bluuebunny/crossref_metadata_2025 huggingface dataset:
Data MiningMycobacterium tuberculosisPathogenic Gene Transcription Factors and Their Regulatory Network Nodes
Authors: Yuan Guangxin , Bai Yu , Zhang Yuhang , Xu Guangyu
Published: March 2018

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide. InMycobacterium tuberculosis, changes in gene expression are highly variable and involve many genes, so traditional single-gene screening ofM. tuberculosistargets has been unable to meet the needs of clinical diagnosis. In this study, using the National Center for Biotechnology Information (NCBI) GEO Datasets, whole blood gene expression profile data were obtained in patients with active pulmonary tuberculosis. Linear model-experience Bayesian statistics using the Limma package in R combined witht-tests were applied for nonspecific filtration of the expression profile data, and the differentially expressed human genes were determined. Using DAVID and KEGG, the functional analysis of differentially expressed genes (GO analysis) and the analysis of signaling pathways were performed. Based on the differentially expressed gene, the transcriptional regulatory element databases (TRED) were integrated to construct theM. tuberculosispathogenic gene regulatory network, and the correlation of the network genes with disease was analyzed with the DAVID online annotation tool. It was predicted that IL-6, JUN, and TP53, along with transcription factors SRC, TNF, and MAPK14, could regulate the immune response, with their function being extracellular region activity and protein binding during infection withM. tuberculosis.
Src Is a Prime Target Inhibited by Celtis choseniana Methanol Extract in Its Anti‐Inflammatory Action
Authors: Kim Han Gyung , Choi Subin , Lee Jongsung , Hong Yo Han , Jeong Deok , Yoon Keejung , Yoon Deok Hyo , Sung Gi-Ho , Lee Seungihm , Hong Suntaek , Yi Young-Su , Kim Jong-Hoon , Cho Jae Youl
Published: March 2018

Celtis choseniana is the traditional plant used at Korea as a herbal medicine to ameliorate inflammatory responses. Although Celtis choseniana has been traditionally used as a herbal medicine at Korea, no systemic research has been conducted on its anti‐inflammatory activity. Therefore, the present study explored an anti‐inflammatory effect and its underlying molecular mechanism using Celtis choseniana methanol extract (Cc‐ME) in macrophage‐mediated inflammatory responses. In vitro anti‐inflammatory activity of Cc‐ME was evaluated using RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS), pam3CSK4 (Pam3), or poly(I:C). In vivo anti‐inflammatory activity of Cc‐ME was investigated using acute inflammatory disease mouse models, such as LPS‐induced peritonitis and HCl/EtOH‐induced gastritis. The molecular mechanism of Cc‐ME‐mediated anti‐inflammatory activity was examined by Western blot analysis and immunoprecipitation using whole cell and nuclear fraction prepared from the LPS‐stimulated RAW264.7 cells and HEK293 cells. Cc‐ME inhibited NO production and mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX‐2), and tumor necrosis factor‐alpha (TNF‐α) in the RAW264.7 cells and peritoneal macrophages induced by LPS, pam3, or poly(I:C) without cytotoxicity. High‐performance liquid chromatography (HPLC) analysis showed that Cc‐ME contained anti‐inflammatory flavonoids quercetin, luteolin, and kaempferol. Among those, the content of luteolin, which showed an inhibitory effect on NO production, was highest. Cc‐ME suppressed the NF‐κB signaling pathway by targeting Src and interrupting molecular interactions between Src and p85, its downstream kinase. Moreover, Cc‐ME ameliorated the morphological finding of peritonitis and gastritis in the mouse disease models. Therefore, these results suggest that Cc‐ME exerted in vitro and in vivo anti‐inflammatory activity in LPS‐stimulated macrophages and mouse models of acute inflammatory diseases. This anti‐inflammatory activity of Cc‐ME was dominantly mediated by targeting Src in NF‐κB signaling pathway during macrophage‐mediated inflammatory responses.
Performance of Reinforced Reactive Powder Concrete Beam‐Column Joints under Cyclic Loads
Authors: Zheng Wenzhong , Wang Dehong , Ju Yanzhong
Published: March 2018

An experimental research was carried out to investigate the seismic performance and shear strength of reactive powder concrete interior beam‐column joints subjected to reverse cyclic loads. Four beam‐column joint specimens were cast and tested in the investigation. The failure characteristics, deformational properties, ductility, and energy dissipation of reinforced reactive powder concrete interior beam‐column joints were analyzed in this paper. The shear strength of joints was calculated according to the GB5001‐2010 and ACI 318‐14. The results shows that reactive powder concrete beam‐column joints have a higher shear‐cracking strength and shear carrying capacity and strength degradation and rigidity degradation are not notable. Additionally, the use of RPC for beam‐column joints can reduce the congestion of stirrups in joints core. The shear force in the RPC joint is mainly carried by the diagonal strut mechanism; the design expression of ACI 318‐14 can be used for calculating the shear strength of RPC joints, which has a safety margin of 22%∼38% in this test.
Bursting Oscillations in Shimizu‐Morioka System with Slow‐Varying Periodic Excitation
Authors: Ma Xindong , Cao Shuqian
Published: March 2018

