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Background: Eosinophilic esophagitis (EoE) is increasingly diagnosed in patients with dysphagia and upper gastroenteric symptoms. Elimination diets and/or pharmacologic agents may accomplish temporary remission, but long-term control is challenging. Type-2 immunity to ingested antigens can induce EoE histopathology via non-IgE-dependent mechanisms, possibly involving IgG4 and IL-10 production. To elucidate the contribution of IgG4- and IL-10-producing cells to EoE pathogenesis, we examined their frequencies and association with clinical and histologic endpoints in adult EoE patients given a two-food elimination diet (TFED). Methods: Sixteen patients with EoE were prescribed a TFED. Biopsies collected at baseline and follow-up were used for immunofluorescent detection of IgG4- and IL-10-expressing cells and serum food-specific IgG4 were measured. All variables were correlated with established histologic measures of disease activity. Results: Patients exhibited significant clinical improvement and significant reduction in esophageal eosinophilia and overall histology. A significant decrease in the frequencies of IL-10-expressing cells was also observed, which correlated with histologic changes. In contrast, a concomitant decline in serum and esophageal IgG4, while substantial, did not correlate with IL-10 -cell frequencies or any histologic parameter of EoE activity. Conclusions: The close association of esophageal IL-10 expression with histologic features and their changes after a TFED suggests a critical role of this cytokine in EoE pathogenesis. Conversely, IgG4 serum and mucosal expression, while reflecting the level of exposure to relevant food antigens, is not obviously related to EoE histopathology or IL-10 expression. Studies are needed to characterize IL-10 cellular sources and their functions in EoE progression and treatment response.

The hypothalamus–pituitary–testis axis controls the production of spermatozoa, and the kisspeptin system, comprising Kiss1 and Kiss1 receptor (Kiss1R), is the main central gatekeeper. The activity of the kisspeptin system also occurs in testis and spermatozoa, but currently the need of peripheral kisspeptin to produce gametes is not fully understood. Hence, we characterized kisspeptin system in rat spermatozoa and epididymis caput and cauda and analyzed the possible presence of Kiss1 in the epididymal fluid. The presence of Kiss1 and Kiss1R in spermatozoa collected from epididymis caput and cauda was evaluated by Western blot; significant high Kiss1 levels in the caput (p < 0.001 vs. cauda) and constant levels of Kiss1R proteins were observed. Immunofluorescence analysis revealed that the localization of Kiss1R in sperm head shifts from the posterior region in the epididymis caput to perforatorium in the epididymis cauda. In spermatozoa-free epididymis, Western blot revealed higher expression of Kiss1 and Kiss1R in caput (p < 0.05 vs. cauda). Moreover, immunohistochemistry revealed that Kiss1 and Kiss1R proteins were mainly localized in the secretory epithelial cell types and in contractile myoid cells, respectively. Finally, both dot blot and Elisa revealed the presence of Kiss1 in the epididymal fluid collected from epididymis cauda and caput, indicating that rat epididymis and spermatozoa possess a complete kisspeptin system. In conclusion, we reported for the first time in rodents Kiss1R trafficking in spermatozoa during the epididymis transit and Kiss1 measure in the epididymal fluid, thus suggesting a possible role for the system in spermatozoa maturation and storage within the epididymis.

Background: Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T lymphocytes expressing a semi-invariant α/β T-cell receptor (TCR). The physiological functions of these cells, which are particularly abundant in normal liver and mucosal sites, have become clear only in recent years, but their role in most human diseases is still unknown. Since the cellular origin and etiopathogenesis of most T-lymphomas are still elusive, we decided to explore the presence of MAIT cells in biopsies from these neoplasms. Methods: Sixteen biopsies obtained from patients with a T-cell lymphoma diagnosis were analyzed via immunofluorescence staining using an anti-Vα7.2 antibody and the MR1-antigen tetramer. Positive cases were subjected to a polymerase chain reaction for the detection of Vα7.2–Jα33, Vα7.2–Jα20, or Vα7.2–Jα12 rearrangements, followed by sequencing of the CDR3α region. Results: CD3+/Vα7.2+ and CD3+/MR1-Ag-tetramer+ cells were found in 4 of 16 samples analyzed. The identification of specific TCR rearrangements confirmed the presence of these cells in all four samples. PCR and sequencing results documented the presence of multiple clones of MAIT cells in each positive sample. Conclusions: MAIT cells are frequently found in T-cell lymphomas. More in-depth studies and a larger number of samples are needed to better clarify the contribution of MAIT cells to this rare neoplasm.

