Quantitative Proteomic Analysis Identifies MAPK15 as a Potential Regulator of Radioresistance in Nasopharyngeal Carcinoma Cells

Since resistance to radiotherapy remains refractory for the clinical management of nasopharyngeal cancer (NPC), further understanding the mechanisms of radioresistance is necessary in order to develop more effective NPC treatment and improve prognosis. In this study, an integrated quantitative proteomic approach involving tandem mass tag labeling and liquid chromatograph-mass spectrometer was used to identify proteins potentially responsible for the radioresistance of NPC. The differential radiosensitivity in NPC model cells was examined through clonogenic survival assay, CCK-8 viability assay, and BrdU incorporation analysis. Apoptosis of NPC cells after exposure to irradiation was detected using caspase-3 colorimetric assay. Intracellular reactive oxygen species (ROS) was detected by a dichlorofluorescin diacetate fluorescent probe. In total, 5,946 protein groups were identified, among which 5,185 proteins were quantified. KEGG pathway analysis and protein-protein interaction enrichment analysis revealed robust activation of multiple biological processes/pathways in radioresistant CNE2-IR cells. Knockdown of MAPK15, one up-regulated protein kinase in CNE2-IR cells, significantly impaired clonogenic survival, decreased cell viability and increased cell apoptosis following exposure to irradiation, while over-expression of MAPK15 promoted cell survival, induced radioresistance and reduced apoptosis in NPC cell lines CNE1, CNE2, and HONE1. MAPK15 might regulate radioresistance through attenuating ROS accumulation and promoting DNA damage repair after exposure to irradiation in NPC cells. Quantitative proteomic analysis revealed enormous metabolic processes/signaling networks were potentially involved in the radioresistance of NPC cells. MAPK15 might be a novel potential regulator of radioresistance in NPC cells, and targeting MAPK15 might be useful in sensitizing NPC cells to radiotherapy

Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells

Oncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future

First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety results of the randomised, phase III CHANGE-2 trial.

Abstract Background The EXTREME regimen (chemotherapy [CT; cisplatin/carboplatin and 5-fluorouracil]) plus cetuximab is a standard-of-care first-line (1L) treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), as supported by international guidelines. The phase III CHANGE-2 trial assessed the efficacy and safety of a modified CT regimen (with a reduced dose of both components) and cetuximab versus CT for the 1L treatment of Chinese patients with R/M SCCHN. Methods Patients were randomised to receive up to six cycles of CT plus cetuximab followed by cetuximab maintenance until progressive disease or CT alone. The primary end-point was the progression-free survival (PFS) time assessed by the independent review committee (IRC). Results Overall, 243 patients were randomised (164 to CT plus cetuximab; 79 to CT). The hazard ratios for PFS by IRC and overall survival (OS) were 0.57 (95% CI: 0.40–0.80; median: 5.5 versus 4.2 months) and 0.69 (95% CI: 0.50–0.93; median: 11.1 versus 8.9 months), respectively, in favour of CT plus cetuximab. The objective response rates (ORR) by IRC were 50.0% and 26.6% with CT plus cetuximab and CT treatment, respectively. Treatment-emergent adverse events of maximum grade 3 or 4 occurred in 61.3% (CT plus cetuximab) and 48.7% (CT) of patients. Conclusions CHANGE-2 showed an improved median PFS, median OS and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regimen, with no new or unexpected safety findings, thereby confirming CT plus cetuximab as an effective and safe 1L treatment for Chinese patients with R/M SCCHN. Clinical trial registration number NCT02383966

CT-based radiomics for predicting radio-chemotherapy response and overall survival in nonsurgical esophageal carcinoma

