Publications by authors named "Baolin Wu"

115 Publications

Dynamic functional connectivity changes in the triple networks and its association with cognitive impairment in hemodialysis patients.

Brain Behav 2021 08 1;11(8):e2314. Epub 2021 Aug 1.

Department of Magnetic Resonance, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.

Introduction: Cognitive impairment is common in hemodialysis (HD) patients; however, the underlying mechanisms have not been fully understood. The "triple-network model" that consists of the salience network (SN), central executive network (CEN), and default mode network (DMN) has been suggested to play an important role in various cognitive functions. However, dynamic functional connectivity (FC) alterations within the triple networks have not been investigated in HD patients.

Methods: Sixty-six HD patients and 66 healthy controls (HCs) were included in this study. The triple networks were identified using a group spatial independent component analysis, and dynamic FC was analyzed using a sliding window approach and k-means clustering algorithm. Furthermore, we analyzed the relationships between altered dynamic FC parameters and clinical variables in HD patients.

Results: The intrinsic brain FC within the triple networks was clustered into four configuration states. Compared with HCs, HD patients spent more time in State 1, which was characterized by weak connections between the DMN and CEN and SN. HD patients showed lower number of transitions across different states than HCs. Moreover, the number of transitions and mean dwell time in State 1 were associated with cognitive performance in HD patients.

Conclusion: Our findings suggest abnormal dynamic FC properties within the triple networks in HD patients, which may provide new insights into the pathophysiological mechanisms of their cognitive deficits from the perspective of dynamic FC.
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http://dx.doi.org/10.1002/brb3.2314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413764PMC
August 2021

Regional gray matter volume associated with exercise dependence: A voxel-based morphometry study.

Hum Brain Mapp 2021 Oct 8;42(15):4857-4868. Epub 2021 Jul 8.

Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, China.

Although regular physical exercise has multiple positive benefits for the general population, excessive exercise may lead to exercise dependence (EXD), which is harmful to one's physical and mental health. Increasing evidence suggests that stress is a potential risk factor for the onset and development of EXD. However, little is known about the neural substrates of EXD and the underlying neuropsychological mechanism by which stress affects EXD. Herein, we investigate these issues in 86 individuals who exercise regularly by estimating their cortical gray matter volume (GMV) utilizing a voxel-based morphometry method based on structural magnetic resonance imaging. Whole-brain correlation analyses and prediction analyses showed negative relationships between EXD and GMV of the right orbitofrontal cortex (OFC), left subgenual cingulate gyrus (sgCG), and left inferior parietal lobe (IPL). Furthermore, mediation analyses found that the GMV of the right OFC was an important mediator between stress and EXD. Importantly, these results remained significant even when adjusting for sex, age, body mass index, family socioeconomic status, general intelligence and total intracranial volume, as well as depression and anxiety. Collectively, the results of the present study provide crucial evidence of the neuroanatomical basis of EXD and reveal a potential neuropsychological pathway in predicting EXD in which GMV mediates the relationship between stress and EXD.
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http://dx.doi.org/10.1002/hbm.25585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449116PMC
October 2021

T1ρ and T2 mapping detect acute ischemic injury in a piglet model of Legg-Calvé-Perthes disease.

J Orthop Res 2021 Mar 31. Epub 2021 Mar 31.

Center for Excellence in Hip, Scottish Rite for Children, Dallas, Texas, USA.

This study investigated the sensitivity of T1ρ and T2 relaxation time mapping to detect acute ischemic injury to the secondary ossification center (SOC) and epiphyseal cartilage of the femoral head in a piglet model of Legg-Calvé-Perthes disease. Six piglets underwent surgery to induce global right femoral head ischemia and were euthanized 48 h later. Fresh operated and contralateral-control femoral heads were imaged ex vivo with T1, T2, and T1ρ mapping using a 9.4T magnetic resonance imaging scanner. The specimens were imaged a second time after a freeze/thaw cycle and then processed for histology. T1, T2, and T1ρ measurements in the SOC, epiphyseal cartilage, articular cartilage, and metaphysis were compared between operated and control femoral heads using paired t tests. The effects of freeze/thaw, T1ρ spin-lock frequency, and fat saturation were also investigated. Five piglets with histologically confirmed ischemic injury were quantitatively analyzed. T1ρ was increased in the SOC (101 ± 15 vs. 73 ± 16 ms; p = 0.0026) and epiphyseal cartilage (84.9 ± 9.2 vs. 74.3 ± 3.6 ms; p = 0.031) of the operated versus control femoral heads. T2 was also increased in the SOC (28.7 ± 2.0 vs. 22.7 ± 1.7; p = 0.0037) and epiphyseal cartilage (57.4 ± 4.7 vs. 49.0 ± 2.7; p = 0.0041). No changes in T1 were detected. The sensitivities of T1ρ and T2 mapping in detecting ischemic injury were maintained after a freeze/thaw cycle, and T1ρ sensitivity was maintained after varying spin-lock frequency and applying fat saturation. In conclusion, T1ρ and T2 mapping are sensitive in detecting ischemic injury to the SOC and epiphyseal cartilage of the femoral head as early as 48 h after ischemia induction.
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http://dx.doi.org/10.1002/jor.25044DOI Listing
March 2021

Abnormal brain functional networks in end-stage renal disease patients with cognitive impairment.

Brain Behav 2021 04 19;11(4):e02076. Epub 2021 Feb 19.

Department of Magnetic Resonance, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.

