p53 Gene Status as a Predictor of Tumor Response to Induction Chemotherapy of Patients With Locoregionally Advanced Squamous Cell Carcinomas of the Head and Neck

2000 ◽  
Vol 18 (2) ◽  
pp. 385-385 ◽  
Author(s):  
Stéphane Temam ◽  
Antoine Flahault ◽  
Sophie Périé ◽  
Guy Monceaux ◽  
Florence Coulet ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Odds Ratio ◽  
Objective Response ◽  
P53 Gene ◽  
Tumor Stage ◽  
Squamous Cell Carcinomas ◽  
P53 Mutations ◽  
P53 Expression ◽  
Major Response ◽  
Gene Status

PURPOSE: To determine whether p53 gene status predicts tumor responses to platinum- and fluorouracil-based induction chemotherapy in locoregionally advanced squamous cell carcinomas of the head and neck. PATIENTS AND METHODS: Tumor responses of 105 patients were measured at the primary tumor site. Objective response and major response were defined by a 50% and 80% reduction in tumor size, respectively. All coding parts of p53 gene were directly sequenced. p53 expression in tumor cells was determined by immunohistochemistry. Human papillomavirus infection was detected by polymerase chain reaction. Odd ratios were adjusted by stepwise logistic regression analysis. RESULTS: p53 mutations, p53 expression, and tumor stage were sufficient to explain the variation in tumor responses to chemotherapy in multivariate models. p53 mutation was the only variable to significantly predict objective response (odds ratio, 0.23; 95% confidence interval, 0.10 to 0.57; P = .002) and was the strongest predictor of major response (odds ratio, 0.29; 95% confidence interval, 0.11 to 0.74; P = .006). p53 expression (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.98) and tumor stage (odds ratio, 0.31; 95% confidence interval, 0.10 to 0.96) also predicted major response. Specific mutations (contact mutations) accounted for much of the reduction in the risk of major response associated with overall mutations. In complementary analyses, p53 expression was weakly predictive of major response in the subgroup with wild-type p53, and p53 mutations also predicted histologic response. CONCLUSION: p53 gene mutations are strongly associated with a poor risk of both objective and major responses to chemotherapy. Contact mutations are associated with the lowest risk of major response to chemotherapy.

scholarly journals Efficient Generation of P53 Biallelic Mutations in Diannan Miniature Pigs Using RNA-Guided Base Editing

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1417
Author(s):  
Honghui Li ◽  
Wenmin Cheng ◽  
Bowei Chen ◽  
Shaoxia Pu ◽  
Ninglin Fan ◽  
...  
Keyword(s):  
Disease Model ◽  
P53 Gene ◽  
P53 Mutation ◽  
P53 Mutations ◽  
P53 Expression ◽  
Base Editing ◽  
System A ◽  
Reconstructed Embryos ◽  
Monoallelic Mutation ◽  
Biallelic Mutations

The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than 50% of human malignancies. Due to the similarities between humans and pigs at the molecular level, pig models carrying P53 mutations can be used to research the mechanism of tumorigenesis and improve tumor diagnosis and treatment. According to pathogenic mutations of the human P53 gene at W146* and Q100*, sgRNAs were designed to target exon 4 and exon 5 of the porcine P53 gene. The target editing efficiencies of the two sgRNAs were 61.9% and 50.0%, respectively. The editing efficiency of the BE3 system was highest (about 60%) when C (or G) was at the 5th base. Puromycin screening revealed that 75.0% (21/28) and 68.7% (22/32) of cell colonies contained a P53 mutation at sgRNA-Exon5 and sgRNA-Exon4, respectively. The reconstructed embryos from sgRNA-Exon5-5# were transferred into six recipient gilts, all of which aborted. The reconstructed embryos from sgRNA-Exon4-7# were transferred into 6 recipient gilts, 3 of which became pregnant, resulting in 14 live and 3 dead piglets. Sequencing analyses of the target site confirmed 1 P53 monoallelic mutation and 16 biallelic mutations. The qPCR analysis showed that the P53 mRNA expression level was significantly decreased in different tissues of the P53 mutant piglets (p < 0.05). Additionally, confocal microscopy and western blot analysis revealed an absence of P53 expression in the P53 mutant fibroblasts, livers, and lung tissues. In conclusion, a porcine cancer model with a P53 point mutation can be obtained via the BE3 system and somatic cell nuclear transfer (SCNT).

