Management and outcome of fetal abdominal cysts in first trimester: systematic review of the literature.

OBJECTIVES: The finding of an abdominal cyst during pregnancy has an estimated prevalence of 1 in 1000 pregnancies, mostly in second and third trimester. The detection of a fetal abdominal cyst during the first trimester scan is a rare event, whose natural history and prognosis are often unknown and unpredictable as these anomalies can be related to various underlying conditions and originate from different structures. The aim of this study is to evaluate the outcome of fetal abdominal cysts detected in the first trimester in order to understand their possible clinical significance and to offer the proper management according to the available data. METHODS: We present a case report of a first trimester fetal abdominal cyst detected with subsequent diagnosis of congenital multiple arthrogryposis and we performed a systematic review of the literature to identify the incidence and the outcomes of similar cases. The systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 25 and registered with PROSPERO (CRD42023491729). RESULTS: A total of 60 cases of first trimester abdominal cysts were included. Of these, 35% were associated with concurrent or late onset structural anomalies, as in our case report, and 65% were isolated. In pregnancies with isolated fetal abdominal cysts, 56% had a completely normal outcome. CONCLUSIONS: The finding of an abdominal cyst during the first trimester of pregnancy is in most cases an isolated event with a moderate to good prognosis but it could also be an early sign of other associated abnormalities, including arthrogryposis. Increased ultrasound surveillance and additional genetic testing to rule out possible associated anomalies are pivotal to assess the risk of adverse pregnancy outcomes and to provide appropriate counselling to the patient. This article is protected by copyright. All rights reserved.

miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance.

The ErbB tyrosine kinase receptor family has been shown to have an important role in tumorigenesis, and the expression of its receptor members is frequently deregulated in many types of solid tumors. Various drugs targeting these receptors have been approved for cancer treatment. Particularly, in breast cancer, anti-Her2/EGFR molecules represent the standard therapy for Her2-positive malignancies. However, in a number of cases, the tumor relapses or progresses thus suggesting that not all cancer cells have been targeted. One possibility is that a subset of cells capable of regenerating the tumor, such as cancer stem cells (CSCs), may not respond to these therapeutic agents. Accumulating evidences indicate that miR-205-5p is significantly downregulated in breast tumors compared with normal breast tissue and acts as a tumor suppressor directly targeting oncogenes such as Zeb1 and ErbB3. In this study, we report that miR-205-5p is highly expressed in BCSCs and represses directly ERBB2 and indirectly EGFR leading to resistance to targeted therapy. Furthermore, we show that miR-205-5p directly regulates the expression of p63 which is in turn involved in the EGFR expression suggesting a miR-205/p63/EGFR regulation.

Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment.

A number of studies suggest that cancer stem cells are essential for tumour growth, and failure to target these cells can result in tumour relapse. As this population of cells has been shown to be resistant to radiation and chemotherapy, it is essential to understand their biology and identify new therapeutic approaches. Targeting cancer metabolism is a potential alternative strategy to counteract tumour growth and recurrence. Here we applied a proteomic and targeted metabolomic analysis in order to point out the main metabolic differences between breast cancer cells grown as spheres and thus enriched in cancer stem cells were compared with the same cells grown in adherent differentiating conditions. This integrated approach allowed us to identify a metabolic phenotype associated with the stem-like condition and shows that breast cancer stem cells (BCSCs) shift from mitochondrial oxidative phosphorylation towards fermentative glycolysis. Functional validation of proteomic and metabolic data provide evidences for increased activities of key enzymes of anaerobic glucose fate such as pyruvate kinase M2 isoform, lactate dehydrogenase and glucose 6-phopshate dehydrogenase in cancer stem cells as well as different redox status. Moreover, we show that treatment with 2-deoxyglucose, a well known inhibitor of glycolysis, inhibits BCSC proliferation when used alone and shows a synergic effect when used in combination with doxorubicin. In conclusion, we suggest that inhibition of glycolysis may be a potentially effective strategy to target BCSCs.

