With the rapid development and wide application of next generation sequencing (NGS) technology, a series of researches have revealed that concurrent genetic alterations play an important role in the response and resistance of epidermal growth factor receptor (EGFR)-mutant NSCLC to EGFR-tyrosine kinase inhibitor (TKI). Besides, TP53 mutation is the most common co-mutation gene in EGFR-mutant NSCLC, which has been proved to confer a worse prognosis in EGFR-mutated patients treated with first, second and third generation of EGFR-TKIs. Currently, it is still being explored how to select the best treatment strategies for patients with concomitant presence of TP53 mutation in EGFR-mutant NSCLC. Here, we review the literature on recent research progress of TP53 concurrent mutation in EGFR-mutant advanced NSCLC.
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Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/genetics* ; Humans ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Tumor Suppressor Protein p53/genetics*

OBJECTIVE: To investigate the difference of Pax2 and P53 expressions in children with primary nephritic syndrome (PNS) and the effect of Pax2 on glucocorsteroid (GC)-resistance. METHODS: Renal Pax2 and P53 expressions in children with PNS (40 patients) were detected by immunohistochemistry. A semiquantitative score was used to evaluate the injury degree of the glomeruli and the tubulointerstitium, and correlation analysis was done among Pax2, P53 and pathologic score. RESULTS: Pax2 and P53 expressions were not found in the control group. Pax2 expression of renal tubule epithelia exsisted in children with PNS and there was weak or no expression of Pax2 in the podocytes. Pax2 expressions in the proximal tubule and the distal tubule in the GC-resistant group were more intense than those in the GC-intensive group (P <0.01). The more the Pax2 expression in the tubule, the more abnormal structure such as dilation and atrophy. Pax2 expression in the tubule epithelia was positively correlated with pathologic score of tubulointerstitium (P < 0.01). There was no P53 expression in the GC-intensive group, but there exsisted P53 expression in parts of the patients from the GC-resistant group, mainly distributing in the renal tubular epithelia. P53 expression was positively correlated with P53 expression and the pathologic score of tubulointerstitium (P < 0.01). CONCLUSION Over-expression of Pax2 in the renal tubule epithelia may improve P53 expression to a certain degree, which may aggravate the lesion of the renal tubule. It may be one of the mechanisms resulting in GC-resistant in children with PNS.
Adolescent ; Child ; Child, Preschool ; Drug Resistance ; Female ; Glucocorticoids ; therapeutic use ; Humans ; Male ; Nephrotic Syndrome ; drug therapy ; metabolism ; PAX2 Transcription Factor ; biosynthesis ; genetics ; Tumor Suppressor Protein p53 ; biosynthesis ; genetics

We report two rare cases of multiple myeloma (MM) with dural intracranial disease and TP53 deletion. The two patients presented with skull lytic lesion and dural involvement of myeloma. The association between intracranial involvement in MM and TP53 deletion has not been determined. The two patients received bortezomib-based intensive induction and got good response, just as that reported in literature. MM presenting with dural intracranial disease and TP53 deletion at diagnosis is associated with poor outcome. Multi-drug regime containing bortezomib followed by autologous or allogeneic stem cell transportation would improve the prognosis.
Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; Bortezomib ; therapeutic use ; Brain Neoplasms ; drug therapy ; genetics ; pathology ; Gene Deletion ; Humans ; Multiple Myeloma ; drug therapy ; genetics ; pathology ; Prognosis ; Treatment Outcome ; Tumor Suppressor Protein p53 ; genetics

OBJECTIVETo investigate the anti-tumor effect of intraportal administration of Adv-p53 in the treatment of the liver metastasis in mice.

METHODS2 x 10(5) of MCA-205 cells were injected into the mouse portal vein to establish a murine liver metastasis model. The spleen was transpositioned subcutaneously to enable the administration of Adv-p53 continually into the portal system. Different doses of Adv-p53 were injected intraportally, while HBSS and Adv-CMV were injected intraportaly in the control group. Tumors in the liver were examined on day 21 after Adv-p53 administration.

RESULTSThe liver weight in the Adv-p53 treated mice on day 0 group (1.20 +/- 0.34 g) was significantly less than that in the Adv-CMV group (2.59 +/- 0.48 g, P < 0.05). The number of metastatic nodules in the Adv-p53 treated mice on day 0 group (9.0 +/- 9.9) was significantly less than that in the Adv-CMV group (57.1 +/- 11.3, P < 0.05), indicating that intraportal administration of Adv-p53 inhibited the formation of liver metastasis. This anti-tumor effect was in a dose-dependent manner. After the liver metastasis was formed, Adv-p53 was administered intraportally. The liver weight in the Adv-p53 treated mice on day 5 group (1.22 +/- 0.09 g) was significantly less than that in the Adv-CMV group (3.98 +/- 1.01 g , P < 0.05). The number of metastatic nodules in the Adv-p53 treaed mice on day 5 group (5.5 +/- 3.5) was significantly less than that in the Adv-CMV group (113.2 +/- 5.8, P < 0.05). Repeatedly intraportal administration of Adv-p53 could enhance this anti-tumor effect.

