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Background and objectives: To explore the ethical and legal complexities arising from the controversial issue of surrogacy, particularly in terms of how they affect fundamental rights of children and parents. Surrogacy is a form of medically-assisted procreation (MAP) in which a woman “lends” her uterus to carry out a pregnancy on behalf of a third party. There are pathological conditions, such as uterine agenesis or hysterectomy outcomes, that may prevent prospective mothers from becoming pregnant or carry a pregnancy to term; such patients may consider finding a surrogate mother. Many issues relating to surrogacy remain unresolved, with significant disagreements and controversy within the scientific community and public opinion. There are several factors called into play and multiple parties and stakeholders whose objectives and interests need to somehow be reconciled. First and foremost, the authors contend, it is essential to prioritize and uphold the rights of children born through surrogacy and heterologous MAP. Materials and methods: To draw a parallel between Italy and the rest of the world, the legislation in force in twelve European countries was analyzed, eleven of which are part of the European Union (France, Germany, Italy, Spain, Greece, Netherlands, Belgium, Denmark, Lithuania, Czech Republic and Portugal) and three non-members of the same (United Kingdom, Ukraine and Russia), as well as that of twelve non-European countries considered exemplary (United States, Canada, Australia, India, China, Thailand, Israel, Nigeria and South Africa); in particular, legislative sources and legal databases were drawn upon, in order to draw a comparison with the Italian legislation currently in force and map out the evolution of the Italian case law on the basis of the judgments issued by Italian courts, including the Constitutional and Supreme Courts and the European Court of Human Rights (ECHR); search engines such as PubMed and Google Scholar were also used, by entering the keywords “surrogacy” and “surrogate motherhood”, to find scientific articles concerning assisted reproduction techniques with a close focus on surrogacy. Results: SM is a prohibited and sanctioned practice in Italy; on the other hand, it is allowed in other countries of the world, which leads Italian couples, or couples from other countries where it is banned, to often contact foreign centers in order to undertake a MAP pathway which includes surrogacy; in addition, challenges may arise from the legal status of children born through surrogacy abroad: to date, in most countries, there is no specific legislation aimed at regulating their legal registration and parental status. Conclusion: With reference to the Italian context, despite the scientific and legal evolution on the subject, a legislative intervention aimed at filling the regulatory gaps in terms of heterologous MAP and surrogacy has not yet come to fruition. Considering the possibility of “fertility tourism”, i.e., traveling to countries where the practice is legal, as indeed already happens in a relatively significant number of cases, the current legislation, although integrated by the legal interpretation, does not appear to be effective in avoiding the phenomenon of procreative tourism. Moreover, to overcome some contradictions currently present between law 40 and law 194, it would be appropriate to outline an organic and exhaustive framework of rules, which should take into account the multiplicity of interests at stake, in keeping with a fair and sustainable balance when regulating such practices.

Endometrial cancer (EC) has been classified over the years, for prognostic and therapeutic purposes. In recent years, classification systems have been emerging not only based on EC clinical and pathological characteristics but also on its genetic and epigenetic features. Noncoding RNAs (ncRNAs) are emerging as promising markers in several cancer types, including EC, for which their prognostic value is currently under investigation and will likely integrate the present prognostic tools based on protein coding genes. This review aims to underline the importance of the genetic and epigenetic events in the EC tumorigenesis, by expounding upon the prognostic role of ncRNAs.

