Novel histone deacetylase inhibitors in the treatment of thyroid cancer.

Histone deacetylases (HDAC) and histone acetyltransferases exert opposing enzymatic activities that modulate the degree of acetylation of histones and other intracellular molecular targets, thereby regulating gene expression, cellular differentiation, and survival. HDAC inhibition results in accumulation of acetylated histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on thyroid carcinoma cell lines, including lines originating from anaplastic and medullary carcinomas. In these models, both SAHA and m-carboxycinnamic acid bis-hydroxamide induced growth arrest and caspase-mediated apoptosis and increased p21 protein levels, retinoblastoma hypophosphorylation, BH3-interacting domain death agonist cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-x(L) expression, and cleavage of poly(ADP-ribose) polymerase and caspase-8, -9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed SAHA-induced cell death. SAHA down-regulated the expression of the apoptosis inhibitors FLIP and cIAP-2 and sensitized tumor cells to cytotoxic chemotherapy and death receptor activation. Our studies provide insight into the tumor type-specific mechanisms of antitumor effects of HDAC inhibitors and a framework for future clinical applications of HDAC inhibitors in patients with thyroid cancer, including histologic subtypes (e.g., anaplastic and medullary thyroid carcinomas) for which limited, if any, therapeutic options are available.     

Expression of MMPs and TIMP-1 in smoker and nonsmoker chronic periodontitis patients before and after periodontal treatment

Mouzakiti E, Pepelassi E, Fanourakis G, Markopoulou C, Tseleni‐Balafouta S, Vrotsos I. Expression of MMPs and TIMP‐1 in smoker and nonsmoker chronic periodontitis patients before and after periodontal treatment. J Periodont Res 2012; 47: 532–542. © 2012 John Wiley & Sons A/S Background and Objective: Nonsurgical periodontal treatment controls periodontal inflammation. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are implicated both in the destruction and in the healing of periodontal tissues. The aim of the present study was to compare the mRNA expression of MMP‐1, ‐3, ‐8, ‐9 and ‐13 and TIMP‐1 in chronic periodontitis before and after initial periodontal treatment. Material and Methods: Ninety gingival samples were harvested from 30 patients with chronic periodontitis (15 nonsmokers and 15 smokers) before and after nonsurgical treatment and from 30 periodontally healthy control subjects (15 nonsmokers and 15 smokers). Clinical parameters were assessed before and after treatment. Total RNA was isolated, and mRNA expression of MMPs and TIMP‐1 was assessed by RT‐PCR. Results: Periodontal treatment significantly increased TIMP‐1 expression and decreased the ratios of MMPs/TIMP‐1. Post‐treatment, nonsmokers with periodontitis had significantly higher MMP‐8 and TIMP‐1 expression than healthy nonsmokers, and smokers with periodontitis had significantly higher MMP‐13 and TIMP‐1 expressions than healthy smokers. Post‐treatment, smokers had significantly higher TIMP‐1 expression and lower MMP‐8/TIMP‐1 ratio than nonsmokers. Post‐treatment, there was no correlation among MMPs, and the expression of MMPs and TIMP‐1 was not correlated with clinical measurements. Conclusion: Periodontal treatment increased TIMP‐1 expression and decreased the ratios of MMPs/TIMP‐1 in chronic periodontitis. The post‐treatment increase in TIMP‐1 expression was higher for smokers. The TIMP‐1 expression was higher post‐treatment than in health. Post‐treatment, MMP‐8 expression was higher in nonsmokers with periodontitis than in healthy nonsmokers, whereas MMP‐13 expression was higher in smokers with periodontitis than in healthy smokers.     

Expression of receptor activator of NF‐κB ligand and osteoprotegerin in peripheral giant cell granulomas of the jaws

J Oral Pathol Med (2010) 39 : 687–689 Background: Peripheral giant cell granuloma is a tumor of the jaw characterized by the presence of multinucleated giant cells and mononuclear cells within a fibrous stroma. These lesions are considered to be of a reactive nature rather than neoplastic. Although peripheral giant cell granulomas is a well‐described clinical entity, little is known on its pathogenesis. The aim of this study was to investigate the receptor activator of NF‐κB ligand (RANKL) and osteoprotegerin (OPG) expression and immunolocalization in giant cell granulomas. Methods: RANKL and OPG protein expression was evaluated in 22 peripheral giant cell granulomas samples, by means of immunohistochemistry. Staining was evaluated semi‐quantitatively, according to the extent and intensity of the stain. Results: RANKL was expressed in all cases with a cytoplasmic staining pattern, whereas OPG expression was detected in 21 of the 22 cases examined. Active multinucleated giant cells exhibited intense immunoreactivity for both proteins. Conclusion: RANKL and OPG are expressed in peripheral giant cell granulomas of the jaw in a manner supporting the osteoclastic nature of giant cells whereas the possible osteoclastic lineage of stromal monocytes remains ambiguous.     

