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

Pharmacological activation of autophagy favors the clearing of intracellular aggregates of misfolded prion protein peptide to prevent neuronal death

According to the "gain-of-toxicity mechanism", neuronal loss during cerebral proteinopathies is caused by accumulation of aggregation-prone conformers of misfolded cellular proteins, although it is still debated which aggregation state actually corresponds to the neurotoxic entity. Autophagy, originally described as a variant of programmed cell death, is now emerging as a crucial mechanism for cell survival in response to a variety of cell stressors, including nutrient deprivation, damage of cytoplasmic organelles, or accumulation of misfolded proteins. Impairment of autophagic flux in neurons often associates with neurodegeneration during cerebral amyloidosis, suggesting a role in clearing neurons from aggregation-prone misfolded proteins. Thus, autophagy may represent a target for innovative therapies. In this work, we show that alterations of autophagy progression occur in neurons following in vitro exposure to the amyloidogenic and neurotoxic prion protein-derived peptide PrP90-231. We report that the increase of autophagic flux represents a strategy adopted by neurons to survive the intracellular accumulation of misfolded PrP90-231. In particular, PrP90-231 internalization in A1 murine mesencephalic neurons occurs in acidic structures, showing electron microscopy hallmarks of autophagosomes and autophagolysosomes. However, these structures do not undergo resolution and accumulate in cytosol, suggesting that, in the presence of PrP90-231, autophagy is activated but its progression is impaired; the inability to clear PrP90-231 via autophagy induces cytotoxicity, causing impairment of lysosomal integrity and cytosolic diffusion of hydrolytic enzymes. Conversely, the induction of autophagy by pharmacological  blockade of mTOR kinase or trophic factor deprivation restored autophagy resolution, reducing intracellular PrP90-231 accumulation and neuronal death. Taken together, these data indicate that PrP90-231 internalization induces an autophagic defensive response in A1 neurons, although incomplete and insufficient to grant survival; the pharmacological enhancement of this process exerts neuroprotection favoring the clearing of the internalized peptide and could represents a promising neuroprotective tool for neurodegenerative proteinopathies

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumorinitiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype

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

Potential of Energy Saving of Propane Heat Pump as replacement of gas boilers with low and high temperature emitters

This work deals with the analysis of the energy performance and the environmental impact of a Heating, Ventilation and Air Conditioning (HVAC) system based on an innovative Air-to-Water electrical Heat Pump (AWHP) using propane (R290) as the refrigerant. A building of the University of Bologna located in Forlì (North of Italy) is considered for replacing a condensing gas boiler and a conventional chiller with an AWHP using R290. To evaluate the efficiency of the existing heating system and the potential savings linked to the adoption of the propane AWHP, the building energy model was created and calibrated by collecting monthly thermal and electrical consumptions as a function of the actual climate data. In this paper, the main features of the R290-based AWHP are described in detail by emphasising the device performance as a function of the operating conditions (i.e., air and water temperature and speed of the scroll compressor). A series of scenarios have been studied to evaluate the energy performance of the propane AWHP with respect to the reference scenario under various operating conditions. The results show that while the total primary energy demand increases adopting the propane AWHP with respect to the case of a gas boiler, the non-renewable primary energy fraction decreases significantly, with a dramatic increase in the renewable quote. From an economic point of view, lower annual costs are obtained by adopting a propane AWHP coupled to fan coils, mainly when the electrical heat pump is used in a thermally insulated building in which a photovoltaic system is installed

MT. ETNA FEBRUARY-APRIL 2013 ERUPTION

European FP7 MED-SUV (MEditerranean SUpersite Volcanoes). Grant Number: 308665 European Research Council European FP7 (FP/2007-2013)/ERC. Grant Number: 279802 SIGMA (Sistema Integrato di sensori in ambiente cloud per la Gestione Multirischio Avanzata