Activation Of Proto-oncogenes Research Articles

Participation of retroelements in chromoanagenesis in cancer development

Purpose of the study: to determine the role of retroelements in chromoanagenesis mechanisms in cancer etiopathogenesis.Material and Methods. The search for relevant sources was carried out in the Scopus, Web of Science, PubMed, Elibrary systems, including publications from February 2002 to December 2023. Of the 864 scientifc articles found, 60 were used to write a systematic review.Results. According to original works and meta-analyses results, the cause of complex chromosomal rearrangements during cancer development may be retroelement pathological activation. Chromoanagenesis involves LINE1, SVA, Alu, HERV, which cause double-stranded DNA breaks, insertions in tumor suppressor genes region, the formation of chimeric oncogenes due to retroelement use as new promoters, and function as molecular “band-aids” in non-homologous end junctions and form bridges of distal DNA fragments. Global structural rearrangements of chromosomes observed during chromoanagenesis may be consequences of retroelements activation, which participate in non-allelic homologous recombination and in microhomology-mediated joining of ends characteristic. Certain types of neoplasms, such as colon cancer, are characterized by both high levels of chromothripsis and retroelement activity. In head and neck squamous cell carcinoma, chromoplexy is specifc, the sources of sequences at the breakpoints of which are retroelements. During chromoanagenesis, activation of proto-oncogenes and inactivation of tumor suppressor genes are observed, which is also a consequence of retroelement activation. This is due to the presence of retroelement sequences in proto-oncogenes promoter regions and introns (which become the basis for chimeric oncogene formation) and hot spots of insertional mutagenesis in tumor suppressor genes (transpositions into these regions inactivate these genes).Conclusion. The results obtained on the driver effect of retroelements in chromothripsis, chromoplexy and chromoanasynthesis mechanisms, which are the basis for the formation of clonal evolution of tumors, indicate promise of targeted therapy aimed at silencing the activity of retroelements in cancer patients treatment. For this purpose, it is possible to use microRNAs complementary to retroelements, which are also involved in tumor development, as tools.

Malignant Pleural Mesothelioma: A Comprehensive Review.

Mesotheliomas are hyperplastic tumors that envelop the serosal membranes that safeguard the body's external surfaces. Although certain instances may exhibit indolent characteristics, a significant number of tumors demonstrate rapid progression and a poor prognosis. Mesotheliomas are typically categorized as benign or malignant, with malignant mesothelioma being more frequently linked to asbestos exposure. Malignant pleural mesothelioma (MPM) predominantly impacts males and often emerges in the late 50 s or beyond, characterized by a median age of early 70 s among patients exposed to asbestos lasting from 2 to 4 decades. Respiratory exposure to asbestos particles leads to the development of malignant mesothelioma, characterized by recurrent inflammation, disruption of cell division, activation of proto-oncogenes, and generation of free radicals. In pleural mesothelioma, BAP1, CDKN2A, and NF are the most often mutated genes. Accurate diagnosis and assessment usually require the use of chest computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET). Radiation therapy, immunotherapy, chemotherapy, and surgery are some of the treatment options that are currently available. This systematic review provides a comprehensive analysis of the latest research, biomarkers, evaluation, and management strategies for malignant pleural mesothelioma.

Disparity landscapes of viral-induced structural variations in HCC: Mechanistic characterization and functional implications.

HCC is the most common type of primary liver cancer and is a common malignancy worldwide. About half of all new liver cancers worldwide each year occur in China, including Hong Kong, due to a high prevalence of HBV infection. HBV DNA integrates into the human genome, disrupting the endogenous tumor suppressors/regulatory genes or enhancing the activity of proto-oncogenes. It would be useful to examine the different NGS-based databases to provide a more unbiased and comprehensive survey of HBV integration. We aimed to take advantage of publicly available data sets of different regional cohorts to determine the disparity landscapes of integration events among sample cohorts, tissue types, chromosomal positions, individual host, and viral genes, as well as genic locations. By comparing HCC tumors with non tumorous livers, the landscape of HBV integration was delineated in gene-independent and gene-dependent manners. Moreover, we performed mechanistic investigations on how HBV-TERT integration led to TERT activation and derived a score to predict patients' prognostication according to their clonal disparity landscape of HBV integration. Our study uncovered the different levels of clonal enrichment of HBV integration and identified mechanistic insights and prognostic biomarkers. This strengthens our understanding of HBV-associated hepatocarcinogenesis.

