Browsing by Author "Beeraka, Narasimha M."
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Item Association of Definitive Radiotherapy for Esophageal Cancer and the Incidence of Secondary Head and Neck Cancers: A SEER Population-Based Study(Elmer Press, 2024) Guo, Qian Qian; Ma, Shi Zhou; Zhao, De Yao; Beeraka, Narasimha M.; Gu, Hao; Zheng, Yu Fei; Zhao, Rui Wen; Li, Si Ting; Nikolenko, Vladimir N.; Bulygin, Kirill V.; Basappa, Basappa; Fan, Rui Tai; Liu, Jun Qi; Pediatrics, School of MedicineBackground: Impact of radiotherapy (RT) for esophageal cancer (EC) patients on the development of secondary head and neck cancer (SHNC) remains equivocal. The objective of this study was to investigate the link between definitive RT used for EC treatment and subsequent SHNC. Methods: This study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database to collect the data of primary EC patients. Fine-Gray competing risk regression and standardized incidence ratio (SIR) and propensity score matching (PSM) method were used to match SHNC patients with only primary head and neck cancer (HNC) patients. Overall survival (OS) rates were applied by Kaplan-Meier analysis. Results: In total, 14,158 EC patients from the SEER database were included, of which 9,239 patients (65.3%) received RT and 4,919 patients (34.7%) received no radiation therapy (NRT). After a 12-month latency period, 110 patients (1.2%) in the RT group and 36 patients (0.7%) in the NRT group experienced the development of SHNC. In individuals with primary EC, there was an increased incidence of SHNC compared to the general US population (SIR = 5.95, 95% confidence interval (CI): 5.15 - 6.84). Specifically, the SIR for SHNC was 8.04 (95% CI: 6.78 - 9.47) in the RT group and 3.51 (95% CI: 2.64 - 4.58) in the NRT group. Patients who developed SHNC after RT exhibited significantly lower OS compared to those after NRT. Following PSM, the OS of patients who developed SHNC after RT remained significantly lower than that of matched patients with only primary HNC. Conclusion: An association was discovered between RT for EC and increased long-term risk of SHNC. This work enables radiation oncologists to implement mitigation strategies to reduce the long-term risk of SHNC in patients who have received RT following primary EC.Item Chinese Clinical Trial Registry 13-year data collection and analysis: geographic distribution, financial support, research phase, duration, and disease categories(Frontiers Media, 2023-10-12) Fan, Ruitai; Zheng, Yufei; Zhou, Runze; Beeraka, Narasimha M.; Sukocheva, Olga A.; Zhao, Ruiwen; Li, Shijie; Zhao, Xiang; Liu, Chunying; He, Song; Mahesh, P. A.; Gurupadayya, B. M.; Nikolenko, Vladimir N.; Zhao, Di; Liu, Junqi; Pediatrics, School of MedicineObjective: To evaluate the current status of trial registration on the Chinese Clinical Trial Registry (ChiCTR). Design: In this descriptive study, a multi-dimensional grouping analysis was conducted to estimate trends in the annual trial registration, geographical distribution, sources of funding, targeted diseases, and trial subtypes. Setting: We have analyzed all clinical trial records (over 30,000) registered on the Chinese Clinical Trial Registry (ChiCTR) from 2007 to 2020 executed in China. Main outcomes and measures: The main outcome was the baseline characteristics of registered trials. These trials were categorized and analyzed based on geographical distribution, year of implementation, disease type, resource and funding type, trial duration, trial phase, and the type of experimental approach. Results: From 2008 to 2017, a consistent upward trend in clinical trial registrations was observed, showing an average annual growth rate of 29.2%. The most significant year-on-year (yoy%) growth in registrations occurred in 2014 (62%) and 2018 (68.5%). Public funding represented the predominant source of funding in the Chinese healthcare system. The top five ChiCTR registration sites for all disease types were highly populated urban regions of China, including Shanghai (5,658 trials, 18%), Beijing (5,127 trials, 16%), Guangdong (3,612 trials, 11%), Sichuan (2,448 trials, 8%), and Jiangsu (2,196 trials, 7%). Trials targeting neoplastic diseases accounted for the largest portion of registrations, followed by cardio/cerebrovascular disease (CCVD) and orthopedic diseases-related trials. The largest proportions of registration trial duration were 1-2 years, less than 1 year, and 2-3 years (at 27.36, 26.71, and 22.46%). In the case of the research phase, the top three types of all the registered trials are exploratory research, post-marketing drugs, and clinical trials of new therapeutic technology. Conclusion and relevance: Oncological and cardiovascular diseases receive the highest share of national public funding for medical clinical trial-based research in China. Publicly funded trials represent a major segment of the ChiCTR registry, indicating the dominating role of public governance in this health research sector. Furthermore, the growing number of analyzed records reflect the escalation of clinical research activities in China. The tendency to distribute funding resources toward exceedingly populated areas with the highest incidence of oncological and cardiovascular diseases reveals an aim to reduce the dominating disease burden in the urban conglomerates in China.Item Correlation of time trends of air pollutants, greenspaces and tracheal, bronchus and lung cancer incidence and mortality among the adults in United States(Frontiers Media, 2024-07-25) Zhao, Jia; Ren, Ruihang; Beeraka, Narasimha M.; PA, Mahesh; Xue, Nannan; Lu, Pengfei; Bai, Wenhua; Mao, Zhihan; Vikram PR, Hemanth; Bulygin, Kirill V.; Nikolenko, Vladimir N.; Fan, Ruitai; Liu, Junqi; Pediatrics, School of MedicineBackground: Tracheal, Bronchus, and Lung (TBL) cancer continues to represent the majority of cancer-related incidence and mortality in United States (U.S.). While air pollutants are considered essential risk factors, both global and national average concentrations of major harmful air pollutants have significantly decreased over the decades. Green space may have a beneficial effect on human health. Methods: We obtained data on national and state-level burden of TBL cancer, the annual average concentration of main air pollutants, and levels of green spaces in 2007, 2013, and 2019. According to generalized estimating equation (GEE), we examine the associations among incidence and mortality of TBL cancer, air pollutants, and greenspaces, represented by the Normalized Difference Vegetation Index (NDVI) in different age groups with models adjusted with meteorological, and socio-demographic. We observed additional effects of the interaction between the NDVI, Ozone, PM2.5, and other factors, which helped us to interpret and understand our results. Also, we collated states that witnessed net increments in forest coverage and conducted the same analysis separately. Results: In our analysis, the majority of associations between NDVI and air pollutants with TBL cancer remained significantly positive, particularly noticeable among individuals aged 20 to 54. However, our findings did not explore air pollution as a potential mediator between greenspace exposure and TBL cancer. While the associations of PM2.5 with TBL cancer remained positive, the other four pollutants showed positive but statistically insignificant associations. Our interaction analysis yielded that there were positive associations between NDVI and ozone, PM2.5, and tobacco use. Max NDVI acts as a protective factor along with high HDI. Additionally, PM2.5 and HDI also showed a negative association. In 18 states with more forest, NDVI acts as a protective factor along with higher health care coverage, better health status, and participation in physical activities. Conclusion: In the state-level of U.S., the effects of total greenspace with TBL cancer are mixed and could be modified by various socio-economic factors. PM2.5 has a direct correlation with TBL cancer and the effects can be influenced by underlying socioeconomic conditions.Item Corrigendum to “Nitrosamines crisis in pharmaceuticals − Insights on toxicological implications, root causes and risk assessment: A systematic review” [J. Pharm. Anal. 14 (2024) 100919](Elsevier, 2024) Vikram, Hemanth