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As the initial point for digestion, the balance of oral microorganisms plays an important role in maintaining local and systemic health. Oral dysbiosis, or an imbalance in the oral microbial community, may lead to the onset of various diseases. The presence or abnormal increase of microbes in the oral cavity has attracted significant attention due to its complicated relationship with oral cancer. Oral cancer can remodel microbial profiles by creating a more beneficial microenvironment for its progression. On the other hand, altered microbial profiles can promote tumorigenesis by evoking a complex inflammatory response and affecting host immunity. This review analyzes the oncogenic potential of oral microbiome alterations as a driver and biomarker. Additionally, a potentially therapeutic strategy via the reversal of the oral microbiome dysbiosis in oral cancers has been discussed. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) account for more than 30% of cancer cases, with definite identification of the oncogenic role of viral E6 and E7 genes. However, the identification of high-risk HPV genotypes has largely relied on lagged biological exploration and clinical observation, with types unclassified and oncogenicity unknown for many HPVs. In the present study, we retrieved and cleaned HPV sequence records with high quality and analyzed their genomic compositional traits of dinucleotide (DNT) and DNT representation (DCR) to overview the distribution difference among various types of HPVs. Then, a deep learning model was built to predict the oncogenic potential of all HPVs based on E6 and E7 genes. Our results showed that the main three groups of Alpha, Beta, and Gamma HPVs were clearly separated between/among types in the DCR trait for either E6 or E7 coding sequence (CDS) and were clustered within the same group. Moreover, the DCR data of either E6 or E7 were learnable with a convolutional neural network (CNN) model. Either CNN classifier predicted accurately the oncogenicity label of high and low oncogenic HPVs. In summary, the compositional traits of HPV oncogenicity-related genes E6 and E7 were much different between the high and low oncogenic HPVs, and the compositional trait of the DCR-based deep learning classifier predicted the oncogenic phenotype accurately of HPVs. The trained predictor in this study will facilitate the identification of HPV oncogenicity, particularly for those HPVs without clear genotype or phenotype. [ABSTRACT FROM AUTHOR]

Abstract Background Abnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain. Methods The FABD-deficient adenovirus vectors Ad-BCR/ABL△FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright‒Giemsa staining and haematoxylin and eosin (HE) staining. Results We report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice. Conclusions These findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL.

Background: Abnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain. Methods: The FABD-deficient adenovirus vectors Ad-BCR/ABL△FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright‒Giemsa staining and haematoxylin and eosin (HE) staining. Results: We report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice. Conclusions: These findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL. [ABSTRACT FROM AUTHOR]

Gene fusions involving the neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3, are well established oncogenic drivers in a broad range of pediatric and adult tumors. These fusions are also important actionable markers, predicting often dramatic response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK fusions is a high priority for diagnostic laboratories, but remains challenging and time consuming given the rapid pace of new data accumulation, the diversity of fusion partners and tumor types, and heterogeneous and incomplete information in variant databases and knowledgebases. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically address these challenges and create an expert-curated resource to support clinicians, researchers, patients and their families in making accurate interpretations and informed treatment decisions for NTRK fusion-driven tumors. We describe a system for NTRK fusion interpretation (including compilation of key elements and annotations) developed by the NTRK fusions SC-VCEP. We illustrate this stepwise process on examples of LMNA::NTRK1 and KANK1::NTRK2 fusions. Finally, we provide detailed analysis of current representation of NTRK fusions in public fusion databases and the CIViC knowledgebase, performed by the NTRK fusions SC-VCEP to determine existing gaps and prioritize future curation activities.

As one of the most important avian immunosuppressive and neoplastic diseases, Marek's disease (MD), caused by oncogenic Marek's disease virus (MDV), has caused huge economic losses worldwide over the past five decades. In recent years, MD outbreaks have occurred frequently in MD-vaccinated chicken flocks, but the key pathogenic determinants and influencing factors remain unclear. Herein, we analyzed the pathogenicity of seven newly isolated MDV strains from tumor-bearing chickens in China and found that all of them were pathogenic to chicken hosts, among which four MDV isolates, SDCW01, HNXZ05, HNSQ05 and HNSQ01, were considered to be hypervirulent MDV (HV-MDV) strains. At 73 days of the virus infection experiment, the cumulative incidences of MD were 100%, 93.3%, 90% and 100%, with mortalities of 83.3%, 73.3%, 60% and 86.7%, respectively, for the four viruses. The gross occurrences of tumors were 50%, 33.3%, 30% and 63.3%, respectively, accompanied by significant hepatosplenomegaly and serious atrophy of the immune organs. Furthermore, the immune protection effects of four commercial MD vaccines against SDCW01, CVI988, HVT, CVI988+HVT, and 814 were explored. Unexpectedly, during the 67 days of post-virus challenge, the protection indices (PIs) of these four MD vaccines were only 46.2%, 38.5%, 50%, and 28%, respectively, and the birds that received the monovalent CVI988 or HVT still developed tumors with cumulative incidences of 7.7% and 11.5%, respectively. To our knowledge, this is the first demonstration of the simultaneous comparison of the immune protection efficacy of multiple commercial MD vaccines with different vaccine strains. Our study revealed that the HV-MDV variants circulating in China could significantly break through the immune protection of the classical MD vaccines currently widely used. For future work, there is an urgent need to develop novel, more effective MD vaccines for tackling the new challenge of emerging HV-MDV strains or variants for the sustainable control of MD. [ABSTRACT FROM AUTHOR]

