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Adequate androgen levels are necessary for regular follicular growth, progression beyond the pre-antral stage, and prevention of follicular atresia. The main purpose of this study was to investigate whether baseline androgen levels had a predictive value on stimulation outcomes in IVF cycles. The secondary purpose was to compare the possible predictive value of androgens with that of already known markers.The study included 91 infertile patients aged 30-45 years awaiting the first IVF cycle. All women underwent the same stimulation protocol and the same starting dose of recombinant FSH. As stimulation outcomes, the number of follicles recruited, estradiol and progesterone levels on the day of trigger, the total dose of gonadotropins administered, and the number of oocytes collected were recorded. Multiple linear regression and multivariate logistic regression were used to evaluate the significant predictive value of the variables for response to controlled ovarian stimulation (COS). By studying the reliability of different markers, an attempt was made to develop a single index with the highest predictive value.Pearson's correlation revealed a statistically significant inverse correlation between oocytes collected and age (r = - 0.333, p 0.001) and a positive correlation with AMH (anti-müllerian hormone) (r = 0.360, p 0.001), antral follicle count (AFC) (r = 0.639, p 0.001), and androstenedione (Δ4-A) (r = 0.359, p 0.001). No significant correlation was reported with FSH (r = - 0.133, p = 0.207) and total testosterone (r = 0.180, p = 0.088). In COS good responders, the G-index (= AMH ng/mL*AFC/Δ4-A ng/dL) revealed a significantly higher level (p 0.001) than AMH, AFC, and Δ4-A alone.Baseline serum Δ4-A, presumably crucial for ensuring a regular follicular growth, is a reliable marker of ovarian response to stimulation. Since the ovarian capacity to respond to gonadotropins does not depend exclusively on the presence of follicles, we suggest a new index, the G-index, able to contemplate both the ovarian reserve and the Δ4-A level.

Space environment provides many challenges to pilots, astronauts, and space scientists, which are constantly subjected to unique conditions, including microgravity, radiations, hypoxic condition, absence of the day and night cycle, etc. These stressful stimuli have the potential to affect many human physiological systems, triggering physical and biological adaptive changes to re-establish the homeostatic state. A particular concern regards the risks for the effects of spaceflight on the central nervous system (CNS), as several lines of evidence reported a great impact on neuroplasticity, cognitive functions, neurovestibular system, short-term memory, cephalic fluid shift, reduction in motor function, and psychological disturbances, especially during long-term missions. Aside these potential detrimental effects, the other side of the coin reflects the potential benefit of applicating space-related conditions on Earth-based life sciences, as cancer research. Here, we focused on examining the effect of real and simulated microgravity on CNS functions, both in humans and in cellular models, browsing the different techniques to experience or mime microgravity on-ground. Increasing evidence demonstrate that cancer cells, and brain cancer cells in particular, are negatively affected by microgravity, in terms of alteration in cell morphology, proliferation, invasion, migration, and apoptosis, representing an advancing novel side of space-based investigations. Overall, deeper understandings about the mechanisms by which space environment influences CNS and tumor biology may be promisingly translated into many clinical fields, ranging from aerospace medicine to neuroscience and oncology, representing an enormous pool of knowledge for the implementation of countermeasures and therapeutic applications.

Simple Summary Glioblastoma is the most aggressive primary brain tumor, with the highest incidence and the worst prognosis. Life expectancy from diagnosis remains dismal, at around 15 months, despite surgical resection and treatment with radiotherapy and chemotherapy. Given the aggressiveness of the tumor and the inefficiency of the treatments adopted to date, the scientific research investigates innovative therapeutic approaches. Importantly, angiogenesis represents one of the main features of glioblastoma, becoming in the last few years a major candidate for target therapy. Metformin, a well-established therapy for type 2 diabetes, offered excellent results in preventing and fighting tumor progression, particularly against angiogenic mechanisms. Therefore, the purpose of this review is to summarize and discuss experimental evidence of metformin anti-cancer efficacy, with the aim of proposing this totally safe and tolerable drug as add-on therapy against glioblastoma. Abstract Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin’s potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.

