Publications by authors named "Siyuan Hou"

29 Publications

  • Page 1 of 1

Efficacy of Selective Vidian Neurectomy for Allergic Rhinitis Combined with Chronic Rhinosinusitis.

ORL J Otorhinolaryngol Relat Spec 2021 May 5:1-8. Epub 2021 May 5.

Department of Otorhinolaryngology Head and Neck Surgery, XuanWu Hospital, Capital Medical University, Beijing, China.

Objective: The aim of this study was to investigate the efficacy of endoscopic selective vidian neurectomy in the treatment of severe persistent allergic rhinitis (AR) combined with chronic rhinosinusitis (CRS) with nasal polyps (ARwCRSwNP).

Methods: One hundred thirty patients with moderate to severe persistent ARwCRSwNP were enrolled at Xuanwu Hospital, Capital Medical University, from September 2015 to September 2017. Patients were divided into 2 groups. Sixty-one patients (the control group) underwent conventional surgical treatment for CRS with nasal polyps and received conservative treatment for AR. Sixty-nine patients (the experimental group) received conventional surgical treatment for CRS with nasal polyps plus endoscopic selective vidian neurectomy with amputation of the posterior nasal nerve and pharyngeal branch of the vidian nerve. Clinical parameters, including visual analog scale (VAS) score, Lund-Kennedy endoscopic mucosal morphology score, and Lund-Mackay sinus computed tomography (CT) scan lesion range score, were used to analyze and evaluate the preoperative and postoperative data. Comparisons were based on patient scores, and preoperative and postoperative scores obtained at 6, 12, and 24 months were analyzed.

Results: The experimental group had higher therapeutic efficacy in nasal obstruction, nasal itching, rhinorrhea, sneezing, and general symptoms than the control group (p < 0.05). No complications such as tear-secretion disorder or atrophic rhinitis occurred in the experimental group, and no significant difference in complications incidence was observed between the 2 groups (p > 0.05).

Conclusion: Endoscopic selective vidian neurectomy is an effective and safe technique for the management of moderate to severe persistent ARwCRSwNP.
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http://dx.doi.org/10.1159/000512083DOI Listing
May 2021

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment.

J Med Chem 2021 01 31;64(1):629-643. Epub 2020 Dec 31.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China.

In a pancreatic tumor microenvironment, activated pancreatic stellate cells (PSCs) produce extracellular matrix (ECM) to form a barrier to drug penetration. Moreover, the interaction between cancer cells and activated PSCs promotes the tumor growth. Vitamin D receptor (VDR), as a key regulator to promote the recovery of PSCs to the resting state, is an attractive therapeutic target for pancreatic cancer. Herein, we reported the design and synthesis of 57 nonsecosteroidal VDR modulators based on the skeleton of phenyl-pyrrolyl pentane. Among them, compounds , , and exhibited excellent VDR affinity and effective inhibition of the activation of PSCs, as well as potent suppression of the interaction between cancer cells and PSCs . , compound combined with gemcitabine achieved efficacious antitumor activity without causing hypercalcemia. In conclusion, the compounds designed in our study can remodel the tumor microenvironment and are expected to be candidates for the treatment of pancreatic cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01197DOI Listing
January 2021

Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy.

Sci Transl Med 2020 11;12(571)

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China.

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8 T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.
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http://dx.doi.org/10.1126/scitranslmed.aaz6667DOI Listing
November 2020

Populus euphratica annexin1 facilitates cadmium enrichment in transgenic Arabidopsis.

J Hazard Mater 2021 03 28;405:124063. Epub 2020 Sep 28.

Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, College of Biological Sciences and Technology (Box 162), Beijing Forestry University, Beijing 100083, China. Electronic address:

Phytoremediation offers a great potential for affordable remediation of heavy metal (HM)-polluted soil and water. Screening and identifying candidate genes related to HM uptake and transport is prerequisite for improvement of phytoremediation by genetic engineering. Using the cadmium (Cd)-hypersensitive Populus euphratica, an annexin encoding gene facilitating Cd enrichment was identified in this study. With a 12 h exposure to CdCl (50-100 μM), P. euphratica cells down-regulated transcripts of annexin1 (PeANN1). PeANN1 was homologue to Arabidopsis annexin1 (AtANN1) and localized mainly to the plasma membrane (PM) and cytosol. Compared with wild type and Atann1 mutant, PeANN1 overexpression in Arabidopsis resulted in a more pronounced decline in survival rate and root length after a long-term Cd stress (10 d, 50 μM), due to a higher cadmium accumulation in roots. PeANN1-transgenic roots exhibited enhanced influx conductance of Cd under cadmium shock (30 min, 50 μM) and short-term stress (12 h, 50 μM). Noteworthy, the PeANN1-facilitated Cd influx was significantly inhibited by a calcium-permeable channel (CaPC) inhibitor (GdCl) but was promoted by 1 mM HO, indicating that Cd entered root cells via radical-activated CaPCs in the PM. Therefore, PeANN1 can serve as a candidate gene for improvement of phytoremediation by genetic engineering.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124063DOI Listing
March 2021

Embryonic endothelial evolution towards first hematopoietic stem cells revealed by single-cell transcriptomic and functional analyses.

