SRC homology-2-containing protein tyrosine phosphatase-1 restrains cell proliferation in human medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid parafollicular C cells, where, in the inherited form, constitutive activation of the RET protooncogene is responsible for unrestrained cell proliferation. We previously demonstrated that somatostatin (SRIF) reduces cell growth in the human MTC cell line TT, which expresses all SRIF receptor (SSTR) subtypes and responds differently to selective SSTR agonists. The antiproliferative mechanism of SRIF and its analogs in MTC is still unclear. Src homology-2-containing protein tyrosine phosphatase-1 (SHP-1), a cytoplasmic protein tyrosine phosphatase (PTP), is activated by somatotropin release-inhibiting factor and reduces mutated RET autophosphorylation in a heterologous system. In this study, we explore the role of PTP activation, in particular of SHP-1, in TT cells, where RET is constitutively activated. In TT cells, SRIF stimulated the PTP activity of SHP-1, which was associated with proliferation inhibition and with reduction in the MAPK pathway activation. Blockade of PTP activity with sodium orthovanadate induced cell proliferation and MAPK phosphorylation and blunted the inhibitory effects of SRIF. Moreover, SHP-1 associates with SSTR2 depending on its activation. By using a MAPK kinase inhibitor, we demonstrated that TT cell growth depends on MAPK pathway activation. Furthermore, in TT cells overexpressing SHP-1, cell proliferation and MAPK signaling were strongly down-regulated, whereas in TT cells transfected with a dominant negative form of SHP-1, cell proliferation and MAPK signaling were markedly induced. Our data demonstrate that SRIF inhibitory effects on TT cell proliferation are mediated, at least in part, by SHP-1, which acts through a MAPK-dependent mechanism.     

Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing's disease

OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.     

Electrochemical and optoelectronic properties of terthiophene- and bithiophene-based polybenzofulvene derivatives

The electrochemical behavior of some polybenzofulvene derivatives bearing bithiophene (BT) or terthiophene (TT) side chains was investigated by cyclic voltammetry. Very interestingly, the presence of unsubstituted terminal thiophene moieties allowed poly-6-BT-BF3k and poly-6-TT-BF3k to be cross-linked by electrochemical procedures. Conductive films were obtained by electrodeposition from solutions of these polymers onto electrode surfaces through the formation of covalent cross-linking due to dimerization (i.e. electrochemical oxidation) of the BT or TT side chains. The films showed electrochromic features and switched from yellow-orange (neutral) to green (positively charged) by switching the potential, and were stable to tenths of cycles, without degradation in the wet state in the electrolyte solution. Finally, the thin film obtained by electrodeposition of poly-6-TT-BF3k on a indium tin oxide (ITO) glass substrate showed in the neutral state a significantly red-shifted photoluminescence (PL) emission (∼40 nm red-shifted with respect to that of the corresponding film obtained by casting procedures), which was consistent with the presence of more conjugated moieties produced by the oxidative dimerization of the TT side chains. The innovative architecture and the easy preparation could lead to a broad range of applications in optoelectronics and bioelectronics for these cross-linked hybrid materials based on π-stacked polybenzofulvene backbones bearing oligothiophene side chains.

The electrochemical behavior of some polybenzofulvene derivatives bearing bithiophene (BT) or terthiophene (TT) side chains was investigated by cyclic voltammetry and cross-linked materials were obtained by dimerization of the BT or TT side chains.     

Myocardial Salvage Imaging: Where Are We and Where Are We Heading? A Cardiac Magnetic Resonance Perspective

Purpose of Review

Cardiac magnetic resonance (CMR) has emerged in recent years as a reliable tool to assess, in a single examination after a reperfused myocardial infarction, the initially area at risk (AAR), the final infarct size (IS), and from their difference the salvaged myocardium (SM). The aim of the present review is to summarize recent advances in the CMR imaging of SM.

