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Cancer represents a leading cause of death in developed and developing countries, accounting for 8.8 million deaths in 2015. These numbers are expected to continue rising with 13.1 million deaths estimated in 2030. Although the earlier diagnosis and increasing treatment options have improved the survival rates for the majority of cancers, many tumors exhibit therapeutic resistance and severe adverse effects remain major therapeutic hurdles. Thus, the main challenge of the cancer research area is the definition of additional treatment options tailored on the distinct tumor characteristics and the expression of appropriate targets. Nuclear receptors, controlling many biological features of cancers as proliferation, survival, apoptosis, and differentiation, possess a significant clinical relevance in disease management, representing a “druggable” class of molecules useful for potential therapeutic intervention. In the last years, among the nuclear receptors, the metabolic sensor Farnesoid X Receptor was recognized to play a role in carcinogenesis, acting either as an oncogene or as a tumor suppressor gene. Here, we will summarize the current knowledge on the FXR role in human cancers, highlighting its ligands as new potential anticancer tools.
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Ageing is a natural and physiological condition that is the result of compromised stress response, homeostatic imbalance and increased risk of developing diseases. However, if aging with good health and functions (successful ageing) and aging with disease and disability (unsuccessful ageing) depends on a combination of “positive features”, including genetic, epigenetic and phenotypic characteristics in combination with favourable environment, economic status and social involvement. In our study, we summarize some key points for the identification of a longevity signature, with a particular focus on long-living Sicilian individuals and centenarians. Analysing three different Sicilian cohorts (young, people with no centenarian parents and long-living individuals (LLI) aged >90) we found APOE e3\e3 in our LLIs and no presence of e4. Regarding FOXO rs2802292 G-allele (G>T) we did not observe an association with longevity, probably because of the small sample of centenarians studied. Regarding haematological and anthropometric results, it is still difficult to point specific longevity features and so far, we cannot specify a single one. On the other hand, we believe that the synergy among genetics and environment might create successful interaction to achieve and obtain effective longevity.
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The discovery that mesenchymal stem cells (MSCs) modulate inflammation and promote tissue regeneration has revolutionized stem cells-based therapy. However, some observations have raised questions about the limitations of their clinical use. On the other hand, recent findings have demonstrated that exosomes released by MSCs contribute significantly to their therapeutic effect and may be used as an alternative MSCs-based therapy in regenerative medicine. In this review, we summarize the current knowledge about the immunosuppressive capacity of MSCs-derived exosomes and we discuss the critical role of the surrounding microenvironment in the modulation of their regenerative and therapeutic potential.
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Recent clinical evidences suggested that the expansion of epicardial adipose tissue (EAT) and its transformation into a pro-inflammatory organ in visceral obesity are related to maladaptive heart remodeling and heart failure (HF). However, the sustained molecular mechanisms are poorly understood. The ST2/IL33 system has recently obtained great attention in the field of cardiovascular diseases due to its cardio-protective role in different stress conditions that can promote cardiomyocyte hyperthrophy and deposition of extracellular proteins (fibrosis). Any imbalance in ST2/IL33 signaling may thus lead toward HF. Discussing how dysfunctional EAT may interfere with the protective role of ST2/IL33 pathway and its association with heart remodeling in visceral obesity are the aims of the present review.
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The biological role of a protein seldom coincides with the function first described, i.e. the easiest to observe (the two aspects usually coexist). First observations usually settle down and address subsequent research during years to follow. However, it often happens, that from an out of frame data, indications later emerge that something else (possibly more interesting) may hide beneath the surface. An analysis free from preconceptions may therefore allow other aspects such as unexpected processes and novel functions of the protein under investigation, to emerge. This is well illustrated in the case of gammaglutamyltransferase (GGT), whose pathophysiological significance we could specify and redefine in experimental studies carried out in our laboratories, first in Siena and then in Pisa.
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Gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. To date, gastrectomy and chemotherapy are the only therapeutic options, but drug resistance is the main cause for treatment failure. Vasculogenic mimicry (VM) is a new model of neovascularization in aggressive tumors and has been correlated with poor prognosis in GC patients. Our group has developed chemotherapy-resistant GC cells using the Caucasian adenocarcinoma cell line AGS and three drugs among the most used in clinic (5-fluorouracil, cisplatin and paclitaxel) henceforward denominated 5FUr, CISr, TAXr. Our study has highlighted phenotypical differences among chemo-sensitive and chemo-resistant cell lines such as acquisition of stem-like phenotype and increased capacity to form vessels.
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Lysinuric protein intolerance (LPI) is a recessively inherited aminoaciduria caused by mutations of SLC7A7, the gene that encodes y+LAT1 light chain of system y+L for cationic amino acids (CAA; namely arginine, lysine, and ornithine) transport. Clinical signs of LPI are highly heterogeneous and only poorly understood: while hyperammonemia and protein intolerance can be explained by urea cycle slowdown due to the impairment of CAA absorption/reabsorption in intestinal and renal epithelial cells, little is known about the pathogenesis of the often fatal complications affecting lungs and immune system. Here, we explore the possibility that y+LAT1 protein directly exerts immunomodulatory functions and that LPI defects, besides affecting CAA transport, also activate inflammatory mononuclear phagocytes, ultimately leading to immunological complications.
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Receptor for advanced glycation end-products (receptor for AGEs, RAGE) is a cell-surface protein identified as a receptor for AGEs. RAGE activation mainly induces oxidative stress and inflammation. Indeed, in different organs, such as the adipose tissue and the liver, RAGE engagement has also been shown to promote lipid accumulation. Besides the cell-membrane form, RAGE exists as a soluble circulating molecule (sRAGE), a decoy receptor able to prevent the detrimental effects of AGEs at cellular level. As most of the obesity-related complications are due to the ectopic fat accumulation and no data are available about RAGE, sRAGE and heart steatosis, our aim was to explore any potential association of these molecules with heart steatosis in obesity.
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End stage renal disease patients on dialysis (CKD-G5D) have a high mortality rate mainly due to cardiovascular diseases (CVD). In addition to traditional CVD risk factors, which are common in these patients, excessive oxidative stress, uremia and chronic inflammation may further increase the production of advanced glycation end-products (AGEs) which in turn promote CVD and CVD-related morbidity and mortality. Much attention has been paid recently to the soluble receptor for AGEs (sRAGE) as a marker of inflammation, oxidative stress, atherosclerosis and heart failure (HF) in CKD-G5D. However, its relationship with patient outcomes is still debated.
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Tumor-derived exosomes are emerging mediators of tumorigenesis. Exosomes are small membrane vesicles (40-150nm) derived from the luminal membranes of multivesicular bodies, and are released via fusion with the cell membrane. Exosomes mediate local and systemic cell communication through the horizontal transfer of information (mRNAs, microRNAs and proteins). It is well recognized that uPAR, is one of the main systems involved in tumor invasion and metastasis. Several malignant tumors show a positive correlation between uPAR levels and a more aggressive phenotype together with a poor prognosis. We have showed that uPAR is strongly upregulated in A375 and in metastasis-prone A375M6 melanoma cells with respect to normal melanocytes. Here we explored the uPAR function in melanomaderived exosomes and their pro-angiogenic capacity in ECFCs (Endothelial Colony Forming Cells).
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The function of ST2 fibro-mediator and IL-33 alarmin protein has been mainly investigated on immunological aspects, but recent data suggest that this pathway plays also an important role in cardiovascular system and adipose tissue inflammation. Whereas IL-33 has been demonstrated to exert anti-inflammatory and protective effects, circulating ST2 (sST2) has emerged as a prognostic biomarker in patients with myocardial infarction and heart failure. Furthermore, the IL-33/ST2 expression system is increased in severe obesity, although its role in the pathogenesis of detrimental cardiac remodeling associated with obesity is still not well defined. The aim of this study is to investigate the molecular pattern of IL-33/ST2 system and profibrotic genes activation in experimental model of obese fa/fa- Zucker rat model.
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Tyrosine kinase inhibitors (TKi) targeting BCR/ABL are very effective for the treatment of Chronic Myeloid Leukemia (CML). However, discontinuation and/or inefficacy on CML leukemia stem cells (LSC) may lead to relapse. To identify new druggable targets alternative to BCR/ABL, we investigated the role of the Extracellular signal-Regulated Kinase 5 (ERK5) pathway in CML LSC maintenance.
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Tyrosine kinase inhibitors (TKi) targeting BCR/ABL are very effective for the treatment of Chronic Myeloid Leukemia (CML). However, discontinuation and/or inefficacy on CML leukemia stem cells (LSC) may lead to relapse. To identify new druggable targets alternative to BCR/ABL, we investigated the role of the Extracellular signal-Regulated Kinase 5 (ERK5) pathway in CML LSC maintenance.
