MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation.

The molecular feature of Burkitt lymphoma (BL) is the translocation that places c-Myc under the control of immunoglobulin gene regulatory elements. However, there is accumulating evidence that some cases may lack an identifiable MYC translocation. In addition, during the EUROFISH project, aiming at the standardization of FISH procedures in lymphoma diagnosis, we found that five cases out of 35 classic endemic BLs were negative for MYC translocations by using a split-signal as well as a dual-fusion probe. Here we investigated the expression pattern of miRNAs predicted to target c-Myc, in BL cases, to clarify whether alternative pathogenetic mechanisms may be responsible for lymphomagenesis in cases lacking the MYC translocation. miRNAs are a class of small RNAs that are able to regulate gene expression at the post-transcriptional level. Several studies have reported their involvement in cancer and their association with fragile sites in the genome. They have also been shown to control cell growth, differentiation, and apoptosis, suggesting that these molecules could act as tumour suppressors or oncogenes. Our results demonstrated a modulation of specific miRNAs. In particular, down-regulation of hsa-let-7c was observed in BL cases, compared to normal controls. More interestingly, hsa-mir-34b was found to be down-regulated only in BL cases that were negative for MYC translocation, suggesting that this event might be responsible for c-Myc deregulation in such cases. This hypothesis was further confirmed by our in vitro experiments, which demonstrated that increasing doses of synthetic hsa-mir-34b were able to modulate c-Myc expression. These results indicate for the first time that hsa-mir-34b may influence c-Myc expression in Burkitt lymphoma as the more common aberrant control exercised by the immunoglobulin enhancer locus.

The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis.

The role of HPV in the carcinogenesis of intraepithelial and invasive anogenital lesions is currently well established. E6 and E7 oncoproteins of high-risk HPV genotypes are known to inactivate p53 and pRb pathways. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative cases. For these reasons, cervical cancer is considered an AIDS-defining neoplasm. Unlike other AIDS-associated neoplasms, the occurrence of cervical cancer is independent of immune suppression. HIV-1 infection in patients with high grade precancerous lesions and invasive cervical cancers results in a therapy refractory and more aggressive disease phenotype, which is not yet well understood at the molecular level. An upregulation of HPV E6 and E7 gene expressions by HIV-1 proteins such as Tat has been documented by some authors. However, the role of HIV-1 in cervical carcinomas is still unclear. It is already known that HIV-1 Tat protein is able to influence cell cycle progression. Altogether, these facts led us to investigate the effects of Tat on the expression of cell cycle regulator genes. After transfection of HeLa cells with Tat, we analyzed the expression of cell cycle regulators from these cells by IHC and Real-time PCR. A significant reduction in the expression of cell cycle inhibitors of transcription and an increase in the levels of proliferation markers were observed. These results suggest that HIV-1 may enhance cervical carcinogenesis by promoting cell cycle progression. We also found that this HIV-1 Tat-induced cell proliferation was not dependent on the E2F family of transcription factors, and therefore postulate that Sp factors may be involved.

[On the job training at construction sites of the hospital corporation of Careggi (Florence)]. / Tutoraggio formativo in itinere nei cantieri edili dell'Azienda Ospedaliera di Careggi (Firenze).

The "Careggi Safety" project has like objective to guarantee the safety execution of Careggi Hospital (Florence) restoration and development works, thanks to an in itinere training program into building sites and through tutor figure using. The project aim is to overcomes traditional indoor training limits, not effective in complex and dynamics reality like as building sites, constrained by contracts deadline and high labour turnover (subcontracts) inside carry out process. Solutions chose are: (a) a training projected in itinere, following site works evolution and safety and coordination plan, and through a constant agreement between customer and operative enterprises; (b) a building site's tutor, standing beside workers during realization phases, contributing to form on respective safety carry out job. In to "Careggi Safety" project training has been chose as preliminary and obligatory condition for labours admission and control into the building site.

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis.

Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis. Rab29 depletion resulted in the inability of TCRs to undergo recycling to the IS, thereby compromizing IS assembly. Under these conditions, recycling TCRs accumulated in Rab11(+) endosomes that failed to polarize to the IS due to defective Rab29-dependent recruitment of the dynein microtubule motor. Remarkably, Rab29 participates in a similar pathway in ciliated cells to promote primary cilium growth and ciliary localization of Smoothened. These results provide a function for Rab29 as a regulator of receptor recycling and identify this GTPase as a shared participant in IS and primary cilium assembly.

