Communication between cells: exosomes as a delivery system in prostate cancer.

Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database ( https://pubmed.ncbi.nlm.nih.gov ) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented. Video Abstract.

DiGeorge-like syndrome in a child with a 3p12.3 deletion involving MIR4273 gene born to a mother with gestational diabetes mellitus.

Chromosome 22q11.2 deletion is the most common chromosomal alteration associated with DiGeorge syndrome (DGS), even though this is not the only underlying cause of DGS. In rare patients, mutations in a single gene, TBX1, have been described resulting in a DGS phenotype. Recently, it has been reported that at least part of the TBX1 mutant phenotype is due to excessive bone morphogenetic proteins (BMP) signaling. Evidence suggests that miRNA may modulate the expression of critical T-box transcriptional regulators during midface development and Bmp-signaling. We report on a 7-year-old Caucasian male born to a mother affected with gestational diabetes (GDM) who had a 371Kb-interstitial deletion of 3p12.3 identified by array CGH, involving the ZNF717, MIR1243, and 4273 genes. The child presented with a DiGeorge anomaly (DGA) associated with unilateral renal agenesis and language delay. The immunological evaluation revealed a severe reduction and impairment of T lymphocytes. FISH analysis and TBX1 sequencing were negative. Among the miRNA-4273 predicted target genes, we found BMP3, which is involved in several steps of embryogenesis including kidney and lung organogenesis and in insulin gene expression. Since, DGA is not commonly found in newborns of diabetic mothers, we hypothesize that the pathogenesis of DGA associated with GDM is multifactorial, involving both genetic and/or epigenetic cofactors.

Endoscopy management of sleeve gastrectomy stenosis: what we learned from 202 consecutive patients.

BACKGROUND: Gastric sleeve stenosis (GSS) is described in 1%-4% of patients. OBJECTIVE: To evaluate the role of endoscopy in the management of stenosis after laparoscopic sleeve gastrectomy using a standardized approach according to the characteristic of stenosis. SETTING: Retrospective, observational, single-center study on patients referred from several bariatric surgery departments to an endoscopic referral center. METHODS: We enrolled 202 patients. All patients underwent endoscopy in a fluoroscopy setting, and a systematic classification of the type, site, and length of the GSS was performed. According to the characteristics of the stenosis, patients underwent pneumatic dilatation or placement of a self-expandable metal stent or a lumen-apposed metal stent. Failure of endoscopic treatment was considered an indication for redo surgery, whereas patients with partial or complete response were followed up for 2 years. In the event of a recurrence, a different endoscopic approach was used. RESULTS: We found inflammatory strictures in 4.5% of patients, pure narrowing in 11%, and functional stenosis in 84.5%. Stenosis was in the upper tract of the stomach in 53 patients, whereas medium and distal stenosis was detected in 138 and 11 patients, respectively, and short stenosis in 194 patients. A total of 126 patients underwent pneumatic dilatation, 8 self-expandable metal stent placement, 64 lumen-apposed metal stent positioning, and 36 combined therapy. The overall rate of endoscopy success was 69%. CONCLUSION: GSS should be considered to be a chronic disease, and the endoscopic approach seems to be the most successful treatment, with a prolonged positive outcome of 69%. Characteristics of the stenosis should guide the most suitable endoscopic approach.

New Insights and Emerging Therapeutic Approaches in Prostate Cancer.

Prostate cancer is the second most frequently diagnosed cancer in men and several therapeutic approaches are currently available for patient's care. Although the androgen receptor status represents a good predictor of response to androgen deprivation therapy, prostate cancer frequently becomes resistant to this approach and spreads. The molecular mechanisms that contribute to progression and drug-resistance of this cancer remain still debated. However, few therapeutic options are available for patient's management, at this stage. Recent years have seen a great expansion of the studies concerning the role of stromal-epithelial interactions and tumor microenvironment in prostate cancer progression. The findings so far collected have provided new insights into diagnostic and clinical management of prostate cancer patients. Further, new fascinating aspects concerning the intersection of the androgen receptor with survival factors as well as calcium channels have been reported in cultured prostate cancer cells and mouse models. The results of these researches have opened the way for a better understanding of the basic mechanisms involved in prostate cancer invasion and drug-resistance. They have also significantly expanded the list of new biomarkers and druggable targets in prostate cancer. The primary aim of this manuscript is to provide an update of these issues, together with their translational aspects. Exploiting the power of novel promising therapeutics would increase the success rate in the diagnostic path and clinical management of patients with advanced disease.

