Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

The aim of this study was to investigate the ability of N-acetylcysteine (NAC) to prevent cadmium (Cd)-induced renal damage and whether NAC would reverse cadmium damage to the kidney. Fifty adult male rats were divided into five experimental groups: group 1 received tap water for 3 months and 7 days, group 2 received cadmium chloride (CdCl(2)) for 3 months, group 3 (NAC cotreatment group) received CdCl(2) and 0.5% NAC in tap water for 3 months, group 4 received CdCl(2) in tap water for 3 months and 3 months later received only tap water for 7 days, and group 5 (NAC posttreatment group) received CdCl(2) in tap water for 3 months and 3 months later received 2% NAC in tap water for 7 days. NAC significantly decreased the elevated kidney malondialdehyde levels, as a marker of lipid peroxidation, in both cotreatment and posttreatment modalities. Cotreatment and posttreatment with NAC significantly increased kidney superoxide dismutase enzyme activity and glutathione level but did not change kidney catalase enzyme activity. NAC decreased fractional excretion of sodium in posttreatment group. Neither Cd nor NAC affected the glomerular filtration rate (GFR). Cotreatment and posttreatment with NAC reduced the effects of Cd on proximal tubules. It was found that NAC showed these effects without changing kidney accumulation of cadmium. Exogenously administrated NAC might reduce toxic effects of Cd on the kidney without any reduction in tissue Cd level.

Chest wall hamartomas are extremely rare. Frequently mesenchymal hamartomas are presented as a single mass and contain some primitive mesenchymal elements such as chondroid and trabecular bone structures. A 60-year-old man presented to hospital with chest pain. Thirteen years earlier, his CXR and thoracic CT showed three masses on the right and two masses on the left, but he had not received any treatment thereafter. His CT showed the same masses present 13 years earlier, but they were bigger and right thoracotomy was undertaken. At thoracotomy, two sections of the mass in the right posterior mediastinum and one section of the mass in the right apex were excised. They had an occasional bloody appearance and contained small cystic areas, and some areas were extremely hard. Microscopic examination showed that the lesions consisted of mature adipose tissue, a large number of veins of different diameters and collagen tissue. Besides, primitive mesenchymal elements, lymphoid cell accumulations and trabecular bone structures were seen focally. Bilateral chest wall hamartomas are extremely rare and may be confused with malignancy.

Inflammatory pseudotumor (IPT) of the spleen is a rare benign tumor with unknown etiology. It causes problems in the diagnosis because of mimicking some hematopoetic malignancies. Here we report the case of a 36-yr-old woman complaining of nausea and insomnia. Laboratory investigations were limited to increase of leukocyte and thrombocyte count. Ultrasonography and magnetic resonance (MR) imaging showed circumscribed solid lobulated mass, measuring about 6.5 cm in diameter, located in the dorsal region of the spleen. Splenectomy was performed with the differential diagnosis including hamartoma and lymphoma of the spleen. Histological examination of the sharply demarcated splenic mass consisted of myofibroblasts and admixture of inflammatory cells. Immunohistochemistry and in situ hybridization were performed. IPT of the spleen was diagnosed. Epstein-Barr virus (EBV) was detected in the tumor by in situ hybridization. This rare entity is presented because of its clinical, radiological and pathological difficulties in the differential diagnosis.

Purpose Clear cell renal cell cancers frequently harbor Von Hippel-Lindau gene mutations, leading to stabilization of the hypoxia-inducible factors (HIFs) and their target genes. In this study, we investigated the relationship between vascular endothelial growth factor (VEGF), HIF-1α, HIF-2α, p53 positivity, microvessel density, and Ki-67 rates with prognostic histopathologic factors (Fuhrman nuclear grade, stage, and sarcomatoid differentiation) and survival in clear cell renal cell carcinomas.Material and Methods Seventy-two nephrectomy specimens diagnosed as clear cell renal cell carcinoma between 2000 and 2012 were reevaluated. Immunohistochemically VEGF, HIF-1α, HIF-2α, p53, CD34 (for microvessel density evaluation), and Ki-67 antibodies were applied to the tumor areas. The relationships of these antibodies with prognostic factors and survival rates were evaluated with statistical analyses.Results Mean survival time was 105.6 months in patients with ccRCC. Patients with high expression of VEGF, HIF-1α and HIF-2α positivity, a high Ki-67 proliferation index, and a high microvessel density evaluation score had a shorter survival time (p<0.05).Conclusions Our findings supported that with the use of these immunohistochemical markers, prognosis of renal cell carcinoma may be predicted at the first step of patient management. New treatment modalities targeted to HIF-1α and HIF-2α might be planned as well as VEGF-targeted therapies in the management of clear cell renal cell carcinomas.