BackgroundTo predict treatment response and 2 years overall survival (OS) of radio-chemotherapy in patients with esophageal cancer (EC) by radiomics based on the computed tomography (CT) images.MethodsThis study retrospectively collected 171 nonsurgical EC patients treated with radio-chemotherapy from Jan 2010 to Jan 2019. 80 patients were randomly divided into training (n=64) and validation (n=16) cohorts to predict the radiochemotherapy response. The models predicting treatment response were established by Lasso and logistic regression. A total of 156 patients were allocated into the training cohort (n=110), validation cohort (n=23) and test set (n=23) to predict 2-year OS. The Lasso Cox model and Cox proportional hazards model established the models predicting 2-year OS.ResultsTo predict the radiochemotherapy response, WFK as a radiomics feature, and clinical stages and clinical M stages (cM) as clinical features were selected to construct the clinical-radiomics model, achieving 0.78 and 0.75 AUC (area under the curve) in the training and validation sets, respectively. Furthermore, radiomics features called WFI and WGI combined with clinical features (smoking index, pathological types, cM) were the optimal predictors to predict 2-year OS. The AUC values of the clinical-radiomics model were 0.71 and 0.70 in the training set and validation set, respectively.ConclusionsThis study demonstrated that planning CT-based radiomics showed the predictability of the radiochemotherapy response and 2-year OS in nonsurgical esophageal carcinoma. The predictive results prior to treatment have the potential to assist physicians in choosing the optimal therapeutic strategy to prolong overall survival

MicroRNA-204 modulates colorectal cancer cell sensitivity in response to 5-fluorouracil-based treatment by targeting high mobility group protein A2

MicroRNAs (miRNAs) are a conserved class of ∼22 nucleotide RNAs that playing important roles in various biological processes including chemoresistance. Recently, many studies have revealed that miR-204 is significantly attenuated in colorectal cancer (CRC), suggesting that this miRNA may have a function in CRC. However, whether miR-204 modulates chemosensitivity to 5-fluorouracil (5-Fu) in colorectal cancer is still unclear. In our present study, we discuss this possibility and the potential mechanism exerting this effect. We identified high mobility group protein A2 (HMGA2) as a novel direct target of miR-204 and showed that miR-204 expression was decreased while HMGA2 expression was increased in CRC cell lines. Additionally, both MiR-204 overexpression and HMGA2 inhibition attenuated cell proliferation, whereas forced expression of HMGA2 partly restored the inhibitory effect of miR-204 on HCT116 and SW480 cells. Moreover, the miR-204/HMGA2 axis modulated the resistance of tumor cells to 5-Fu in HCT-116 and SW480 colon cancer cells via activation of the PI3K/AKT pathway. These results demonstrate that the miR-204/HMGA2 axis could play a vital role in the 5-Fu resistance of colon cancer cells. Taken together, our present study elucidated that miR-204 upregulated 5-Fu chemosensitivity via the downregulation of HMGA2 in colorectal cancer and provided significant insight into the mechanism of 5-Fu resistance in colorectal cancer patients. More importantly, our present study suggested that miR-204 has potential as a therapeutic strategy for 5-Fu-resistant colorectal cancer

Emerging role of inositol monophosphatase in cancer

Inositol monophosphatase (IMPase) is an enzyme with two homologs—IMPA1 and IMPA2—that is responsible for dephosphorylating myo-inositol monophosphate to generate myo-inositol. IMPase has been extensively studied in neuropsychiatric diseases and is regarded as a susceptibility gene. Recently, emerging evidence has implied that IMPase is linked to cancer development and progression and correlates with patient survival outcomes. Interestingly, whether it acts as a tumor-promoter or tumor-suppressor is inconsistent among different research studies. In this review, we summarize the latest findings on IMPase in cancer, focusing on exploring the underlying mechanisms for its pro- and anticancer roles. In addition, we discuss the potential methods of IMPase regulation in cancer cells and the possible approaches for IMPase intervention in clinical practice

Integrative Analysis of the Predictive Value of Perilipin Family on Clinical Significance, Prognosis and Immunotherapy of Glioma

Gliomas are common tumors of the central nervous system. The PLINs family is widely involved in the regulation of lipid metabolism and has been associated with the development and invasive metastasis of various malignancies. However, the biological role of the PLINs family in gliomas is still unclear. TIMER and UALCAN were used to assess PLINs mRNA expression in gliomas. “Survminer” and “Survival” were used to evaluate the connection between PLINs expression and glioma patients’ survival. cBioPortal was applied to assess PLINs’ genetic alterations in glioblastoma multiforme (GBM) and low-grade glioma (LGG). The correlation of PLINs expression with tumor immune cells was analyzed by TIMER. The expressions of PLIN1, PLIN4, and PLIN5 were decreased in GBM compared to normal tissues. However, PLIN2 and PLIN3 were significantly increased in GBM. Prognostic analysis showed that LGG patients with high PLIN1 expression had better overall survival (OS), and high expression of PLIN2/3/4/5 was associated with unfavorable OS. We further determined that the expression of PLINs members in gliomas was strongly related to tumor immune cells and immune checkpoint-associated genes. PLINS may be potential biomarkers for regulating the tumor microenvironment and predicting the efficacy of immunotherapy. In addition, we determined that PLIN1 may affect glioma patients’ therapeutic sensitivity to temozolomide. Our results demonstrated the biological significance and clinical values of PLINs in gliomas and provide a basis for future in-depth exploration of the specific mechanisms of each member of PLINs in gliomas

