The findings of Liang and co workers add to current

The findings of Liang and co-workers add to current knowledge on gastric and colorectal carcinogenesis, uncovering the cooperation between deranged genetic and epigenetic mechanism in two extensively studied tumor models. In addition, novel CRC prognostic biomarkers might allow for improved patient risk stratification, assisting in therapeutic decision-making. Several issues, however, require further clarification. At molecular level, the mechanism underlying ASF1A overexpression remains elusive. Is it a cause or a consequence of neoplastic transformation? Although no mechanism was proposed, it is tempting to speculate whether this might be due to impaired ASF1A degradation, which is controlled by RAD6 (). Furthermore, the association of ASF1A overexpression and tumor aggressiveness needs to be explored in more depth. An interesting hint derives from the observation that ASF1A wee1 was higher in the less differentiated cancer cell lines (). In GC, poorly differentiated tumors, such as signet ring cell carcinomas, frequently display E-cadherin loss of expression, a feature that is associated with gene mutations, but that might be also related with ASF1A overexpression. Because detailed pathological information is lacking, inferences cannot be made regarding this possibility. The clinical relevance of Liang and co-workers\' findings also demand additional investigation. The prognostic value of ASF1A overexpression in GC was not explored and it could be even more valuable than that in CRC, owing to globally worse prognosis of GC patients compared to CRC patients. Moreover, even in CRC, prognostic value was demonstrated only for overall survival. However, other equally or more relevant endpoints such as disease-specific and disease-free survival need to be considered. Importantly, multivariable analysis is also required, to determine whether ASF1A overexpression is an independent predictor of poor outcome. Finally, the recent identification of pyrimidine-2,4,6-trione derivative small molecules that inhibit Asf1 and H3K56 acetylation, without disturbing other histone modification (), provides a support to Liang and co-workers\' claim about the potential therapeutic implications of their results. Thus, like most scientific endeavors, this study not only provides some answers but it raises more profound questions that will certainly stimulate future research on the hinge between genetics and epigenetics in Cancer. Disclosure
In a small number of HIV-1 infected individuals natural restriction of viremia to very low or undetectable levels is achieved without the use of combined antiretroviral therapy (cART). Identifying the factors underpinning viral suppression in these so-called elite controllers (EC) has long been a goal with the aim of informing potential therapeutic and infection prevention strategies. A number of viral and host factors associated with EC have been identified, implying that viral control within EC as a whole and probably within at least some individual EC is multifactorial. Host HIV-specific cellular immune responses that have been associated with EC include potent Gag-specific CD8+ T cells, especially when associated with expression of the HLA-B*57 allele () and CD4+ T cell responses. The role of humoral immunity is less clear. It was reported that EC had elevated polyfunctional HIV-specific non-neutralizing antibody responses in the absence of significantly increased individual effector functions (). One individual non-neutralizing antibody activity, antibody dependent cell-mediated cytotoxicity (ADCC) has been linked to EC, particularly in those that are HLA-B*57− (). The role of neutralizing antibodies in natural viral control is not well established. In general, studies have shown that while some EC possess antibodies capable of broad neutralizing activity this is not a general or specific property of this group as a whole. The present study by Rouers and coworkers found that within EC there was a much higher frequency of HIV Env-specific memory B cell responders compared to patients that have been rendered aviremic through the use of cART (). Remarkably, this was despite the fact that members of the EC cohort were infected a number of years previously and had presumably controlled viremia to very low levels for an extended period and consequently had experienced minimal ongoing exposure to viral antigen. Equivalent response frequencies to Influenza vaccine antigens were observed in EC and cART recipients, indicating that the reduced HIV-specific B cell frequency observed for the cART group was specific for HIV antigens and did not represent a global disruption of B cell responses. Importantly, it was found that when EC were separated based on their HLA-B*57 allele status, HLA-B*57+ individuals showed a positive correlation between the frequency of HIV Env-specific memory B cells and the breadth of neutralizing activity mediated by sera antibodies, whereas in HLA-B*57− individuals this correlation was not observed. HIV Env-specific binding titers measured by ELISA were similar for both groups indicating that this difference was qualitative rather than quantitative. HIV Env-specific memory B cell responses in EC were found to be predominantly IgG1, although some subjects also preserved IgG2 and IgG3 responses. HLA-B*57+ and negative EC did not show the preferential preservation of HIV Env-specific B cells expressing a specific isotype. This differs from the potentially protective HIV Gag-specific antibody responses present in sera that have been reported to be more likely to be of the IgG2 isotype in HLA-B*57– controllers (), although in that study less stringent criteria were used to define controllers compared to those used to define EC in Rouers and coworkers here. The question of whether isotype can influence natural control of HIV infection by antibodies may depend on factors such as the particular antigen targeted and the specific cohort being assessed.