Background: MTDH is overexpressed in solid tumors and is involved in metastasis and chemoresistance. Results: Cytoplasmic MTDH associates with RNA and RNA-associated proteins, blocks Rad51 nuclear accumulation, and increases survival and drug resistance. Conclusion: Cytoplasmic MTDH promotes cancer cell proliferation and resistance to treatment by acting as an RNA-binding protein.Significance: Targeting MTDH may increase sensitivity to anti-cancer treatments.

Objective Endometrial tumors with non-functional p53, such as serous uterine endometrial carcinomas, are aggressive malignancies with a poor outcome, yet they have an Achilles’ heel: due to loss of p53 function, these tumors may be sensitive to treatments which abrogate the G2/M checkpoint. Our objective was to exploit this weakness to induce mitotic cell death using two strategies: (1) EGFR inhibitor gefitinib combined with paclitaxel to arrest cells at mitosis, or (2) BI2536, an inhibitor of polo-like kinase 1 (PLK1), to block PLK1 activity. Methods We examined the impact of combining gefitinib and paclitaxel or PLK1 inhibitor on expression of G2/M checkpoint controllers, cell viability, and cell cycle progression in endometrial cancer cells with mutant p53. Results In cells lacking normal p53 activity, each treatment activated CDC25C and inactivated Wee1, which in turn activated cdc2 and sent cells rapidly through the G2/M checkpoint and into mitosis. Live cell imaging demonstrated irreversible mitotic arrest and eventual cell death. Combinatorial therapy with paclitaxel and gefitinib was highly synergistic and resulted in a 10-fold reduction in the IC50 for paclitaxel, from 14 nM as a single agent to 1.3 nM in the presence of gefitinib. However, BI2536 alone at low concentrations (5 nM) was the most effective treatment and resulted in massive mitotic cell death. In a xenograft mouse model with p53-deficient cells, low dose BI2536 significantly inhibited tumor growth. Conclusions These findings reveal induction of mitotic cell death as a therapeutic strategy for endometrial tumors lacking functional p53.

Background-Chemoresistance and metastasis are the main reasons for the failure of current treatments with sarcoma patients. Novel biomarkers are required to predict metastasis and response to treatment. The oncogene MTDH/AEG1 and the long noncoding RNA (lincRNA) HOTAIR are two novel factors involved in drug resistance and metastasis in various types of solid tumors. However, the correlation between MTDH/AEG-1 and HOTAIR expression with metastasis and drug resistance in sarcoma is unknown.

Serous uterine endometrial carcinomas are aggressive type II cancers with poor outcomes for which new treatment strategies are urgently needed, in particular, strategies that augment sensitivity to established chemotherapy regimens. The tumor suppressor gene TP53 is dysregulated in more than 90% of serous tumors, altering master regulators of the G2/M cell cycle checkpoint in unique and predictable ways and desensitizing cells to chemotherapy. We hypothesized that synthetic lethality can be achieved in endometrial cancer cells with mutant p53 by combining paclitaxel with agents to overcome G2/M arrest and induce mitotic catastrophe. The combination of BIBF1120, an investigational VEGFR, PDGFR, and FGFR multityrosine kinase inhibitor with established anti-angiogenic activity, with paclitaxel abrogated the G2/M checkpoint in p53-null endometrial cancer cells via modulation of G2/M checkpoint regulators followed by induction of mitotic cell death. In endometrial cancer cells harboring an oncogenic gain-of-function p53 mutation, synthetic lethality was created by combining paclitaxel with BIBF1120 and a histone deacetylase inhibitor, which serves to destabilize mutant p53. These cells were also sensitive to an inhibitor of the G2/M kinase Wee1 in combination with paclitaxel. These findings reveal that, in addition to antiangiogenic activity, the angiokinase inhibitor BIBF1120 can be used to restore sensitivity to paclitaxel and induce mitotic cell death in endometrial cancer cells with non-functional p53. These preclinical data serve as a critical platform for the creative design of future clinical trials utilizing molecularly enhanced chemotherapy to achieve synthetic lethality based on the mutational landscape.

ObjectiveTo compare the effect, safety, and patient satisfaction of pulsed radiofrequency combined with methylene blue paravertebral nerve block and pulsed radiofrequency alone in the treatment of thoracic postherpetic neuralgia (PHN).MethodsA total of seventy-two patients with PHN diagnosed in the Department of Pain Management of Shengjing Hospital at China Medical University, from September 2019 to April 2021, were enrolled in the study. Patients were randomly divided into two groups. Group A (n = 36) received pulsed radiofrequency treatment. Group B (n = 36) received pulsed radiofrequency + methylene blue paravertebral nerve block. Patients were followed-up at 1 day, 1 week, 1 month, 3 months, and 6 months after treatment. Observation at each follow-up included basic patient characteristics, Visual Analog Scale (VAS), Hospital Anxiety and Depression Scale (HAD), the Insomnia Severity Index (ISI), patient satisfaction, complications, and side effects.ResultsCompared with preoperative values, the VAS scores significantly decreased in both groups at each postoperative time point (1 day, 1 week, and 1, 3, and 6 months; all p < 0.05). Compared with group A, VAS scores in group B were significantly lower 1 week and 1 month after surgery (p < 0.05). Patients in group B had lower HAD scores than those in group A 1 week after surgery (p < 0.05). Patients in group B had lower ISI scores than those in group A 1 day, 1 week, and 1, 3, and 6 months after surgery (p < 0.05). The pregabalin dosage in group B was lower than that in group A at 1 and 6 months after surgery (p < 0.05). Patient satisfaction was higher in group B than in group A at 1 week and 6 months after surgery (p < 0.05). There were no serious complications or side effects in either group.ConclusionPulsed radiofrequency combined with methylene blue paravertebral nerve block is superior to pulsed radiofrequency alone in the treatment of thoracic PHN, which can significantly relieve PHN and improve the condition of sleep and emotional disorders. Therefore, it is a safe and effective treatment method.