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Although, it is widely recognized that cancer cells actively utilize exosomes to promote tumor growth and metastasis, the biology of tumor-derived exosomes (TEX) is incompletely understood and much remains to be study in order to define the molecular and genetic mechanism by which exosomes operate in cancer. Increased expression and activity of toll-like receptor 4 (TLR4) in chronic infectious and inflammatory conditions is associated with cancer progression: its activation induces an inflammatory signaling that increases the tumorigenic potential of cancer cells promoting their immune evasion. The purpose of this study is to investigate the immunosuppressive properties of TEX released upon TLR4 activation.
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The fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases expressed, by tissuespecific alternative splicing, in epithelial IIIb or mesenchymal IIIc isoforms and controlling key physiological processes, such as cell proliferation, differentiation, survival and migration. We have previously demonstrated that the tumor suppressor epithelial isoform of the FGFR2 (FGFR2b) induces early differentiation of human keratinocytes. Since protein kinases C (PKCs) are known to regulate the differentiation program in several cellular contexts, including keratinocytes, aim of our present study was to clarify if FGFR2b could play a role also in the late steps of keratinocyte differentiation and to assess if this receptor-induced process would involve PKC isoforms.
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Cerebral small vessel disease (CSVD), detected as white matter hyperintensities (WMH) on brainMRI, could be a distinct pathological entity within cerebrovascular diseases. The increasing use of MRIhas lead to more incidental finding also in young people without classical vascular risk factor. The purposeof this work was to investigate different pathways implicated in endothelial dysfunction (inflammation,autoimmunity, coagulation, nitric oxide pathway) in a well selected, homogeneous population of patientswith WMH, without significant vascular risk factors or neurological diseases.
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Progesterone receptors (PRs) belong to the steroid receptor superfamily and regulate development, growth and transformation of breast tissues. Different mechanisms, such as ligand binding, posttranscriptional modifications, interaction with signalling effectors or scaffold proteins control the steroid receptor subcellular localization, thereby influencing their activity. Derangement of steroid receptor import/export process often causes receptor delocalization and proliferative diseases of target tissues, such as breast and prostate. However, while the mechanism of steroid receptor nuclear import is well documented, the mechanism of their nuclear export is still unclear.
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The poor outcome of patients resistant to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive (ER+) breast cancers (BC) and demands additional studies. In this context, the role of FoxO3a transcription factor was investigated.
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Extracellular signal-Regulated Kinase 5 (ERK5) is a member of the Mitogen Activated Protein Kinase (MAPK) family. ERK5 is activated by MEK5 in response to numerous stimuli and is involved in several cellular processes including the proliferation of both normal and neoplastic cells. We previously demonstrated that ERK5 is required for the proliferation of melanoma cells, a neoplasia that, especially in the advanced stages, has a very poor prognosis. Human melanomas are frequently characterized by the loss or the reduced expression of markers of cellular senescence that results in tumor growth and progression. We evaluated the effects of the inhibition of the MEK5-ERK5 pathway on cellular senescence in melanoma cells.
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Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recentlyapproved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL).We employed both immortalized and primary cells derived from CD22-positive lymphoproliferativedisorders to investigate the signaling pathways contributing to IO sensitivity or resistance.
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The endothelium is the gate-keeper of vascular health. Accordingly, endothelial dysfunction is acrucial event in macro-vascular and in small vessel diseases. Since the morbidity and mortality dueto micro- and macro-vascular complications in patients with diabetes is very high, understanding themolecular bases of endothelial dysfunction in response to high glucose is a major issue.
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The endothelium is the gate-keeper of vascular health. Accordingly, endothelial dysfunction is acrucial event in macro-vascular and in small vessel diseases. Since the morbidity and mortality dueto micro- and macro-vascular complications in patients with diabetes is very high, understanding themolecular bases of endothelial dysfunction in response to high glucose is a major issue.
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The major limitation of traditional chemotherapeutic agents is their poor selectivity for cancer cellsand their severe toxicity to normal cells. Therefore, localized drug delivery would, ideally, improve thetherapeutic efficacy, minimizing side effects. The properties of mesoporous silica nanoparticles (MSNs)seem to cope with this aim. A MSN-based device, FOL-MSN-BTZ, bearing the antineoplastic drugbortezomib (BTZ), linked to MSNs by means of a pH-sensitive bond and the folic acid (FOL, a targetingfunction), was then developed and tested on folate receptor (FR+ cells) overexpressing cancer cells andon FR- normal cells, in order to investigate MSNs behaviouor.
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The neuromuscular junction (NMJ) is one of the few human tissues capable of complete regenerationafter major damages (1). We want to identify the cross-talk taking place among the different cell type ofthe NMJ: neuron, muscle, Schwann cells.
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Behçet’s Disease (BD) is a systemic vasculitis, prevalent in males, with a chronic and inflammatorycourse and with multi-organ involvement. Are affected young subjects (20-30 years). The etiologyremains unknown but appears to be mediated by exogenous factors (bacterials or virals) that, throughimmunopathological mechanisms, start humoral or cellular responses. The main clinical manifestationsare represented by: oral ulcers, genital ulcers, cutaneous, ocular, articular, vascular and neurologicalinvolvement. Frequent is the association (about 72%) with HLA-B51 histocompatibility antigen, whichsuggested that the disease is present, following external factors, in genetically predisposed patients. HLA(Human Leukocyte Antigen) is a highly polymorphic gene with different haplotypes that can agree theresponse of the human adaptive immune system or predispose individuals to a particular immune systemdisease. The diagnostic utility of HLA-B51, associated with Behçet’s disease, has been clearly identified;however, its correlation with other autoimmune diseases has not yet been clarified. This study evaluatethe presence of the HLA-B51 allele with other autoimmune diseases.
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Melanoma is the deadliest skin cancer, with a very poor prognosis in advanced stages. Availabletreatments for melanoma, including immunotherapy or inhibitors for BRAF-MEK1/2, have greatlyimproved the survival for this disease although they are not applicable to all patients and/or their longtermbenefits are still unsatisfactory. As a member of Mitogen-Activated Protein kinase family, ERK5could play a relevant role in melanoma regulating cell functions critical for tumor development, such asproliferation, invasion and angiogenesis.
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Multiple myeloma (MM) is the second most common hematological malignancy. Although clinicaladvances, it is still incurable disease, sustained by a tight interaction of malignant plasma cells withthe bone marrow (BM) microenvironment that promotes tumor growth, immunosuppression, drugresistance, neoangiogenesis and bone destruction. The oncogenic Notch signaling plays a crucial role inMM. In particular, aberrant Notch2 receptor activation and Jag1 and 2 ligands overexpression stimulateMM cells to establish pathological interactions with BM that trigger MM progression. Our previousdata showed that these effects can be interfered by knocking down of Jag1 and 2 expression. Indirectapproaches to inhibit Notch signaling are mainly based on inhibition of γ-Secretase that catalyzesNotch activation along with other several g-Secretase substrates. Moreover, inhibition of all four Notchreceptors is associated with a gut toxicity. This evidence prompted us to develop a therapeutic tool toselectively inhibit Notch2 signaling triggered by Jag1 and 2.
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The BCR-ABL oncoprotein is the culprit of CML as it transforms the hematopoietic stem cell by alteringits survival and proliferation properties. The efficacy of Tyrosine Kinase Inhibitors (TKIs) of the canonicalBCR-ABL variants e1a2 (p190), e13a2 or e14a2 (p210) has been well established. Alternative breakpointsinvolving different BCR and/or ABL exons have been previously described but yet to be characterized.We analyzed 50 CML patients, not presenting the canonical isoforms, finding three atypical BCR-ABLbreakpoints in five subjects: one e12a2ins/del, three 13a3 and one e14a3 transcripts. These atypical isoforms(with the addition of two further deletion mutants lacking the BCR DC2 domain or the ABL SH3 domain)were investigated for their catalytic activity, transforming potential and TKI responsiveness.
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Blood vessels are lined by cells (ECs) that are crucial to maintain vascular and tissue homeostasis.Endothelial function is shaped by mechanical forces, i.e. shear stress and gravity (1G). Since life evolvedunder the influence of the earth’s gravitational pull, it is not surprising that microgravity activatesadaptive responses that impact also on the endothelium. Several studies have shown that real andsimulated microgravity affect ECs behaviour in different aspects but very little is known about themetabolic adaptation of these cells. In particular, we focused our attention on the mitochondria, rodshapedorganelles that convert oxygen and nutrients into adenosine triphosphate (ATP).
