Aptasensor for Mycobacterium tuberculosis antigen MPT64 detection using anthraquinone derivative confined in ordered mesoporous carbon as a new redox nanoprobe.

Rapid and sensitive tuberculosis (TB) diagnoses remain big challenges to current detection tools. In this work, a sensitive electrochemical aptasensor was constructed for the determination of Mycobacterium tuberculosis antigen MPT64 using a new redox nanoprobe. We found that anthraquinone derivative, anthraquinone-2-carboxylic acid (AQCA), a redox mediator, could be confined in ordered mesoporous carbon material of CMK-3. Due to the large loading amount of AQCA, as well as the confined space and electron transfer promotion effect of CMK-3, the obtained AQCA/CMK-3 nanohybrid with mass ratio of 2:1 showed excellent electroactivity and was employed as a new redox nanoprobe for signal amplification for the first time. Additionally, urchin-like Ce-MOFs were used to load a large amount of deposited gold nanocrystals (dep-Au), leading to dense immobilization of capture probe. The proposed electrochemical aptasensor for MPT64 detection showed a good linear relationship in the range from 100 fg/mL to 10 ng/mL with a low detection limit of 67.6 fg/mL. Besides, the aptasensor was utilized to detect MTP64 in human serum samples for TB diagnosis and presented satisfactory results.

Association between risk stratification for pulmonary embolism and deep vein thrombosis of lower extremities.

BACKGROUND: The association of clinical risk factors, in particular deep vein thrombosis (DVT), with risk stratification for pulmonary embolism (PE) remains to be identified. We therefore aimed to establish the relationship between risk stratification of PE patients and DVT of lower extremities. METHODS: In this retrospective study, 93 out of 485 PE patients with uncompleted clinical data were excluded, resulting in 392 patients included for analysis. Based on the ESC criteria, 24, 171, and 197 patients were categorized into high (6.1%), intermediate (43.6%), and low risk (50.3%) subgroups, respectively. RESULTS: DVT was detected in 304 patients (77.6%). The incidence of DVT in patients with high and intermediate risk PE was much lower than in those patients with low risk PE (67.2% vs 87.8%, P < .0001). Further analyses of the 304 patients with DVT showed higher incidence of high and intermediate risk PE in patients with isolated distal DVT than proximal DVT (59.0% vs 39.1%, P = .005), with asymptomatic DVT than symptomatic DVT (63.0% vs 36.8%, P < .0001), and with bilateral DVT than unilateral DVT (54.5% vs 39.9%, P = .03). Stepwise logistic regression showed that symptomatic or asymptomatic DVT was an independent risk factor for risk stratification of PE patients with DVT (0.320, 95% confidence interval, 0.186-0.550). CONCLUSIONS: Patients with high and intermediate risk PE presented lower incidence of DVT compared with patients with low risk PE. In PE patients with comorbid DVT, asymptomatic DVT is an independent risk factor for high and intermediate risk of PE.

A serine in exon 11 determines the full transcriptional activity of TCF-4 in lung carcinoma cells.

Activation of T cell factor-4 (TCF-4) is causally linked to the development of lung carcinoma, while the mechanism of sequence-dependent TCF-4 activity is still obscure. Using reverse transcription-polymerase chain reaction (RT-PCR), here, we demonstrated that sequences of exon 11 in TCF-4 were present in lung carcinoma cells but not in normal lung epithelial cells. Loss of exon 11 in TCF-4 inhibited TCF-4-induced cell growth of lung carcinoma and prolonged the survival time of Lewis lung carcinoma (LLC) tumor-bearing mice. Mechanistically, loss of exon 11 in TCF-4 attenuated the binding activity between TCF-4 protein and its canonical binding site, inhibited TOP/FOP luciferase activity and suppressed mRNA expression of Wnt signaling targets. By performing truncated and site-directed mutations, we further demonstrated that the 16th amino acid serine in exon 11 was responsible for TCF-4-mediated Wnt signaling. In vivo experiments indicated that a mutation of the 16th amino acid serine in exon 11 of TCF-4 could mimic the anti-tumor effect of Wnt signaling inhibitor. Taken together, we identified a serine determining the transcriptional activity of TCF-4 in lung carcinoma cells, and sequencing of TCF-4 mRNA might be an effective strategy to evaluate the Wnt pathway activation and prognosis in lung cancer.

Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advanced Nonsmall-Cell Lung Cancer: A Meta-Analysis and Systemic Review.

