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Testis Cancer: Genes, Environment, Hormones
Alberto Ferlin,Carlo Foresta
Frontiers in Endocrinology , 2014, DOI: 10.3389/fendo.2014.00172
Profiling Insulin Like Factor 3 (INSL3) Signaling in Human Osteoblasts
Alberto Ferlin, Lisa Perilli, Lisa Gianesello, Giuseppe Taglialavoro, Carlo Foresta
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029733
Abstract: Background Young men with mutations in the gene for the INSL3 receptor (Relaxin family peptide 2, RXFP2) are at risk of reduced bone mass and osteoporosis. Consistent with the human phenotype, bone analyses of Rxfp2?/? mice showed decreased bone volume, alterations of the trabecular bone, reduced mineralizing surface, bone formation, and osteoclast surface. The aim of this study was to elucidate the INSL3/RXFP2 signaling pathways and targets in human osteoblasts. Methodology/Principal Findings Alkaline phosphatase (ALP) production, protein phosphorylation, intracellular calcium, gene expression, and mineralization studies have been performed. INSL3 induced a significant increase in ALP production, and Western blot and ELISA analyses of multiple intracellular signaling pathway molecules and their phosphorylation status revealed that the MAPK was the major pathway influenced by INSL3, whereas it does not modify intracellular calcium concentration. Quantitative Real Time PCR and Western blotting showed that INSL3 regulates the expression of different osteoblast markers. Alizarin red-S staining confirmed that INSL3-stimulated osteoblasts are fully differentiated and able to mineralize the extracellular matrix. Conclusions/Significance Together with previous findings, this study demonstrates that the INSL3/RXFP2 system is involved in bone metabolism by acting on the MAPK cascade and stimulating transcription of important genes of osteoblast maturation/differentiation and osteoclastogenesis.
Mechanism of Human Papillomavirus Binding to Human Spermatozoa and Fertilizing Ability of Infected Spermatozoa
Carlo Foresta,Cristina Patassini,Alessandro Bertoldo,Massimo Menegazzo,Felice Francavilla,Luisa Barzon,Alberto Ferlin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015036
Abstract: Human papillomaviruses (HPVs) are agents of the most common sexually transmitted diseases in females and males. Precise data about the presence, mechanism of infection and clinical significance of HPV in the male reproductive tract and especially in sperm are not available. Here we show that HPV can infect human sperm, it localizes at the equatorial region of sperm head through interaction between the HPV capsid protein L1 and syndecan-1. Sperm transfected with HPV E6/E7 genes and sperm exposed to HPV L1 capsid protein are capable to penetrate the oocyte and transfer the virus into oocytes, in which viral genes are then activated and transcribed. These data show that sperm might function as vectors for HPV transfer into the oocytes, and open new perspectives on the role of HPV infection in males and are particularly intriguing in relation to assisted reproduction techniques.
Multivariate Multi-Scale Permutation Entropy for Complexity Analysis of Alzheimer’s Disease EEG
Francesco Carlo Morabito,Domenico Labate,Fabio La Foresta,Alessia Bramanti,Giuseppe Morabito,Isabella Palamara
Entropy , 2012, DOI: 10.3390/e14071186
Abstract: An original multivariate multi-scale methodology for assessing the complexity of physiological signals is proposed. The technique is able to incorporate the simultaneous analysis of multi-channel data as a unique block within a multi-scale framework. The basic complexity measure is done by using Permutation Entropy, a methodology for time series processing based on ordinal analysis. Permutation Entropy is conceptually simple, structurally robust to noise and artifacts, computationally very fast, which is relevant for designing portable diagnostics. Since time series derived from biological systems show structures on multiple spatial-temporal scales, the proposed technique can be useful for other types of biomedical signal analysis. In this work, the possibility of distinguish among the brain states related to Alzheimer’s disease patients and Mild Cognitive Impaired subjects from normal healthy elderly is checked on a real, although quite limited, experimental database.
