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Activated phosphoinositide 3-kinase (PI3Kδ) Syndrome (APDS) is an inborn error of immunity (IEI) with a variable clinical presentation, characterized by infection susceptibility and immune dysregulation that may overlaps with other Primary Immune Regulatory Disorders (PIRDs). The rarity of the disease, its recent discovery, and the multiform /multifaced clinical presentation make it difficult to establish a correct diagnosis, especially at an early stage. As a result, the true prevalence of the pathology remains unknown. There is no treatment protocol for APDS, and drug therapy is primarily focused on treating symptoms. The most common therapies include immunoglobulin replacement therapy, antimicrobial prophylaxis, and immunosuppressive drugs. Hematopoietic stem cell transplantation (HSCT) has been used in some cases, but the risk-benefit balance remains unclear. With the upcoming introduction of specific medications, such as selective inhibitors for PI3Kδ, clinicians are shifting their attention towards target therapy. This review provides a comprehensive overview of APDS with a focus on diagnostic and treatments procedures available. This review may be useful in implementing strategies for a more efficient patients' management and therapeutic interventions. Main Text. [ABSTRACT FROM AUTHOR]

Context: Bergamot, mainly produced in the Ionian coastal areas of Southern Italy (Calabria), has been used since 1700 for its balsamic and medicinal properties. Phytochemical profiling has confirmed that bergamot juices are rich in flavonoids, including flavone and flavanone glycosides which are responsible for its beneficial effects. Objective: Recently, it was shown that the combination of natural compounds with conventional treatments improves the efficacy of anticancer therapies. Natural compounds with anticancer properties attack cancerous cells without being toxic to healthy cells. Bergamot can induce cytotoxic and apoptotic effects and prevent cell proliferation in various cancer cells. Methods: In this review, the antiproliferative, pro-apoptotic, anti-inflammatory, and antioxidant effects of bergamot are described. Information was compiled from databases such as PubMed, Web of Science, and Google Scholar using the key words 'bergamot' accompanied by 'inflammation' and, 'cancer' for data published from 2015–2021. Results:In vitro and in vivo studies provided evidence that different forms of bergamot (extract, juice, essential oil, and polyphenolic fraction) can affect several mechanisms that lead to anti-proliferative and pro-apoptotic effects that decrease cell growth, as well as anti-inflammatory and antioxidant effects. Conclusions: Considering the effects of bergamot and its new formulations, we affirm the importance of its rational use in humans and illustrate how bergamot can be utilized in clinical applications. Numerous studies evaluated the effect of new bergamot formulations that can affect the absorption and, therefore, the final effects by altering the therapeutic profile of bergamot and enhancing the scientific knowledge of bergamot. [ABSTRACT FROM AUTHOR]

Vinca sardoa (Stearn) Pignatti, known as Sardinian periwinkle, is widely diffused in Sardinia (Italy). This species contains indole alkaloids, which are known to have a great variety of biological activities. This study investigated the antileukemic activity against a B lymphoblast cell line (SUP-B15) of V. sardoa alkaloid-rich extracts obtained from plants grown in Italy, in Iglesias (Sardinia) and Rome (Latium). All the extracts showed a good capacity to induce reductions in cell proliferation of up to 50% at the tested concentrations (1–15 µg/mL). Moreover, none of the extracts showed cytotoxicity on normal cells at all the studied concentrations. [ABSTRACT FROM AUTHOR]

Background: Children with Down syndrome (DS) show a high susceptibility to recurrent infections (RI), caused by immune defects and abnormalities of the airways. Our goal was to investigate the effects of Pidotimod on RI prevention in children with DS, comparing immune and clinical parameters before (T0) and after (T1) the treatment with Pidotimod. Methods: The study was conducted at the Down syndrome outpatient Center of Bambino Gesù Children's Hospital, in Rome. We reviewed the medical records of all children with a positive history for RI and who received oral prophylaxis of Pidotimod from September 2016 to February 2017. Results: Thirty-three children met the inclusion criteria (males: 51.5%; average age: 6 years ±SD: 3). We found a significant decrease in the number of children with upper respiratory infections (82% at T0 vs 24% at T1; p = 0,0001) and with lower respiratory infections (36% at T0 vs 9% at T1; p = 0.003) after treatment with Pidotimod. We also demonstrated a significant decrease in the number of children hospitalized for respiratory infections (18% at T0 vs 3% at T1; p = 0.03). We measured T and B cells in the peripheral blood and B cell function in vitro at T0 and T1. We found that the response to CpG improved at T1. A significant increase of B cell frequency (p = 0.0009), B cell proliferation (p = 0.0278) and IgM secretion (p = 0.0478) were observed in children with DS after treatment. Conclusions: Our results provided evidence that Pidotimod may be able to prevent RI in children with Down syndrome. [ABSTRACT FROM AUTHOR]