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Altered cancer metabolism satisfies high demand for nutrients but also has an impact on non-cancercells of tumor microenvironment. In the bone marrow (BM) of multiple myeloma (MM) patients,glutamine (Gln) is lowered, while glutamate (Glu) and ammonium increase (Bolzoni, Chiu et al.,Blood 2016; 128:667-679). Glutamine Synthetase (GS), which catalyzes Gln synthesis from Glu andammonium, is lowered in most MM cells and down-regulated during osteoblastogenesis. Since bonelesions of MM patients are characterized by low osteoblast viability and function, we hypothesize thatMM cells negatively affect osteoblastogenesis through the peculiar low-Gln, high-Glu bone marrowmicroenvironment.
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Several evidence indicates a strong correlation between healthy lifestyle and age-related pathology,in particular neurodegenerative diseases, including Alzheimer’s disease (AD). This pathology ischaracterized by two histo-pathological hallmarks, the amyloid plaques, formed by Ab oligomers, andneurofibrillary tangles, due to hyperphosphorylation of tau protein. At molecular level, Ab inducesmitochondrial and endoplasmatic reticulum dysfunctions, oxidative stress and apoptosis. The brain issusceptible to oxidative stress and several prevention strategy based on use of antioxidant moleculeshave been proposed. Traditional Mediterranean Diet (MD) includes high consumption of vegetables,fruits and herbs, food rich in antioxidant molecules, such as polyphenols. Some studies indicatethat MD influences longevity as confirmed by studies on centenarian subjects. In vitro studied havedemonstrated that Caffeic Acid (CA), one of the main polyphenol present in several foods that makeup the MD, has high anti-inflammatory and antioxidant properties.
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Progesterone Receptor (PR) positivity is associated with a good prognosis and better response to breast cancer treatment. Conversely, cyclin D1 (CD1) is retained a marker of poor outcome since it has been associated with breast cancer metastasis in clinical studies.
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Ageing is a natural and physiological condition that is the results of compromised stress response,homeostatic imbalance and increased risk of developing diseases. However, if we age having a goodhealth and functioning (successful aging) or with disease and disability (unsuccessful aging), it dependson a combination of “positive features”, including genetic, epigenetic and phenotypic characteristicsin combination with favorable environment, economic status and social involvement. In our study, wesummarize some key points for the identification of a longevity signature, with a particular focus onSicilian long-lived individuals and centenarians.
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The prevalence of obesity is increasing at an alarming rate in developed countries throughout theworld. Epidemiologic studies indicate that obesity is important risk factors for diabetes, cardiovasculardisease and cancer. In particular, obesity is associated with a greater increase of aggressive prostatecancer (PCa) with increased local dissemination. Prostatic gland is surrounded by periprostatic adiposetissue (PPAT). PPAT is an active endocrine organ able to secrete molecules known as adipokines. Thehigh prevalence of both obesity and PCa highlights the importance of understanding the biologicalfeatures of this relationship. Recent studies uncovered that the secretion of mature adipocytes can affectthe early stage of PCa progression by promoting the spread of cancer cells outside the prostate gland. It isclear that tumor-surrounding adipocytes might affect cancer phenotype, but the molecular mechanismsinvolved in this cross-talk are still unknown.
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Interaction between breast tumor epithelial and stromal cells is central for tumor growth and progression.Indeed, while providing a scaffold for the breast, the stroma also regulates epithelial cell function throughphysical and hormonal paracrine exchanges, providing a favorable environment for proliferation andmetastasis. There is extensive knowledge of androgen receptor (AR) signaling in breast epithelial cancercells, but less regarding AR-mediated action in breast tumor stroma. In the present report, we provideevidence of AR expression in breast cancer-associated fibroblasts (CAFs) isolated from breast cancerpatients. We also examined the effect of CAFs exposure to androgens on: 1) secretory phenotype and 2) themigratory behavior of the estrogen-responsive breast cancer MCF-7, T47D and ZR-75 cells.
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Uveal melanoma (UM) represents the most common intraocular malignancy in adults andapproximately 50% of patients develops metastatic disease. The new genomic sequencing technologies onUM tumors allowed to identify mutations in the Gq alpha subunits GNAQ and GNA11. These mutationsappear in a mutually exclusive manner and are consequently of prognostic importance (Van Raamsdonket al., Nature 2009). FAK (focal adhesion kinase) is a cytoplasmatic tyrosine kinase localized at thesites of cell adhesion to the extracellular matrix. FAK is overexpressed in several tumors and mediatesdiverse signaling promoting cancer growth and metastasis. To date, it has been considered as a potentialtarget for cancer therapeutics (Sulzmaier et al., Nat Rev Canc 2014).
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Many cancers acquire aberrant growth and invasion capacity through the dysregulation of fibroblastgrowth factors (FGFs)-mediated signaling (Carter EP, Trends Cell Biol. 2015). In particular, FGFs secretedby the tumor cells or stromal compartment activate the cognate receptors leading to cancer progression(Babina IS, Nat Rev Cancer. 2017). For instance, FGF2-FGFR1 autocrine and/or paracrine loop activationhas been involved in the migration and invasion of cancer cells (Coleman SJ, EMBO Mol. Med. 2014).Remarkably, estrogens induced via the estrogen receptor (ER) the up-regulation and secretion of FGF2in breast and lung cancer (Fillmore CM, PNAS. 2010, Siegfried JM, Oncotarget. 2017). Likewise, the Gprotein estrogen receptor (GPER) was also involved in the regulation of FGF2 by estrogens toward theactivation of downstream signaling pathways in astroglial cells (Huang C, Neuroscience. 2016).
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We previously found that the adaptation of Chronic Myeloid Leukaemia (CML) cells to energyrestrictions in paralleled by the suppression of BCR/Ablprotein, the oncogenic driver of CML,notably in a subset of leukaemia stem cells (LSC). These LSC, while remaining genetically leukaemic,are independent of BCR/Abl signaling for maintenance in tissues (within the “stem cell niches”) andtherefore refractory to tyrosine kinase inhibitors (TKi) used for CML therapy. We envisioned on thesebases a “metabolic” stem cell niche model to explain the long-term persistence of LSC responsible forMinimal Residual Disease (MRD) of CML. In this model, glutamine plays an important role.
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Cardiomyopathies are a group of diseases leading to adverse outcome. Due to clinical heterogeneity andphenotypic overlapping, the identification of specific non-invasive diagnostic and prognostic markerscan be useful and remains a challenge. Our aim is to exploit cardiac cfDNA as new cardiac biomarkerbased on the following assumptions: i) methylation patterns are unique and conserved in a specifictissue, hence their analysis could be used to identify the tissue of origin of circulating cell free DNA(cfDNA); ii) cfDNA levels of cardiac origin may be higher in the presence of cardiac disorder.
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Bicuspid aortic valve (BAV) is frequently associated with development of ascending aortic aneurysm,even if the underlying mechanisms remain to be clarified. Here, we investigated if a deregulation ofNotch1 signaling pathway and endothelial progenitor cells (EPCs) number is associated with BAVdisease and an early ascending aortic aneurysm (AAA) onset.
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Immunoglobulin A nephropathy (IgAN) is an immune complex disease and a major cause ofglomerulonephritis in pediatric patients. Clinical picture includes hematuria and proteinuria, and canprogress into renal failure. Urinalysis, as well as renal biopsy, serve to confirm the diagnosis. We reporta case of a 12-year-old girl with persistent haematuria and severe proteinuria, in whom subsequently anIgAN was diagnosed.
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ccRCC cells show an adipocyte-like morphology due to neutral lipid accumulation. The molecularmechanism responsible for this phenotype has yet to be clarify. Notably, ccRCC cells show a geneexpression signature consistent with adipogenesis and can undergo adipogenic transdifferentiation.The Ca2+-dependent phospholipid-binding praotein Annexin A3 (AnxA3) has been recently described asnegative regulator of adipocyte differentiation. In RCC, we evidenced that AnxA3 is downregulated andshows a specific pattern of two isoforms of 36 and 33 kDa originated by an alternative splicing event.In the current study, we have investigated the role of AnxA3 isoforms in the modulation of lipid storageresponsible of the adipocyte-like morphology of ccRCC cells.
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Nephrosphere (NS) model permits to culture a heterogeneous population of renal stem-like cells(RSC) and progenitors. RSC are the quiescent (PKHhigh) cells with a CD133+/CD24- phenotype. Wedemonstrated that NS cells cultured on decellularized scaffolds repopulated proximal and distal tubularportions, the Bowman’s capsule, and vascular portions differentiating into endothelial cells. We now aimto evaluate the capacity of endothelial commitment of RSC isolated from human NS.
