Publications by authors named "Yilong Zhang"

82 Publications

Quantitative measurement of mechanical properties in wound healing processes in a corneal stroma model by using vibrational optical coherence elastography (OCE).

Biomed Opt Express 2021 Jan 22;12(1):588-603. Epub 2020 Dec 22.

School of Science and Engineering, University of Dundee, Dundee DD1 4HN, Scotland, UK.

Corneal wound healing, caused by frequent traumatic injury to the cornea and increasing numbers of refractive surgeries, has become a vital clinical problem. In the cornea, wound healing is an extremely complicated process. However, little is known about how the biomechanical changes in wound healing response of the cornea. Collagen-based hydrogels incorporating corneal cells are suitable for replicating a three-dimensional (3D) equivalent of the cornea . In this study, the mechanical properties of corneal stroma models were quantitatively monitored by a vibrational optical coherence elastography (OCE) system during continuous culture periods. Specifically, human corneal keratocytes were seeded at 5 × 10 cells/mL in the hydrogels with a collagen concentration of 3.0 mg/mL. The elastic modulus of the unwounded constructs increased from 2.950 ± 0.2 kPa to 11.0 ± 1.4 kPa, and the maximum thickness decreased from 1.034 ± 0.1 mm to 0.464 ± 0.09 mm during a 15-day culture period. Furthermore, a traumatic wound in the construct was introduced with a size of 500 µm. The elastic modulus of the neo-tissue in the wound area increased from 1.488 ± 0.4 kPa to 6.639 ± 0.3 kPa over 13 days. This study demonstrates that the vibrational OCE system is capable of quantitative monitoring the changes in mechanical properties of a corneal stroma wound model during continuous culture periods and improves our understanding on corneal wound healing processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/BOE.404096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899504PMC
January 2021

A hydrogen sulfide donor suppresses pentylenetetrazol-induced seizures in rats via PKC signaling.

Eur J Pharmacol 2021 May 19;898:173959. Epub 2021 Feb 19.

Dept. of Physiology, Key Laboratory of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address:

Epilepsy is a serious neurological disorder. Available antiepileptic drugs are still lacking. Hydrogen sulfide (HS), a neuron-protective endogenous gasotransmitter, is reported to have effect on epilepsy. But it remains to be determined for its mechanism. In the present study, we found that a novel carbazole-based HS donor could effectively suppress pentylenetetrazol-induced seizures in rats. The HS donor could alleviate not only the epileptic behavior of animals but also the hippocampal EEG activity of seizures. The HS donor down-regulated the expression of aquaporin 4 in the hippocampus of epilepsy rats. The HS donor also decreased the seizure-induced release of inflammatory cytokines including IL-1β, IL-6 and TNF-α. In addition, the HS donor increased protein kinase C (PKC) expression in the hippocampus of epilepsy rats. These effects of the HS donor on epilepsy rats were attenuated after blockade of PKC signaling by Go6983, suggesting that PKC signaling participated in the antiepileptic process of HS donor. Taken together, the HS donor has a beneficial effect on epilepsy control in a PKC-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2021.173959DOI Listing
May 2021

The pressure relief protection effect of different strip widths, dip angles and pillar widths of an underside protective seam.

PLoS One 2021 28;16(1):e0246199. Epub 2021 Jan 28.

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

To design underside protective seam strip layout. Similarity model experiments, numerical simulations and theoretical calculations are used to quantitatively study the pressure relief protection effect of different strip widths, dip angles and coal pillar widths of a thin underside protective seam under deeply buried conditions. The optimal strip width range is obtained according to the change law of strain during the mining process of the underside protective seam in a similar model experiment. The change law of the expansion of the protected coal seam is obtained and the fitting surfaces among the dip angle and strip width of the coal seam with the protection distance and pressure relief angle along the strike and dip of the protected coal seam are established according to the numerical simulation results of underside protective seam mining. It is concluded that the best pressure relief effect can be achieved when the dip angle is 16.7° and the strip width is 70 m. According to the stability threshold of coal pillars considered in strip mining theory, the coal pillar width is calculated to be 50 m. Similarity model experiments and numerical simulations of protected coal seam mining verify the pressure relief effect of the designed protective seam strip width and pillar width. A calculation method of the protective seam strip width, position and pillar width required by the specific width of the protected seam is proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246199PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842979PMC
January 2021

The ROC of Cox proportional hazards cure models with application in cancer studies.

Lifetime Data Anal 2021 04 28;27(2):195-215. Epub 2021 Jan 28.

Departments of Population Health & Environmental Medicine, NYU Grossman School of Medicine, 180 Madison Ave, 4th Floor, Suite 455, New York, NY, 10016, USA.

With recent advancement in cancer screening and treatment, many patients with cancers are identified at early stage and clinically cured. Importantly, uncured patients should be treated timely before the cancer progresses to advanced stages for which therapeutic options are rather limited. It is also crucial to identify uncured subjects among patients with early-stage cancers for clinical trials to develop effective adjuvant therapies. Thus, it is of interest to develop statistical predictive models with as high accuracy as possible in predicting the latent cure status. The receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC) are among the most widely used statistical metrics for assessing predictive accuracy or discriminatory power for a dichotomous outcome (cured/uncured). Yet the conventional AUC cannot be directly used due to incompletely observed cure status. In this article, we proposed new estimates of the ROC curve and its AUC for predicting latent cure status in Cox proportional hazards (PH) cure models and transformation cure models. We developed explicit formulas to estimate sensitivity, specificity, the ROC and its AUC without requiring to know the patient cure status. We also developed EM type estimates to approximate sensitivity, specificity, ROC and AUC conditional on observed data. Numerical studies were used to assess their finite-sample performance of the proposed methods. Both methods are consistent and have similar efficiency as shown in our numerical studies. A melanoma dataset was used to demonstrate the utility of the proposed estimates of the ROC curve for the latent cure status. We also have developed an [Formula: see text] package called [Formula: see text] to efficiently compute the proposed estimates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10985-021-09516-6DOI Listing
April 2021

Molecular model construction of Danhou lignite and study on adsorption of CH by oxygen functional groups.

