The A subunit of vacuolar H+-ATPase gene (CmVHA-A) plays opposite roles in plant growth and drought tolerance of chrysanthemum under different growing conditions.

As the most prominent proton pumps in plants, vacuolar H+-ATPases (VHAs) comprise multiple subunits that are important for physiological processes and stress tolerance in plants. However, few studies on the roles of subunit genes of VHAs in chrysanthemum have been reported to date. In this study, the gene of A subunit of V-ATPase in chrysanthemum (CmVHA-A) was cloned and identified. CmVHA-A was conserved with VHA-A proteins from other plants. Expression analysis showed that CmVHA-A was highly expressed in most tissues of chrysanthemum except for the flower bud, and was readily induced by polyethylene glycol (PEG) treatment. Functional analysis demonstrated that CmVHA-A exerted a negative influence on the growth and development of shoot and root of chrysanthemum under normal conditions. RNA-sequencing (RNA-seq) analysis revealed the possible explanations for phenotypic differences between transgenic and wild-type (WT) plants. Under drought conditions, CmVHA-A positively affected the drought tolerance of chrysanthemum by enhancing antioxidase activity and alleviating photosynthetic disruption. Overall, CmVHA-A plays opposite roles in plant growth and drought tolerance of chrysanthemums under different growing conditions.

The BTB/TAZ domain-containing protein CmBT1-mediated CmANR1 ubiquitination negatively regulates root development in chrysanthemum.

Roots are fundamental for plants to adapt to variable environmental conditions. The development of a robust root system is orchestrated by numerous genetic determinants and, among them, the MADS-box gene ANR1 has garnered substantial attention. Prior research has demonstrated that, in chrysanthemum, CmANR1 positively regulates root system development. Nevertheless, the upstream regulators involved in the CmANR1-mediated regulation of root development remain unidentified. In this study, we successfully identified bric-a-brac, tramtrack and broad (BTB) and transcription adapter putative zinc finger (TAZ) domain protein CmBT1 as the interacting partner of CmANR1 through a yeast-two-hybrid (Y2H) screening library. Furthermore, we validated this physical interaction through bimolecular fluorescence complementation and pull-down assays. Functional assays revealed that CmBT1 exerted a negative influence on root development in chrysanthemum. In both in vitro and in vivo assays, it was evident that CmBT1 mediated the ubiquitination of CmANR1 through the ubiquitin/26S proteasome pathway. This ubiquitination subsequently led to the degradation of the CmANR1 protein and a reduction in the transcription of CmANR1-targeted gene CmPIN2, which was crucial for root development in chrysanthemum. Genetic analysis suggested that CmBT1 modulated root development, at least in part, by regulating the level of CmANR1 protein. Collectively, these findings shed new light on the regulatory role of CmBT1 in degrading CmANR1 through ubiquitination, thereby repressing the expression of its targeted gene and inhibiting root development in chrysanthemum.

Self-Assembled Monolayer for Low-Power-Consumption, Long-Term-Stability, and High-Efficiency Quantum Dot Light-Emitting Diodes.

Quantum dot light-emitting diodes (QLEDs) are an emerging class of optoelectronic devices with a wide range of applications. However, there still exist several drawbacks preventing their applications, including long-term stability, electron leakage, and large power consumption. To circumvent the difficulties, QLEDs based on a self-assembled hole transport layer (HTL) with reduced device complexity are proposed and demonstrated. The self-assembled HTL is prepared from poly[3-(6-carboxyhexyl)thiophene-2,5-diyl] (P3HT-COOH) solution in N,N-dimethylformamide (DMF) forming a well-ordered monolayer on an indium-tin-oxide (ITO) anode. The P3HT-COOH monolayer has a smaller HOMO band offset and a sufficiently large electron barrier with respect to the CdSe/ZnS quantum dot (QD) emission layer, and thus it is beneficial for hole injection into and electron leakage blocking from the QD layer. Interestingly, the QLEDs exhibit an excellent conversion efficiency (97%) in turning the injected electron-hole pairs into light emission. The performance of the resulting QLEDs possesses a low turn-on voltage of +1.2 V and a maximum external quantum efficiency of 25.19%, enabling low power consumption with high efficiency. Additionally, those QLEDs also exhibit excellent long-term stability without encapsulation with over 90% luminous intensity after 200 days and superior durability with over 70% luminous intensity after 2 h operation under the luminance of 1000 cd m-2. The outstanding device features of our proposed QLEDs, including low turn-on voltage, high efficiency, and long-term stability, can advance the development of QLEDs toward facile large-area mass production and cost-effectiveness.

