O-GlcNAcylation of CSNK2A1 by OGT is Involved in the Progression of Colorectal Cancer.

Colorectal cancer (CRC) metastasis is challenging for improved clinical outcomes. The casein kinase 2 alpha 1 (CSNK2A1) is an oncogene involved in several cancers. This study aimed to investigate the influence of CSNK2A1 on CRC progression and the related molecular mechanism. The CSNK2A1 levels were predicted using bioinformatic analysis and were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Cell phenotypes were analyzed using cell-counting kit-8, colony formation, transwell assay, and western blot. Tumor growth was evaluated in a tumor-bearing mouse model in vivo. Similarly, O-GlcNAc modification of CSNK2A1 was assessed by immunoprecipitation, western blot, and immunofluorescence. Results indicated that CSNK2A1 was upregulated in CRC and was related to poor prognosis. Interference with CSNK2A1 suppressed CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition, inhibiting tumor growth. Moreover, OGT promoted the glycosylation modification of CSNK2A1, enhanced its protein stability, and reversed tumor progression when CSNK2A1 was knocked down. The CSNK2A1 might also affect CRC progression via the PI3K/AKT pathway. In conclusion, the OGT-O-GlcNAcylation-CSNK2A1 axis accelerated the malignant advancement of CRC, suggesting potential CRC therapeutic targets.

RAB6A functions as a critical modulator of the stem-like subsets in cholangiocarcinoma.

RAB6A is a member of RAB GTPase family and plays an important role in the targeted transport of neurotrophic receptors and inflammatory cytokines. RAB6A-mediated secretory pathway is involved in many physiological and pathological processes. Defects in RAB6A-mediated secretory pathway may lead to the development of many diseases, including cancer. However, its role in cholangiocarcinoma (CCA) has not yet been revealed. We explored the regulatory role of RAB6A in the stem-like subsets of CCA. We showed that RAB6A knockdown (KD) impedes cancer stem cells (CSCs) properties and epithelial-mesenchymal transition in vitro and that suppression of RAB6A inhibits tumor growth in vivo. We screened target cargos of RAB6A in CCA cells and identified a extracellular matrix component as the target cargo. RAB6A binds directly to OPN, and RAB6A KD suppressed OPN secretion and inhibited the interaction between OPN and αV integrin receptor. Moreover, RAB6A KD inhibited the AKT signaling pathway, which is a downstream effector of the integrin receptor signaling. In addition, shRNA targeting OPN blocked endogenous expression of OPN and consequently weakened CSCs properties in RAB6A-formed spheres. Similarly, inhibitor of AKT signaling, MK2206 also impedes oncogenic function of RAB6A in the stem-like subsets of CCA cells. In conclusion, our findings showed that RAB6A sustains CSCs phenotype maintenance by modulating the secretion of OPN and consequentially activating the downstream AKT signaling pathway. Targeting the RAB6A/OPN axis may be an effective strategy for CCA therapy.

Curcumol ß-cyclodextrin inclusion complex enhances radiosensitivity of esophageal cancer under hypoxic and normoxic condition.

PURPOSE: Radiotherapy is an indispensable treatment for esophageal cancer (EC), but radioresistance is not uncommon. Curcumol, as an active extract from traditional Chinese medicines, has been reported to have antitumor activity in various types of human tumor cells. However, its reversal of radioresistance has been rarely reported. MATERIALS AND METHODS: In the present study, curcumol was prepared as an inclusion complex with ß-cyclodextrin. EC cell lines were treated with radiation and curcumol ß-cyclodextrin inclusion complex (CßC), and the effect of radiosensitization of CßC was investigated in vitro and in vivo. The in vitro experiments included cell proliferation assay, clonogenic survival assay, apoptosis assay, cell cycle assay, and western blot assay. RESULTS: The in vitro data revealed that CßC and irradiation synergistically inhibited the proliferation, reduced the colony formation, promoted the apoptosis, increased the G2/M phase, inhibited DNA damage repair, and reversed the hypoxia-mediated radioresistance of EC cells to a greater extent than did CßC alone or irradiation alone. The sensitization enhancement ratios (SERs) were 1.39 for TE-1 and 1.48 for ECA109 under hypoxia. The SERs were 1.25 for TE-1 and 1.32 for ECA109 under normoxia. The in vivo data demonstrated that the combination of CßC and irradiation could inhibit tumor growth to the greatest extent compared with either monotherapy alone. The enhancement factor was 2.45. CONCLUSION: This study demonstrated that CßC could enhance radiosensitivity of EC cells under hypoxic and normoxic condition. Thus, CßC can be used as an effective radiosensitizer for EC.

Efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A retrospective study.

Background: This study aims to compare the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) with different radiotherapy doses (45Gy and 50.4Gy) in patients with locally advanced rectal cancer (LARC). Methods: Herein, 120 patients with LARC were retrospectively enrolled between January 2016 and June 2021. All patients underwent two courses of induction chemotherapy (XELOX), chemoradiotherapy, and total mesorectum excision (TME). A total of 72 patients received a radiotherapy dose of 50.4 Gy, while 48 patients received a dose of 45 Gy. Surgery was then performed within 5-12 weeks following nCRT. Results: There was no statistically significant difference between the baseline characteristics of the two groups. The rate of good pathological response in the 50.4Gy group was 59.72% (43/72), while in the 45Gy group achieved 64.58% (31/48) (P>0.05). The disease control rate (DCR) in the 50.4Gy group was 88.89% (64/72), compared to 89.58% (43/48) in the 45Gy group (P>0.05). The incidence of adverse reactions for radioactive proctitis, myelosuppression, and intestinal obstruction or perforation differed significantly between the two groups (P<0.05). The anal retention rate in the 50.4Gy group was significantly higher in contrast to the 45Gy group (P<0.05). Conclusions: Patients receiving a radiotherapy dose of 50.4Gy have a better anal retention rate but also a higher incidence of adverse events such as radioactive proctitis, myelosuppression, and intestinal obstruction or perforation, and a comparable prognosis to patients treated with a radiotherapy dose of 45Gy.

Positive response to niraparib in chemo-refractory patients with metastatic appendiceal mucinous adenocarcinoma harboring ATM mutations: A case report.

Background: Appendiceal mucinous adenocarcinoma, one kind of specific colorectal cancer, is lowly prevalent and rarely diagnosed in clinical practice. In addition, there have been limited standard treatment strategies established for patients with appendiceal mucinous adenocarcinoma, especially with metastatic disease. The regimens for colorectal cancer, which were adopted in appendiceal mucinous adenocarcinoma, usually resulted in limited effectiveness. Case presentation: Herein, we presented a case of chemo-refractory patient with metastatic appendiceal mucinous adenocarcinoma harboring ATM pathological mutation of exon 60, c.8734del, p.R2912Efs*26, and who has achieved a persistent response to salvage treatment of niraparib, with disease control time that reached 17 months and still in extension. Conclusions: We supposed that appendiceal mucinous adenocarcinoma patients harboring ATM pathological mutations may respond to the treatment of niraparib, even without a homologous recombination deficiency (HRD) status; however, it needs further confirmation in a larger cohort.

FBXO31 sensitizes cancer stem cells-like cells to cisplatin by promoting ferroptosis and facilitating proteasomal degradation of GPX4 in cholangiocarcinoma.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a malignant tumour originating from the biliary epithelium that easily infiltrates, metastasizes and recurs. The deficiency of FBXO31 facilitates the initiation and progression of several types of cancer. However, the involvement of FBXO31 in CCA progression has remained unclear. METHODS: qRT-PCR was used to detect the expression of FBXO31 in CCA. The biological functions of FBXO31 were confirmed in vivo and in vitro. Sphere formation and flow cytometry were used to identify the stem cell properties of CCA. RESULTS: FBXO31 is downregulated in CCA and that deficiency of FBXO31 is associated with the TNM stage of CCA. Functional studies showed FBXO31 inhibits cell growth, migration, invasion, cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) in vitro and impedes tumour growth in vivo. In addition, overexpression of FBXO31 increases the cisplatin (CDDP) sensitivity of CCA cells. RNA-sequencing analysis revealed that FBXO31 is involved in redox biology and metal ion metabolism in CCA cells during CDDP treatment. Further studies revealed that FBXO31 enhances ferroptosis induced by CDDP in CCA and CSC-like cells. FBXO31 enhances ubiquitination of glutathione peroxidase 4 (GPX4), which leads to proteasomal degradation of GPX4. Moreover, overexpression of GPX4 compromises the promoting effects of FBXO31 on CDDP-induced ferroptosis in CCA and CSC-like cells. CONCLUSIONS: Our studies indicate that FBXO31 functions as a tumour suppressor in CCA and sensitizes CSC-like cells to CDDP by promoting ferroptosis and facilitating the proteasomal degradation of GPX4.

A Phase III Multicenter Randomized Clinical Trial of 60 Gy versus 50 Gy Radiation Dose in Concurrent Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma.

