Emerging Advances in Endometrial Cancer: Integration of Molecular Classification into Staging for Enhanced Prognostic Accuracy and Implications for Racial Disparities.

Since the 2009 FIGO staging update, focused exclusively on the anatomic extent of disease, there have been several advances in the understanding of the pathologic and molecular features of endometrial cancer. In a significant departure from the 2009 FIGO staging system, the 2023 FIGO staging update integrates both histopathological and molecular classification. With the inclusion of non-anatomic pathologic parameters such as histology, tumor grade, lymphovascular space invasion, and molecular subtype, the 2023 FIGO staging update aims to create more clinically relevant substages that improve prognostic value and allows for more individualized treatment paradigms. This review will evaluate the clinical impact of the 2023 FIGO staging update, describe the stage shifts that lead to higher prognostic precision, and illustrate the current state of molecular analysis in clinical practice. Furthermore, this review will explore how incorporating factors such as molecular subtype into endometrial cancer staging can offer valuable insights into the racial disparities seen in morbidity and mortality.

Therapeutic potential of combating cancer by restoring wild-type p53 through mRNA nanodelivery.

Among the tumor suppressor genes, TP53 is the most frequently mutated in human cancers, and most mutations are missense mutations causing production of mutant p53 (mutp53) proteins. TP53 mutations not only results in loss of function (LOH) as a transcription factor and a tumor suppressor, but also gain wild-type p53 (WTp53)-independent oncogenic functions that enhance cancer metastasis and progression (Yamamoto and Iwakuma, 2018; Zhang et al., 2022). TP53 has extensively been studied as a therapeutic target as well as for drug development and therapies, however with limited success. Achieving targeted therapies for restoration of WTp53 function and depletion or repair of mutant p53 (mutp53) will have far reaching implication in cancer treatment and therapies. This review briefly discusses the role of p53 mutation in cancer and the therapeutic potential of restoring WTp53 through the advances in mRNA nanomedicine.

Mutant p53R211* ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1-IRF3 innate immune response.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammation disease characterized by imbalance of immune homeostasis. p53 mutants are commonly described as the guardian of cancer cells by conferring them drug-resistance and immune evasion. Importantly, p53 mutations have also been identified in RA patients, and this prompts the investigation of its role in RA pathogenesis. METHODS: The cytotoxicity of disease-modifying anti-rheumatic drugs (DMARDs) against p53 wild-type (WT)/mutant-transfected RA fibroblast-like synoviocytes (RAFLSs) was evaluated by MTT assay. Adeno-associated virus (AAV) was employed to establish p53 WT/R211* adjuvant-induced arthritis (AIA) rat model. The arthritic condition of rats was assessed by various parameters such as micro-CT analysis. Knee joint samples were isolated for total RNA sequencing analysis. The expressions of cytokines and immune-related genes were examined by qPCR, ELISA assay and immunofluorescence. The mechanistic pathway was determined by immunoprecipitation and Western blotting in vitro and in vivo. RESULTS: Among p53 mutants, p53R213* exhibited remarkable DMARD-resistance in RAFLSs. However, AAV-induced p53R211* overexpression ameliorated inflammatory arthritis in AIA rats without Methotrexate (MTX)-resistance, and our results discovered the immunomodulatory effect of p53R211* via suppression of T-cell activation and T helper 17 cell (Th17) infiltration in rat joint, and finally downregulated expressions of pro-inflammatory cytokines. Total RNA sequencing analysis identified the correlation of p53R211* with immune-related pathways. Further mechanistic studies revealed that p53R213*/R211* instead of wild-type p53 interacted with TANK-binding kinase 1 (TBK1) and suppressed the innate immune TBK1-Interferon regulatory factor 3 (IRF3)-Stimulator of interferon genes (STING) cascade. CONCLUSIONS: This study unravels the role of p53R213* mutant in RA pathogenesis, and identifies TBK1 as a potential anti-inflammatory target.

