Long-term outcomes of central neurocytoma - an institutional experience.

INTRODUCTION: Central Neurocytoma (CN) is a rare, WHO grade 2 brain tumor that predominantly affects young adults. Gross total resection (GTR) is often curative for CNs, but the optimal treatment paradigm including incorporation of RT, following subtotal resection (STR) and for scarcer pediatric cases has yet to be established. METHODS: Patients between 2001 and 2021 with a pathologic diagnosis of CN were reviewed. Demographic, treatment, and tumor characteristics were recorded. Recurrence free survival (RFS) and overall survival (OS) were calculated according to the Kaplan Meier-method. Post-RT tumor volumetric regression analysis was performed. RESULTS: Seventeen adults (≥ 18 years old) and 5 children (< 18 years old) met the criteria for data analysis (n = 22). With a median follow-up of 6.9 years, there was no tumor-related mortality. Patients who received STR and/or had atypical tumors (using a cut-off of Ki-67 > 4%) experienced decreased RFS compared to those who received GTR and/or were without atypical tumors. RFS at 5 years for typical CNs was 67% compared to 22% for atypical CNs. Every pediatric tumor was atypical and 3/5 recurred within 5 years. Salvage RT following tumor recurrence led to no further recurrences within the timeframe of continued follow-up; volumetric analysis for 3 recurrent tumors revealed an approximately 80% reduction in tumor size. CONCLUSION: We provide encouraging evidence that CNs treated with GTR or with RT after tumor recurrence demonstrate good long-term tumor control.

A cost-effective, machine learning-based new unified risk-classification score (NU-CATS) for patients with endometrial cancer.

INTRODUCTION: Treatment for endometrial cancer (EC) is increasingly guided by molecular risk classifications. Here, we aimed at using machine learning (ML) to incorporate clinical and molecular risk factors to optimize risk assessment. METHODS: The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (n = 596), Memorial Sloan Kettering-Metastatic Events and Tropisms (n = 1315) and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (n = 4561) datasets were used to identify genetic alterations and clinicopathological features. Software packages including Keras, Pytorch, and Scikit Learn were tested to build artificial neural networks (ANNs) with a binary output as either intra-abdominal metastatic progression ('1') vs. non-metastatic ('0'). RESULTS: Black patients with EC have worse prognosis than White patients, adjusting for TP53 or POLE mutation status. Over 75% of Black patients carry TP53 mutations as compared to approximately 40% of White patients. Older age is associated with an increasing likelihood of TP53 mutation, high risk histology, and distant metastasis. For patients above age 70, 91% of Black and 60% of White EC patients carry TP53 mutations. A ML-based New Unified classifiCATion Score (NU-CATS) that incorporates age, race, histology, mismatch repair status, and TP53 mutation status showed 75% accuracy in prognosticating intra-abdominal progression. A higher NU-CATS is associated with an increasing risk of having positive pelvic or para-aortic lymph nodes and distant metastasis. NU-CATS was shown to outperform Leiden/TransPORTEC model for estimating risk of FIGO Stage I/II disease progression and survival in Black EC patients. CONCLUSION: The NU-CATS, a ML-based, cost-effective algorithm, incorporates diverse clinicopathologic and molecular variables of EC and yields superior prognostication of the risk of nodal involvement, distant metastasis, disease progression, and overall survival.

AcMNPV-BmK IT improves the progeny virus production via baculovirus GP64 envelope fusion protein.

OBJECTIVES: To analyze the mechanisms underlying the impact of recombinant Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV)-mediated BmK IT expression on the function of baculovirus GP64 envelope fusion protein and progeny virus production. RESULTS: Viral propagation assay indicated that overexpression GP64 could promote replication of AcMNPV. AcMNPV-mediated expression of BmK IT also promoted replication of AcMNPV. Immunofluorescence analysis showed BmK IT, which was regulated by very early promoter IE1 in AcMNPV, could make the GP64 protein move to the cytomembrane soon after transfection. BmK IT, which is regulated by P10 protein promoter (P10) and polyhedrosis promoter (PH), could promote the expression of GP64. CONCLUSION: BmK IT, regulated by very early promoter IE1, P10 protein promoter (P10) and PH, accelerated the expression of GP64 protein, promoted its early cytomembrane localization and then triggered virus budding and progeny virus production.