Natural substances produced by venomous marine organisms are thought to be possible sources of useful compounds and new drugs having the potential to open new ways for pharmacology, nutrition and environmental applications. In this framework, cnidarians are very interesting being widely distributed and all are venomous organisms; so, a deep knowledge of their occurrence, morphology of venomous structures and of effects of venoms at cellular level is fundamental to evaluate the possible utilization of venomous compounds or extracts. In this research, the morphology and occurrence of nematocysts in two cnidarian species (Aurelia aurita , Velella velella), and the preliminary evaluation of the cytotoxicity of V. velella crude extract, of which cytotoxicity on cell cultures at present is unknown, were considered. The specimens were sampled in Güllük Bay, Southwestern coast of Turkey, and in the Gulf of Genova, Northwestern coast of Italy. Six nematocyst types (a-isorhiza, A-isorhiza, O-isorhiza, eurytele, polyspiras, birhopaloid) having different sizes, were observed in A. aurita , and two types (eurytele and stenotele) in V. velella. The crude extract from V. velella showed cytotoxic activity against cultured fibroblasts L929 at high doses, while inducing cell proliferation at low doses. The protein content in the extract increased remarkably after disruption of nematocysts. Image 1098 • The shape of some nematocyst types differs in A. aurita sampled in different zones. • Nematocyst number-bell diameter relationship was not observed in A. aurita. • Only eurytele and stenotele nematocyst types were observed in V. velella. • High doses of V. velella crude venom caused decrease of survival in L929 cells. • Low doses of V. velella crude venom had positive effects on L929 cells. [ABSTRACT FROM AUTHOR]

Background: Sclerosing nevus with pseudomelanomatous features (SNPFs) is a clinical and pathologic entity that mimics melanoma both clinically and histologically. The lesion is a melanocytic nevus, histologically characterized by fibrosis and a pseudomelanomatous proliferation. It is typically seen in young to middle‐aged individuals, mainly on the back, where microtrauma or inflammatory changes are more frequent. Dermoscopic description of SNPF has been reported so far in one case series. Objective: The aim of our study was to describe the dermoscopic and confocal features of SNPF. Methods: Histopathologically confirmed cases of SNPF were retrospectively collected from three referral centres in Italy. Only lesions with available clinical, dermoscopic and histopathological data were included; confocal images were also retrieved, when available. Lesions were evaluated for the presence of 12 dermoscopic and five confocal criteria previously described. Results: The study population included 93 lesions in as many patients (71 men and 22 women; median age: 38 years). Dermoscopically, we found a predominance of dark colours, in particular brown and blue, which were found in all lesions and the vast majority of the lesions (86/93; 92.5%) displayed at least one structureless area. By the combination of colours and structures, we observed that the majority of the lesions (67/92; 72%) were characterized by more than one structure and more than one colour. Confocal evaluation was performed on a subset of 24/93 lesions showing a regular architecture pattern (19/24 cases, 79%), with a predominance of the ringed pattern. The presence of focal cytologic atypia at the dermal‐epidermal junction was present in 12/24 cases (50%) with a prevalent dendritic‐shaped cell proliferation. Conclusions: The current study demonstrated that SNPF was frequently characterized, on dermoscopic examination, by more than one structure and more than one colour and on confocal microscopy by a regular ringed pattern with focal dendritic atypical cells. [ABSTRACT FROM AUTHOR]

Vitis vinifera cv Falanghina is an ancient grape variety of Southern Italy. A thorough phytochemical analysis of the Falanghina leaves was conducted to investigate its specialised metabolite content. Along with already known molecules, such as caftaric acid, quercetin-3- O -β- d -glucopyranoside, quercetin-3- O -β- d -glucuronide, kaempferol-3- O -β- d -glucopyranoside and kaempferol-3- O -β- d -glucuronide, a previously undescribed biflavonoid was identified. For this last compound, a moderate bioactivity against metastatic melanoma cells proliferation was discovered. This datum can be of some interest to researchers studying human melanoma. The high content in antioxidant glycosylated flavonoids supports the exploitation of grape vine leaves as an inexpensive source of natural products for the food industry and for both pharmaceutical and nutraceutical companies. Additionally, this study offers important insights into the plant physiology, thus prompting possible technological researches of genetic selection based on the vine adaptation to specific pedo-climatic environments. [ABSTRACT FROM AUTHOR]