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The excessive scar tissue deposition of fibrotic process and the tumor stroma have in the activatedfibroblasts (myofibroblasts) the main players. Myofibroblasts remodel the extra cellular matrix (ECM)by specialised cytoskeletal contractile features (stress fibres and focal adhesions) that reorganise thesupportive tumour stroma. The non-receptor tyrosine kinase Arg binds directly to the cytoskeletontransducing extracellular signals into cytoskeletal rearrangements. ARG, through alternative splicingevents, codes eight Arg isofoms that differently modulate stress fibers and motility. We analysed therole of 1ALCTL and 1BLCTL Arg isoforms in fibroblast activation using Arg KO murine embryonalfibroblast (MEF).
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Multiple myeloma (MM) is the second most diffuse hematological malignancy and nowadays is stillincurable, despite the development of innovative therapies. MM cells accumulate in the bone marrow(BM) and establish vicious interactions with the surrounding normal cells, inducing them to promotetumor progression and the development of drug resistance. In this process, a crucial role is played bythe dyregulated Notch ligands Jagged1 and 2, whose overexpression boosts Notch both in MM cellsand in the BM cells. Here, we investigated how Jagged1/2 inhibition affects MM cells resistance to thestandard-of-care drug Bortezomib.
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An involvement of TGF-b1 in promoting bone metastases affecting about 30% of clear cell Renal CellCarcinoma (ccRCC) patients was described. The extracellular matrix enzyme Lysyl oxidase (Lox) throughosteoclast activation and osteoblast inhibition induces pre-metastatic bone lesions in breast and coloncancer. We evidenced Lox overexpression in ccRCC and TGF-b1 production modulated by Arg tyrosinekinase in renal tubular cells. Arg modulates invasion and metastasis of breast and prostate cancer throughcytoskeleton regulation. These data suggest that Arg, TGF-b1 and Lox might interact to promote tumorinvasion and metastasis. Here we analyse the molecular and functional interactions among Arg, TGF-b1and Lox in ccRCC and their effects on osteoclast and osteoblast pre-metastatic functions.
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The prevalence of obesity has been increasing at an alarming rate in several developed anddeveloping countries, reaching pandemic proportions over the last two decades. This growing incidencehas deep clinical implications, since obesity is a key driver of serious health problems, such as type IIdiabetes, cardiovascular diseases, hypertension and cancer. Indeed, prospective epidemiological studieshave shown that excessive adiposity strongly influences risk, prognosis and progression of multiplemalignancies, including breast cancer. Several hypotheses have been proposed to unravel the direct linkbetween obesity and breast cancer and these include hyperinsulinemia, estrogen signaling, inflammationand adipokine expression. Certainly, the revised concept of adipose tissues from an inert depot for bodyenergy to endocrine and immunologically active organs placed particular emphasis on the potentialrole of adipokines in various biological processes and metabolic pathways. Acting through endocrine,paracrine and autocrine mechanisms, adipokines, that are not only produced by adipocytes but also bystromal cells, macrophages and cancer cells, impact the development and progression of obesity-relatedcancers. In this talk, I will present an overview of the clinical and experimental evidences highlightingthe adipokines leptin and adiponectin, as the most important molecular mediators of obesity-breastcancer axis.
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Despite the revolution in the field of melanoma treatment with the introduction of novel therapies(immunotherapy and target therapy), there is still a percentage of melanoma patients that oftenexperiences drug-resistance and therapeutic failure. The early recognition of therapeutic failure, bythe identification of new biomarkers of therapeutic response, is the main challenge of medical oncologyin order to personalize the therapeutic strategies and avoid the toxicity of ineffective treatments. Thecirculating-free DNA BRAFV600E mutation was proposed as a marker of therapeutic response. However,it cannot be revealed in all melanoma patients with this mutation, detected in tumour biopsy specimens.Therefore, there is a need to identify new prognostic biomarkers. Matrix Metalloproteinase-9 (MMP-9)could be one of them since its role in tumour invasiveness have been demonstrated.
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A major group of plant antimicrobial compounds is represented by essential oils (EOs), complexmixtures of volatile secondary metabolites belonging to different chemical families. Cannabis sativa L.has been grown for thousands of years for a multiplicity of purposes; in recent years, some genotypescontaining low cannabinoid concentrations have been selected and used for research purposes. Listeriamonocytogenes is a facultative intracellular food pathogen, mobile for the presence of several flagella.In humans, the treatment of listeriosis is hampered by the intracellular location of listeriae and thepoor intracellular penetration of some antibiotics. Flagellum-based motility has been implicated invirulence since it is critical for initial surface attachment. The purpose of this study was to investigate theantibacterial and anti-virulence properties of an EO extracted from a legal C. sativa L. variety against aclinical isolate of L. monocytogenes.
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Cancer transformation is a multistep process sustained by several molecular alterations includingthose of DNA methylation. The high-throughput technology allowed understanding the functional roleof global methylation patterns in the regulation of genes involved in cancer development. In order toidentify specific methylation patterns associated with gene expression, an R package algorithm able toperform integrated analysis of gene expression and methylation profiles datasets was developed.
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Yin Yang 1 (YY1) is transcription factor ubiquitously expressed, able to either activate or represstranscription through direct or indirect interaction with the chromatin. YY1 is thought to be involvedin the modulation of a large number of mammalian genes. The ability of this DNA binding proteinto promote or inhibit gene expression depends on its specific target sequence, chromatin structure aswell as its specific protein interactors. YY1, found expressed at different levels in many cancer types,has been seen to have the effect of either stimulating or inhibiting cancer growth. The mechanism(s)responsible for such diverging effects needs to be further clarified.
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Leishmaniasis comprises a group of neglected vector-borne diseases caused by intracellularprotozoa of the genus Leishmania. The promastigotes are deposited into the human skin by the biteof phlebotomine sandflies and internalized by phagocytic cells where they develop into amastigotes,multiply and cause the cutaneous or visceral disease. Neutrophils, immediately recruited to the bitesite, phagocytize Leishmania promastigotes, which elude the neutrophils killing mechanisms and infectmacrophages. Although endothelial cells represent one of the first cells type encountered by Leishmaniapromastigotes, little is known on their role in the establishment of the infection. Here, the interactionbetween human endothelial cells and Leishmania promastigotes was studied.
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Sensors performances are highly improved when single sensor arrays are organized in multidimensionalsystems or networks for particular applications. This result is facilitated by the large improvementsin the miniaturization process, power consumption reduction and data analysis techniques nowadaysavailable. Multidimensional sensor systems are conceived to mimic the mechanisms of human senses.Among them, the so-called electronic nose and tongue are becoming more and more popular.
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Portal vein thrombosis (PVT) is occurring frequently in advanced liver cirrhosis and in Hepatocellularcarcinoma and often diagnosed in the course of a routine patient evaluation and surveillance for livercancer. PVT may relate to metabolic alterations and thrombophilic conditions. The purpose of this studyis to investigate the relationship between folate status and portal vein thrombosis.
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Cancer cell transition from a low-invasive phenotype into a more malignant one constitutes a criticalevent during tumor progression. The Epithelial-Mesenchymal Transition (EMT) occurring in solid cancersis at the core of such transformation. A recurrent metaphor for the complex developmental path of cellsystems across different phenotypic states is given by the Waddington landscape in which cell phenotypesare depicted as stable attractors, while metastable or unstable states represent unstable attractors.
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Cells, tissues and organs of astronauts aboard the International Space Station (ISS) are exposedto the damaging effects of microgravity and cosmic radiation. Space Agencies are forced to findeffective therapeutic countermeasures to safeguard astronauts’ health. Since retina is one of the mostvulnerable target, we undertook a project entitled The Coenzyme Q10 (CoQ10) as countermeasurefor retinal damage onboard the International Space Station: the CORM project, funded by the ItalianSpace Agency (ASI) and launched in the summer 2017. We selected CoQ10 as promising candidatedrug, having previously first demonstrated its direct antiapoptotic property due to its ability to inhibitmitochondrial depolarization.
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The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment ofChronic Myeloid Leukemia (CML) has generated a need for early molecular parameters predictive ofinadequate responses to the first-generation TKI imatinib mesylate (IM). Several groups have shown thatBCR-ABL/ABLIS transcript levels <10% after 3 months (mos) or <1% after 6 mos of IM are stronglyassociated with superior clinical outcomes. We wanted to investigate which BCR-ABL threshold wouldbe more reliable in predicting treatment outcome in patients (pts) with discordant molecular transcriptsat the 3 and 6 mos time points, and also wished to evaluate if early molecular responses predicted theprobability of achieving a sustained deep molecular response.
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Adipose tissue is an endocrine organ secreting active molecules, the adipokines, e.g., leptin and resistin).In a condition of dysfunctional visceral fat depots, adipokines are detrimental for cardiovascular system.Aim: To evaluate some of the molecular mechanisms linking the biology of adipokines and PCSK9.
