Oncofertility: the importance of counseling for fertility preservation in cancer patients.

Scientific and technological advances in the diagnosis of neoplastic disease and the introduction of increasingly accurate and personalized anti-cancer treatments have significantly improved the chances of survival of most cancer patients, particularly at a young age. Since the interest of the research community in the life prospects of young cancer survivors has been growing, a new branch of medicine has emerged in recent years that reconciles the potentially gonadotoxic treatments of cancer with the preservation of fertility: oncofertility. The possibility of preserving one's fertility can be of great benefit for the psychological well-being of cancer patients, whose mental health is already severely tested by the cancer diagnosis. Although national and international guidelines urge doctors to start early a discussion on fertility conservation issues (reproductive counseling), still little is known as to the awareness of oncofertility by young cancer survivors and the information they receive about it.

CRISPR -Cas9: a groundbreaking new technique which ushers in new prospects and just as many doubts.

Human germline engineering arguably constitutes one of the most promising and at the same time controversial prospects in the realm of gene editing overall, and particularly in the context of the current state of research. The issues raised by such techniques have sparked heated debate worldwide: the scientific and industrial establishments have been strongly supporting CRISPR-Cas9 research, but a well-balanced approach needs to be adopted in order to reconcile the needs of scientific research with the life and dignity of human embryos.

Recombinant PAPP-A resistant insulin-like growth factor binding protein 4 (dBP4) inhibits angiogenesis and metastasis in a murine model of breast cancer.

BACKGROUND: The Insulin-like growth factor (IGF) pathway plays a role in tumour development and progression. In vivo, IGF1 activity is regulated by the IGF binding proteins (IGFBPs). IGFBP4 inhibits the activity of IGF1 but proteolytic cleavage by pregnancy-associated plasma protein-A (PAPP-A) releases active IGF1. A modified IGFBP4, dBP4, which was resistant to PAPP-A cleavage but retained IGF1 binding capacity, was engineered, expressed in Human Embryonic Kidney (HEK) 293 cells and purified. This study examined the effects of dBP4 on IGF1-induced cell migration, invasion and angiogenesis in vitro. The effect of intra-tumour injections of dBP4 on tumour angiogenesis and metastasis was examined using the 4T1.2luc orthotopic model of breast cancer. METHODS: PAPP-A resistance and IGF binding capacity of dBP4 were characterized by Western blot and surface plasmon resonance, respectively. 4T1.2luc are mouse mammary adenocarcinoma cells transfected with luciferase to allow in vivo imaging. The effect of dBP4 on IGF1-induced Akt activation in 4T1.2luc cells was assessed by Western blot. Cell migration and invasion assays were performed using 4T1.2luc cells. Angiokit™ assays and Matrigel® implants were used to assess the effects of dBP4 on angiogenesis in vitro and in vivo, respectively. An orthotopic breast cancer model - 4T1.2luc cells implanted in the mammary fat pad of BALB/c mice - was used to assess the effect of intra tumour injection of purified dBP4 on tumour angiogenesis and metastasis. Tumour growth and lung metastasis were examined by in vivo imaging and tumour angiogenesis was evaluated by CD31 immunohistochemistry. RESULTS: Our engineered, PAPP-A resistant IGFBP4 (dBP4) retained IGF1 binding capacity and inhibited IGF1 activation of Akt as well as IGF1-induced migration and invasion by 4T1.2 mammary adenocarcinoma cells. dBP4 inhibited IGF1-induced angiogenesis in vitro and in Matrigel implants in vivo. Direct intra-tumour injection of soluble dBP4 reduced angiogenesis in 4T1.2 luc mammary tumours tumour and reduced lung metastasis. CONCLUSION: A PAPP-A resistant IGFBP4, dBP4, inhibits angiogenesis and metastasis in 4T1.2 mammary fat pad tumours. This study highlights the therapeutic potential of dBP4 as an approach to block the tumour-promoting actions of IGF1.

Reproductive medicine between advancement and ethics.

Over the past five decades, sweeping changes have occurred in the realm of childbirth. Thanks to medically assisted procreation, child- birth as an event has come to be characterized by the interweaving of biological as well as social elements. Research has been forging ahead, the first uterus transplant has been carried out and the experimental cloning of apes has taken place in China. All such innovations entail a wide array of ethical and medical issues, involving different parties in the process of generating new life: parents, children and gamete donors.