Infertility is a global health issue affecting women and men of reproductive age with increasing incidence worldwide, in part due to greater awareness and better diagnosis. Assisted reproduction technologies (ART) are considered the ultimate step in the treatment of infertility. Recently, artificial intelligence (AI) has been progressively used in the many fields of medicine, integrating knowledge and computer science through machine learning algorithms. AI has the potential to improve infertility diagnosis and ART outcomes estimated as pregnancy and/or live birth rate, especially with recurrent ART failure. A broad-ranging review has been conducted, focusing on clinical AI applications up until September 2022, which could be estimated in terms of possible applications, such as ultrasound monitoring of folliculogenesis, endometrial receptivity, embryo selection based on quality and viability, and prediction of post implantation embryo development, in order to eliminate potential contributing risk factors. Oocyte morphology assessment is highly relevant in terms of successful fertilization rate, as well as during oocyte freezing for fertility preservation, and substantially valuable in oocyte donation cycles. AI has great implications in the assessment of male infertility, with computerised semen analysis systems already in use and a broad spectrum of possible AI-based applications in environmental and lifestyle evaluation to predict semen quality. In addition, considerable progress has been made in terms of harnessing AI in cases of idiopathic infertility, to improve the stratification of infertile/fertile couples based on their biological and clinical signatures. With AI as a very powerful tool of the future, our review is meant to summarise current AI applications and investigations in contemporary reproduction medicine, mainly focusing on the nonsurgical aspects of it; in addition, the authors have briefly explored the frames of reference and guiding principles for the definition and implementation of legal, regulatory, and ethical standards for AI in healthcare.

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Risk factors for EC include metabolic alterations (obesity, metabolic syndrome, insulin resistance), hormonal imbalance, age at menopause, reproductive factors, and inherited conditions, such as Lynch syndrome. For the inherited forms, several genes had been implicated in EC occurrence and development, such as POLE, MLH1, TP53, PTEN, PIK3CA, PIK3R1, CTNNB1, ARID1A, PPP2R1A, and FBXW7, all mutated at high frequency in EC patients. However, gene function impairment is not necessarily caused by mutations in the coding sequence of these and other genes. Gene function alteration may also occur through post-transcriptional control of messenger RNA translation, frequently caused by microRNA action, but transcriptional impairment also has a profound impact. Here, we review how chromatin modifications change the expression of genes whose impaired function is directly related to EC etiopathogenesis. Chromatin modification plays a central role in EC. The modification of chromatin structure alters the accessibility of genes to transcription factors and other regulatory proteins, thus altering the intracellular protein amount. Thus, DNA structural alterations may impair gene function as profoundly as mutations in the coding sequences. Hence, its central importance is in the diagnostic and prognostic evaluation of EC patients, with the caveat that chromatin alteration is often difficult to identify and needs investigations that are specific and not broadly used in common clinical practice. The different phases of the healthy endometrium menstrual cycle are characterized by differential gene expression, which, in turn, is also regulated through epigenetic mechanisms involving DNA methylation, histone post-translational modifications, and non-coding RNA action. From a medicolegal and policy-making perspective, the implications of using epigenetics in cancer care are briefly explored as well. Epigenetics in endometrial cancer is not only a topic of biomedical interest but also a crossroads between science, ethics, law, and public health, requiring integrated approaches and careful regulation.

Background/Objectives: The effect of metformin on the secretory function of thyrotropic cells is sex-dependent. The current study aimed to investigate whether the impact of this drug on activity of the hypothalamic–pituitary–thyroid axis in women is impacted by the androgen status of patients. Methods: The study population included 48 levothyroxine-naïve reproductive-aged women with subclinical hypothyroidism and prediabetes receiving 3.0 g of metformin daily. Women with (n = 24) and without (n = 24) polycystic ovary syndrome were matched for age, insulin sensitivity, TSH, and reasons for thyroid hypofunction. Circulating levels of glucose, glycated hemoglobin, insulin, TSH, thyroid hormones, gonadotropins, androgens, estradiol, SHBG, prolactin, ACTH, and IGF-1 were measured before metformin treatment and six months later. Results: At entry, women with and without polycystic ovary syndrome differed in LH, LH/FSH ratio, androgens, and estradiol. The decrease in TSH, fasting glucose and glycated hemoglobin, and the improvement in insulin sensitivity were less pronounced in women with than in women without polycystic ovary syndrome. In each group, there were no differences in the impact on TSH and thyroid hormones between patients with subclinical hypothyroidism of autoimmune and non-autoimmune origin. The changes in TSH inversely correlated with total testosterone and free androgen index. Only in women with coexisting polycystic ovary syndrome, did metformin slightly reduce LH, LH/FSH ratio, testosterone, and free androgen index. Conclusions: The results suggest that concurrent polycystic ovary syndrome attenuates metformin action on TSH secretion, which can be explained by increased androgen production. Moreover, the drug seems to alleviate PCOS-associated changes in the activity of the reproductive axis.