PURPOSE: In this multicenter phase 3 trial, the efficacy and safety of 60 Gy and 50 Gy doses delivered with modern radiotherapy technology for definitive concurrent chemoradiotherapy (CCRT) in patients with inoperable esophageal squamous cell carcinoma (ESCC) were evaluated. PATIENTS AND METHODS: Patients with pathologically confirmed stage IIA‒IVA ESCC were randomized 1:1 to receive conventional fractionated 60 Gy or 50 Gy to the tumor and regional lymph nodes. Concurrent weekly chemotherapy (docetaxel 25 mg/m2; cisplatin 25 mg/m2) and two cycles of consolidation chemotherapy (docetaxel 70 mg/m2; cisplatin 25 mg/m2 days 1‒3) were administered. RESULTS: A total of 319 patients were analyzed for survival, and the median follow-up was 34.0 months. The 1- and 3-year locoregional progression-free survival (PFS) rates for the 60 Gy group were 75.6% and 49.5% versus 72.1% and 48.4%, respectively, for the 50 Gy group [HR, 1.00; 95% confidence interval (CI), 0.75‒1.35; P = 0.98]. The overall survival rates were 83.7% and 53.1% versus 84.8% and 52.7%, respectively (HR, 0.99; 95% CI, 0.73‒1.35; P = 0.96), whereas the PFS rates were 71.2% and 46.4% versus 65.2% and 46.1%, respectively (HR, 0.97; 95% CI, 0.73‒1.30; P = 0.86). The incidence of grade 3+ radiotherapy pneumonitis was higher in the 60 Gy group (nominal P = 0.03) than in the 50 Gy group. CONCLUSIONS: The 60 Gy arm had similar survival endpoints but a higher severe pneumonitis rate compared with the 50 Gy arm. Fifty Gy should be considered as the recommended dose in CCRT for ESCC.

Effect of quadratus lumborum block on postoperative cognitive function in elderly patients undergoing laparoscopic radical gastrectomy: a randomized controlled trial.

BACKGROUND: Quadratus lumborum block (QLB) is a novel and effective postoperative analgesia method for abdominal surgeries. However, whether QLB can affect early postoperative cognitive function by inhibiting surgical traumatic stress and the inflammatory response remains unclear. This study aimed to explore the effect of QLB on postoperative cognitive function in elderly patients undergoing laparoscopic radical gastrectomy. METHODS: Sixty-four elderly patients who underwent laparoscopic radical gastrectomy were randomly divided into the QLB group (Q group, n = 32) and control group (C group, n = 32). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to measure cognitive function 1 day before and 7 days after surgery. Postoperative cognitive dysfunction (POCD) was defined as a decline of ≥ 1 SD in both tests. The visual analog scale (VAS) scores 6 h (T1), 24 h (T2), and 48 h (T3) after surgery were measured. The serum levels of high mobility group box protein 1 (HMGB1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated 1 day before surgery (baseline), and 1 day (day 1) and 3 days after surgery (day 3). The intraoperative remifentanil dosage, sufentanil consumption 24 h after surgery, recovery time from anesthesia, and adverse effects were also compared. RESULTS: POCD was present in two patients in the QLB group and eight patients in the C group 7 days after surgery (6.7 % vs. 27.6 %, P = 0.032). The MMSE and MoCA scores were similar in both groups preoperatively, and the two scores were higher in the QLB group than in the C group 7 days after surgery (P < 0.05). The VAS scores were significantly lower in the Q group at all times after surgery (P < 0.05). Compared with the C group, the levels of HMGB1, TNF-α, and IL-6 were significantly decreased 1 and 3 days after surgery in the QLB group (P < 0.05). The remifentanil consumption intraoperatively and sufentanil 24 h postoperatively were significantly lower in the QLB group (P < 0.05). The recovery time from anesthesia was shorter in the QLB group (P < 0.05). No severe adverse effects occurred in either group. CONCLUSIONS: QLB could improve postoperative cognitive function in elderly patients undergoing laparoscopic radical gastrectomy. This may be related to the suppression of the inflammatory response after surgery. TRIAL REGISTRATION: Chictr.org.cn identifier ChiCTR1900027574 (Date of registry: 19/11/2019, prospectively registered).

Comparison of intravitreal dexamethasone implant and anti-VEGF drugs in the treatment of retinal vein occlusion-induced oedema: a meta-analysis and systematic review.

