040). Adaptive behaviour (life skills) was low in all areas (>2 SD below mean). Scores in communication were markedly lower than for daily living (p = 0.008) and socialisation (p  less then  0.001). A common linguistic profile was characterised by severe impairment across receptive, expressive and social language domains. Yet data indicated greater communicative intent than appeared to be capitalised by current therapies. Early implementation of augmentative (e.g. computer-assisted) modes of communication, alongside promotion of oral language, is essential to harness this intent, accelerate language development and reduce frustration. Future trials should examine the added benefit of targeted speech motor interventions in those with greater verbal capacity.Despite nearly three decades of advances in the management of rheumatoid arthritis (RA), a substantial minority of patients are exposed to multiple DMARDs without necessarily benefitting from them; a group of patients variously designated as having 'difficult to treat', 'treatment-resistant' or 'refractory' RA. This Review of refractory RA focuses on two types of patients those for whom multiple targeted therapies lack efficacy and who have persistent inflammatory pathology, which we designate as persistent inflammatory refractory RA (PIRRA); and those with supposed refractory RA who have continued disease activity that is predominantly independent of objective evidence of inflammation, which we designate as non-inflammatory refractory RA (NIRRA). These two types of disease are not mutually exclusive, but identifying those individuals with predominant PIRRA or NIRRA is important, as it informs distinct treatment and management approaches. This Review outlines the clinical differences between PIRRA and NIRRA, the genetic and epigenetic mechanisms and immune pathways that might contribute to the immunopathogenesis of recalcitrant synovitis in PIRRA, and a possible basis for non-inflammatory symptomatology in NIRRA. Future approaches towards the definition of refractory RA and the application of single-cell and integrated omics technologies to the identification of refractory RA endotypes are also discussed.MicroRNAs (miRs) are small non-coding RNAs that can have large impacts on oncogenic pathways. Possible functions of dysregulated miRs have not been studied in neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNFs). In PNFs, Schwann cells (SCs) have biallelic NF1 mutations necessary for tumorigenesis. We analyzed a miR microarray comparing with normal and PNF SCs and identified differences in miR expression, and we validated in mouse PNFs versus normal mouse SCs by qRT-PCR. Among these, miR-155 was a top overexpressed miR, and its expression was regulated by RAS/MAPK signaling. Overexpression of miR-155 increased mature Nf1-/- mouse SC proliferation. In SC precursors, which model tumor-initiating cells, pharmacological and genetic inhibition of miR-155 decreased PNF-derived sphere numbers in vitro, and we identified Maf as a miR-155 target. In vivo, global deletion of miR-155 significantly decreased tumor number and volume, increasing mouse survival. Fluorescent nanoparticles entered PNFs, suggesting that an anti-miR might have therapeutic potential. However, treatment of established PNFs using anti-miR-155 peptide nucleic acid-loaded nanoparticles marginally decreased tumor numbers and did not reduce tumor growth. These results suggest that miR-155 plays a functional role in PNF growth and/or SC proliferation, and that targeting neurofibroma miRs is feasible, and might provide novel therapeutic opportunities.The tumor suppressor SMAD4 is frequently mutated in colorectal cancer (CRC). However, no effective targeted therapies exist for CRC with SMAD4 loss. Here, we employed a synthetic lethality drug screening in isogenic SMAD4+/+ and SMAD4-/- HCT116 CRC cells and found that bromodomain and extra-terminal motif (BET) inhibitors, as selective drugs for the growth of SMAD4-/- HCT116 cells. BET inhibition selectively induced G1 cell cycle arrest in SMAD4-/- cells and this effect was accompanied by the reprogramming of the MYC-p21 axis. https://www.selleckchem.com/products/4sc-202.html Mechanistically, SMAD4 is a transcription repressor of MYC, and MYC in turn represses p21 transcription. SMAD4-/- cells lost MYC repression ability, thereby causing the cells addicted to the MYC oncogenic signaling. BET inhibition significantly reduced MYC level and restored p21 expression in SMAD4-/- cells, inducing the selective growth arrest. The ectopic overexpression of MYC or the silencing of p21 could rescue the BET inhibitor-induced growth arrest in SMAD4-/- cells, verifying this model. Tumor xenograft mouse experiments further demonstrated the synthetic lethality interaction between BET and SMAD4 in vivo. Taken together, our data suggest that BET could be a potential drug target for the treatment of SMAD4-deficient CRC.An amendment to this paper has been published and can be accessed via a link at the top of the paper. Data from population-based cancer registries are often used to compare cancer survival between countries or regions. The ICBP SURVMARK-2 study is an international partnership aiming to quantify and explore the reasons behind survival differences across high-income countries. However, the magnitude and relevance of differences in cancer survival between countries have been questioned, as it is argued that observed survival variations may be explained, at least in part, by differences in cancer registration practice, completeness and the availability and quality of the respective data sources. As part of the ICBP SURVMARK-2 study, we used a simulation approach to better understand how differences in completeness, the characteristics of those missed and inclusion of cases found from death certificates can impact on cancer survival estimates. Bias in 1- and 5-year net survival estimates for 216 simulated scenarios is presented. Out of the investigated factors, the proportion of cases not registered through sources other than death certificates, had the largest impact on survival estimates. Our results show that the differences in registration practice between participating countries could in our most extreme scenarios explain only a part of the largest observed differences in cancer survival. Our results show that the differences in registration practice between participating countries could in our most extreme scenarios explain only a part of the largest observed differences in cancer survival.