Publications by authors named "Xufang Wang"

28 Publications

  • Page 1 of 1

On the Optimal Lawful Intercept Access Points Placement Problem in Hybrid Software-Defined Networks.

Sensors (Basel) 2021 Jan 9;21(2). Epub 2021 Jan 9.

Fujian Provincial Engineering Technology Research Center of Photoelectric Sensing Application, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou 350007, China.

For the law enforcement agencies, lawful interception is still one of the main means to intercept a suspect or address most illegal actions. Due to its centralized management, however, it is easy to implement in traditional networks, but the cost is high. In view of this restriction, this paper aims to exploit software-defined network (SDN) technology to contribute to the next generation of intelligent lawful interception technology, i.e., to optimize the deployment of intercept access points (IAPs) in hybrid software-defined networks where both SDN nodes and non-SDN nodes exist simultaneously. In order to deploy IAPs, this paper puts forward an improved equal-cost multi-path shortest path algorithm and accordingly proposes three SDN interception models: T interception model, ECMP-T interception model and Fermat-point interception model. Considering the location relevance of all intercepted targets and the operation and maintenance cost of operators from the global perspective, by the way, we further propose a restrictive minimum vertex cover algorithm (RMVCA) in hybrid SDN. Implementing different SDN interception algorithms based RMVCA in real-world topologies, we can reasonably deploy the best intercept access point and intercept the whole hybrid SDN with the least SDN nodes, as well as significantly optimize the deployment efficiency of IAPs and improve the intercept link coverage in hybrid SDN, contributing to the implementation of lawful interception.
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http://dx.doi.org/10.3390/s21020428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827824PMC
January 2021

Adaptive Residual Weighted -Nearest Neighbor Fingerprint Positioning Algorithm Based on Visible Light Communication.

Sensors (Basel) 2020 Aug 8;20(16). Epub 2020 Aug 8.

Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou 350007, China.

The weighted -nearest neighbor (WKNN) algorithm is a commonly used fingerprint positioning, the difficulty of which lies in how to optimize the value of to obtain the minimum positioning error. In this paper, we propose an adaptive residual weighted -nearest neighbor (ARWKNN) fingerprint positioning algorithm based on visible light communication. Firstly, the target matches the fingerprints according to the received signal strength indication (RSSI) vector. Secondly, is a dynamic value according to the matched RSSI residual. Simulation results show the ARWKNN algorithm presents a reduced average positioning error when compared with random forest (81.82%), extreme learning machine (83.93%), artificial neural network (86.06%), grid-independent least square (60.15%), self-adaptive WKNN (43.84%), WKNN (47.81%), and KNN (73.36%). These results were obtained when the signal-to-noise ratio was set to 20 dB, and Manhattan distance was used in a two-dimensional (2-D) space. The ARWKNN algorithm based on Clark distance and minimum maximum distance metrics produces the minimum average positioning error in 2-D and 3-D, respectively. Compared with self-adaptive WKNN (SAWKNN), WKNN and KNN algorithms, the ARWKNN algorithm achieves a significant reduction in the average positioning error while maintaining similar algorithm complexity.
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http://dx.doi.org/10.3390/s20164432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471980PMC
August 2020

Effect of astragaloside IV and the role of nuclear receptor RXRα in human peritoneal mesothelial cells in high glucose‑based peritoneal dialysis fluids.

Mol Med Rep 2019 Oct 22;20(4):3829-3839. Epub 2019 Aug 22.

Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China.

Peritoneal fibrosis is a serious complication that can occur during peritoneal dialysis (PD), which is primarily caused by damage to peritoneal mesothelial cells (PMCs). The onset of peritoneal fibrosis is delayed or inhibited by promoting PMC survival and inhibiting PMC epithelial‑to‑mesenchymal transition (EMT). In the present study, the effect of astragaloside IV and the role of the nuclear receptor retinoid X receptor‑α (RXRα) in PMCs in high glucose‑based PD fluids was investigated. Human PMC HMrSV5 cells were transfected with RXRα short hairpin RNA (shRNA), or an empty vector, and then treated with PD fluids and astragaloside IV. Cell viability, apoptosis and EMT were examined using the Cell Counting Kit‑8 assay and flow cytometry, and by determining the levels of caspase‑3, E‑cadherin and α‑smooth muscle actin (α‑SMA) via western blot analysis. Cell viability and apoptosis were increased, as were the levels of E‑cadherin in HMrSV5 cells following treatment with PD fluid. The protein levels of α‑SMA and caspase‑3 were increased by treatment with PD fluid. Exposure to astragaloside IV inhibited these changes; however, astragaloside IV did not change cell viability, apoptosis, E‑cadherin or α‑SMA levels in HMrSV5 cells under normal conditions. Transfection of HMrSV5 cells with RXRα shRNA resulted in decreased viability and E‑cadherin expression, and increased apoptosis and α‑SMA levels, in HMrSV5 cells treated with PD fluids and co‑treated with astragaloside IV or vehicle. These results suggested that astragaloside IV increased cell viability, and inhibited apoptosis and EMT in PMCs in PD fluids, but did not affect these properties of PMCs under normal condition. Thus, the present study suggested that RXRα is involved in maintaining viability, inhibiting apoptosis and reducing EMT of PMCs in PD fluid.
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http://dx.doi.org/10.3892/mmr.2019.10604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755149PMC
October 2019

Vascular endothelial growth factor over-expressed mesenchymal stem cells-conditioned media ameliorate palmitate-induced diabetic endothelial dysfunction through PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathway.

Biomed Pharmacother 2018 Oct 11;106:491-498. Epub 2018 Jul 11.