OBJECTIVE: To compare the efficacy and safety of intravitreal dexamethasone (DEX) implant and anti-vascular endothelial growth factor (anti-VEGF) agents in the treatment of macular oedema secondary to retinal vein occlusion (RVO). DESIGN: Systematic review and meta-analysis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SOURCES: PubMed, Cochrane Library and ClinicalTrials.gov registry were searched from inception to 10 December 2019, without language restrictions. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and real-world observation studies comparing the efficacy of DEX implant and anti-VEGF agents for the treatment of patients with RVO, naïve or almost naïve to both arms, were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data for mean changes in best-corrected visual acuity (BCVA), central subfield thickness (CST) and product safety. Review Manager V.5.3 and GRADE were used to synthesise the data and validate the evidence, respectively. RESULTS: Four RCTs and 12 real-world studies were included. An average lower letter gain in BCVA was determined for the DEX implant (mean difference (MD) = -6.59; 95% CI -8.87 to -4.22 letters) administered at a retreatment interval of 5-6 months. Results were similar (MD6 months=-12.68; 95% CI -21.98 to -3.37 letters; MD12 months=-9.69; 95% CI -12.01 to -7.37 letters) at 6 and 12 months. The DEX implant resulted in comparable or marginally less CST reduction at months 6 and 12 but introduced relatively higher risks of elevated intraocular pressure (RR=3.89; 95% CI 2.16 to 7.03) and cataract induction (RR=5.22; 95% CI 1.67 to 16.29). Most real-life studies reported an insignificant numerical gain in letters for anti-VEGF drugs relative to that for DEX implant. However, the latter achieved comparable efficacy with a 4-month dosage interval. CONCLUSION: Compared with anti-VEGF agents, DEX implant required fewer injections but had inferior functional efficacy and safety. Real-life trials supplemented the efficacy data for DEX implant.

Meta-analysis on the risk of fatal adverse events by bevacizumab, cetuximab, and panitumumab in 31 randomized trials including 25,000 patients with colorectal carcinoma.

BACKGROUND: Targeted drugs including bevacizumab, cetuximab, and panitumumab have been widely used during the management of patients diagnosed with colorectal carcinoma, especially as palliative treatment. The present meta-analysis was performed to evaluate the fatal adverse events (FAEs) of targeted drugs including bevacizumab, cetuximab, and panitumumab in patients with colorectal cancer. PATIENTS AND METHODS: Studies of prospective, randomized, and controlled feature from EMBASE, Medline, and Cochrane Library, which reported FAEs potentially associated with bevacizumab, cetuximab, and panitumumab were adopted. Clinical characteristics and FAEs were collected from the enrolled literatures, with the quality of which been evaluated. Pooled analysis of FAEs, caused by each agent as first line, second/further line, and adjuvant treatment were performed with relative risks (RRs) and their corresponding 95% confidence intervals (CIs) in software RevMan 5.3. RESULTS: Thirty-one studies including 25,939 patients were brought into the final analysis. The RR and its 95% CI of the FAEs among all the agents including bevacizumab, cetuximab, and panitumumab was 1.07 (95% CI, 0.89-1.29; P = .50). The RRs and their 95% CIs of the FAEs as first line, second or further line, and adjuvant treatment related to bevacizumab were 0.91 (95% CI, 0.62-1.32; P = .61), 1.14 (95% CI, 0.57-2.28; P = .71), and 1.10 (95% CI, 0.67-1.79; P = .72). The RRs and their 95% CIs of the FAEs as first line, second or further line, and adjuvant treatment related to cetuximab were 1.02 (95% CI, 0.60-1.76; P = .93), 2.51 (95% CI, 0.49-12.88; P = .27), and 2.40 (95% CI, 1.00-5.77; P = .05). The RRs and their 95% CIs of the FAEs as first line, second or further line treatment related to panitumumab were 1.40 (95% CI, 0.89-2.18; P = .14) and 0.68 (95% CI, 0.43-1.09; P = .11), respectively. CONCLUSIONS: The present meta-analysis did not show any significantly increased RR of FAEs belonging to bevacizumab, cetuximab, or panitumumab, whether as first line, second/further line, or adjuvant treatment among patients with colorectal carcinoma comparing to placebo or blank treatment.

Factors associated with compassion satisfaction, burnout, and secondary traumatic stress among Chinese nurses in tertiary hospitals: A cross-sectional study.

