P53 Overexpression Research Articles

Exploring the Role of Lower Genital Tract Microbiota and Cervical–Endometrial Immune Metabolome in Unknown Genesis of Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL) of unknown genesis is a complex condition with multifactorial origins, including genetic, hormonal, and immunological factors. However, the specific mechanisms underlying endocervical cell proliferation disorders in women with RPL remain inadequately understood, particularly concerning the role of microbiota and viral infections. The aim of this study was to investigate the mechanisms of endocervical cell proliferation disorders in women with RPL of unknown genesis by examining microbiota, human papillomavirus (HPV) typing, and the expression levels of key molecular biological markers, including p16/Ki-67, BCL-2, miR-145, and miR-34a. A prospective observational comparative study was executed on women with RPL and healthy pregnant controls with full ethical approval. Samples were collected for HPV typing and immunocytochemical analysis to evaluate the expression of p16, Ki-67, BCL-2, and the anti-oncogenic microRNAs (miR-145 and miR-34a). The expression of mRNA for the progesterone receptor (PGR-A) was also assessed, alongside local immune status markers, including proinflammatory T-lymphocytes (Th17/Th1) and regulatory CD4+ Tregs. Overexpression of p16, Ki-67, and BCL-2 was observed in 52.5% of women with RPL who had an ASC-US/LSIL cytogram, with the average double expression of p16/Ki-67 being three times higher than in the healthy pregnant group. A significant decrease in PGR-A mRNA expression in the endocervix of women with RPL was noted, accompanied by a dysregulated local immune status characterized by an increased prevalence of Th17/Th1 cells and a reduction in regulatory CD4+ Tregs. Additionally, the expression of miR-145 and miR-34a in the endocervix and endometrium of women with RPL significantly differed from the physiological pregnancy group, particularly in the context of high-risk HPV infection. The findings describe that disorders of endocervical cell proliferation in women with RPL of unknown genesis are associated with overexpression of specific molecular markers, impaired immune regulation, and altered microRNA profiles. These alterations may contribute to the pathophysiology of RPL, highlighting the need for further research into targeted interventions that could improve reproductive outcomes in affected individuals.

PTOV1 exerts pro-oncogenic role in colorectal cancer by modulating SQSTM1-mediated autophagic degradation of p53.

Prostate Tumor Overexpressed 1 (PTOV1) is overexpressed and associated with malignant phenotypes in various types of tumors. However, the detailed roles of PTOV1 and its underlying mechanism in CRC remain unclear. The clinical significance of PTOV1 was assessed in clinical databases and CRC samples. The effects of PTOV1 on the tumor-associated phenotypes of CRC were detected by several in vitro assays and in vivo mouse models. Immunoprecipitation (IP) combined with protein mass spectrometry and Co-Immunoprecipitation (Co-IP) was used to identify p53 interacting with PTOV1. Immunofluorescence assay, western blot and transmission electron microscopy (TEM) analysis were used to evaluated the effects of PTOV1 on autophagy. Here, we revealed that PTOV1 was highly expressed in human CRC tissues, especially at advanced stages, and associated with reduced survival time among CRC patients. The upregulated PTOV1 promoted cell proliferation, migration, invasion, tumor growth and metastasis of CRC cells in vitro and in vivo. At the molecular level, PTOV1 destabilized p53 by activating autophagy and recruiting p53 for the cargo receptor SQSTM1 directed autophagic degradation. There was a negative expression correlation between PTOV1 and p53 in CRC tissues. Moreover, p53 overexpression or SQSTM1 knockdown reversed the pro-tumor phenotypes of PTOV1 in CRC. Our study unveils the oncogenic role of PTOV1 in CRC progression, which was achieved by promoting SQSTM1 directed autophagic degradation of p53. These findings highlight the potential of targeting the PTOV1-SQSTM1-p53 axis as a therapeutic approach for CRC.

ERα, HER-2, pan-RAS, p53, and aromatase expression in spontaneous malignant canine mammary tumors: Prognostic relevance and association with clinicohistological parameters.