Preclinical researches indicated a potential synergistic effect of taxanes-containing chemotherapy (TCC) and antiangiogenic agents (AAs) on the treatment of advanced nonsmall-cell lung cancer (NSCLC). The advantage of adding AA to TCC in the real world remains confusing. We summarized the current evidences from relevant phase II/III randomized controlled trials (RCTs) by performing this meta-analyses.Electronic databases were searched for eligible literatures. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using RevMan 5.2.A total of 14 phase II/III RCTs involving 9703 participants were included. Compared to standard TCC, the addition of AA was associated with the significant better OS (HR 0.92, 95% CI 0.87-0.97, P = 0.002), prolonged progression-free survival (HR 0.79, 95% CI 0.71-0.87, P < 0.00001), superior response rate (risk ratio [RR] 1.69, 95% CI 1.47-1.95, P < 0.0001), and disease control rate (RR 1.19, 95% CI 1.08-1.32, P < 0.00001). Subgroup analyses indicated that patient treated with monoclonal antibodies (HR 0.89, 95% CI 0.82-0.96, P = 0.02) as well as application in second-line (HR 0.91, 95% CI 0.85-0.96, P = 0.02) acquired significant OS improvement. Other clinical factors directing significant OS improvement by the combination strategy included nonsquamous cancer (P = 0.002), nonsmokers (P = 0.0005), and female (P = 0.02). Toxicities were greater but generally mild or moderate in the combination group, and were mostly manageable.In summary, the addition of AAs to TCC could improve prognosis of advanced NSCLC. Furthermore, proper selection of patient population and AAs is crucial for clinical trials design and clinical practice in the future.

The efficacy of combining antiangiogenic agents with chemotherapy for patients with advanced non-small cell lung cancer who failed first-line chemotherapy: a systematic review and meta-analysis.

BACKGROUND: The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients. METHODS: We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second-line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients. RESULTS: Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02). CONCLUSIONS: This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy.

Pharmacokinetics, metabolism, biodistribution, radiation dosimetry, and toxicology of (18)F-fluoroacetate ((18)F-FACE) in non-human primates.

INTRODUCTION: To facilitate the clinical translation of (18)F-fluoroacetate ((18)F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of (18)F-FACE were determined in non-human primates. METHODS: (18)F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with (18)F-FACE (165.4 ± 28.5 MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0-30 min post-injection and static whole-body PET imaging at 40, 100, and 170 min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of (18)F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of (18)F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of (18)F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans. RESULTS: The blood clearance of (18)F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of (18)F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that (18)F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180 min after the (18)F-FACE injection. The uptake of free (18)F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90-7.81 mSv from the administration of 185-370 MBq of (18)F-FACE. CONCLUSIONS: The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of (18)F-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of (18)F-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging.

Whole-body biodistribution kinetics, metabolism, and radiation dosimetry estimates of 18F-PEG6-IPQA in nonhuman primates.

UNLABELLED: We recently developed the radiotracer 4-[(3-iodophenyl)amino]-7-(2-[2-{2-(2-[2-{2-((18)F-fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide) ((18)F-PEG(6)-IPQA) for noninvasive detection of active mutant epidermal growth factor receptor kinase-expressing non-small cell lung cancer xenografts in rodents. In this study, we determined the pharmacokinetics, biodistribution, metabolism, and radiation dosimetry of (18)F-PEG(6)-IPQA in nonhuman primates. METHODS: Six rhesus macaques were injected intravenously with 141 ± 59.2 MBq of (18)F-PEG(6)-IPQA, and dynamic PET/CT images covering the thoracoabdominal area were acquired for 30 min, followed by whole-body static images at 60, 90, 120, and 180 min. Blood samples were obtained from each animal at several time points after radiotracer administration. Radiolabeled metabolites in blood and urine were analyzed using high-performance liquid chromatography. The (18)F-PEG(6)-IPQA pharmacokinetic and radiation dosimetry estimates were determined using volume-of-interest analysis of PET/CT image datasets and blood and urine time-activity data. RESULTS: (18)F-PEG(6)-IPQA exhibited rapid redistribution and was excreted via the hepatobiliary and urinary systems. (18)F-PEG(6) was the major radioactive metabolite. The critical organ was the gallbladder, with an average radiation-absorbed dose of 0.394 mSv/MBq. The other key organs with high radiation doses were the kidneys (0.0830 mSv/MBq), upper large intestine wall (0.0267 mSv/MBq), small intestine (0.0816 mSv/MBq), and liver (0.0429 mSv/MBq). Lung tissue exhibited low uptake of (18)F-PEG(6)-IPQA due to the low affinity of this radiotracer to wild-type epidermal growth factor receptor kinase. The effective dose was 0.0165 mSv/MBq. No evidence of acute cardiotoxicity or of acute or delayed systemic toxicity was observed. On the basis of our estimates, diagnostic dosages of (18)F-PEG(6)-IPQA up to 128 MBq (3.47 mCi) per injection should be safe for administration in the initial cohort of human patients in phase I clinical PET studies. CONCLUSION: The whole-body and individual organ radiation dosimetry characteristics and pharmacologic safety of diagnostic dosages of (18)F-PEG(6)-IPQA in nonhuman primates indicate that this radiotracer should be acceptable for PET/CT studies in human patients.