Molecular Karyotyping of Human Single Sperm by Array- Comparative Genomic Hybridization
Cristina Patassini, Andrea Garolla, Alberto Bottacin, Massimo Menegazzo, Elena Speltra, Carlo Foresta, Alberto Ferlin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060922
Abstract: No valid method is currently available to analyze the entire genome of sperm, including aneuploidies and structural chromosomal alterations. Here we describe the optimization and application of array-Comparative Genomic Hybridization (aCGH) on single human sperm. The aCGH procedure involves screening of the entire chromosome complement by DNA microarray allowing having a molecular karyotype, and it is currently used in research and in diagnostic clinical practice (prenatal diagnosis, pre-implantation genetic diagnosis), but it has never been applied on sperm. DNA from single human sperm isolated by micromanipulator was extracted, decondensed and amplified by whole-genome amplification (WGA) and then labeled, hybridized to BAC array, and scanned by microarray scanner. Application of this protocol to 129 single sperm from normozoospermic donors identified 7.8% of sperm with different genetic anomalies, including aneuploidies and gains and losses in different chromosomes (unbalanced sperm). On the contrary, of 130 single sperm from men affected by Hodgkin lymphoma at the end of three months of chemotherapy cycles 23.8% were unbalanced. Validation of the method also included analysis of 43 sperm from a man with a balanced translocation [46,XY,t(2;12)(p11.2;q24.31)], which showed gains and losses corresponding to the regions involved in the translocation in 18.6% of sperm and alterations in other chromosomes in 16.3% of sperm. Future application of this method might give important information on the biology and pathophysiology of spermatogenesis and sperm chromosome aberrations in normal subjects and in patients at higher risk of producing unbalanced sperm, such as infertile men, carriers of karyotype anomalies, men with advanced age, subjects treated with chemotherapy, and partners of couples with repeated miscarriage and repeated failure during assisted reproduction techniques.
Testicular cancer and HPV semen infection
Andrea Garolla,Damiano Pizzol,Alessandro Bertoldo,Marco Ghezzi,Umberto Carraro,Alberto Ferlin,Carlo Foresta
Frontiers in Endocrinology , 2012, DOI: 10.3389/fendo.2012.00172
Abstract: Testicular cancer represents the more frequent solid tumor affecting males aged 15–35 years. In the last decades, its incidence showed a progressive increased probably due to genetic and environmental factors. Despite exposure to some viruses such as HIV, HCV, EBV, and HPV is frequently related to cancer development, there are no studies aimed to evaluate the possible implication of viral infections in the pathogenesis of testicular cancer. In this study, we analyzed sperm parameters and prevalence of HPV on sperm in 155 testicular cancer patients at diagnosis (T?1), after orchiectomy (T0) and after 12 months from surgery or from the end of adjuvant treatments (T12). All patients showed a significantly higher prevalence of semen infection than controls (9.5% and 2.4% respectively,) and altered sperm parameters both at T?1 and T0. Considering sperm parameters, at T?1 we observed a reduction of progressive motility, and after orchiectomy patients showed a reduction of sperm concentration and count and a further worsening of motility. Thereafter, patients were assigned to three groups on the basis of medical option after surgery: S = surveillance, R = radiotherapy, and C = chemotherapy +/? radiotherapy. At T12, untreated patients had an improvement of sperm parameters while R group and even more C group had a strong decrease of sperm number (p < 0.01 both vs. T0 and S group). Moreover, patients who received radio and/or chemotherapy had a very high prevalence of HPV semen infection (S = 7.7%, R = 30.8%, and C = 61.5%). In conclusion, patients with testicular cancer had frequently altered sperm parameters and higher prevalence of HPV semen infection that were worsened after radio and chemotherapy. Because HPV infection is a risk factor for cancer development and it may further reduce fertility, we suggest screening for HPV in testicular cancer patients at diagnosis and particularly after adjuvant treatments.
The Network Metaphor & the New Renaissance
Foresta, Don
Journal of New Frontiers in Spatial Concepts , 2012,
Abstract: This article is about art and science and a certain parallelism between them in the evolution of Western culture, particularly over the last 150 years. I will try to describe what changes have taken place in our society’s operational schema and our shared paradigm. My construct will be one of art, though a strong influence from science will be evident. I propose that we have been living through a second renaissance provoked by a profound change in the definition and representation of reality by both art and science. Throughout the 20th century, the ideas put forth by both have been extremely unconventional and the two have interacted in ways not always obvious, providing new metaphors, new patterns for defining the future shape of our culture.