scholarly journals Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2922-2930 ◽  
Author(s):  
MH Hsiao ◽  
AL Yu ◽  
J Yeargin ◽  
D Ku ◽  
M Haas
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
P53 Gene ◽  
Tumor Formation ◽  
Missense Mutations ◽  
P53 Mutations ◽  
P53 Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract We have previously reported that greater than 60% of human leukemic T- cell lines possess mutations in the p53 tumor suppressor gene. To determine whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess p53 mutations, we screened peripheral blood-and bone marrow-derived leukemia samples, taken at diagnosis and at relapse, for p53 mutations. Exons 4 through 9 and selected intron regions of the p53 gene were analyzed using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To determine whether p53 mutations play a role in the recurrence (relapse) of T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8 relapse patients whose disease was refractory to chemotherapeutic treatment, and (2) a group of 6 “paired” T-ALL cell samples from patients for whom we possess both diagnosis and relapse samples. Three of 8 relapsed patients (37.5%) whose disease was refractory to the reinduction of remission by chemotherapy possessed missense mutations of the p53 gene. All 3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients harbored p53 mutations at disease recurrence, but possessed only wild- type p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon 5, and 1 case in exon 8 with loss of heterozygosity. These data clearly indicate that recurrence of T-ALL is associated with missense mutations in p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in vivo, and such mutations are associated with the relapse phase of the disease; and (2) p53 mutation is involved in the progression of T-ALL. This conclusion is supported by our observation that the introduction of T-ALL-derived mutant p53 expression constructs into T-ALL cell lines further increases their growth rate in culture, enhances cell cloning in methylcellulose, and increases tumor formation in nude mice.

scholarly journals Endogenous p53 gene status predicts the response of human squamous cell carcinomas to wild-type p53

2000 ◽  
Vol 7 (5) ◽  
pp. 749-756 ◽  
Author(s):  
Lisa S St. John ◽  
Edward R Sauter ◽  
Meenhard Herlyn ◽  
Samuel Litwin ◽  
Karen Adler-Storthz
Keyword(s):  
Squamous Cell ◽  
P53 Gene ◽  
Squamous Cell Carcinomas ◽  
Wild Type ◽  
Wild Type P53 ◽  
Gene Status

scholarly journals Outcomes in Clinically Relevant Patient Subgroups From the EMBRACA Study: Talazoparib vs Physician’s Choice Standard-of-Care Chemotherapy

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Hope S Rugo ◽  
Johannes Ettl ◽  
Sara A Hurvitz ◽  
Anthony Gonçalves ◽  
Kyung-Hun Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Confidence Interval ◽  
Clinical Benefit ◽  
Odds Ratio ◽  
Objective Response ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Free Survival ◽  
Duration Of Response ◽  
Patient Subgroups

Abstract Background Talazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. Methods EMBRACA (NCT01945775) was a randomized phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician’s choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) or triple-negative breast cancer (TNBC) subgroups. Results Of 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/HER2−: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71; TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/HER2− and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia. Conclusions Across all patient subgroups with gBRCA-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT.

scholarly journals Role of Stat3 in Regulating p53 Expression and Function

2005 ◽  
Vol 25 (17) ◽  
pp. 7432-7440 ◽  
Author(s):  
Guilian Niu ◽  
Kenneth L. Wright ◽  
Yihong Ma ◽  
Gabriela M. Wright ◽  
Mei Huang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Tumor Development ◽  
P53 Gene ◽  
P53 Mutations ◽  
Oncogenic Signaling ◽  
P53 Expression ◽  
And Function ◽  
Oncogenic Signaling Pathways