The interaction between the individual and the environment has a strategic significance for welfare purposes and shows the importance of the bilateral nature of the relationship. It highlights how promoting health means acting on the environment and on the individual. In terms of health education, for health workers it is no longer a question of intervening from the outside on behavior, but of inserting themselves into situations, in the processes of interaction, as active protagonists of a complex system. This orientation of the health system requires a reinterpretation of the role of operators, through the adoption of the participatory planning method, which requires interpreting one's work as a problem solving process. To get to the solution of the problems it is necessary to identify the elements of difficulty that the patient encounters, thus adopting methodologies that allow for an exchange relationship. Nurses, in all health systems, have a privileged position due to the capillarity of their action, inherent in the “to care” of nursing care, and of their contacts with citizens and clients. In particular towards the patient he teaches the correct assistance maneuvers and the most appropriate attitudes to be adopted to favor the change of behaviors and the achievement of awareness of a new state of health and a new degree of autonomy. The most suitable educational method that should be used by the nurse in the path of therapeutic education, is to link learning to action, in clinical practice, alongside the patient, promoting healthy lifestyles and the dissemination of a culture of health. Educational intervention aims at personalizing care and can improve health status and reduce healthcare costs. Alongside the ethical value and professional duty, it is necessary to use methodologies, techniques and methods to provide a structured set of specific information, with a simple and understandable language, speaking.

Introduction: Few studies have focused on the long-term effects of the COVID-19 pandemic on mental health. The objective of our work was to evaluate the changes in emotional and behavioral symptoms in patients with neuropsychiatric disorders and the impact on parenting stress 1 year after the first national lockdown. Methods: We enrolled 369 patients aged 1.5–18 years of age referred to the Child and Adolescent Neuropsychiatry Unit of the University Hospital of Salerno (Italy) by their parents. We asked their parents to complete two standardized questionnaires for the assessment of emotional/behavioral symptoms (Child Behavior CheckList, CBCL) and parental stress (Parenting Stress Index, PSI) prior to the pandemic (Time 0), during the first national lockdown (Time 1) and after 1 year (Time 2), and we monitored the changes in symptoms over time. Results: After 1 year from the start of the first national lockdown, we found a significant increase of internalizing problems, anxiety, depression, somatization, and social and oppositional-defiant problems in older children (6–18 years), and a significant increase of somatization, anxiety problems, and sleep problems in younger children (1.5–5 years). We also observed a significant relationship between emotional/behavioral symptoms and parental stress. Conclusion: Our study showed that parental stress levels increased compared to the pre-pandemic months and continues to persist over time, while internalizing symptoms of children and adolescents showed a significant worsening during 1 year follow-up from the first COVID-19 lockdown.

The goal of this study was to evaluate the impact of a two-quarter freshman course series entitled “Food: A Lens for Environment and Sustainability” (Food cluster) on the carbon footprint of food choices by college freshmen attending a large public university in California. Students enrolled in the course completed a baseline questionnaire about their diets in early fall quarter and then again at follow-up, about 6 months later at the end of the winter quarter. The control group consisted of freshmen enrolled in a different course series entitled “Evolution of the Cosmos and Life” (Cosmos cluster). The instruction in the Food cluster included lecture material on general environmental science and life cycle analyses of food, an analysis of a reading comparing the environmental footprint of various types of meats, and classroom exercises to calculate the environmental footprint of typical foods. The Cosmos cluster instruction included climate change, but no information about food. While the two groups were statistically indistinguishable at baseline, throughout the period of the study, Food cluster students decreased (a) their overall dietary carbon footprint for a 2000-kcal normalized diet by 7% (p = 0.062), (b) the beef component of their dietary carbon footprint by 19% (p = 0.024), and (c) their reported ruminant consumption by 28% (p