Next-generation sequencing technology has created many new opportunities for clinical diagnostics, but it faces the challenge of functional annotation of identified mutations. Various algorithms have been developed to predict the impact of missense variants that influence oncogenic drivers. However, computational pipelines that handle biological data must integrate multiple software tools, which can add complexity and hinder non-specialist users from accessing the pipeline. Here, we have developed an online user-friendly web server tool PredictONCO that is fully automated and has a low barrier to access. The tool models the structure of the mutant protein in the first step. Next, it calculates the protein stability change, pocket level information, evolutionary conservation, and changes in ionisation of catalytic amino acid residues, and uses them as the features in the machine-learning predictor. The XGBoost-based predictor was validated on an independent subset of held-out data, demonstrating areas under the receiver operating characteristic curve (ROC) of 0.97 and 0.94, and the average precision from the precision-recall curve of 0.99 and 0.94 for structure-based and sequence-based predictions, respectively. Finally, PredictONCO calculates the docking results of small molecules approved by regulatory authorities. We demonstrate the applicability of the tool by presenting its usage for variants in two cancer-associated proteins, cellular tumour antigen p53 and fibroblast growth factor receptor FGFR1. Our free web tool will assist with the interpretation of data from next-generation sequencing and navigate treatment strategies in clinical oncology: https://loschmidt.chemi.muni.cz/predictonco/., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In recent years, outbreaks of Marek's disease (MD) have been frequently reported in vaccinated chicken flocks in China. Herein, we have demonstrated that four Marek's disease virus (MDV) isolates, HN502, HN302, HN304, and HN101, are all pathogenic and oncogenic to hosts. Outstandingly, the HN302 strain induced 100% MD incidence, 54.84% mortality, and 87.10% tumor incidence, together with extensive atrophy of immune organs. Pathotyping of HN302 was performed in comparison to a standard very virulent (vv) MDV strain Md5. We found that both CVI988 and HVT vaccines significantly reduced morbidity and mortality induced by HN302 or Md5 strains, but the protection indices (PIs) provided by these two vaccines against HN302 were significantly lower (27.03%) or lower (33.33%) than that against Md5, which showed PIs of 59.89% and 54.29%, respectively. These data suggested that HN302 possesses a significant higher virulence than Md5 and at least could be designated as a vvMDV strain. Together with our previous phylogenetic analysis on MDV-1 meq genes, we have presently suggested HN302 to be a typical highly virulent MDV variant belonging to an independent Chinese branch. To our knowledge, this is the first report to provide convincible evidence to identify a pathogenic MDV variant strain with a higher virulence than Md5 in China, which may have emerged and circulating in poultry farms in China for a long time and involved in the recent MD outbreaks. [ABSTRACT FROM AUTHOR]

Objective: New therapeutic approaches are needed to improve the prognosis of glioblastoma (GBM) patients. Methods: With the objective of identifying alternative oncogenic mechanisms to abnormally activated epidermal growth factor receptor (EGFR) signalling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We then conducted gain of function as well as genetic and pharmocological inhibition assays in GBM patient‐derived cell lines to functionnally validate our finding. Results: We identified that growth hormone receptor (GHR) signalling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of suppressor of cytokine signalling 2 (SOCS2) expression due to SOCS2 promoter hypermethylation. In GBM patient‐derived cell lines, GHR signalling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro and promotes tumourigenesis, tumour growth, and tumour invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro. Conclusion: This study pioneers a new field of investigation to improve the prognosis of GBM patients. [ABSTRACT FROM AUTHOR]

Abstract Objective New therapeutic approaches are needed to improve the prognosis of glioblastoma (GBM) patients. Methods With the objective of identifying alternative oncogenic mechanisms to abnormally activated epidermal growth factor receptor (EGFR) signalling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We then conducted gain of function as well as genetic and pharmocological inhibition assays in GBM patient‐derived cell lines to functionnally validate our finding. Results We identified that growth hormone receptor (GHR) signalling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of suppressor of cytokine signalling 2 (SOCS2) expression due to SOCS2 promoter hypermethylation. In GBM patient‐derived cell lines, GHR signalling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro and promotes tumourigenesis, tumour growth, and tumour invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro. Conclusion This study pioneers a new field of investigation to improve the prognosis of GBM patients.

Еnzymes are able to effectively interact with various organophosphorus compounds (OPC), entering into (bio)chemical reactions with them. Changes in the initial activity of enzymes as a result of their inhibition by OPC, the formation of OPC degradation products under the action of hydrolytic enzymes, etc. can be determined using different physical and chemical methods and used in bioanalytic systems to determine the concentrations of OPC. The purpose of the review is to analyze the main scientific results achieved over the past 10 years in the development of analytical systems based on enzymes intended for the determination of OPC. It is shown in the article, that the requirements for the sensitivity of biosensors are based on the norms of the content of the analyzed substances detected in/at the objects of mandatory control. The cholinesterases compose a basis for the development of the largest number of ultra-sensitive biosensors, although other enzymes can be successfully used as a biosensitive element. The most technologically advanced solution that is close to the practical implementation seems to be bioanalytical systems using immobilized enzymes. Improving the detection limits of the OPC can be achieved by using nanoobjects together with modern methods of signal transducers, for example, with nanomechanical detectors and signal converters. This combination of technical solutions ensures the sensitivity of the OPC analysis up to pg/l. At present, «reagentless» systems have received significant development, which have become the basis for the production of a large number of commercially available strips for the express determination of OPC. Modern demands stimulate the rapid development of portable and, especially, wearable biosensors that can be attached to various surfaces, including a clothing. The progress in the development of affine amino acid sequences, in the future, will allow the creation of enzyme biosensors on any surface.