Role of Endoscopic Internal Drainage in Treating Gastro-Bronchial and Gastro-Colic Fistula After Sleeve Gastrectomy.

BACKGROUND: Gastro-bronchial and gastro-colic fistulas (GB-GC) represent a rare, but serious complication after laparoscopic sleeve gastrectomy (LSG). The aim of this study is to evaluate the efficacy of endoscopic first-line approach with endoscopic internal drainage (EID) by inserting double pigtail stents (DPS) METHODS: We retrospectively analyzed data from 40 consecutive patients referred at two tertiary centers for gastro-bronchial (N=30) and gastrocolic (N=10) fistulas following LSG. Nineteen patients previously experienced emergency surgical drainage. The mean interval between the index surgery and endoscopic fistula treatment was 265.6±521 days. RESULTS: Healing of the fistulous tract was achieved in 19 patients (47.5%), with complete resolution at an average follow-up of 16 months. Mean time of treatment duration was 157.8±141 days with 5.0±2.9 endoscopic sessions. No major adverse events were registered. CONCLUSIONS: Despite complete fistula healing was achieved in less than 50% of our population, EID for GB/GC fistula after LSG still represents the most conservative approach with low complications rate. Previous surgical drainage seems to be a positive prognostic factor for endoscopic healing. While the longer the interval between the index surgery and endoscopic treatment, the lower was the rate of treatment success.

The Role of Curcumin in Prostate Cancer Cells and Derived Spheroids.

A major challenge in the clinical management of prostate cancer (PC) is to inhibit tumor growth and prevent metastatic spreading. In recent years, considerable efforts have been made to discover new compounds useful for PC therapy, and promising advances in this field were reached. Drugs currently used in PC therapy frequently induce resistance and PC progresses toward metastatic castration-resistant forms (mCRPC), making it virtually incurable. Curcumin, a commercially available nutritional supplement, represents an attractive therapeutic agent for mCRPC patients. In the present study, we compared the effects of chemotherapeutic drugs such as docetaxel, paclitaxel, and cisplatin, to curcumin, on two PC cell lines displaying a different metastatic potential: DU145 (moderate metastatic potential) and PC-3 (high metastatic potential). Our results revealed a dose-dependent reduction of DU145 and PC-3 cell viability upon treatment with curcumin similar to chemotherapeutic agents (paclitaxel, cisplatin, and docetaxel). Furthermore, we explored the EGFR-mediated signaling effects on ERK activation in DU145 and PC-3 cells. Our results showed that DU145 and PC-3 cells overexpress EGFR, and the treatment with chemotherapeutic agents or curcumin reduced EGFR expression levels and ERK activation. Finally, chemotherapeutic agents and curcumin reduced the size of DU145 and PC-3 spheroids and have the potential to induce apoptosis and also in Matrigel. In conclusion, despite different studies being carried out to identify the potential synergistic curcumin combinations with chemopreventive/therapeutic efficacy for inhibiting PC growth, the results show the ability of curcumin used alone, or in combinatorial approaches, to impair the size and the viability of PC-derived spheroids.

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer is a heterogeneous disease that still lacks specific therapeutic approaches. The identification of new biomarkers, predictive of the disease's aggressiveness and pharmacological response, is a challenge for a more tailored approach in the clinical management of patients. Nerve growth factor, initially identified as a key factor for neuronal survival and differentiation, turned out to be a multifaceted molecule with pleiotropic effects in quite divergent cell types, including cancer cells. Many solid tumors exhibit derangements of the nerve growth factor and its receptors, including the tropomyosin receptor kinase A. This receptor is expressed in triple-negative breast cancer, although its role in the pathogenesis and aggressiveness of this disease is still under investigation. We now report that triple-negative breast cancer-derived MDA-MB-231 and MDA-MB-453 cells express appreciable levels of tropomyosin receptor kinase A and release a biologically active nerve growth factor. Activation of tropomyosin receptor kinase by nerve growth factor treatment positively affects the migration, invasion, and proliferation of triple-negative breast cancer cells. An increase in the size of triple-negative breast cancer cell spheroids is also detected. This latter effect might occur through the nerve growth factor-induced release of matrix metalloproteinase 9, which contributes to the reorganization of the extracellular matrix and cell invasiveness. The tropomyosin receptor kinase A inhibitor GW441756 reverses all these responses. Co-immunoprecipitation experiments in both cell lines show that nerve growth factor triggers the assembly of the TrkA/ß1-integrin/FAK/Src complex, thereby activating several downstream effectors. GW441756 prevents the complex assembly induced by nerve growth factor as well as the activation of its dependent signaling. Pharmacological inhibition of the tyrosine kinases Src and FAK (focal adhesion kinase), together with the silencing of ß1-integrin, shows that the tyrosine kinases impinge on both proliferation and motility, while ß1-integrin is needed for motility induced by nerve growth factor in triple-negative breast cancer cells. The present data support the key role of the nerve growth factor/tropomyosin receptor kinase A pathway in triple-negative breast cancer and offer new hints in the diagnostic and therapeutic management of patients.

