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Effect of Vitamin D on Relapse-Free Survival in a Subgroup of Patients with p53 Protein-Positive Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Trial.
Akutsu, T, Okada, S, Hirooka, S, Ikegami, M, Ohdaira, H, Suzuki, Y, Urashima, M
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020;(2):406-413
Abstract
BACKGROUND The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation. METHODS The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles. RESULTS The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31-0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (P interaction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed. CONCLUSIONS These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer. IMPACT The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.
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Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer.
Chiappori, AA, Williams, CC, Gray, JE, Tanvetyanon, T, Haura, EB, Creelan, BC, Thapa, R, Chen, DT, Simon, GR, Bepler, G, et al
Cancer immunology, immunotherapy : CII. 2019;(3):517-527
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Abstract
Small cell lung cancer TP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type TP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval [CI], 5.3-48.6) and 43.3% of arm C (95% CI 23.9-65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7-46.3), 16.7% (95% CI 2.9-49.1), and 23.8% (95% CI 9.1-47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.
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p53 and ki67 as biomarkers in determining response to chemoprevention for oral leukoplakia.
Nagao, T, Warnakulasuriya, S, Sakuma, H, Miyabe, S, Hasegawa, S, Machida, J, Suzuki, K, Fukano, H, Shimozato, K, Hashimoto, S
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2017;(5):346-352
Abstract
BACKGROUND We performed a randomized controlled chemoprevention trial of oral leukoplakia by administrating a low dose of beta-carotene and vitamin C supplements. 17% of subjects in the experimental arm (4/23) demonstrated clinical remission (complete or partial response) at completion of the trial. The objective of this study was to determine whether baseline expression of p53 and ki67 demonstrated any differences between those responding or not responding to our intervention. A secondary objective was to elucidate any relationship between dietary factors and clinical responses. METHODS For this biomarker study, we included all subjects in the experimental group (n = 23) who were non-smokers. Among 16 who completed the trial for 1 year of supplementation, there were four responders and 12 non-responders at 1-year follow-up. Following immuno-staining for p53 and ki67, the percentage of positive cell nuclei were analyzed as labeling index (LI). RESULTS Expression of p53 was greater in basal layers than in para-basal layers. Mean para-basal LI of p53 was higher in non-responding (26.0) than in responding subjects (11.2) (P = 0.028). ki67 LIs were not significantly different in the two groups. CONCLUSIONS Expression of p53 was inversely related to clinical response to the supplements. Other biomarkers that may recognize subject's responsiveness to chemoprevention require further study.
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The Prognostic Value of the Immunohistochemical Expression of Phosphorylated RB and p16 Proteins in Association with Cyclin D1 and the p53 Pathway in a Large Cohort of Patients with Breast Cancer Treated with Taxane-based Adjuvant Chemotherapy.
Gavressea, T, Kalogeras, KT, Koliou, GA, Zagouri, F, Lazaridis, G, Gogas, H, Tsigaridas, K, Koutras, A, Petraki, K, Markopoulos, C, et al
Anticancer research. 2017;(6):2947-2957
Abstract
BACKGROUND The retinoblastoma (RB) gene is a tumor-suppressor gene that plays a central role in regulating the cell cycle. Inactivation of this gene is involved in breast cancer. PATIENTS AND METHODS A total of 827 patients with breast cancer treated with taxane-based adjuvant chemotherapy were included in the study. Protein expression of RB, phosphorylated RB (pRB), p16, cyclin D1 and p53 was evaluated by immunohistochemistry. RESULTS Neither of the retinoblastoma markers (RB and pRB) reached statistical significance in terms of their association with disease-free or overall survival. Nevertheless, when clustering analysis was performed, patients with tumors featuring low levels of p16, cyclin D1 and p53 with concomitantly high levels of pRB had reduced risk for relapse (Wald's p=0.015). CONCLUSION The p53-mediated sensitivity of breast cancer cells to chemotherapeutic agents appears to be driven mostly by pRB. Using agents that enhance RB phosphorylation might possibly increase the chemosensitivity of breast cancer cells.
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Expression of p53 and caspase-8 in lens epithelial cells of diabetic cataract.
Lim, SA, Joo, CK, Kim, MS, Chung, SK
Journal of cataract and refractive surgery. 2014;(7):1102-8
Abstract
PURPOSE To determine expression of apoptotic factors p53 and caspase-8 in human lens epithelial cells (LECs) of cataract patients with or without diabetic retinopathy (DR), the duration of diabetes mellitus (DM), and the level of glycated hemoglobin (hemoglobin A1c [HbA1c]). SETTING St. Mary's Hospital, Catholic University of Korea, Seoul, South Korea. DESIGN Randomized prospective study. METHODS The LECs were isolated during cataract surgery. The isolated samples were classified into 4 groups as follows: patients without DM (Group 1), patients with DM but not DR (Group 2), diabetic patients with nonproliferative DR (Group 3), and diabetic patients with proliferative DR (Group 4). To explore the mechanism of apoptosis, the expressions of p53 and caspase-8 were measured by immunohistochemical staining and compared with the data according to the duration of DM, HbA1c levels, and severity of DR. RESULTS All groups comprised 15 eyes. The expressions of P53 and caspase-8 were higher in Groups 2, 3, and 4 than in Group 1 (P<.001). The expressions were statistically significantly increased with a longer duration of DM, higher HbA1c levels, and advanced DR. CONCLUSIONS The expressions of P53 and caspase-8 were strong in patients with DM and advanced DR. Knowledge of these relationships may lead to a better understanding of the development of diabetic cataract. FINANCIAL DISCLOSURE No author has a financial or proprietary interest in any material or method mentioned.