Mortality of Italian lead smelter workers.

OBJECTIVES: The purpose of this study was to evaluate the health consequences of employment in the lead-smelting industry. METHODS: A mortality study of 1388 workers and laborers in production and maintenance departments was conducted in an Italian lead-smelting plant. The vital status of cohort members was determined from 1950 to 1992. Standardized mortality ratios were calculated for specific causes of death on the basis of national and regional reference rates. The relative risk for selected causes of death was also modeled as a function of age, calendar period, latency, and duration of employment with Poisson regression analysis. RESULTS: A significant 4.5-fold excess mortality from pneumoconiosis and other diseases of the respiratory system was observed, but the risk of pneumoconiosis did not show a significant trend by duration of employment. Mortality from all cancers, stomach cancer, and lung cancer was lower than expected. The standardized mortality ratios for genitourinary diseases and kidney cancer were not significantly elevated, but the Poisson regression analysis showed that both risks increased significantly by duration of employment. CONCLUSIONS: These findings provide limited evidence that long-term employment in lead-smelting plants increases the risk of genitourinary diseases and kidney cancer. The observed increase in mortality from pneumoconiosis and other diseases of the respiratory system was more likely related to silica exposure in other workplaces.

Evaluation of non-invasive haemodynamic parameters in patients with intermittent claudication subjected to physical training.

In a group of 26 patients, all smokers (mean age 56.9 +/- 8 years), with intermittent claudication due to arterial obliterative disease. We investigated some of the haemodynamic, haematologic and clinical parameters before and after a 3 months physical training program. During the training period, none of the patients were given vasoactive, anticoagulant, antiaggregant or other drugs which could affect blood lipid. Patients were instructed to walk for a minimum period of 1 hour daily, in addition to normal everyday activities. Statistically significant differences of claudication pain distance were obtained: 177 +/- 88 m vs 107 +/- 40 m, +65% (p less than 0.001); maximal walking distance: 456 +/- 205 m vs 250 +/- 138 m, +82% (p less than 0.0001) determined during treadmill test at 2 mph up 12% and t/2 peak flow: 30 +/- 11.6 sec vs 46.3 +/- 32.3 sec (p less than 0.02), determinated with plethysmographic venous occlusion strain-gauges studies. An important, but not significant decrease of fibrinogen was obtained: 302 +/- 60 mg% vs 328 +/- 57 (p = 0.06), whereas no statistically significant differences were found for the more important haemodynamic parameters: (1) Widsor index determinated before (60 +/- 14% vs 58 +/- 15%) and after (26 +/- 17% vs 26 +/- 17%) treadmill-test with Doppler ultrasound; (2) peak-flow (10.5 +/- 2 ml/100/min vs 10.2 +/- 3); (3) time to peak-flow (17 +/- 10.5 sec vs 19.3 +/- 12.1). We also didn't find any significant differences in total cholesterol (227 +/- 53 mg% vs 228 +/- 48) and haematocrit (43.6 +/- 3.5% vs 43.5 +/- 3.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adequate staging for an adequate management in uterine cancers. Clinical experience.

Clinical experience of the value of surgical-pathological staging in planning adequate treatment and in prognosis of uterine cancer is reported. Some new concepts concerning early stage definition, aggressiveness of tumours factors and adequate surgical strategy or integrated therapy are discussed. The Authors draw the conclusion that surgical-pathological staging in every uterine cancer is mandatory.

Endometrial cancer treatment today.

The Authors stress the role of surgery in the clinical management of endometrial cancer. The half Century case-series of Padua Gynaecologic Institute is considered.

Clinical experience in gynaecological cancer management. D) Ovarian tumors--non-epithelial: report from the Gynaecological Institute of Padua University.

All the non-epithelial ovarian tumors observed from 1963 to 1991 in the Gynaecologic and Obstetric Institute of Padua University (I clinic Padova, II clinic Verona) are evaluated in order to outline the value of some risk factors: Post-Surgical FIGO stage, histotype and treatments. Sex-cord stromal tumors, germ cell tumors, sarcomas and gonadoblastomas are analyzed separately because of their different epidemiology and biology. The most important risk factor for prognosis is certainly the tumor stage at the first diagnosis.