The androgen receptor/filamin A complex as a target in prostate cancer microenvironment.

Prostate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signaling pathways. Tumor microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumor area in androgen-treated 3D co-culture. The androgen receptor in association with ß1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. This study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer.

Long-Term Functional Results of a Modified Caudal-to-Cranial Approach in Laparoscopic Segmental Left Colectomy for Diverticular Disease.

A modified caudal-to-cranial approach to perform laparoscopic left colectomy for benign diseases has been recently designed to facilitate the low-tie mesenteric dissection. A chart review has been performed including all consecutive patients with uncomplicated diverticulitis who have been treated by segmental left colectomy with a caudal-to-cranial approach. A total of 34 patients were included in the study. 21 patients were male, mean age was 54.1 ± 11.3, and mean BMI was 26 ± 5.5. Patients with ASA Score I were 7, with ASA II were 9, and with ASA Score III were 5. Incontinence Score (IS) resulted in an average of 5 ± 2, 2 grade of incontinence and the CS score showed an average of 10 ± 3, 2 grade of constipation. Health status, evaluated by Short Form-36 questionnaire, was demonstrated in these patients' great physical function, role, general health, and social function. The anorectal manometry performed 6 months after surgery showed a normal value in terms of the anal resting pressure (47 ± 13 mmHg) and an increased volume to stimulate desire to defecate (197 ± 25 ml). The length of the anal sphincter was normal compared to the reference value (37 ± 5.4 mm). Although further studies are required to obtain definitive conclusions, our results are encouraging to propose low-tie segmental colectomy as the standard procedure for the treatment of uncomplicated diverticulitis, and our modified surgical approach could be considered useful to facilitate the surgical approach.

H9c2 Cardiomyocytes under Hypoxic Stress: Biological Effects Mediated by Sentinel Downstream Targets.

The association between diabetes and cardiovascular diseases is well known. Related diabetes macro- and microangiopathies frequently induce hypoxia and consequently energy failure to satisfy the jeopardized myocardium basal needs. Additionally, it is widely accepted that diabetes impairs endothelial nitric oxide synthase (eNOS) activity, resulting in diminished nitric oxide (NO) bioavailability and consequent endothelial cell dysfunction. In this study, we analyzed the embryonic heart-derived H9c2 cell response to hypoxic stress after administration of a high glucose concentration to reproduce a condition often observed in diabetes. We observed that 24 h hypoxia exposure of H9c2 cells reduced cell viability compared to cells grown in normoxic conditions. Cytotoxicity and early apoptosis were increased after exposure to high glucose administration. In addition, hypoxia induced a RhoA upregulation and a Bcl-2 downregulation and lowered the ERK activation observed in normoxia at both glucose concentrations. Furthermore, a significant cell proliferation rate increases after the 1400 W iNOS inhibitor administration was observed. Again, hypoxia increased the expression level of myogenin, a marker of skeletal muscle cell differentiation. The cardiomyocyte gene expression profiles and morphology changes observed in response to pathological stimuli, as hypoxia, could lead to improper ventricular remodeling responsible for heart failure. Therefore, understanding cell signaling events that regulate cardiac response to hypoxia could be useful for the discovery of novel therapeutic approaches able to prevent heart diseases.

ROS in cancer therapy: the bright side of the moon.

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.

The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?