Environ Sci Pollut Res Int 2021 Jan 17. Epub 2021 Jan 17.

School of Emergency Management and Safety Engineering, China University of Mining and Technology (Beijing), No. ding 11 College Road, Haidian District, Beijing, 100083, China.

In view of the frequent occurrence of gas accidents in coal mines, the mechanism of oxygen-containing functional groups (OCFGs) in Danhou lignite adsorbing gas was studied by experiment and simulation. Elemental analysis, X-ray photoelectron spectroscopy (XPS), solid-state C nuclear magnetic resonance spectroscopy (C-NMR), and adsorption experiment of CH were applied to establish the macromolecular model of Danhou lignite. Then, molecular mechanics (MM) and molecular dynamics (MD) were utilized to optimize the coal macromolecular model, and the density of coal was determined via adding periodic boundary conditions. The mechanism of gas adsorption by OCFGs was studied by grand canonical Monte Carlo (GCMC) and density functional theory (DFT). The results showed that the aromatic structures mostly exist in the form of pyrenes; the structure of aliphatic carbons are mostly methylene and methine groups; the alkanes are mostly long chains; oxygen atoms are mainly in the form of hydroxyl groups and ether groups; nitrogen atoms are mainly in the form of pyridines; and the density of Danhou lignite is 1.25 g/cm. The isotherm adsorption curve and Langmuir adsorption curve have a good fit, a single coal molecule reaches saturation after absorbing four CH molecules, and the error between experiment and simulation is small. The results of DFT calculation showed that the adsorption of CH by OCFGs is affected by the adsorption positions and adsorption directions. Due to CH molecules are affected by different electrostatic forces, the adsorption capacities of OCFGs are different, and the order is carbonyl groups > ether bonds > hydroxyl groups > carboxyl groups. The results can be used for reference in the prevention and control of coal and gas outburst.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11356-021-12399-7DOI Listing
January 2021

Biological evaluation of 7-O-amide hesperetin derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease.

Chem Biol Interact 2021 Jan 8;334:109350. Epub 2020 Dec 8.

The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China. Electronic address:

A series of 7-O-amide hesperetin derivatives were subjected to multi-target biological evaluation of anti-Alzheimer's disease. Most of the compounds showed good in vitro inhibitory activity against cholinesterase, of which compound 7c (7-O-(4-(morpholinoethyl)-acetamide) hesperetin) was the most effective anti-eqBuChE derivative (IC = 0.28 ± 0.05 μM) and exerted neuroprotective effects. Further biological evaluation found that compounds 4d, 4e and 7c showed strong antioxidant, anti-Aβ self-aggregation and anti-neuroinflammatory activities. Compound 7c could inhibit the expression of iNOS and COX-2 proteins and prevent LPS-induced inflammatory response in BV2 cells. In addition, compound 7c could chelate biometal ions such as Cu and Zn. In the vivo study, the MWM test confirmed that compound 7c could improve the cognitive impairment caused by scopolamine. In summary, the above studies have shown that the optimized compound 7c has great development potential as MTDL for the treatment of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cbi.2020.109350DOI Listing
January 2021

Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) in mainland China: an investigation of reliability, validity, and responsiveness.

Health Qual Life Outcomes 2020 Oct 22;18(1):349. Epub 2020 Oct 22.

Department of Orthopedics, Peking University Third Hospital, Beijing, China.

Background: The aim of this study is to investigate the reliability, validity, and responsiveness of JOACMEQ for CSM patients in mainland China.

Methods: A retrospective review was performed on 91 patients with CSM in our hospital from March 2015 to June 2015. Patients completed the JOACMEQ, the mJOA and the SF-36 questionnaires during the process. Cronbach's α was used to evaluate the internal consistency reliability, and test-retest reliability was checked. An exploratory factor analysis was used to determine the correlations among the JOACMEQ questions and the construct validity. The concurrent validity was assessed by Spearman correlation coefficient. The internal responsiveness was determined by effect sizes and standardized response means. External responsiveness was determined by the area under the receiver operating characteristic curve on the basis of the Youden Index.

Results: The mean age of patients was 57.61 years old. The mean follow-up was 24 months. JOACMEQ showed a good internal consistency (Cronbach's α, 0.897). Test-retest reliability showing good result (Pearson's correlation, 0.695-0.905). Our data were amenable to factor analysis (KMO = 0.816, Bartlett's test, χ(45) = 1199.99, p < 0.001), and five factors above 1 were strongly loaded and clustered for each of the five factors. Comparing the scales preoperative to those 2 years postoperative, the average scores of the subscales all increased, and both the ES and SRM showing satisfied responsiveness. In external responsiveness analysis, the recovery rate a appeared to be most responsive to post-operative improvement.

Conclusions: The Simplified Chinese version of JOACMEQ was well-developed with great reliability and sensitive responsiveness. Our study demonstrated that JOACMEQ has content psychometric properties to identify postoperative improvements in CSM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12955-020-01602-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579864PMC
October 2020

Numerical simulation of the dynamic distribution characteristics of the stress, strain and energy of coal mass under impact loads.

Sci Rep 2020 Oct 8;10(1):16849. Epub 2020 Oct 8.