P. R.; Kumar, Tegginamath Pramod; Kumar, Gunjan; Beeraka, Narasimha M.; Deka, Rajashree; Suhail, Sheik Mohammed; Jat, Sandeep; Bannimath, Namitha; Padmanabhan, Gayatiri; Chandan, Ravandur S.; Kumar, Pramod; Gurupadayya, Bannimath; Pediatrics, School of Medicine[This corrects the article DOI: 10.1016/j.jpha.2023.12.009.].Item Exploring the relationship between anastasis and mitochondrial ROS-mediated ferroptosis in metastatic chemoresistant cancers: a call for investigation(Frontiers Media, 2024-07-02) Cao, Yu; Lu, Chang; Beeraka, Narasimha M.; Efetov, Sergey; Enikeev, Mikhail; Fu, Yu; Yang, Xinyi; Basappa, Basappa; He, Mingze; Li, Zhi; Pediatrics, School of MedicineFerroptosis induces significant changes in mitochondrial morphology, including membrane condensation, volume reduction, cristae alteration, and outer membrane rupture, affecting mitochondrial function and cellular fate. Recent reports have described the intrinsic cellular iron metabolism and its intricate connection to ferroptosis, a significant kind of cell death characterized by iron dependence and oxidative stress regulation. Furthermore, updated molecular insights have elucidated the significance of mitochondria in ferroptosis and its implications in various cancers. In the context of cancer therapy, understanding the dual role of anastasis and ferroptosis in chemoresistance is crucial. Targeting the molecular pathways involved in anastasis may enhance the efficacy of ferroptosis inducers, providing a synergistic approach to overcome chemoresistance. Research into how DNA damage response (DDR) proteins, metabolic changes, and redox states interact during anastasis and ferroptosis can offer new insights into designing combinatorial therapeutic regimens against several cancers associated with stemness. These treatments could potentially inhibit anastasis while simultaneously inducing ferroptosis, thereby reducing the likelihood of cancer cells evading death and developing resistance to chemotherapy. The objective of this study is to explore the intricate interplay between anastasis, ferroptosis, EMT and chemoresistance, and immunotherapeutics to better understand their collective impact on cancer therapy outcomes. We searched public research databases including google scholar, PubMed, relemed, and the national library of medicine related to this topic. In this review, we discussed the interplay between the tricarboxylic acid cycle and glycolysis implicated in modulating ferroptosis, adding complexity to its regulatory mechanisms. Additionally, the regulatory role of reactive oxygen species (ROS) and the electron transport chain (ETC) in ferroptosis has garnered significant attention. Lipid metabolism, particularly involving GPX4 and System Xc- plays a significant role in both the progression of ferroptosis and cancer. There is a need to investigate the intricate interplay between anastasis, ferroptosis, and chemoresistance to better understand cancer therapy clinical outcomes. Integrating anastasis, and ferroptosis into strategies targeting chemoresistance and exploring its potential synergy with immunotherapy represent promising avenues for advancing chemoresistant cancer treatment. Understanding the intricate interplay among mitochondria, anastasis, ROS, and ferroptosis is vital in oncology, potentially revolutionizing personalized cancer treatment and drug development.Item Global burden of gynaecological cancers in 2022 and projections to 2050(International Society of Global Health, 2024-08-16) Zhu, Binhua; Gu, Hao; Mao, Zhihan; Beeraka, Narasimha M.; Zhao, Xiang; Anand, Mahesh Padukudru; Zheng, Yufei; Zhao, Ruiwen; Li, Siting; Manogaran, Prasath; Fan, Ruitai; Nikolenko, Vladimir N.; Wen, Haixiao; Basappa, Basappa; Liu, Junqi; Pediatrics, School of MedicineBackground: The incidence and mortality of gynaecological cancers can significantly impact women's quality of life and increase the health care burden for organisations globally. The objective of this study was to evaluate global inequalities in the incidence and mortality of gynaecological cancers in 2022, based on The Global Cancer Observatory (GLOBOCAN) 2022 estimates. The