As one of the most important avian immunosuppressive and neoplastic diseases, Marek’s disease (MD), caused by oncogenic Marek’s disease virus (MDV), has caused huge economic losses worldwide over the past five decades. In recent years, MD outbreaks have occurred frequently in MD-vaccinated chicken flocks, but the key pathogenic determinants and influencing factors remain unclear. Herein, we analyzed the pathogenicity of seven newly isolated MDV strains from tumor-bearing chickens in China and found that all of them were pathogenic to chicken hosts, among which four MDV isolates, SDCW01, HNXZ05, HNSQ05 and HNSQ01, were considered to be hypervirulent MDV (HV-MDV) strains. At 73 days of the virus infection experiment, the cumulative incidences of MD were 100%, 93.3%, 90% and 100%, with mortalities of 83.3%, 73.3%, 60% and 86.7%, respectively, for the four viruses. The gross occurrences of tumors were 50%, 33.3%, 30% and 63.3%, respectively, accompanied by significant hepatosplenomegaly and serious atrophy of the immune organs. Furthermore, the immune protection effects of four commercial MD vaccines against SDCW01, CVI988, HVT, CVI988+HVT, and 814 were explored. Unexpectedly, during the 67 days of post-virus challenge, the protection indices (PIs) of these four MD vaccines were only 46.2%, 38.5%, 50%, and 28%, respectively, and the birds that received the monovalent CVI988 or HVT still developed tumors with cumulative incidences of 7.7% and 11.5%, respectively. To our knowledge, this is the first demonstration of the simultaneous comparison of the immune protection efficacy of multiple commercial MD vaccines with different vaccine strains. Our study revealed that the HV-MDV variants circulating in China could significantly break through the immune protection of the classical MD vaccines currently widely used. For future work, there is an urgent need to develop novel, more effective MD vaccines for tackling the new challenge of emerging HV-MDV strains or variants for the sustainable control of MD.

Objective: This study aims to explore the effects of miR-342-3p on liver cancer stem cells (LCSC) and related mechanism. Methods: LCSC were sorted using immunomagnetic beads and flow cytometry was used to determine CD133+ and CD133− sorted cells. The self-renewal ability and growth ability of LCSC were measured by tumor spheroid formation assay and soft agar colony formation assay. Protein and mRNA expressions of CD44, ALDH1, Bmi1, Sox2 and Oct4 were detected by western blot and quantitative PCR. The relationship between miR-342-3p and HDAC7 was analyzed by dual-luciferase assay. The acetylation level of H3 protein was measured by acetyl Lysine antibody. Results: miR-342-3p overexpression in LCSC lead to lower tumor volume, reduced tumor spheroid formation and agar colony formation rates, as well as lower mRNA and protein expressions of CD44, ALDH1, Bmi1, Sox2, and Oct4. Dual-luciferase reporter assay confirmed HDAC7 as a target gene of miR-342-3p. Inhibition of HDAC7 or overexpression of PTEN suppressed the carcinogenicity and stemness of LCSC. PTEN expression was increased in sh-HDAC7 group and decreased in pcDNA3.1-HDAC7 group. HDAC7 promoted H3 deacetylation and inhibited PTEN expression. Overexpression of HDAC7 or silencing of PTEN could reverse the inhibitory effect of overexpression of miR-342-3p on LCSC carcinogenicity and cell stemness. Conclusion: MiR-342-3p inhibited LCSC oncogenicity and cell stemness by promoting PTEN and inhibiting HDAC7. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) account for more than 30% of cancer cases, with definite identification of the oncogenic role of viral E6 and E7 genes. However, the identification of high-risk HPV genotypes has largely relied on lagged biological exploration and clinical observation, with types unclassified and oncogenicity unknown for many HPVs. In the present study, we retrieved and cleaned HPV sequence records with high quality and analyzed their genomic compositional traits of dinucleotide (DNT) and DNT representation (DCR) to overview the distribution difference among various types of HPVs. Then, a deep learning model was built to predict the oncogenic potential of all HPVs based on E6 and E7 genes. Our results showed that the main three groups of Alpha, Beta, and Gamma HPVs were clearly separated between/among types in the DCR trait for either E6 or E7 coding sequence (CDS) and were clustered within the same group. Moreover, the DCR data of either E6 or E7 were learnable with a convolutional neural network (CNN) model. Either CNN classifier predicted accurately the oncogenicity label of high and low oncogenic HPVs. In summary, the compositional traits of HPV oncogenicity-related genes E6 and E7 were much different between the high and low oncogenic HPVs, and the compositional trait of the DCR-based deep learning classifier predicted the oncogenic phenotype accurately of HPVs. The trained predictor in this study will facilitate the identification of HPV oncogenicity, particularly for those HPVs without clear genotype or phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hao, Jiang, Zhang and Han.)