Prognostic Value of Vimentin in Triple Negative Breast Cancer Patients Depends on Chemotherapy Regimen and p53 Mutant Expression.

Purpose: To determine the prognostic value of vimentin in triple negative breast cancer (TNBC) patients, specifically in relation to chemotherapy regimen and p53 mutant expression. Patient and Methods: We retrospectively analyzed the association of pre-treatment tumor expression of vimentin with 48-month overall survival (OS) of 72 all stages TNBC patients diagnosed between 2014 and 2018 in relation to chemotherapy regimen and expression of p53 mutant. Vimentin and p53 mutant expressions were examined using immunohistochemistry. Analysis was conducted on all patients collectively, then repeated on two cohorts divided according to the chemotherapy regimen. Sub-analysis was performed to determine the effect of p53 mutant expression on the prognostic value of vimentin. Results: Vimentin was expressed in 43.1% of patients and was not associated with clinicopathologic characteristics. Vimentin was associated with improved 48-month OS in all patients in univariate analysis but not significant in multivariate analysis. When analyzed according to chemotherapy regimen, vimentin was independently associated with improved 48-month OS in patients receiving non-platinum-based chemotherapy (80% vs 15.8%; HR: 0.17, 95% CI: 0.05-0.58, p: 0.005). Other independent prognostic factors include T (HR: 6.18, 95% CI: 1.38-27.7, p: 0.017) and M (HR: 5.64, 95% CI: 1.2-26.33, p: 0.028). On subanalysis, vimentin was significantly associated with improved 48-month OS in patients expressing p53 mutant (69.2% vs 22.2%, p: 0.006) but was not significant in patients not expressing p53 mutant. Conclusion: Vimentin expression was independently associated with improved 48-month OS in TNBC patients treated with non-platinum-based chemotherapy. Expression of p53 mutant significantly affected the prognostic value of vimentin.

Gain-of-Function p53N236S Mutation Drives the Bypassing of HRasV12-Induced Cellular Senescence via PGC-1α.

One of the key steps in tumorigenic transformation is immortalization in which cells bypass cancer-initiating barriers such as senescence. Senescence can be triggered by either telomere erosion or oncogenic stress (oncogene-induced senescence, OIS) and undergo p53- or Rb-dependent cell cycle arrest. The tumor suppressor p53 is mutated in 50% of human cancers. In this study, we generated p53N236S (p53S) mutant knock-in mice and observed that p53S heterozygous mouse embryonic fibroblasts (p53S/+) escaped HRasV12-induced senescence after subculture in vitro and formed tumors after subcutaneous injection into severe combined immune deficiency (SCID) mice. We found that p53S increased the level and nuclear translocation of PGC-1α in late-stage p53S/++Ras cells (LS cells, which bypassed the OIS). The increase in PGC-1α promoted the biosynthesis and function of mitochondria in LS cells by inhibiting senescence-associated reactive oxygen species (ROS) and ROS-induced autophagy. In addition, p53S regulated the interaction between PGC-1α and PPARγ and promoted lipid synthesis, which may indicate an auxiliary pathway for facilitating cell escape from aging. Our results illuminate the mechanisms underlying p53S mutant-regulated senescence bypass and demonstrate the role played by PGC-1α in this process.

2,2-Diphenethyl Isothiocyanate Enhances Topoisomerase Inhibitor-Induced Cell Death and Suppresses Multi-Drug Resistance 1 in Breast Cancer Cells.

