Final analysis of a phase II trial of neoadjuvant chemoimmunotherapy for locoregionally advanced head and neck squamous cell carcinoma.

OBJECTIVES: Neoadjuvant chemoimmunotherapy has shown promising results for resectable, locoregionally advanced (LA) head and neck squamous cell carcinoma (L/A HNSCC). We published the first phase II trial of neoadjuvant camrelizumab combined with chemotherapy in resectable, L/A HNSCC, demonstrating it was safe and feasible with favorable pathological complete response (pCR). Here, we report the final analysis results for neoadjuvant chemoimmunotherapy in L/A HNSCC (minimum 2.0 years of follow-up). MATERIALS AND METHODS: Three cycles of chemoimmunotherapy were administered before surgery to patients with L/A HNSCC. Two-year disease-free survival (DFS), overall survival (OS) and quality of life (QOL) were reported. RESULTS: The overall two-year DFS and OS rates were 90 % and 100 %, respectively. With a median follow-up of 33.7 months, 9 of 10 (90 %) patients with pCR were alive and disease free. Patients with TNM stage (II/III) or < 20 % of residual viable tumor trended toward improved DFS; hazard ratio (HR), 0.44 [95 % confidence interval (CI), 0.04-5.28] and HR, 0.26 (95 % CI, 0.03-2.36), respectively. All QLQ-C30 functioning and symptom scales other than nausea and vomiting were resolved at 2 years after the completion of radiotherapy. CONCLUSION: Neoadjuvant camrelizumab in combination with chemotherapy provided encouraging clinical outcomes for patients with L/A HNSCC. Further studies with longer follow-up and larger samples are warranted. TRIAL REGISTRATION: Chictr.org.cn, ChiCTR1900025303. Registered Aug 22, 2019. https://www.chictr.org.cn/showproj.html?proj=41380.

Exosomal lncRNA ROR1-AS1 from cancer-associated fibroblasts inhibits ferroptosis of lung cancer cells through the IGF2BP1/SLC7A11 signal axis.

BACKGROUND: Targeting ferroptosis is a potential strategy for cancer treatment. Activated cancer-associated fibroblasts (CAFs) can affect the progression of lung cancer through exosomes. This study investigated the mechanism by which exosomal lncRNA ROR1-AS1 derived from CAFs affects ferroptosis of lung cancer cells. METHODS: CAFs were identified by western blot and immunofluorescence. Exosomes derived from CAFs (CAF-exo) were analyzed by transmission electron microscope, nanoparticle tracking analysis and western blot. The expression levels of ROR1-AS1, IGF2BP1 and SLC7A11 in lung cancer were analyzed by bioinformatics analysis and detected by qPCR and western blot. The lung cancer cells were treated with Erastin and/or CAF-exo, then cell viability was detected by cell counting kit-8, and the ferroptosis-related indicators were detected by corresponding kits. The relationship between IGF2BP1 and ROR1-AS1 or SLC7A11 was determined by RNA pull down and RNA immunoprecipitation, and their effects on cell ferroptosis were confirmed by rescue experiments. Xenotransplantation experiment was used to determine the effect of CAF-exo on tumor growth and ferroptosis in vivo. Immunohistochemistry was used to identify the Ki-67 and 4-HNE expression. RESULTS: ROR1-AS1, IGF2BP1 and SLC7A11 were upregulated in lung cancer and indicated poor prognosis. LncRNA ROR1-AS1 increased the stability of SLC7A11 mRNA by interacting with IGF2BP1. Exosomal ROR1-AS1 from CAFs inhibited ferroptosis of lung cancer cells in vitro and in vivo. The effect of ROR1-AS1 overexpression or IGF2BP1 overexpression on ferroptosis of lung cancer cells was partially reversed by IGF2BP1 silencing or SLC7A11 inhibition. CONCLUSIONS: CAFs secrete exosomal ROR1-AS1 to promote the expression of SLC7A11 by interacting with IGF2BP1, thereby inhibiting ferroptosis of lung cancer cells.

OTUB1 Targets CHK1 for Deubiquitination and Stabilization to Facilitate Lung Cancer Progression and Radioresistance.