Shuai Wang, Shanshan Du, Yong Lv, Fengyan Zhang, Wenzhan WangDepartment of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People’s Republic of ChinaPurpose: Previous studies have revealed that microRNA-665 (miR-665) is dysregulated in a variety of human cancers. However, little is known regarding its expression profiles and functions in retinoblastoma (RB). Therefore, the aims of our study were to evaluate miR-665 expression in RB and determine the precise roles of miR-665 in the progression of RB.Patients and methods: Herein, RT-qPCR was used to determine miR-665 expression levels in RB tissues and cell lines, and a series of functional experiments were performed to explore the influence of miR-665 on RB cell proliferation, colony formation, apoptosis, migration, and invasion as well as tumor growth. The molecular mechanisms underlying the tumor-suppressive action of miR-665 in RB were also explored.Results: We found that miR-665 was markedly reduced in RB tissues and cell lines and that lower miR-665 expression was strongly associated with tumor size, TNM stage, and differentiation in patients with RB. Exogenous expression of miR-665 suppressed cell proliferation, colony formation, migration, and invasion, and induced cell apoptosis in RB cells, while silencing miR-665 expression had the opposite effects. In addition, upregulation of miR-665 decreased the tumor growth of RB cells in vivo. High-mobility group box 1 (HMGB1) was identified as a direct target of miR-665 in RB cells, and decreasing the expression of HMGB1 simulated the regulatory effects of miR-665 overexpression in RB cells, while knockdown of HMGB1 expression counteracted the miR-665-mediated antitumor effects in RB cells. Moreover, miR-665 was shown to regulate the Wnt/β-catenin signaling pathway by targeting HMGB1 in vitro and in vivo.Conclusion: Taken together, our in vitro and in vivo results suggest that miR-665 acts as a tumor-suppressive miRNA in RB by directly targeting HMGB1 and inactivating the Wnt/β-catenin pathway. Hence, this miRNA is a candidate prognostic biomarker and therapeutic target in patients with RB.Keywords: microRNA-665, retinoblastoma, high-mobility group box 1, Wnt/β-catenin pathway, oncogenicity

In recent years, outbreaks of Marek’s disease (MD) have been frequently reported in vaccinated chicken flocks in China. Herein, we have demonstrated that four Marek’s disease virus (MDV) isolates, HN502, HN302, HN304, and HN101, are all pathogenic and oncogenic to hosts. Outstandingly, the HN302 strain induced 100% MD incidence, 54.84% mortality, and 87.10% tumor incidence, together with extensive atrophy of immune organs. Pathotyping of HN302 was performed in comparison to a standard very virulent (vv) MDV strain Md5. We found that both CVI988 and HVT vaccines significantly reduced morbidity and mortality induced by HN302 or Md5 strains, but the protection indices (PIs) provided by these two vaccines against HN302 were significantly lower (27.03%) or lower (33.33%) than that against Md5, which showed PIs of 59.89% and 54.29%, respectively. These data suggested that HN302 possesses a significant higher virulence than Md5 and at least could be designated as a vvMDV strain. Together with our previous phylogenetic analysis on MDV-1 meq genes, we have presently suggested HN302 to be a typical highly virulent MDV variant belonging to an independent Chinese branch. To our knowledge, this is the first report to provide convincible evidence to identify a pathogenic MDV variant strain with a higher virulence than Md5 in China, which may have emerged and circulating in poultry farms in China for a long time and involved in the recent MD outbreaks.

Background: Osteosarcoma (OS) is an exceptionally aggressive bone neoplasm that predominantly impacts the paediatric and adolescent population, exhibiting unfavourable prognosis. The importance of RNA binding motif protein 14 ( RBM14 ) in the aetiology of OS is not well understood, despite its established involvement in several other types of cancer., Methods: In this study, we conducted an analysis of the expression profiles of RBM14 in cancer tissues and cell lines. To achieve this, we will utilised data obtained from various databases including The Cancer Genome Atlas Program (TCGA) project, The Genotype-Tissue Expression (GTEx) Project, Gene Expression Omnibus (GEO) database, and cancer cell line encyclopedia (CCLE) data. Furthermore, this study also aims to examine the effects of RBM14 on the proliferation, migration, and invasive properties of OS cells using cell functional gain and loss studies. In this study, we carried out an in-depth investigation to explore possible molecular pathways that underlie the regulation of the malignant phenotype found in OS by RBM14 . This investigation involved integrating data from RBM14 overexpression, RBM14 knockdown RNA-seq experiments, and an array comprising 6,096 perturbed genes obtained from the Genetic Perturbation Similarity Analysis Database (GPSAdb). This research offers an opportunity to build a robust conceptual framework for the potential advancement of novel therapeutic approaches that are especially aimed at attacking OS., Results: RBM14 plays an active role in OS by significantly contributing to the enhancement of cellular proliferation, migration, and invasion. At the molecular level, it is probable that RBM14 exerts control over the malignant characteristics of OS through its modulation of the Hippo signalling system., Conclusions: The above-mentioned findings underscore the significant importance of RBM14 as an intriguing target for therapy for the mitigation and management of OS. This particular protein holds an excellent opportunity for the development of novel and efficacious therapeutic approaches that possess the potential to yield favorable results for patients affected with OS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-2070/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs.

The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed.

A heterozygous point mutation of p53 gene at codon 280 from AGA to ACA (R280T) frequently occurs in nasopharyngeal carcinoma (NPC) cell lines, and about 10% NPC tissues. However, the role of this mutation in the pathogenesis of NPC remains unclear. In this study, we generated p53 knockout (KO) NPC cell lines from CNE2 cells carrying heterozygous p53 R280T (p53-R280T) mutation and C666-1 cells carrying wild-type p53 by CRISPR-Cas9 gene editing system, and found that KO of heterozygous p53-R280T significantly decreased NPC cell proliferation and increased NPC cell apoptosis, whereas KO of wild-type p53 had opposite effects on NPC cell proliferation and apoptosis. Moreover, KO of heterozygous p53-R280T inhibited the anchorage-independent growth and in vivo tumorigenicity of NPC cells. mRNA sequencing of heterozygous p53-R280T KO and control CNE2 cells revealed that heterozygous p53-R280T mutation activated PI3K-Akt signaling pathway. Moreover, blocking of PI3K-Akt signaling pathway abolished heterozygous p53-R280T mutation-promoting NPC cell proliferation and survival. Our data indicate that p53 with heterozygous R280T mutation functions as an oncogene, and promotes the oncogenicity of NPC cells by activating PI3K-Akt signaling pathway.