The coupling effect of two different frequency scales between the exciting frequency and the natural frequency of the Shimizu‐Morioka system with slow‐varying periodic excitation is investigated. First, based on the analysis of the equilibrium states, homoclinic bifurcation, fold bifurcation, and supercritical Hopf bifurcation are observed in the system under a certain parameter condition. When the exciting frequency is much smaller than the natural frequency, we can regard the periodic excitation as a slow‐varying parameter. Second, complicated dynamic behaviors are analyzed when the slow‐varying parameter passes through different bifurcation points, of which the mechanisms of four different bursting patterns, namely, symmetric “homoclinic/homoclinic” bursting oscillation, symmetric “fold/Hopf” bursting oscillation, symmetric “fold/fold” bursting oscillation, and symmetric “Hopf/Hopf” bursting oscillation via “fold/fold” hysteresis loop, are revealed with different values of the parameter b by means of the transformed phase portrait. Finally, we can find that the time interval between two symmetric adjacent spikes of bursting oscillations exhibits dependency on the periodic excitation frequency.
Tunable Multilayers of Self-Organized Silica Nanospheres by Spin Coating
Authors: Kasmi Sofiane , Solard Jeanne , Tijunelyte Inga , Fischer Alexis P. A. , Lamy de la Chapelle Marc , Lidgi-Guigui Nathalie
Published: March 2018

The coating of fused silica by an organized layer of silica nanospheres (NS) is an important issue for the design of optical and topographic properties especially for lithography techniques such as nanosphere lithography (NSL) or nanosphere photolithography (NSPL). Here, the spin coating of NS dispersed in N,N-dimethylformamide (DMF) is studied. The role of the NS diameter, the spin-coating acceleration, and the volume fraction are the parameters to take into account for the formation and organization of NS in single or double closely packed layers. We propose an explanation for this behavior based on the transition between sedimentation and a viscous regime on the basis of the silica NS organization.
Dynamic Neuro-Cognitive Imagery Improves Mental Imagery Ability, Disease Severity, and Motor and Cognitive Functions in People with Parkinson’s Disease
Authors: Abraham Amit , Hart Ariel , Andrade Isaac , Hackney Madeleine E.
Published: March 2018

People with Parkinson’s disease (PD) experience kinesthetic deficits, which affect motor and nonmotor functions, including mental imagery. Imagery training is a recommended, yet underresearched, approach in PD rehabilitation. Dynamic Neuro-Cognitive Imagery (DNI™) is a codified method for imagery training. Twenty subjects with idiopathic PD (Hoehn and Yahr stages I–III) were randomly allocated into DNI training (experimental;n=10) or in-home learning and exercise program (control;n=10). Both groups completed at least 16 hours of training within two weeks. DNI training focused on anatomical embodiment and kinesthetic awareness. Imagery abilities, disease severity, and motor and nonmotor functions were assessed pre- and postintervention. The DNI participants improved (p<.05) in mental imagery abilities, disease severity, and motor and spatial cognitive functions. Participants also reported improvements in balance, walking, mood, and coordination, and they were more physically active. Both groups strongly agreed they enjoyed their program and were more mentally active. DNI training is a promising rehabilitation method for improving imagery ability, disease severity, and motor and nonmotor functions in people with PD. This training might serve as a complementary PD therapeutic approach. Future studies should explore the effect of DNI on motor learning and control strategies.
Development of Chloroplast Genomic Resources in Chinese Yam (Dioscorea polystachya)
Authors: Cao Junling , Jiang Dan , Zhao Zhenyu , Yuan Subo , Zhang Yujun , Zhang Teng , Zhong Wenhao , Yuan Qingjun , Huang Luqi
Published: March 2018

Chinese yam has been used both as a food and in traditional herbal medicine. Developing more effective genetic markers in this species is necessary to assess its genetic diversity and perform cultivar identification. In this study, new chloroplast genomic resources were developed using whole chloroplast genomes from six genotypes originating from different geographical locations. The Dioscorea polystachya chloroplast genome is a circular molecule consisting of two single-copy regions separated by a pair of inverted repeats. Comparative analyses of six D. polystachya chloroplast genomes revealed 141 single nucleotide polymorphisms (SNPs). Seventy simple sequence repeats (SSRs) were found in the six genotypes, including 24 polymorphic SSRs. Forty-three common indels and five small inversions were detected. Phylogenetic analysis based on the complete chloroplast genome provided the best resolution among the genotypes. Our evaluation of chloroplast genome resources among these genotypes led us to consider the complete chloroplast genome sequence of D. polystachya as a source of reliable and valuable molecular markers for revealing biogeographical structure and the extent of genetic variation in wild populations and for identifying different cultivars.
Pharmacokinetic Comparisons of Typical Constituents in Curcumae Rhizoma and Vinegar‐Processed Curcumae Rhizoma after Oral Administration to Rats
Authors: Gu Wei , Li Jin-ci , Ji De , Li Lin , Zhang Ji , Pan Zi-hao , Yang Jun-jie , Lu Tu-lin , Mao Chun-qin
Published: March 2018

