Pyrimidine-Dependent UV-Mediated Cross-Linking Magnifies Minor Genetic or Epigenetic Changes in Clinical Samples.

BACKGROUND: Detection of minor DNA allele alterations is becoming increasingly important for early detection and monitoring of cancer. We describe a new method that uses ultraviolet light to eliminate wild-type DNA alleles and enables improved detection of minor genetic or epigenetic changes. METHODS: Pyrimidine-dependent UV-based minor-allele enrichment (PD-UVME) employed oligonucleotide probes that incorporated a UVA-sensitive 3-cyanovinylcarbazole (CNVK), placed directly opposite interrogated pyrimidines, such as thymine (T) or cytosine (C) in wild-type (WT) DNA. Upon UVA-illumination, CNVK cross-linked with T/C, preventing subsequent amplification. Mutations that removed the T/C escaped cross-linking and were amplified and detected. Similarly, CNVK discriminated between methylated and unmethylated cytosine in CpG dinucleotides, enabling direct enrichment of unmethylated DNA targets. PD-UVME was combined with digital droplet PCR (ddPCR) to detect serine/threonine-protein kinase B-Raf (BRAF) V600E mutations in model systems, thyroid patient cancer tissue samples, and circulating DNA of tumor origin (ctDNA) from melanoma patients. RESULTS: One thyroid cancer sample out of 9, and 6 circulating-DNA samples out of 7 were found to be BRAF V600E-positive via PD-UVME while classified as negative by conventional ddPCR. Positive samples via conventional ddPCR were also found positive via PD-UVME. All 10 circulating cell-free DNA (cfDNA) samples obtained from normal volunteers were negative via both approaches. Furthermore, preferential enrichment of unmethylated alleles in MAGEA1 promoters using PD-UVME was demonstrated. CONCLUSIONS: PD-UVME mutation/methylation enrichment performed prior to ddPCR magnifies low-level mutations or epigenetic changes and increases sensitivity and confidence in the results. It can assist with clinical decisions that hinge on the presence of trace alterations like BRAF V600E.

Evaluation of Circ_0000977-Mediated Regulatory Network in Breast Cancer: A Potential Discriminative Biomarker for Triple-Negative Tumors.

Previous investigations have revealed that circular RNAs (circRNAs) play pivotal roles in cancer development and progression by participating in several biological procedures, such as competing endogenous RNA (ceRNA) networks. Recently, circRNAs have been proposed as non-invasive, stable, and affordable cell-free biomarkers for cancer screening and test monitoring. Although, their clinical usefulness vastly remains to be evaluated in breast cancer (BC). Triple-negative breast cancer (TNBC), as the most challenging BC subtype, is an urgent requirement of identifying specific biomarkers and discovering the molecular mechanisms that lead to aggressive behaviors of tumor cells. The therapeutic strategies for TN patients have remained limited due to the impracticality of endocrine therapies and a remarkable portion of patients with TNBC experience recurrence, chemoresistance, and metastasis. TNBC Microarray expression profile analysis found that circ_0000977 is one of the most dysregulated circRNA in TNBC in comparison with non-TNBC. It could be a clue referring to the potential clinical utility of circ_0000977 in TNBC. The current study aims to assess the clinical implications and potential ceRNA regulatory network of circ_0000977 in TNBC. We confirmed circ_0000977 down-regulation in TNBC cell lines and tumors versus non-TNBC samples by real-time PCR. Subsequently, an assessment of the diagnostic value of circ_0000977 in plasma samples from triple-negative patients revealed a potential diagnostic cell-free biomarker in triple-negative BC. Finally, our integrative approach uncovered potential circ-0000977/miR-135b-5p/mRNAs regulatory network in TNBC. The inhibitory effect of miR-135b-5p on its downstream mRNAs was assessed by knocking down it in MDA-MB-231 cells. Functional and correlation analyses revealed APC and GATA3 could be regulated by circ_0000977/miR-135b-5p ceRNA axis, which presents valuable insight into circ-0000977-mediated gene silencing involved in the ceRNA network of TNBC. This study uncovered the potential clinical implication of circ_0000977 for the diagnosis and treatment of TNBC patients.

Enzymatic Methods for Mutation Detection in Cancer Samples and Liquid Biopsies.

