Therapeutic targeting of advanced or metastatic non-small-cell lung cancer (NSCLC) represents a major goal of clinical treatment. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in cell cycle progression and is associated with oncogenesis in a large spectrum of cancer types, including NSCLC. Volasertib (BI 6727) is a potent, selective, PLK1 inhibitor that is currently under phase 2 clinical trials with modest antitumor activity against solid tumors. As the combination of volasertib with pemetrexed does not improve efficacy for NSCLC treatment, it is crucial to identify compounds that could enhance efficacy with volasertib. Immunomodulatory drugs (IMiDs) bind to E3 ligase CRBN and repurposes it to ubiquitinate other proteins as neo-substrates, representing an effective treatment for hematologic malignancies. In this study, by screening IMiDs, we found that a novel CRBN modulator, CC-885, can synergistically inhibit NSCLC with volasertib both in vitro and in vivo . This synergistic effect overcomes volasertib resistance caused by PLK1 mutations and is compromised in CRBN-or p97-depleted cells. Mechanistically, CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation, thereby enhancing the sensitivity of NSCLC to volasertib. In conclusion, our findings reveal that PLK1 is a neo-substrate of CUL4-CRBN induced by CC-885 and represent a combinational approach for treating NSCLC.
Objectives To evaluate the diagnostic yield and safety of brainstem stereotactic biopsy for brainstem lesions. Methods We performed a meta-analysis of English articles retrieved from the PubMed, Web of Science, Cochrane Library, and APA psycInfo databases up to May 12, 2021. A binary fixed-effect model, the inverse variance method, or a binary random-effect model, the Dersimonian Laird method, were utilized for pooling the data. This meta-analysis was registered with INPLASY, INPLASY202190034. Findings A total of 41 eligible studies with 2792 participants were included. The weighted average diagnostic yield was 97.0% (95% confidential interval [CI], 96.0-97.9%). The weighted average proportions of temporary complications, permanent deficits, and deaths were 6.2% (95% CI, 4.5–7.9%), .5% (95% CI, .2–.8%), and .3% (95% CI, .1–.5%), respectively. The subgroup analysis indicated a nearly identical weighted average diagnostic yield between MRI-guided stereotactic biopsy and CT-guided stereotactic biopsy (95.9% vs 95.8%) but slightly increased proportions of temporary complications (7.9% vs 6.0%), permanent deficits (1.9% vs .2%), and deaths (1.1% vs .4%) in the former compared to the latter. Moreover, a greater weighted average diagnostic yield (99.2% vs 97.6%) and lower proportions of temporary complications (5.1% vs 6.8%) and deaths (.7% vs 1.5%) were shown in the pediatric patient population than in the adult patient population. Conclusions Brainstem stereotactic biopsy demonstrates striking accuracy plus satisfying safety in the diagnosis of brainstem lesions. The diagnostic yield, morbidity, and mortality mildly vary based on the diversity of assistant techniques and subject populations.
Background Brain metastasis is an important cause of breast cancer-related death. Aim We evaluated the relationships between breast cancer subtype and prognosis among patients with brain metastasis at the initial diagnosis. Methods The Surveillance, Epidemiology, and End Results database was searched to identify patients with brain metastasis from breast cancer between 2010 and 2015. Multivariable Cox proportional hazard models were used to identify factors that were associated with survival among patients with initial brain metastases. The Kaplan–Meier method was used to compare survival outcomes according to breast cancer subtype. Results Among 752 breast cancer patients with brain metastasis at diagnosis, 140 patients (18.6%) underwent primary surgery and 612 patients (81.4%) did not undergo surgery, while 460 patients (61.2%) received chemotherapy and 292 patients (38.8%) did not receive chemotherapy. Multivariable analysis revealed that, relative to HR+/HER2– breast cancer, HR–/HER2– breast cancer was associated with significantly poorer overall survival (hazard ratio: 2.52, 95% confidence interval: 1.99–3.21), independent of age, sex, race, marital status, insurance status, grade, liver involvement, lung involvement, primary surgery, radiotherapy, and chemotherapy. The median overall survival intervals were 12 months for HR+/HER2−, 19 months for HR+/HER2+, 11 months for HR−/HER2+, and 6 months for HR–/HER2– ( P < .0001). Relative to HR+/HER2– breast cancer, HR–/HER2– breast cancer was associated with a significantly higher risk of mortality among patients, and the association was stronger among patients who received chemotherapy ( p for interaction = .005). Conclusions Breast cancer subtype significantly predicted overall survival among patients with brain metastasis at diagnosis.
