bluuebunny/crossref_metadata_2025 huggingface dataset:
Supply Chain Optimization under Risk and Uncertainty using Nondominated Sorting Genetic Algorithm II for Automobile Industry
Authors: Bahari Arman , Nouri Sattar , Moody Behnoosh
Published: April 2023

In recent decades, the use of supply chain management is essential for developing new technologies and setting the ground in expanding major global markets to integrate suppliers, manufacturers, warehouses, and stores effectively. In addition, the growing competition in the modern business environment has created an increasing trend of new products and improved product quality for attracting more consumers. However, an increase in the related costs and uncertainty in these innovations requires the development of algorithms to solve optimization problems. Therefore, this study is aimed to implement a multi-product supply chain including raw material suppliers, factories, distributors, and customers to maximize the quality and minimize costs. To this aim, supplier quality, distribution centers, and manufacturing products were considered for the quality model, while warehousing costs, product production, transportation, defective raw materials, and the like were regarded for the cost model. Then, the NSGAII algorithm was used for solving the created optimization problem, and accordingly, the optimal Pareto points were calculated. Based on the results, the proposed model can give the manufacturer the ability to decide on a multi-product and multi-time supply chain by involving cost and quality variables. Thus, the owner can manage the supply chain of the factory effectively.
An IoT-Fuzzy-Based Jamming Detection and Recovery System in Wireless Video Surveillance System
Authors: Jasim Mohammed A. , Atia Tayseer S.
Published: April 2023

Wireless video surveillance system is one of the cyber-physical security systems kinds, which transmits the signal of IP cameras through a wireless medium using a radio band. WVSSs are widely deployed with large systems for use in strategic places such as city centers, public transportation, public roads, airports, and play a significant role in critical infrastructure protection. WVSSs are vulnerable to jamming attacks creating an unwanted denial of service. Hence, it is essential to secure this system from jamming attacks. In this paper, three models of IoT-fuzzy inference system-based jamming detection system are proposed for detecting and countermeasure the presence of jamming by computing two jamming detection metrics; PDR and PLR, and based on the result, the system countermeasures this attack by storing the video feed locally in the subsystem nodes. FIS models are based on Mamdani, Tsukamoto, and Sugeno fuzzy logic which optimizes the jamming detection metrics for detecting the jamming attack. The efficiency of these proposed models is compared in detecting jamming signals. The experimental results show that the proposed Tsukamoto model detects jamming attacks with high accuracy and efficiency. Finally, the proposed IoT-Tsukamoto-based model was compared with the existing systems and proved to be superior to them in terms of central processing complexity, accuracy, and countermeasure for this attack.
Fake Colorized Image Detection Based on Special Image Representation and Transfer Learning
Authors: Salman Khalid A. , Shaker Khalid , Al-Janabi Sufyan
Published: April 2023

Nowadays, images have become one of the most popular forms of communication as image editing tools have evolved. Image manipulation, particularly image colorization, has become easier, making it harder to differentiate between fake colorized images and actual images. Furthermore, the RGB space is no longer considered to be the best option for color-based detection techniques due to the high correlation between channels and its blending of luminance and chrominance information. This paper proposes a new approach for fake colorized image detection based on a novel image representation created by combining color information from three separate color spaces (HSV, Lab, and Ycbcr) and selecting the most different channels from each color space to reconstruct the image. Features from the proposed image representation are extracted based on transfer learning using the pre-trained CNNs ResNet50 model. The Support Vector Machine (SVM) approach has been used for classification purposes due to its high ability for generalization. Our experiments indicate that our proposed models outperform other state-of-the-art fake colorized image detection methods in several aspects.
Chromium-Benzenedicarboxylates Metal Organic Framework for Supersensitive and Selective Electrochemical Sensor of Toxic Cd2+, Pb2+, and Hg2+ Metal Ions: Study of their Interactive Mechanism
Authors: Deore Kamlesh B. , Patil Shubham S. , Narwade Vijaykiran N. , Takte Mahesh A. , Khune Abhaysinh S. , Mohammed Hamed Y. , Farea Maamon A. , Sayyad Pasha W. , Tsai Meng-Lin , Shirsat Mahendra D.
Published: April 2023

Voltammetric determination of toxic Cd2+, Pb2+, and Hg2+ metal ions using Cr-BDC/GCE (chromium-benzenedicarboxylates/ Glassy Carbon Electrode) electrochemical sensor has been investigated. Cr-BDC (chromium-benzenedicarboxylate ) metal–organic framework was synthesized by using the facile hydrothermal technique and its efficacy investigated using P-XRD, FTIR, RAMAN, AFM, FE-SEM, and BET, while the electrochemical performance was investigated by CV and EIS technique. The determination capability of Cr-BDC/GCE as an electrochemical sensor has been investigated by DPASV technique. Effective Voltammetric parameters such as pH of buffer solution, pre-accumulation potential, and pre-accumulation time have been optimized to enhance the sensitivity, selectivity, LOD, repeatability, reproducibility, and stability of the sensor. The proposed Cr-BDC/GCE electrochemical sensor exhibits a sensitivity of 16.55, 3.45, and 3.33 μA M−1 and LOD of 0.186, 0.116, and 0.124 nM for Cd2+, Pb2+ and Hg2+ ions, respectively. Moreover, the sensor exhibited good selectivity, reproducibility, repeatability and stability. The sensor also exhibited good recovery and low RSD values for actual tap water samples. Interaction mechanism of Heavy Metal Ions with the Cr-BDC/GCE evidenced by CV and FTIR confirms the surface adsorption-controlled reaction. These findings suggest that the Cr-BDC/GCE platform is well-suited to serve as a next-generation electrochemical sensor for detecting alcohol, ketone, hydrocarbons, medicines, etc.
Supplementary Table S6 from The Intersectionality between Race, Ethnicity, and Residential-Level Socioeconomic Status in Disparities of Head and Neck Cancer Outcomes: A SEER Study
Authors: Karanth Shama D. , Akinyemiju Tomi , Walker Courtney J. , Yang Danting , Migliorati Cesar A. , Yoon Hyung-Suk , Hong Young-Rock , Washington Caretia J. , Lattimore Chayil , Fredenburg Kristianna M. , Braithwaite Dejana
Published: April 2023