Cryopreservation effects on Wharton's Jelly Stem Cells proteome.

Cryopreservation is the only method for long-term storage of viable cells and tissues used for cellular therapy, stem cell transplantation and/or tissue engineering. However, the freeze-thaw process strongly contributes to cell and tissue damage through several mechanisms, including oxidative stress, cell injury from intracellular ice formation and altered physical cellular properties. Our previous proteomics investigation was carried out on Wharton's Jelly Stem Cells (WJSCs) having similar properties to adult mesenchymal stem cells and thus representing a rich source of primitive cells to be potentially used in regenerative medicine. The aim of the present work was to investigate molecular changes that occur in WJSCs proteome in different experimental conditions: fresh primary cell culture and frozen cell. To analyze changes in protein expression of WJSCs undergoing different culturing procedures, we performed a comparative proteomic analysis (2DE followed by MALDI-TOF MS/MS nanoESI-Q-TOF MS coupled with nanoLC) between WJSCs from fresh and frozen cell culturing, respectively. Frozen WJSCs showed qualitative and quantitative changes compared to cells from fresh preparation, expressing proteins involved in replication, cellular defence mechanism and metabolism, that could ensure freeze-thaw survival. The results of this study could play a key role in elucidating possible mechanisms related to maintaining active proliferation and maximal cellular plasticity and thus making the use of WJSCs in cell therapy safe following bio-banking.

Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals.

Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.

Modulation of multidrug resistance P-glycoprotein activity by antiemetic compounds in human doxorubicin-resistant sarcoma cells (MES-SA/Dx-5): implications on cancer therapy.

Multidrug resistance (MDR) in cancer cells is often caused by the high expression of the plasma membrane drug transporter P-glycoprotein (Pgp) associated with an elevated intracellular glutathione (GSH) content in various human tumors. Several chemosensitizers reverse MDR but have significant toxicities. Antiemetic medications are often used for controlling chemotherapy-induced nausea and vomiting in cancer patient. In this in vitro study we investigated if the effects of two common antiemetic drugs such as dimenhydrinate (dime) and ondansentron (onda) and a natural compound (6)-gingerol (ginger), the active principle of ginger root, interfere on Pgp activity and intracellular GSH content in order to evaluate their potential use as chemosensitizing agents in anticancer chemotherapy. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp, were treated with each antiemetic alone (1, 10 and 20 microM) or in combination with different doxo concentrations (2, 4, and 8 microM). We measured the intracellular accumulation and cytotoxicity of doxo (MTT assay), the cellular GSH content (GSH assay) and ROS production (DFC-DA assay), in comparison with verapamil (Ver), a specific inhibitor for Pgp, used as reference molecule. We found that exposure at 2, 4 and 8 microM doxo concentrations in the presence of dime, onda and ginger enhanced significantly doxo accumulation and cytotoxicity on resistant MES-SA/Dx5 cells when compared with doxo alone. Moreover, treatment with ginger (20 microM) increased cellular GSH content (greater than 10 percent) in resistant cells, while ROS production remained below the control values for all antiemetic compounds at all concentrations. These findings provide the rationale for innovative clinical trials of antiemetics or their derivatives as a new potential generation of chemosensitizers to improve effectiveness of the anticancer drugs in MDR human tumours.

p63/p73 in the control of cell cycle and cell death.

The p53 family apparently derives from a common ancient ancestor that dates back over a billion years, whose function was protecting the germ line from DNA damage. p63 and p73 would maintain this function through evolution while acquiring novel roles in controlling proliferation and differentiation of various tissues. p53 on the other hand would appear in early vertebrates to protect somatic cells from DNA damage with similar mechanism used by its siblings to protect germ line cells. For the predominant role played by p53 mutations in cancer this was the first family member to be identified and soon became one of the most studied genes. Its siblings were identified almost 20 years later and interestingly enough their ancestral function as guardians of the germ-line was one of the last to be identified. In this review we shortly summarize the current knowledge on the structure and function of p63 and p73.