PURPOSE: Radioresistance of lung cancer poses a significant challenge when it comes to the treatment of advanced, recurrent, and metastatic cases. Ovarian tumor domain ubiquitin aldehyde binding 1 (OTUB1) is a key member of the deubiquitinase OTU superfamily. This protein is involved in various cellular functions, including cell proliferation, iron death, lipid metabolism, and cytokine secretion as well as immune response processes. However, its specific role and molecular mechanism in lung cancer radioresistance remain to be clarified. METHODS AND MATERIALS: The expression levels of OTUB1 in paired lung cancer tissues were determined by immunohistochemistry. In vitro and in vivo experiments were conducted to investigate the impact of OTUB1 on the growth and proliferation of lung cancer. Coimmunoprecipitation and Western blotting techniques were performed to examine the interaction between OTUB1 and CHK1. The DNA damage response was measured by comet tailing and immunofluorescence staining. KEGG pathways and Gene Ontology terms were analyzed based on RNA sequencing. RESULTS: Our findings reveal a high frequency of OTUB1 overexpression, which is associated with an unfavorable prognosis in patients with lung cancer. Through comprehensive investigations, we demonstrate that OTUB1 depletion impairs the process of DNA damage repair and overcomes radioresistance. In terms of the underlying mechanism, our study uncovers that OTUB1 deubiquitinates and stabilizes CHK1, which enhances CHK1 stability, thereby regulating DNA damage and repair. Additionally, we identify CHK1 as the primary downstream effector responsible for mediating the functional effects exerted by OTUB1 specifically in lung cancer. Importantly, OTUB1 has the potential to be a valuable marker for improving the efficacy of radiation therapy for lung adenocarcinoma. CONCLUSIONS: These findings unveil a novel role for OTUB1 in enhancing radioresistance by deubiquitination and stabilization of the expression of CHK1 in lung cancer and indicate that targeting OTUB1 holds great potential as an effective therapeutic approach for enhancing the efficacy of radiation therapy in lung cancer.

Injectable dexamethasone-loaded peptide hydrogel for therapy of radiation-induced ototoxicity by regulating the mTOR signaling pathway.

Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in clinical settings is limited due to anatomical barriers in the inner ear and pharmacokinetic instability. To address this issue, we developed an injectable hydrogel called RADA32-HRN-dexamethasone (RHD). The RHD hydrogel possesses self-anti-inflammatory properties and can self-assemble into nanofibrous structures, ensuring controlled and sustained release of dexamethasone in the local region. Flow cytometry analysis revealed that the uptake of FITC-conjugated RHD gel by hair cells increased in a time-dependent manner. Compared to free dexamethasone solutions, dexamethasone-loaded RHD gel achieved a longer and more controlled release profile of dexamethasone. Additionally, RHD gel effectively protected against the inflammatory response, reduced excessive reactive oxygen species production, and reversed the decline in mitochondrial membrane potentials induced by ionizing radiation, leading to attenuation of apoptosis and DNA damage. Moreover, RHD gel promoted the recovery of outer hair cells and partially restored auditory function in mice exposed to ionizing radiation. These findings validated the protective effects of RHD gel against radiation-induced ototoxicity in both cell cultures and animal models. Furthermore, RHD gel enhanced the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which was inhibited by ionizing radiation, thereby promoting the survival of hair cells. Importantly, intratympanic injections of RHD gel exhibited excellent biosafety and do not interfere with the anti-tumor effects of radiotherapy. In summary, our study demonstrates the therapeutic potential of injectable dexamethasone-loaded RHD hydrogel for the treatment of radiation-induced hearing loss by regulating the mTOR signaling pathway.

Multi-omics analysis and validation of the tumor microenvironment of hepatocellular carcinoma under RNA modification patterns.