"Add-on" procedures are actively promoted on some fertility clinic websites as proven means to improve IVF success rates, especially for couples with repeated implantation/IVF failures. However, the actual contribution of these interventions to live birth rates remains inconclusive. At present, little is known about the type and quality of the information provided on the IVF clinics' websites regarding the merits of "add-ons." A systematic evaluation of the quality of information on "add-on" procedures in fertility clinic websites was performed using 10-criteria structured questionnaire. We included English language websites that presented in the Google.com search engine after typing the following key-words:"endometrial scratching"(ES), "intralipid infusions"(ILI), "assisted hatching"(AHA), "PGT-A," or "PGS". In total, 254 websites were evaluated. In most cases, an accurate description of the "add-on" procedures was provided (78.8%). However, only a minority (12%) reported their undetermined effectiveness. The use of PGT-A was more often encouraged (52.8%) than ES (23.6%) and AHA (16%). The cost was infrequently presented (6.9%). Scientific references were only rarely provided for ILI, versus 12.7% for ES, 4.0% for AHA, and 5.6% for PGT-A. The information entry date was often missing. None of the websites reported the clinic's pregnancy-rate following the "add-on" procedures. Information on "add-ons" available to patients from IVF clinic websites is often inaccurate. This could perpetuate false myths among infertile patients about these procedures and raises concern regarding possible commercial bias. It is imperative that IVF clinic websites will better communicate the associated risks and uncertainties of "add-ons" to prospective patients.

To describe a rare case of unilateral massive hydrothorax after controlled ovarian stimulation for IVF and to analyze the diagnostic complexities in a patient lacking both risk factors and typical features of ovarian hyperstimulation syndrome (OHSS). We present a case of a 35-year-old woman suffering from primary infertility due to a severe male factor. Admitted to hospital for dyspnea, the patient initially underwent a thoracentesis. Later, due to the recurrence of massive hydrothorax, permanent pleural drainage was placed. Recognized as a severe manifestation of the OHSS, it was treated by pleural drainage, hydration, albumin perfusion, and management of the intercurrent pregnancy, up to improvement in clinical and hematological laboratory parameters and resolution of pleural effusion and respiratory symptoms. A total of 42 l of pleural fluid was drained during the 40 days of hospitalization. Since the pathogenesis of isolated acute hydrothorax in ovarian stimulation probably lies in the presence of anatomical defects of the diaphragm, this may justify that the relationship between this pathology and the OHSS risk factors may be less close. Massive pleural effusion may exceptionally be the only clinical presentation of OHSS. A high index of suspicion is necessary to make the correct diagnosis and to promptly administer treatment.

The hypoglycemic properties of curcumin supplements in therapeutic doses are well-known and may represent a useful tool for the treatment of chronic diseases such as metabolic syndrome, insulin resistance and type 2 diabetes. The poor bioavailability of curcumin can be improved with the concomitant administration of piperine, with no severe adverse effects on glycemia reported so far in the literature. In this article, we further discuss a previously reported case of a helicopter pilot, affected by grade I obesity who, under curcumin and piperine treatment, experienced a transient loss of consciousness (TLOC), during a low-altitude flight. This episode led to a diagnosis of insulinoma, previously asymptomatic. We hypothesized that the combined effects of curcumin and piperine might have caused a severe hypoglycemic episode and subsequent TLOC. Therefore, further studies should be conducted to evaluate the safety of curcumin and piperine supplementation in subjects with impaired glucose metabolism and insulin secretion.

A 50-year-old man who worked as a helicopter rescue pilot transiently lost consciousness while piloting a helicopter rescue. In the diagnostic process, all tests for the main possible differential diagnoses of loss of consciousness (cardiological and neurological) were performed and yielded normal results. Blood chemistry tests revealed recurrent fasting hypoglycemia and Chromogranin A was at the upper limit of normal. Fine needle aspiration guided by endoscopic ultrasonography was used to diagnose insulinoma-type neuroendocrine tumor of the pancreas. According to the Italian policies, the occupational physician aims to maintain professional skills without neglecting flight safety. A careful analysis of the relationship between the characteristics of the state of health of the aviator and his specific work needs was carried out, and he was given the opportunity to continue working as a rescue pilot thanks to medical therapies associated with organizational interventions in the workplace.