Abstract: Human type II alveolar cells (A549) were exposed to aqueous- and organic-solvent PM10 extracts to evaluate their effects on cell proliferation, proinflammatory cytokine release and cytotoxicity (assayed by lactate dehydrogenase, LDH, activity). PM10 samples collected in Torino (northwest Italy) were analysed for inorganic chemical species (bioavailable iron and secondary particulates) and endotoxins, which are potentially inflammatory promoters in human airways. During the sampling period, PM10 concentration was 55.4±39.1μg/m3, secondary particles constituted 42±9% of the PM10 total mass, and bioavailable iron concentration was 0.078±0.095μg/m3. PM10 inhibits cell proliferation and induces both IL-6 and LDH release in a dose- and time-dependent manner, with a seasonal trend. The different effects of aqueous and organic PM10 extracts demonstrate the importance of particle composition for the induction of cytotoxic effects on A549 cells. A first comparison between the biological effects induced by PM10 extracts and PM10 components was performed. [Copyright &y& Elsevier]

Abstract: Mature apples of ‘Fuji’ and ‘Fuji’ sports sourced from around the world were found to possess clumps of multicellular, branched callus hairs in the outer 17mm of the outer cortex. The clumps of callus hairs were particularly well developed in samples of ‘Fuji Suprema’ from Brazil, moderately developed in ‘Fuji KIKU’ from Italy and in ‘Fuji’ from South Africa, Chile, New Zealand and the USA, and were consistently least developed in ‘Fuji’ from China. These previously unreported callus hairs grow in the intercellular air spaces between the parenchyma cells and also in larger air lacunae in the apple flesh. In both of these locations they have the potential to reduce the efficiency of gas exchange into and out of the fruit during storage. Initial observations suggest that the callus hairs within a clump do not continue to develop after harvest. In ripe apples, the cells of the callus hairs contain chlorophyll and starch and under UV light the contents of the vacuoles autofluoresce an intense blue colour. The outer surface of each callus hair cell is covered with characteristic globular protuberances which attach the hairs to each other and to the surrounding parenchyma. After a period of storage, many of the clumps of callus hairs remain packed with starch granules even though starch has been metabolised from the surrounding parenchyma. [Copyright &y& Elsevier]