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Neural Stem Cell (NSC) maintenance is of great interest since NSCs can be used to treat impairedcells and tissues or improve regenerative power of degenerating cells in neurodegenerative diseases orspinal cord injuries. Under maintenance conditions, NSCs require Hedgehog-Gli (Hh-Gli) signallingand express a number of stemness genes (e.g. Nanog, Oct4, Sox2) whose mechanisms of regulation havebeen investigated. However the interplay between other transcription factors and NSC maintenanceis still being charted. Technological advances allow us to use next generation RNA sequencing (RNAseq),a powerful method for quantifying steady-state mRNA expression levels and detecting alternativesplicing events in transcriptomes.
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Chronic wounds are an emerging issue in Western countries, but their pathogenetic mechanismshave not been clarified, yet. Oxygen availability is crucial for tissue healing. Thus, hypoxia is detrimentalin chronic wounds and new oxygen-based therapies should be investigated. Here, oxygen-loadednanodroplets (OLND) with an oxygen-binding fluorocarbon (2H, 3H-decafluoropentane) in the innercore and dextran or chitosan in the outer shell are proposed as carriers of oxygen to the hypoxic milieu,to counteract the effects of hypoxia in wound healing.
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Gametocytes (GCT), the sexual stage of malaria parasites, develop in five stages (I-V). Stages I-IVare predominantly sequestered and differentiate in the extravascular compartment of the bone marrow,while stage V are released in the circulation from where they are taken up by a mosquito during a bloodmeal, causing malaria transmission. Few information are available about the role of the innate immunityagainst GCT. The aim of this work was to set up a model to study of the ability of P. falciparum (Pf) GCTto activate and be phagocytised by bone marrow macrophages.
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Vascular endothelial cells (ECs) line the entire circulatory tree. In spite of their well knownheterogeneity, ECs display a myriad of fundamental homeostatic functions such as keeping bloodfluid, regulating blood flow, regulating macromolecule and fluid exchange with the tissues, preventingleukocyte and platelet activation, and participating in immune surveillance. Most of present knowledgehas been achieved using 2D monolayer cell culture systems. However, they do not accurately recapitulatethe structure and function of living tissues. To bridge the gap between classical 2D cell culture and invivo models, 3D culture techniques have been generated.
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Mesenchymal stem cell (MSCs) are crucial in bone repair and regeneration, since they differentiateinto osteoblasts in response to specific stimuli from the microenvironment. It is known that magnesiumis important for the osteogenic differentiation of MSCs. Since the kinase and cation channel TRPM7 andthe magnesium transporter MagT1 regulate intracellular Mg homeostasis, we investigated the role ofTRPM7 and MagT1 in the osteogenic differentiation of MSCs.
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Besides the epithelial barriers, macrophages represent the first cells that interact with engineerednanomaterials (ENM) upon exposure. Many studies report that several ENM are able to triggermacrophage activation. However, possible interference of ENM with the effects of typical macrophageactivators, such as PAMPs, has been much less investigated thus far. In this study, we have used two wellcharacterized, food-grade nanoparticles of amorphous SiO2 (ASNP), the precipitated NM200 and thepyrogenic NM203, to assess their effects on LPS-dependent activation of human macrophage-like cells.
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The potential mechanisms underlying the evolution toward an anti-estrogen resistant phenotypehave been attributed to various causes, including the alteration of normal metabolism. In this context,the involvement of FoxO3 was evaluated.
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The ability to counteract oxidative stress (OS) plays a pivotal role in neuronal survival. Thedifferentiation of neuroblastoma (NB) cells with retinoic acid (RA) generates a small amount of ROSinvolved in neurite elongation (Nitti, 2010). However, differentiated cells are more sensitive to the exposureto OS than undifferentiated ones (Piras, 2017). In the present study, we analyzed the behavior of two RAdifferentiatedNB cell lines, SH-SY5Y and SK-N-BE(2C) in response to OS. Furthermore, the regulation ofHO-1 expression has been analyzed evaluating Nrf2 as the main activator and Bach1 as negative regulator.
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Colorectal cancer is one of the most common malignant tumors and an important associated-factoris intestinal microbiota. This may enhance the carcinogenicity by proliferation and differentiation ofepithelial cells and by decreasing immune response to pathogenic organisms. The aim of the study isto analyze the link between the presence of Fusobacterium nucleatum (FN) in a series of matched oralbrushing, colon adenomas/carcinomas and adjacent mucosa, and finally to elucidate the FN disseminationmechanism from oral cavity to colon. FN is detected in saliva, especially in smokers, with its quantitiesincreased in patients with gingivitis and periodontitis, compared to the healthy controls.
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Pancreatic cancer is a very aggressive malignant disease due to lack of early diagnosis andchemotherapeutic resistance of the tumor cells. There is distinct evidence that food derived polyphenolspossess chemopreventive effects in the development of several cancers including pancreatic carcinoma.Resveratrol, a phenolic compound found in grape skins and other fruits, is a nutraceutical with severaltherapeutic effects and known anticancer activity. The aim of the study is to analyze the expression ofWnt/ β-catenin signaling pathway genes after treatment with resveratrol.
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In subjects with moderate hypercholesterolemia, probiotics incorporated into dairy products canreduce circulating total (TC) and LDL cholesterol (LDL-C). Probiotics with high biliary salt hydrolaseactivity, e.g. Bifidobacterium longum BB536, decrease TC and LDL-C by lowering intestinal cholesterolreabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemiain subjects with low cardiovascular (CV) risk. The objective of the study was to evaluate efficacy andsafety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR)extract (10 mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo®). The end-pointswere changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides(TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein (a) [Lp(a)], proproteinconvertase subtilisin/kexin type 9 (PCSK9) and of markers of cholesterol synthesis and absorption.
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Surgical Site Infections (SSIs) are the most common nosocomial infections. Surgical suturesare optimal surfaces for bacterial adhesion and biofilm formation. The most commonly isolatedmicroorganisms in SSIs are Staphyloccocus aureus (Sa), coagulase-negative Staphylococcus spp.,Enterococcus spp., Escherichia coli (Ec) and other Gram-negative bacilli. The aim of this study was toevaluate the antibiofilm activity of a Medical Device (MD) containing TIAB, which is titanium dioxidelinked with monovalent silver ions.
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Estrogen Receptor alpha (ERa) is the master regulator of estrogen signaling in hormone-responsivebreast cancer (BC) and it is the primary target of specific anticancer therapies. Nevertheless, thedevelopment of resistance to treatment represents the key problem in clinical management of patientsaffected by this disease. We reported that the epigenetic writer DOT1L (DOT1-Like Histone LysineMethyltransferase) associates with ERa [1] as part of a multiprotein chromatin regulatory complex. Weinvestigated here the role of this enzyme in estrogen signaling to the genome in luminal-like BC cells.
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The onset of thyroid gland nodules (TN) is determined by loss of homeostasis regulation by interactionof endogenous/genetic and environmental factors. The nature of the oxidative processes that lead tophysiologic synthesis of thyroid hormones together with environmental factors may be the root causesof thyroid nodular transformation due to an increase in DNA damages. A link between EGF and DNAdamage repair signalling has been documented in cancer, but their cross-regulation is poorly understoodin TN. In order to define the role of Base Excision Repair (BER) and ErbB signaling in TN, we analysedeuthyroid goitres tissues that are not theoretically affect by any hormonal dysfunction.
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Immunosenescence impacts on the immune system of older people leading to an inefficient reactionto pathogens and reduced ability to develop a powerful immune response after vaccination. Recently,research in immunological ageing have suggested that stimulation of Toll-like receptors (TLRs) isa promising strategy to enhance vaccine efficacy in the elderly by activation of innate immune cellsand production of inflammatory cytokines. In this scenario, great importance assume dendritic cells(DCs), the most potent antigen presenting cells, specialized for the uptake, processing, transport andpresentation of antigens to T cells.
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The impact of host genetic variation on outcome of HIV infection in the absence of combinationantiretroviral therapy (cART) has been well documented. Growing evidence reports relationshipbetween specific killer-cells immunoglobulin-like receptor (KIR) polymorphisms and different HIVprogression in the absence of treatment. The goal of the present study is to determine the association ofKIR genes and their human leukocytes antigen (HLA) ligands with viral load and HIV progression inpatients on cART.
