A model for accelerated aging in mice was developed: CB6F2 mice aged 39-45 days were exposed to fractionated 4-fold relatively uniform γ-radiation (137Cs, 0.98 Gy/min) at a total dose of 6.8 Gy. Radiation exposure led to delayed active growth, leukopenia, and lymphopenia for over 1 year during the post-radiation period. The death of irradiated males and females occurred significantly earlier than in control group animals. Median lifespans in the experimental group were 35-38% lower than in the control group (p<0.001). Ionizing radiation exposure led to the early development of hair depigmentation, cachexia, and the development of aging-associated diseases. In irradiated mice, oncological pathology constituted 30-35% in the mortality structure, which is twice as often as in the control group. The developed model can be used to study the pathogenesis of accelerated aging under radiation exposure and the search for means of its prevention and treatment.

Colorectal cancer (CRC) is among the most prevalent types of cancer globally. It is well established that the development of CRC primarily results from the sequential activation of oncogenes and the simultaneous inactivation of tumor suppressor genes. It has also been noted that after the initial oncogenic mutation, many subpopulations with different mutational profiles are created, causing heterogeneity among the tumors. This retrospective study analyzed 100 patients diagnosed with CRC through colectomy over an eighteen-month period at a tertiary referral center in mid-Kerala, India. Pathology records and histological slides were reviewed by two pathologists, and clinicopathological data were collected from pathology reports. Immunohistochemical analysis for BRAF mutation and possible microsatellite instability (MSI) (by mismatch repair (MMR) protein study) was conducted on tumor tissue blocks sent to an external center due to the lack of an automated platform at the hospital. The study utilized Roche\'s Benchmark XT platform for BRAF analysis and assessed MMR protein expression using antibodies for MLH1, MSH2, MSH6, and PMS2. The mean age of patients was 58.36 years, with a male predominance (58.0%). Most tumors were classified as T3 (71.0%, n-71) and T2/T4a (14.0% each, n-14), while nodal involvement included N0 (35.0%, n-35), N1 (26.0%, n-26), N2 (19.0%, n-19), and NX (20.0%, n-20). Histological examination revealed predominantly well-differentiated tumors (78.0%, n-78), with lymphatic invasion noted in 41.0% (n-41) and vascular invasion in 5.0% (n-5) of cases. Left-sided tumors predominated (33.0%, n-33), followed by rectal carcinoma (37.0%, n-37), and right-sided colon cancers (30.0%, n-30). Genetic profiling showed sparse BRAF mutations (1.0%, n-1) and MSI (1.0%, n-1), with some cases exhibiting loss of MMR proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry (IHC). The study highlights the rarity of BRAF mutations in this cohort and emphasizes the diverse pathological and molecular characteristics observed. The discussion focuses on the implications of these findings, suggesting that CRC in this population exhibits unique clinicopathological features potentially influenced by factors beyond genetic mutations. Further multicentric studies are warranted to comprehensively explore these factors and refine risk stratification and treatment strategies for CRC patients in similar demographics.

The tumor suppressor p53 regulates metabolic homeostasis. Recently, Tsaousidou et al. reported that selective activation of p53 via downregulation of Tudor interacting repair regulator (TIRR) confers protection against cancer despite obesity and insulin resistance, providing new insights into the role of p53 at the intersection of oncogenesis and systemic metabolism.

Acute myeloid leukemia (AML) is the most prevalent form of leukemia among adults, characterized by aggressive behavior and significant genetic diversity. Despite decades of reliance on conventional chemotherapy as the mainstay treatment, patients often struggle with achieving remission, experience rapid relapses, and have limited survival prospects. While intensified induction chemotherapy and allogeneic stem cell transplantation have enhanced patient outcomes, these benefits are largely confined to younger AML patients capable of tolerating intensive treatments. DNMT3A, a crucial enzyme responsible for establishing de novo DNA methylation, plays a pivotal role in maintaining the delicate balance between hematopoietic stem cell differentiation and self-renewal, thereby influencing gene expression programs through epigenetic regulation. DNMT3A mutations are the most frequently observed genetic abnormalities in AML, predominantly in older patients, occurring in approximately 20-30% of adult AML cases and over 30% of AML with a normal karyotype. Consequently, the molecular underpinnings and potential therapeutic targets of DNMT3A mutations in AML are currently being thoroughly investigated. This article provides a comprehensive summary and the latest insights into the structure and function of DNMT3A, examines the impact of DNMT3A mutations on the progression and prognosis of AML, and explores potential therapeutic approaches for AML patients harboring DNMT3A mutations.

