Thyroid-stimulating hormone (TSH)-secreting tumors (TSH-omas) are pituitary tumors that constitutively secrete TSH. The molecular genetics underlying this abnormality are not known. We discovered that a knockin mouse harboring a mutated thyroid hormone receptor (TR) ␤ (PV; TR␤ PV/PV mouse) spontaneously developed TSH-omas. TR␤ PV/PV mice lost the negative feedback regulation with highly elevated TSH levels associated with increased thyroid hormone levels (3,3,5-triiodo-L-thyronine [T3]). Remarkably, we found that mice deficient in all TRs (TR␣1 ؊/؊ TR␤ ؊/؊ ) had similarly increased T3 and TSH levels, but no discernible TSH-omas, indicating that the dysregulation of the pituitary-thyroid axis alone is not sufficient to induce TSH-omas. The thyroid hormone T3 (3,3Ј,5-triiodo-L-thyronine) is critical for growth, differentiation, and development and for maintenance of metabolic homeostasis. Thyroid hormone receptors (TRs) act as ligand-activated transcription factors and occupy a central position in mediating the functions of T3. TRs are encoded by two genes, TR␣ and TR␤, located on human chromosomes 17 and 3, respectively (4, 8). Alternative splicing of the primary transcripts gives rise to four major T3-binding TR isoforms: TR␣1, ␤1, ␤2, and ␤3. These isoforms differ in their length and amino acid sequence at the amino terminal A/B domain but bind T3 with high affinity to mediate gene regulatory activity. Like other nuclear receptors, these isoforms have an amino terminal A/B domain, a central DNA-binding domain, and a carboxyl-terminal ligand-binding domain. The carboxyl-terminal region also contains multiple contact surfaces that are important for dimerization with its partner, the retinoid X receptor, and for interactions with corepressors and coactivators (4,8,20). The expression of TR isoforms is tissue dependent and developmentally regulated (4,8).Thyroid-stimulating hormone (TSH)-secreting pituitary tumors (TSH-omas) represent about 2% of all pituitary adenomas in humans. TSH-omas are usually large at diagnosis and are associated with headaches and visual field disturbances. Because diagnosis occurs late in the natural course, the rate of curative surgical resection of TSH-omas remains under 50% (5, 6).The molecular genetics underlying this abnormality are not well understood. Somatic mutations of the TR␤ gene have been found in several patients with TSH-omas. Safer et al. reported R438H mutation in the TR␤ gene in a patient with pituitary adenoma (26). This mutation has also been reported in other patients with resistance to thyroid hormone (10). The R438H mutant has impairment in T3 binding and exhibits dominant negative activity (10). Recently, Ando et al. identified mutated TR␤ in the TSH-omas of two patients (2, 3). One patient had a somatic mutation in the ligand-binding domain of TR␤2 (His450Tyr) (2), and the other patient had a 165-bp deletion within the sixth exon of the ligand-binding domain of TR␤2 (3). Both TR␤ mutants had impaired T3 binding and abnormal regulation of TSH␤ and ␣-glycoprotein co...

Background: Cutaneous squamous-cell carcinoma (SCC) sometimes causes lymph node metastasis and results in poor prognosis. However, little is known about cytogenetic alterations underlying tumor progression or metastasis. The aim of the present study was to investigate the genetic aberrations and expression of epidermal growth factor receptor (EGFR) in metastatic SCC of the skin. Methods: We undertook comparative genomic hybridization (CGH) analysis of 4 specimens which were obtained from a case of cutaneous SCC, including the primary lesion and 3 lymph nodes of the metastatic lesion. Results: Only one amplified locus (7p12–13) was detected in any metastatic lymph node, in which the EGFR gene is located. Therefore, we applied immunohistochemistry for EGFR to 5 cases of metastatic SCC including the case analyzed using CGH and 4 other cases (5 primary and 5 metastatic lesions). EGFR was expressed in 4 of 5 cases (both primary and metastatic lesions, including the case analyzed using CGH), and the staining patterns of primary and metastatic lesions were different. The primary tumors were focally weakly positive for immunostaining (+), whereas the 4 metastases were diffusely and strongly positive (+++). Conclusions: Our findings suggest that the clone with EGFR expression might selectively metastasize in some cutaneous SCCs. The existence of an EGFR-negative case reveals that EGFR expression is not always required for skin carcinogenesis, but expression of EGFR might confer metastatic potential of cutaneous SCCs.

High-quality 3D-CT images clearly revealed the anatomies of pulmonary vessels, which could play important roles in safe and efficient VATS anatomical resection.

Background: Overexpression of p53 protein has been demonstrated in a variety of human malignant tumors, and its role in oncogenesis and tumor progression is thought to be important. Recently, some reports have suggested that p53 overexpression might be an indicator of immaturity or proliferative activity of cells in cutaneous lesions. Objective: The aim of the present study was to clarify the relationship between overexpression of p53 protein and the proliferative activity evaluated by Ki-67 immunostaining in well-differentiated squamous cell carcinoma (SCC) of the skin. Methods: Sixteen cases of well-differentiated SCC were analyzed by immunohistochemistry for the expression of p53 protein and Ki-67 antigen. Results p53 protein was detected in 12 out of the 16 cases (75%). The percentage of p53-protein-positive tumor cells (DO-7 index) ranged from 0 to 80.4 (mean ± SD = 33.8 ± 29.7) and the percentage of Ki-67-antigen-positive tumor cells (MIB-1 index) from 23.4 to 65.1 (mean ± SD = 42.3 ± 15.8). Cases with higher DO-7 indices tended to show higher MIB-1 indices and the correlation was statistically significant. Conclusion: Overexpression of the p53 protein seems to be a useful indicator of proliferative activity in cutaneous SCC.

Our results suggest that EGFR mutations might be a prognostic factor in patients with pathological stage I lung adenocarcinoma.