The interlacing interaction between proto-oncoproteins and tumor-suppressing proteins in malignant canine mammary tumors (mCMT) microenvironment remains largely unexplored. The present study intended to decipher the i) association between the intratumoral expression of ERα, HER-2, pan-RAS, p53 and aromatase, ii) their relationship with the clinicohistological parameters and serum sex hormones, and iii) their prognostic relevance in mCMT. Tumor samples from animals with mCMT (n=27) were subjected to histopathology and immunohistochemistry for ERα, HER-2, pan-RAS, p53, and aromatase. Serum estradiol and progesterone levels from dogs with mCMT and healthy dogs (n=10) were estimated using chemiluminescence immunoassay. Kaplan-Meier analysis (log-rank test), univariable and multivariable Cox regression, and Mann-Whitney U test were employed for statistical analysis. The expression of aromatase, ERα, pan-RAS, p53, and HER-2 were detected in 100%, 88%, 67%, 12% and 11% of mCMT cases, respectively. Serum estradiol and progesterone were significantly higher in mCMT-affiliated patients than healthy dogs. Also, a positive association of ERα expression with aromatase (stromal component) and HER2 expression in mCMT patients was detected. Furthermore, intratumoral aromatase expression and p53 overexpression were correlated with tumor size and angiogenesis, respectively. No relationship was detected between other tumor markers, serum steroid hormones and clinicohistological parameters. P53 overexpression was associated with poor survival in mCMT patients. Overexpression of aromatase and p53 overexpression has clinical relevance in mCMT, and an intratumoral ERα expression is positively associated with HER-2 expression and aromatase production by stromal components.

Chronic Exposure to Lead Causes Neurotoxicity by Generating Oxidative Stress and Inducing DNA Damages in Zebrafish Brain: Involvement of Nrf2-Keap1 Regulation and DNA Repair Pathways.

Toxicity of lead (Pb) causes several health problems in human beings. The present study reveals the potential effects of Pb on adult zebrafish (Danio rerio) brain at an environmentally relevant concentration. Pb generated reactive oxygen species-mediated oxidative stress, as evidenced by alterations of GSH, MDA levels, and CAT activity. The Nrf2-Keap1 pathway counteracted this stress as a part of cytoprotection. The gene expression and immunolocalization studies confirmed the augmentation of Nrf2 in the brain. Activation of the Nrf2-Keap1 pathway influenced downstream nqo1 and ho1 gene expressions. The alterations in histopathology and mRNA expressions of biomarker genes like hsp70 and ache revealed the toxic insults of Pb in the brain. DNA damage assay verified the genotoxic potential of Pb. The expression pattern of the candidate genes of two critical repair pathways (base excision and mismatch repair) was studied to assess the DNA damage responses. The damages in DNA caused by 15days of Pb exposure were sufficient to trigger the expression of BER (ogg1, apex1, polβ, and creb1) and MMR (msh2, msh6, and mlh1) genes to protect cells. Chronic exposure for 30days suppressed both the machinery, predisposing mutations. The overexpression of crucial tumor suppressor genes p53 and brca2 indicated their protective role against cancer progression. Understanding the molecular mechanisms underlying Pb-induced neurotoxicity and the DNA damage response may help to improve our current knowledge for the prevention of Pb poisoning.

Rationale for Testing TP53 Mutations in Thyroid Cancer—Original Data and Meta-Analysis

The p53 protein is a tumor-suppressing transcription factor that is critical in tumorigenesis. While TP53 mutations are rare in differentiated thyroid cancer (DTC), they are significantly more common in anaplastic thyroid cancer (ATC). This study presents original results and a meta-analysis reevaluating the prognostic value of TP53 mutations in thyroid cancer, including surrogate markers such as immunohistochemical p53 expression and serum p53-Abs levels. TP53 mutations were analyzed using SSSP and direct sequencing in a DTC group (15 patients), an ATC group (3 patients), and a control group (25 patients). The immunohistochemical p53 expression was assessed in tissue samples. A meta-analysis of 14 eligible studies identified through the PubMed, Scopus, Google Scholar, and Cochrane databases was conducted. Our results showed TP53 mutations in all ATC cases, 6.67% of DTC cases (1 out of 15), and none in the control group. Immunohistochemical p53 overexpression was observed in 4 out of 15 DTC (26.67%) and all ATC cases but absent in controls. A meta-analysis confirmed that TP53 mutations are significantly more frequent in ATC than controls (OR 8.95; 95% CI: 1.36–58.70; p = 0.02) but not in DTC vs. controls (OR 1.87; 95% CI: 0.53–6.58; p = 0.33). p53 overexpression was significantly higher in both DTC and ATC vs. controls (OR 7.99; 95% CI: 5.11–12.51; p < 0.01 and OR 64.37; 95% CI: 27.28–151.89; p < 0.01, respectively). The serum p53-Abs positivity was also elevated in patients with PTC vs. controls (OR 2.07; 95% CI: 1.24–3.47; p < 0.01). TP53 mutations are frequent events in the pathogenesis of ATC. In DTC, further prospective studies are needed to determine the prognostic value of TP53 mutations and related surrogate markers (immunohistochemical p53 expression, p53-Abs positivity).