Specific ion effects of the large halide anions have been shown to moderate anion adsorption to the air–water interface (AWI), but little quantitative attention has been paid to the behavior of alkali cations. Here we investigate the concentration and local distribution of sodium (Na+) at the AWI in dilute (

Bisphenol A (BPA) is a synthetic xenoestrogen diffused worldwide. Humans are chronically exposed to low doses of BPA from food and drinks, thus BPA accumulates in tissues posing human health risk. In this study, we investigated the effects of BPA on peripheral blood mononuclear cells (PBMC) from human healthy donors, and in glia and microglia of rat offspring at postnatal day 17 (17PND) from pregnant females who received BPA soon after coupling and during lactation and weaning. Results indicated that BPA affected Phytoemagglutinin (PHA) stimulated PBMC proliferation causing an S-phase cell cycle accumulation at nanomolar concentrations while BPA was almost ineffective in resting PBMC. Furthermore, BPA induced chromosome aberrations and the appearance of shattered cells characterized by high number of fragmented and pulverized chromosomes, suggesting that the compound could cause a massive genomic rearrangement by inducing catastrophic events. The BPA-induced DNA damage was observed mainly in TCD4+ and TCD8+ subsets of T lymphocytes and was mediated by the increase of ERK1/2 phosphorylation, p21/Waf1 and PARP1 protein expression. Intriguingly, we observed for the first time that BPA-induced effects were associated to a sex specific modulation of ERα and ERβ in human PBMC. Immunofluorescence analysis of rat hippocampus corroborated in vitro findings showing that BPA induced ɣH2AX phosphorylation in microglia and astrocytosis by decreasing ERα expression within the dentate gyrus. Overall these results suggest that BPA can alter immune surveillance functions at both peripheral and central level with a potential risk for cancer, neuroinflammation and neurodegeneration.

Specific ion interactions of KF, and the Na+ salts of SO42−, F−, Cl−, NO3−, I−, and ClO4− with benzene in aqueous solutions were investigated using molecular dynamics simulations and compared with experimental Raman multivariate curve resolution (Raman-MCR) and thermodynamic results. Good agreement is found with the hydration-shell partition coefficients of salts obtained from the thermodynamic analysis and of halogen anions obtained from the Raman-MCR spectra of benzene and pyridine. Larger discrepancies between the simulation and thermodynamic cation partitioning results point to the influence of counter-ion interaction on cation partitioning.

Specific ion effects of the large halide anions have been shown to moderate anion adsorption to the air-water interface (AWI), but little quantitative attention has been paid to the behavior of alkali cations. Here we investigate the concentration and local distribution of sodium (Na

We have studied the OHCl(-) complex in a six-water cluster and in bulk liquid water by means of Born−Oppenheimer molecular dynamics based on generalized gradient-corrected BLYP density functional theory. Self-interaction-corrected results, which predict a hydrogen-bonded OH···Cl(-) complex, are compared to the uncorrected results, which predict a hemibonded (HO-Cl)(-). A second-order Møller−Plesset potential energy landscape of the gas-phase complex in its ground-state was computed to determine which of the two configurations represents the true nature of the complex. Because no evidence of a local minimum was found in the vicinity of the geometry corresponding to (HO-Cl)(-), we conclude that the self-interaction-corrected results are more accurate and, therefore, that the complex is held together by a hydrogen-bond-like interaction in both an asymmetric solvation environment, as represented by the cluster, and a symmetric solvation environment, as represented by the bulk system. We postulate that the mechanism that governs the atmospheric oxidation of Cl(-)(aq) to Cl(2)(g) on the surface of marine aerosols is initiated by the formation of a H-bonded OH···Cl(-) complex. Furthermore, because no evidence of charge transfer from Cl(-) to OH was found, in either the liquid or the cluster environment, we propose that the second step of the oxidation of Cl(-) is the reaction of the complex with a second Cl(-), resulting in the formation of the species Cl(2)(-) and OH(-). Cl(2)(g) could then be formed via an electron-transfer reaction with an impinging OH molecule.