BackgroundThe initiation and progression of tumors were due to variations of gene sets rather than individual genes. This study aimed to identify novel biomarkers based on gene set variation analysis (GSVA) in hepatocellular carcinoma.MethodsThe activities of 50 hallmark pathways were scored in three microarray datasets with paired samples with GSVA, and differential analysis was performed with the limma R package. Unsupervised clustering was conducted to determine subtypes with the ConsensusClusterPlus R package in the TCGA-LIHC (n = 329) and LIRI-JP (n = 232) cohorts. Differentially expressed genes among subtypes were identified as initial variables. Then, we used TCGA-LIHC as the training set and LIRI-JP as the validation set. A six-gene model calculating the risk scores of patients was integrated with the least absolute shrinkage and selection operator (LASSO) and stepwise regression analyses. Kaplan–Meier (KM) and receiver operating characteristic (ROC) curves were performed to assess predictive performances. Multivariate Cox regression analyses were implemented to select independent prognostic factors, and a prognostic nomogram was integrated. Moreover, the diagnostic values of six genes were explored with the ROC curves and immunohistochemistry.ResultsPatients could be separated into two subtypes with different prognoses in both cohorts based on the identified differential hallmark pathways. Six prognostic genes (ASF1A, CENPA, LDHA, PSMB2, SRPRB, UCK2) were included in the risk score signature, which was demonstrated to be an independent prognostic factor. A nomogram including 540 patients was further integrated and well-calibrated. ROC analyses in the five cohorts and immunohistochemistry experiments in solid tissues indicated that CENPA and UCK2 exhibited high and robust diagnostic values.ConclusionsOur study explored a promising prognostic nomogram and diagnostic biomarkers in hepatocellular carcinoma.
Background: DNA methylation is an important form of epigenetic regulation and is closely related to atherosclerosis (AS). The purpose of this study was to identify DNA methylation–related biomarkers and explore the immune-infiltrate characteristics of AS based on methylation data.Methods: DNA methylation data of 15 atherosclerotic and paired healthy tissues were obtained from Gene Expression Omnibus database. Differential methylation positions (DMPs) and differential methylation regions (DMRs) were screened by the ChAMP R package. The methylation levels of DMPs located on CpG islands of gene promoter regions were averaged. The limma R package was used to screen differentially methylated genes in the CpG islands of the promoter regions. The diagnostic values of the methylation levels were evaluated using the pROC R package. The EpiDISH algorithm was applied to quantify the infiltration levels of seven types of immune cells. Subsequently, three pairs of clinical specimens of coronary atherosclerosis with Stary’s pathological stage III were collected, and the methylation levels were detected by the methylation-specific PCR (MS-PCR) assay. Western blot was performed to detect the protein expression levels of monocyte markers.Results: A total of 110, 695 DMPs, and 918 DMRs were screened in the whole genome. Also, six genes with significant methylation differences in the CpG islands of the promoter regions were identified, including 49 DMPs. In total, three genes (GRIK2, HOXA2, and HOXA3) had delta beta greater than 0.2. The infiltration level of monocytes was significantly upregulated in AS tissues. MS-PCR assay confirmed the methylation status of the aforementioned three genes in AS samples. The Western blot results showed that the expression levels of the monocyte marker CD14 and M1-type macrophage marker CD86 were significantly increased in AS while M2-type macrophage marker protein CD206 was significantly decreased.Conclusion: This study identified potential DNA methylation–related biomarkers and revealed the role of monocytes in early AS.
BackgroundIncreasing evidence indicates that immune cell infiltration (ICI) affects the prognosis of multiple cancers. This study aims to explore the immunotypes and ICI-related biomarkers in ovarian cancer.MethodsThe ICI levels were quantified with the CIBERSORT and ESTIMATE algorithms. The unsupervised consensus clustering method determined immunotypes based on the ICI profiles. Characteristic genes were identified with the Boruta algorithm. Then, the ICI score, a novel prognostic marker, was generated with the principal component analysis of the characteristic genes. The relationships between the ICI scores and clinical features were revealed. Further, an ICI signature was integrated after the univariate Cox, lasso, and stepwise regression analyses. The accuracy and robustness of the model were tested by three independent cohorts. The roles of the model in the immunophenoscores (IPS), tumor immune dysfunction and exclusion (TIDE) scores, and immunotherapy responses were also explored. Finally, risk genes (GBP1P1, TGFBI, PLA2G2D) and immune cell marker genes (CD11B, NOS2, CD206, CD8A) were tested by qRT-PCR in clinical tissues.ResultsThree immunotypes were identified, and ICI scores were generated based on the 75 characteristic genes. CD8 TCR pathways, chemokine-related pathways, and lymphocyte activation were critical to immunophenotyping. Higher ICI scores contributed to better prognoses. An independent prognostic factor, a three-gene signature, was integrated to calculate patients’ risk scores. Higher TIDE scores, lower ICI scores, lower IPS, lower immunotherapy responses, and worse prognoses were revealed in high-risk patients. Macrophage polarization and CD8 T cell infiltration were indicated to play potentially important roles in the development of ovarian cancer in the clinical validation cohort.ConclusionsOur study characterized the immunotyping landscape and provided novel immune infiltration-related prognostic markers in ovarian cancer.
