Antiviral activity of bone morphogenetic proteins and activins

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN

HCV interferisce con la via di segnale BMP6-SMAD e sopprime l'espressione di epcidina: risultatI in vivo ed in vitro

Background Chronic inflammatory states are often associated with anaemia that is attributed to increased levels of the iron regulatory hormone hepcidin. An exception is chronic hepatitis C virus (HCV) infection, which is accompanied by reduced hepcidin and predisposes to hepatic iron accumulation that exacerbates disease. Hepcidin synthesis by hepatocytes is largely controlled by bone morphogenetic proteins (BMP) and the SMAD signalling cascade. This pathway involves different factors: BMP6, emojuvelin (the BMP6 coreceptor), SMAD 1/5/8 (transcriptional factors) and the inhibitors SMAD6 and SMAD7 (which act through a negative feedback loop). Recently, BMP7 showed a synergistic effect with IFN-alfa in suppressing viral replication, in HCV+ cell cultures treated with both these drugs. So, our hypothesis is that HCV could influence the BMP6-SMADs signalling, in order to antagonize the possible antiviral effect of BMP6; in this case, low expression of hepcidin in HCV infection should be only a secondary event, given that hepcidin is the main target gene of the BMP6-SMADs pathway. Materials and Methods We assessed mRNA quantification by qRT-PCR for mRNA encoding hepcidin, emojuvelin, BMP6, SMAD6 and SMAD7 in biopsies obtained from HCV chronically infected patients, before antiviral treatment. We compared the gene expression in HCV+ patients vs controls and in non responders vs responders to antiviral therapy. We confirmed the in vivo results by an in vitro viral replication model of HCV infection. Results In vivo We found altered gene expression of components of the BMP6-SMADs pathway in liver biopsies from HCV positive patients: HCV positive patients showed significantly low levels of hepcidin and high levels of SMAD6 and SMAD7 in comparison to controls. Pre-treatment biopsies from patients non-responsive to antiviral therapy showed reduced levels of the BMP co-receptor HJV (p=0.0027), reduced levels of both the BMP target genes hepcidin (p=0.008) and ID1 (0.05). In vitro An in vitro virus replication model showed similar alterations in BMP pathway gene expression, and HCV infected cells exhibited a blunted hepcidin response to BMP6. BMP pathway inhibition was caused at least in part by virally-induced TNF-alpha. TNF-alpha suppressed induction of hepcidin by BMP and neutralizing anti-TNF-alpha antibodies restored the response to BMP6 by HCV+ infected cells. Conclusions HCV interferes with the BMP6/SMAD1/5/8 pathway both directly and indirectly, through the enhancement of TNF-α. The identification of BMP signal inhibition by HCV that correlates with hepcidin suppression and treatment response suggests new options for antiviral therapy.Razionale Lo stato di infiammazione cronica è spesso associato ad anemia attribuita all’incremento dell’epcidina, ormone regolatore dell’assorbimento del ferro. L’epatite cronica C rappresenta un’eccezione, essendo accompagnata da ridotta espressione di epcidina e predisposizione all’accumulo