Correlation between p53 immunoexpression and TP53 mutation status in extrapulmonary small cell neuroendocrine carcinomas and its association with patient survival.

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular TP53 alteration was detected in 92 out of 125 tumors (73.6%). The TP53 mutation was shown to be prognostic andassociated with shorter overall survival (p = 0.041). The multivariate analysis of p53 and TP53 mutational status found that it impacted overall survival relative to distinct sites of tumor locations (p = 0.004 and p = 0.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and TP53 (p = 0.002; p < 0.001resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a TP53 mutation (p < 0.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, TP53 genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression / TP53 molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis.

Molecular and Immunohistochemical Classification of Extrapulmonary Small Cell Neuroendocrine Carcinomas: A Study of 181 Cases.

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Most patients with EP-SCNC have metastatic disease upon presentation, and their average overall survival (OS) is less than 12 months. Our study aimed to conduct a complex analysis of EP-SCNC. One hundred and eighty-one EP-SCNC tissue samples were subjected to a complex analysis. One hundred and fifty-five tumors were pure EP-SCNC, while 26 were combined tumors. Immunohistochemistry for ASCL1, NEUROD1, YAP1, POU2F3, Rb1, p53, cyclin D1, p16, PTEN, DLL3, PD-L1, CD56, synaptophysin, chromogranin A, and INSM1 was performed, and 128 samples were analyzed molecularly using next generation sequencing (NGS), comprising DNA and RNA analysis. Detailed results on immunohistochemical and molecular analyses were provided for each primary origin of EP-SCNC separately. Median survival for the whole cohort of patients was 8.94 months. Patient age (≥ 70 years), tumor mutational burden (TMB) < 15, and TP53 and BRCA2 mutations were negative prognostic factors. High expression of ASCL-1 was associated with shorter OS, whereas high expression of YAP1 was associated with longer OS. Patients with genitourinary tumors had significantly better OS than those with gastrointestinal tract EP-SCNC tumors. Rb1 expression loss was detected more often in genitourinary tract SCNCs. In contrast, p16 overexpression was found more often in genitourinary tract SCNCs. POU2F3 expression was detected more often in combined tumors, whereas NEUROD1 was detected more often in pure EP-SCNC. Regarding "druggable markers," DLL3 was expressed in 66% of tumors and PD-L1 in 17.4%. Detailed analyses of different prognostic and predictive markers are needed to better understand EP-SCNC biology and create more personalized therapy to improve patient prognosis.

PLAC8 attenuates pulmonary fibrosis and inhibits apoptosis of alveolar epithelial cells via facilitating autophagy

Idiopathic pulmonary fibrosis (IPF) is an irreversible lung condition that progresses over time, which ultimately results in respiratory failure and mortality. In this study, we found that PLAC8 was downregulated in the lungs of IPF patients based on GEO data, in bleomycin (BLM)-induced lungs of mice, and in primary murine alveolar epithelial type II (pmATII) cells and human lung epithelial cell A549 cells. Overexpression of PLAC8 facilitated autophagy and inhibited apoptosis of pmATII cells and A549 cells in vitro. Moreover, inhibition of autophagy or overexpression of p53 partially abolished the effects of PLAC8 on cell apoptosis. ATII cell-specific overexpression of PLAC8 alleviated BLM-induced pulmonary fibrosis in mice. Mechanistically, PLAC8 interacts with VCP-UFD1-NPLOC4 complex to promote p53 degradation and facilitate autophagy, resulting in inhibiting apoptosis of alveolar epithelial cells and attenuating pulmonary fibrosis. In summary, these findings indicate that PLAC8 may be a key target for therapeutic interventions in pulmonary fibrosis.

A Mechanism Study on the Antioxidant Pathway of Keap1-Nrf2-ARE Inhibiting Ferroptosis in Dopaminergic Neurons.

