Nuclear inositides: facts and perspectives

Strong evidence has been accumulating over the last 15 years suggesting that phosphoinositides, which are involved in the regulation of a large variety of cellular processes in the cytoplasm and in the plasma membrane, are present within the nucleus. Several advances have resulted in the discovery that nuclear phosphoinositides are involved in cell growth and differentiation. Remarkably, the nuclear inositide metabolism is regulated independently from that present elsewhere in the cell. Although nuclear inositol lipids generate second messengers such as diacylglycerol and inositol 1,4,5-trisphosphate, it is becoming increasingly clear that in the nucleus polyphosphoinositides may act by themselves to influence pre-mRNA splicing and chromatin structure. This review aims at highlighting the most significant and updated findings about inositol lipid metabolism in the nucleus.     

Risk of malignant lymphoma following viral hepatitis infection

We investigated lymphoma risk following hepatitis infection in a case-control study of 274 incident lymphoma cases, defined according to the WHO classification, and 336 population controls in Sardinia, Italy. Part of our study population (198 cases and 219 controls) was included in the EPILYMPH study of Hepatitis C virus (HCV) infection in relation to non-Hodgklin's lymphoma risk. Based on questionnaire information on whether and at what age a diagnosis of hepatitis was posed by a physician, systematic anti-HCV antibodies testing in cases and controls by enzyme-linked immunoassay, and HCV-RNA assessment by PCR analyses in positive samples, we investigated more in detail whether hepatitis non-C is also associated with lymphoma risk, and whether risk varies by clinical form of hepatitis (acute or chronic infection). After adjusting by age, gender, education, and area of birth whether from the study area or elsewhere in Italy, a previous generic diagnosis of hepatitis was associated with a significantly elevated lymphoma risk [odds ratio (OR) = 1.8; 95% CI 1.1, 2.8], which was equally increased for hepatitis B (OR = 1.8; 95% CI 0.9, 3.5), for HCV positive subjects overall (OR = 2.0; 95% CI 0.8, 4.8), and for hepatitis non-B non-C (OR = 1.6; 95% CI 0.7, 3.9). Once concurrent infection from other hepatitis viruses was excluded, acute or chronic hepatitis C was the only one showing a consistent risk increase in all lymphoma subtypes, but follicular lymphoma. Some indications of an excess risk of lymphoma were observed also for acute, but not chronic forms of hepatitis B and hepatitis non-B, non C. Self-limited hepatitis C did not show an association. No significant heterogeneity in the risk of major lymphoma subtype was observed. Our results confirm a role of either acute or chronic active HCV infection in lymphomagenesis. Further studies are warranted to test the hypothesis that acute infection from other hepatitis viruses might also increase lymphoma risk.     

Colchicine in clinical medicine. A guide for internists

Colchicine (COL) has been used in medicine for a long time. It is well recognized as a valid therapy in acute flares of gouty arthritis, familial Mediterranean fever (FMF), Behçet's disease, and recurring pericarditis with effusion. It has also been used to treat many inflammatory disorders prone to fibrosis, mostly with disappointing therapeutic results.The pharmacotherapeutic mechanism of action of COL in diverse diseases is not fully understood, thought it is known that the drug accumulates preferentially in neutrophils, and this effect is useful in FMF.COL shows a large interindividual bioavailability. Furthermore, interactions with drugs interfering with CYP3A4 dependent enzymes and P-glycoprotein occur and are clinically important. The dosage of COL must be reduced in patients with relevant hepatic and/or renal dysfunction. However, when appropriately used and contraindications have been excluded, oral COL is a safe treatment.     

VGF: an inducible gene product, precursor of a diverse array of neuro-endocrine peptides and tissue-specific disease biomarkers

The vgf gene (non-acronymic) is induced in vivo by neurotrophins including Nerve Growth Factor (NGF), Brain Derived Growth Factor (BDNF) and Glial Derived Growth Factor (GDNF), by synaptic activity and by homeostatic and other stimuli. Post-translational processing of a single VGF precursor gives raise to a varied multiplicity of neuro-endocrine peptides, some of which are secreted upon stimulation both in vitro and in vivo. Several VGF peptides, accounting for ～20% of the VGF precursor sequence, have shown biological roles including regulation of food intake, energy balance, reproductive and homeostatic mechanisms, synaptic strengthening, long-term potentiation (LTP) and anti-depressant activity. From a further ～50% of VGF derive multiple "fragments", largely identified in the human cerebro-spinal fluid by proteomic studies searching for disease biomarkers. These represent an important starting point for discovery of further VGF products relevant to neuronal brain functions, as well as to neurodegenerative and psychiatric disease conditions. A distinct feature of VGF peptides is their cell type specific diversity in all neuroendocrine organs studied so far. Selective differential profiles are found across the cell populations of pituitary, adrenal medulla and pancreatic islets, and in gastric neuroendocrine as well as some further mucosal cells, and are yet to be investigated in neuronal systems. At the same time, specific VGF peptide/s undergo selective modulation in response to organ or cell population relevant stimuli. Such pattern argues for a multiplicity of roles for VGF peptides, including endocrine functions, local intercellular communication, as well as the possible mediation of intracellular mechanisms.     