The dysfunction of several types of regulators, including miRNAs, has recently attracted scientific attention for their role in cancer-associated changes in gene expression. MiRNAs are small RNAs of ~22 nt in length that do not encode protein information but play an important role in post-transcriptional mRNA regulation. Studies have shown that miRNAs are involved in tumour progression, including cell proliferation, cell cycle, apoptosis, and tumour angiogenesis and invasion, and play a complex and important role in the regulation of tumourigenesis. The detection of selected miRNAs may help in the early detection of cancer cells, and monitoring changes in their expression profile may serve as a prognostic factor in the course of the disease or its treatment. MiRNAs may serve as diagnostic and prognostic biomarkers, as well as potential therapeutic targets for colorectal cancer. In recent years, there has been increasing evidence for an epigenetic interaction between DNA methylation and miRNA expression in tumours. This article provides an overview of selected miRNAs, which are more frequently expressed in colorectal cancer cells, suggesting an oncogenic nature.

A certain degree of chromatin openness is necessary for the activity of transcription-regulating regions within the genome, facilitating accessibility to RNA polymerases and subsequent synthesis of regulatory element RNAs (regRNAs) from these regions. The rapidly increasing number of studies underscores the significance of regRNAs across diverse cellular processes and diseases, challenging the paradigm that these transcripts are non-functional transcriptional noise. This review explores the multifaceted roles of regRNAs in human cells, encompassing rather well-studied entities such as promoter RNAs and enhancer RNAs (eRNAs), while also providing insights into overshadowed silencer RNAs and insulator RNAs. Furthermore, we assess notable examples of shorter regRNAs, like miRNAs, snRNAs, and snoRNAs, playing important roles. Expanding our discourse, we deliberate on the potential usage of regRNAs as biomarkers and novel targets for cancer and other human diseases.

Effective cancer therapy with limited adverse effects is a major challenge in the medical field. This is especially complicated by the development of acquired chemoresistance. Understanding the mechanisms that underlie these processes remains a major effort in cancer research. In this review, we focus on the dual role that Bid protein plays in apoptotic cell death via the mitochondrial pathway, in oncogenesis and in cancer therapeutics. The BH3 domain in Bid and the anti-apoptotic mitochondrial proteins (Bcl-2, Bcl-XL, mitochondrial ATR) it associates with at the outer mitochondrial membrane provides us with a viable target in cancer therapy. We will discuss the roles of Bid, mitochondrial ATR, and other anti-apoptotic proteins in intrinsic apoptosis, exploring how their interaction sustains cellular viability despite the initiation of upstream death signals. The unexpected upregulation of this Bid protein in cancer cells can also be instrumental in explaining the mechanisms behind acquired chemoresistance. The stable protein associations at the mitochondria between tBid and anti-apoptotic mitochondrial ATR play a crucial role in maintaining the viability of cancer cells, suggesting a novel mechanism to induce cancer cell apoptosis by freeing tBid from the ATR associations at mitochondria.

Epstein-Barr virus (EBV), Kaposi sarcoma human virus (KSHV), human papillomavirus (HPV), hepatitis B and C viruses (HBV, HCV), human T-lymphotropic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV) are the seven human oncoviruses reported so far. While traditionally viewed as a benign virus causing mild symptoms in healthy individuals, human cytomegalovirus (HCMV) has been recently implicated in the pathogenesis of various cancers, spanning a wide range of tissue types and malignancies. This perspective article defines the biological criteria that characterize the oncogenic role of HCMV and based on new findings underlines a critical role for HCMV in cellular transformation and modeling the tumor microenvironment as already reported for the other human oncoviruses.

Parecoxib, a well-recognized nonsteroidal anti-inflammatory drug, has been reported to possess anticancer properties in various tumor types. In this work, we aimed to investigate the potential anticancer effects of parecoxib on hepatocellular carcinoma (HCC) cells. To assess the impact of parecoxib on HCC cell proliferation, we employed Cell Counting Kit-8, colony formation, and 5-ethynyl-2\'-deoxyuridine assays. Hoechst/propidium iodide (PI) double staining and flow cytometry were performed to evaluate apoptosis and cell cycle analysis. Wound healing and transwell assays were utilized to assess cell migration and invasion. Tube formation assay was employed to analyze angiogenesis. Protein levels were determined using western blotting, and mRNA expression levels were assessed using quantitative real-time polymerase chain reaction (PCR). A xenograft mouse model was used to confirm the antitumor effects of parecoxib on HCC tumors in vivo. Our data demonstrated that parecoxib effectively inhibited the proliferation of HCC cells in a dose- and time-dependent manner. In addition, parecoxib induced cell cycle arrest in the G2 phase and promoted apoptosis. Moreover, parecoxib hindered tumor migration and invasion by impeding the epithelial-mesenchymal transition process. Further investigation showed that parecoxib could significantly suppress angiogenesis through the inhibition of extracellular signal-regulated kinase (ERK)-vascular endothelial growth factor (VEGF) axis. Notably, treatment with the ERK activator phorbol myristate acetate upregulated the expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF and reversed the function of parecoxib in HCC cells. Besides, parecoxib displayed its antitumor efficacy in vivo. Collectively, our results suggest that parecoxib ameliorates HCC progression by regulating proliferation, cell cycle, apoptosis, migration, invasion, and angiogenesis through the ERK-VEGF/MMPs signaling pathway.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.