P53 Tumor Research Articles

Thiolated chitosan hydrogel-embedded niosomes: A promising crocin delivery system toward the management of aphthous stomatitis

Aphthous stomatitis is a common inflammatory oral disease with challenging management. Crocin is a natural carotenoid that has shown great anti-inflammatory properties. The aim of this study was to develop thiolated chitosan (TCS)-based hydrogels containing niosomes to serve as a mucoadhesive crocin delivery system for aphthous stomatitis. Crocin-loaded niosomes were prepared and the impact of surfactant type, cholesterol content, and lipid to drug ratio on the characteristics of niosomes was evaluated. TCS was synthesized and the success of thiolation was investigated. The optimum niosomal formulation was loaded into the hydrogel and the hybrid system was characterized regarding the morphology, mucoadhesive properties, viscosity, chemical structure, in vitro drug release, and in vivo efficacy. The optimized niosome formulation showed 77% crocin entrapment, a particle diameter of 59 nm, and a zeta potential of −18 mV. The niosome-containing hydrogel exhibited pseudoplastic rheological behavior, mucoadhesive properties, suitable swelling, and sustained release of crocin. In vivo study revealed that the niosome-containing hydrogel improved ulcer healing and decreased the expression of tumor necrosis factor-alpha (TNF-α) and p53 while increasing the expression of vascular endothelial growth factor (VEGF) and alpha-smooth muscle actin (α-SMA). Collectively, TCS hydrogel-embedded crocin-loaded niosomes is a promising therapeutic option for aphthous stomatitis. Chemical compounds studied in this articleCrocin (PubChem CID: 5281233)Chitosan (PubChem CID: 71853)Thioglycolic acid (PubChem CID: 1133)1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (PubChem CID: 2723939)5,5′-dithiobis (2-nitrobenzoic acid) (PubChem CID: 6254)Cholesterol (PubChem CID: 5997)

Expression of p16 Tumor Suppressor Protein in Malignant Ovarian Germ Cell Tumors; Immunohistochemical Study.

Malignant ovarian germ cell tumors represent small percentage of malignant ovarian neoplasms but they affect significantly young age group. To investigate the immunohistochemical expression of p16 tumor suppressor protein in malignant ovarian germ cell tumors. Twenty-two malignant ovarian germ cell tumors (five dysgerminoma, eight immature teratoma, and nine yolk sac tumors), twenty mature cystic teratoma tumors and twenty normal ovarian tissue were immunohistochemically stained with p16 monoclonal antibody. Ki67 immunohistochemical staining was done for malignant ovarian germ cell tumors to assess proliferation. We found that p16 tumor suppressor protein is overexpressed in all malignant ovarian germ cell tumors in both nuclear and cytoplasmic locations compared to control and to mature cystic teratoma (p-value <0.001). Cytoplasmic p16 expression was significantly correlated to Ki67 proliferation index in malignant ovarian germ cell tumors (p-value = 0.033, r = 0.445). Overexpression of p16 in malignant ovarian germ cell tumors denotes that dysfunction of the cyclin dependent kinase pathway is involved in tumorigenesis of malignant ovarian germ cell tumors.

Expression of IL-13Rα2 and FUS in glioma: clinicopathological and prognostic correlation