Mechanism of gabapentinoid potentiation of opioid effects on cyclic AMP signaling in neuropathic pain

Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). Increasing intracellular Ca2+ or activation of L-type VGCCs (L-VGCCs) suffices to mimic SCI effects on opioid sensitivity, in a manner dependent on the activity of the Raf1 proto-oncogene, serine/threonine-protein kinase C-Raf, but independent of neuronal depolarization. Together, our results provide a mechanism for potentiation of opioid effects by gabapentinoids after injury, via reduction of calcium influx through L-VGCCs, and suggest that other inhibitors targeting these channels may similarly enhance opioid treatment of neuropathic pain.

The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes.

Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing-which produces various mature mRNAs and, eventually, protein variants from a single gene-may also result in driving neoplastic transformation because of the different and often opposed functions of the variants of driver genes. The present review analyses the different alternative splicing events that result in driving neoplastic transformation, with an emphasis on their molecular mechanisms. To do this, we collected a list of 568 gene drivers of cancer and revised the literature to select those involved in the alternative splicing of other genes as well as those in which its pre-mRNA is subject to alternative splicing, with the result, in both cases, of producing an oncogenic isoform. Thirty-one genes fall into the first category, which includes splicing factors and components of the spliceosome and splicing regulators. In the second category, namely that comprising driver genes in which alternative splicing produces the oncogenic isoform, 168 genes were found. Then, we grouped them according to the molecular mechanisms responsible for alternative splicing yielding oncogenic isoforms, namely, mutations in cis splicing-determining elements, other causes involving non-mutated cis elements, changes in splicing factors, and epigenetic and chromatin-related changes. The data given in the present review substantiate the idea that aberrant splicing may regulate the activation of proto-oncogenes or inactivation of tumour suppressor genes and details on the mechanisms involved are given for more than 40 driver genes.

Pathological mechanisms of cold and mechanical stress in modulating cancer progression.

Environmental temperature and cellular mechanical force are the inherent factors that participate in various biological processes and regulate cancer progress, which have been hot topics worldwide. They occupy a dominant part in the cancer tissues through different approaches. However, extensive investigation regarding pathological mechanisms in the carcinogenic field. After research, we found cold stress via two means to manipulate tumors: neuroscience and mechanically sensitive ion channels (MICHs) such as TRP families to regulate the physiological and pathological activities. Excessive cold stimulation mediated neuroscience acting on every cancer stage through the hypothalamus-pituitary-adrenocorticoid (HPA) to reach the target organs. Comparatively speaking, mechanical force via Piezo of MICHs controls cancer development. The progression of cancer depends on the internal activation of proto-oncogenes and the external tumorigenic factors; the above two means eventually lead to genetic disorders at the molecular level. This review summarizes the interaction of bidirectional communication between them and the tumor. It covers the main processes from cytoplasm to nucleus related to metastasis cascade and tumor immune escape.

Abstract 1481: Disparity landscapes of HBV integration in hepatocellular carcinoma: Mechanistic characterization and functional implications

Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a common malignancy worldwide. About half of all new liver cancers worldwide each year occur in China due to a high prevalence of hepatitis B virus (HBV) infection. HBV DNA integrates into the human genome, disrupting the endogenous tumor suppressors/regulatory genes or enhancing the activity of proto-oncogenes. It would be useful to examine the different NGS-based databases to provide a more unbiased and comprehensive survey of HBV integration. We aimed to take advantage of publicly available datasets of different regional cohorts to determine the disparity landscapes of integration events among sample cohorts, tissue types, chromosomal positions, individual host and viral genes, and genic locations. By comparing HCC tumor with non-tumorous liver, landscape of HBV integration was delineated at gene-independent and gene-dependent manners. Moreover, we performed mechanistic investigations on how HBV-TERT integration led to TERT activation and derived a score to predict patients’ prognostication according to their clonal disparity landscape of HBV integration. We revealed a global geographical disparity of HBV integration that the landscape of HBV integration between HCC and non-tumorous liver varied in regional cohorts, suggesting the different degrees of clonal enrichment. In the Mainland China, Hong Kong and Mongolia cohorts, HCC tumors had higher numbers of events than the non-tumorous livers, whereas in the French and US cohorts, the reverse was true. Moreover, most HBV integrations were positionally enriched at the telomeres and centromeres, and this highlighted the novel co-involvement of HBV integration at these regions, which likely introduces greater genomic instability. Furthermore, we constructed a large meta-cohort of multiple ethnicities to refine the landscape of HBV integration. This enabled the identification of events at key HCC-related genes (e.g., TERT, KMT2B, and CCNA2) and gene families (e.g., cyclin, cadherin, and contactin). As TERT is the most frequently integrated gene by HBV, we further investigated the mechanistic modulation of TERT transcription activation by combining and analyzing our in-house sample cohort with a previous report and luciferase reporter assays. This revealed the positive concurrent influence by both the orientation and relative distance of HBV integration (closer to transcription start site) from the TERT gene. Additionally, we observed clonal disparity of HBV integration among patients and the higher level of the clonal disparity score correlated with poor prognostication of HCC patients. Our study uncovered the different levels of clonal enrichment of HBV integration and identified mechanistic insights and prognostic biomarker. This strengthens our understanding of HBV-associated hepatocarcinogenesis. Citation Format: Xueying Lyu, Karen Man-Fong Sze, Joyce Man-Fong Lee, Abdullah Husain, Irene Oi-Lin Ng, Daniel Wai-Hung Ho. Disparity landscapes of HBV integration in hepatocellular carcinoma: Mechanistic characterization and functional implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1481.

Molecular and clinicopathologic characteristics of CNS embryonal tumors with BRD4::LEUTX fusion.

Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.

Targeting RET alterations in non-small cell lung cancer

Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell lung cancer (NSCLC), RET mutations often manifest as RET fusion genes and are observed in 1–2 % of patients with NSCLC. In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. While first-generation RET inhibitors have become part of the standard of care for RET-fusion positive NSCLC, a new challenge has emerged: acquired resistance to RET inhibitors. RET resistance is a complex phenomenon that can manifest as either on-target or off-target resistance. Numerous studies have been conducted to identify the mechanisms behind this resistance. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.

Decoding HiPSC-CM’s Response to SARS-CoV-2: mapping the molecular landscape of cardiac injury

BackgroundAcute cardiac injury caused by coronavirus disease 2019 (COVID-19) increases mortality. Acute cardiac injury caused by COVID-19 requires understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly infects cardiomyocytes. This study provides a solid foundation for related studies by using a model of SARS-CoV-2 infection in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) at the transcriptome level, highlighting the relevance of this study to related studies. SARS-CoV-2 infection in hiPSC-CMs has previously been studied by bioinformatics without presenting the full molecular biological process. We present a unique bioinformatics view of the complete molecular biological process of SARS-CoV-2 infection in hiPSC-CMs.MethodsTo validate the RNA-seq datasets, we used GSE184715 and GSE150392 for the analytical studies, GSE193722 for validation at the cellular level, and GSE169241 for validation in heart tissue samples. GeneCards and MsigDB databases were used to find genes associated with the phenotype. In addition to differential expression analysis and principal component analysis (PCA), we also performed protein-protein interaction (PPI) analysis, functional enrichment analysis, hub gene analysis, upstream transcription factor prediction, and drug prediction.ResultsDifferentially expressed genes (DEGs) were classified into four categories: cardiomyocyte cytoskeletal protein inhibition, proto-oncogene activation and inflammation, mitochondrial dysfunction, and intracellular cytoplasmic physiological function. Each of the hub genes showed good diagnostic prediction, which was well validated in other datasets. Inhibited biological functions included cardiomyocyte cytoskeletal proteins, adenosine triphosphate (ATP) synthesis and electron transport chain (ETC), glucose metabolism, amino acid metabolism, fatty acid metabolism, pyruvate metabolism, citric acid cycle, nucleic acid metabolism, replication, transcription, translation, ubiquitination, autophagy, and cellular transport. Proto-oncogenes, inflammation, nuclear factor-kappaB (NF-κB) pathways, and interferon signaling were activated, as well as inflammatory factors. Viral infection activates multiple pathways, including the interferon pathway, proto-oncogenes and mitochondrial oxidative stress, while inhibiting cardiomyocyte backbone proteins and energy metabolism. Infection limits intracellular synthesis and metabolism, as well as the raw materials for mitochondrial energy synthesis. Mitochondrial dysfunction and energy abnormalities are ultimately caused by proto-oncogene activation and SARS-CoV-2 infection. Activation of the interferon pathway, proto-oncogene up-regulation, and mitochondrial oxidative stress cause the inflammatory response and lead to diminished cardiomyocyte contraction. Replication, transcription, translation, ubiquitination, autophagy, and cellular transport are among the functions that decline physiologically.ConclusionSARS-CoV-2 infection in hiPSC-CMs is fundamentally mediated via mitochondrial dysfunction. Therapeutic interventions targeting mitochondrial dysfunction may alleviate the cardiovascular complications associated with SARS-CoV-2 infection.

