Publications by authors named "Yin Gu"

27 Publications

  • Page 1 of 1

Human physiological responses of exposure to extremely cold environments.

J Therm Biol 2021 May 3;98:102933. Epub 2021 Apr 3.

School of Emergency Management & Safety Engineering, China University of Mining and Technology, Beijing, 100083, China.

Extremely cold events have occurred more frequently in the past few years. People exposed to extremely cold exposure could suffer the threats of human health and safety like cold stress and injury. This study aims to investigate human physiological responses of exposure to extremely cold environments and the moment of temperature step. The experiments of 12 subjects exposed to three different cold exposure conditions (-5 °C, -10 °C, -15 °C) were carried out in a climate chamber. Most critical physiological parameters, including the core temperature, local skin temperature, blood pressure, heart rate, respiration rate and blood oxygen saturation, were measured to evaluate human physiological responses. In the particular short term study, the results show that the local skin temperature and blood pressure are the most significant indexes for evaluating the risk of cold strain in extremely cold environment. The finger temperature is a critical index of hand and finger flexibility, and it will lead to serious injuries and reduced manual performance when exposed to below -5 °C for more than 20 min. The high physiological strain at the very beginning moment of cold exposure can significantly affect the ability to make correct judgment and action, and it is suggested that the personnel adapt for 3 min after entering into the extremely cold environment to stabilize physiological parameters and thus enhancing the safety and occupational performance. The experimental data of this study is also of great significance for the development and validation of thermophysiological models.
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http://dx.doi.org/10.1016/j.jtherbio.2021.102933DOI Listing
May 2021

TRIM52 positively mediates NF-κB to promote the growth of human benign prostatic hyperplasia cells through affecting TRAF2 ubiquitination.

Life Sci 2020 Oct 6;259:118380. Epub 2020 Sep 6.

Department of Urology and Reproductive Medicine, Seventh People's Hospital of Shanghai University of TCM, Shanghai 200137, China.

Aims: Benign prostatic hyperplasia (BPH) is a progressive disease, which severely affects men's health. Here, we sought to analyze the functions and mechanism of action of the tripartite motif protein 52 (TRIM52), a novel prostate basal cell biomarker in BPH.

Materials And Methods: Immunohistochemistry assay was performed in sectioned human BPH tissues, BPH-1 cells, and prostate RWPE-1 cells, to detect the expressions of TRIM52 and NF-κB. Western blotting and qRT-PCR analyses were conducted to measure the relative protein and mRNA expression levels, respectively. Further, lentiviral transfection was performed in BPH-1 and RWPE-1 cells to study the overexpression and siRNA knockdown of TRIM52. Dual-luciferase reporter assay was applied to evaluate the relationship between NF-κB and TRIM52. Furthermore, CCK-8 assay and flow cytometry were employed to analyze cell proliferation and apoptosis.

Key Findings: TRIM52 and NF-κB levels were elevated in BPH tissues, and TRIM52 expression positively correlated with NF-κB expression. TRIM52 silencing suppressed the growth of BPH-1 cells and decreased the promoter activity of NF-κB. Moreover, the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), suppressed TRIM52-induced proliferation of RWPE-1 cells and inhibited NF-κB promoter activity in oeTRIM52 transfected RWPE-1 cells. Silencing TRIM52 also inhibited TRAF2 ubiquitination in BPH-1 cells. Further, NF-κB promoter activity in siNC transfected cells was enhanced by the recombinant protein TNF-α and inhibited by siTRIM52.

Significance: TRIM52 accelerated the growth of BPH-1 cells by upregulating NF-κB, and TRIM52 could promote TRAF2 ubiquitination. These findings might contribute to the understanding of the biological functions and action mechanisms of TRIM52 in BPH.
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http://dx.doi.org/10.1016/j.lfs.2020.118380DOI Listing
October 2020

A Fully Integrated In Vitro Diagnostic Microsystem for Pathogen Detection Developed Using a "3D Extensible" Microfluidic Design Paradigm.

Micromachines (Basel) 2019 Dec 12;10(12). Epub 2019 Dec 12.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China.