EGFRvIII Promotes the Proneural-Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis.

(1) Background: Glioblastoma multiforme (GBM) is the most common and malignant intracranial tumor in adults. At present, temozolomide (TMZ) is recognized as the preferred chemotherapeutic drug for GBM, but some patients have low sensitivity to TMZ or chemotherapy resistance to TMZ. Our previous study found that GBM patients with EGFRvIII (+) have low sensitivity to TMZ. However, the reasons and possible mechanisms of the chemoradiotherapy resistance in GBM patients with EGFRvIII (+) are not clear. (2) Methods: In this study, tissue samples of patients with GBM, GBM cell lines, glioma stem cell lines, and NSG mice were used to explore the causes and possible mechanisms of low sensitivity to TMZ in patients with EGFRvIII (+)-GBM. (3) Results: The study found that EGFRvIII promoted the proneural-mesenchymal transition of GBM and reduced its sensitivity to TMZ, and EGFRvIII regulated of the expression of ALDH1A3. (4) Conclusions: EGFRvIII activated the NF-κB pathway and further regulated the expression of ALDH1A3 to promote the proneural-mesenchymal transition of GBM and reduce its sensitivity to TMZ, which will provide an experimental basis for the selection of clinical drugs for GBM patients with EGFRvIII (+).

Spine-Related Malpractice Claims in China: A 2-year National Analysis.

STUDY DESIGN: Retrospective cross-sectional study. OBJECTIVE: To investigate the prevalence, characteristics, and risk factors of spine-related malpractice claims in China in a 2-year period. METHODS: The arbitration files of the Chinese Medical Association (CMA) were reviewed for spine-related malpractice claims. Descriptive statistics and correlation analysis were conducted on claim characteristics, clinical data, plaintiff's main allegations, and arbitration outcomes. RESULTS: A total of 288 cases of spinal claims filed in the CMA between January 2016 and December 2017 were included. Most claims were found in lumbar degenerative disorders (59.4%), lumbar trauma (13.2%), and cervical degenerative disorders (11.8%). The most common adverse events (AEs) leading to claims were new neurologic deficit (NND) (47.6%), infection (11.5%), and insufficient symptom relief (10.4%). The most common patient allegation was surgical error (66.0%), although the main arbitrated cause of AEs was disease/treatment itself (49.0%), while providers were judged as mainly responsible in only 47.3% cases. In multivariate regression analysis, cervical spine, misdiagnosis/mistreatment, and unpredictable emergency correlated with more severe damage to patients; minimally invasive surgery was predictive of judgment in plaintiff's favor, while claims in the eastern region and unpredictable emergencies were predictive of defendant's favor; only NND was associated with being arbitrated as surgical error in surgical cases where surgeons accepted major liability. CONCLUSION: The current study provided a descriptive overview and risk factor analysis of spine-related malpractice claims in China. Gaining improved understanding of the facts and causes of malpractice claims may help providers reduce the risk of claims and subsequent litigation.

Immunological profiles of human oligodendrogliomas define two distinct molecular subtypes.

