Molecular aspects of hepatic carcinogenesis

Exogenous agents correlated with hepatocellular carcinoma (HCC) have been identified and well characterized. These agents, including the different viruses that cause chronic hepatitis and cirrhosis, can lead to regenerative nodules and dysplastic nodules/adenomatous hyperplasia. These conditions associated with several molecular alterations of hepatocyte ultimately culminate in hepatocellular carcinoma. Recently, there has been a great progress in the identification of somatic and germinative mutations that may be correlated with the development of HCC, justifying a review on the subject. Hence, the factors involved in the process of hepatic carcinogenesis, such as infection by the hepatitis B and C viruses, with a special focus in the molecular alterations described in recent years are discussed herein, pointing out areas potentially relevant for clinical development.     

The use of NaOCl in combination with CHX produces cytotoxic product

Objectives

The combination of sodium hypochlorite (NaOCl) and chlorhexidine (CHX) yields a “precipitate potentially toxic” (PPT). The aim of this study was to evaluate the tissue response to implanted polyethylene tubes filled with PPT-soaked fibrin sponge.

Methods

Forty rats received four polyethylene tubes each; each tube was filled with fibrin sponge soaked by 2.5 % NaOCl, 2.0 % CHX, PPT (2.5 % NaOCl plus 2.0 % CHX), or not soaked (control). The observation time points were 7, 15, 30, 60, and 90 days. At each time point, eight animals were killed, and the tubes and surrounding tissues were removed, fixed, and prepared for light microscopic analysis by performing glycol methacrylate embedding, serial cutting into 3-μm sections, and hematoxylin–eosin staining. Qualitative and quantitative evaluations of the reactions were performed. Results were statistically analyzed by Kruskal–Wallis test (p?<?0.05).

Results

All chemical solutions caused moderate reactions at 7 days. On day 30, PPT group was more cytotoxic than the control group and the CHX group (p?<?0.05). On days 15 and 60, PPT group was more cytotoxic than the control group (p?<?0.05). On day 90, there was no statistically significant difference between the different groups.

Conclusion

PPT is more cytotoxic than NaOCl and CHX alone, particularly in the short term.

Clinical significance

Protocols which suggest the use of CHX and NaOCl must be revised because this mixture produces cytotoxic product.     

Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects

Outbreaks of the Zika, dengue, and chikungunya viruses, especially in the Americas, pose a global threat due to their rapid spread and difficulty controlling the vector. Extreme phenotypes are often observed, from asymptomatic to severe clinical manifestations, which are well-studied in dengue. Host variations are also important contributors to disease outcomes, and many case-control studies have associated single nucleotide polymorphisms (SNPs) with severe dengue. Here, we found that the TC genotype and T-carriers for SNP rs1285933 in the C-type lectin superfamily member 5 (CLEC5A) gene was associated with severe dengue in a Northern Brazilian population (OR = 2.75 and p-value = 0.01, OR = 2.11 and p-value = 0.04, respectively). We also tested the functional effect of the CLEC5A protein and found that it is upregulated on the surface of human monocytes after in vitro dengue infection. CLEC5A was correlated with viral load inside the monocytes (Spearman r = 0.55, p = 0.008) and TNF production in culture supernatants (Spearman r = 0.72, p = 0.03). Analysis of mRNA in blood samples from DENV4-infected patients exhibiting mild symptoms showed that CLEC5A mRNA expression is correlated with TNF (r = 0.67, p = 0.0001) and other immune mediators. Monocytes from rs1285933 TT/TC individuals showed lower CLEC5A expression compared to CC genotypes. However, in these cells, CLEC5A was not correlated with TNF production. In summary, we confirmed that CLEC5A is genetically associated with dengue severity outcome, playing a central role during the immune response triggered by a dengue viral infection, and rs1285933 is a relevant SNP that is able to regulate signaling pathways after interactions between the dengue virus and CLEC5A receptors.     

Untersuchungen zum Mechanismus der serologischen Luesreaktionen

Zusammenfassung Durch Verwendung von künstlichen serologischen Systemen zeigen die Verff., daß einige unspezifische Veränderungen der serologischen Syphilis-Reaktionen durch Erhöhung der Konzentration der totalen Proteine oder Gammaglobuline hervorgerufen werden können, die allerdings nur die Flockungsreaktionen beeinflussen.Die Erhöhung der Konzentration von normalen Lipoiden in solchen Systemen, hat Veränderungen nur der Komplementbindungsreaktionen zu Folge, wohingegen die Hyperkonzentration von aus syphilitischen Sera gewonnenen Lipoiden besonders deutlich die Komplementbindungsreaktion, in viel geringerem Maße auch die Flockungsreaktionen positiviert.Durch Kombination der Wirkung der Syphilislipoide mit derjenigen der Gammaglobuline erzielt man deutliche Positivierungen sowohl der Komplementbindungsreaktion als auch der Flockungsreaktionen, die bis zur Notierung +++ oder ++++ ansteigen.Durch diese Untersuchungen wird die Hypothese der lipoproteischen Zusammensetzung der syphilitischen Reagins bestätigt.Die Tatsache, daß die Komplementbindungsreaktion durch lipoproteische Komplexe, die Flockungsreaktionen hingegen durch Gammaglobulin positiviert werden, spricht für die Dualität der Antikörper dieser beiden Reaktionsmethoden.     

Average spectral power changes at the hippocampal electroencephalogram in schizophrenia model induced by ketamine

The use of ketamine (Ket) as a pharmacological model of schizophrenia is an important tool for understanding the main mechanisms of glutamatergic regulated neural oscillations. Thus, the aim of the current study was to evaluate Ket‐induced changes in the average spectral power using the hippocampal quantitative electroencephalography (QEEG). To this end, male Wistar rats were submitted to a stereotactic surgery for the implantation of an electrode in the right hippocampus. After three days, the animals were divided into four groups that were treated for 10 consecutive days with Ket (10, 50, or 100 mg/kg). Brainwaves were captured on the 1st or 10th day, respectively, to acute or repeated treatments. The administration of Ket (10, 50, or 100 mg/kg), compared with controls, induced changes in the hippocampal average spectral power of delta, theta, alpha, gamma low or high waves, after acute or repeated treatments. Therefore, based on the alterations in the average spectral power of hippocampal waves induced by Ket, our findings might provide a basis for the use of hippocampal QEEG in animal models of schizophrenia.     

Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling

Intestinal barrier function requires intricate cooperation between intestinal epithelial cells and immune cells. Enteropathogens are able to invade the intestinal lymphoid tissue known as Peyer's patches (PPs) and disrupt the integrity of the intestinal barrier. However, the underlying molecular mechanisms of this process are poorly understood. In mice infected with Yersinia pseudotuberculosis, we found that PP barrier dysfunction is dependent on the Yersinia virulence plasmid and the expression of TLR-2 by hematopoietic cells, but not by intestinal epithelial cells. Upon TLR-2 stimulation, Y. pseudotuberculosis-infected monocytes activated caspase-1 and produced IL-1β. In turn, IL-1β increased NF-κB and myosin light chain kinase activation in intestinal epithelial cells, thus disrupting the intestinal barrier by opening the tight junctions. Therefore, Y. pseudotuberculosis subverts intestinal barrier function by altering the interplay between immune and epithelial cells during infection.