Contextualizing the Genes Altered in Bladder Neoplasms in Pediatric andTeen Patients Allows Identifying Two Main Classes of Biological ProcessesInvolved and New Potential Therapeutic Targets.

Research on bladder neoplasms in pediatric and teen patients (BNPTP) has described 21 genes, which are variously involved in this disease and are mostly responsible for deregulated cell proliferation. However, due to the limited number of publications on this subject, it is still unclear what type of relationships there are among these genes and which are the chances that, while having different molecular functions, they i) act as downstream effector genes of well-known pro- or anti- proliferative stimuli and/or interplay with biochemical pathways having oncological relevance or ii) are specific and, possibly, early biomarkers of these pathologies. A Gene Ontology (GO)-based analysis showed that these 21 genes are involved in biological processes, which can be split into two main classes: cell regulation-based and differentiation/development-based. In order to understand the involvement/overlapping with main cancer-related pathways, we performed a meta-analysis dependent on the 189 oncogenic signatures of the Molecular Signatures Database (OSMSD) curated by the Broad Institute. We generated a binary matrix with 53 gene signatures having at least one hit; this analysis i) suggests that some genes of the original list show inconsistencies and might need to be experimentally re- assessed or evaluated as biomarkers (in particular, ACTA2) and ii) allows hypothesizing that important (proto)oncogenes (E2F3, ERBB2/HER2, CCND1, WNT1, and YAP1) and (putative) tumor suppressors (BRCA1, RBBP8/CTIP, and RB1-RBL2/p130) may participate in the onset of this disease or worsen the observed phenotype, thus expanding the list of possible molecular targets for the treatment of BNPTP.

p53 regulates myogenesis by triggering the differentiation activity of pRb.

The p53 oncosuppressor protein regulates cell cycle checkpoints and apoptosis, but increasing evidence also indicates its involvement in differentiation and development. We had previously demonstrated that in the presence of differentiation-promoting stimuli, p53-defective myoblasts exit from the cell cycle but do not differentiate into myocytes and myotubes. To identify the pathways through which p53 contributes to skeletal muscle differentiation, we have analyzed the expression of a series of genes regulated during myogenesis in parental and dominant-negative p53 (dnp53)-expressing C2C12 myoblasts. We found that in dnp53-expressing C2C12 cells, as well as in p53(-/-) primary myoblasts, pRb is hypophosphorylated and proliferation stops. However, these cells do not upregulate pRb and have reduced MyoD activity. The transduction of exogenous TP53 or Rb genes in p53-defective myoblasts rescues MyoD activity and differentiation potential. Additionally, in vivo studies on the Rb promoter demonstrate that p53 regulates the Rb gene expression at transcriptional level through a p53-binding site. Therefore, here we show that p53 regulates myoblast differentiation by means of pRb without affecting its cell cycle-related functions.

Androgen insensitivity syndrome.

OBJECTIVE: We provide a review of the literature about the Androgen Insensitivity Syndrome (AIS), its onset and associated developmental anomalies and the genetic alterations causing it. MATERIALS AND METHODS: We searched PubMed with a larger emphasis on the physiology, genetics and current management of AIS. RESULTS: AIS is an X-linked recessive Disorder of Sex Development (DSD). It is caused by mutations of the Androgen Receptor, and their large amount and heterogeneity (missense and nonsense mutations, splicing variants, deletions, and insertions) are responsible for the wide spectrum of possible phenotypes of patients, divided into Partial AIS (PAIS) and Complete AIS (CAIS). Once the clinical and laboratory investigations have laid the foundation for a diagnostic hypothesis, it is important to identify the actual karyotype of the individual and search for the mutation in the Androgen Receptor to diagnose with certainty the syndrome. Alternatively, in the absence of such evidence, the diagnosis should more properly be an AIS-like condition, which we describe as well in our report. CONCLUSIONS: The management of this DSD is based on pharmacotherapies, surgery and psychological support: all of them must be directed to facilitate the patient's life, considering his/her sexual identity.

