Integrated multi-omic analysis of HCC formation in the SRF-VP16iHep mouse model

SRF-VP16iHep mice activate the constitutive transcription factor SRF-VP16 in a hepatocyte-specific mosaic fashion and consequently, develop hepatocellular carcinoma (mHCC) (Ohrnberger* and Thavamani*, et al., 2015). Using the SRF-VP16iHep mouse model, this thesis focuses on the characterization of mHCC formation from pre-malignant liver nodules. The objective of the current study was to identify carcinogenic driver events responsible for malignant transformation and tumor formation in SRF-VP16iHep livers. To this end, an integrated multi-omics analysis approach was undertaken, which involved the investigation of the genome (exome), transcriptome and proteome at the premalignant and advanced stages of HCC development. Sanger sequencing of genomic candidate loci revealed the presence of Ctnnb1 and Trp53 mutations in two different subsets of mHCCs, respectively. Transcriptome and proteome profiles of Ctnnb1 mutant and Ctnnb1 wildtype mHCCs showed significant differences between the two subsets. SRF-VP16iHep tumor transcriptomes showed striking similarities to that of a distinct subset of human HCCs. This identified SRF-VP16iHep to resemble the G1/G2 subtype of human HCCs, as was indicated by common gene expression signatures, for example activated oncofetal genes. Whole exome sequencing (WES) analysis of mHCCs and pre-malignant nodular tissues revealed an inherent heterogeneity of each mHCC, even when originating within one individual liver. In addition, integrated omics analysis of mHCCs from SRF-VP16iHep mice indicated the occurrence of metabolic reprogramming, for example the activation of aerobic glycolysis and of the mitochondrial 1C-metabolism.SRF-VP16iHep Mäuse zeigen Aktivität das SRF-VP16 Protein, einem konstitutiven Transkriptionsfaktor und Aktivator von CArG-box-regulierten Zielgenen, im hepatozellulären Mosaikmuster. Die dadurch ausgelöste Hyperproliferation von Hepatozyten führt zur Ausbildung von prä-malignen Knoten (“nodules”), aus denen sich Hepatozelluläre Karzinome (murine HCCs, mHCCs) entwickeln (Ohrnberger* and Thavamani* et al., 2015). Die vorliegenden Arbeit konzentriert sich auf die Charakterisierung der HCC Tumorgewebe, sowie die bei deren Entstehung durchlau-fenen Progressionstadien, indem verschiedene genomweite Omic Analyseplattformen zum Einsatz gebracht werden. Dabei war es Ziel dieser Arbeit, essentielle molekulare und zelluläre Ereignisse bei der HCC Tumorentstehung zu identifizieren. Die eingesetzten Omic Analyseplattformen waren Transkriptomic (RNAseq), Proteomik/Phospho-Proteomik, und Exom-Sequenzierung. Genomische Sanger-Sequenzierung von Kandidaten-Loci zeigte die Anwesenheit von Ctnnb1 und Trp53 Mutationen in zwei verschiedenen Untergruppen der mHCCs. Die Transkriptom- und Proteomprofile von Ctnnb1-Wildtyp und Ctnnb1-mutierten mHCCs zeigten signifikante Unterschiede. Vergleichende Clusteranalyse der Transkriptionsprofile der SRF-VP16iHep-Proben mit humanen HCC Tumorproben zeigte signifikante Überlappung der SRF-VP16iHep HCCs mit der G1/G2 Untergruppe humaner HCCs. Dabei wurden gemeinsame Gensignaturen identifiziert, z. B. bezüglich der erhöhten Expression von „oncofetal liver genes“. Eine vollständige Exom-Sequenzierung (WES) von prä-malignen Knoten und mHCCs der SRF-VP16iHep Mäuse zeigte die inhärente Heterogenität der mHCCs. Die durchgeführte multi-Omics Analyse gibt Hinweise auf erfolgte metabolische Reprogrammierung in mHCC Geweben, speziell auf die Aktivierung der aeroben Glycolyse und des mitochondrialen 1C-Metabolismus

EGFR Mutations in Indian Lung Cancer Patients: Clinical Correlation and Outcome to EGFR Targeted Therapy

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The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