SfP53 and filamentous actin (F-actin) are the targets of viral pesticide AcMNPV-BmK IT (P10/PH) in host Spodoptera frugiperda 9 cells.

OBJECTIVES: To analyze the anti-insect mechanism of viral pesticide AcMNPV-BmK IT(P10/PH) in the host Spodoptera frugiperda 9 (Sf9) cells. RESULTS: Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV)- mediated expression of BmK IT, regulated by P10 protein promoter (P10) and polyhedrosis promoter (PH), promoted the replication of progeny virus in host Sf9 cells. AcMNPV-BmK IT(P10) could accelerate the budding process (or speed) of budded virus (BV) in Sf9 cells. The impact of AcMNPV-BmK IT(P10) on the nuclear polymerization of filamentous actin (F-actin) participated in regulating the accelerated budding process. Unexpectedly, both AcMNPV-BmK IT(P10) and AcMNPV-BmK IT(PH) delayed the nuclear polymerization of F-actin and promoted the clearance of F-actin in the nucleus. SfP53, an important apoptosis factor, was involved in the regulation of AcMNPV-BmK IT(P10/PH) in Sf9 cells. AcMNPV-BmK IT(P10/PH) could also delay and promote the nuclear recruitment of SfP53 after 27 h post infection (h p.i.). CONCLUSION: SfP53 and F-actin are the targets of viral pesticide AcMNPV-BmK IT (P10/PH) in host Sf9 cells, which provides the experimental basis for the development of recombinant baculovirus biopesticides.

Regulation analysis of AcMNPV-mediated expression of a Chinese scorpion neurotoxin under the IE1, P10 and PH promoter in vivo and its use as a potential bio-insecticide.

OBJECTIVE: To analyze the regulation mechanism of AcMNPV (Autographa californica multicapsid nucleopolyhedrovirus)-mediated expression of BmK IT under IE1, P10 and PH promoters in the larva of Heliothis armigera.. RESULTS: The transcription level of BmK IT gene in midgut and epidermal tissue was analyzed by quantitative PCR. The start time of transcription of recombinant BmK IT gene was early under the regulation of IE promoter, whereas transcription of BmK IT was high under the regulation of P10 promoter in the midgut tissue of infected larvae. TdT-UTP nick-end labeling (TUNEL) assay showed the degree of apoptotic cell death in the midgut tissue of AcMNPV-BmK IT-transfected insect larvae was higher than that in the AcMNPV treatment group at 8 h post-infection. The time-effect relationship between the insect's humoral immunity and regulation of promoters was confirmed in the phenoloxidase activity assay. CONCLUSION: The anti-insect mechanism and regulation of different promoters in AcMNPV-BmK IT at molecular and cellular levels provide an experimental basis for the development of recombinant baculovirus biopesticides.

Race, Prevalence of POLE and POLD1 Alterations, and Survival Among Patients With Endometrial Cancer.