ABSTRACT Loss of p53 function by mutation is common in cancer. However, most natural p53 mutations occur at a late stage in tumor development, and many clinically detectable cancers have reduced p53 expression but no p53 mutations. It remains to be fully determined what mechanisms disable p53 during malignant initiation and in cancers without mutations that directly affect p53. We show here that oncogenic signaling pathways inhibit the p53 gene transcription rate through a mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo. Site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially abrogates Stat3-induced inhibition. Stat3 activity also influences p53 response genes and affects UV-induced cell growth arrest in normal cells. Furthermore, blocking Stat3 in cancer cells up-regulates expression of p53, leading to p53-mediated tumor cell apoptosis. As a point of convergence for many oncogenic signaling pathways, Stat3 is constitutively activated at high frequency in a wide diversity of cancers and is a promising molecular target for cancer therapy. Thus, repression of p53 expression by Stat3 is likely to have an important role in development of tumors, and targeting Stat3 represents a novel therapeutic approach for p53 reactivation in many cancers lacking p53 mutations.

Smoking correlates with the presence of p53 mutations in squamous cell carcinomas of the head and neck (SCCHN)

1998 ◽  
Vol 23 (3) ◽  
pp. 268-269
Author(s):  
Liloglou ◽  
Scholes ◽  
Spandidos ◽  
Jones ◽  
Vaughan ◽  
...  
Keyword(s):  
Head And Neck ◽  
Squamous Cell ◽  
Squamous Cell Carcinomas ◽  
P53 Mutations

scholarly journals Sex modulates the association of radial artery augmentation index with renal function decline in individuals without chronic kidney disease

2021 ◽  
Author(s):  
Qiao Qin ◽  
Fangfang Fan ◽  
Jia Jia ◽  
Yan Zhang ◽  
Bo Zheng
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Arterial Stiffness ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Adjusted Odds Ratio ◽  
Augmentation Index ◽  
Renal Function Decline

Abstract Purpose An increase in arterial stiffness is associated with rapid renal function decline (RFD) in patients with chronic kidney disease (CKD). The aim of this study was to investigate whether the radial augmentation index (rAI), a surrogate marker of arterial stiffness, affects RFD in individuals without CKD. Methods A total of 3165 Chinese participants from an atherosclerosis cohort with estimated glomerular filtration rates (eGFR) of ≥ 60 mL/min/1.73 m2 were included in this study. The baseline rAI normalized to a heart rate of 75 beats/min (rAIp75) was obtained using an arterial applanation tonometry probe. The eGFRs at both baseline and follow-up were calculated using the equation derived from the Chronic Kidney Disease Epidemiology Collaboration. The association of the rAIp75 with RFD (defined as a drop in the eGFR category accompanied by a ≥ 25% drop in eGFR from baseline or a sustained decline in eGFR of > 5 mL/min/1.73 m2/year) was evaluated using the multivariate regression model. Results During the 2.35-year follow-up, the incidence of RFD was 7.30%. The rAIp75 had no statistically independent association with RFD after adjustment for possible confounders (adjusted odds ratio = 1.12, 95% confidence interval: 0.99–1.27, p = 0.074). When stratified according to sex, the rAIp75 was significantly associated with RFD in women, but not in men (adjusted odds ratio and 95% confidence interval: 1.23[1.06–1.43], p = 0.007 for women, 0.94[0.76–1.16], p = 0.542 for men; p for interaction = 0.038). Conclusion The rAI might help screen for those at high risk of early rapid RFD in women without CKD.

scholarly journals Plasma acylcarnitines and risk of lower-extremity functional impairment in older adults: a nested case–control study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Francisco Félix Caballero ◽  
Ellen A. Struijk ◽  
Alberto Lana ◽  
Antonio Buño ◽  
Fernando Rodríguez-Artalejo ◽  
...  
Keyword(s):  
Older Adults ◽  
Confidence Interval ◽  
Lower Extremity ◽  
Functional Impairment ◽  
Odds Ratio ◽  
Case Control Study ◽  
Case Control ◽  
Community Dwelling ◽  
Control Study ◽  
Long Chain