Introduction: Cognitive impairment (CI) is common in patients with end-stage renal disease (ESRD). Neuroimaging studies have demonstrated structural and functional brain alterations underlying CI in patients with ESRD. However, the patterns of change in whole-brain functional networks in ESRD patients with CI remain poorly understood.

Methods: We enrolled 66 patients with ESRD (36 patients with CI and 30 patients without CI) and 48 healthy control subjects (HCs). We calculated the topological properties using a graph theoretical analysis. An analysis of covariance (ANCOVA) was used to compare network metrics among the three groups. Moreover, we analyzed the relationships between altered network measures and clinical variables in ESRD patients with CI.

Results: Compared with HCs, both patient groups showed lower local efficiency and small-worldness. ESRD patients had decreased nodal centralities in the default mode regions and right amygdala. Comparison of the two patient groups showed significantly decreased global (small-worldness) and nodal (nodal centralities in the default mode regions) properties in the CI group. Altered nodal centralities in the bilateral medial part of the superior frontal gyrus, left posterior cingulate gyrus, and right precuneus were associated with cognitive performance in the CI group.

Conclusion: Disrupted brain functional networks were demonstrated in patients with ESRD, which were more severe in those with CI. Moreover, impaired nodal centralities in the default mode regions might underlie CI in patients with ESRD.
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http://dx.doi.org/10.1002/brb3.2076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035483PMC
April 2021

Altered intrinsic brain activity in patients with hepatic encephalopathy.

J Neurosci Res 2021 May 13;99(5):1337-1353. Epub 2021 Feb 13.

Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, P.R. China.

Neuropsychiatric deficits are common in patients with liver cirrhosis (LC), especially in those with hepatic encephalopathy (HE). Previous studies reveal abnormalities in brain activity underlying the neuropsychiatric deficits in LC patients; however, the results are inconsistent. We conducted a meta-analysis of resting-state functional magnetic resonance imaging studies using anisotropic effect-size signed differential mapping software on LC patients to characterize the most consistent regional activity alterations, and to evaluate the potential effect of liver transplantation (LT) on brain function. Meta-regression analyses were performed to explore the relationship between brain alterations and clinical variables. Compared with healthy controls, the typical patterns of increased regional activity in the fronto-striato-cerebellar network and decreased activity in the visuo-sensorimotor network and cingulate gyrus were identified in LC patients, which remained significant in the subgroup meta-analyses of minimal HE (MHE) and overt HE (OHE) patients. Functional deficits in the default mode network (DMN) were found in OHE patients compared with MHE patients. Ammonia level positively correlated with brain activity in the right middle temporal gyrus, and the completion time of number connection test A negatively correlated with brain activity in the left anterior cingulate gyrus. In addition, patients showed increased activity in the visuo-sensorimotor network and precuneus after LT. Our study suggests that alterations in the fronto-striato-cerebellar and visuo-sensorimotor networks may be the potential pathophysiological mechanisms underlying HE, and deficits in the DMN may indicate the progression of HE. LT may improve brain function in the visuo-sensorimotor network. This study has registered in the PROSPERO (CRD42020212758).
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http://dx.doi.org/10.1002/jnr.24788DOI Listing
May 2021

Precision Dosing for Tacrolimus Using Genotypes and Clinical Factors in Kidney Transplant Recipients of European Ancestry.

J Clin Pharmacol 2021 08 26;61(8):1035-1044. Epub 2021 Feb 26.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra- and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin-induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate-release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed-effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49 ng/mL, 6.5%, and 3.09 ng/mL, respectively. Prospective testing of this equation is warranted.
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http://dx.doi.org/10.1002/jcph.1823DOI Listing
August 2021

How Do You Feel Now? The Salience Network Functional Connectivity in End-Stage Renal Disease.

Front Neurosci 2020 11;14:533910. Epub 2020 Nov 11.

Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Objective: The network connectivity basis of cognitive declines in end-stage renal disease (ESRD) remains unclear. A triple-network model of the salience (SN), executive control, and default mode networks has been suggested to be critical for efficient cognition. Here, we aimed to test the hypothesis that SN may play a role in cognitive impairment in patients with ESRD.

Materials And Methods: We investigated functional connectivity (FC) alterations within the SN between 43 ESRD patients (19 females/24 males, 46 ± 10 years) and 43 healthy controls (HC) (19 females/24 males, 47 ± 10 years), and performed linear support vector machine (LSVM) analysis on significant FC pairs within the SN to discriminate the two groups, and tested the accuracy of the classifier. Association and mediation analyses were conducted among the significant FC pairs within the SN nodes, clinical indicators, and neuropsychological tests scores.

Results: We identified significant between-group FC pairs within the SN and fairly good classification efficiency with significant accuracy (72.09%, < 0.001). We found that FC between the right supramarginal gyrus and right anterior insula (AISL) was positively correlated with MoCA ( = 0.4010, = 0.008); FC between the dorsal anterior cingulate cortex (dACC) and left AISL was positively correlated with the level of hemoglobin ( = 0.4979, < 0.001). Mediation analysis found that the indirect effect of hemoglobin on forward digit span test scores via the FC between the dACC and right AISL ( < 0.05).

Conclusion: Disrupted SN connectivity may help explain cognitive declines in ESRD patients and act as a potential early biomarker. Moreover, the SN connectivity may interact with anemia to promote cognitive impairment.
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http://dx.doi.org/10.3389/fnins.2020.533910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693456PMC
November 2020

Comparative Study of Amide Proton Transfer Imaging and Intravoxel Incoherent Motion Imaging for Predicting Histologic Grade of Hepatocellular Carcinoma.