There is a rising incidence of infertility worldwide, and many couples experience difficulties conceiving nowadays. Thyroid autoimmunity (TAI) is recognized as one of the major female infertility causes related to a diminished ovarian reserve and potentially impaired oocyte maturation and embryo development, causing adverse pregnancy outcomes. Growing evidence has highlighted its impact on spontaneously achieved pregnancy and pregnancy achieved by in vitro fertilization. Despite the influence of thyroid hormones on the male reproductive system, there is insufficient data on the association between TAI and male infertility. In past years, significant progress has been achieved in cell and gene therapies as emerging treatment options for infertility. Cell therapies utilize living cells to restore healthy tissue microenvironment and homeostasis and usually involve platelet-rich plasma and various stem cells. Using stem cells as therapeutic agents has many advantages, including simple sampling, abundant sources, poor immunogenicity, and elimination of ethical concerns. Mesenchymal Stem Cells (MSCs) represent a heterogeneous fraction of self-renewal, multipotent non-hematopoietic stem cells that display profound immunomodulatory and immunosuppressive features and promising therapeutic effects. Infertility has a genetic component in about half of all cases, although most of its genetic causes are still unknown. Hence, it is essential to identify genes involved in meiosis, DNA repair, ovarian development, steroidogenesis, and folliculogenesis, as well as those involved in spermatogenesis in order to develop potential gene therapies for infertility. Despite advances in therapy approaches such as biological agents, autoimmune disorders remain impossible to cure. Recent research demonstrates the remarkable therapeutic effectiveness of MSCs in a wide array of autoimmune diseases. TAI is one of many autoimmune disorders that can benefit from the use of MSCs, which can be derived from bone marrow and adipose tissue. Cell and gene therapies hold great potential for treating autoimmune conditions, although further research is still needed.

Following isotonitazene scheduling in 2019, the availability of alternative 2-benzylbenzimidazole opioids (nitazenes) on the global drug market increased, resulting in many fatalities worldwide. Nitazenes are potent µ-opioid receptor agonists with strong narcotic/analgesic effects, and their concentrations in biological matrices are low, making the detection of metabolite biomarkers of consumption crucial to document use in clinical and forensic settings. However, there is little to no data on the metabolism of the most recently available nitazenes, especially desnitro-analogues. The aim of the research was to assess isotonitazene, metonitazene, etodesnitazene, and metodesnitazene human metabolism and identify specific metabolite biomarkers of consumption. The four analogues were incubated with 10-donor-pooled human hepatocytes, and the incubates were analyzed by liquid chromatography-high-resolution tandem mass spectrometry and data mining with Compound Discoverer (Thermo Scientific); the analysis was supported by in silico metabolite predictions with GLORYx open-access software. Metabolites were identified in postmortem blood and/or urine samples from two metonitazene-positive and three etodesnitazene-positive cases following the same workflow, with and without glucuronide hydrolysis in urine, to confirm in vitro results. Twelve, nine, twenty-two, and ten metabolites were identified for isotonitazene, metonitazene, etodesnitazene, and metodesnitazene, respectively. The main transformations were N-deethylation at the N,N-diethylethanamine side chain, O-dealkylation, and further O-glucuronidation. In vitro and autopsy results were consistent, demonstrating the efficacy of the 10-donor-pooled human hepatocyte model to predict human metabolism. We suggest the parent and the corresponding O-dealkyl- and N-deethyl-O-dealkyl metabolites as biomarkers of exposure in urine after glucuronide hydrolysis, and the corresponding N-deethyl metabolite as additional biomarker in blood.