Testis transcriptome analysis in male infertility: new insight on the pathogenesis of oligo-azoospermia in cases with and without AZFc microdeletion
Valentina Gatta, Florina Raicu, Alberto Ferlin, Ivana Antonucci, Anna Scioletti, Andrea Garolla, Giandomenico Palka, Carlo Foresta, Liborio Stuppia
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-401
Abstract: An intriguing and unexpected finding is that all the samples showing the AZFc deletion cluster together irrespectively of their testicular phenotypes. This cluster, including also four patients affected by idiopathic infertility, showed a downregulation of several genes related to spermatogenesis that are mainly involved in testicular mRNA storage. Interestingly, the four idiopathic patients present in the cluster showed no testicular expression of DAZ despite the absence of AZFc deletion in the peripheral blood.Our expression profiles analysis indicates that several forms of infertility can be triggered by a common pathogenic mechanism that is likely related to alterations in testicular mRNA storage. Our data suggest that a lack of testicular DAZ gene expression may be the trigger of such mechanism. Furthermore, the presence of AZFc deletions in mosaic or the loss of function of AZFc genes in absence of Yq deletion can perhaps explain these findings. Finally, based on our data, it is intriguing to hypothesize that DAZ gene dysfunctions can account for a larger number of previously thought "idiopathic" infertility cases and investigation of such testicular gene dysfunction can be important to reveal the molecular determinant of infertility than are undetected when only testing Yq deletions in peripheral blood.Microdeletions of the Y chromosome long arm (Yq) represent the main molecular determinants of male infertility and account for about 10% of cases of non obstructive azoospermia or severe hypospermatogenesis [1-5]. Yq microdeletions involve three Azoospermia Factors (AZF) loci, AZFa, AZFb and AZFc [6] and remove many genes likely involved in male germ cell development and maintenance [7]. The most frequent deletion of the Y chromosome (AZFc, b2/b4) spans 3.5 Mb and eliminates 21 genes and transcription units of the AZFc region. Among these, the main candidate for spermatogenesis failure is the Deleted in Azoospermia (DAZ) gene, a testis specific gene present in
Rome consensus conference - statement; Human Papilloma Virus diseases in males
Andrea Lenzi, Vincenzo Mirone, Vincenzo Gentile, Riccardo Bartoletti, Vincenzo Ficarra, Carlo Foresta, Luciano Mariani, Sandra Mazzoli, Saverio G Parisi, Antonio Perino, Mauro Picardo, Carla Maria Zotti
BMC Public Health , 2013, DOI: 10.1186/1471-2458-13-117
Abstract: The Sponsoring Panel put a series of questions to the members of the Scientific Committee who prepared a summary of the currently available information, relevant for each question, after the review and grading of the existing scientific literature. The summaries were presented to a Jury, also called multidisciplinary Consensus Panel, who drafted a series of recommendations.The prevalence of HPV in males ranges between 1.3--72.9%. The prevalence curve in males is much higher than that in females and does not tend to decline with age. Women appear to have a higher probability of acquiring HPV genotypes associated with a high oncogenic risk, whereas in males the probability of acquiring low- or high-risk genotypes is similar. The HPV-related diseases that affect males are anogenital warts and cancers of the penis, anus and oropharynx. The quadrivalent vaccine against HPV has proved to be effective in preventing external genital lesions in males aged 16--26 years in 90.4% (95% CI: 69.2--98.1) of cases. It has also proved to be effective in preventing precancerous anal lesions in 77.5% (95% CI: 39.6--93.3) of cases in a per-protocol analysis and in 91.7% (95% CI: 44.6--99.8) of cases in a post-hoc analysis. Early ecological studies demonstrate reduction of genital warts in vaccinated females and some herd immunity in males when vaccine coverage is high, although males who have sex with males gained no benefit at all. Males with an immunodeficiency disease are at greater risk of developing disease. Infertility seems to be caused by HPV in some cases. Studies demonstrate vaccination to both genders can be more efficacious and social equity matters are to be taken into consideration.The Jury made Recommendations based on the scientific evidence presented by the Scientific Committee. Accordingly, for prevention purposes and social fairness and equality, as both sexes are affected by the disease, the vaccination of 12-year-old males against HPV should be recommended in order
Update on perioperative management of the child with asthma
Francesco Dones,Grazia Foresta,Vincenzo Russotto
Pediatric Reports , 2012, DOI: 10.4081/pr.2012.e19
Abstract: Asthma represents the leading cause of morbidity from a chronic disease among children. Dealing with this disease during the perioperative period of pediatric surgical procedures is, therefore, quite common for the anesthesiologist and other professionalities involved. Preoperative assessment has a key role in detecting children at increased risk of perioperative respiratory complications. For children without an optimal control of symptoms or with a recent respiratory tract infection elective surgery should be postponed, if possible, after the optimization of therapy. According to clinical setting, loco-regional anesthesia represents the desirable option since it allows to avoid airway instrumentation. Airway management goals are preventing the increase of airflow resistance during general anesthesia along with avoiding triggers of bronchospasm. When their use is possible, face mask ventilation and laringeal mask are considered more reliable than tracheal intubation for children with asthma. Sevoflurane is the most commonly used anesthetic for induction and manteinance. Salbutamol seems to be useful in preventing airflow resistance rise after endotracheal intubation. Mechanical ventilation should be tailored according to pathophysiology of asthma: an adequate expiratory time should be setted in order to avoid a positive end-expiratory pressure due to expiratory airflow obstruction. Pain should be prevented and promptly controlled with a loco-regional anesthesia technique when it is possible. Potential allergic reactions to drugs or latex should always be considered during the whole perioperative period. Creating a serene atmosphere should be adopted as an important component of interventions in order to guarantee the best care to the asthmatic child.
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