Front Oncol 2020 29;10:562049. Epub 2020 Oct 29.

Department of Magnetic Resonance, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.

Preoperative grading of hepatocellular carcinoma (HCC) is an important factor associated with prognosis after liver resection. The promising prediction of the differentiation of HCC remains a challenge. The purpose of our study was to investigate the value of amide proton transfer (APT) imaging in predicting the histological grade of HCC, compared with the intravoxel incoherent motion (IVIM) imaging. From September 2018 to February 2020, 88 patients with HCC were enrolled and divided into four groups (G1, G2, G3, and G4) based on the histologic grades. Preoperative APT signal intensity (SI), apparent diffusion coefficient (ADC), true molecular diffusion coefficient (D), pseudo-diffusion coefficient (D), and perfusion fraction ( ) of HCC were independently measured by two radiologists. The averaged values of those parameters were compared using an analysis of variance. The Spearman rank analysis was used to compare the correlation between those imaging parameters and the histological grades. Receiver operating characteristic (ROC) curve analysis was used to explore the predictive performance. There were significant differences in APT SI, ADC, D, and among the four grades of HCC (all < 0.001). A moderate to good relationship was found between APT SI and the histologic grade of HCC ( = 0.679, < 0.001). APT SI had an area under the ROC curve (AUC) of 0.890 (95% CI: 0.805-0.947) for differentiating low- from high-grade HCC, and the corresponding sensitivity and specificity were 85.71% and 82.05%, respectively. Comparison of ROC curves demonstrated that the AUC of APT SI was significantly higher than those of IVIM-derived parameter ( = 2.603, = 0.0092; = 2.099, = 0.0358; = 4.023, = 0.0001; = 2.435, = 0.0149, compared with ADC, D, D, and , respectively). Moreover, the combination of both techniques further improved the diagnostic performance, with an AUC of 0.929 (95% CI: 0.854-0.973). APT imaging may be a potential noninvasive biomarker for the prediction of histologic grading of HCC and complements IVIM imaging for the more accurate and comprehensive characterization of HCC.
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http://dx.doi.org/10.3389/fonc.2020.562049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659984PMC
October 2020

Amide Proton Transfer Imaging vs Diffusion Kurtosis Imaging for Predicting Histological Grade of Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2020 9;7:159-168. Epub 2020 Oct 9.

Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, People's Republic of China.

Background: To investigate the value of amide proton transfer (APT) imaging in predicting the histological grade of hepatocellular carcinoma (HCC), compared with diffusion kurtosis imaging (DKI).

Methods: A total of 88 patients with HCC were enrolled and divided into four groups (G1, G2, G3, and G4) based on histologic grades. Preoperative APT signal intensity (SI), mean diffusivity (MD), mean kurtosis (MK) of HCC were measured and compared. Those quantitative magnetic resonance imaging (qMRI) parameters were compared using an analysis of variance. The correlations between the qMRI parameters and the histological grades were determined using Spearman's rank analysis. In addition, the predictive performance for differentiating low- (G1 and G2) from high-grade (G3 and G4) HCC was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: Significant differences were found in APT SIs, MD, and MK among the four groups (<0.05). Moderate to good relationships were found between the histologic grade of HCC and APT SI and MK (=0.679, <0.001 and =0.539, <0.001, respectively). The area under the ROC curves (AUCs) of APT SI, MK, and MD for differentiating low- from high-grade HCC were 0.890 (95%CI: 0.805-0.947), 0.765 (95%CI: 0.662-0.849) and 0.717 (95%CI: 0.611-0.808), respectively. Comparison of ROC curves showed a significantly higher AUC of APT SI compared with those of the DKI-derived parameters ( <0.05).

Conclusion: The APT imaging may be more accurate than DKI for predicting the histological grade of HCC.
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http://dx.doi.org/10.2147/JHC.S272535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555354PMC
October 2020

Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis.

Mol Psychiatry 2020 Oct 15. Epub 2020 Oct 15.

Department of Experimental and Clinical Pharmacology and Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.
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http://dx.doi.org/10.1038/s41380-020-00914-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046847PMC
October 2020

Disrupted brain functional networks in patients with end-stage renal disease undergoing hemodialysis.

J Neurosci Res 2020 12 15;98(12):2566-2578. Epub 2020 Sep 15.

Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China.

Patterns of change in whole-brain functional networks remain poorly understood in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). We conducted a prospective research to investigate the topological properties of whole-brain functional networks in those patients using a graph-based network analysis. Resting-state functional magnetic resonance imaging was performed on 51 ESRD patients (25 HD and 26 nondialysis patients) and 36 healthy controls (HCs). We compared the topological properties of brain functional networks among the three groups, and analyzed the relationships between those significant parameters and clinical variables in ESRD patients. Progressively disrupted global topological organizations were observed from nondialysis patients to HD patients compared with HCs (all p < 0.05 after Bonferroni correction). HD patients, relative to HCs, showed significantly decreased nodal centralities in the left temporal pole: superior temporal gyrus, bilateral median cingulate and paracingulate gyri, bilateral hippocampus, bilateral parahippocampal gyrus, and bilateral amygdala, and showed increased nodal centralities in the orbital part of the bilateral middle frontal gyrus, left cuneus, and left superior occipital gyrus (all p < 0.05 after Bonferroni correction). Furthermore, nodal centralities in the bilateral hippocampus were significantly decreased in HD patients compared with nondialysis patients (p < 0.05 after Bonferroni correction). Dialysis duration negatively correlated with global efficiency in ESRD patients undergoing HD (r = -0.676, FDR q = 0.004). This study indicates that ESRD patients exhibit disruptions in brain functional networks, which are more severe in HD patients, and these alterations are correlated with cognitive performance and clinical markers.
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http://dx.doi.org/10.1002/jnr.24725DOI Listing
December 2020

Omentin-1 promotes mitochondrial biogenesis via PGC1α-AMPK pathway in chondrocytes.