Fas signaling in thyroid carcinomas is diverted from apoptosis to proliferation.

PURPOSE: The death receptor Fas is present in thyroid carcinomas, yet fails to trigger apoptosis. Interestingly, Fas has been reported to be actually overexpressed in papillary thyroid carcinomas, suggesting that it may confer a survival advantage. EXPERIMENTAL DESIGN: We investigated the expression and activation status of Fas pathway mediators in thyroid carcinoma cell lines and tumor specimens. RESULTS: All cell lines tested express Fas-associated death domain, procaspase-8, procaspase-9, and procaspase-3; resistance to Fas-mediated apoptosis could not be attributed to lack of any of these apoptosis mediators. Moreover, Fas death domain mutations were not found in our study. The proteasome inhibitors MG132 and PS-341 (bortezomib, Velcade), which lead to accumulation of the nuclear factor kappaB (NF-kappaB) inhibitor IkappaB, did not sensitize SW579 cells to Fas-mediated apoptosis, suggesting that resistance to Fas-mediated apoptosis is not due to proteasome or NF-kappaB activity. Cross-linking of Fas in vitro induced recruitment of Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP) instead of procaspase-8. Inhibition of FLIP expression with a FLIP antisense oligonucleotide resulted in significant sensitization to Fas-mediated apoptosis. Fas cross-linking promoted BrdUrd incorporation; activated the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase, NF-kappaB, and activator protein-1 pathways in thyroid carcinoma cells in vitro; and protected cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. We also found that good prognosis papillary thyroid carcinoma specimens exhibited higher immunoreactivity for cleaved (activated) caspase-8 than poor prognosis tumors. CONCLUSIONS: In thyroid carcinomas, the proteolytic cleavage and activation of caspase-8 depends on the balance between expression levels for procaspase-8 and FLIP and correlates with favorable clinical prognosis. Fas may actually stimulate proliferation and confer a survival advantage to thyroid cancer cells.     

Spontaneous remodeling of the peripheral retinal vasculature in sickling disorders.

Periodic photographic and angiographic surveys of patients with the earliest stages of sickle retinopathy showed a number of fundus findings. In seven cases (sickle cell anemia, four; sickle cell hemoglobin C, three), these findings included: (1) a variety of vascular abnormalities in the equatorial and post-equatorial retina such as segmented dilations of the vessel walls, hairpin-shaped vascular loops, hypertrophic, tortuous A-V anastomoses, intraluminal plugs, closure and loss of capillary bed, and terminal budding of capillaries; and (2) a continuous, spontaneous remodeling of the peripheral retinal vasculature due to successive closures and reopenings of equatorial retinal vessels. A centripetal recession of the peripheral retinal vasculature usually resulted. No correlation between the ophthalmoscopic and the systemic condition of the patients could be made.     

Impact of positive fluid balance on critically ill surgical patients: A prospective observational study

Purpose

The purpose of this study is to determine the effect of postoperative fluid balance (FB) on subsequent outcomes in acute care surgery (ACS) patients admitted to the surgical intensive care unit (ICU).

Material and methods

Acute care surgery patients admitted to the surgical ICU from 06/2012 to 01/2013 were followed up prospectively. Patients were stratified by FB into FB-positive (+) and FB-negative (−) groups by surgical ICU day 5 or day of discharge from the surgical ICU.

Results

A total of 144 ACS patients met inclusion criteria. Although there was no statistically significant difference in crude mortality (11% for FB [−] vs 15.5% for FB [+]; P = .422], after adjusting for confounding factors, achieving an FB (−) status by day 5 during the surgical ICU stay was associated with an almost 70% survival benefit (adjusted odds ratio [95% confidence interval], 0.31 [0.13, 0.76]; P = .010). In addition, achieving a fluid negative status by day 1 provided a protective effect for both overall and infectious complications (adjusted odds ratio [95% confidence interval], 0.63 [0.45, 0.88]; P = .006 and 0.64 [0.46, 0.90]; P = .010, respectively).

Conclusions

In a cohort of critically ill ACS patients, achieving FB (−) status early during surgical ICU admission was associated with a nearly 70% reduction in the risk for mortality.     

Angioma-like lesion in hemoglobin sickle cell disease

A lesion resembling a retinal angioma is reported in a 52-year-old man with hemoglobin S-C disease. Following surgery to destroy the tumor, the patient died. Postmortem examination confirmed sickle cell disease and the ocular findings revealed an angioma on the anterior side of the retina. It is believed this is the first report of sickle cell disease showing a large retinal angioma.