Insight into ion behavior at mixed organic/aqueous liquid surfaces is crucial for understanding the chemistry of atmospheric aerosols, which frequently contain mixtures of water, electrolytes, and organics. The addition of 1-butanol to an aqueous potassium iodide solution modifies the interfacial profile of ions at the liquid−vapor interface. Our experiments probe atomic composition at the liquid surface with ambient pressure X-ray photoelectron spectroscopy. Photoelectron kinetic energies are varied to produce a depth profile of the liquid−vapor interface. Molecular dynamics simulations of butanol in an aqueous electrolyte solution are used to develop a detailed understanding of the ion−solvent interactions in the interfacial region. Our previous work on pure aqueous salt solutions observed substantial ion concentrations at the liquid−vapor interface and an increased anion/cation ratio at the interface. A question has arisen as to whether covering the surface with an organic monolayer might change or sup...

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.

The uptake of nitric acid by protonated water (hydronium cation, H3O+) clusters and the characteristic structures of the resulting mixed aggregates, H+·(H2O)n·(HNO3)m, have been studied theoretically. As baseline simulations, B3LYP/6-311++G(d,p) geometry optimizations and energy calculations for n = 1−9 and m = 0−1 have been employed. To establish the mechanism of nitric acid uptake by hydronium ion−water clusters, the energetics of the various reaction pathways involving H3O+·(H2O)n and HNO3 are evaluated. In the presence of hydronium ion−water clusters, protonated nitric acid forms by a charge exchange reaction involving H3O+ and HNO3. Successive hydration of H+·HNO3 is an energetically favorable phenomena resulting in the formation of the mixed clusters containing one nitric acid molecule. However, when the number of water ligands on the clusters is less than about five, water binds more strongly to protonated water aggregates than to the mixed clusters. Accordingly, water will preferentially react wit...

We read with great interest the article by Zhang et al 1 showing that CD8+ cell infiltration in pancreatic tumours can be enhanced by depletion of myeloid cells (CD11b+ macrophages and myeloid-derived suppressor cells) and that the depletion of CD11b+ cells resulted in decreased PD-L1 expression on cancer cells thus impairing the triggering of the inhibitory receptor PD-1 on T cells.1 Recruitment and activation of CD8+ lymphocytes in tumours are suppressed by mechanisms only partially understood and rescuing CD8+ cell infiltrate in tumours is one of the objectives of immunotherapies.1 2 Tumour-associated macrophages (TAMs) play a crucial role in the relation between tumour cells and their environment.3 Here, we confirm the interplay between macrophages and CD8+ cells in pancreatic cancer and identify a potential way to exploit this enhancing effect of anti-PD-1 treatment. Indeed, we show that reduction of macrophage infiltrate, through treatment with an anti-Bcl-2-Associated athanoGene 3 (BAG3) antibody,4 results in increased number of CD8+ cells in pancreatic tumours in a murine model. BAG3 is a co-chaperone of …

A new hybrid model describing the formation of molecular clusters around naturally occurring ions has been applied to study the conditions found in the lower polar stratosphere in the winter season. The key ion species expected under these conditions include positive hydronium water clusters, and aggregates of water and nitric acid on nitrate anions. Our approach combines basic thermodynamic data with the classical Thomson representation of a charged liquid sphere to derive enthalpies and entropies for cluster formation over the entire mass spectrum from the smallest clusters to nanometer-size droplets. We find that, at the lowest temperatures achieved in the polar regions, water and nitric acid ions can readily accumulate 10 or more ligands. The size distributions of several ion families are calculated, uncertainties in these distributions are discussed, and the rates of interaction of cluster ions with aerosols and reactive vapors are estimated.

There is a considerable controversy surrounding the nature of the Cl-/OH complex in aqueous solution, which appears as a byproduct of the irradiation of salt solutions in nuclear reactor operation, radioactive waste storage, medicine, and environmental problems. In this work, we report results of combined quantum mechanical molecular mechanics calculations of ground-state free-energy surfaces and absorption spectrum through the CCSDT level of theory that are consistent with the experimental data and suggest that hemibonded HOCl- species may indeed exist in bulk aqueous solution.