Arch Physiol Biochem 2020 Sep 15:1-7. Epub 2020 Sep 15.

Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China.

Objective: Omentin-1 is a newly discovered metabolic regulatory adipokine. Studies have shown that omentin-1 possesses pleiotropic effects in different types of cells. This study aims to investigate the regulation by omentin-1 on mitochondrial biogenesis in chondrocytes.

Methodology: C-28/I2 chondrocytes were treated with omentin-1 (150 and 300 ng/ml) for 24 h. The expression of mitochondrial regulators, markers and the DNA copy was assessed. The mitochondrial morphology was observed by electron microscopy. The mitochondrial respiratory rate and ATP production in chondrocytes were measured by cell lysates.

Results: Omentin-1 treatment up-regulated PGC-1α, NRF-1 and mitochondrial transcription factor A (TFAM) in cultured chondrocytes, indicating that omentin-1 could be involved in the regulation of mitochondrial function. Omentin-1 promoted mtDNA/nDNA and four mitochondrial genes (Tomm20, Tomm40, Timm9 and Atp5c1), mRNA transcripts as well as two mitochondrial protein expressions (SDHB and MTCO1). At a cellular level, omentin-1 enhanced the mitochondrial respiratory rate and ATP production. Mechanistically, we proved that omentin-1 increased AMPKα activation, and the blockage of AMPKα by its inhibitor compound C abolished the inductive effect of omentin-1 on PGC1α expression and mtDNA/nDNA ratio, indicating that the effect of omentin-1 is dependent on AMPKα activation.

Conclusion: Omentin-1 is a positive regulator of mitochondrial biogenesis in chondrocytes, and its action is dependent on the AMPK-PGC1α pathway. This study, therefore, implies that omentin-1 has the potential to remedy chondrocyte damage in the prevention and treatment of osteoarthritis.
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http://dx.doi.org/10.1080/13813455.2020.1819337DOI Listing
September 2020

Abnormal degree centrality in end-stage renal disease (ESRD) patients with cognitive impairment: a resting-state functional MRI study.

Brain Imaging Behav 2021 Jun;15(3):1170-1180

Departments of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.

To investigate functional connectivity (FC) changes in end-stage renal disease (ESRD) patients with and without cognitive impairment (CI) by using resting-state functional magnetic resonance imaging (rs-fMRI). Twenty-three ESRD patients with CI, 22 ESRD patients with non-CI (NCI) and 23 matched healthy controls (HC) were included. Rs-fMRI scans were performed in all subjects. Full-range, long-range, and short-range FC defined voxel-wise based degree centrality (DC) and seed based FC were computed and contrasted among the groups. Compared with HC, the DC value of short functional connectivity (SFC), in ESRD patients have increased on the left supramarginal gyrus, while it reduced on the left insula and right postcentral gyrus in CI and decreased on the right precentral gyrus in NCI. Compared with NCI, the DC value of LFC in CI increased on the left fusiform gyrus, while the DC value of short functional connectivity (SFC) increased on the left middle orbital gyrus. In the seed-based FC analyses, the CI showed significantly decreased FC between the left insula and bilateral middle temporal gyrus, between the left fusiform gyrus and the right hippocampus, and between the left postcentral gyrus and the right parahippocampus compared to HC; the CI showed significantly increased FC between the left precuneus and the left fusiform gyrus, between the left postcentral gyrus and the right precuneus compared with NCI. Positive correlations were found between DC values on the right superior frontal gyrus and LDL and BDST, and between MoCA and the DC values on the left insula and the left postcentral gyrus. The altered degree centrality may serve as early biomarkers for CI in ESRD patients.
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http://dx.doi.org/10.1007/s11682-020-00317-3DOI Listing
June 2021

Penalized Fieller's confidence interval for the ratio of bivariate normal means.

Biometrics 2020 Aug 31. Epub 2020 Aug 31.

Department of Epidemiology and Biostatistics, School of Public Health, Indiana University Bloomington, Bloomington, Indiana.

Constructing a confidence interval for the ratio of bivariate normal means is a classical problem in statistics. Several methods have been proposed in the literature. The Fieller method is known as an exact method, but can produce an unbounded confidence interval if the denominator of the ratio is not significantly deviated from 0; while the delta and some numeric methods are all bounded, they are only first-order correct. Motivated by a real-world problem, we propose the penalized Fieller method, which employs the same principle as the Fieller method, but adopts a penalized likelihood approach to estimate the denominator. The proposed method has a simple closed form, and can always produce a bounded confidence interval by selecting a suitable penalty parameter. Moreover, the new method is shown to be second-order correct under the bivariate normality assumption, that is, its coverage probability will converge to the nominal level faster than other bounded methods. Simulation results show that our proposed method generally outperforms the existing methods in terms of controlling the coverage probability and the confidence width and is particularly useful when the denominator does not have adequate power to reject being 0. Finally, we apply the proposed approach to the interval estimation of the median response dose in pharmacology studies to show its practical usefulness.
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http://dx.doi.org/10.1111/biom.13363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914261PMC
August 2020

Pharmacogenomics in kidney transplant recipients and potential for integration into practice.

