Reprogramming cancer cells in endocrine-related tumors: open issues.

Reprogramming technologies have been developed to revert somatic differentiated cells into pluripotent stem cells that can be differentiated into different lineages potentially useful in stem cell therapy. Reprogramming methods have been progressively refined to increase their efficiency, to obtain a cell population suitable for differentiation, and to eliminate viral plasmid which could be responsible for many unwanted side-effects when used in personalized medicine. All these methods are aimed to introduce into the cell genes or mRNAs encoding a set of four transcription factors (OCT- 4, SOX-2, KLF-4 and c-MYC) or a set of three lincRNAs (large intragenic non-coding RNAs) acting downstream of the reprogramming transcription factors OCT-4, SOX-2 and NANOG. Translational clinical applications in human pathologies and in developmental, repair and cancer biology have been numerous. Cancer cells can be, at least in principle, reprogrammed into a normal phenotype. This is a recently raised issue, rapidly advancing in many human tumors, especially endocrine-related cancers, such as breast, prostate and ovarian ca. The present review aims to describe basic phenomena observed in reprogramming tumor cells and solid tumors and to discuss their meaning in human hormone-related cancers. We will also discuss the fact that some of the targeted transcription factors are "normally" activated in a number of physiological processes, such as morphogenesis, hypoxia and wound healing, suggesting an in vivo role of reprogramming for development and homeostasis. Finally, we will review concerns and warnings raised for in vivo reprogramming of human tumors and for the use of induced pluripotent stem cells (iPSCs) in human therapy.

Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study.

AIMS: To assess the effects of more than 4 years' treatment with the anti-androgen bicalutamide on human testis by clinical, ultrastructural and morphometric analysis. METHODS AND RESULTS: Two patients (aged 74 and 69 years) with prostate cancer were treated for more than 4 years with bicalutamide 50 mg daily. Clinical characterization and follow-up included luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and prostate-specific antigen (PSA) measurements and clinical response of the tumours. Due to progression of the disease, patients underwent surgical orchidectomy as a further androgen withdrawal therapy. Testis biopsies were studied by light and electron microscopy and analysed by morphometry. Control samples were obtained from the normal testis of two patients with testicular cancer who underwent orchidectomy. Clinical follow-up showed a good response in the control of tumour growth and serum PSA decreased to < 4 ng/mL; concentrations of serum LH, FSH and testosterone were within the normal range. Testicular morphology of treated patients was unexpectedly well preserved; the organization of seminiferous tubules was normal with all the germ line elements and mature spermatozoa present. In some areas, a net increase of peritubular connective tissue was evident which may be a consequence of the age of the patients. CONCLUSIONS: Long-term bicalutamide (50 mg) treatment appears to have very little impact on testis ultrastructure and sperm maturation, while it is effective in the control of androgen-dependent prostatic tumours.

Plasma 25-hydroxyvitamin D responses of younger and older men to three weeks of supplementation with 1800 IU/day of vitamin D.

OBJECTIVE: The objective of this study was to compare changes in plasma 25-hydroxyvitamin D (25(OH)D) levels of younger and older men after three weeks of oral vitamin D supplementation. METHODS: Nine younger men (22 to 28 years) and nine older men (65 to 73 years) with self-reported vitamin D intakes below 200 IU/d were enrolled in February and randomized to 1800 IU/d of ergocalciferol (vitamin D2, n=11) or to a control group (n=7) and followed for three weeks. Blood was collected at baseline, and after one, two and three weeks for measurement of plasma concentrations of total 25(OH)D, 25(OH)D2 and 25(OH)D3. RESULTS: In both the younger and older supplemented men, 25(OH)D2 and total 25(OH)D concentrations increased significantly during the study, whereas values of these metabolites did not change in younger or older control subjects. No group showed significant changes in 25-hydroxyvitamin D3. There was a significant interaction between age group and supplement group, suggesting that the effect of vitamin D2 supplementation on changes in 25(OH)D2 changes with age. The mean increase in 25(OH)D2 was greater in the younger supplemented men than in the older supplemented men (37+/-9 nmol/L vs. 19.5 nmol/L, p=0.027), and this accounted for their significantly greater increase in total 25(OH)D. CONCLUSION: These data are consistent with an age-related decline in the absorption, transport or liver hydroxylation of orally-consumed vitamin D.