Classical molecular dynamics simulations of aqueous solutions of sodium chloride and potassium fluoride at two different concentrations have been carried out using polarizable force fields and standard additive force fields (not including polarizability explicitly). We show that the presence of chloride ions at the air-solution interface, as predicted from the polarizable simulations of NaCl solutions, is reconcilable with the classical thermodynamics results of Gibbs absorption theory. We discuss the role of system size in the establishment of a bulklike region in which the ion densities have converged to the same value. We compare the results for NaCl solutions with those obtained for KF at two concentrations. We find that the computed surface tension and the surface excess follow the experimental trend for each salt solution. We have characterized the extent of adsorption by calculating the fraction of the solution surface area that is occupied by each ion. The analysis reveals that, as expected, in the KF solution neither the cation nor the anion is present on the surface, regardless of whether or not a polarizable force field is employed. On the other hand, in the NaCl solutions, chloride anions occupy the surface to an extent that is roughly proportional to their bulk concentration, but only when a polarizable model is used.

X-Ray photoemission spectroscopy operating under ambient pressure conditions is used to probe ion distributions throughout the interfacial region of a free-flowing aqueous liquid micro-jet of 6 M potassium fluoride. Varying the energy of the ejected photoelectrons by carrying out experiments as a function of X-ray wavelength measures the composition of the aqueous-vapor interfacial region at various depths. The F(-) to K(+) atomic ratio is equal to unity throughout the interfacial region to a depth of 2 nm. The experimental ion profiles are compared with the results of a classical molecular dynamics simulation of a 6 M aqueous KF solution employing polarizable potentials. The experimental results are in qualitative agreement with the simulations when integrated over an exponentially decaying probe depth characteristic of an APPES experiment. First principles molecular dynamics simulations have been used to calculate the potential of mean force for moving a fluoride anion across the air-water interface. The results show that the fluoride anion is repelled from the interface, consistent with the depletion of F(-) at the interface revealed by the APPES experiment and polarizable force field-based molecular dynamics simulation. Together, the APPES and MD simulation data provide a detailed description of the aqueous-vapor interface of alkali fluoride systems. This work offers the first direct observation of the ion distribution at an aqueous potassium fluoride solution interface. The current experimental results are compared to those previously obtained for saturated solutions of KBr and KI to underscore the strong difference in surface propensity between soft/large and hard/small halide ions in aqueous solution.

Doxorubicin (Doxo) is a widely used anticancer drug given for the treatment of leukemias, lymphomas, and solid tumors. Despite its potent antitumor effects, the cardiotoxicity of this drug limits its clinical use. The biochemical mechanisms of Doxo-induced cardiotoxicity remain unclear. Doxo has been shown to induce apoptosis in cardiomyocytes that seems to be responsible, at least in part, for Doxo cardiotoxicity. In this study, we investigated tumor necrosis factor-alpha (TNF-alpha) receptor-mediated signaling to better understand the causes of Doxo-induced cardiotoxicity. Here, we report that Doxo is a potent inducer of apoptosis in both H9c2 cardiomyocytes and U2OS osteosarcoma tumor cells, with significant differences in terms of kinetics and caspase activation between the two cell lines. Interestingly, Doxo-induced apoptosis is accompanied by relevant changes in TNF-alpha receptor levels in H9c2 cardiomyocytes but not in U2OS cells. Moreover, treatment with exogenous TNF-alpha strongly potentiates the apoptotic effect of Doxo in H9c2 cardiomyocytes but not in U2OS cells. Our findings show that the function of TNF receptors I and II is affected by Doxo to ultimately modulate apoptosis and cell survival in H9c2 cardiomyocytes, reinforcing the recent evidence of the relevant role of TNF-alpha receptor-mediated signaling in cardiotoxicity induced by anthracyclines.