BACKGROUND: Multiple types of RNA modifications are associated with the prognosis of hepatocellular carcinoma (HCC) patients. However, the overall mediating effect of RNA modifications on the tumor microenvironment (TME) and the prognosis of patients with HCC is unclear. METHODS: Thoroughly analyze the TME, biological processes, immune infiltration and patient prognosis based on RNA modification patterns and gene patterns. Construct a prognostic model (RNA modification score, RNAM-S) to predict the overall survival (OS) in HCC patients. Analyze the immune status, cancer stem cell (CSC), mutations and drug sensitivity of HCC patients in both the high and low RNAM-S groups. Verify the expression levels of the four characteristic genes of the prognostic RNAM-S using in vitro cell experiments. RESULTS: Two modification patterns and two gene patterns were identified in this study. Both the high-expression modification pattern and the gene pattern exhibited worse OS. A prognostic RNAM-S model was constructed based on four featured genes (KIF20A, NR1I2, NR2F1 and PLOD2). Cellular experiments suggested significant dysregulation of the expression levels of these four genes. In addition, validation of the RNAM-S model using each data set showed good predictive performance of the model. The two groups of HCC patients (high and low RNAM-S groups) exhibited significant differences in immune status, CSC, mutation and drug sensitivity. CONCLUSION: The findings of the study demonstrate the clinical value of RNA modifications, which provide new insights into the individualized treatment for patients with HCC.

Identification and validation of novel lung adenocarcinoma subtypes and construction of prognostic models: based on cuprotosis-related genes.

Cuprotosis is a novel and unique form of cell death that is of great value in a variety of cancers. However, the prognostic role of cuprotosis-related genes (CRGs) in lung cancer remains undetermined. We compared the expression profile of CRGs in lung adenocarcinoma (LUAD) patients, revealing the genetic alterations and inter-gene correlations of CRGs. Based on 13 CRGs, LUAD patients could be well differentiated into two molecular subgroups, and the differentially expressed genes (DEGs) in these molecular subtypes were identified. Furthermore, 10 cuprotosis pattern-related DEGs with a significant prognostic value were obtained for constructing a prognostic model. Through validation in an external validation set, the prognostic model based on the CRGs-risk score showed the robust and effective predictive ability and served as an independent prognostic indicator for LUAD patients. Therefore, combining the CRGs-risk score with multiple factors such as clinicopathological characteristics, a quantitative nomogram was developed to predict the survival and prognosis of LUAD patients, improving the clinical application value of the CRGs-risk score. In the low CRGs-risk score group, the related immune cell infiltration was increased and the immune function was activated in LUAD patients. This study may add to the knowledge of CRGs in LUAD, partly contribute to evaluating the prognosis of LUAD patients, and provide direction for the development of targeted therapy and immunotherapy.

Molecular characteristics of pediatric nasopharyngeal carcinoma using whole-exome sequencing.

OBJECTIVES: While a number of genetic and epigenetic events contributing to adult nasopharyngeal carcinomas (aNPC) development has been established, the scarcity of pediatric nasopharyngeal carcinoma (pNPC) hinders the understanding of the biology of the disease and rational treatment approach. We aim to identify the molecular characteristics of pNPC. MATERIALS AND METHODS: pNPC primary tumors with paired blood samples were collected and sequenced using whole-exome sequencing. Samples were collected from four tertiary academic medical centers in China. A total of 30 patients (25 male and 5 female) with pathologically confirmed NPC under the age of 20 were enrolled. RESULTS: Several genes such as C9orf84 (20 %), ZFHX4 (16.7 %), ZC3H6 (16.7 %), RBM38 (16.7 %) were frequently mutated in pNPC. Copy number analysis revealed highly recurring gain/amplification of the HLA class II genes at 6p21.32 (63.3 %) and losses of TOLLIP at 11p15.5 (20 %). Recurrent NUTM1 (16.7 %) fusion variants were found for the first time with pNPC. We also investigated germline genomic signatures and showed 8 of 30 (26.7 %) of the pNPC patients carrying germline pathogenic and/or likely pathogenic variants in known cancer-predisposing genes. Multi-dimensional comparison suggested that pNPC might exhibit distinct genomic profile compared to aNPC. In addition, pNPC exhibited significantly elevated level of PD-L1 expression than aNPC (percent of patients with >50 % PD-L1 expression: 92.0 % vs 32.1 %), suggesting high possibility of benefit from immunotherapy. CONCLUSION: Our results provide the first insight into the molecular basis of pNPC, and might offer novel targets and therapeutic approaches such as immunotherapy for this rare disease.

