Maya M Abdallah, Beatriz Desanti de Oliveira, Clark DuMontier, Ariela R Orkaby, Lisa Nussbaum, Michael Gaziano, Luc Djousse, David Gagnon, Kelly Cho, Sarah R Preis, Jane A Driver
{"title":"Risk of Incident Cancer in Veterans with Diabetes Who Use Metformin Versus Sulfonylureas.","authors":"Maya M Abdallah, Beatriz Desanti de Oliveira, Clark DuMontier, Ariela R Orkaby, Lisa Nussbaum, Michael Gaziano, Luc Djousse, David Gagnon, Kelly Cho, Sarah R Preis, Jane A Driver","doi":"10.15430/JCP.24.012","DOIUrl":"10.15430/JCP.24.012","url":null,"abstract":"<p><p>Prior research suggests metformin has anti-cancer effects, yet data are limited. We examined the association between diabetes treatment (metformin versus sulfonylurea) and risk of incident diabetes-related and non- diabetes-related cancers in US veterans. This retrospective cohort study included US veterans, without cancer, aged ≥ 55 years, who were new users of metformin or sulfonylureas for diabetes between 2001 to 2012. Cox proportional hazards models, with propensity score-matched inverse probability of treatment weighting (IPTW) were constructed. A total of 88,713 veterans (mean age 68.6 ± 7.8 years; 97.7% male; 84.1% White, 12.6% Black, 3.3% other race) were followed for 4.2 ± 3.0 years. Among metformin users (n = 60,476), there were 858 incident diabetes-related cancers (crude incidence rate [IR; per 1,000 person-years] = 3.4) and 3,533 non-diabetes-related cancers (IR = 14.1). Among sulfonylurea users (n = 28,237), there were 675 incident diabetes-related cancers (IR = 5.5) and 2,316 non-diabetes-related cancers (IR = 18.9). After IPTW adjustment, metformin use was associated with a lower risk of incident diabetes-related cancer (hazard ratio [HR] = 0.66, 95% CI 0.58-0.75) compared to sulfonylurea use. There was no association between treatment group (metformin versus sulfonylurea) and non-diabetes-related cancer (HR = 0.96, 95% CI 0.89-1.02). Of diabetes-related cancers, metformin users had lower incidence of liver (HR = 0.39, 95% CI 0.28-0.53), colorectal (HR = 0.75, 95% CI 0.62-0.92), and esophageal cancers (HR = 0.54, 95% CI 0.36-0.81). Among US veterans, metformin users had lower incidence of diabetes-related cancer, particularly liver, colorectal, and esophageal cancers, as compared to sulfonylurea users. Use of metformin was not associated with non-diabetes-related cancer. Further studies are needed to understand how metformin use impacts cancer incidence in different patient populations.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"140-147"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Therapeutic Potential of Hongjam in A Diethylnitrosamine and Thioacetamide-induced Hepatocellular Carcinoma Mouse Model.","authors":"Young-Min Han, Hye-Rin Ahn, Da-Young Lee, Moon-Young Song, Seung-Won Lee, You-Kyung Jang, Byeong Yeob Jeon, Eun-Hee Kim","doi":"10.15430/JCP.24.029","DOIUrl":"10.15430/JCP.24.029","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most common and lethal type of primary liver cancer, frequently arising from chronic liver injury and inflammation. Despite treatment advancements, HCC prognosis remains poor, emphasizing the need for effective preventive and therapeutic strategies. This study investigates the hepatoprotective and anti-tumor effects of Hongjam, a steamed freeze-dried silkworm powder, in a diethylnitrosamine (DEN) and thioacetamide (TAA)-induced HCC mouse model. Mice were administered DEN intraperitoneally for 8 weeks, followed by TAA in drinking water for 9 weeks, with Hongjam supplementation (0.01, 0.1, and 1 g/kg) provided daily through food. Hongjam markedly reduced the tumor incidence, the size, and the histological lesions compared to the DEN/TAA group. Serum biochemical analysis revealed reduction in liver damage markers, including alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin, with a notable decrease in total bilirubin surpassing. Immunohistochemical and Western blot analyses demonstrated that Hongjam downregulated expression of proliferation markers, including Ki67, phosphorylation of protein kinase B, and proliferating cell nuclear antigen, while upregulating the pro-apoptotic protein Bcl-2-associated X protein, indicating its dual role in suppressing proliferation and promoting apoptosis. Furthermore, Hongjam inhibited angiogenesis by suppressing the expression of key markers, including interleukin 6, VEGF, hypoxia-inducible factor-1 subunit alpha, platelet-derived growth factor subunit beta, matrix metalloproteinase-2, and cluster of differentiation 31, thereby disrupting the tumor microenvironment. These findings suggest that Hongjam exerts multifaceted protective effects against HCC by targeting proliferation, apoptosis, and angiogenesis pathways, while also mitigating liver damage. This study highlights the potential of Hongjam as a functional food or a complementary therapeutic agent for HCC prevention and management.