Serum anti-p53 antibodies as a useful marker for prognosis of gastric carcinoma.

Mutations in the TP53 gene are the most common genetic alterations in cancer. Accumulation of mutated protein may induce circulating anti-p53 antibodies (anti-p53Ab) in sera of cancer patients. The aim of our work was to evaluate the presence and prognostic value of anti-p53Ab in gastric cancer patients and to investigate whether their presence is related to p53 overexpression in tumor tissue. Anti-p53Ab were analyzed in sera from 111 patients with gastric carcinoma and from 64 healthy donors by ELISA. p53 expression was also quantified by ELISA in biopsies of 54 gastric cancers and 22 healthy gastric mucosas. Significant anti-p53Ab levels were found in 15.3% of patients, whereas none of the 64 donor sera were positive. High levels of p53 expression were detected only in tumor tissue, in 72.2% of cases. A significant correlation was observed between anti-p53Ab and high levels of mutated p53 in tissue (p<0.05). The survival time of serum-positive patients was significantly longer than that of patients with low/negative serum levels, with a survival rate of 41.2% and 14.9%, respectively, over 48 months (p<0.05). Thus, detection of serum anti-p53Ab in gastric cancer patients can be useful to identify a subset of patients with better prognosis.

Vesicoureteral reflux in infants: what do we know about the gender prevalence by age?

OBJECTIVE: Vesicoureteral reflux (VUR) affects up to 1% of Caucasian children. Primary VUR is characterized by failure of the ureterovesicular junction to prevent urine from traveling in a retrograde fashion from the bladder to the ureters and the kidneys. Several reports in the literature describe the prevalence of this condition in pediatric patients; overall, VUR affects more males during infancy and with higher grades. However, a thorough consideration of these articles reveals important contradictions regarding the prevalence by gender and age. We analyzed those contradictions and suggested a possible explanation based on our single center experience with this patient group. In particular, for the age interval 0-2 years: we have found that (1) VUR mostly affects boys; (2) the male/female ratio steadily declines over time; (3) the unequal prevalence between males and females essentially disappears when children reach the age of two years. CONCLUSIONS: The natural history of VUR in infant boys differs from that of infant girls, and therefore requires a gender-specific approach. Available data support the need to redefine the categorization and clinical guidelines for this disease.

Oncology of companion animals as a model for humans. an overview of tumor histotypes.

The need for more appropriate animal models in cancer research has led, over the past 20 years, to consider pets with spontaneously occurring neoplasms as a valuable and still under used resource. The role of companion animals in the struggle to eradicate cancer can be multiple: they may act as environmental sentinels, help in gaining insights on tumor biology and finally may be enrolled in therapeutic trials which might act as a bridge to the clinic applications. This paper will focus on the most valuable spontaneous neoplasms in companion animals and will analyze the potentials of each histotype as a model for basic research and for new therapeutic strategies. It is conceivable that in the next years comparative oncology will play a paramount role in translational medicine allowing a rapid flow of data from laboratories to clinical application in humans.

COX-2 overexpression in canine tumors: potential therapeutic targets in oncology.

Cyclooxygenases catalyze the initial, rate-limiting steps of prostaglandin synthesis from arachidonic acid. Two isoforms of this enzyme exist in mammalian and avian species: COX-1 and COX-2. COX-1 is constitutively expressed and is the major isoform of gastrointestinal tissue. COX-2 is induced in response to inflammatory stimuli. COX-2 has been implicated in carcinogenesis of several neoplasms. Furthermore, COX-2 over-expression has been noted in many solid tumours and has been correlated with a worse prognosis in colorectal cancer, non-small-cell lung cancer, mesothelioma and gastric cancer. In this review, the most recent findings on the mechanisms by which COX-2 promote tumorigenesis are discussed, with particular emphasis on the studies involving spontaneous canine neoplasms.