BACKGROUND: Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy development for this tumor is hindered by incomplete knowledge of somatic driving alterations and suboptimal disease classification. We herein aim to identify intrinsic molecular subtypes through integrated analysis of transcriptome, genome and methylome. METHODS: 137 oligodendroglioma patients from the Cancer Genome Atlas (TCGA) dataset were collected for unsupervised clustering analysis of immune gene expression profiles and comparative analysis of genome and methylome. Two independent datasets containing 218 patients were used for validation. FINDINGS: We identified and independently validated two reproducible subtypes associated with distinct molecular characteristics and clinical outcomes. The proliferative subtype, named Oligo1, was characterized by more tumors of CNS WHO grade 3, as well as worse prognosis compared to the Oligo2 subtype. Besides the clinicopathologic features, Oligo1 exhibited enrichment of cell proliferation, regulation of cell cycle and Wnt signaling pathways, and significantly altered genes, such as EGFR, NOTCH1 and MET. In contrast, Oligo2, with favorable outcome, presented increased activation of immune response and metabolic process. Higher T cell/APC co-inhibition and inhibitory checkpoint levels were observed in Oligo2 tumors. Finally, multivariable analysis revealed our classification was an independent prognostic factor in oligodendrogliomas, and the robustness of these molecular subgroups was verified in the validation cohorts. INTERPRETATION: This study provides further insights into patient stratification as well as presents opportunities for therapeutic development in human oligodendrogliomas. FUNDING: The funders are listed in the Acknowledgement.

Thoracolumbar surgery for degenerative spine diseases complicated with tethered cord syndrome: A case report.

BACKGROUND: Tethered cord syndrome (TCS) secondary to split cord malformation (SCM) is rare in adulthood. There is as yet no consensus about the optimal treatment method for adult patients with SCMs and degenerative spine diseases such as lumbar stenosis, spondylolisthesis and ossification of the ligamentum flavum (OLF). The tethered cord poses a great challenge to the decompression and fusion procedures for the intraoperative stretching of the spinal cord, which might lead to deteriorated neural deficits. Here, we report on a case to add our treatment experience to the medical literature. CASE SUMMARY: We treated a 67-year-old female patient with type II SCM suffering from lumbar disc herniation, degenerative lumbar spondylolisthesis and thoracic OLF. The patient underwent thoracolumbar spinal fusion and decompression surgery for severe lower back pain, extensive left lower limb muscle weakness and intermittent claudication. After the thoracolumbar surgery, without stretching the tethered cord, the patient achieved complete relief of pain and lower extremity weakness at final follow-up. CONCLUSION: For adult patients with underlying TCS secondary to SCM coupled with thoracic OLF and lumbar spondylolisthesis, a thoracolumbar fusion surgery could be safe and effective with the tethered cord untreated. It is critical to design individualized surgical protocols to reduce the stretch of the low-lying spinal cord.

All-carbon stretchable and cavity-free white lasers.

Flexible, stretchable, and bendable electronics and optoelectronics have a great potential for wide applications in smart life. An environmentally friendly, cost effective and wide-angle emission laser is indispensable for the emerging technology. In this work, circumvent the challenge issue, cavity-free and stretchable white light lasers based on all carbon materials have been demonstrated by integration of fluorescent carbon quantum dots (CQDs) and crumpled graphene. The typical emission spectrum of the cavity-free laser based on all-carbon materials has a CIE chromaticity coordinate of (0.30, 0.38) exhibiting an intriguing broadband white-light emission. The unprecedented and non-toxic stretchable and white light cavity-free lasers based on all-carbon materials can serve as next-generation optoelectronic devices for a wide range application covering solid-state lighting and future wearable technologies.

All-carbon stretchable and cavity-free white lasers: publisher's note.

This publisher's note contains corrections to [Opt. Express30, 20213 (2022)10.1364/OE.457921].

Identification of tumor-associated antigens and immune subtypes of lower-grade glioma and glioblastoma for mRNA vaccine development.