A 15 years survey for dental malpractice claims in Rome, Italy.

INTRODUCTION: In recent years, dental malpractice claims seems to have increased dramatically worldwide without a clear explanation. The aim of our work is to shed more light on this phenomenon to better understand its magnitude and trend, and to point out possible critical factors that, if changed, can mitigate it. MATERIAL AND METHOD: 458 cases of dental malpractice sentenced by the civil court of Rome, Italy, from 2001 to 2015, were collected. Useful information was extracted, reported in a grid and statistically analyzed. Data was compared between years and overall evaluated. RESULTS: Multiple information were obtained, among which: the number of dental malpractice claims has decreased in most recent years; Dental professionals are found guilty in 74% of cases; the average compensation granted is 18.820,15 €; only 47,7% of the insured dentist found guilty was fully covered by their insurance. CONCLUSIONS: Contrary to what we expected, dental malpractice claims in court have decreased in recent years. The limit liability of dental professional insurances is high compared to the average compensation granted and the insurance doesn't always cover all the expenses for the presence of peculiar clauses in the contract.

Medical advancements: emergency contraception (EC). Medico-legal implications of EC on adolescents.

The article's main focus is documenting what the best options are in order to make sure that minors are allowed to play a key role in the management of issues arising from the use of emergency contraception. In that regard, there is a lack of clean-cut legislative measures and, although there are several legal and ethical norms designed to get parents or legal guardians involved in such decisions, there seems to be an increasingly widespread tendency to give weight to the minor's will, thus acknowledging her decision-making capacity. Lastly, the paper's authors undertake a thorough examination as to what the duties of doctors are, and the measures that need to be put in place in order to safeguard the minor patients' conditions. They arrive at the conclusion that emergency contraception is suitable for minors even in absence of the stated consent from their parents or guardians, but it is of utmost importance to implement adequate measures aimed at the provision of proper care, prevention and education.

Cosmetic surgery for children and adolescents. Deontological and bioethical remarks.

The only interventions deemed ethically acceptable are those that serve the "objective interest" of the minors involved from the standpoint of and conducive to sound mental health and balance in a patient's teenage years; by the same token, disproportionate interventions (e.g. overly invasive or pointlessly risky), or all those deemed unsuitable with regards to a poor cost-benefit ratio are viewed as unacceptable. In the process of considering the best interest of the minors involved, a wide array of factors come into play, such as: age, maturity, psychological and emotional conditions, motivations put forth by the underage patient, the opportunity to procrastinate the operation: parents, who are naturally entitled to give consent to the surgical procedures, and physicians are primarily liable to safeguard and act in the minor's best interest. The authors attempt to lay out how medical science has evolved over the past century, and aim to set forth an array of considerations centered on cosmetic surgery for adolescents.

2014-2017. How medically assisted reproduction changed in Italy. A short comparative synthesis with European countries.

More than ten years after law n. 40 of February 19, 2004 became effective, regulation on medically assisted reproduction has dramatically changed outlook. The authors report on the steps that led to these changes through Courts' rulings, the Supreme Court's verdicts and the European Court of Human Rights' decisions, as well as ministerial regulations and guidelines concerning medically assisted reproduction. The aforementioned jurisprudential evolution was set to reach a new balance between the embryo's right to its own dignity and the woman's right to health and freedom of self-determination in reproduction. No court ruling denies that embryos have also to be safeguarded. In fact, there are still numerous prohibitions, including using embryos for experimental purposes. Judges aim primarily at avoiding that embryos' rights overcome the right to parenthood. The authors review the legislation of the various European countries: some have adopted a legislation to regulate medically assisted reproduction, while others have developed in this field some recommendations or guidelines. This is why they call for enactment of a European law governing the implementation/operational methods of medically assisted reproduction in order to avoid the scourge of procreative tourism to countries that have a more permissive law.

The role of fillers in aesthetic medicine: medico-legal aspects.