Cell Res 2020 05 20;30(5):376-392. Epub 2020 Mar 20.

Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, Guangdong, 510632, China.

Hematopoietic stem cells (HSCs) in adults are believed to be born from hemogenic endothelial cells (HECs) in mid-gestational embryos. Due to the rare and transient nature, the HSC-competent HECs have never been stringently identified and accurately captured, let alone their genuine vascular precursors. Here, we first used high-precision single-cell transcriptomics to unbiasedly examine the relevant EC populations at continuous developmental stages with intervals of 0.5 days from embryonic day (E) 9.5 to E11.0. As a consequence, we transcriptomically identified two molecularly different arterial EC populations and putative HSC-primed HECs, whose number peaked at E10.0 and sharply decreased thereafter, in the dorsal aorta of the aorta-gonad-mesonephros (AGM) region. Combining computational prediction and in vivo functional validation, we precisely captured HSC-competent HECs by the newly constructed Neurl3-EGFP reporter mouse model, and realized the enrichment further by a combination of surface markers (ProcrKitCD44, PK44). Surprisingly, the endothelial-hematopoietic dual potential was rarely but reliably witnessed in the cultures of single HECs. Noteworthy, primitive vascular ECs from E8.0 experienced two-step fate choices to become HSC-primed HECs, namely an initial arterial fate choice followed by a hemogenic fate conversion. This finding resolves several previously observed contradictions. Taken together, comprehensive understanding of endothelial evolutions and molecular programs underlying HSC-primed HEC specification in vivo will facilitate future investigations directing HSC production in vitro.
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http://dx.doi.org/10.1038/s41422-020-0300-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196075PMC
May 2020

Corrigendum to "Discovery of novel nonsteroidal VDR agonists with novel diarylmethane skeleton for the treatment of breast cancer" [Eur. J. Med. Chem. 163 (2019) 787-803].

Eur J Med Chem 2020 01 30;186:111907. Epub 2019 Nov 30.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. Electronic address:

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http://dx.doi.org/10.1016/j.ejmech.2019.111907DOI Listing
January 2020

Populus euphratica WRKY1 binds the promoter of H+-ATPase gene to enhance gene expression and salt tolerance.

J Exp Bot 2020 02;71(4):1527-1539

Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, College of Biological Sciences and Technology (Box 162), Beijing Forestry University, Beijing, PR China.

Plasma membrane proton pumps play a crucial role in maintaining ionic homeostasis in salt-resistant Populus euphratica under saline conditions. High levels of NaCl (200 mM) induced PeHA1 expression in P. euphratica roots and leaves. We isolated a 2022 bp promoter fragment upstream of the translational start of PeHA1 from P. euphratica. The promoter-reporter construct PeHA1-pro::GUS was transferred to tobacco plants, demonstrating that β-glucuronidase activities increased in root, leaf, and stem tissues under salt stress. DNA affinity purification sequencing revealed that PeWRKY1 protein targeted the PeHA1 gene. We assessed the salt-induced transcriptional response of PeWRKY1 and its interaction with PeHA1 in P. euphratica. PeWRKY1 binding to the PeHA1 W-box in the promoter region was verified by a yeast one-hybrid assay, EMSA, luciferase reporter assay, and virus-induced gene silencing. Transgenic tobacco plants overexpressing PeWRKY1 had improved expression of NtHA4, which has a cis-acting W-box in the regulatory region, and improved H+ pumping activity in both in vivo and in vitro assays. We conclude that salt stress up-regulated PeHA1 transcription due to the binding of PeWRKY1 to the W-box in the promoter region of PeHA1. Thus, we conclude that enhanced H+ pumping activity enabled salt-stressed plants to retain Na+ homeostasis.
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http://dx.doi.org/10.1093/jxb/erz493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031066PMC
February 2020

Single-Cell RNA Sequencing Resolves Spatiotemporal Development of Pre-thymic Lymphoid Progenitors and Thymus Organogenesis in Human Embryos.

Immunity 2019 11 8;51(5):930-948.e6. Epub 2019 Oct 8.

Department of Rheumatology and Immunology, Rare Disease Center, the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. Collaboration and Innovation Center for Biotherapy. Chengdu 610041, China. Electronic address:

Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.
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http://dx.doi.org/10.1016/j.immuni.2019.09.008DOI Listing
November 2019

Self-assembled micelles based on N-octyl-N'-phthalyl-O-phosphoryl chitosan derivative as an effective oral carrier of paclitaxel.

