Publications by authors named "Xiaoming Cui"

42 Publications

DNA Methylome Mapping Identifies Epigenetic Abnormalities in Intestinal Lymphocyte Regulation in Human Necrotizing Enterocolitis.

Dig Dis Sci 2021 Nov 30. Epub 2021 Nov 30.

Department of General Surgery, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, 200040, China.

Background: Epigenetic changes occur in response to environmental factors during the pathogenesis of necrotizing enterocolitis (NEC) in animal models, but the DNA methylation signature in human patients with NEC has not been examined.

Aim: To illustrate the signature and function of DNA methylation in the intestine of human NEC.

Methods: DNA methyltransferases (DNMTs) were compared between intestinal tissue with NEC and control. Genome-wide DNA methylation was analyzed by reduced representation bisulfite sequencing (RRBS). The biological functions of the potential methylation regulated genes were analyzed by Gene Ontology. Gene methylation and expression were confirmed by bisulfite genomic sequencing (BGS) and RT-qPCR.

Results: By screening the expression of DNMTs, we identified a marked reduction in DNMT3A at both the mRNA and protein levels in NEC. Genome-wide variation of DNA methylation was detected in NEC lesions. The CG methylation level in almost all unique regions except CpG islands (CGIs) was lower in NEC compared with control. A total of 287 differentially methylated regions (DMRs) were identified across the whole genome in NEC, 123 of them are located on the CGI in the promoter. The DMR-associated genes were linked to intestinal epithelial permeability, platelet aggregation, and lymphocyte proliferation. Four genes (ZNF335, MPL, RASAL3, and KDM6A) with roles in the regulation of lymphocytes that may predispose the intestine to imbalanced immune processes were further confirmed to be hypermethylated and transcriptionally downregulated.

Conclusions: These findings underscore the novel relationship between epigenetic changes and lymphocyte regulation in human NEC, which may have potential diagnostic and therapeutic relevance for NEC.
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http://dx.doi.org/10.1007/s10620-021-07314-6DOI Listing
November 2021

Transmission dynamics and the effects of non-pharmaceutical interventions in the COVID-19 outbreak resurged in Beijing, China: a descriptive and modelling study.

BMJ Open 2021 09 7;11(9):e047227. Epub 2021 Sep 7.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China

Objective: To evaluate epidemiological characteristics and transmission dynamics of COVID-19 outbreak resurged in Beijing and to assess the effects of three non-pharmaceutical interventions.

Design: Descriptive and modelling study based on surveillance data of COVID-19 in Beijing.

Setting: Outbreak in Beijing.

Participants: The database included 335 confirmed cases of COVID-19.

Methods: To conduct spatiotemporal analyses of the outbreak, we collected individual records on laboratory-confirmed cases of COVID-19 from 11 June 2020 to 5 July 2020 in Beijing, and visitor flow and products transportation data of Xinfadi Wholesale Market. We also built a modified susceptible-exposed-infected-removed model to investigate the effect of interventions deployed in Beijing.

Results: We found that the staff working in the market (52.2%) and the people around 10 km to this epicentre (72.5%) were most affected, and the population mobility entering-exiting Xinfadi Wholesale Market significantly contributed to the spread of COVID-19 (p=0.021), but goods flow of the market had little impact on the virus spread (p=0.184). The prompt identification of Xinfadi Wholesale Market as the infection source could have avoided a total of 25 708 (95% CI 13 657 to 40 625) cases if unnoticed transmission lasted for a month. Based on the model, we found that active screening on targeted population by nucleic acid testing alone had the most significant effect.

Conclusions: The non-pharmaceutical interventions deployed in Beijing, including localised lockdown, close-contact tracing and community-based testing, were proved to be effective enough to contain the outbreak. Beijing has achieved an optimal balance between epidemic containment and economic protection.
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http://dx.doi.org/10.1136/bmjopen-2020-047227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424429PMC
September 2021

Bilayer Membrane Composed of Mineralized Collagen and Chitosan Cast Film Coated With Berberine-Loaded PCL/PVP Electrospun Nanofiber Promotes Bone Regeneration.

Front Bioeng Biotechnol 2021 19;9:684335. Epub 2021 Jul 19.

Department of Microbiology, Weifang Medical University, Weifang, China.

Bone defects are difficult to repair and reconstruct as bone regeneration remains technically challenging, with exogenous factors required to accelerate this process. Biodegradable synthetic scaffolds are promising materials for stimulating bone tissue repair. In this study, we investigated whether a bilayer membrane that includes mineralized collagen (MC) and chitosan (CS) delivering berberine (BER)-a typical Chinese herbal monomer-could promote bone healing in a rat model. An MC/CS cast film was coated with polycaprolactone (PCL)/polyvinylpyrrolidone (PVP) electrospun nanofibers loaded with BER, yielding the [email protected]/PVP-MC/CS bilayer membrane. The 3-dimensional structure had nanofibers of uniform diameter and showed good hydrophilicity; the bilayer membrane showed favorable mechanical properties. [email protected]/PVP-MC/CS enhanced the proliferation and attachment of MC3T3-E1 cells and induced bone regeneration when implanted into a rat femoral bone defect. These findings provide evidence that [email protected]/PVP-MC/CS has clinical potential for effective bone repair.
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http://dx.doi.org/10.3389/fbioe.2021.684335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327095PMC
July 2021

Trichosanthin inhibits cervical cancer by regulating oxidative stress-induced apoptosis.

Bioengineered 2021 12;12(1):2779-2790

Department of Gynaecology and Obstetrics, Dongtai Hospital of Traditional Chinese Medicine, Dongtai, Yancheng City, Jiangsu Province, 224200, China.