J Clin Pharm Ther 2020 Dec 14;45(6):1457-1465. Epub 2020 Jul 14.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

What Is Known And Objective: Pharmacogenomic biomarkers are now used in many clinical care settings and represent one of the successes of precision medicine. Genetic variants are associated with pharmacokinetic and pharmacodynamic changes leading to medication adverse effects and changes in clinical response. Actionable pharmacogenomic variants are common in transplant recipients and have implications for medications used in transplant, but yet are not broadly incorporated into practice.

Methods: From the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, and PharmGKB databases, 12 pharmacogenomic genes with 30 variants were selected and used to create diplotypes and actionable pharmacogenomic phenotypes. A total of 853 kidney allograft recipients who had genomic information available from a genome-wide association study were included.

Results: Each recipient had at least one actionable pharmacogenomic diplotype/phenotype, whereas the majority (58%) had three or four actionable diplotypes/phenotypes and 17.4% had five or more among the 12 genes. The participants carried actionable diplotypes/phenotypes for multiple medications, including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants and proton-pump inhibitors.

What Is New And Conclusion: Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants.

Clinical Trial: Genomics of Transplantation, clinicaltrials.gov (NCT01714440).
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http://dx.doi.org/10.1111/jcpt.13223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719579PMC
December 2020

Altered Whole-Brain Functional Networks in Drug-Naïve, First-Episode Adolescents With Major Depression Disorder.

J Magn Reson Imaging 2020 12 3;52(6):1790-1798. Epub 2020 Jul 3.

Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Background: Neuroimaging studies have demonstrated disrupted brain functional networks in major depression disorder (MDD); however, alterations to whole-brain networks specifically associated with adolescent MDD remain poorly understood.

Purpose: To investigate the topological architecture of intrinsic brain functional networks in drug-naïve, first-episode adolescent MDD patients using graph theoretical analysis.

Study Type: Prospective.

Subjects: In all, 109 adolescent MDD patients and 70 healthy control subjects.

Field Strength/sequences: 3.0T; gradient-echo echo-planar imaging sequence.

Assessment: After the construction of whole-brain functional networks by thresholding partial correlation matrices of 90 brain regions, we calculated the topological properties (eg, small-world, efficiency, and nodal centrality) using graph theoretical analysis.

Statistical Tests: A chi-squared test was used to compare the gender-ratio difference, and a two-sample t-test was used in the comparison of age. We compared network measures between the two groups using nonparametric permutation tests. Exploratory partial correlation analyses were used to determine the relationships between the topological metrics showing significant between-group differences and the clinical variables for adolescent MDD patients.

Results: Small-world architecture in brain functional networks was identified for both the MDD and control groups. However, depressed adolescents exhibited lower characteristic path length, normalized characteristic path length and clustering coefficient, and higher global efficiency than controls (false discovery rate [FDR] q < 0.05). Compared with controls, depressed adolescents exhibited increased nodal centralities in the default mode regions, including the right anterior cingulate and paracingulate gyri, left posterior cingulate gyrus, right superior frontal gyrus (medial part), bilateral hippocampus, and bilateral parahippocampal gyrus, and decreased nodal centralities in the orbitofrontal, temporal, and occipital regions (FDR q < 0.05).

Data Conclusion: This study indicated that drug-naïve, first-episode adolescent MDD patients exhibit disruptions in whole-brain functional networks.

Level Of Evidence: 1 TECHNICAL EFFICACY STAGE: 2 J. MAGN. RESON. IMAGING 2020;52:1790-1798.
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http://dx.doi.org/10.1002/jmri.27270DOI Listing
December 2020

Using a simplified version of a common surgical grading scale for acetabular labral tears improves the utility of preoperative hip MRI for femoroacetabular impingement.

Skeletal Radiol 2020 Dec 20;49(12):1987-1994. Epub 2020 Jun 20.

Department of Radiology, University of Minnesota Mayo Memorial Building, 420 Delaware Street SE, Minneapolis, MN, 55455, USA.

Objective: To evaluate whether a commonly used surgical grading scale, when applied to acetabular labral findings on MRI, could improve preoperative planning and counseling for patients undergoing hip arthroscopy.

Materials And Methods: We evaluated 76 clinical MRIs performed on patients with femoroacetabular impingement. Three musculoskeletal radiologists and one musculoskeletal fellow reviewed each scan in a blinded fashion, classifying the acetabular labrum from 12:00 to 4:00 using the Beck scale, a common surgical grading scale. Clinical correlation was provided via surgical examination and classification. Reliability was determined between readers and between reader and surgical data using Cohen's kappa and Krippendorff's alpha at each clock position and for the worst grading for each scan. In addition, a simplified version of the scale comprised of only two grades, potentially reparable and not potentially reparable, was evaluated.

Results: When the scale was simplified into categories of potentially reparable and not potentially reparable, the sensitivity was excellent, ranging from 85.5 to 96%. Observer agreement when using individual Beck grades was found to range from poor to fair; Kappa ranged from 0.03 to 0.19, and Alpha ranged from - 0.27 to 0.22.

Conclusion: The simplified version of the Beck labral scale when applied to MRI is a highly sensitive predictor of potentially reparable labral pathology while excluding normal and grossly degenerative tissue. Use of this scale provides clinically relevant information that can drive preoperative planning and improve patient counseling. It does so in a standardized fashion that can be applied across practice sites and without additional cost.
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http://dx.doi.org/10.1007/s00256-020-03495-9DOI Listing
December 2020

Prediction Model for Intermediate-Stage Hepatocellular Carcinoma Response to Transarterial Chemoembolization.