BackgroundIL-13Rα2 is one of the most widely studied tumor-associated antigens in glioma research. Fused in sarcoma (FUS) is a DNA/RNA binding protein that is dysfunctional in various malignant tumors. However, the expression of IL-13Rα2 and FUS, their relationship with clinicopathological parameters and their prognostic value in glioma remain unclear.MethodsIn the present study, the expression of IL-13Rα2 and FUS was measured in a glioma tissue array by immunohistochemistry. Pearson’s X2 test was used to determine the correlation between immunohistochemical expressions and clinicopathological parameters. Pearson’s or Spearman's correlation test was used to determine the association between these two proteins expression. The Kaplan–Meier analysis was used to investigate the effect of these proteins on prognosis.ResultsThe expressions of IL-13Rα2 were significantly higher in high-grade gliomas (HGG) than that in low-grade gliomas (LGG) and was associated with IDH mutation status, whereas FUS location demonstrated no significant correlation with clinicopathological parameters. Moreover, a positive relationship was found between nuclear and cytoplasmic co-localization FUS and IL-13Rα2 expression. Kaplan–Meier analysis revealed that patients with IDH wide type or IL-13Rα2 had worst overall survival (OS) compared to other biomarkers. In HGG, IL-13Rα2 combined with nuclear and cytoplasmic co-localization of FUS was associated with worse OS. Multivariate analysis showed that tumor grade, Ki-67, P53 and IL-13Rα2 could be the independent prognostic factors for OS.ConclusionIL-13Rα2 expression was significantly associated with cytoplasmic distribution of FUS in human glioma samples and could be the independent prognostic factors for OS, while the prognostic value of its co-expression with cytoplasmic FUS in glioma need to be addressed in the future studies.

Enteral Nutrition during Radiotherapy for Oropharyngeal Cancers: Prevalence and Prognostic Factors Based on HPV Status (A GETTEC Study).

Nutritional support during radiotherapy is crucial to tolerating and completing oropharyngeal squamous cell carcinoma (OPSCC) treatment. The impact of HPV status on nutritional support is debated. The objective was to evaluate the rate of Reactive Feeding Tube (RFT) use and determine its prognostic factors during definitive radiotherapy for OPSCC. All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. The impact of tumor p16 status on the risk of RFT was assessed through multivariate analyses. Among the 543 patients, 103 patients required an RFT (19.0%). The use of RFT differed between centers (5% to 32.4%). In multivariate analysis, only tongue base involvement and concurrent chemotherapy were significantly associated with RFT (OR = 2.18 and 3.7, respectively). Tongue base involvement and concomitant chemotherapy were prognostic factors for RFT. HPV status was not a prognostic factor for enteral nutrition during radiotherapy for OPSCC.

Potential diagnostic utility of PRAME and p16 immunohistochemistry in melanocytic nevi and malignant melanoma.

PRAME (PReferentially expressed Antigen in MElanoma) is a tumor-associated antigen that has been studied in various cutaneous melanocytic lesions. p16, on the other hand, has been proposed to aid in distinguishing between benign and malignant melanocytic neoplasms. Studies on the diagnostic utility of PRAME and p16 in combination in differentiating nevi from melanoma are limited. We aimed to assess the diagnostic utility of PRAME and p16 in melanocytic tumors and their role in distinguishing between malignant melanomas and melanocytic nevi. This is a single-center retrospective cohort analysis over a 4-year period (2017-2020). We used the pathological database of malignant melanomas (77 cases) and melanocytic nevi (51 cases) specimens from patients who underwent shave/punch biopsies or surgical excisions and evaluated immunohistochemical staining percentage positivity and intensity for PRAME and p16. Most malignant melanomas showed positive/diffuse PRAME expression (89.6%); on the other hand, 96.1% of nevi did not express PRAME diffusely. p16 was expressed consistently in nevi (98.0%). However, p16 expression in malignant melanoma was infrequent in our study. PRAME had a sensitivity and specificity of 89.6% and 96.1%, respectively, for melanomas versus nevi; on the other hand, p16 had a sensitivity and specificity of 98.0% and 28.6%, respectively, for nevi versus melanoma. Also, a PRAME+/p16- melanocytic lesion is unlikely to be a nevus where most nevi were PRAME-/p16+. In conclusion, we confirm the potential utility of PRAME and p16 for distinguishing melanocytic nevi from malignant melanomas.