Low-level tumor somatic DNA mutations in tissue and liquid biopsies obtained from cancer patients can have profound implications for development of metastasis, prognosis, choice of treatment, follow-up, or early cancer detection. Unless detected, such low-frequency DNA alterations can misinform patient management decisions or become missed opportunities for personalized medicine. Next-generation sequencing technologies and digital-PCR can resolve low-level mutations but require access to specialized instrumentation, time, and resources. Enzymatic-based approaches to detection of low-level mutations provide a simple, straightforward, and affordable alternative to enrich and detect such alterations and is broadly available to low-resource laboratory settings. This review summarizes the traditional uses of enzymatic mutation detection and describes the latest exciting developments, potential, and applications with specific reference to the field of liquid biopsy in cancer.

Recent Developments in Mutation Enrichment and Detection Technologies.

BACKGROUND: Presence of excess unaltered, wild-type DNA (wtDNA) providing information of little clinical value may often mask low-level mutations containing important diagnostic or therapeutic clues. This is a recurring hurdle in biotechnology and medicine, including cancer, prenatal diagnosis, infectious diseases, and organ transplantation. Mutation enrichment techniques that allow reduction of unwanted DNA to enable the detection of low-level mutations have emerged since the early 1990s. They are continuously being refined and updated with new technologies. The burgeoning interest in liquid biopsies for residual cancer monitoring, detection of resistance to therapy, and early cancer detection has driven an expanded interest in new and improved methodologies for practical and effective mutation enrichment and detection of low-level mutations of clinical relevance. CONTENT: Newly developed mutation enrichment technologies are described and grouped according to the main principle of operation, PCR-blocking technologies, enzymatic methods, and physicochemical approaches. Special emphasis is given to technologies enabling pre-PCR blockage of wtDNA to bypass PCR errors [nuclease-assisted minor-allele enrichment assay with overlapping probes (NaME-PrO) and UV-mediated cross-linking minor allele enrichment (UVME)] or providing high multiplexity followed by next-generation sequencing [Minor allele enriched sequencing through recognition oligonucleotides (MAESTRO)]. SUMMARY: This review summarizes technological developments in rare mutation enrichment over the last 12 years, complementing pre-2010 reviews on this topic. The expanding field of liquid biopsy calls for improved limits of detection (LOD) and highly parallel applications, along with the traditional requirements for accuracy, speed, and cost-effectiveness. The current technologies are reviewed with regards to these new requirements.

Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

The concept of the 'BRCAness' phenotype implies the properties that some sporadic breast cancers (BC) share with BRCA1/2-mutation carriers with hereditary BC. Breast tumors with BRCAness have deficiencies in homologous recombination repair (HRR), like BRCA1/2-mutation carriers, and consequently could benefit from poly-(ADP)-ribose polymerase (PARP) inhibitors and DNA-damaging chemotherapy. Triple-negative breast cancers (TNBC) show a higher frequency of BRCAness than the other BC subtypes. Therefore, looking for BRCAness-related biomarkers could improve personalized management of TNBC patients. microRNAs (miRNAs) play a pivotal role in onco-transcriptomic profiles of tumor cells besides their suitable features as molecular biomarkers. The current study aims to evaluate the expression level of some critical miRNAs-mRNA axes in HRR pathway in tumors and plasma samples from BC patients. The expression levels of three multi-target miRNAs, including miR-182-5p, miR-146a-5p, and miR-498, as well as six downstream HRR-related protein-coding genes, have been investigated in the breast tumors and paired adjacent normal tissues by Real-time PCR. In the next step, based on the results derived from the previous step, we examined the level of cell-free miR-182-5p in the blood plasma samples from the patients. Our results highlight the difference between TNBC and non-TNBC tumor subgroups regarding the dysregulation of the key miRNA/mRNA axes involved in the HRR pathway. Also, for the first time, we show that the level of cell-free miR-182-5p in plasma samples from BC patients could be a clue for screening BC patients eligible for receiving PARP inhibitors through a personalized manner. Altogether, some sporadic BC patients, especially sporadic TNBC, have epigenetically dysregulated HRR pathway that could be identified and benefit from BRCAness-specific therapeutic agents.

