Endometriosis is a chronic estrogen-dependent inflammatory disease affecting approximately 10% of women of reproductive age and characterized by ectopic endometrial-like tissue growth. Although traditionally considered a benign gynecological condition, increasing evidence indicates that endometriosis shares several molecular and cellular features with malignant processes, including enhanced proliferation, resistance to apoptosis, invasive behavior, and the ability to remodel the surrounding microenvironment. Recent studies suggest that dysregulated estrogen signaling, particularly the imbalance between estrogen receptor subtypes, plays a central role in driving these processes and may contribute to the persistence and progression of ectopic lesions. In parallel, also the involvement of stem or progenitor cells has been highly investigated because they may support lesion establishment, cellular plasticity, and long-term disease maintenance. These mechanisms overlap with pathways commonly involved in tumor initiation and progression. Recognizing endometriosis as a stem cell-driven and estrogen-dependent condition, the perspective, in both clinical management and therapeutic strategies fields, can change. Indeed, it is essential to emphasize that endometriosis is a benign condition and that the risk of developing an associated tumor is very low, approximately 1.5-2%. This review aims to discuss current evidence on the molecular aspects, focusing on estrogen signaling, stem cell-related mechanisms, and inflammatory and microenvironmental pathways that contribute to disease development. By highlighting these mechanisms, an integrated perspective on the pathophysiology of endometriosis is provided, also to outline potential implications for biomarker discovery and targeted therapeutic strategies.

Endometriosis is a pathological condition characterized by the presence of the endometrial tissue, outside the uterine cavity. It affects nearly 10% of women of reproductive age and is responsible for infertility, chronic pain, and the weakening of the quality of life. Various pathogenetic mechanisms have been suggested; however, the essential pathogenesis of endometriosis remains insufficiently comprehended. A comprehensive literature search was conducted in databases such as PubMed, Scopus, and Web of Science up to December 2024. Inclusion criteria encompassed studies investigating the pathogenetic mechanisms of endometriosis, while exclusion criteria included reviews, case reports, and studies lacking primary data. The analyzed studies explored multiple pathogenetic mechanisms, including retrograde menstruation, coelomic metaplasia, embryological defects, stem cell involvement, and epigenetic modifications. Special emphasis was placed on the role of uterine adenogenesis factors in the development and progression of endometriosis. A deeper understanding of the various pathogenetic mechanisms underlying endometriosis is crucial for advancing targeted therapeutic strategies. Further research into uterine adenogenesis factors may provide new insights into the disease’s pathophysiology and pave the way for novel treatment approaches.

BACKGROUND/AIM:The anatomy of the mandibular canal (MC) has been extensively described in the literature. Numerous studies have investigated its anatomical variations and anomalies. Different methods have been used to study the mandibular bone over the years and different classifications have been proposed. PATIENTS AND METHODS:A literature search was performed to identify articles regarding Mandibular Canal, Bifid and Trifid Mandibular Canal. This search used the PUBMED and WoS computer databases in the years from 1931 to 2023. Studies that did not fall within the scope of the search were excluded, such as those in which the abstract provided insufficient information for the preliminary evaluation. In addition, some articles not selected by the database search, including those on etiopathogenesis were manually entered. For all studies considered eligible, the full texts of the articles were searched and downloaded. RESULTS:Based on the analysis of the literature, the variants of the MC should be classified as bifid MC, trifid MC, intramandibular accessory canals and dental canals. Extramandibular buccal and lingual canals require focused research, because they are very frequent, numerous, and they have nutrient functions. CONCLUSION:This article highlights some important radiological and anatomic aspects regarding variations of the MC and their clinical implications in relation to their actual classification. Some classifications have only statistical and historical value without real utility for dentists and oral surgeons. The presence of duplications may cause perioperative complications if they are not correctly recognized. New studies should be conducted on the different variations of MC in its anterior, middle and posterior. A more useful classification is proposed.

Endometriosis is a chronic inflammatory pathology estrogen-dependent. It is a condition affecting 5%-10% of women of reproductive age worldwide. Recent evidence indicating an embryological origin of endometriosis has provided new insights into its pathogenesis and potential therapeutic approaches. In this study, we compared the immunohistochemical expression of extracellular matrix molecules involved in the interaction between epithelium and stroma in endometriotic lesions and normal endometrial tissue. A total of 41 cases were analyzed. We examined the immunohistochemical expression of chondroitin sulfate proteoglycan 4 (CSPG4), keratan sulfate, chondroitin sulfate (CS-56), hyaluronic acid, and heparan sulfate (HEP). Our results showed higher expression of CSPG4 and CS-56 in epithelial endometriosis samples compared with normal endometrial tissue, while HEP, keratan sulfate, and hyaluronic acid showed decreased expression in epithelial endometriosis samples relative to normal endometrial tissue. Additionally, endometriotic stroma exhibited more frequent low intensity of hyaluronic acid and HEP compared with normal endometrial stroma. Investigating the levels of these molecules in eutopic and ectopic endometrial tissues enables the identification of potential therapeutic targets, and the development of novel treatments aimed at disrupting the adhesive and invasive properties of endometriotic lesions.