Trends in immune-related adverse events for colorectal cancer: A bibliometric analysis.

Purpose: We used bibliometric methods to assess the global scientific output on the IRAEs for colorectal cancer and to explore the current status and trends in the field over the last three decades. Methods: Studies on immune-related adverse events for colorectal cancer published from 1996 to 2022 were retrieved from the Web of Science. For quantitative and qualitative assessments of publication outputs and author contributions, the R bibliometrix package was used. VOSviewer was used to construct networks based on the co-authorship of countries/institutions/authors, co-citation analysis of journals/references, citation analysis of documents, and co-occurrence of keywords. Results: A total of 237 relevant articles were included in the final analysis. The number of publications has increased significantly over time. The countries and institutions that contributed most to the field were the USA and the University of Texas MD Anderson Cancer Center. Jefferey Schlom was the most productive author, ranking first in cited authors. The most cited document was Topalian et al. in The New England Journal of Medicine (2012). The journals with the highest number of selected articles and citations were The New England Journal of Medicine and the Journal of Clinical Oncology, respectively. Co-occurrence analysis showed that IRAEs for colorectal cancer were associated with immunotherapy, open-label, chemotherapy, nivolumab, and PD-1. Trend analysis showed that immune checkpoint inhibitors, gut-microbiota, inflammatory-bowel disease, and PD-1has been on the rise in recent years to IRAEs for colorectal cancer. Conclusion: Our bibliometric analysis showed that studying IRAEs for colorectal cancer is increasingly a hot topic. The focus of the research had evolved from traditional treatment modalities such as targeted therapy to gut microbiota. Inflammatory bowel disease may be a future research hotspot of IRAEs for colorectal cancer.

m7G-Associated subtypes, tumor microenvironment, and validation of prognostic signature in lung adenocarcinoma.

Background: 7-Methylguanosine (m7G) is an important posttranscriptional modification that regulates gene expression and is involved in tumorigenesis and development. Tumor microenvironment has been proven to be highly involved in tumor progression and prognosis. However, how m7G-associated genes affect the tumor microenvironment of patients with lung adenocarcinoma (LUAD) remains to be further clarified. Methods: The genetic alterations of m7G-associated genes and their associations with the prognosis and tumor microenvironment in LUAD patients were systemically analyzed. An m7G-Riskscore was established and analyzed for its performance in disease prognosis and association with patient response to immunotherapy. Expression of the model genes at the protein level was investigated through ex vivo experiments. A nomogram was finally obtained based on the m7G-Riskscore and several significant clinical pathological features. Results: m7G-Associated genes were obtained from five LUAD datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases, and their expression pattern was determined. Based on the m7G-associated genes, three LUAD clusters were defined. The differentially expressed genes from the three clusters were screened and used to further divide the LUAD patients into two gene clusters. It was demonstrated that the alterations of m7G-associated genes were associated with the clinical pathological features, prognosis, and tumor immune infiltration in LUAD patients. An m7G-Riskscore including CAND1, RRM2, and SLC2A1 was obtained with robust and accurate prognostic performance. WB and cell immunofluorescence also showed significant dysregulation of CAND1, RRM2, and SLC2A1 in LUAD. In addition, a nomogram was established to improve the clinical feasibility of the m7G-Riskscore. Correlation analysis revealed that patients with a lower m7G-Riskscore had higher immune and stromal scores, responded well to chemotherapeutics and multiple targeted drugs, and survived longer. Patients with a higher m7G-Riskscore tended to suffer from a higher tumor mutation burden. Furthermore, the m7G-Riskscore exhibited significant associations with immune cell infiltration and cancer stemness. Conclusion: This study systemically analyzed m7G-associated genes and identified their potential role in tumor microenvironment and prognosis in patients with LUAD. The findings of the present study may help better understand LUAD from the m7G perspective and also provide a new thought toward the prognosis and treatment of LUAD.

Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial.

PURPOSE: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: In this single-center, single-arm, phase 2 trial, patients with resectable stage III-IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety. RESULTS: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%-57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%-88.9%). The median follow-up duration was 16.1 months (range, 8.3-28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%-99.4%). Grade 3 neoadjuvant therapy-related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%). CONCLUSIONS: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.

Nuanxinkang protects against ischemia/reperfusion-induced heart failure through regulating IKKß/IκBα/NF-κB-mediated macrophage polarization.

BACKGROUND: Heart failure (HF) is a leading cause of death worldwide. Nuanxinkang (NXK) is an effective Chinese herbal formula used in treating HF, but its underlying potential mechanisms have not been fully elucidated. PURPOSE: To explore the protective activities of NXK in ischemia/reperfusion (IR)-induced HF through modulating the ratio of proinflammatory (M1) and anti-inflammatory (M2) macrophage populations and leading to the alleviation of inflammation. MATERIALS AND METHODS: In vivo, mice were subjected to myocardial IR to generate HF mouse models. Mice in the NXK group were treated with NXK for 28 days. Cardiac function was detected by echocardiography. Major lesions on mouse hearts were determined by hematoxylin-eosin (HE) staining, Masson staining, and TUNEL staining. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay (ELISA) and qPCR examination. Flow cytometric analyses and qPCR examination were utilized for monitoring the temporal dynamics of macrophage infiltration following IR. In vitro, two polarized models were established by stimulating RAW264.7 cells with 200 ng/ml lipopolysaccharide (LPS) or 20 ng/ml interleukin-4 (IL-4). The RAW264.7 cells with nuclear factor-κB (NF-κB) overexpression was generated by transient transfection of NF-κB plasmids, and NXK intervention was conducted on this cell model to further clarify the involvement of NF-κB signaling in the NXK-mediated HF process. RESULTS: In the present study, NXK was found to significantly contribute the cardiac function and ameliorate cardiac fibrosis and apoptosis after myocardial IR injury in vivo, which may be partially due to a decrease in inflammation. We therefore hypothesized that NXK reduced inflammatory damage by modulating subtypes of macrophages. And the results demonstrated that the percentage of proinflammatory macrophages infiltrated in the post-IR period was reduced with NXK treatment, and thereby blunting the wave of proinflammatory response and shifting the peak of the anti-inflammatory macrophage-mediated wound healing process towards an earlier time point. The further investigation showed that macrophage polarization was mediated by NXK through inhibiting the phosphorylation and the nuclear translocation of NF-κB. Besides, the phosphorylated IKKß and IκBα, upstream mediators of the NF-κB pathway, also decreased by NXK. Moreover, the overexpression of NF-κB partially reversed the NXK-induced favorable activities; and successfully compensated the suppressive effect on inflammation and the phosphorylation of NF-κB. CONCLUSION: In conclude, our results demonstrated that NXK induced the cardioprotective effects against IR injury through a regulatory axis of IKKß/IκBα/NF-κB-mediated macrophage polarization. The information gained from this study provide a possible natural strategy for anti-inflammatory treatment of HF.

A Novel Prognostic Model Based on Seven Necroptosis-Related miRNAs for Predicting the Overall Survival of Patients with Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related deaths worldwide. This study is aimed at constructing a risk scoring model based on necroptosis-related miRNAs to predict prognosis of LUAD. Expression profile of miRNA in LUAD was downloaded from The Cancer Genome Atlas (TCGA) database. We screened the differentially expressed necroptosis-related miRNAs between LUAD patients and normal samples, thus constructed a seven miRNA-based risk stratification on the basis of the TGCA cohort. This risk stratification was prove to be effective in predicting the overall survival (OS) of patients with LUAD. Furthermore, we constructed a nomogram model based on the combination of risk characteristics and clinicopathological features, which was also prove to be accurate and efficient in predicting OS of LUAD patients. Functional enrichment analyses on the targeted genes of these miRNAs with prognostic value were carried out. Results indicated that these targeted genes were closely related to the development and metastasis of tumors. In summary, our research has developed a prognostic model based on the expression of miRNAs related to necroptosis. This model might be used to predict the prognosis of LUAD accurately, which might be helpful in improving treatment efficacy of LUAD.

