OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness.

OCT4 (Octamer-binding transcription factor 4) is essential for embryonic stem cell self-renewal. Here we show that OCT4 increases the aggressiveness of high-grade serous ovarian cancer (HG-SOC) by inactivating the Retinoblastoma tumor suppressor pathway and enhancing mitotic stability in cancer cells. OCT4 drives the expression of Nuclear Inhibitor of Protein Phosphatase type 1 (NIPP1) and Cyclin F (CCNF) that together inhibit Protein Phosphatase 1 (PP1). This results in pRB hyper-phosphorylation, accelerated cell proliferation and increased in vitro tumorigenicity of ovarian cancer cells. In parallel, OCT4 and NIPP1/CCNF drive the expression of the central Chromosomal Passenger Complex (CPC) components, Borealin, Survivin and the mitotic kinase Aurora B, promoting the clustering of supernumerary centrosomes to increase mitotic stability. Loss of OCT4 or NIPP1/CCNF results in severe mitotic defects, multipolar spindles and supernumerary centrosomes, finally leading to the induction of apoptosis. These phenotypes were recapitulated in different cancer models indicating general relevance for human cancer. Importantly, activation of these parallel pathways leads to dramatically reduced overall survival of HG-SOC patients. Altogether, our data highlights an unprecedented role for OCT4 as central regulator of mitotic fidelity and RB tumor suppressor pathway activity. Disrupting this pathway represents a promising strategy to target an aggressive subpopulation of HG-SOC cells.

[Retroperitoneal tumors. Tactics, technics and surgical results]. / I tumori retroperitoneali. Tattica, tecniche e risultati chirurgici.

Out of 33 cases of retroperitoneal tumours (TRP), collected throughout 11 years (1970-1981), 8 (24%) resulted benign, 25 (76%) malignant. Liposarcoma resulted the most frequent tumour. In 11 of the 25 cases of malignant TRP (44%), a radical removal of the tumour was performed; in 8 (32%), a palliative demolition, and in the remaining 6 (24%) a simple diagnostic laparotomy. In 10 of the 19 demolitive operations (53%) the removal was extended to contiguous organs: kidney, adrenal glands, colon, pancreas, spleen, bladder, stomach. The postoperative mortality was 6%. The cases of recurrence after operations considered radical were 5 (45%). Out of the 8 patients suffering from benign neoformations, 7 underwent simple removal, and result recovered. The global survival for malignant TRP was 20% after 5 years and 8% after 10 years; as related to the cases subjected to radical removal, it results 45% and 18% respectively. The Authors maintain the essential function of computerized axial tomography (TAC) in the preoperative anatomo-topographic outlining of the retroperitoneal mass and in the early recognition of the remote recurrences. An aggressive surgical behaviour seems to be presently the primary therapeutical solution; nevertheless, the encouraging results obtained through the complementary treatment (radiotherapy and chemotherapy) command the necessity of a pluridisciplinary management of the treatment of TRP as an essential condition for the improvement of the remote results.

[Cystic neoformations of the retroperitoneal space (4 case reports)]. / Neoformazioni cistiche dello spazio retroperitoneale (contributo di 4 casi).

Based on the study of four cases of retroperitoneal cysts, the complex histopathogenesis of these neoplasms - the clinical diagnosis of which has recorded substantial progress thanks to the use of the computed tomography - has been analyzed. The practice of exeresis, though comparatively simple and radical in most cases (as recorded in 3 out of the 4 cases reported) owing to the little adhesions of these neoplasms to the contiguous anatomical formations and also to their histological benignity, may, in some instances, present such unexpected difficulties due to the expansion in volume and the complex and delicate anatomical connections, that palliative operations have to be opted for.

Gemination of maxillary incisors.

Gemination is defined as a shape anomaly of teeth caused by an incomplete division of a single tooth bud. Its aesthetic and functional implications usually require a complex endodontic, restorative, periodontal, surgical, and orthodontic treatments. Three cases of gemination of maxillary incisors, resolved by different therapeutic approaches, are reported. The 1st case (germination of 2.1) was resolved by a simple crown-plasty. The 2nd case (gemination of 1.1 and 2.1) was resolved by a crown-plasty of 2.1 and an interradicular section of 1.1 with extraction of lateral root. The 3rd case (2.2 supernumerary and gemination of 1.2) was resolved by sacrifice of 1.2, extraction of 2.2 and its implantation in 1.2 region. In order to obtain an acceptable aesthetic and functional restoration, as in the cases presented, a good team-work, where all the specialists contribute to the selection of the more suitable treatment possible, is mandatory.