Table S6a shows the Cox proportional hazards model for laryngeal cancer, stratified by race/ethnicity and socioeconomic status. Table S6b shows the Cox proportional hazards model for sinonasal cancers, stratified by race/ethnicity and socioeconomic status.
Supplementary Table S3 from The Intersectionality between Race, Ethnicity, and Residential-Level Socioeconomic Status in Disparities of Head and Neck Cancer Outcomes: A SEER Study
Authors: Karanth Shama D. , Akinyemiju Tomi , Walker Courtney J. , Yang Danting , Migliorati Cesar A. , Yoon Hyung-Suk , Hong Young-Rock , Washington Caretia J. , Lattimore Chayil , Fredenburg Kristianna M. , Braithwaite Dejana
Published: April 2023

Table S3 shows demographic and clinical characteristics of patients with primary head and neck cancer by socioeconomic status.
Supplementary Table 3 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma
Authors: Wang Chen , Block Matthew S. , Cunningham Julie M. , Sherman Mark E. , McCauley Bryan M. , Armasu Sebastian M. , Vierkant Robert A. , Traficante Nadia , Talhouk Aline , Ramus Susan J. , Pejovic Nadja , Köbel Martin , Jorgensen Brooke D. , Garsed Dale W. , Fereday Sian , Doherty Jennifer A. , Ariyaratne Dinuka , Anglesio Michael S. , Widschwendter Martin , Pejovic Tanja , Bosquet Jesus Gonzalez , Bowtell David D. , Winham Stacey J. , Goode Ellen L.
Published: April 2023

Supplementary Table 3: Differential Methylation Analysis for Mayo Training and Testing Sets for all QC-passed CpG loci from 450k
Supplementary Table 2 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma
Authors: Wang Chen , Block Matthew S. , Cunningham Julie M. , Sherman Mark E. , McCauley Bryan M. , Armasu Sebastian M. , Vierkant Robert A. , Traficante Nadia , Talhouk Aline , Ramus Susan J. , Pejovic Nadja , Köbel Martin , Jorgensen Brooke D. , Garsed Dale W. , Fereday Sian , Doherty Jennifer A. , Ariyaratne Dinuka , Anglesio Michael S. , Widschwendter Martin , Pejovic Tanja , Bosquet Jesus Gonzalez , Bowtell David D. , Winham Stacey J. , Goode Ellen L.
Published: April 2023

Supplementary Table 2: CpGs That Defined Previously Reported Methylation Subtypes Using a Semi-Supervised Clustering Approach
Supplementary Methods 1 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma
Authors: Wang Chen , Block Matthew S. , Cunningham Julie M. , Sherman Mark E. , McCauley Bryan M. , Armasu Sebastian M. , Vierkant Robert A. , Traficante Nadia , Talhouk Aline , Ramus Susan J. , Pejovic Nadja , Köbel Martin , Jorgensen Brooke D. , Garsed Dale W. , Fereday Sian , Doherty Jennifer A. , Ariyaratne Dinuka , Anglesio Michael S. , Widschwendter Martin , Pejovic Tanja , Bosquet Jesus Gonzalez , Bowtell David D. , Winham Stacey J. , Goode Ellen L.
Published: April 2023

Supplementary Methods 1: The original 60 CpG loci defining methylation-based subtypes, and the approximation method for methylation signature
Supplementary Figure 4 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma
Authors: Wang Chen , Block Matthew S. , Cunningham Julie M. , Sherman Mark E. , McCauley Bryan M. , Armasu Sebastian M. , Vierkant Robert A. , Traficante Nadia , Talhouk Aline , Ramus Susan J. , Pejovic Nadja , Köbel Martin , Jorgensen Brooke D. , Garsed Dale W. , Fereday Sian , Doherty Jennifer A. , Ariyaratne Dinuka , Anglesio Michael S. , Widschwendter Martin , Pejovic Tanja , Bosquet Jesus Gonzalez , Bowtell David D. , Winham Stacey J. , Goode Ellen L.
Published: April 2023