Carbohydr Polym 2019 Mar 6;207:428-439. Epub 2018 Dec 6.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

Herein, we describe a novel amphipathic chitosan derivative (N-octyl-N'-phthalyl-O-phosphoryl chitosan, abbreviated as OPPC) as an effective oral delivery platform for P-gp substrates, especially paclitaxel (PTX). OPPC could readily self-assemble into micelles, solubilize and encapsulate PTX into the hydrophobic inner core of OPPC with superior loading capacity to chitosan. PTX/OPPC micelles possessed improved intestinal epithelial permeability and oral bioavailability of PTX evaluated by in situ perfusion and pharmacokinetic studies. In vivo fluorescence imaging revealed enhanced stability and integrity of OPPC micelles in mice gastrointestine. Furthermore, cellular uptake studies revealed effective transport and accumulation of OPPC micelles loading PTX or rhodamine-123 into Caco-2 cells via clathrin/cavelin-mediated endocytosis and OPPC-mediated P-gp inhibition. Mechanistically, the inhibition of P-gp efflux pumps by OPPC resulted from the reduction of membrane fluidity and decreased P-gp ATPase activity. In summary, OPPC micelles may serve as an efficient and promising delivery system for enhancing oral bioavailability of P-gp substrates.
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http://dx.doi.org/10.1016/j.carbpol.2018.11.099DOI Listing
March 2019

Discovery of novel nonsteroidal VDR agonists with novel diarylmethane skeleton for the treatment of breast cancer.

Eur J Med Chem 2019 Feb 14;163:787-803. Epub 2018 Dec 14.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China. Electronic address:

Vitamin D receptor (VDR) is recognized as a potential target for the treatment of breast cancer which is the most common malignancy among women in the world. In this study, a series of nonsecosteroidal VDR agonists with a novel diarylmethane skeleton was designed, synthesized and the anti-tumor activities of these compounds were determined. Compound 28 was identified as the most effective agents in reducing the viability of MCF-7 cells, with a low IC via the inhibition of cell cycle and induction of apoptosis by regulating the expression of p21, Bcl2 and Bax. In addition, compound 28 showed high VDR-binding affinity and displayed significant VDR-agonistic activities. Further investigation revealed that compound 28 inhibited tumor growth in an orthotopic breast-tumor model without causing hypercalcemia which is the main side effect of secosteroidal VDR modulators. In summary, these findings discovered novel VDR modulators as promising candidates for cancer chemotherapy.
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http://dx.doi.org/10.1016/j.ejmech.2018.12.024DOI Listing
February 2019

Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton.

J Med Chem 2018 12 3;61(23):10573-10587. Epub 2018 Dec 3.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery , China Pharmaceutical University , 24 Tong Jia Xiang , Nanjing 210009 , China.

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and results in impaired liver function. Vitamin D plays a critical role in the development of liver fibrosis as it inhibits transforming growth factor β1 (TGFβ1)-induced excessive deposition of ECM in activated hepatic stellate cells (HSCs). Here, a series of novel nonsecosteroidal vitamin D receptor (VDR) agonists with phenyl-pyrrolyl pentane skeleton was designed and synthesized. Among them, seven compounds including 15a exhibited more efficient inhibitory activity in collagen deposition and fibrotic gene expression. Histological examination results displayed that compound 15a treatment prevented the development of hepatic fibrosis that induced by carbon tetrachloride (CCl) injections in mice. In addition, compound 15a, unlike the positive control calcipotriol and 1,25(OH)D, did not cause hypercalcemia that is toxic to nerve, heart, and many other organs. These findings provide novel insights into drug discoveries for hepatic fibrosis using nonsecosteroidal VDR modulators.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01165DOI Listing
December 2018

Synergistic Effects of Mesenchymal Stem Cell Transplantation and Repetitive Transcranial Magnetic Stimulation on Promoting Autophagy and Synaptic Plasticity in Vascular Dementia.

J Gerontol A Biol Sci Med Sci 2019 08;74(9):1341-1350

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, China.

Repetitive transcranial magnetic stimulation (rTMS) and mesenchymal stem cells (MSCs) transplantation both showed therapeutic effects on cognition impairment in vascular dementia (VD) model rats. However, whether these two therapies have synergistic effects and the molecular mechanisms remain unclear. In our present study, rats were randomly divided into six groups: control group, sham operation group, VD group, MSC group, rTMS group, and MSC+rTMS group. The VD model rats were prepared using a modified 2VO method. rTMS treatment was implemented at a frequency of 5 Hz, the stimulation intensity for 0.5 Tesla, 20 strings every day with 10 pulses per string and six treatment courses. The results of the Morris water maze test showed that the learning and memory abilities of the MSC group, rTMS group, and MSC+rTMS group were better than that of the VD group, and the MSC+rTMS group showed the most significant effect. The protein expression levels of brain-derived neurotrophic factor, NR1, LC3-II, and Beclin-1 were the highest and p62 protein was the lowest in the MSC+rTMS group. Our findings demonstrated that rTMS could further enhance the effect of MSC transplantation on VD rats and provided an important basis for the combined application of MSC transplantation and rTMS to treat VD or other neurological diseases.
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http://dx.doi.org/10.1093/gerona/gly221DOI Listing
August 2019

Inhibition of PPARγ, adipogenesis and insulin sensitivity by MAGED1.