Interactions between cancer cells and stromal cells are critically involved in tumor formation, progression and development of metastasis. Here we report for the first time that human pancreatic adenocarcinoma (PDAC) cells secrete BAG3 that binds and activates macrophages, inducing their activation and the secretion of pancreatic cancer- supporting factors. We also identify IFITM-2 as a BAG3 receptor, by its co-precipitation with BAG3 from macrophage cell membrane and by impairment of BAG3- induced activation in IFITM-2- silenced macrophages. Finally we show the importance of this pathway in vivo since in nu/nu mice carrying orthotopic xenografts of human PDAC (MIA PaCa-2) cells, BAG3 sequestration by an anti-BAG3 antibody results in reduced tumor growth and prevents metastastasis formation. In conclusion we have identified a novel paracrine loop involved in PDAC growth and metastatic spreading and shown that its pharmacological blockage with an anti-BAG3 antibody has therapeutic potential. Citation Format: Alessandra Rosati, Anna Basile, Raffaella D'Auria, Morena d'Avenia, Margot De Marco, Antonia Falco, Michelina Festa, Luana Guerriero, Vittoria Iorio, Maria Pascale, Renato Franco, Claudio Arra, Antonio Barbieri, Domenica Rea, Giulio Menichini, Michael Hahne, Marteen Bijlsma, Daniela Barcaroli, David A. Tuveson, Jelena Todoric, Michael Karin, Vincenzo De Laurenzi, Maria Caterina Turco. PDAC cells release BAG3 that activates a paracrine loop with stromal macrophages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2393. doi:10.1158/1538-7445.AM2015-2393

We use quantum mechanical evaluations of the Gibbs free energy of the hydrates of sulfuric acid, H2SO4. nH2O and (H2SO4)2 . nH2O to evaluate an empirical surface tension for sulfuric acid-water clusters containing few molecules. We use this surface tension to evaluate nucleation rates using classical heteromolecular theory. At low temperatures (T 213 K) the nucleation rates obtained with the empirical surface tensions are signifi cantly greater than those using bulk values of the surface tension. At higher temperatures the difference disappears.

Breast cancer is a major cause of cancer death in women in the world. Triple-negative breast cancers, which accounts for 10-20% of all mammary tumours, are characterised by an aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer occurrence. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological approaches are warranted. The obesity-linked adipokine, leptin, is a well known mitogen/survival factor in breast cancer cells and several studies have addressed the role of leptin in breast cancer pathogenesis and progression. Surprisingly, recent in vitro studies have shown that leptin enhances the anti-proliferative effects of cAMP elevation in triple-negative breast cancer cells by apoptosis induction. In the current review, we discuss on the role of cAMP as a growth suppressor and of leptin as a growth promoting factor in breast cancer cells and we will focus on the molecular pathways involved in the antiproliferative interaction between leptin and cAMP elevation. The rationale for the possible development of a simple, cheap and innovative approach for therapeutic intervention in triple-negative breast cancer, based on the use of cAMP elevating drugs at lower and tolerable doses, will be also discussed.

"Osteosarcoma is the most common malignant. primary bone tumor in children and adolescents and is. characterized by a high metastatic potential. Its clinical. outcome remains discouraging despite aggressive. treatments. Thus, novel therapeutic approaches are needed.. Recent results indicate that inorganic phosphate (Pi) is. capable of affecting specific signal transduction pathways. and of acting as an active regulator of cell behaviour.. Previously, we found that Pi inhibits proliferation of human. osteosarcoma U2OS cells via an adenylate cyclase/cAMP. mediated mechanism. Here, we report that upon Pi. treatment, U2OS cells become extremely hard to dislodge. with trypsin. The lack of sensitivity to the trypsin action. was paralleled by relevant changes in integrin subunits. expression and accompanied by an increase of cell. adhesion in cell-matrix adhesion assays. Interestingly,. exposure of U2OS cells to Pi results also in a strong. activation and protein level up-regulation of Rap1 small. GTPase and in an early increase followed by a sustained. inhibition of Erk1/2 phosphorylation. Importantly, the Piinduced. increase of cell adhesion was enforced by a cAMP. analogue which specifically activated Epac/Rap1 and. insensitive to PKA and MEK1/2 inhibitors. Our results. enforce the evidences of inorganic phosphate as a. signalling molecule, identify beta3 integrin, Rap1, ERK1/2. as proteins whose expression and function are relevantly. affected by Pi in osteosarcoma U2OS cells The clinical. significance and potential therapeutic applications by our. data will be discussed."