BACKGROUND: mRNA became a promising therapeutic approach in many diseases. This study aimed to identify the tumor antigens specifically expressed in tumor cells for lower-grade glioma (LGG) and glioblastoma (GBM) patients. METHODS: In this work, the mRNA microarray expression profile and clinical data were obtained from 301 samples in the Chinese Glioma Genome Atlas (CGGA) database, the mRNA sequencing data and clinical data of 701 samples were downloaded from The Cancer Genome Atlas (TCGA) database. Genetic alterations profiles were extracted from CGGA and cBioPortal datasets. R language and GraphPad Prism software were applied for the statistical analysis and graph work. RESULTS: PTBP1 and SLC39A1, which were overexpressed and indicated poor prognosis in LGG patients, were selected as tumor-specific antigens for LGG patients. Meanwhile, MMP9 and SLC16A3, the negative prognostic factors overexpressed in GBM, were identified as tumor-specific antigens for GBM patients. Besides, three immune subtypes (LGG1-LGG3) and eight WGCNA modules were identified in LGG patients. Meanwhile, two immune subtypes (GBM1-GBM2) and 10 WGCNA modules were selected in GBM. The immune characteristics and potential functions between different subtypes were diversity. LGG2 and GBM1 immune subtype were associated with longer overall survival than other subtypes. CONCLUSION: In this study, PTBP1 and SLC39A1 are promising antigens for mRNA vaccines development in LGG, and MMP9 and SLC16A3 were potential antigens in GBM. Our analyses indicated that mRNA vaccine immunotherapy was more suitable for LGG2 and GBM1 subtypes. This study was helpful for the development of glioma immunotherapies.

Optically Encodable and Erasable Multilevel Nonvolatile Flexible Memory Device Based on Metal-Organic Frameworks.

Multilevel and flexible nonvolatile memory (NVM) is a promising candidate for data storage in next-generation devices but its high bias and low mobility of conducting channels are often its drawbacks. In this study, we demonstrate a low bias of smaller than 0.1 V and a high-mobility graphene layer as a conducting channel for flexible optoelectronic NVM based on a composite thin film of indium-based MOF-derived InCl3 and 4,4-oxydiphthalic anhydride (odpta), Na[In3(odpt)2(OH)2(H2O)2](H2O)4, and reduced graphene oxide (rGO). The optoelectronic NVM device can be encoded and erased optically by ultraviolet (UV) light and visible light, respectively. Our device also achieves memory states over 192 (6-bit storage) distinct levels, which can emerge as mass data storage. It also shows an excellent endurance of write-erase cycles under irradiation with a laser of varying wavelengths, the mechanical stability of more than 1000 bending cycles, and stable retention for longer than 10 000 s. These results open an alternative route for developing low bias and innovative optoelectronic technologies.

Impact of intraoperative intravenous magnesium on spine surgery: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The effectiveness and safety of intraoperative intravenous magnesium (IIM) on spine surgery remain uncertain, as recent randomized controlled trials (RCTs) yielded conflicting results. The purpose of this study was to determine the impact of IIM on spine surgery. METHODS: A literature search was performed on multiple electronic databases, ClinicalTrial.gov and Google Scholar on July 12th 2021, and reference lists were examined. We selected RCTs comparing the effects of IIM with placebo treatment on spine surgery. We calculated pooled standard mean difference (SMD) or risk ratio (RR) with 95% confident interval (CI) under a random-effect model. We assessed risk of bias using Cochrane risk-of-bias tool and Jadad score was applied to assess the quality of each included trial. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to determine the confidence in effect estimates. Sensitivity analysis was conducted by omitting each included study one by one from the pooled analysis. PROSPERO Registration: CRD42021266170. FINDINGS: Fourteen trials of 781 participants were included. Low- to moderate-quality evidence suggested that IIM reduces postoperative morphine consumption at 24 h (SMD: -1·61 mg, 95% CI: -2·63 to -0·58) and intraoperative remifentanil requirement (SMD: -2·09 ug/h, 95% CI: -3·38 to -0·81). High-quality evidence suggested that IIM reduces the risk of postoperative nausea and vomiting compared with placebo (RR: 0·43, 95% CI: 0·26 to 0·71). Besides, moderate-quality evidence suggested that recovery orientation time in the IIM group is longer than control group (SMD: 1·13 min, 95% CI: 0·83 to 1·43). INTERPRETATION: IIM as adjuvant analgesics showed overall benefits on spine surgery in terms of reducing analgesic requirement and postoperative nausea and vomiting; however, potential risks of IIM, such as delayed anesthetic awakening, should not be ignored. Future evidence will inform the optimal strategy of IIM administration for patients undergoing spine surgery. FUNDING: This study was funded by Beijing Municipal Natural Science Foundation (Grant No :7212117).