Importance: Black patients with endometrial cancer (EC) in the United States have higher mortality than patients of other races with EC. The prevalence of POLE and POLD1 pathogenic alterations in patients of different races with EC are not well studied. Objective: To explore the prevalence of and outcomes associated with POLE and POLD1 alterations in differential racial groups. Design, Setting, and Participants: This retrospective cohort study incorporated the largest available data set of patients with EC, including American Association for Cancer Research Project GENIE (Genomics Evidence Neoplasia Information Exchange; 5087 participants), Memorial Sloan Kettering-Metastatic Events and Tropisms (1315 participants), and the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (517 participants), collected from 2015 to 2023, 2013 to 2021, and 2006 to 2012, respectively. The prevalence of and outcomes associated with POLE or POLD1 alterations in EC were evaluated across self-reported racial groups. Exposure: Patients of different racial groups with EC and with or without POLE or POLD1 alterations. Main Outcomes and Measures: The main outcome was overall survival. Data on demographic characteristics, POLE and POLD1 alteration status, histologic subtype, tumor mutation burden, fraction of genome altered, and microsatellite instability score were collected. Results: A total of 6919 EC cases were studied, of whom 444 (6.4%), 694 (10.0%), and 4869 (70.4%) patients were self-described as Asian, Black, and White, respectively. Within these large data sets, Black patients with EC exhibited a lower weighted average prevalence of pathogenic POLE alterations (0.5% [3 of 590 cases]) compared with Asian (6.1% [26 of 424]) or White (4.6% [204 of 4520]) patients. By contrast, the prevalence of POLD1 pathogenic alterations was 5.0% (21 cases), 3.2% (19 cases), and 5.6% (255 cases) in Asian, Black, and White patients with EC, respectively. Patients with POLD1 alterations had better outcomes regardless of race, histology, and TP53 alteration status. For a total of 241 clinically annotated Black patients with EC, a composite biomarker panel of either POLD1 or POLE alterations identified 7.1% (17 patients) with positive outcomes (1 event at 70 months follow up) in the small sample of available patients. Conclusions and Relevance: In this retrospective clinicopathological study of patients of different racial groups with EC, a composite biomarker panel of either POLD1 or POLE alteration could potentially guide treatment de-escalation, which is especially relevant for Black patients.

GlioPredictor: a deep learning model for identification of high-risk adult IDH-mutant glioma towards adjuvant treatment planning.

Identification of isocitrate dehydrogenase (IDH)-mutant glioma patients at high risk of early progression is critical for radiotherapy treatment planning. Currently tools to stratify risk of early progression are lacking. We sought to identify a combination of molecular markers that could be used to identify patients who may have a greater need for adjuvant radiation therapy machine learning technology. 507 WHO Grade 2 and 3 glioma cases from The Cancer Genome Atlas, and 1309 cases from AACR GENIE v13.0 datasets were studied for genetic disparities between IDH1-wildtype and IDH1-mutant cohorts, and between different age groups. Genetic features such as mutations and copy number variations (CNVs) correlated with IDH1 mutation status were selected as potential inputs to train artificial neural networks (ANNs) to predict IDH1 mutation status. Grade 2 and 3 glioma cases from the Memorial Sloan Kettering dataset (n = 404) and Grade 3 glioma cases with subtotal resection (STR) from Northwestern University (NU) (n = 21) were used to further evaluate the best performing ANN model as independent datasets. IDH1 mutation is associated with decreased CNVs of EGFR (21% vs. 3%), CDKN2A (20% vs. 6%), PTEN (14% vs. 1.7%), and increased percentage of mutations for TP53 (15% vs. 63%), and ATRX (10% vs. 54%), which were all statistically significant (p < 0.001). Age > 40 was unable to identify high-risk IDH1-mutant with early progression. A glioma early progression risk prediction (GlioPredictor) score generated from the best performing ANN model (6/6/6/6/2/1) with 6 inputs, including CNVs of EGFR, PTEN and CDKN2A, mutation status of TP53 and ATRX, patient's age can predict IDH1 mutation status with over 90% accuracy. The GlioPredictor score identified a subgroup of high-risk IDH1-mutant in TCGA and NU datasets with early disease progression (p = 0.0019, 0.0238, respectively). The GlioPredictor that integrates age at diagnosis, CNVs of EGFR, CDKN2A, PTEN and mutation status of TP53, and ATRX can identify a small cohort of IDH-mutant with high risk of early progression. The current version of GlioPredictor mainly incorporated clinically often tested genetic biomarkers. Considering complexity of clinical and genetic features that correlate with glioma progression, future derivatives of GlioPredictor incorporating more inputs can be a potential supplement for adjuvant radiotherapy patient selection of IDH-mutant glioma patients.

