Sinomenine Attenuates Traumatic Spinal Cord Injury by Suppressing Oxidative Stress and Inflammation via Nrf2 Pathway.

Traumatic spinal cord injury (SCI) is a devastating condition with few efficacious drugs. Sinomenine, a bioactive alkaloid extracted from medicinal herb, has been used as a treatment of rheumatoid diseases. This present study explored the therapeutic effects of sinomenine on locomotor dysfunction and neuropathology in SCI. Our findings revealed that sinomenine mitigated neurological deficits and enhanced neuronal preservation, paralleled with a reduction of apoptosis. Also, sinomenine significantly reduced inflammatory cytokines and oxidative stress factors. We further examined erythroid-2-related factor 2 (Nrf2) nuclear translocation, which mainly controls the coordinated expression of important antioxidant and detoxification genes. An increase in Nrf2 translocation from cytoplasm to nucleus and Nrf2-mediated transactivation was observed after sinomenine administration. Knocking down Nrf2 by siRNA could counteract sinomenine-mediated anti-oxidant stress and anti-inflammation following H2O2-stimulated and LPS-stimulated PC12 cells. Together, our findings indicated that sinomenine has the potential to be an effective therapeutic agent for SCI by inhibiting inflammation and oxidative stress via Nrf2 activation.

Vemurafenib in Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma: an open-label, multicenter phase I study.

BACKGROUND: Melanoma is a rare, deadly disease without effective treatment options in China. Vemurafenib is a selective inhibitor of oncogenic BRAFV600 kinase approved in more than 90 countries, based on results obtained primarily in Caucasian patients. Limited data are available regarding the efficacy and safety of vemurafenib in Asian patients. METHODS: This phase I study investigated the pharmacokinetics, efficacy, and tolerability of vemurafenib (960 mg twice daily) in Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. The study included two cohorts: a pharmacokinetic cohort (n = 20) and an expansion cohort (n = 26). RESULTS: After 21 days of dosing, vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure over the dosing period. Confirmed best overall response rate was 52.2% (95% CI 37.0-67.1%). Median progression-free survival was 8.3 months (95% CI 5.7-10.9%); median overall survival was 13.5 months (95% CI 12.2%-not estimable). The most common adverse events were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin level increase, melanocytic nevus, and alopecia. A total of nine grade 3 or 4 adverse events were reported in seven patients (15.2%). CONCLUSION: Overall, vemurafenib showed a favorable benefit-risk profile among Chinese patients. Pharmacokinetics, safety, and efficacy were generally consistent with those reported in Caucasian patients. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT01910181 . Registered 29 July 2013, prospectively registered.

BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma.

BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.

Intramedullary and extramedullary fixations for the treatment of unstable femoral intertrochanteric fractures: a meta-analysis of prospective randomized controlled trials.

PURPOSE: Intramedullary and extramedullary fixation methods are widely used to treat unstable femoral intertrochanteric fractures, but the optimal surgical method remains controversial. The aim of this study was to estimate the outcomes of intramedullary fixation versus extramedullary fixation in treating unstable femoral intertrochanteric fractures. METHODS: Electronic literature databases were used for searching including MEDLINE (Ovid interface), EMBASE (Ovid interface) and the Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Online Library) (up to March 30, 2016). Only human studies, which were designed as randomized controlled clinical trials, were included. Two authors independently evaluated the quality of original literature and extracted data from eligible literature. RESULTS: Eleven randomized controlled trials involving 1,543 patients were included. Intramedullary fixation was significantly better in functional scores (SMD 0.43, 95 % CI 0.14-0.73, P = 0.004) and had less blood loss (SMD -0.96, 95 % CI -1.77 to -0.11, P = 0.03) in contrast with extramedullary fixation. No obvious discrepancies were found in adverse events, operative time, blood transfusion, and hospital stay between intramedullary and extramedullary fixations. CONCLUSION: Our meta-analysis of 11 prospective randomized controlled trials suggested: no obvious discrepancies were found in adverse events, operative time, blood transfusion, and hospital stay between intramedullary and extramedullary fixations. Given the better results of intramedullary fixation in terms of functional scores and blood loss, we recommend the intramedullary fixation technique in treating unstable femoral intertrochanteric fractures. Large multi-center RCTs, which focused on unstable femoral intertrochanteric fractures, are needed to evaluate the efficiency of alternative internal fixation strategies in the future.

