Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.Gastrointestinal-based drug delivery is considered the preferred mode of drug administration owing to its convenience for patients, which improves adherence. However, unique characteristics of the gastrointestinal tract (such as the digestive environment and constraints on transport across the gastrointestinal mucosa) limit the absorption of drugs. As a result, many medications, in particular biologics, still exist only or predominantly in injectable form. In this Review, we examine the fundamentals of gastrointestinal drug delivery to inform clinicians and pharmaceutical scientists. We discuss general principles, including the challenges that need to be overcome for successful drug formulation, and describe the unique features to consider for each gastrointestinal compartment when designing drug formulations for topical and systemic applications. We then discuss emerging technologies that seek to address remaining obstacles to successful gastrointestinal-based drug delivery.The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations.Omeprazole is a proton pump inhibitor that has recently been reported to exhibit anticancer activity against several types of cancer. However, the anticancer mechanisms of omeprazole remain elusive. Snail is an oncogenic zinc finger transcription factor; aberrant activation of Snail is associated with the occurrence and progression of cancer. In this study, we investigated whether Snail acted as a direct anticancer target of omeprazole. We showed that omeprazole displayed a high binding-affinity to recombinant Snail protein (Kd = 0.076 mM), suggesting that omeprazole directly and physically binds to the Snail protein. We further revealed that omeprazole disrupted CREB-binding protein (CBP)/p300-mediated Snail acetylation and then promoted Snail degradation through the ubiquitin-proteasome pathway in HCT116 cells. Omeprazole treatment markedly suppressed Snail-driven epithelial-mesenchymal transition (EMT) in aggressive HCT116, SUM159, and 4T1 cancer cells in vitro and reduced EMT-associated tumor invasion and metastasis in cancer cell xenograft models. Omeprazole also inhibited tumor growth by limiting Snail-dependent cell cycle progression. Overall, this study, for the first time, identifies Snail as a target of omeprazole and reveals a novel mechanism underlying the therapeutic effects of omeprazole against cancer. This study strongly suggests that omeprazole may be an excellent auxiliary drug for treating patients with malignant tumors.

A body shape index (ABSI) is an emerging anthropometric indicator, challenging two traditional parameters body mass index (BMI) and waist circumference (WC). We aimed to systematically compare and validate the capability of anthropometric indicators for determining pediatric high blood pressure (HBP).

A total of 3150 participants aged 7-17 years were enrolled from Suzhou, China. Areas under the receiver operating characteristic curve (AUC) were obtained to evaluate the performance of anthropometric indicators in detecting HBP. DeLong’s test was used to examine whether the AUCs of anthropometric indicators in contrast to BMI or original ABSI were statistically different. Furthermore, a meta-analysis was performed to combine results from this study and five similar articles from databases.