The Raw Curcumae Rhizoma (R‐CR), included in the Chinese Pharmacopoeia Edition 2015, is a well‐known Chinese herbal medicine. However, the vinegar‐processed Curcumae Rhizoma (V‐CR) is used more widely than R‐CR. The pharmacokinetics comparison of R‐CR and V‐CR after oral administration to rats is poorly understood. A novel method, rapid resolution liquid chromatography‐tandem mass spectrometry (RRLC‐MS) coupled with a sensitive, specific, and convenient microdialysis sampling method, free from endogenous interference was developed in this research. The extracts of R‐CR and V‐CR were administered orally to each group of rats. The blood and liver microdialysis probes were positioned within the jugular vein toward the right atrium and the median lobe near the center of the liver, respectively. Then, a double‐peak phenomenon was observed in the concentration‐time curves of curdione in R‐CR group, while it was not observed in V‐CR group. The liver‐to‐blood distribution ratio of curdione in V‐CR group increased significantly (P < 0.05) compared to that of R‐CR group. However, compared with V‐CR group, the pharmacokinetic parameters of curcumol exhibited no statistically significant differences from those of R‐CR group. These results indicate that vinegar‐processed procedure has influence on the pharmacokinetic process of Curcumae Rhizoma in/ns. RRLC-MS coupled with microdialysis system could be used to evaluate the pharmacokinetics of typical constituents in Curcumae Rhizoma after oral administration.
Multiple Impossible Differentials Cryptanalysis on 7-Round ARIA-192
Authors: Jiang Zi-Long , Jin Chen-Hui
Published: March 2018

This paper studies the security of 7-round ARIA-192 against multiple impossible differentials cryptanalysis. We propose six special 4-round impossible differentials which have the same input difference and different output difference with the maximum number of nonzero common bytes. Based on these differentials, we construct six attack trails including the maximum number of common subkey bytes. Under such circumstances, we utilize an efficient sieving process to improve the efficiency of eliminating common subkeys; therefore, both data and time complexities are reduced. Furthermore, we also present an efficient algorithm to recover the master key via guess-and-determine technique. Taking advantage of the above advances, we have obtained the best result so far for impossible differential cryptanalysis of ARIA-192, with time, data, and memory complexities being 2189.8 7-round ARIA encryptions, 2116.6 chosen plaintexts, and 2139.3 bytes, respectively.
Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study
Authors: Vespasiani-Gentilucci Umberto , Dell’Unto Chiara , De Vincentis Antonio , Baiocchini Andrea , Delle Monache Marco , Cecere Roberto , Pellicelli Adriano Maria , Giannelli Valerio , Carotti Simone , Galati Giovanni , Gallo Paolo , Valentini Francesco , Del Nonno Franca , Rosati Davide , Morini Sergio , Antonelli-Incalzi Raffaele , Picardi Antonio
Published: March 2018

Background & Aims. Identifying NAFLD patients at risk of progression is crucial to orient medical care and resources. We aimed to verify if the effects determined by different single nucleotide polymorphisms (SNPs) could add up to multiply the risk of NAFLD and NASH-cirrhosis. Methods. Three study populations, that is, patients diagnosed with NASH-cirrhosis or with noncirrhotic NAFLD and healthy controls, were enrolled. PNPLA3 rs738409, TM6SF2 rs58542926, KLF6 rs3750861, SOD2 rs4880, and LPIN1 rs13412852 were genotyped. Results. One hundred and seven NASH-cirrhotics, 93 noncirrhotic NAFLD, and 90 controls were enrolled. At least one difference in allele frequency between groups was significant, or nearly significant, for the PNPLA3, TM6SF2, and KLF6 variants (p<0.001, p<0.05, and p=0.06, resp.), and a risk score based on these SNPs was generated. No differences were observed for SOD2 and LPIN1 SNPs. When compared to a score of 0, a score of 1-2 quadrupled, and a score of 3-4 increased 20-fold the risk of noncirrhotic NAFLD; a score of 3-4 quadrupled the risk of NASH-cirrhosis. Conclusions. The effects determined by disease-associated variants at different loci can add up to multiply the risk of NAFLD and NASH-cirrhosis. Combining different disease-associated variants may represent the way for genetics to keep strength in NAFLD diagnostics.
STAT3/HOTAIR Signaling Axis Regulates HNSCC Growth in an EZH2-dependent Manner
Authors: Sun Shanshan , Wu Yansheng , Guo Wenyu , Yu Feng , Kong Lingping , Ren Yu , Wang Yu , Yao Xiaofeng , Jing Chao , Zhang Chao , Liu Mingyang , Zhang Yuqing , Zhao Minghui , Li Zhaoqing , Wu Chuanqiang , Qiao Yu , Yang Jingxuan , Wang Xudong , Zhang Lun , Li Min , Zhou Xuan
Published: March 2018

Purpose: PI3K and STAT3 are frequently activated in cancer progression. However, little is known about the underlying mechanisms by which PI3K and STAT3 regulate head and neck squamous cell cancer (HNSCC) growth. The lncRNA HOX transcript antisense RNA (HOTAIR) was found to modulate the progression of HNSCC. In this study, we attempted to establish the correlation of PI3K/STAT3/HOTAIR signaling with the progression of HNSCC and its sensitivity toward platinum-based and targeted anti-EGFR combination therapy.