Abstract Background The bcr-abl fusion gene is the pathological origin of chronic myeloid leukemia (CML) and plays a critical role in the resistance of imatinib. Thus, bcr-abl disruption-based novel therapeutic strategy may warrant exploration. In our study, we were surprised to find that the characteristics of bcr-abl sequences met the design requirements of zinc finger nucleases (ZFNs). Methods We constructed the ZFNs targeting bcr-abl with high specificity through simple modular assembly approach. Western blotting was conducted to detect the expression of BCR-ABL and phosphorylation of its downstream STAT5, ERK and CRKL in CML cells. CCK8 assay, colony-forming assay and flow cytometry (FCM) were used to evaluate the effect of the ZFNs on the viablity and apoptosis of CML cells and CML CD34+ cells. Moreover, mice model was used to determine the ability of ZFNs in disrupting the leukemogenesis of bcr-abl in vivo. Results The ZFNs skillfully mediated 8-base NotI enzyme cutting site addition in bcr-abl gene of imatinib sensitive and resistant CML cells by homology-directed repair (HDR), which led to a stop codon and terminated the translation of BCR-ABL protein. As expected, the disruption of bcr-abl gene induced cell apoptosis and inhibited cell proliferation. Notably, we obtained similar result in CD34+ cells from CML patients. Moreover, the ZFNs significantly reduced the oncogenicity of CML cells in mice. Conclusion These results reveal that the bcr-abl gene disruption based on ZFNs may provide a treatment choice for imatinib resistant or intolerant CML patients.

Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are emerging biomarkers in biological processes and the role of miR‐495‐3p has been identified in melanoma, while the detailed molecular mechanisms remain to be further explored. We aim to explore the effect of histone deacetylase 3 (HDAC3) and miR‐495‐3p on epithelial‐mesenchymal transition (EMT) and oncogenicity of melanoma cells by regulating tumour necrosis factor receptor‐associated factor 5 (TRAF5). Levels of HDAC3, miR‐495‐3p and TRAF5 in melanoma tissues and pigmented nevus tissues were determined, and the predictive roles of HDAC3 and miR‐495‐3p in prognosis of melanoma patients were measured. The melanoma cells were screened and transfected with relative oligonucleotides and plasmids, and the expression of HDAC3, miR‐495‐3p and TRAF5, and phenotypes of melanoma cells were gauged by a series of assays. The relations between HDAC3 and miR‐495‐3p, and between miR‐495‐3p and TRAF5 were confirmed. HDAC3 and TRAF5 were increased while miR‐495‐3p was decreased in melanoma cells and tissues, and the low expression of miR‐495‐3p as well as high expression of HDAC3 indicated a poor prognosis of melanoma patients. Inhibited HDAC3 elevated miR‐495‐3p to suppress EMT and oncogenicity of melanoma cells by reducing TRAF5. HDAC3 particularly bound to miR‐495‐3p and TRAF5 was the target gene of miR‐495‐3p. Our results revealed that down‐regulated HDAC3 elevates miR‐495‐3p to suppress malignant phenotypes of melanoma cells by inhibiting TRAF5, thereby repressing EMT progression of melanoma cells. This study may provide novel targets for melanoma treatment. [ABSTRACT FROM AUTHOR]

Purposes: Long intergenic non-protein coding RNA 525 (LINC00525), a long noncoding RNA, has been implicated in the carcinogenesis and progression of many human cancer types. However, the detailed roles of LINC00525 in chordoma and the underlying mechanisms are not fully understood. Here, we aimed to determine whether LINC00525 could modulate the oncogenicity of chordoma cells and to elucidate in detail the molecular events underlying these tumor-promoting activities. Methods: Reverse-transcription quantitative polymerase chain reactions were performed to assess LINC00525 expression in chordoma. The effects of LINC00525 silencing on chordoma cell proliferation, apoptosis, migration, and invasiveness in vitro and tumor growth in vivo were respectively tested using CCK-8 assay, flow cytometry, migration and invasion assays, and xenograft experiments. Results: High LINC00525 expression levels were detected in chordoma tissues. The proliferative, migratory, and invasive abilities of chordoma cells in vitro and their tumor growth in vivo were suppressed by the LINC00525 knockdown, whereas apoptosis was induced by it. Mechanistically, LINC00525 acted as a molecular sponge of microRNA-505-3p (miR-505-3p) and upregulated the expression of high mobility group box 1 (HMGB1), which is directly targeted by miR-505-3p. Rescue assays indicated that increasing the output of miR-505-3p–HMGB1 axis attenuated the effects of LINC00525 depletion on chordoma cells. Conclusion: LINC00525, a pro-oncogenic long noncoding RNA, promotes chordoma progression by regulating the miR-505-3p–HMGB1 axis. The LINC00525–miR-505-3p–HMGB1 pathway may be a novel therapeutic target in chordoma. [ABSTRACT FROM AUTHOR]

The bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a mitochondrial one-carbon folate metabolic enzyme whose role in cancer was not known until recently. MTHFD2 is highly expressed in embryos and a wide range of tumors but has low or absent expression in most adult differentiated tissues. Elevated MTHFD2 expression is associated with poor prognosis in both hematological and solid malignancy. Its depletion leads to suppression of multiple malignant phenotypes including proliferation, invasion, migration, and induction of cancer cell death. The non-metabolic functions of this enzyme, especially in cancers, have thus generated considerable research interests. This review summarizes current knowledge on both the metabolic functions and non-enzymatic roles of MTHFD2. Its expression, potential functions, and regulatory mechanism in cancers are highlighted. The development of MTHFD2 inhibitors and their implications in pre-clinical models are also discussed. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Our previous international epidemiological studies revealed that HPV58 carrying an E7 natural variant, T20I/G63S (designated V1), was associated with a higher risk of cervical cancer. We recently showed that V1 possesses a greater ability to immortalize and transform primary cells, as well as degrading pRB more effectively, than the prototype and other common variants. In this study, we performed a series of phenotypic and molecular assays using physiologically relevant in vitro and in vivo models to compare the oncogenicity of V1 with that of the prototype and other common natural variants. Through activation of the AKT and K-Ras/extracellular signal-regulated kinase (ERK) signaling pathways, V1 consistently showed greater oncogenicity than the prototype and other variants, as demonstrated by increased cell proliferation, migration, and invasion, as well as induction of larger tumors in athymic nude mice. This study complements our previous epidemiological and molecular observations pinpointing the higher oncogenicity of V1 than that of the prototype and all other common variants. Since V1 is more commonly found in eastern Asia, our report provides insight into the design of HPV screening assays and selection of components for HPV vaccines in this region. [ABSTRACT FROM AUTHOR]

A heterozygous point mutation of p53 gene at codon 280 from AGA to ACA (R280T) frequently occurs in nasopharyngeal carcinoma (NPC) cell lines, and about 10% NPC tissues. However, the role of this mutation in the pathogenesis of NPC remains unclear. In this study, we generated p53 knockout (KO) NPC cell lines from CNE2 cells carrying heterozygous p53 R280T (p53-R280T) mutation and C666-1 cells carrying wild-type p53 by CRISPR-Cas9 gene editing system, and found that KO of heterozygous p53-R280T significantly decreased NPC cell proliferation and increased NPC cell apoptosis, whereas KO of wild-type p53 had opposite effects on NPC cell proliferation and apoptosis. Moreover, KO of heterozygous p53-R280T inhibited the anchorage-independent growth and in vivo tumorigenicity of NPC cells. mRNA sequencing of heterozygous p53-R280T KO and control CNE2 cells revealed that heterozygous p53-R280T mutation activated PI3K-Akt signaling pathway. Moreover, blocking of PI3K-Akt signaling pathway abolished heterozygous p53-R280T mutation-promoting NPC cell proliferation and survival. Our data indicate that p53 with heterozygous R280T mutation functions as an oncogene, and promotes the oncogenicity of NPC cells by activating PI3K-Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase (RPTK), plays an oncogenic role by activating an unidentified TKI-258 (dovitinib)-sensitive RPTK in esophageal squamous cell carcinoma (ESCC) cells. Here, we demonstrate that among TKI-258-sensitive RPTKs, fibroblast growth factor receptor (FGFR) 1 is significantly up-regulated in ESCC tissues and cell lines. We show that PTK7 colocalizes with FGFR1 and binds it via its extracellular domain in human embryonic kidney 293 and ESCC TE-10 cells. PTK7 knockdown not only reduced ligand-free and fibroblast growth factor (FGF)-induced phosphorylation of FGFR1 but also the interaction of signaling adaptor proteins with FGFR1 and activation of downstream signaling proteins in TE-10 cells. In addition, PTK7 knockdown reduced FGF-induced oncogenic phenotypes including proliferation, anchorage-independent colony formation, wound healing, and invasion in ESCC cells. Taken together, our data demonstrate that PTK7 binds and activates FGFR1 independent of FGF and thus increases oncogenicity of PTK7- and FGFR1-positive cancers such as ESCC. [ABSTRACT FROM AUTHOR]

The use of diagnostic imaging involving ionising radiation may be necessary in pregnancy and requires an assessment of the most appropriate and safest imaging modality which will provide the necessary information balanced with the potential risks to the mother and fetus. In most cases, this will involve a potential fetal radiation dose well below 50 mGy. At these doses, there is no risk of lethality, genetic damage/epigenetic change, teratogenicity, growth impairment or sterility. Older epidemiological data indicating a potential increased cancer risk have been contradicted by newer data and better understanding of the biology of low dose radiation. The linear no-threshold rule has been challenged by many and more realistic estimates of oncogenicity risk along with the potential risks of contrast agents are summarised in this review. Imaging in the pregnant population is increasing in both the number of examinations performed and the number of patients being imaged, with the greatest increase being computed tomography scans. Counselling and obtaining informed consent for imaging that involves radiation requires the clinician to communicate with the woman and her family a realistic estimate of the potential radiation dose to herself and her fetus, to describe and quantitate the risks of this estimated dose, to outline the benefits of the imaging procedure and to respond to any questions or concerns. As almost all diagnostic imaging involves doses below the 50 mGy threshold, clinically indicated investigations should not be withheld during pregnancy. All allied staff must also be well informed to ensure the patient receives a consistent message about the risks and benefits of the proposed test. [ABSTRACT FROM AUTHOR]

