Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway.

DPC4 (deleted in pancreatic cancer 4)/Smad4 is an essential factor in transforming growth factor (TGF)-ß signaling and is also known as a frequently mutated tumor suppressor gene in human pancreatic and colon cancer. However, considering the fact that TGF-ß can contribute to cancer progression through transcriptional target genes, such as Snail, MMPs, and epithelial-mesenchymal transition (EMT)-related genes, loss of Smad4 in human cancer would be required for obtaining the TGF-ß signaling-independent advantage, which should be essential for cancer cell survival. Here, we provide the evidences about novel role of Smad4, serum-deprivation-induced apoptosis. Elimination of serum can obviously increase the Smad4 expression and induces the cell death by p53-independent PUMA induction. Instead, Smad4-deficient cells show the resistance to serum starvation. Induced Smad4 suppresses the PAK1, which promotes the PUMA destabilization. We also found that Siah-1 and pVHL are involved in PAK1 destabilization and PUMA stabilization. In fact, Smad4-expressed cancer tissues not only show the elevated expression of PAK1, but also support our hypothesis that Smad4 induces PUMA-mediated cell death through PAK1 suppression. Our results strongly suggest that loss of Smad4 renders the resistance to serum-deprivation-induced cell death, which is the TGF-ß-independent tumor suppressive role of Smad4.

Dumbbell shaped exophytic and endobronchial lipomatous hamartoma.

A 63-year-old man presented with a dumbbell-shaped mass obstructing his left upper lobe. He underwent a left upper lobectomy for suspected malignancy. An unexpected pathological diagnosis of endobronchial lipomatous hamartoma was made. Only 6 other cases have been reported in the English literature and only two cases were both endobronchial and exophytic.

Macrophagic myofasciitis unrelated to vaccination.

Macrophagic myofasciitis (MMF) is known to be closely associated to vaccination containing aluminium as an adjuvant. Here we describe a case of MMF unrelated to vaccination, and presented as focal tender muscle in a 59-year-old woman. Magnetic resonance imaging showed evidence of unilateral myofasciitis involving muscles and fascias of the vastus lateralis. Open biopsy showed a unique pathological pattern of MMF. Our case suggests that other causes unrelated to vaccination need to be investigated in the pathogenesis of MMF, and MMF could be considered in the differential diagnosis of patients with focal muscle tenderness.

Overexpression of Id-1 is significantly associated with tumour angiogenesis in human pancreas cancers.

It has been suggested that Id-1 has a critical role in the tumour progression and aggressiveness of several human cancers. However, the clinicopathological and biological significance of Id-1 overexpression remains unclear in human primary cancer. To investigate the association between Id-1 expression and cell proliferation or tumour angiogenesis, we examined the cell cycle kinetic indices (the proliferation and apoptotic indices, PI and AI) and intratumoral microvessel density (MVD) in 65 human pancreatic cancers. We also investigated the relationship between its expression and various clinicopathological factors to determine the clinical significance of Id-1 overexpression. Out of a total 65 cases, 32 (49.3%) showed overexpression of Id-1 vs normal tissues. Id-1 expression was found to be significantly associated with MVD (P=0.002). In further analysis of subgroups with higher and lower Id-1 expression, tumours with higher Id-1 expression (scores 4 and 5) showed significantly higher MVD than tumours with lower expression of Id-1 (scores 2 and 3) (111.18+/-57.14 vs 64.13+/-28.19, P<0.001). However, no significant association was found between Id-1 overexpression and patient survival rate. No significant association was also found between Id-1 expression and cell cycle kinetic indices (PI or AI) in pancreatic cancer. Moreover, the overexpression of Id-1 protein was not correlated with any significant clinicopathologic factors. These findings indicate that Id-1 overexpression is closely related with tumour angiogenesis and a higher density of intratumoral vessel, but that it is not associated with a poorer prognosis of survival or a higher cell proliferative potential in human pancreatic cancer.

Run-up of gamma-aminobutyric acid(C) responses in catfish retinal cone-horizontal cell axon-terminals is modulated by protein kinase A and C.

Using whole-cell voltage-clamp techniques, we investigated the protein kinase modulation of gamma-aminobutyric acid(C) (GABA(C))-activated currents relating to run-up regulation in dissociated cone-horizontal cell (HC) axon-terminals from catfish retina. GABA induced an inward chloride current in cells voltage-clamped at -70 mV. With repetitive applications of 10 microM GABA, the peaks of the GABA responses increased up to approximately 135% of the control responses during a period of 10 min. Intracellular application of forskolin, an adenylate cyclase activator, decreased the run-up of GABA(C) responses. H8 dihydrochloride, a cAMP inhibitor, enhanced this run-up to 190% of the control responses. 1-oleoyl-2-acetyl-sn-glycerol, a protein kinase C activator, accelerated the run-up of GABA(C) responses. GF 109203X, a PKC inhibitor, decreased the run-up. These results suggest that retinal GABA(C) responses in cone-HC axon-terminals are modulated by both protein kinase A and C.

The GABA(C) receptor is present in cone-horizontal cell axon terminals isolated from catfish retina.