Based on many studies, trichosanthin (TCS) has an antiviral effect that regulates immune response, and targets cancer cells to exert broad-spectrum anti-tumor pharmacological activities. It is speculated that TCS may be a potential natural active drug for preventing as well as treating cervical cancer. But the clearer impact along with underlying TCS mechanism on cervical cancer are still unclear. The purpose of this study is to investigate the function and potential mechanism of TCS in cervical cancer. We measured the viability of cervical cancer cell lines (HeLa & caski cells) using CCK-8 analysis, detected cell proliferation efficiency through Ki-67 staining, analyzed cell apoptosis rate via flow cytometry as well as annexin V-FITC/PI double staining, performed apoptosis-related protein expression through western blotting, evaluated cell migration along with invasion by wound as well as transwell assays, carried out MMP via JC-1 and Rh123 fluorescent probes, as well as detected intracellular ATP and ROS levels by flow cytometry, respectively, to evaluate the effects of TCS. We found that TCS inhibited viability along with proliferation, induced apoptosis, as well as inhibited HeLa & caski cell migration along with invasion in a time- and dose-dependent manner. Additionally, TCS also reduced MMP, and the production of adenosine triphosphate, as well as induced the increase of intracellular reactive oxygen species in cancer cell lines. In accordance with the present studies, TCS inhibits HeLa & caski cell proliferation along with migration but promotes their apoptosis, which may be mediated by regulating oxidative stress.
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http://dx.doi.org/10.1080/21655979.2021.1930335DOI Listing
December 2021

Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors.

Clin Ther 2021 06 27;43(6):1092-1111. Epub 2021 May 27.

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

Purpose: In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors.

Methods: This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety.

Findings: Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median T for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUC and C) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%).

Implications: Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.
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http://dx.doi.org/10.1016/j.clinthera.2021.04.006DOI Listing
June 2021

Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study.

Br J Clin Pharmacol 2021 May 27. Epub 2021 May 27.

Orlando Clinical Research Center, Orlando, Florida, USA.

Aims: Capmatinib, a mesenchymal-epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function.

Methods: This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function.

Results: Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476-1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563-1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669-1.55). Compared with the normal group, GM area under the plasma concentration-time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532-1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652-1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858-1.78).

Conclusion: Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study.
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http://dx.doi.org/10.1111/bcp.14929DOI Listing
May 2021

Long noncoding RNA MST1P2 promotes cervical cancer progression by sponging with microRNA miR-133b.

Bioengineered 2021 12;12(1):1851-1860

Department of Obstetrics and Gynecology, Dongtai Traditional Chinese Medicine Hospital, Dongtai City, Jiangsu Province, China.

Long noncoding RNA (lnc RNA) is aberrant expressed in many kinds of tumors and may be concerned with the occurrence and progression of tumors. Lnc RNA MST1P2 is increased in cervical cancer (CC), but its mechanism in CC has not been clarified. In this study, RT-qPCR was employed to analyze Lnc MST1P2 and miR-133b expression. CCK8 and cell apoptosis assay detect the proliferation optical density (OD) value and apoptosis rate. Cell metastasis was evaluated by Wound-healing assay and Transwell assay. Dual-Luciferase assay analyzed the relationship between Lnc MST1P2 and miR-133b. In vivo experiment was performed by establishing xenograft animal model. We found that Lnc MST1P2 is obviously overexpression in CC tissues and cells. Si-Lnc MST1P2 obviously repressed cell growth, cell migration, and cell invasion in Hela and SIHA cells. Moreover, Si-Lnc MST1P2 suppressed CC tumorigenesis in vivo. Dual-Luciferase assay and RT-qPCR assay further proved that Lnc MST1P2 has a negative regulation to miR-133b. miR-133b up-regulation inhibited cell viability and metastasis of Hela and SIHA cells. miR-133b inhibition notably decreased the anti-cancer effect of si-Lnc MST1P2. LncRNA MST1P2 serves as a Cervical Cancer oncogene by sponging with miR-133b.
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http://dx.doi.org/10.1080/21655979.2021.1921550DOI Listing
December 2021

Fabrication and Characterization of Chitosan/Poly(Lactic-Co-glycolic Acid) Core-Shell Nanoparticles by Coaxial Electrospray Technology for Dual Delivery of Natamycin and Clotrimazole.

Front Bioeng Biotechnol 2021 5;9:635485. Epub 2021 Mar 5.

College of Pharmacy, Weifang Medical University, Weifang, China.

Natamycin (NAT) is the drug of choice for the treatment of fungal keratitis (FK). However, its inherent shortcomings, such as poor solubility, high dosing frequency, and long treatment cycle, need to be urgently addressed by designing a new delivery to widen its clinical utility. Growing research has confirmed that clotrimazole (CLZ) plays a significant role in fungal growth inhibition. Hence, coaxial electrospray (CO-ES) technology is used herein to prepare nano-systems with an average hydrodynamic particle size of 309-406 nm for the co-delivery of NAT and CLZ in chitosan (CTS) and poly(lactic-co-glycolic acid) (PLGA). The resulting NAT/[email protected]/PLGA formulations were characterized by a transmission electron microscope (TEM) and release test. The results show that the formulations had obvious core-shell structures, uniform particle distribution, and also can sustain the release of drugs over 36 h. Furthermore, hemolysis, corneal irritation test, local allergenic test, and antifungal activity analyses are performed to evaluate the safety and efficiency of the formulations. Thus, good biosafety along with a significant anti-candidiasis effect are found in the NAT/[email protected]/PLGA nanoparticles (NPs). Taken together, the results suggest that this design may provide a promising drug delivery system and a new option for the treatment of FK.
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http://dx.doi.org/10.3389/fbioe.2021.635485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973235PMC
March 2021

Targeted delivery of quercetin by nanoparticles based on chitosan sensitizing paclitaxel-resistant lung cancer cells to paclitaxel.

Mater Sci Eng C Mater Biol Appl 2021 Feb 25;119:111442. Epub 2020 Aug 25.