1153 AHR controls keratinocyte stress responses to UVB radiation: Role of the p27 tumor suppressor protein

1153 AHR controls keratinocyte stress responses to UVB radiation: Role of the p27 tumor suppressor protein

Abstract LB273: An emerging paradigm of heterogeneous midkine expression in thyroid cancer

Abstract Midkine (MDK) is a pleiotropic heparin-binding growth factor, contributing to both normal tissue homeostasis and disease development. MDK expression is gradually increased during carcinogenesis, acting as a mediator for the acquisition of cancer hallmarks, such as invasion/metastasis, and immunosuppression. Tissue-wide gene expression analysis using publicly available databases reveal that MDK is significantly upregulated in most human carcinomas. In the thyroid, MDK has been associated with increased metastatic potential in the context of papillary thyroid cancer, which is an otherwise relatively non-aggressive thyroid tumor. We thus theorized that more aggressive types of thyroid cancers may be linked to increased MDK expression/function from an earlier onset. To gain such insights, we developed a digital pathology infrastructure to investigate MDK expression in a characterized mouse model of Anaplastic Thyroid Carcinoma (ATC), the most aggressive and lethal type of thyroid cancer with low but increased prevalence in the human population, and an intrinsic resistance to available therapeutic options. Mice with conditional ablation of tumor suppressors, Pten and p53, in thyrocytes [Pten, p53]thyr-/− develop thyroid carcinomas with mixed follicular and anaplastic components, and histological hallmarks of high aggressiveness, including giant cells, bone metaplasia, and muscular/tracheal invasion, which are all recapitulated in human disease. MDK was more highly expressed in anaplastic, when compared to follicular components of the same animal tumors. When the above hallmarks were topographically and microanatomically demarcated within the anaplastic component, it was found that MDK expression was higher near and around giant cell islets, as well as within the anaplastic lesions invading beyond the cartilaginous rings of tracheal mucosal epithelium. Based on recent evidence that MDK does not solely function in the extracellular space, but can also be endocytosed within tumor cells, whereby it exerts tumor-promoting functions, we further quantified the intra/extranuclear MDK fraction using intensity thresholding immunofluorescence. Of interest, MDK+ follicular lesions, were primarily characterized by nuclear MDK expression, whereas MDK was mostly found secreted in the extracellular space of anaplastic lesions, thus implying different modes of MDK trafficking, secretion, and possibly function in them. The take home message is to work towards establishing and developing gain- and loss-of-function experiments, to elucidate mechanistic underpinnings on the role of MDK in the development of aggressive ATC lesions. Citation Format: Dimitra P. Anastasiadou, Antonio Di Cristofano, George S. Karagiannis. An emerging paradigm of heterogeneous midkine expression in thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB273.

Abstract 3779: Evaluation of anti-cancer efficacy of lipid nanoparticles containing siRNA against HPV16 E6 and E7 combined with cisplatin in xenograft model of cervical cancer