Recent Findings

While there is consensus on the use of late gadolinium enhancement (LGE) to calculate IS, how to assess the AAR is a debated topic. The use of T2-weighted short-TI inversion recovery (T2W-STIR) is to date supported by a large amount of data, but it is affected by several limitations. Newer techniques have been developed to overcome T2W-STIR limitations, some of them have been already used in randomized clinical trials (RCTs) while others are showing promising results. The use of CMR to generate surrogate endpoints in RCTs is gaining attention; in this context, analysis of data from recent RCTs suggests that the assessment of SM as outcome measure could be useful to reduce sample sizes and costs of trials.

Summary

CMR is a reliable technique for the assessment of SM. LGE is the gold standard for IS measurement, while which is the best technique for the evaluation of AAR is still debated. When using CMR-derived endpoints in RCTs, the assessment of SM is advisable.

     

Gluten Psychosis: Confirmation of a New Clinical Entity

Non-celiac gluten sensitivity (NCGS) is a syndrome diagnosed in patients with symptoms that respond to removal of gluten from the diet, after celiac disease and wheat allergy have been excluded. NCGS has been related to neuro-psychiatric disorders, such as autism, schizophrenia and depression. A singular report of NCGS presenting with hallucinations has been described in an adult patient. We report a pediatric case of a psychotic disorder clearly related to NCGS and investigate the causes by a review of literature. The pathogenesis of neuro-psychiatric manifestations of NCGS is unclear. It has been hypothesized that: (a) a “leaky gut” allows some gluten peptides to cross the intestinal membrane and the blood brain barrier, affecting the endogenous opiate system and neurotransmission; or (b) gluten peptides may set up an innate immune response in the brain similar to that described in the gut mucosa, causing exposure from neuronal cells of a transglutaminase primarily expressed in the brain. The present case-report confirms that psychosis may be a manifestation of NCGS, and may also involve children; the diagnosis is difficult with many cases remaining undiagnosed. Well-designed prospective studies are needed to establish the real role of gluten as a triggering factor in neuro-psychiatric disorders.     

Suture pull-through insertion of graft donor in Descemet stripping automated endothelial keratoplasty: Results of 4-year follow-up

Purpose:

To report our clinical experience and 4-year follow-up results of Descemet stripping automated endothelial keratoplasty (DSAEK) with the suture pull-through insertion technique.

Methods:

This is a retrospective study of 195 eyes in which a posterior lamellar keratoplasty was performed between 2007 and 2011. The insertion of a folded donor lenticule was performed with a double-armed 10-0 suture using a straight transchamber needle and half-circle needle. Endothelial cell density was measured annually up to 4 years after the surgery, and cell loss was calculated based on the median preoperative donor endothelial cell density. Postoperative complications, primary graft failure, pupillary block, and dislocation of the donor tissue were assessed.

Results:

All patients underwent uncomplicated DSAEK. Data were available for 195 eyes (100%) at 1 year, 186 eyes (95.3%) at 2 years, 176 eyes (90.2%) at 3 years, and 160 eyes (82%) at 4 years. Median preop-erative donor endothelial cell density was 2688 cells/mm² [interquartile range (IQR) 207.5 cells/mm²], which decreased by 27% at 1 year (1956 cells/mm², IQR 264.8 cells/mm²), 31% at 2 years (1855 cells/mm², IQR 320.5 cells/mm²), 35% at 3 years (1756.5 cells/mm², IQR 306.5 cells/mm²), and 36% at 4 years (1709.5 cells/mm², IQR 288,0 cells/mm²). Nine patients (4.6%) had a dislocation of donor tissue; all were successfully reattached with a second air injection. Only three eyes (1.5%) developed graft failure. Pupillary block was present in 15 eyes (7.7%).

Conclusion:

DSAEK with suture pull-through insertion of donor graft represents a simplified and safe technique that has endothelial cell loss comparable with other techniques and low rates of intraoperative and postoperative complications.