School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. Electronic address:

In the pathogenesis of diabetes mellitus (DM), islet microvasculares are severely damaged due to glucolipotoxicity and other reasons. Vascular endothelial growth factor (VEGF) is an indispensable and specific angiogenic factor in the pathogenesis and treatment of diabetic islet microvascular disease. Mesenchymal stem cells (MSCs) are regarded as a promising treatment of diabetes because of their immunosuppressive effect and multipotential differentiation potency. In this study, we tested whether MSCs over-expressing VEGF conditioned medium (MSC-VEGF-CM) could ameliorate pancreatic islet endothelial cells (MS-1) dysfunction induced by a common diabetic inducer palmitate (PA). We found that cell survival and migration were restrained by PA and partly repaired by the pro-protected of MSC-VEGF-CM. Meanwhile, PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathways were also up-regulated. Though apoptosis-related proteins, caspase-3 and caspase-9, had no significantly suppressed between MSC-VEGF-CM and MSC-CM alone, the expression levels of vascular surface factors such as CD31, VE-cadherin, occludin and ICAM-1, were remarkably up-regulated by the pro-protected of MSC-VEGF-CM. Our data suggested that MSC-VEGF-CM had therapeutic effect on the PA-induced dysfunction through the re-activation of PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathways.
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http://dx.doi.org/10.1016/j.biopha.2018.06.129DOI Listing
October 2018

An Indirect Comparison of Everolimus Versus Axitinib in US Patients With Advanced Renal Cell Carcinoma in Whom Prior Sunitinib Therapy Failed.

Clin Ther 2015 Oct 22. Epub 2015 Oct 22.

LASER Analytica, New York, New York. Electronic address:

Purpose: The purpose of this study was to perform a weight-adjusted indirect comparison to approximate the relative efficacy of everolimus versus axitinib among patients with second-line metastatic renal cell carcinoma in whom sunitinib therapy previously failed.

Methods: Individual patient data from the RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) Phase III clinical trial provided information for patients taking everolimus. Summary baseline clinical and demographic characteristics and progression-free survival (PFS) outcomes were available for patients taking axitinib who were included in the AXIS (axitinib versus sorafenib) Phase III clinical trial. A Bayesian latent class mixture model differentiating responders and nonresponders and with imbedded Weibull regression on PFS was used to identify sex, Memorial Sloan-Kettering Cancer Center risk score, and time receiving prior sunitinib therapy as prognostic factors for PFS based on posterior probability >95%. Patients taking everolimus were weighted up or down based on their combination of prognostic variables. Weights were calculated by dividing the proportion of patients observed in AXIS for a given characteristic by the proportion observed in RECORD-1 and taking the product of the values derived for all three weighting variables considered. Weighted PFS distributions were derived with bootstrapped 95% CIs and compared with those reported for the AXIS trial.

Findings: After weighting, distributions of the 3 key baseline characteristics were more closely aligned between the 2 studies; however, some differences remained. A slightly lower rate of poor-risk patients was evident in RECORD-1 (30%) versus AXIS (36%), and a 9% lower proportion of males was observed in the everolimus group compared with the axitinib group. Distributions of time receiving prior sunitinib therapy were almost equivalent between the treatment arms. A median PFS of 4.7 months (95% CI, 3.5-10.6 months) was observed for patients in the weighted everolimus group compared with 4.8 months (95% CI, 4.5-6.4 months) in the AXIS trial.

Implications: Similar median PFS point estimates and overlapping CIs suggest that everolimus and axitinib have similar efficacy. Although these results do not negate the need for direct comparison, this study may be used to inform clinical and reimbursement decisions until such evidence is available.
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http://dx.doi.org/10.1016/j.clinthera.2015.09.013DOI Listing
October 2015

Prognostic factors for survival following initiation of second-line treatment with everolimus for metastatic renal cell carcinoma: evidence from a nationwide sample of clinical practice in the United States.

Expert Opin Pharmacother 2015 Apr 12;16(6):805-19. Epub 2015 Mar 12.

University of Southern California Norris Comprehensive Cancer Center , Los Angeles, CA , USA.

Objective: Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials.

Research Design And Methods: Two separate chart sets (2009 - 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI).

Main Outcome Measures: Prognostic factors for OS have been identified and validated in separate samples.

Results: One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months - higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score < 80%, duration of mRCC < 1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 - 2 risk factors, 63% for 3 risk factors and 22% for 4 - 5 risk factors (log-rank p < 0.001).

Conclusion: Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.
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http://dx.doi.org/10.1517/14656566.2015.1020298DOI Listing
April 2015

Comparative Effectiveness of Second-Line Targeted Therapies for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World Observational Studies.

PLoS One 2014 10;9(12):e114264. Epub 2014 Dec 10.

Department of Oncology, British Columbia Cancer Agency, Vancouver, Canada.

Objective: The optimal sequencing of targeted therapies for metastatic renal cell carcinoma (mRCC) is unknown. Observational studies with a variety of designs have reported differing results. The objective of this study is to systematically summarize and interpret the published real-world evidence comparing sequential treatment for mRCC.

Methods: A search was conducted in Medline and Embase (2009-2013), and conference proceedings from American Society of Clinical Oncology (ASCO), ASCO Genitourinary Cancers Symposium (ASCO-GU), and European Society for Medical Oncology (ESMO) (2011-2013). We systematically reviewed observational studies comparing second-line mRCC treatment with mammalian target of rapamycin inhibitors (mTORi) versus vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI). Studies were evaluated for 1) use of a retrospective cohort design after initiation of second-line therapy, 2) adjustment for patient characteristics, and 3) use of data from multiple centers. Meta-analyses were conducted for comparisons of overall survival (OS) and progression-free survival (PFS).

Results: Ten studies reported OS and exhibited significant heterogeneity in estimated second-line treatment effects (I2 = 68%; P = 0.001). Four of these were adjusted, multicenter, retrospective cohort studies, and these showed no evidence of heterogeneity (I2 = 0%; P = 0.61) and a significant association between second-line mTORi (>75% everolimus) and longer OS compared to VEGF TKI (>60% sorafenib) (HR = 0.82, 95% CI: 0.68 to 0.98) in a meta-analysis. Seven studies comparing PFS showed significant heterogeneity overall and among the adjusted, multicenter, retrospective cohort studies. Real-world observational data for axitinib outcomes was limited at the time of this study.

