The PAX8/PPARgamma fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARgamma inhibition.

Follicular thyroid carcinoma (FTC) frequently harbors the PAX8/PPARgamma fusion gene (PPFP); however, its oncogenic role and mechanism(s) of action remain undefined. We investigated PPFP's effects on cell growth, apoptosis, cell-cell, and cell-matrix interactions in immortalized human thyroid cells (Nthy-ori 3-1) and NIH 3T3 cells. PPFP expression increased the growth of transient and stable Nthy-ori transfectants ( approximately threefold by 72 h). There was an 8.4% increase of cells in the S+G2/M phase, a 7.8% decrease in cells in the G0+G1 phase and a 66% decline in apoptosis at 72 h. Stable Nthy-ori PPFP transfectants grew in soft agar, and PPFP-transfected NIH 3T3 cells exhibited efficient focus formation, suggesting loss of anchorage-dependent growth and contact inhibition, respectively. Overexpression of PPARgamma in Nthy-ori cells did not recapitulate PPFP's growth effects. Treatment of Nthy-ori cells with an irreversible PPARgamma inhibitor mimicked the growth-promoting effects of PPFP and co-expression of PPFP and PPARgamma blocked PPARgamma transactivation activity. Our data provide functional evidence that PPFP acts as an oncoprotein, whose transforming properties depend in part on inhibition of PPARgamma. Our data suggest that PPFP contributes to malignant transformation during FTC oncogenesis by acting on several cellular pathways, at least some of which are normally regulated by PPARgamma.

PPARgamma staining as a surrogate for PAX8/PPARgamma fusion oncogene expression in follicular neoplasms: clinicopathological correlation and histopathological diagnostic value.

The PAX8/PPARgamma (PPFP) fusion-oncogene is moderately specific for follicular thyroid carcinomas (FTC). It remains unknown whether this can be translated into improved diagnosis, classification, or outcome prediction. We studied a cohort of well-characterized follicular adenomas (FA), FTC, and Hurthle cell carcinomas (HCC) from patients with complete clinical follow-up, to determine whether PPARgamma immunohistochemistry (as a surrogate of PAX8/PPARgamma expression) helps to distinguish FA from FTC and to assess its diagnostic accuracy as an adjunct to frozen section. We also correlated PPARgamma staining with clinical outcomes to assess its role as a prognostic marker.PPARgamma staining was more common in FTC (31 of 54; 57%) than in HCC (one of 23; 4%) or FA (four of 31; 13%) (P < 0.000001). Adjunctive use of PPARgamma immunohistochemistry improved diagnostic sensitivity of intraoperative frozen section from 84% to 96% (P < 0.05) but reduced specificity from 100% to 90% (P < 0.05). PPARgamma staining was associated with favorable prognostic indicators (female gender, better tumor differentiation, and lesser risk of metastases).PPARgamma staining may be helpful in the differential diagnosis of FA, FTC, and HCC, particularly when diagnostic sensitivity of histomorphology is reduced (e.g. during intraoperative frozen section). PPARgamma staining also shows an association with favorable prognosis and may have a role in risk stratification.

Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats.

Withdrawal responses to heat and mechanical stimuli applied to the plantar surface of the rat hindpaw were measured before and after an intraplantar injection of capsaicin. In separate groups of rats, capsaicin doses of 1, 10 and 30 micrograms, and the vehicle were given into the center of the plantar surface in a volume of 10 microliters. Withdrawal latency evoked by radiant heat and the frequency of withdrawal evoked by mechanical stimuli (von Frey monofilaments) were obtained from both hindpaws before and after injection. Hyperalgesia to heat was defined as a decrease in withdrawal latency and mechanical hyperalgesia was indicated by an increase in withdrawal response frequency. Intraplantar injection of capsaicin evoked nocifensive behavior characterized by lifting and guarding the injected paw which typically lasted up to 3 min following injection. Capsaicin produced a decrease in withdrawal latency to heat and increased the frequency of withdrawal to mechanical stimuli in a dose-dependent manner. These effects were observed on the injected paw only. The duration of hyperalgesia produced by capsaicin was also dose-dependent. Withdrawal latencies to heat were decreased up to 45 min following capsaicin while withdrawal responses to mechanical stimuli remained elevated up to 4 h. The area of mechanical hyperalgesia included most of the plantar surface and extended approximately 9 mm proximal and distal to the injection. Injection of the vehicle did not significantly alter withdrawal responses to heat or mechanical stimuli. These studies demonstrate that intraplantar injection of capsaicin in rats produces hyperalgesia to heat and mechanical stimuli. This model should be useful for correlative behavioral, physiological and pharmacological studies of underlying mechanisms of capsaicin-evoked hyperalgesia.

Hypercalcemia: an unusual etiology of a common menopausal symptom.

OBJECTIVE: To describe atypical vasomotor symptoms that were secondary to primary hyperparathyroidism. DESIGN: Case report. SETTING: University medical center. PATIENT(S): A 57-year-old, postmenopausal woman with recalcitrant hot flushes. INTERVENTION(S): Parathyroid adenomectomy. MAIN OUTCOME MEASURE(S): Vasomotor symptom relief. RESULT(S): Postoperative relief of atypical vasomotor symptoms. CONCLUSION(S): A patient 17 years postmenopause presented with atypical vasomotor symptoms that did not respond to hormone therapy and proved to be due to hypercalcemia secondary to primary hyperparathyroidism. An atypical manifestation of a common condition or an uncharacteristic therapeutic response should alert health care providers to the possibility of a different diagnosis.