di ferro. La sintesi di epcidina da parte degli epatociti, che ne rappresentano la fonte primaria, è largamente controllata da proteine dette BMPs (Bone Morphogenetic Proteins), in particolare il BMP6. Nella via sono implicati altri fattori quali l’emojuvelina, corecettore del BMP6, i fattori trascrizionali SMAD1/5/8, ed i fattori inibitori SMAD6 e SMAD7, che, indotti in risposta all’attivazione della via di segnale stessa, inibiscono l’espressione di epcidina, con un feedback negativo. L’importanza dello studio del ruolo dei BMP è sostenuta dal fatto che recentemente BMP7 ha presentato in uno studio in vitro un effetto sinergico con IFN-α, per aumentare l’effetto antivirale e sopprimere la replicazione virale. Si potrebbe ipotizzare, perciò, che il virus dell’epatite C, per contrastare fattori che hanno effetto antivirale, produca come evento collaterale la riduzione di espressione di epcidina, che solo in alcuni casi (compresenza di altri fattori predisponenti genetici, comportamentali, ambientali) potrebbe portare all’accumulo di ferro. Materiali e metodi Con metodica qRT-PCR è stata quantificata l’espressione di emojuvelina, epcidina, BMP6 e SMAD in mRNA proveniente da biopsie ottenute da pazienti HCV positivi, prima di qualsiasi trattamento antivirale e controlli non epatopatici. Inoltre, è stato fatto un confronto tra pazienti HCV positivi con Sustained Virological Response (SVR) e pazienti Non Responders a terapia antivirale. E’ stato poi allestito un modello in vitro con cellule di epatoma infette e non infette, per confermare i dati ottenuti in vivo. Risultati In vivo: L’espressione di epcidina era significativamente ridotta nei pazienti HCV positivi rispetto ai controlli non epatopatici (p=0.002), mentre quella di SMAD6 (p=0.008) e SMAD7 (p=n.s.) era aumentata. L’espressione del gene dell’epcidina e di ID1, target della via di segnale di BMP6/SMAD1/5/8, era significativamente ridotta nei pazienti NR confrontati coi pazienti SVR (rispettivamente p=0.008 e p=0.05), come anche quella di emojuvelina (p=0.0027). In vitro: I risultati in esperimenti su colture cellulari hanno confermato alterazioni simili a quelle ottenute in vivo riguardo all’espressione dei geni coinvolti nella via di segnale analizzata: cellule infette con HCV erano meno sensibili all’azione del BMP6, in termini di espressione di epcidina. L’inibizione della via di segnale in presenza di infezione da HCV era dovuta, almeno parzialmente, all’azione del TNF-α. Il TNF-α sopprimeva l’induzione di epcidina da parte di BMP6, mentre anticorpi anti-TNF-α ripristinavano la risposta cellulare a BMP6 in colture infettate. Conclusioni Il virus dell’epatite C interferisce con una nuova via di segnale: la via attivata dal BMP6, coinvolgente i fattori trascrizionali SMAD1/5/8, cruciale nella regolazione dell’espressione di epcidina, ormone regolatore del metabolismo del ferro nell’organismo. Il virus HCV inibisce la via di segnale sia direttamente che indirettamente, attraverso produzione di TNF-α. La comprensione dell’interazione tra HCV e i fattori implicati nella via di segnale BMP6/SMAD1/5/8 è importante anche per definire eventuali nuovi target terapeutici in corso di infezione da HCV