The importance of regulatory pathway mediated by Circ0001955 in colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) has become one of the most common cancers in recent years. Given the importance that non-coding RNAs have recently acquired in various diseases including cancers, we decided to design this study to evaluate the expression levels of circ0001955/miR-145-5p/ONECUT2 axis in CRC. METHODS: After bioinformatics analysis of GEO datasets related to CRC, a putative circ0001955/ miR-145-5p/ ONECUT2 pathway was assumed. Then, the expression levels of these genes were measured in 50 CRC samples and adjacent tissues by qRT- PCR. Also, correlation coefficients, receiver operating characteristic (ROC) curves, and correlation between circ0001955 levels with clinicopathological parameters of patients were analyzed. RESULTS: Circ0001955 and ONECUT2 were considerably up-regulated, while the expression level of miR-145-5p was decreased in CRC samples compared with adjacent tissues (p < 0.05). Moreover, statistically significant correlations were observed between expression levels of circ0001955, miR-145-5p, and ONECUT2. We did not find any significant correlation between circ0001955 expression and clinicopathological parameters. CONCLUSION: Our study showed that circ0001955 is dysregulated in CRC. This finding can open a new window for researchers for a better understanding of the potential pathways involved in CRC pathogenesis and, consequently, to find new treatment pathways.

Interindividual immunogenic variants: Susceptibility to coronavirus, respiratory syncytial virus and influenza virus.

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.

Prospect of exosomal circular RNAs in breast Cancer: presents and future.

Implementing precision oncology for breast cancer (BC) is a critical method for improving patient outcomes, which relies on the use of reliable biomarkers to be effective and safe. exosomes represent a potential alternative for the diagnosis and therapy of BC, As a "liquid biopsy" and a novel source for biomarkers. Exosomes are nanoscale phospholipid bilayer vesicles released by most cells that contain a large payload of various RNA species that can alter recipient cell activity. Circular RNAs (circRNAs) were recently revealed as a looping subclass of competing endogenous noncoding RNAs (ceRNAs) capable of microRNA sponging to regulate gene expression. They provide critical regulatory functions in carcinogenesis, proliferation, invasion, metastasis, and treatment resistance, as well as cancer prognostic. However, there is still a major gap in our understanding of the role of circRNA in the advancement of BC. CircRNAs are abundant in exosomes, according to various studies, and exosomal circRNAs (exo-circRNAs) play a significant role in cancer biology. Exo-circRNAs can be picked up by nearby or distant cells, affecting many features of the target cells' pathophysiological states, thus boosting cell communication and tumor spread. In this review, we have briefly summarized the major properties and functions of exosomes. Then, we have focused on exo-circRNAs, discussing their potential roles in both driving and inhibiting BC, as well as for cancer diagnosis, prognosis, and monitoring.

The role of FOXC1/FOXCUT/DANCR axis in triple negative breast cancer: a bioinformatics and experimental approach.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer and does not benefit from the existing targeted therapies. In the present study, we used bioinformatics and experimental approaches to assess the genes that are somehow involved in the epithelial-mesenchymal transition (EMT) pathway which may explain the invasive features of TNBC. METHOD AND RESULTS: We analyzed five GEO datasets consisting of 657 breast tumors by GEO2R online software to achieve common differentially expressed genes (DEGs) between TNBC and non-TNBC tumors. The expression of the selected coding and non-coding genes was validated in 100 breast tumors, including fifty TNBC and fifty non-TNBC samples, using quantitative Real-Time PCR (qRT-PCR). The bioinformatics approach resulted in a final DEG list consisting of ten upregulated and seventeen downregulated genes (logFC ≥|1| and P < 0.05). Co-expression network construction indicated the FOXC1 transcription factor as a central hub node. Considering the notable role of FOXC1 in EMT, the expression levels of FOXC1-related lncRNAs, lnc-FOXCUT and lnc-DANCR, were also evaluated in the studied tumors. The results of qRT-PCR confirmed notable upregulation of FOXC1, lnc-FOXCUT, and lnc-DANCR in TNBC tissues compared to non-TNBC samples (P < 0.0001, P = 0.0005, and P = 0.0008, respectively). Moreover, ROC curve analysis revealed the potential biomarker role of FOXC1 in TNBC samples. CONCLUSION: Present study suggested that the deregulation of FOXC1/lnc-FOXCUT/lnc-DANCR axis may contribute to the aggressive features of triple-negative breast tumors. Therefore, this axis may be considered as a new probable therapeutic target in the treatment of TNBC.

The Immunogenetics of Melanoma.

Melanoma is a relatively common and deadly type of skin cancer that originates from melanocytes. Cutaneous malignant melanoma results from the interplay between genetic susceptibility and environmental factors. Though the majority of melanoma cases are sporadic, several high and low penetrance mutations have been identified as underlying factors of heritable melanoma. Genetic variations in immune system components are among the most studied factors in melanoma heritability. They are involved in several aspects of the pathogenesis of the tumor including predisposition, cell proliferation, and apoptosis as well as immunotherapy. In this chapter, the hitherto available immunogenetic-related reports on melanoma predisposition and progression are summed up.