Integrating POLE/POLD1 mutated for immunotherapy treatment planning of advanced stage non-small cell lung cancer.

BACKGROUND: In this study, we evaluated the potential of DNA polymerase epsilon (POLE) and DNA polymerase delta 1 (POLD1) as prognostic biomarkers for immune checkpoint inhibitor (ICI) treatment in patients with advanced stage non-small cell lung cancer (NSCLC). METHODS: Disease stage, PD-L1 positivity, histological subtypes, POLE/POLD1 mutation status, tumor mutation burden (TMB), and response to ICIs in NSCLC cases were derived from AACR GENIE dataset (n = 24 120), TCGA-Pan Lung Cancer dataset (n = 1144), AACR GENIE BPC NSCLC v2.0-public (n = 2004), and Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets dataset (n = 350). The smoking history from TCGA and AACR GENIE datasets was grouped into current, former or never-smokers. RESULTS: POLE and POLD1 genetic alterations were identified in 5% and 2.6% of NSCLC patients, respectively. Current smokers had 9% and 4% of POLE/POLD1 mutations, respectively, versus 1.7% for both POLE and POLD1 mutations prevalence in never-smokers. POLE/POLD1 mutations were associated with elevated mutation counts than those with wild-type (median mutation counts 16 vs. 7, p < 0.0001), more advanced disease stages (stage I disease 15.19% vs. 29.42%), more prevalent squamous histology subtype (21.69% vs. 9.05%, p = 0.0427), and a higher percentage of PD-L1 positivity (66.67% vs. 43.87%, p < 0.001). Treatment with ICIs improved survival in patients with both POLE/POLD1 mutated and those with TMB > 18 (p < 0.001). CONCLUSION: Current smokers have a five-fold increased risk of having POLE mutations than never-smokers. POLE/POLD1 mutation status and TMB > 18 can be a composite biomarker for selecting NSCLC patients with survival benefits to ICI treatment.

A potential strategy for high-grade gliomas: combination treatment with lithium chloride and BmK CT.

Therapies for high-grade gliomas (HHG) that have strong tendency of infiltration and resistance to chemotherapies are currently unavailable. Here, we report that lower-dose combination therapy of Buthus martensii Karsch (BmK) CT, a type of scorpion toxin peptide, and LiCl, clinically used as mood stabilizer, could synergistically inhibit the migration, invasion and proliferation of C6 glioma cells. The decreased invasiveness of C6 glioma cells was accompanied by inhibited activation, catalytic activity and/or expression of matrix metalloproteinase-2. Moreover, TOPfalsh luciferase reporter and immunofluorescence staining showed altered localization pattern of ß-catenin at the leading edge of 2D scratch. Our results suggested that the combination treatment of lithium and BmK CT may constitute a novel and potential strategy for HHG therapy.

Mutations in isocitrate dehydrogenase 2 accelerate glioma cell migration via matrix metalloproteinase-2 and 9.

The gene encoding isocitrate dehydrogenase (IDH) is somatically mutated predominantly in secondary glioblastoma multiforme. Glioma-specific mutations in IDH1 always produced a single amino acid substitution at R132, but mutations in IDH2 were exclusively at R172 which was the analogous site to R132 in IDH1. Mutations of IDH1 and IDH2 led to simultaneous loss and gain of activities in the production of α-ketoglutarate and 2-hydroxyglutarate, respectively. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteinases involved in the degradation of the extracellular matrix. The exact role of IDH2 mutant on MMPs activity and cell migration has not been fully studied. Here, we show that in response to IDH2 mutations, low levels of α-ketoglutarate increased the stabilization of HIF-1α which can contribute to tumor growth. Moreover, mutant IDH2-induced HIF-1α improved the secretion levels of pro-MMP-2 and pro-MMP-9 as well as the conversion from pro-MMP-2 to its active form, giving C6 glioma cells a higher migration potential. The HIF-1α pathway is probably a critical pathway for release of MMPs in the glioma cancer harboring IDH mutant.

