Coadministration of bedaquiline and pyrifazimine reduce exposure to toxic metabolite N-desmethyl bedaquiline

Background: A new, effective anti-tuberculosis (TB) regimen containing bedaquiline (BDQ) and pyrifazimine (TBI-166) has been recommended for a phase IIb clinical trial. Preclinical drug–drug interaction (DDI) studies of the combination of BDQ and TBI-166 have been designed to support future clinical trials. In this study, we investigated whether a DDI between BDQ and TBI-166 affects the pharmacokinetics of BDQ.Methods: We performed in vitro quantification of the fractional contributions of the fraction of drug metabolism by individual CYP enzymes (fm) of BDQ and the inhibition potency of key metabolic pathways of TBI-166. Furthermore, we conducted an in vivo steady-state pharmacokinetics study in a murine TB model and healthy BALB/c mice.Results: The in vitro fm value indicated that the CYP3A4 pathway contributed more than 75% to BDQ metabolism to N-desmethyl-bedaquiline (M2), and TBI-166 was a moderate (IC50 2.65 µM) potential CYP3A4 inhibitor. Coadministration of BDQ and TBI-166 greatly reduced exposure to metabolite M2 (AUC0-t 76310 vs 115704 h ng/mL, 66% of BDQ alone), whereas the exposure to BDQ and TBI-166 did not changed. The same trend was observed both in healthy and TB model mice. The plasma concentration of M2 decreased significantly after coadministration of BDQ and TBI-166 and decreased further during treatment in the TB model.Conclusions: In conclusion, our results showed that the combination of BDQ and TBI-166 significantly reduced exposure to the toxic metabolite M2 by inhibiting the activity of the CYP3A4 pathway. The potential safety and efficacy benefits demonstrated by the TB treatment highly suggest that coadministration of BDQ and TBI-166 should be studied further

Enzymatic catalysis for sustainable production of high omega‐3 triglyceride oil using imidazolium‐based ionic liquids

Two different fish oil preparations, namely triglycerides and ethyl esters containing, respectively, 30.02% and 74.38% of omega‐3 fatty acids, were employed as the substrates for transesterification. Catalyzed by immobilized lipase using imidazolium‐based ionic liquid systems, the total content of eicosapentaenoic acid (EPA ) and docosahexaenoic acid (DHA ) in the resulting triglyceride reached 63.60% when 4% hydrophobic ionic liquid was used, which was 11.74% higher than that of the triglyceride produced in a solvent‐free reaction system. The activation energy of the product (triglyceride‐type fish oil) was 173.64 KJ mol−1, which was not significantly different from that of the commercial ethyl ester‐type fish oil, so were the other thermal oxidative kinetic parameters. The kinetic parameters depicting the thermal and oxidative stability of the fish oil product provide the basis for industrial processing, storage, and applications

Treatment Outcomes of 257 Patients with Locoregionally Advanced Nasopharyngeal Carcinoma Treated with Nimotuzumab Plus Intensity-Modulated Radiotherapy with or without Chemotherapy: A Single-Institution Experience

OBJECTIVES: To report the long-term outcome and toxicity of locoregionally advanced nasopharyngeal carcinoma (LA NPC) treated with nimotuzumab (h-R3) plus intensity-modulated radiotherapy (IMRT) with or without chemotherapy. METHODS: From May 2008 to March 2014, 3022 newly histology-proven, nonmetastatic NPC patients were retrospectively reviewed; among them, 257 patients treated with h-R3 were enrolled in this study. The patients' age range was between 10 and 76 years. The distribution of patients by disease stage was 150 (58.4%) in stage III, 88 (34.2%) in stage IV A, and 19 (7.4%) in stage IV B. All the patients received the treatment of h-R3 plus IMRT, and from them, 239 cases were also treated with cisplatin-based chemotherapy. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of Radiation Therapy Oncology Group. The accumulated survival was calculated according to the Kaplan-Meier method. Log-rank test was used to compare the survival difference. Multivariate analysis was performed using Cox's proportional-hazard model. RESULTS: All 257 patients had completed combined treatment; 231 patients received h-R3 plus IMRT with induction chemotherapy (IC), while 26 patients received only h-R3 plus IMRT. With a median follow-up of 48 months (range, 13-75 months), the estimated 5-year local recurrence-free survival, regional recurrence-free survival, distant metastases-free survival, progression-free survival, and overall survival (OS) rates were 94.3%, 94.8%, 91.9%, 83.4%, and 86.2%, respectively. Univariate analysis showed that age, T stage, clinical stage, and IC were related with OS. Multivariate analysis indicated that T stage and IC were independent prognostic factors for OS. The incidence of grade 3 to 4 acute mucositis and leukocytopenia was 10.9% and 19.8%, respectively, with no cases of skin rash and infusion reaction. Xerostomia was the most common late complication, and the degree of dry mouth in most survivors was mild to moderate at the last follow-up time. CONCLUSION: h-R3 plus IMRT with or without chemotherapy showed promising outcomes in terms of locoregional control and survival without increasing the incidence of radiation-related toxicities for patients

