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.

Inhibition of tPA-induced hemorrhagic transformation involves adenosine A2b receptor activation after cerebral ischemia.

Tissue plasminogen activator (tPA) is administered after ischemic stroke to dissolve intravascular clots, but its use can lead to hemorrhagic transformation (HT). Therapeutic strategies to reduce hemorrhagic complications of tPA might be of benefit for stroke patients. Adenosine A2b receptor (A2bR) plays pivotal roles in regulating vascular protection in peripheral organs. This study explored whether A2bR agonist BAY 60-6583 reduces hemorrhage risk after tPA usage. Using a rat transient middle cerebral artery occlusion model, we showed that mRNA and protein expression of A2bR increased to a greater extent after ischemia-reperfusion than did expression of the other three adenosine receptors (A1, A2a, and A3). tPA administration reduced A2bR expression in ischemic brain microvessels. Post-treatment with BAY 60-6583 (1mg/kg) at the start of reperfusion reduced lesion volume in the absence or presence of tPA (10mg/kg) and attenuated brain swelling, blood-brain barrier disruption, and tPA-exacerbated HT at 24h. Additionally, BAY 60-6583 mitigated sensorimotor deficits in the presence of tPA. BAY 60-6583 inhibited tPA-enhanced matrix metalloprotease-9 activation, probably through elevation of tissue inhibitor of matrix metalloproteinases-1 expression, and thereby reduced degradation of tight junction proteins. These effects would likely protect cerebrovascular integrity. A2bR agonists as an adjuvant to tPA could be a promising strategy for decreasing the risk of HT during treatment for ischemic stroke.

[Effect of Jiangtang Xiaozhi Tablet on Insulin Resistance KK-AY Transgenic Mice Model of Diabetes Mellitus].

Objective To observe effects of Jiangtang Xiaozhi Tablet (JTXZT) on homeostasis model of assessment for insulin resistance index (HOMA-IR) , insulin sensitivity index ( ISI) , expres- sions of insulin (INS) and insulin receptor (InsR) in pancreas tissues of KK-A(y) transgenic mice model of diabetes mellitus (DM). Methods KK-A(y) transgenic mice were fed with high fat forage to induce hyper- glycemic obese DM model. The C,7ice at same age were used as a normal control group (fed with e- qual volume of sterile water, n =11). Successful modeled 55 mice with DM obesity were divided into 5 groups by random digit table (11 in each group) , including the model group (fed with equal volume of ster- ile water, with no treatment) , the Pioglitazone Hydrochloride Tablet treatment group (8 mg/kg; as a posi- tive control group) , and JTXZT groups [high (10. 0 g crude drugs/kg) , middle (5. 0 g crude drugs/kg) and low dose (2. 5 g crude drugs/kg) ]. All medications were fed by gastrogavage, once per day for 8 succes- sive weeks. All mice were weighed and levels of random blood glucose (RBG) determined after 8 weeks of treatment. Blood was collected from ophthalmic vein. Levels of insulin (INS) , serum total cholesterol (TC) and triglyceride (TG) were detected. HOMA-IR and ISI were calculated. The morphological changes of pancreas tissues were extracted for performed pathological examinations. The expressions of INS and insulin receptor (InsR ) were measured by immunohistochemistry ( IHC ). Expressions of insulin receptorp ßInsRP) and insulin receptor substrate-1 (IRS-1) in pancreas tissues were detected using Western blot. Results Compared with the normal control group, obesity, obviously increased blood glu- cose and blood lipids occurred in each group after modeling (P <0. 01). After 8 weeks of medication mice in the model group had put up body weight (P <0. 01) , blood glucose and blood lipids were kept on quite higher levels. Compared with the model group, body weight, serum levels of TG, INS, and HOMA-IR obvi- ously decreased in each JTXZT group (P <0. 05, P <0. 01). Besides, RBG decreased obviously lower in the high dose JTXZT group (P <0. 01). ISI obviously increased in low and high dose JTXZT groups (P < 0. 05, P <0. 01). Pathological results of HE staining in pancreas showed that atrophied islets with obvious- ly reduced numbers in the model group. They were sparsely distributed with reduced islet density.-Islet cells were compensatively hypertrophy, with degenerated vacuoles. Apoptosis of islet cells could also be seen in the model group, manifested as swollen cytoplasm and paryopyknosis. Islet number was obvious- ly increased in high and middle dose JTXZT groups, with reduced apoptosis and degenerated cells. Re- sults of IHC assay showed, as compared with the normal control group, the grey values of INS and InsR were significantly decreased in the model group (P <0. 01). Compared with the model group, IOD values of INS and InsR (IOD) were significantly increased in each JTXZT group (P <0. 05, P <0. 01). Results from Western blot showed that protein expressions of InsRP ßnd IRS-1 were obviously decreased in the model group, as compared with the normal control group (P <0. 01). Compared with the model group, protein expressions of InsRP ßnd IRS-1 were obviously increased in each JTXZT group (P <0. 01) , but with no statistical difference as compared with the Pioglitazone Hydrochloride Tablet treatment group (P > 0. 05). Conclusions JTXZT had obvious roles in decreasing levels of blood glucose, serum lipids, and improving insulin resistance in KK-Ayt(r) ansgenic mice model with diabetic obesity. Its mechanism might involve in increasing expressions of lnsRp and IRS-1 in pancreas cells, promoting the integration of INS to its receptors, and thereby improving glucose metabolism , lipid metabolism , and IR state.

