Special Issue "Ovarian Cancer: Advances on Pathophysiology and Therapies".

Ovarian cancer is a gynecologic cancer with a high mortality rate, and its incidence has increased significantly over the past 50 years [...].

Special Issue "Physiology and Pathophysiology of Placenta 2.0".

We are pleased to present this Special Issue of the International Journal of Molecular Sciences, entitled "Physiology and Pathophysiology of Placenta 2 [...].

Special Issue "Physiology and Pathophysiology of the Placenta".

The placenta is a transient but essential organ for normal in utero development, playing several essential functions in normal pregnancy [...].

Macroscopic and Microscopic Cerebral Findings in Drug and Alcohol Abusers: The Point of View of the Forensic Pathologist.

Drug abuse still represents a significant challenge for forensic pathologists; it must always be considered during the autopsy examination when the brain morphological alterations observed are not characteristic of any known disease of the central nervous system (CNS). Nonetheless, no specific brain lesions had been found to characterize the precise drug that caused the poisoning. In fact, a broad spectrum of changes affecting the CNS are seen in drug abusers. Thus, forensic pathology plays a key role in identifying the encephalic morphological alterations underlying the death. The aim of this review is to present an updated overview of the literature regarding the correlation between the main substances of abuse and the morphological alterations of the CNS to help the forensic pathologist to discriminate drug-induced alterations of the brain. The authors used the PRISMA criteriology to perform the bibliographic search for the present review. Among the articles identified according to the selected search criteria, 116 articles were chosen which allow us to define a picture of the main macroscopic and microscopic alterations of the brain in drug abuse.

The "Bad Father": Paternal Role in Biology of Pregnancy and in Birth Outcome.

Pregnancy is generally studied as a biological interaction between a mother and a fetus; however, the father, with his characteristics, lifestyle, genetics, and living environment, is by no means unrelated to the outcome of pregnancy. The half of the fetal genetic heritage of paternal derivation can be decisive in cases of inherited chromosomal disorders, and can be the result of de novo genetic alterations. In addition to the strictly pathological aspects, paternal genetics may transmit thrombophilic traits that affect the implantation and vascular construction of the feto-placental unit, lead to placenta-mediated diseases such as pre-eclampsia and fetal growth retardation, and contribute to the multifactorial genesis of preterm delivery. Biological aspects of immunological tolerance to paternal antigens also appear to be crucial for these pathologies. Finally, this review describes the biological findings by which the environment, exposure to pathogens, lifestyle, and nutritional style of the father affect fetal pathophysiological and epigenetic definition.

HELLP Syndrome and Differential Diagnosis with Other Thrombotic Microangiopathies in Pregnancy.

Thrombotic microangiopathies (TMAs) comprise a distinct group of diseases with different manifestations that can occur in both pediatric and adult patients. They can be hereditary or acquired, with subtle onset or a rapidly progressive course, and they are particularly known for their morbidity and mortality. Pregnancy is a high-risk time for the development of several types of thrombotic microangiopathies. The three major syndromes are hemolysis, elevated liver function tests, and low platelets (HELLP); hemolytic uremic syndrome (HUS); and thrombotic thrombocytopenic purpura (TTP). Because of their rarity, clinical information and therapeutic results related to these conditions are often obtained from case reports, small series, registries, and reviews. The collection of individual observations, the evolution of diagnostic laboratories that have identified autoimmune and/or genetic abnormalities using von Willebrand factor post-secretion processing or genetic-functional alterations in the regulation of alternative complement pathways in some of these TMAs, and, most importantly, the introduction of advanced treatments, have enabled the preservation of affected organs and improved survival rates. Although TMAs may show different etiopathogenesis routes, they all show the presence of pathological lesions, which are characterized by endothelial damage and the formation of thrombi rich in platelets at the microvascular level, as a common denominator, and thrombotic damage to microcirculation pathways induces "mechanical" (microangiopathic) hemolytic anemia, the consumption of platelets, and ischemic organ damage. In this review, we highlight the current knowledge about the diagnosis and management of these complications during pregnancy.

Mechanisms of action of mineral fibres in a placental syncytiotrophoblast model: An in vitro toxicology study.