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Progesterone-Receptor (PR) is good prognostic marker for breast cancer patients. The effects ofProgesterone on its target tissues are mediated by the Progesterone Receptors (PR-A and PR-B). Inbreast tumors from patients with poor prognosis, a loss of PR-B occurs suggesting a protective role ofPR-B in breast cancer. The molecular mechanisms of PR-B–protective effects are still to be defined.Recently, we reported in breast cancer cells a novel functional interplay between PR-B and PTEN inmodulating autophagy, which is retained a way to reprogram cellular metabolism activating oncogenesand inactivating tumor suppressors. Among them, the p53 tumor suppressor gene has emerged asimportant mediator of energy metabolism. To deepen the PR-B anticancer role and given the relationshipbetween autophagy and cellular metabolism, we investigated a role for OHPg/PR-B signaling throughp53 in altering metabolic reprogramming of breast cancer cells.
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Portal vein thrombosis (PVT) is one of the severe complications of Hepatocellular Carcinoma (HCC).PVT deteriorates the liver and its dysfunction increases the risk of bleeding, influencing the prognosis ofpatients with liver cirrhosis and HCC. The aim of our study was to investigate whether D-dimer testingcould be a sensitive marker for the diagnosis and prognosis of HCC patients with PVT.
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Glutamine (Gln) plays a critical role in supporting cell growth and proliferation of different cancercell types. Several studies have focused on the sodium-dependent Gln transporter ASCT2 as a potentialtherapeutic target and different approaches, including its inhibition or silencing, are commonly used.L-γ-glutamyl-p-nitroanilide (GPNA) is a widely used ASCT2 inhibitor, even if several concerns about itsspecificity have recently emerged since GPNA has a limited selectivity for ASCT2, being able to inhibitmany other transporters for amino acids.. Moreover, it is rarely considered that GPNA is also a wellknownsubstrate of the enzyme gamma-glutamyltransferase (GGT). The aim of this study was thus toevaluate the effect of GPNA catabolism by GGT on its efficacy as an inhibitor of cell proliferation.
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The current anticancer therapies for human neuroblastoma (NB) include the use of etoposide, a drugthat exerts its cytotoxic effect by inducing oxidative stress. Although the therapeutic approach withetoposide is initially efficacious, subsequently, it selects a chemoresistant cell population, which is able toadapt to the oxidative environment induced by the drug, increasing the levels of intracellular glutathione(GSH). The chemoresistance is also due to the presence of cancer stem cells (CSCs), which have a lowproliferative rate and are less susceptible to therapies acting on highly proliferating cells. Moreover,CSCs expressing CD44, a PKC-alpha-modulated staminality marker, are able to influence GSH levelsby stabilizing xCT, a transporter promoting the influx of cystine, essential for GSH synthesis. Basedon this evidence, our aim was to investigate whether targeting CD44/xCT might be a useful strategy toincrease neuroblastoma sensitivity to etoposide.
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Here we present a clinical case of 2 year-misdiagnosed polymyositis (PM), where patient underwentunnecessary invasive procedure while he developed progressive muscular weakness. Erroneous diagnosiscould have been correctly addressed by evaluation of serum Creatine kinase (CK), a cheap and easy toperform lab exam.
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Increasing body of data suggest a key role for epigenetics in the etiopathogenesis/development ofautoimmune disorders. Indeed, epigenetic dysregulations have already been described in rheumatoidarthritis (RA), lupus erythematosus (SLE), and multiple sclerosis (MS) patients. Decitabine (5-aza-2’-deoxycytidine, Dacogen, (DAC) is a hypomethylating agent used for the treatment of myelodysplasticsyndrome. We have previously shown that DAC has both prophylactic and therapeutic disease-modifyingproperties in two mouse models of MS.
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Testicular germ cell tumors (TGCTs) represent the most common invasive malignant tumors inyoung male. The most widely accepted model of TGCTs development proposes a tumorigenic eventin utero followed by a dormancy period until puberty when TGCTs emerge, suggesting hormonalinvolvement and the estrogen-dependence of these tumors has been reported. Estrogens act throughestrogen receptors and human testis mainly express ERβ. ERβ loss is associated with advanced tumorstage, however the molecular mechanisms of the ERβ–protective effects are not defined yet. Recently,we showed that estradiol (E2) induced death in human testicular seminoma cells TCAM2 by a crosstalkbetween E2/ERa and the tumor suppressor gene PTEN, inducing autophagy and necroptosis. Cellsurvival is closely coupled to the cellular metabolism and tumor metabolism is considered a cancerhallmark and a novel target for cancer therapy. To further elucidate the role of ERβ in human seminomawe studied its effect on glucose and lipid metabolism in TCAM2 cells.
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Cell redox balance is crucially maintained by heme oxygenase 1 (HO-1) activity through its metabolicproducts which exert antioxidant, anti-apoptotic and anti-inflammatory effects. HO-1 up-regulation hasbeen correlated with the gain of resistance to therapy in different types of cancers and its involvementin cancer immune-escape has been hypothesized. In this work, we have investigated the involvementof HO-1 in BRAFV600E mutated melanoma cell resistance to Vemurafenib/PLX4032 (PLX) and inNatural Killer (NK)-dependent killing.
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Ovarian cancer is characterized by a high mortality rate among gynaecological malignanciesworldwide. Accumulating evidence indicates that impairments of DNA repair and energy metabolismare implicated in the initiation and progression of ovarian cancer (OC). However, the relationshipsamong these aspects are not extensively studied in ovarian cancer physiopathology. The Extracts of Oleaeuropaea L. may be used as a potential source of both antioxidant and anticancer effects, although theconcentration of the phenolic fraction is several times higher in olive leaf than in olive oil and variesdepending on the cultivar and climate. This study investigates the effect, on OC cell model, of phenolicbioactive compounds of Olea europaea L: Verbascoside (VB) and Oleuropein (OL), the two majorbiocompatible extracts from olive leaf and extra-virgin olive oil.
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Circadian clocks are intrinsic, coordinated systems that operates in all cells and enable organisms toanticipate environmental changes, thereby adapting their behaviour, physiology and metabolism to theappropriate time of day, thus contributing to maintain body homeostasis. Disruption of these rhythmshas a profound influence to human health and has been linked to many diseases, from depression tometabolic disorders to cancer. Indeed, the circadian timing system controls rhythmic events in cellcycle, DNA repair and apoptosis in both normal tissue and cancer and drives daily rhythmic changesin drug metabolism. Consequently, the toxicity and anticancer activity of common anticancer drugscan be significantly modified by the time of administration in both experimental models and in cancerpatients. The molecular mechanisms at the base of this event are still poorly understood and this is oneof the factors that limit the establishment of a successful cancer chronotherapy in clinical practice. Ourresearch is focused on identifying the molecular mechanisms linking circadian rhythm to cancer cellproliferation, explore the mechanisms responsible for the beneficial effects of circadian administrationof anticancer drugs, and deciphering the direct effect of specific clock components on different cellularfunctions in response to anticancer treatment.
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Helicobacter pylori (Hp) is a microorganism capable of adapting itself in both the human hostand natural environment. Hp persistence and resistance may be associated to both its broad geneticvariability as well as its capability of developing a biofilm. Outer Membrane Vesicles (OMVs) associatedwith extracellular DNA (eDNA) are a component of the Hp biofilm. OMVs are involved in severalmechanisms such as pathogenesis, biofilm formation, cell-cell communication, bacterial-host interactionsand nutrient supply. OMVs are able to spread and transport virulence factors into the host. The aim ofthis study was to detect and quantify the OMVs secreted from Hp ATCC 43629 and Hp NCTC 11637in the biofilm (bOMVs) and planktonic (pOMVs) phenotypes as well as being able to detect the eDNAOMVsassociation with the use of Flow Cytometry.
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Doxorubicin (Doxo) is a chemotherapeutic agent whose clinical use is hampered by the serious dosedependentcardiotoxicity. The accumulation of Reactive Oxygen Species (ROS) is widely accepted asa key factor of cardiotoxic effects. Mitochondrial Connexin 43 (Cx43) conferred cardioprotection byreducing cytosolic and mitochondrial ROS production. Topic of this work was the identification ofantioxidant enzymes and molecules involved in Doxo-induced damage, in absence and in presence ofRadicicol (Rad), an inhibitor of Cx43 translocation to mitochondria. Due to increasing numbers of youngcancer survivors and the raising concerns for their fertility state, elucidating the biological mechanismsof chemotherapy risk is highly relevant. Moreover, it is known that Doxo-induced ovarian toxicity isassociated with apoptosis of mouse granulosa cells.