College of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, PR China; Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang Medical University, Weifang 261053, Shandong, PR China; Institute for Smart Materials and Regenerative Medicine, Weifang Medical University, Weifang 261053, Shandong, PR China. Electronic address:

Chemotherapy plays crucial roles in the clinical treatment of non-small cell lung cancer (NSCLC). Nevertheless, acquired chemoresistance is a common and critical problem that limits the clinical application of chemotherapy. Quercetin (QUE), a natural bioflavonoid, has significant antitumor potential, which has been verified in many drug-resistant cancer cell lines and animal models. Here, we explored whether QUE could reverse the resistance of NSCLC to paclitaxel (PTX)-based therapy. The results of cell viability revealed that QUE could synergistically enhance the cytotoxicity of PTX in A549 and A549/Taxol cells. Furthermore, Akt and ERK phosphorylation had no significant changes in A549/Taxol cells treated with PTX. However, it was significantly inhibited by the combination treatment of QUE and PTX. To improve the antitumor activity of PTX due to its hydrophobicity and eliminate its toxicity, we prepared targeted biodegradable cetuximab chitosan nanoparticles (Cet-CTS NPs) to deliver PTX and QUE using ionic cross-linking technique. The targeted NPs displayed a particle size of 290 nm and sustained release of PTX and QUE. In addition, the targeted Cet-CTS NPs loaded with PTX and QUE inhibited tumor growth in PTX-resistant A549/Taxol cells. Cet-QUE NPs decreased tumor growth in PTX-resistant xenografts. In conclusion, the administration of QUE by using Cet-CTS NPs could provide a prospective strategy for the treatment of PTX-resistant lung cancer.
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http://dx.doi.org/10.1016/j.msec.2020.111442DOI Listing
February 2021

Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a 2-drug cocktail in patients with MET-dysregulated advanced solid tumours: A phase I, multicentre, open-label, single-sequence drug-drug interaction study.

Br J Clin Pharmacol 2021 07 29;87(7):2867-2878. Epub 2020 Dec 29.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Aims: Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET-dysregulated advanced solid tumours.

Methods: This was a multicentre, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumours on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated.

Results: Thirty-two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% confidence interval) of area under the concentration-time curve from time zero to infinity and maximum concentration for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting.

Conclusion: This study demonstrated that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant drug-drug interaction potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed.
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http://dx.doi.org/10.1111/bcp.14697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359310PMC
July 2021

Effects of Rhein-8-O-β-D-glucopyranoside on the Biofilm Formation of Streptococcus mutans.

Curr Microbiol 2021 Jan 31;78(1):323-328. Epub 2020 Oct 31.

College of Stomatology, Xi'an Medical University, South 2nd Ring Road NO.168, Yan ta District, Xi'an, Shaanxi Province, China.

Dental caries is the most frequent biofilm-related human infectious disease in the oral cavity. Streptococcus mutans is one of the primary etiological agents of dental caries. The aim of our study was to investigate the effects of rhein-8-O-β-D-glucopyranoside (Rg) on the development of S. mutans biofilms. Growth curves were generated, and biofilm oxygen sensitivity was detected after Rg treatment. The expression levels of luxS, brpA, ffh, recA, nth, and smx were analyzed by real-time PCR. The trypan blue exclusion assay was used to measure the effect of Rg on monocyte viability. The results showed that Rg could significantly inhibit the growth of S. mutans and suppress the biofilm formation of S. mutans in a concentration-dependent manner. In Rg-treated biofilms, the expression levels of luxS, brpA, ffh, recA, nth, and smx were all decreased. Our results further showed that Rg was nontoxic, as Rg did not affect monocyte viability or lactate dehydrogenase activity in the exposed cells. These results suggested that Rg inhibited the biofilm formation of S. mutans, and the decrease in luxS, brpA, ffh, recA, nth, and smx expression might contribute to the antibacterial effects of Rg.
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http://dx.doi.org/10.1007/s00284-020-02248-0DOI Listing
January 2021

Capmatinib in Exon 14-Mutated or -Amplified Non-Small-Cell Lung Cancer.

N Engl J Med 2020 09;383(10):944-957

From the Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne and University of Cologne, Cologne (J.W.), Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg, Heidelberg (M.T.), the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (T.R.O.), and Hämato-Onkologie Hamburg, Hamburg (E.L.) - all in Germany; the National Hospital Organization Kyushu Cancer Center, Fukuoka (T.S.), Aichi Cancer Center, Nagoya (T.H.), the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (M.N.), the Department of Respiratory Medicine, Okayama University Hospital, Okayama (K.O.), and the National Kyushu Cancer Center, Fukuoka (R.T.) - all in Japan; the National Cancer Center, Gyeonggi-do (J.-Y.H.), and the Department of Internal Medicine, Seoul National University Hospital, Seoul (T.-M.K.) - both in South Korea; the Hospital Clinic of Barcelona (N.R.), Translational Genomic and Targeted Therapeutics in Solid Tumors (IDIBAPS) (N.R.), and Vall d'Hebron University Hospital-Vall d'Hebron Institute of Oncology (E.F.), Barcelona; David Geffen School of Medicine at UCLA, Los Angeles (E.B.G.); the University of Groningen and University Medical Center Groningen, Groningen (H.J.M.G.), Erasmus MC Cancer Institute, Rotterdam (M.J.), and the Netherlands Cancer Institute, Amsterdam (E.F.S.) - all in the Netherlands; the National Cancer Centre Singapore, Singapore (D.S.W.T.); St. Petersburg Pavlov State Medical University, St. Petersburg, Russia (S.V.O.); University Hospital of Lyon-Sud, Lyon (P.-J.S.), and Novartis Pharma, Rueil-Malmaison (S.L.M.) - both in France; the Respiratory Oncology Unit, University Hospitals KU Leuven, Leuven, Belgium (J.V.); the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna (M.H.); the Thoracic Oncology Division, European Institute of Oncology, IRCCS, Milan (F.M.); Novartis Pharmaceuticals, East Hanover, NJ (A.R., M.G.); Novartis Pharma, Basel, Switzerland (M.W.-L., M.A.); and Novartis Institutes for BioMedical Research, Cambridge (B.S., O.A.B., X.C.), and Massachusetts General Hospital, Boston (R.S.H.) - both in Massachusetts.

Background: Among patients with non-small-cell lung cancer (NSCLC), exon 14 skipping mutations occur in 3 to 4% and amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.