Conclusions: Real-world studies employed different designs and reported heterogeneous results comparing the effectiveness of second-line mTORi and VEGF TKI in the treatment of mRCC. Within the subset of adjusted, multicenter observational studies, second-line use of mTORi was associated with significantly prolonged survival compared with second-line use of VEGF TKI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114264PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262396PMC
October 2017

Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.

J Med Econ 2015 Mar 26;18(3):200-9. Epub 2014 Nov 26.

LASER Analytica , New York, NY , USA.

Objective: Everolimus and axitinib are approved in the US to treat patients with advanced renal cell carcinoma (RCC) after failure on sunitinib or sorafenib, and one prior systemic therapy (e.g., sunitinib), respectively. Two indirect comparisons performed to evaluate progression-free survival in patients treated with everolimus vs axitinib suggested similar efficacy between the two treatments. Therefore, this analysis compares the lifetime costs of these two therapies among sunitinib-refractory advanced RCC patients from a US payer perspective.

Research Design And Methods: A Markov model was developed to simulate a cohort of sunitinib-refractory advanced RCC patients and estimate the cost of treating patients with everolimus vs axitinib. The following health states were included: stable disease without adverse events (AEs), stable disease with AEs, disease progression (PD), and death. The model included the following resources: active treatments, post-progression treatments, adverse events, physician and nurse visits, scans and tests, and palliative care. Resource utilization inputs were derived from a US claims database analysis. Additionally, a 3% annual discount rate was applied to costs, and the robustness of the model results was tested by conducting sensitivity analyses, including those on dosing scheme and post-progression treatment costs.

Results: Base case results demonstrated that patients treated with everolimus cost an average of $12,985 (11%) less over their lifetimes than patients treated with axitinib. The primary difference in costs was related to active treatment, which was largely driven by axitinib's higher dose intensity. RESULTS remained consistent across sensitivity analyses for AE and PD treatment costs, as well as dose intensity and discount rates.

Conclusion: The results suggest that everolimus likely leads to lower lifetime costs than axitinib for sunitinib-refractory advanced RCC patients in the US.
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http://dx.doi.org/10.3111/13696998.2014.985789DOI Listing
March 2015

Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: synthesis of findings from two multi-practice chart reviews in the United States.

Curr Med Res Opin 2014 Nov 27;30(11):2343-53. Epub 2014 Aug 27.

Analysis Group Inc. , Boston, MA , USA.

Background: Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study compares the effectiveness of these therapies in a multi-practice chart review and synthesizes the findings with those of a similarly designed study.

Methods: Medical oncologists/hematologists (N = 36) were recruited to review charts for patients aged ≥18 years, received a first-line TKI and initiated second-line targeted therapy in 2010 or later. The primary outcome was time from second-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving second-line everolimus (EVE), temsirolimus (TEM), or TKI as a class, using a Cox proportional hazards model adjusting for type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled, in a meta-analysis, with previously reported HRs for progression-free survival from a chart review with a similar design.

Results: A total of 138, 64 and 79 patients received second-line therapy with EVE, TEM or a TKI, respectively. Adjusting for baseline characteristics, EVE was associated with numerical, but not statistically significant, reductions of 28% (HR = 0.72; 95% CI [0.45-1.16]) and 26% (HR = 0.74; 95% CI [0.48-1.15]) in the hazard of TTF compared to TEM and TKI, respectively. After pooling the HRs from both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (HR = 0.73; 95% CI [0.57-0.93]; and HR = 0.75; 95% CI [0.57-0.98], respectively).

Limitations: LIMITATIONS include retrospective analyses with possible missing or erroneous chart data, confounding of unobserved factors due to non-randomization, and limited data for axitinib during the study period.

Conclusions: In pooled results from two independent multi-practice chart reviews of second-line mRCC treatment, EVE was associated with significantly reduced hazards of treatment failure compared to TEM and to TKIs as a class.
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http://dx.doi.org/10.1185/03007995.2014.949645DOI Listing
November 2014

Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma.

J Clin Oncol 2014 Sep 21;32(25):2765-72. Epub 2014 Jul 21.

Robert J. Motzer, Memorial Sloan-Kettering Cancer Center, New York, NY; Carlos H. Barrios, PUCRS School of Medicine, Porto Alegre, Brazil; Tae Min Kim, Seoul National University Hospital; and Sun Young Rha, Severance Hospital, Yonsei Cancer Center, Seoul, Korea; Silvia Falcon, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; Thomas Cosgriff, Hematology and Oncology Specialists, Metairie, LA; Graydon Harker, Utah Cancer Specialists, Salt Lake City, UT; Vichien Srimuninnimit, Siriraj Hospital, Mahidol, Thailand; Ken Pittman, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia; Roberto Sabbatini, Azienda Ospedaliero Universitaria Policlinico di Modena, Italy; Thomas W. Flaig, University of Colorado Cancer Center, Aurora, CO; Ray Page, Center for Cancer and Blood Disorders, Fort Worth, TX; Sevil E. Bavbek, American Hospital, Istanbul, Turkey; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Poulam Patel, University of Nottingham, United Kingdom; Foon-yiu Cheung, Queen Elizabeth Hospital, Kowloon, Hong Kong; Sunil Yadav, Saskatoon Cancer Centre, Saskatoon, Saskatchewan; and Jennifer J. Knox, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada; Edward M. Schiff, Dalila Sellami, and Xufang Wang, Novartis Oncology, East Hanover, NJ; Julie Niolat, Novartis Pharma SAS, Rueil-Malmaison, France; and Oezlem Anak, Novartis Pharma AG, Basel, Switzerland.

Purpose: A multicenter, randomized phase II trial, RECORD-3, was conducted to compare first-line everolimus followed by sunitinib at progression with the standard sequence of first-line sunitinib followed by everolimus in patients with metastatic renal cell carcinoma.

Patients And Methods: RECORD-3 used a crossover treatment design. The primary objective was to assess progression-free survival (PFS) noninferiority of first-line everolimus compared with first-line sunitinib. Secondary end points included combined PFS for each sequence, overall survival (OS), and safety.

