 5 minutes (p < 0.05). Nuclear factor-kappa B levels remained high in the Thr group but not in the Thr + CS group, while Egr-1 levels were elevated in the Thr + CS group. We demonstrated CS-delayed, Thr-induced TF mRNA expression in HUVEC, which may be modulated by p38 and ERK inhibitors.     

A Food-Based Intervention in a Military Dining Facility Improves Blood Fatty Acid Profile

Enhancing dietary omega-3 highly unsaturated fatty acids (n-3 HUFA) intake may confer neuroprotection, brain resiliency, improve wound healing and promote cardiovascular health. This study determined the efficacy of substituting a few common foods (chicken meat, chicken sausage, eggs, salad dressings, pasta sauces, cooking oil, mayonnaise, and peanut butter) lower in omega-6 polyunsaturated fatty acids (n-6 PUFA) and higher in n-3 HUFA in a dining facility on blood fatty acid profile. An eight-week prospective, between-subjects (n = 77), repeated measures, parallel-arm trial was conducted. Participants self-selected foods consumed from conventionally produced foods (control), or those lower n-6 PUFA and higher n-3 HUFA versions (intervention). Changes in blood omega-3 index, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), n-6 PUFA, lipid profile, and food satisfaction were main outcomes. Between-group differences over time were assessed using a linear mixed model to measure the effect of diet on blood serum fatty acids and inflammatory markers. The intervention group achieved a higher omega-3 index score (3.66 ± 0.71 vs. 2.95 ± 0.77; p < 0.05), lower total n-6 (10.1 ± 4.6 vs. 15.3 ± 6.7 µg/mL; p < 0.05), and higher serum concentration of EPA (5.0 ± 1.31 vs. 4.05 ± 1.56 µg/mL; p < 0.05) vs. controls. Satisfaction in intervention foods improved or remained consistent. Substitution of commonly eaten dining facility foods with like-items higher in DHA and EPA and lower in n-6 PUFA can favorably impact fatty acid status and the omega-3 index.     

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.     

A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies

ObjectiveMultiple studies have identified single-nucleotide polymorphisms (SNPs) that are associated with coronary heart disease (CHD). We examined whether SNPs selected based on predefined criteria will improve CHD risk prediction when added to traditional risk factors (TRFs).MethodsSNPs were selected from the literature based on association with CHD, lack of association with a known CHD risk factor, and successful replication. A genetic risk score (GRS) was constructed based on these SNPs. Cox proportional hazards model was used to calculate CHD risk based on the Atherosclerosis Risk in Communities (ARIC) and Framingham CHD risk scores with and without the GRS.ResultsThe GRS was associated with risk for CHD (hazard ratio [HR] = 1.10; 95% confidence interval [CI]: 1.07–1.13). Addition of the GRS to the ARIC risk score significantly improved discrimination, reclassification, and calibration beyond that afforded by TRFs alone in non-Hispanic whites in the ARIC study. The area under the receiver operating characteristic curve (AUC) increased from 0.742 to 0.749 (Δ = 0.007; 95% CI, 0.004–0.013), and the net reclassification index (NRI) was 6.3%. Although the risk estimates for CHD in the Framingham Offspring (HR = 1.12; 95% CI: 1.10–1.14) and Rotterdam (HR = 1.08; 95% CI: 1.02–1.14) Studies were significantly improved by adding the GRS to TRFs, improvements in AUC and NRI were modest.ConclusionAddition of a GRS based on direct associations with CHD to TRFs significantly improved discrimination and reclassification in white participants of the ARIC Study, with no significant improvement in the Rotterdam and Framingham Offspring Studies.     

Immunogenicity in humans of an edible vaccine for hepatitis B

A double-blind placebo-controlled clinical trial evaluated the immunogenicity of hepatitis B surface antigen (HBsAg) expressed in potatoes and delivered orally to previously vaccinated individuals. The potatoes accumulated HBsAg at approximately 8.5 microg/g of potato tuber, and doses of 100 g of tuber were administered by ingestion. The correlate of protection for hepatitis B virus, a nonenteric pathogen, is blood serum antibody titers against HBsAg. After volunteers ate uncooked potatoes, serum anti-HBsAg titers increased in 10 of 16 volunteers (62.5%) who ate three doses of potatoes; in 9 of 17 volunteers (52.9%) who ate two doses of transgenic potatoes; and in none of the volunteers who ate nontransgenic potatoes. These results were achieved without the coadministration of a mucosal adjuvant or the need for buffering stomach pH. We conclude that a plant-derived orally delivered vaccine for prevention of hepatitis B virus should be considered as a viable component of a global immunization program.     

Functional effects of single dose first- and second-generation antipsychotic administration in subjects with schizophrenia

Using PET with (15)O water, we characterized the time course of functional brain changes following the acute administration of a first- and a second-generation antipsychotic. Volunteers with schizophrenia were scanned while drug-free (baseline) and after single dose administration of haloperidol (n=6) or olanzapine (n=6) during a time course adapted to their plasma kinetics. To obtain brain location information, we contrasted each post-drug scan to baseline-acquired scans. We plotted the regional cerebral blood flow (rCBF) extracted in these locations and calculated the kinetic characteristics of the curves. Further, we compared and contrasted the rCBF changes induced by the drugs over the first 4 h post-drug administration. Dorsal and ventral striatum, thalamus and anterior cingulate cortex were activated with haloperidol, while frontal, temporal and cerebellum regions evidenced reduced flow. With olanzapine, ventral striatum, anterior cingulate and temporal cortices evidenced increases, and thalamus and lingual cortex decreases, in rCBF. Both drugs activated the caudate nucleus. Haloperidol induced greater activation of the dorsal striatum than did olanzapine. These data reveal important differences in patterns of brain activation between the drugs. Differences in the involvement in basal ganglia parallel known differences between the drugs in the emergence of acute EPS upon emergency administration.     

The Effects of Chronic Ethanol Consumption on Carcinogen Metabolism and on O6-Methylguanine Transferase-Mediated Repair of Alkylated DNA

This article presents a review and update of recent experiments conducted in collaboration with Dr. C. S. Lieber on mechanisms underlying the increased cancer risk associated with alcohol abuse. Ethanol has been found to be a potent inducer of microsomal enzymes involved in carcinogen metabolism in a variety of rat tissues including liver, esophagus, lungs, and intestines. In some of these tissues, ethanol's inductive effect on microsomal cytochrome P-450 enzyme activity may result in enhanced levels of electrophilic metabolites of procarcinogens which are not readily detoxified. In addition, chronic ethanol feeding has been found to depress the activity of O⁶-methylguanine transferase, an enzyme involved in the repair of carcinogen-induced DNA alkylation. The effects of ethanol on carcinogen metabolism and on DNA repair would be expected to enhance the initiation phase of chemically induced cancers.