We previously reported that phenethyl isothiocyanate (PEITC), a dietary-related compound, can rescue mutant p53. A structure-activity relationships study showed that the synthetic analog 2,2-diphenylethyl isothiocyanate (DPEITC) is a more potent inducer of apoptosis than natural or synthetic ITCs. Here, we showed that DPEITC inhibited the growth of triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468, and Hs578T) expressing "hotspot" p53 mutants, structural (p53R280K, p53R273H) or contact (p53V157F), at IC50 values significantly lower than PEITC. DPEITC inhibited the growth of HER2+ (p53R175H SK-BR-3, p53R175H AU565) and Luminal A (p53L194F T47D) breast cancer (BC) cells harboring a p53 structural mutant. DPEITC induced apoptosis, irrespective of BC subtypes, by rescuing p53 mutants. Accordingly, the rescued p53 mutants induced apoptosis by activating canonical WT p53 targets and delaying the cell cycle. DPEITC acted synergistically with doxorubicin and camptothecin to inhibit proliferation and induce apoptosis. Under these conditions, DPEITC delayed BC cells in the G1 phase, activated p53 canonical targets, and enhanced pS1981-ATM. DPEITC reduced the expression of MDR1 and ETS1. These findings are the first report of synergism between a synthetic ITC and a chemotherapy drug via mutant p53 rescue. Furthermore, our data demonstrate that ITCs suppress the expression of cellular proteins that play a role in chemoresistance.

Absence of Association Between Serum Mutant p53 with HbA1c and Insulin in Brain Tumor Patients with Type 2 Diabetes Mellitus.

AIMS: This study aims to determine the prevalence of Type 2 Diabetes Mellitus (T2DM) in primary Brain Tumor (BT) subjects and assess the relationship between serum mutant p53 serum and HbA1c and insulin. BACKGROUND: T2DM is known to increase the risk of various types of cancer, which are thought to be caused by hyperglycemia, hyperinsulinemia, and inflammation. A cohort study that looked at more than 500,000 subjects with DM over 11 years showed an increased risk of different types of cancer, including brain tumors. However, several recent studies have shown the opposite. One of the important pathways in the pathogenesis of brain tumors is the p53 pathway, in which mutations in the TP53 gene can cause brain cell growth abnormalities. OBJECTIVE: The first stage involved taking subject data for the period January 2017-November 2020 from the medical records of the RSUPN Dr. Cipto Mangunkusumo Hospital Indonesia to assess the prevalence of T2DM in BT subjects. The second stage was an observational study with a crosssectional design that collected primary data on subjects (n=86) to assess the relationship between serum mutant p53 serum and HbA1c and insulin. METHODS: The analysis of serum mutant p53 serum and insulin was made using the ELISA method, while measurement of HbA1c was made using the boronate affinity method. RESULT: The results show the prevalence of T2DM in BT subjects at Dr. Cipto Mangunkusumo Hospital Indonesia was relatively low (9%). Serum mutant p53 levels in T2DM (1.53 ng/mL ± 0.60) were significantly higher than in BT+T2DM and BT (P < 0.001). The HbA1c value was significantly lower in BT (5.15% ± 0.44) compared to BT+T2DM and T2DM (P < 0.001), while T2DM insulin levels (39.54 IU/mL ± 19.1) were significantly higher than BT+T2DM and BT (P < 0.001). There was no correlation between serum mutant p53 levels and HbA1c and insulin in the three groups. CONCLUSION: The study concludes that the prevalence of BT with T2DM is relatively low (9%) and that serum levels of mutant p53 in T2DM subjects are higher than in subjects with BT, but there is no correlation between serum mutant p53 levels and HbA1c and insulin values. Further research needs to be conducted by analyzing p53 mutants from other specimens, such as brain tumor tissue.

Discovery of a Potent and Selective Degrader for USP7.

The tumor suppressor p53 is the most frequently mutated gene in human cancer and more than half of cancers contain p53 mutations. The development of novel and effective therapeutic strategies for p53 mutant cancer therapy is a big challenge and highly desirable. Ubiquitin-specific protease 7 (USP7), also known as HAUSP, is a deubiquitinating enzyme and proposed to stabilize the oncogenic E3 ubiquitin ligase MDM2 that promotes the proteosomal degradation of p53. Herein, we report the design and characterization of U7D-1 as the first selective USP7-degrading Proteolysis Targeting Chimera (PROTAC). U7D-1 showed selective and effective USP7 degradation, and maintained potent cell growth inhibition in p53 mutant cancer cells, with USP7 inhibitor showing no activity. These data clearly demonstrated the practicality and importance of PROTAC as a preliminary chemical tool for investigating USP7 protein functions and a promising method for potential p53 mutant cancer therapy.

p53 and Zinc: A Malleable Relationship.