Experimental Design: We first analyzed the STAT3/HOTAIR and PI3K/AKT level in human HNSCC samples. We then activated or suppressed STAT3/HOTAIR and determined the effects on HNSCC cell proliferation in vitro and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells toward cisplatin and cetuximab was determined by in vitro assays.

Results: HNSCC samples showed significantly robust expression/activation of STAT3, HOTAIR, PI3K, and AKT, compared with normal squamous epithelium. STAT3 inhibition with WP1066 decreased HOTAIR level and sensitized HNSCC to cisplatin or cetuximab. STAT3 promoted HOTAIR transcription and its interaction with pEZH2-S21, resulting in enhanced growth of HNSCC cells. In addition, overexpression of HOTAIR promoted the growth of UM1 xenograft tumors in vivo.

Conclusions: Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating patients with HNSCC. Clin Cancer Res; 24(11); 2665–77. ©2018 AACR.
Survivin Monoclonal Antibodies Detect Survivin Cell Surface Expression and Inhibit Tumor Growth In Vivo
Authors: Fenstermaker Robert A. , Figel Sheila A. , Qiu Jingxin , Barone Tara A. , Dharma Sanam S. , Winograd Evan K. , Galbo Phillip M. , Wiltsie Laura M. , Ciesielski Michael J.
Published: March 2018

Purpose: Survivin is an inhibitor of apoptosis protein (IAP) that is highly expressed in many cancers and represents an attractive molecule for targeted cancer therapy. Although primarily regarded as an intracellular protein with diverse actions, survivin has also been identified in association with circulating tumor exosomes.

Experimental Design: We have reported that active, specific vaccination with a long peptide survivin immunogen leads to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival in tumor-bearing mice. In addition to cellular antitumor responses, circulating anti-survivin antibodies are detected in the serum of mice and human glioblastoma patients following vaccination with the survivin immunogen.

Results: Here we demonstrate that survivin is present on the outer cell membrane of a wide variety of cancer cell types, including both murine and human glioma cells. In addition, antibodies to survivin that are derived from the immunogen display antitumor activity against murine GL261 gliomas in both flank and intracranial tumor models and against B16 melanoma as well.

Conclusions: In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the survivin immunogen have antitumor activity in vivo. Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches. Clin Cancer Res; 24(11); 2642–52. ©2018 AACR.
Non-Proximal Renal Tubule-Derived Urinary Exosomal miR-200b as a Biomarker of Renal Fibrosis
Authors: Yu Yanting , Bai Feng , Qin Nan , Liu Wenjin , Sun Qi , Zhou Yang , Yang Junwei
Published: March 2018

Background: Renal fibrosis is a common outcome of nearly all kinds of chronic kidney disease (CKD) and eventually progresses to end-stage renal disease. The identification of an optimal biomarker of renal fibrosis to replace the invasive renal biopsy will have important clinical implications. Methods: We isolated urinary exosomes from 50 participants and examined the exosomal protein content and particle number in 38 CKD patients with different degrees of renal fibrosis and in 12 normal individuals. We examined the levels of exosomal microRNAs (miRNAs), namely, miR-200a, miR-200b, miR-200c, miR-141, miR-429, miR-29a, miR-29b, miR-29c, miR-192, and miR-21, by sorting the exosomes and comparing the levels of proximal tubular, non-proximal tubular, and total exosomal miR-200b. Results: The exosome content was higher in the CKD group, but no differences were evident among the mild, moderate, and severe fibrosis groups. Among the 10 exosomal miRNAs, miR-200b was lower in the CKD group than in the normal group and decreased more significantly with fibrosis progression as well as in IgA nephropathy and diabetic kidney disease. CD13+ CD63+ exosomes constituted 18.6% of all urinary exosomes. Sorting the proximal tubular exosomes with the CD13 protein marker revealed that miR-200b in the CD13+ group was extremely low; however, the result was significantly different in the CD13– group but not in the CD13+ group. The magnitude of the decline was greater in the CD13– groups than in the non-sorted whole groups between the fibrosis and normal patients. Conclusions: Non-proximal renal tubule-derived urinary exosomal miR-200b is a biomarker of renal fibrosis. Exosomes can be used as a liquid biopsy and may replace the traditional invasive renal biopsy in the diagnosis of renal fibrosis.
Evaluating Colposcopy with Dynamic Spectral Imaging During Routine Practice at Five Colposcopy Clinics in Wales: Clinical Performance
Authors: Budithi Srividya , Peevor Richard , Pugh David , Papagiannakis Emmanouil , Durman Amanda , Banu Nassera , Alalade Aderemi , Leeson Simon
Published: March 2018