A Bayesian network meta-analysis of the primary definitive therapies for locoregionally advanced nasopharyngeal carcinoma: IC+CCRT, CCRT+AC, and CCRT alone.

BACKGROUND: The major aim of this Bayesian network analysis was to determine the optimal treatment strategy for locoregionally advanced nasopharyngeal carcinoma (LANPC). METHOD: We systematically searched databases and extracted data from randomized clinical trials involving LANPC patients randomly assigned to receive induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT), CCRT followed by adjuvant chemotherapy (CCRT+AC), or CCRT. RESULTS: In the network analysis, IC+CCRT was significantly better than CCRT alone for 5-year FFS (odds ratio [OR]: 1.63, 95% credible interval [CrI] 1.16-2.29), DMFS (OR: 1.56, 95% CrI 1.08-2.22), and LFRS (OR: 1.62, 95% CrI 1.02-2.59), but not OS (OR: 1.35, 95% CrI 0.92-2.00). Rank probabilities showed that IC+CCRT was ranked the best followed by CCRT+AC and CCRT for all 5-year outcomes. Although compared to IC+CCRT and CCRT, CCRT+AC did not significantly improve survival but had the highest 5-year survival rates. CONCLUSIONS: IC+CCRT could be recommended as a front-preferred primary definitive therapy for patients with LANPC.

Tumor factors associated with in-field failure for nasopharyngeal carcinoma after intensity-modulated radiotherapy.

BACKGROUND: To identify the tumor factors of in-field failure for nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. METHODS: Patterns of recurrence were classified as in-field, marginal, and out-field failures. Multivariate analyses with the Cox proportional hazards model were used to identify tumor-related factors of in-field failure. RESULTS: A total of 1039 patients with NPC received IMRT from 2012 to 2019 and 75 developed recurrences, with 88.0% (66/75) considered as having in-field failures. Multivariate analysis showed that pretreatment gross tumor volume of nasopharynx ≥68.8 mL and histopathological type of nonkeratinizing differentiated carcinoma (NKDC) were the independent tumor factors of in-field local failure, while gross tumor volume of involved lymph nodes ≥19.9 mL and cervical nodal necrosis (CNN) were associated with in-field regional failure (all p < 0.05). CONCLUSIONS: In-field failure was the major pattern of recurrence in patients with NPC. Large tumor volume, NKDC, and CNN were the tumor factors associated with in-field failure.

Prognostic value of EGFR and p-EGFR in nasopharyngeal carcinoma: A systematic review and meta-analysis.