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"165-174"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advances in Preventive and Therapeutic Strategies for Oral Cancer: A Short Review.","authors":"Lei Ma, Myoung Ok Kim","doi":"10.15430/JCP.24.027","DOIUrl":"10.15430/JCP.24.027","url":null,"abstract":"<p><p>Oral cancer is a major global health concern, with high incidence and mortality rates, especially in high-risk populations. Early diagnosis remains a challenge, and current treatments, such as surgery, radiation, and chemotherapy, have limited effectiveness, particularly in advanced stages. Recent advances in targeted therapies and immunotherapy offer promising alternatives, providing more precise and personalized treatment options. Targeted therapies, such as epidermal growth factor receptor inhibitors, aim to disrupt specific molecular pathways in tumor growth, while immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor-T cell therapy, enhance the body's immune response to fight cancer. Combination therapies, integrating both targeted and immune strategies, are being explored to overcome the limitations of single-agent treatments. This review highlights the current strategies in the prevention and treatment of oral cancer, discusses emerging therapies, explores future research directions, focusing on optimizing existing treatments, identifying new biomarkers, and developing innovative therapeutic approaches. The potential of personalized medicine and combination therapies offers new hope for improving survival rates and quality of life for oral cancer patients.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"113-119"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Kelch-like ECH-associated Protein 1/Nuclear Factor Erythroid 2-related Factor 2 Pathway and Its Interplay with Oncogenes in Lung Tumorigenesis.","authors":"Taegeun Bae, Mi-Kyoung Kwak","doi":"10.15430/JCP.24.021","DOIUrl":"10.15430/JCP.24.021","url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor regulating cellular redox homeostasis, exhibits a complex role in cancer biology. Genetic mutations in the Kelch-like ECH-associated protein 1 (KEAP1)/NRF2 system, which lead to NRF2 hyperactivation, are found in 20% to 30% of lung cancer cases. This review explores the intricate interplay between NRF2 and key oncogenic pathways in lung cancer, focusing on the interaction of KEAP1/NRF2 system with Kirsten rat sarcoma virus (KRAS), tumor protein P53 (TP53), epidermal growth factor receptor (EGFR), and phosphatidylinositol 3-kinases (PI3K)/AKT signaling. While NRF2 activation alone is insufficient to initiate tumorigenesis, it can significantly impact tumor initiation and progression when combined with oncogenic drivers such as KRAS. The review highlights the context-dependent effects of NRF2, from its protective role against chemical carcinogen-induced tumor initiation to its potential promotion of tumor growth in established cancers. These findings suggest the need for nuanced, stage-specific approaches to targeting the NRF2 pathway in cancer therapy.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"89-98"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yanymee N Guillen-Quispe, Su-Jung Kim, Soma Saeidi, Gyo-Jin Choi, Chaithanya Chelakkot, Tianchi Zhou, Sang-Beom Bang, Tae-Won Kim, Young Kee Shin, Young-Joon Surh
{"title":"Non-canonical Function of Prolyl Hydroxylase Domain 2 in Breast Cancer Cell Growth and Progression: Role of Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1.","authors":"Yanymee N Guillen-Quispe, Su-Jung Kim, Soma Saeidi, Gyo-Jin Choi, Chaithanya Chelakkot, Tianchi Zhou, Sang-Beom Bang, Tae-Won Kim, Young Kee Shin, Young-Joon Surh","doi":"10.15430/JCP.24.031","DOIUrl":"10.15430/JCP.24.031","url":null,"abstract":"<p><p>Prolyl hydroxylase domain 2 (PHD2) is the primary oxygen sensing enzyme involved in hydroxylation of hypoxia-inducible factor (HIF). Under normoxic conditions, PHD2 hydroxylates specific proline residues in HIF-1α and HIF-2α, promoting their ubiquitination and subsequent proteasomal degradation. Although PHD2 activity decreases in hypoxia, notable residual activity persists, but its function in these conditions remains unclear<i>.