J Magn Reson Imaging 2020 12 19;52(6):1657-1667. Epub 2020 May 19.

Department of MR, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.

Background: The outcome of intermediate-stage hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) is greatly heterogeneous. Current means for predicting HCC response to TACE are lacking.

Purpose: To investigate whether the combination of parameters derived from amide proton transfer (APT) and intravoxel incoherent motion (IVIM) imaging, and morphological characteristics of tumor can establish a better prediction model than the univariant model for HCC response to TACE.

Study Type: Prospective.

Subjects: 56 patients with intermediate-stage HCC (50 males and six females).

Field Strength/sequences: 3.0T; T -weighted-fast spin echo, 3D liver acquisition with volume flex, single-shot fast spin echo-planar imaging (EPI), spin echo-EPI.

Assessment: Pretreatment APT signal intensities (SIs), apparent diffusion coefficient (ADC), true molecular diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) for tumor, peritumoral, and normal tissues were measured. Follow-up MRI scanning was performed, and the patients were classified as responders or nonresponders based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.

Statistical Tests: The imaging parameters were compared among the three tissues and between the two groups using analysis of variance (ANOVA) or two-sample t-test. The prediction model's variables were derived from univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was used to explore the predictive performance.

Results: Based on the logistic regression analysis results, we established a prediction model that integrated the APT SI and D values in the tumor tissue and the tumor size. ROC analyses revealed that the model was better able to predict tumor response to TACE (area under the ROC curve = 0.851) than the individual parameters on their own.

Data Conclusion: A prediction model incorporating pretreatment APT SI, D in the tumor tissue and tumor size may be useful for predicting the response of intermediate-stage HCC to TACE.

Level Of Evidence: 1 TECHNICAL EFFICACY: Stage 1 J. MAGN. RESON. IMAGING 2020;52:1657-1667.
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http://dx.doi.org/10.1002/jmri.27189DOI Listing
December 2020

Chest CT imaging characteristics of COVID-19 pneumonia in preschool children: a retrospective study.

BMC Pediatr 2020 05 18;20(1):227. Epub 2020 May 18.

Huaxi MR Research Center (HMRRC), Functional and molecular imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, PR China.

Background: Recently, the World Health Organization has declared the coronavirus disease 2019 (COVID-19) outbreak a public health emergency of international concern. So far, however, limited data are available for children. Therefore, we aimed to investigate the clinical and chest CT imaging characteristics of COVID-19 in preschool children.

Methods: From January 26, 2020 to February 20, 2020, the clinical and initial chest CT imaging data of eight preschool children with laboratory-confirmed COVID-19 from two hospitals were retrospectively collected. The chest CT imaging characteristics, including the distribution, shape, and density of lesions, and the pleural effusion, pleural changes, and enlarged lymph nodes were evaluated.

Results: Two cases (25%) were classified as mild type, and they showed no obvious abnormal CT findings or minimal pleural thickening on the right side. Five cases (62.5%) were classified as moderate type. Among these patients, one case showed consolidation located in the subpleural region of the right upper lobe, with thickening in the adjacent pleura; one case showed multiple consolidation and ground-glass opacities with blurry margins; one case displayed bronchial pneumonia-like changes in the left upper lobe; and two cases displayed asthmatic bronchitis-like changes. One case (12.5%) was classified as critical type and showed bronchial pneumonia-like changes in the bilateral lungs, presenting blurred and messy bilateral lung markings and multiple patchy shadows scattered along the lung markings with blurry margins.

Conclusions: The chest CT findings of COVID-19 in preschool children are atypical and various. Accurate diagnosis requires a comprehensive evaluation of epidemiological, clinical, laboratory and CT imaging data.
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http://dx.doi.org/10.1186/s12887-020-02140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232932PMC
May 2020

Neural-Network-Based Adaptive Event-triggered Control for Spacecraft Attitude Tracking.

IEEE Trans Neural Netw Learn Syst 2020 Oct 5;31(10):4015-4024. Epub 2019 Dec 5.

The problem of attitude tracking control for spacecraft with limited communication rate is addressed in this article. To reduce the communication burden, an adaptive event-triggered control scheme is proposed. In the control scheme, only the sampling states at the event-triggering instants are sent to the control module, which can considerably decrease the data transmission rate. To address the inertia uncertainties and external disturbances, a radial basis function neural network (NN) is introduced. The bound of the uncertainties and disturbances is estimated for the proposed control scheme, which can simplify the NN and reduce the computation. Since the event-triggered error signal is discontinuous due to the event-triggered mechanism, the closed-loop system is formulated as an impulsive dynamical system to obtain the stability properties of the system. Finally, simulation results are given to demonstrate the effectiveness of the proposed control scheme.
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http://dx.doi.org/10.1109/TNNLS.2019.2951732DOI Listing
October 2020

Extraordinary Room-Temperature Tensile Ductility of Pure Magnesium.

Materials (Basel) 2019 Nov 20;12(23). Epub 2019 Nov 20.

School of Materials Science & Engineering, Shenyang Aerospace University, Shenyang 110136, China.