In Suzhou population, BMI exhibited the largest AUC (AUC = 0.705), followed by WC (AUC = 0.669) and original ABSI (AUC = 0.514). Modified ABSI (AUC 0.537-0.681), although had slightly better performance than original AB not perform as well as traditional anthropometric indicators, such as BMI and WC. BMI remains the optimal indicator in pediatric HBP screening. This study provides a theoretical basis for the early identification of HBP in children and adolescents by adopting effective predictors.Obese youth with sleep-disordered breathing are treated with positive airway pressure to improve sleep and cardiovascular status. While improvements in sleep parameters have been confirmed, a study by Katz et al. showed no major improvement in ambulatory blood pressure. The aim of this ancillary study was to analyze short-term blood pressure variability, following positive airway pressure treatment, as a more sensitive marker of cardiovascular health. We analyzed 24-h blood pressure variability data in 17 children, taken at baseline and after 12 months of treatment. These data were derived from an already published prospective, multicenter cohort study conducted in 27 youth (8-16 years) with obesity who were prescribed 1-year of positive airway pressure for moderate-severe sleep-disordered breathing. Significant decreases were found in 24 h systolic blood pressure (p = 0.040) and nighttime diastolic blood pressure (p = 0.041) average real variability, and diastolic blood pressure (p = 0.035) weighted standard deviation. Significant decreases were noted in nighttime diastolic blood pressure time rate variability (p = 0.007). Positive airway pressure treatment resulted in a significant decrease in blood pressure variability, suggesting a clinically significant improvement of sympathetic nerve activity in youth with obesity and sleep-disordered breathing. IMPACT Cardiovascular variability, as measured by blood pressure variability, is improved in children following positive airway pressure treatment. Our novel findings of improved blood pressure time rate variability are the first described in the pediatric literature. Future studies aimed at analyzing target organ damage in this patient population will allow for a better understanding as to whether alterations in blood pressure variability translate to decreasing target organ damage in children, as seen in adults.As the p53 tumor suppressor is rarely mutated in conjunctival melanoma (CM), we investigated its activation as a potential therapeutic strategy. Preventing p53/Mdm2 interaction by Nutlin-3, the prototypical Mdm2 antagonist, or via direct siRNA Mdm2 depletion, increased p53 and inhibited viability in CM cell lines. The sensitivity to Nutlin-3 p53 reactivation with concomitant Mdm2 stabilization was higher than that achieved by siRNA, indicative of effects on alternative Mdm2 targets, identified as the cancer-protective IGF-1R. Nutlin-3 treatment increased the association between IGF-1R and β-arrestin1, the adaptor protein that brings Mdm2 to the IGF-1R, initiating receptor degradation in a ligand-dependent manner. Controlled expression of β-arrestin1 augmented inhibitory Nutlin-3 effects on CM survival through enhanced IGF-1R degradation. Yet, the effect of IGF-1R downregulation on cell proliferation is balanced by β-arrestin1-induced p53 inhibition. As mitomycin (MMC) is a well-established adjuvant treatment (IGF-1R) and tumor-suppressor (p53), which ultimately mitigates recurrent and metastatic potential, thus opening up targeted therapy to CM.Aberrant function of epigenetic modifiers plays an important role not only in the progression of cancer but also the development of drug resistance. N-alpha-acetyltransferase 40 (NAA40) is a highly specific epigenetic enzyme catalyzing the transfer of an acetyl moiety at the N-terminal end of histones H4 and H2A. Recent studies have illustrated the essential oncogenic role of NAA40 in various cancer types but its role in chemoresistance remains unclear. Here, using transcriptomic followed by metabolomic analysis in colorectal cancer (CRC) cells, we demonstrate that NAA40 controls key one-carbon metabolic genes and corresponding metabolites. In particular, through its acetyltransferase activity NAA40 regulates the methionine cycle thereby affecting global histone methylation and CRC cell survival. Importantly, NAA40-mediated metabolic rewiring promotes resistance of CRC cells to antimetabolite chemotherapy in vitro and in xenograft models. Specifically, NAA40 stimulates transcription of the one-carbon metabolic gene thymidylate synthase (TYMS), whose product is targeted by 5-fluorouracil (5-FU) and accordingly in primary CRC tumours NAA40 expression associates with TYMS levels and poorer 5-FU response. Mechanistically, NAA40 activates TYMS by preventing enrichment of repressive H2A/H4S1ph at the nuclear periphery. Overall, these findings define a novel regulatory link between epigenetics and cellular metabolism mediated by NAA40, which is harnessed by cancer cells to evade chemotherapy.Nerve infiltration in the tumor microenvironment is emerging as a promoter of cancer progression that could be targeted in therapies, but the mechanisms initiating tumor innervation remain to be elucidated. Here we report that endoplasmic reticulum (ER) stress in cancer cells is transmitted to neuronal cells, resulting in neurite outgrowth and tumor innervation. In vitro, the induction of ER stress in various human cancer cells resulted in the synthesis and release of the precursor for brain-derived neurotrophic factor (proBDNF) through a mechanism dependent on the transcription factor X-box binding protein 1 (XBP1). Cancer cell-released proBDNF was found to mediate the transmission of ER stress to neurons, resulting in the stimulation of neurite outgrowth. Next-generation sequencing indicated the increased expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) that was mediated by c-MYC and necessary to neurite outgrowth induced by proBDNF. In orthotopic tumor xenograft, ER stress stimulated XBP1 and proBDNF expression as well as tumor innervation.