Background: The diagnostic accuracy of colposcopy is poor for detecting precancerous cervical lesions. Objectives: We assessed the performance of colposcopy for identifying cervical intraepithelial neoplasia grade 2 or worse (CIN2+), before and after including a dynamic spectral imaging (DSI) map that quantifies and maps acetowhitening to assist subsequent biopsy of suspicious lesions. Methods: Four hundred and twenty-five women were examined at a multi-center setting in Wales, of which 393 women were included in the final analysis. Results: For all referrals, the sensitivity of conventional colposcopy for histologically confirmed CIN2+ was 51.5%, the specificity was 92.0%, the positive predictive value was 56.7%, and the negative predictive value (NPV) was 90.4%. With the incorporation of the DSI map in predicting CIN2+, these became 84.8, 61.5, 30.8, and 95.3% respectively. The increase of sensitivity was statistically significant (p < 0.001). For the 236 women having colposcopy after low-grade (LG) cytology, with the incorporation of DSI, the sensitivity for CIN2+ increased from 27.3 to 86.4% (p < 0.001) and the NPV from 92.6 to 97.8%. Conclusions: Colposcopy with DSI results in improved sensitivity to detect CIN2+ and maintains a high NPV for all referrals and especially for those with LG referral cytology.
The Prognosis of Single Large Hepatocellular Carcinoma Was Distinct from Barcelona Clinic Liver Cancer Stage A or B: The Role of Albumin-Bilirubin Grade
Authors: Fang Kuan-Chieh , Kao Wei-Yu , Su Chien-Wei , Chen Po-Chun , Lee Pei-Chang , Huang Yi-Hsiang , Huo Teh-Ia , Chang Chun-Chao , Hou Ming-Chih , Lin Han-Chieh , Wu Jaw-Ching
Published: March 2018

Background/Aims: Whether single large hepatocellular carcinoma (SLHCC) is classified as Barcelona Clinic Liver Cancer (BCLC) stage A or B is still controversial. We aimed to compare the clinical manifestations, treatment modalities, and prognoses among patients with SLHCC and those in BCLC stage A and B. Methods: We enrolled 2,285 treatment-naive hepatocellular carcinoma (HCC) patients with BCLC stage A or B from October 2007 to December 2015. Factors in terms of prognoses were analyzed by multivariate analysis. Results: We enrolled 1,210, 466, and 609 patients in a BCLC-A, SLHCC, and BCLC-B group, respectively. After a median follow-up duration of 21.2 months, 898 patients had died. The cumulative 5-year survival rates were 57.0, 42.6, and 27.3% for patients in the BCLC-A, SLHCC, and BCLC-B groups, respectively, which were significantly different (p < 0.001). Multivariate analysis indicated that the following independent risk factors were associated with poor prognosis: age > 65 years, alkaline phosphatase > 100 U/L, creatinine > 1.0 mg/dL, alpha-fetoprotein > 20 mg/mL, noncurative treatment, albumin-bilirubin (ALBI) grade, and HCC staging. Subgroup analysis also confirmed that patients in the SLHCC group had a survival rate intermediate to those in the BCLC-A and BCLC-B groups. However, for patients in the SLHCC group and with ALBI grade 1, outcomes were close to those in the BCLC-A group, especially in the setting of curative treatment. For those with ALBI grades 2 or 3, the prognoses were similar to those of the SLHCC and BCLC-B groups. Conclusion: Patients in the SLHCC group had an overall survival rate intermediate to those of the BCLC-A and BCLC-B groups. It is suggested that the SLHCC group could be classified as occupying a different stage from the BCLC stages A and B. The ALBI grade could help to stratify SLHCC into a different prognostic group. However, the results need to be validated externally in other regions of the world.
Renal Function Variability: An Independent Risk Factor for Graft Loss and Death following Kidney Transplantation
Authors: Pilch Nicole A. , Rohan Vinayak , Rao Vinaya , Mauldin Patrick D. , Su Zemin , Dubay Derek A. , Morinelli Thomas A. , Taber David J.
Published: March 2018

Background: Several studies have been performed to evaluate surrogate markers of long-term allograft function in renal transplant recipients. These include serum creatinine, estimated glomerular filtration rate (eGFR), slope of eGFR, and more recently eGFR variability. The aim of this study was to measure eGFR slope while assessing the variability of this slope and if high variability occurring at any time post-transplant was predictive of poorer long-term outcomes in a large cohort of kidney transplant recipients. Methods: Adult solitary kidney transplant recipients transplanted between July 1, 2005 and July 31, 2015 were included. The primary outcome was time to graft loss, defined as return to chronic dialysis, retransplant, or death. Secondary outcomes were death-censored graft loss and acute allograft rejection. Cox regression was utilized for primary and secondary outcomes. Multivariate logistic regression was used to determine baseline factors predictive of high eGFR variability. Results: A total of 1,543 patients were included in the analysis. The percentage of patients who experienced an eGFR coefficient of variation of <30% was 79.6% (1,229/1,543), while 20.4% (314/1,543) patients had high eGFR variability (≥30%). Patients with high eGFR variability tended to be younger, African-American and female. Those with higher eGFR variability, accounting for confounding and other eGFR measures (peak and slope), had significantly lower overall patient and graft survival. Conclusion: This study provides a novel analysis of the utility of eGFR variability in a large cohort. The clinical use of the slope of eGFR and eGFR variability may aid in predicting long-term graft outcomes and facilitate early patient discussions to change the trajectory of allograft function.
The Cytochrome P450 3A5 Non-Expressor Kidney Allograft as a Risk Factor for Calcineurin Inhibitor Nephrotoxicity
Authors: Udomkarnjananun Suwasin , Townamchai Natavudh , Chariyavilaskul Pajaree , Iampenkhae Kroonpong , Pongpirul Krit , Sirichindakul Boonchoo , Panumatrassamee Kamol , Vanichanan Jakapat , Avihingsanon Yingyos , Eiam-Ong Somchai , Praditpornsilpa Kearkiat
Published: March 2018