Carcinoma of the vulva: critical analysis of survival and treatment of recurrences.

Survival analysis of 181 vulvar cancer patients shows that stage and lymph nodal spread remain the most important prognostic factors. Other prognostic elements are: depth of stromal infiltration, thickness and site of the lesion, vascular space invasion. Precise definition of these pathological prognostic elements may be obtained only after appropriate surgical pathological evaluation of the primary lesion and regional nodes. Treatment must be adequate in the cost-benefit balance and surgery is the cornerstone in vulvar cancer management. Risk of relapse is statistically correlated with site of primary tumour, depth of infiltration, lymph nodal invasion and vascular space invasion. The treatment of recurrence is personalized for different sites but surgery is the elective treatment of the local recurrences.

Surgical strategies in vulvar cancer.

The evolution of surgical strategies in vulvar cancer over thirty years of personal experience is considered. The knowledge of aggressiveness and risk factors of every tumor correlated with the patients' age allows today to perform adequate radical surgery even without the large multilations of the past. 5-year survival rate and incidence of relapses are the same while quality of life is highly improved. The Authors stress the new conservative trend in every field of oncological surgery.

Hormones and risk of breast cancer.

PIP: This paper reports the results of a study of 50 menopausal women receiving hormonal replacement therapy. The majority (29) had surgical menopause; their mean age was 45.7 years. It was hypothesized that progestins could equilibrate the effects of the estrogenic stimulation on the mammary and endometrial target tissues of women on hormonal replacement therapy. The treatment schedule consisted of conjugated estrogens (Premarin) 1.25 mg/day for 21 days and Medroxyprogesterone acetate 10 mg/day for 10 days in each month. The mean treatment period was 18 months. During the follow-up period, attention was paid to breast modifications as evidenced by symptomatology, physical examination, and plate thermography. Mastodynia was reported by 21 patients, and physical examination revealed a light increase in breast firmness in 12 women and a moderate increase in breast nodularity in 2 women. Themography confirmed the existence of an excessive breast stimulation in 1 women who complained of moderate mastodynia and in 5 of the 7 women who complained of severe mastodynia. Normalization was obtained by halving the estrogen dose. These results suggest that hormonal replacement therapy can be safely prescribed if the following criteria are satisfied: 1) preliminary evaluation of patients from a clinical, metabolic, cytologic, and mammographic perspective; 2) cyclic treatment schedule, with a progestative phase of 10 days; and 3) periodic complete follow-up, with accurate thermographic evaluation of the breast target tissues.^ieng

Surgery as diagnostic and therapeutic moment in the management of cervical cancer.

Therapeutical program in cervical cancer usually include surgical or radiotherapeutical interventions or a combination of the two, variously integrated with techniques and sequences of application. Treatment planning and evaluation of results are normally based on the classification into clinical stages codified by the FIGO. But this classification, though providing useful prognostic standards of judgement, has proved to be inadequate to identify specific therapeutical guidance. Within a single clinical stage different risk factors have been identified which influence prognosis thus determining the therapeutical treatment more than staging itself. Furthermore clinical staging has failed to predict the surgical stage correctly in a significant number of cases. The index of correction after surgical staging shows discrepancy in about 1/3 of cases. In these cases a therapeutical program based on clinical examination exclusively may prove to be inadequate. The results reported by Authors warrant a rational resort to operative staging in cervical cancer in order to establish the real topography of the original focus more correctly. This indication is further strengthened by the need to identify lymphatic involvement, notably of para-aortic nodes, in locally advanced cases since such an occurrence bears a significant influence on the patient's prognosis and possibility of treatment. On the bases of these considerations the Authors suggest surgery as primary treatment in the management of cervical cancer.

Malignant trophoblastic neoplasias. Clinical experiences.

The Authors describe a treatment program for malignant trophoblastic disease based on a combination chemotherapy. The results of their clinical experience concerning 41 cases confirms the high cure rate for low risk metastatic disease (100%) with the only failures limited to the high risk patients (64.7% cure rate).

Neoadjuvant chemotherapy in advanced ovarian cancer.