A large percentage of transcription factors require zinc to bind DNA. In this review, we discuss what makes p53 unique among zinc-dependent transcription factors. The conformation of p53 is unusually malleable: p53 binds zinc extremely tightly when folded, but is intrinsically unstable in the absence of zinc at 37°C. Whether the wild-type protein folds in the cell is largely determined by the concentration of available zinc. Consequently, zinc dysregulation in the cell as well as a large percentage of tumorigenic p53 mutations can cause p53 to lose zinc, misfold, and forfeit its tumor suppressing activity. We highlight p53's noteworthy biophysical properties that give rise to its malleability and how proper zinc binding can be restored by synthetic metallochaperones to reactivate mutant p53. The activity and mechanism of metallochaperones are compared to those of other mutant p53-targeted drugs with an emphasis on those that have reached the clinical trial stage.

Lead Borate Nanoparticles Induce Apoptotic Gene Activity in P53 Mutant Cancer Cells.

Cancer is a complex and multistage disease that causes suffering worldwide. Several mutations in tumor suppressor proteins are mostly responsible for tumorigenic development. Thus, determination of the mutations and developing a mutation targeted therapy are crucial in order to cure cancer. Moreover, since healthy cells do not have mutations in their tumor suppressor genes, mutation-specific treatment is responsible for selective treatment without harming a healthy tissue in the body. In this current study, lead borate nanoparticles (LB-Np) have been synthesized, and their effects on P53 mutant cancer cells were investigated. The synthesis method includes steps of mixing a borate buffer solution with the lead nitrate solution, washing the resulting precipitate with distilled water and eventually preparing stable LB-Np solutions. Cell viability analysis was conducted to identify the toxicity of LB-Np in HaCaT, A549, MCF7, and T47D cell lines. The changes in morphologies of breast cancer cell lines were demonstrated by using microscopical analysis. Additionally, alterations in gene expressions were determined in breast cancer cell lines after LB-Np treatment. This multidisciplinary study also identified the selective effect of LB-Np in cancer cell lines, in vitro. MTS and quantitative polymerase chain reaction assays demonstrated the effect of LB-Np were specific for p53 mutation cell line, T47D. Breast cancer cell line T47D has 580 C/T mutation which affects the activation of p53 tumor suppressor protein. However, LB-Np treatment effectively killed T47D cell lines and did not affect any other cell lines that have no p53 mutations such as MCF7, A549, and healthy HaCaT. Overall, synthesized LB-Np were found to be effective in p53-mutated cell lines and showed a remarkable selective anti-cancer activity.

CDC20 regulates the cell proliferation and radiosensitivity of P53 mutant HCC cells through the Bcl-2/Bax pathway.

Purpose: The incidence of hepatocellular carcinoma (HCC) is extremely high, and China accounts for approximately 50% of global liver cancer cases. Previous studies reported that CDC20 is involved in the occurrence and progression of a variety of malignant tumors. So, whether CDC20 will affect the development of HCC, we have conducted in-depth research on this. Methods: We selected Hep3B and HepG2 for cell culture, and performed siRNA transfection, lentiviral infection, western blot, MTS determination, cell cycle determination, apoptosis test, immunodeficiency test, clone survival test and subcutaneous parthenogenesis in nude mice. Results: Knockdown of CDC20 greatly enhanced the radiation efficacy on the growth retardation in HepG2, and protein level of CDC20 was decreased for the activation of P53 by radiation. Downregulation of CDC20 combined with radiation can inhibit proliferation, aggravate DNA damage, increase G2/M arrest, and promote apoptosis of HCC cells to a greater extent, and the relative survival fraction of HCC cells was gradually reduced with radiation dose increased in P53 mutated Hep3B cells. After knocking down CDC20 in HCC, Bcl-2 was down-regulated and Bax expression increased. Down-regulation of CDC20 can inhibit further invasion by promoting the radiosensitivity of HCC. Conclusion: In this study, we found that that CDC20 was highly expressed in HCC and participated in radio resistance of HCC cells with P53 mutation Bcl-2/Bax via signaling pathway. This study is the first to present evidence that CDC20 may play a role in improving the efficacy of radiotherapy in HCC.

Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy.

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells.

Missense p53 mutations (mutp53) occur in approx. 70% of pancreatic ductal adenocarcinomas (PDAC). Typically, mutp53 proteins are aberrantly stabilized by Hsp90/Hsp70/Hsp40 chaperone complexes. Notably, stabilization is a precondition for specific mutp53 alleles to acquire powerful neomorphic oncogenic gain-of-functions (GOFs) that promote tumor progression in solid cancers mainly by increasing invasion and metastasis. In colorectal cancer (CRC), we recently established that the common hotspot mutants mutp53R248Q and mutp53R248W exert GOF activities by constitutively binding to and hyperactivating STAT3. This results in increased proliferation and invasion in an autochthonous CRC mouse model and correlates with poor survival in patients. Comparing a panel of p53 missense mutations in a series of homozygous human PDAC cell lines, we show here that, similar to CRC, the mutp53R248W protein again undergoes a strong Hsp90-mediated stabilization and selectively promotes migration. Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. In response to mutp53 depletion, only mutp53R248W harboring PDAC cells show STAT3 de-phosphorylation and reduced migration, again suggesting an allele-specific GOF in this cancer entity, similar to CRC. Moreover, mutp53R248W also exhibits the strongest constitutive complex formation with phosphorylated STAT3. The selective mutp53R248W GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53R248W-containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities.

Immunotherapy in endometrial cancer: rationale, practice and perspectives.

Tumor immunotherapy has attracted more and more attention nowadays, and multiple clinical trials have confirmed its effect in a variety of solid tumors. Immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), and lymphocyte-promoting cytokines are the main immunotherapy methods. Endometrial cancer (EC) is one of the most frequent tumors in women and the prognosis of recurrent or metastatic EC is poor. Since molecular classification has been applied to EC, immunotherapy for different EC subtypes (especially POLE and MSI-H) has gradually attracted attention. In this review, we focus on the expression and molecular basis of the main biomarkers in the immunotherapy of EC firstly, as well as their clinical application significance and limitations. Blocking tumor immune checkpoints is one of the most effective strategies for cancer treatment in recent years, and has now become the focus in the field of tumor research and treatment. We summarized clinical date of planned and ongoing clinical trials and introduced other common immunotherapy methods in EC, such as cancer vaccine and ACT. Hormone aberrations, metabolic syndrome (MetS) and p53 mutant and that affect the immunotherapy of endometrial cancer will also be discussed in this review.

Anti-proliferative and apoptotic effect of gemini curcumin in p53-wild type and p53-mutant colorectal cancer cell lines.

BACKGROUND: Despite recent advances in therapy, colorectal cancer remains a leading cause of death in affected people. Curcumin is the main bioactive compound of turmeric that has been demonstrated as an effective agent against cancer. However, its poor stability and bioavailability limit therapeutic application. We previously showed that delivery of curcumin by using gemini surfactant nanoparticles called gemini curcumin (Gemini-Cur) could improve its solubility, uptake and toxic effect on breast and ovarian cancer cells. Here, we aimed to investigate the anticancer activity of Gemini-Cur in both p53-mutant and p53-wild type colorectal cancer cells. The toxicity of Gemini-Cur on HT-29 and HCT116 was studied through MTT, uptake kinetics, fluorescence microscopy, annexin V/FITC, and cell cycle assays. Also, real-time PCR and western blotting were performed to evaluate the expression of p53, p21, BAX, BCL-2, and NOXA genes. Our data showed that Gemini-Cur not only enters cells quite rapidly compared to free curcumin crystals, but also suppresses HT-29 and HCT-116 cells proliferation in a time- and dose-dependent manner (p < 0.001). The IC50 values as well as apoptosis assays showed that p53-wild type cells are sensitive to Gemini-Cur. Flow cytometry also revealed that the number of apoptotic cells is dramatically increased in HCT-116 cells earlier than HT-29 cells (p < 0.0001). Gemini-Cur upregulated apoptotic genes including p53 (in both mutant and wild-type forms), p21, NOXA and BAX while decreased anti-apoptotic BCL-2 in mRNA and protein level (p < 0.0001). As a hallmark of apoptosis, the expression ratio of BAX/BCL-2 was significantly increased in all treated cells. Taken together, our findings demonstrated that Gemini-Cur suppresses the proliferation of cancer cells via induction of apoptosis and could be considered as novel nano-formulated phytochemical for cancer targeting.