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Matched work high-intensity interval and continuous running induce similar increases in PGC-1α mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle.
Bartlett, JD, Hwa Joo, C, Jeong, TS, Louhelainen, J, Cochran, AJ, Gibala, MJ, Gregson, W, Close, GL, Drust, B, Morton, JP
Journal of applied physiology (Bethesda, Md. : 1985). 2012;(7):1135-43
Abstract
The aim of the present study was to test the hypothesis that acute high-intensity interval (HIT) running induces greater activation of signaling pathways associated with mitochondrial biogenesis compared with moderate-intensity continuous (CONT) running matched for work done. In a repeated-measures design, 10 active men performed two running protocols consisting of HIT [6 × 3-min at 90% maximal oxygen consumption (Vo(2max)) interspersed with 3-min recovery periods at 50% Vo(2max) with a 7-min warm-up and cool-down period at 70% Vo(2max)] or CONT (50-min continuous running at 70% Vo(2max)). Both protocols were matched, therefore, for average intensity, duration, and distance run. Muscle biopsies (vastus lateralis) were obtained preexercise, postexercise, and 3 h postexercise. Muscle glycogen decreased (P < 0.05) similarly in HIT and CONT (116 ± 11 vs. 111 ± 17 mmol/kg dry wt, respectively). Phosphorylation (P-) of p38MAPK(Thr180/Tyr182) (1.9 ± 0.1- vs. 1.5 ± 0.2-fold) and AMPK(Thr172) (1.5 ± 0.3- vs. 1.5 ± 0.1-fold) increased immediately postexercise (P < 0.05) in HIT and CONT, respectively, and returned to basal levels at 3 h postexercise. P-p53(Ser15) (HIT, 2.7 ± 0.8-fold; CONT, 2.1 ± 0.8-fold), PGC-1α mRNA (HIT, 4.2 ± 1.7-fold; CONT, 4.5 ± 0.9-fold) and HSP72 mRNA (HIT, 4.4 ± 2-fold; CONT, 3.5 ± 1-fold) all increased 3 h postexercise (P < 0.05) although neither parameter increased (P > 0.05) immediately postexercise. There was no difference between trials for any of the above signaling or gene expression responses (P > 0.05). We provide novel data by demonstrating that acute HIT and CONT running (when matched for average intensity, duration, and work done) induces similar activation of molecular signaling pathways associated with regulation of mitochondrial biogenesis. Furthermore, this is the first report of contraction-induced p53 phosphorylation in human skeletal muscle, thus highlighting an additional pathway by which exercise may initiate mitochondrial biogenesis.
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Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon-alpha.
Esuvaranathan, K, Chiong, E, Thamboo, TP, Chan, YH, Kamaraj, R, Mahendran, R, Teh, M
Cancer. 2007;(6):1097-105
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Abstract
BACKGROUND Nuclear p53 and retinoblastoma protein (pRb) were reported to be poor prognostic indicators for transitional cell carcinoma of the bladder. The authors sought to determine the prognostic value of nuclear p53 and pRb in superficial bladder transitional cell carcinoma patients who were treated with intravesical bacille Calmette-Guerin (BCG) or BCG with interferon-alpha (IFN-alpha). METHODS A prospective histological review was performed for 80 superficial bladder transitional cell carcinoma patients who underwent postresection intravesical regimes of BCG (81 mg, n = 33 or 27 mg, n = 20) or BCG (27 mg) with IFN-alpha (n = 27), and followed for a mean of 4.5 years. Hematoxylin and eosin (H & E) and immunoperoxidase staining were performed on tissue sections. Nuclear p53 and pRb immunoreactivity were assessed semiquantitatively, by using a combination of staining extent and intensity, to categorize overexpression or underexpression. Data were analyzed by using chi-square analysis, multiple logistic regression, and Kaplan-Meier curves. RESULTS pRb expression was not associated with patient outcome after BCG-alone therapy, but pRb underexpression was significantly associated with BCG nonresponse and tumor recurrence (P = .047) after BCG and IFN-alpha (BCG + IFN-alpha) therapy. Low-grade tumors were associated with pRb overexpression, with or without nuclear p53 underexpression (P = .019; P = .043, respectively). p53 expression alone or in combination with pRb expression had no significant relation with tumor response to BCG alone or BCG + IFN-alpha with respect to recurrence, progression, or cancer-specific death. CONCLUSIONS Nuclear pRb underexpression may be predictive of nonresponse and cancer recurrence after intravesical BCG + IFN-alpha therapy. Nuclear p53 expression or its combination with pRb expression is not associated with post-BCG clinical outcome, so p53 expression or p53 with pRb expression should not be used to influence decisions concerning BCG-alone or BCG + IFN-alpha therapy.