Room-temperature tensile behavior and associated deformation mechanisms of multiple-axial forged (MAFed) pure Mg has been investigated. The as-MAFed Mg, with a coarsely recrystallized structure, exhibited a balanced strain-hardening behavior with strain, resulting in extraordinary mechanical properties with high ultimate stress (~200 MPa) and extensive true strain (~0.30). The observation on the microstructural evolution suggests that the balanced strain-hardening behavior is correlated with de-twinning behavior cooperated with pyramidal dislocations at the plastic straining stage.
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http://dx.doi.org/10.3390/ma12233813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926701PMC
November 2019

A general statistic to test an optimally weighted combination of common and/or rare variants.

Genet Epidemiol 2019 12 9;43(8):966-979. Epub 2019 Sep 9.

Department of Mathematics, University of North Texas, Denton, Texas.

Both genome-wide association study and next-generation sequencing data analyses are widely employed to identify disease susceptible common and/or rare genetic variants. Rare variants generally have large effects though they are hard to detect due to their low frequencies. Currently, many existing statistical methods for rare variants association studies employ a weighted combination scheme, which usually puts subjective weights or suboptimal weights based on some adhoc assumptions (e.g., ignoring dependence between rare variants). In this study, we analytically derived optimal weights for both common and rare variants and proposed a general and novel approach to test association between an optimally weighted combination of variants (G-TOW) in a gene or pathway for a continuous or dichotomous trait while easily adjusting for covariates. Results of the simulation studies show that G-TOW has properly controlled type I error rates and it is the most powerful test among the methods we compared when testing effects of either both rare and common variants or rare variants only. We also illustrate the effectiveness of G-TOW using the Genetic Analysis Workshop 17 (GAW17) data. Additionally, we applied G-TOW and other competitive methods to test disease-associated genes in real data of schizophrenia. The G-TOW has successfully verified genes FYN and VPS39 which are associated with schizophrenia reported in existing publications. Both of these genes are missed by the weighted sum statistic and the sequence kernel association test. Simulation study and real data analysis indicate that G-TOW is a powerful test.
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http://dx.doi.org/10.1002/gepi.22255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829034PMC
December 2019

Gene expression profiles and bioinformatics analysis of insulin-like growth factor-1 promotion of osteogenic differentiation.

Mol Genet Genomic Med 2019 10 16;7(10):e00921. Epub 2019 Aug 16.

Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China.

Background: Insulin-like growth factor-1 (IGF-1) promotes osteoblast differentiation and mineralization. The objective of this study was to investigate the effects of IGF-1 on proliferation, mineralization, alkaline phosphatase (ALP) synthesis, and gene expression of osteoblast differentiation in MC3T3-E1 osteoblasts cells, and to explore gene expression profiling differential genes.

Methods: MC3T3-E1 osteoblasts cells were cultured in medium with or without IGF-1. The ALP assay was employed to determine the osteoblast mineralization, and Alizarin red S to stain for calcium deposits, which were the indicators of mature osteocytes. The living cell number was assessed by the Cell Counting Kit-8 method. RNA-seq analysis was applied to identify genes that were differentially expressed in with or without IGF-1 as well as genes that varied between these two groups. The expression of osteogenic marker genes was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis.

Result: The cell number of osteoblasts exposed to IGF-1 at 200 μg/L significantly increased compared with the control group. The ALP activity in IGF-1-treated cells was higher than that in the control group. IGF-1 can increase ALP synthesis in osteoblasts in vitro. RNA-seq analysis showed that 677 triggered differentially expressed genes by IGF, of which 383 genes were downregulated and 294 genes were upregulated. Gene ontology (GO) analysis showed that IGF-1 caused a significant change in gene expression patterns.

Conclusions: This result suggested that IGF-1 could probably promote the synthesis of organic matrix and mineralize action of bone. Osteogenic-related genes (DMP1, PHEX, SOST, BMP2, RUNX2, OPN, and OCN) were significantly upregulated both in GO analysis and in pathway analysis to perform qRT-PCR. Western blot analysis demonstrated that the Notch pathway was highly upregulated in MC3T3-E1 cells.
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http://dx.doi.org/10.1002/mgg3.921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082822PMC
October 2019

Powerful statistical method to detect disease-associated genes using publicly available genome-wide association studies summary data.

Genet Epidemiol 2019 12 7;43(8):941-951. Epub 2019 Aug 7.

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.

Genome-wide association studies (GWAS) have thus far achieved substantial success. In the last decade, a large number of common variants underlying complex diseases have been identified through GWAS. In most existing GWAS, the identified common variants are obtained by single marker-based tests, that is, testing one single-nucleotide polymorphism (SNP) at a time. Generally, the basic functional unit of inheritance is a gene, rather than a SNP. Thus, results from gene-level association test can be more readily integrated with downstream functional and pathogenic investigation. In this paper, we propose a general gene-based p-value adaptive combination approach (GPA) which can integrate association evidence of multiple genetic variants using only GWAS summary statistics (either p-value or other test statistics). The proposed method could be used to test genetic association for both continuous and binary traits through not only one study but also multiple studies, which would be helpful to overcome the limitation of existing methods that can only be applied to a specific type of data. We conducted thorough simulation studies to verify that the proposed method controls type I errors well, and performs favorably compared to single-marker analysis and other existing methods. We demonstrated the utility of our proposed method through analysis of GWAS meta-analysis results for fasting glucose and lipids from the international MAGIC consortium and Global Lipids Consortium, respectively. The proposed method identified some novel trait associated genes which can improve our understanding of the mechanisms involved in -cell function, glucose homeostasis, and lipids traits.
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http://dx.doi.org/10.1002/gepi.22251DOI Listing
December 2019

Pleiotropy informed adaptive association test of multiple traits using genome-wide association study summary data.