Results: Of 471 enrolled patients, 238 were randomly assigned to first-line everolimus followed by sunitinib, and 233 were randomly assigned to first-line sunitinib followed by everolimus. The primary end point was not met; the median PFS was 7.9 months for first-line everolimus and 10.7 months for first-line sunitinib (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.8). Among patients who discontinued first-line, 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus. The median combined PFS was 21.1 months for sequential everolimus then sunitinib and was 25.8 months for sequential sunitinib then everolimus (HR, 1.3; 95% CI, 0.9 to 1.7). The median OS was 22.4 months for sequential everolimus and then sunitinib and 32.0 months for sequential sunitinib and then everolimus (HR, 1.2; 95% CI, 0.9 to 1.6). Common treatment-emergent adverse events during first-line everolimus or sunitinib were stomatitis (53% and 57%, respectively), fatigue (45% and 51%, respectively), and diarrhea (38% and 57%, respectively).

Conclusion: Everolimus did not demonstrate noninferiority compared with sunitinib as a first-line therapy. The trial results support the standard treatment paradigm of first-line sunitinib followed by everolimus at progression.
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http://dx.doi.org/10.1200/JCO.2013.54.6911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569681PMC
September 2014

Review of US Comparative Economic Evidence for Treatment of Metastatic Renal Cell Carcinoma after Failure of First-Line VEGF Inhibitor Therapy.

Am Health Drug Benefits 2013 Jul;6(5):275-86

Dr Liu is Director, Oncology US Health Economics & Outcomes Research, Novartis Pharmaceuticals, East Hanover, NJ.

Background: In 2006, the economic burden of metastatic renal cell carcinoma (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually. With the continuing increase of the economic burden of this disease in the United States, there is a growing need for economic analyses to guide treatment and policy decisions for this patient population.

Objective: To evaluate available comparative economic data on targeted therapies for patients with mRCC who have failed first-line targeted therapies.

Method: A broad and comprehensive literature review was conducted of US-based studies between January 1, 2005, and February 11, 2013, evaluating comparative economic evidence for targeted agents that are used as second-line therapy or beyond. Based on the specific search parameters that focused on cost-effectiveness and economic comparisons between vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFr) inhibitors and mammalian target of rapamycin (mTOR) inhibitors, only 7 relevant, US-based economic evaluations were found appropriate for inclusion in the analysis. All authors, who are experts in the health economics and outcomes research field, reviewed the search results. Studies of interest were those with a targeted agent, VEGF/VEGFr or mTOR inhibitor, in at least 1 study arm.

Discussion: As a group, targeted therapies were found to be cost-effective options in treating patients with refractory mRCC in the United States. Oral therapies showed an economic advantage over intravenous agents, presumably because oral therapies have a lower impact on outpatient resources. Based on 3 studies, everolimus has been shown to have an economic advantage over temsirolimus and to be cost-effective compared with sorafenib. No economic comparison between everolimus and axitinib, the only 2 drugs with a National Comprehensive Cancer Network category 1 recommendation for use after the failure of VEGFr tyrosine kinase inhibitors, is available.

Conclusion: The limited and heterogeneous sum of the currently available economic evidence does not allow firm conclusions to be drawn about the most cost-effective targeted treatment option in the second-line setting and beyond in patients with mRCC. It is hoped that ongoing head-to-head therapeutic trials and biomarker studies will help improve the economic efficiency of these expensive agents.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031714PMC
July 2013

Comparative outcomes of everolimus, temsirolimus and sorafenib as second targeted therapies for metastatic renal cell carcinoma: a US medical record review.

Curr Med Res Opin 2014 Apr 17;30(4):537-45. Epub 2013 Dec 17.

Norris Comprehensive Cancer Center, University of Southern California , Los Angeles, CA , USA.

Objective: To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US.

Research Design And Methods: Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments.

Results: A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42-0.85; p = 0.004) and PFS (HR 0.73; CI 0.54-0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44-0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib.

Limitations: Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected.

Conclusions: In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.
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http://dx.doi.org/10.1185/03007995.2013.871243DOI Listing
April 2014

Everolimus and sunitinib for advanced pancreatic neuroendocrine tumors: a matching-adjusted indirect comparison.

Exp Hematol Oncol 2013 Dec 6;2(1):32. Epub 2013 Dec 6.

Analysis Group, Inc,, 111 Huntington Ave 10th Floor, Boston, MA 02199, USA.

Background: Everolimus and sunitinib have been approved for the treatment advanced pancreatic neuroendocrine tumors, but have not been compared to each other in a randomized trial and have not demonstrated prolonged overall survival compared to placebo. This study aimed to indirectly compare overall and progression-free among everolimus, sunitinib and placebo across separate randomized trials.

Methods: A matching adjusted indirect comparison was conducted in which individual patient data from the pivotal trial of everolimus (n = 410) were adjusted to match the inclusion criteria and average baseline characteristics reported for the pivotal trial of sunitinib (n = 171). Prior to matching, trial populations differed in baseline performance status and prior treatments. After matching, these and all other available baseline characteristics were balanced between trials.

Results: Compared to the placebo arm in the sunitinib trial, everolimus was associated with significantly prolonged overall survival (HR = 0.61, 95% CI = 0.38-0.98, p = 0.042).Compared to sunitinib, everolimus was associated with similar progression-free (hazard ratio for death (HR) = 0.84, 95% CI = 0.46-1.53, p = 0.578) and overall survival (HR = 0.81, 95% CI = 0.49-1.31, p = 0.383).

Conclusion: After adjusting for observed cross-trial differences, everolimus treatment was associated with longer overall survival than the placebo arm in the sunitinib trial for advanced pancreatic neuroendocrine tumors.
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http://dx.doi.org/10.1186/2162-3619-2-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175512PMC
December 2013

United States-based practice patterns and resource utilization in advanced neuroendocrine tumor treatment.

World J Gastroenterol 2013 Apr;19(15):2348-54

H Lee Moffitt Cancer Center and Research Institute, Gastrointestinal Tumor Department, Tampa, FL 33612, USA.