The human microbiota shows pivotal roles in urologic health and disease. Emerging studies indicate that gut and urinary microbiomes can impact several urological diseases, both benignant and malignant, acting particularly on prostate inflammation and prostate cancer. Indeed, the microbiota exerts its influence on prostate cancer initiation and/or progression mechanisms through the regulation of chronic inflammation, apoptotic processes, cytokines, and hormonal production in response to different pathogenic noxae. Additionally, therapies' and drugs' responses are influenced in their efficacy and tolerability by microbiota composition. Due to this complex potential interconnection between prostate cancer and microbiota, exploration and understanding of the involved relationships is pivotal to evaluate a potential therapeutic application in clinical practice. Several natural compounds, moreover, seem to have relevant effects, directly or mediated by microbiota, on urologic health, posing the human microbiota at the crossroad between prostatic inflammation and prostate cancer development. Here, we aim to analyze the most recent evidence regarding the possible crosstalk between prostate, microbiome, and inflammation.

Antioxidant Effect of Beer Polyphenols and Their Bioavailability in Dental-Derived Stem Cells (D-dSCs) and Human Intestinal Epithelial Lines (Caco-2) Cells.

Beer is one of the most consumed alcoholic beverages in the world, rich in chemical compounds of natural origin with high nutritional and biological value. It is made up of water, barley malt, hops, and yeast. The main nutrients are carbohydrates, amino acids, minerals, vitamins, and other compounds such as polyphenols which are responsible for the many health benefits associated with this consumption of drinks. Hops and malt are one of the raw materials for beer and are a source of phenolic compounds. In fact, about 30% of the polyphenols in beer comes from hops and 70%-80% from malt. Natural compounds of foods or plants exert an important antioxidant activity, counteracting the formation of harmful free radicals. In the presence of an intense stressing event, cells activate specific responses to counteract cell death or senescence which is known to act as a key-task in the onset of age-related pathologies and in the loss of tissue homeostasis. Many studies have shown positive effects of natural compounds as beer polyphenols on biological systems. The main aims of our research were to determine the polyphenolic profile of three fractions, coming from stages of beer production, the mashing process (must), the filtration process (prehopping solution), and the boiling process with the addition of hops (posthopping solution), and to evaluate the effects of these fractions on Dental-derived Stem Cells (D-dSCs) and human intestinal epithelial lines (Caco-2 cells). Furthermore, we underline the bioavailability of beer fraction polyphenols by carrying out the in vitro intestinal absorption using the Caco-2 cell model. We found an antioxidant, proliferating, and antisenescent effects of the fractions deriving from the brewing process on D-dSCs and Caco-2 cells. Finally, our results demonstrated that the bioavailability of polyphenols is greater in beer than in the control standards used, supporting the future clinical application of these compounds as potential therapeutic tools in precision and translational medicine.

Breast cancer stem cells: The role of sex steroid receptors.

Breast cancer (BC) is the most common cancer among women, and current available therapies often have high success rates. Nevertheless, BC might acquire drug resistance and sometimes relapse. Current knowledge about the most aggressive forms of BC points to the role of specific cells with stem properties located within BC, the so-called "BC stem cells" (BCSCs). The role of BCSCs in cancer formation, growth, invasiveness, therapy resistance and tumor recurrence is becoming increasingly clear. The growth and metastatic properties of BCSCs are regulated by different pathways, which are only partially known. Sex steroid receptors (SSRs), which are involved in BC etiology and progression, promote BCSC proliferation, dedifferentiation and migration. However, in the literature, there is incomplete information about their roles. Particularly, there are contrasting conclusions about the expression and role of the classical BC hormonal biomarkers, such as estrogen receptor alpha (ERα), together with scant, albeit promising information concerning ER beta (ERß) and androgen receptor (AR) properties that control different transduction pathways in BCSCs. In this review, we will discuss the role that SRs expressed in BCSCs play to BC progression and recurrence and how these findings have opened new therapeutic possibilities.

Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer.

Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients.

Estrogens Modulate Somatostatin Receptors Expression and Synergize With the Somatostatin Analog Pasireotide in Prostate Cells.