BACKGROUND: Compassion fatigue is a work-related professional hazard acquired when providing healthcare for patients. This hazard can lead to physical and mental health problems for nurses and may also affect the nursing care quality for patients. However, studies on Chinese nurses' compassion fatigue are scarce, especially large sampled, multi-center empirical research. OBJECTIVES: The goal of this study was to assess the prevalence of compassion fatigue among Chinese nurses, and to explore the factors associated with compassion satisfaction, burnout and second traumatic stress. DESIGN: A cross-sectional design with a convenience sample. SETTINGS: Participants were recruited from 11 tertiary hospitals in western (Chengdu, Chongqing), eastern (Hefei), southern (Shenzhen) and central China (Wuhan, Huangshi). PARTICIPANTS: A total of 1044 registered nurses from different nursing departments were surveyed. METHODS: Demographic, work-related information, lifestyle questionnaire and the Professional Quality of Life Scale were used in this study. Descriptive statistics, t-tests, one-way analysis of variance, and Pearson or Spearman's correlation analyses were used to compare the differences and examine the relationships between participants' demographic and work-related variables and compassion satisfaction, burnout and secondary traumatic stress. Multiple linear regression models were performed to identify salient variables associated with compassion satisfaction, burnout and secondary traumatic stress from among demographic and work-related factors. RESULTS: The mean scores for the dimensions of compassion satisfaction, burnout and secondary traumatic stress were 32.63±6.46, 27.36±5.29, and 26.88±5.13, respectively. The age of 36 or higher, being married, higher job satisfaction, good sleep quality and regular exercise were positively associated with compassion satisfaction, while smoking was a negative factor; these five factors explained 25.7% of the total variance. The average number of hours worked per day was a positive factor for burnout, while being married/member of an unmarried couple, job satisfaction, sleep hours per day and sleep quality were negative factors of burnout, explaining 38.8% of the total variance. In addition, we also found that four factors, poor sleep quality, low job satisfaction, more work hours, and second-hand smoke exposure were related to secondary traumatic stress, explaining 9% of the variance. CONCLUSIONS: Our findings reveal a serious phenomenon of the poor professional quality of life among Chinese nurses. The results may provide clues to help nursing managers identify nurses' vulnerability to compassion fatigue and implement targeted strategies to reduce nurses' burnout and secondary traumatic stress, while supporting compassion satisfaction.

FBXO31 modulates activation of hepatic stellate cells and liver fibrogenesis by promoting ubiquitination of Smad7.

Liver fibrosis is a critical pathological process in the early stage of many liver diseases, including hepatic cirrhosis and liver cancer. However, the molecular mechanism is not fully revealed. In this study, we investigated the role of F-box protein 31 (FBXO31) in liver fibrosis. We found FBXO31 upregulated in carbon tetrachloride (CCl4 ) induced liver fibrosis and in activated hepatic stellate cells, induced by transforming growth factor-ß (TGF-ß). The enforced expression of FBXO31 caused enhanced proliferation and increased expression of α-smooth muscle actin (α-SMA) and Col-1 in HSC-T6 cells. Conversely, suppression of FBXO31 resulted in inhibition of proliferation and decreased accumulation of α-SMA and Col-1 in HSC-T6 cells. In addition, upregulation of FBXO31 in HSC-T6 cells decreased accumulation of Smad7, the negative regulator of the TGF-ß/smad signaling pathway, and suppression of the FBXO31 increased accumulation of Smad7. Immunofluorescence staining showed FBXO31 colocalized with Smad7 in HSC-T6 cells and in liver tissues of BALB/c mice treated with CCl4 . Immunoprecipitation demonstrated FBXO31 interacted with Smad7. Moreover, FBXO31 enhanced ubiquitination of Smad7. In conclusion, FBXO31 modulates activation of HSCs and liver fibrogenesis by promoting ubiquitination of Smad7.

Analgesic effect of the ultrasound-guided subcostal approach to transmuscular quadratus lumborum block in patients undergoing laparoscopic nephrectomy: a randomized controlled trial.