Purpose: Several microRNAs (miRNAs) that are aberrantly expressed in glioblastoma multiforme (GBM) play a significant role in GBM formation and progression. The expression profile and functions of miR-559 in GBM remain unclear. Here, we quantified the expression and investigated the involvement of miR-559 in the oncogenicity of GBM cells in vitro and in vivo. Material and methods: Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) was carried out to determine miR-559 expression in GBM tissues and cell lines. A series of functional assays was performed to evaluate the effects of miR-559 overexpression on GBM cell proliferation, apoptosis, migration, and invasion in vitro and on GBM tumor growth in vivo. The regulatory mechanisms of miR-559 action in GBM cells were then explored. Results: The expression of miR‑559 was lower in GBM tissues and cell lines and significantly correlated with the Karnofsky performance score and tumor size among patients with GBM. Exogenous miR‑559 expression inhibited GBM cell proliferation, migration, and invasion and promoted apoptosis. MiR-559 overexpression decreased tumor growth in vivo. Mechanistic experiments confirmed metadherin (MTDH) as a direct target gene of miR-559 in GBM. Silencing of MTDH induced effects similar to those of miR-559 upregulation in GBM cells, whereas MTDH expression restoration attenuated the antitumor effects of miR‑559 in GBM cells. Protein kinase B (AKT) in the phosphatase and tensin homolog (PTEN)–AKT signaling pathway was found to be deactivated in GBM cells after upregulation of miR-559 both in vitro and in vivo. Conclusion: MiR-559 acts as a tumor suppressor in GBM cells in vitro and in vivo, at least in part through the downregulation of MTDH and inhibition of AKT in the PTEN–AKT pathway. Therefore, targeting the miR-559–MTDH axis may be a promising therapeutic strategy for patients with GBM. [ABSTRACT FROM AUTHOR]

Abstract It is well recognized that the association of human papillomavirus (HPV) and cervical carcinogenesis is based on the presence of HPV DNA sequence. The E6 and E7 oncoproteins encoded by high-risk HPV types play a key role in carcinogenesis. HPV58 type accounts for a larger share of cervical disease in China, whereas data on HPV58 genetic variability in China is limited. We aimed to evaluate the diversity of HPV58 genetic variants by sequencing the entire E6 and E7 genes. Phylogenetic trees were constructed by Maximum likelihood method by MEGA 5.05 software. In this study, the overall HPV infection rate was 22.6% (2891/12780) in Southeast China and the prevalence of HPV58 infection rate was 2.6% (335/12780). 26 nucleotides substitutions were observed in E6 and E7 genes with 10 novel substitutions and 17 non-synonymous substitutions. We obtained 25 distinct variation patterns which the accession GenBank numbers as MH348918-MH348942. All of HPV58 variants belong to lineage A, while no lineage B, C and D were detected in Taizhou area, Southeast China. The sublineage A1, A2, and A3 variants were found in 136 (68.3%), 39 (19.6%), and 24 (12.1%) of HPV58 isolates, respectively. The sublineage A3 variants with T20I/G63S substitutions at E7 oncoprotein carried a significantly higher risk for high-grade cervical intraepithelial neoplasia (CIN2 or worse, CIN2+) when compared with other HPV58 variants (odds ratio = 4.41, P < 0.05). Nevertheless, there was no association between HPV58 (sub) lineages and cervical lesions. These data provide the critical characteristics of HPV58 variants to assist further investigation of carcinogenic association and the development of next generation vaccines and diagnostic assays in China. Highlights • The data on HPV58 genetic variability and evolutionary history in Southeast China are limited. • We obtained 25 distinct variation patterns denoted as MH348918-MH348942. • All of HPV58 variants belong to lineage A, while no lineage B, C and D were detected in Taizhou area, Southeast China. • T20I/G63S substitutions carried a significantly higher risk for CIN2+ when compared with other HPV58 variants. • There was no association between HPV58 (sub) lineages and cervical lesions. [ABSTRACT FROM AUTHOR]

Human papillomavirus 58 (HPV58) ranks the second or third in East Asian cervical cancers. Current studies on HPV58 are scarce and focus on the prototype. Previously, we identified the three most common circulating HPV58 E7 strains contained amino acid alterations: G41R/G63D (51%), T20I/G63S (22%) and T74A/D76E (14%) respectively. Among them, the T20I/G63S variant (V1) had a stronger epidemiological association with cervical cancer. We therefore suggested that V1 possessed stronger oncogenicity than the other two variants. Here, we performed phenotypic assays to characterize and compare their oncogenicities with HPV58 E7 prototype. Our results showed that overexpression of V1 conferred a higher colony‐forming ability to primary murine epithelial cells than prototype (P < 0.05) and other variants, implicating its higher immortalising potential. Further experiments showed that both V1 and prototype enhanced the anchorage‐independent growth of NIH/3T3 cells (P < 0.001), implicating their stronger transforming power than the two other variants. Moreover, they possessed an increased ability to degrade pRb (P < 0.001), which is a major effector pathway of E7‐driven oncogenesis. Our work represents the first study to compare the oncogenicities of HPV58 E7 prototype and variants. These findings deepened our understanding of HPV58 and might inform clinical screening and follow‐up strategy. [ABSTRACT FROM AUTHOR]