Microfluidics is facing critical challenges in the quest of miniaturizing, integrating, and automating in vitro diagnostics, including the increasing complexity of assays, the gap between the macroscale world and the microscale devices, and the diverse throughput demands in various clinical settings. Here, a "3D extensible" microfluidic design paradigm that consists of a set of basic structures and unit operations was developed for constructing any application-specific assay. Four basic structures-check valve (in), check valve (out), double-check valve (in and out), and on-off valve-were designed to mimic basic acts in biochemical assays. By combining these structures linearly, a series of unit operations can be readily formed. We then proposed a "3D extensible" architecture to fulfill the needs of the function integration, the adaptive "world-to-chip" interface, and the adjustable throughput in the X, Y, and Z directions, respectively. To verify this design paradigm, we developed a fully integrated loop-mediated isothermal amplification microsystem that can directly accept swab samples and detect automatically with a sensitivity one order higher than that of the conventional kit. This demonstration validated the feasibility of using this paradigm to develop integrated and automated microsystems in a less risky and more consistent manner.
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http://dx.doi.org/10.3390/mi10120873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953088PMC
December 2019

How Lifestyle Factors Affect Cognitive and Executive Function and the Ability to Learn in Children.

Nutrients 2019 Aug 20;11(8). Epub 2019 Aug 20.

Department of Kinesiology, Curry School of Education and Human Development, University of Virginia, Charlottesville, VA 22903, USA.

In today's research environment, children's diet, physical activity, and other lifestyle factors are commonly studied in the context of health, independent of their effect on cognition and learning. Moreover, there is little overlap between the two literatures, although it is reasonable to expect that the lifestyle factors explored in the health-focused research are intertwined with cognition and learning processes. This thematic review provides an overview of knowledge connecting the selected lifestyle factors of diet, physical activity, and sleep hygiene to children's cognition and learning. Research from studies of diet and nutrition, physical activity and fitness, sleep, and broader influences of cultural and socioeconomic factors related to health and learning, were summarized to offer examples of research that integrate lifestyle factors and cognition with learning. The literature review demonstrates that the associations and causal relationships between these factors are vastly understudied. As a result, current knowledge on predictors of optimal cognition and learning is incomplete, and likely lacks understanding of many critical facts and relationships, their interactions, and the nature of their relationships, such as there being mediating or confounding factors that could provide important knowledge to increase the efficacy of learning-focused interventions. This review provides information focused on studies in children. Although basic research in cells or animal studies are available and indicate a number of possible physiological pathways, inclusion of those data would distract from the fact that there is a significant gap in knowledge on lifestyle factors and optimal learning in children. In a climate where childcare and school feeding policies are continuously discussed, this thematic review aims to provide an impulse for discussion and a call for more holistic approaches to support child development.
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http://dx.doi.org/10.3390/nu11081953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723730PMC
August 2019

Modular-Based Integrated Microsystem with Multiple Sample Preparation Modules for Automated Forensic DNA Typing from Reference to Challenging Samples.

Anal Chem 2019 06 14;91(11):7435-7443. Epub 2019 May 14.

Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Tsinghua University , Beijing , 100084 , China.

The realization of an automated short tandem repeat (STR) analysis for forensic investigations is facing a unique challenge, that is DNA evidence with wide disparities in sample types, quality, and quantity. We developed a fully integrated microsystem in a modular-based architecture to accept and process various forensic samples in a "sample-in-answer-out" manner for forensic STR analysis. Two sample preparation modules (SPMs), the direct and the extraction SPM, were designed to be easily assembled with a capillary array electrophoresis (CAE) chip using a chip cartridge to efficiently achieve an adequate performance to different samples at a low cost. The direct SPM processed buccal swabs to produce STR profiles without DNA extraction in about 2 h. The extraction SPM analyzed more challenging blood samples based on chitosan-modified quartz filter paper for DNA extraction. This newly developed quartz filter provided a 90% DNA extraction efficiency and the "in situ" PCR capability, which enabled DNA extraction and PCR performed within a single chamber with all the DNA concentrated in the filter. We demonstrated that minute amounts of blood (0.25 μL), highly diluted blood (0.5 μL blood in 1 mL buffer), and latent bloodstains (5-μL bloodstain on cloth washed with detergent) can be automatically analyzed using our microsystem, reliably producing full STR profiles with a 100% calling of all the alleles. This modular-based microsystem with the capability of analyzing a wide range of samples should be able to play an increasing role in both urgent situations and routine forensic investigations, dramatically extending the applications and utility of automated DNA typing.
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http://dx.doi.org/10.1021/acs.analchem.9b01560DOI Listing
June 2019

Multiplex sample-to-answer detection of bacteria using a pipette-actuated capillary array comb with integrated DNA extraction, isothermal amplification, and smartphone detection.