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HBV DNA integration into the host hepatocyte genome is an early event in HBV infection and itis found in about 85% of HCC. Most of the data on HBV integration in HCC have been generatedby specific restriction enzymes and cloning methods that may favor preferential amplification andbias identification of unique integration sites. On the other hand, a limitation of the more recent nextgenerationsequencing (NGSs) approaches is the low coverage of HBV reads. Aims. To conduct a highthroughputviral integration detection analysis on tumor (T) and non-tumor (NT) liver tissues, and onPLC/PRF/5 cells, using NGS of enriched HBV integrants. To characterize the HBV DNA integrationevents and enumerate clones of expanded hepatocytes that bear identical integrations. To identify HBVjunctures at the whole-transcriptome level and define the transcribed viral-human fusions.
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Psoriasis, a chronic immune-inflammatory skin disease, is characterized by intense proliferationand abnormal differentiation of keratinocytes. It is a complex multifactorial disease and the exactpathogenesis remains to be elucidated. The cyclin dependent kinase inhibitor p27Kip1 is known to play akey role in cell cycle regulation by controlling the G1 to S phase transition. It is a negative regulator ofcell cycle progression, as well as an inducer of apoptosis. The aim of the present study was to investigatep27Kip1 expression in skin samples from healthy subjects and psoriatic patients.
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Thyroid diseases affect about 20% of the Italian Population and thyroid cancer (TC) is the mostcommon endocrine neoplasm. TC incidence showed an increase over the past few years, especially amongwomen. The recent attention of researchers has turned to the possible role of environmental factors ableto interfere as Endocrine Disrupting Chemicals (EDCs) may affect thyroid function. Some EDCs mayplay a role in the etiology of thyroid disorders and increase the risk of TC, based on interactions betweenmetabolic homeostasis and DNA repair systems. Triphenyl phosphate (TPHP) is a commonly used flameretardant and plasticizer the exposure of them were been recently suggested to alter thyroid function.This study investigates the effect of TPhP and its metabolite, diphenyl phosphate (DPhP), on DNA repairand metabolism in a normal human thyroid cells model, Nthy-ori3-1.
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Malignant Pleural Mesothelioma (MPM) is a rare cancer type mainly caused by asbestos exposure.MPM has limited treatment options and a poor outcome. New therapeutic approaches are urgentlyneeded. Promising anticancer therapeutics are Oncolytic viruses (OVs) that selectively replicate in andkill cancer cells, leading to the tumor lysis.
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The chaotic and incomplete vasculature of tumor stroma is frequently responsible for a transient and/orpersistent state of hypoxia, and tumor cells adapt their metabolism to anaerobic glycolysis. Therefore, lactateand protons are produced in large excess and transported outside by redundant families of lactate and H+transporters in order to maintain an intracellular pH compatible with survival and/or proliferation. Therefore,the extracellular pH of tumors turns to acidic for a different period of time, conferring new adaptive aspects tocancer cells, characterizing the transient-exposed and chronically-exposed tumor cell subpopulations.
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Excess of visceral fat is a major culprit in the development of type 2 diabetes and related disorders.A growing body of evidence indicates that epicardial adipose tissue (EAT), the visceral fat of the heart,may play an active role in dysregulation of cardiac function. Indeed, EAT thickness positively correlateswith the release of inflammatory molecules and with the severity of heart pathologies. In patientswith diabetes, prolonged hyperglycemia damages several organs, including heart. Thus, potent proinflammatoryactivation of EAT suggests a direct involvement of cardiac visceral fat in inflammatoryphenomena occurring in patients with cardiovascular diseases. This study aims at investigating whetherdifferent glucose concentrations may impact on EAT functions.
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Adipose microenvironment is involved in signaling pathways that influence breast cancer developmentand progression, through the secretion of different adipocytokines. Among these, adiponectin plays a pivotalrole in the pathogenesis of breast cancer. An inverse correlation is reported between obesity and adiponectin,suggesting that low levels represent a risk factor for mammary cancer. In the recent years, our researchgroup has identified ERa as an important regulator of adiponectin action in breast cancer, clarifying thatthe role of this adipocytokine seems to be dependent on cell phenotypes. LKB1 is an important target ofadiponectin action, being involved in multiple cellular functions, such as cell metabolism, cell cycle arrest,apoptosis, motility and cell polarity. Here, we investigated the effect of adiponectin on expression andfunction of LKB1 in ERa-positive (MCF-7) and negative (MDA-MB-231) breast cancer cells.
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Hyperglycaemia increases breast cancer (BC) incidence and progression. Glucose may exert its effectson both BC cells and tumour microenvironment. Here, we analysed whether glucose could interfere on thecrosstalk between mammary adipose tissue derived- mesenchymal stem cells (MAT-MSCs) and oestrogenpositive-MCF7 BC cells, thereby modifying MSC phenotype and affecting tumour progression.
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ABL001 (Asciminib) is a selective allosteric inhibitor of the BCR-ABL oncoprotein that binds to themyristoyl pocket of ABL favouring the formation of an inactive kinase conformation. We evaluated thesensitivity to ABL001 - alone or in combination with the tyrosine kinase inhibitors (TKIs) Imatinib (IM)and Nilotinib (NIL) - of CD34+ leukemic progenitors isolated from 30 patients displaying either high(n=15) or low (n=15) BCR-ABL/GUSIS levels at diagnosis.
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Despite progress in the clinical management of advanced-stage melanoma with different treatmentoptions available, mainly based on targeted therapy and immunotherapy, many concerns still existdealing with the observed overall toxicity. Effective dosing regimens and the insurgence of resistancemechanisms lead to tumor relapse and progression to a metastatic disease with incredibly aggressivefeatures. Given the involvement of multiple, yet strictly related biological targets and signaling cascadesin the metastatic melanoma disease, the combination therapy has become the standard-of-care treatment,in both small molecule-based (e.g. vemurafenib+cobinetinib in BRAFV600E/K-mutant disease) andantibody-based therapies (e.g. ipilimumab+nivolumab), with the primary goal to improve clinical benefitwhile overcoming the insurgence of drug resistance and compensating mechanisms often observed usingtargeted monotherapy. In these cases, however, off-organ (and possible synergistic) toxicity remains astill unsolved issue. Thus, the creation of new molecular conjugates which combine the ability to targetmelanoma cells using recognition of specific surface-exposed receptors, enter melanoma cells via receptormediatedendocytosis, and modulate key intracellular targets and signaling pathways, is an appealingapproach toward enhanced drug efficacy at lowered drug dosage and increased safety window.
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Natural medicine has been practiced for centuries and, today, has receiving attentions in bothpharmaceutical industry and academia. Although, many mechanisms of action of plant productsremain unknown, new possible mechanisms are becoming evident: exosomes and their content, miRNAincluded, might regulate gene expression with potential therapeutic activities in human chronic diseases.Plant miRNAs are found in sera and tissues of mammals after plant ingestion, supporting an effectivecommunication between the two kingdoms. In our lab, we have utilized exosomes isolated from Brassicaoleracea sprouts to inhibit the growth of tumor cell lines, as assayed by in vitro wound scratch test andby 3D cultures. To better understand the molecular mechanisms, we performed an in silico study usingthe Brassica miRNA database to predict the human target transcripts. Among others, MIR414 exhibiteda perfect base paring to Spindlin 1 (SPIN1), a human gene upregulated in melanoma cancer
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By catalyzing cGMP hydrolysis, phosphodiesterase (PDE) type 5 acts as a critical regulator ofits concentration and effects in different (patho) physiologic processes, including cancers. We havepreviously shown that PDE5 overexpression greatly enhances the invasive potential of breast cancer cellsand reduces survival in patients, highlighting the benefit of therapeutic targeting PDE5. To extend theseobservations, we propose to assess PDE5 function in tumor microenvironment, which has increasinglyknown as an active contributor to breast cancer growth and progression.
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Paragangliomas (PGLs) are neurovascular autonomic nervous system tumors, still incurable whenradical surgery is not possible. They are frequently associated with susceptibility mutations in genesencoding the mitochondrial SDH complex components. However, the etiology of PGLs remains unclearas the penetrance of SDHx mutations is incomplete (21% at age 50). Studying a large set of freshlycollectedhead and neck PGLs (HNPGLs) by electron microscopy we found herpesvirus-like particles inall tumors. These were similar to particles attributed to cytomegalovirus (HCMV) reported in 1971 byHeine et al. in a retroperitoneal PGL.
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Glioblastoma Multiforme (GBM), a high-grade glioma (WHO grade IV), is the most aggressive formof brain cancer. Treatment options for GBM involving a combination of surgery, chemotherapy andradiation resulted in a poor survival outcome. Epigenetic mechanisms are increasingly implicated inGBM pathogenesis. Unlike genetic mutations, epigenetic changes are reversible and can be targetedby drugs. We evaluated whether different Histone Deacetylase Inhibitors (HDACis) are able to affectmigration, invasion and vasculogenic mimicry in GBM cells.