Whole cell voltage-clamp recordings were performed on isolated terminals and somata from catfish retina to compare the distribution of excitatory and inhibitory receptors in both structures. Saturating concentrations of glutamate or kainate produced small currents in axon terminals, averaging less than 8% of the current evoked in the soma. In contrast, application of high concentrations of gamma-aminobutyric acid (GABA) produced approximately similar current amplitudes in both structures. Based on estimates of membrane surface area, GABA-induced current densities were around 0.05 pA/microm2 for both structures. The GABA-activated current in the axon terminal was not blocked by bicuculline or SR95531, but was completely inhibited by picrotoxin. Baclofen did not mimic the GABA effect, but trans-4-aminocrotonic acid (TACA, 300 microM) and muscimol (1 mM) elicited currents of 100 and 40 pA, respectively. These results suggest that the axon terminals of cone-horizontal cells possess GABA(C) receptors at a high density, do not possess GABA(A) or GABA(B) receptors, and have few glutamate receptors. The GABA(C) receptors could function as postsynaptic receptors in the inner plexiform layer or as autoreceptors.

Expression of cyclin dependent kinase inhibitor p21WAF1 alone and in combination with p27KIP1 shows prognostic value in gastric carcinoma.

Evidence suggests that multiple molecular events, including alteration of cell cycle regulators are involved in the development and progression of gastric carcinoma. Recently, it has been reported that the expression of p21 and p27, integrating the effects of one or more cell cycle regulators, consequently, acting as a single indicator of several possible cell cycle gene alterations is associated with tumor suppression. In the present study, we studied the immunohistochemical expression of p21 and p27 in gastrectomy specimens from 84 patients with gastric adenocarcinoma, and analysed its correlation to clinicopathologic data, including patients survival. Loss of p21 and p27 expression was noted in 45 (53.6%) and 44 (52.4%) of the 84 gastric carcinoma tissues, respectively. The expression of p21 was significantly correlated with histological type (p= 0.005), recurrence (p=0.002) and death (p=0.002) after surgery, and p27 expression (p=0.001). Kaplan-Meier survival plots showed p21 negative group (p= 0.0014) or both p21 and p27 negative group (p=0.0048) was significantly poorer in overall survival than both p21 and p27 positive or one of both positive group. Our results suggest that the status of p21 and p27 expression in immunohistochemical stain may be a useful prognostic marker of gastric carcinoma.

Lymphoepithelial carcinoma of the submandibular gland--a case report.

A case of lymphoepithelial carcinoma occurring in the left submandibular salivary gland is presented. Histologic features of this rare malignancy are described in detail. This unusual carcinoma has been described frequently in Eskimos and is usually located in the parotid gland. The raised serum IgG to Epstein-Barr virus capsid antigen suggests a causal relationship between Epstein-Barr virus and this type of salivary gland carcinoma.

Poorly differentiated ("insular") carcinoma of the thyroid gland--two cases report.

Poorly differentiated ("insular") carcinoma of the thyroid shares insular, trabecular, and solid histological patterns that are different from those of papillary, follicular, medullary, and anaplastic varieties. This tumor is situated morphologically and biologically in the intermediate position between the well differentiated (papillary and follicular) and the totally undifferentiated (anaplastic) thyroid tumors. We report two cases of insular carcinoma of the thyroid, occurring in 39-year-old and 52-year-old women. Grossly, these cases showed a lobulated mass with fibrous septa. The histologic finding showed characteristic "insular" growth pattern with focal follicular or papillary areas. Thyroglobulin was demonstrated within cytoplasmic paranuclear vacuoles of the neoplastic cells. Calcitonin and amyloid were not demonstrated. The aspiration cytology showed high cellularity, low grade of atypia, presence of clusters, nests, and trabeculae of cells with poorly outlined cytoplasm. The ultrastructural finding showed primordial cells having cytoplasmic organelles such as rough endoplasmic reticulum, mitochondria, and free ribosomes. We believe that its separation from other types of thyroid carcinoma will lead to a more accurate estimate of its biologic behavior and a more appropriate therapeutic approach.

Pleomorphic adenoma of the trachea.

A case of salivary gland type pleomorphic adenoma of the trachea in a 48-year-old woman is presented. Pleomorphic adenoma is extremely rare in the trachea. The behavior of this tumor in the trachea appears to be similar to its counterpart in other sites and distinctly different from the more frequently encountered epithelial tumors.

Microcystic meningioma. A case report.

Microcystic meningioma is a distinct morphological variant of meningioma, characterized by loose texture and microcysts with formation of large extracellular spaces containing edematous fluid. The tumor cells have stellate and vacuolated cytoplasm with long cytoplasmic processes. We experienced a case of typical microcystic meningioma occurring in the falx cerebri adjacent to the left superior parasagittal sinus in a 41-year-old man. The tumor showed the typical histologic features with a few nests of meningothelial whorls. The tumor cells showed diffuse immunoreactivity for vimentin, epithelial membrane antigen (EMA), and S-100 protein. Ultrastructural study confirmed the meningiomatous nature of the tumor.