Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation.

Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a "Yin-Yang" counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the "Yin-Yang" homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.

Efficacy of EGFR Tyrosine Kinase Inhibitors in the Adjuvant Treatment for Operable Non-small Cell Lung Cancer by a Meta-Analysis.

BACKGROUND: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the adjuvant treatment of non-small cell lung cancer (NSCLC) has not been well-established. Our meta-analysis aimed to determine whether the administration of EGFR-TKIs could improve the outcomes of patients with NSCLC undergoing complete resection. METHODS: We comprehensively searched databases and extracted data from eligible studies. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) as well as disease relapse with odds ratios (OR) were calculated using random and/or fixed-effects models. Meta-regression analysis and test for interaction between subgroups were also carried out. RESULTS: A total of 1,960 patients in five studies were included. Adjuvant EGFR-TKI treatment was associated with a significant benefit on DFS (HR, 0.63; 95% CI, 0.41-0.99), corresponding to an absolute benefit of 3.1% at 3 years, yet with significant heterogeneity (I(2) = 83.4%, P < .001). The survival benefit was superior (Pinteraction = .03) in studies with more than an 18-month median treatment duration. EGFR mutation rate was also identified as a source of heterogeneity (P = .017). In the population with EGFR mutations, HR for DFS was 0.48 (95% CI, 0.36-0.65), corresponding to an absolute benefit of 9.5% at 3 years, with a reduced risk of distant metastasis (OR, 0.71; 95% CI, 0.56-0.92). Adjuvant EGFR-TKI treatment resulted in a marginally statistically significant benefit on OS (HR, 0.72; 95% CI, 0.49-1.06). The rate of overall grade 3 or greater adverse events was 42.3% (95% CI, 39.1-45.6). CONCLUSIONS: Adjuvant EGFR-TKI treatment may enhance disease-free survival and reduce the risk of distant metastasis in patients with EGFR-mutant NSCLC undergoing complete resection.

Massage therapy for fibromyalgia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Although some studies evaluated the effectiveness of massage therapy for fibromyalgia (FM), the role of massage therapy in the management of FM remained controversial. OBJECTIVE: The purpose of this systematic review is to evaluate the evidence of massage therapy for patients with FM. METHODS: Electronic databases (up to June 2013) were searched to identify relevant studies. The main outcome measures were pain, anxiety, depression, and sleep disturbance. Two reviewers independently abstracted data and appraised risk of bias. The risk of bias of eligible studies was assessed based on Cochrane tools. Standardised mean difference (SMD) and 95% confidence intervals (CI) were calculated by more conservative random-effects model. And heterogeneity was assessed based on the I(2) statistic. RESULTS: Nine randomized controlled trials involving 404 patients met the inclusion criteria. The meta-analyses showed that massage therapy with duration ≥ 5 weeks significantly improved pain (SMD, 0.62; 95% CI 0.05 to 1.20; p = 0.03), anxiety (SMD, 0.44; 95% CI 0.09 to 0.78; p = 0.01), and depression (SMD, 0.49; 95% CI 0.15 to 0.84; p = 0.005) in patients with FM, but not on sleep disturbance (SMD, 0.19; 95% CI -0.38 to 0.75; p = 0.52). CONCLUSION: Massage therapy with duration ≥ 5 weeks had beneficial immediate effects on improving pain, anxiety, and depression in patients with FM. Massage therapy should be one of the viable complementary and alternative treatments for FM. However, given fewer eligible studies in subgroup meta-analyses and no evidence on follow-up effects, large-scale randomized controlled trials with long follow-up are warrant to confirm the current findings.

[Effect of electric acupoint stimulation on shivering in cesarean section].

OBJECTIVE: To explore the efficacy of electric acupoint stimulation on shivering in cesarean section. METHODS: Eighty cases of parturients, under the America Society of Anesthesiologists (ASA) physical status II , were randomized into a transcutaneous electrical acupoint stimulation (TEAS) assisted anesthesia group (group A) and an anesthesia group (group B). Spinal-epidural anesthesia(CSEA) puncture was applied to both groups and 8 mg of 0. 75% bubivacaine was given by spinal injection, the block level was T4 T8. In group A, TEAS was applied before CSEA at paired acupoints-ipsilateral Hegu (LI 4)-Laogong (PC 8) and Sanyinjiao (SP 6)-Zusanli (ST 36) till ending the surgery. The 4 pair of bilateral acupoints were fixed with self-adhesive electrodes and connected with Han's acupoint and nerve stimulator (HANS, LH402H), the frequency was 2 Hz/ 15 Hz, the intensity was 10- 30 mA and the form was densedisperse wave within the patients' tolarance. The heart rate (HR), mean arterial pressure (MAP), oxyhemoglobin saturation (SPO) and shivering degree were recorded before anesthesia (To), 1 min after anesthesia puncture (Ti), 1 min after the delivery (Tz), during abdomen closure (T3) and at the end of surgery (T4). RESULTS: The occurrence rate of shivering was 35. 0% (14/40) in group A, which was lower to 67. 5% (27/40, P<0. 05) in group B; the degree of shivering was lighter in group A than that in group B at T2, T3 and T4 (all P<0. 01). In group A, HR was faster at T1 and T2 compared to that at To (all P<0. 05), while at T3 and T4, the HR was the same with that before anesthesia (all P>0. 05). In group B, the HR was faster at T1, T2, T3 and T4 compared to that at T0 (P<0. 05, P<0. 01). In both groups, the MAP was lower at T1, T2 (P<0.05,P<0.01) and resumed to that before anesthesia at T3 and T4 (all P>0.05); there was no statistical significance of SPO2 in both groups (all P>0.05). CONCLUSION: TEAS can reduce the occurrence rate of shivering and steady the heart rate in cesarean section.