BackgroundMalignant mesothelioma (MM) is a rare and aggressive form of cancer that affects the mesothelial surfaces, associated with exposure to asbestos fibres. To date, no cure is available for MM and therapeutically approved treatments are based on the use of platinum compounds often used in combination with other drugs. We have previously analysed the efficacy of a cisplatin/piroxicam (CDDP/P) combined treatment showing that this treatment was able to reduce in vivo tumor growth. Several studies reported that platinum-drug sensitivity in cancer is connected to modulation of the expression of non-coding RNAs. In this study we analysed if the CDDP/P treatment was able to modulate miRNAs expression in MM.MethodsmiRNA sequencing performed on MSTO-211 H cells treated with CDDP with CDDP/P led us to identify miRNA-503 - downregulated by CDDP/P - as a novel miRNA that acts as an oncomiR in MM. The effect of miRNA-503 inhibition was evaluated in vitro in mesothelioma cells analysing apoptosis induction and reduction of cancer properties. Inhibition of miR-503 expression in vivo, was analysed in ectopic mouse model of MM by using LNP encapsulating anti-mir-503 and miR-503 expression was evaluated in human MM samples.ResultsIn vitro and in vivo analysis confirmed miR-503 acts as oncogene in MM since its inhibition was able to reduce cell cancer properties and tumor growth in ectopic mouse model of MM. Its expression was found upregulated in human MM patients compared to normal pleura. Bioinformatic analysis indicated BTG1, CCNG1, EDG1, and TIMP2 as putative target genes of miRNA-503. These genes showed an opposite expression compared to miR-503 levels both in cells and in MM samples. Finally, microarray analysis indicated that miR-503 inhibition affected the expression of the well-known MM biomarkers: CXCL8, SERPINE1 and Osteopontin.ConclusionsOur study is the first reporting an oncomiR role for miR-503 in MM and suggests that its inactivation could have a clinical value in MM patients. This study reveals that miRNA-503 acts as an oncomiR in MM suggesting that its inhibition, through LNP delivery, has the potential to be considered as a novel therapeutic strategy in MM.

Previous studies demonstrated that integrase-strand-transfer-inhibitors (INSTIs) promote adipocyte differentiation, while nucleoside-reverse-transcriptase-inhibitors (NRTIs) tenofovir-alafenamide-fumarate (TAF) and tenofovir-disoproxil-fumarate (TDF), inhibit adipogenesis. NRTIs were shown to counteract the pro-adipogenic effects of INSTIs[6]. However, the effects of non-nucleoside-reverse-transcriptase-inhibitors (NNRTIs) and of the novel long-acting INSTI cabotegravir (CAB), on adipogenesis, alone or in combination with NRTIs or other INSTIs, remain unclear. This study aims to elucidate the impact of NNRTIs and recent INSTIs on adipogenesis. 3T3-L1 cells were used as an adipogenesis in vitro model. The NNRTIs doravirine (DOR) and rilpivirine (RPV) were tested alone and in combination with DTG, CAB, TDF, TAF. Adipogenesis was assessed by Oil-Red-O-staining and by measuring expression-levels of peroxisome-proliferator-activated-receptor-gamma (PPARγ) and CCAAT/enhancer-binding-protein-alpha (C/EBPα). Moreover, Fibroblast-marker ER-TR7 was assessed by immunohistochemistry. CAB, DOR, and RPV promoted adipogenesis, with CAB and DOR showing greater effects. In combination, NNRTIs enhanced the adipogenic effects of CAB and DTG. Conversely, TAF and TDF, when paired with RPV or DOR, inhibited adipogenesis. NNRTIs and CAB increased ER-TR7 expression, suggesting fibroblastic differentiation. Finally, NNRTIs and INSTIs promote adipogenesis and induce fibroblastic features in 3T3-L1 cells. Contrarily, TAF and TDF exhibited an antagonistic effect on adipogenesis when combined with certain antiretrovirals, supporting our previous research.