Aim: To assess advanced neuroendocrine tumor (NET) treatment patterns and resource utilization by tumor progression stage and tumor site in the United States.

Methods: United States Physicians meeting eligibility criteria were provided with online data extraction forms to collect patient chart data on recent NET patients. Resource utilization and treatment pattern data were collected over a baseline period (after diagnosis and before tumor progression), as well as initial and secondary progression periods, with progression defined according to measureable radiographic evidence of tumor progression. Resource categories used in the analysis include: Treatments (e.g., surgery, chemotherapy, radiotherapy, targeted therapies), hospitalizations and physician visits, diagnostic tests (biomarkers, imaging, laboratory tests). Comparisons between categories of resource utilization and tumor progression status were examined using univariate (by tumor site) and multivariate analyses (across all tumor sites).

Results: Fifty-five physicians were included in the study and completed online data extraction forms using the charts of 110 patients. The physician sample showed a relatively even distribution for those affiliated with academic versus community hospitals (46% vs 55%). Forty (36.3%) patients were reported to have pancreatic NET (pNET), while 70 (63.6%) patients had gastrointestinal tract (GI)/Lung as the primary NET site. Univariate analysis showed the proportion of patients hospitalized increased from 32.7% during baseline to 42.1% in the progression stages. While surgeries were performed at similar proportions overall at baseline and progression, pNET patients, were more likely than GI/Lung NET patients to have undergone surgery during the baseline (33.3% vs 25.0%) and any progression periods (26.7% vs 23.4%). While peptide-receptor radionuclide and targeted therapy utilization was low across NET types and tumor stages, GI/Lung types exhibited greater utilization of these technologies compared to pNET. Chemotherapy utilization was also greater among GI/Lung types. Multivariate analysis results demonstrated that patients in first progression period were over 3 times more likely to receive chemotherapy when compared to baseline (odds ratio: 3.31; 95%CI: 1.46-7.48, P = 0.0041). Further, progression was associated with a greater likelihood of having a study physician visit [relative risk (RR): 1.54; 95%CI: 1.10-2.17, P = 0.0117], and an increased frequency of other physician visits (RR: 1.84; 95%CI: 1.10-3.10, P = 0.0211).

Conclusion: Resource utilization in advanced NET in the United States is significant overall and data suggests progression has an impact on resource utilization regardless of NET tumor site.
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http://dx.doi.org/10.3748/wjg.v19.i15.2348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631986PMC
April 2013

GC/TOFMS analysis of metabolites in serum and urine reveals metabolic perturbation of TCA cycle in db/db mice involved in diabetic nephropathy.

Am J Physiol Renal Physiol 2013 Jun 6;304(11):F1317-24. Epub 2013 Mar 6.

Laboratory of Metabolomics, Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

Early diagnosis of diabetic nephropathy (DN) is difficult although it is of crucial importance to prevent its development. To probe potential markers and the underlying mechanism of DN, an animal model of DN, the db/db mice, was used and serum and urine metabolites were profiled using gas chromatography/time-of-flight mass spectrometry. Metabolic patterns were evaluated based on serum and urine data. Principal component analysis of the data revealed an obvious metabonomic difference between db/db mice and controls, and db/db mice showed distinctly different metabolic patterns during the progression from diabetes to early, medium, and later DN. The identified metabolites discriminating between db/db mice and controls suggested that db/db mice have perturbations in the tricarboxylic acid cycle (TCA, citrate, malate, succinate, and aconitate), lipid metabolism, glycolysis, and amino acid turnover. The db/db mice were characterized by acidic urine, high TCA intermediates in serum at week 6 and a sharp decline thereafter, and gradual elevation of free fatty acids in the serum. The sharp drop of serum TCA intermediates from week 6 to 8 indicated the downregulated glycolysis and insulin resistance. However, urinary TCA intermediates did not decrease in parallel with those in the serum from week 6 to 10, and an increased portion of TCA intermediates in the serum was excreted into the urine at 8, 10, and 12 wk than at 6 wk, indicating kidney dysfunction occurred. The relative abundances of TCA intermediates in urine relative to those in serum were suggested as an index of renal damage.
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http://dx.doi.org/10.1152/ajprenal.00536.2012DOI Listing
June 2013

International practice patterns and resource utilization in the treatment of neuroendocrine tumors.

Pancreas 2013 Mar;42(2):339-47

LA-SER Analytica, New York, NY, USA.

Objectives: This study compared resource use and practice patterns in patients with advanced neuroendocrine tumors (NETs) on disease progression, across countries, and by tumor type.

Methods: Physicians in the United States, United Kingdom, Germany, France, Brazil, and Italy completed data extraction forms to extract chart data of patients with NET relating to health care resource utilization and treatment practice. Data were assessed in a cross-sectional manner, by country, and by NET subtype. Univariate and multivariate analyses were performed to compare categories of resource use by disease progression status.

Results: A total of 197 physicians provided data on 394 patients. Overall resource utilization was high across tumor types, countries, and progression. Nearly half of all patients received chemotherapy (49%); moreover, high rates of hospitalization (65%), surgery (47%), and use of somatostatin analog (77%) were observed, with lower rates of peptide receptor radionuclide therapy (10%) and targeted therapies (6%). These patterns were consistent across gastrointestinal tract/lung NET and pancreatic NET. However, a certain variation in resource utilization was observed across countries. Disease progression was associated with increasing utilization of chemotherapy, hospitalization, and targeted therapy.

Conclusions: Advanced NET is associated with significant resource use across subtypes and countries, and resource utilization is likely to increase on disease progression. There remains an unmet need for therapeutic options after disease progression.
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http://dx.doi.org/10.1097/MPA.0b013e31826707ccDOI Listing
March 2013

Roles of mast cells and monocyte chemoattractant protein-1 in the renal injury of obesity-related glomerulopathy.

Am J Med Sci 2013 Oct;346(4):295-301

Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

Background: Inflammation contributes to renal injury of obesity-related glomerulopathy (ORG). As mast cells are regarded as regulators of inflammation, this study aimed to investigate whether mast cell infiltration is involved in renal damage of ORG.