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Not AvailablePolycyclic Aromatic Hydrocarbons (PAHs) are among the most ubiquitous environmental pollutants of high global concern. PAHs belong to a diverse family of hydrocarbons with over one hundred compounds known, each containing at least two aromatic rings in their structure. Due to hydrophobic nature, PAHs tend to accumulate in the aquatic sediments, leading to bioaccumulation and elevated concentrations over time. In addition to their well-manifested mutagenic and carcinogenic effects in humans, they pose severe detrimental effects to aquatic life. The high eco-toxicity of PAHs has attracted a number of reviews, each dealing specifically with individual aspects of this global pollutant. However, efficient management of PAHs warrants a holistic approach that combines a thorough understanding of their physico-chemical properties, modes of environmental distribution and bioaccumulation, efficient detection, and bioremediation strategies. Currently, there is a lack of a comprehensive study that amalgamates all these aspects together. The current review, for the first time, overcomes this constraint, through providing a high level comprehensive understanding of the complexities faced during PAH management, while also recommending future directions through potentially viable solutions. Importantly, effective management of PAHs strongly relies upon reliable detection tools, which are currently non-existent, or at the very best inefficient, and therefore have a strong prospect of future development. Notably, the currently available biosensor technologies for PAH monitoring have not so far been compiled together, and therefore a significant focus of this article is on biosensor technologies that are critical for timely detection and efficient management of PAHs. This review is focussed on inland aquatic ecosystems with an emphasis on fish biodiversity, as fish remains a major source of food and livelihood for a large proportion of the global population. This thought provoking study is likely to instigate new collaborative approaches for protecting aquatic biodiversity from PAHs-induced eco-toxicity.Not Availabl

Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity.

BACKGROUND:During the past decade, the incidence of EGFR mutation has been shown to vary across different ethnicities. It occurs at the rate of 10-15% in North Americans and Europeans, 19% in African-Americans, 20-30% in various East Asian series including Chinese, Koreans, and Japanese. Frequency of EGFR mutations in India however remains sparsely explored. METHODOLOGY/PRINCIPAL FINDINGS:We report 23% incidence of Epidermal growth factor receptor (EGFR) mutations in 907 Non small cell lung cancer (NSCLC) patients of Indian ethnicity, in contrast to 10-15% known in Caucasians and 27-62% among East Asians. In this study, EGFR mutations were found to be more common in never-smokers 29.4% as compared to smokers 15.3%. Consistent with other populations, mutation rates among adenocarcinoma-males were predominantly lower than females with 32% incidence. However unlike Caucasians, EGFR mutation rate among adenocarcinoma-never-smoker females were comparable to males suggesting lack of gender bias among never smokers likely to benefit from EGFR targeted therapy. CONCLUSIONS/SIGNIFICANCE:This study has an overall implication for establishing relevance for routine EGFR mutation diagnostics for NSCLC patients in clinics and emphasizes effectiveness for adoption of EGFR inhibitors as the first line treatment among Indian population. The intermediate frequency of EGFR mutation among Indian population compared to Caucasians and East Asians is reminiscent of an ancestral admixture of genetic influence from Middle Easterners, Central Asians, and Europeans on modern- Indian population that may confer differential susceptibility to somatic mutations in EGFR

Serum Response Factor (SRF) Drives the Transcriptional Upregulation of the MDM4 Oncogene in HCC

Simple Summary Hepatocellular carcinoma (HCC) represents the most common type of liver cancer and has a poor prognosis. Therefore, there is an urgent need for the identification of new therapeutic options. The mouse double minute homolog 4 (MDM4) gene, a known p53 inhibitor, is upregulated in most HCCs. Here, we aimed to investigate the mechanisms leading to MDM4 transcriptional upregulation and to evaluate whether therapeutic targeting of these mechanisms might represent a suitable approach for future therapy. Using human HCC cell lines, a mouse model, and human HCC cohorts, we have identified serum response factor (SRF), ETS transcription factors ELK1 and ELK4 as transcription factors (TFs) driving MDM4 expression. Treatment of HCC cell lines with XI-011, a pharmaceutical inhibitor of MDM4 transcription, reduced the expression of both the TFs and MDM4 and impaired tumor growth, suggesting that targeting the MDM4 transcription may provide a rationale for future targeted therapy of HCC. Different molecular mechanisms support the overexpression of the mouse double minute homolog 4 (MDM4), a functional p53 inhibitor, in human hepatocellular carcinoma (HCC). However, the transcription factors (TFs) leading to its transcriptional upregulation remain unknown. Following promoter and gene expression analyses, putative TFs were investigated using gene-specific siRNAs, cDNAs, luciferase reporter assays, chromatin immunoprecipitation, and XI-011 drug treatment in vitro. Additionally, MDM4 expression was investigated in SRF-VP16(iHep) transgenic mice. We observed a copy-number-independent upregulation of MDM4 in human HCCs. Serum response factor (SRF), ELK1 and ELK4 were identified as TFs activating MDM4 transcription. While SRF was constitutively detected in TF complexes at the MDM4 promoter, presence of ELK1 and ELK4 was cell-type dependent. Furthermore, MDM4 was upregulated in SRF-VP16-driven murine liver tumors. The pharmacological inhibitor XI-011 exhibited anti-MDM4 activity by downregulating the TFs driving MDM4 transcription, which decreased HCC cell viability and increased apoptosis. In conclusion, SRF drives transcriptional MDM4 upregulation in HCC, acting in concert with either ELK1 or ELK4. The transcriptional regulation of MDM4 may be a promising target for precision oncology of human HCC, as XI-011 treatment exerts anti-MDM4 activity independent from the MDM4 copy number and the p53 status