[The Papillon-Lefèvre syndrome. A clinical and ultrastructural study of 2 cases]. / Sindrome di Papillon-Lefèvre. Studio clinico e ultrastrutturale su due casi.

Two cases of Papillon-Lefèvre syndrome, a rare hereditary affection of unknown etiology, whose clinical signs are hyperkeratosis palmoplantaris and parodontitis, are described. The results obtained with the ultrastructural examination of the lesions are shown. A therapeutic protocol which can reduce the evolution of the pathology, is also suggested.

Ascorbic acid and plasma lipids.

We examined the association between plasma lipids and total ascorbic acid in 256 men and 221 women age 20-65 years. Among men, we observed that high-density lipoprotein (HDL) cholesterol was 2.1 mg per dl higher, total:HDL cholesterol was 5.4% lower, total cholesterol was 4.8 mg per dl lower, low-density lipoprotein (LDL) cholesterol was 5.6 mg per dl lower, and triglyceride was 5.2% lower for each 0.5 mg per dl increment in ascorbic acid. The association between ascorbic acid and total:HDL cholesterol ratio in men was modified by glucose concentration. Among women, we observed that HDL cholesterol was 14.9 mg per dl higher for women with ascorbic acid levels < or = 1.05 mg per dl and 0.9 mg per dl lower for women with ascorbic acid levels > 1.05 mg per dl for each 0.5 mg per dl increment in ascorbic acid. Total:HDL cholesterol ratio was 10.9% lower for women with ascorbic acid concentrations < or = 1.45 mg per dl and 0.6% higher for women with ascorbic acid concentrations > 1.45 mg per dl for each 0.5 mg per dl increment. The associations among ascorbic acid concentration, total and LDL cholesterol, and triglyceride concentrations were weak or absent among women. These results are consistent with earlier observations relating ascorbic acid and HDL cholesterol and indicate that ascorbic acid might also be related to total and LDL cholesterol concentrations in men.

Acute myopathy associated with chronic licorice ingestion: reversible loss of myoadenylate deaminase activity.

A patient with acute rhabdomyolysis and absence of myoadenylate deaminase (MADA) associated with chronic licorice intoxication is presented. Clinical and laboratory examination of the patient and morphologic study over skeletal muscle were performed. The major effect of licorice intoxication is hypokalemia, which may explain most of the observed clinical symptoms and morphological changes. The absence of MADA may be a consequence of the direct toxic effect of licorice glycosides. To our knowledge, this is the first report in which a lack of MADA and chronic licorice intoxication has been shown to be associated with clinical, histochemical, biochemical, and morphological changes, which were completely reversed with potassium supplementation and licorice withdrawal.

Reversible dilated cardiomyopathy due to growth hormone deficiency.

An unusual case of severe dilated cardiomyopathy is described in a woman with postpartum hypopituitary function, which was characterized by marked decrease of cardiac myofibrils (decreased ratio of myofibrillar volume:cell volume) and somatomedin C deficiency. The patient was treated with a daily intramuscular dose of 4 UI of recombinant human growth hormone for 3 months. Clinical and laboratory assessment and follow-up consisted of noninvasive (echocardiograms, Doppler study, and clinical laboratory tests) and invasive procedures (angiography and endomyocardial biopsy). Morphologic study included optical and electron microscopic examinations and morphometric analysis. The patient exhibited a relevant improvement of cardiac function after recombinant human growth hormone administration. The clinical improvement was confirmed by normalization of electrocardiographic voltages, increased myocardial mass, angiography, and optical and electron microscopic examination, which showed a dramatic recovery of myofibrillar content in myocardiocytes. Furthermore, withdrawal of growth hormone was followed by reduction of electrocardiographic voltages and myocardial mass as well as by impairment of left ventricular function. The authors suggest that there are forms of dilated cardiomyopathy that may benefit dramatically by growth hormone administration. These forms should be identified by growth hormone/somatomedin C axis deficiency and by decrease in myofibrillar content at endomyocardial biopsy.