Supplementary Figure 4: Correlations between Methylation at CpG Sites and TAP1 mRNA Expression
Supplementary Table S3 from Comparative Microbiomics Analysis of Antimicrobial Antibody Response between Patients with Lung Cancer and Control Subjects with Benign Pulmonary Nodules
Authors: Shome Mahasish , Gao Weimin , Engelbrektson Anna , Song Lusheng , Williams Stacy , Murugan Vel , Park Jin G. , Chung Yunro , LaBaer Joshua , Qiu Ji
Published: April 2023

Supplementary Table S3 from Comparative Microbiomics Analysis of Antimicrobial Antibody Response between Patients with Lung Cancer and Control Subjects with Benign Pulmonary Nodules
Supplementary Table S1 from Comparative Microbiomics Analysis of Antimicrobial Antibody Response between Patients with Lung Cancer and Control Subjects with Benign Pulmonary Nodules
Authors: Shome Mahasish , Gao Weimin , Engelbrektson Anna , Song Lusheng , Williams Stacy , Murugan Vel , Park Jin G. , Chung Yunro , LaBaer Joshua , Qiu Ji
Published: April 2023

Supplementary Table S1 from Comparative Microbiomics Analysis of Antimicrobial Antibody Response between Patients with Lung Cancer and Control Subjects with Benign Pulmonary Nodules
Supplementary Table 4 from Risk of Renal or Urinary Related Hospitalization in Survivors of Childhood Cancer: Results from the French Childhood Cancer Survivor Study
Authors: Mansouri Imene , Schwartz Boris , Vu-Bezin Giao , Bejarano-Quisoboni Daniel , Fresneau Brice , El-Fayech Chiraz , Dufour Christelle , Bolle Stéphanie , Surun Aurore , Orbach Daniel , Allodji Rodrigue S. , Diallo Ibrahima , Demoor-Goldschmidt Charlotte , de Vathaire Florent , Haddy Nadia
Published: April 2023

Supplementary Table 4 shows the observed and expected numbers, standardised hospitalisation ratios and absolute excess risks of urinary hospitalisations.
Supplementary Table 2 from Risk of Renal or Urinary Related Hospitalization in Survivors of Childhood Cancer: Results from the French Childhood Cancer Survivor Study
Authors: Mansouri Imene , Schwartz Boris , Vu-Bezin Giao , Bejarano-Quisoboni Daniel , Fresneau Brice , El-Fayech Chiraz , Dufour Christelle , Bolle Stéphanie , Surun Aurore , Orbach Daniel , Allodji Rodrigue S. , Diallo Ibrahima , Demoor-Goldschmidt Charlotte , de Vathaire Florent , Haddy Nadia
Published: April 2023

Supplementary Table 2 shows the estimated relative risks from multivariable analyses, with and without cardiac pathologies adjustment.
Table S9 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Shared hypomethylated loci with (P < 0.01) in solid breast tissue and breast milk parity
Table S8 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Shared hypermethylated loci (P < 0.01) in solid breast tissue and breast milk with parity
Table S7 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Shared hypomethylated loci (P < 0.01) in solid breast tissue and breast milk with increasing BMI
Table S5 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Differentially methylated CpG loci (FDR < 0.05) in breast milk with increasing maternal pre-pregnancy BMIpre-pregnancy BMI
Table S4 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Shared hypomethylated loci (P < 0.01) in solid breast tissue and breast milk with family history of disease
Table S3 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Shared hypermethylated loci (P < 0.01) in solid breast tissue and breast milk with family history of disease
Table S10 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Shared hypermethylated loci (P < 0.01) in solid breast tissue and breast milk with increasing age
Figure S9 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Correlation between subject BMI (kg/m2) and estimated relative proportions of cells in breast milk (n = 48). Component cell types include epithelial cells, endothelial cells, fibroblasts, adipocytes, B cells, CD4+ T cells, CD8+ T cells, monocytes, neutrophils, and NK cells.
Figure S8 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Correlation between subject age (years) and estimated relative proportions of cells in breast milk (n = 48). Component cell types include epithelial cells, endothelial cells, fibroblasts, adipocytes, B cells, CD4+ T cells, CD8+ T cells, monocytes, neutrophils, and NK cells.
Figure S6 from Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C.
Published: April 2023

Distribution of the estimated relative proportion of each component cell type in (A) solid breast tissue (n = 95) and (B) breast milk (n = 48) by subject parity. Component cell types include epithelial cells, endothelial cells, fibroblasts, adipocytes, B cells, CD4+ T cells, CD8+ T cells, monocytes, neutrophils, and NK cells. Bonferroni-corrected P values shown from two sample t-tests.
Supplementary Table S3 from Regular Glucosamine Use May Have Different Roles in the Risk of Site-Specific Cancers: Findings from a Large Prospective Cohort
Authors: Li Fu-Xiao , Zhao Hou-Yu , Lin Teng-Fei , Jiang Yi-Wen , Liu Di , Wei Chang , Zhao Zi-Yi , Yang Zu-Yao , Sha Feng , Yang Zhi-Rong , Tang Jin-Ling
Published: April 2023

Supplementary Table S3 shows baseline characteristics of all study participants and those included in the main analysis.
Supplementary Figure S9 from Regular Glucosamine Use May Have Different Roles in the Risk of Site-Specific Cancers: Findings from a Large Prospective Cohort
Authors: Li Fu-Xiao , Zhao Hou-Yu , Lin Teng-Fei , Jiang Yi-Wen , Liu Di , Wei Chang , Zhao Zi-Yi , Yang Zu-Yao , Sha Feng , Yang Zhi-Rong , Tang Jin-Ling
Published: April 2023