Abstract: Workshop participants agreed that genotoxicity tests in mammalian cells in vitro produce a remarkably high and unacceptable occurrence of irrelevant positive results (e.g. when compared with rodent carcinogenicity). As reported in several recent reviews, the rate of irrelevant positives (i.e. low specificity) for some studies using in vitro methods (when compared to this “gold standard”) means that an increased number of test articles are subjected to additional in vivo genotoxicity testing, in many cases before, e.g. the efficacy (in the case of pharmaceuticals) of the compound has been evaluated. If in vitro tests were more predictive for in vivo genotoxicity and carcinogenicity (i.e. fewer false positives) then there would be a significant reduction in the number of animals used. Beyond animal (or human) carcinogenicity as the “gold standard”, it is acknowledged that genotoxicity tests provide much information about cellular behaviour, cell division processes and cellular fate to a (geno)toxic insult. Since the disease impact of these effects is seldom known, and a verification of relevant toxicity is normally also the subject of (sub)chronic animal studies, the prediction of in vivo relevant results from in vitro genotoxicity tests is also important for aspects that may not have a direct impact on carcinogenesis as the ultimate endpoint of concern. In order to address the high rate of in vitro false positive results, a 2-day workshop was held at the European Centre for the Validation of Alternative Methods (ECVAM), Ispra, Italy in April 2006. More than 20 genotoxicity experts from academia, government and industry were invited to review data from the currently available cell systems, to discuss whether there exist cells and test systems that have a reduced tendency to false positive results, to review potential modifications to existing protocols and cell systems that might result in improved specificity, and to review the performance of some new test systems that show promise of improved specificity without sacrificing sensitivity. It was concluded that better guidance on the likely mechanisms resulting in positive results that are not biologically relevant for human health, and how to obtain evidence for those mechanisms, is needed both for practitioners and regulatory reviewers. Participants discussed the fact that cell lines commonly used for genotoxicity testing have a number of deficiencies that may contribute to the high false positive rate. These include, amongst others, lack of normal metabolism leading to reliance on exogenous metabolic activation systems (e.g. Aroclor-induced rat S9), impaired p53 function and altered DNA repair capability. The high concentrations of test chemicals (i.e. 10mM or 5000μg/ml, unless precluded by solubility or excessive toxicity) and the high levels of cytotoxicity currently required in mammalian cell genotoxicity tests were discussed as further potential sources of false positive results. Even if the goal is to detect carcinogens with short in vitro tests under more or less acute conditions, it does not seem logical to exceed the capabilities of cellular metabolic turnover, activation and defence processes. The concept of “promiscuous activation” was discussed. For numerous mutagens, the decisive in vivo enzymes are missing in vitro. However, if the substrate concentration is increased sufficiently, some other enzymes (that are unimportant in vivo) may take over the activation—leading to the same or a different active metabolite. Since we often do not use the right enzyme systems for positive controls in vitro, we have to rely on their promiscuous activation, i.e. to use excessive concentrations to get an empirical correlation between genotoxicity and carcinogenicity. A thorough review of published and industry data is urgently needed to determine whether the currently required limit concentration of 10mM or 5000μg/ml, and high levels of cytotoxicity, are necessary for the detection of in vivo genotoxins and DNA-reactive, mutagenic carcinogens. In addition, various measures of cytotoxicity are currently allowable under OECD test guidelines, but there are few comparative data on whether different measures would result in different maximum concentrations for testing. A detailed comparison of cytotoxicity assessment strategies is needed. An assessment of whether test endpoints can be selected that are not intrinsically associated with cytotoxicity, and therefore are less susceptible to artefacts produced by cytotoxicity, should also be undertaken. There was agreement amongst the workshop participants that cell systems which are p53 and DNA-repair proficient, and have defined Phase 1 and Phase 2 metabolism, covering a broad set of enzyme forms, and used within the context of appropriately set limits of concentration and cytotoxicity, offer the best hope for reduced false positives. Whilst there is some evidence that human lymphocytes are less susceptible to false positives than the current rodent cell lines, other cell systems based on HepG2, TK6 and MCL-5 cells, as well as 3D skin models based on primary human keratinocytes also show some promise. Other human cell lines such as HepaRG, and human stem cells (the target for carcinogenicity) have not been used for genotoxicity investigations and should be considered for evaluation. Genetic engineering is also a valuable tool to incorporate missing enzyme systems into target cells. A collaborative research programme is needed to identify, further develop and evaluate new cell systems with appropriate sensitivity but improved specificity. In order to review current data for selection of appropriate top concentrations, measures and levels of cytotoxicity, metabolism, and to be able to improve existing or validate new assay systems, the participants called for the establishment of an expert group to identify the in vivo genotoxins and DNA-reactive, mutagenic carcinogens that we expect our in vitro genotoxicity assays to detect as well as the non-genotoxins and non-carcinogens we expect them not to detect. [Copyright &y& Elsevier]

The article offers information on the Second Hippo Tumor Suppressor Pathway Workshop that was held on November 2-5, 2010 at Chigi Palace in Ariccia, Rome, Italy. The workshop discusses the role of drosophila, which has Hippo (Hpo) kinase cascade, in the regulation of cell proliferation and apoptosis. The workshop also explains the association of Hpo pathway with ovarian and liver cancer.

Abstract: An 18-year-old female lion (Panthera leo) was referred to the Department of Animal Pathology of the University of Turin (Italy). At necropsy, multiple nodular, 4–20-mm, confluent white firm nodules were scattered throughout the pleural surfaces of the thoracic wall and of the lungs. Histological lesions were represented by proliferations of papillary structures lined by cuboidal basophilic mesothelial cells with large, oval nuclei and abundant granular eosinophilic cytoplasm. Immunohistochemistry revealed immunoreactivity for pancytokeratin and vimentin. None of the cells expressed calretinin antigen. Asbestos fibers and asbestos bodies were not detected respectively by light microscopy and by Scanning Electron Microscope–Energy Dispersive Spectrometer investigations. On the contrary, chrysotile asbestos were identified in samples from shelter material. Histological and immunohistochemical findings were consistent with the diagnosis of an epithelial malignant mesothelioma. To our best knowledge, this is the first report of a pleural mesothelioma in a lion. [Copyright &y& Elsevier]