Androgen-regulated metabolism and biosynthesis in prostate cancer

Metabolic changes are a well-described hallmark of cancer and are responses to changes in the activity of diverse oncogenes and tumour suppressors. For example, steroid hormone biosynthesis is intimately associated with changes in lipid metabolism and represents a therapeutic intervention point in the treatment of prostate cancer (PCa). Both prostate gland development and tumorigenesis rely on the activity of a steroid hormone receptor family member, the androgen receptor (AR). Recent studies have sought to define the biological effect of the AR on PCa by defining the whole-genome binding sites and gene networks that are regulated by the AR. These studies have provided the first systematic evidence that the AR influences metabolism and biosynthesis at key regulatory steps within pathways that have also been defined as points of influence for other oncogenes, including c-Myc, p53 and hypoxia-inducible factor 1α, in other cancers. The success of interfering with these pathways in a therapeutic setting will, however, hinge on our ability to manage the concomitant stress and survival responses induced by such treatments and to define appropriate therapeutic windows.

Deregulated expression of selected histone methylases and demethylases in prostate carcinoma

Prostate cancer (PCa), a leading cause of cancer-related morbidity and mortality, arises through the acquisition of genetic and epigenetic alterations. Deregulation of histone methyltransferases (HMTs) or demethylases (HDMs) has been associated with PCa development and progression. However, the precise influence of altered HMTs or HDMs expression and respective histone marks in PCa onset and progression remains largely unknown. To clarify the role of HMTs and HDMs in prostate carcinogenesis, expression levels of 37 HMTs and 20 HDMs were assessed in normal prostate and PCa tissue samples by RT-qPCR. SMYD3, SUV39H2, PRMT6, KDM5A, and KDM6A were upregulated, whereas KMT2A-E (MLL1-5) and KDM4B were downregulated in PCa, compared with normal prostate tissues. Remarkably, PRMT6 was the histone modifier that best discriminated normal from tumorous tissue samples. Interestingly, EZH2 and SMYD3 expression levels significantly correlated with less differentiated and more aggressive tumors. Remarkably, SMYD3 expression levels were of independent prognostic value for the prediction of disease-specific survival of PCa patients with clinically localized disease submitted to radical prostatectomy. We concluded that expression profiling of HMTs and HDMs, especially SMYD3, might be of clinical usefulness for the assessment of PCa patients and assist in pre-therapeutic decision-making.

Factors affecting treatment decision making for women with breast cancer

This study examined the factors affecting treatment decision making for young women with early stage breast cancer. Thirty women, aged 35 to 52 years, were presented information about two equally effective chemotherapy treatments following surgery for breast cancer using an educational instrument called a "decision board." Although equally effective, the treatments differ with regards to side effects and treatment schedule. The purpose of this research was to investigate what factors affect the decision-making process. Following administration of the decision board, women were given a take-home version to review and asked to return one to two weeks later with a decision, at which time they completed a questionnaire. theoretical framework for this study was constructed from the literature on self-directed learning and critical thinking. The Overall, the factors rated most important to the treatment decision were related to quality of life, side effects, and length of treatment. Five factors were found to be rated significantly different by the women who chose one treatment versus the other in terms of importance to their decision. These were side effects in general, vomiting, hair loss, family role, and the number of trips to the cancer centre required for treatment.Implications and recommendations for patient education, research, and practice evolved from the findings of this study.

Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer

The last decade has seen successful clinical application of polymer–protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer–anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80–320 mg/m2, consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.

Dietary resistant starch interacts with non-starch polysaccharide and protein to influence colonic protein fermentation, with possible implications for colon cancer risk in humans

Resistant starch is dietary starch that passes undigested into the colon where it can have effects similar to non-starch polysaccharide (dietary fibre). The results support the potential health benefits of incorporating foods containing high levels of both resistant starch and non-starch polysaccharide, such as whole grain breads and legumes, as part of well balanced diets containing fruit, vegetables, cereals, meat/alternatives and dairy foods.

Psychosocial epidemiology of colorectal cancer

The research explored the role played by personality and stress in the development and progress of colorectal cancer. Personality type was related to health outcomes following diagnosis, and to participation in bowel cancer screening. The personality types also differed in terms of their capacity to deal with stress.

Study of myeloid leukemogenesis in Zebrafish

In this study zebrafish were used to identify, characterize and study leukemic "cancer"-genes as well as to investigate their role in normal development, particularly blood cell development. The experiments demonstrated that zebrafish represent an excellent tool for studying leukemogenesis, the genes involved in this process and for testing anti-cancer therapeutics.

Bacterial biofilms with emphasis on coagulase-negative staphylococci

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ulnar ray a/hypoplasia: evidence for a developmental field defect on the basis of genetic heterogeneity. Report of three Brazilian families.

We report on five Brazilian patients from three unrelated families with congenital anomalies of the upper limbs. Ulnar aplasia/hypoplasia was the main reason for examining these patients. Evidence for existence of an ulnar developmental field is based on genetic heterogeneity. Clinical and genetic aspects of the ulnar ray defects are discussed.