MR in Cystic Tumors of the Pancreas

Cystic neoplasms of the pancreas are rare pancreatic tumors; nowadays they are diagnosed more frequently due to the spread of accurate imaging techniques. The WHO classification distinguishes serous cystic neoplasms (SCNs), mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and solid pseudopapillary neoplasms (SPNs). Those with a greater potential for malignant transformation are MCNs, IPMNs of the main pancreatic duct, and SPNs; surgical resection is indicated for these neoplasms. SCNs and branch-duct IPMNs have a very low malignant potential, so long-term radiological follow-up is indicated. Pancreatic neuroendocrine tumors (NETs) present as cystic lesions in approximately 5\u2009% of cases, with radiological features similar to SCNs, MCNs, or SPNs. Magnetic resonance imaging (MRI), completed with MR cholangiopancreatography (MRCP) sequences and contrast administration, is the most important technique in the evaluation of cystic neoplasms of the pancreas

Magnetic resonance imaging of autoimmune pancreatitis: A review of literature [Resonancia magnética de la pancreatitis autoinmune: una revisión de la literatura]

Autoimmune pancreatitis (AIP) is a distinct form of chronic pancreatitis caused by an autoimmune pathogenetic mechanism. It affects males (60%) slightly more frequently, and generally occurs between 40 to 60 years, although the possible range is much wider (14-80 years). Histologically AIP is characterised by the presence of a dense inflammatory infiltrate, with variable extension. It can be focal or diffuse throughout the whole pancreas. Clinical presentation in most cases is non-specific, with patients presenting with mild abdominal pain, rarely, acute pancreatitis symptoms, weight loss, and jaundice. Several studies reported multiple organ involvement due to the autoimmune process, suggesting a systemic nature of the disease. In 2011 the International Consensus Diagnostic Criteria for autoimmune pancreatitis (ICDC) defined the guidelines, and magnetic resonance imaging (MRI) and MR-cholangiopancreatography (MRCP) became the reference diagnostic technique in the diagnosis of the disease. This paper will review the imaging characteristics, the differential diagnosis, and the imaging features after treatment and follow up. Furthermore, our experience in this uncommon and challenging disease is reviewe

Pancreatic duct stenosis: Differential diagnosis between malignant and benign conditions at secretin-enhanced MRCP

To define imaging criteria of benign and malignant nature in patients with main pancreatic duct (MPD) stenosis

Stenosis of the main pancreatic duct in focal form of autoimmune pancreatitis: imaging findings on MR-MRCP

No availabl

Mucinous cystic neoplasms and serous cystadenomas arising in the body-tail of the pancreas: MR imaging characterization

PURPOSE:To identify magnetic resonance (MR)/MR cholangiopancreatography (MRCP) imaging signs helpful in the differential diagnosis between serous cystadenomas (SCAs) and mucinous cystic neoplasms (MCNs), arising from the body/tail of the pancreas.MATERIAL AND METHODS:This retrospective study had institutional review board approval and informed consent was waived. Fifty-three patients with non-communicating cystic pancreatic neoplasm of the body/tail, undergoing MR/MRCP, were included. Qualitative image analysis assessed the macroscopic pattern, number of cysts, presence of central scar, contrast enhancement of peripheral wall, and mural nodules. Quantitative analysis assessed the maximum diameter of the neoplasm, thickness of the peripheral wall, and calibre of the upstream main pancreatic duct.RESULTS:Histopathology results revealed that 27/53 (51 %) were SCAs, 26/53 (49 %) were MCNs. Microcystic pattern was observed in 88.2 % of SCAs and 11.8 % of MCNs; macrocystic pattern was observed in 90.5 % of MCNs and 9.5 % of SCAs (p\u2009<\u20090.0001). Central scar was detected in 29.6 % of SCAs and no MCNs (p\u2009=\u20090.003). Contrast enhancement of the peripheral wall was evident in 99.5 % of MCNs and 11.5 % of SCAs (p\u2009<\u20090.0001); mural nodules were depicted in 94.1 % of MCNs and 5.9 % of SCAs (p\u2009<\u20090.0001). Median maximum diameter was 54 mm for MCNs, 32 mm for SCAs (p\u2009=\u20090.001); median wall thickness was 4 mm for MCNs, 2 mm for SCAs (p\u2009<\u20090.0001).CONCLUSIONS:Macrocystic pattern, enhancement of a peripheral wall and mural nodules are suggestive of MCNs; whereas microcystic pattern, lack of peripheral wall and central scar are suggestive of SCAs

Advanced pancreatic adenocarcinoma: CT evaluation before and after neoadjuvant treatment with fluorouracil, leucovorin, oxaliplatin and irinotecan and correlation with histopathology

no availabl

Added Value of MRI Tractography of Periprostatic Nerve Plexus to Conventional t2-WI in Detection of Extra-Capsular Extension of Prostatic Cancer

not abstract availabl

Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance

Insulin resistance (IR) reduces response to pegylated-interferon (PEG-IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment - insulin resistance (HOMA-IR) for assessment of IR in non-diabetic patients, and the 'acute' virological response to PEG-IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG-IFN/Ribavirin, serum insulin and HOMA-IR were assessed at baseline, while hepatitis C virus (HCV)-RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 +/- 8.51 U/L and mean HOMA-IR was 2.65 +/- 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus-RNA decay observed 24 h after the first injection of PEG-IFN was significantly lower (0.7 +/- 0.8 log) in patients with HOMA > or =3 compared with those with HOMA or =3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24-h response to PEG-IFN. Hyperinsulinaemia reduces the cellular response to Pegylated-interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti-viral treatment