PURPOSE: To evaluate the prognostic effect and clinical significance of epidermal growth factor receptor and its phosphorlated form (EGFR/p-EGFR) in nasopharyngeal carcinoma. METHODS: A systematic review and meta-analysis was designed. We visited PubMed, Embase, China National Knowledge Infrastructure Database, Database of Chinese sci-tech periodicals, WanFang Database, and China Biology Medicine disc to search for Chinese and English publications of prospective studies and retrospective studies investigating the association of EGFR/p-EGFR and nasopharyngeal carcinoma prognosis from inception to April 2021. The inclusion criteria were that the samples should be pathologically confirmed as nasopharyngeal carcinoma and the expression of EGFR/p-EGFR should be detected via immunohistochemistry; the study should analyze the prognostic significance of EGFR/p-EGFR in nasopharyngeal carcinoma; hazard ratio (HR) and 95% confidence interval (CI) should be reported in the study or could be derived from survival curves; and the outcomes of the study should include overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). RESULTS: A total of 18 studies evaluating 1451 samples were included. For studies that reported OS as an outcome, EGFR overexpression indicated worse OS of nasopharyngeal carcinoma patients. The heterogeneity between studies was high (I2 = 91%, P < .01), and a random-effect model was used to combine the effect size (HR = 1.71, 95% CI [1.21, 2.41], P < .01). Further sensitivity analysis and prespecified subgroup analysis were performed to detect the source of heterogeneity, and the results showed that the heterogeneity could not be eliminated. Publication bias assessed by funnel plots and Begg test and Egger test was low (Begg test: P = .846 and Egger test: P = .074). p-EGFR was not correlated with the OS of nasopharyngeal carcinoma patients (HR = 1.01, 95% CI [0.88, 1.15], P = .92). For studies that reported DFS, EGFR overexpression was associated with worse DFS in patients with nasopharyngeal carcinoma (HR = 2.53, 95% CI [1.84, 3.47], P < .01). For studies that reported PFS, EGFR overexpression was not correlated with the PFS of nasopharyngeal carcinoma patients (HR = 1.86, 95% CI [0.90, 3.82], P = .09). For studies that reported DMFS, EGFR overexpression was not correlated with the DMFS of nasopharyngeal carcinoma patients, and high heterogeneity between studies was detected (I2 = 97%, P < .01). A random-effect model was used to combine the effect size (HR = 1.80, 95% CI [0.56, 5.76], P = .32). A sensitivity analysis was conducted. Publication bias was detected to be low (Begg test: P = .817 and Egger test: P = .954). There was no correlation between p-EGFR overexpression and DMFS in patients with nasopharyngeal carcinoma (HR = 1.20, 95% CI [0.95, 1.52], P = .12). CONCLUSION: In nasopharyngeal carcinoma patients, EGFR overexpression could be used as a biomarker that predicts poor OS and DFS, but not a prognostic biomarker for PFS and DMFS. The overexpression of p-EGFR was not shown to be associated with the prognosis of nasopharyngeal carcinoma patients and could not be used as a prognostic biomarker. ETHICS AND DISSEMINATION: This study was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), and reported as stated by the Preferred Reporting Items for Systematic reviews and Meta-Analyses. Neither ethical approval nor informed consent was required since this study was conducted based on previous publications. INPLASY REGISTRATION NUMBER: INPLASY 202150010.

Identification of Cuproptosis-Related Subtypes in Lung Cancer, Characterization of Tumor Microenvironment Infiltration, and Establishment of a Prognostic Model.

Cuproptosis, a recently found kind of programmed cell death, has been linked to tumor development, prognosis, and therapeutic response. The roles of cuproptosis-related genes (CRG) in the tumor microenvironment (TME) are, nevertheless, unknown. We evaluated alterations in CRG and assessed the related expression patterns in 1445 lung cancer (LC) samples from three separate datasets, analyzing genetic, and transcriptional domains. We discovered two separate molecular subtypes of CRG and discovered that various subtypes of CRG were connected with patient clinical features and prognosis. Furthermore, we discovered connections between distinct CRG subtypes and TME cell infiltration features. The CRG_score was then developed and validated for predicting overall survival (OS). Following that, we investigated the relationship between CRG_score and the cancer stem cell (CSC) index and chemotherapeutic treatment sensitivity. In addition, we created a very accurate nomogram to increase the clinical usefulness of CRG_score. The potential roles of CRG in the tumor-immune-microenvironment, clinical characteristics, and prognosis in LC are demonstrated by our multiplex study. These findings expand our understanding of CRG in LC and may open up new options for assessing LC patients' prognosis and generating more effective immunotherapeutic treatments.

[Rule of acupoint selection for cancer pain based on association rule and entropy clustering].