Lab Chip 2018 09;18(18):2854-2864

Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, 100084, China.

A pipette-actuated capillary array comb (PAAC) system operated on a smartphone-based hand-held device has been successfully developed for the multiplex detection of bacteria in a "sample-to-answer" manner. The PAAC consists of eight open capillaries inserted into a cylindrical plastic base with a piece of chitosan-modified glass filter paper embedded in each capillary. During the sample preparation, a PAAC was mounted into a 1 mL pipette tip with an enlarged opening and was operated with a 1 mL pipette for liquid handling. The cell lysate was drawn and expelled through the capillaries three times to facilitate the DNA capture on the embedded filter discs. Following washes with water, the loop-mediated isothermal amplification (LAMP) reagents were aspirated into the capillaries, in which the primers were pre-fixed with chitosan. After that, the PAAC was loaded into the smartphone-based device for a one-hour amplification at 65 °C and end-point detection of calcein fluorescence in the capillaries. The DNA capture efficiency of a 1.1 mm-diameter filter disc was determined to be 97% of λ-DNA and the coefficient of variation among the eight capillaries in the PAAC was only 2.2%. The multiplex detection of genomic DNA extracted from Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus provided limits of detection of 200, 500, and 500 copies, respectively, without any cross-contamination and cross reactions. "Sample-to-answer" detection of E. coli samples was successfully completed in 85 minutes, demonstrating a sensitivity of 200 cfu per capillary. The multiplex "sample-to-answer" detection, the streamlined operation, and the compact device should facilitate a broad range of applications of our PAAC system in point-of-care testing.
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http://dx.doi.org/10.1039/c8lc00543eDOI Listing
September 2018

A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies.

Blood Adv 2017 Jun 21;1(15):1088-1100. Epub 2017 Jun 21.

Oncology Research & Development.

The chemokine receptor CXCR4 is highly expressed and associated with poor prognosis in multiple malignancies. Upon engagement by its ligand, CXCL12, CXCR4 triggers intracellular signaling pathways that control trafficking of cells to tissues where the ligand is expressed, such as the bone marrow (BM). In hematologic cancers, CXCR4-driven homing of malignant cells to the BM protective niche is a key mechanism driving disease and therapy resistance. We developed a humanized CXCR4 immunoglobulin G1 (IgG1) antibody (Ab), PF-06747143, which binds to CXCR4 and inhibits CXCL12-mediated signaling pathways, as well as cell migration. In in vivo preclinical studies, PF-06747143 monotherapy rapidly and transiently mobilized cells from the BM into the peripheral blood. In addition, PF-06747143 effectively induced tumor cell death via its Fc constant region-mediated effector function. This Fc-mediated cell killing mechanism not only enhanced antitumor efficacy, but also played a role in reducing the duration of cell mobilization, when compared with an IgG4 version of the Ab, which does not have Fc-effector function. PF-06747143 treatment showed strong antitumor effect in multiple hematologic tumor models including non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM). Importantly, PF-06747143 synergized with standard-of-care agents in a chemoresistant AML patient-derived xenograft model and in an MM model. These findings suggest that PF-06747143 is a potential best-in-class anti-CXCR4 antagonist for the treatment of hematologic malignancies, including in the resistant setting. PF-06747143 is currently in phase 1 clinical trial evaluation (registered at www.clinicaltrials.gov as #NCT02954653).
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http://dx.doi.org/10.1182/bloodadvances.2016003921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728311PMC
June 2017

Integrated Graphene Oxide Purification-Lateral Flow Test Strips (iGOP-LFTS) for Direct Detection of PCR Products with Enhanced Sensitivity and Specificity.

Anal Chem 2017 11 7;89(22):12137-12144. Epub 2017 Nov 7.

Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing, 100084, China.