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

To research the dynamic response characteristics of coal mass under impact loads, based on LS-DYNA software, rigid body bars are simulated to impact coal mass under different speed conditions, and the dynamic distribution characteristics of the stress, strain and energy of coal mass are analyzed. The results demonstrate that (1) the peaks of the axial and radial stresses and strain on the central axis and the radial line obey the power function distribution; at the same position, the axial and the radial stress peaks are close, and the axial strain peak is from much larger than the radial strain peak to close to. (2) The axial and radial stresses generate tensile stresses in the axial and radial propagation directions, respectively, and the coal mass is prone to damage under tensile stress. (3) When the speed is large, the axial stress-strain curve is similar to that of the dynamic load experiment. The axial stress peak, axial strain peak, critical effective stress, critical time and secant modulus have a linear relationship with the velocity. (4) When the dynamic load is large, most of the energy is in the form of kinetic energy, and the total energy loss also increases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-74063-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544829PMC
October 2020

Identification of novel CDK 9 inhibitors based on virtual screening, molecular dynamics simulation, and biological evaluation.

Life Sci 2020 Oct 8;258:118228. Epub 2020 Aug 8.

The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The key laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei 230032, China. Electronic address:

Aims: Cyclin-dependent kinase 9 (CDK9) is a member of the CDK subfamily and plays a major role in the regulation of transcriptional elongation. It has attracted widespread attention as a therapeutic target for cancer. Here, we aimed to explore novel CDK 9 inhibitors by using a hybrid virtual screening strategy.

Main Methods: A hybrid virtual screening strategy was constructed with computer-aided drug design (CADD). First, compounds were filtered in accordance with Lipinski's rule of five and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Second, a 3D-QSAR pharmacophore model was built and used as a 3D query to screen the obtained hit compounds. Third, the hit compounds were subjected to molecular docking studies. Fourth, molecular dynamics (MD) simulations were performed on CDK9 in complex with the final hits to examine the structural stability. Finally, CDK9 kinase biochemical assay was performed to identify the biological activity of the hit compounds.

Key Findings: Seven hit compounds were screened out. These hit compounds showed drug-like properties in accordance with Lipinski's rule of five and ADMET. Complexes involving the six hit compounds bound to CDK9 exhibited good structural stability in the MD simulation. Furthermore, these six hit compounds had strong inhibitory activity against CDK9 kinase. In particular, hit 3 showed the most promising activity with the percentage of 71%.

Significance: The six hit compounds may be promising novel CDK9 inhibitors, and the hybrid virtual screening strategy designed in this study provides an important reference for the design and synthesis of novel CDK9 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2020.118228DOI Listing
October 2020

Quantitative analysis of the correlation between preoperative cervical degeneration and postoperative heterotopic ossification after cervical disc replacement: minimum 10-year follow-up data.

J Neurosurg Spine 2020 Jul 17:1-6. Epub 2020 Jul 17.

1Department of Orthopaedics, Peking University Third Hospital, Beijing, China; and.

Objective: The authors aimed to identify factors that may be useful for quantifying the amount of degenerative change in preoperative patients to identify ideal candidates for cervical disc replacement (CDR) in patients with a minimum of 10 years of follow-up data.

Methods: During the period from December 2003 to August 2008, 54 patients underwent CDR with a Bryan cervical disc prosthesis performed by the same group of surgeons, and all of the patients in this group with at least 10 years of follow-up data were enrolled in this retrospective analysis of cases. Postoperative bone formation was graded in radiographic images by using the McAfee classification for heterotopic ossification. Preoperative degeneration was evaluated in radiographs based on a quantitative scoring system. After univariate analysis, the authors performed multifactor logistic regression analysis to identify significant factors. To determine the cutoff points for the significant factors, a receiver operating characteristic (ROC) curve analysis was conducted.

Results: Study patients had a mean age of 43.6 years and an average follow-up period of 120.3 months. The patients as a group had a 68.2% overall incidence of bone formation. Based on univariate analysis results, data for patient sex, disc height, and the presence of anterior osteophytes and endplate sclerosis were included in the multivariate analysis. According to the analysis results, the identified independent risk factors for postoperative bone formation included disc height, the presence of anterior osteophytes, and endplate sclerosis, and according to a quantitative scoring system for degeneration of the cervical spine based on these variables, the ROC curve indicated that the optimal cutoff scores for these risk factors were 0.5, 1.5, and 1.5, respectively.

Conclusions: Among the patients who were followed up for at least 10 years after CDR, the incidence of postoperative bone formation was relatively high. The study results indicate that the degree of degeneration in the target level before surgery has a positive correlation with the incidence of postoperative ossification. Rigorous indication criteria for postoperative ossification should be applied in patients for whom CDR may be a treatment option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2020.4.SPINE191303DOI Listing
July 2020

A numerical strategy to evaluate performance of predictive scores via a copula-based approach.

Stat Med 2020 09 11;39(20):2671-2684. Epub 2020 May 11.

Division of Biostatistics, New York University School of Medicine, New York, New York, USA.

Assessing and comparing the performance of correlated predictive scores are of current interest in precision medicine. Given the limitations of available theoretical approaches for assessing and comparing the predictive accuracy, numerical methods are highly desired which, however, have not been systematically developed due to technical challenges. The main challenges include the lack of a general strategy on effectively simulating many kinds of correlated predictive scores each with some given level of predictive accuracy in either concordance index or the area under a receiver operating characteristic curve area under the curves (AUC). To fill in this important knowledge gap, this paper is to provide a general copula-based numeric framework for assessing and comparing predictive performance of correlated predictive or risk scores. The new algorithms are designed to effectively simulate correlated predictive scores with given levels of predictive accuracy as measured in terms of concordance indices or time-dependent AUC for predicting survival outcomes. The copula-based numerical strategy is convenient for numerically evaluating and comparing multiple measures of predictive accuracy of correlated risk scores and for investigating finite-sample properties of test statistics and confidence intervals as well as assessing for optimism of given performance measures using cross-validation or bootstrap.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/sim.8566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478334PMC
September 2020

Prediction of prostate cancer Gleason score upgrading from biopsy to radical prostatectomy using pre-biopsy multiparametric MRI PIRADS scoring system.