Extracorporeal Shockwave Therapy for Treating Chronic Low Back Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To assess the effectiveness and safety of extracorporeal shockwave therapy (ESWT) for the treatment of chronic low back pain (CLBP). METHODS: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement standard. We identified relevant studies by searching multiple electronic databases, trial registries, and websites up to April 30, 2021, and examining reference lists. We selected RCTs that compared ESWT, in unimodal or multimodal therapeutic approaches, with sham ESWT or other active therapies. Two investigators independently extracted data and assessed the risk of bias and quality of the evidence. The main outcomes were pain intensity and disability status, examined as standardized mean differences (SMD) with 95% confidence intervals (CI). The risk of bias was assessed by using Cochrane Back and Neck (CBN) Group risk of bias tool and Jadad score, and GRADE was applied to determine the confidence in effect estimates. Heterogeneity was explored using sensitivity analysis and meta-regression. RESULTS: Ten RCTs, including a total of 455 young to middle-aged individuals (29.2-55.8 years), were identified. Compared with control, the ESWT group showed lower pain intensity at month 1 (SMD = -0.81, 95% CI -1.21 to -0.42), as well as lower disability score at month 1 (SMD = -1.45, 95% CI -2.68 to -0.22) and at month 3 (SMD = -0.69, 95% CI -1.08 to -0.31). No serious shockwave-related adverse events were reported. CONCLUSION: The use of ESWT in CLBP patients results in significant and quantifiable reductions in pain and disability in the short term. However, further well-conducted RCTs are necessary for building high-quality evidence and promoting the application of ESWT in clinical practice.

MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas.

BACKGROUND: Dysregulated receptor tyrosine kinases, such as the mesenchymal-epidermal transition factor (MET), have pivotal role in gliomas. MET and its interaction with the tumor microenvironment have been previously implicated in secondary gliomas. However, the contribution of MET gene to tumor cells' ability to escape immunosurveillance checkpoints in primary gliomas, especially in glioblastoma (GBM), which is a WHO grade 4 glioma with the worst overall survival, is still poorly understood. METHODS: We investigated the relationship between MET expression and glioma microenvironment by using multiomics data and aimed to understand the potential implications of MET in clinical practice through survival analysis. RNA expression data from a total of 1243 primary glioma samples (WHO grades 2-4) were assembled, incorporating The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and GSE16011 data sets. RESULTS: Pearson's correlation test from the three data sets indicated that MET showed a robust correlation with programmed death-ligand 1 (PD-L1) and STAT pathways. Western blot analysis revealed that in GBM cell lines (N33 and LN229), PD-L1 and phosphorylated STAT4 were upregulated by MET activation treatment with hepatocyte growth factor and were downregulated on MET suppression by PLB-1001. Tumor tissue microarray analysis indicated a positive correlation between MET and PD-L1 and macrophage-associated markers. Chromatin immunoprecipitation-PCR assay showed enrichment of STAT4 in the PD-L1 DNA. Transwell co-culture and chemotaxis assays revealed that knockdown of MET in GBM cells inhibited macrophage chemotaxis. Moreover, we performed CIBERSORTx and single-cell RNA sequencing data analysis which revealed an elevated number of macrophages in glioma samples with MET overexpression. Kaplan-Meier survival analysis indicated that activation of the MET/STAT4/PD-L1 pathway and upregulation of macrophages were associated with shorter survival time in patients with primary GBM. CONCLUSIONS: These data indicated that the MET-STAT4-PD-L1 axis and tumor-associated macrophages might enforce glioma immune evasion and were associated with poor prognosis in GBM samples, suggesting potential clinical strategies for targeted therapy combined with immunotherapy in patients with primary GBM.

Metabolic expression profiling stratifies diffuse lower-grade glioma into three distinct tumour subtypes.

