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Introduction: Glioblastoma IDH -wildtype (GBM) is the most malignant brain tumor in adults, with a poor prognosis of approximately 15 months after diagnosis. Most patients suffer from a recurrence in <1 year, and this renders GBM a life-threatening challenge. Among molecular mechanisms driving GBM aggressiveness, angiogenesis mediated by GBM endothelial cells (GECs) deserves consideration as a therapeutic turning point. In this scenario, calpains, a family of ubiquitously expressed calcium-dependent cysteine proteases, emerged as promising targets to be investigated as a novel therapeutic strategy and prognostic tissue biomarkers., Methods: To explore this hypothesis, GECs were isolated from n=10 GBM biopsies and characterized phenotypically by immunofluorescence. The expression levels of calpains were evaluated by qRT-PCR and Western blot, and their association with patients' prognosis was estimated by Pearson correlation and Kaplan-Meier survival analysis. Calpain targeting efficacy was assessed by a time- and dose-dependent proliferation curve, MTT assay for viability, caspase-3/7 activity, migration and angiogenesis in vitro , and gene and protein expression level modification., Results: Immunofluorescence confirmed the endothelial phenotype of our primary GECs. A significant overexpression was observed for calpain-1/2/3 (CAPN) and calpain-small-subunits-1/2 (CAPNS1), whereas calpastatin gene, the calpain natural inhibitor, was reported to be downregulated. A significant negative correlation was observed between CAPN1/CAPNS1 and patient overall survival. GEC challenging revealed that the inhibition of calpain-1 exerts the strongest proapoptotic efficacy, so GEC mortality reached the 80%, confirmed by the increased activity of caspase-3/7. Functional assays revealed a strong affection of in vitro migration and angiogenesis. Gene and protein expression proved a downregulation of MAPK, VEGF/VEGFRs, and Bcl-2, and an upregulation of caspases and Bax-family mediators., Conclusion: Overall, the differential expression of calpains and their correlation with patient survival suggest a novel promising target pathway, whose blockade showed encouraging results toward precision medicine strategies., Competing Interests: Authors EB, GA, LR have been involved, as researchers, thanks to the participation of Andremacon Srl in the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Guarnaccia, Navone, Begani, Barilla, Garzia, Campanella, Miozzo, Fontana, Alotta, Cordiglieri, Gaudino, Schisano, Ampollini, Riboni, Locatelli and Marfia.)

Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.

Background: Despite the current advances in antenatal care and imaging methodologies in obstetrics, cases of advanced abdominal pregnancies are still reported, mostly in low- and middle-income countries where frequently only a few perinatal checks are performed and where these methodologies are sometimes not adopted in obstetrical outpatient settings., Case Presentation: We report the video of a case of a 20-year-old I gravida Ivorian patient, sent to CHU de T reichville in Abidjan, Ivory Coast, for management of abdominal 39 weeks pregnancy after routine antenatal care. She was asymptomatic with a live foetus in transverse lie position. The anamnesis revealed four prenatal checks without ultrasound evaluation, the first one at 24 weeks of pregnancy. Emergency median longitudinal sub-umbilical laparotomy incision was performed. Foetal extraction was realized by transplacental incision due to omental placental implantation. A live female baby weighting 3350 grams was delivered, presenting bilateral clubfeet and an enlarged neck. The release of the adherent placenta required a partial omentectomy and left adnexectomy and was carefully removed following active bleeding from its detached margins. The newborn died of respiratory distress on the first day after birth. No autopsy was performed. Postoperative morbidity for the woman was minimal and she was discharged on the seventh post-operative day in good general condition., Conclusion: Abdominal pregnancies with a normal live foetus at such an advanced gestational age are extremely rare, and there are no available videos in the extant literature of the surgical procedure performed. Standardization of treatment principles, pre-operative preparation with imaging techniques (MRI, embolization of placental vessels) and adequately equipped and staffed neonatal units are necessary to optimize the foetus-maternal outcomes., (© 2023 Pietro Iovenitti et al., published by Sciendo.)

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.