Biometrics 2019 12 2;75(4):1076-1085. Epub 2019 Aug 2.

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.

Genetic variants associated with disease outcomes can be used to develop personalized treatment. To reach this precision medicine goal, hundreds of large-scale genome-wide association studies (GWAS) have been conducted in the past decade to search for promising genetic variants associated with various traits. They have successfully identified tens of thousands of disease-related variants. However, in total these identified variants explain only part of the variation for most complex traits. There remain many genetic variants with small effect sizes to be discovered, which calls for the development of (a) GWAS with more samples and more comprehensively genotyped variants, for example, the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program is planning to conduct whole genome sequencing on over 100 000 individuals; and (b) novel and more powerful statistical analysis methods. The current dominating GWAS analysis approach is the "single trait" association test, despite the fact that many GWAS are conducted in deeply phenotyped cohorts including many correlated and well-characterized outcomes, which can help improve the power to detect novel variants if properly analyzed, as suggested by increasing evidence that pleiotropy, where a genetic variant affects multiple traits, is the norm in genome-phenome associations. We aim to develop pleiotropy informed powerful association test methods across multiple traits for GWAS. Since it is generally very hard to access individual-level GWAS phenotype and genotype data for those existing GWAS, due to privacy concerns and various logistical considerations, we develop rigorous statistical methods for pleiotropy informed adaptive multitrait association test methods that need only summary association statistics publicly available from most GWAS. We first develop a pleiotropy test, which has powerful performance for truly pleiotropic variants but is sensitive to the pleiotropy assumption. We then develop a pleiotropy informed adaptive test that has robust and powerful performance under various genetic models. We develop accurate and efficient numerical algorithms to compute the analytical P-value for the proposed adaptive test without the need of resampling or permutation. We illustrate the performance of proposed methods through application to joint association test of GWAS meta-analysis summary data for several glycemic traits. Our proposed adaptive test identified several novel loci missed by individual trait based GWAS meta-analysis. All the proposed methods are implemented in a publicly available R package.
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http://dx.doi.org/10.1111/biom.13076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814451PMC
December 2019

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups.

Am J Transplant 2019 10 13;19(10):2795-2804. Epub 2019 May 13.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.

Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10 -8.8 × 10 ) and one suggestive variant in Asian Americans (P = 5.6 × 10 ). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants.
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http://dx.doi.org/10.1111/ajt.15385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763344PMC
October 2019

SIRT1 inhibits apoptosis in in vivo and in vitro models of spinal cord injury via microRNA-494.

Int J Mol Med 2019 Apr 22;43(4):1758-1768. Epub 2019 Feb 22.

Department of Orthopaedics, Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China.

The aim of the present study was to investigate the function and mechanism of sirtuin 1 (SIRT1) in spinal cord injury (SCI). Reverse transcription‑quantitative polymerase chain reaction was used to measure the expression levels of microRNA (miR)‑494. MTT assay, lactate dehydrogenase activity assay and flow cytometry were used to analyze the effects of miR‑494 on cell growth and apoptosis in a model of SCI. The present study demonstrated that SIRT1 expression was reduced; whereas miR‑494 expression was increased in a rat model of SCI. Overexpression of miR‑494 suppressed the protein expression levels of SIRT1, and induced p53 protein expression. Conversely, knockdown of miR‑494 induced SIRT1 protein expression in an in vitro model of SCI. Furthermore, overexpression of miR‑494 promoted cell apoptosis and decreased cell growth in an in vitro model of SCI; however, miR‑494 knockdown enhanced cell growth and inhibited cell apoptosis. Administration of a SIRT1 agonist reduced the effects of miR‑494 overexpression on cell apoptosis in an SCI model, whereas treatment with a p53 agonist reduced the effects of miR‑494 knockdown on cell apoptosis in an SCI model. Together, these findings suggested that SIRT1 may inhibit apoptosis of SCI in vivo and in vitro through the p53 signaling pathway, whereas miR‑494 suppressed SIRT1 and induced apoptosis.
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http://dx.doi.org/10.3892/ijmm.2019.4106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414168PMC
April 2019

Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies.

Transplantation 2019 06;103(6):1131-1139

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN.

Background: The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes.

Methods: We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes.

Results: Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified.

Conclusions: These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.
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http://dx.doi.org/10.1097/TP.0000000000002625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597284PMC
June 2019

Analysis of 75 Candidate SNPs Associated With Acute Rejection in Kidney Transplant Recipients: Validation of rs2910164 in MicroRNA MIR146A.

Transplantation 2019 08;103(8):1591-1602

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN.

Background: Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR. However, there are additional publications reporting a lack of this association when a different cohort of recipients is analyzed for the same single-nucleotide polymorphism.

Methods: In this report, we attempted to validate 75 common genetic variants, which have been previously reported to be associated with AR, using a large kidney allograft recipient cohort of 2390 European Americans and 482 African Americans.

Results: Of those variants tested, only 1 variant, rs2910164, which alters the expression of the microRNA MIR146A, was found to exhibit a significant association within the African American cohort. Suggestive variants were found in the genes CTLA and TLR4.

Conclusions: Our results show that most variants previously reported to be associated with AR were not validated in our cohort. This shows the importance of validation when reporting the associations with complex clinical outcomes such as AR. Additional work will need to be done to understand the role of MIR146A in the risk of AR in kidney allograft recipients.
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http://dx.doi.org/10.1097/TP.0000000000002659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913779PMC
August 2019
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