Explore the vast range of titles available.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients’ prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

The role of surgery compared with reirradiation in the primary treatment of patients with resectable, locally recurrent nasopharyngeal carcinoma (NPC) who have previously received radiotherapy is a matter of debate. In this trial, we compared the efficacy and safety outcomes of salvage endoscopic surgery versus intensity-modulated radiotherapy (IMRT) in patients with resectable locally recurrent NPC. This multicentre, open-label, randomised, controlled, phase 3 trial was done in three hospitals in southern China. We included patients aged 18–70 years with a Karnofsky Performance Status score of at least 70 who were histopathologically diagnosed with undifferentiated or differentiated, non-keratinising, locally recurrent NPC with tumours confined to the nasopharyngeal cavity, the post-naris or nasal septum, the superficial parapharyngeal space, or the base wall of the sphenoid sinus. Eligible patients were randomly assigned (1:1) to receive either endoscopic nasopharyngectomy (ENPG group) or IMRT (IMRT group). Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre. Treatment group assignment was not masked. The primary endpoint was overall survival, compared between the groups at 3 years. Efficacy analyses were done by intention to treat. Safety analysis was done in patients who received treatment according to the treatment they actually received. This trial was prospectively registered at the Chinese Clinical Trial Registry, ChiCTR-TRC-11001573, and is currently in follow-up. Between Sept 30, 2011, and Jan 16, 2017, 200 eligible patients were randomly assigned to receive either ENPG (n=100) or IMRT (n=100). At a median follow-up of 56·0 months (IQR 42·0–69·0), 74 patients had died (29 [29%] of 100 patients in the ENPG group and 45 [45%] of 100 patients in the IMRT group). The 3-year overall survival was 85·8% (95% CI 78·9–92·7) in the ENPG group and 68·0% (58·6–77·4) in the IMRT group (hazard ratio 0·47, 95% CI 0·29–0·76; p=0·0015). The most common grade 3 or worse radiation-related late adverse event was pharyngeal mucositis (in five [5%] of 99 patients who underwent ENPG and 26 [26%] of 101 patients who underwent IMRT). Five [5%] of the 99 patients who underwent ENPG and 20 [20%] of the 101 patients who underwent IMRT died due to late toxic effects specific to radiotherapy; attribution to previous radiotherapy or trial radiotherapy is unclear due to the long-term nature of radiation-related toxicity. Endoscopic surgery significantly improved overall survival compared with IMRT in patients with resectable locally recurrent NPC. These results suggest that ENPG could be considered as the standard treatment option for this patient population, although long-term follow-up is needed to further determine the efficacy and toxicity of this strategy. Sun Yat-sen University Clinical Research 5010 Program

The methyltransferase like 3 （METTL3）-containing methyltransferase complex catalyzes the N6-methyladenosine （m6A） formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms＇ tumor 1-associating protein （WTAP） and methyltransferase like 14 （METTL14）. WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic ac- tivity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-en- hanced crosslinking and immunoprecipitation （PAR-CLIP） illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.

Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3′ untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24–AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets. Yuan et al.  show that the MBNL3 splicing factor promotes alternative splicing of the lncRNA-PXN-AS1 antisense transcript of PXN, leading to the stabilization of PXN mRNA and increasing its protein levels to promote liver cancer growth.

ObjectiveAutophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis.DesignGain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality.ResultsThe expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment.ConclusionsDysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients’ responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

Emergency Department (ED) healthcare workers (HCWs) have had one of the highest incidences of burnout [4-6] even prior to the pandemic. To evaluate the prevalence of burnout in this population and the preferred methods of coping with the COVID-19 situation, we conducted a cross-sectional study amongst doctors and nurses in our regional health cluster's Emergency Departments (EDs) and Urgent Care Center (UCC). Besides the use of technological media, spending time with family and friends and acts of gratitude from the department and peers were preferred methods for coping with the pandemic.

Background Long non-coding RNAs play an important role in tumorigenesis, hence, identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are important for understanding the development and progression of cancer. Recently, the downregulation of lncRNA MEG3 has been observed in various human cancers. However, its role in non-small cell lung cancer (NSCLC) is unknown. The aim of this study was to examine the expression pattern of MEG3 in NSCLC and to evaluate its biological role and clinical significance in tumor progression. Methods Expression of MEG3 was analyzed in 44 NSCLC tissues and 7 NSCLC cell lines by qRT-PCR. Over-expression approaches were used to investigate the biological functions of MEG3 in NSCLC cells. Bisulfite sequencing was used to investigate DNA methylation on MEG3 expression. The effect of MEG3 on proliferation was evaluated by MTT and colony formation assays, and cell apoptosis was evaluated by Hoechst staining and Flow-cytometric analysis. NSCLC cells transfected with pCDNA-MEG3 were injection into nude mice to study the effect of MEG3 on tumorigenesis in vivo . Protein levels of MEG3 targets were determined by western blot analysis. Differences between groups were tested for significance using Student’s t -test (two-tailed). Results MEG3 expression was decreased in non-small cell lung cancer (NSCLC) tumor tissues compared with normal tissues, and associated with advanced pathologic stage, and tumor size. Moreover, patients with lower levels of MEG3 expression had a relatively poor prognosis. Overexpression of MEG3 decreased NSCLC cells proliferation and induced apoptosis in vitro and impeded tumorigenesis in vivo . MDM2 and p53 protein levels were affected by MEG3 over-expression in vitro . Conclusions Our findings indicate that MEG3 is significantly down-regulated in NSCLC tissues that could be affected by DNA methylation, and regulates NSCLC cell proliferation and apoptosis, partially via the activition of p53. Thus, MEG3 may represent a new marker of poor prognosis and is a potential therapeutic target for NSCLC intervention.

This paper presents a real-time and non-contact dual-mode embedded impulse-radio (IR) ultra-wideband (UWB) radar system designed for microwave imaging and vital sign applications. The system is fully customized and composed of three main components, an RF front-end transmission block, an analog signal processing (ASP) block, and a digital processing block, which are integrated in an embedded system. The ASP block enables dual-path receiving for image construction and vital sign detection, while the digital part deals with the inverse scattering and direct current (DC) offset issues. The self-calibration technique is also incorporated into the algorithm to adjust the DC level of each antenna for DC offset compensation. The experimental results demonstrate that the IR-UWB radar, based on the proposed algorithm, successfully detected the 2D image profile of the object as confirmed by numerical derivation. In addition, the radar can wirelessly monitor vital sign behavior such as respiration and heartbeat information.