Sci Rep 2020 05 7;10(1):7722. Epub 2020 May 7.

Division of Imaging Sciences and Technology, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK.

An increase or 'upgrade' in Gleason Score (GS) in prostate cancer following Transrectal Ultrasound (TRUS) guided biopsies remains a significant challenge to overcome. to evaluate whether MRI has the potential to narrow the discrepancy of histopathological grades between biopsy and radical prostatectomy, three hundred and thirty men treated consecutively by laparoscopic radical prostatectomy (LRP) between July 2014 and January 2019 with localized prostate cancer were included in this study. Independent radiologists and pathologists assessed the MRI and histopathology of the biopsies and prostatectomy specimens respectively. A multivariate model was constructed using logistic regression analysis to assess the ability of MRI to predict upgrading in biopsy GS in a nomogram. A decision-analysis curve was constructed assessing impact of nomogram using different thresholds for probabilities of upgrading. PIRADS scores were obtained from MRI scans in all the included cases. In a multivariate analysis, the PIRADS v2.0 score significantly improved prediction ability of MRI scans for upgrading of biopsy GS (p = 0.001, 95% CI [0.06-0.034]), which improved the C-index of predictive nomogram significantly (0.90 vs. 0.64, p < 0.05). PIRADS v2.0 score was an independent predictor of postoperative GS upgrading and this should be taken into consideration while offering treatment options to men with localized prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-64693-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205887PMC
May 2020

Survey of asymptomatic malaria and mosquito vectors in Muang Khua District of Phongsaly Province, China-Laos Border.

Int J Infect Dis 2020 Jul 3;96:141-147. Epub 2020 Apr 3.

Department of Tropical Diseases, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China. Electronic address:

Objectives: The China-Laos border has been identified as an important origin of imported malaria outside China. The aim of this study was to describe the asymptomatic malaria infections and epidemic trend of malaria in the China-Laos border region.

Methods: A prevalence survey and surveillance of mosquito vectors was conducted in Muang Khua District of Phongsaly Province, China-Laos border, to determine the parasite carriage rate using nested PCR and microscopy. The species composition of malaria vectors was determined by overnight trapping. Blood samples were collected from 354 local residents aged 1-72 years in Sankang village in 2016. A total of 2430 adult mosquitoes were collected from four other villages in Muang Khua District from June to August 2016.

Results: The parasite carriage rate was 7.63% (27/354) by microscopy or 7.91% (28/354) by nested PCR. The results of surveillance of the mosquito vectors revealed that the predominant genera of adult mosquitoes were Culex (69.92%, 1699/2430) and Anopheles (21.48%, 522/2430). Anopheles sinensis (82.95%, 433/522) was identified as the predominant species among the seven members of Anopheles found in this border region.

Conclusions: A high prevalence of asymptomatic malaria was present and the most important malaria vector was Anopheles sinensis, suggesting that the malaria epidemic situation on the China-Laos border is serious.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2020.03.066DOI Listing
July 2020

Genome-Wide Analysis of Genetic Diversity in Isolates From China-Myanmar Border.

Front Genet 2019 29;10:1065. Epub 2019 Oct 29.

Department of Tropical Diseases, Naval Medical University, Shanghai, China.

isolates from China-Myanmar border (CMB) have experienced regional special selective pressures and adaptive evolution. However, the genomes of isolates from this region to date are poorly characterized. Herein, we performed whole-genome sequencing of 34 isolates from CMB and a series of genome-wide sequence analyses to reveal their genetic diversity, population structures, and comparisons with the isolates from other epidemic regions (Thai-Cambodia border, Thai-Myanmar border, and West Africa). Totally 59,720 high-quality single-nucleotide polymorphisms (SNPs) were identified in the isolates from CMB, with average nucleotide diversity (π = 4.59 × 10) and LD decay (132 bp). The Tajima's and Fu and Li's values of the CMB isolates were -0.8 ( < 0.05) and -0.84 ( < 0.05), respectively, suggesting a demographic history of recent population expansion or purifying selection. Moreover, 78 genes of the parasite were identified that could be under positive selection, including those genes conferring drug resistance such as . In addition, 33 SNPs were identified for tracing the source of the parasites with a high accuracy by analysis of the most differential SNPs among the four epidemic regions. Collectively, our data demonstrated high diversity of the CMB isolates' genomes forming a distinct population, and the identification of 33-SNP barcode provides a valuable surveillance of parasite migration among the regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2019.01065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830057PMC
October 2019

FEV1:FVC Thresholds for Defining Chronic Obstructive Pulmonary Disease.

JAMA 2019 10;322(16):1611

Merck & Co Inc, Kenilworth, New Jersey.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2019.13957DOI Listing
October 2019

Design, Synthesis and Investigation of the Potential Anti-Inflammatory Activity of 7--Amide Hesperetin Derivatives.

Molecules 2019 Oct 11;24(20). Epub 2019 Oct 11.

The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.

To develop new anti-inflammatory agents, a series of 7--amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7--(2-(Propylamino)-2-oxoethyl)hesperetin () and 7--(2-(Cyclopentylamino)-2-oxoethyl)hesperetin () with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC = 19.32 and 16.63 μM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) than indomethacin and celecoxib at 10 μM. The structure-activity relationships (SARs) suggested that the 7--amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24203663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832651PMC
October 2019

Author Correction: Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2.