BACKGROUND: Quadratus lumborum block (QLB) is an effective analgesia that lowers opioid consumption after lower abdominal and hip surgeries. The subcostal approach to transmuscular QLB is a novel technique that can provide postoperative analgesia by blocking more dermatomes. The aim of this study is to evaluate the efficacy and viability of subcostal approach to QLB after laparoscopic nephrectomy. METHODS: Sixty patients who underwent laparoscopic nephrectomy were randomly divided into the subcostal approach to QLB group (QLB group, n = 30) and the control group (C group, n = 30). All patients underwent ultrasound-guided subcostal approach to QLB in an ipsilateral parasagittal oblique plane at the L1-L2 level. The QLB group received 0.4 cc/kg of 0.3% ropivacaine, and the C group received 0.4 cc/kg of 0.9% saline. Postoperatively, a patient-controlled intravenous analgesic pump with sufentanil was attached to all the patients. The primary outcome was sufentanil consumption within the first 24 h after surgery. The secondary outcomes included the Ramsey sedation scale (RSS) scores and Bruggemann comfort scale (BCS) scores 6 h (T1), 12 h (T2), and 24 h (T3) after surgery, intraoperative remifentanil consumption, number of patients requiring rescue analgesia, time to recovery of intestinal function, mobilization time after surgery, and presence of side effects. RESULTS: Sufentanil consumption within the first 24 h after surgery was significantly lower in the QLB group than in the C group (mean [standard deviation]: 34.1 [9.9] µg vs 42.1 [11.6] µg, P = .006). The RSS scores did not differ between the two groups, and the BCS scores of the QLB group at T1 and T2 time points was significantly higher than those of the C group(P<0.05). The consumption of remifentanil intraoperatively and the number of patients requiring rescue analgesia were significantly lower in the QLB group (P<0.05). Time to recovery of intestinal function and mobilization time after surgery were significantly earlier in the QLB group (P<0.05). The incidence of postoperative nausea and vomiting was significantly lower in the QLB group (P<0.05). CONCLUSIONS: The ultrasound-guided subcostal approach to QLB is an effective analgesic technique in patients undergoing laparoscopic nephrectomy as it reduces the consumption of sufentanil postoperatively. TRIAL REGISTRATION: ChiCTR1800020296 0 (Prospective registered). Initial registration date was 22/12/2018.

ctDNA assessment of EGFR mutation status in Chinese patients with advanced non-small cell lung cancer in real-world setting.

BACKGROUND: The prevalence of EGFR mutations in circulating free tumor-derived DNA (ctDNA) was still unknown in China. This large-scale study (NCT02623257) aimed to explore the prevalence of epidermal growth factor receptor (EGFR) mutations and determine the correlation of EGFR mutation status with clinical characteristics. METHODS: Plasma DNA samples from 1,001 patients with stage III/IV NSCLC who received ≤1st line chemotherapy were collected from 65 hospitals. EGFR mutations were tested by amplification refractory mutation system (ARMS) method. The EGFR mutation rate was calculated and the associations between EGFR status and patients' demographic data, disease status as well as treatment pattern were explored. RESULTS: EGFR mutations were detected in 251 of 1,001 (25.1%) patients, 26.8% in adenocarcinoma and 11.7% in squamous carcinoma. A total of 189 harbored sensitizing mutations alone, 28 had resistance mutations alone, 3 had a combination of activating mutations, and 31 had a combination of activating and resistance mutations. Higher detection rate was observed in chemotherapy-naïve patients than those received 1st line chemotherapy (27.0% vs. 18.0%; P=0.006). Of which, the mutation rate of exon 19 deletion was 9.31% for naïve patients and 7.37% for the 1st chemotherapy patients; while the mutation rate of L858R decreased obviously from 10.20% (naïve) to 3.69% (1st line). We also noticed the mutation rate was 37.1% in patients with ≥2 organ metastases. Multivariate analysis showed female, chemotherapy-naïve, or ≥2 metastatic organs patients had higher EGFR mutation rate. CONCLUSIONS: ctDNA based EGFR mutation test is feasible and could be a surrogate when tissue biopsy is not available.

Efficacy and safety of adalimumab in the treatment of non-infectious uveitis: a meta-analysis and systematic review.

OBJECTIVE: To summarize updated evidences on the efficacy and safety of adalimumab (ADA) in the treatment of patients with non-infectious uveitis. PATIENTS AND METHODS: A systematic search between January 2000 and September 2017 was conducted using PubMed, Embase, and Cochrane libraries. We investigated control of inflammation, improvement of visual acuity (VA), corticosteroid-sparing effect, and adverse events (AEs) or serious adverse events. RESULTS: Three randomized clinical trials (RCTs) and 20 non-RCTs were included and analyzed. The pooled proportions of inflammation control were 74% (95% CI 64%-82%) and 79% (95% CI 69%-87%) in groups of ≤6- and ≥12-months follow-up durations. No significant difference was found between the two groups (χ2 = 0.920, p = 0.337). Analysis of subgroups classified by degree of being treatment-naïve for anti-TNFα agents showed the inflammation control reached a high of 87% (95% CI 80%-92%) when subjects were "almost naïve" to anti-TNFα before ADA treatment. VA was improved by three or more lines in 41.3% (52/126) eyes, and was equal to or better than the baseline in 88.8% (142/160) eyes. Corticosteroid sparing was observed in 82.0% (91/111) of the patients; among them, 48.8% (40/82) discontinued use of corticosteroid completely. Minor drug-related adverse events were reported. The treatment effects of ADA were generally consistent in the three RCTs, and ADA reduced the risk of treatment failure by 43%-75%. CONCLUSION: The current review provided evidences that ADA might be a promising choice in reducing inflammatory activity, gaining VA, and sparing corticosteroid use with minor AEs when applied in treating non-infectious uveitis.