The pathology of Parkinson's disease (PD) indicates that iron deposition exists in dopaminergic neurons, which may be related to the death of cellular lipid iron peroxide. The extracellular autophagy adaptor SQSTM1(p62) of dopamine (DA) neurons can activate the intracellular Keap1-Nrf2-ARE signaling pathway to inhibit ferroptosis, which has a protective effect on DA neurons. The objective of this study was to investigate the protective mechanism of the Keap1- Nrf2-ARE antioxidant pathway against iron death in dopaminergic neurons. The experiment was divided into a control group (Control group), 1-methyl-4- phenylpyridiniumion control group (MPP+ Control group), p62 overexpression group (MPP+OVp62), and p62 overexpression no-load group (MPP+ OV-P62-NC). The inhibitors brusatol and ZnPP inhibited the activation of NF-E2-related factor 2(Nrf2) and Heme oxygenase-1(HO-1), respectively, and were divided into brusatol group (MPP+OV-p62+brusatol) and ZnPP group (MPP+OV-p62+ZnPP). RT-qPCR was used to detect transfection efficiency, and Cell Counting Kit-8 (CCK8) was used to detect cell activity. FerroOrange, 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA), and Liperfluo probes were used to detect intracellular iron, reactive oxygen species (ROS), and lipid peroxidation (LPO) levels. Western Blotting detected the levels of Nrf2, HO-1, Kelch-like ECH-associated protein1 (Keap1), and their downstream Glutathione peroxidase 4(GPX4) and Acyl-CoA synthetase long-chain family member 4(ACSL4). The levels of LGlutathione (GSH) and Malondialdehyde (MDA) were detected by GSH and MDA kits, and the activation of Keap1-Nrf2-ARE pathway was verified at the cellular level to have an antioxidant protective effect on iron death in dopaminergic neurons. (1) The results of RT-qPCR showed that compared with the control group, the expression of the p62 gene was significantly increased in the MPP+OV-p62 groups (P = 0.039), and the p62 gene was significantly increased in the brusatol and ZnPP groups, indicating successful transfection (P =0.002; P=0.008). (2) The immunofluorescence probe flow results showed that compared to the normal control group, the contents of three kinds of probes in MPP+ model group were significantly increased (P =0.001; P ＜0.001; P＜0.001), and the contents of three kinds of probes in MPP+OV-p62 group were decreased compared to the MPP+ model group (P =0.004). The results indicated that the levels of iron, ROS, and LPO were increased in the MPP+ group and decreased in the MPP+OV-p62 group. (3) Compared with the control group, the expressions of Nrf2, HO-1, and GPX4 in the MPP+OV-p62 group were increased (P =0.007; P =0.004; P=0.010), and the expressions of Keap1 and ACSL4 in MPP+p62 overexpression group were decreased (P =0.017; P =0.005). Compared with the MPP+ control group, Nrf2 and GPX4 were increased in the MPP+OV-p62 group, and ACSL4 was decreased in the MPP+OVp62 group (P =0.041; P ＜0.001; P ＜0.001). The results of the GSH and MDA kit showed that compared with the normal control group, the content of GSH in the MPP+ control group was decreased (P < 0.01), and the content of MDA was increased (P < 0.01). Compared with the MPP+ model group, GSH content was increased (P = 0.003), and MDA content was decreased in the MPP+OV-p62 group (P < 0.001). Nrf2, HO-1, and GPX4 increased in the MPP+p62 overexpression group but decreased in the brusatol group and ZnPP group (P < 0.001). Based on the transfection of P62 plasmid, it was found that P62 plasmid can inhibit the lipid peroxidation of iron death in dopaminergic nerve cells by activating the Nrf2 signaling pathway, thus playing a protective role in dopaminergic nerve cells.

Bufalin Ameliorates Myocardial Ischemia/Reperfusion Injury by Suppressing Macrophage Pyroptosis via P62 Pathway.

Bufalin, which is isolated from toad venom, exerts positive effects on hearts under pathological circumstance. We aimed to investigate the effects and mechanisms of bufalin on myocardial I/R injury. In vivo, bufalin ameliorated myocardial I/R injury, which characteristics with better ejection function, decreased infarct size and less apoptosis. The levels of pyroptotic proteins were increased in I/R-treated macrophages and inflammatory cytokines expressed more in I/R-induced mouse, which could be attenuated by bufalin. Bufalin also reduced H/R-treated macrophage pyroptosis in vitro. Autophagic flux blockage and ROS accumulation were reduced by bufalin in impaired macrophages. Overexpression of p62 abrogated the anti-proptosis and anti-oxidative effects of bufalin. The levels of apoptosis related proteins were changed and TUNEL-positive ratio was raised in cardiomyocytes that received conditioned medium treatment with H/R-treated macrophages, while bufalin pretreatment could reduce apoptosis. These findings indicate that bufalin may attenuate myocardial I/R injury by suppressing macrophage pyroptosis via P62 pathway.