Methods: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with -dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and status ( exon 14 skipping mutation or amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.

Results: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.

Conclusions: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a exon 14 skipping mutation, particularly in those not treated previously. The efficacy in -amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).
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http://dx.doi.org/10.1056/NEJMoa2002787DOI Listing
September 2020

Distribution of Haemaphysalis longicornis and associated pathogens: analysis of pooled data from a China field survey and global published data.

Lancet Planet Health 2020 08;4(8):e320-e329

Institute of EcoHealth, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. Electronic address:

Background: Haemaphysalis longicornis, a vector of various pathogens with medical and veterinary importance, is native to eastern Asia, and recently reached the USA as an emerging disease threat. In this study, we aimed to identify the geographical distribution, hosts, and associated pathogens of H longicornis.

Methods: Data were collected from multiple sources, including a field survey, reference book, literature review, and related websites. The thematic maps showing geographical distribution of H longicornis and associated pathogens were produced by ArcGIS. Hosts of H longicornis and positive rates for H longicornis-associated pathogens were estimated by meta-analysis. Ecological niche modelling was used to predict potential global distribution of H longicornis.

Findings: H longicornis was found to be present in ten countries, predominantly in eastern Asia, the USA, Australia, and New Zealand. The tick was known to feed on a variety of domestic and wild animals, and humans. At least 30 human pathogens were associated with H longicornis, including seven species of spotted fever group rickettsiae, seven species in the family of Anaplasmataceae, four genospecies in the complex Borrelia burgdorferi sensu lato, two Babesia species, six species of virus, and Francisella, Bartonella, Coxiella, and Toxoplasma, which were mainly reported in eastern Asia. The predictive modelling revealed that H longicornis might affect more extensive regions, including Europe, South America, and Africa, where the tick has never been recorded before.

Interpretation: H longicornis is relatively common in the world, and is associated with various human and animal pathogens. Authorities and health-care workers should be aware of the threat of the tick species to public health and veterinary medicine. Surveillance and further investigations should be enhanced globally.

Funding: National Natural Science Foundation of China and National Key Research and Development Program of China.
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http://dx.doi.org/10.1016/S2542-5196(20)30145-5DOI Listing
August 2020

The association of outdoor temperature with blood pressure, and its influence on future cardio-cerebrovascular disease risk in cold areas.

J Hypertens 2020 06;38(6):1080-1089

Collaborative Innovation Center for Biomedicine, Medical Technology College, Shanghai University of Medicine & Health Sciences, Shanghai.

Objectives: To explore whether lower outdoor temperature increases cardio-cerebrovascular disease risk through regulating blood pressure and whether indoor heating in winter is beneficial to prevent cardio-cerebrovascular disease in cold areas.

Methods: We analyzed the data of 38 589 participants in Harbin from the China Kadoorie Biobank (CKB) during 2004-2008, with an average of 7.14-year follow-up. Linear regression analysis was performed to estimate the relationship between outdoor temperature and blood pressure. Cox regression analysis and logistic regression analysis were used to analyze the association of blood pressure with cardio-cerebrovascular event risk. Mediation analysis was performed to explore the role of blood pressure in the association between outdoor temperature and cardio-cerebrovascular events risk.

Results: There was an increase of 6.7 mmHg in SBP and 2.1 mmHg in DBP for each 10 °C decrease in outdoor temperature when outdoor temperature was higher than 5 °C. There was an inverse association between outdoor temperature and cardio-cerebrovascular event morbidity. The increases in blood pressure and cardio-cerebrovascular event morbidity were attenuated in months when central heating was fully provided. Participants with hypertension have higher risks of cardio-cerebrovascular disease (hazard ratio 1.347; 95% CI 1.281--1.415), CVD (hazard ratio 1.347; 95% CI 1.282--1.416), MACE (hazard ratio 1.670; 95% CI 1.560--1.788) and stroke (hazard ratio 1.683; 95% CI 1.571--1.803). Mediation analysis demonstrated that the association between outdoor temperature and cardio-cerebrovascular events risk was potentially mediated by blood pressure.

Conclusion: Temperature-driven blood pressure potentially mediates the association between outdoor temperature and cardio-cerebrovascular events risk. Indoor heating in winter is probably beneficial to cardio-cerebrovascular disease prevention by inhibition of blood pressure increase.
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http://dx.doi.org/10.1097/HJH.0000000000002387DOI Listing
June 2020

Astragalus Polysaccharides/Chitosan Microspheres for Nasal Delivery: Preparation, Optimization, Characterization, and Pharmacodynamics.

Front Pharmacol 2020 18;11:230. Epub 2020 Mar 18.

School of Pharmacy, Weifang Medical University, Weifang, China.

Chitosan (CTS) constitutes a promising area in treatment of nose-related diseases as a nasal drug delivery carrier. Astragalus polysaccharide (APS) significantly attenuates eosinophils and neutrophil-dominant airway inflammation, and it has a potential pharmaceutical application in the treatment of severe asthma. The purpose of this work was to prepare APS/CTS microspheres intended for nasal drug delivery by the spray-drying method. The characteristics of APS/CTS microspheres were evaluated by a scanning electron microscope, Fourier transform infrared spectroscopy, differential scanning calorimetry, and drug release. The effect of APS/CTS microspheres on rats with allergic rhinitis (AR) was investigated by eosinophil and neutrophil counts in nasal lavage fluid. Results of SEM showed that microspheres were spherical and wrinkled. release showed that 67.48-93.76% APS was released from APS/CTS microspheres at pH 6.8 within 24 h. The effects showed that APS/CTS microspheres alleviated allergic symptoms and reduced eosinophils infiltration and the expression of interleukin-4 in the nasal mucosa tissue of rats that had no liver and kidney toxicity by hematoxylin-eosin staining observation. In conclusion, these results indicated that APS/CTS microspheres had excellent characteristics for the treatment of AR.
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http://dx.doi.org/10.3389/fphar.2020.00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093564PMC
March 2020

Rebamipide-loaded chitosan nanoparticles accelerate prostatic wound healing by inhibiting M1 macrophage-mediated inflammation via the NF-κB signaling pathway.