Dynamic MRI follow-up of radiation encephalopathy in the temporal lobe following nasopharyngeal carcinoma radiotherapy.

The natural course of radiation encephalopathy following nasopharyngeal carcinoma (NPC) radiotherapy remains poorly understood. The present study aimed to investigate the magnetic resonance imaging (MRI) characteristics and evolution of radiation encephalopathy. A series of 162 follow-up MRI examinations from 68 NPC patients with radiation encephalopathy in the temporal lobes were analyzed retrospectively. Each component of radiation encephalopathy was defined as follows: i) contrast enhanced lesions were enhanced lesions on contrast enhanced T1-weighted images (T1WI); ii) white matter lesions were lesions of homogeneous hyperintensity on T2-weighted images (T2WI) and hypointensity on T1WI; iii) cysts were round or oval well-defined lesions of hyperintensity on T2WI; iv) hemosiderin deposition were nodular or annular hypointense lesions with lower hypointense than normal white matter on both T1WI and T2WI; v) gray matter lesions were defined as disruption or erosion of hyperintensity in the cortex on T2WI. Contrast enhanced lesions, white matter lesions, gray matter lesions, cysts and hemosiderin deposition were detected in 105 (100.0%), 98 (93.3%), 94 (89.5%), 2 (1.7%) and 2 (1.7%) cases of the 105 initial diagnosed temporal lobe lesions. Contrast enhanced lesions were the most commonly observed, followed by white matter lesions, gray matter lesions, temporal lobe atrophy, cysts and hemosiderin deposition. In addition, 12 new lesions were identified during the follow-up, 4 of which presented as solid enhanced nodular lesions. Importantly, in 11 of the 117 (9.4%) affected temporal lobes, solid enhanced nodular lesions were observed to be the only initial abnormalities to occur. For those enhanced nodular lesions measuring <0.8 cm, no necrosis could be detected. On the contrary, all the contrast enhanced lesions measuring >2.0 cm exhibited a necrotic core. To the best of our knowledge, the present study revealed for the first time solid enhanced nodular lesions as the earliest MRI abnormalities of radiation encephalopathy following NPC radiotherapy.

MiR-4673 Modulates Paclitaxel-Induced Oxidative Stress and Loss of Mitochondrial Membrane Potential by Targeting 8-Oxoguanine-DNA Glycosylase-1.

BACKGROUND: Our previous study identified a novel microRNA, miR-4673, which is upregulated in A549 cells exposed to paclitaxel (PTX). In this study, we investigated the role of miR-4673 in PTX-induced cytotoxicity. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, apoptosis assay, 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide (JC-1) staining and 2',7'-Dichlorofluorescein (DCFH) staining were used to evaluate cell viability, apoptosis, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis and Luciferase reporter assay were used to explore whether 8-oxoguanine-DNA glycosylase-1 (OGG1) is a target gene of miR-4673. RESULTS: Enforced expression of miR-4673 decreased cell viability and increased PTX-induced apoptosis, MMP loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis, which was used to identify potential target of miR-4673, revealed a binding site of miR-4673 in 3'UTR of OGG1. Luciferase reporters assays showed that miR-4673 specifically binds to 'CUGUUGA' in 3'UTR of OGG1. Enforced expression of miR-4673 decreased accumulation of OGG1. In addition, silencing OGG1 enhanced inhibitory effects of PTX on apoptosis, MMP loss and ROS generation, which is similar to effects of miR-4673. Moreover, enforced expression of OGG1 compromised promoting effects of miR-4673 on PTX-induced apoptosis, MMP loss and ROS generation. CONCLUSION: miR-4673 modulates PTX-induced apoptosis, MMP loss and ROS generation by targeting OGG1.

miR-363-3p inhibits tumor growth by targeting PCNA in lung adenocarcinoma.