CONCLUSIONLocal administration of Adv-p53 into the portal system would be a useful strategy for the liver metastasis treatment.

Adenoviridae ; genetics ; Animals ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Female ; Fibrosarcoma ; pathology ; Genetic Therapy ; Liver Neoplasms, Experimental ; secondary ; therapy ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Recombinant Proteins ; genetics ; therapeutic use ; Tumor Suppressor Protein p53 ; administration & dosage ; genetics ; therapeutic use

OBJECTIVETo study the mechanism of antisense epidermal growth factor receptor cDNA in growth suppression of glioblastomas cells.

METHODSGlioblastoma U87MG cells, which over-express epidermal growth factor receptor (EGFR), were transfected with antisense-EGFR constructs. Several clones with stable expression of lower or undetectable levels of EGFR protein were obtained. The effect of antisense-EGFR on cell differentiation was studied using morphological evaluation and western blotting analysis of glial fibrillary acidic protein (GFAP) expression. The effect of antisense-EGFR on cell cycle was studied by flow cytometry and immunohistochemical analysis of p53, Rb, p16 and CDK4 expressions. The effect of antisense-EGFR on telomerase activity was studied by telomeric repeat amplification protocol (TRAP) assay.

RESULTSU87MG cells that were transfected with antisense-EGFR constructs had smaller cell bodies and longer processes, and expressed higher level of GFAP compared with that of the control cells. Flow cytometric analysis showed that the proportion of cells in G(0)/G(1) phases of the cell cycle in the antisense EGFR cDNA transfected clones increased significantly when compared with control cells, whereas the proportion of cells in S phase decreased markedly. In addition, immunohistochemical analysis showed that the expression of wild-type p53 was significantly increased in the antisense-EGFR cDNA transfected clones, whereas the expressions of Rb, p16 and CDK4 were not altered. TRAP assay revealed that telomerase activity in the antisense-EGFR clones was significantly decreased.

CONCLUSIONSAntisense-EGFR transfection inhibits U87MG cell growth by inducing cell differentiation and p53 expression, G(1) cell cycle arrest and inhibition of telomerase activity.

Cell Line, Tumor ; DNA, Antisense ; therapeutic use ; DNA, Complementary ; therapeutic use ; Flow Cytometry ; Glioblastoma ; chemistry ; drug therapy ; pathology ; Humans ; Immunohistochemistry ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; genetics ; Retinoblastoma Protein ; analysis ; Transfection ; Tumor Suppressor Protein p53 ; analysis

Lung squamous cell carcinoma (LSCC) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is the second most common histological type of lung cancer. Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for only 2%-5% of all NSCLC cases, and is almost exclusively detected in patients with lung adenocarcinoma. Thus, ALK testing is not routinely performed in the LSCC population, and the efficacy of such treatment for ALK-rearranged LSCC remains unknown. Echinoderm microtubule associated protein like 4 (EML4)-ALK (V1) and TP53 co-mutations were identified by next generation sequencing (NGS) in this patient with advanced LSCC. On December 3, 2020, Ensatinib was taken orally and the efficacy was evaluated as partial response (PR). The progression-free survival (PFS) was 19 months. When the disease progressed, the medication was changed to Loratinib. To our knowledge, Enshatinib created the longest PFS of ALK-mutant LSCC patients treated with targeted therapy since literature review. Herein, we described one case treated by Enshatinib involving a patient with both EML4-ALK and TP53 positive LSCC, and the relevant literatures were reviewed for discussing the treatment of this rare disease.
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Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms/pathology* ; Anaplastic Lymphoma Kinase/metabolism* ; Carcinoma, Squamous Cell/genetics* ; Mutation ; Cytoskeletal Proteins/genetics* ; Lung/pathology* ; Oncogene Proteins, Fusion/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Tumor Suppressor Protein p53/genetics*

BACKGROUNDGene therapy and epigenetic therapy have gained more attention in cancer treatment. However, the effect of a combined treatment of gene therapy and epigenetic therapy on head and neck squamous cell carcinoma have not been studied yet. To study the mechanism and clinical application, human laryngeal carcinoma cell (Hep-2) tumor-bearing mice were used.

METHODSA xenograft tumor model was established by the subcutaneous inoculation of Hep-2 cells in the right armpit of BALB/c nu/nu mice. The mice with well-formed tumor were randomly divided into six groups. Multisite injections of rAd-p53 and/or 5-aza-dC were used to treat tumor. Tumor growth was monitored by measuring tumor volume and growth rate. p53 and E-cadherin protein levels in tumor tissues were detected by immunohistochemical staining. The mRNA levels were monitored with FQ-PCR.

RESULTSGene therapy was much more effective than single epigenetic therapy and combined therapy. The gene therapy group has the lowest tumor growth rate and the highest expression levels of p53 and E-cadherin.