FLASH is essential during early embryogenesis and cooperates with p73 to regulate histone gene transcription.

Replication-dependent histone gene expression is a fundamental process occurring in S-phase under the control of the cyclin-E/CDK2 complex. This process is regulated by a number of proteins, including Flice-Associated Huge Protein (FLASH) (CASP8AP2), concentrated in specific nuclear organelles known as HLBs. FLASH regulates both histone gene transcription and mRNA maturation, and its downregulation in vitro results in the depletion of the histone pull and cell-cycle arrest in S-phase. Here we show that the transcription factor p73 binds to FLASH and is part of the complex that regulates histone gene transcription. Moreover, we created a novel gene trap to disrupt FLASH in mice, and we show that homozygous deletion of FLASH results in early embryonic lethality, owing to arrest of FLASH(-/-) embryos at the morula stage. These results indicate that FLASH is an essential, non-redundant regulator of histone transcription and cell cycle during embryogenesis.

The effect of the plasticizer diethylhexyl phthalate on transport activity and expression of P-glycoprotein in parental and doxo-resistant human sarcoma cell lines.

Multidrug resistance (MDR) to cancer therapy is frequently associated with the over-expression of the multidrug transporter MDR1 gene product P-glycoprotein (Pgp) in several types of human tumours. Various chemosensitizers have been used to inhibit Pgp activity but toxicity limits their clinical application. Di(2-ethylhexyl)phthalate (DEHP) is a plasticizer that is released from polyvinyl chloride (PVC) medical devices. Therefore, cancer patients undertaking chemotherapy are exposed to a clinically important amount of DEHP through blood and blood component transfusions, apheresis products, intravenous chemotherapy, parenteral nutrition and other medical treatments. The present study was designed to investigate the effects of DEHP on transport activity and expression of Pgp in order to evaluate its potential use as a chemosensitizer in cancer therapy. Human doxorubicin (doxo) resistant sarcoma cells (MES-SA/Dx5) that over-express Pgp were treated with different doses of doxo (2, 4 and 8 µM) in the presence or absence of various concentrations of DEHP (3, 6 and 12 µM) that were clinically achievable in vivo. Our results show that co-treatment with 2, 4 and 8 µM doxo in the presence of the lowest concentration of DEHP (3 µM) enhanced significantly doxo accumulation in MES-SA/Dx5 cells and, consistently increased the sensitivity to doxo, when compared to controls receiving only doxo. In contrast, higher DEHP concentrations (6 and 12 µM) induced MES-SA/Dx5 to extrude doxo decreasing doxo cytotoxicity toward resistant cells below control values. These results are consistent with the increase in Pgp expression levels in parental MES-SA cells treated with 3, 6 and 12 µM DEHP for 24 h and compared to untreated controls. All in all, these findings suggest a potential clinical application of DEHP as a chemosensitizer to improve effectiveness of the antineoplastic drugs in MDR human tumours.

Modulation of multidrug resistance p-glycoprotein activity by flavonoids and honokiol in human doxorubicin- resistant sarcoma cells (MES-SA/DX-5): implications for natural sedatives as chemosensitizing agents in cancer therapy.