Abstract Background: High-risk human papillomavirus (HPV) type 16 is the major etiological agent found in more than 60% of patients with cervical cancer and associated with cancer development and progression. Persistent expression HPV E6 and E7 oncoproteins are essential for the initiation and maintenance of cervical cancer. The therapeutic approaches targeting HPV E6 and E7 have been proved to be highly efficient in killing malignant cells. The suppression of HPV 16 E6/E7 expression by the short interfering RNA (siRNA) was more effective in combination therapy with cisplatin (CDDP) for cervical cancer. ENB101-LNP is an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16 for delivery to the tumor cells. Methods: To investigate the anticancer efficacy and mechanism of ENB101-LNP combined with cisplatin in cervical cancer; the xenograft model was generated by the injection of CaSki cells subcutaneously into BALB/c nude mice. Mice were randomly divided into six groups: 1) blank control; 2) 1mg/kg ENB101-LNP; 3) 3mg/kg ENB101-LNP; 4) CDDP; 5) 1mg/kg ENB101-LNP-CDDP; 6) 3mg/kg ENB101-LNP-CDDP. ENB101-LNP was treated with intravenous injection three times weekly for 3 weeks and CDDP was treated with IP injection once a week for 3 weeks. Tumor growth curves were plotted to calculate the tumor inhibition rate. Mice were sacrificed one week after the last treatment and the tumor tissues were investigated using histopathology, immunohistochemical staining and western blotting. Results: Compared with the control and the other treatment groups, the tumor growth was significantly inhibited (P &amp;lt; 0.05). The tumor inhibition rate was 29.7% in 1mg/kg ENB101-LNP group, 29.6% in 3mg/kg ENB101-LNP group, 34.0% in CDDP group, 47.0% in 1mg/kg ENB101-LNP-CDDP group. At the dose of 3mg ENB101-LNP/kg combined with CDDP exhibited superior antitumor efficacy, the tumor inhibition rate was 68.8%. The successful ENB101-LNP mediated knockdown (with up to 80%) of HPV16 E6/E7 in tumors of both 1mg/kg and 3mg/kg groups was confirmed by RT-PCR. The ENB101-LNP increased p53 and p21 expression in tumors compared to control and CDDP alone groups and combination treatment with CDDP showed decreased expression of PD-L1 expression compared to CDDP alone group. The treatment of ENB101-LNP and combination with CDDP showed significant increase in apoptotic cells compared to control and single-agent groups respectively. Conclusions: The ENB101-LNP inhibiting E6 and E7 of HPV 16 in combination with CDDP showed promising anticancer activity in the cervical cancer cells xenograft mouse model. Citation Format: Sung Wan Kang, Shin-Wha Lee, Ji-young Lee, Ok Ju Kang, Hyejeong Kim, Yisak Kim, Yong-Man Kim. Evaluation of anti-cancer efficacy of lipid nanoparticles containing siRNA against HPV16 E6 and E7 combined with cisplatin in xenograft model of cervical cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3779.

Abstract 6222: Clinical impact of p53 and AXL immunostaining on the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor mutant non-small cell lung cancer

Abstract Background: Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. Methods: We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations. Results: A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively). Conclusion: The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted. Citation Format: Kenji Morimoto, Tadaaki Yamada, Shinsaku Tokuda, Koichi Takayama. Clinical impact of p53 and AXL immunostaining on the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6222.

Radiomic tumor phenotypes augment molecular profiling in predicting recurrence free survival after breast neoadjuvant chemotherapy

BackgroundEarly changes in breast intratumor heterogeneity during neoadjuvant chemotherapy may reflect the tumor’s ability to adapt and evade treatment. We investigated the combination of precision medicine predictors of genomic and MRI data towards improved prediction of recurrence free survival (RFS).MethodsA total of 100 women from the ACRIN 6657/I-SPY 1 trial were retrospectively analyzed. We estimated MammaPrint, PAM50 ROR-S, and p53 mutation scores from publicly available gene expression data and generated four, voxel-wise 3-D radiomic kinetic maps from DCE-MR images at both pre- and early-treatment time points. Within the primary lesion from each kinetic map, features of change in radiomic heterogeneity were summarized into 6 principal components.ResultsWe identify two imaging phenotypes of change in intratumor heterogeneity (p < 0.01) demonstrating significant Kaplan-Meier curve separation (p < 0.001). Adding phenotypes to established prognostic factors, functional tumor volume (FTV), MammaPrint, PAM50, and p53 scores in a Cox regression model improves the concordance statistic for predicting RFS from 0.73 to 0.79 (p = 0.002).ConclusionsThese results demonstrate an important step in combining personalized molecular signatures and longitudinal imaging data towards improved prognosis.