An integrated graphene oxide purification-lateral flow test strip (iGOP-LFTS) was developed for on-strip purifying and visually detecting polymerase chain reaction (PCR) products with an improved sensitivity as well as a more stringent specificity. PCR products amplified with a pair of biotin- and digoxin-labeled primers were directly pipetted onto GO pads, on which graphene oxide selectively adsorbed residual primers and primer-dimers with the aid of a running buffer containing MgCl and Tween 20. By stacking up three GO pads to increase the surface area for adsorption, 83.4% of double-stranded DNA with a length of 30 bp and 98.6% of 20-nt primers could be removed from a 10-μL DNA mixture. Since no primers interfered with detection, the increase of the sample loading volume from 5 to 20 μL could improve the signal-to-noise ratio of the test line 1.6 fold using the iGOP-LFTS while no changes were observed using the conventional LFTS. The limit of detection of the iGOP-LFTS was determined to be 30 copies of bacteriophage λ-DNA with naked eyes and this limit could be further decreased to 3 copies by loading 20 μL of the sample, which corresponded to a 1000-fold improvement compared to that of the LFTS detected by naked eyes. When the ImageJ analysis was employed, a 100-fold decrease of the detection limit can be obtained. In addition, due to the removal of the primer-dimers, the dim test line observed in the negative control of the LFTS was eliminated using the iGOP-LFTS. A mock clinical specimen spiked with defective HIV-1 (human immunodeficiency virus) viruses was successfully analyzed using a two-step reverse transcription-PCR with 30 amplification cycles followed by the iGOP-LFTS detection. These significant improvements were achieved without introducing any additional hands-on operations and instrumentations.
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http://dx.doi.org/10.1021/acs.analchem.7b02769DOI Listing
November 2017

Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143).

Sci Rep 2017 08 4;7(1):7305. Epub 2017 Aug 4.

INSERM, UMR 1170, 114 rue Edouard Vaillant, 94805, Villejuif, France.

The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25-30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17 and P15 models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.
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http://dx.doi.org/10.1038/s41598-017-07848-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544749PMC
August 2017

Intravenous vs Oral Acetaminophen as an Adjunct to Multimodal Analgesia After Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Clinical Trial.

J Arthroplasty 2017 10 18;32(10):3029-3033. Epub 2017 May 18.

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: The efficacy of intravenous (IV) acetaminophen compared with its oral formulation for postoperative analgesia is unknown. We hypothesized that the addition of acetaminophen to a multimodal analgesia regimen would provide improved pain management in patients after total knee arthroplasty (TKA) and that the effect of acetaminophen would be variable based on the route of delivery.

Methods: The study was a single-center, randomized, double-blinded, placebo-controlled clinical trial on the efficacy of IV vs oral acetaminophen in patients undergoing unilateral TKA. One hundred seventy-four subjects were randomized to one of the 3 groups: IV acetaminophen group (IV group, n = 57) received 1 g IV acetaminophen and oral placebo before postanesthesia care unit (PACU) admission; oral acetaminophen group (PO group, n = 58) received 1 g oral acetaminophen and volume-matched IV normal saline; placebo group (Placebo group, n = 59) received oral placebo and volume-matched IV normal saline. Pain scores were obtained every 15 minutes during PACU stay. Average pain scores, maximum pain score, and pain scores before physical therapy were compared among the 3 groups. Secondary outcomes included total opiate consumption, time to PACU discharge, time to rescue analgesia, and time to breakthrough pain.

Results: The average PACU pain score was similar in the IV group (0.56 ± 0.99 [mean ± standard deviation]) compared with the PO group (0.67 ± 1.20; P = .84) and Placebo group (0.58 ± 0.99; P = .71). Total opiate consumption at 6 hours (0.47 mg hydromorphone equivalents ± 0.56 vs 0.54 ± 0.53 vs 0.54 ± 0.61; P = .69) and at 24 hours (1.25 ± 1.30 vs 1.49 ± 1.34 vs 1.36 ± 1.31; P = .46) were also similar between the IV, PO, and Placebo groups. No significant differences were found between all groups for any other outcome.

Conclusion: Neither IV nor oral acetaminophen provides additional analgesia in the immediate postoperative period when administered as an adjunct to multimodal analgesia in patients undergoing TKA in the setting of a spinal anesthetic.
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http://dx.doi.org/10.1016/j.arth.2017.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605416PMC
October 2017

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.

J Hematol Oncol 2017 05 19;10(1):112. Epub 2017 May 19.