In recent years there has been an exponential increase of fillers use in aesthetic medicine. The popularity of this anti-wrinkle product is based on their capacity to offer significant improvement in the aesthetic field, particularly to skin rejuvenating processes with non-invasive and less expensive techniques, if compared to the surgical methods (i.e. surgical lifting). The great number of fillers on the market is composed of a large heterogenic number of biomaterials. The aim of this review was to provide an overview and a classification of the filling materials that are most commonly used. A synthesis of the literature concerning fillers and related side effects was also reported. The law decree no. 23 of 1998, converted in the law no. 94 of 1998 and the principal judgments of the Italian Court of Cassation have been examined with the medico-legal issues related to fillers use in medicine. With respect to their degradation, filler materials may be classified as temporary (degradable), semi-permanent and permanent (not degradable). The temporary fillers such as hyaluronic acid and collagen are completely degraded by the surrounding tissue in a few months. The permanent fillers, such as the ones derived from silicon oil and minerals are not biodegradable and may cause serious and irreversible side effects. Their use requires a physician with a high level of specialization to perform the treatment, a deep knowledge of face anatomy and a great degree of experience.

Clinical applications of sodium oxybate (GHB): from narcolepsy to alcohol withdrawal syndrome.

Gamma-hydroxybutyrate (GHB) is a short chain fatty acid endogenously produced within the central nervous system (CNS) and acts as a precursor and metabolite of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Although, it is an illegal recreational drug of abuse, its sodium salt (sodium oxybate) has been utilized as a medication for a number of medical conditions. The first aim of this review was to focus on current applications of sodium oxybate for the treatment of narcolepsy, with a particular emphasis on the key symptoms of this disorder: cataplexy and excessive daytime sleepiness (EDS). Secondly, the effectiveness of sodium oxybate therapy for the treatment of alcohol withdrawal syndrome (AWS) and the maintenance of alcohol abstinence has been assessed. Nowadays, sodium oxybate is the first-line treatment for narcolepsy and it is highly effective in meliorating sleep architecture, decreasing EDS and the frequency of cataplexy attacks in narcoleptic patients. Sodium oxybate currently finds also application in the treatment of AWS and the maintenance of alcohol abstinence in alcoholics. Most of the studies evaluating the efficacy of GHB in the treatment of AWS use a dosage of 50 mg/kg divided in three or four administrations per day. Human studies showed that GHB (dose of 50 mg/kg, divided in three administrations per day) is capable to increase the number of abstinent days, reduce alcohol craving and decrease the number of drinks per day. However, there is limited randomized evidence and, thus, GHB cannot be reliably compared to clomethiazole or benzodiazepines. Some randomized data suggest that GHB is better than naltrexone and disulfiram regarding abstinence maintenance and prevention of craving in the medium term i.e. 3-12 months. It is recommended that GHB should be used only under strict medical supervision, since concerns about the abuse/misuse of the drug and the addiction potential have been arisen.

Mephedrone related fatalities: a review.

OBJECTIVE: Synthetic cathinones are an emerging class of designer drugs abused of due to their psychostimulant and hallucinogenic effects, similar to those of cocaine, methylenedioxymethamphetamine (MDMA), amphetamines and methamphetamines. Mephedrone is a cathinone analogue (4-methyl aromatic analogue of methcathinone) that was reported to be implicated in several fatalities in the media across Europe, but only a few have actually resulted in mephedrone cited as the cause of death. In this paper, we aim to systematically review analytically confirmed cases of mephedrone-related fatalities. MATERIALS AND METHODS: Relevant scientific articles were identified from Medline, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE and Google Scholar, through May 2015 using the following keywords: "Mephedrone", "fatal intoxication," "fatalities", "acute intoxication" and "death". RESULTS: In total, 10 citations met the criteria for inclusion, representing 18 fatal cases with analytically confirmed mephedrone in biological sample/s of the deceased. The death was attributed to mephedrone intoxication in 9 cases (range of post-mortem blood mephedrone concentration: 1.33-22 mg/L), whereas multiple drug toxicity, involving mephedrone was cited as cause of death in 6 cases (range of post-mortem blood mephedrone concentration: 0.04-1.3 mg/L). CONCLUSIONS: Data suggest that the abuse of mephedrone remains to be a public health issue. Mephedrone appears to have a rather narrow therapeutic window that makes its use dangerous. Dosages which supposedly fall within recreational use limits could also lead to death when combined with other drugs in certain circumstances. Forensic Toxicology laboratories must assess their testing procedures to ensure they can achieve both an appropriate screening regime and targeted quantitative analysis for the detection of mephedrone in various biological matrices.