Incidence and related clinical factors of falls among older Chinese veterans in military communities: a prospective study.

[Purpose] The aim of this study was to determine fall incidence and explore clinical factors of falls among older Chinese veterans in military communities. [Subjects and Methods] We carried out a 12-month prospective study among 13 military communities in Beijing, China. Fall events were obtained by self-report to military community liaisons and monthly telephone interviews by researchers. [Results] Among the final sample of 447 older veterans, 86 fell once, 25 fell twice or more, and 152 falls occurred altogether. The incidence of falls and fallers were 342/1,000 person-years and 249/1,000 person-years. In Cox regression models, independent clinical factors associated with falls were visual acuity (RR=0.47), stroke (RR=2.43), lumbar diseases (RR=1.73), sedatives (RR=1.80), fall history in the past 6 months (RR=2.77), multiple chronic diseases (RR=1.53), multiple medications (RR=1.34), and five-repetition sit-to-stand test score (RR=1.41). Hearing acuity was close to being statistically significant. [Conclusion] The incidences of falls and fallers among older Chinese veterans were lower than those of Hong Kong and western countries. The clinical risk factors of falls were poor senses, stroke, lumbar diseases, taking sedatives, fall history in the past 6 months, having multiple chronic diseases, taking multiple medications, and poor physical function. The preventive strategies targeting the above risk factors are very significant for reducing falls.

CAR-NK cells for cancer immunotherapy: recent advances and future directions.

Natural Killer (NK) cells, intrinsic to the innate immune system, are pivotal in combating cancer due to their independent cytotoxic capabilities in antitumor immune response. Unlike predominant treatments that target T cell immunity, the limited success of T cell immunotherapy emphasizes the urgency for innovative approaches, with a spotlight on harnessing the potential of NK cells. Despite tumors adapting mechanisms to evade NK cell-induced cytotoxicity, there is optimism surrounding Chimeric Antigen Receptor (CAR) NK cells. This comprehensive review delves into the foundational features and recent breakthroughs in comprehending the dynamics of NK cells within the tumor microenvironment. It critically evaluates the potential applications and challenges associated with emerging CAR-NK cell therapeutic strategies, positioning them as promising tools in the evolving landscape of precision medicine. As research progresses, the unique attributes of CAR-NK cells offer a new avenue for therapeutic interventions, paving the way for a more effective and precise approach to cancer treatment.

STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance.

Background: Cervical cancer poses a significant global threat to women's health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of the disease. Given the immunosuppressive microenvironment in cervical cancer, it is imperative to explore novel perspectives. In this regard, STING agonists have emerged as promising candidates. Methods: The expression profiles and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Prognostic analysis of STING downstream genes (CCL5, CXCL9, CXCL10) and immune infiltration analysis were conducted using Kaplan-Meier Plotter, ESTIMATE, and deconvo_CIBERSOR. Single-cell RNA-seq (scRNA-seq) analysis was conducted to evaluate the potential of MSA-2 in cervical cancer treatment employing SingleR, chi-squared test, and Gene Set Enrichment Analysis (GSEA). Cellular interaction analysis utilized the CellChat package to assess the potentiation of cellular interaction following MSA-2 administration. Murine tumor models involving U14 and TC-1, were conducted, and the IF of tissue was subsequently conducted to assess the tumor microenvironment status after treatment. Results: Prognosis in cervical cancer correlated with elevated expression of STING downstream genes, indicating prolonged survival and reduced recurrence. These genes positively correlated with immune infiltration, influencing stromal scores, immune scores, and estimate scores. Specific immune cell populations, including CD8+ T cells, M1-type macrophages, NK cells, and T follicular helper cells, were associated with STING downstream genes. scRNA-seq in a classic immune-excluded model revealed that MSA-2 exerts priming and activating functions on vital components within TME, and intensifies their intercellular communications. The in vivo assay ultimately demonstrated that MSA-2, either as a standalone treatment or in combination with anti-PD-1, effectively suppressed the growth of subcutaneous cervical tumors. Moreover, the combination strategy significantly augmented efficacy compared to anti-PD-1 monotherapy by eliciting a robust antitumor immune response. Conclusion: This study highlights the pivotal role of the STING pathway and the potential of MSA-2 in reshaping the immune microenvironment in cervical cancer. Combining MSA-2 with immune checkpoint inhibitors presents a transformative approach, holding promise for improved prognosis. Further investigations are warranted to explore the broader immune landscape and potential long-term effects of MSA-2 in cervical cancer treatment.