[Discussion on releasing price of Chinese patent medicine to market economy to achieve sustainable development].

OBJECTIVE: To analyze costs of the traditional Chinese medicine industry focusing on production costs. METHOD: Data of 50 planted Chinese herbal medicines and 50 wild Chinese herbal medicines were summarized and analyzed to see the changes of price of Chinese herbal medicines. RESULT: The derivative problems of limited price were analyzed by crude drug, quality of Chinese medicine and sustainable utilization of resource. CONCLUSION: The price of Chinese medicine shall be adapted to sustainable development of market economy.

A functional artificial neural network for noninvasive pretreatment evaluation of glioblastoma patients.

BACKGROUND: Pretreatment assessments for glioblastoma (GBM) patients, especially elderly or frail patients, are critical for treatment planning. However, genetic profiling with intracranial biopsy carries a significant risk of permanent morbidity. We previously demonstrated that the CUL2 gene, encoding the scaffold cullin2 protein in the cullin2-RING E3 ligase (CRL2), can predict GBM radiosensitivity and prognosis. CUL2 expression levels are closely regulated with its copy number variations (CNVs). This study aims to develop artificial neural networks (ANNs) for pretreatment evaluation of GBM patients with inputs obtainable without intracranial surgical biopsies. METHODS: Public datasets including Ivy-GAP, The Cancer Genome Atlas Glioblastoma (TCGA-GBM), and the Chinese Glioma Genome Atlas (CGGA) were used for training and testing of the ANNs. T1 images from corresponding cases were studied using automated segmentation for features of heterogeneity and tumor edge contouring. A ratio comparing the surface area of tumor borders versus the total volume (SvV) was derived from the DICOM-SEG conversions of segmented tumors. The edges of these borders were detected using the canny edge detector. Packages including Keras, Pytorch, and TensorFlow were tested to build the ANNs. A 4-layered ANN (8-8-8-2) with a binary output was built with optimal performance after extensive testing. RESULTS: The 4-layered deep learning ANN can identify a GBM patient's overall survival (OS) cohort with 80%-85% accuracy. The ANN requires 4 inputs, including CUL2 copy number, patients' age at GBM diagnosis, Karnofsky Performance Scale (KPS), and SvV ratio. CONCLUSION: Quantifiable image features can significantly improve the ability of ANNs to identify a GBM patients' survival cohort. Features such as clinical measures, genetic data, and image data, can be integrated into a single ANN for GBM pretreatment evaluation.

ß-catenin as a potential key target for tumor suppression.

ß-catenin is a multifunctional protein identified to be pivotal in embryonic patterning, organogenesis and adult homeostasis. It plays a critical structural role in mediating cadherin junctions and is also an essential transcriptional co-activator in the canonical Wnt pathway. Evidence has been documented that both the canonical Wnt pathway and cadherin junctions are deregulated or impaired in a plethora of human malignancies. In the light of this, there has been a recent surge in elucidating the mechanisms underlying the etiology of cancer development from the perspective of ß-catenin. Here, we focus on the emerging roles of ß-catenin in the process of tumorigenesis by discussing novel functions of old players and new proteins, mechanisms identified to mediate or interact with ß-catenin and the most recently unraveled clinical implications of ß-catenin regulatory pathways toward tumor suppression.

A model of BmK CT in inhibiting glioma cell migration via matrix metalloproteinase-2 from experimental and molecular dynamics simulation study.

The significance of BmK CT, a key chlorotoxin-like peptide isolated from the scorpion venom of Buthus martensii Karsch, is a novel blocker of the chloride ion channel and matrix metalloproteinase-2 (MMP-2). Site-directed mutagenesis of BmK CT, wound healing assay, gelatin zymography assay and computational simulation highlight the importance of electrostatic contribution to BmK CT-MMP-2 catalytic domain complex and a model of BmK CT-MMP-2 catalytic domain complex is therefore proposed. This is the first documentation of the structural mechanism of in the inhibition of glioma cell migration by BmK CT and may lead to the molecular design of specific inhibitors of MMP-2.