Heterojunction solar cells with asymmetrically carrier-selective contact structure of molybdenum-oxide/silicon/magnesium-oxide

New functional materials that are constantly introduced into carrier-selective contacts (CSCs), which allow one type of carrier passing through while blocking the other type via energy band alignment at contact region, promote the fabrication of crystalline silicon (c-Si) solar cells towards low-temperature and dopant-free. Here, electron-beam-evaporated molybdenum oxide (MoOx) and magnesium oxide (MgOx) are directly deposited upon the front and rear surface of c-Si substrates, respectively, to form CSCs with asymmetric band offset for holes and electrons. Contact resistivity, passivation effect, interfacial structures and chemical states for both MoOx/c-Si and MgOx/c-Si are systematically characterized. Considering good carrier-selectivity at the front and the rear side, the optimum thickness in terms of contact resistivity and photovoltaic performance is 10 nm for MoOx and 1.5 nm for MgOx, respectively. Finally, an efficiency over 14% for the planar MoOx/c-Si/MgOx heterojunction solar cells is achieved, demonstrating huge economic potential in fabrication procedure over conventional high temperature diffused homojunction solar cells

Efficacy and Safety of Nimotuzumab Plus Radiotherapy With or Without Cisplatin-Based Chemotherapy in an Elderly Patient Subgroup (Aged 60 and Older) With Nasopharyngeal Carcinoma

OBJECTIVE: This study was conducted to assess the efficacy and safety of nimotuzumab combined with radiotherapy (RT) in elderly patients with nasopharyngeal carcinoma. MATERIALS AND METHODS: The clinical data of 75 nasopharyngeal carcinoma patients, who were initially treated with nimotuzumab combined with RT, were collected and retrospectively reviewed from December 2008 to April 2014. They were aged 60 to 81 years (median 64 years). The distribution of disease was stage II in 10 (13.3%), stage III in 33 (44.0%), and stage IV in 32 (42.7%). Among these patients, 59 cases received cisplatin-based chemotherapy. Survival outcomes and treatment toxicity were analyzed using IBM SPSS 19.0 software. RESULTS: With a median follow-up of 45 months (range, 13-78 months), the estimated 3-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), progression failure-free survival (PFS), and overall survival (OS) rates were 95.6%, 95.5%, 98.6%, 89.7%, and 89.2%, respectively. In the subgroup, 3-year OS rate in the patients with concurrent chemotherapy was 90.5% and 77.4% in patients without concurrent chemotherapy (Log-Rank = 1.795, P = .180). Univariate analysis showed that T stage and clinical stage were correlated with OS. Multivariate analysis indicated that age, T stage and tumor response at the end of treatment were independent prognosticators. Nine patients experienced grade 3 to 4 acute mucositis and 26 patients experienced grade 3-4 leukocytopenia, with no cases of skin rash and infusion reaction. Twelve patients developed mild liver function damage. No serious gastrointestinal or renal toxicities were observed. CONCLUSION: The efficacy of combined nimotuzumab with RT in elderly NPC patients was encouraging and the toxicities were accepted. In addition, nimotuzumab provides a better option for elderly patients who cannot be tolerate chemotherapy

An Artificial Sensory Neuron with Tactile Perceptual Learning

Sensory neurons within skin form an interface between the external physical reality and the inner tactile perception. This interface enables sensory information to be organized identified, and interpreted through perceptual learningthe process whereby the sensing abilities improve through experience. Here, an artificial sensory neuron that can integrate and differentiate the spatiotemporal features of touched patterns for recognition is shown. The system comprises sensing, transmitting, and processing components that are parallel to those found in a sensory neuron. A resistive pressure sensor converts pressure stimuli into electric signals, which are transmitted to a synaptic transistor through interfacial ionic/electronic coupling via a soft ionic conductor. Furthermore, the recognition error rate can be dramatically decreased from 44% to 0.4% by integrating with the machine learning method. This work represents a step toward the design and use of neuromorphic electronic skin with artificial intelligence for robotics and prosthetics