"Add-on" procedures are actively promoted on some fertility clinic websites as proven means to improve IVF success rates, especially for couples with repeated implantation/IVF failures. However, the actual contribution of these interventions to live birth rates remains inconclusive. At present, little is known about the type and quality of the information provided on the IVF clinics' websites regarding the merits of "add-ons." A systematic evaluation of the quality of information on "add-on" procedures in fertility clinic websites was performed using 10-criteria structured questionnaire. We included English language websites that presented in the Google.com search engine after typing the following key-words:"endometrial scratching"(ES), "intralipid infusions"(ILI), "assisted hatching"(AHA), "PGT-A," or "PGS". In total, 254 websites were evaluated. In most cases, an accurate description of the "add-on" procedures was provided (78.8%). However, only a minority (12%) reported their undetermined effectiveness. The use of PGT-A was more often encouraged (52.8%) than ES (23.6%) and AHA (16%). The cost was infrequently presented (6.9%). Scientific references were only rarely provided for ILI, versus 12.7% for ES, 4.0% for AHA, and 5.6% for PGT-A. The information entry date was often missing. None of the websites reported the clinic's pregnancy-rate following the "add-on" procedures. Information on "add-ons" available to patients from IVF clinic websites is often inaccurate. This could perpetuate false myths among infertile patients about these procedures and raises concern regarding possible commercial bias. It is imperative that IVF clinic websites will better communicate the associated risks and uncertainties of "add-ons" to prospective patients.

The severity of coronavirus disease 2019 (COVID‐19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine‐1‐phosphate (S1P) along with severity markers, in COVID‐19 patients. One hundred eleven COVID‐19 patients and forty‐seven healthy subjects were included. The severity of COVID‐19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil‐to‐lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C‐reactive protein (CRP), and D‐dimer. Serum S1P level was inversely associated with COVID‐19 severity, being significantly correlated with CRP, LDH, ferritin, and D‐dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient’s outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID‐19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID‐19.

Simple Summary Glioblastoma is the most common and malignant primary brain tumor, with a median survival of around 14 months. The aggressiveness of glioblastoma is due to intense cell proliferation, angiogenesis, invasiveness, genetic instability, resistance to therapies and high frequency of relapses. These features render glioblastoma almost incurable, considered an extreme therapeutic challenge. In the last few decades, it has been observed a reduced cancer incidence in diabetic patients treated with metformin, an oral hypoglycemic drug. The reported ability of metformin to arrest cancer cell growth in in vitro and in vivo experimental tumor models, have suggested the possibility to reconsider metformin as an anti-cancer add-on therapy, but further investigations about molecular mechanisms and optimal therapeutic regimens are needed. Here, we tested the efficacy of metformin against primary glioblastoma endothelial cells, responsible for tumor angiogenesis, invasiveness and resistance to therapy, reporting promising results and advancing a novel target of metformin, the "sphingolipid rheostat". Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. Methods: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. Results: Data resulting revealed a time- and mu-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. Conclusions: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.