Neutral loss and precursor ion scan tandem mass spectrometry for study of activated benzopyrene-DNA adducts.

Methodology for detection of activated benzo[a]pyrene (B[a]P)-nucleoside adducts by liquid chromatography-tandem mass spectrometry is reported. Adducts of B[a]P-dihydrodiol epoxide (B[a]PDE) with guanosine and adenosine have been detected for the first time by use of precursor ion scan and neutral loss scan. B[a]P was then activated by use of UV irradiation and some of the products obtained have been identified by taking advantage of the information obtained for B[a]PDE. Photoactivation has also been carried out in the presence of hydrogen peroxide; this resulted in a higher yield of products with increased production of BaP diones. The reactivity of these compounds toward nucleosides has been tested. The proposed method was successfully used for detection of one stable guanosine-B[a]P dione adduct.

Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer.

BACKGROUND: Insulin-like growth factor 1 (IGF1) promotes breast cancer and disease progression. Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1. METHODS: Expression of IGF pathway components and PAPP-A was assessed by western blot or RT-PCR. IGFBP4 (dBP4) resistant to PAPP-A cleavage, but retaining IGF-binding capacity, was used to block IGF activity in vivo. 4T1.2 mouse mammary adenocarcinoma cells transfected with empty vector, vector expressing wild-type IGFBP4 or vector expressing dBP4 were implanted in the mammary fat pad of BALB/c mice and tumour growth was assessed. Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry. RESULTS: 4T1.2 cells expressed the IGF1R receptor and IGFBP4. PAPP-A was expressed within mammary tumours but not by 4T1.2 cells. Proliferation and vascular endothelial growth factor (VEGF) production by 4T1.2 cells was increased by IGF1(E3R) (recombinant IGF1 resistant to binding by IGFBPs) but not by wild-type IGF1. IGF1-stimulated microvascular endothelial cell proliferation was blocked by recombinant IGFBP4. 4T1.2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild-type IGFBP4. Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis. CONCLUSION: Protease-resistant IGFBP4 blocks IGF activity, tumour growth and angiogenesis.

CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis.

Expression microarray analysis identified CITED1 among a group of genes specifically upregulated in the pubertal mouse mammary gland. At puberty, CITED1 localizes to the luminal epithelial cell population of the mammary ducts and the body cells of the terminal end buds. Generation of CITED1 gene knockout mice showed that homozygous null mutants exhibit retarded mammary ductal growth at puberty and, in addition, dilated ductal structures with a lack of spatial restriction of the subtending branches. Analysis of CITED1 homozygous null and heterozygous null mammary gland gene expression using microarrays suggested that the mammary-specific phenotype seen in the homozygous null females is due to a disturbance in the transcription of a number of key mediators of pubertal ductal morphogenesis. These include estrogen and TGFbeta responsive genes, such as the EGFR/ErbB2 ligand, amphiregulin, whose transcription we suggest is directly or indirectly regulated by CITED1.

Thyroid hormones regulate DNA-synthesis and cell-cycle proteins by activation of PKCalpha and p42/44 MAPK in chick embryo hepatocytes.

The molecular mechanism by which thyroid hormones exert their effects on cell growth is still unknown. In this study, we used chick embryo hepatocytes at different stages of development as a model to investigate the effect of the two thyroid hormones, T3 and T4, and of their metabolite T2, on the control of cell proliferation. We observed that T2 provokes increase of DNA-synthesis as well as T3 and T4, independently of developmental stage. We found that this stimulatory effect on the S phase is reverted by specific inhibitors of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (p42/44 MAPK), Ro 31-8220 or PD 98059. Furthermore, the treatment with thyroid hormones induces the activation of PKCalpha and p42/44 MAPK, suggesting their role as possible downstream mediators of cell response mediated by thyroid hormones. The increase of DNA-synthesis is well correlated with the increased levels of cyclin D1 and cdk4 that control the G1 phase, and also with the activities of cell-cycle proteins involved in the G1 to S phase progression, such as cyclin E/A-cdk2 complexes. Interestingly, the activity of cyclin-cdk2 complexes is strongly repressed in the presence of PKC and p42/44 MAPK inhibitors. In conclusion, we demonstrated that the thyroid hormones could modulate different signaling pathways that are able to control cell-cycle progression, mainly during G1/S transition.