Moores Cancer Center, University of California San Diego, 3855 Health Science Drive, La Jolla, CA, 92093-0820, USA.

Background: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.

Methods: Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.

Results: PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.

Conclusions: We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.
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http://dx.doi.org/10.1186/s13045-017-0435-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438492PMC
May 2017

Chitosan-Modified Filter Paper for Nucleic Acid Extraction and "in Situ PCR" on a Thermoplastic Microchip.

Anal Chem 2017 03 8;89(6):3568-3575. Epub 2017 Mar 8.

Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, China.

Plastic microfluidic devices with embedded chitosan-modified Fusion 5 filter paper (unmodified one purchased from GE Healthcare) have been successfully developed for DNA extraction and concentration, utilizing two different mechanisms for DNA capture: the physical entanglement of long-chain DNA molecules with the fiber matrix of the filter paper and the electrostatic adsorption of DNA to the chitosan-modified filter fibers. This new method not only provided a high DNA extraction efficiency at a pH of 5 by synergistically combining these two capture mechanisms together, but also resisted the elution of DNA from filters at a pH > 8 due to the entanglement of DNA with fibers. As a result, PCR buffers can be directly loaded into the extraction chamber for "in situ PCR", in which the captured DNA were used for downstream analysis without any loss. We demonstrated that the capture efficiencies of a 3-mm-diameter filter disc in a microchip were 98% and 95% for K562 human genomic DNA and bacteriophage λ-DNA, respectively. The washes with DI water, PCR mixture, and TE buffer cannot elute the captured DNA. In addition, the filter disc can enrich 62% of λ-DNA from a diluted sample (0.05 ng/μL), providing a concentration factor more than 30-fold. Finally, a microdevice with a simple two-chamber structure was developed for on-chip cell lysis, DNA extraction, and 15-plex short tandem repeat amplification from blood. This DNA extraction coupled with "in situ PCR" has great potential to be utilized in fully integrated microsystems for rapid, near-patient nucleic acid testing.
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http://dx.doi.org/10.1021/acs.analchem.6b04882DOI Listing
March 2017

Anesthesia management for cesarean section 10 years after heart transplantation: a case report.

Springerplus 2016 7;5(1):993. Epub 2016 Jul 7.

Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, 518028 Guangdong China.

Introduction: Pregnancy after organ transplantation is becoming increasingly common. However, reports of the anesthesia for such patients are rare. Heart transplant recipients are always accompanied with pathophysiological changes and present anesthesiologists with challenge.

Case Description: We reported a case of anesthesia management of gravida undergoing cesarean section 10 years after cardiac transplantation. We used two points spinal and epidural anesthesia, combined with phenylephrine throughout the surgery. The course was absolutely successful and both mother and baby got good results.

Discussion And Evaluation: Physiology of heart transplant recipients and key points of anesthesia management were discussed.

Conclusions: Spinal anesthesia can be performed in heart transplant recipients, however, we have to think twice before anesthesia for this kind of patients.
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http://dx.doi.org/10.1186/s40064-016-2701-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937040PMC
July 2016

Association of gene polymorphisms of FV, FII, MTHFR, SERPINE1, CTLA4, IL10, and TNFalpha with pre-eclampsia in Chinese women.

Inflamm Res 2016 Sep 27;65(9):717-24. Epub 2016 May 27.

Department of Obstetrics and Gynecology, Maternal and Children's Hospital of Shenzhen City, Southern Medical University, Shenzhen, 518000, China.

Objectives: To investigate the association of polymorphisms in genes involved in coagulation, fibrinolysis, and inflammation with pre-eclampsia (PE) in a Chinese population.

Methods: It is a case-control study of patients with PE (n = 117) and controls (n = 286) from the Maternal and Children's Hospital of Shenzhen City carried out between June 2014 and May 2015. The rs6025, rs6020, rs1801133, rs1799963, rs1799889, rs231775, rs1800896, rs1800629, and rs1799724 polymorphisms were analyzed using Snap Shot. Multifactor dimensionality reduction (MDR) and logistic regression analyses were carried out to assess the interactions among these SNPs.

Results: The frequencies of polymorphisms in tumor necrosis factor-α (TNF-α) (rs1800629 and rs1799724) and interleukin 10 (IL-10) (rs1800896) were significantly different between patients with PE and controls (P < 0.05). The best interaction model identified a marginally significant interaction between rs1799724 and rs1800896 (P = 0.05).