Authors:
Evan Bolyen Jai Ram Rideout Matthew R Dillon Nicholas A Bokulich Christian C Abnet Gabriel A Al-Ghalith Harriet Alexander Eric J Alm Manimozhiyan Arumugam Francesco Asnicar Yang Bai Jordan E Bisanz Kyle Bittinger Asker Brejnrod Colin J Brislawn C Titus Brown Benjamin J Callahan Andrés Mauricio Caraballo-Rodríguez John Chase Emily K Cope Ricardo Da Silva Christian Diener Pieter C Dorrestein Gavin M Douglas Daniel M Durall Claire Duvallet Christian F Edwardson Madeleine Ernst Mehrbod Estaki Jennifer Fouquier Julia M Gauglitz Sean M Gibbons Deanna L Gibson Antonio Gonzalez Kestrel Gorlick Jiarong Guo Benjamin Hillmann Susan Holmes Hannes Holste Curtis Huttenhower Gavin A Huttley Stefan Janssen Alan K Jarmusch Lingjing Jiang Benjamin D Kaehler Kyo Bin Kang Christopher R Keefe Paul Keim Scott T Kelley Dan Knights Irina Koester Tomasz Kosciolek Jorden Kreps Morgan G I Langille Joslynn Lee Ruth Ley Yong-Xin Liu Erikka Loftfield Catherine Lozupone Massoud Maher Clarisse Marotz Bryan D Martin Daniel McDonald Lauren J McIver Alexey V Melnik Jessica L Metcalf Sydney C Morgan Jamie T Morton Ahmad Turan Naimey Jose A Navas-Molina Louis Felix Nothias Stephanie B Orchanian Talima Pearson Samuel L Peoples Daniel Petras Mary Lai Preuss Elmar Pruesse Lasse Buur Rasmussen Adam Rivers Michael S Robeson Patrick Rosenthal Nicola Segata Michael Shaffer Arron Shiffer Rashmi Sinha Se Jin Song John R Spear Austin D Swafford Luke R Thompson Pedro J Torres Pauline Trinh Anupriya Tripathi Peter J Turnbaugh Sabah Ul-Hasan Justin J J van der Hooft Fernando Vargas Yoshiki Vázquez-Baeza Emily Vogtmann Max von Hippel William Walters Yunhu Wan Mingxun Wang Jonathan Warren Kyle C Weber Charles H D Williamson Amy D Willis Zhenjiang Zech Xu Jesse R Zaneveld Yilong Zhang Qiyun Zhu Rob Knight J Gregory Caporaso

Nat Biotechnol 2019 Sep;37(9):1091

Center for Applied Microbiome Science, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-019-0252-6DOI Listing
September 2019

Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2.

Authors:
Evan Bolyen Jai Ram Rideout Matthew R Dillon Nicholas A Bokulich Christian C Abnet Gabriel A Al-Ghalith Harriet Alexander Eric J Alm Manimozhiyan Arumugam Francesco Asnicar Yang Bai Jordan E Bisanz Kyle Bittinger Asker Brejnrod Colin J Brislawn C Titus Brown Benjamin J Callahan Andrés Mauricio Caraballo-Rodríguez John Chase Emily K Cope Ricardo Da Silva Christian Diener Pieter C Dorrestein Gavin M Douglas Daniel M Durall Claire Duvallet Christian F Edwardson Madeleine Ernst Mehrbod Estaki Jennifer Fouquier Julia M Gauglitz Sean M Gibbons Deanna L Gibson Antonio Gonzalez Kestrel Gorlick Jiarong Guo Benjamin Hillmann Susan Holmes Hannes Holste Curtis Huttenhower Gavin A Huttley Stefan Janssen Alan K Jarmusch Lingjing Jiang Benjamin D Kaehler Kyo Bin Kang Christopher R Keefe Paul Keim Scott T Kelley Dan Knights Irina Koester Tomasz Kosciolek Jorden Kreps Morgan G I Langille Joslynn Lee Ruth Ley Yong-Xin Liu Erikka Loftfield Catherine Lozupone Massoud Maher Clarisse Marotz Bryan D Martin Daniel McDonald Lauren J McIver Alexey V Melnik Jessica L Metcalf Sydney C Morgan Jamie T Morton Ahmad Turan Naimey Jose A Navas-Molina Louis Felix Nothias Stephanie B Orchanian Talima Pearson Samuel L Peoples Daniel Petras Mary Lai Preuss Elmar Pruesse Lasse Buur Rasmussen Adam Rivers Michael S Robeson Patrick Rosenthal Nicola Segata Michael Shaffer Arron Shiffer Rashmi Sinha Se Jin Song John R Spear Austin D Swafford Luke R Thompson Pedro J Torres Pauline Trinh Anupriya Tripathi Peter J Turnbaugh Sabah Ul-Hasan Justin J J van der Hooft Fernando Vargas Yoshiki Vázquez-Baeza Emily Vogtmann Max von Hippel William Walters Yunhu Wan Mingxun Wang Jonathan Warren Kyle C Weber Charles H D Williamson Amy D Willis Zhenjiang Zech Xu Jesse R Zaneveld Yilong Zhang Qiyun Zhu Rob Knight J Gregory Caporaso

Nat Biotechnol 2019 08;37(8):852-857

Center for Applied Microbiome Science, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-019-0209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015180PMC
August 2019

Prediction of Postprostatectomy Biochemical Recurrence Using Quantitative Ultrasound Shear Wave Elastography Imaging.

Front Oncol 2019 9;9:572. Epub 2019 Jul 9.

Division of Imaging Science and Technology, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, United Kingdom.