Identification of Novel Transcriptome Signature as a Potential Prognostic Biomarker for Anti-Angiogenic Therapy in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common and devastating type of primary brain tumor, with a median survival time of only 15 months. Having a clinically applicable genetic biomarker would lead to a paradigm shift in precise diagnosis, personalized therapeutic decisions, and prognostic prediction for GBM. Radiogenomic profiling connecting radiological imaging features with molecular alterations will offer a noninvasive method for genomic studies of GBM. To this end, we analyzed over 3800 glioma and GBM cases across four independent datasets. The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases were employed for RNA-Seq analysis, whereas the Ivy Glioblastoma Atlas Project (Ivy-GAP) and The Cancer Imaging Archive (TCIA) provided clinicopathological data. The Clinical Proteomic Tumor Analysis Consortium Glioblastoma Multiforme (CPTAC-GBM) was used for proteomic analysis. We identified a simple three-gene transcriptome signature-SOCS3, VEGFA, and TEK-that can connect GBM's overall prognosis with genes' expression and simultaneously correlate radiographical features of perfusion imaging with SOCS3 expression levels. More importantly, the rampant development of neovascularization in GBM offers a promising target for therapeutic intervention. However, treatment with bevacizumab failed to improve overall survival. We identified SOCS3 expression levels as a potential selection marker for patients who may benefit from early initiation of angiogenesis inhibitors.

Integrating cullin2-RING E3 ligase as a potential biomarker for glioblastoma multiforme prognosis and radiosensitivity profiling.

BACKGROUND AND PURPOSE: Positive epidermal growth factor receptor (EGFR) immunoreactivity in glioblastoma multiforme (GBM) often predicts poor radiation response. Meanwhile, all attempts to target EGFR pharmaceutically have been unsuccessful, mainly due to molecular heterogeneity of EGFR expression in GBM. A molecular biology-based and efficient way to access cellular protein levels of EGFR is urgently needed. EGFR, together with HIF-1α and Cyclin B1, is degraded via cullin2-RING E3 ligase (CRL2). It is worthwhile to investigate the possible involvement of CRL2 on GBM survival and radiosensitivity. MATERIALS AND METHODS: Clinicopathological features, radiographic images, survival data, RNA-Seq, copy number variations (CNVs), and other genetic changes were studied on over 3800 glioma and GBM cases, which are derived from 5 independent cohorts. These datasets include the Chinese Glioma Genome Atlas, The Cancer Genome Atlas, Ivy Glioblastoma Atlas Project, Clinical Proteomic Tumor Analysis Consortium, and the 2008 Parson's GBM dataset. RESULTS: Expression of CUL2, which encodes the scaffold protein cullin2 in the CRL2 E3 ligase, can predict GBM progression and survival rate. Cullin2 protein levels are inversely related to those of HIF-1α, VEGF-A, Cyclin B1, and EGFR. Elevated CUL2 expression predicts increased radiosensitivity and dampened signal intensities in perfusion imaging. CUL2 expression are regulated via CNVs, which are inheritable structural DNA variations. CONCLUSION: CUL2 expression levels and CNVs can be integrated as potential biomarkers in facilitating GBM and prognosis and radiosensitivity profiling.

Ectopic B7-H4-Ig expression attenuates concanavalin A-induced hepatic injury.

Previous studies demonstrate that both membrane B7-H4 and B7-H4-Ig fusion protein could inhibit T-cell responses. In the present study, we explored the potential effect of B7-H4-Ig on liver injury in a hepatitis mouse model induced by concanavalin A (ConA). A B7-H4-Ig construct was introduced into animals by the hydrodynamic gene delivery approach. It was found that ectopic expression of B7-H4-Ig could inhibit ConA-induced elevation of serum levels of ALT and AST, suppress liver necrosis and even mortality of mice. Furthermore, we observed that pretreatment of B7-H4-Ig dramatically decreased serum levels and the expression of mRNA for IL-2, IFN-gamma and IL-4, but increased IL-10 in ConA-treated mice. Our results suggest that B7-H4-Ig may protect animals from liver injury induced by ConA, which could be associated with reduced serum levels for IL-2, IFN-gamma and IL-4 as well as enhanced IL-10 production.