Grading of Gliomas by Using Monoexponential, Biexponential, and Stretched Exponential Diffusion-weighted MR Imaging and Diffusion Kurtosis MR Imaging.

PURPOSE: To quantitatively compare the potential of various diffusion parameters obtained from monoexponential, biexponential, and stretched exponential diffusion-weighted imaging models and diffusion kurtosis imaging in the grading of gliomas. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all subjects. Both diffusion-weighted imaging and diffusion kurtosis imaging were performed in 69 patients with pathologically proven gliomas by using a 3-T magnetic resonance (MR) imaging unit. An isotropic apparent diffusion coefficient (ADC), true ADC, pseudo-ADC, and perfusion fraction were calculated from diffusion-weighted images by using a biexponential model. A water molecular diffusion heterogeneity index and distributed diffusion coefficient were calculated from diffusion-weighted images by using a stretched exponential model. Mean diffusivity, fractional anisotropy, and mean kurtosis were calculated from diffusion kurtosis images. All values were compared between high-grade and low-grade gliomas by using a Mann-Whitney U test. Receiver operating characteristic and Spearman rank correlation analysis were used for statistical evaluations. RESULTS: ADC, true ADC, perfusion fraction, water molecular diffusion heterogeneity index, distributed diffusion coefficient, and mean diffusivity values were significantly lower in high-grade gliomas than in low-grade gliomas (U = 109, 56, 129, 6, 206, and 229, respectively; P < .05). Pseudo-ADC and mean kurtosis values were significantly higher in high-grade gliomas than in low-grade gliomas (U = 98 and 8, respectively; P < .05). Both water molecular diffusion heterogeneity index (area under the receiver operating characteristic curve [AUC] = 0.993) and mean kurtosis (AUC = 0.991) had significantly greater AUC values than ADC (AUC = 0.866), mean diffusivity (AUC = 0.722), and fractional anisotropy (AUC = 0.500) in the differentiation of low-grade and high-grade gliomas (P < .05). CONCLUSION: Water molecular diffusion heterogeneity index and mean kurtosis values may provide additional information and improve the grading of gliomas compared with conventional diffusion parameters.

Quantitative assessment of amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging with extrapolated semi-solid magnetization transfer reference (EMR) signals: Application to a rat glioma model at 4.7 Tesla.

PURPOSE: To quantify amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) contributions to in vivo chemical exchange saturation transfer MRI signals in tumors. THEORY AND METHODS: Two-pool (free water and semi-solid protons) and four-pool (free water, semi-solid, amide, and upfield NOE-related protons) tissue models combined with the super-Lorentzian lineshape for semi-solid protons were used to fit wide and narrow frequency-offset magnetization-transfer (MT) data, respectively. Extrapolated semi-solid MT signals at 3.5 and -3.5 ppm from water were used as reference signals to quantify APT and NOE, respectively. Six glioma-bearing rats were scanned at 4.7 Tesla. Quantitative APT and NOE signals were compared at three saturation power levels. RESULTS: The observed APT signals were significantly higher in the tumor (center and rim) than in the contralateral normal brain tissue at all saturation powers, and were the major contributor to the APT-weighted image contrast (based on MT asymmetry analysis) between the tumor and the normal brain tissue. The NOE (a positive confounding factor) enhanced this APT-weighted image contrast. The fitted amide pool sizes were significantly larger, while the NOE-related pool sizes were significantly smaller in the tumor than in the normal brain tissue. CONCLUSION: The extrapolated semi-solid magnetization transfer reference provides a relatively accurate approach for quantitatively measuring pure APT and NOE signals.

Applying amide proton transfer-weighted MRI to distinguish pseudoprogression from true progression in malignant gliomas.

PURPOSE: To assess amide proton transfer-weighted (APTW) imaging features in patients with malignant gliomas after chemoradiation and the diagnostic performance of APT imaging for distinguishing true progression from pseudoprogression. MATERIALS AND METHODS: After approval by the Institutional Review Board, 32 patients with clinically suspected tumor progression in the first 3 months after chemoradiation were enrolled and scanned at 3T. Longitudinal routine magnetic resonance imaging (MRI) changes and medical records were assessed to confirm true progression versus pseudoprogression. True progression was defined as lesions progressing on serial imaging over 6 months, and pseudoprogression was defined as lesions stabilizing or regressing without intervention. The APTWmean and APTWmax signals were obtained from three to five regions of interests for each patient and compared between the true progression and pseudoprogression groups. The diagnostic performance was assessed with receiver operating characteristic curve analysis. RESULTS: The true progression was associated with APTW hyperintensity (APTWmean = 2.75% ± 0.42%), while pseudoprogression was associated with APTW isointensity to mild hyperintensity (APTWmean = 1.56% ± 0.42%). The APTW signal intensities were significantly higher in the true progression group (n = 20) than in the pseudoprogression group (P < 0.001; n = 12). The cutoff APTWmean and APTWmax intensity values to distinguish between true progression and pseudoprogression were 2.42% (with a sensitivity of 85.0% and a specificity of 100%) and 2.54% (with a sensitivity of 95.0% and a specificity of 91.7%), respectively. CONCLUSION: The APTW-MRI signal is a valuable imaging biomarker for distinguishing pseudoprogression from true progression in glioma patients. J. Magn. Reson. Imaging 2016;44:456-462.

