TERT Mutations in Non-Small Cell Lung Cancer: Clinicopathologic Features and Prognostic Implications.

Introduction: The associations between the clinical characteristics of non-small cell lung cancer (NSCLC) and mutations in telomerase reverse transcriptase (TERT) gene remain unclear. In this study, we used next-generation sequencing (NGS) to investigate the incidence rate and clinical correlates of TERT mutations in patients with NSCLC. Methods: In total, 283 tumor samples from patients with NSCLC were tested using an NGS panel from September 2017 to May 2020. The genetic testing results and clinical data of all patients were collected. Results: TERT mutations were found in 30 patients, which were significantly associated with age, smoking history, sex, and metastasis (P < 0.05). Survival analyses showed that patients who carried TERT mutations had a poorer prognosis. Of the 30 TERT-mutation carriers, 17 harbored epidermal growth factor receptor (EGFR) mutations, which were significantly associated with sex, histopathology type, and metastasis (P < 0.05; overall survival [OS], 21 months; 95% confidence interval [CI], 8.153-33.847 months). Three TERT mutation patients harbored Kirsten rat sarcoma virus (KRAS) mutations, which were significantly associated with metastasis risk (P < 0.05), KRAS mutations carriers had a worse prognosis, with an OS of 10 months (95% CI, 8.153-33.847 months). Multivariate Cox regression analyses showed that age, cancer stage, and TERT mutation carrier status were independent risk factors for NSCLC, and the TERT mutation was 2.731 times higher than that without TERT mutation (95% CI, 1.689-4.418, P < 0.001). Conclusions: TERT mutations were present in 11% of patients with NSCLC. TERT mutations were associated with age, smoking history, sex, and distant metastasis. Co-mutations in TERT and EGFR/KRAS indicated a poor prognosis. The co-mutations of TERT and EGFR differed according to sex, histopathology type, and metastasis, whereas TERT and KRAS co-mutations were only associated with patient metastasis. Age, cancer stage, and TERT mutation carrier status were independent risk factors for poor prognosis in patients with NSCLC.

[Effect of acupuncture combined with low frequency rTMS on comorbid mild-to-moderate depressive disorder and insomnia: a randomized controlled trial].

OBJECTIVE: To observe the impacts of acupuncture on depressive mood and sleep quality in patients with comorbid mild-to-moderate depressive disorder and insomnia, and explore its effect mechanism. METHODS: A total of 60 patients with comorbid mild-to-moderate depressive disorder and insomnia were randomly divided into an observation group (30 cases, 1 case dropped off) and a control group (30 cases, 2 cases dropped off). In the observation group, acupuncture and low frequency repeated transcranial magnetic stimulation (rTMS) were combined for the intervention. Acupuncture was applied to Baihui (GV 20), Yintang (GV 24+), Neiguan (PC 6) and Yanglingquan (GB 34), etc., the needles were retained for 30 min; and the intradermal needles were embedded at Xinshu (BL 15) and Danshu (BL 19) for 2 days. After acupuncture, the rTMS was delivered at the right dorsolateral prefrontal cortex (R-DLPFC), with 1 Hz and 80% of movement threshold, lasting 30 min in each treatment. In the control group, the sham-acupuncture was adopted, combined with low frequency rTMS. The acupoint selection and manipulation were the same as the observation group. In the two groups, acupuncture was given once every two days, 3 times weekly; while, rTMS was operated once daily, for consecutive 5 days a week. The duration of treatment consisted of 4 weeks. Hamilton depression scale-17 (HAMD-17) and Pittsburgh sleep quality index (PSQI) scores were observed before and after treatment, as well as 1 month after the treatment completion (follow-up period) separately. Besides, the levels of nerve growth factor (BDNF) and γ-aminobutyric acid (GABA) in the serum were detected before and after treatment in the two groups. RESULTS: After treatment and in follow-up, the HAMD-17 scores were lower than those before treatment in the two groups (P<0.05), and the scores in the observation group were lower than the control group (P<0.05). After treatment, the total scores and the scores of each factor of PSQI were reduced in the two groups in comparison with those before treatment except for the score of sleep efficiency in the control group (P<0.05); the total PSQI score and the scores for sleep quality, sleep latency, sleep efficiency and daytime dysfunction in the observation group were all lower than those in the control group (P<0.05). In the follow-up, except for the scores of sleep duration and sleep efficiency in the control group, the total PSQI score and the scores of all the other factors were reduced compared with those before treatment in the two groups (P<0.05); the total PSQI score and the scores of sleep quality, sleep latency, sleep duration, sleep efficiency and daytime dysfunction in the observation group were lower than the control group (P<0.05). After treatment, the levels of serum BDNF and GABA were increased in comparison with those before treatment in the observation group (P<0.05), and the level of serum BDNF was higher than that in the control group (P<0.05). CONCLUSION: Acupuncture relieves depressive mood and improves sleep quality in patients with comorbid mild-to-moderate depressive disorder and insomnia. The effect mechanism may be related to the regulation of BDNF and GABA levels and the promotion of brain neurological function recovery.

