Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation.

BACKGROUND AND PURPOSE: Targeted therapy and immunotherapy have led to dramatic change in the treatment of lung cancer, however, the overall 5-year survival rate of lung cancer patients is still suboptimal. It is important to exploit new potential of molecularly targeted therapies. High-frequency somatic mutations in KEAP1/NRF2 (27.9%) have been identified in lung squamous cell carcinoma. In this research, we explored the role of KEAP1 somatic mutations in the development of LSCC and whether a nuclear factor erythroid 2-related factor 2(NRF2) inhibitor be potential to target lung cancer carrying KEAP1/NRF2 mutations. METHODS: Lung cancer cell lines A549 and H460 with loss-of-function mutations in KEAP1 stably transfected with wild-type (WT) KEAP1 or somatic mutations in KEAP1 were used to investigate the functions of somatic mutations in KEAP1. Flow cytometry, plate clone formation experiments, and scratch tests were used to examine reactive oxygen species, proliferation, and migration of these cell lines. RESULTS: The expression of NRF2 and its target genes increased, and tumor cell proliferation, migration, and tumor growth were accelerated in A549 and H460 cells stably transfected with KEAP1 mutants compared to control cells with a loss-of-function KEAP1 mutation and stably transfected with WT KEAP1 in both in vitro and in vivo studies. The proliferation of A549 cell line trasfected with the R320Q KEAP1 mutant was inhibited more apparent than that of the A549 cell line trasfected with WT KEAP1 after treatment with NRF2 inhibitor ML385. CONCLUSION: Somatic mutations of KEAP1 identified from patients with LSCC likely promote tumorigenesis mediated by activation of the KEAP1/NRF2 antioxidant stress response pathway. NRF2 inhibition with ML385 could inhibit the proliferation of tumor cells with KEAP1 mutation. Video abstract.

Association of Admission Blood Glucose Level with All-Cause Mortality According to Age in Patients with Community Acquired Pneumonia.

OBJECTIVE: To assess the impact of blood glucose levels on the prognosis of patients with community-acquired pneumonia (CAP) who were elderly or middle-aged. METHODS: From January 1, 2018, to December 31, 2020, patients with CAP (≥45 years) were retrospectively enrolled in this observational study. They were stratified by age (45-64 or ≥65 years) and blood glucose level (≥11.1 or <11.1 mmol/l). The effect of admission blood glucose on 28-day mortality was assessed with the Cox proportional hazards model, adjusted for demographic factors and comorbidity. RESULTS: Among 1656 patients with CAP, increased blood glucose (HR=2.08, 95% CI: 1.38-3.49; P<0.01) and advanced age (HR=2.76, 95% CI: 1.65-3.77; P<0.01) were significantly associated with a higher risk of 28-day mortality, after controlling for potential confounding factors. The strength of the association of blood glucose level with 28-day mortality decreased with age (P=0.01 for the interaction) as the adjusted HRs for death were 4.48 (95% CI: 1.40-13.65; P<0.01) for middle-age patients 45-64 years and 1.52 (95% CI: 1.09-2.17; P=0.05) for elderly patients ≥65 years. CONCLUSION: The association of blood glucose level upon admission for CAP with all-cause mortality was stronger at younger ages.

Efficacy of Electroacupuncture Therapy in Patients With Postherpetic Neuralgia: Study Protocol for a Multicentre, Randomized, Controlled, Assessor-Blinded Trial.

Introduction: The efficacy of conventional treatments for treating postherpetic neuralgia (PHN) remains unsatisfactory. Thus, this multicentre, randomized controlled, assessor-blinded trial aims to investigate the efficacy and safety of electroacupuncture (EA) therapy in patients with PHN. Methods and Analysis: This multicentre randomized controlled trial will enroll 132 patients with PHN from 3 hospitals. All patients will be randomly assigned to either the EA combined with medication group or medication group through a computerized central randomization system in a 1:1 ratio. Outcome measures will be assessed before intervention, at 2, 4, 6 weeks after intervention and at the end of 8-week follow-up. Primary outcomes will be sensory thresholds and pain intensity. Secondary outcomes will include dosage of analgetic, quality of life, anxiety, and depression severity and sleep quality. All adverse effects will be assessed during the trial. Conclusions: This study will provide evidence to ascertain whether EA is effective and safe for treating PHN. Ethics and Dissemination: Ethics approval (No.ZSLL-KY-2017-025) has been obtained from the Ethics Committee of The Third Affiliated Hospital of Zhejiang Chinese Medical University. Informed consent will be signed prior to subject enrolment. The results will be submitted to international peer-reviewed journals and presented at international conferences. Trial Registration Number: The study protocol has been registered in the clinicaltrials registry with the identification code NCT04594226.