AbstractElevated concentrations of acylcarnitines have been associated with higher risk of obesity, type 2 diabetes and cardiovascular disease. The aim of the present study was to assess the association between L-carnitine and acylcarnitine profiles, and 2-year risk of incident lower-extremity functional impairment (LEFI). This case–control study is nested in the Seniors-ENRICA cohort of community-dwelling older adults, which included 43 incident cases of LEFI and 86 age- and sex- matched controls. LEFI was assessed with the Short Physical Performance Battery. Plasma L-carnitine and 28 acylcarnitine species were measured. After adjusting for potential confounders, medium-chain acylcarnitines levels were associated with 2-year incidence of LEFI [odds ratio per 1-SD increase: 1.69; 95% confidence interval: 1.08, 2.64; p = 0.02]. Similar results were observed for long-chain acylcarnitines [odds ratio per 1-SD increase: 1.70; 95% confidence interval: 1.03, 2.80; p = 0.04]. Stratified analyses showed a stronger association between medium- and long-chain acylcarnitines and incidence of LEFI among those with body mass index and energy intake below the median value. In conclusion, higher plasma concentrations of medium- and long-chain acylcarnitines were associated with higher risk of LEFI. Given the role of these molecules on mitochondrial transport of fatty acids, our results suggest that bioenergetics dysbalance contributes to LEFI.

scholarly journals Efficacy of two-week therapy with doxycycline-based quadruple regimen versus levofloxacin concomitant regimen for helicobacter pylori infection: a prospective single-center randomized controlled trial

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Marouf Alhalabi ◽  
Mohammed Waleed Alassi ◽  
Kamal Alaa Eddin ◽  
Khaled Cheha
Keyword(s):  
Clinical Trial ◽  
Helicobacter Pylori ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Controlled Trial ◽  
Helicobacter Pylori Infection ◽  
First Line ◽  
Link Type ◽  
Syrian Population

Abstract Background Antibiotic-resistance reduces the efficacy of conventional triple therapy for Helicobacter Pylori infections worldwide, which necessitates using various treatment protocols. We used two protocols, doxycycline-based quadruple regimen and concomitant levofloxacin regimen. The aim was to assess the effectiveness of doxycycline-based quadruple regimen for treating Helicobacter Pylori infections compared with levofloxacin concomitant regimen as empirical first-line therapy based on intention-to-treat (ITT) and per-protocol analyses (PPA) in Syrian population. Settings and design An open-label, randomised, parallel, superiority clinical trial. Methods We randomly assigned 78 naïve patients who tested positive for Helicobacter Pylori gastric infection, with a 1:1 ratio to (D-group) which received (bismuth subsalicylate 524 mg four times daily, doxycycline 100 mg, tinidazole 500 mg, and esomeprazole 20 mg, each twice per day for 2 weeks), or (L-group) which received (levofloxacin 500 mg daily, tinidazole 500 mg, amoxicillin 1000 mg, and esomeprazole 20 mg each twice per day for two weeks). We confirmed Helicobacter Pylori eradication by stool antigen test 8 weeks after completing the treatment. Results Thirty-nine patients were allocated in each group. In the D-group, 38 patients completed the follow-up, 30 patients were cured. While in the L-group, 39 completed the follow-up, 32patients were cured. According to ITT, the eradication rates were 76.92%, and 82.05%, for the D-group and L-group respectively. Odds ratio with 95% confidence interval was 1.371 [0.454–4.146]. According to PPA, the eradication rates were 78.9%, and 82.05% for the D-group and L-group respectively. The odds ratio with 95% confidence interval was 1.219 [0.394–3.774]. We didn’t report serious adverse effects. Conclusions Levofloxacin concomitant therapy wasn’t superior to doxycycline based quadruple therapy. Further researches are required to identify the optimal first-line treatment for Helicobacter-Pylori Infection in the Syrian population. Trial registration We registered this study as a standard randomized clinical trial (Clinicaltrial.gov, identifier-NCT04348786, date:29-January-2020).

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