[Effect of Shugan Tiaoshen acupuncture combined with western medication on depression-insomnia comorbidity due to COVID-19 quarantine: a multi-central randomized controlled trial].

OBJECTIVE: To observe the effect of Shugan Tiaoshen acupuncture (acupuncture for soothing the liver and regulating the mentality) combined with western medication on depression and sleep quality in the patients with depression-insomnia comorbidity due to COVID-19 quarantine, and investigate the potential mechanism from the perspective of cortical excitability. METHODS: Sixty patients with depression-insomnia comorbidity due to COVID-19 quarantine were randomly divided into an acupuncture group and a sham-acupuncture group, 30 cases in each one. The patients of both groups were treated with oral administration of sertraline hydrochloride tablets. In the acupuncture group, Shugan Tiaoshen acupuncture was supplemented. Body acupuncture was applied to Yintang (GV 24+), Baihui (GV 20), Hegu (LI 4), Zhaohai (KI 6), Qihai (CV 6), etc. The intradermal needling was used at Xin (CO15), Gan (CO12) and Shen (CO10). In the sham-acupuncture group, the sham-acupuncture was given at the same points as the acupuncture group. The compensatory treatment was provided at the end of follow-up for the patients in the sham-acupuncture group. In both groups, the treatment was given once every two days, 3 times a week, for consecutive 8 weeks. The self-rating depression scale (SDS) and insomnia severity index (ISI) scores were compared between the two groups before and after treatment and 1 month after the end of treatment (follow-up) separately. The cortical excitability indexes (resting motor threshold [rMT], motor evoked potential amplitude [MEP-A], cortical resting period [CSP]) and the level of serum 5-hydroxytryptamine (5-HT) were measured before and after treatment in the two groups. RESULTS: After treatment and in follow-up, SDS and ISI scores were decreased in both groups compared with those before treatment (P<0.05), and the scores in the acupuncture group were lower than those in the sham-acupuncture group (P<0.05), and the decrease range in the acupuncture group after treatment was larger than that in the sham-acupuncture group (P<0.05). After treatment, rMT was reduced (P<0.05), while MEP-A and CSP were increased (P<0.05) in the acupuncture group compared with that before treatment. The levels of serum 5-HT in both groups were increased compared with those before treatment (P<0.05). The rMT in the acupuncture group was lower than that in the sham-acupuncture group, while MEP-A and CSP, as well as the level of serum 5-HT were higher in the acupuncture group in comparison with the sham-acupuncture group (P<0.05). CONCLUSION: Shugan Tiaoshen acupuncture combined with western medication can relieve depression and improve sleep quality in the patients with depression-insomnia comorbidity due to COVID-19 quarantine, which is probably related to rectifying the imbalanced excitatory and inhibitory neuronal functions.

[Effects of electroacupuncture on the expression of serum exosomes and pro-inflammatory factors in spinal cord of rats with spinal cord injury].