future burden of gynaecological cancers (GCs) in 2050 was also projected. Methods: Data regarding to the total cases and deaths related to gynaecological cancer, as well as cases and deaths pertaining to different subtypes of GCs, gathered from the GLOBOCAN database for the year 2022. Predictions for the number of cases and deaths in the year 2050 were derived from global demographic projections, categorised by world region and Human Development Index (HDI). Results: In 2022, there were 1 473 427 new cases of GCs and 680 372 deaths. The incidence of gynecological cancer reached 30.3 per 100 000, and the mortality rate hit 13.2 per 100 000. The age-standardised incidence of GCs in Eastern Africa is higher than 50 per 100 000, whereas the age-standardised incidence in Northern Africa is 17.1 per 100 000. The highest mortality rates were found in East Africa (ASMR (age-standardised mortality rates) of 35.3 per 100 000) and the lowest in Australia and New Zealand (ASMR of 8.1 per 100 000). These are related to the endemic areas of HIV and HPV. Very High HDI countries had the highest incidence of GCs, with ASIR (age-standardised incidence rates) of 34.8 per 100 000, and low HDI countries had the second highest incidence rate, with an ASIR of 33.0 per 100 000. Eswatini had the highest incidence and mortality (105.4 per 100 000; 71.1 per 100 000) and Yemen the lowest (5.8 per 100 000; 4.4 per 100 000). If the current trends in morbidity and mortality are maintained, number of new cases and deaths from female reproductive tract tumours is projected to increase over the next two decades. Conclusions: In 2022, gynaecological cancers accounted for 1 473 427 new cases and 680 372 deaths globally, with significant regional disparities in incidence and mortality rates. The highest rates were observed in Eastern Africa and countries with very high and low HDI, with Eswatini recording the most severe statistics. If current trends continue, the number of new cases and deaths from gynaecological cancers is expected to rise over the next two decades, highlighting the urgent need for effective interventions.Item Incidence Trends, Clinicopathologic Characteristics, and Overall Survival Prediction in Retinoblastoma Children: SEER Prognostic Nomogram Analysis(Oxford University Press, 2024) Guo, Xiaohong; Wang, Li; Beeraka, Narasimha M.; Liu, Chunying; Zhao, Xiang; Zhou, Runze; Yu, Huiming; Fan, Ruitai; Liu, Junqi; Pediatrics, School of MedicineBackground: Retinoblastoma is the most common intraocular malignant tumor occurring among children, with an incidence rate of 1/15 000. This study built a joinpoint regression model to assess the incidence trend of retinoblastoma from 2004 to 2015 and constructed a nomogram to predict the overall survival (OS) in children. Materials and methods: Patients less than 19 years diagnosed with retinoblastoma from 2004 to 2015 were selected from the SEER database. Joinpoint regression analysis (version 4.9.0.0) was performed to evaluate the trends in retinoblastoma incidence rates from 2004 to 2015. Cox Regression Analysis was applied to investigate prognostic risk factors that influence OS. Results: Joinpoint regression revealed that retinoblastoma incidence exhibited no significant increase or decrease from 2004 to 2015. As per the multiple Cox regression, tumor size, laterality, and residence (rural-urban continuum code) were correlated with OS and were used to construct a nomogram. The nomogram exhibited a good C-index of 0.71 (95% CI, 0.63 to 0.79), and the calibration curve for survival probability demonstrated that the predictions corresponded well with actual observations. Conclusions and relevance: A prognostic nomogram integrating the risk factors for retinoblastoma was constructed to provide comparatively accurate individual survival predictions. If validated, this type of assessment could be used to guide therapy in patients with retinoblastoma.Item Molecular classification of human papilloma virus-negative head and neck squamous cell carcinomas: Cell cycle-based classifier and prognostic signature(Public Library of Science, 2023-10-30) Gu, Hao; Li, Tingxuan; Beeraka, Narasimha