J Endocrinol 2018 11;239(2):167-180

Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE family member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and loss of MAGED1 promoted preadipocyte proliferation and differentiation in vitro. MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to WT littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors and hyperplasia of white adipose tissues (WATs). Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity, normal levels of serum lipids and enhanced secretion of adipokines such as leptin and adiponectin. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.
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http://dx.doi.org/10.1530/JOE-18-0349DOI Listing
November 2018

A simple, fast, and accurate thermodynamic-based approach for transfer and prediction of gas chromatography retention times between columns and instruments Part III: Retention time prediction on target column.

J Sep Sci 2018 Jun 25;41(12):2559-2564. Epub 2018 Apr 25.

Department of Chemistry, University of Alberta, Edmonton, AB, Canada.

This is the third part of a three-part series of papers. In Part I, we presented a method for determining the actual effective geometry of a reference column as well as the thermodynamic-based parameters of a set of probe compounds in an in-house mixture. Part II introduced an approach for estimating the actual effective geometry of a target column by collecting retention data of the same mixture of probe compounds on the target column and using their thermodynamic parameters, acquired on the reference column, as a bridge between both systems. Part III, presented here, demonstrates the retention time transfer and prediction from the reference column to the target column using experimental data for a separate mixture of compounds. To predict the retention time of a new compound, we first estimate its thermodynamic-based parameters on the reference column (using geometric parameters determined previously). The compound's retention time on a second column (of previously determined geometry) is then predicted. The models and the associated optimization algorithms were tested using simulated and experimental data. The accuracy of predicted retention times shows that the proposed approach is simple, fast, and accurate for retention time transfer and prediction between gas chromatography columns.
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http://dx.doi.org/10.1002/jssc.201701345DOI Listing
June 2018

A simple, fast, and accurate thermodynamic-based approach for transfer and prediction of gas chromatography retention times between columns and instruments Part I: Estimation of reference column geometry and thermodynamic parameters.

J Sep Sci 2018 Jun 2;41(12):2544-2552. Epub 2018 May 2.

Department of Chemistry, University of Alberta, Edmonton, AB, Canada.

The transfer of retention times based on thermodynamic models between columns can aid in separation optimization and compound identification in gas chromatography. Although earlier investigations have been reported, this problem remains unsuccessfully addressed. One barrier is poor predictive accuracy when moving from a reference column or system to a new target column or system. This is attributed to challenges associated with the accurate determination of the effective geometric parameters of the columns. To overcome this, we designed least squares-based models that account for geometric parameters of the columns and thermodynamic parameters of compounds as they partition between mobile and stationary phases. Quasi-Newton-based algorithms were then used to perform the numerical optimization. In this first of three parts, the model used to determine the geometric parameters of the reference column and the thermodynamic parameters of compounds subjected to separation is introduced. As will be shown, the overall approach significantly improves the predictive accuracy and transferability of thermodynamic data (and retention times) between columns of the same stationary phase chemistry. The data required for the determination of the thermodynamic parameters and retention time prediction are obtained from fast and simple experiments. The proposed model and optimization algorithms were tested and validated using simulated and experimental data.
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http://dx.doi.org/10.1002/jssc.201701343DOI Listing
June 2018

A simple, fast, and accurate thermodynamic-based approach for transfer and prediction of GC retention times between columns and instruments Part II: Estimation of target column geometry.

J Sep Sci 2018 Jun 25;41(12):2553-2558. Epub 2018 Apr 25.

Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.

The transfer of thermodynamic parameters governing retention of a molecule in gas chromatography from a reference column to a target column is a difficult problem. Successful transfer demands a mechanism whereby the column geometries of both columns can be determined with high accuracy. This is the second part in a series of three papers. In Part I of this work we introduced a new approach to determine the actual effective geometry of a reference column and thermodynamic-based parameters of a suite of compounds on the column. Part II, presented here, illustrates the rapid estimation of the effective inner diameter (or length) and the effective phase ratio of a target column. The estimation model based on the principle of least squares; a fast Quasi-Newton optimization algorithm was developed to provide adequate computational speed. The model and optimization algorithm were tested and validated using simulated and experimental data. This study, together with the work in Parts I and III, demonstrates a method that improves the transferability of thermodynamic models of gas chromatography retention between gas chromatography columns.
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http://dx.doi.org/10.1002/jssc.201701344DOI Listing
June 2018

Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents.

J Med Chem 2018 04 16;61(7):3059-3075. Epub 2018 Mar 16.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery , China Pharmaceutical University , 24 Tong Jia Xiang , Nanjing 210009 , China.