OBJECTIVE: To investigate the effect of electroacupuncture (EA) on the morphology and microstructure of spinal cord tissue, the expression of serum exosomes, and the pro-inflammatory factors interleukin (IL)-1ß and IL-6 in spinal cord of rats with spinal cord injury (SCI), so as to explore the underlying mechanism of EA in the treatment of SCI. METHODS: Twenty-four female Wistar rats were randomly divided into sham operation group, model group, EA group, EA+GW4869 group, with 6 rats in each group. The SCI model was established by impinging spinal cord at T10 with a hammer, while the vertebral lamina was only opened without impingement for rats in sham operation group. Rats in EA group received EA intervention at "Jiaji"(EX-B7) acupoints at bilateral T9 and T10 (0.4-0.6 mA, 100 Hz), 3 h after modeling, once a day, for 7 concecutive days. Besides the treatment as EA group, rats in the EA+GW4869 group received injection of exosome inhibitor GW4869(200 µL, 300 µg/mL) once every 2 days from the day before modeling. Motor function of hind limbs of rats was evaluated using BBB scores. The histopathological changes of spinal cord were observed under light mircoscope after H.E. staining. Microstructure of spinal cord was observed and extracted serum exosomes were identified by using transmission electron microscopy. The expression of exosome marker proteins in serum exosomes, the levels of IL-1ß and IL-6 in spinal cord were detected by Western blot. RESULTS: H.E. stanining showed severe tissue looseness, inflammatory cell infiltration, cellular hydropic degeneration in spinal cord of the model group, which were relatively milder in the EA and EA+GW4869 groups. Under transmission electron microscopy, there were nerve fiber disintegration, myelin sheath structure dispersion, axonal atrophy with submembrane edema and widened space, and mitochondrial swelling in spinal cord of rats in the model group, with the lesions in EA group milder than EA+GW4869 group, which were both moderate. Typical exosomes were detected by transmission electron microscope in the extracted serum of rats in each group after ultracentrifugation. Compared with the sham operation group, the motor function scores was significantly decreased (P<0.01), the expression of IL-6 and IL-1ß in the spinal cord was significantly increased (P<0.01), while the expression of serum exosome marker protein CD81 was slightly increased in rats of the model group. Compared with the model group, the motor function scores was significantly increased (P<0.01), the expression of IL-6 and IL-1ß in the spinal cord was significantly decreased (P<0.01) in rats of the EA and EA+GW4869 group, while the expression of serum CD81 protein was slightly increased in rats of the EA group. Compared with the EA+GW4869 group, the expression of IL-6 and IL-1ß in the spinal cord was significantly decreased (P<0.01), while the expression of serum CD81 protein was slightly increased in rats of the EA group. However, there was no significance in expression of CD81 between each group mentioned above. CONCLUSION: EA can promote the secretion of serum exosomes and inhibit the expression of pro-inflammatory cytokines IL-6 and IL-1ß, so as to improve the microenvironment of injured spinal cord and SCI.

[Effect of electroacupuncture at back-shu points of five zang on fatigue status and cortical excitability in chronic fatigue syndrome].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at back-shu points of five zang on fatigue status, quality of life and motor cortical excitability in patients with chronic fatigue syndrome (CFS), so as to explore the possible mechanism of EA for CFS. METHODS: A total of 72 patients with CFS were randomized into an EA group (36 cases, 4 cases dropped off) and a sham EA group (36 cases, 3 cases dropped off). In the EA group, EA at Ganshu (BL 18), Xinshu (BL 15), Pishu (BL 20), Feishu (BL 13) and Shenshu (BL 23) was adopted, with continuous wave, 2 Hz in frequency. In the sham EA group, sham EA at non-acupoints (1.5-2.0 cm lateral to back-shu points of five zang) was applied, with shallow needling, and no current was connected. The treatment in the both groups was 20 min each time, once every other day, 2 weeks as one course, 3 courses were required. Before and after treatment, the scores of fatigue scale-14 (FS-14) and the MOS 36-item short form health survey (SF-36) were observed, and cortical excitability (the resting motor threshold [RMT], amplitude of motor-evoked potential [MEP-A] and latency of motor-evoked potential [MEP-L]) was detected in the two groups. RESULTS: After treatment, the physical fatigue score, mental fatigue score and total score of FS-14, as well as RMT of motor cortex in the EA group were decreased compared with those before treatment (P<0.01), the physical fatigue score and total score of FS-14 in the sham EA group were decreased compared with those before treatment (P<0.05); each item score and total score of FS-14 and RMT of motor cortex in the EA group were lower than those in the sham EA group (P<0.01, P<0.05). After treatment, each item score and total score of SF-36 and MEP-A of motor cortex in the EA group were increased compared with those before treatment (P<0.01), which were higher than those in the sham EA group (P<0.01, P<0.05). CONCLUSION: EA at back-shu points of five zang can effectively improve the fatigue status and quality of life in patients with CFS, its mechanism may be related to the up-regulating excitability of cerebral motor cortex.