Background: Since December 2019, COVID-19 has widely spread throughout the world, causing thousands of deaths. Clinical characteristics of COVID-19 patients have been widely reported, but significative disease-associated biomarkers are needed. We aimed to evaluate the prognostic power of circulating sphingosine-1-phosphate (S1P) in COVID-19, to propose S1P as a novel prognostic and predictive biomarker. Methods: Clinical and blood parameters were investigated in 111 COVID-19 patients (COV) and 47 healthy subject (HLT), with a particular focus on patients who required intensive care unit (ICU) admission. We measured serum levels of S1P and its main transporter apolipoprotein M (apoM) by ELISA assay. Correlation with clinical and blood parameters were performed by Pearson correlations. Univariable and multivariable regression analysis were performed to assess the interaction between clinically significant factors and ICU admission. Further, Cox regression was used to evaluate the prognostic power of S1P for ICU admission and mortality. Findings: We reported statistically significant alterations of several blood parameters in COV, as an increase of white blood cells, neutrophil-to-lymphocyte ratio, ferritin, D-dimer and fibrinogen, and a decrease in hemoglobin, lymphocyte count and total proteins. Our major finding is the drop of serum S1P level in COV, strongly associated with the decrease of red blood cells, the major source of plasmatic S1P, and both apoM and albumin, the most important transporters of circulating S1P. The multivariable regression analysis revealed that S1P is the most important predictor for ICU admission (OR:39·45, [95%CI:1·51-1031·60]; p=0·027), and Cox proportional-hazards model demonstrated a high power of S1P in predicting patient’s outcome. Interpretation: COVID-19 patients showed a drastic decrease of serum S1P, suggesting that circulating S1P levels may be clinically used as negative biomarkers to predict severity/mortality of COVID-19. Taken together, our results suggest that restoring S1P at physiological level may represent a novel therapeutic strategy. Funding: Italian Ministry of Health. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement:This prospective, case-control study was approved by the Ethic Committee of Ospedale San Paolo in Milan, Lombardy, Italy (COST Action n.2020/ST/057).

Beckwith-Wiedemann syndrome (BWS) is a clinically and genetically heterogeneous overgrowth disease. BWS is caused by (epi)genetic defects at the 11p15 chromosomal region, which harbors two clusters of imprinted genes, IGF2/H19 and CDKN1C/KCNQ1OT1, regulated by differential methylation of imprinting control regions, H19/IGF2:IG DMR and KCNQ1OT1:TSS DMR, respectively. A subset of BWS patients show multi-locus imprinting disturbances (MLID), with methylation defects extended to other imprinted genes in addition to the disease-specific locus. Specific (epi)genotype-phenotype correlations have been defined in order to help clinicians in the classification of patients and referring them to a timely diagnosis and a tailored follow-up. However, specific phenotypic correlations have not been identified among MLID patients, thus causing a debate on the usefulness of multi-locus testing in clinical diagnosis. Finally, the high incidence of BWS monozygotic twins with discordant phenotypes, the high frequency of BWS among babies conceived by assisted reproductive technologies, and the female prevalence among BWS-MLID cases provide new insights into the timing of imprint establishment during embryo development. In this review, we provide an overview on the clinical and molecular diagnosis of single- and multi-locus BWS in pre- and post-natal settings, and a comprehensive analysis of the literature in order to define possible (epi)genotype-phenotype correlations in MLID patients.

To investigate the association between polycystic ovary syndrome (PCOS) and psychological disturbances, including anger. To analyze whether the biochemical/phenotypical features of PCOS play a role in the type and severity of psychological disorders.This case-control study included 30 PCOS patients meeting NIH criteria and 30 non-PCOS women referring to Reproductive Medicine Unit for infertility. Complete clinical and biochemical screening and the self-reported psychological data [Symptom Check List 90-R (SCL-90-R); Short-Form Health Survey 36 (SF-36); and State-Trait Anger Expression Inventory-2 (STAXI-2)] were collected. Statistical analyses were performed with SPSS-21.Compared with control women, women with PCOS reported significantly higher scores on SCL-90-R scales of somatization, anxiety, hostility, psychoticism, overall psychological distress and a number of symptoms. At STAXI-2, patients with PCOS scored higher in trait-anger and in the outward expression of anger, while lower in outward anger-control; PCOS patients had significantly lower scores on SF-36 scales of physical functioning and bodily pain. Hirsutism was directly associated with anxiety. Regarding the associations between phenotypical/biochemical features and psychological distress in PCOS patients, results showed that waist-to-hip ratio is inversely related to anxiety, psychoticism, hostility and to the indexes of psychological distress; such inverse relationship was also seen between plasmatic levels of testosterone and trait-anger, and between total cholesterol and hostility.Results were consistent with the previous literature on the well-being of PCOS women (in particular for anxiety and quality of life [QoL]) but failed to find evidence for depression. The relationship between psychological distress and the features of the syndrome highlighted the role of hirsutism. With respect to hyperandrogenemia, our data rejected its involvement in the elevated negative mood states and affects. Adopting an interdisciplinary approach in the PCOS patients' care, anger showed to be common and deserves major consideration.