DeepCBS: shedding light on the impact of mutations occurring at CTCF binding sites.

CTCF-mediated chromatin loops create insulated neighborhoods that constrain promoter-enhancer interactions, serving as a unit of gene regulation. Disruption of the CTCF binding sites (CBS) will lead to the destruction of insulated neighborhoods, which in turn can cause dysregulation of the contained genes. In a recent study, it is found that CTCF/cohesin binding sites are a major mutational hotspot in the cancer genome. Mutations can affect CTCF binding, causing the disruption of insulated neighborhoods. And our analysis reveals a significant enrichment of well-known proto-oncogenes in insulated neighborhoods with mutations specifically occurring in anchor regions. It can be assumed that some mutations disrupt CTCF binding, leading to the disruption of insulated neighborhoods and subsequent activation of proto-oncogenes within these insulated neighborhoods. To explore the consequences of such mutations, we develop DeepCBS, a computational tool capable of analyzing mutations at CTCF binding sites, predicting their influence on insulated neighborhoods, and investigating the potential activation of proto-oncogenes. Futhermore, DeepCBS is applied to somatic mutation data of liver cancer. As a result, 87 mutations that disrupt CTCF binding sites are identified, which leads to the identification of 237 disrupted insulated neighborhoods containing a total of 135 genes. Integrative analysis of gene expression differences in liver cancer further highlights three genes: ARHGEF39, UBE2C and DQX1. Among them, ARHGEF39 and UBE2C have been reported in the literature as potential oncogenes involved in the development of liver cancer. The results indicate that DQX1 may be a potential oncogene in liver cancer and may contribute to tumor immune escape. In conclusion, DeepCBS is a promising method to analyze impacts of mutations occurring at CTCF binding sites on the insulator function of CTCF, with potential extensions to shed light on the effects of mutations on other functions of CTCF.

Mechanisms of the role of proto-oncogene activation in promoting malignant transformation of mature B cells.

Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes. Among these, the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells. Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs. Several preclinical and clinical studies have revealed that the development pathway of B cells, and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites. Therefore, summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.

Harmony unveiled: Intricate the interplay of dietary factor, gut microbiota, and colorectal cancer-A narrative review.

Diet plays a critical role in shaping the gut microbiome, which in turn regulates molecular activities in the colonic mucosa. The state and composition of the gut microbiome are key factors in the development of colorectal cancer. An altered gut microbiome, linked to weakened immune responses and the production of carcinogenic substances, is a significant contributor to colorectal cancer pathogenesis. Dietary changes that involve low-fiber and phytomolecule intake, coupled with higher consumption of red meat, can raise the risk of colorectal cancer. Salutary filaments, which reach the colon undigested, are metabolized by the gut microbiome, producing short-chain fatty acids. Short-chain fatty acids possess beneficial anti-inflammatory and antiproliferative properties that promote colon health. A well-balanced microbiome, supported by beneficial fibers and phytochemicals, can regulate the activation of proto-oncogenes and oncogenic pathways, thereby reducing cell proliferation. Recent research suggests that an overabundance of specific microbes, such as Fusobacterium nucleatum, may contribute to adverse changes in the colonic mucosa. Positive lifestyle adjustments have been demonstrated to effectively inhibit the growth of harmful opportunistic organisms. Synbiotics, which combine probiotics and prebiotics, can protect the intestinal mucosa by enhancing immune responses and decreasing the production of harmful metabolites, oxidative stress, and cell proliferation. This narrative review provides a concise understanding of evolving evidence regarding how diet influences the gut microbiome, leading to the restoration of the colonic epithelium. It underscores the importance of a healthy, plant-based diet and associated supplements in preventing colorectal cancer by enhancing gut microbiome health.