Methods: Forty patients with ORG, 18 with idiopathic focal segmental glomerulosclerosis and 10 normal controls were included in this study. Tryptase and CD68 were used for detecting mast cells and macrophages, respectively, by immunohistochemistry. Associations between mast cells and inflammation as well as clinicopathological parameters were assessed.

Results: Tubulointerstitial mast cell infiltration increased in the ORG group compared with that in the focal segmental glomerulosclerosis and the control groups. The number of mast cells was positively correlated with body mass index (r = 0.432, P = 0.006), systolic blood pressure (r = 0.445, P = 0.005), serum creatinine (r = 0.489, P = 0.002), tubular atrophy (r = 0.470, P = 0.003) and interstitial fibrosis (r = 0.669, P < 0.001). Increased expression of monocyte chemoattractant protein-1, which was partly colocalized with tryptase, was observed. CD68-positive macrophages were also found to be increased and distributed around the mast cells. The area of tubulointerstitial monocyte chemoattractant protein-1 was correlated with the number of mast cells (r = 0.695, P < 0.001) and interstitial fibrosis (r = 0.327, P = 0.042). Multivariate regression showed that the number of mast cells was an independent predictor for epidermal growth factor receptor (R(2) = 0.313, P < 0.001).

Conclusions: Mast cell infiltration is involved in renal damage of ORG, and inflammation may contribute to such a process.
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http://dx.doi.org/10.1097/MAJ.0b013e31827559f8DOI Listing
October 2013

Disease burden and treatment outcomes in second-line therapy of patients with estrogen receptor-positive (ER+) advanced breast cancer: a review of the literature.

Breast 2012 Dec 23;21(6):701-6. Epub 2012 Oct 23.

Xcenda, 4114 Woodlands Parkway, Suite 500, Palm Harbor, FL 34685, USA.

Objective: To determine the variable burden of disease of patients with advanced estrogen receptor-positive (ER+) breast cancer and assess the current treatment landscape after failure of first-line endocrine therapy.

Methods: A comprehensive literature review was performed (2000-2011) by searching Medline via PubMed, and Embase and Cochrane databases, to assess disease burden (i.e. societal, humanistic, and/or economic burden) and treatment landscape for second-line therapy of ER+ advanced breast cancer in postmenopausal women.

Results: Only 1 study was identified that evaluated burden of disease based on ER status (ER+, ER-negative, or ER-unknown); this study was a subgroup analysis assessing the impact of breast cancer recurrence over 10 years. The investigators reported that only minor differences in survival and medical costs were noted based on ER status in relapsing patients. Regardless of ER status, patients with breast cancer recurrence consumed more healthcare resources and were associated with more costly care than those without recurrence. A total of 7 studies were identified related to treatment outcomes of second-line therapy in ER+ patients. A combined international population totaled >3800 patients who had progressed on prior hormonal therapy, including tamoxifen and aromatase inhibitors. Three trials performed a comparative efficacy/safety assessment of an ER antagonist vs. aromatase inhibitor, 1 trial compared an aromatase inhibitor to megestrol acetate, and 1 trial compared 2 aromatase inhibitors. Among each of the studies evaluated, no significant differences were observed in the primary efficacy endpoint, and the safety profiles were similar. Two additional studies demonstrated a similar or better efficacy and safety profile based on different dosing evaluations.

Conclusions: Currently, there is insufficient evidence on the economic and humanistic burden associated with ER status, and this gap warrants further research. With increasing drug resistance and greater economic burden associated with breast cancer recurrence, there is an unmet medical need for improved treatment in this patient population.
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http://dx.doi.org/10.1016/j.breast.2012.09.005DOI Listing
December 2012

Cost-effectiveness of everolimus vs sunitinib in treating patients with advanced, progressive pancreatic neuroendocrine tumors in the United States.

J Med Econ 2012 3;15 Suppl 1:55-64. Epub 2012 Sep 3.

The LA-SER Group, New York, NY, USA.

Background: Everolimus (Afinitor) and sunitinib (Sutent) were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). (Afinitor is a registered trademark of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Sutent is a registered trademark of Pfizer Inc., New York, NY, USA.) This analysis examined the projected cost-effectiveness of everolimus vs sunitinib in this setting from a US payer perspective.

Methods: A semi-Markov model was developed to simulate a cohort of patients with advanced, progressive pNET and to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) gained when treating with everolimus vs sunitinib. Efficacy data were based on a weight-adjusted indirect comparison of the agents using phase 3 trial data. Model health states included: stable disease with no adverse events, stable disease with adverse events, disease progression, and death. Therapy costs were based on wholesale acquisition cost. Other costs such as physician visits, tests, hospitalizations, and adverse event costs were obtained from literature and/or primary research. Utility inputs were based on primary research. Sensitivity analyses were conducted to test the model's robustness.

Results: In the base-case analysis, everolimus was associated with an incremental 0.448 LYG (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LYG ($41,702/QALY gained). The ICER fell within the cost per QALY range for many widely used oncology drugs. Sensitivity analyses demonstrated that, overall, there is a trend that everolimus is cost-effective compared to sunitinib in this setting.

Limitations: Results of the indirect analysis were not statistically significant (p > 0.05). Assumptions that treatment patterns are the same across therapies may not represent real-world practice.

Conclusions: While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies, everolimus is expected to be cost-effective relative to sunitinib in advanced, progressive pNET.
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http://dx.doi.org/10.3111/13696998.2012.720319DOI Listing
May 2013

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity.

Toxicol Appl Pharmacol 2012 Feb 7;258(3):376-83. Epub 2011 Dec 7.

School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui, PR China.

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p<0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity.
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http://dx.doi.org/10.1016/j.taap.2011.11.020DOI Listing
February 2012

Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

Value Health 2011 Sep-Oct;14(6):846-51. Epub 2011 Jul 28.

Analytica International, New York, NY 10018, USA.

Background: A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective.

Methods: A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted.

Results: The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations.