Asbestos has been widely used due to its unique characteristics. It is known that exposure to asbestos causes serious damage to health but one species, chrysolite, is still used because it is considered less toxic and not biopersistent in some countries. The aim of our study was to investigate if cellular process underlying the proliferation, differentiation and cell death of placental tissues could be modify in presence of asbestos fibres (50 µg/ml final concentration), long chrysolite fibres (CHR-L) and short chrysolite fibres (CHR-S), using BeWo cell line, an in vitro model that mimics the syncytiotrophoblast (STB), the outer layer of placental villi. Our data demonstrated that none of the fibres analysed alter syncytiotrophoblast formation but all of them induce ROS formation and reduced cell proliferation. Moreover, we showed that only CHR-L fibre induced was able to induce irreversible DNA alterations that carried cells to apoptosis. In fact, BeWo cells exposed to CHR-L fibre showed a significant increase in cleaved CASP3 protein, a marker of apoptosis. These data suggest that CHR-L may induce death of the placental villi leading to impaired placental development. The impairment of placental development is the basis of many gestational pathologies such as preeclampsia and intrauterine growth retardation. Since these pathologies are very dangerous for foetal and maternal life, we suggest to the gynaecologists to carefully evaluate the area of maternal residence, the working environment, the food used, and the materials used daily to avoid contact with these fibres as much as possible.

Role of SLC7A11/xCT in Ovarian Cancer.

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, chemoresistance weakens the therapeutic effects, worsening the outcome of this pathology. Solute Carrier Family 7 Member 11 (SLC7A11, also known as xCT) is the functional subunit of the Xc- system, an anionic L-cystine/L-glutamate antiporter expressed on the cell surface. SLC7A11 expression is significantly upregulated in several types of cancers in which it can inhibit ferroptosis and favor cancer cell proliferation, invasion and chemoresistance. SLC7A11 expression is also increased in ovarian cancer tissues, suggesting a possible role of this protein as a therapeutic target. In this review, we provide an overview of the current literature regarding the role of SLC7A11 in ovarian cancer to provide new insights on SLC7A11 modulation and evaluate the potential role of SLC7A11 as a therapeutic target.

Diagnostic Methods in Forensic Pathology: Autoptic Findings and Immunohistochemical Study in Cases of Sudden Death Due to a Colloid Cyst of the Third Ventricle.

The colloid cyst is a non-malignant tumor growth made of a gelatinous material covered by a membrane of epithelial tissue. It is usually located posterior to the foramen of Monro, in the anterior aspect of the third ventricle of the brain. Due to its location, it can cause obstructive hydrocephalus, increased intracranial pressure, and sudden cardiac death, catecholamine-mediated, through hypothalamus compression. All the mechanisms are still controversial, but the role of catecholamine has been confirmed with histological findings that highlighted myocardial injury (coagulative myocytolysis and contraction band necrosis, CBN). This study presents a case of sudden death in a previously healthy 22-year-old male due to a colloid cyst of the third ventricle. A complete autopsy was performed, highlighting in the brain an abundant quantity of cerebrospinal fluid (CSF) and a 2 cm pale grayish-green rounded cyst formation partially filling and distending the third ventricle. The diagnosis was confirmed through immunohistochemical investigation: positivity for Periodic acid-Schiff (PAS) staining and CK7 expression. In cases such as the one reported here, a combined approach of autopsy, histology, and immunohistochemistry is mandatory in order to identify the neoformation's location and morpho-structural characteristics for a correct differential diagnosis, as well as to identify the cause of death.

First Trimester CD93 as a Novel Marker of Preeclampsia and Its Complications: A Pilot Study.

INTRODUCTION: CD93 plays a crucial role in endothelial homeostasis and angiogenesis. Recently its role in hypertension has been investigated, holding promise for novel targeted diagnostic and therapeutic strategies. AIM: We assessed for the first time differences in first trimester serum CD93 levels in women who lately developed preeclampsia (PE) vs. normotensive pregnancy (NP). METHODS: First trimester serum CD93 concentrations were assessed in a multicenter cohort of 83 women (34 PE and 49 NP) by ELISA Immunoassay. RESULTS: Serum CD93 was lower in women who developed PE vs. NP (111.8 ± 24.4 vs. 137.5 ± 22.3 ng/ml; p < 0.001). Serum CD93 was associated with a decreased risk of developing PE (OR 0.950, 95% CI 0.922-0.978) and composite neonatal outcome (OR 0.952, CI 0.923-0.982), after adjustment for confounders. CONCLUSIONS: PE is accompanied by decreased serum CD93 levels. CD93 might play a role during placentation leading to defective angiogenesis, vascular dysfunction, and PE development.

Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Prostate cancer is the second most common malignancy in men worldwide. Prostate cancer can be treated by surgery, radiotherapy and hormone therapy. The latter, in the form of androgen-deprivation therapy is needed to reduce prostate cancer progression at an advanced stage. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development and progression and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) pathway is affected by reactive oxygen species (ROS). Furthermore, the NRF2/KEAP1 signaling pathway has been investigated by several studies related to anti-androgen therapy, biochemical recurrence and radiotherapy. In this review we analysed the current literature regarding the indirect modulators involved in NRF2/KEAP1 pathway regulation and their role as possible therapeutic targets in prostate cancer cells.

Role of CD93 in Health and Disease.

CD93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp), is a transmembrane glycoprotein encoded by a gene located on 20p11.21 and composed of 652 amino acids. CD93 can be present in two forms: soluble (sCD93) and membrane-bound (CD93). CD93 is mainly expressed on endothelial cells, where it plays a key role in promoting angiogenesis both in physiology and disease, such as age-related macular degeneration and tumor angiogenesis. In fact, CD93 is highly expressed in tumor-associated vessels and its presence correlates with a poor prognosis, poor immunotherapy response, immune cell infiltration and high tumor, node and metastasis (TNM) stage in many cancer types. CD93 is also expressed in hematopoietic stem cells, cytotrophoblast cells, platelets and many immune cells, i.e., monocytes, neutrophils, B cells and natural killer (NK) cells. Accordingly, CD93 is involved in modulating important inflammatory-associated diseases including systemic sclerosis and neuroinflammation. Finally, CD93 plays a role in cardiovascular disease development and progression. In this article, we reviewed the current literature regarding the role of CD93 in modulating angiogenesis, inflammation and tumor growth in order to understand where this glycoprotein could be a potential therapeutic target and could modify the outcome of the abovementioned pathologies.

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer.

Serum uric acid to creatinine ratio and risk of preeclampsia and adverse pregnancy outcomes.

OBJECTIVE: Preeclampsia is one of the most severe diseases among the hypertensive disorders of pregnancy (HDP) and the leading cause of maternal and fetal morbidity and mortality. It is of crucial importance to early identify women at a high risk for preeclampsia to implement appropriate preventive strategies. In our study, we aimed to test the hypothesis that serum uric acid to creatinine ratio (SUA/sCr) is related to the development of preeclampsia and maternal and neonatal complications. METHODS: We searched for uric acid and creatine values in the medical records of 269 women who consecutively attended our HDP Clinic from December 2018 to December 2022. We compared the baseline characteristics of participants with normotensive pregnancy ( n  = 57), to those with HDP without preeclampsia (HDP-non-PE) ( n  = 100) and those with preeclampsia ( n  = 112), and we performed adjusted logistic regression analysis to test the associations between SUA/sCr and the development of preeclampsia and maternal and neonatal complications. RESULTS: SUA/sCr was consistently higher in women with preeclampsia in all trimesters of pregnancy. Higher SUA/sCr at the third trimester was associated with an increased odd of developing preeclampsia [odds ratio (OR) 1.29, confidence interval (CI) 1.15-1.50, P  = 0.001], preterm birth (OR 1.23, CI 1.05-1.45, P  = 0.011), and composite neonatal outcome (OR 1.33, CI 1.12-1.59, P  = 0.001), after adjustment for age, BMI before pregnancy, nulliparity, antihypertensive therapy, and acetylsalicylic acid therapy during pregnancy. CONCLUSIONS: Having higher SUA/sCr during pregnancy is associated with the development of PE and adverse pregnancy outcomes. Controlled prospective studies are warranted to clarify the predictive power of this novel marker during pregnancy.

Melanoma and subcutaneous adipose tissue: Role of peritumoral adipokines in disease characterization and prognosis.

In the last decades, the concept of adipose organ has emerged, giving adipose tissue an active endocrine and immunologic function through the secretion of multiple cytokines and chemokines that seem to be implicated in the development and progression of several cancer, including cutaneous melanoma. In this pilot experimental study, we analyzed the expression in the peritumor subcutaneous adipose tissue of the most significant adipokines involved in the processes of carcinogenesis and metastasis in a population of melanoma patients and in two control groups composed of melanocytic nevi and epidermoid cysts, respectively. We correlated the results obtained with the main disease prognostic factors observing a statistically significant increase in the expression of PAI1, LEP, CXCL1, NAMPT, and TNF-α at the level of the peritumor tissue of the melanoma samples compared to the control groups and a correlation of the same with the histopathological prognostic factor of melanoma. Our preliminary study shows that the overexpression of PAI1, LEP, CXCL1, NAMPT, and TNF-α may contribute to the growth and to the local aggressiveness of cutaneous melanoma. It opens the hypothesis of a direct oncogenic role of subcutaneous adipose tissue and adipokines in the tumorigenesis of melanoma.