Detection of Esophageal Cancer Lesions Based on CBAM Faster R-CNN

Esophageal cancer is a common malignant tumor in daily life, which seriously affects human health. Esophageal cancer in China. The incidence rate is among the highest in the world, and there are a large number of new cases of esophageal cancer every year. At present, the diagnosis of esophageal cancer is mainly based on the use of electronic gastroscopy, which reflects the observed situation on the fluorescent screen and conducts detection through the fluorescent screen. With the increasing number of patients, the pressure and intensity of the doctor's work are getting greater and greater[1]. From the perspective of molecular level, the occurrence and development of esophageal cancer, like other cancers, are related to the activation of proto-oncogenes and the inhibition of anti-apoptosis genes. CBAM Faster R-CNN is proposed to solve the problems such as the esophageal region is not obvious and the background region occupies a large proportion in the feature map obtained by the backbone network of Faster R-CNN in barium meal imaging. CBAM is added to the convolutional attention module CBAM on the basis of the original Faster R-CNN model. To enhance the saliency of the features of the esophageal region in the feature map. CBAM Faster R-CNN model was used to train the training set after data enhancement, and Recall, Precision and AP values were used for evaluation and analysis.

Lung Cancer: A Literature Review

Lung cancer is a cancer whose onset starts in the lungs where there is an abnormal cell growth that is very fast and uncontrolled. The abnormal cell growth is triggered by deoxyribonucleic acid (DNA) damage, including deletions in the DNA section, inactivation of tumor suppressor genes, activation of proto-oncogenes to oncogenes, the absence of apoptosis, and the activity of the telomerase enzyme. Lung cancer is initiated by oncogeneous activity and inactivation of tumor suppressor genes. Oncogenes are genes that help cells grow and divide and are believed to cause a person to develop lung cancer. In general, lung cancer is divided into two types, namely non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). World Health Organization (WHO) classifies lung cancer based on histopathology into 4 major cell types, namely SCLC, NSCLC which includes adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma (LCC). The difference between the two is that SCLC has a higher aggressiveness than NSCLC. Cancer treatment is based on the type, size, location and stage of the cancer, as well as the patient's overall condition.

Spatial and clonality-resolved 3D cancer genome alterations reveal enhancer-hijacking as a potential prognostic marker for colorectal cancer

The regulatory effect of non-coding large-scale structural variations (SVs) on proto-oncogene activation remains unclear. This study investigated SV-mediated gene dysregulation by profiling 3D cancer genome maps from 40 patients with colorectal cancer (CRC). We developed a machine learning-based method for spatial characterization of the altered 3D cancer genome. This revealed a frequent establishment of "de novo chromatin contacts" that can span multiple topologically associating domains (TADs) in addition to the canonical TAD fusion/shuffle model. Using this information, we precisely identified super-enhancer (SE)-hijacking and its clonal characteristics. Clonal SE-hijacking genes, such as TOP2B, are recurrently associated with cell-cycle/DNA-processing functions, which can potentially be used as CRC prognostic markers. Oncogene activation and increased drug resistance due to SE-hijacking were validated by reconstructing the patient's SV using CRISPR-Cas9. Collectively, the spatial and clonality-resolved analysis of the 3D cancer genome reveals regulatory principles of large-scale SVs in oncogene activation and their clinical implications.

The Potential of miR-21 in Stem Cell Differentiation and its Application in Tissue Engineering and Regenerative Medicine.

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two important types of non-coding RNAs that are not translated into protein. These molecules can regulate various biological processes, including stem cell differentiation and self-renewal. One of the first known miRNAs in mammals is miR-21. Cancer-related studies have shown that this miRNA has proto-oncogene activity and is elevated in cancers. However, it is confirmed that miR-21 inhibits stem cell pluripotency and self-renewal and induces differentiation by targeting various genes. Regenerative medicine is a field of medical science that tries to regenerate and repair damaged tissues. Various studies have shown that miR-21 plays an essential role in regenerative medicine by affecting stem cell proliferation and differentiation. In this review, we will discuss the function of miR-21 in regenerative medicine of the liver, nerve, spinal cord, wound, bone, and dental tissues. In addition, the function of natural compounds and lncRNAs will be analyzed as potential regulators of miR-21 expression in regenerative medicine.