To determine the prognostic significance of tissue stiffness measurement using transrectal ultrasound shear wave elastography in predicting biochemical recurrence following radical prostatectomy for clinically localized prostate cancer. Eligible male patients with clinically localized prostate cancer and extraperitoneal laparoscopic radical prostatectomy between November 2013 and August 2017 were retrospectively selected. Information of potential biochemical recurrence predictors, including imaging (ultrasound shear wave elastography and magnetic resonance imaging), clinicopathological characteristics, and preoperative prostate specific antigen (PSA) levels were obtained. Recurrence-free survival (Kaplan-Meier curve) and a multivariate model were constructed using Cox regression analysis to evaluate the impact of shear wave elastography as a prognostic marker for biochemical recurrence. Patients experienced biochemical recurrence in an average of 26.3 ± 16.3 months during their follow-up. A cutoff of 144.85 kPa for tissue stiffness measurement was estimated for recurrence status at follow-up with a sensitivity of 74.4% and a specificity of 61.7%, respectively ( < 0.05). In univariate analysis, shear wave elastography performed well in all preoperative factors compared to biopsy Gleason Score, PSA and magnetic resonance imaging; in multivariate analysis with postoperative pathological factors, shear wave elastography was statistically significant in predicting postoperative biochemical recurrence, which improved the C-index of predictive nomogram significantly (0.74 vs. 0.70, < 0.05). The study revealed that quantitative ultrasound shear wave elastography-measured tissue stiffness was a significant imaging marker that enhanced the predictive ability with other clinical and histopathological factors in prognosticating postoperative biochemical recurrence following radical prostatectomy for clinically localized prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.00572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629866PMC
July 2019

PM2.5 air pollution and cause-specific cardiovascular disease mortality.

Int J Epidemiol 2020 02;49(1):25-35

Department of Population Health, New York University School of Medicine, New York, NY, USA.

Background: Ambient air pollution is a modifiable risk factor for cardiovascular disease, yet uncertainty remains about the size of risks at lower levels of fine particulate matter (PM2.5) exposure which now occur in the USA and elsewhere.

Methods: We investigated the relationship of ambient PM2.5 exposure with cause-specific cardiovascular disease mortality in 565 477 men and women, aged 50 to 71 years, from the National Institutes of Health-AARP Diet and Health Study. During 7.5 x 106 person-years of follow up, 41 286 cardiovascular disease deaths, including 23 328 ischaemic heart disease (IHD) and 5894 stroke deaths, were ascertained using the National Death Index. PM2.5 was estimated using a hybrid land use regression (LUR) geostatistical model. Multivariate Cox regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CI).

Results: Each increase of 10  μg/m3 PM2.5 (overall range, 2.9-28.0  μg/m3) was associated, in fully adjusted models, with a 16% increase in mortality from ischaemic heart disease [hazard ratio (HR) 1.16; 95% CI 1.09-1.22] and a 14% increase in mortality from stroke (HR 1.14; CI 1.02-1.27). Compared with PM2.5 exposure <8  μg/m3 (referent), risks for CVD were increased in relation to PM2.5 exposures in the range of 8-12  μg/m3 (CVD: HR 1.04; 95% CI 1.00-1.08), in the range 12-20  μg/m3 (CVD: HR 1.08; 95% CI 1.03-1.13) and in the range 20+ μg/m3 (CVD: HR 1.19; 95% CI 1.10-1.28). Results were robust to alternative approaches to PM2.5 exposure assessment and statistical analysis.

Conclusions: Long-term exposure to fine particulate air pollution is associated with ischaemic heart disease and stroke mortality, with excess risks occurring in the range of and below the present US long-term standard for ambient exposure to PM2.5 (12  µg/m3), indicating the need for continued improvements in air pollution abatement for CVD prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyz114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124502PMC
February 2020

The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes.

ISME J 2019 05 16;13(5):1280-1292. Epub 2019 Jan 16.

Department of Medicine, New York University Langone Medical Center, New York, NY, 10016, USA.

The high-fat, high-calorie diets of westernized cultures contribute to the global obesity epidemic, and early life exposure to antibiotics may potentiate those dietary effects. Previous experiments with mice had shown that sub-therapeutic antibiotic treatment (STAT)-even restricted to early life-affected the gut microbiota, altered host metabolism, and increased adiposity throughout the lifetime of the animals. Here we carried out a large-scale cohousing experiment to investigate whether cohousing STAT and untreated (Control) mice would transfer the STAT-perturbed microbiota and transmit its impact on weight. We exposed pregnant dams and their young offspring to either low-dose penicillin (STAT) or water (Control) until weaning, and then followed the offspring as they grew and endured a switch from normal to high-fat diet at week 17 of life. Cohousing, which started at week 4, rapidly approximated the microbiota within cages, lowering the weight of STAT mice relative to non-cohoused mice. The effect, however, varied between cages, and was restricted to the first 16 weeks when diet consisted of normal chow. Once mice switched to high-fat diet, the microbiota α- and β-diversity expanded and the effect of cohousing faded: STAT mice, again, were heavier than control mice independently of cohousing. Metabolomics revealed serum metabolites associated with STAT exposure, but no significant differences were detected in glucose or insulin tolerance. Our results show that cohousing can partly ameliorate the impact of STAT on the gut microbiota but not prevent increased weight with high-fat diet. These observations have implications for microbiota therapies aimed to resolve the collateral damage of antibiotics and their load on human obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41396-019-0349-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474226PMC
May 2019

q2-longitudinal: Longitudinal and Paired-Sample Analyses of Microbiome Data.

mSystems 2018 Nov-Dec;3(6). Epub 2018 Nov 20.

The Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA.