Supplementary Figure S9 shows subgroup analyses for the association between glucosamine use and incidence of ovary cancer in female participants.
Supplementary Figure S3 from Regular Glucosamine Use May Have Different Roles in the Risk of Site-Specific Cancers: Findings from a Large Prospective Cohort
Authors: Li Fu-Xiao , Zhao Hou-Yu , Lin Teng-Fei , Jiang Yi-Wen , Liu Di , Wei Chang , Zhao Zi-Yi , Yang Zu-Yao , Sha Feng , Yang Zhi-Rong , Tang Jin-Ling
Published: April 2023

Supplementary Figure S3 shows subgroup analyses for the association between glucosamine use and incidence of brain cancer.
Supplementary Figure S15 from Regular Glucosamine Use May Have Different Roles in the Risk of Site-Specific Cancers: Findings from a Large Prospective Cohort
Authors: Li Fu-Xiao , Zhao Hou-Yu , Lin Teng-Fei , Jiang Yi-Wen , Liu Di , Wei Chang , Zhao Zi-Yi , Yang Zu-Yao , Sha Feng , Yang Zhi-Rong , Tang Jin-Ling
Published: April 2023

Supplementary Figure S15 shows subgroup analyses for the association between glucosamine use and incidence of other male cancer.
Data from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma
Authors: Wang Chen , Block Matthew S. , Cunningham Julie M. , Sherman Mark E. , McCauley Bryan M. , Armasu Sebastian M. , Vierkant Robert A. , Traficante Nadia , Talhouk Aline , Ramus Susan J. , Pejovic Nadja , Köbel Martin , Jorgensen Brooke D. , Garsed Dale W. , Fereday Sian , Doherty Jennifer A. , Ariyaratne Dinuka , Anglesio Michael S. , Widschwendter Martin , Pejovic Tanja , Bosquet Jesus Gonzalez , Bowtell David D. , Winham Stacey J. , Goode Ellen L.
Published: April 2023

AbstractBackground:
Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features.
Methods:
We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1.
Results:
Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17–3.81; P = 2.2 × 10−13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66–2.95; P = 4.1 × 10−8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10−7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10−4) in covariate-adjusted analysis.
Conclusions:
Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment.
Impact:
This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.
Data from Comparative Microbiomics Analysis of Antimicrobial Antibody Response between Patients with Lung Cancer and Control Subjects with Benign Pulmonary Nodules
Authors: Shome Mahasish , Gao Weimin , Engelbrektson Anna , Song Lusheng , Williams Stacy , Murugan Vel , Park Jin G. , Chung Yunro , LaBaer Joshua , Qiu Ji
Published: April 2023

AbstractBackground:
CT screening can detect lung cancer early but suffers a high false-positive rate. There is a need for molecular biomarkers that can distinguish malignant and benign indeterminate pulmonary nodules (IPN) detected by CT scan.
Methods:
We profiled antibodies against 901 individual microbial antigens from 27 bacteria and 29 viruses in sera from 127 lung adenocarcinoma (ADC), 123 smoker controls (SMC), 170 benign nodule controls (BNC) individuals using protein microarrays to identify ADC and BNC specific antimicrobial antibodies.
Results:
Analyzing fourth quartile ORs, we found more antibodies with higher prevalence in the three BNC subgroups than in ADC or SMC. We demonstrated that significantly more anti-Helicobacter pylori antibodies showed higher prevalence in ADC relative to SMC. We performed subgroup analysis and found that more antibodies with higher prevalence in light smokers (≤20 pack-years) compared with heavy smokers (>20 pack-years), in BNC with nodule size >1 cm than in those with ≤1 cm nodules, and in stage I ADC than in stage II and III ADC. We performed multivariate analysis and constructed antibody panels that can distinguish ADC versus SMC and ADC versus BNC with area under the ROC curve (AUC) of 0.88 and 0.80, respectively.
Conclusions:
Antimicrobial antibodies have the potential to reduce the false positive rate of CT screening and provide interesting insight in lung cancer development.
Impact:
Microbial infection plays an important role in lung cancer development and the formation of benign pulmonary nodules.
Data from Risk of Renal or Urinary Related Hospitalization in Survivors of Childhood Cancer: Results from the French Childhood Cancer Survivor Study
Authors: Mansouri Imene , Schwartz Boris , Vu-Bezin Giao , Bejarano-Quisoboni Daniel , Fresneau Brice , El-Fayech Chiraz , Dufour Christelle , Bolle Stéphanie , Surun Aurore , Orbach Daniel , Allodji Rodrigue S. , Diallo Ibrahima , Demoor-Goldschmidt Charlotte , de Vathaire Florent , Haddy Nadia
Published: April 2023

