Geldanamycin-induced osteosarcoma cell death is associated with hyperacetylation and loss of mitochondrial pool of heat shock protein 60 (hsp60)

Osteosarcoma is one of the most malignant tumors of childhood and adolescence that is often resistant to standard chemo- and radio-therapy. Geldanamycin and geldanamycin analogs have been recently studied as potential anticancer agents for osteosarcoma treatment. Here, for the first time, we have presented novel anticancer mechanisms of geldanamycin biological activity. Moreover, we demonstrated an association between the effects of geldanamycin on the major heat shock proteins (HSPs) and the overall survival of highly metastatic human osteosarcoma 143B cells. We demonstrated that the treatment of 143B cells with geldanamycin caused a subsequent upregulation of cytoplasmic Hsp90 and Hsp70 whose activity is at least partly responsible for cancer development and drug resistance. On the other hand, geldanamycin induced upregulation of Hsp60 gene expression, and a simultaneous loss of hyperacetylated Hsp60 mitochondrial protein pool resulting in decreased viability and augmented cancer cell death. Hyperacetylation of Hsp60 seems to be associated with anticancer activity of geldanamycin. In light of the fact that mitochondrial dysfunction plays a critical role in the apoptotic signaling pathway, the presented data may support a hypothesis that Hsp60 can be another functional part of mitochondria-related acetylome being a potential target for developing novel anticancer strategies

Characterization of a new pathway that activates lumisterol <i>in vivo</i> to biologically active hydroxylumisterols

Abstract Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved

46. Stereotactic Mammotome Breast Biopsy – analisis of results

The purpose of work is to assess stereotactic mammotome biopsy technology in diagnostics of nonpalpable breast lesions. In the period from April to December 2000 mammotome biopsy procedure was performed on395 female patients at the I Oncological Surgery department the Greatpoland CancerCenter in Poznań. In all patients, diagnosed lesions were non-palpable and categorisedas BI-RADS III, IV, V. Patients were aged between 16 and 78 (average 52.6 years). They divided into three groups depending on radiological characteristics of the examined lesions – separate analyses were carried out for patients with microcalcifications suspicious tumores and radial scar. Diagnostic examination was performed on an ambulatory basis. Procedurewas carried out on a Fischer mammotome table using the Mammotome Biopsy System. The Cancers were detected in 17 % cases. All patients with diagnosed cancer underwent further surgical procedure. In 83 % patients in whom begin lesions were found mammography screening was recommended at 6 month intervals. The Stereotactic Mammotome Breast Biopsy System is a sensitive, minimally invasive diagnostic technology characterised by: very high diagnostic precision, minimal traumatisation of surrounding tissues, excellent cosmetic effect, economical procedure

46. Stereotactic Mammotome Breast Biopsy – analisis of results

The purpose of work is to assess stereotactic mammotome biopsy technology in diagnostics of nonpalpable breast lesions. In the period from April to December 2000 mammotome biopsy procedure was performed on395 female patients at the I Oncological Surgery department the Greatpoland CancerCenter in Poznań. In all patients, diagnosed lesions were non-palpable and categorisedas BI-RADS III, IV, V. Patients were aged between 16 and 78 (average 52.6 years). They divided into three groups depending on radiological characteristics of the examined lesions – separate analyses were carried out for patients with microcalcifications suspicious tumores and radial scar. Diagnostic examination was performed on an ambulatory basis. Procedurewas carried out on a Fischer mammotome table using the Mammotome Biopsy System. The Cancers were detected in 17 % cases. All patients with diagnosed cancer underwent further surgical procedure. In 83 % patients in whom begin lesions were found mammography screening was recommended at 6 month intervals. The Stereotactic Mammotome Breast Biopsy System is a sensitive, minimally invasive diagnostic technology characterised by: very high diagnostic precision, minimal traumatisation of surrounding tissues, excellent cosmetic effect, economical procedure

54. Ocena wartości biopsji węzła wartowniczego (WW) w czerniaku skóry

CelPotwierdzenie wiarygodności biopsji węzła wartowniczego (WW) w ocenie stanu regionalnych węzłów chłonnych w czerniaku skóry (CS).MateriałW okresie od stycznia 1997 do kwietnia 2003 r. ogółem wykonano 225 biopsji WW u 206 chorych w I stopniu zaawansowania klinicznego CS. W tej grupie znajdowało się 125 kobiet i 81 mężczyzn (K:M 1,54:1), w wieku 14–85 (śr. 55,2). Lokalizacja zmiany pierwotnej: kończyna dolna 88 (42,7%), tułów 75 (36,4%), kończyna górna 42 (20,4%), głowa 1 (0,5%) Stopień zaawansowania: wg Breslow’a 3,45 mm (0,3–20 mm), poziom naciekania wg Clark’a CII 6 (2,9%), C III 128 (62,1%), C IV 47 (22,8%), C V 16 (7,8%), NSKL 9 (4,4%).Metoda1)Wyłącznie barwnikowa (Patent Blau V -PBD) – 18.2)Barwnikowo-izotopowa (PBD + Nannocol znaczony Technetem 99 + limfoscyntygrafia) – 150.3)Wyłącznie izotopowa (Nannocol znaczony Technetem 99 + limfoscyn-tygrafia) – 38.WynikiU 206 pacjentów stwierdzono 225 spływów – 2 lokalizacje u 19 pacjentów (9,2%). Identyfikacja WW w 98,5% przypadków, w 44 przypadkach (21,4%) stwierdzono przerzut w WW i wykonano limfadenektomię przy czym w 30 przypadkach (68,2%) WW był jedynym zwierającym przerzut. Wyniki fałszywie ujemne- 3 przypadki (1,45%).Wnioski1. Biopsja WW jest metodą wiarygodną w ocenie stanu regionalnych węzłów chłonnych w CS. 2. Stwierdzenie w limfoscyntygrafii pojedynczego WW pozwala na zastosowanie wyłącznie metody izotopowej. 3. W 68,2% stwierdzano przerzuty tylko w węźle wartowniczym, co świadczy o wartości biologicznej tego badania w ocenie stopnia zaawansowania