Multidrug resistance (MDR) in cancer cells is often caused by the high expression of the plasma membrane drug transporter P-glycoprotein (Pgp) associated with an elevated intracellular glutathione (GSH) content in various human tumors. Several chemosensitizers reverse MDR but have significant toxicities. Sedatives are often used to control anxiety and depression in cancer patients. In this in vitro study we investigated the effects of three plant derived sedatives such as apigenin (Api), fisetin (Fis), flavonoids and honokiol (Hnk) on Pgp activity and cellular GSH content in order to evaluate their potential use as chemosensitizing agents in anticancer chemotherapy. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp, were treated with each sedative alone (10 microM) or in combination with different doxo concentrations (2-8 microM). We measured the intracellular accumulation and cytotoxicity of doxo (MTT assay), the cellular GSH content (GSH assay) and ROS production (DFC-DA assay), in comparison with verapamil (Ver), a specific inhibitor for Pgp, used as reference molecule. We found that exposure at 2 and 8 microM doxo concentrations in the presence of Api, Fis and Hnk enhanced significantly doxo accumulation by 29+/-3.3, 20+/-4.8, 24+/-6.6 percent and 14+/-1.7, 8.3+/-4.2, 10.7+/-3.1 percent, respectively, when compared with doxo alone. These results were consistent with the increase of sensitivity towards doxo in MES-SA/Dx5, resulting in 1.7, 1.2, 1.4-fold and 1.2, 1.0 and 1.1-fold increases, respectively. Moreover, treatment with Api decreased markedly cellular GSH content (18 percent) and increased ROS production (greater than 20 percent) on MES-SA/Dx5 cells, while a significant reduction in ROS levels was observed in Hnk and Fis treated cells, when compared to untreated control. Our in vitro findings provide a rationale for innovative clinical trials to assess the use of natural sedatives or their derivatives as potential adjuvants to anticancer treatment for overcoming multidrug resistance Pgp-mediated in cancer patients.

FLASH degradation in response to UV-C results in histone locus bodies disruption and cell-cycle arrest.

Eucaryotic cell nuclei contain a number of different organelles that are highly dynamic structures and respond to a variety of stimuli. Here we investigated the effect of UV irradiation on a recently identified group of organelles, Histone Locus Bodies. Histone Locus Bodies contain at least two main proteins, FLASH and NPAT, and have been shown to be involved in replication-dependent histone gene transcription. We show that these organelles are disrupted after sublethal irradiation and both FLASH and NPAT are degraded, which in turn results in cell-cycle arrest at the S/G2 transition. The effect on the cell cycle is due to reduced transcription of histone genes and restoring normal histone protein levels by stabilizing histone mRNA allows cells to progress through the cell cycle. This provides a novel mechanism of S-phase arrest in response to DNA damage that potentially allows DNA repair before cells continue into mitosis, and thus prevents transmission of genomic alterations.

Antileukotriene drugs: clinical application, effectiveness and safety.

Cysteinyl leukotrienes (Cys-LTs) are potent proinflammatory mediators derived from arachidonic acid through the 5-lypoxigenase (5-LO) pathway. They exert important pharmacological effects by interaction with at least two different receptors: Cys-LT(1) and Cys-LT(2). By competitive binding to the Cys-LT(1) receptor, leukotriene receptor antagonist drugs such as montelukast, zafirlukast, and pranlukast, block the effects of Cys-LTs and alleviate the symptoms of many chronic diseases, especially bronchial asthma and allergic rhinitis. Evidence obtained by randomized clinical trials as also by direct experience derived from patients suffering from asthma and allergic rhinitis justifies a broader role for leukotrienes receptor antagonists (LTRAs). Recently published studies and case reports have demonstrated beneficial effects of LTRAs on other diseases commonly associated with asthma (exercise induced asthma, rhinitis, chronic obstructive pulmonary disease, interstitial lung disease, chronic urticaria, atopic dermatitis, allergic fungal disease, nasal polyposis, and paranasal sinus disease) as well as other diseases not connected to asthma (migraine, respiratory syncytial virus postbronchiolitis, systemic mastocytosis, cystic fibrosis, pancreatitis, vulvovaginal candidiasis, cancer, atherosclerosis, eosinophils cystitis, otitis media, capsular contracture, and eosinophilic gastrointestinal disorders). The aim of this review is to show the most recent applications and effectiveness in clinical practice of the LTRAs.

Plasma lycopene and antioxidant vitamins in asthma: the PLAVA study.