Biomater Sci 2020 Feb 12;8(3):912-925. Epub 2019 Dec 12.

Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. and Institute of Urology, Shanghai Jiao Tong University, Shanghai 200080, China.

A large proportion of benign prostatic hyperplasia (BPH) patients suffer from lower urinary tract symptoms after surgery due to the presence of prostatic urothelium wounds. Rebamipide (RBM) exerts wound healing promotion and anti-inflammatory effects on various tissues, including the urothelium. However, intravesical administration of RBM is hindered due to its low solubility and resulting unsustainable drug concentrations in the bladder. In this study, RBM-loaded chitosan nanoparticles (RBM/CTS NPs) were prepared using the ionic cross-linking method. Physicochemical characteristics and the wound healing promotion effect, as well as in vitro influence on macrophages were evaluated. The results show that RBM/CTS NPs are spherical with uniform size distribution, while slower and sustained in vitro release of RBM is presented. In vivo, faster wound healing and improved re-epithelialization progress were observed after treatment with RBM/CTS NPs in a model of thulium laser resection of the prostate (TmLRP). The degree of local inflammatory response decreased, as confirmed by decreasing numbers of pro-inflammatory M1 phenotype macrophages and levels of IL-1β, IL-6, IL-12 and TNF-α in the urine of canines. We also found that RBM/CTS NPs suppress macrophage M1 polarization induced by lipopolysaccharide and interferon-γ and inhibit the activation of the NF-κB signaling pathway. Therefore, as a novel therapeutic strategy, intravesical administration of RBM/CTS NPs can effectively avoid drug intolerance and drug wastage, accelerating the postoperative wound repairing of the prostatic urethra by suppressing macrophage M1 phenotype polarization.
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http://dx.doi.org/10.1039/c9bm01512dDOI Listing
February 2020

Electroacupuncture for reproductive hormone levels in patients with diminished ovarian reserve: a prospective observational study.

Acupunct Med 2016 Oct 13;34(5):386-391. Epub 2016 May 13.

Acupuncture Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

Background: Effective methods for the treatment of reproductive dysfunction are limited. Previous studies have reported that acupuncture can modulate female hormone levels, improve menstrual disorders, alleviate depression and improve pregnancy rates. However, studies of acupuncture for diminished ovarian reserve (DOR) are lacking.

Objective: To carry out a prospective observational study aimed at assessing the effect of EA on the reproductive hormone levels of patients with DOR seeking fertility support and consider its safety.

Methods: Eligible patients with DOR received EA for 12 weeks: five times a week for 4 weeks followed by three times a week for 8 weeks. The primary outcome was the change in mean follicle-stimulating hormone (FSH) level at week 12. Mean luteinising hormone (LH) and serum oestradiol (E2) levels, FSH/LH ratios and symptom scale scores were simultaneously observed.

Results: Twenty-one patients with DOR were included in the final analysis. Mean FSH levels fell from 19.33±9.47 mIU/mL at baseline to 10.58±6.34 mIU/mL at week 12 and 11.25±6.68 mIU/mL at week 24. Change in mean FSH from baseline was -8.75±11.13 mIU/mL at week 12 (p=0.002) and -8.08±9.56 mIU/mL at week 24 (p=0.001). Mean E2 and LH levels, FSH/LH ratios and irritability scores were improved at weeks 12 and/or 24. Approximately 30% patients reported subjective increases in menstrual volume after treatment.

Conclusions: EA may modulate reproductive hormone levels and the effects seem to persist for at least 12 weeks after treatment with no significant side effects. EA may improve the ovarian reserve of patients with DOR, though further research is needed.

Trial Registration Number: NCT02229604; Results.
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http://dx.doi.org/10.1136/acupmed-2015-011014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099178PMC
October 2016

Acupuncture for Erectile Dysfunction: A Systematic Review.

Biomed Res Int 2016 17;2016:2171923. Epub 2016 Jan 17.

Department of Acupuncture, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.

Background: Acupuncture is increasingly used to treat patients with erectile dysfunction (ED), and our systematic review aimed to evaluate the current evidence for the efficacy and safety of acupuncture in treating ED.

Methods: An electronic search was conducted in eight databases to identify randomized controlled trials (RCTs) of acupuncture for treating erectile dysfunction that were published in English and Chinese. The Cochrane Risk of Bias tool was used to assess the risk of bias.

Results: Three RCTs with a total of 183 participants met the inclusion criteria. One trial showed the beneficial effects of acupuncture compared with sham acupuncture while the others did not. One trial suggested that acupuncture combined with psychological therapy was superior to psychological therapy alone. However, the overall methodological and reporting quality of the studies was low. The safety of acupuncture for ED was unclear because there were too few reports on this topic.

Conclusion: The available evidence supporting that acupuncture alone improves ED was insufficient and the available studies failed to show the specific therapeutic effect of acupuncture. Future well-designed and rigorous RCTs with a large sample size are required. This trial is registered with CRD42014013575.
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http://dx.doi.org/10.1155/2016/2171923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738993PMC
November 2016

[Effect of local application of insulin like growth factor-1 gelatin sponge complex on osseointegration around implant in osteoporosis rats].

Zhonghua Kou Qiang Yi Xue Za Zhi 2015 Jul;50(7):418-22

Email:

Objective: To investigate the effects of local application of insulin like growth factor-1 (IGF-1) absorbable gelatin sponge complex in implant fossa on osseointegration around implant in osteoporosis rats.