Non-coding RNAs, guardians of the p53 galaxy.

The TP53 gene is arguably the most important tumor suppressor gene known, contributing multifaceted roles to the process of tumor development. Its protein product p53, is a crucial sequence-specific transcription factor which regulates the expression of a large network of protein-coding genes, as well as thousands of noncoding RNAs (ncRNAs), notably microRNAs and long ncRNAs (lncRNAs). Through a variety of direct and indirect mechanisms, ncRNAs in turn modulate p53 levels and activity. Here the numbers of studies are steadily building which link the contributions of dysregulated ncRNAs to tumorigenesis via their participation throughout the p53 regulatory network. In this review, we will examine how the principal forms of ncRNAs, namely microRNAs, lncRNAs and circular RNAs (circRNAs) function as either effectors or regulators amongst the diversity of p53's cellular responses. We first discuss the more recently discovered connections between miRNAs and p53 signaling before focusing on the remarkable diversity of crosstalk evident between lncRNAs and p53, and subsequently, developing reports linking circRNAs to p53. Highlighted throughout the review are the mechanistic impacts of dysregulated ncRNAs on p53 functions as well as the possible prognostic implications of these interactions. We also describe the emerging connections between ncRNAs and the often-perplexing functions of mutant p53. Finally, in the context of p53 therapeutic approaches, we describe some of the challenges in ncRNA research and their potential for translation.

A p53-JAK-STAT connection involved in myeloproliferative neoplasm pathogenesis and progression to secondary acute myeloid leukemia.

Since the discovery of JAK2 V617F as a highly prevalent somatic acquired mutation in the majority of myeloproliferative neoplasms (MPNs), it has become clear that these diseases are driven by pathologic activation of JAK2 and eventually of STAT5 and other members of the STAT family. The concept was strengthened by the discovery of the other activating driver mutations in MPL (thrombopoietin receptor, TpoR) and in calreticulin gene, which all lead to persistent activation of wild type JAK2. Although with a rare frequency, MPNs can evolve to secondary acute myeloid leukemia (sAML), a condition that is resistant to treatment. Here we focus on the role of p53 in this transition. In sAML mutations in TP53 or amplification in genes coding for negative regulators of p53 are much more frequent than in de novo AML. We review studies that explore a signaling and biochemical interaction between activated STATs and p53 in MPNs and other cancers. With the development of advanced sequencing efforts, strong evidence has been presented for dominant negative effects of mutated p53 in leukemia. In other studies, gain of function effects have been described that might be cell type specific. A more profound understanding of the potential interaction between p53 and activated STATs is necessary in order to take full advantage of novel p53-targeted therapies.

The Close Interplay of Nitro-Oxidative Stress, Advanced Glycation end Products and Inflammation in Inflammatory Bowel Diseases.