The vitamin D receptor (VDR), which belongs to the nuclear-receptor superfamily, is a potential molecular target for anticancer-drug discovery. In this study, a series of nonsteroidal vitamin D mimics with phenyl-pyrrolyl pentane skeletons with therapeutic potentials in cancer treatment were synthesized. Among them, 11b and 11g were identified as the most effective agents in reducing the viability of four cancer-cell lines, particularly those of breast-cancer cells, with IC values in the submicromolar-concentration range. In addition, 11b and 11g possessed VDR-binding affinities and displayed significant partial VDR-agonistic activities determined by dual-luciferase-reporter assays and human-leukemia-cell-line (HL-60)-differentiation assays. Furthermore, 11b and 11g inhibited tumor growth in an orthotopic breast-tumor model via inhibition of cell proliferation and induction of cell apoptosis. More importantly, 11b and 11g exhibited favorable pharmacokinetic behavior in vivo and did not increase serum calcium levels or cause any other apparent side effects. In summary, 11b and 11g act as novel VDR modulators and may be promising candidates for cancer chemotherapy.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00106DOI Listing
April 2018

HOXD-AS1 functions as an oncogenic ceRNA to promote NSCLC cell progression by sequestering miR-147a.

Onco Targets Ther 2017 28;10:4753-4763. Epub 2017 Sep 28.

State Key Laboratory of Pharmaceutical Biotechnology.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and it occurs at a higher frequency in males. HOXD-AS1, an important cancer-associated long noncoding RNA (lncRNA), contributes to the development and progression of several cancers. However, the exact roles of HOXD-AS1 in NSCLC progression are still unknown. Here, we investigated the underlying mechanisms of HOXD-AS1 in human NSCLC tissues. We found that lncRNA HOXD-AS1 was specifically upregulated (<0.001) in NSCLC tissues and promoted cancer cell growth by targeting miR-147a. Moreover, HOXD-AS1 expression positively correlated with NSCLC clinical pathologic characteristics (tumor size, =0.006; tumor stage, =0.044; recurrence, =0.031) and survival rate (=0.003). HOXD-AS1 knockdown reduced proliferation and promoted apoptosis of NSCLC cells. The dual-luciferase reporter assay showed that HOXD-AS1 could negatively regulate the expression of miR-147a. miR-147a inhibition abrogated the effect of HOXD-AS1 knockdown on the proliferation and apoptosis of NSCLC cells. Furthermore, HOXD-AS1 positively regulated the expression of pRB (a tumor suppressor protein) in NSCLC cells. Taken together, our data indicated that HOXD-AS1 might be an oncogenic lncRNA that promotes proliferation of NSCLC and could be a therapeutic target in NSCLC.
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http://dx.doi.org/10.2147/OTT.S143787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628688PMC
September 2017

Gastric Bypass Surgery Reverses Diabetic Phenotypes in Bdnf-Deficient Mice.

Am J Pathol 2016 08 11;186(8):2117-2128. Epub 2016 Jul 11.

State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China; Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing, China. Electronic address:

Duodenum-jejunum gastric bypass (DJB) has been used to treat morbid diabetic patients. However, neither the suitability among patients nor the mechanisms of this surgical treatment is clear. Previously, we reported a new mouse strain named Timo as type 2 diabetes model caused by brain-derived neurotrophic factor (Bdnf) deficiency. In this study, we found that DJB on Timo mice reversed their metabolic abnormalities without altering the expression of Bdnf. Glucose tolerance and insulin sensitivity were improved greatly, along with reduction of fat accumulation in liver and white adipose tissue. The gut flora population was altered by DJB with increased proportion of Firmicutes and decreased Actinobacteria and Proteobacteria in the ileum after surgery. Systemic inflammation in Timo mice was greatly suppressed with less macrophage infiltration and lower tumor necrosis factor-α levels in liver and white adipose tissue after surgery. Interestingly, the alteration of gut microflora abundance and improved metabolism preceded the inflammation alleviation after DJB surgery. These results suggested that DJB can reverse Bdnf deficiency-associated metabolic abnormality. In addition, the reduced inflammation may not be the initial cause for the DJB-associated metabolic and microbiota alterations. The increased BDNF protein levels in hypothalamus and hippocampus may result from microbiota change after DJB surgery.
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http://dx.doi.org/10.1016/j.ajpath.2016.04.009DOI Listing
August 2016

The Magea gene cluster regulates male germ cell apoptosis without affecting the fertility in mice.

Sci Rep 2016 05 26;6:26735. Epub 2016 May 26.

State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, China.