CONCLUSIONSThe combined treatment of gene and epigenetic therapy is not suggested for treating head and neck carcinoma, because gene therapy shows an antagonistic effect to epigenetic therapy. However, the mechanisms of action are still unclear.

Animals ; Azacitidine ; analogs & derivatives ; therapeutic use ; Cadherins ; analysis ; DNA Modification Methylases ; antagonists & inhibitors ; Epigenesis, Genetic ; Genes, p53 ; Genetic Therapy ; Humans ; Laryngeal Neoplasms ; genetics ; pathology ; therapy ; Male ; Mice ; Mice, Inbred BALB C ; Tumor Suppressor Protein p53 ; analysis ; Xenograft Model Antitumor Assays

Animals ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Humans ; Liver Cirrhosis ; drug therapy ; genetics ; metabolism ; Liver Neoplasms ; drug therapy ; genetics ; metabolism ; Phytotherapy ; Procollagen ; biosynthesis ; genetics ; Tumor Suppressor Protein p53 ; biosynthesis ; genetics

OBJECTIVETo evaluate the efficacy and toxicity of combination therapy with surgery and recombinant adenovirus-p53 injection of recurrent malignant gliomas.

METHODS38 patients with recurrent malignant gliomas were included in this study. Among them, 18 patients of combined treatment group had Ommaya reservoirs placed into the tumor cavities after the resection of the tumors and received regular recombinant adenovirus-p53 injections after the operation. The other 20 patients received surgery alone.

RESULTSThe 6-month and 1-year survival rates after the combination therapy were 66.7% (14/18) and 44.4% (8/18), respectively. The median survival time was 9.7 months. Compared with the surgery-alone group, the combined treatment group achieved significant improvement (P < 0.05). The Karnofsky score was significantly improved at 6 months after the combination therapy compared with that before the treatment (P < 0.05).

CONCLUSIONThe recombinant adenovirus-p53 injection is safe and effective in treatment of recurrent malignant gliomas. The combination therapy of surgery and recombinant adenovirus-p53 injection may improve the life quality and the prognosis in patients with recurrent malignant gliomas.

Adenoviridae ; genetics ; Adult ; Brain Neoplasms ; pathology ; surgery ; therapy ; Combined Modality Therapy ; Female ; Follow-Up Studies ; Genes, p53 ; Genetic Therapy ; Glioma ; pathology ; surgery ; therapy ; Humans ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Recombinant Proteins ; therapeutic use ; Survival Rate ; Tumor Suppressor Protein p53 ; genetics ; therapeutic use

OBJECTIVETo investigate the presence of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia and its clinical significance.

METHODSInterphase fluorescence in situ hybridization (FISH) was used to detect the p53 gene deletion in 77 patients with CLL. Presence of the deletion and its association with clinical and laboratory features as well as prognostic factors were analyzed. Kaplan-Meier method was used to calculate survivals, and the results were compared using a Log-rank test.

RESULTSp53 gene deletion was found in 10 (12.9%) of the patients but none from the control group (P<0.05). The deletion was found in 12.5% (4/32) of ethnic Hans and 13.3% (6/45) of ethnic Uyghurs (P>0.05). No significant different distribution of p53 gene deletion was found in regard to sex, age, ethnicity, peripheral blood cell count (except for Hb) or the levels of lactate dehydrogenase, β2-micro globulin and CD38 (P>0.05). The deletion rate was higher in the group with high expression of ZAP-70 and patients with advanced stage disease than that in the group of low expression and early-stage CLL (P<0.05). Among 20 patients who received fludarabine therapy, the overall remission rate for those with p53 gene deletion (20%) was lower than those without (75%) (P<0.05). With a median follow-up time of 39.0 (8.0-136.0) months, 11 cases had died (14.3%), among them, 7 cases died from CLL and related complications, and all of them were founded p53 gene deletion. In patients with p53 gene deletion, the progression-free survival (18 months) was shorter than those without the deletion (55 months) (P<0.05).

CONCLUSIONThe p53 gene deletion has been found in more than 10% of patients with CLL, and the deletion rate did not significantly differ between ethnic Han and Uyghur patients. The deletion is associated with advanced stage of the disease. High-level ZAP-70 expression and the presence of p53 deletion are associated with shorter survival and poor response to fludarabine containing therapy. Therefore, drugs affecting the p53 signaling pathway should be avoided.

Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents ; therapeutic use ; Asian Continental Ancestry Group ; ethnology ; genetics ; Female ; Gene Deletion ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Lymphocytic, Chronic, B-Cell ; diagnosis ; drug therapy ; ethnology ; genetics ; Male ; Middle Aged ; Prognosis ; Tumor Suppressor Protein p53 ; genetics ; Vidarabine ; analogs & derivatives ; therapeutic use ; ZAP-70 Protein-Tyrosine Kinase ; genetics