Modulation of NRF2/KEAP1 Signaling in Preeclampsia.

Placentation is a key and tightly regulated process that ensures the normal development of the placenta and fetal growth. Preeclampsia (PE) is a hypertensive pregnancy-related disorder involving about 5-8% of all pregnancies and clinically characterized by de novo maternal hypertension and proteinuria. In addition, PE pregnancies are also characterized by increased oxidative stress and inflammation. The NRF2/KEAP1 signaling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. ROS activate NRF2, allowing its binding to the antioxidant response element (ARE) region present in the promoter of several antioxidant genes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase that neutralize ROS, protecting cells against oxidative stress damages. In this review, we analyze the current literature regarding the role of the NRF2/KEAP1 pathway in preeclamptic pregnancies, discussing the main cellular modulators of this pathway. Moreover, we also discuss the main natural and synthetic compounds that can regulate this pathway in in vivo and in vitro models.

Diagnostic and Prognostic Role of CD93 in Cardiovascular Disease: A Systematic Review.

INTRODUCTION: Cluster of Differentiation (CD) 93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp) is a transmembrane glycoprotein that can also be present in a soluble (sCD93) form. Recent studies have investigated the role of this protein in cardiovascular disease (CVD). The present systematic review aims to assess the associations between CD93 and cardiovascular (CV) risk factors and disease at both the proteomic and genomic levels. METHODS: We conducted systematic searches in the PubMed, EMBASE, and Web of Science databases to identify all human studies since inception to February 2023 that investigated the role of CD93 in CV risk factors, CVD, and CV-associated outcomes. The data collection and analysis have been independently conducted by two reviewers. The search terms included: cardiovascular, heart failure, acute stroke, myocardial infarction, stroke, peripheral artery disease, cardiovascular death, MACE, hypertension, metabolic syndrome, hyperuricemia, diabetes, cd93, c1qr, C1qR1, complement protein 1 q subcomponent receptor. RESULTS: A total of 182 references were identified, and 15 studies investigating the associations between CD93 protein levels or CD93 genetic polymorphisms and the development or prevalence of CV risk factors (i.e., hypertension, dyslipidemia, and obesity) and CVD (i.e., heart failure, coronary artery disease, and ischemic stroke) were included. Although promising, the quality and dimension of the analyzed studies do not allow for a definitive answer to the question of whether CD93 may hold diagnostic and prognostic value in CVD.

HTRA1 in Placental Cell Models: A Possible Role in Preeclampsia.

The HtrA serine peptidase 1 (HTRA1) is a multidomain secretory protein with serine-protease activity involved in the regulation of many cellular processes in both physiological and pathological conditions. HTRA1 is normally expressed in the human placenta, and its expression is higher in the first trimester compared to the third trimester, suggesting an important role of this serine protease in the early phases of human placenta development. The aim of this study was to evaluate the functional role of HTRA1 in in vitro models of human placenta in order to define the role of this serine protease in preeclampsia (PE). BeWo and HTR8/SVneo cells expressing HTRA1 were used as syncytiotrophoblast and cytotrophoblast models, respectively. Oxidative stress was induced by treating BeWo and HTR8/SVneo cells with H2O2 to mimic PE conditions in order to evaluate its effect on HTRA1 expression. In addition, HTRA1 overexpression and silencing experiments were performed to evaluate the effects on syncytialization, cell mobility, and invasion processes. Our main data showed that oxidative stress significantly increased HTRA1 expression in both BeWo and HTR8/SVneo cells. In addition, we demonstrated that HTRA1 has a pivotal role in cell motility and invasion processes. In particular, HTRA1 overexpression increased while HTRA1 silencing decreased cell motility and invasion in HTR8/SVneo cell model. In conclusion, our results suggest an important role of HTRA1 in regulating extravillous cytotrophoblast invasion and motility during the early stage of placentation in the first trimester of gestation, suggesting a key role of this serine protease in PE onset.

Ovarian Cancer: Advances in Pathophysiology and Therapies.

We are pleased to present this Special Issue of the International Journal of Molecular Sciences, entitled "Ovarian Cancer: Advances in Pathophysiology and Therapies" [...].

Physiology and Pathophysiology of the Placenta.

We are pleased to present this Special Issue of the International Journal of Molecular Sciences, entitled "Physiology and Pathophysiology of Placenta" [...].