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A new study now reports recurrent somatic mutation of EZH2, a histone methyltransferase that modifies H3K27, in diffuse large B-cell lymphoma (DLBCL). There is now evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in cancer, suggesting that a precise balance of this methylation is critical for normal cell growth.

Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of MMSET by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.

We have developed a targeted method to quantify all combinations of methylation on an H3 peptide containing lysines 27 and 36 (H3K27-K36). By using stable isotopes that separately label the histone backbone and its methylations, we tracked the rates of methylation and demethylation in myeloma cells expressing high vs. low levels of the methyltransferase MMSET/WHSC1/NSD2. Following quantification of 99 labeled H3K27-K36 methylation states across time, a kinetic model converged to yield 44 effective rate constants qualifying each methylation and demethylation step as a function of the methylation state on the neighboring lysine. We call this approach MS-based measurement and modeling of histone methylation kinetics (M4K). M4K revealed that, when dimethylation states are reached on H3K27 or H3K36, rates of further methylation on the other site are reduced as much as 100-fold. Overall, cells with high MMSET have as much as 33-fold increases in the effective rate constants for formation of H3K36 mono- and dimethylation. At H3K27, cells with high MMSET have elevated formation of K27me1, but even higher increases in the effective rate constants for its reversal by demethylation. These quantitative studies lay bare a bidirectional antagonism between H3K27 and H3K36 that controls the writing and erasing of these methylation marks. Additionally, the integrated kinetic model was used to correctly predict observed abundances of H3K27-K36 methylation states within 5% of that actually established in perturbed cells. Such predictive power for how histone methylations are established should have major value as this family of methyltransferases matures as drug targets.

Most of the current Machine Translation systems are designed to translate a document sentence by sentence ignoring discourse information and producing incoherencies in the final translations. In this paper we present some document-level-oriented post-processes to improve translations' coherence and consistency. Incoherences are detected and new partial translations are proposed. The work focuses on studying two phenomena: words with inconsistent translations throughout a text and also, gender and number agreement among words. Since we deal with specific phenomena, an automatic evaluation does not reflect significant variations in the translations. However, improvements are observed through a manual evaluation.

Tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor and has been approved for the treatment of rheumatoid arthritis (RA) patients who have had an inadequate response to previous biological therapies. Psoriasiform skin lesions, especially palmoplantar pustulosis lesions, are well described following anti-tumour necrosis factor therapy. We describe a 79-year-old woman with rheumatoid factor-positive, anti-citrullinated protein antibody-positive erosive RA, who developed a psoriasiform palmoplantar pustulosis reaction following treatment with TCZ therapy (IL-6 receptor). The rash showed histological features compatible with psoriasis and disappeared following discontinuation of TCZ.

Epigenetic deregulation of gene expression has a role in the initiation and progression of prostate cancer (PCa). The histone methyltransferase MMSET/WHSC1 (Multiple Myeloma SET domain) is overexpressed in a number of metastatic tumors, but its mechanism of action has not been defined. In this work, we found that PCa cell lines expressed significantly higher levels of MMSET compared with immortalized, non-transformed prostate cells. Knockdown experiments showed that, in metastatic PCa cell lines, dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 (H3K36me2 and H3K27me3, respectively) depended on MMSET expression, whereas depletion of MMSET in benign prostatic cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation, colony formation in soft agar and strikingly diminished cell migration and invasion. Conversely, overexpression of MMSET in immortalized, non-transformed RWPE-1 cells promoted cell migration and invasion, accompanied by an epithelial–mesenchymal transition (EMT). Among a panel of EMT-promoting genes analyzed, TWIST1 expression was strongly activated in response to MMSET. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus and leads to an increase in H3K36me2, suggesting a direct role of MMSET in the regulation of this gene. Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT, indicating that TWIST1 was a critical target of MMSET, responsible for the acquisition of an invasive phenotype. Collectively, these data suggest that MMSET has a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes.