Conclusions: This study suggests that polymorphisms in the TNF-α and IL-10 genes could be associated with PE, but additional studies are necessary to explore the mechanisms involving these polymorphisms and the gene-gene interactions involved in the susceptibility to PE.
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http://dx.doi.org/10.1007/s00011-016-0953-yDOI Listing
September 2016

Intrathecal dexmedetomidine as adjuvant to ropivacaine in hysteroscopic surgery: a prospective, randomized control study.

Int J Clin Pharmacol Ther 2016 Mar;54(3):185-92

Background: To compare the effects and side effects of intrathecal ropivacaine supplemented with dexmedetomidine and fentanyl in hysteroscopic surgery under spinal anesthesia.

Methods: Female patients (n = 108) undergoing operative hysteroscopic procedures under spinal anesthesia were randomly allocated to the following groups for subarachnoid drug delivery: R (n = 36) received 7.5 mg ropivacaine; RD (n = 36) received 7.5 mg ropivacaine plus 5 μg dexmedetomidine; RF (n = 36) received 7.5 mg ropivacaine plus 15 μg fentanyl. The onset and regression time of sensory and motor blockade, together with the postoperative analgesia and side effects were recorded.

Results: There was no significant difference as to sensory and motor onset time between groups. RD had significantly longer sensory and motor blockade time than RF and R. The mean time of sensory regression to the S1 segment was 191.25 ± 40.24 minutes in RD, 149.86 ± 37.46 minutes in RF, and 139.44 ± 38.97 minutes in R (RD vs. R and RD vs. RF, p < 0.001). The regression time of motor blockade to Bromage score 0 was 146.31 ± 40.72 minutes in RD, 80.28 ± 41.18 minutes in RF, and 84.94 ± 26.11 minutes in R (RD vs. R and RD vs. RF, p < 0.001). RD produced similar analgesia effect with RF, (2 hour visual analog scale (VAS) was 0.00 ± 0.00 and 0.31 ± 0.79, respectively) better than the R group (1.35 ± 1.65, p < 0.005). No pruritus occurred in the RD group, while the rate was 36.1% in the RF group. However, the RD group produced milder postsurgical hypotension (RD vs. R and RD vs. RF, p < 0.05).

Conclusion: Intrathecal dexmedetomidine (5 μg) produced prolonged motor and sensory blockade and less pruritus compared with fentanyl (15 μg) in hysteroscopic surgery.
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http://dx.doi.org/10.5414/CP202427DOI Listing
March 2016

Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation.

PLoS One 2013 27;8(6):e67258. Epub 2013 Jun 27.

Oncology Research Unit, Pfizer Global Research & Development, San Diego, California, United States of America.

PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs) in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R) mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT) (S473), a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R) mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695076PMC
October 2017

Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line.

Front Med 2013 Dec 2;7(4):462-76. Epub 2013 Jul 2.

Oncology Research Unit, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA, 92121, USA,

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.
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http://dx.doi.org/10.1007/s11684-013-0270-6DOI Listing
December 2013

Survival benefit of traditional Chinese herbal medicine (a herbal formula for invigorating spleen) for patients with advanced gastric cancer.

Integr Cancer Ther 2013 Sep 9;12(5):414-22. Epub 2012 Jul 9.

Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Background: Traditional Chinese herbal medicine (TCHM) is widely used for advanced gastric cancer (AGC) in China. In this study, the authors analyzed the prognostic factors of selected patients with AGC, and further studied the efficacy of TCHM (a herbal formula for invigorating spleen, formerly named Wei Chang' An) on AGC.

Methods: Patients with uncured AGC were prospectively enrolled. All patients were enrolled to either the TCHM group or non-TCHM group. TCHM was administered orally to the patients in the TCHM group for 3 months or more. Cox regression analysis was performed to determine survival trends adjusted for clinical and demographic factors. Kaplan-Meier curves were used to assess the differences in survival time.