Studies of host-associated and environmental microbiomes often incorporate longitudinal sampling or paired samples in their experimental design. Longitudinal sampling provides valuable information about temporal trends and subject/population heterogeneity, offering advantages over cross-sectional and pre-post study designs. To support the needs of microbiome researchers performing longitudinal studies, we developed q2-longitudinal, a software plugin for the QIIME 2 microbiome analysis platform (https://qiime2.org). The q2-longitudinal plugin incorporates multiple methods for analysis of longitudinal and paired-sample data, including interactive plotting, linear mixed-effects models, paired differences and distances, microbial interdependence testing, first differencing, longitudinal feature selection, and volatility analyses. The q2-longitudinal package (https://github.com/qiime2/q2-longitudinal) is open-source software released under a 3-clause Berkeley Software Distribution (BSD) license and is freely available, including for commercial use. Longitudinal sampling provides valuable information about temporal trends and subject/population heterogeneity. We describe q2-longitudinal, a software plugin for longitudinal analysis of microbiome data sets in QIIME 2. The availability of longitudinal statistics and visualizations in the QIIME 2 framework will make the analysis of longitudinal data more accessible to microbiome researchers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSystems.00219-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247016PMC
November 2018

Double-blind, randomized clinical trial comparing the efficacy and safety of continuing or discontinuing the dipeptidyl peptidase-4 inhibitor sitagliptin when initiating insulin glargine therapy in patients with type 2 diabetes: The CompoSIT-I Study.

Diabetes Obes Metab 2019 04 9;21(4):781-790. Epub 2018 Dec 9.

Merck & Co., Inc., Kenilworth, New Jersey.

Aims: To compare the effects of continuing versus discontinuing sitagliptin when initiating and intensively titrating insulin glargine.

Materials And Methods: Eligible patients had inadequately controlled type 2 diabetes on metformin (≥1500 mg/d) in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sulphonylurea. Those on metformin + sitagliptin were directly randomized; all others were switched to metformin + sitagliptin (discontinuing other DPP-4 inhibitors and sulphonylureas) and stabilized during a run-in period. At randomization, patients were allocated to continuing sitagliptin or discontinuing sitagliptin, with both groups initiating insulin glargine and titrating to a target fasting glucose of 4.0 to 5.6 mmol/L.

Results: A total of 743 participants (mean glycated haemoglobin [HbA1c] 72.6 mmol/mol [8.8%], disease duration 10.8 years), were treated. After 30 weeks, the mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 51.4 mmol/mol (6.85%) and -20.5 mmol/mol (-1.88%) in the sitagliptin group and 56.4 mmol/mol (7.31%) and -15.5 mmol/mol (-1.42%) in the placebo group; the difference in LS mean changes from baseline HbA1c was -5.0 mmol/mol (-0.46%; P < 0.001). The percentage of participants with HbA1c <53 mmol/mol (<7.0%) was higher (54% vs. 35%) and the mean daily insulin dose was lower (53 vs. 61 units) in the sitagliptin group. Despite lower HbA1c, event rates and incidences of hypoglycaemia were not higher in the sitagliptin group. Adverse events overall and changes from baseline in body weight were similar between the two treatment groups.

Conclusion: When initiating insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycaemia. ClinicalTrials.gov Identifier: NCT02738879.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.13574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587501PMC
April 2019

The stage analysis and countermeasures of coal spontaneous combustion based on "five stages" division.

PLoS One 2018 23;13(8):e0202724. Epub 2018 Aug 23.

School of Resources and Safety Engineering, China University of Mining & Technology (Beijing), Beijing, China.

The "three stages" division of coal spontaneous combustion is fuzzy and lacks adequate risk and warning levels corresponding to its divisions; additionally, the targeted prevention measures for each stage have not been described. To address the shortcomings of the "three stages" division, the "five stages" division was proposed to more clearly analyze the stage changes of the spontaneous combustion of coal. The "five stages" method divides the process of the spontaneous combustion of coal into five stages, including: the latent stage, heat accumulating stage, evaporation stage, active stage, and hypoxic stage. The critical point of each stage was determined using adiabatic oxidation experiments and programmed heat experiments. As the critical point of the latent stage, the temperature of zero activation energy is approximately 55-70°C. In the heat accumulating stage, the critical point is the temperature (approximately 90°C) where the external moisture of coal evaporates violently while the internal moisture of coal has not yet fully evaporated. During the evaporation stage, the temperature (approximately 105°C) where the internal moisture has evaporated completely represents the end of this stage and the start of the active stage (105-170°C). When the oxygen concentration drops to 5%, the spontaneous combustion of coal enters the hypoxic stage. Thus, an oxygen concentration of 5% represents the critical point of the start of the hypoxic stage (above 170°C). After the analysis of each stage, risk and warning levels were determined. Considering the major prevention measures of the spontaneous combustion of coal, a staged warning and disposal table was created.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202724PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107200PMC
February 2019

Association between Ki-67 expression and clinical outcomes among patients with clinically node-negative, thick primary melanoma who underwent nodal staging.

J Surg Oncol 2018 Jul 7;118(1):150-156. Epub 2018 Jun 7.

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.

Background: Patients with thick primary melanomas (≥4 mm) have highly variable survival outcomes. Cell proliferation marker Ki-67 has been identified as promising biomarker in thick melanoma but has not been evaluated since the wide spread adoption of sentinel lymph node biopsy. We revisit its prognostic relevance in the sentinel node era.

Methods: We studied patients with thick (≥4 mm) primary melanoma prospectively enrolled in a clinicopathological biospecimen database from 2002 to 2015, and evaluated the prognostic value of Ki-67 expression while controlling for features included in the existing staging criteria.

Results: We analyzed 68 patients who underwent lymph node sampling and who had an available tumor for Ki-67 immunohistochemical (IHC) staining. The median tumor thickness was 6.0 mm; the median follow-up was 2.6 years. In multivariable analysis including nodal status and primary tumor ulceration, Ki-67 expression was an independent predictor of worse recurrence-free survival (HR 2.19, P = 0.024) and overall survival (HR 2.49, P = 0.028). Natural log-transformed tumor thickness (ln [thickness]) was also significantly associated with worse OS (HR 2.39, P = 0.010).