While apoptosis is essential for male germ cell development, improper activation of apoptosis in the testis can affect spermatogenesis and cause reproduction defects. Members of the MAGE-A (melanoma antigen family A) gene family are frequently clustered in mammalian genomes and are exclusively expressed in the testes of normal animals but abnormally activated in a wide variety of cancers. We investigated the potential roles of these genes in spermatogenesis by generating a mouse model with a 210-kb genomic deletion encompassing six members of the Magea gene cluster (Magea1, Magea2, Magea3, Magea5, Magea6 and Magea8). Male mice carrying the deletion displayed smaller testes from 2 months old with a marked increase in apoptotic germ cells in the first wave of spermatogenesis. Furthermore, we found that Magea genes prevented stress-induced spermatogenic apoptosis after N-ethyl-N-nitrosourea (ENU) treatment during the adult stage. Mechanistically, deletion of the Magea gene cluster resulted in a dramatic increase in apoptotic germ cells, predominantly spermatocytes, with activation of p53 and induction of Bax in the testes. These observations demonstrate that the Magea genes are crucial in maintaining normal testicular size and protecting germ cells from excessive apoptosis under genotoxic stress.
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http://dx.doi.org/10.1038/srep26735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880894PMC
May 2016

Smad4 Deficiency in Smooth Muscle Cells Initiates the Formation of Aortic Aneurysm.

Circ Res 2016 Feb 23;118(3):388-99. Epub 2015 Dec 23.

From the State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR China (P.Z., S.H., J.C., J.Z., F.L., R.J., X.C., Y.L., X.Y.); Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University, Shanghai, PR China (P.Z., J.C., X.Y.); Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, PR China (X.M., Y.S., Y.Z.); Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study and School of Medicine, Nanjing University, Nanjing, PR China (M.Z.); and Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing, PR China (J.D.).

Rationale: Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-β (TGF-β) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-β signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown.

Objective: To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms.

Methods And Results: Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-β receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-β in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs.

Conclusions: The findings reveal that Smad4-dependent TGF-β signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-β signaling loss-of-function mutations.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.308040DOI Listing
February 2016

A rapid field test for the measurement of bovine serum immunoglobulin G using attenuated total reflectance infrared spectroscopy.

BMC Vet Res 2015 Aug 20;11:218. Epub 2015 Aug 20.

Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, PEI C1A 4P3, Canada.

Background: Following the recent development of a new approach to quantitative analysis of IgG concentrations in bovine serum using transmission infrared spectroscopy, the potential to measure IgG levels using technology and a device better designed for field use was investigated. A method using attenuated total reflectance infrared (ATR) spectroscopy in combination with partial least squares (PLS) regression was developed to measure bovine serum IgG concentrations. ATR spectroscopy has a distinct ease-of-use advantage that may open the door to routine point-of-care testing. Serum samples were collected from calves and adult cows, tested by a reference RID method, and ATR spectra acquired. The spectra were linked to the RID-IgG concentrations and then randomly split into two sets: calibration and prediction. The calibration set was used to build a calibration model, while the prediction set was used to assess the predictive performance and accuracy of the final model. The procedure was repeated for various spectral data preprocessing approaches.

Results: For the prediction set, the Pearson's and concordance correlation coefficients between the IgG measured by RID and predicted by ATR spectroscopy were both 0.93. The Bland Altman plot revealed no obvious systematic bias between the two methods. ATR spectroscopy showed a sensitivity for detection of failure of transfer of passive immunity (FTPI) of 88 %, specificity of 100 % and accuracy of 94 % (with IgG <1000 mg/dL as the FTPI cut-off value).

Conclusion: ATR spectroscopy in combination with multivariate data analysis shows potential as an alternative approach for rapid quantification of IgG concentrations in bovine serum and the diagnosis of FTPI in calves.
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http://dx.doi.org/10.1186/s12917-015-0539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546031PMC
August 2015

Exploration of attenuated total reflectance mid-infrared spectroscopy and multivariate calibration to measure immunoglobulin G in human sera.

Talanta 2015 Sep 23;142:110-9. Epub 2015 Apr 23.

Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3. Electronic address:

Immunoglobulin G (IgG) is crucial for the protection of the host from invasive pathogens. Due to its importance for human health, tools that enable the monitoring of IgG levels are highly desired. Consequently there is a need for methods to determine the IgG concentration that are simple, rapid, and inexpensive. This work explored the potential of attenuated total reflectance (ATR) infrared spectroscopy as a method to determine IgG concentrations in human serum samples. Venous blood samples were collected from adults and children, and from the umbilical cord of newborns. The serum was harvested and tested using ATR infrared spectroscopy. Partial least squares (PLS) regression provided the basis to develop the new analytical methods. Three PLS calibrations were determined: one for the combined set of the venous and umbilical cord serum samples, the second for only the umbilical cord samples, and the third for only the venous samples. The number of PLS factors was chosen by critical evaluation of Monte Carlo-based cross validation results. The predictive performance for each PLS calibration was evaluated using the Pearson correlation coefficient, scatter plot and Bland-Altman plot, and percent deviations for independent prediction sets. The repeatability was evaluated by standard deviation and relative standard deviation. The results showed that ATR infrared spectroscopy is potentially a simple, quick, and inexpensive method to measure IgG concentrations in human serum samples. The results also showed that it is possible to build a united calibration curve for the umbilical cord and the venous samples.
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http://dx.doi.org/10.1016/j.talanta.2015.04.010DOI Listing
September 2015

Procrustes rotation as a diagnostic tool for projection pursuit analysis.