P62 Binding to Protein Kinase C Regulates HIV-1 gp120 V3 Loop Induced Microglial Inflammation.

The main pathogenic mechanism of HIV-associated neurocognitive disorders (HAND) is neuronal apoptosis induced by inflammatory mediators, in which microglial inflammation plays a crucial role. However, the exact pathogenic mechanism remains unclear. Previous studies have shown that the HIV-1 gp120 V3 loop can trigger inflammation in CHME-5 microglia. p62 is a post-translational modified multidomain protein that is involved in the regulation of autophagy and is closely related to neuroinflammation. In this study, we found that p62 knockout down-regulated the expression of MCP-1, IL-6 and COX-2, and improved the inflammation of HIV-1 gp120 V3 loop induced microglia, while overexpression of p62 up-regulated the expression of MCP-1, IL-6 and COX-2, and promoted the inflammation of microglia. In addition, protein kinase C (PKC) knockout down-regulated the expression of MCP-1, IL-6 and COX-2 and inhibited the activation of IKK/ NF-κ B pathway, while tumor necrosis factor receptor-associated factor 6 (TRAF6) knockout had no significant effect on the expression of MCP-1, IL-6 and COX-2. Co-immunoprecipitation showed that p62 was bound and interacted with PKC. Inhibition of IKK/ NF-κ B pathway can down-regulate the expression of MCP-1, IL-6 and COX-2, and improve the inflammatory response of microglia. Our research further found that inhibition of IKK/ NF-κ B can decrease the expression of Caspase-3 and reduce the apoptosis of neurons in the co-culture of CHME-5 microglia and primary mouse neurons. The results of this study suggest that HIV-1 gp120 V3 loop induced CHME-5 microglial inflammation may be activated by the direct binding of p62 and PKC through the IKK/ NF-κ B signaling pathway, and these findings provide an important reference for the prevention and treatment of HAND.

Immunohistochemical Analysis of the p53 Protein in Colorectal Cancer: A Clinicopathological Study.

The role of p53 expression in colorectal cancer (CRC) was investigated in this immunohistochemical analysis of 110 CRC patients. The study aimed to explore the relationship between p53 expression and clinicopathological features, such as tumor grade, size, lymph node involvement, and molecular subtypes. The mean age of patients was 52.6 years, with a higher prevalence in men (60.7%). Tumor grades were balanced, with 12.9% in grade 1, 13.6% in grade 2, and 12.9% in grade 3. The majority of patients exhibited low to moderate p53 expression, with a mean of 32.58%. Higher p53 expression correlated with larger tumor size and more advanced stages. Notably, p53 overexpression was associated with lymph node involvement, suggesting its role in metastasis. The study also examined molecular markers, such as BRAF and KRAS mutations, and found their association with p53 expression. Microsatellite instability was present in 21.4% of cases, with implications for treatment decisions. The findings highlight p53 as a key marker in CRC progression, with potential prognostic value for personalized treatment strategies. Further studies, including survival analysis, are necessary to fully understand the clinical impact of p53 expression in CRC.

The clinicopathological and molecular features of primary high-grade neuroendocrine tumour in the breast.