Cancer is one of the main diseases causing one-third of the worldwide death every year. The recent progresses achieved in chemotherapy have increased patients' survival, however, drug efficacy is limited by the occurrence of serious side effects and the development of drug resistance. To overcome these problems, research interests, aim to develop alternative therapies based on the use of polyphenols, such as curcumin. Polyphenols are effective against different cancers and in combination with standard drugs, display synergism enhancing anticancer effects. Malignant mesothelioma (MM) is an aggressive cancer associated with exposure to asbestos fibers for which to date, neither surgical nor chemotherapy, based on the use of cisplatin and other platinum drugs, result in a favorable prognosis. We previously reported that daily administration of a curcumin standardized extract exerted anticancer effects in MM in vitro and in vivo. The efficacy of this formulation has been tested in several clinical trials in combination to standard drugs. Since curcumin is known to increase cisplatin sensitivity in different cancer, here we evaluated the ability of this formulation in enhancing cisplatin sensitivity in MM. The effect of combined treatment was evaluated in 2D and 3D cultures by using two MM cell lines, MSTO-211H and Ist-Mes2, that are sensitive or less responsive to the piroxicam/cisplatin combined treatment respectively. Results indicate that this treatment determines a dramatic apoptotic increase linked to a concomitant inactivation of Nrf2, a transcription factor with a key role in carcinogenesis, and of NUPR1, a transcriptional regulator involved in drug chemoresistance.

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

Electroporation (EP) is a broadly accepted procedure that, through the application of electric pulses with appropriate amplitudes and waveforms, promotes the delivery of anticancer molecules in various oncology therapies. EP considerably boosts the absorptivity of targeted cells to anticancer molecules of different natures, thus upgrading their effectiveness. Its use in veterinary oncology has been widely explored, and some applications, such as electrochemotherapy (ECT), are currently approved as first-line treatments for several neoplastic conditions. Other applications include irreversible electroporation and EP-based cancer vaccines. In human oncology, EP is still mostly restricted to therapies for cutaneous tumors and the palliation of cutaneous and visceral metastases of malignant tumors. Fields where veterinary experience could help smooth the clinical transition to humans include intraoperative EP, interventional medicine and cancer vaccines. This article recapitulates the state of the art of EP in veterinary and human oncology, recounting the most relevant results to date.

GATA3 plays critical roles in the development and function of various tissues and organs throughout the body. Likewise, TGF-β signaling is critical for placental development and can interact with GATA3. We aimed to investigate the involvement of the multifunctional cytokine and transcription factor in trophoblast development. By using immunohistochemistry, we evaluated the localization and expression level of GATA3 and TGF-β in placentas at term of normal pregnancy and with pre-eclampsia. Up-regulation of both GATA3 and TGF-β was observed in pathological placentas, with localization in the villus epithelium (syncytiotrophoblast) stroma and decidua. Our data show altered expression of TGF-β and GATA3, which downstream could lead to a cascade of events that negatively influence trophoblast development and contribute to the pathogenesis of pre-eclampsia.

Endometriosis, a very common disease in women, is characterized by endometrial structures outside the uterine cavity. The lack of a reliable noninvasive diagnostic test and the often nonspecific symptoms of this pathology are responsible for the delay in definitive diagnosis of this disease. Recently, through a proteomics approach, our research group has identified two potential diagnostic markers for endometriosis in serum (Zn-alpha2-glycoprotein and complement C3 precursor). In this article, we describe the experimental conditions of a simple ELISA for rapid quantification of these two biomarkers in the saliva of patients with endometriosis. Finally, preliminary experiments on a small cohort of patients and controls have confirmed the potential diagnostic value of this assay.

GATA3 plays critical roles in the development and function of various tissues and organs throughout the body. Likewise, TGF-(3 signaling is critical for placental development and can interact with GATA3. We aimed to investigate the involvement of the multifunctional cytokine and transcription factor in trophoblast development. By using immunohistochemistry, we evaluated the localization and expression level of GATA3 and TGF-(3 in placentas at term of normal pregnancy and with pre-eclampsia. Up-regulation of both GATA3 and TGF-(3 was observed in pathological placentas, with localization in the villus epithelium (syncytiotrophoblast) stroma and decidua. Our data show altered expression of TGF-(3 and GATA3, which downstream could lead to a cascade of events that negatively influence trophoblast development and contribute to the pathogenesis of pre-eclampsia.