Methods: Female SD rats, aged 4 months, were randomly individed into ovariectomy group (OVX group) and sham-ovariectomy group (sham-ovx group). The rats in OVX group (n = 15) were ovariectomized, and the rats in Sham-OVX group (n = 10) underwent Sham-ovariectomy. Eight weeks later, 5 rats in each group were randomly selected to confirm the osteoporosis model. The ovariectomized rats were randomly divided into osteoporosis group (OP group) and IGF-1 group after the model was successfully established, 5 rats in each group. Pure titanium implants were implanted in the distal part of right femoral epiphyseal in all groups. Absorbable gelatin sponge particles containing 10 µg IGF-1 were placed in the planting fossa in the IGF-1 group, and absorbable gelatin sponge particles without IGF-1 were used in OP group and sham-OVX group. The rats were sacrificed, and then the distal part of right and left femoral epiphyses were taken out to make undecalcified and decalcified tissue sections respectively after 8 weeks. Combined bone lamella width (CBLW) and implant bone contact rate (IBCR) around implant, trabecular width (TW) and trabecular area percentage (TA) around implant and in the cortical bone of left femoral epiphyses were observed by histomorphometric measurement.

Results: The CBLW, IBCR, TW and TA around implant was (55.43 ± 3.50) µm, (81.79 ± 4.45) %, (57.73 ± 4.29) µm and (62.21 ± 7.42) % respectively in sham-OVX group, (60.22 ± 4.70) µm, (83.67 ± 6.63) %, (48.08 ± 3.63) µm and (58.20 ± 8.93) % respectively in IGF-1 group, and (37.11 ± 2.18) µm, (64.60 ± 5.44) %, (41.19 ± 2.93) µm and (42.21 ± 4.34) % respectively in OP group. The CBLW, IBCR and TW around implant had no differences between IGF-1 and sham-OVX group (P > 0.05), which were significantly higher than those in OP group (P < 0.05). The TW and TA of cortical bone in left distal femoral epiphyses was (60.85 ± 6.64) µm, (61.24 ± 6.98) % respectively in sham-OVX group, (38.68 ± 4.74) µm, (43.89 ± 7.76) % respectively IGF-1 group, (40.46 ± 5.38) µm, (44.63 ± 5.39) % respectively in OP group (P < 0.05). The TW and TA of cortical bone in left distal femoral epiphyses had no differences between IGF-1 group and OP group (P > 0.05), which were all significantly lower than those in sham-OVX group (P < 0.05).

Conclusions: The local application of IGF-1 gelatin sponge complex can increase bone tissue around implant and improve osseointegration in osteoporosis.
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July 2015

IDH1/2 mutation status combined with Ki-67 labeling index defines distinct prognostic groups in glioma.

Oncotarget 2015 Oct;6(30):30232-8

Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China.

The current World Health Organization (WHO) classification of human gliomas is mainly based on morphology. However, it has limitations in prognostic prediction. We examined whether combining isocitrate dehydrogenase (IDH) 1/2 mutation status with the Ki-67 labeling index would improve the definition of prognostically distinct entities. We investigated the correlation of Ki-67 expression with IDH1/2 mutation status and their impact on clinical outcome in 703 gliomas. Low Ki-67 expression closely overlapped with IDH1/2 mutation in our cohort (P < 0.0001). Patients with IDH1/2 mutation survived significantly longer than patients with wild-type IDH1/2 did (P < 0.0001); higher Ki-67 expression was associated with shorter progression-free survival and overall survival (OS) (P < 0.0001). IDH1/2 combined with Ki-67 was used to re-classify glioma patients into five groups. IDH1/2 mutant patients with low and moderate Ki-67 expression (Group1) had the best prognosis, whereas patients with wild-type IDH1/2 and high Ki-67 expression (Group5) had the worst prognosis (Median OS = 1527 vs. 355 days, P < 0.0001). To summarize, our new classification model distinguishes biologically distinct subgroups and provides prognostic information regardless of the conventional WHO grade. Classification based on IDH1/2 mutation status and Ki-67 expression level could be more convenient for clinical application and guide personalized treatment in malignant gliomas.
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http://dx.doi.org/10.18632/oncotarget.4920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745793PMC
October 2015

Acupuncture for erectile dysfunction: a systematic review protocol.

BMJ Open 2015 Mar 24;5(3):e007040. Epub 2015 Mar 24.

Department of Acupuncture, Guang'anmen Hospital, China Academy of Chinese Sciences, Beijing, China.

Introduction: This systematic review protocol aims to provide a protocol for assessing the safety and effectiveness of acupuncture for the treatment of erectile dysfunction(ED). Previous systematic reviews did not draw convincing conclusions owing to high heterogeneity and few included randomised controlled trials, so it is necessary to reassess the efficacy and safety of acupuncture for ED.

Methods And Analysis: Eight electronic databases will be searched: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed, EMBASE, PsycInfo, the Chinese Biomedical Literature Database (CBM), the Chinese Medical Current Content (CMCC) and the China National Knowledge Infrastructure (CNKI). Related Chinese literature will be searched in other Chinese databases. All relevant randomised controlled trials in English or Chinese without any restrictions of publication type will be included. The main outcome measure will be improvements in sexual activity assessed by validated questionnaires. Assessment of risk of bias, data synthesis and subgroup analysis will be carried out using Review Manager 5.3.

Ethics And Dissemination: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. The data we will use do not include individual patient data, so ethical approval is not required.

Trial Registration Number: PROSPERO CRD42014013575.
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http://dx.doi.org/10.1136/bmjopen-2014-007040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386219PMC
March 2015

High-definition computed tomography for coronary artery stents imaging: Initial evaluation of the optimal reconstruction algorithm.

Eur J Radiol 2015 May 16;84(5):834-9. Epub 2015 Feb 16.

Department of Radiology, General Hospital of Chinese People's Armed Police Forces, No 69, Yongding Road, Beijing 100039, China. Electronic address:

Objective: The aim of this study was to evaluate the in vivo performance of four image reconstruction algorithms in a high-definition CT (HDCT) scanner with improved spatial resolution for the evaluation of coronary artery stents and intrastent lumina.

Materials And Methods: Thirty-nine consecutive patients with a total of 71 implanted coronary stents underwent coronary CT angiography (CCTA) on a HDCT (Discovery CT 750 HD; GE Healthcare) with the high-resolution scanning mode. Four different reconstruction algorithms (HD-stand, HD-detail; HD-stand-plus; HD-detail-plus) were applied to reconstruct the stented coronary arteries. Image quality for stent characterization was assessed. Image noise and intrastent luminal diameter were measured. The relationship between the measurement of inner stent diameter (ISD) and the true stent diameter (TSD) and stent type were analysed.