AbstractBackground:
Hospitalization rates can be used as an indirect indicator of the burden and severity of adverse health outcomes in childhood cancer survivors (CCS). We aimed to determine the long-term risks of hospitalization related to renal and urinary diseases among 5-year CCS.
Methods:
The French Childhood Cancer Survivor Study cohort was linked with data from the French National Healthcare System database, which enabled the identification of hospitalizations related to renal or urinary diseases. Clinical and detailed treatment data were collected from medical records. Dose-volume histograms were estimated for all patients treated with radiotherapy. Standardized Hospitalization Ratios and absolute excess risks (AER) were calculated. Relative risks were estimated using Poisson regression.
Results:
A total of 5,498 survivors were followed for 42,118 person-years (PY). Survivors experience 2.9 times more renal hospitalizations than expected in the general population, with an AER of 21.2/10,000 PY. Exposing more than 10% of the kidneys’ volume to at least 20 Gray increases the risk of being hospitalized for renal causes by 2.2 (95% confidence interval, 1.3–3.6). Nephrectomized survivors treated with high doses of ifosfamide (>60 g/m²) have an extremely high risk of hospitalization for renal causes. Patients with comorbidities have about a 3-fold higher risk, and nephrectomized patients a 2-fold higher risk of being hospitalized for renal causes compared with other subjects. In the case of hospitalization for urinary causes, treatment by anthracycline administration was found to be associated with an almost 2-fold higher risk of hospitalization compared with the general population.
Conclusions:
These results support the need for careful monitoring of long-term renal diseases in survivors who have undergone nephrectomy, those treated with high doses of radiation (≥20 Gy) even to small volumes of the kidneys, and those with predisposing risk factors.
Impact:
This study provides new evidence with potential impact on surveillance guidelines related to dose-volume indicators associated with renal toxicity.
Data from Serum Lipid Profiles and Cholesterol-Lowering Medication Use in Relation to Subsequent Risk of Colorectal Cancer in the UK Biobank Cohort
Authors: Yuan Fangcheng , Wen Wanqing , Jia Guochong , Long Jirong , Shu Xiao-Ou , Zheng Wei
Published: April 2023

AbstractBackground:
Dyslipidemia is closely associated with metabolic syndrome, a known risk factor for colorectal cancer. However, the association of dyslipidemia with colorectal cancer risk is controversial. Most previous studies did not consider cholesterol-lowering medication use at the time of lipid measurements, which could bias findings.
Methods:
We analyzed data from 384,862 UK Biobank participants to disentangle the associations between blood lipids and colorectal cancer risk. Serum levels of total cholesterol, high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), and triglyceride were measured at study baseline. Multivariable-adjusted Cox models were used to estimate HRs and 95% confidence intervals (CI).
Results:
During a median follow-up time of 8.2 years, 3,150 incident primary colorectal cancer cases were identified. Triglyceride levels were positively, while HDL-C levels were inversely associated with colorectal cancer risk (both Ptrend < 0.005). No significant associations were found for total cholesterol and LDL-C. However, among nonusers of cholesterol-lowering medications, a high total cholesterol level (> 6.7 mmol/L, HR = 1.11; 95% CI, 1.00–1.24) and LDL-C level (>4.1 mmol/L, HR = 1.11; 95% CI, 0.99–1.23) was associated with an increased colorectal cancer risk compared with the referent group (5.2–6.2 mmol/L and 2.6–3.4 mmol/L for total and LDL cholesterol, respectively). Compared with nonusers, cholesterol-lowering medication users had 15% increased colorectal cancer risk (HR = 1.15; 95% CI, 1.04–1.26).
Conclusions:
Circulating total cholesterol, LDL-C, HDL-C and triglyceride were modestly associated with colorectal cancer risk.
Impact:
Our findings call for careful consideration of cholesterol-lowering medication use in future studies of blood lipid–colorectal cancer associations.
Current Approaches to Serving Catchment Areas in Cancer Centers: Insights from the Big Ten Cancer Research Consortium Population Science Working Group
Authors: Manne Sharon L. , Knott Cheryl L. , Berger Ann , Champion Victoria L. , Chrischilles Elizabeth , Fitzgibbon Marian L. , Kinney Anita Y. , Lengerich Eugene J. , Nash Sarah H. , Simon Melissa A. , Trentham-Dietz Amy , Paskett Electra D.
Published: April 2023

In 2021, the NCI issued updated guidance clarifying the mission and organizational structure for Community Outreach and Engagement (COE) for Cancer Center Support Grants. These guidelines outlined how cancer centers should address the cancer burden of the catchment area (CA) and define how COE would partner with the community to inform cancer research and implement programs to reduce the cancer burden. In this paper, the Common Elements Committee of the Population Science Working Group in the Big Ten Cancer Research Consortium describes their respective approaches to implementing these guidelines. We discuss our definitions and rationales for each CA, data sources used, and our approach to assessing the impact of COE efforts on the burden of cancer in our respective CA. Importantly, we describe methods of translating unmet CA needs into our cancer-relevant outreach activities, and cancer research addressing the needs of respective CAs. Implementing these new guidelines is a challenge, and we hope that sharing approaches and experiences will foster cross-center collaborations that may more effectively reduce the burden of cancer in the US and meet the mission of the NCI's Cancer Center Program.
Supplementary Table S3 from Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma
Authors: Osman Abdullah A. , Arslan Emre , Bartels Mason , Michikawa Chieko , Lindemann Antje , Tomczak Katarzyna , Yu Wangjie , Sandulache Vlad , Ma Wencai , Shen Li , Wang Jing , Singh Anand K. , Frederick Mitchell J. , Spencer Nakia D. , Kovacs Jeffery , Heffernan Timothy , Symmans William F. , Rai Kunal , Myers Jeffrey N.
Published: April 2023