During pregnancy, SARS-CoV-2 infection is associated with several adverse outcomes, including an increased risk of pre-eclampsia, preterm delivery, hypertensive disorders, gestational diabetes, and fetal growth restriction related to the development of placenta vascular abnormalities. We analyzed human placenta from full-term, uncomplicated pregnancies with SARS-CoV-2 infection during the first, second, or third trimesters of gestation. We studied, by the immunohistochemistry technique, the expression of CD34 and podoplanin (PDPN) as markers of vasculogenesis to find any differences. As secondary outcomes, we correlated maternal symptoms with placental histological alterations, including fibrin deposits, lymphocyte infiltration in the villi, edema, and thrombi. Our results showed a PDPN expression around the villous stroma as a plexiform network around the villous nucleus of fetal vessels; significant down-regulation was observed in the villous stroma of women infected during the third trimester. CD34 showed no changes in expression levels. During SARS-CoV-2 infection, the most common maternal symptoms were fever, anosmia, ageusia and asthenia, and the majority were treated with paracetamol, corticosteroids and azithromycin. Patients that required multiple symptomatic treatments evidenced a large amount of fibrin deposition in the villi. Certainly, PDPN plays a key role in healthy placental vasculogenesis and thus in its proper physiology, and SARS-CoV-2 surely alters its normal expression. Further studies are necessary to understand what mechanisms are being altered to try to avoid possible complications for both the mother and fetus in terms of the contagions that will still occur.

Background: Foot drop (FD) is characterized by an inability to lift the foot against gravity because of dorsiflexor muscle weakness. The aim of the present study is to report a clinical case of acute non-traumatic FD in patients with peroneal intraneural ganglion, after performing a scoping review on the methodological management of this disease. Methods: We performed a review of the literature and reported the case of a 49-year-old man with acute FD caused by an intraneural ganglion cyst of the peroneal nerve. Results: Out of a total of 201 articles, 3 were suitable for our review beyond our case report. The acute FD caused by peroneal intraneural ganglion can be managed by a careful clinical–instrumental differential diagnosis. A targeted surgery with subsequent rehabilitation produced a satisfactory motor recovery. Conclusions: Acute FD requires an appropriate diagnostic–therapeutic framework to identify and effectively treat the causes in order to promote complete recovery

Endometriosis is characterized by the presence of endometrial glandular and stromal structures outside the uterine cavity. It is an inflammatory estrogen dependent disease characterized by gene polymorphisms. This is a very frequent pathology and represents one of the most important causes of infertility, as well as having an important level of morbidity in patients. Recently, an alteration of the processes of organogenesis of the uterus has been proposed as a pathogenetic mechanism of endometriosis. In this article we have compared the expression in deep endometriotic lesions and in normal endometrial tissue of some of the molecular factors known to be involved in the embryonic development of the uterine glands. In detail, we found by immunohistochemistry a significant higher expression both for epithelium and stroma in the controls respect to the endometriosis samples for insulin growth factor 1 (IGF1) and IGF2, whereas for the prolactin receptor (PRL-R), this result was detected only for the epithelium. On the other hand, we found for growth hormone (GH) a significant higher expression in the epithelium of endometriosis samples respect to the controls. The correlation data generated can give indications on some of the molecular mechanisms responsible for the adenogenesis and survival of endometriosis structures outside of the uterus.

The figure shows the immunostaining analysis of Ki67 in organs from Cdkn1b T197A/T197A mice treated with Vehicle or Bortezomib

OBJECTIVE:Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral therapy (ART) medications with a good tolerability profile and a high genetic barrier to HIV drug resistance. However, several studies report significant weight gain among persons receiving INSTI-based ART regimens compared with other regimens.DESIGN:In-vitro model of adipogenesis.METHODS:We used 3T3-L1 cells to investigate the effects of the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), alone or in combination with INSTIs: raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG), and bictegravir (BIC) on adipose differentiation. To monitor adipocyte differentiation, expression levels of PPARɣ and C/EBPα and the intracellular lipid accumulation by Red Oil staining were used. Furthermore, we evaluated the immunohistochemical expression of ER-TR7, a fibroblastic marker, after INSTIs treatment.RESULTS:Compared with control, INSTIs were able to increase adipogenesis, especially RAL and ELV. TAF and TDF inhibited adipogenesis alone and in combination with INSTIs. This ability was more evident when TAF was used in combination with DTG and BIC. Finally, INSTIs increased the expression of ER-TR7 compared with control and cells treated with TAF or TDF.CONCLUSION:Our data support the evidence that in-vitro challenge of 3T3-L1 cells with INSTIs is able to increase adipocytic differentiation and to drive a number of these cells toward the expression of fibroblastic features, with a different degree according to the various drugs used whereas TAF and TDF have an antagonistic role on this phenomenon.

On line Materials and Methods

The file contains a detailed description of the generation of the Cdkn1b T197A/T197A mice