OBJECTIVE: To analyze the rule of acupoint selection for cancer pain based on data mining. METHODS: The published literature regarding acupuncture for cancer pain in the recent 10 years was searched in PubMed, CNKI, VIP and Wanfang database. The acupoint selection was summarized and analyzed by TCMISS V2.5. RESULTS: Totally 68 literature was collected and 73 acupoint prescriptions were included, involving 117 acupoints. These acupoints were mainly in bladder meridian, stomach meridian, liver meridian and spleen meridian. Among them, 40 acupoints used more than 4 times were identified, and the top three acupoints were Zusanli (ST 36, 65 times), Neiguan (PC 6, 55 times) and Taichong (LR 3, 50 times). A total of 68 acupoint combinations used more than 19 times were identified, and the top three acupoint combinations were Zusanli (ST 36)-Neiguan (PC 6), Taichong (LR 3)-Zusanli (ST 36) and Zusanli (ST 36)-Sanyinjiao (SP 6). There were 103 acupoint combinations with strong association; based on the entropy clustering algorithm, 20 new acupoint combinations and 10 new acupoint prescriptions were obtained. CONCLUSION: The main meridians for cancer pain are bladder meridian, stomach meridian, liver meridian and spleen meridian, with Zusanli (ST 36), Neiguan (PC 6), Taichong (LR 3), Hegu (LI 4), Sanyinjiao (SP 6) and ashi points as core acupoints, and regulating spleen-stomach and treating qi-blood are the main principles.

Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC.

PURPOSE: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non-small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. EXPERIMENTAL DESIGN: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCH mut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. RESULTS: Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALK WT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46-0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32-0.96; P = 0.035). Del-NOTCH mut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCH mut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCH mut. CONCLUSIONS: This work distinguishes del-NOTCH mut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

Long non-coding RNA ZNFX1-AS1 promotes the tumor progression and metastasis of colorectal cancer by acting as a competing endogenous RNA of miR-144 to regulate EZH2 expression.

Mounting evidences indicated that long non-coding RNA is dysregulated and involved in the pathology of tumors. However, the role of lncRNAs in colorectal cancer (CRC) progression is not fully determined. Differentially expressed lncRNA profile in CRC was conducted by lncRNA microarray in 15 pairs of CRC tissues and adjacent normal tissues, and validated by real-time PCR analysis in another 106 pairs of tissues. The biological effect of lncRNA ZNFX1-AS1 was evaluated by in vitro and in vivo assays. The regulation between lncRNA ZNFX1-AS1 and miR-144 was evaluated by a series of experiments. We found that lncRNA ZNFX1-AS1 expression was significantly upregulated in CRC tissues and cell lines, and the expression of lncRNA ZNFX1-AS1 was associated with aggressive tumor phenotype and poor prognosis in CRC. Functionally, knockdown of lncRNA ZNFX1-AS1 inhibited cell proliferation, invasion, in vitro and tumorigenesis and metastasis in vivo. Further investigation demonstrated that lncRNA ZNFX1-AS1 functioned as a competing endogenous RNA (ceRNA) for miR-144, thereby leading to the depression of its endogenous target gene Polycomb group protein enhancer of zeste homolog 2 (EZH2). We found that lncRNA ZNFX1-AS1 is significantly upregulated in CRC, and the newly identified lncRNA ZNFX1-AS1-miR-144-EZH2 axis is involved in the regulation of CRC progression, which might be used as potential therapeutic targets for CRC patients.

Application of metabolomics by UHPLC-MS/MS in diagnostics and biomarker discovery of non-small cell lung cancer.

BACKGROUND: Targeted metabolomics was utilized in case studies of non-small cell lung cancer (NSCLC) to develop and test metabolite classifiers in serum as potential biomarkers for new lung cancer diagnostic strategies, cancer staging, and subtype determination in the Chinese population. METHODS: A total of 77 samples, including 45 NSCLC patients from stage I to IV, and 32 healthy controls were included in this study. After serum extraction, metabolic assays based on a wide range of targeted metabolome technologies and the UPLC-MS-MS detection platform were performed to detect metabolites in them. Custom database and multivariate statistical analysis were utilized to evaluate the difference of metabolome between different arms. RESULTS: A total of 296 metabolites were detected in all samples, of which 81 were found differentially expressed among lung cancer patients and controls. While the principal component analysis indicated that the metabolome analysis is clearly powerful in differentiating lung cancer patients from normal controls, no significant differences in the serum metabolites between different lung cancer stages or between adenocarcinoma and squamous cell carcinoma were observed. CONCLUSIONS: This study showed the power of the novel UPLC-MS/MS platform in serum metabolic profiling for the detection of NSCLC, which might provide new potential tumor biomarkers and can accelerate the development of new diagnostic strategies in NSCLC.