Conclusion: We identify Ki-67 and ln (thickness) as potential biomarkers for patients with thick melanoma who have undergone nodal staging. If validated in additional studies, these biomarkers could be integrated into the staging criteria to improve risk-stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25111DOI Listing
July 2018

Determination of Tumor Marker Carcinoembryonic Antigen with Biosensor Based on Optical Quantum Weak Measurements.

Sensors (Basel) 2018 May 14;18(5). Epub 2018 May 14.

Shenzhen Maternity & Child Healthcare Hospital, Shenzhen 518055, China.

A phase-sensitive weak measurement biosensor was proposed for the detection of carcinoembryonic antigen (CEA), one common category of tumor markers. The total internal reflection (TIR) at the interface of the prism without precious metal coating was exploited to introduce the phase delay between horizontal and vertical polarizations, which can be determined through the central wavelength shift of output spectra for the sensing of the refractive index of the sample. In the weak measurement analysis, the specific binding reaction of tumor markers with a refractive index change on the surface of the prism can be monitored in real time through the central wavelength shift. With the specific absorption measurement, the feasibility of this weak measurement-based biosensor was experimentally demonstrated. We provide a low cost and convenient approach for tumor marker detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/s18051550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982534PMC
May 2018

Quantitative parameters in dynamic contrast-enhanced magnetic resonance imaging for the detection and characterization of prostate cancer.

Oncotarget 2018 Mar 23;9(22):15997-16007. Epub 2018 Mar 23.

Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.

Objectives: to assess the diagnostic accuracy of quantitative parameters of DCE-MRI in multi-parametric MRI (mpMRI) in comparison to the histopathology (including Gleason grade) of prostate cancer.

Patients And Methods: 150 men with suspected prostate cancer (abnormal digital rectum examination and or elevated prostate-specific antigen) received pre-biopsy 3T mpMRI and were recruited into peer-reviewed, protocol-based prospective study. The DCE-MRI quantitative parameters ( (influx transfer constant) and (efflux rate constant)) of the cancerous and normal areas were recorded using four different kinetic models employing Olea Sphere (Olea Medical, La Ciotat, France). The correlation between these parameters and the histopathology of the lesions (biopsy and in a sub-cohort 41 radical prostatectomy specimen) was assessed.

Results: The quantitative parameters showed a significant difference between non-cancerous (benign) and cancerous lesions (Gleason score≥3+3) in the prostate gland. The cut-off values for prostate cancer differentiation were: (0.205 min) and (0.665 min) in the extended Tofts model (ET) and (0.205 min and (0.63 min) in the Lawrence and Lee delay (LD) models respectively. The mean value also showed a difference between low-grade cancer (Gleason score=3+3) and high-grade cancer (Gleason score ≥ 3+4). With the addition of DCE-MRI quantitative parameters, the sensitivity of the PIRAD scoring system was increased from 56.6% to 92.1% ( _ET), 93.1% ( _ET), 91.0%, ( _LD) and 89.4% ( _LD).

Conclusion: Quantitative DCE-MRI parameters improved the diagnostic performance of conventional MRI in distinguishing normal and prostate cancers, including characterization of grade of cancers. The ET and LD models in post-image processing analysis provided better cut-off values for prostate cancer differentiation than the other quantitative DCE-MRI parameters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.24652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882313PMC
March 2018

A Phase 1/1b tolerability study of rilotumumab alone or in combination with cisplatin and capecitabine in Japanese patients with gastric cancer.

Jpn J Clin Oncol 2017 Nov;47(11):1002-1009

Shizuoka Cancer Center, Nagaizumi-cho, Shizuoka, Japan.

Objective: To evaluate the safety (including adverse events and dose-limiting toxicities [DLTs]), tolerability, pharmacokinetics and antitumor activity of the investigational MET inhibitor rilotumumab alone in patients with advanced solid tumors (Part 1) or in combination with cisplatin plus capecitabine (CX) in patients with MET-positive advanced gastric or gastroesophageal junction cancer (Part 2).

Methods: Adult patients received 10 or 20 mg/kg intravenous (IV) rilotumumab every 2 weeks (Part 1) or 15 mg/kg IV rilotumumab every 3 weeks plus 80 mg/m2 cisplatin on Day 1 and 1000 mg/m2 capecitabine twice daily on Days 1-14 of every 21-day cycle (Part 2).

Results: Nine patients enrolled in Part 1; 12 patients enrolled in Part 2. One DLT occurred (Grade 3 decreased appetite and stomatitis [Part 2]). Adverse events related to any treatment occurred in 17 patients (81%) and were Grade ≥3 in nine patients (43%). Rilotumumab pharmacokinetics appeared linear, and exposure was unaffected by CX. No patient who received rilotumumab monotherapy in Part 1 had a response. In Part 2, five of eight patients (63%) with measureable disease at baseline had a partial response and two patients (25%) had stable disease; median (95% CI) progression-free survival was 7.0 (2.4-15.4) months; overall survival was 18.2 (5.6-20.4) months.

Conclusions: In combination with CX, rilotumumab appeared tolerable and showed antitumor activity in Japanese patients with MET-positive gastric/gastroesophageal junction cancer. However, owing to the results of recent Phase 3 trials of MET inhibitors (including rilotumumab), further development of rilotumumab in this setting is not being pursued. ClinicalTrials.gov Identifier: NCT01791374.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jjco/hyx114DOI Listing
November 2017

Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2017 11 25;18(11):1467-1482. Epub 2017 Sep 25.

Royal Marsden Hospital, London and Surrey, UK. Electronic address:

Background: Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma.

Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m intravenously; cisplatin 60 mg/m intravenously; capecitabine 625 mg/m orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072.

Findings: Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6-12·0) for patients in the rilotumumab group and 9·4 months (5·3-13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression.

Interpretation: Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma.

Funding: Amgen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(17)30566-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898242PMC
November 2017