OBJECTIVE: Scientific evidence suggests that lycopene and antioxidant vitamins have significant antioxidant and protective effects. METHODS: This case-control study included 96 subjects (40 asthmatics, 56 healthy control subjects). Baseline blood samples, pulmonary function tests, and clinical and alimentary histories were collected. All subjects were grouped by age, sex, cigarette smoking habit, body mass index, alimentary intake, and atopic status. RESULTS: Serum lycopene concentration was significantly lower in asthmatic subjects than in healthy control subjects (0.10+/-0.7 micromoL/L vs. 0.16+/-0.8 micromoL/L--p<0.001). Serum vitamin A concentration was significantly lower in asthmatics (2.38+/-0.37 micromoL/L) in respect to control subjects (3.06+/-0.56 micromoL/L) (p<0.01). Plasma serum concentration of vitamin E and beta-carotene were not found to be different in the two groups. CONCLUSIONS: Dietary supplementation or adequate intake of lycopene and vitamin A rich foods may be beneficial in asthmatic subjects.

High levels of antioxidant enzymatic defence assure good protection against hypoxic stress in spontaneously diabetic rats.

Recent data from literature report that reactive oxygen species (ROS) seem to play a crucial role in the etiology of both types I and II diabetes. This may render diabetic individuals more prone to oxidative injury when challenged with hypoxic stress. It is in fact well known that many diabetic complications cause ischaemic episodes, with a consequent reduction in oxygen supply to various tissues and organs. To check this hypothesis, in this work we tested type I diabetic individuals' antioxidant capability towards a hypoxic-mediated oxidative challenge. In particular, spontaneously diabetic and age-matched non-diabetic biobreeding (BB) Wistar rats were submitted to chronic normobaric hypoxia, and the response of antioxidant enzymes, as well as redox-sensitive transcription factor NF-kappaB and p53, were monitored. Results show that diabetic subjects present a dramatic enhancement in the major antioxidant enzymes activities, thus supporting the notion of diabetes-related changes in cellular redox status. This allows diabetic individuals to counteract hypoxia-mediated oxidative challenge better than the non-diabetic counterpart. Also the behaviour of both the redox-sensitive nuclear transcription factor NF-kappaB and p53 protein in response to hypoxic stimulation seems to support the hypothesis of a better ROS scavenging efficiency in diabetics under hypoxic conditions. In conclusion, high levels of antioxidant enzymatic defences in diabetic BB rats reflect a positive adaptive response able to assure an efficient protection not only against chronic, diabetes-mediated reactive oxygen species (ROS) overproduction, but also versus further oxidative damage.

Prevalence and severity of airway obstruction in an Italian adult population.

BACKGROUND: This study sets out to estimate the prevalence and the degree of severity of bronchial obstruction in an adult population with three different diagnostic criteria: the European Respiratory Society (ERS), the American Thoracic Society (ATS), and the World Health Organization (WHO) defined as Global Obstructive Lung Disease (GOLD). METHODS: 1514 subjects underwent complete medical evaluation and spirometry. RESULTS: The prevalence of bronchial obstruction was respectively 27.5 % (ERS), 33% (GOLD), and 47.3 % (ATS). The prevalence of bronchial obstruction in the smoker group was 33.4% (ERS), 38.1% (GOLD), and 52.3% (ATS). The prevalence of obstruction in the ex-smoker group was 33% (ERS), 41.4% (GOLD), and 57.1% (ATS). The prevalence of obstruction in the non-smoker group was 21.1% (ERS), 24.9% (GOLD), and 38.6% (ATS). CONCLUSIONS: The results show that the prevalence of airway obstruction increases proportionally with age; the cigarette smoking represents an important conditioning factor. These observations warrant the necessity of a more complete and multi-parametric analysis in the evaluation of patients with airway obstruction using methodologies that explore the functional state and the risk factors that cause the airway obstruction.

Food-intake and nutrients pattern in Italian adult male subjects.