Simultaneous detection and separation of hyperacute intracerebral hemorrhage and cerebral ischemia using amide proton transfer MRI.

PURPOSE: To explore the capability of amide proton transfer (APT) imaging in the detection of hemorrhagic and ischemic strokes using preclinical rat models. METHODS: The rat intracerebral hemorrhage (ICH) model (n = 10) was induced by injecting bacterial collagenase VII-S into the caudate nucleus, and the permanent ischemic stroke model (n = 10) was induced by using a 4-0 nylon suture to occlude the origin of the middle cerebral artery. APT-weighted (APTw) MRI was acquired on a 4.7T animal imager and quantified using the magnetization transfer-ratio asymmetry at 3.5 ppm from water. RESULTS: There was a consistently high APTw MRI signal in hyperacute ICH during the initial 12 h after injection of collagenase compared with the contralateral brain tissue. When hemorrhagic and ischemic stroke were compared, hyperacute ICH and cerebral ischemia demonstrated opposite APTw MRI contrasts-namely, hyperintense versus hypointense compared with contralateral brain tissue, respectively. There was a stark contrast in APTw signal intensity between these two lesions. CONCLUSION: APT-MRI could accurately detect hyperacute ICH and distinctly differentiate hyperacute ICH from cerebral ischemia, thus opening up the possibility of introducing to the clinic a single MRI scan for the simultaneous visualization and separation of hemorrhagic and ischemic strokes at the hyperacute stage. Magn Reson Med 74:42-50, 2015. © 2014 Wiley Periodicals, Inc.

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.

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.

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.

Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations.

Cell cycle regulation, apoptosis, oxidative stress and inflammation response play critical roles in the development of smoking-induced lung cancer. However, it is still not well known whether their genetic variants are associated with lung cancer susceptibility. In this study, we performed imputation-based association analyses to investigate the influence of common genetic variants in these pathways and their interactions with smoking on lung cancer susceptibility. We first selected 24 042 unvalidated genetic variants in 798 genes from the imputed dataset of the previous lung cancer genome-wide association study in 2331 cases and 3077 controls, and then conducted additional two-stage validations in 4133 cases and 4522 controls. We found a genome-wide significant (P < 5.0 × 10(-8)) association for rs2282987 in CDK6 at 7q21.2 [odds ratio (OR) = 1.18, combined P add = 2.27 × 10(-9)] and a consistent association for rs2706748 in SH3RF1 at 4q32.3 (OR = 1.17, combined P add = 5.10 × 10(-6)). Interaction analyses showed that rs2282987 and rs2706748 interacted with both smoking status (P interaction were 1.04 × 10(-2) and 3.03 × 10(-2), respectively) and smoking history (P interaction were 1.21 × 10(-2) and 5.21 × 10(-2), respectively) to contribute to lung cancer susceptibility in subjects aged 51-60 years. These results further underscore the contribution of genetic variants involved in pathways of cell cycle regulation and apoptosis to lung cancer susceptibility, and highlight gene-environment interactions in lung cancer etiology, especially in subjects aged 51-60 years.

APT-weighted and NOE-weighted image contrasts in glioma with different RF saturation powers based on magnetization transfer ratio asymmetry analyses.

PURPOSE: To investigate the saturation-power dependence of amide proton transfer (APT)-weighted and nuclear Overhauser enhancement-weighted image contrasts in a rat glioma model at 4.7 T. METHODS: The 9L tumor-bearing rats (n = 8) and fresh chicken eggs (n = 4) were scanned on a 4.7-T animal magnetic resonance imaging scanner. Z-spectra over an offset range of ±6 ppm were acquired with different saturation powers, followed by the magnetization transfer-ratio asymmetry analyses around the water resonance. RESULTS: The nuclear Overhauser enhancement signal upfield from the water resonance (-2.5 to -5 ppm) was clearly visible at lower saturation powers (e.g., 0.6 µT) and was larger in the contralateral normal brain tissue than in the tumor. Conversely, the APT effect downfield from the water resonance was maximized at relatively higher saturation powers (e.g., 2.1 µT) and was larger in the tumor than in the contralateral normal brain tissue. The nuclear Overhauser enhancement decreased the APT-weighted image signal, based on the magnetization transfer-ratio asymmetry analysis, but increased the APT-weighted image contrast between the tumor and contralateral normal brain tissue. CONCLUSION: The APT and nuclear Overhauser enhancement image signals in tumor are maximized at different saturation powers. The saturation power of roughly 2 µT is ideal for APT-weighted imaging at clinical B0 field strengths.

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.

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.

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.

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.

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.

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.

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.