M.; Zheng, Yufei; Zhang, Xintan; Song, Ruixia; Zhou, Runze; Wang, Xiaoyan; Sukocheva, Olga; Fan, Ruitai; Liu, Junqi; Pediatrics, School of MedicineThe molecular classification of human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) remains questionable. Differentially expressed genes were detected between tumor and normal tissues and GSEA showed they are associated with cell cycle pathways. This study aimed to classify HPV-negative HNSCCs based on cell cycle-related genes. The established gene pattern was correlated with tumor progression, clinical prognosis, and drug treatment efficacy. Biological analysis was performed using HNSCC patient sample data obtained from the Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Gene Expression Omnibus (GEO) databases. All samples included in this study contained survival information. RNA sequencing data from 740 samples were used for the analysis. Previously characterized cell cycle-related genes were included for unsupervised consensus clustering. Two subtypes of HPV-negative HNSCCs (C1, C2) were identified. Subtype C1 displayed low cell cycle activity, 'hot' tumor microenvironment (TME), earlier N stage, lower pathological grade, better prognosis, and higher response rate to the immunotherapy and targeted therapy. Subtype C2 was associated with higher cell cycle activity, 'cold' TME, later N stage, higher pathological grade, worse prognosis, and lower response rate to the treatment. According to the nearest template prediction method, classification rules were established and verified. Our work explored the molecular mechanism of HPV-negative HNSCCs in the view of cell cycle and might provide new sights for personalized anti-cancer treatment.Item Nitrosamines crisis in pharmaceuticals - Insights on toxicological implications, root causes and risk assessment: A systematic review(Elsevier, 2024) Vikram, Hemanth P. R.; Kumar, Tegginamath Pramod; Kumar, Gunja; Beeraka, Narasimha M.; Deka, Rajashree; Suhail, Sheik Mohammed; Jat, Sandeep; Bannimath, Namitha; Padmanabha, Gayatiri; Chandan, Ravandur S.; Kumar, Pramod; Gurupadayya, Bannimath; Pediatrics, School of MedicineThe presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.Item Screening fructosamine-3-kinase (FN3K) inhibitors, a deglycating enzyme of oncogenic Nrf2: Human FN3K homology modelling, docking and molecular dynamics simulations(Public Library of Science, 2023-11-01) Beeraka, Narasimha M.; Zhang, Jin; Mandal, Subhankar; Vikram P. R., Hemanth; Liu, Junqi; B. M., Namitha; Zhao, Di; Vishwanath, Prashanth; Gurupadayya, B. M.; Fan, Ruitai; Pediatrics, School of MedicineFructosamine-3-kinase (FN3K) is involved in the deglycation of Nrf2, a significant regulator of oxidative stress in cancer cells. However, the intricate functional aspects of FN3K and Nrf2 in breast cancers have not been explored vividly. The objectives of this study are to design the human FN3K protein using homology modeling followed by the screening of several anticancer molecules and examining their efficacy to modulate FN3K activity, Nrf2-mediated antioxidant signalling. Methods pertinent to homology modeling, virtual screening, molecular docking, molecular dynamics simulations, assessment of ADME properties, cytotoxicity assays for anticancer molecules of natural/synthetic origin in breast cancer cells (BT-474, T-47D), and Western blotting were used in this study. The screened anticancer molecules including kinase inhibitors of natural and synthetic origin interacted with the 3-dimensional structure of the catalytic domain in human FN3K protein designed through homology modeling by significant CDOCKER interaction energies. Subsequently, gefitinib, sorafenib, neratinib, tamoxifen citrate, and cyclosporine A enhanced the expression of FN3K in BT-474 cell lines with simultaneous alteration in Nrf2-driven antioxidant signalling. Oxaliplatin significantly downregulated FN3K expression and modulated Nrf2-driven antioxidant signalling when compared to cisplatin and other anticancer drugs. Hence, the study concluded the potential implications of existing anticancer drugs to modulate FN3K activity in breast cancers.