Targeting Cullin-RING E3 Ligases for Radiosensitization: From NEDDylation Inhibition to PROTACs.

As a dynamic regulator for short-lived protein degradation and turnover, the ubiquitin-proteasome system (UPS) plays important roles in various biological processes, including response to cellular stress, regulation of cell cycle progression, and carcinogenesis. Over the past decade, research on targeting the cullin-RING (really interesting new gene) E3 ligases (CRLs) in the UPS has gained great momentum with the entry of late-phase clinical trials of its novel inhibitors MLN4924 (pevonedistat) and TAS4464. Several preclinical studies have demonstrated the efficacy of MLN4924 as a radiosensitizer, mainly due to its unique cytotoxic properties, including induction of DNA damage response, cell cycle checkpoints dysregulation, and inhibition of NF-κB and mTOR pathways. Recently, the PROteolysis TArgeting Chimeras (PROTACs) technology was developed to recruit the target proteins for CRL-mediated polyubiquitination, overcoming the resistance that develops inevitably with traditional targeted therapies. First-in-class cell-permeable PROTACs against critical radioresistance conferring proteins, including the epidermal growth factor receptor (EGFR), androgen receptor (AR) and estrogen receptor (ER), cyclin-dependent kinases (CDKs), MAP kinase kinase 1 (MEK1), and MEK2, have emerged in the past 5 years. In this review article, we will summarize the most important research findings of targeting CRLs for radiosensitization.

Identification of a cullin5-RING E3 ligase transcriptome signature in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the deadliest type of brain tumor. The median survival time for patients with GBM is only 15 months, even following maximal surgical resection and chemotherapy and radiation therapy. A genetic biomarker could enable a paradigm shift in precise diagnosis, personalized therapeutics and prognosis. In this study, we employed the Chinese Glioma Genome Atlas, The Cancer Genome Atlas, and the Ivy Glioblastoma Atlas Project databases for RNA sequencing (RNA-seq) analysis and clinicopathological studies. We demonstrated that elevated expression of the RNF7, TCEB1, SOCS1 and SOCS3 genes, which encode components of cullin5-RING E3 ligase (CRL5), predict unfavorable GBM prognoses. In GBM and glioma cases carrying IDH1 mutations, SOCS1 and SOCS3 methylation was increased and their expression was downregulated. This study has thus identified a simple transcriptome signature for GBM prognosis.

Age-related copy number variations and expression levels of F-box protein FBXL20 predict ovarian cancer prognosis.

About 70% of ovarian cancer (OvCa) cases are diagnosed at advanced stages (stage III/IV) with only 20-40% of them survive over 5 years after diagnosis. A reliably screening marker could enable a paradigm shift in OvCa early diagnosis and risk stratification. Age is one of the most significant risk factors for OvCa. Older women have much higher rates of OvCa diagnosis and poorer clinical outcomes. In this article, we studied the correlation between aging and genetic alterations in The Cancer Genome Atlas Ovarian Cancer dataset. We demonstrated that copy number variations (CNVs) and expression levels of the F-Box and Leucine-Rich Repeat Protein 20 (FBXL20), a substrate recognizing protein in the SKP1-Cullin1-F-box-protein E3 ligase, can predict OvCa overall survival, disease-free survival and progression-free survival. More importantly, FBXL20 copy number loss predicts the diagnosis of OvCa at a younger age, with over 60% of patients in that subgroup have OvCa diagnosed at age less than 60 years. Clinicopathological studies further demonstrated malignant histological and radiographical features associated with elevated FBXL20 expression levels. This study has thus identified a potential biomarker for OvCa prognosis.