The large amount of waste generated by the orange juice industry has sparked the interest of many researchers in incorporating recycling systems and following a much more sustainable circular economy model. This work proposes the valorization of the co-product generated in the orange juice extraction industry after freeze-drying for its subsequent reuse as a natural ingredient in the food industry. In addition, the possible protective effect of gum Arabic and corn starch esterified with octenyl succinic groups, in proportions optimised in previous studies 0.25 and 0.45 g/g orange co-product dry solutes, on the main bioactive compounds of orange peel during the freeze-drying process has been studied. The samples were characterised for their content of vitamin C (ascorbic and dehydroascorbic acids), flavonoids (hesperidin and narirutin), total phenols and total carotenoids, as well as their antioxidant capacity (DPPH and FRAP assays). In addition, samples were digested, mimicking the human enzymatic oral gastro-intestinal digestion process, and the bioaccessibility of the bioactive compounds was evaluated. It was observed that the addition of both biopolymers improved the stability of the hydrophilic compounds during freeze-drying. This conservative effect was more remarkable for higher biopolymer concentrations. However, no protective effect on carotenoid compounds was observed. This trend was reflected in the antioxidant activity of the different samples. In addition, the incorporation of biopolymers improved the bioaccessibility of the bioactive compounds studied. In conclusion, the results supported the feasibility of the freeze-dried orange juice co-product as a natural, sustainable source of health-promoting compounds.

Much attention has been paid to the health benefits of including fruits and vegetables in the diet. However, for the compounds responsible for this beneficial effect to be effective at the level of the human organism, they must be available for absorption after digestion. In this sense, in vivo studies are needed to demonstrate the bioavailability of these compounds and their physiological activity. In order to provide information in this regard, this study collects data on the levels of vitamin C (VC) and naringenin (NAG) in the blood serum of the 11 volunteer participants in this trial, before and after consuming two different grapefruit juices. The juices were prepared by rehydrating the grapefruit powder obtained by freeze-drying (FD) the fruit puree or by spray-drying (SD) the liquefied grapefruit. No significant differences (p > 0.05) neither by juice nor by participant were observed in any case. The mean relative increase of VC, NAG and the radical scavenging ability (RSA) in blood serum due to grapefruit juices intake was 12%, 28% and 26%, respectively. Just VC showed a positive and significant Pearson’s correlation with RSA. The mean bioavailability of VC was quantified as 1.529 ± 0.002 mg VC/L serum per 100 mg of VC ingested.

MMSET/WHSC1 is a histone methyltransferase (HMT) overexpressed in t(4;14)+ multiple myeloma (MM) patients, believed to be the driving factor in the pathogenesis of this MM subtype. MMSET overexpression in MM leads to an increase in histone 3 lysine 36 dimethylation (H3K36me2), and a decrease in histone 3 lysine 27 trimethylation (H3K27me3), as well as changes in proliferation, gene expression and chromatin accessibility. Prior work linked methylation of histones to the ability of cells to undergo DNA damage repair. In addition, t(4;14)+ patients frequently relapse after regimens that include DNA damage-inducing agents, suggesting that MMSET may play a role in DNA damage repair and response. In U2OS cells, we found that MMSET is required for efficient non-homologous end joining as well as homologous recombination. Loss of MMSET led to loss of expression of several DNA repair proteins, as well as decreased recruitment of DNA repair proteins to sites of DNA double-strand breaks (DSBs). By using genetically matched MM cell lines that had either high (pathological) or low (physiological) expression of MMSET, we found that MMSET-high cells had increased damage at baseline. Upon addition of a DNA-damaging agent, MMSET-high cells repaired DNA damage at an enhanced rate and continued to proliferate, whereas MMSET-low cells accumulated DNA damage and entered cell cycle arrest. In a murine xenograft model using t(4;14)+ KMS11 MM cells harboring an inducible MMSET shRNA, depletion of MMSET enhanced the efficacy of chemotherapy, inhibiting tumor growth and extending survival. These findings help explain the poorer prognosis of t(4;14) MM and further validate MMSET as a potential therapeutic target in MM and other cancers.

Interest in fruit/vegetable consumption is not always linked to a particular diet but rather derives from their high antioxidant activity (AOA), with potential health benefits provided, in part, by polyphenols. Although phenols can be found in free form (FP) or bound to plant tissues (BP), the experimental methodology most frequently used for the quantification of total phenols (TP) is based on the extraction of a portion of FP, which may justify the lack of correlation often found between them and AOA. In this context, four successive extractions were performed to obtain FP and BP of powdered orange juice by-product, and their contribution to the AOA was studied. The first extract (MeOH, 30 °C) can be assumed to be one of the conventional methods for the quantification of TP. Re-extraction with MeOH (60 °C) afforded the FP. Two subsequent basic and acidic extractions yielded the BP. Although the FPs were the most abundant, the AOA (DPPH method) of the last fraction of BP was of the same order found in the first fraction of FP. This highlights the interest in extracting the BP from the by-product of orange juice if its antioxidant capacity is to be exploited.