Eighty-eight patients out of 396 were treated for advanced ovarian cancer first by some cycles of chemotherapy--neoadjuvant chemotherapy-- and after by surgery. An improvement in the quality of surgery and disease-free period was observed while survival rate did not improve, compared with the patients treated by surgery before chemotherapy. It should be stressed that neoadjuvant chemotherapy was applied only in very advanced PS Figo stages. The results are the same in the three studied decades: even in the last one, when cases were selected following new protocols. In our case series all patients after chemotherapy underwent surgery and not only those with partial or complete response to chemotherapy.

Oral contraceptives and breast disease.

PIP: The influence of oral contraceptives (OCs) on breast disease can vary according to their pharmacologic content and interaction with the patient's endocrine habits. Data on this topic are taken from: 1) histologic examinations on patients undergoing contraceptive treatment, 2) studies on experimental toxicity in animals, and 3) epidemiologic examinations. The tests have thus far failed to prove that the administration of OCs causes breast cancer or influences the experimental carcinogenesis in primates or sub-primates. Many epidemiologic studies have even shown a decreased risk of mastopathy in contraceptive users. Not only the doses and hormonal content but also the duration of administration, and any simultaneous or subsequent estrogen administration must be considered when evaluating risk. Combinations of OCs with estrogen predominance must be avoided in patients affected by mastosis.^ieng

Clinical experience in gynecological cancer management. c). Cervical cancer: report from the Gynecologic Institutes of Padua University (1963-1989).

The retrospective analysis of 1876 cases of invasive cervical cancer allows some considerations and conclusions on the clinical management of this neoplasia. Always led by the Gynaecologist, in the aims of prophylaxis and early diagnosis, personalized screening are necessary, with regard to risk factors. Surgical Pathological Staging (SPS) is mandatory for adequate treatment and prognosis. By personalizing surgical radicality and avoiding the application, in all cases, of the routine and standard extended operations of the past, it may be possible to reduce the complication rate with 5 year survival rate unchanged. In early stages personalized radical operations with systemic pelvic lymphadenectomy allow the best results (94% 5 year survival rate). Integrated therapies must be planned only in lymph nodal positive or in vascular space invasion cases. In advanced cases, surgery must be personalized in enlarged operations and integrated with adjuvant treatments on the basis of surgical pathological findings. In very advanced stages, integrated therapies, even without surgery, are justified, due to the poor prognosis of these cases.

Clinical experience in gynecological cancer management. d). Ovarian tumors--1) Epithelial: report from the Gynaecological Institutes of Padua University (1963-1990).

A complete review of case series from 1963 to 1990 allows some considerations and conclusions on the clinical management of epithelial ovarian cancer. In the aim of early diagnosis, the ovarian condition must be evaluated also by ultrasound scans, in every woman, at every gynaecological control, and every ovarian or pelvic mass must be carefully examined and removed. Staging is generally recognized as reliable only by surgical pathological evaluation, (SPS) as in post-surgical FIGO staging. Therapy is based on adequate chemosurgical strategy. Surgery, performed in maximum effort, must aim at radicality or adequate debulking, avoiding, however too heavy mutilations, almost always useless for prognosis. Lymphadenectomy, in advanced cases, should be selectively and not systematically performed. Cyclophosphamide and Cis-Platinum appear to be, today too, the most effective regimens as first line chemotherapy. Neoadjuvant chemotherapy must still be well evaluated in its cost-benefit balance and personalized in particular cases. Second laparotomic look must be personalized in respect to residual disease after primary surgery and tumoral aggressiveness factors.

Prognostic significance of epidermal growth factor receptor (EGFR) and c-erbB-2 protein overexpression in adenocarcinoma of the uterine cervix.

The authors studied the prognostic value of EGFR and c-erbB-2 overexpression in adenocarcinoma of the uterine cervix. The aim of this research was to find a new pathway to prognosis for more adequate therapy.

Predictive value of proliferative cellular nuclear antigen (PCNA) and Ki-67 antigen in advanced stage serous papilliferous ovarian cancer.

The cell nuclear antigens PCNA (Proliferative cell nuclear antigen) and Ki-67 in selected advanced serous papilliferous ovarian cancers were evaluated by histochemical assays. PCNA and Ki-67 expression in primitive tumor cells appeared to be correlated with grading, stage and survival. High expression was found in G3 and in more advanced stages while in low expression survival rate was better.