Whole exome sequencing showing mutational status in the parental HN30-P versus HN30-R8 cisplatin resistant cell lines.
Supplementary Table S2 from Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma
Authors: Osman Abdullah A. , Arslan Emre , Bartels Mason , Michikawa Chieko , Lindemann Antje , Tomczak Katarzyna , Yu Wangjie , Sandulache Vlad , Ma Wencai , Shen Li , Wang Jing , Singh Anand K. , Frederick Mitchell J. , Spencer Nakia D. , Kovacs Jeffery , Heffernan Timothy , Symmans William F. , Rai Kunal , Myers Jeffrey N.
Published: April 2023

NRF2 regulated genes significantly upregulated in distant metastasis compared to paired primary tumors in HN30-R8 CDDP group.
Supplementary Figure S1 from IL6 Mediates Suppression of T- and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC
Authors: Patel Sonia A. , Nilsson Monique B. , Yang Yan , Le Xiuning , Tran Hai T. , Elamin Yasir Y. , Yu Xiaoxing , Zhang Fahao , Poteete Alissa , Ren Xiaoyang , Shen Li , Wang Jing , Moghaddam Seyed Javad , Cascone Tina , Curran Michael , Gibbons Don L. , Heymach John V.
Published: April 2023

EGFR-mutant NSCLC tumor cells with acquired resistance to an EGFR-TKI display augmented IL-6 gene expression.
Supplementary Figure S7 from Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma
Authors: Osman Abdullah A. , Arslan Emre , Bartels Mason , Michikawa Chieko , Lindemann Antje , Tomczak Katarzyna , Yu Wangjie , Sandulache Vlad , Ma Wencai , Shen Li , Wang Jing , Singh Anand K. , Frederick Mitchell J. , Spencer Nakia D. , Kovacs Jeffery , Heffernan Timothy , Symmans William F. , Rai Kunal , Myers Jeffrey N.
Published: April 2023

Restoration of KEAP1/NRF2 pathways increases cisplatin sensitivity in resistant HNSCC cells through ferroptosis.
Supplementary Figure S6 from Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma
Authors: Osman Abdullah A. , Arslan Emre , Bartels Mason , Michikawa Chieko , Lindemann Antje , Tomczak Katarzyna , Yu Wangjie , Sandulache Vlad , Ma Wencai , Shen Li , Wang Jing , Singh Anand K. , Frederick Mitchell J. , Spencer Nakia D. , Kovacs Jeffery , Heffernan Timothy , Symmans William F. , Rai Kunal , Myers Jeffrey N.
Published: April 2023

Cisplatin sensitivity following knockdown of NRF2 or restoration of wildtype KEAP1 in cisplatin resistant HNSCC cells is not mediated through apoptosis.
Supplementary Table S2 from Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax
Authors: Satta Toshihisa , Li Lin , Chalasani Sri Lakshmi , Hu Xiaoyan , Nkwocha Jewel , Sharma Kanika , Kmieciak Maciej , Rahmani Mohamed , Zhou Liang , Grant Steven
Published: April 2023

Clinical, molecular, and cytogenetic characteristics of patient samples (CD34+CD38-CD123+ population) exposed to ABT-199 ± INK-128
Supplementary Figure S1 from Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma
Authors: Osman Abdullah A. , Arslan Emre , Bartels Mason , Michikawa Chieko , Lindemann Antje , Tomczak Katarzyna , Yu Wangjie , Sandulache Vlad , Ma Wencai , Shen Li , Wang Jing , Singh Anand K. , Frederick Mitchell J. , Spencer Nakia D. , Kovacs Jeffery , Heffernan Timothy , Symmans William F. , Rai Kunal , Myers Jeffrey N.
Published: April 2023

Cisplatin resistant HNSCC cells migrate faster than their Cisplatin sensitive counterparts.
Supplementary fig 3 from Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management
Authors: McGee Rose B. , Oak Ninad , Harrison Lynn , Xu Ke , Nuccio Regina , Blake Alise K. , Mostafavi Roya , Lewis Sara , Taylor Leslie M. , Kubal Manish , Ouma Annastasia , Hines-Dowell Stacy J. , Cheng Cheng , Furtado Larissa V. , Nichols Kim E.
Published: April 2023

Supplementary Figure 3. HRD Sum scores from ScarHRD analysis for biallelic, monoallelic, or no loss of HR genes in aoCPG and control samples.
Supplementary Table S1 from Protein Kinase B (PKB/AKT) Protects IDH-Mutated Glioma from Ferroptosis via Nrf2
Authors: Liu Yang , Chou Fu-Ju , Lang Fengchao , Zhang Meili , Song Hua , Zhang Wei , Davis Dionne L. , Briceno Nicole J. , Zhang Yang , Cimino Patrick J. , Zaghloul Kareem A. , Gilbert Mark R. , Armstrong Terri S. , Yang Chunzhang
Published: April 2023