Third molar extraction is the most common procedure in oral and maxillofacial surgery. Third molars are considered less functional than other teeth and are often extracted. Sometimes, they are also used for auto-transplantation for the benefit of oral rehabilitation. Since many biological factors are involved in this surgical approach, herein, we outline a review of the biological characteristics of medico-legal/forensic interest, in addition to presenting a successful clinical case. A scoping review of currently available research data (following the principles of PRISMA-ScR or the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) on third molar auto-transplantation was conducted by drawing upon the main databases (Scopus, PubMed, Google Scholar and LILACS) to evaluate biological and clinical characteristics possibly relatable to forensic issues. All the collected data were summarized and elaborated on for the purpose of this article. A patient underwent extraction of the right upper first molar and auto-transplantation of the unerupted ipsilateral third molar. Many biologic and clinical factors are involved in the success of this clinical procedure. Knowledge of third molar anatomy, of its development and viable surgical approaches are all essential elements; just as important are the treatment of the tooth before and after transplantation and the integrity of the periodontal ligament. Follow-up of the clinical case for 5 years made it possible to verify the stability of the procedure over time. Third molar auto-transplantation is feasible and cost-effective. However, the use of third molars as donor teeth in auto-transplantation may have medico-legal implications. The lack of official protocols and consistent evidence-based guidelines for operators still prevent such a procedure from becoming mainstream; therefore, it is viewed with suspicion by clinicians and patients, even though the biological factors herein detected point to a reasonably high degree of safety. The understanding of many specific biological and clinical factors involved in the stability of third molar auto-transplantation allows for a thorough understanding of the forensic implications relevant to clinical practice. Effective communication and information provision are therefore of utmost importance, in the interest of both patients and doctors.

The CRISPR-Cas system is a powerful tool for in vivo editing the genome of most organisms, including man. During the years this technique has been applied in several fields, such as agriculture for crop upgrade and breeding including the creation of allergy-free foods, for eradicating pests, for the improvement of animal breeds, in the industry of bio-fuels and it can even be used as a basis for a cell-based recording apparatus. Possible applications in human health include the making of new medicines through the creation of genetically modified organisms, the treatment of viral infections, the control of pathogens, applications in clinical diagnostics and the cure of human genetic diseases, either caused by somatic (e.g., cancer) or inherited (mendelian disorders) mutations. One of the most divisive, possible uses of this system is the modification of human embryos, for the purpose of preventing or curing a human being before birth. However, the technology in this field is evolving faster than regulations and several concerns are raised by its enormous yet controversial potential. In this scenario, appropriate laws need to be issued and ethical guidelines must be developed, in order to properly assess advantages as well as risks of this approach. In this review, we summarize the potential of these genome editing techniques and their applications in human embryo treatment. We will analyze CRISPR-Cas limitations and the possible genome damage caused in the treated embryo. Finally, we will discuss how all this impacts the law, ethics and common sense.

Breast Cancer (BC) is one of the most common cancer types worldwide, and it is characterized by a complex etiopathogenesis, resulting in an equally complex classification of subtypes. MicroRNA (miRNA or miR) are small non-coding RNA molecules that have an essential role in gene expression and are significantly linked to tumor development and angiogenesis in different types of cancer. Recently, complex interactions among coding and non-coding RNA have been elucidated, further shedding light on the complexity of the roles these molecules fulfill in cancer formation. In this context, knowledge about the role of miR in BC has significantly improved, highlighting the deregulation of these molecules as additional factors influencing BC occurrence, development and classification. A considerable number of papers has been published over the past few years regarding the role of miR-125 in human pathology in general and in several types of cancer formation in particular. Interestingly, miR-125 family members have been recently linked to BC formation as well, and complex interactions (competing endogenous RNA networks, or ceRNET) between this molecule and target mRNA have been described. In this review, we summarize the state-of-the-art about research on this topic.