BACKGROUND: Inflammatory Bowel Disease (IBD) exhibits no defined aetiology. However, factors such as genetic and nitro-oxidative stress are associated with chronic inflammation and IBD progression to Colorectal Cancer (CRC). The present review discusses the association of nitro-oxidative stress, inflammation and Advanced Glycation End products (AGE) and their corresponding receptor (RAGE) in IBD and examines the connection between these factors and nuclear factors, such as Nuclear Factor Kappa B (NF-κB), factorerythroid 2-related factor-2 (Nrf2), and p53 Mutant (p53M). METHODS: We searched the PubMed, ScienceDirect and Web of Science databases using a combination of the following terms: IBD, CRC, oxidative stress, inflammation, NF-κB, Nrf2, p53M, AGE and RAGE. RESULTS: Oxidative stress and inflammation activated two cellular pathways, the nuclear expression of pro-inflammatory, pro-oxidant and pro-oncogenic genes based on NF-κB and p53M, which is associated with NF-κB activation, Deoxyribonucleic acid (DNA) damage and the expression of pro-oncogenic genes. Nrf2 stimulates the nuclear expression of enzymatic and non-enzymatic antioxidant systems and anti-inflammatory genes, and is inhibited by chronic oxidative stress, NF-κB and p53M. AGE/RAGE are involved in inflammation progression because RAGE polymorphisms and increased RAGE levels are found in IBD patients. Alterations of these pathways in combination with oxidative damage are responsible for IBD symptoms and the progression to CRC. CONCLUSION: IBD is an inflammatory and nitro-oxidative stress-based bowel disease. Achieving a molecular understanding of the biochemical events and their complicated interactions will impact basic and applied research, animal models, and clinical trials.

The Decreased of p53 Mutant Expression on Squamous Cell Epithelial of Oral in Mus musculus by Moderate Intensity of Exercise

@#Introduction: Cancer is a deadly disease, caused by benzopyrene which found in cigarettes. The moderate intensity of exercise can affect cancer growth, but how the role it to p53 mutant is not clear. This research proved the expression of p53 mutant in Mus musculus by moderate intensity of exercise. Method: Eighteen animals, were divided into three groups namely, group A, injected by oleum olivarium in the upper buccal mucosa and not given moderate intensity of exercise and benzopyrene; group B, injected benzopyrenes in the same regio, not given moderate intensity of exercise; group C injected benzopyrenes in same region, given moderate intensity of exercise. Moderate intensity of exercise given 3 times every week for 3 months. Oleum olivarum and benzopyrene injection, was given 3 times every week for 1 month, starting at week 5. At the beginning of the 13th week, a bend was taken in the right upper buccal mucosa, then the tissue was processed, painted by immunohistochemical methods. p53 mutant expression was determined by looking at preparations, using an Olympus light microscope with a magnification of 400x. p53 mutan expression was observed in 10 different visual field, then the mean was taken. Result: There were differences in p53 mutant expression in the three groups (p= 0.000), and the highest expression was in group B. Conclusion: The moderate intensity of exercise could decrease p53 mutant expression on squamous cell epithelial of oral Mus musculus.

Treating p53 Mutant Aggregation-Associated Cancer.

p53 is a tumor suppressor protein. Under stressful conditions, p53 tightly regulates cell growth by promoting apoptosis and DNA repair. When p53 becomes mutated, it loses its function, resulting in abnormal cell proliferation and tumor progression. Depending on the p53 mutation, it has been shown to form aggregates leading to negative gain of function of the protein. p53 mutant associated aggregation has been observed in several cancer tissues and has been shown to promote tumor growth. Recent studies show correlation between p53 mutant aggregation, functional loss, and tumor growth. Moreover, p53 aggregation has been observed in biopsies, patient tissues, and in vivo studies. Given the fact that over fifty percent of cancers have p53 mutation and several of them are prone to aggregation, therapeutic strategies are needed for treating p53 mutant aggregation associated cancers. Recent studies using polyarginine analogues and designer peptides for inhibiting p53 aggregation and tumor growth gives further encouragement in treating cancer as a protein aggregation disease. In this review, we highlight the recent efforts in targeting p53 aggregation in cancer and propose the use of small stress molecules as potential p53-antiaggregation drugs.