Macrophage migration inhibitory factor (MIF) was discovered as an activated T-lymphocyte-derived protein that inhibits the random migration of macrophages in vitro. Subsequently, knowledge of the physiological actions of MIF was extended to include its role as a proinflammatory cytokine that affects several functions of macrophages and lymphocytes. Previous reports have suggested an involvement of MIF in reproduction. However, no data are currently available on the presence of this cytokine in the human endometrium. In this study, the expression and tissue localization of MIF was evaluated in specimens of cycling endometrium, first trimester placenta bed biopsy, and isolated endometrial glands by Western blot analysis, immunohistochemistry, ELISA, and reverse transcription-polymerase chain reaction. The results demonstrated that MIF is expressed in human endometrium across the menstrual cycle and in early pregnancy. Immunohistochemical localization identified the protein in glandular epithelium, in stromal and predecidualized stromal cells of cycling endometrium, as well as in the decidua of first-trimester placenta. The proinflammatory features and specific actions of MIF on lymphoid cells suggest its potential involvement in several aspects of endometrial physiology.

Objective To investigate the expression of prolactin (PRL), PRL-receptor (PRL-R), and the T H 1 cytokines interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) at the maternofetal interface. Design Case-control study. Setting University hospital unit of gynecology and obstetrics and research laboratories. Patient(s) Women undergoing suction curettage for spontaneous miscarriage (study group) and voluntary termination of pregnancy (control group) in the first trimester. Intervention(s) Samples of decidua and villi collected and histologically examined at the time of suction curettage. Main Outcome Measure(s) Evaluation of all villous samples for karyotype with only euploid cases included; detection of transcripts of PRL, PRL-R, TNF-α, IFN-γ, and IL-2 by qualitative reverse-transcriptase-polymerase chain reaction (RT-PCR); investigation of pattern and site of expression by immunohistochemistry. Result(s) In both groups, PRL-R and IFN-γ were broadly expressed. The expression of PRL was impaired or absent in the villi of the study group compared with controls. Expression of TNF-α was reduced, although not statistically significantly, in both decidual and villous samples of the study group. Immunohistochemical analysis showed the lack of IL-2 expression in decidual specimens of the control group versus the full expression shown in the study group. Conclusion(s) Our results highlight the correspondence between PRL expression and vital pregnancy and the involvement of the T H 1 cytokines with different specific roles at the implantation site. Prolactin and IL-2 may reciprocally influence expression.

BACKGROUND: Animal models and experimental studies suggest a role for paracrine prolactin (PRL) signalling in decidualization and embryo implantation. We investigated the expression of endometrial prolactin (e-PRL) and prolactin receptor (PRL-R) in the endometrium of women affected by unexplained infertility (UI) and repeated miscarriages (RM). METHODS: Patients (n 5 24) were divided into three groups: RM, n 5 5; UI, n 5 11; controls, n 5 8. Endometrial samples were collected at the time of hysteroscopy in the late luteal phase. The presence of transcripts of e-PRL and PRL-R was investigated by qualitative RT –PCR. Pattern and site of expression of e-PRL were studied by immunohistochemistry. RESULTS: PRL-R mRNA was detected in all endometrial samples of the three groups. PRL gene expression was detected in all control samples, only in three of five samples of the RM group and in four of 11 samples of the UI group. RT –PCR results were largely confirmed by immunohistochemistry, study groups showing a defect of expression of e-PRL. CONCLUSIONS: In this pilot study we report a lack of expression of endometrial prolactin during the ‘implantation window’ in some patients affected by unexplained infertility and repeated miscarriages. These data, in association with those obtained in experimental animals, suggest that the lack of endometrial PRL expression is involved in reproduction failure.