Enhancers are fast-evolving genomic sequences that control spatiotemporal gene expression patterns. By examining enhancer turnover across mammalian species and in multiple tissue types, we uncover a ...relationship between the emergence of enhancers and genome organization as a function of germline DNA replication time. While enhancers are most abundant in euchromatic regions, enhancers emerge almost twice as often in late compared to early germline replicating regions, independent of transposable elements. Using a deep learning sequence model, we demonstrate that new enhancers are enriched for mutations that alter transcription factor (TF) binding. Recently evolved enhancers appear to be mostly neutrally evolving and enriched in eQTLs. They also show more tissue specificity than conserved enhancers, and the TFs that bind to these elements, as inferred by binding sequences, also show increased tissue-specific gene expression. We find a similar relationship with DNA replication time in cancer, suggesting that these observations may be time-invariant principles of genome evolution. Our work underscores that genome organization has a profound impact in shaping mammalian gene regulation.
After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in ...cancer. Many solid and liquid tumours are associated with drastic increases in IR, and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue.
In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR.
Strikingly, we found that aberrantly decreasing IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly dividing tumour cells have the lowest number of IR events. Aberrant RNA-binding protein expression and changes in tissue composition are among the causes of aberrantly decreasing IR in BrCa.
Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.
The article is concerned with a new method that minimizes the vibration level of non-rigid axisymmetric parts on lathes. A schematic diagram of the vibration absorber control path is given. Its ...configuration is changing due to fictitious elastic stiffness parameters, as well as damping and the part–support subsystem weight. A functional dual circuit diagram of an automatic vibration level control system for non-rigid shafts machining is presented and its working principle is described
Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of ...healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.
Gastrointestinal stromal tumors (GIST) comprise about 80% of gastrointestinal sarcomas. In patients with localized disease, surgery is considered as "Gold Standard" treatment. Organ-sparing radical ...en-block resection is widely accepted practice. Since lymph node dissection is not routinely indicated, minimally invasive approach is of particular interest. The aim of this study is to investigate the short-term outcomes of different surgical treatment of GISTs.
We analyzed data of 116 patients who received surgical treatment for localized forms of GIST. Tumors were located in the stomach in 87 (75%) cases, in the small intestine in 26 (22.4%) cases, and extragastrointestinal GISTs were found in 3 (2.6%) patients. Four different approaches were used-open surgery (OpS, n=48), laparoscopic surgery (LS, n=40), endoscopic procedures (EP, n=22) and hybrid rendezvous (HR, n=6). Patient demographics, clinical presentation of tumors, characteristics of operation procedures (duration, intraoperative blood loss, frequency of R0-resection and fragmentation of tumor), postoperative complications and length of hospital stay were examined in all these groups.
Radical treatment (R0-resection) was performed in all patients. There were no cases of tumor ruptures during surgical procedure. Mean size of GIST in OpS was 9.1±2.0 2-35 cm; in LS: 4.9±0.8 (1.5-15) cm; in HR: 3.5±0.8 (2-4.5) cm and in EP: 2.3±0.3 (0.4-3.5) cm. Intraoperative blood loss in OpS was 369.7±209.5 0-4,000 mL; LS: 63.9±16.0 0-150 mL; in HR: 96.7±44.3 50-200 mL; in EP: 33.3±11.0 0-150 mL. Duration of operation in OpS was 160±20.4 50-310 min; in LS: 104.7±12.7 50-185; in HR: 176.7±44.0 110-260 min and in EP: 89.8±15.5 25-190 min. Complication rate in OpS was 5 (10.4%); in LS: 3 (7.5%); in HR: 0% and in EP: 3 (13.6%). Length of hospital stay in OpS was 13.8±2.2 7-52 days; in LS: 11, 4±2.2 4-21 days; in HR: 11±3.2 7-15 days and in EP: 11, 9±2.1 5-22 days. There were no postoperative deaths.
There is a diversity of surgical approaches for GISTs treatment. From our point of view, the main selection criteria for certain procedure are size, localization, growth type of the tumor and status of overlying mucosa. Nevertheless, due to relative rarity and heterogeneity of this pathology, individualization is necessary in each specific case. Laparoscopic and endoscopic surgery is proved to be safe and feasible for resection of the gastric GISTs, with a reasonable operation time, low blood loss, and an acceptable complication rate. Immediate results indicate that all interventions were performed radically without mortality or serious morbidity.
Intron retention (IR) in cancer was for a long time overlooked by the scientific community, as it was previously considered to be an artifact of a dysfunctional spliceosome. Technological ...advancements made in the last decade offer unique opportunities to explore the role of IR as a widespread phenomenon that contributes to the transcriptional diversity of many cancers. Numerous studies in cancer have shed light on dysregulation of cellular mechanisms that lead to aberrant and pathologic IR. IR is not merely a mechanism of gene regulation, but rather it can mediate cancer pathogenesis and therapeutic resistance in various human diseases. The burden of IR in cancer is governed by perturbations to mechanisms known to regulate this phenomenon and include epigenetic variation, mutations within the gene body, and splicing factor dysregulation. This review summarizes possible causes for aberrant IR and discusses the role of IR in therapy or as a consequence of disease treatment. As neoepitopes originating from retained introns can be presented on the cancer cell surface, the development of personalized cancer vaccines based on IR-derived neoepitopes should be considered. Ultimately, a deeper comprehension about the origins and consequences of aberrant IR may aid in the development of such personalized cancer vaccines.
Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an ...opioid analgesic for acute low back pain and neck pain.
OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone–naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516).
Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI –0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 7·5% of 174 participants in the opioid group reported constipation vs six 3·5% of 173 in the placebo group).
Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions.
Australia's National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and ReturnToWorkSA.
Dynamic intron retention (IR) in vertebrate cells is of widespread biological importance. Aberrant IR is associated with numerous human diseases including several cancers. Despite consistent reports ...demonstrating that intrinsic sequence features can help introns evade splicing, conflicting findings about cell type- or condition-specific IR regulation by trans-regulatory and epigenetic mechanisms demand an unbiased and systematic analysis of IR in a controlled experimental setting. We integrated matched mRNA sequencing (mRNA-Seq), whole-genome bisulfite sequencing (WGBS), nucleosome occupancy methylome sequencing (NOMe-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) data from primary human myeloid and lymphoid cells. Using these multi-omics data and machine learning, we trained two complementary models to determine the role of epigenetic factors in the regulation of IR in cells of the innate immune system. We show that increased chromatin accessibility, as revealed by nucleosome-free regions, contributes substantially to the retention of introns in a cell-specific manner. We also confirm that intrinsic characteristics of introns are key for them to evade splicing. This study suggests an important role for chromatin architecture in IR regulation. With an increasing appreciation that pathogenic alterations are linked to RNA processing, our findings may provide useful insights for the development of novel therapeutic approaches that target aberrant splicing.
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