Prognostic role of multiple abnormal genes in non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has the highest morbidity and mortality rates among all malignant tumor types. Although therapies targeting the mutated genes such as KRAS have been used in the clinic for many years, the prognosis remains poor. Therefore, it is necessary to further study the aberrant expression or mutation of non-target genes affecting the survival and prognosis. AIM: To explore the impact of simultaneous abnormalities of multiple genes on the prognosis and survival of patients. METHODS: We used R packages to analyze gene expression data and clinical data downloaded from The Cancer Genome Atlas (TCGA) database. We also collected samples from 85 NSCLC patients from the First People's Hospital of Jingzhou City and retrospectively followed the patients. Multivariate Cox regression analysis and survival analysis were performed. RESULTS: Analysis of gene expression data from TCGA revealed that the overexpression of the following single genes affected overall survival: TP53 (P = 0.79), PTEN (P = 0.94), RB1 (P = 0.49), CTNNB1 (P = 0.24), STK11 (P = 0.32), and PIK3CA (P = 0.013). However, the probability of multiple genes (TP53, PTEN, RB1, and STK11) affecting survival was 0.025. Retrospective analysis of clinical data revealed that sex (hazard ratio [HR] = 1.29; [95%CI: 0.64-2.62]), age (HR = 1.05; [95%CI: 1.02-1.07]), smoking status (HR = 2.26; [95%CI: 1.16-4.39]), tumor histology (HR = 0.58; [95%CI: 0.30-1.11]), cancer stage (HR = 16.63; [95%CI: 4.8-57.63]), epidermal growth factor receptor (EGFR) mutation (HR = 1.82; [95%CI: 1.05-3.16]), abundance (HR = 4.95; [95%CI: 0.78-31.36]), and treatment with tyrosine kinase inhibitors (TKIs) (HR = 0.58; [95%CI: 0.43-0.78]) affected patient survival. Co-occurring mutations of TP53, PTEN, RB1, and STK11 did not significantly affect the overall survival of patients receiving chemotherapy (P = 0.96) but significantly affected the overall survival of patients receiving TKIs (P = 0.045). CONCLUSION: Co-occurring mutation or overexpression of different genes has different effects on the overall survival and prognosis of NSCLC patients. Combined with TKI treatment, the co-occurring mutation of some genes may have a synergistic effect on the survival and prognosis of NSCLC patients.

[Lateral needling at Lianquan (CV 23) for post-stroke dysphagia: a randomized controlled trial].

OBJECTIVE: To observe the effect of lateral needling at Lianquan (CV 23) for post-stroke dysphagia, and explore its mechanism. METHODS: A total of 64 patients with post-stroke dysphagia were randomly divided into an observation group and a control group, 32 cases in each group. Both groups were treated with conventional basic treatment. The observation group was treated with lateral needling at CV 23, without needle retaining, once a day. The control group was treated with swallowing rehabilitation training, once a day. Both groups were treated for 5 days a week, with 2 days interval, 1 week as one course and 4 courses were required. Before and after treatment, the Kubota water swallowing test grade and standardized swallowing assessment (SSA) score were compared in the two groups. Before and after treatment, the video fluoroscopic swallowing study (VFSS) was used to measure the hyoid bone movement displacement and pharyngeal delivery time in the observation group. RESULTS: Compared before treatment, the Kubota water swallowing test grade after treatment was improved in the two groups (P<0.05), and the observation group was superior to the control group (P<0.05); the SSA scores after treatment were decreased in the two groups (P<0.05), and the observation group was lower than the control group (P<0.05). Compared before treatment, the hyoid bone movement displacement was increased and pharyngeal delivery time was shortened after treatment in the observation group (P<0.05). CONCLUSION: Lateral needling at CV 23 could improve dysphagia symptoms in patients with post-stroke dysphagia, its mechanism may be related to the increasing of hyoid bone movement displacement and shortening of pharyngeal delivery time.