Stress-induced cardiomyopathy: A review

In clinical practice it is essential to bear stress-induced cardiomyopathy (SICMP) in mind as it is an insufficiently known cardiac pathology that mimics acute coronary syndromes (ACS), often with signs of cardiac failure. In the chronic phase, it poses differential diagnostic problems with regard to coronary artery pathology. Taxonomic confusion, due to the pathology also being called "takotsubo" or "ampulla cardiomyopathy", has resulted in inappropriate diagnoses and therapy. Available evidence strongly suggests that, in the presence of several cardiac risk factors, excessive sympathetic stimulation may induce this cardiomyopathy. The predilection of this cardiomyopathy for Mediterranean and Indo-Asian women, who represent 85% of cases, is probably explained by the fact that there is a significant correlation between female gender, a short (<158 cm) stature, a small (<1.9 m(2)) body surface area, and hypoplastic coronary arteries. Furthermore, 40% of SICMP patients have a hypoplastic branching of the coronary arteries in the apical region of the heart. This anomaly strongly favors the apical localization of the dyskinesia. The prognosis of SICMP is good as far as life expectancy is concerned. However, in most cases, the symptoms become chronic, medical treatment rarely improves dyspnea and chest pain, and the quality of life is, therefore, reduced. In this paper, we address diagnostic misunderstandings and we review the clinical and pathophysiological features of SICMP.     

Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia

Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.     

Uterine and ovarian carcinosarcomas overexpressing Trop-2 are sensitive to hRS7, a humanized anti-Trop-2 antibody

Background

We evaluated the expression of human trophoblastic cell-surface marker (Trop-2) and the potential of hRS7 - a humanized monoclonal anti-Trop-2 antibody - as a therapeutic strategy against treatment-refractory human uterine (UMMT) and ovarian (OMMT) carcinosarcoma cell lines.

Materials and methods

Trop-2 expression was evaluated by immunohistochemistry (IHC) in paraffin-embedded tumor tissues, by real-time polymerase-chain-reaction (RT-PCR) and flow-cytometry in cell lines. Sensitivity to hRS7 antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested using 5-hour chromium-release assays against UMMT and OMMT cells.

Results

Trop-2 expression was elevated in 9 of 26 (35%) UMMT and 8 of 14 (57%) OMMT tissues tested by IHC. Positivity for Trop-2 mRNA by RT-PCR and surface expression by flow cytometry were detected in 2 of 4 cell lines, with high positivity noted in OMMT-ARK-2. OMMT-ARK-2 was highly sensitive to hRS7 ADCC (range: 34.7-41.0%; P < 0.001) with negligible cytotoxicity seen in the absence of hRS7 or in the presence of control antibody (range: 1.1-2.5%). Human IgG did not significantly inhibit ADCC while human complement increased, hRS7-mediated-cytotoxicity against OMMT-ARK-2.

Conclusion

Trop-2 is overexpressed in a proportion of UMMT and OMMT, and hRS7 may represent a novel, potentially highly effective treatment option for patients with treatment-refractory carcinosarcomas overexpressing Trop-2.     

Toxicity of antimony trioxide nanoparticles on human hematopoietic progenitor cells and comparison to cell lines

Nanoparticles (NPs) are materials with one dimension in the range of 1–100 nm. The toxicity of NPs remains widely unknown and still poses concerns, due to the peculiar characteristics of materials in the nano-size range. We analyze the toxicity of seven NPs (Fe₂O₃, Fe₃O₄, Sb₂O₃, Au, TiO₂, Co, and Ag) on primary cultures of human hematopoietic progenitor cells from the bone marrow of healthy donors with CFU assays, and show that antimony oxide (Sb₂O₃) NPs and cobalt (Co) NPs have a toxic effect, while the other NPs have no effect at the tested concentrations (5, 25 and 100 μg/ml). While Co NPs suspension is toxic to both erythroid and granulocytic–monocytic precursors, Sb₂O₃ NPs at 5 μg/ml are specifically toxic to erythroid colony development, suggesting a highly selective type of toxicity. With liquid culture assays we show that Sb₂O₃ NPs impair the proliferation of erythroid progenitors, while no toxic effect is observed when Sb₂O₃ NPs are added during erythroid differentiation. CFU assays and liquid culture assays on seven human cell lines of hematopoietic origin (K562, HL-60, CEM, CEM-R, Thp-1, Jurkat, and Molt-4) show that, contrary to what observed on primary cultures of bone marrow progenitors, Sb₂O₃ NPs have no toxic effect on proliferation of any of the cell lines, raising concerns about the use of immortalized cell lines for nanotoxicology tests.