Rational design of new electrodes for electrochemotherapy.

Electrochemotherapy associates the local delivery of anticancer drugs with the administration of permeabilizing electric pulses that support the antiblastic action. The basic instrumentation for this therapy is constituted by a pulse generator and various specific electrodes. While many efforts have been profuse by researchers in this field to obtain the standardization of the pulse generating equipment over the past 15 years, the delivery apparatus still needs refinements in order to reach most of the body districts, to control the homogeneity and stability of the electric fields and to further reduce morbidity. With the aim to develop innovative electrodes able to satisfy, at least partially, these requirements, extensive studies on pet patients with spontaneous neoplasms have been conducted, leading to the manufacturing of several different prototypes. In this paper we discuss the rationale of 11 different electrodes, briefly summarize the results obtained and their experimental validation, also presenting five paradigmatic clinical cases. In particular, it is shown that the caliper electrodes are more suited for the treatment of cutaneous and subcutaneous lesions, while the needle arrays are more efficacious in intraoperative settings. Furthermore, relevant peculiarities of unipolar electrodes are examined with a particular focus on the irregular current paths that they produce and on the potentialities of this feature. Remarkably, the decrease of the steric encumbrance turned out to be a stronger factor in electrode design than the containment of the total number of electric fields covered in serial ECT sessions. In the conclusions, perspectives and new challenges of electrode design for electrochemotherapy are illustrated.

Potentiation of chemotherapy in companion animals with spontaneous large neoplasms by application of biphasic electric pulses.

The objectives of this phase I/II study were: i) to determine whether electrochemotherapy (intralesional bleomycin + electric pulses) could be effective in companion animals with different, large neoplasms compared to chemotherapy (conventional intralesional bleomycin); ii) to identify potential toxicities; iii) to preliminarily assess the electric field requirements. Twenty-two patients received intralesional bleomycin + administration of permeabilizing electric pulses. Specifically, after the injection of the drug, sequences of 8 biphasic electric pulses lasting 50 + 50 micros each, with 1 ms interpulse intervals, were delivered in bursts of 1300 V/cm for cutaneous and soft tissue lesions, and of 800 V/cm for oral mucosal and exposed soft tissue neoplasms, using caliper electrodes. The treatment was well tolerated and side effects were infrequent. Nevertheless, two previously unreported toxicities (drug-induced vasculitis and pulmonary thromboembolism) have been identified. A high response rate (complete remission + partial remission: > 80%), often long lasting (> 40%) was obtained. Furthermore, results of this trial were compared to a subset of veterinary cancer patients treated with bleomycin single agent, observing a remarkable superiority of the combined treatment (p < 0.01). Altogether, results suggest that electrochemotherapy is a potentially advantageous rescue protocol for bulky, even relapsing neoplasms of companion animals. Further investigations in this field might allow developing improved protocols for the treatment of down-staged relapsing cancer in pets as well as in humans.

Pet models in cancer research: general principles.

Oncology has made great advancements in the past 50 years, moving from preliminary to complex studies and developing in the process numerous models. An important function in this development has been played by animal investigations that have displayed many aspects of cancer and led to the discovery of new therapies. Nevertheless, the debate about preclinical "tools" suited to predict efficacy as well as side effects of anticancer compounds and treatments is open. In this review we focus on the role of pet models in cancer research, whose continuously increasing importance is due to the disclosure of striking histopathological, anatomical, genetical, and biomolecular similarities among feline, canine, and human tumors. Remarkably, the improvement of clinical condition of companion animals, obtained by their enrolment in cancer trials, is generally perceived as an added value for the whole society. In the first paragraphs we examine crucial ethical, clinical, and financial issues that make up the framework of this area of translational research. Then we illustrate the new figures of researchers, namely experts in laboratory-clinic interface, who are needed in this field, and describe the relevant potentialities of pet cancer registries and genome projects. In the conclusions are summarized the principal arguments that support the adoption of pet models in tumor studies.