Effects of a rainwater harvesting system on the soil water, heat and growth of apricot in rain-fed orchards on the Loess Plateau.

Rainwater is the main water source in arid and semiarid areas of the Loess Plateau, where rainfall is generally insufficient, ineffective and underutilized during the growing season. Thus, improving rainwater utilization efficiency is essential for sustainable agricultural development. A new system composed of rainwater harvesting, an infiltrator bucket with multiple holes and mulching (RHM), was designed to maintain soil moisture at a proper level in rain-fed orchards in arid and semiarid areas of the Loess Region of China. However, there is a lack of clarity on the effectiveness of RHM. In this study, changes in the soil environment and the growth and physiology of apricot trees were monitored via two treatments: (1) Rain-harvesting irrigation system (RHM) treatment and (2) traditional orchard treatment (CK) as a baseline. The results showed that (1) RHM could effectively improve soil water storage at depths of 0-45 cm and at a horizontal distance of 40 cm from the trunk. For the 1.4 mm light rain event, the soil water content increased by 6.3-12%, and for the two moderate rains, the soil water content increased by 12-25%. The change in the soil relative water content predicted by the LSTM model is consistent with the overall trend of the measured value and gradually decreases, and the prediction accuracy is high, with an error of 0.65. (2) The average soil temperatures at 5 cm, 20 cm and 40 cm under RHM were 17.0% (2.4 °C), 13.6% (1.9 °C) and 7.5% (1 °C) greater than those under CK, respectively. (3) Compared with the control treatment, RHM improved the growth and WUEL of apricot trees. The results highlighted the efficiency of the RHM system in enhancing the soil environment and regulating the growth and physiology of apricot trees, which has greater popularization value in arid and semiarid areas.

Determinants and Assembly Mechanism of Bacterial Community Structure in Ningxia Section of the Yellow River.

The Yellow River is a valuable resource in the Ningxia Hui Autonomous Region and plays a vital role in local human activities and biodiversity. Bacteria are a crucial component of river ecosystems, but the driving factors and assembly mechanisms of bacterial community structure in this region remain unclear. Herein, we documented the bacterial community composition, determinants, co-occurrence pattern, and assembly mechanism for surface water and sediment. In comparison to sediment, the bacterioplankton community showed significant seasonal variation, as well as less diversity and abundance. The network topology parameters indicated that the sediment bacterial network was more stable than water, but the bacterioplankton network had higher connectivity. In this lotic ecosystem, CODMn, Chl a, and pH affected the structure of the bacterioplankton community, while TP was the primary factor influencing the structure of the sediment bacterial community. The combined results of the neutral community model and the phylogenetic null model indicate that Bacterial communities in both habitats were mainly affected by stochastic processes, with ecological processes dominated by ecological drift for bacterioplankton and dispersal limitation for sediment bacteria. These results provide essential insights into future research on microbial ecology, environmental monitoring, and classified management in the Ningxia section of the Yellow River.

Eres-UNet++: Liver CT image segmentation based on high-efficiency channel attention and Res-UNet+.

Computerized tomography (CT) is of great significance for the localization and diagnosis of liver cancer. Many scholars have recently applied deep learning methods to segment CT images of liver and liver tumors. Unlike natural images, medical image segmentation is usually more challenging due to its nature. Aiming at the problem of blurry boundaries and complex gradients of liver tumor images, a deep supervision network based on the combination of high-efficiency channel attention and Res-UNet++ (ECA residual UNet++) is proposed for liver CT image segmentation, enabling fully automated end-to-end segmentation of the network. In this paper, the UNet++ structure is selected as the baseline. The residual block feature encoder based on context awareness enhances the feature extraction ability and solves the problem of deep network degradation. The introduction of an efficient attention module combines the depth of the feature map with spatial information to alleviate the uneven sample distribution impact; Use DiceLoss to replace the cross-entropy loss function to optimize network parameters. The liver and liver tumor segmentation accuracy on the LITS dataset was 95.8% and 89.3%, respectively. The results show that compared with other algorithms, the method proposed in this paper achieves a good segmentation performance, which has specific reference significance for computer-assisted diagnosis and treatment to attain fine segmentation of liver and liver tumors.