Total intravenous anaesthesia in ponies using detomidine, ketamine and guaiphenesin: Pharmacokinetics, cardiopulmonary and endocrine effects

Pharmacokinetics and some pharmacological effects of anaesthesia induced by a combination of detomidine, ketamine and guaiphenesin were investigated in eight ponies. Cardiopulmonary function was studied and plasma met-enkephalin, dynorphin, β-endorphin; arginine vasopressin, adrenocorticotrophin, cortisol, 11-deoxycortisol and catecholamine concentrations were measured. The combination produced slight cardiorespiratory depression, hyperglycaemia and a reduction in haematocrit. There were no changes in plasma opioids, pituitary peptides or catecholamines. Plasma cortisol concentration decreased and plasma 11-deoxycortisol increased indicating a suppression of steroidogenesis. Steady state ketamine and guaiphenesin concentrations were attained during the infusion period, and ketamine concentrations likely to provide adequate analgesia for surgical operations were achieved (more than 2.2 μg ml-1). Steady state detomidine concentration was not attained. The ponies took on average 68 minutes to recover to standing and the recovery was uneventful.

Localization of myosin-Va in subpopulations of cells in rat endocrine organs

Myosin-Va is a Ca 2+/calmodulin-regulated unconventional myosin involved in the transport of vesicles, membranous organelles, and macromolecular complexes composed of proteins and mRNA. The cellular localization of myosin-Va has been described in great detail in several vertebrate cell types, including neurons, melanocytes, lymphocytes, auditory tissues, and a number of cultured cells. Here, we provide an immunohistochemical view of the tissue distribution of myosin-Va in the major endocrine organs. Myosin-Va is highly expressed in the pineal and pituitary glands and in specific cell populations of other endocrine glands, especially the parafollicular cells of the thyroid, the principal cells of the parathyroid, the islets of Langerhans of the pancreas, the chromaffin cells of the adrenal medulla, and a subpopulation of interstitial testicular cells. Weak to moderate staining has been detected in steroidogenic cells of the adrenal cortex, ovary, and Leydig cells. Myosin-Va has also been localized to non-endocrine cells, such as the germ cells of the seminiferous epithelium and maturing oocytes and in the intercalated ducts of the exocrine pancreas. These data provide the first systematic description of myosin-Va localization in the major endocrine organs of rat. © 2008 Springer-Verlag.

The endangered species Brycon orbignyanus: genetic analysis and definition of priority areas for conservation

Currently, biodiversity is threatened by several factors often associated with human population growth and the extension of areas occupied by human activity. In particular, freshwater fish fauna is affected by overfishing, deforestation, water pollution, introduction of exotic species and habitat fragmentation promoted by hydroelectric dams, among other environmental impact factors. Several action plans to preserve ichthyofauna biodiversity have been adopted; however, these plans frequently cover only a small number of species, and decisions are often made without strong scientific support. This study aimed to evaluate the genetic aspects of wild groups of Brycon orbignyanus, an endangered fish species, using microsatellites and D-loop regions to identify the genetic structure of the samples and to establish priority areas for conservation based on the genetic patterns of this species. The results indicated that the samples showed levels of genetic variability compatible with others studies with Neotropical fishes. However, the results obtained in the analysis of molecular variance (AMOVA) for microsatellites (F (ST) = 0.258) and D-loop (F (ST) = 0.234) and the interpopulation fixation index revealed that B. orbignyanus was structured in different subpopulations in the La Plata River basin; the areas with better environmental conditions also showed subgroups with higher rates of genetic variability. Future conservation actions addressing these sites should consider two different management units: the complex formed by the Ivinhema River, Upper Parana, Camargo Port and Ilha Grande groups; and the complex formed by the Verde River and Sucuriu River groups.

[White sponge naevus. Report of a family with respect to histopathologic, cytopathologic and DNA-cytometric aspects]

The white sponge naevus is a rare benign, hereditary autosomal dominant disorder of the mucosa. The oral mucosa is most often affected, but vaginal and anal mucosal surfaces may also be involved. Clinically, a whitish-grey, ragged, and folded surface that has no clear demarcation and appears sponge-like is characteristic, often creating problems in differential diagnosis. A potential risk for malignant transformation of white sponge naevus lesions has not been reported. The therapy for this benign hereditary disorder is unknown, however does not appear to be necessary. In the present report of a family with known white sponge naevus in three different generations, clinical, histopathologic, cytopathologic, DNA-cytomertric, and genetic aspects are described and discussed.

Prolactin upregulates sphingosine kinase-1 expression and activity in the human breast cancer cell line MCF7 and triggers enhanced proliferation and migration

Sphingosine kinases (SK) catalyze the formation of sphingosine-1-phosphate (S1P) which plays a crucial role in cell growth and survival. Here, we show that prolactin (PRL) biphasically activates the SK-1, but not the SK-2 subtype, in the breast adenocarcinoma cell-line MCF7. A first peak occurs after minutes of stimulation and is followed by a second delayed activation after hours of stimulation. A similar biphasic effect on SK-1 activity is seen for 17beta-estradiol (E(2)). The delayed activation of SK-1 derives from an upregulated mRNA and protein expression and is due to increased SK-1 promoter activity and mechanistically involves STAT5 activation as well as protein kinase C and the classical mitogen-activated protein kinases. Furthermore, glucocorticoids also block both hormone-induced SK-1 expression and activity. Functionally, long-term stimulation of MCF7 cells with PRL or E(2) is well known to trigger increased cell proliferation and migration. Both hormone-induced cell responses critically involve SK-1 activation since the depletion of SK-1, but not SK-2, by siRNA transfection abolishes the hormone-induced cell proliferation and migration. In summary, our data show that PRL and E(2) cause a pronounced delayed SK-1 activation which is due to increased gene transcription, and critically determines the capability of cells to grow and move. Thus, the SK-1 may represent a novel attractive target for anti-tumor therapy.