Patient sample information
Figure S8 from An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas
Authors: Lu Xiaofan , Vano Yann , Helleux Alexandra , Su Xiaoping , Lindner Véronique , Davidson Guillaume , Mouawad Roger , Spano Jean-Philippe , Rouprêt Morgan , Elaidi Reza , Compérat Eva , Verkarre Virginie , Sun Chengming , Chevreau Christine , Bennamoun Mostefa , Lang Hervé , Tricard Thibault , Cheng Wenxuan , Xu Li , Davidson Irwin , Yan Fangrong , Fridman Wolf Herman , Sautes-Fridman Catherine , Oudard Stéphane , Malouf Gabriel G.
Published: April 2023

Figure S8. a) Heatmap showing the regulon activity landscape of three regulon phenotypes identified by unsupervised clustering in the target therapy arm of the CheckMate cohort. Kaplan-Meier survival curves showing the overall survival rate of different regulon phenotypes in the target therapy arm of the CheckMate cohort.
Figure S3 from An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas
Authors: Lu Xiaofan , Vano Yann , Helleux Alexandra , Su Xiaoping , Lindner Véronique , Davidson Guillaume , Mouawad Roger , Spano Jean-Philippe , Rouprêt Morgan , Elaidi Reza , Compérat Eva , Verkarre Virginie , Sun Chengming , Chevreau Christine , Bennamoun Mostefa , Lang Hervé , Tricard Thibault , Cheng Wenxuan , Xu Li , Davidson Irwin , Yan Fangrong , Fridman Wolf Herman , Sautes-Fridman Catherine , Oudard Stéphane , Malouf Gabriel G.
Published: April 2023

Figure S3. Heatmap showing the methylation profiles of two 𝑇𝐸𝐷 phenotypes by supervised clustering using the enhancer signature in the immunotherapy arm of the BIONIKK cohort.
Figure S2 from An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas
Authors: Lu Xiaofan , Vano Yann , Helleux Alexandra , Su Xiaoping , Lindner Véronique , Davidson Guillaume , Mouawad Roger , Spano Jean-Philippe , Rouprêt Morgan , Elaidi Reza , Compérat Eva , Verkarre Virginie , Sun Chengming , Chevreau Christine , Bennamoun Mostefa , Lang Hervé , Tricard Thibault , Cheng Wenxuan , Xu Li , Davidson Irwin , Yan Fangrong , Fridman Wolf Herman , Sautes-Fridman Catherine , Oudard Stéphane , Malouf Gabriel G.
Published: April 2023

Figure S2. Focal copy number deletion identified by the GISTIC algorithm for a) 𝑇𝐸𝐷+ and b) 𝑇𝐸𝐷−, respectively, in the TCGA-KIRC cohort.
Figure S3 from Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
Authors: Tucker Elizabeth R. , Jiménez Irene , Chen Lindi , Bellini Angela , Gorrini Chiara , Calton Elizabeth , Gao Qiong , Che Harvey , Poon Evon , Jamin Yann , Martins Da Costa Barbara , Barker Karen , Shrestha Sumana , Hutchinson J. Ciaran , Dhariwal Simran , Goodman Angharad , Del Nery Elaine , Gestraud Pierre , Bhalshankar Jaydutt , Iddir Yasmine , Saberi-Ansari Elnaz , Saint-Charles Alexandra , Geoerger Birgit , Marques Da Costa Maria Eugénia , Pierre-Eugène Cécile , Janoueix-Lerosey Isabelle , Decaudin Didier , Nemati Fariba , Carcaboso Angel M. , Surdez Didier , Delattre Olivier , George Sally L. , Chesler Louis , Tweddle Deborah A. , Schleiermacher Gudrun
Published: April 2023

GEMM ALK inhibitor data
Figure S2 from Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
Authors: Tucker Elizabeth R. , Jiménez Irene , Chen Lindi , Bellini Angela , Gorrini Chiara , Calton Elizabeth , Gao Qiong , Che Harvey , Poon Evon , Jamin Yann , Martins Da Costa Barbara , Barker Karen , Shrestha Sumana , Hutchinson J. Ciaran , Dhariwal Simran , Goodman Angharad , Del Nery Elaine , Gestraud Pierre , Bhalshankar Jaydutt , Iddir Yasmine , Saberi-Ansari Elnaz , Saint-Charles Alexandra , Geoerger Birgit , Marques Da Costa Maria Eugénia , Pierre-Eugène Cécile , Janoueix-Lerosey Isabelle , Decaudin Didier , Nemati Fariba , Carcaboso Angel M. , Surdez Didier , Delattre Olivier , George Sally L. , Chesler Louis , Tweddle Deborah A. , Schleiermacher Gudrun
Published: April 2023

PDTC experimental data
Supplementary Table 5 from Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma
Authors: Tobin Richard P. , Cogswell Dasha T. , Cates Victoria M. , Davis Dana M. , Borgers Jessica S.W. , Van Gulick Robert J. , Katsnelson Elizabeth , Couts Kasey L. , Jordan Kimberly R. , Gao Dexiang , Davila Eduardo , Medina Theresa M. , Lewis Karl D. , Gonzalez Rene , McFarland Ross W. , Robinson William A. , McCarter Martin D.
Published: April 2023