TAL1 activation in T-cell acute lymphoblastic leukemia: a novel oncogenic 3' neo-enhancer.

T-cell acute lymphocytic leukemia protein 1 (TAL1) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). Its deregulation can occur through diverse cis-alterations, including SIL-TAL1 microdeletions, translocations with T-cell Receptor loci, and more recently described upstream intergenic non-coding mutations. These mutations consist of recurrent focal microinsertions that create an oncogenic neo-enhancer accompanied by activating epigenetic marks. This observation laid the groundwork for an innovative paradigm concerning the activation of proto-oncogenes via genomic alterations of non-coding intergenic regions. However, for the majority of T-ALL expressing TAL1 (TAL1+), the deregulation mechanism remains 'unresolved'. We took advantage of H3K27ac and H3K4me3 chromatin immunoprecipitation sequencing data of eight cases of T-ALL, including five TAL1+ cases. We identified a putative novel oncogenic neo-enhancer downstream of TAL1 in an unresolved monoallelic TAL1+ case. A rare but recurrent somatic heterozygous microinsertion within this region creates a de novo binding site for MYB transcription factor. Here we demonstrate that this mutation leads to increased enhancer activity, gain of active epigenetic marks, and TAL1 activation via recruitment of MYB. These results highlight the diversity of non-coding mutations that can drive oncogene activation.

Biochemical and pharmacological properties of reporter systems and nanoparticles: For better tumors imaging and treatment

Reporter systems can analyze the biochemical and molecular processes in viable cells and organs and help imaging of cancer. That includes gene transcription activity, protein–protein interactions, sub-cellular localization and proteases activities. This helps studying the aspects of neoplastic trans¬formation, drug development, monitoring specific cancer-related events and tracing complex patho¬logical events (angiogenesis, apoptosis, proto-oncogene activity, oncongenes, tumor suppressor genes and tumor promoting signals). Resolution and sensitivity govern the choice of reporters. Nanoparticles have diverse uses (magnetic, catalytic, optical, thermodynamic, and electrochemical). Nanoparti¬cles include aptamers, quantum dots, core-shell silica particles, gold nanoparticles, carbon nanotubes, liposomes, dendrimers, oligonucleotides and magnetic nanoparticles. Superparamagnetic iron oxide nanoparticles (SPIONs) have the advantages of easy visualization using Magnetic resonance imaging (MRI), easy cellular targeting, possibility of generating hyperthermia, and easy biodegradation into metabolizable iron particles. Magnetic nanoparticles can be used in chemotherapy, magnetic hyper¬thermia, photodynamic therapy and photothermal therapy. MRI is the most valuable noninvasive imaging techniques to overcome magnetic nanoparticles colloidal instability. In conclusion, SPIONs are among the best nanoparticles to date owing to their easy visualization using MRI, easy cellular targeting, possibility of generating hyperthermia, and easy biodegradation into metabolizable iron particles. Research regarding reporter systems and nanoparticles is quite interesting and challenging. More research efforts are needed to optimize in vivo cancer imaging and therapeutics monitoring.

Bimodal Age Distribution in Cancer Incidence.

Cancer is caused by accumulation of genetic changes which include activation of protooncogenes and loss of tumor suppressor genes. The age-specific incidence of cancer in general increases with advancing age. However, some cancers exhibit a bimodal distribution. Commonly recognized cancers with bimodal age distribution include acute lymphoblastic leukemia, osteosarcoma, Hodgkin's lymphoma, germ cell tumors and breast cancer. Delayed infection hypothesis has been used to provide explanation for the early childhood peak in leukemias and lymphomas, whereas the peak at an older age is associated with accumulation of protooncogenes and weakened immune system. Further genetic analysis and histopathological variations point to distinctly different cancers, varying genetically and histologically, which are often combined under a single category of cancers. Tumor characteristics and age distribution of these cancers varies also by population groups and has further implications on cancer screening methods. Although significant advances have been made to explain the bimodal nature of such cancers, the specific genetic mechanisms for each age distribution remain to be elucidated. Further distinction among the different cancer subtypes may lead to improvements in individual risk assessments, prevention and enhancement of treatment strategies.