Background: Tacrolimus is mainly metabolized by cytochrome P450 3A5 (CYP3A5), which is expressed in the liver. However, CYP3A5 is also expressed in the kidney tissue and may contribute to local tacrolimus clearance in the kidney allograft. We aimed to evaluate the association between the allograft CYP3A5 genotype and transplant outcomes. Methods: We conducted a retrospective cohort study at the King Chulalongkorn Memorial Hospital, Thailand, comparing 2 groups of donor and recipient CYP3A5 genotypes, the expressor (*1/*1 and *1/*3) and the non-expressor (*3/*3). The primary outcomes were allograft complications including calcineurin inhibitor (CNI) nephrotoxicity and acute rejection episode. Results: Of the 50 enrolled patients, 21 donors were expressors and 29 donors were the non-expressors. Tacrolimus trough concentrations were similar between the 2 genotypes. The incidence of CNI nephrotoxicity was higher in recipients with non-expressor donor genotype compared with the expressor donor genotype (72.4 vs. 33.3%, p = 0.006). CNI nephrotoxicity incidence was not different when recipient’s genotypes were compared. Multivariate analysis from Cox-regression showed a hazard ratio of 3.18 (p = 0.026) for CNI nephrotoxicity in the non-expressor compared with the expressor donor. The recipient CYP3A5 genotypes did not significantly contribute to CNI nephrotoxicity. Kaplan-Meier analysis demonstrated the lowest CNI nephrotoxicity-free survival in recipients with the expressor genotype who received allograft from the non-expressor donors (p = 0.005). Conclusion: In conclusion, our results suggest that donor CYP3A5 non-expressor genotype (*3/*3) is a risk for CNI nephrotoxicity.
CTLA-4 Polymorphisms in Patients with IgA Nephropathy Correlate with Proteinuria
Authors: Jacob Marius , Ohl Kim , Goodarzi Tannaz , Harendza Sigrid , Eggermann Thomas , Fitzner Christina , Hilgers Ralf-Dieter , Bolte Anna , Floege Jürgen , Rauen Thomas , Tenbrock Klaus
Published: March 2018

Background/Aims: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and still constitutes one of the most important causes of end-stage renal disease. Abnormal T cell responses may play a role in IgAN pathogenesis. Co-stimulatory molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are important for naive T cells to initiate and terminate immune responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 gene locus are associated with several autoimmune diseases. Methods: We aimed to investigate the occurrence of the SNPs -318C/T, +49A/G and CT60 G/A within the CTLA4 locus in healthy blood donors (n=455) and IgAN patients (n=252) recruited from the recently published STOP-IgAN trial. The presence of these SNPs was then associated with baseline proteinuria in IgAN patients. Results: We observed a significantly increased frequency of the CTLA4 -318C/T genotype in IgAN patients as compared to controls (CC vs. CT+TT: OR 1.65, 95%-CI 1.03-2.65, p=0.035). No significant associations, neither with the +49A/G nor for the CT60 G/A SNP, were detected. However, when we stratified for proteinuria at time of inclusion into the STOP-IgAN trial (<1 g/day vs. >1 g/day), we observed significant differences in the frequencies of the CT60 G/A genotype, i.e. a significantly increased risk for higher proteinuria in patients carrying the G allele (OR 2.81, 95%-CI 1.03-7.64, p=0.042). Conclusion: The CTLA4 -318/C/T SNP was associated with an increased risk to develop IgAN, while the CT60 G/A genotype significantly associated with the risk for higher proteinuria suggesting a possible role for CTLA-4 in IgAN.
Methods of Blood Oxygen Level-Dependent Magnetic Resonance Imaging Analysis for Evaluating Renal Oxygenation
Authors: Chen Fen , Li Shulin , Sun Dong
Published: March 2018

Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) has recently been utilized as a noninvasive tool for evaluating renal oxygenation. Several methods have been proposed for analyzing BOLD images. Regional ROI selection is the earliest and most widely used method for BOLD analysis. In the last 20 years, many investigators have used this method to evaluate cortical and medullary oxygenation in patients with ischemic nephropathy, hypertensive nephropathy, diabetic nephropathy, chronic kidney disease (CKD), acute kidney injury and renal allograft rejection. However, clinical trials of BOLD MRI using regional ROI selection revealed that it was difficult to distinguish the renal cortico-medullary zones with this method, and that it was susceptible to observer variability. To overcome these deficiencies, several new methods were proposed for analyzing BOLD images, including the compartmental approach, fractional hypoxia method, concentric objects (CO) method and twelve-layer concentric objects (TLCO) method. The compartmental approach provides an algorithm to judge whether the pixel belongs to the cortex or medulla. Fractional kidney hypoxia, measured by using BOLD MRI, was negatively correlated with renal blood flow, tissue perfusion and glomerular filtration rate (GFR) in patients with atherosclerotic renal artery stenosis. The CO method divides the renal parenchyma into six or twelve layers of thickness in each coronal slice of BOLD images and provides a R2* radial profile curve. The slope of the R2* curve associated positively with eGFR in CKD patients. Indeed, each method invariably has advantages and disadvantages, and there is generally no consensus method so far. Undoubtedly, analytic approaches for BOLD MRI with better reproducibility would assist clinicians in monitoring the degree of kidney hypoxia and thus facilitating timely reversal of tissue hypoxia.
Basic Research Advances on Pituitary Stem Cell Function and Regulation
Authors: Russell John P. , Lodge Emily J. , Andoniadou Cynthia L.
Published: March 2018