Circular RNA-associated ceRNA network involved in HIF-1 signalling in triple-negative breast cancer: circ_0047303 as a potential key regulator.

The aggressive and highly metastatic nature of triple-negative breast cancer (TNBC) causes patients to suffer from the poor outcome. HIF-1 signalling pathway is a prominent pathway that contributes to angiogenesis and metastasis progression in tumours. On the contrary, the undeniable importance of circular RNAs (circRNAs) as multifunctional non-coding RNAs (ncRNAs) has been identified in breast cancer. These ncRNAs owing to their high stability and specificity have been becoming a hotspot in cancer researches. circRNAs act as competing endogenous RNAs (ceRNAs) and compete with mRNAs for shared miRNAs, thus modulate gene expression. Since the most dysregulated biological functions in TNBC are associated with cellular invasion, understanding the molecular pathogenesis of these processes is a crucial step towards the development of new treatment approaches. The purpose of this study is to undermine the circRNA-associated ceRNA network involved in HIF-1 signalling in TNBC using an integrative bioinformatics approach. In the next step, the novel circ_0047303-mediated ceRNA regulatory axes have been extracted and validated across TNBC samples. We show that circ_0047303 has the highest degree in the circRNA-associated ceRNA network and shows a significant up-expression in TNBC. Moreover, our results suggest that circ_0047303 could mediate the upregulation of key angiogenesis-related genes, including HIF-1, EIF4E2 and VEGFA in TNBC through sponging the tumour-suppressive miRNAs. The circ_0047303 could be a promising molecular biomarker and/or therapeutic target for TNBC.

Circular RNA hsa_circ_0044234 as distinct molecular signature of triple negative breast cancer: a potential regulator of GATA3.

BACKGROUND: Circular RNAs (circRNAs) have been implicated in the initiation and development of breast cancer as functional non-coding RNAs (ncRNA). The roles of circRNAs as the competing endogenous RNAs (ceRNAs) to sponge microRNAs (miRNAs) have also been indicated. However, the functions of circRNAs in breast cancer have not been totally elucidated. This study aimed to explore the clinical implications and possible roles of circ_0044234 in carcinogenesis of the most problematic BC subtype, triple negative breast cancer (TNBC), which are in desperate need of biomarkers and targeted therapies. METHODS: The importance of circ_0044234 as one of the most dysregulated circRNAs in TNBC was discovered through microarray expression profile analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the downregulation of circ_0044234 in triple negative tumors and cell lines versus non-triple negative ones. The bioinformatics prediction revealed that circ_0044234 could act as an upstream sponge in the miR-135b/GATA3 axis, two of the most dysregulated transcripts in TNBC. RESULTS: Our experimental investigation of circ_0044234 expressions in various BC subtypes as well as cell lines reveals that TNBC expresses circ_0044234 at a substantially lower level than non-TNBC. The ROC curve analysis indicates that it could be applied as a discriminative biomarker to identify TNBC from other BC subtypes. Moreover, circ_0044234 expression could be an independent prognostic biomarker in BC. Interestingly, a substantial inverse expression correlation was detected between circ_0044234 and miR-135b-5p as well as between miR-135b-5p and GATA3 in breast tumors. CONCLUSIONS: The possible clinical usefulness of circ_0044234 as a promising distinct biomarker and upcoming therapeutic target for TNBC have been indicated in this research. Our comprehensive approach revealed the potential circ_0044234/miR135b-5p/GATA3 ceRNA axis in TNBC.

Coronavirus: Pure Infectious Disease or Genetic Predisposition.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes novel coronavirus disease (COVID-19), is the seventh pathogenic coronavirus recently discovered in December 2019 in Wuhan, China. To date, our knowledge about its effect on the human host remains limited. It is well known that host genetic factors account for the individual differences in the susceptibility to infectious diseases. The genetic susceptibility factors to COVID-19 and its severity are associated with several unanswered questions. However, the experience gained from an earlier strain of coronavirus, SARS-CoV-1, which shows 78% genetic similarity to SARS-CoV-2 and uses the same receptor to bind to host cells, could provide some clues. It, therefore, seems possible to assemble new evidence in order to solve a potential genetic predisposition puzzle for COVID-19. In this chapter, the puzzle pieces, including virus entry receptors, immune response, and inflammation-related genes, as well as the probable genetic predisposition models to COVID-19, are discussed.