A novel predictive model of microvascular invasion in hepatocellular carcinoma based on differential protein expression

BackgroundThis study aims to construct and verify a nomogram model for microvascular invasion (MVI) based on hepatocellular carcinoma (HCC) tumor characteristics and differential protein expressions, and explore the clinical application value of the prediction model.MethodsThe clinicopathological data of 200 HCC patients were collected and randomly divided into training set and validation set according to the ratio of 7:3. The correlation between MVI occurrence and primary disease, age, gender, tumor size, tumor stage, and immunohistochemical characteristics of 13 proteins, including GPC3, CK19 and vimentin, were statistically analyzed. Univariate and multivariate analyzes identified risk factors and independent risk factors, respectively. A nomogram model that can be used to predict the presence of MVI was subsequently constructed. Then, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were conducted to assess the performance of the model.ResultsMultivariate logistic regression analysis indicated that tumor size, GPC3, P53, RRM1, BRCA1, and ARG were independent risk factors for MVI. A nomogram was constructed based on the above six predictors. ROC curve, calibration, and DCA analysis demonstrated the good performance and the clinical application potential of the nomogram model.ConclusionsThe predictive model constructed based on the clinical characteristics of HCC tumors and differential protein expression patterns could be helpful to improve the accuracy of MVI diagnosis in HCC patients.

Immunohistochemical Expression of p16 and CDK4 in Soft Tissue Tumors.

The aim of this study was to determine the immunohistochemical expression of p16 (p16INK4a) and cyclin-dependent kinase 4 (CDK4) and CDK4 markers in various lineages of soft tissue tumors and to evaluate their role in differentiating atypical lipomatous tumors/well-differentiated liposarcomas from benign lipomas. A total of 70 cases of both excisional and incisional biopsies of soft tissue tumors were included in this study. Histopathological examination was done by using formalin-fixed, paraffin-embedded tissue samples. After that, we performed IHC expressions of p16 and CDK4 markers on the unstained slides of these soft tissue tumors. Results: Immunohistochemical study showed that positive expressions of p16, CDK4, and combined (p16+CDK4) markers were 51.4%, 10.0%, and 12.9%, respectively in soft tissue tumors. Positive p16 expression was observed among a higher proportion of malignant cases (66.7%) as compared to benign (20.0%) and intermediate (50.0%) cases. This difference was found to be statistically significant (p=0.009). Negative expression of only CDK4 and combined (p16 and CDK4) were observed among a higher proportion of benign as compared to malignant and intermediate cases (90.0% vs. 78.6% & 75.0%, p=0.393 and 65.0% vs. 26.2% & 37.5%, p=0.028, respectively). This difference was not found to be statistically significant. For adipocytic tumors, the majority of malignant and intermediate tumors had positive p16 (7/7; 100%) and CDK4 (6/7; 85.7%) immunohistochemical expression. These differences were found to be statistically significant. Immunohistochemical marker p16 can be used to differentiate between malignant and benign soft tissue tumors. Amongst adipocytic tumors, combination of p16 and CDK4 immunohistochemical expression can be used to differentiate liposarcomasfrom benign ones.

Validation of p53 Immunohistochemistry (PAb240 Clone) in Canine Tumors with Next-Generation Sequencing (NGS) Analysis

In human medicine, p53 immunohistochemistry (IHC) is a common method that is used for the identification of tumors with TP53 mutations. In veterinary medicine, several studies have performed IHC for p53 in canine tumors, but it is not known how well it actually predicts the mutation. The aim of this study was to estimate the accuracy of the IHC method for p53 (clone PAb240) using a lab-developed NGS panel to analyze TP53 mutations in a subset of malignant tumors in dogs. A total of 176 tumors were analyzed with IHC and then 41 were subjected to NGS analysis; among them, 15 were IHC positive and 26 were negative, and 16 out of 41 (39%) were found to be inadequate for NGS analysis. Excluding the non-evaluable cases at NGS, of the remaining eight IHC-positive cases, six were mutants and two were wild-type. Among the 17 IHC-negative cases, 13 were wild type, and 4 were mutants. The sensitivity was 60%, specificity was 86.7%, and the accuracy was 76%. These results suggest that when using IHC for p53 with this specific antibody to predict mutation, up to 25% wrong predictions can be expected.

Loco-Regional Control and Sustained Difference in Serum Immune Protein Expression in Patients Treated for p16-Positive and p16-Negative Head and Neck Squamous Cell Carcinoma.