As a central regulator of major physiological processes, the pituitary gland is a highly dynamic organ, capable of responding to hormonal demand and hypothalamic influence, through adapting secretion as well as remodelling cell numbers among its seven populations of differentiated cells. Stem cells of the pituitary have been shown to actively generate new cells during postnatal development but remain mostly quiescent during adulthood, where they persist as a long-lived population. Despite a significant body of research characterising attributes of anterior pituitary stem cells, the regulation of this population is poorly understood. A better grasp on the signalling mechanisms influencing stem proliferation and cell fate decisions can impact on our future treatments of pituitary gland disorders such as organ failure and pituitary tumours, which can disrupt endocrine homeostasis with life-long consequences. This minireview addresses the current methodologies aiming to understand better the attributes of pituitary stem cells and the normal regulation of this population in the organ, and discusses putative future avenues to manipulate pituitary stem cells during disease states or regenerative medicine approaches.
Follow-Up for Resected Gastroenteropancreatic Neuroendocrine Tumours: A Practice Survey of the Commonwealth Neuroendocrine Tumour Collaboration (CommNETS) and the North American Neuroendocrine Tumor Society (NANETS)
Authors: Chan David L. , Moody Lesley , Segelov Eva , Metz David C. , Strosberg Jonathan R. , Pavlakis Nick , Singh Simron
Published: March 2018

Objectives: There is no consensus regarding optimal follow-up in resected gastroenteropancreatic neuroendocrine tumours (NETs). We aimed to perform a practice survey to ascertain follow-up patterns by health care practitioners and highlight areas of variation that may benefit from further quantitative research. Methods: A Web-based survey targeted at NET health care providers in Australia, New Zealand, Canada, and the USA was developed by a steering committee of medical oncologists and a research methodologist. Thirty-seven questions elicited information regarding adherence to guidelines, the influence of risk factors on follow-up, and the frequency and choice of modality in follow-up. Results: There were 163 respondents: 59 from Australia, 25 from New Zealand, 46 from Canada, and 33 from the USA (50% medical oncology, 23% surgery, 13% nuclear medicine, and 15% other). Thirty-eight percent of the respondents were “very familiar” with the NCCN NET guidelines, 33% with the ENETS guidelines, and 17% with the ESMO guidelines; however, only 15, 27, and 10%, respectively, found them “very useful”; 63% reported not using guidelines at their institution. The commonest investigations used were CT scans (66%) and chromogranin A (86%). The US respondents were more likely to follow patients up past 5 years, and the Australian respondents utilized more functional and less cross-sectional imaging. When poor prognostic factors were introduced, the respondents recommended more visits and tests. Conclusions: This large international survey highlights variation in current follow-up practices not well addressed by the current guidelines. More quantitative research is required to inform the development of evidence-based guidelines tailored to the pattern of recurrence in NETs.
Jornalismo em gêneros: volume 4: jornalismo especializado
Authors:   Universidade de São Paulo. Escola de Comunicações e Artes, Barbosa Alexandre
Published: March 2018

Esta obra é o quarto volume da coleção Jornalismo em Gêneros que tem como tema o Jornalismo Especializado. A proposta é que o leitor compreenda a especialização no jornalismo sem considerá-la um dilema. Ou seja, durante a graduação é possível pensar em atividades, pesquisas e disciplinas que ofereçam aos alunos condições de conhecerem as principais especializações de modo que, ao final, eles possam navegar por elas e, se quiserem, cursarem pós-graduações. Este livro pretende ser uma dessas atividades. O que o leitor irá encontrar nas próximas páginas é prática da textos informativos e da edição de entrevistas sobre a presença de quatro jornalistas especializados em coletivas de imprensa. É a prática do texto interpretativo na construção de quatro perfis diferentes. É a prática da construção do gênero opinativo mais brasileiro, a crônica, a partir de fatos do jornalismo.​
Outcomes After Continuous-Flow Left Ventricular Assist Device Implantation as Destination Therapy at Transplant Versus Nontransplant Centers
Authors: Brinkley D. Marshall , DeNofrio David , Ruthazer Robin , Vest Amanda R. , Kapur Navin K. , Couper Gregory S. , Kiernan Michael S.
Published: March 2018

Background:

Since Food and Drug Administration’s approval of the HeartMate II left ventricular assist device (LVAD) as destination therapy, the number of hospitals offering LVAD therapy has grown rapidly. A rising number are performed at centers without internal transplant programs. We sought to determine whether outcomes after destination therapy LVAD implantation are similar at transplant and nontransplant centers.

