Malignant Peripheral Nerve Sheath Tumors (MPNSTs) represent a group of highly aggressive soft tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1-), or after radiotherapy1–3. Using comprehensive genomic approaches, we identified loss-of-function (LOF) somatic alterations of the Polycomb repressive complex 2 (PRC2) core components, EED or SUZ12, in 92% of sporadic, 70% of NF1-associated and 90% of radiotherapy-associated MPNSTs. MPNSTs with PRC2 loss showed complete loss of H3K27me3 and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 and decreased cell growth. Additionally, we identified frequent somatic alterations of CDKN2A (81% of all MPNSTs) and NF1 (72% of non-NF1-associated MPNSTs), and they significantly co-occur with PRC2 alterations. The highly recurrent and specific inactivation of PRC2, NF1, CDKN2A posits their critical and potentially cooperative roles in MPNST pathogenesis.

Background and Aim Emerging evidence indicates that psychological stress is involved in the pathogenesis of irritable bowel syndrome, which is characterized by visceral hypersensitivity and may be accompanied by gut dysbiosis. However, how such stress contributes to the development of visceral hypersensitivity is incompletely understood. Here, we aimed to investigate the influence that stress‐induced microbial changes exert on visceral sensitivity, as well as the possible underlying mechanisms associated with this effect. Methods Male Sprague–Dawley rats underwent chronic water avoidance stress (WAS) to induce visceral hypersensitivity. Visceral sensitivity, colonic tight junction protein expression, and short‐chain fatty acids of cecal contents were measured. Fecal samples were collected to characterize microbiota profiles. In a separate study, oral gavage of Roseburia in WAS rats was conducted to verify its potential role in the effectiveness on visceral hypersensitivity. Results Repeated WAS caused visceral hypersensitivity, altered fecal microbiota composition and function, and decreased occludin expression in the colon. Stressed rats exhibited reduced representation of pathways involved in the metabolism of butyrate and reduced abundance of several operational taxonomic units associated with butyrate‐producing bacteria, such as Lachnospiraceae. Consistently, supplementation with Roseburia hominis, a species belonging to Lachnospiraceae, significantly increased cecal butyrate content. Moreover, Roseburia supplementation alleviated visceral hypersensitivity and prevented the decreased expression of occludin. Conclusions Reduction in the abundance of butyrate‐producing Lachnospiraceae, which is beneficial for the intestinal barrier, was involved in the formation of visceral hypersensitivity. R. hominis is a potential probiotic for treating stress‐induced visceral hypersensitivity.

The use of biomarkers ensures breast cancer patients receive optimal treatment. Established biomarkers such as estrogen receptor (ER) and progesterone receptor (PR) have been playing significant roles in the selection and management of patients for endocrine therapy. HER2 is a strong predictor of response to trastuzumab. Recently, the roles of ER as a negative and HER2 as a positive indicator for chemotherapy have been established. Ki67 has traditionally been recognized as a poor prognostic factor, but recent studies suggest that measurement of Ki67-positive cells during treatment will more effectively predict treatment efficacy for both anti-hormonal and chemotherapy. p53 mutations are found in 20–35% of human breast cancers and are associated with aggressive disease with poor clinical outcome when the DNA-binding domain is mutated. The utility of cyclin D1 as a predictor of breast cancer prognosis is controversial, but cyclin D1b overexpression is associated with poor prognosis. Likewise, overexpression of the low molecular weight form of cyclin E1 protein predicts poor prognosis. Breast cancers from BRCA1/2 carriers often show high nuclear grades, negativity to ER/PR/HER2, and p53 mutations, and thus, are associated with poor prognosis. The prognostic values of other molecular markers, such as p14ARF, TBX2/3, VEGF in breast cancer are also discussed. Careful evaluation of these biomarkers with current treatment modality is required to determine whether their measurement or monitoring offer significant clinical benefits.

Gastrointestinal stromal tumour (GIST), originating from the interstitial cells of Cajal (ICCs), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib that targets KIT, most advanced GIST patients develop resistance and eventually die of the disease. The ETS family transcription factor, ETV1, is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that Etv1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target. We further uncover a positive feedback circuit where MAP kinase activation downstream of KIT stabilizes the ETV1 protein and ETV1 positively regulates KIT expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression in vitro and complete tumour regression in vivo. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management.

INTRODUCTION: Alterations of gut microbiota have been thought to be associated with irritable bowel syndrome (IBS). Many studies have reported significant alterations of gut microbiota in patients with IBS based on 16S ribosomal RNA-targeted sequencing. However, results from these studies are inconsistent or even contradictory. We performed a systematic review to explore the alterations of gut microbiota in patients with IBS compared with healthy controls (HCs). METHODS: The databases PubMed, Cochrane Library, Web of Science, and Embase were searched for studies published until February 28, 2018, for case–control studies detecting gut microbiota in patients with IBS. Methodological quality was assessed using the Newcastle–Ottawa Scale. The α-diversity and alterations of gut microbiota in patients with IBS compared with HCs were analyzed. RESULTS: Sixteen articles involving 777 patients with IBS and 461 HCs were included. Quality assessment scores of the studies ranged from 5 to 7. For most studies, patients with IBS had a lower α-diversity than HCs in both fecal and mucosal samples. Relatively consistent changes in fecal microbiota for patients with IBS included increased Firmicutes, decreased Bacteroidetes, and increased Firmicutes:Bacteroidetes ratio at the phylum level, as well as increased Clostridia and Clostridiales, decreased Bacteroidia and Bacteroidales at lower taxonomic levels. Results for mucosal microbiota were inconsistent. CONCLUSIONS: Alterations of gut microbiota exist in patients with IBS and have significant association with the development of IBS. Further studies are needed to draw conclusions about gut microbiota changes in patients with IBS. TRANSLATIONAL IMPACT: This knowledge might improve the understanding of microbial signatures in patients with IBS and would guide future therapeutic strategies.