Nottingham grade for breast cancers, rather than gastro-entero-pancreatic (GEP) grade for neuroendocrine tumours (NETs), is currently applied to primary breast NETs, which need further clarification. High-grade NETs in breast also remain poorly recognised. Among 595 breast carcinomas with diffuse synaptophysin (Syn) or chromogranin A (CgA) immunostaining (≥ 90%), 197 eligible cases were selected, including 69 NETs, 123 invasive breast carcinomas of no special type (IBC-NSTs) and five neuroendocrine carcinomas (NECs). The prognostic significance of these two grading systems in breast NETs was assessed. Furthermore, the clinicopathological features were compared in Nottingham G3 cases among three entities. Targeted sequencing and immunostaining (INSM1/p53/Rb/p16) were also performed in all Nottingham G3 NETs, NECs and 10 Nottingham G3 IBC-NSTs. All Nottingham G3 NETs (9 of 69, 13.0%) fell into GEP G3 cases (20 of 69,29.0%). Nottingham grade provided better prognostic discrimination between G1/G2 and G3 NETs than GEP grade. Among Nottingham G3 cases, there was a trend towards reduced progression-free survival (PFS) in NETs compared with IBC-NSTs (P = 0.057), and the former were more often immunoreactive for INSM1 (44.4 versus 0%, P = 0.033). Nottingham G3 NETs were all of luminal-like phenotype (P < 0.001) and exhibited less aberrant p53 patterns (11.1 versus 80.0%, P = 0.023) as well as more favourable PFS (P = 0.012) and disease-specific survival (P = 0.002) than NECs. Rb loss (4of 5, 80%), p16 overexpression (5 of 5, 100%) and RB1 mutation (2 of 5, 40%) were observed exclusively in NECs. Based on expression data, epithelial-mesenchymal transition and KRAS signalling pathways were significantly up-regulated in Nottingham G3 NETs (P < 0.05). Nottingham grade, rather than GEP grade, holds important prognostic significance in primary breast NETs. Nottingham G3 NETs represent a small proportion of breast NETs, and may demonstrate distinct clinicopathological and molecular features from other high-grade breast carcinomas with diffuse neuroendocrine markers expression.

Differential Expression of p53 in Mycosis Fungoides, Sezary Syndromes, and Their Transformed Forms.

Mycosis fungoides (MF) and Sezary syndrome (SS) are common entities among primary cutaneous lymphomas. Large cell transformation is challenging for diagnosis and therapy. Molecular mechanisms by which these lymphomas undergo this transformation are poorly defined. We studied the immunohistochemical status of p53 in these entities and assessed whether p53 expression could be a useful tool for diagnosis and assessment of transformation. We extracted patients with transformed and untransformed SS or MF from the French Study Group on Cutaneous Lymphoma database between 2014 and 2021, followed in the Rennes University Hospital. An immunohistochemical study of p53 expression was performed on the biopsies sampled as part of routine care. We compared p53 overexpression in the different groups. We included 25 patients with MF, 7 patients with transformed MF (T-MF), 11 patients with SS, and 5 patients with transformed SS (T-SS). Using a cut-off set at 30% expression of neoplastic cells, we noted an overexpression of p53 in T-MF and T-SS compared with nontransformed forms (47% vs. 12%, respectively, P < 0.01) and in MF compared with SS (23% vs. 7%, respectively, P < 0.01). Overexpression of p53 with a cut-off at 30% therefore seems to be a discriminating tool in the differential diagnosis of MF/SS versus their transformed forms as well as the differential diagnosis between MF and SS.

Urine Proteomics in Schistosoma haematobium-induced Bladder Cancer

Schistosomiasis, or Bilharziasis, is a neglected tropical disease caused by Schistosoma parasites, which significantly impacts public health, particularly in Africa. Schistosoma haematobium, the primary species responsible for urogenital schistosomiasis (UGS), is associated with severe chronic conditions, including squamous cell carcinoma (SCC) of the bladder. This review explores the pathogenesis of UGS and its link to bladder cancer, highlighting the molecular mechanisms involved. The chronic inflammation caused by S. haematobium eggs leads to tissue damage, fibrosis, and granuloma formation, creating a pre-cancerous environment. Notably, the role of the p53 pathway in UGS-associated bladder cancer is emphasized, with mutations in the TP53 gene and overexpression of p53 contributing to genetic instability and malignant transformation. Additionally, the review discusses the presence of oestrogen-like metabolites in the urine of UGS patients, which are suspected to be involved in carcinogenesis through an oestrogen-DNA adduct-mediated pathway. Mass spectrometric analysis of urine samples from UGS patients revealed specific metabolites, including 8-oxodG, a marker of oxidative DNA damage, which could serve as potential biomarkers for early detection and progression of bladder cancer. The urine proteome profiling also identified distinct molecular pathways activated in UGS-related bladder cancer, including Th2-type immune responses, oxidative stress, and inflammation. These findings underscore the need for further research into the host-parasite interactions and the development of diagnostic biomarkers for schistosome-induced carcinogenesis. Understanding these mechanisms could enhance treatment strategies and improve prevention efforts for UGS-related bladder cancer, particularly in endemic regions where the disease burden remains high.