</i> Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) targets proteins with phosphorylated serine/threonine-proline (pSer/Thr-Pro) motifs. As PHD2 contains several pSer/Thr-Pro motifs, it may be a potential substrate of Pin1. In the present study, we found Pin1 and PHD2 interactions in human breast cancer MDA-MB-231 cells. The breast cancer tissue array revealed higher levels of PHD2 and Pin1 in tumors compared to adjacent normal tissues. Through liquid chromatography-tandem mass spectrometry spectrometry, three phosphorylation sites (S125, T168, and S174) on PHD2 were identified, with serine 125 as the main site for Pin1 binding. As a new Pin1 binding partner, oncogenic PHD2 could be a potential therapeutic target for breast cancer treatment.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"129-139"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sunghee Hong, Jihye Kim, Kunhee Park, Boyoung Park, Bo Youl Choi
{"title":"Risk of Lung Cancer and Risk Factors of Lung Cancer in People Infected with Tuberculosis.","authors":"Sunghee Hong, Jihye Kim, Kunhee Park, Boyoung Park, Bo Youl Choi","doi":"10.15430/JCP.24.016","DOIUrl":"10.15430/JCP.24.016","url":null,"abstract":"<p><p>This study investigated lung cancer risk in people infected with tuberculosis (TB) compared to the general population and evaluated factors associated with lung cancer in TB-infected individuals. Mandatory reported TB infection case data in Gyeonggi Province, South Korea (2010 to 2016) were obtained and linked with medical usage and health screening data from the National Health Information Database. Lung cancer incidence in patients with TB was compared to that in the general population using standardized incidence ratio (SIR), adjusted for age and sex. Lung cancer risk factors in patients with TB were studied using the Cox proportional hazards model. By April 2022, 1.26% (n = 444) of 35,140 patients developed lung cancer after TB diagnosis. Compared to the incidence in the general population, increased lung cancer risk in people with TB was observed (SIR: 2.04, 95% CI: 1.85-2.23). Multivariate analysis showed increased lung cancer in TB-infected individuals, associated with being male (hazard ratio [HR]: 2.24, 95% CI: 1.65-3.04), 1-year increase of age (HR: 1.09, 95% CI: 1.08-1.10), ever smoking (HR: 1.42, 95% CI: 1.02-1.97), and amount of daily smoking with one pack or more (HR: 2.17, 95% CI: 1.63-2.89). Increased lung cancer risk was noted in patients with TB compared to the general population, and sex, age, and smoking were factors associated with lung cancer in patients with TB.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"157-164"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Relationship between Cancer Incidence and Health Behaviors from Ecological Study in Korea.","authors":"Kwang-Pil Ko","doi":"10.15430/JCP.24.025","DOIUrl":"10.15430/JCP.24.025","url":null,"abstract":"<p><p>The aim of this ecological study was to examine the correlation between cancer incidence and health behaviors such as smoking, alcohol consumption, and obesity, and investigated whether there were differences in this correlation between metropolitan areas and other regions. Data on health behaviors exposure/prevalence and cancer incidence rates for 227 administrative districts (cities and counties) were obtained. The average exposure proportion measured annually from 2008 to 2011 in the Korea Community Health Survey data and the age-standardized cancer incidence data from 2014 to 2018, obtained through the cancer registry data, were downloaded from the Statistics Korea website. To examine the relationship between smoking, alcohol consumption, obesity exposure rate (prevalence), and cancer incidence, a correlation analysis was conducted, and Pearson's correlation coefficient was calculated. The correlation coefficient between male smoking and male cancer incidence rate across 227 districts was 0.259. This significance was more pronounced in large metropolitan areas, where the correlation coefficient was 0.631 in the 73 districts belonging to these areas. In large metropolitan areas, the correlation coefficient between alcohol consumption rate and cancer incidence rate was 0.390. In the correlation analysis between obesity prevalence and cancer incidence rate, no correlation was found in large metropolitan areas, while in areas outside of large cities, the correlation coefficient was -0.295, indicating a significant negative correlation. This ecological study demonstrated that the relationship between cancer incidence and health behaviors differed between large metropolitan areas and areas outside of large cities.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"185-189"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Darshika Amarakoon, Wu-Joo Lee, Jing Peng, Seong-Ho Lee