Conclusions: As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC.
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http://dx.doi.org/10.1016/j.jval.2011.04.008DOI Listing
November 2011

An adjusted indirect comparison of everolimus and sorafenib therapy in sunitinib-refractory metastatic renal cell carcinoma patients using repeated matched samples.

Expert Opin Pharmacother 2011 Jul 21;12(10):1491-7. Epub 2011 May 21.

University Federico II of Napoli, Medical Oncology, Endocrinology and Oncology Department, Naples, Italy.

Objective: To date, no trial data exist comparing treatment outcomes for everolimus versus sorafenib. The current analysis indirectly compares the overall survival (OS) benefit of everolimus and sorafenib as second-line treatment options.

Research Design And Methods: A single-arm sorafenib study is selected as a basis to match an everolimus sunitinib-refractory subpopulation of the RECORD-1 trial. Only patients with clear cell histology are included. An adjusted matching approach is taken where 1000 repeated random samples matched to the sorafenib population on risk score distribution are produced, and a 95% CI around the mean of all sampled median OS is generated.

Main Outcome Measures: The main outcome measures include adjusted median OS and progression-free survival.

Results: In all, 45 clear cell histology sorafenib patients and 1000 samples of N=41 sunitinib-refractory everolimus patients are considered for analysis. After adjusted matching, the estimated median OS benefit is 32.0 [corrected] weeks (95% CI: 22, 64) and 81.5 weeks (95% CI:78, 86) for sorafenib and everolimus patients, respectively.

Conclusion: Results suggest that sunitinib-refractory metastatic renal cell carcinoma patients treated with everolimus may experience significantly improved OS outcomes compared to those treated with sorafenib. However, because this is not a randomized controlled trial, the results should be interpreted as those from an observational study.
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http://dx.doi.org/10.1517/14656566.2011.587119DOI Listing
July 2011

Cyclophosphamide-evoked heart failure involves pronounced co-suppression of cytoplasmic thioredoxin reductase activity and non-protein free thiol level.

Eur J Heart Fail 2009 Feb;11(2):154-62

School of Chemistry and Material Science, University of Science and Technology of China, Southern Campus, Meiling Avenue No.121, Hefei 230052, Anhui, People's Republic of China.

Aims: Heart failure is a life-threatening complication of high-dose cyclophosphamide (CTX) chemotherapy, and the present study aimed at identifying the mechanism involved in mice.

Methods And Results: CTX at 800 mg/kg resulted in heart failure, in which cytoplasmic thioredoxin reductase (TrxR1) activity and non-protein free thiol (NPFT) level were suppressed by 90 and 62%, respectively. The combination of 350 mg/kg CTX and the glutathione synthesis inhibitor buthionine sulfoximine (BSO) also evoked heart failure, in which TrxR1 activity and NPFT level were suppressed by 66 and 62%, respectively. NPFT depletion alone by BSO did not cause cardiac toxicity. CTX at 350 mg/kg alone also did not cause cardiac toxicity, even though it suppressed TrxR1 activity by 68%. Previous studies have shown that half inactivation of TrxR1 in tumour, bladder, and kidneys was associated with toxicological consequences. Cardiac TrxR1 is dispensable, but cardiac cytoplasmic thioredoxin (Trx1) is essential. The potential uncoupling between TrxR1 and Trx1 may explain why there is no cardiac toxicity following TrxR1 inhibition. However, TrxR1 inactivation may still play a role in CTX-evoked heart failure because inactivated TrxR1 gains cytotoxic function, which may engender noticeable toxicity when massive NPFT is deleted.

Conclusion: CTX-evoked heart failure involves pronounced co-suppression of TrxR1 activity and NPFT level.
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http://dx.doi.org/10.1093/eurjhf/hfn012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639423PMC
February 2009

MS07116 sodium selenosulfate synthesis and demonstration of its in vitro cytotoxic activity against HepG2, Caco2, and three kinds of leukemia cells.

Biol Trace Elem Res 2008 Oct 24;125(1):13-21. Epub 2007 Oct 24.

School of Chemistry and Material Science, University of Science and Technology of China, Anhui, People's Republic of China.

The biological profile of sodium selenosulfate, Na(2)SeSO(3), is still largely unknown. The present study found that sodium sulfite reacted with elemental selenium at nanoparticle size already at 37 degrees C to yield sodium selenosulfate. Additionally, selenosulfate was obtained by mixing sodium selenite, glutathione, and sodium sulfite at room temperature. In vitro, sodium selenosulfate killed HepG2 or Caco2 cells, in a dose-dependent fashion, and 12.5 microM fully suppressed their proliferation. In addition, sodium selenosulfate showed a consistent cytotoxic effect when added to three kinds of leukemia cell lines (HL60, T lymph adenoma, and Daudi).
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http://dx.doi.org/10.1007/s12011-007-8044-0DOI Listing
October 2008

Amifostine increases cure rate of cisplatin on ascites hepatoma 22 via selectively protecting renal thioredoxin reductase.

Cancer Lett 2008 Feb 26;260(1-2):127-36. Epub 2007 Nov 26.

School of Chemistry and Material Science, University of Science and Technology of China, Southern Campus, Meiling Avenue No. 121, Hefei 230052, Anhui, PR China.

It has been demonstrated via in vitro experiments that the anti-cancer drug cisplatin (CDDP) can inactivate thioredoxin reductase (TrxR), a molecular target for cancer therapy. The present study in mice revealed that CDDP at pharmacological doses inhibited TrxR activity in both ascitic hepatoma 22 (H22) cells and kidney, leading to suppression of H22 cells proliferation along with nephrotoxicity. Amifostine, a clinical used cytoprotective agent, protected against CDDP-induced TrxR inactivation in kidney but not in H22 cells. Such an excellent selective modulation of amifostine on TrxR led us to exploit the potential of amifostine in increasing cure rate of CDDP on cancer. In mice, CDDP at the doses of 5 and 7.5 mg/kg once weekly for 4 weeks could not completely control H22 ascites development and the cure rate was no more than 12.5%; CDDP 9 mg/kg by the same schedule prominently suppressed the ascites development, but finally resulted in 87.5% mortality caused by CDDP toxicity. Thus, these dose-dependent therapeutic results well recapitulated the clinical dilemma of chemotherapy on cancer. However, co-treatment of CDDP (9 mg/kg) and amifostine largely reduced CDDP toxicity, and obtained a cure rate as high as 87.5%. Overall, the present study demonstrates both pharmacological and toxicological effects of CDDP involve TrxR inactivation, and the large enhancement on CDDP cure rate in H22 ascites model by using amifostine is, at least in part, ascribed to its selective modulation on TrxR.
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http://dx.doi.org/10.1016/j.canlet.2007.10.023DOI Listing
February 2008

Thioredoxin reductase inactivation as a pivotal mechanism of ifosfamide in cancer therapy.