Importance of Circ0009910 in colorectal cancer pathogenesis as a possible regulator of miR-145 and PEAK1.

INTRODUCTION: Colorectal cancer (CRC) is one of the most frequent neoplasms in the world. Based on the emerging role of noncoding RNAs, particularly circular RNAs in pathogenesis of cancers, we designed this study to inspect the expression levels of a circ0009910-mediated regulatory pathway in colorectal cancer. METHODS: After bioinformatics analyses and construction of putative circ0009910/ miR-145-5p/PEAK1 pathway, the expression levels of these components were evaluated in 50 CRC tissues and adjacent specimens by quantitative real-time PCR. Moreover, we appraised the correlation coefficients between these transcripts and calculated the correlation between circ0009910 expression levels with clinicopathological features of patients. RESULTS: Circ0009910 and PEAK1 were significantly upregulated, while miR-145-5p was decreased in CRC samples compared with adjacent tissues (p < 0.05). Moreover, statistically significant correlations were observed between expression levels of circ0009910, miR-145-5p, and PEAK1. We also reported considerable correlations between circ0009910 expression and clinicopathological parameters including sex and perineural invasion. Finally, ROC curve analysis showed circ0009910 level as a discriminative biomarker for CRC. CONCLUSION: For the first time, we could introduce circ0009910 as an important biomarker in CRC. Collectively, this investigation helped us to identify a newly diagnosed pathway in CRC that can be a potential axis for designing effective drugs for treatment of CRC patients.

Integrative analyses of triple negative dysregulated transcripts compared with non-triple negative tumors and their functional and molecular interactions.

Triple-negative (TN) tumors are a subtype of breast cancer with aggressive behaviors and limited targeted therapies. Microarray studies were not concerned with interactions and functional relations of dysregulated transcripts. Here, we aimed to conduct integrative strategy to analyze gene and miRNA available microarray data as well as bioinformatic analyses to catch a more inclusive picture of pivotal dysregulated transcripts and their interactions in TN tumors. Several online datasets and offline bioinformatic tools were used to detect differentially expressed (DE) transcripts, both protein and nonprotein coding, in TN compared with non-TN tumors and their functional and molecular interactions. Sixteen upregulated and 58 downregulated genes with a log fold change higher or equal to | 2 | were identified, including nine transcription factors. Coexpression network revealed EN1 as a hub gene, moreover Kaplan-Meier plotter survival analysis indicated that it was an appropriate prognostic marker for TN patients with breast cancer. Functional annotation analysis of protein-protein interaction network showed FOXM1 as an upexpressed and ESR1 as a downexpressed hub genes are suitable targets as far as antitumor protein therapy is concerned in TN breast cancers. The consensus analysis of two microRNA datasets revealed seven DE miRNAs. The gene-transcriptional factor (TF)-miRNA network revealed mir-135b and mir-29b are the hub nodes and involved in feedback loops with GATA3. This study suggests that dysregulated TFs and miRNAs have pivotal roles in regulation of TN oncotranscriptomic profile and might become both biomarkers and therapeutic targets.

miR-939, as an important regulator in various cancers pathogenesis, has diagnostic, prognostic, and therapeutic values: a review.

BACKGROUND: MicroRNAs (miRNAs or miRs) are highly conserved non-coding RNAs with a short length (18-24 nucleotides) that directly bind to a complementary sequence within 3'-untranslated regions of their target mRNAs and regulate gene expression, post-transcriptionally. They play crucial roles in diverse biological processes, including cell proliferation, apoptosis, and differentiation. In the context of cancer, miRNAs are key regulators of growth, angiogenesis, metastasis, and drug resistance. MAIN BODY: This review primarily focuses on miR-939 and its expanding roles and target genes in cancer pathogenesis. It compiles findings from various investigations. MiRNAs, due to their dysregulated expression in tumor environments, hold potential as cancer biomarkers. Several studies have highlighted the dysregulation of miR-939 expression in human cancers. CONCLUSION: Our study highlights the potential of miR-939 as a valuable target in cancer diagnosis, prognosis, and treatment. The aberrant expression of miR-939, along with other miRNAs, underscores their significance in advancing our understanding of cancer biology and their promise in personalized cancer care.

Competing endogenous RNAs regulatory crosstalk networks: The messages from the RNA world to signaling pathways directing cancer stem cell development.

Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. The cancer cells arrest in G0 and generate non-CSC progeny through self-renewal and pluripotency, resulting in tumor recurrence, metastasis, and resistance to chemotherapy. They can stimulate tumor relapse and re-grow a metastatic tumor. So, CSCs is a promising target for eradicating tumors, and developing an anti-CSCs therapy has been considered. In recent years competing endogenous RNA (ceRNA) has emerged as a significant class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. Recent findings show that ceRNA network can cause tumor progression through the effect on CSCs. To overcome therapeutic resistance due to CSCs, we need to improve our current understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed to discuss the role of ceRNAs in CSCs' function. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.

Long non-coding RNAs and JAK/STAT signaling pathway regulation in colorectal cancer development.

Colorectal cancer (CRC) is one of the main fatal cancers. Cell signaling such as Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling substantially influences the process of gene expression and cell growth. Long non-coding RNAs (lncRNAs) play regulatory roles in cell signaling, cell proliferation, and cancer fate. Hence, lncRNAs can be considered biomarkers in cancers. The inhibitory or activating effects of different lncRNAs on the JAK/STAT pathway regulate cancer cell proliferation or tumor suppression. Additionally, lncRNAs regulate immune responses which play a role in immunotherapy. Mechanisms of lncRNAs in CRC via JAK/STAT regulation mainly include cell proliferation, invasion, metastasis, apoptosis, adhesion, and control of inflammation. More profound findings are warranted to specifically target the lncRNAs in terms of activation or suppression in hindering CRC cell proliferation. Here, to understand the lncRNA cross-talk in CRC through the JAK/STAT signaling pathway, we collected the related in vitro and in vivo data. Future insights may pave the way for the development of novel diagnostic tools, therapeutic interventions, and personalized treatment strategies for CRC patients.

NRF2 signaling pathway: A comprehensive prognostic and gene expression profile analysis in breast cancer.

Breast cancer is the most frequently diagnosed malignant tumor in women and a major public health concern. NRF2 axis is a cellular protector signaling pathway protecting both normal and cancer cells from oxidative damage. NRF2 is a transcription factor that binds to the gene promoters containing antioxidant response element-like sequences. In this report, differential expression of NRF2 signaling pathway elements, as well as the correlation of NRF2 pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, tumor grade, tumor stage, and methylation status, has been investigated in breast cancer using METABRIC and TCGA datasets. In the current report, our findings revealed the deregulation of several NRF2 signaling elements in breast cancer patients. Moreover, there were negative correlations between the methylation of NRF2 genes and mRNA expression. The expression of NRF2 genes significantly varied between different breast cancer subtypes. In conclusion, substantial deregulation of NRF2 signaling components suggests an important role of these genes in breast cancer. Because of the clear associations between mRNA expression and methylation status, DNA methylation could be one of the mechanisms that regulate the NRF2 pathway in breast cancer. Differential expression of Hippo genes among various breast cancer molecular subtypes suggests that NRF2 signaling may function differently in different subtypes of breast cancer. Our data also highlights an interesting link between NRF2 components' transcription and tumor grade/stage in breast cancer.

MGMT Gene rs1625649 Polymorphism in Iranian Patients with Brain Glioblastoma: A Case Control Study.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor with poor prognosis and high potential of dispersion to other brain tissues in adult. Effective and modern choices of treatment including chemotherapy with alkylating agents marginally extend survival of GBM. However, alkylating agents can lead to highly harmful mismatch during DNA replication causing apoptosis and cell death. Accordingly, O6-Methylguanine-DNA methyltransferase (MGMT) removes alkyl adducts, thereby causing resistance to alkylating drugs. Single-Nucleotide Polymorphisms (SNPs) in MGMT promoter region may play a role in the regulation of MGMT expression and prediction of glioma development risk. In order to evaluate the clinical significance of rs1625649 SNP in the MGMT promoter region of glioblastoma, genomic DNA from a series of 54 patients with GBM and 50 healthy individuals in Iranian population were collected for tetra ARMS PCR amplification. None of the "A" or "C" alleles were associated with tumor occurrence, the "AA" genotype was more frequent in healthy subjects, and the "AC" genotype was 4.6 times more common in patients with GBM. The longest survival time was observed in the "CC" genotype; however, this difference was not statistically significant. On the other hand, homozygous rs1625649 (AA genotype) was significantly associated with a better survival than the cases with heterozygous rs1625649 (CA genotype) or wild type rs1625649 (CC genotype), predicting better response to temozolomide-based chemotherapy.