New therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is often diagnosed at an advanced stage when most potentially curative therapies such as resection, transplantation or percutaneous and transarterial interventions are of limited efficacy. The fact that HCC is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy, leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver disease. However, in spite of this heterogeneity recent insights into the biology of HCC suggest that certain signaling pathways and molecular alterations are likely to play essential roles in HCC development by promoting cell growth and survival. The identification of such mechanisms may open new avenues for the prevention and treatment of HCC through the development of targeted therapies. In this review we will describe the new potential therapeutic targets and clinical developments that have emerged from progress in the knowledge of HCC biology, In addition, recent advances in gene therapy and combined cell and gene therapy, together with new radiotherapy techniques and immunotherapy in patients with HCC will be discussed

Papel de SLU7 en la diferenciación hepática y en la protección del hígado frente al daño: regulación de HNF4A

El hígado es un órgano con un papel central en el organismo puesto que realiza numerosas funciones esenciales para mantener la homeostasis sistémica. A nivel histológico, el hígado presenta una arquitectura compleja y muy organizada, formada por diferentes poblaciones celulares que desarrollan funciones concretas y, en conjunto, permiten el correcto funcionamiento del órgano. Así, el hígado está formado por las células parenquimales que incluyen a los hepatocitos y a los colangiocitos, y las células no parenquimales, que engloban a las células estrelladas hepáticas (HSC, hepatic stellate cells), las células de Kupffer o las células endoteliales sinusoidales. La población celular más abundante son los hepatocitos, que constituyen alrededor de un 80 % de la masa hepática total, y son los que más contribuyen al desarrollo de la función hepática. Se trata de unas células epiteliales polarizadas, muy diferenciadas y quiescentes, aunque presentan una gran capacidad de regeneración en respuesta a estímulos nocivos 1–4 . Las células hepáticas se organizan en el hígado alrededor de una estructura anatómica peculiar y compleja, determinada por el patrón del flujo sanguíneo, y que es esencial para que se puedan llevar a cabo las funciones hepáticas. Brevemente, el hígado recibe sangre de la vena porta rica en nutrientes y productos de deshecho, y sangre de la arteria hepática rica en oxígeno, que fluye a través de una red de capilares sinusoidales entre las células hepáticas, hasta drenar en las venas centrales. Junto a las venas porta y las arterias hepáticas se encuentran los conductos biliares que conducen la bilis hasta la vesícula biliar y el intestino, y los tres conductos juntos forman la triada portal. La unidad funcional del hígado son los lobulillos hepáticos, que consisten en fragmentos poligonales de células hepáticas dispuestas en torno a una vena central y rodeadas de triadas portales. Los capilares sinusoidales conectan la vena central con los espacios porta y, en paralelo a ellos, se organizan los hepatocitos formando cordones gruesos unicelulares (Figura 1A). Tanto la vena porta como la arteria hepática suministran la sangre a los hepatocitos conforme fluye a través de la red de sinusoides hasta drenar en las venas centrales. En función de si los hepatocitos se localizan más cerca de la región periportal o más cerca de la región pericentral, presentan diferencias fenotípicas en cuanto a la expresión de enzimas metabólicas, por lo que realizan funciones metabólicas diferentes. Esta distribución diferencial de las funciones metabólicas y secretoras del hígado a lo largo del eje porto-central se conoce como zonación, y constituye un marcador clave de la maduración hepática (Figura 1B) 1–5

Antimicrobial resistance of three common molecularly identified pathogenic bacteria to Allium aqueous extracts

Articulo principal de estudiante de doctoradoThe aim of this work was to evaluate the in vitro bacterial inhibition of different types of garlic on Escherichia coli ATCC 25922, Listeria monocytogenes and Staphylococcus aureus. The bacterial strains were molecularly identified using gen 16S rDNA molecular identification. Four different types of garlics were used: 1) white, 2) Japanese, 3) elephant and 3) black, and these were evaluated at two different concentrations (0.25 and 0.125 g/mL) per garlic type. Bioactive compounds present in the garlics were identified using high-performance liquid chromatography coupled to ultraviolet detector (HPLC-UV), and total polyphenols were quantified by the Folin-Ciocalteu technique. The Kirby-Bauber method was used for the bacterial evaluation. Aqueous extract of black garlic had the highest amount of polyphenols 6.26 ± 0.21 mg GAE/mL. The area of inhibition was measured and classified as sensitive, intermediate or resistant. Using the disc diffusion assay, higher concentration (0.25 g/mL) of aqueous extract of white garlic had the highest antibacterial activity area, with 21.46 ± 3.94 mm for L. monocytogenes, 20.61 ± 2.47 mm for S. aureus and 17.83 ± 2.21 mm for E. coli. White garlic had comparable antimicrobial activity as the control (tetracycline at 30 μg) as indicated by the size of the inhibition halos. Based on your results, white garlic can be used as an alternative to synthetic antimicrobials.SIyE

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis ( 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells

Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning

Ischemia-reperfusion (I/R) liver injury occurs when blood flow is restored after prolonged ischemia. A short interruption of blood flow (ischemic preconditioning [IP]) induces tolerance to subsequent prolonged ischemia through ill-defined mechanisms. Cardiotrophin (CT)-1, a cytokine of the interleukin-6 family, exerts hepatoprotective effects and activates key survival pathways like JAK/STAT3. Here we show that administration of CT-1 to rats or mice protects against I/R liver injury and that CT-1–deficient mice are exceedingly sensitive to this type of damage. IP markedly reduced transaminase levels and abrogated caspase-3 and c-Jun–NH2-terminal kinase activation after I/R in normal mice but not in CT-1–null mice. Moreover, the protective effect afforded by IP was reduced by previous administration of neutralizing anti–CT-1 antibody. Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1–null mice. Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes. Interestingly, brief ischemia followed by short reperfusion caused mild serum transaminase elevation and strong STAT3 activation in normal and IL-6–deficient mice, but failed to activate STAT3 and provoked marked hypertransaminasemia in CT-1–null animals. In conclusion, CT-1 is an essential endogenous defense of the liver against I/R and is a key mediator of the protective effect induced by IP

Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities

: Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment

Detection of anti-hepatitis C virus antibodies by ELISA using synthetic peptides

A novel ELISA assay for the detection of anti-hepatitis C virus antibodies in the sera of infected individuals is described. This assay is based on a mixture of three 15-amino acid synthetic peptides encompassing regions of core and NS4 proteins of hepatitis C virus. Comparison with other available ELISA assays based on recombinant polypeptides shows that, short synthetic peptides have the advantage over some larger recombinant peptides by giving higher specificity without loss of sensitivity

S-adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S-adenosylmethionine in the maintenance of the differentiated status of the liver

Methionine metabolism starts with the formation of S-adenosylmethionine (AdoMet), the most important biological methyl donor. This reaction is catalyzed by methionine adenosyltransferase (MAT). MAT is the product of two different genes: MAT1A, which is expressed only in the adult liver, and MAT2A, which is widely distributed, expressed in the fetal liver, and replaces MAT1A in hepatocarcinoma. In the liver, preservation of high expression of MAT1A and low expression of MAT2A is critical for the maintenance of a functional and differentiated organ. Here we describe that in cultured rat hepatocytes MAT1A expression progressively decreased, as described for other liver-specific genes, and MAT2A expression was induced. We find that this switch in gene expression was prevented by adding AdoMet to the culture medium. We also show that in cultured hepatocytes with decreased MAT1A expression AdoMet addition markedly increased MAT1A transcription in a dose-dependent fashion. This effect of AdoMet was mimicked by methionine, and blocked by 3-deazaadenosine and L-ethionine, but not D-ethionine, indicating that the effect was specific and mediated probably by a methylation reaction. These findings identify AdoMet as a key molecule that differentially regulates MAT1A and MAT2A expression and helps to maintain the differentiated status of the hepatocyte

Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology

BACKGROUND: The histopathological spectrum and role of hepatitis viruses in cases of hypertransaminasaemia of unknown aetiology have not been correctly analysed in a sufficiently large number of patients. METHODS: We studied 1075 consecutive patients referred for liver biopsy because of elevation of alanine aminotransferase (ALT) levels for more than six months. From this population we selected those cases in whom the aetiology could not be defined from clinical, biochemical, and serological data obtained before biopsy. In these patients liver biopsies were reviewed, and hepatitis B virus (HBV)-DNA and hepatitis C virus (HCV)-RNA were assayed in serum by polymerase chain reaction (PCR). Serum hepatitis G virus (HGV)-RNA was determined by PCR in 74 patients. RESULTS: Of 1075 patients studied, the cause of the increased serum ALT levels remained elusive after appropriate testing in 109 patients (10.1%). Liver biopsies from these patients showed non-specific changes in 32.7% of cases, non-alcoholic steatohepatitis (NASH) in 15.8%, and chronic hepatitis or cirrhosis in 51.5%. HBV-DNA and/or HCV-RNA was detected more frequently in cryptogenic liver disease than in healthy blood donors (26.7% v 3.4%; p<0.001). HGV-RNA was found in only one patient. The proportion of cases with detectable HBV-DNA or HCV-RNA was 14.3% in patients with non-specific changes or NASH, 30.7% in patients with chronic hepatitis, and 61.5% in patients with cirrhosis. Cirrhosis was found more frequently in patients with positive HBV-DNA and/or HCV-RNA in serum than in those who tested negatively (p=0.005). CONCLUSIONS: In our series, patients in whom biochemical and serological data did not determine the aetiology of the disease represented 10% of all cases referred for liver biopsy for persistent elevation of serum transaminases. Approximately 50% of patients had chronic hepatitis or cirrhosis and the remainder had NASH or non-specific changes. Occult viral infections were found in a high proportion of cases in the first group and in a low percentage of patients in the second