Comparative Effectiveness of Different Combinations of Treatment Interventions in Patients with Stroke at the Convalescence Stage Based on the Markov Decision Process.

OBJECTIVE: The objective of this study was to compare the effectiveness of different combinations of interventions in patients with stroke at the convalescence stage based on the electronic health records (EHRs) by using the Markov decision process (MDP) theory and explore the feasibility of the Markov model in the real-world study (RWS). METHODS: Screening was conducted for patients with stroke at the convalescence stage who were admitted to the Third Affiliated Hospital of Zhejiang Chinese Medical University from January 2012 to January 2017 based on the EHRs. The relevant clinical data were extracted, and the appropriate conversion was made (state-action-reward) according to the Markov model. The transformed data were analysed and solved by the MDP to obtain the best interventions for patients with various stroke recovery periods. RESULTS: 926 patients with stroke at the convalescence stage were initially selected. And according to the inclusion exclusion criteria, 854 patients were screened. Through the MDP, we obtained the following results: (1)when the patients with stroke at the convalescence stage have a medical history, but no complications, and mild neurological impairment, ≥66-year- and 18-45-year-old patients are advised to choose acupuncture treatment. 46-65-year-old patients are advised to choose rehabilitation treatment. When patients with moderate to severe neurological impairment, patients are advised to choose rehabilitation, Chinese herbal decoction, and acupuncture combined therapy. (2) Without complications or medical history, patients who are ≥ 66 years old are recommended to choose rehabilitation treatment when the nerve function impairment is mild; rehabilitation and acupuncture treatment are recommended when moderate and severe injuries are caused. (3) The combination of rehabilitation, Chinese herbal decoction, and acupuncture treatment is recommended for patients with phlegm and blood stasis. Acupuncture treatment is recommended for patients with mild impairment of nerve function in qi deficiency and blood stasis type. Rehabilitation, Chinese herbal decoction, and acupuncture treatment are recommended for moderate-severe injuries. CONCLUSIONS: The MDP makes it possible to study the effectiveness of various treatment methods in stroke patients who are at the convalescence stage. Further exploratory studies using MDP theory in other areas in which complex interventions are common would be worthwhile.

Acupuncture for rehabilitation after surgery for cerebellopontine angle meningioma: A case report.

RATIONALE: In some cases, surgery of cerebellopontine angle meningioma (CPAM) might result in multiple cranial nerve injury, which could bring serious impact on the patients, especially when it affects the function of facial muscles and eyeballs. This report describes a successful application of acupuncture for rehabilitation in a patient after surgery for CPAM. PATIENT CONCERNS: A 27-year-old patient presented with limitation of left eye abduction, accompanied with frontal and facial sensory disturbance on the left after resection of the pontocerebellar angle tumor. The patient also suffered from significant anxiety and depression as concomitant symptoms. DIAGNOSES: Based on medical history, clinical symptoms, and magnetic resonance imaging results, the patient was diagnosed with the fourth, fifth, sixth, and seventh cranial nerve injury after surgery for CPAM. INTERVENTIONS: Acupuncture treatment was applied for this patient. One acupuncture session was given every 2 days in 35 days, and the needles were retained for 30 minutes per session. OUTCOMES: After acupuncture treatment, the limitation of left eye abduction had totally recovered. The superficial sensory disturbance in the frontal and facial region was significantly relived. Besides, the scores of Hamilton Anxiety and Depression Scale showed a significant reduction. However, the superficial sensory of the alar and nasolabial groove on the left side still decreased mildly when compared with the right side. CONCLUSION: Acupuncture might be an option for rehabilitation after surgery for CPAM.