BACKGROUND: Lower-grade gliomas (LGGs) show highly metabolic heterogeneity and adaptability. To develop effective therapeutic strategies targeting metabolic processes, it is necessary to identify metabolic differences and define metabolic subtypes. Here, we aimed to develop a classification system based on metabolic gene expression profile in LGGs. METHODS: The metabolic gene profile of 402 diffuse LGGs from the Cancer Genome Atlas (TCGA) was used for consensus clustering to determine robust clusters of patients, and the reproducibility of the classification system was evaluated in three Chinese Glioma Genome Atlas (CGGA) cohorts. Then, the metadata set for clinical characteristics, immune infiltration, metabolic signatures and somatic alterations was integrated to characterise the features of each subtype. RESULTS: We successfully identified and validated three highly distinct metabolic subtypes in LGGs. M2 subtype with upregulated carbohydrate, nucleotide and vitamin metabolism correlated with worse prognosis, whereas M1 subtype with upregulated lipid metabolism and immune infiltration showed better outcome. M3 subtype was associated with low metabolic activities and displayed good prognosis. Three metabolic subtypes correlated with diverse somatic alterations. Finally, we developed and validated a metabolic signature with better performance of prognosis prediction. CONCLUSIONS: Our study provides a new classification based on metabolic gene profile and highlights the metabolic heterogeneity within LGGs.

Development of ratiometric electrochemical molecular switches to assay endogenous formaldehyde in live cells, whole blood and creatinine in saliva.

Formaldehyde is a reactive carbonyl species (RCS) that is produced naturally in the human body via metabolic and epigenetic biochemical processes, yet in high concentrations is highly toxic to the environment as well as to living organisms. Therefore, we designed two ratiometric electrochemical molecular redox probes, Formaldehyde oxidative latent probe (FOLP) and dihydroxy-formaldehyde oxidative latent probe (HFOLP), for the selective profiling of endogenous formaldehyde. FOLP and HFOLP each underwent the aza-Cope reaction with formaldehyde followed by hydrolysis to eliminate unmask redox reporter N-alkylated aminoferrocene (AAF) to monitor their response current. The FOLP and HFOLP sensors showed broad dynamic ranges of 0.12-1000 µM and 0.09-3 mM for formaldehyde with detection limits of 48.2 nM and 31.6 µM, respectively. Also, since formaldehyde is the byproduct of biochemical reactions for detecting creatinine and creatinine is an important biomarker for chronic kidney disease (CKD), we tested the FOLP probe for its ability to monitor creatinine. It successfully did so, and this ability was used to develop an electrochemical platform for the quantification of creatinine; it showed a dynamic range of 3.25-200 µM and a limit of detection (1.3 µM). In addition, the FOLP-based assay platform delivered a reliable analytical performance for the quantification of formaldehyde in human whole blood and of creatinine in saliva, and also for the real-time monitoring of endogenous formaldehyde secretion in HeLa cells. Moreover, the concentrations determined using our method were found to be consistent with those determined using formaldehyde and creatinine fluorometric assay kits.

Head and Face Protection of the Health Care Workers in the Operating Room of Peking Union Medical College Hospital during the Corona Virus Disease-19 Pandemic / 中国医学科学院学报

Objective To investigate the understanding of the head and face protection of the health care workers in operating room of Peking Union Medical College Hospital during the corona virus disease-19(COVID-19) pandemic.Methods The knowledge of head and face protection of health care workers in the operating room was evaluated based on the non-registered questionnaires for protection measures collected on-line.Results The survey was conducted in two phases.In the first phase(COVID-19 outbreak),153 questionnaires were collected.In the second phase(when Beijing lowered the emergency response to level 3 and normalized the epidemic prevention and control),101 questionnaires were collected.The results showed that 98% of health care workers had used any form of protective devices during the pandemic and anesthesiologists had the highest usage rate(93.0%)of ear-loop face mask with eye shield.During the pandemic,health care workers mainly used goggles(71.2%)for protection to diagnose and treat the patients with fever and ear-loop face mask with eye shield(56.2%)for protection to diagnose and treat the non-fever patients.In the first-and second-phase survey,43% and 68% of health care workers still used protection,and they mainly used face shield(50.0% and 56.5%)and ear-loop face mask with eye shield(56.1% and 68.1%).Conclusions During the pandemic,more than 90% of the health care workers in the operating room of Peking Union Medical College Hospital were aware of head and face protection.Different healthcare workers in the operating room had different choices of head and face protection,and more than 40% of them would still keep such protection during the normalized stage of pandemic prevention and control.

