51,403 research outputs found
Gene-environment interactions in the pre-Industrial Era: the cancer of King Ferrante I of Aragon (1431-1494)
No full textKing Ferrante I of Aragon, leading figure of the Italian Renaissance, died in 1494. The autopsy of his mummy revealed a tumor infiltrating the small pelvis. We examined the histologic and molecular features of this ancient tumor to investigate its primary origin. Hematoxylin-eosin, Van
Gieson, and Alcian Blue staining showed neoplastic cells infiltrating muscular fibers and forming pseudo-glandular lumina disseminated in fibrous stroma with scarce mucus. A strong immunoreactivity of the neoplastic cells was shown for pancytokeratins and proliferating cell nuclear antigen. Molecular fingerprints were investigated by examining K-ras, BRAF, and microsatellite instability in ancient
tumor DNA. Sequencing analysis showed G-to-A transition in codon 12 of K-ras. BRAF mutations and microsatellite instability were not observed. Because the presence of K-ras codon 12 mutation could be associated with exposure to chemical carcinogens, possibly present in some food items, paleodietary reconst..
Genetic markers of osteoarticular disorders: facts and hopes.
No full textpeer reviewedOsteoarthritis and osteoporosis are the two most common age-related chronic disorders of articular joints and skeleton, representing a major public health problem in most developed countries. Apart from being influenced by environmental factors, both disorders have a strong genetic component, and there is now considerable evidence from large population studies that these two disorders are inversely related. Thus, an accurate analysis of the genetic component of one of these two multifactorial diseases may provide data of interest for the other. However, the existence of confounding factors must always be borne in mind in interpreting the genetic analysis. In addition, each patient must be given an accurate clinical evaluation, including family history, history of drug treatments, lifestyle, and environment, in order to reduce the background bias. Here, we review the impact of recent work in molecular genetics suggesting that powerful molecular biology techniques will soon make possible both a rapid accumulation of data on the genetics of both disorders and the development of novel diagnostic, prognostic, and therapeutic approaches
Genetics of osteoporosis: role of steroid hormone receptor gene polymorphisms
No full textOsteoporosis is a common skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. In the past years, twin and family study have shown that this disease recognizes a strong genetic component and that genetic factors play an important role in regulating bone mineral density (BMD). While in few isolate conditions osteoporosis can be inherited in a simple Mendelian pattern, due to single gene mutations, in the majority of cases has to be considered a multifactorial polygenic disease in which genetic determinants are modulated by hormonal, environmental and nutritional factors. Given the important role that steroid hormones play in bone cell development and in the maintenance of normal bone architecture, polymorphisms at receptor of the steroid/thyroid hormone receptor superfamily, such as estrogen receptor alpha (ERalpha) and Vitamin D receptor (VDR) have been thoroughly investigated in the last years and appeared to represent important candidate genes. The individual contribution of these genetic polymorphisms to the pathogenesis of osteoporosis remains to be universally confirmed and an important aim in future work will be to define their functional molecular consequences and how these polymorphisms interact with each other and with the environment to cause the osteoporotic phenotype. A further promising application of genetic studies in osteoporosis comes from their pharmacogenomic implications, with the possibility to give a better guidance for therapeutic agents commonly used to treat this invalidating disorder or to identify target molecules for new therapeutic agents
Glioblastoma cells do not affect axitinib‐ dependent senescence of HUVECs in a transwell coculture model