The main prognostic factors for patients with head and neck cancer are the tumour site and stage, yet immunological and metabolic factors are certainly important, although knowledge is still limited. Expression of the biomarker p16INK4a (p16) in oropharyngeal cancer tumour tissue is one of the few biomarkers for the diagnosis and prognosis of head and neck cancer. The association between p16 expression in the tumour and the systemic immune response in the blood compartment has not been established. This study aimed to assess whether there is a difference in serum immune protein expression profiles between patients with p16+ and p16- head and squamous cell carcinoma (HNCC). The serum immune protein expression profiles, using the Olink® immunoassay, of 132 patients with p16+ and p16- tumours were compared before treatment and one year after treatment. A significant difference in the serum immune protein expression profile was observed both before and one year after treatment. In the p16- group, a low expression of four proteins: IL12RB1, CD28, CCL3, and GZMA before treatment conferred a higher rate of failure. Based on the sustained difference between serum immune proteins, we hypothesise that the immunological system is still adapted to the tumour p16 status one year after tumour eradication or that a fundamental difference exists in the immunological system between patients with p16+ and p16- tumours.

Immunohistochemical assessment of possible anticancer effect mechanisms of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)- 5,6,7-trichloro-1,3-tropolone in PDX models of lung cancer

Purpose of the study. Evaluation of the expression of immunohistochemical tumor markers Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43 when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in mice with xenographs of squamous cell lung cancer.Materials and methods. Subcutaneous PDX models of human squamous cell lung cancer were created in immunodeficient BALB/c Nude mice. A fragment of the patient’s tumor (3 × 3 × 3 mm) was implanted subcutaneously in the right thigh of a previously anesthetized mouse. 200 μl of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone was administered orally using a probe in 12 doses once every 3 days. All animals were divided into groups depending on the tropolone doses: experimental groups 2–5 with doses of 0.0055, 0.055, 0.55 and 2.75 mg/g, respectively. The control group received 1 % starch gel which was tropolone carrier. The animals were euthanized 36 days after the start of the substance administration, and the tumor tissue was isolated and prepared for the IHC study according to the standard protocol. IHC reactions were performed using antibodies for Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43.Results. Higher tropolone doses were associated with decreased expression of Ki-67, b-catenin, and the Bcl-2 protein, but increased expression of the P53 protein. The dosage of tropolone and expression of connexin 43 were directly proportional.Conclusion. Immunohistochemical analysis of expression of proteins in PDX models of human squamous cell lung cancer when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone showed the changes indicating its antitumor efficacy and suggesting a possible mechanism of action based on the activation of apoptosis.

Targeting Y220C mutated p53 by Foeniculum vulgare-derived phytochemicals as cancer therapeutics.

The mutations in the TP53 gene are the most frequent (50-60% of human cancer) genetic alterations in cancer cells, indicating the critical role of wild-type p53 in the regulation of cell proliferation and apoptosis upon oncogenic stress. Most missense mutations are clustered in the DNA-binding core domain, disrupting DNA binding ability. However, some mutations like Y220C occur outside the DNA binding domain and are associated with p53 structure destabilization. Overall, the results of these mutations are single amino acid substitutions in p53 and the production of dysfunctional p53 protein in large amounts, consequently allowing the escape of apoptosis and rapid progression of tumor growth. Thus, therapeutic targeting of mutant p53 in tumors to restore its wild-type tumor suppression activity has immense potential for translational cancer research. Various molecules have been discovered with modern scientific techniques to reactivate mutant p53 by reverting structural changes and/or DNA binding ability. These compounds include small molecules, various peptides, and phytochemicals. TP53 protein is long thought of as a potential target; however, its translation for therapeutic purposes is still in its infancy. The study comprehensively analyzed the therapeutic potential of small phytochemicals from Foeniculum vulgare (Fennel) with drug-likeness and capability to reactivate mutant p53 (Y220C) through molecular docking simulation. The docking study and the stable molecular dynamic simulations revealed juglalin (- 8.6kcal/mol), retinol (- 9.14kcal/mol), and 3-nitrofluoranthene (- 8.43kcal/mol) significantly bind to the mutated site suggesting the possibility of drug designing against the Y220C mutp53. The study supports these compounds for further animal based in vivo and in vitro research to validate their efficacy. For the purposes of drug repurposing, recently in-silico methods have presented with opportunity to rule out many compounds which have less probability to act as a drug based on their structural moiety and interaction with the target macromolecule. The study here utilizes molecular docking via Autodock 4.2.6 and molecular dynamics using Schrodinger 2021 to find potential therapeutic options which are capable to reactive the mutated TP53 protein.