1. The aim of the present study was to compare the protective effects of L-carnitine and amifostine against radiation-induced late nephrotoxicity using technetium-99m diethylenetriaminepentaacetic acid scintigraphy and histopathological examination. 2. Seventy-one Albino rats were randomly divided into six groups as follows: (i) AMI + RAD (n = 15), 200 mg/kg, i.p., amifostine 30 min prior to irradiation (a single dose of 9 Gy); (ii) LC + RAD (n = 15), 300 mg/kg, i.p., L-carnitine 30 min prior to irradiation; (iii) LC (n = 10), 300 mg/kg, i.p., L-carnitine 30 min prior to sham irradiation; (iv) AMI (n = 10), 200 mg/kg, i.p., amifostine 30 min prior to sham irradiation; RAD (n = 11), 1 mL/kg, i.p., normal saline 30 min prior to irradiation; and (vi) control (n = 10), 1 mL/kg, i.p., normal saline 30 min prior to sham irradiation. Scintigraphy was performed before treatment and again 6 months after treatment. Kidneys were examined by light microscopy and a histopathological scoring system was used to assess the degree of renal damage. 3. The main histopathological findings were proximal tubular damage and interstitial fibrosis. Glomerular injury was similar in all groups. Tubular degeneration and atrophy were less common in the AMI + RAD group than in the RAD group (P = 0.011 and P = 0.015, respectively), as well as in the LC + RAD group compared with the RAD group (P = 0.028 and P = 0.036, respectively). Interstitial fibrosis in the AMI + RAD and LC + RAD groups was significantly less than that in the RAD group (P = 0.015 and P = 0.015, respectively). The highest total renal injury score (9) was seen in the RAD group. On scintigraphy, there were significant differences in post-treatment time to peak count (T(max)) and time from peak count to half count (T((1/2))) values (P = 0.01 and 0.02, respectively) between groups in the right kidney. In the control and RAD groups, the T((1/2)) of the right kidney was 8 +/- 2 and 21 +/- 2 min, respectively. The T(max) values for the AMI + RAD and LC + RAD groups (2.8 +/- 0.2 and 3.2 +/- 0.2 min, respectively) were similar to those in the control group (2.5 +/- 0.3 min). 4. Based on the results of the present study, L-carnitine and amifostine have comparable and significant protective effects against radiation-induced late nephrotoxicity.

Recent studies have suggested that protein kinase C (PKC) activation plays an important role in survival of chronic lymphocytic leukemia (CLL). In order to characterize the role of PKC in CLL, we investigated the expression pattern of PKC isoforms in CLL cells (7 cases) and evaluated the effect of PKC inhibition on the survival of CLL cells (20 cases). Expression of the classical PKC isoforms b and g, the novel isoform d and the atypical isoform z was seen in all analyzed patient samples by Western blot analysis. Expression of the PKC isoforms a, e, and i was variable. Following incubation with the PKC inhibitor, safingol, CLL cells underwent marked apoptosis in all cases. In order to characterize the molecular events associated with the apoptotic effect of PKC inhibition, gene expression patterns in CLL cells were evaluated by cDNA-microarray analysis. Following safingol treatment, several genes showed marked downregulation and PKCrelated proteins demonstrated decreased hybridization signals. Among these proteins, CREB and Daxx were further studied by using Western blotting, nuclear binding assay and confocal immunofluorescent microscopy. These studies showed significant inhibition of these proteins, consistent with the results of microarray gene analysis. Overall, these findings suggest that PKC activation is important for CLL cell survival and that inhibitors of PKC may have a role in the treatment of patients with CLL. Am.

Solitary fibrous tumor (SFT) of the pleura is an uncommon neoplasm with non-specific symptoms and non-pathognomonical radiological findings. Surgery allows establishment of a definitive diagnosis as well as a cure of the disease. The role of radiotherapy or chemotherapy in the management of the disease is unclear because of the rarity of the disease and the successful results of the surgical treatment. Long-term clinical follow-up may be useful for the patients with SFT because of the potential adverse biological behavior of this tumor, which may lead to repeated recurrences and/or malignant transformation. We reported a 66-year-old woman with recurrence of SFT in the right lung, which had significant response to external thoracic radiotherapy.