The environmental conditions to which astronauts and other military pilots are subjected represent a unique example for understanding and studying the biomechanical events that regulate the functioning of the human body. In particular, microgravity has shown a significant impact on various biological systems, such as the cardiovascular system, immune system, endocrine system, and, last but not least, musculoskeletal system. Among the potential risks of flying, low back pain (LBP) has a high incidence among astronauts and military pilots, and it is often associated with intervertebral disc degeneration events. The mechanisms of degeneration determine the loss of structural and functional integrity and are accompanied by the aberrant production of pro-inflammatory mediators that exacerbate the degenerative environment, contributing to the onset of pain. In the present work, the mechanisms of disc degeneration, the conditions of microgravity, and their association have been discussed in order to identify possible molecular mechanisms underlying disc degeneration and the related clinical manifestations in order to develop a model of prevention to maintain health and performance of air- and space-travelers. The focus on microgravity also allows the development of new proofs of concept with potential therapeutic implications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marfia, Guarnaccia, Navone, Ampollini, Balsamo, Benelli, Gaudino, Garzia, Fratocchi, Di Murro, Ligarotti, Campanella, Landolfi, Perelli, Locatelli and Ciniglio Appiani.)

Introduction: Functional hypothalamic amenorrhea (FHA) is a clinical condition associated with high levels of physiological and psychological stress ranging from weight loss to maladaptive behavior and coping skills. A reliable measure of the psychophysiological response to stress and the ability to cope with stimuli is heart rate variability (HRV). Through the sympathetic (SNS) and parasympathetic nervous system (PNS), the autonomic nervous system (ANS) promotes various changes in HRV that reflect the individual's psychophysiological response to stress. FHA patients are characterized by high levels of PNS activation during psychological load, suggesting that parasympathetic hyperactivation could be a pathology marker., Methods: In the present study, we examine changes in HRV during observation of erotic, neutral, and disgusting images in 10 patients with FHA [(mean ± S.D.) age: 26.8 ± 5.9] and in 9 controls (age: 25.4 ± 6.4; BMI: 22.47 ± 2.97) to assess the differential activation of PNS and SNS between FHA patients and controls matched for age and without other clinical conditions., Results: Our results showed that FHA patients had significantly higher HRV activation while observing high emotional value images and not during the observation of neutral images confirming a parasympathetic hyperactivation., Discussion: HRV and cognitive and psychological testing, could provide new insights into understanding such a clinically understudied condition and provide further tools for clinical diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maiorana, Brugnera, Galiano, Ferrara, Poletti, Marconi, Garzia, Ticozzi, Silani, Priori and Ferrucci.)

Purpose: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 μ-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.

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.

Background: Moving from the correlation between insulin-resistance and PCOS, metformin has been administered in some PCOS women improving ovulatory and metabolic functions and decreasing androgen levels. Inconsistency and unpredictability of response to metformin limit its extensive use. Aim of this study was to identify reliable predictors of response to metformin therapy for weight loss and reduction in plasma androgen levels using ANNs (artificial neural networks)., Methods: One hundred eight consecutive women with PCOS (ESHRE/ASRM 2003 Rotterdam criteria) treated with metformin 1500 mg/day, at inclusion and every 6 months underwent to a complete clinical, endocrine/metabolic assessment and ultrasonographic evaluation. Therapy outcomes were BMI reduction (≥1 kg/m 2 ) in overweight/obese and free-androgen-index (FAI) decrease (≥1%) in hyperandrogenemic women. Semantic connectivity maps (SCMs) were obtained through Auto-CM, a fourth generation ANN, to compare patients' baseline clinical features to the treatment outcomes. Multivariate logistic regression analysis was used to assess the major predictor in drop-out patients and the associated risk., Results: At 6 months 54 out of 103 (52,4%) obese patients showed BMI reduction and 45 out of 89 (50,6%) hyperandrogenemic women showed FAI decrease. The further response rates at 12 months were 30,6 and 47%, respectively. SCMs showed a clear polarization for both the outcomes with elevated accuracy. Treatment responsiveness resulted strictly related to oligo-amenorrhea and hyperandrogenemia at baseline. In addition, lower serum testosterone levels at baseline were found to be the major predictor of treatment discontinuation., Conclusions: In women with PCOS, menstrual pattern imbalance and ovarian androgens excess are the best predictors of metformin response. They may pave the way for a rethinking of the criteria for evaluating hyperandrogenism in order to better define the large population included in the diagnosis of PCOS. Baseline plasma testosterone level can serve as a sensitive marker to predict treatment compliance., (© 2021. The Author(s).)

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.

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.

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., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To investigate the expression of prolactin (PRL), PRL-receptor (PRL-R), and the TH1 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 TH1 cytokines with different specific roles at the implantation site. Prolactin and IL-2 may reciprocally influence expression., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)