{"title":"Identification of Translocon-associated Protein Delta as An Oncogene in Human Colorectal Cancer Cells.","authors":"Darshika Amarakoon, Wu-Joo Lee, Jing Peng, Seong-Ho Lee","doi":"10.15430/JCP.24.014","DOIUrl":"10.15430/JCP.24.014","url":null,"abstract":"<p><p>Identifying the roles of genes in cancer is critical in discovering potential genetic therapies for cancer care. Translocon-associated protein delta (TRAPδ), also known as signal sequence receptor 4 (SSR4), is a constituent unit in the TRAP/SSR complex that resides in the endoplasmic reticulum and plays a key role in transporting newly synthesized proteins into the endoplasmic reticulumn. However, its biological role in disease development remains unknown to date. This is the first study to identify the role of TRAPδ/SSR4 in colorectal cancer cells in vitro. Upon successful transient knockdown of <i>TRAPδ/SSR4</i>, we observed significant reduction of cell viability in all colorectal cancer cell lines tested. Both HCT 116 and SW480 cell lines were significantly arrested at S and G1 phases, while DLD-1 cells were significantly apoptotic. Moreover, <i>TRAPδ/SSR4</i> stable knockdown HCT 116 and SW480 cells showed significantly lower viability, anchorage-independent growth, and increased S and G1 phase arrests. Overall, we conclude <i>TRAPδ/SSR4</i> is a potential oncogene in human colorectal cancer cells.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"175-184"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolving Therapeutic Strategies in Esophageal Squamous Cell Carcinoma: Advances and Perspectives.","authors":"Zhibin Liu, Myoung Ok Kim","doi":"10.15430/JCP.24.026","DOIUrl":"10.15430/JCP.24.026","url":null,"abstract":"<p><p>Esophageal squamous cell carcinoma (ESCC) is among the most prevalent forms of esophageal cancer globally, with a particularly high incidence in developing countries. Notably, Asia accounts for approximately 80% of global esophageal cancer cases, with China alone contributing to 54% of this burden. The primary treatment modality for ESCC remains esophagectomy, primarily employed for locally advanced disease, often in combination with chemotherapy and radiotherapy for advanced-stage cases. Despite significant advancements in surgical techniques and the advent of precision medicine, which has facilitated the development of targeted and immune-based therapies, critical challenges persist, including suboptimal therapeutic efficacy and the emergence of drug resistance. A comprehensive understanding of the current treatment landscape for ESCC is essential to overcoming these barriers and improving patient outcomes.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"99-104"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Challenges in Metabolite Biomarkers as Avenues of Diagnosis and Prognosis of Cancer.","authors":"Nilesh Kumar Sharma, Sachin C Sarode, Gopinath Sekar, Kaveri Sonawane, Dhanashree Bomle","doi":"10.15430/JCP.24.015","DOIUrl":"10.15430/JCP.24.015","url":null,"abstract":"<p><p>Given the evolutionary nature of tumor complexities and heterogeneity, the early diagnosis of cancer encounters various challenges. Complexities at the level of metabolite reprogramming are compelling in the background of invasiveness, metastasis, drug- and radiation-induced metabolic alterations, immunotherapy-influenced changes, and pro-tumor niche including microbiome. Therefore, it is crucial to examine both current and future obstacles associated with early cancer detection specifically in the context of tumor metabolite biomarkers at preclinical and clinical levels. In conclusion, the significance of tumor metabolite biomarkers must be aligned with a comprehensive approach to achbieve diagnosis and prognosis of cancer patients by securing solutions to formidable challenges.</p>","PeriodicalId":15120,"journal":{"name":"Journal of Cancer Prevention","volume":"29 4","pages":"105-112"},"PeriodicalIF":2.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}