A comprehensive intervention program on the long-term placement of peripherally inserted central venous catheters

Background: Peripherally inserted central venous catheters (PICCs) have been increasingly utilized in treating patients in intensive care. The purpose of this study is to analyze the related complications and to evaluate effect of a comprehensive intervention on long-term PICCs. Materials and Methods: We selected 217 and 243 cases before and after comprehensive intervention respectively from the department of radiotherapy in our hospital. Various possible factors affecting PICCs insertions and maintenance were analyzed. A quality control circle was formed for nursing care. The comprehensive intervention was performed both on catheter insertion and post-PICCs care. Complication rates were compared before and after the intervention. Results: The duration for PICCs was 90 days. In the control group (before intervention), the complications were as follows: Tube feeding difficulties (23.5%), catheter dislodgment (23.5%), infection (17.6%), catheter obstruction (17.6%), puncture failure (5.9%), allergy (5.9%), and pain (5.9%). The incidence of unplanned extubations was 7.8%. The incidence of complications was significantly decreased in the test group (after intervention). Moreover, one episode of catheter obstruction (5.9%) and one episode of allergy (5.9%) were found (P < 0.01) in this study. Conclusion: Comprehensive intervention programs effectively reduce the incidence of complications in long-term PICCs lines

Induced coiling action : exploring the intrinsic defects in five-fold twinned silver nanowires

Growth of polythiophene (PTh) on five-fold twinned Ag nanowires (NWs) is not symmetrical due to preferred etching of their intrinsic defects. This imbalance of polymer formation leads to consistent bending action along the etched NWs, coiling the resulting Ag-PTh nanocomposites into planar spirals. We studied the etching intermediates and also the effects of the surface ligands in order to understand the symmetry-breaking action. The defect-dependent etching chemistry offers a new means to induce motion and a novel perspective in the ordered occurrence of certain defects. We demonstrate that Ag can be deposited back onto the coiled Ag-PTh composite to form metallic spirals

A Study of 358 Cases of Locally Advanced Nasopharyngeal Carcinoma Receiving Intensity-Modulated Radiation Therapy: Improving the Seventh Edition of the American Joint Committee on Cancer T-Staging System

To evaluate the rationality and limitations of the seventh edition of the American Joint Committee on Cancer (the 7th AJCC edition) T-staging system for locally advanced nasopharyngeal carcinoma (NPC). The prognosis of 358 patients with stage T3/T4 NPC treated with intensity-modulated radiotherapy (IMRT) was analyzed with the Kaplan–Meier method or the log-rank test. The 7th AJCC staging system of NPC has some limitations in that the T category is neither the significant factor in OS/LRFS nor the independent prognostic factor in OS/LRFS/DMFS/DFS (P>0.05). After adjustment by anatomic structures, univariate analysis has shown that the adjusted-T category has statistical significance between T3 and T4 for OS (86.4% and 71.3%, P=0.002), LRFS (97% and 90.9%, P=0.048), DMFS (90.9% and 77.2%, P=0.001), and DFS (86.2% and 67.5%, P=0.000), and multivariate analysis has shown that the adjusted-T category is an independent prognostic factor for OS/DMFS/DFS (with the exception of LRFS). Then, GTV-P was taken into consideration. Multivariate analysis showed that these nT categories serve as suitable independent prognostic factors for OS/DMFS/DFS (P<0.001) and LRFS (HR = 3.131; 95% CI, 1.090–8.990; P=0.043). The 7th AJCC staging system has limitations and should be improved by including the modifications suggested, such as anatomic structures and tumor volume adjustment