Results: The stent-dedicated kernel (HD-detail) offered the highest percentage (53.5%) of good image quality for stent characterization and the highest ratio (68.0±8.4%) of visible stent lumen/true stent lumen for luminal diameter measurement at the expense of an increased overall image noise. The Pearson correlation coefficient between the ISD and TSD measurement and spearman correlation coefficient between the ISD measurement and stent type were 0.83 and 0.48, respectively.

Conclusions: Compared with standard reconstruction algorithms, high-definition CT imaging technique with dedicated high-resolution reconstruction algorithm provides more accurate stent characterization and intrastent luminal diameter measurement.
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http://dx.doi.org/10.1016/j.ejrad.2015.02.004DOI Listing
May 2015

Prediction of advanced ovarian cancer recurrence by plasma metabolic profiling.

Mol Biosyst 2015 Feb 26;11(2):516-21. Epub 2014 Nov 26.

Department of Epidemiology and Biostatistics, Harbin Medical University, Harbin 150081, P.R. China.

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies due to the high rate of recurrence and poor prognosis. Predicting the prognosis in patients with EOC is clinically challenging, partly because appropriate biomarkers of recurrence have yet to be explored. In this prospective study, pre-treatment plasma samples were collected from 38 patients with stage III or IV EOC who were subsequently followed up. Ultra-performance liquid chromatography mass spectrometry was used to perform metabolic profiling, which yielded five metabolites that were potential biomarkers for EOC recurrence: l-tryptophan, kynurenine, bilirubin, LysoPC (14 : 0) and LysoPE (18 : 2). A combination of these five potential biomarkers strongly predicted recurrence, the area under the curve being 0.91. In summary, the candidate biomarkers identified in this study may both facilitate clinical prediction of EOC recurrence and prognosis and serve as potential therapeutic targets in patients with EOC.
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http://dx.doi.org/10.1039/c4mb00407hDOI Listing
February 2015

Optimizing the imaging protocol for ex vivo coronary artery wall using high-resolution MRI: an experimental study on porcine and human.

Korean J Radiol 2013 Jul-Aug;14(4):581-8. Epub 2013 Jul 17.

Department of Medical, The General Hospital of Chinese People's Armed Police Forces, Beijing 100039, China.

Objective: To optimize the MR imaging protocol for coronary arterial wall depiction in vitro and characterize the coronary atherosclerotic plaques.

Materials And Methods: MRI examination was prospectively performed in ten porcine hearts in order to optimize the MR imaging protocol. Various surface coils were used for coronary arterial wall imaging with the same parameters. Then, the image parameters were further optimized for high-resolution coronary wall imaging. The signal-noise ratio (SNR) and contrast-noise ratio (CNR) of images were measured. Finally, 8 human cadaver hearts with coronary atherosclerotic plaques were prospectively performed with MRI examination using optimized protocol in order to characterize the coronary atherosclerotic plaques.

Results: The SNR and CNR of MR image with temporomandibular coil were the highest of various surface coils. High-resolution and high SNR and CNR for ex vivo coronary artery wall depiction can be achieved using temporomandibular coil with 512 × 512 in matrix. Compared with histopathology, the sensitivity and specificity of MRI for identifying advanced plaques were: type IV-V (lipid, necrosis, fibrosis), 94% and 95%; type VI (hemorrhage), 100% and 98%; type VII (calcification), 91% and 100%; and type VIII (fibrosis without lipid core), 100% and 98%, respectively.

Conclusion: Temporomandibular coil appears to be dramatically superior to eight-channel head coil and knee coil for ex vivo coronary artery wall imaging, providing higher spatial resolution and improved the SNR. Ex vivo high-resolution MRI has capability to distinguish human coronary atherosclerotic plaque compositions and accurately classify advanced plaques.
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http://dx.doi.org/10.3348/kjr.2013.14.4.581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725352PMC
July 2014

Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.

J Med Chem 2013 Jul 26;56(14):5675-90. Epub 2013 Jun 26.

Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.
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http://dx.doi.org/10.1021/jm400402qDOI Listing
July 2013

Dynamic susceptibility contrast-enhanced first-pass perfusion MR imaging in patients with subclinical hepatic encephalopathy.

J Neuroradiol 2012 Dec 1;39(5):290-4. Epub 2011 Nov 1.

Department of Radiology, The General Hospital of Chinese People's Armed Police Forces, No 69, Yongding Road, 100039 Beijing, China.

Background And Purpose: Subclinical hepatic encephalopathy (SHE) is frequently reported on single-photon emission computed tomography (SPECT), but is rarely described with magnetic resonance (MR) techniques. This study aimed to investigate hemodynamic changes in brain basal ganglia in patients with SHE using dynamic susceptibility contrast (DSC)-enhanced MR perfusion imaging.

Methods: Twelve patients with SHE and ten age- and education-matched volunteers agreed to undergo MR examination. The scanning protocol included conventional anatomical images and DSC-enhanced perfusion MR imaging. Using MGH perfusion software, parameter maps of cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were created. The bilateral caudate nucleus head, globus pallidus, putamen and thalamus were selected as regions of interest (ROI), with ipsilateral white matter of the frontal lobe used as reference. Ratios (ROI versus ipsilateral white matter in frontal lobe) for CBF, CBV and MTT in the patient group were compared with those in the control group.

Results: The CBF ratios for every ROI were higher in SHE patients versus the controls. Statistically, significant increases were detected in the left globus pallidus, putamen and thalamus (P<0.05). For MTT, the reduction in values reached statistical significance in the right head of the caudate nucleus and bilateral thalamus (P<0.05). CBV values were not significantly different compared with those of the control group (P>0.05).