Oleanen induces apoptosis of cervical cancer cells by up-regulation of Bim.

OBJECTIVE: Plants belonging to the genus Celastrus exhibit antitumor activity and the ability to reverse multidrug resistance in tumor cells; however, it remains unclear whether the compound oleanen from Celastrus hypoleucus also exhibits antitumor activity. The objective of this study was to explore the inhibitory effect of 12-oleanene-3ß, 6α-diol (oleanen) on the proliferation of cervical cancer HeLa cells in vitro, as well as its relative mechanism. METHODS: HeLa cells were treated with different concentrations of oleanen for different times. Cell proliferation was determined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay. Cell apoptosis was evaluated by flow cytometry and caspases activities assay. The expression of several proapoptotic proteins belonging to the Bcl-2 family, such as Bax, Bim, and Bad, was detected by Western blot. RESULTS: Oleanen mainly inhibited the proliferation of HeLa cells at the G0 to G1 and G2 to M phases, and the IC50 of oleanen for cells was significantly higher at 24 hours compared to 48 hours (17.45 ± 3.71 vs 9.02 ± 0.83 µg/mL, respectively; P < 0.05). The significant increase in activity of caspase 3/7, caspase 6 in oleanen-treated HeLa cells indicated that oleanen promoted the apoptosis of HeLa cells. The activity of caspase 9 representing the endogenous apoptotic pathways also increased obviously in oleanen treatment. Furthermore, the increase in the expression of Bim was the most significant among the Bcl-2 family after oleanen treatment. CONCLUSION: Oleanen up-regulates the expression of Bim and other proapoptotic molecules to activate the endogenous apoptosis pathway, thus promoting apoptosis and inhibiting proliferation of human cervical cancer HeLa cells in vitro.

[Characteristics of soil microbial communities in different restoration models in the ecological immigrants' emigration area in southern Ningxia, China]. / 宁夏南部生态移民迁出区不同恢复模式土壤微生物群落特征.

To reveal the effects of plantations on soil microbial environment,the composition and diversity of soil fungi and bacterial communities in five restoration models (Robinia pseudoacacia, Populus hopeiensis, Pinus tabuliformis, Picea crassifolia, natural restoration) in the mountainous area of southern Ningxia were compared by using high-throughput sequencing technology. The correlation between soil physical-chemical properties and dominant microbial groups was analyzed. The results showed that: 1) Dominant fungi in different restoration models were Ascomycota, Basidiomycota, Mortierellomycota, and unclassified fungi, which accounted for 90% of total fungal community. The dominant soil bacteria were Actinobacteria, Proteobacteria, Acidobacteriota, Chloroflexi, and other bacteria, accounting for more than 80% of total bacterial community. 2) The diversity of soil fungi in P. tabuliformis forest was the highest, with Shannon index, and Simpson index being 3.72±0.37 and 0.07±0.04, respectively. The richness of fungi in naturally restored forest land was the highest, with Ace and Chao1 index of 708.19±137.25 and 706.26±125.34, respectively. The bacterial diversity and richness of species in P. tabuliformis forest land was the highest. The Shannon, Simpson, Ace and Chao1 indices were 6.57±0.04, 0.004±0.00, 3439.81±41.67, 3463.14±32.16, respectively. 3) The fungus with significant difference among restoration models were Solicoccozyma, Cladosporium, and Alternaria. Bacteria from Norank_f_67-14, Rubrobacter_f_Rubrobacteraceae, Sphingomonas_f_Sphingomonadaceae had significant difference among restoration models. 4) The RDA ordination of the dominant microbial flora and soil physical-chemical properties showed that soil bulk density (BD), carbon to nitrogen ratio (C/N), and pH were the major factors affecting the dominant fungal flora. BD, nitrogen to phosphorus ratio (N/P), total phosphorus (TP), and total carbon (TC) were the main factors affecting the dominant bacterial flora. In general, the difference of composition and diversity in the fungal community of different restoration models was higher than that of the bacterial community, indicating that the fungal communities were more sensitive to the changes of tree species and soil environment than bacterial communities. Our results could provide the theoretical foundation for vegetation restoration measures and the maintenance of ecosystem function stability in southern Ningxia.

Evaluation of 5-aminolevulinic acid-mediated photodynamic therapy on cervical low-grade squamous intraepithelial lesions with high-risk HPV infection.