Representativeness of study participants
Supplementary Data 3 from Liquid Biopsy of Cerebrospinal Fluid Enables Selective Profiling of Glioma Molecular Subtypes at First Clinical Presentation
Authors: Orzan Francesca , De Bacco Francesca , Lazzarini Elisabetta , Crisafulli Giovanni , Gasparini Alessandra , Dipasquale Angelo , Barault Ludovic , Macagno Marco , Persico Pasquale , Pessina Federico , Bono Beatrice , Giordano Laura , Zeppa Pietro , Melcarne Antonio , Cassoni Paola , Garbossa Diego , Santoro Armando , Comoglio Paolo M. , Indraccolo Stefano , Simonelli Matteo , Boccaccio Carla
Published: April 2023

SNP ID.
Figure S4 from Theranostic Targeting of CUB Domain–Containing Protein 1 (CDCP1) in Multiple Subtypes of Bladder Cancer
Authors: Chopra Shalini , Trepka Kai , Sakhamuri Sasank , Carretero-González Alberto , Zhu Jun , Egusa Emily , Zhou Jie , Leung Kevin , Zhao Ning , Hooshdaran Nima , Feng Felix Y. , Wells James A. , Chou Jonathan , Evans Michael J.
Published: April 2023

CDCP1 mRNA expression in locally-advanced vs metastatic patients, from the IMvigor210 dataset. p=0.55 by Wilcoxon test, n=316 patients.
Data from Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax
Authors: Satta Toshihisa , Li Lin , Chalasani Sri Lakshmi , Hu Xiaoyan , Nkwocha Jewel , Sharma Kanika , Kmieciak Maciej , Rahmani Mohamed , Zhou Liang , Grant Steven
Published: April 2023

AbstractPurpose:
Acute myelogenous leukemia (AML) is an aggressive disease with a poor outcome. We investigated mechanisms by which the anti-AML activity of ABT-199 (venetoclax) could be potentiated by dual mTORC1/TORC2 inhibition.
Experimental Design:
Venetoclax/INK128 synergism was assessed in various AML cell lines and primary patient AML samples in vitro. AML cells overexpressing MCL-1, constitutively active AKT, BAK, and/or BAX knockout, and acquired venetoclax resistance were investigated to define mechanisms underlying interactions. The antileukemic efficacy of this regimen was also examined in xenograft and patient-derived xenograft (PDX) models.
Results:
Combination treatment with venetoclax and INK128 (but not the mTORC1 inhibitor rapamycin) dramatically enhanced cell death in AML cell lines. Synergism was associated with p-AKT and p-4EBP1 downregulation and dependent upon MCL-1 downregulation and BAK/BAX upregulation as MCL-1 overexpression and BAX/BAK knockout abrogated cell death. Constitutive AKT activation opposed synergism between venetoclax and PI3K or AKT inhibitors, but not INK128. Combination treatment also synergistically induced cell death in venetoclax-resistant AML cells. Similar events occurred in primary patient-derived leukemia samples but not normal CD34+ cells. Finally, venetoclax and INK128 co-treatment displayed increased antileukemia effects in in vivo xenograft and PDX models.
Conclusions:
The venetoclax/INK128 regimen exerts significant antileukemic activity in various preclinical models through mechanisms involving MCL-1 downregulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax-resistant AML cells, and in in vivo AML models. Further investigation of this strategy appears warranted.
Data from Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
Authors: Tucker Elizabeth R. , Jiménez Irene , Chen Lindi , Bellini Angela , Gorrini Chiara , Calton Elizabeth , Gao Qiong , Che Harvey , Poon Evon , Jamin Yann , Martins Da Costa Barbara , Barker Karen , Shrestha Sumana , Hutchinson J. Ciaran , Dhariwal Simran , Goodman Angharad , Del Nery Elaine , Gestraud Pierre , Bhalshankar Jaydutt , Iddir Yasmine , Saberi-Ansari Elnaz , Saint-Charles Alexandra , Geoerger Birgit , Marques Da Costa Maria Eugénia , Pierre-Eugène Cécile , Janoueix-Lerosey Isabelle , Decaudin Didier , Nemati Fariba , Carcaboso Angel M. , Surdez Didier , Delattre Olivier , George Sally L. , Chesler Louis , Tweddle Deborah A. , Schleiermacher Gudrun
Published: April 2023

AbstractPurpose:
ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%–2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway.
Experimental Design:
We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX).
Results:
Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth.
Conclusions:
In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.
Data from Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma
Authors: Osman Abdullah A. , Arslan Emre , Bartels Mason , Michikawa Chieko , Lindemann Antje , Tomczak Katarzyna , Yu Wangjie , Sandulache Vlad , Ma Wencai , Shen Li , Wang Jing , Singh Anand K. , Frederick Mitchell J. , Spencer Nakia D. , Kovacs Jeffery , Heffernan Timothy , Symmans William F. , Rai Kunal , Myers Jeffrey N.
Published: April 2023

AbstractPurpose:
Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC.
Experimental Design:
Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole-exome sequencing, single-cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms.
Results:
Implantation of CDDP-resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance.
Conclusions:
CDDP resistance and development of DM are associated with dysregulated and epigenetically reprogrammed KEAP1–NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP-resistant head and neck tumors.