Transcriptional Characteristics of IDH-Wild Type Glioma Subgroups Highlight the Biological Processes Underlying Heterogeneity of IDH-Wild Type WHO Grade IV Gliomas.

Isocitric dehydrogenase (IDH)-wild type diffuse gliomas, which have a poorer prognosis than their IDH-mutant counterparts, are also accompanied with high heterogeneity. Here, we aimed to identify the key biological processes associated with the three groups of IDH-wild type diffuse gliomas in 323 patients. By The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommendation, the three groups are Group A, diffuse astrocytic glioma, World Health Organization (WHO) grade II/III; Group B, diffuse astrocytic glioma, with one (or more) of the three genetic alterations: TERT promoter mutation, EGFR gene amplification, gain of chromosome 7 combined with loss of chromosome 10, WHO grade IV; and Group C, glioblastoma, WHO grade IV. Consistent with their histologic and genetic molecular features, we successfully identified that biological activities associated with "cell cycle" and "cell mitosis" are significantly elevated in Group B compared with Group A; microenvironment-related hallmarks "angiogenesis" and "hypoxia," and biological processes of "extracellular matrix," "immune response," and "positive regulation of transcriptional activities" were more enriched in Group C than Group B. We also constructed a nine-gene signature from differentially expressed genes among the three groups to further stratify the WHO grade IV gliomas (Groups B and C) whose survival cannot be clearly stratified by current classification systems. This signature was an independent prognosis factor for WHO grade IV gliomas and had better prognostic value than other known factors in both training and validation dataset. In addition, the signature risk score was positively correlated with the amount of infiltrated immune cells, expression of immune checkpoints, and the genes enriched in biological processes of "immune response," "cell cycle," and "extracellular matrix." The bioinformatic analysis results were also validated by immunohistochemistry and patient-derived cell proliferation assay. Overall, our findings revealed the key biological processes underlying the new classifications of IDH-wild type diffuse glioma. Meanwhile, we constructed a signature, which could properly stratify the prognosis, cell proliferation activates, extracellular matrix-mediated biological activities, and immune-microenvironment of IDH-wild type WHO grade IV gliomas.

Characterization and prognostic significance of alternative splicing events in lower-grade diffuse gliomas.

Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower-grade diffuse gliomas were profiled. Subtype-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS-related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas.

Whole-transcriptome sequencing profiling identifies functional and prognostic signatures in patients with PTPRZ1-MET fusion-negative secondary glioblastoma multiforme.

Gliomas are the most common type of primary brain tumor in adults with a high mortality rate. Low-grade gliomas progress to glioblastoma multiforme (GBM) in the majority of cases, forming secondary GBM (sGBM), followed by rapid fatal clinical outcomes. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1)-MET proto-oncogene receptor tyrosine kinase (MET) (ZM) fusion has been identified as a biomarker for sGBM that is involved in glioma progression, but the mechanism of gliomagenesis and pathology of ZM-negative sGBM has remained to be fully elucidated. A whole-transcriptome signature is thus required to improve the outcome prediction for patients with sGBM without ZM fusion. In the present study, whole-transcriptome sequencing on 42 sGBM samples with or without ZM fusion from the Chinese Glioma Genome Atlas database identified mRNAs with differential expression between patients with and without ZM fusion and the most significant survival-associated genes were identified. A 6-gene signature was identified as a novel prognostic model reflecting survival probability in patients with ZM-negative sGBM. Clinical characteristics in patients with a high or low risk score value were analyzed with the Kaplan-Meier method and a two-sided log-rank test. In addition, ZM-negative sGBM patients with a high risk score exhibited an increase in immune cells, NF-κB-induced pathway activation and a decrease in endothelial cells compared with those with a low risk score. The present study demonstrated the potential use of a next-generation sequencing-based cancer gene signature in patients with ZM-negative sGBM, indicating possible clinical therapeutic strategies for further treatment of such patients.