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Breast cancer is a highly heterogeneous disease and one of the few tumour types molecularlycharacterized. While luminal and human epidermal growth factor receptor 2 positive (HER2+) tumourscan be controlled by hormonal and anti-HER2 interventions, the triple-negative breast cancers (TNBC)are resistant to standard treatments. Since the tumour microenvironment is an important player in breasttumour progression, the stromal components could represent a source of new prognostic biomarkers andtargets for potential therapeutic strategies mainly in tumors lacking molecular sites of intervention. Wepreviously found that Met-F-AEA, agonist at cannabinoid receptor 1 (CB1) inhibited cell migration andepithelial-mesenchymal transition of the TNBC cell line MDA-MB-231, through modulation of MMP2and Wnt/ß-catenin signaling, respectively.
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The importance of aberrant regulation of Wnt/β-Catenin signaling in the pathogenesis and colorectalcancer progression has long been recognised. Recent studies have shown that reactive oxygen species(ROS) production activates the Wnt/β-Catenin pathways, but the mechanisms involved remain unclear.Excess in ROS production is linked to chronic inflammation and promotes DNA damages and repairsystems. We aim to evaluate the relationship among oxidative stress response and canonical/noncanonicalWnt pathways in colorectal cancer cell line models with different Wnt signaling behaviour.
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The antidiabetic drug phenformin displays potent anticancer activity in different tumors but itsmechanism of action remains elusive. In this study we have investigated the mechanism of cancergrowth inhibition of phenformin, using as a model SHH Medulloblastoma, a cerebellar brain tumorcharacterized by an inappropriate activation of the Sonic Hedgehog signaling.
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Age is the main risk factor for many pathologies, neurodegenerative disorders included. With theworld population getting older, aging will represent the disease of the future leaving an increasing need tounderstand the molecular basis of this process in normal and pathological conditions. Egr-1 (early growthresponse 1) is a transcriptional factor rapidly induced by many stress stimuli and it is involved in cellsurvival, proliferation and differentiation, as well as in memory, cognition and synaptic plasticity. Anothermolecule with neuroprotective properties is HO-1 (heme oxygenase-1), which converts heme to iron,carbon monoxide and biliverdin and it was shown to regulate the metabolism of oxysterols (derivatives ofcholesterol oxidation) which represent new markers of oxidative stress. The only evidence of a link betweenEgr-1 and HO-1 was described in mouse lung cells exposed to cigarettes smoke. The aim of this study wasto investigate whether Egr-1 can be implicated in oxysterol metabolism during brain aging.
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Pancreatic cancer (PC) is the fourth most common cause of cancer death. Classical chemotherapeuticdrugs, used alone or in combination, have a limited advantage in term of 5-year survival, at the cost of arelevant toxicity. Thus, novel therapeutic options with minimal side effects are urgently needed for thislethal disease. In this regard, the use of several non-toxic repurposed drug candidates has been exploredin preclinical models of several tumors. In the present study, we investigated the potential repurposingin PC of the FDA-approved anthelmintic drug parbendazole.
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KCTD containing Cullin3 adaptor, suppressor of Hedgehog (KCASH2) belongs to the KCASH familyof proteins, which are involved in the negative regulation of the Sonic Hedgehog (Hh) signaling pathway.All members of KCASH family have shown to be downregulated in Hh dependent Medulloblastoma(Mb), by either allelic loss or promoter methylation. Particularly, KCASH2 expression is reduced alsoin other tumors, not directly connected with Hh pathway modulation; moreover, chromosome 11q,where KCASH2 is localized, is lost in several sporadic tumors. In turn, correlation studies and dataof laboratory show a role of KCASH2 in differentiation and cell cycle regulation, suggesting its fineregulation during development.
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Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma (MB), is a centralplayer of Hh signalling, a crucial pathway for development and deregulated in tumours. Althoughthe control of Gli transcription factors by SuFu is critical in Hh pathway, our understanding of themechanism regulating this key event remains limited. To this end, the main objective of this study is toinvestigate the role of the ubiquitylation processes in the regulation of SuFu/Gli interaction.
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Glioblastomas (GBMs) are brain tumors of glial origin characterized by a heavy hypoxicmicroenvironment, which correlates with tumor aggressiveness. GBM cells abundantly express largeconductance,calcium-activated potassium (BK) channels and, since hypoxia modulates their activity inGBM cells, the aim of the present work was to explore their role in the hypoxia-induced chemoresistanceand to better understand the molecular mechanisms underlying the effect of the hypoxic microenvironmenton BK channels-dependent drug resistance of GBM cells.
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The Hedgehog (Hh) signalling pathway is evolutionarily conserved and its fine regulation is essentialfor proper development and tissues homeostasis. Aberrant activation of the Hh pathway is responsiblefor the onset of several malignancies, including medulloblastoma (MB), the most frequent pediatricbrain tumor. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) orthe downstream effector Gli1 have thus emerged recently as valuable anticancer agents. The aim of thisproposal is to discover novel powerful Smo and Gli inhibitors targeting Hh signaling at both upstreamand downstream level, and to investigate their pharmacological effects on MB.
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Immune checkpoint inhibitors, such as PD-1/PD-L1 targeting monoclonal antibodies, have shown efficacyin the treatment of non-small cell lung cancer (NSCLC) in the adjuvant, first- and subsequent-line settings,in monotherapy or combined to standard chemotherapy regimens in both adeno and squamous histologies.Recent results from KEYNOTE-189 trial indicates that the addition of pembrolizumab to pemetrexed andplatinum-based drug results in longer OS and PFS than chemotherapy alone even in originally PD-L1negative patients with lung adenocarcinoma (Gandhi L. et al. NEJM 2018). Nevertheless, the success of thistherapy is limited and there is an urgent need for developing strategies to sensitize NSCLC to immune-checkpointinhibitors. In this study, we evaluated whether chemotherapeutic agents may alter PD-L1 expression inorder to guide optimal combination/sequencing with Immune checkpoint inhibitors in the clinic.
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The aim of this study is to attention the important role that laboratory medicine plays today in theevaluation of hematological diseases. The utility of the collaboration between the laboratory staff andthe clinicians has emerged as fundamental to diagnose complex diseases in a short time interval.
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The aim of the study is to attention the important role that laboratori medicine has in the evaluationof hematological diseases. The utility of the collaboration between the laboratory staff and the clinicianshas emerged as fundamental to diagnose complex and specialistic diseases in a short time interval.
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Alcohol-induced liver fibrosis/disease (ALD) is characterized by excessive deposition of extracellularmatrix (ECM) components in response to chronic abuse that could lead to cirrhosis and hepatocellularcarcinoma development. Sarcosine is a derivative of the amino acid glycine, formed by the enzymesglycine N-methyl transferase (GNMT) or dimethylglycine dehydrogenase (DMGDH) and convertedback into glycine via sarcosine dehydrogenase (SARDH). GNMT is silenced in human alcohol-inducedcirrhosis. In addition, GNMT knockout mice develop oxidative stress, liver injury, fibrosis, and HCC.SUMOylation is a post-translational modification that requires an essential E2-conjugating enzyme 9(UBC9) to covalently bind of small ubiquitin modifier (SUMO) and plays an important role in a widerange of cellular processes. We previously demonstrated that UBC9 level is induced in intragastricethanol-infusion (EI) treated mouse liver. We performed SUMO-proteomics of alcohol-fed mouse liverand identified altered sumoylation of GNMT and SARDH. The goal of this work is to examine whetherthe dysregulated SUMOylation could regulate GNMT and SARDH enzymatic function in ethanolinducedliver fibrosis and elucidate the molecular mechanism(s).
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Reaching exceptional longevity is a consequence of aging delay driven by genetic and epigenetic factors,which are either inherited or acquired. It has been postulated that aging is driven by imbalance betweeninflammatory and anti-inflammatory networks that results in the low grade chronic pro-inflammatorystatus causing most of the physiopathological changes triggered by aging. In this respect, the activation ofmonocyte-macrophages plays a major roles in finely tune the immune responses as they cover a continuumof functional states which oscillate from a patrolling protective effect toward an inflammatory ones. Wepreviously identified a four-SNPs haplotype, the Longevity-associated variant (LAV) of bactericidal/permeabilityincreasing fold-containing-family-B-member-4 (BPIFB4) able to activate calcium, PKC-a,eNOS, rescuing endothelial dysfunction in aged mice and inducing revascularization through homing ofprogenitor cells. BPIFB4 abundance in serum of healthy centenarians as compared to non-healthy ones,the therapeutic potentials LAV-BPIFB4 in improving vascular homeostasis, at least in part mediated byLy6Chigh monocytes, and BPIFB4 expression in bone marrow myeloid cells induced us to evaluate ifLAV-BPIFB4 may improve immune regulation.