Results: There were a total of 399 eligible patients with histologically confirmed adenocarcinoma of the stomach from 2001 to 2009. In the overall group, Cox regression analysis suggested that histological type (P = .016), radiotherapy (P = .000), cycle of chemotherapy (P = .000), and TCHM (P = .000) were independent prognostic factors. In a stratification analysis of stage for 213 patients who received 3 or more cycles of chemotherapy, there was a significant increase in median overall survival from 14.0 (non-TCHM group) to 20.0 (TCHM group) months (hazard ratio [HR] = 0.538, 95% confidence interval [CI] 0.385-0.750, P = .000). Among 186 patients who did not receive chemotherapy, but best supportive care, there was a significant increase in median overall survival from 7.0 (non-TCHM group) to 14.8 (TCHM group) months (HR = 0.443, 95% CI = 0.299-0.657, P = .000).

Conclusions: TCHM has an important potential value for improving the prognosis of patients with AGC.
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http://dx.doi.org/10.1177/1534735412450512DOI Listing
September 2013

Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors.

Bioorg Med Chem Lett 2010 Jul 25;20(14):4060-4. Epub 2010 May 25.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A pyridazin-4-one fragment 4 (hCatS IC(50)=170 microM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC(50)=430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC(50)=60 nM) and 27 (hCatS IC(50)=40 nM).
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http://dx.doi.org/10.1016/j.bmcl.2010.05.086DOI Listing
July 2010

Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: optimization of cellular potency.

Bioorg Med Chem Lett 2009 Nov 10;19(21):6135-9. Epub 2009 Sep 10.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50=80-420 nM) and imparted cellular potency (IC50=0.8-4.0 microM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50=10-30 nM) and sub-micromolar cellular potency (JY Ii IC50=200-720 nM).
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http://dx.doi.org/10.1016/j.bmcl.2009.09.013DOI Listing
November 2009

Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements.

Bioorg Med Chem Lett 2009 Nov 10;19(21):6131-4. Epub 2009 Sep 10.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC50=40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme.
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http://dx.doi.org/10.1016/j.bmcl.2009.09.014DOI Listing
November 2009

Pyrazole-based cathepsin S inhibitors with improved cellular potency.

Bioorg Med Chem Lett 2007 Oct 22;17(20):5525-8. Epub 2007 Aug 22.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
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http://dx.doi.org/10.1016/j.bmcl.2007.08.038DOI Listing
October 2007

CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion.

J Cell Biol 2006 Mar;172(7):1057-68

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, CA 92121, USA.

Toll-like receptors (TLRs) recognize molecular patterns preferentially expressed by pathogens. In endosomes, TLR9 is activated by unmethylated bacterial DNA, resulting in proinflammatory cytokine secretion via the adaptor protein MyD88. We demonstrate that CpG oligonucleotides activate a TLR9-independent pathway initiated by two Src family kinases, Hck and Lyn, which trigger a tyrosine phosphorylation-mediated signaling cascade. This cascade induces actin cytoskeleton reorganization, resulting in cell spreading, adhesion, and motility. CpG-induced actin polymerization originates at the plasma membrane, rather than in endosomes. Chloroquine, an inhibitor of CpG-triggered cytokine secretion, blocked TLR9/MyD88-dependent cytokine secretion as expected but failed to inhibit CpG-induced Src family kinase activation and its dependent cellular responses. Knock down of Src family kinase expression or the use of specific kinase inhibitors blocked MyD88-dependent signaling and cytokine secretion, providing evidence that tyrosine phosphorylation is both CpG induced and an upstream requirement for the engagement of TLR9. The Src family pathway intersects the TLR9-MyD88 pathway by promoting the tyrosine phosphorylation of TLR9 and the recruitment of Syk to this receptor.
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http://dx.doi.org/10.1083/jcb.200508058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063763PMC
March 2006

The SAR of 4-substituted (6,6-bicyclic) piperidine cathepsin S inhibitors.

Bioorg Med Chem Lett 2006 Apr 3;16(8):2209-12. Epub 2006 Feb 3.

Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication.
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http://dx.doi.org/10.1016/j.bmcl.2006.01.038DOI Listing
April 2006

Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor tipifarnib.

J Pharmacol Exp Ther 2006 Apr 13;317(1):53-60. Epub 2005 Dec 13.

Alza/Johnson & Johnson Pharmaceutical Research & Development-La Jolla, San Diego, California, USA.