BACKGROUND: The treatment options for low-grade squamous intraepithelial neoplasia (LSIL) of the cervix with high-risk HPV infection have not been standardized. Studies show that photodynamic therapy (PDT) mediated by 5-aminolevulinic acid (ALA-PDT) might be effective. In this retrospective study, the clinical efficacy and safety of ALA-PDT in the treatment of LSIL were evaluated. METHODS: ALA-PDT was performed in 55 LSIL patients aged 21-45 years who also showed high-risk HPV infection and cervical ectropion. HPV test, cytology, colposcopy and pathology were examined before and after treatment. Meanwhile, PDT-related symptoms and adverse reactions were also reviewed. RESULTS: At 6-month follow-up after PDT, except for 5 patients who showed the persistence of LSIL lesions, the pathological regression ratio of 90.1% (50/55) was achieved. No HPV-DNA was detected in exfoliated cervical cells in 81.8% (45/55) patients. Among them, the HPV clearance ratio of I Degree cervical ectropion was 96.2%, significantly higher than that of II Degree (70.8%) and III Degree (60%). Significant shrunk of cervical ectropion and reduction of vaginal secretions after PDT were seen in 78.0% patients. CONCLUSION: ALA-PDT is a safe and effective therapeutic option for patients of reproductive age who suffer from LSIL with high-risk HPV infection and cervical ectropion.

A Preliminary Study of Bacterioplankton Community Structure in the Taiyangshan Wetland in Ningxia and Its Driving Factors.

The Taiyangshan Wetland, a valuable wetland resource in the arid zone of central Ningxia, is critical for flood storage and drought resistance, climate regulation, and biodiversity protection. Nevertheless, the community structure and diversity of bacterioplankton in the Taiyangshan Wetland remains unclear. High-throughput sequencing was used to analyze the differences in bacterioplankton structure and major determinants in the Taiyangshan Wetland from April to October 2020. The composition and diversity of the bacterioplankton community varied significantly in different sampling periods but showed negligible differences across lake regions. Meanwhile, the relative abundances of bacterioplankton Bacteroidetes, Actinobacteria, Firmicutes, Chloroflexi, Tenericutes, Epsilonbacteraeota, and Patescibacteria were significantly different in different sampling periods, while the relative abundances of Cyanobacteria in different lake regions were quite different. Network analysis revealed that the topological attributes of co-occurrence pattern networks of bacterioplankton were high, and bacterioplankton community compositions were complicated in the month of July. A mantel test revealed that the bacterioplankton community in the entire wetland was affected by water temperature, electrical conductivity, dissolved oxygen, salinity, total nitrogen, ammonia nitrogen, chemical oxygen demand, fluoride, and sulfate. The bacterioplankton community structure was affected by ten environmental parameters (e.g., water temperature, dissolved oxygen, salinity, and permanganate index) in April, while the bacterioplankton community was only related to 1~2 environmental parameters in July and October. The bacterioplankton community structure in Lake Region IV was related to seven environmental parameters, including dissolved oxygen, pH, total nitrogen, and chemical oxygen demand, whereas the bacterioplankton community structures in the other three lake regions were related to two environmental parameters. This study facilitates the understanding of the bacterioplankton community in wetlands in arid areas and provides references to the evaluation of aquatic ecological management of the Taiyangshan Wetland.

Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose of Emicizumab in Healthy Chinese Subjects.

This phase 1, open-label, single-center study evaluated the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of single-dose emicizumab in healthy Chinese males. Overall, 16 subjects received a single subcutaneous dose of 1-mg/kg emicizumab. Blood samples were obtained before dosing on day 1 and at regular intervals over 16 weeks after dosing for PK evaluation. A single 1-mg/kg subcutaneous dose of emicizumab was safe and well tolerated in healthy Chinese male subjects in the study. Mean (± standard deviation) area under the concentration-time curve from time 0 to infinity and maximum concentration were 287 ± 74.2 µg⋅d/mL and 7.11 ± 1.77 µg/mL, respectively, with a terminal half-life of 26.7 (±4.3) days. Emicizumab administration did not show significant impact on pharmacodynamic markers tested, which mostly remained stable throughout the study. One subject tested positive for antidrug antibody, with no impact on his PK or safety profile. Compared with results from healthy Japanese and Caucasian subjects receiving the same dose in previous clinical trials, the current results further indicated the absence of difference of emicizumab PK profile across Chinese, Japanese, and Caucasian subjects, validating the use of similar therapeutic doses in Asian and non-Asian populations.

Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the Steady-State Pharmacokinetics of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAFV600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.

Proliferation suppression and apoptosis of ovarian carcinoma cells induced by small interfering RNA against vascular endothelial growth factor.

AIM: The aim of this study was to investigate whether RNA interference (RNAi) targeting vascular endothelial growth factor (VEGF) could inhibit the proliferation and induce apoptosis of ovarian carcinoma cells. METHODS: Human epithelial ovarian carcinoma cell line CaoV3 was transfected with VEGF-targeted small interfering RNA (siRNA) for 48 h. The down-regulation of VEGF expression was determined by real-time polymerase chain reaction and Western blot. The proliferation of CaoV3 cells was detected by a colorimetric BrdU assay. Caspase-3 activity and TUNEL assay were also detected to study the apoptosis of ovarian carcinoma cells induced by VEGF siRNA. The protein levels of survivin, MMP2 and MMP9 were measured by Western blot. RESULTS: mRNA and protein of VEGF were significantly down-regulated by VEGF siRNA. Down-regulation of VEGF expression dramatically suppressed the proliferation of CaoV3 cells, and increased the Caspase-3 activity. Nearly 100% of cells indicated TUNEL-positive. The expression of anti-apoptotic protein survivin was decreased, and the invasive related protein MMP2 and MMP9 were also significantly reduced by VEGF siRNA. CONCLUSION: Our study implied that siRNA targeting VEGF could effectively inhibit cell proliferation, induce cell apoptosis, and decrease the cell invasive potential. These findings suggest that the RNAi approach targeting VEGF may be an effective therapeutic strategy for ovarian cancer.

Simultaneous removal of NO(x) and SO2 in exhausted gas through landfill leachate.

Simultaneous removal of NO(x) and SO2 from exhausted gas were investigated by studying co-culture of sulfate reducing bacteria and anaerobic denitrifying bacteria, separated from landfill leachate. When H2S, generated by sulfate reducing bacteria was chosen as the sole electron donor for anaerobic denitrifying bacteria, the co-culture system demonstrated a faster NO removal rate, higher stability and better permanence. When the feed gas flow rates of N2 and SO2 were maintained constant at 0.1 m3/h and 16 ml/min respectively, the maximum NO-removal rate could be achieved at over 92% with NO feed gas kept between 2-6 ml/min, while the SO2 removal rate was always above 95%. Long-term continuous removal of NO exhibited an evident periodicity of five days, however, the fluctuation range of NO-removal was decreasing. Moreover, the decrease of the gas flow rate and the increase in NO inlet concentration could contribute to a higher NO- removal rate.

Absolute Bioavailability of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAFV600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14 C-labeled vemurafenib in patients with BRAFV600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14 C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14 C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUCτ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC0-inf ) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment-emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade-4 anaphylactic reaction occurring during infusion of 14 C-labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Malignancies.

This phase 1 open-label, multicenter, 3-period, fixed-sequence study evaluated the effect of multiple doses of vemurafenib on the pharmacokinetics of 1 dose of tizanidine, a probe CYP1A2 substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Patients received 1 dose of tizanidine 2 mg on day 1 (period A), vemurafenib 960 mg twice daily on days 2-21 (period B), and 1 dose of tizanidine 2 mg and vemurafenib 960 mg twice daily on day 22 (period C). Log-transformed area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) values for tizanidine in 16 patients were compared between periods A (tizanidine alone) and C (tizanidine plus vemurafenib) using an analysis of variance model. Multiple doses of vemurafenib increased plasma exposure of 1 dose of tizanidine, with geometric mean ratios (period C/period A) for Cmax , AUCinf , and AUClast of 2.15 (90%CI, 1.71-2.71), 4.22 (90%CI, 3.37-5.28), and 4.74 (90%CI, 3.55-6.33), respectively; 90%CIs were all outside predefined limits for lack of drug-drug interaction (0.82-1.22). This study confirmed vemurafenib as a moderate inhibitor of CYP1A2 in vivo, with a statistically significant drug-drug interaction with tizanidine. Caution should be exercised when dosing vemurafenib concurrently with CYP1A2 substrates.