Role of STK11 in ALK-positive non-small cell lung cancer.

Anaplastic lymphoma kinase (ALK) inhibitors have been shown to be effective in treating patients with ALK-positive non-small cell lung cancer (NSCLC), and crizotinib, ceritinib and alectinib have been approved as clinical first-line therapeutic agents. The availability of these inhibitors has also largely changed the treatment strategy for advanced ALK-positive NSCLC. However, patients still inevitably develop resistance to ALK inhibitors, leading to tumor recurrence or metastasis. The most critical issues that need to be addressed in the current treatment of ALK-positive NSCLC include the high cost of targeted inhibitors and the potential for increased toxicity and resistance to combination therapy. Recently, it has been suggested that the serine/threonine kinase 11 (STK11) mutation may serve as one of the biomarkers for immunotherapy in NSCLC. Therefore, the main purpose of this review was to summarize the role of STK11 in ALK-positive NSCLC. The present review also summarizes the treatment and drug resistance studies in ALK-positive NSCLC and the current status of STK11 research in NSCLC.

Tumorigenic effect of TERT and its potential therapeutic target in NSCLC (Review).

Non­small cell lung cancer (NSCLC), which accounts for ~85% of all lung cancer cases, is commonly diagnosed at an advanced stage and has a high patient mortality rate. Despite the increasing availability of treatment strategies, the prognosis of patients with NSCLC remains poor, with a low 5­year survival rate. This poor prognosis may be associated with the tumor heterogeneity of NSCLC, as well as its acquisition and intrinsic resistance to therapeutic drugs. It has been suggested that combination therapy with telomerase inhibition may be an effective strategy for the treatment of drug­sensitive and drug­resistant types of cancer. Telomerase is the key enzyme for cell survival, and ~90% of human cancers maintain telomeres by activating telomerase, which is driven by the upregulation of telomerase reverse transcriptase (TERT). Several mechanisms of telomerase reactivation have been described in a variety of cancer types, including TERT promoter mutation, epigenetic modifications via a TERT promoter, TERT amplification, and TERT rearrangement. The aim of the present study was to comprehensively review telomerase activity and its association with the clinical characteristics and prognosis of NSCLC, as well as analyze the potential mechanism via which TERT activates telomerase and determine its potential clinical application in NSCLC. More importantly, current treatment strategies targeting TERT in NSCLC have been summarized with the aim to promote discovery of novel strategies for the future treatment of NSCLC.

The Role of Acupuncture in Hormonal Shock-Induced Cognitive-Related Symptoms in Perimenopausal Depression: A Randomized Clinical Controlled Trial.

Introduction: Perimenopausal depression is predominantly caused by hormone shock, but the underlying physical and psychological factors are still unclear. Objectives: To explore the constituent components of perimenopausal depression by dynamically depicting its influencing factors and interactive pathways from the perspective of embodied cognition. Methods: This is a randomized clinical controlled trial. In this study, electroacupuncture was compared with escitalopram. A total of 242 participants with mild to moderate perimenopausal depression were enrolled from 6 hospitals in China. Each participant had a 12-week intervention and a 12-week follow-up period. The primary outcome of this study is the Hamilton Depression Rating Scale (HAMD-17), and the secondary outcome is the menopause-specific quality of life scale (MENQOL), serum Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2) levels. Results: The structural equation model suggested that hormone levels were not directly associated with HAMD-17 (P = 0.852), while MENQOL was statistically correlated with HAMD-17 as an intermediary variable (P < 0.001). Electroacupuncture gradually showed positive impacts on MENQOL and HAMD-17 during the follow-up period (P < 0.05). Cognitive impairment is the dominant dimension of perimenopausal depression. Conclusions: Hormonal shock may affect clinical symptoms and poor quality of life to induce cognitive impairment leading perimenopausal depression, and this impact on cognition is embodied. Electroacupuncture has positive effect on perimenopausal depression and quality of life.