[The Gorlin-Goltz syndrome. A report of 2 cases]. / Sindrome di Gorlin-Goltz. Osservazione di due casi.

Two cases of patients with Gorlin-Goltz syndrome are described. The Gorlin-Goltz syndrome is a polydistrectual, hereditary disease characterized by multiple keratocysts and basocellular nevomatosis. It is pointed out that the inconstancy of the main symptoms makes early diagnosis difficult. The histologic characteristics of odontogenic keratocysts and the possible etiopathogenetic relations between cystic lesions and hamartia of adjacent oral mucosa, as considered by Stoelinga, are also discussed. In view of the course of the cases presented, a surgical approach considering such potential findings, is supposed to favorably affect the clinical evolution in respect to a high relapsing drift.

The death substrate Gas2 binds m-calpain and increases susceptibility to p53-dependent apoptosis.

Gas2 is a caspase-3 substrate that plays a role in regulating microfilament and cell shape changes during apoptosis. Here we provide evidence that overexpression of Gas2 efficiently increases cell susceptibility to apoptosis following UV irradiation, etoposide and methyl methanesulfonate treatments, and that these effects are dependent on increased p53 stability and transcription activity. To investigate possible pathways linking Gas2 to p53, a yeast two-hybrid screen swas performed, indicating m-calpain as a strong Gas2- interacting protein. Moreover, we demonstrate that Gas2 physically interacts with m-calpain in vivo and that recombinant Gas2 inhibits calpain-dependent processing of p53. Importantly, the Gas2 dominant-negative form (Gas2171-314) that binds calpain but is unable to inhibit its activity abrogates Gas2's ability to stabilize p53, to enhance p53 transcriptional activity and to induce p53-dependent apoptosis. Finally, we show that Gas2 is able to regulate the levels of p53 independently of Mdm2 status, suggesting that, like calpastatin, it may enhance p53 stability by inhibiting calpain activity.

Caspase-3 and caspase-7 but not caspase-6 cleave Gas2 in vitro: implications for microfilament reorganization during apoptosis.

Apoptosis is characterized by proteolysis of specific cellular proteins by a family of cystein proteases known as caspases. Gas2, a component of the microfilament system, is cleaved during apoptosis and the cleaved form specifically regulates microfilaments and cell shape changes. We now demonstrate that Gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279. Gas2 cleavage was only partially impaired in apoptotic MCF-7 cells which lack caspase-3, thus indicating that different caspases can process Gas2 in vivo. In vitro Gas2 was processed, albeit with low affinity, by caspase-7 thus suggesting that this caspase could be responsible for the incomplete Gas2 processing observed in UV treated MCF-7 cells. In vivo proteolysis of Gas2 was detected at an early stage of the apoptotic process when the cells are still adherent on the substrate and it was coupled to the specific rearrangement of the microfilament characterizing cell death. Finally we also demonstrated that Gas2 in vitro binds to F-actin, but this interaction was unaffected by the caspase-3 dependent proteolytic processing.

Expression of a functional p75 interleukin-2 receptor on lung lymphocytes from patients with human immunodeficiency virus type 1 (HIV-1) infection.

Lung involvement in patients affected by HIV-1 infection is characterized by an alveolitis sustained by the accumulation of CD8+ T lymphocytes. To investigate whether in situ T cell growth plays a relevant role in the pooling of CD8+ lymphocytes, we have analyzed the activity of two lymphokines involved in the mechanisms of T cell proliferation, i.e., interleukin-2 (IL-2) and interleukin-4. To this aim, following appropriate triggering and blocking, the expression and the functional role of IL-2 receptors (IL-2R) (both p55 and p75 chains) and IL-4 receptors have been analyzed on T lymphocytes obtained from the bronchoalveolar lavage (BAL) of 16 HIV-1+ patients. Molecular and phenotypic studies we performed demonstrated that CD8+ lymphocytes from the BAL of HIV-1 + patients strongly expressed the p75 chain of IL-2 receptor, while neither p55 mRNA nor its surface membrane product (Tac antigen) was detectable; in addition, there was no expression of IL-4 receptors. IL-2 stimulation was able to induce T cell growth in a dose-dependent manner, whereas IL-4 did not. Finally, using mAbs which specifically block the p55 or p75 IL-2R, we showed that both subunits of IL-2R were involved in the proliferative activity of lung lymphocytes. The results obtained in the present study directly demonstrate that BAL T lymphocytes of HIV-1 + patients express a fully functional IL-2 receptor apparatus, pointing to the role for this lymphokine in maintaining the alveolitis taking place in the lungs of AIDS patients.