Artemin (ARTN) is a member of glial cell linederived neurotrophic factor (GDNF) family of ligands, and its signaling is mediated via a multi-component receptor complex including the glycosylphosphatidylinositolanchored GDNF family receptors a (GFRa1, GFRa3) and RET receptor tyrosine kinase. The major mechanism of ARTN action is via binding to a non-signaling co-receptor. The major function of ARTN is to drive the molecule to induce migration and axonal projection from sympathetic neurons. It also promotes the survival, proliferation and neurite outgrowth of sympathetic neurons in vitro. ARTN triggers oncogenicity and metastasis by the activation of the AKT signaling pathway. Recent studies have reported that the expression of ARTN in hepatocellular carcinoma is associated with increased tumor size, quick relapse and shorter survival. Furthermore, ARTN promotes drug resistance such as antiestrogens, doxorubicin, fulvestrant, paclitaxel, tamoxifen and trastuzumab. Moreover, ARTN also stimulates the radio-therapeutic resistance. This review highlights the proposed roles of ARTN in cancer cells and discusses recent results supporting its emerging role as an oncogenic, metastatic and drug-resisting agent with a special focus on how these new insights may facilitate rational development of ARTN for targeted therapies in the future. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus-1 (HTLV-1) is the first pathogenic human retrovirus identified in 1979 by the Gallo group. HTLV-1 causes fatal T-cell leukemia (adult T cell leukemia) and a progressive myelopahy (HTLV-1-associated myelopathy/ tropical spastic paraparesis, HAM/TSP) and other disorders. Since the discovery of HTLV-1, several other microorganisms are demonstrated to cause cancer in humans. In this article, we investigated the oncogenic capacity of HTLV-1, in comparison with those of other oncoviruses and one oncobacterium (Helicobacter pylori, H. Pylori) based on published literature. We conclude here that HTLV-1 is one of the most and may be the most carcinogenic among them and arguably one of the most potent of the known human carcinogens. This fact has not been noted before and is particularly important to justify why we need to study HTLV-1 as an important model of human viral oncogenesis.

Human papillomavirus 58 (HPV58) is found in 10 to 18% of cervical cancers in East Asia but is rather uncommon elsewhere. The distribution and oncogenic potential of HPV58 variants appear to be heterogeneous, since the E7 T20I/G63S variant is more prevalent in East Asia and confers a 7- to 9-fold-higher risk of cervical precancer and cancer. However, the underlying genomic mechanisms that explain the geographic and carcinogenic diversity of HPV58 variants are still poorly understood. In this study, we used a combination of phylogenetic analyses and bioinformatics to investigate the deep evolutionary history of HPV58 complete genome variants. The initial splitting of HPV58 variants was estimated to occur 478,600 years ago (95% highest posterior density [HPD], 391,000 to 569,600 years ago). This divergence time is well within the era of speciation between Homo sapiens and Neanderthals/Denisovans and around three times longer than the modern Homo sapiens divergence times. The expansion of present-day variants in Eurasia could be the consequence of viral transmission from Neanderthals/Denisovans to non-African modern human populations through gene flow. A whole-genome sequence signature analysis identified 3 amino acid changes, 16 synonymous nucleotide changes, and a 12-bp insertion strongly associated with the E7 T20I/G63S variant that represents the A3 sublineage and carries higher carcinogenetic potential. Compared with the capsid proteins, the oncogenes E7 and E6 had increased substitution rates indicative of higher selection pressure. These data provide a comprehensive evolutionary history and genomic basis of HPV58 variants to assist further investigation of carcinogenic association and the development of diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Octamethylcyclotetrasiloxane (D 4 ) is a cyclic volatile methylsiloxane primarily used in the synthesis of silicon-based materials used in a variety of consumer products. This paper details the chronic toxicity and oncogenicity evaluation of D 4 in the Fischer 344 rat. Animals were exposed to 0, 10, 30, 150, or 700 ppm D 4 vapor for 6 h/day, 5 days/week for up to 104 weeks in whole-body inhalation chambers. Effects of two year chronic exposure included increased liver, kidney, testes, and uterine weight with correlating microscopic findings of hepatocellular hypertrophy (males only), chronic nephropathy (both sexes), interstitial cell hyperplasia, and cystic endometrial hyperplasia and endometrial adenoma, respectively. Upper respiratory tract irritation and lymphocytic leukocytosis were evident in both sexes. Increased neoplasia was demonstrated only in the uterus. Uterine endometrial adenomas were present in four of sixty animals exposed to 700 ppm D 4 for 24 months. None were present in the other treatment groups. In contrast, in 700 ppm D 4 group males the incidence of pituitary and pancreatic neoplasia was reduced as was thyroid c-cell adenoma/carcinoma in 700 ppm females. This study has identified that D 4 is a mild respiratory irritant and increases liver and kidney weight without inducing neoplasia in these tissues. The increased incidence of uterine adenoma was the only treatment-related neoplastic finding associated with chronic exposure to D 4 . [ABSTRACT FROM AUTHOR]

Particular mutations in the isocitrate dehydrogenase gene (IDH) were discovered in several gliomas citing astrocytoma, oligodendroglioma, and glioblastoma multiform, but also in leukemia; these mutations were discovered in nearly all cases of secondary glioblastomas, they evolve from lower-grade gliomas, but are limited in primary high-grade glioblastoma multiform. These mutations distinctively produce (D)-2-hydroxyglutarate (D-2-HG) from alpha-ketoglutarate (α-KG). (D)-2-hydroxyglutarate is accumulated to very high concentrations which inhibit the function of enzymes that are dependent on alpha-ketoglutarate. This modification leads to a hyper-methylated state of DNA and histones, resulting in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. In our work we review the impact of the mutations that occur in IDH genes, we focus on their impact on distribution in cancer. As IDH mutations appear in many different conditions we expose the extent of IDH mutations and derivate their impact on cancer prognosis, diagnosis, and even their oncogenicity, we will also link their impact to HIF-1α and derivate some target and finally, we present some of the therapeutics under research and out on market. [ABSTRACT FROM AUTHOR]