Prostate cancer (PC) is one of the most frequently diagnosed cancers and a leading cause of cancer-related deaths in Western society. Current PC therapies prevalently target the functions of androgen receptor (AR) and may only be effective within short time periods, beyond which the majority of PC patients progress to castration-resistant PC (CRPC) and metastatic disease. The role of estradiol/estradiol receptor (ER) axis in prostate transformation and PC progression is well established. Further, considerable efforts have been made to investigate the mechanism by which somatostatin (SST) and somatostatin receptors (SSTRs) influence PC growth and progression. A number of therapeutic strategies, such as the combination of SST analogs with other drugs, show, indeed, strong promise. However, the effect of the combined treatment of SST analogs and estradiol on proliferation, epithelial mesenchyme transition (EMT) and migration of normal- and cancer-derived prostate cells has not been investigated so far. We now report that estradiol plays anti-proliferative and pro-apoptotic effect in non-transformed EPN prostate cells, which express both ERα and ERß. A weak apoptotic effect is observed in transformed CPEC cells that only express low levels of ERß. Estradiol increases, mainly through ERα activation, the expression of SSTRs in EPN, but not CPEC cells. As such, the hormone enhances the anti-proliferative effect of the SST analog, pasireotide in EPN, but not CPEC cells. Estradiol does not induce EMT and the motility of EPN cells, while it promotes EMT and migration of CPEC cells. Addition of pasireotide does not significantly modify these responses. Altogether, our results suggest that pasireotide may be used, alone or in combination with other drugs, to limit the growth of prostate proliferative diseases, provided that both ER isoforms (α and ß) are present. Further investigations are needed to better define the cross talk between estrogens and SSTRs as well as its role in PC.

Estrogens and Their Receptors in Prostate Cancer: Therapeutic Implications.

A major challenge in clinical management of prostate cancer (PC) is to limit tumor growth and prevent metastatic spreading. Considerable efforts have been made to discover new compounds for PC therapy and recent years have seen promising progress in this field. Pharmacological approaches have been designed to achieve benefits in PC treatment and avoid the negative side effects resulting from administration of antagonists or agonists or new drugs. Nonetheless, the currently available therapies frequently induce resistance and PC progresses toward castration-resistant forms that can be caused by the androgen receptor reactivation and/or mutations, or derangement of signaling pathways. Preclinical and clinical findings have also shown that other nuclear receptors are frequently altered in PC. In this review, we focus on the role of estradiol/estradiol receptor (ER) axis, which controls PC growth and progression. Selective targeting of ER subtypes (α or ß) may be an attractive way to limit the growth and spreading of prostatic cancer cells.

The Androgen Receptor in Breast Cancer.

Breast cancer (BC) is a hormone-related tumor. Despite the progress in BC therapy, this disease still remains the most common cancer amongst women around the world. This is likely due to the amazing BC heterogeneity. Accumulating evidence suggests a role for androgen signaling in BC. Nevertheless, a precise understanding of the mechanism of androgen action in this disease remains a challenging puzzle. Androgen receptor (AR) is often expressed in BC and several studies suggest that its role depends on the tumor microenvironment as well as the relative levels of circulating estrogens and androgens. However, the AR function in BC is still conflicting. Although AR expression is often associated with a favorable prognosis in EREstradiol Receptorα-positive (ERα +) BC, many findings suggest that, in some instances, high levels of AR can contribute to the therapy-resistance. Again, in ERα negative BC (ERα -), AR is mainly expressed in tumors with apocrine differentiation and a lower Nottingham grade. Moreover, AR stimulates cellular proliferation in triple negative breast cancer (ERα -, PgR -, and HER-2-Neu -). This finding is substantiated by the observation that high levels of circulating androgens are associated with an increased risk of developing BC in post-menopausal woman. Treatment of ERα- BC with AR antagonists, such as bicalutamide or enzalutamide, reduces, indeed, the tumor growth. In this review, we will analyze the putative role of AR in BC. Emerging therapies based on the use of new agonists or antagonists or inhibitors will be here discussed.

ß-TrCP- and Casein Kinase II-Mediated Degradation of Cyclin F Controls Timely Mitotic Progression.

Orderly progressions of events in the cell division cycle are necessary to ensure the replication of DNA and cell division. Checkpoint systems allow the accurate execution of each cell-cycle phase. The precise regulation of the levels of cyclin proteins is fundamental to coordinate cell division with checkpoints, avoiding genome instability. Cyclin F has important functions in regulating the cell cycle during the G2 checkpoint; however, the mechanisms underlying the regulation of cyclin F are poorly understood. Here, we observe that cyclin F is regulated by proteolysis through ß-TrCP. ß-TrCP recognizes cyclin F through a non-canonical degron site (TSGXXS) after its phosphorylation by casein kinase II. The degradation of cyclin F mediated by ß-TrCP occurs at the G2/M transition. This event is required to promote mitotic progression and favors the activation of a transcriptional program required for mitosis.

Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer.

Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.