Anal Chim Acta 2015 Jun 5;877:51-63. Epub 2015 Mar 5.

Departamento de Engenharia Química, Universidade Federal de Pernambuco, Recife, PE, Brazil.

Projection pursuit (PP) is an effective exploratory data analysis tool because it optimizes the projection of high dimensional data using distributional characteristics rather than variance or distance metrics. The recent development of fast and simple PP algorithms based on minimization of kurtosis for clustering data has made this powerful tool more accessible, but under conditions where the sample-to-variable ratio is small, PP fails due to opportunistic overfitting of random correlations to limiting distributional targets. Therefore, some kind of variable compression or data regularization is required in these cases. However, this introduces an additional parameter whose optimization is manually time consuming and subject to bias. The present work describes the use of Procrustes analysis as diagnostic tool that can be used to evaluate the results of PP analysis in an efficient manner. Through Procrustes rotation, the similarity of different PP projections can be examined in an automated fashion with "Procrustes maps" to establish regions of stable projections as a function of the parameter to be optimized. The application of this diagnostic is demonstrated using principal components analysis to compress FTIR spectra from ink samples of ten different brands of pen, and also in conjunction with regularized PP for soybean disease classification.
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http://dx.doi.org/10.1016/j.aca.2015.03.006DOI Listing
June 2015

Liver-specific deletion of Ppp2cα enhances glucose metabolism and insulin sensitivity.

Aging (Albany NY) 2015 Apr;7(4):223-32

Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China.

Protein phosphatase 2A (PP2A) is a key negative regulator of phosphatidylinositol 3-kinase/Akt pathway. Previous study showed that, in the liver, the catalytic subunit of PP2A (PP2Ac) is closely associated with insulin resistance syndrome, which is characterized by glucose intolerance and dyslipidemia. Here we studied the role of liver PP2Ac in glucose metabolism and evaluated whether PP2Ac is a suitable therapeutic target for treating insulin resistance syndrome. Liver-specific Ppp2cα knockout mice (Ppp2cα(loxp/loxp): Alb) exhibited improved glucose homeostasis compared with littermate controls in both normal and high-fat diet conditions, despite no significant changes in body weight and liver weight under chow diet. Ppp2cα(loxp/loxp): Alb mice showed enhanced glycogen deposition, serum triglyceride, cholesterol, low density lipoprotein and high density lipoprotein, activated insulin signaling, decreased expressions of gluconeogenic genes G6P and PEPCK, and lower liver triglyceride. Liver-specific Ppp2cα knockout mice showed enhanced glucose homeostasis and increased insulin sensitivity by activation of insulin signaling through Akt. These findings suggest that inhibition of hepatic Ppp2cα may be a useful strategy for the treatment of insulin resistance syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429087PMC
http://dx.doi.org/10.18632/aging.100725DOI Listing
April 2015

Loss of conserved Gsdma3 self-regulation causes autophagy and cell death.

Biochem J 2015 Jun;468(2):325-36

*Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.

Gasdermin A3 (Gsdma3) was originally identified in association with hair-loss phenotype in mouse mutants. Our previous study found that AE mutant mice, with a Y344H substitution at the C-terminal domain of Gsdma3, display inflammation-dependent alopecia and excoriation [Zhou et al. (2012) Am. J. Pathol. 180, 763-774]. Interestingly, we found that the newly-generated null mutant of Gsdma3 mice did not display the skin dysmorphology, indicating that Gsdma3 is not essential for differentiation of epidermal cells and maintenance of the hair cycle in normal physiological conditions. Consistently, human embryonic kidney (HEK)293 and HaCaT cells transfected with wild-type (WT) Gsdma3 did not show abnormal morphology. However, Gsdma3 Y344H mutation induced autophagy. Gsdma3 N-terminal domain, but not the C-terminal domain, also displayed the similar pro-autophagic activity. The Gsdma3 Y344H mutant protein and N-terminal domain-induced autophagy was associated with mitochondria and ROS generation. Co-expression of C-terminal domain reversed the cell autophagy induced by N-terminal domain. Moreover, C-terminal domain could be co-precipitated with N-terminal domain. These data indicated that the potential pro-autophagic activity of WT Gsdma3 protein is suppressed through an intramolecular inhibition mechanism. Studies on other members of the GSDM family suggested this mechanism is conserved in several sub-families.
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http://dx.doi.org/10.1042/BJ20150204DOI Listing
June 2015

Measurement of serum immunoglobulin G in dairy cattle using Fourier-transform infrared spectroscopy: a reagent free approach.

Vet J 2014 Dec 20;202(3):510-5. Epub 2014 Sep 20.

Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, 550 University Avenue, Charlottetown, Prince Edward Island C1A 4P3, Canada.

Simple, rapid and cost-effective methods are sought for measuring immunoglobulin G (IgG) concentrations in bovine serum, which can be applied for diagnosis of failure of transfer of passive immunity (FTPI). The aim of the present study was to investigate the potential use of Fourier-transform infrared (FTIR) spectroscopy, with partial least squares (PLS) regression, to measure IgG concentrations in bovine serum. Serum samples collected from calves and adult cows were tested in parallel by radial immunodiffusion (RID) assay and FTIR spectroscopy. The sample IgG concentrations obtained by the RID method were linked to pre-processed spectra and divided into two sets: a combined set and a test set. The combined set was used for building a calibration model, while the test set was used to assess the predictive ability of the calibration model, resulting in a root mean squared error of prediction (RMSEP) of 307.5 mg/dL. The concordance correlations between the IgG measured by RID and predicted by FTIR spectroscopy were 0.96 and 0.93 for the combined and test data sets, respectively. Analysis of the data using the Bland-Altman method did not show any evidence of systematic bias between FTIR spectroscopy and RID methods for measurement of IgG. The clinical applicability of FTIR spectroscopy for diagnosis of FTPI was evaluated using the entire data set and showed a sensitivity of 0.91 and specificity of 0.96, using RID as the reference standard. The FTIR spectroscopy method, described in the present study, demonstrates potential as a rapid and reagent-free tool for quantification of IgG in bovine serum, as an aid to diagnosis of FTPI in calves.
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http://dx.doi.org/10.1016/j.tvjl.2014.09.014DOI Listing
December 2014

Immunoglobulin G measurement in blood plasma using infrared spectroscopy.

Appl Spectrosc 2014 ;68(4):466-74

University of Prince Edward Island, Department of Health Management, Atlantic Veterinary College, Charlottetown, PEI, C1A 4P3 Canada.

A rapid, simple, and inexpensive method to measure the immunoglobulin G (IgG) concentrations in blood samples in human and veterinary medicine is highly desired. Infrared spectroscopy (coupled with chemometric manipulation of spectral data) has the advantages of simple sample preparation, rapid implementation of analysis, and low cost. Here a method that exploits infrared spectroscopy as the basis to measure IgG concentration in animal plasma samples is reported, with radial immunodiffusion (RID) used as the reference test method for partial least squares (PLS) calibration model development. Smoothed non-derivative and the second-order derivative spectra were used to develop calibration models. Various additional spectral preprocessing steps were evaluated to optimize the calibration models, and the possible benefits of using an internal standard (potassium thiocyanate [KSCN]) were investigated. Monte Carlo cross-validation was used to determine the optimal number of PLS factors, and an independent prediction set was used to test the predictive performances of provisional models. The effects of various preprocessing options (spectral smoothing, derivation, normalization, region selection, mean-centering, and standard deviation scaling) on quantification accuracy were investigated. The root mean squared error of prediction (RMSEP) for different combinations of spectra preprocessing steps was 394 ± 36 mg/dL for the non-derivative spectra and 427 ± 101 mg/dL for the second-order derivative spectra. Immunoglobulin G concentrations produced by the optimized PLS model for the non-derivative spectra (RMSEP = 352 mg/dL) were found to be stable with respect to different splits of the samples among the calibration, validation, and prediction sets. The precision of the Fourier transform infrared (FT-IR) method is found to be slightly superior to that of the RID method. The results of this work indicate that infrared spectroscopy is a promising technique for economically and rapidly determining the IgG concentrations of plasma and plasma-derived samples.
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http://dx.doi.org/10.1366/12-06869DOI Listing
December 2014

A meta-analysis on Rituximab combined CHOP chemotherapy for non-Hodgkin lymphoma in China.

Authors:
Siyuan Hou Wei Yang

Saudi Med J 2011 Jul;32(7):675-8

Department of Hematology, Affiliated Shengjing Hospital of China Medical University, Shenyang, China.

Objective: To evaluate the curative effect of Rituximab combined CHOP chemotherapy in patients with non-Hodgkin lymphoma in China.

Methods: We conducted this study in the Affiliated Shengjing Hospital of China Medical University, Shenyang, China between June and December 2010. We used the systematic review method of The Cochrane Collaboration to collect randomized controlled trials (RCTs) of Rituximab combined CHOP chemotherapy for non-Hodgkin lymphoma by computer databases during the period 2004-2009.

Results: Seven trials involving 357 patients were retrieved. The complete remission rate of Rituximab combined CHOP chemotherapy was higher than that of CHOP chemotherapy alone (odds ratio = 3.02, 95% confidence interval: 1.94-4.72, p<0.00001).

Conclusion: Non-Hodgkin lymphoma treated by Rituximab combined CHOP chemotherapy can produce a positive therapeutic effect in China.
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July 2011