Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells

Pituitary adenomas, accounting for 15% of diagnosed intracranial neoplasms, are usually benign and pharmacologically and surgically treatable; however, the critical location, mass effects and hormone hypersecretion sustain their significant morbidity. Approximately 35% of pituitary tumors show a less benign course since they are highly proliferative and invasive, poorly resectable, and likely recurring. The latest WHO classification of pituitary tumors includes pituitary transcription factor assessment to determine adenohypophysis cell lineages and accurate designation of adenomas, nevertheless little is known about molecular and cellular pathways which contribute to pituitary tumorigenesis. In malignant tumors the identification of cancer stem cells radically changed the concepts of both tumorigenesis and pharmacological approaches. Cancer stem cells are defined as a subset of undifferentiated transformed cells from which the bulk of cancer cells populating a tumor mass is generated. These cells are able to self-renew, promoting tumor progression and recurrence of malignant tumors, also conferring cytotoxic drug resistance. On the other hand, the existence of stem cells within benign tumors is still debated. The presence of adult stem cells in human and murine pituitaries where they sustain the high plasticity of hormone-producing cells, allowed the hypothesis that putative tumor stem cells might exist in pituitary adenomas, reinforcing the concept that the cancer stem cell model could also be applied to pituitary tumorigenesis. In the last few years, the isolation and phenotypic characterization of putative pituitary adenoma stem-like cells was performed using a wide and heterogeneous variety of experimental models and techniques, although the role of these cells in adenoma initiation and progression is still not completely definite. The assessment of possible pituitary adenoma-initiating cell population would be of extreme relevance to better understand pituitary tumor biology and to identify novel potential diagnostic markers and pharmacological targets. In this review, we summarize the most updated studies focused on the definition of pituitary adenoma stem cell phenotype and functional features, highlighting the biological processes and intracellular pathways potentially involved in driving tumor growth, relapse, and therapy resistance

Emerging Role of Cellular Prion Protein in the Maintenance and Expansion of Glioma Stem Cells

Cellular prion protein (PrPC) is a membrane-anchored glycoprotein representing the physiological counterpart of PrP scrapie (PrPSc), which plays a pathogenetic role in prion diseases. Relatively little information is however available about physiological role of PrPC. Although PrPC ablation in mice does not induce lethal phenotypes, impairment of neuronal and bone marrow plasticity was reported in embryos and adult animals. In neurons, PrPC stimulates neurite growth, prevents oxidative stress-dependent cell death, and favors antiapoptotic signaling. However, PrPC activity is not restricted to post-mitotic neurons, but promotes cell proliferation and migration during embryogenesis and tissue regeneration in adult. PrPC acts as scaold to stabilize the binding between dierent membrane receptors, growth factors, and basement proteins, contributing to tumorigenesis. Indeed, ablation of PrPC expression reduces cancer cell proliferation and migration and restores cell sensitivity to chemotherapy. Conversely, PrPC overexpression in cancer stem cells (CSCs) from dierent tumors, including gliomas\u2014the most malignant brain tumors\u2014is predictive for poor prognosis, and correlates with relapses. The mechanisms of the PrPC role in tumorigenesis and its molecular partners in this activity are the topic of the present review, with a particular focus on PrPC contribution to glioma CSCs multipotency, invasiveness, and tumorigenicity

Neurodegeneration in Alzheimer Disease: Role of Amyloid Precursor Protein and Presenilin 1 Intracellular Signaling

Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder characterized by (1) progressive loss of synapses and neurons, (2) intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3) amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2). The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration

Monitoring the December 2015 summit eruptions of Mt. Etna (Italy): Implications on eruptive dynamics

A lengthy period of eruptive activity fromthe summit craters ofMt. Etna started in January 2011. It culminated in early December 2015 with a spectacular sequence of intense eruptive events involving all four summit craters (Voragine, Bocca Nuova,NewSoutheast Crater, and Northeast Crater). The activity consisted of high eruption columns, Strombolian explosions, lava flows andwidespread ash falls that repeatedly interferedwith air traffic. The most powerful episode occurred on 3 December 2015 from the Voragine. After three further potent episodes fromthe Voragine, activity shifted to the NewSoutheast Crater on 6 December 2015, where Strombolian activity and lava flow emission lasted for two days and were fed by the most primitive magma of the study period. Activity once more shifted to the Northeast Crater, where ash emission and weak Strombolian activity took place for several days. Sporadic ash emissions from all craters continued until 18 December, when all activity ceased. Although resembling the summit eruptions of 1998–1999, which also involved all four summit craters, thismultifaceted eruptive sequence occurred in an exceptionally short time window of less than three days, unprecedented in the recent activity of Mt. Etna. It also produced important morphostructural changes of the summit area with the coalescence of Voragine and Bocca Nuova in a single large crater, the “Central Crater”, reproducing themorphological setting of the summit cone before the formation of Bocca Nuova in 1968. The December 2015 volcanic crisis was followed closely by the staff of the Etna Observatory to monitor the on-going activity and forecast its evolution, in accordance with protocols agreed with the Italian Civil Protection Department.Published53-695V. Dinamica dei processi eruttivi e post-eruttiviJCR Journa

Beta-caryophyllene exhibits anti-proliferative effects through apoptosis induction and cell cycle modulation in multiple myeloma cells