No full textAxitinib is an orally available inhibitor of tyrosine kinases, with high specificity for vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is approved for the treatment of advanced renal cell carcinoma and is in phase II clinical trials for recurrent glioblastoma (GBM). GBM is a brain tumor peculiar in its ability to induce neoangiogenesis. Since both GBM tumor cells and endothelial cells of tumor vasculature express VEGFRs,Axitinib exerts its inhibitory action on both tumor and endothelial cells. We and others previously demonstrated that Axitinib triggers cellular senescence. In particular, Axitinib‐dependent senescence of HUVECs (human umbilical vein endothelial cells) is accompanied by intracellular reactive oxygen species(ROS) increase and early ataxia telangiectasia mutated(ATM) activation. Here we wondered if the presence of glioblastoma tumor cells could affect the HUVEC senescence upon Axitinib exposure. To address this issue, we cocultured HUVECs together with GBM tumor cells in transwell plates. HUVEC senescence did not result in being affected by GBM cells, neither in terms of β galactosidase activity nor of proliferation index or ATM phosphorylation. Conversely, Axitinib modulation of HUVEC gene expression was altered by cocultured GBM cells. These data demonstrate that the GBM secretome modifies HUVECs’ transcriptomic profile upon Axitinib exposure, but does not prevent drug‐induced senescence
Gene expression profiling of hypoxic response in different models of senescent endothelial cells
No full textEndothelial cells senescence is a physiological process affecting vascular integrity. It can contribute to heart and arterial stiffening and remodeling, impaired angiogenesis, defective vascular repair, and with an increasing prevalence of atherosclerosis. Drugs used as antineoplastic therapies, targeting tumor as well as endothelial cells, can also trigger endothelial cells senescence. We demonstrated that a short pulse of axitinib, a specific inhibitor of vascular endothelial growth factor receptors, induces cell senescence of endothelial cells. Here, we performed a high-throughput gene expression analysis to characterize the response of proliferating versus senescent endothelial cells to hypoxia, the main trigger of neo-angiogenetic phenomena in tumors. We compared the response to hypoxia of replicative senescent cells, with that of axitinib or of DNA damage-induced senescence. Overall, we enlightened common and specific responses to different senescence inducers and changes in the Senescent Associated Secretory Phenotype
Correlazione tra indagine biochimica e tecnica di fluorescenza nello studio dell’assetto recettoriale del carcinoma mammario.
No full textCase Report: Medullary thyroid carcinoma’s bone metastasis in a young patient affected by men -2A.
No full textCase Report: Medullary thyroid carcinoma’s bone metastasis in a young patient affected by men -2A
MEN1 family with a novel frameshift mutation.
No full textMultiple endocrine neoplasm type 1 (MEN1) syndrome predisposes to the development of endocrine and non-endocrine tumors with an autosomal dominant pattern of inheritance. Different mutations have been found throughout the gene with a variable phenotype expression. The proband, a Caucasian man, was admitted to our department in 2001, at the age of 51 because of a 1-yr history of diarrhoea and hypertension. He reported a previous intestinal resection for bowel occlusion with a histological diagnosis of unspecified mesenchymal neoplasia. He had also undergone a left adrenalectomy for a large nonfunctioning adrenal adenoma. Subsequently, he had suffered from gastralgia and melena; a gastroduodenoscopy showed an erosive gastritis. His family history was negative for endocrine disorders. On physical examination, multiple abdominal cutaneous lipomas and facial angiofibromas were observed. Biochemical screening revealed a primary hyperparathyroidism and an increase in circulating levels of PRL, chromogranin-A, gastrin and glucagon. The whole body computed tomography (CT) scan, the 111In-octreotide scan and the pituitary magnetic resonance imaging (MRI) did not reveal any abnormality. The presence of small neuroendocrine tumors was suspected by a positron emission tomography uptake in the epigastric region. The endoscopic ultrasound revealed a pancreatic lesion sized 1.1 cm that is under evaluation. Direct DNA sequencing analysis of the proband MEN1 gene revealed the 579delG frameshift mutation in the exon 3. The genetic screening of the family revealed the same mutation in 3 out of 5 offspring. The biochemical screening revealed some features of the MEN1 syndrome in all three of them. In conclusion, a novel frameshift MEN1 mutation was found in kindred with an apparently negative family history. Our experience confirms that MEN1 syndrome is a complex and underestimated condition, unless specifically investigated by trained specialists
Update on the pathogenesis and genetics of Paget's disease of bone
No full textStudies over the past two decades have led to major advances in the pathogenesis of Paget's disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome "Inclusion Body Myopathy, PDB, Fronto-temporal Dementia," characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades. © 2022 Gennari, Rendina, Merlotti, Cavati, Mingiano, Cosso, Materozzi, Pirrotta, Abate, Calabrese and Falchetti
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