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Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer.
Wirtenberger, M, Frank, B, Hemminki, K, Klaes, R, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Kiechle, M, Arnold, N, Weber, BH, et al
Carcinogenesis. 2006;(8):1655-60
Abstract
Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance familial breast cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G>A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on familial breast cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German familial breast cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with familial breast cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk familial breast cancer (OR = 1.32, 95% CI 1.06-1.65). The analysis of p53 MspI 1798G>A, which is completely linked to p53PIN3, showed a significantly increased familial breast cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.12-4.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased breast cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for familial breast cancer susceptibility.
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The effects of calcipotriol and methylprednisolone aseponate on bcl-2, p53 and ki-67 expression in psoriasis.
Adişen, E, Gülekon, A, Erdem, O, Dursun, A, Gürer, MA
Journal of the European Academy of Dermatology and Venereology : JEADV. 2006;(5):527-33
Abstract
OBJECTIVE The decrease of physiological apoptosis in the psoriatic lesions is thought to be involved in the pathogenesis of psoriasis, and induction of apoptosis was shown to contribute to the regression of psoriatic hyperplasia. In the present study, we compared the effects of calcipotriol and methylprednisolone aseponate (MPA) treatments on bcl-2, p53 and ki-67 expressions in psoriatic patients in order to define a relationship between regulation of apoptosis and healing process in psoriasis. METHODS Thirty psoriatic patients with stable and moderate chronic plaque psoriasis applied either calcipotriol or MPA ointment for 6 weeks twice daily. Evaluation of bcl-2, p53 and ki-67 positivity was performed at baseline and was repeated at sixth week for each therapy. RESULTS The mean percentage of positive keratinocytes was 8.63 +/- 7.15% for p53, 20.66 +/- 14.45% for ki-67, and 3.74 +/- 2.83% for bcl-2 in psoriatic skin at baseline. Normal skin values were 3.27 +/- 3.21% for p53, 4.93 +/- 4.77% for ki-67, and 1.80 +/- 0.41% for bcl-2. The psoriatic skin showed higher ki-67 (P < 0.05) and bcl-2 (P < 0.05) expression rates when compared to normal skin. The p53 positivity observed in psoriatic skin and normal skin was not significantly different (P > 0.05). Following calcipotriol and MPA treatments, there was a significant reduction in p53 and ki-67 positivity accompanied by an increase in bcl-2 positivity (P < 0.05 each). No significant differences were found at sixth week between calcipotriol and MPA groups with respect to p53, ki-67 and bcl-2 positivity (P > 0.05). The post-treatment psoriatic skin showed lower expression of p53, higher expressions of ki-67 and bcl-2 when compared to normal skin (P < 0.05 each). CONCLUSION The results of this study provide evidence that both calcipotriol and MPA decrease the p53 and ki-67 expression and increase bcl-2 expression. However, it should further be elucidated if these changes were the common behaviour of psoriatic keratinocytes to any antipsoriatic medication.
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Effects of folic acid on epithelial apoptosis and expression of Bcl-2 and p53 in premalignant gastric lesions.
Cao, DZ, Sun, WH, Ou, XL, Yu, Q, Yu, T, Zhang, YZ, Wu, ZY, Xue, QP, Cheng, YL
World journal of gastroenterology. 2005;(11):1571-6
Abstract
AIM: To evaluate the effects of folic acid on epithelial apoptosis and expression of Bcl-2 and p53 in the tissues of premalignant gastric lesions. METHODS Thirty-eight patients, with premalignant gastric lesions including 18 colonic-type intestinal metaplasia (IM) and 20 mild or moderate dysplasia, were randomly divided into a treatment group (n = 19) receiving folic acid 10 mg thrice daily and a control group (n = 19) receiving sucralfate 1,000 mg thrice daily for 3 mo. All patients underwent endoscopies and four biopsies were taken prior to treatment and repeated after concluding therapy. Folate concentrations in gastric mucosa were measured with chemiluminescent enzyme immunoassay. Epithelial apoptosis and the expression of Bcl-2 and p53 protein in gastric mucosa were detected with flow cytometric assay. RESULTS The mean of folate concentration in gastric mucosa was 9.03+/-3.37 microg/g wet wt in the folic acid treatment group, which was significantly higher than 6.83+/-3.02 microg/g wet wt in the control group. Both the epithelial apoptosis rate and the tumor suppressor p53 expression in gastric mucosa significantly increased after folic acid treatment. In contrast, the expression of Bcl-2 oncogene protein decreased after folic acid therapy. CONCLUSION These data indicate that folic acid may play an important role in the chemoprevention of gastric carcinogenesis by enhancing gastric epithelial apoptosis in the patients with premalignant lesions.