Conclusion: Increased CBF and decreased MTT values in the basal ganglia and thalamus were identified in patients with SHE. The CBF increase was compatible with the idea that the CBF is redistributed from cortical areas to the basal ganglia structures.
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http://dx.doi.org/10.1016/j.neurad.2011.09.002DOI Listing
December 2012

The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety.

Bioorg Med Chem Lett 2009 May 14;19(9):2519-23. Epub 2009 Mar 14.

Department of Chemical Research, CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.
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http://dx.doi.org/10.1016/j.bmcl.2009.03.031DOI Listing
May 2009

Application and interpretation of hPXR screening data: Validation of reporter signal requirements for prediction of clinically relevant CYP3A4 inducers.

Biochem Pharmacol 2008 Sep 3;76(5):680-9. Epub 2008 Jul 3.

Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth K15-2700, NJ 07033, USA.

A human pregnane X receptor (PXR) reporter-gene assay was established and validated using 19 therapeutic agents known to be clinical CYP3A4 inducers, 5 clinical non-inducers, and 6 known inducers in human hepatocytes. The extent of CYP3A4 induction (measured as RIF ratio in comparison to rifampicin) and EC50 was obtained from the dose-response curve. All of the clinical inducers (19/19) and human hepatocyte inducers (6/6) showed positive responses in the PXR assay. One out of five clinical non-inducers, pioglitazone, also showed a positive response. An additional series of 18 commonly used drugs with no reports of clinical induction was also evaluated as putative negative controls. Sixteen of these were negative (89%), whereas two of these, flutamide and haloperidol showed 16-fold (RIF ratio 0.79) and 10-fold (RIF ratio 0.48) maximal induction, respectively in the reporter-gene system. Flutamide and haloperidol were further demonstrated to cause CYP3A4 induction in human cryopreserved hepatocytes based on testosterone 6beta-hydroxylation activity. The induction potential index calculated based on the maximum RIF ratio, EC50, and in vivo maximum plasma concentration was used to predict the likelihood of CYP3A4 induction in humans. When the induction potential index is greater than 0.08, the compound is likely to cause induction in humans. A high-throughput screening strategy was developed based on the validation results at 1microM and 10microM for the same set of drugs. A RIF ratio of 0.4 was set as more practical screening cut-off to minimize the possibility of generating false positives. Thus, a tiered approach was implemented to use the human PXR reporter-gene assay from early lead optimization to late lead characterization in drug discovery.
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http://dx.doi.org/10.1016/j.bcp.2008.06.016DOI Listing
September 2008

Construction and characterization of a fully active PXR/SRC-1 tethered protein with increased stability.

Protein Eng Des Sel 2008 Jul 2;21(7):425-33. Epub 2008 May 2.

Structural Chemistry Department, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.

The nuclear xenobiotic receptor PXR is a ligand-inducible transcription factor regulating drug-metabolizing enzymes and transporters and a master switch mediating potentially adverse drug-drug interactions. In addition to binding a coactivator protein such as SRC-1, the C-terminal ligand-binding domain (LBD) is solely responsible for ligand recognition and thus the ligand-dependent downstream effects. In an effort to facilitate structural studies of PXR to understand and abolish the interactions between PXR and its ligands, several recombinant PXR/SRC-1 constructs were designed and evaluated for expression, stability and activity. Expression strategies employing either dual expression or translationally coupled bicistronic expression were found to be unsuitable for producing stable PXR in a stochiometric complex with a peptide derived from SRC-1 (SRC-1p). A single polypeptide chain encompassing PXR and SRC-1p tethered with a peptidyl linker was designed to promote intramolecular complex formation. This tethered protein was overexpressed as a soluble protein and required no additional SRC-1p for further stabilization. X-ray crystal structures in the presence and absence of the known PXR agonist SR-12813 were determined to high resolution. In addition, a circular dichroism-based binding assay was developed to allow rapid evaluation of PXR ligand affinity, making this tethered protein a convenient and effective reagent for the rational attenuation of drug-induced PXR-mediated metabolism.
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http://dx.doi.org/10.1093/protein/gzn017DOI Listing
July 2008

Development of in vitro pharmacokinetic screens using Caco-2, human hepatocyte, and Caco-2/human hepatocyte hybrid systems for the prediction of oral bioavailability in humans.

J Biomol Screen 2007 Dec 7;12(8):1084-91. Epub 2007 Nov 7.

Department of Exploratory Drug Metabolism, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.

In this study, in vitro systems were used to build 2 pharmacokinetic models that predict human oral bioavailability: the Caco-2/hepatocyte combination model and the Caco-2/hepatocyte hybrid model. Data obtained in vitro on Caco-2 cell permeability and hepatocyte clearance are routinely used to predict the fraction of absorption after oral administration and the extent of first-pass metabolism, respectively. In the Caco-2/hepatocyte combination model, results from a Caco-2 cell permeability assay and a hepatocyte clearance assay were combined to project oral bioavailability. Comparison of oral bioavailabilities predicted by the combination model and reported oral bioavailabilities in humans for 30 marketed compounds resulted in a modest correlation (r(2) = 0.66). The Caco-2/hepatocyte hybrid model, as previously reported, joins the Caco-2 and hepatocyte clearance systems into 1 assay. Improvements to the previous model were made by incorporating an elimination phase into the Caco-2/hepatocyte hybrid model. In the new hybrid model, the compound was added to a Caco-2-containing donor compartment and allowed to permeate for 2 h to a hepatocyte-containing receiver compartment. Subsequently, to mimic an elimination phase, the donor compartment was removed, and permeated compound was incubated with hepatocytes alone for an additional 3 h. The area under the concentration versus time curve (AUC) was determined for each of the same 30 marketed compounds assessed by the combination model. A linear regression analysis comparing the in vitro AUCs and reported oral bioavailabilities in humans showed a reasonable correlation (r(2) = 0.73). This study demonstrates that the Caco-2/hepatocyte hybrid model is more favorable and further proves the potential and feasibility of using in vitro screenings for the prediction of in vivo pharmacokinetics in humans.
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http://dx.doi.org/10.1177/1087057107308892DOI Listing
December 2007
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