Energy is necessary for all physiological functions of the body. Most of the vitamins are enzymes that require additional mineral as cofactors. Aim of the study was to evaluate the food intake and nutrients pattern in an adult population. 620 subjects underwent a complete medical visit, and filling the EPIC alimentary questionnaire. Comparison between nutrients intake and level assumption recommended nutrients (LARN) was assessed using one way analysis of variance (ANOVA) with Tukey-Kramer multiple comparison test. The daily medium caloric intake was 1837 +/- 654 Kcal. The daily mean iron assumption was 15.72 mg/die, statistically significant compared to 10 mg/die (LARN value) (p < 0.001). The calcium and zinc assumption was respectively 908.36 mg/die and 12.73 mg/die statistically different compared to 800 mg/die and 10 mg/die (LARN values) (p < 0.01). The assumption of the niacin was 20.24 mg/die significant different to 1.8 mg/die (LARN value) (p < 0.001). The assumption of vitamin A and C was respectively 1012.6 mcg/die and 142.92 mg/die significant different compared to 700 mcg/die and 60 mg/die (LARN values) (p < 0.01). The alimentary habits of the examined subjects did not present significant disequilibrium and evidenced a regular and good intake of micronutrients with anti-oxidative and anti-neoplastic activity.

Influence of cigarette smoking on vitamin E, vitamin A, beta-carotene and lycopene concentrations in human pre-ovulatory follicular fluid.

Increasing evidence suggests that fat soluble vitamins and micronutrients have the potential for local modulation of follicular development. Cigarette smoking has been associated with accelerated follicular depletion and derangement of reproductive functions. The present study was initiated to investigate the impact of cigarette smoking on follicular and plasma concentrations of vitamin A, vitamin E, lycopene and beta-carotene. Samples were collected from 17 smokers and 43 non-smoking women undergoing assisted reproduction techniques. Assays were carried out by a reverse-phase high-pressure liquid chromatography (HPLC) method. Smokers had significantly (P < 0.05) lower levels of follicular fluid beta-carotene in comparison to non-smokers (0.02 +/- 0.02 vs. 0.09 +/- 0.02, respectively). No other significant influences on follicular and plasma concentrations were noted. Smokers showed a significantly (P < 0.05) lower fertilization rate in comparison to non-smokers, (55.9 % vs. 71.5 % , respectively). It is postulated that follicular depletion of the antioxidant beta-carotene occurs in response to oxidative stress imposed by cigarette smoke.

Prevalence of bronchial asthma in patients with endoscopically-documented esophagitis.

The association of gastroesophageal reflux, esophagitis, and asthma has been studied for a long time, but the results are often conflicting. The aim of this study is to evaluate the prevalence of bronchial asthma and the presence of extra-esophageal symptoms in subjects with endoscopically-documented reflux esophagitis. Forty patients were divided into 2 groups: group A (22 patients) affected by endoscopically-documented esophagitis, and group B (18 patients) with positive endoscopic examination for other pathologies of the gastroenteric tract. All of the patients underwent complete medical examination, skin-prick tests, esophageal-gastric-endoscopy, and pulmonary function tests (basal and after methacholine). The prevalence of asthma was 30% in group A vs 10% in group B (odds ratio = 2.57; confidence interval = 0.75-10.25). Relationships between chronic cough and esophagitis (p<0.01) and between chronic cough and asthma (p<0.05) were found. No significant relationships were observed between esophagitis and the other respiratory symptoms considered (wheezing, chest tightness, hoarseness, bronchospasm, and dysphagia). The results confirm the increased prevalence of asthma in patients with esophagitis and they emphasize the role of gastroesophageal reflux as a trigger factor for asthma. Chronic cough represents an important symptom of asthma in subjects with esophagitis.

Atherosclerotic plaque formation and risk factors.

Atherosclerosis (AT) is a progressive disease characterized by the accumulation of lipids, fibrous materials, and mineral in the arteries. Although many generalized or systemic risk factors predispose to its development, AT affect various regions of the circulation preferentially and yields distinct clinical manifestations depending on the particular circulatory bed affected. The progression of AT is currently believed to involve the interaction of endothelium, monocytes, and leukocytes, as well as the influences of cytokines, oxidized lipoproteins, hypertension, tobacco use, dyslipidemia, homocystinemia, and genetic determinants.