Protein farnesyltransferase inhibitors (FTIs) have shown clinical responses in hematologic malignancies, but the mechanisms are unclear. To better understand potential mechanisms of action, we have studied effects of the FTI tipifarnib on inflammatory responses in vitro and in vivo. In a human leukemia cell line THP-1, tipifarnib inhibited lipopolysaccharide (LPS)-induced transcription of chemokines [monocyte chemotactic protein (MCP)-1 and MCP-2], cytokines [interleukin (IL)-1beta, IL-6, and interferon (IFN)beta], signaling molecules (MyD88 and STAT-1), proteases [matrix metalloproteinase (MMP-9)], and receptors (urokinase receptor). Tipifarnib also inhibited LPS-induced secretion of MMP-9, IL-6, MCP-1, and IL-1beta in THP-1 cells. In primary human peripheral blood mononuclear cells, dose-dependent inhibition of LPS-induced tumor necrosis factor (TNF)-alpha, IL-6, MCP-1, and IL-1beta by tipifarnib was observed with no evidence of cytotoxicity. Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pretreatment with tipifarnib resulted in significant inhibition of TNF-alpha, IL-6, MCP-1, IL-1beta, and MIP-1alpha production. Tipifarnib had no effect in vitro or in vivo on LPS-induced IL-8. Studies in THP-1 cells to address potential mechanism(s) showed that tipifarnib partially inhibited LPS-induced p38 phosphorylation. Tipifarnib significantly inhibited inhibitory subunit of nuclear factor-kappaB (NF-kappaB) (IkappaB)-alpha degradation and p65 nuclear translocation induced by LPS, but not by tumor necrosis factor-alpha, IL-1alpha, or toll-like receptor (TLR)2 ligand, suggesting that the target for inhibition of NF-kappaB activation was exclusive to the LPS/TLR4 signal pathway. The extent of IkappaB-alpha degradation inhibition did not correlate with inhibition of Ras farnesylation, indicating that Ras was not the target for the observed anti-inflammatory activity of tipifarnib. Our findings differ from those for other FTIs, which may have relevance for their dissimilar activity in specific tumor repertoires.
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http://dx.doi.org/10.1124/jpet.105.095976DOI Listing
April 2006

Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors.

Bioorg Med Chem Lett 2005 Mar;15(6):1687-91

Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
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http://dx.doi.org/10.1016/j.bmcl.2005.01.045DOI Listing
March 2005

Identification of a potent and selective noncovalent cathepsin S inhibitor.

J Pharmacol Exp Ther 2004 Jan 17;308(1):268-76. Epub 2003 Oct 17.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., San Diego, California, USA.

Cathepsin S is considered crucial for normal presentation of major histocompatibility complex (MHC) class II-restricted antigens by antigen presenting cells to CD4+ T cells. It is a key enzyme for the degradation of the class II-associated invariant chain, a process that is required for effective antigen loading of class II molecules. Here, we report a selective, orally available, high-affinity cathepsin S inhibitor, 1-[3-[4-(6-Chloro-2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl]-4,5,6,7-tetrahydro-5-(methylsulfonyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine. (JNJ 10329670), that represents a novel class of immunosuppressive compounds. JNJ 10329670 is a highly potent (Ki of approximately 30 nM), nonpeptidic, noncovalent inhibitor of human cathepsin S, but it is much less active against the mouse, dog, monkey, and bovine enzymes. The compound is inactive against other proteases, including the closely related cathepsins L, F, and K. This selectivity makes JNJ 10329670 an excellent tool for exploring the role of cathepsin S in human systems. Treatment of human B cell lines and primary human dendritic cells with JNJ 10329670 resulted in the accumulation of the p10 fragment of the invariant chain (IC50 of approximately 1 microM). In contrast, inhibition of invariant chain proteolysis was much less effective in a human monocytic cell line, suggesting that other enzymes may degrade the invariant chain in this cell type. JNJ 10329670 was shown to block the proteolysis of the invariant chain in vivo by using immunocompromised mice injected with human peripheral blood mononuclear cells (PBMCs). Furthermore, this inhibitor blocks the presentation of tetanus toxoid and giant ragweed by human PBMCs. The properties of JNJ 10329670 make it a candidate for immunosuppressive therapy of allergies and autoimmune diseases.
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http://dx.doi.org/10.1124/jpet.103.056879DOI Listing
January 2004
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