Eur J Pharmacol 2008 Jan 15;579(1-3):66-73. Epub 2007 Oct 15.

University of Science and Technology of China, Hefei 230052, Anhui, PR China.

Thioredoxin reductase reduces thioredoxin, thereby contributing to multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This selenium-containing oxidoreductase is over-expressed in many malignant cells and has been proposed as a target for cancer therapy. Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. The purpose of this study is to test the hypothesis that anticancer efficacy of ifosfamide may rely on its ability to inhibit thioredoxin reductase in tumor. To inspect the consequence of thioredoxin reductase inhibition by ifosfamide on tumor cell proliferation, mice bearing hepatoma 22 (H22) cells in ascites were injected with 350 mg/kg ifosfamide. Thioredoxin reductase activity was maximally inhibited by half at 6 h, and a subsequent pronounced cellular proliferation inhibition due to cell cycle arrest in G(1) phase was found. Moreover, at 6 h, except thioredoxin reductase inhibition, ifosfamide did not affect cell cycle or other measured antioxidant enzymes activity in the tumor cells. Intriguingly, when these cells were injected into healthy mice, they totally lost the capacity of causing either ascitic or solid tumors. Thioredoxin reductase inhibition could also be found in solid H22 tumor by 62%, bladder by 74% and kidney by 37% at 6 h. Overall, these observations provide direct evidence that inhibition of thioredoxin reductase activity in malignant cells by ifosfamide is highly associated with its anticancer effect and the mechanism of ifosfamide systemic toxicity may be related to multi-organ inhibition of thioredoxin reductase activity.
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http://dx.doi.org/10.1016/j.ejphar.2007.10.012DOI Listing
January 2008

Elemental selenium at nano size (Nano-Se) as a potential chemopreventive agent with reduced risk of selenium toxicity: comparison with se-methylselenocysteine in mice.

Toxicol Sci 2008 Jan 28;101(1):22-31. Epub 2007 Aug 28.

University of Science and Technology of China, Hefei 230052, Anhui, P.R. China.

Selenium (Se) is an essential trace element with a narrow margin between beneficial and toxic effects. As a promising chemopreventive agent, its use requires consumption over the long term, so the toxicity of Se is always a crucial concern. Based on clinical findings and recent studies in selenoprotein gene-modified mice, it is likely that the antioxidant function of one or more selenoproteins is responsible for the chemopreventive effect of Se. Furthermore, upregulation of phase 2 enzymes by Se has been implicated as a possible chemopreventive mechanism at supranutritional dietary levels. Se-methylselenocysteine (SeMSC), a naturally occurring organic Se product, is considered as one of the most effective chemopreventive selenocompounds. The present study revealed that, as compared with SeMSC, elemental Se at nano size (Nano-Se) possessed equal efficacy in increasing the activities of glutathione peroxidase, thioredoxin reductase, and glutathione S-transferase, but had much lower toxicity as indicated by median lethal dose, acute liver injury, survival rate, and short-term toxicity. Our results suggest that Nano-Se can serve as a potential chemopreventive agent with reduced risk of Se toxicity.
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http://dx.doi.org/10.1093/toxsci/kfm221DOI Listing
January 2008

Cyclophosphamide as a potent inhibitor of tumor thioredoxin reductase in vivo.

Toxicol Appl Pharmacol 2007 Jan 1;218(1):88-95. Epub 2006 Nov 1.

School of Chemistry and Material Science, University of Science and Technology of China, Southern Campus, Meiling Avenue No.121, Hefei, 230052, Anhui, PR China.

Cyclophosphamide (CTX) is in the nitrogen mustard group of alkylating antineoplastic chemotherapeutic agents. It is one of the most frequently used antitumor agents for the treatment of a broad spectrum of human cancers. Thioredoxin reductase (TrxR) catalyze the NADPH-dependent reduction of thioredoxin and play an important role in multiple cellular events related to carcinogenesis including cell proliferation, apoptosis, and cell signaling. This enzyme represents a promising target for the development of cytostatic agents. The purpose of this study is to determine whether CTX could target TrxR in vivo. Lewis lung carcinoma and solid H22 hepatoma treated with 50-250 mg/kg CTX for 3 h lost TrxR activity in a dose-dependent fashion. Over 75% and 95% of TrxR activity was lost at the dose of 250 mg/kg. There was, however, a recovery of TrxR activity such that it attained normal levels by 120 h after a dose of 250 mg/kg. In addition, we found that CTX caused a preferential TrxR inhibition over other antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase. We also used ascites H22 cells to investigate cancer cells response after TrxR was inhibited by CTX in vivo since CTX is needed to be activated by liver cytochrome P450 enzymes. The time course and dose-dependent changes of cellular TrxR activity were similar with those in tumor tissue. CTX caused a dose-dependent cellular proliferation inhibition which was positively correlated with TrxR inhibition at 3 h. Furthermore, when 3 h CTX-treated cells with various TrxR backgrounds, harvested from ascites-bearing mice, were implanted into mice, the proliferations of these cells were again proportionally dependent on TrxR activity. The TrxR inhibition could thereby be considered as a crucial mechanism contributing to anticancer effect seen upon clinical use of CTX.
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http://dx.doi.org/10.1016/j.taap.2006.10.029DOI Listing
January 2007