P53 marker expression in epithelial ovarian tumours in a centre in Nigeria – a descriptive study

Backgroundp53 is a tumor suppressor gene. p53 expression in epithelial ovarian tumors (EOTs) is correlated with their biological behavior and predicts patient overall survival. However, there is a dearth of knowledge regarding p53 expression in these tumors among women from southwest Nigeria. Our study aimed to determine the patterns of p53 expression in various types of epithelial ovarian tumours.MethodsWe conducted a retrospective study of epithelial ovarian tumours. We retrieved formalin-fixed, paraffin-embedded (FFPE) tissue blocks of previously diagnosed epithelial tumors from the departmental archive. We performed immunohistochemical analysis using p53 antibodies. We scored the expression and staining intensity of p53 as follows: negative (0), focal/weakly positive (1 +), and diffuse/strongly positive (2 +) on the basis of the recommended Cytomation scoring system.ResultsThe spectrum of p53 expression in the 51 histologically diagnosed cases revealed that 29 cases had no expression, consisting of 21 benign EOTs, two borderline EOTs, and six malignant EOTs. Nine cases exhibited wild-type expression, including six serous carcinomas, two mucinous carcinomas, and one signet ring cell carcinoma. p53 overexpression was observed in 13 patients overall, with 12 having serous carcinomas and one having endometrioid carcinoma. Among the 21 serous carcinoma patients, 28.6% (6 patients) presented with wild-type p53 expression, 57.1% (12 patients) presented with p53 overexpression, and 14.3% (three patients) presented negative p53 expression. There was a significant association between p53 expression and the histological grade of serous carcinoma.ConclusionMost epithelial ovarian carcinomas in our hospital are high grade, with many serous carcinomas showing either p53 overexpression or loss of expression. This may contribute to the poor patient survival rate.

Associations between MRI radiomic phenotypes and clinical outcomes in endometrial cancer: Implications for preoperative risk stratification.

This study aimed to investigate the correlation between imaging phenotypes of endometrial cancer (EC) and clinical, pathologic, and molecular characteristics, as well as disease-free survival (DFS). The clinical, pathologic, and molecular characteristics, along with MRI radiomics features, of 356 patients with EC were collected retrospectively. The patients were divided into 2 groups based on radiomics features using unsupervised machine learning. The obtained characteristics and DFS of patients were compared between the various imaging phenotypes. The lesions with deep myometrial invasion (DMI), lymphovascular space invasion (LVSI), cervical stromal invasion (CSI), lymph node metastasis, aggressive histologic type, advanced postoperative International Federation of Gynecology and Obstetrics (FIGO) stage, overexpression of p53, and absent expression of estrogen receptor or progesterone receptor were associated with poor DFS. Two clusters were identified and defined as imaging phenotype 1 and 2, respectively. Compared with phenotype 2, phenotype 1 exhibited a higher correlation with DMI (33.7% vs 13.0%), LVSI (23.8% vs 9.2%), CSI (16.3% vs 3.8%), aggressive histologic type (36.0% vs 17.4%), and advanced FIGO stage (IB or higher, 43.6% vs 22.3%) (p<0.001). The incidence of p53 overexpression was higher in phenotype 1 than in phenotype 2 (20.2% vs 8.5%, p=0.022). Survival analysis exhibited a higher risk of poor DFS in phenotype 1 than in phenotype 2 (log-rank p=0.002). EC imaging phenotypes identified through MRI radiomics features were associated with pathologic, molecular characteristics, and DFS, suggesting potential for preoperative risk stratification.

Clinicopathologic Features of Breast Tumors in Germline TP53 Variant-Associated Li-Fraumeni Syndrome.