Elevated expression of lysyl oxidase-like 2 (LOXL2) contributes to the malignant tumor progression in multiple cancers. However, the role of LOXL2 in the 5-fluorouracil (5-FU) resistance of colorectal cancer (CRC) remains unclear. This study aimed to explore the effects of LOXL2 on 5-FU sensitivity in CRC. The mRNA and protein levels of LOXL2 were explored in public databases by bioinformatics, validated in clinical tissues using immunohistochemistry, and detected in 5-FU treated cell lines. The 50% inhibitory concentrations (IC50) values were quantified based on the cell viability at different concentrations of 5-FU with CCK-8 assays. Colony formation and flow cytometry assays were performed to measure the proliferation and apoptosis rates. Gene set enrichment and correlation analyses were conducted to identify the probable mechanism of LOXL2 in TCGA samples. Critical molecules of the Hedgehog signaling pathway and anti-apoptotic BCL2 in protein levels were detected with Western blotting. It concluded that LOXL2 was up-regulated and positively linked to the unfavorable prognosis of CRC patients. The LOXL2 expression increased with the rising 5-FU concentrations, especially at 20 and 40 μM. Elevated LOXL2 promoted the resistance to 5-FU, augmented the proliferation, and inhibited 5-FU-induced apoptosis of CRC cells. LOXL2 activated the Hedgehog signaling pathway by promoting the expression of SMO, GLI1, and GLI2, leading to the upregulation of downstream target gene BCL2 in CRC cells. Moreover, the Hedgehog signaling pathway inhibitor cyclopamine blocked the BCL2 upregulation mediated by LOXL2. This study has demonstrated that LOXL2 can reduce 5-FU sensitivity through the Hedgehog/BCL2 signaling pathway in CRC.
BackgroundIntraoperative radiotherapy (IORT) and whole-breast irradiation (WBI) are both effective radiotherapeutic interventions for early breast cancer patients undergoing breast-conserving surgery; however, an issue on whether which one can entail the better prognosis is still controversial. Our study aimed to investigate the 5-year oncological efficacy of the IORT cohort and the WBI cohort, respectively, and compare the oncological efficacy between the cohorts.Materials and MethodsWe conducted a computerized retrieval to identify English published articles between 2000 and 2021 in the PubMed, the Web of Science, the Cochrane Library, and APA PsycInfo databases. Screening, data extraction, and quality assessment were performed in duplicate.ResultsA total of 38 studies were eligible, with 30,225 analyzed participants. A non-comparative binary meta-analysis was performed to calculate the weighted average 5-year local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) in the two cohorts, respectively. The LRFS, DMFS, and OS (without restriction on the 5-year outcomes) between the two cohorts were further investigated by a comparative binary meta-analysis. The weighted average 5-year LRFS, DMFS, and OS in the IORT cohort were 96.3, 96.6, and 94.1%, respectively, and in the WBI cohort were 98.0, 94.9, and 94.9%, respectively. Our pooled results indicated that the LRFS in the IORT cohort was significantly lower than that in the WBI cohort (pooled odds ratio [OR] = 2.36; 95% confidential interval [CI], 1.66–3.36). Nevertheless, the comparisons of DMFS (pooled OR = 1.00; 95% CI, 0.76–1.31), and OS (pooled OR = 0.95; 95% CI, 0.79–1.14) between the IORT cohort with the WBI cohort were both not statistically significant.ConclusionsDespite the drastically high 5-year oncological efficacy in both cohorts, the LRFS in the IORT cohort is significantly poorer than that in the WBI cohort, and DMFS and OS do not differ between cohorts.
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