Cannabinoid receptors, which are widely distributed in the body, have been considered as possible pharmacological targets for the management of several tumors. Cannabinoid type 2 receptors (CB2Rs) belong to the G protein-coupled receptor family and are mainly expressed in hematopoietic and immune cells, such as B-cells, T-cells, and macrophages; thus, CB2R activation might be useful for treating cancers affecting plasma cells, such as multiple myeloma (MM). Previous studies have shown that CB2R stimulation may have anti-proliferative effects; therefore, the purpose of the present study was to explore the antitumor effect of beta-caryophyllene (BCP), a CB2R agonist, in an in vitro model of MM. Dexamethasone-resistant (MM.1R) and sensitive (MM.1S) human multiple myeloma cell lines were used in this study. Cells were treated with different concentrations of BCP for 24 h, and a group of cells was pre-incubated with AM630, a specific CB2R antagonist. BCP treatment reduced cell proliferation through CB2R stimulation; notably, BCP considerably increased the pro-apoptotic protein Bax and decreased the anti-apoptotic molecule Bcl-2. Furthermore, an increase in caspase 3 protein levels was detected following BCP incubation, thus demonstrating its anti-proliferative effect through apoptosis activation. In addition, BCP regulated AKT, Wnt1, and beta-catenin expression, showing that CB2R stimulation may decrease cancer cell proliferation by modulating Wnt/β-catenin signaling. These effects were counteracted by AM630 co-incubation, thus confirming that BCP’s mechanism of action is mainly related to CB2R modulation. A decrease in β-catenin regulated the impaired cell cycle and especially promoted cyclin D1 and CDK 4/6 reduction. Taken together, these data revealed that BCP might have significant and effective anti-cancer and anti-proliferative effects in MM cells by activating apoptosis, modulating different molecular pathways, and downregulating the cell cycle

The mechanisms of humic substances self-assembly with biological molecules: The case study of the prion protein

Humic substances (HS) are the largest constituent of soil organic matter and are considered as a key component of the terrestrial ecosystem. HS may facilitate the transport of organic and inorganic molecules, as well as the sorption interactions with environmentally relevant proteins such as prions. Prions enter the environment through shedding from live hosts, facilitating a sustained incidence of animal prion diseases such as Chronic Wasting Disease and scrapie in cervid and ovine populations, respectively. Changes in prion structure upon environmental exposure may be significant as they can affect prion infectivity and disease pathology. Despite its relevance, the mechanisms of prion interaction with HS are still not completely understood. The goal of this work is to advance a structural-level picture of the encapsulation of recombinant, non-infectious, prion protein (PrP) into different natural HS. We observed that PrP precipitation upon addition of HS is mainly driven by a mechanism of “salting-out” whereby PrP molecules are rapidly removed from the solution and aggregate in insoluble adducts with humic molecules. Importantly, this process does not alter the protein folding since insoluble PrP retains its α-helical content when in complex with HS. The observed ability of HS to promote PrP insolubilization without altering its secondary structure may have potential relevance in the context of “prion ecology”. These results suggest that soil organic matter interacts with prions possibly without altering the protein structures. This may facilitate prions preservation from biotic and abiotic degradation leading to their accumulation in the environment

A giant impact as the likely origin of different twins in the Kepler-107 exoplanet system

Measures of exoplanet bulk densities indicate that small exoplanets with radius less than 3 Earth radii ($R_\oplus$) range from low-density sub-Neptunes containing volatile elements to higher density rocky planets with Earth-like or iron-rich (Mercury-like) compositions. Such astonishing diversity in observed small exoplanet compositions may be the product of different initial conditions of the planet-formation process and/or different evolutionary paths that altered the planetary properties after formation. Planet evolution may be especially affected by either photoevaporative mass loss induced by high stellar X-ray and extreme ultraviolet (XUV) flux or giant impacts. Although there is some evidence for the former, there are no unambiguous findings so far about the occurrence of giant impacts in an exoplanet system. Here, we characterize the two innermost planets of the compact and near-resonant system Kepler-107. We show that they have nearly identical radii (about $1.5-1.6~R_\oplus$), but the outer planet Kepler-107c is more than twice as dense (about $12.6~\rm g\,cm^{-3}$) as the innermost Kepler-107b (about $5.3~\rm g\,cm^{-3}$). In consequence, Kepler-107c must have a larger iron core fraction than Kepler-107b. This imbalance cannot be explained by the stellar XUV irradiation, which would conversely make the more-irradiated and less-massive planet Kepler-107b denser than Kepler-107c. Instead, the dissimilar densities are consistent with a giant impact event on Kepler-107c that would have stripped off part of its silicate mantle. This hypothesis is supported by theoretical predictions from collisional mantle stripping, which match the mass and radius of Kepler-107c.Comment: Published in Nature Astronomy on 4 February 2019, 35 pages including Supplementary Information materia

Gaussian Parameters Correlate with the Spread of COVID-19 Pandemic: The Italian Case

Until today, numerous models have been formulated to predict the spreading of Covid-19. Among them, the actively discussed susceptible-infected-removed (SIR) model is one of the most reliable. Unfortunately, many factors (i.e., social behaviors) can influence the outcomes as well as the occurrence of multiple contributions corresponding to multiple waves. Therefore, for a reliable evaluation of the conversion rates, data need to be continuously updated and analyzed. In this work, we propose a model using Gaussian functions, coming from the solution of an ordinary differential equation representing a logistic model, able to describe the growth rate of infected, deceased and recovered people in Italy. We correlate the Gaussian parameters with the number of people affected by COVID-19 as a function of the large-scale anti-contagion control measures strength, and also of vaccines effects adopted to reach herd immunity. The superposition of gaussian curves allow modeling the growth rate of the total cases, deceased and recovered people and reproducing the corresponding cumulative distribution and probability density functions. Moreover, we try to predict a time interval in which all people will be infected or vaccinated (with at least one dose) and/or the time end of pandemic in Italy when all people have been infected or vaccinated with two doses