We present one of the largest cohorts of TP53-pathogenic germline variants (PGVs) associated with patients with Li-Fraumeni syndrome (n = 82) with breast tumors (19 to 76y; median age: 35). Most had missense variants (77%), followed by large gene rearrangements (LGRs; 12%), truncating (6%), and splice-site (5%) variants. Twenty-one unique germline missense variants were found, with hotspots at codons 175, 181, 245, 248, 273, 334, and 337. Of 100 total breast tumors, 63% were invasive (mostly ductal), 30% pure ductal carcinoma in situ, 4% fibroepithelial lesions, and 3% with unknown histology. Unlike BRCA-associated tumors, approximately half of the breast cancers exhibited HER2-positivity, of which ~50% showed estrogen receptor coexpression. Pathology slides were available for review for 61 tumors (44 patients), and no significant correlation between the type of TP53 PGVs and histologic features was noted. High p53 immunohistochemistry expression (>50%) was seen in 67% of tumors tested (mostly missense variant). Null pattern (<1% cells) was seen in 2 (LGR and splicing variants carriers). Surprisingly, 2 tumors from patients with an LGR and 1 tumor from a patient with a truncating variant showed p53 overexpression (>50%). The subset of patients with the Brazilian p.R337H variant presented at a higher age than those with non-p.R337H variant (46 vs 35y) though statistically insignificant (P = 0.071) due to an imbalance in the sample size, and were uniquely negative for HER2-overexpressing tumors. To conclude, breast cancer in carriers of TP53 PGVs has some unique clinicopathological features that suggest differential mechanisms of tumor formation. p53 immunohistochemistry cannot be used as a surrogate marker to identify germline TP53-mutated breast cancers.

Assessing the Effectiveness of Simple Surgical Excision in Breast Cyst Management: Outcomes, Recurrence, and Postoperative Complications

Background: Breast cysts are common benign tumors that are frequently treated surgically to avoid problems and recurrence. Analyzing this strategy helps to maximize results. Objectives: To evaluate the effectiveness of simple surgical excision for treatment of breast cysts focusing on outcomes, recurrence rates, postoperative complications, and multiple biomarkers. Methods: Current prospective observational study was conducted with 150 female patients who underwent simple surgical excision of breast cysts from September 2023 to September 2024. Recurrence rates, postoperative complications, cosmetic outcomes and the relationship between biomarker profiles and recurrence were evaluated in patients and ER, PR, HER2, Ki-67, p53 and BCL-2 were assessed with immunohistochemistry. All data were analyzed using the chi-square test for categorical variables and independent t- tests for continuous variables with (P &lt; 0.05) considered statistically significant. Results: Within 12 month follow up period, 8 patients (5.3%) had a repeat cyst. Ki-67 expression (&gt;20%) was significantly associated with recurrence (P = 0.03), p53 overexpression (P = 0.04), and BCL-2 positivity (P = 0.02). There was no significant association with recurrence of ER, PR, HER2 and triple negative status. Seventeen patients (11.3%) had postoperative complications, most commonly wound infection (4.0%, P = 0.03). Cosmetic outcomes were generally favorable, however, patients reported lower overall satisfaction with the cosmetic outcomes in association with recurrence or complications (P = 0.04). Conclusions: Breast cysts can be successfully treated with simple surgical excision, which has good cosmetic results and a low recurrence rate. Larger cysts raise the likelihood of seroma with controllable consequences, BCL-2 provides protection, and biomarkers such as Ki-67 and p53 indicate high-risk instances.

P53 and Ki67 Biomarkers are Predictors for Malignant Transformation in Oral Submucous Fibrosis: A Prospective Study.

Oral submucous fibrosis (OSMF) is a potentially malignant disorder (PMD) characterized by a high rate of malignant transformation (MT). OSMF exhibits atrophic epithelium yet has a high proliferation rate. Both p53 and Ki67 are nuclear proteins associated with cell proliferation, detectable in the early stages of oral cancer (OC). This study aimed to analyze the efficacy of p53 and Ki67 immuno-expression as tools for predicting malignant transformation in OSMF cases. The objective was to correlate the expression of p53 and Ki67 with demographic and chewing habits data. The study group consisted of 60 histopathologically diagnosed cases of OSMF, 60 cases of OC as positive controls, and 60 cases of NOM as negative controls. Immunohistochemistry was performed on neutral-buffered formalin-fixed, paraffin-embedded tissue sections of 3 μm thickness, using ready-to-use anti-human p53 protein (clone DO-7) and monoclonal antibody for Ki67 antigen (clone MIB-1). Statistical analysis was conducted using SPSS software version 21, employing the chi-square test (p < 0.05). The expression of p53 and Ki67 was significantly higher in OSMF samples compared to NOM samples, but lower than in OC samples. When the expression levels of both p53 and Ki67 were correlated with demographic and chewing habits data, the results were statistically significant. The overexpression of p53 and Ki67 may contribute to the progression of MT in OSM. Early detection of these biomarkers is crucial for preventing MT, which also helps reduce the morbidity and mortality of OC. Therefore, both p53 and Ki67 can serve as predictive biomarkers for the early detection of MT in high-risk OSMF patients.