Relationship Between Serum 25-Hydroxy Vitamin D Level and Breast Cancer Prognostic Factors

Vitamin D deficiency plays an important role in the development of various diseases, including cancer. Regarding the high prevalence of breast cancer and vitamin D deficiency in Iran, this study aimed to investigate the relationship between vitamin D deficiencies and prognostic factors in breast cancer. This descriptive-analytical cross-sectional study was performed from March 2015 to March 2017 at Imam Reza hospital in Kermanshah city, Iran. 145 breast cancer patients with pathologic confirmation and before the neoadjuvant or adjuvant treatments were included by simple and convenient sampling. Serum 25(OH) D levels were measured in all patients before receiving treatment. The collected data were analyzed by using SPSS software (version. 20), and the relationship between the levels of 25(OH) D and the studied factors was assessed by inferential statistical tests in each group. The results showed that there was a statistically significant direct relationship between serum vitamin D levels and some factors, including age, ER, and PR, but a significant inverse relationship was observed between serum vitamin D levels and the level of ki67 and metastasis. There was no statistically significant relationship between the mean serum level of vitamin D and tumor grade and P53 receptor, but high levels of vitamin D were associated with low-grade tumors and P53 negativity. According to the findings, lower levels of vitamin D can be associated with higher levels of ki67 and P53, higher-grade breast cancer, a higher rate of metastases, as well as lower percentage of hormone receptor positivity.

Predictive value of p53 and AXL immunostaining for the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor-mutant non-small cell lung cancer.

Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations. A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively). The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted.

P53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression

Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 degradation. The cytosolic DNA accumulation resulting from TREX1 degradation activates the cytosolic DNA-sensing cGAS/STING pathway, resulting in induction of type I interferons. TREX1 overexpression sufficed to block p53 activation of the cGAS/STING pathway. p53-mediated induction of type I interferon (IFNB1) is suppressed by cGAS/STING knockout, and p53's tumor suppressor activities are compromised by the loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell-intrinsic and cell-extrinsic tumor suppressor activities.

Immunohistochemical Expression of p16 and CDK4 in Soft Tissue Tumors

Background: The large majority of soft tissue tumours are benign.Malignantmesenchymal neoplasms amount to less than 1% of the overall human burden of malignant tumours but they are life threatening and may pose a significant diagnostic and therapeutic challenge since there are more than 50 histological subtypes of STS, which are often associated with unique clinical, prognostic and therapeutic features. Methods: The study was undertaken in department of Pathology, King George’s Medical University, Lucknow. The Study Design was Retrospective and prospective study carried over a period of one year from September 2018 to august 2019 including 70 cases.Results: Most common diagnosis of malignant cases was Synovial saroma (21.4%) followed by Leiomyosarcoma (19.0%) and Undifferentiated pleomorphic sarcoma &amp; Fibromyxoid sarcoma (11.9% each). Less common diagnosis were Ewing’s sarcoma, Liposarcoma and Rhabdomyosarcoma (9.5% each), 1 (2.4%) case each was diagnosed as Chondrosarcoma, MPNST and Myxoid liposarcoma. Conclusions: Genetic alterations involving the 12q13-15 chromosomal region are common in musculoskeletal sarcomas, and many bone and soft-tissue malignant tumors showed amplification of various genes located in this region