Increasing evidence suggests that microRNAs play key roles in lung cancer. Our previous study demonstrated that microRNA 363-3p (miR-363-3p) is downregulated in lung cancer tissues. In this study, we demonstrated that overexpression of miR-363-3p inhibits the proliferation and colony formation of A549 and H441 cells, while silencing of miR-363-3p has the converse effects. The anti-oncogenic function of miR-363-3p was verified in a mouse tumor xenograft model. Furthermore, cell cycle analysis showed miR-363-3p can induce S phase arrest by downregulating Cyclin-D1 and upregulating Cyclin-dependent kinase-2 in lung adenocarcinoma cells. Additionally, miR-363-3p enhances cell apoptosis, whereas miR-363-3p inhibitor prevents apoptosis and leads to downregulation of Bax and Bak expression. The anti-proliferative function of miR-363-3p toward lung cancer cells may be explained by its ability to inhibit the activation of the mTOR and ERK signaling pathways. Using target prediction software and luciferase reporter assays, we identified PCNA as a specific target of miR-363-3p. miR-363-3p can decreased the accumulation of endogenous PCNA in lung adenocarcinoma cells. Moreover, exogenous expression of PCNA relieve the inhibition of miR-363-3p on cell proliferation, colony formation and mTOR and ERK signaling pathways. Taken together, our data indicate that miR-363-3p suppresses tumor growth by targeting PCNA in lung adenocarcinoma.

Tanshinone IIA protects H9c2 cells from oxidative stress-induced cell death via microRNA-133 upregulation and Akt activation.

The aim of the present study was to investigate the cardioprotective effect of tanshinone IIA and the underlying molecular mechanisms. An in vitro model of oxidative stress injury was established in cardiac H9c2 cells, and the effects of tanshinone IIa were investigated using cell viability, reverse transcription-quantitative polymerase chain reaction and western blotting assays. The results demonstrated that tanshinone IIA protects H9c2 cells from H2O2-induced cell death in a concentration-dependent manner, via a mechanism involving microRNA-133 (miR-133), and that treatment with TIIA alone exerted no cytotoxic effects on H9c2. In order to further elucidate the mechanisms underlying the actions of TIIA, reverse transcription-quantitative polymease chain reaction and western blot analysis were performed. Reductions in miR-133 expression levels induced by increasing concentrations of H2O2 were reversed by treatment with tanshinone IIA. In addition, the inhibition of miR-133 by transfection with an miR-133 inhibitor abolished the cardioprotective effects of tanshinone IIA against H2O2-induced cell death. Furthermore, western blot analysis demonstrated that tanshinone IIA activated Akt kinase via the phosphorylation of serine 473. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway by pretreatment with the PI3K specific inhibitors wortmannin and LY294002 also eliminated the cardioprotective effects of tanshinone IIA against H2O2-induced cell death. Western blot analysis demonstrated that H2O2-induced reductions in B cell lymphoma 2 (Bcl-2) expression levels were reversed by tanshinone IIA. In addition, the effect of tanshinone IIA on Bcl-2 protein expression level in an oxidative environment was suppressed by a PI3K inhibitor, wortmannin, indicating that tanshinone IIA exerts cardioprotective effects against H2O2-induced cell death via the activation of the PI3K/Akt signal transduction pathway and the consequent upregulation of Bcl-2. In conclusion, the present study demonstrates that TIIA is able to protcet H9c2 cells from oxidative stress-induced cell death through signalling pathways involving miR-133 and Akt, and that tanshinone IIA is a promising natural cardioprotective agent.

Recurrence patterns in patients with high-grade glioma following temozolomide-based chemoradiotherapy.

There is currently no consensus regarding the optimal radiation volume for high-grade glioma (HGG). The brain volume irradiated is associated with the extent of radiation neurotoxicity. When reducing the treatment volume, the risk of geographic tumor miss should be considered. In such cases, the recurrence patterns and, particularly, the rate of marginal tumor recurrence, are important indices for determining the optimal radiation volume. In the present study, a smaller-target delineation protocol with limited margins was adopted. The postoperative enhancing tumor and resection cavity were defined as gross tumor volume (GTV); 1 and 2 cm were added to the GTV to create clinical target volume (CTV1 and CTV2), which received 60 and 54 Gy, respectively. At a median follow-up of 14 months, 54 HGG patients developed tumor recurrence. The median overall and progression-free survival were 14 and 10.5 months, respectively. A total of 34 patients developed central recurrence, 8 presented with in-field recurrence, 2 developed marginal recurrence, 2 had distant recurrence and 11 patients developed cerebrospinal fluid dissemination, 2 of whom developed central recurrence, with 1 patient simultaneously developing marginal recurrence. Local recurrence (central and in-field) was found to be the main recurrence pattern. As the rate of marginal recurrence was low (<5%), it appears that the smaller irradiated volume in the present study was appropriate. However, clinical trials investigating limited irradiation volume are required to validate our findings.