Methods and Results:

Adult recipients of a primary, continuous-flow LVAD as destination therapy between January 2012 and March 2014 from the Interagency Registry for Mechanically Assisted Circulatory Support were included. Subjects were classified by implanting center as transplant (n=3323) or nontransplant (n=260). Center volume before 2012 was categorized as <15 or ≥15 implants. Outcomes included overall survival, freedom from death or major adverse event, rates of individual adverse events, rehospitalization, and health-related quality of life. Patients treated at nontransplant centers were generally less sick, with higher Interagency Registry for Mechanically Assisted Circulatory Support patient profiles and more normal laboratory and hemodynamic values. One-month (94.2% [95% confidence interval {CI}, 95.0–93.4] versus 94.2% [95% CI, 97.1–91.4]) and 12-month (76.4% [95% CI, 77.9–74.8] versus 71.3% [95% CI, 77.4–65.2]) survival were similar at transplant and nontransplant centers, respectively (hazard ratio, 0.88 [95% CI, 0.70–1.12]). Risk remained similar after adjustment for baseline characteristics (hazard ratio, 0.88 [95% CI, 0.69–1.12]). Freedom from death or major adverse event at 12 months (29.0% [95% CI, 30.6–27.3] versus 29.8% [95% CI, 36.0–23.6]) was similar at transplant and nontransplant centers (adjusted hazard ratio, 1.01 [95% CI, 0.87–1.18]). Individual adverse event rates, rehospitalization, and postimplant health-related quality of life were also similar.

Conclusions:

In a large, modern cohort of destination therapy LVAD recipients, outcomes after implantation were similar at transplant and nontransplant centers.
Biomarkers of Myocardial Fibrosis: Revealing the Natural History of Fibrogenesis in Fabry Disease Cardiomyopathy
Authors: Aguiar Patrício , Azevedo Olga , Pinto Rui , Marino Jacira , Cardoso Carlos , Sousa Nuno , Cunha Damião , Hughes Derralynn , Ducla Soares José Luís
Published: March 2018

Background

Cardiomyopathy is a major determinant of overall Fabry disease (
FD
) prognosis, with the worst outcomes in patients with myocardial fibrosis. Late gadolinium enhancement is currently the gold standard for evaluation of replacement myocardial fibrosis; however, this event is irreversible, thus identification of biomarkers of earlier diffuse fibrosis is paramount.

Methods and Results

Type I collagen synthesis and degradation biomarkers (PICP [carboxyterminal propeptide of procollagen type I], ICTP [carboxyterminal telopeptide of type I collagen], and MMP1 [matrix metalloproteinase 1] and MMP2) and markers of bone synthesis and degradation were evaluated (to adjust type I collagen metabolism to bone turnover) in
FD
patients and controls.
FD
patients were grouped by cardiomyopathy severity, according to echocardiogram: (1) normal, (2) tissue Doppler abnormalities, (3) left ventricular hypertrophy. A significant increase in
PICP
and a significant decrease in matrix metalloproteinases were observed in
FD
patients; even the group with normal echocardiogram had a significant increase in
PICP
. We also found a significant correlation between left ventricular mass and
PICP
(ρ=0.378,
P
=0.003) and
MMP
1 (ρ=−0.484,
P
<0.001).
PICP
(adjusted for bone turnover) was the better predictor of left ventricular mass in multivariable regression, and its diagnostic accuracy to predict late gadolinium enhancement was also significant.

Conclusions

Collagen type I synthesis is increased in
FD
cardiomyopathy, even in the earlier stages of the disease, and this profibrotic state has good predictive value for and is likely to be critical to the development of overt left ventricular hypertrophy. Moreover, inhibition of enzymes involved in collagen type I cleavage also seems crucial to myocardial collagen deposition.
Predictors and Prognostic Value of Worsening Renal Function During Admission in HFpEF Versus HFrEF: Data From the KorAHF (Korean Acute Heart Failure) Registry
Authors: Kang Jeehoon , Park Jin Joo , Cho Young‐Jin , Oh Il‐Young , Park Hyun‐Ah , Lee Sang Eun , Kim Min‐Seok , Cho Hyun‐Jai , Lee Hae‐Young , Choi Jin Oh , Hwang Kyung‐Kuk , Kim Kye Hun , Yoo Byung‐Su , Kang Seok‐Min , Baek Sang Hong , Jeon Eun‐Seok , Kim Jae‐Joong , Cho Myeong‐Chan , Chae Shung Chull , Oh Byung‐Hee , Choi Dong‐Ju
Published: March 2018

Background

Worsening renal function (
WRF
) is associated with adverse outcomes in patients with heart failure. We investigated the predictors and prognostic value of
WRF
during admission, in patients with preserved ejection fraction (
HF
p
EF
) versus those with reduced ejection fraction (
HF
r
EF
).

Methods and Results

A total of 5625 patients were enrolled in the KorAHF (Korean Acute Heart Failure) registry.
WRF
was defined as an absolute increase in creatinine of ≥0.3 mg/
dL
. Transient
WRF
was defined as recovery of creatinine at discharge, whereas persistent
WRF
was indicated by a nonrecovered creatinine level.
HF
p
EF
and
HF
r
EF
were defined as a left ventricle ejection fraction ≥50% and ≤40%, respectively. Among the total population,
WRF
occurred in 3101 patients (55.1%). By heart failure subgroup,
WRF
occurred more frequently in
HF
r
EF
(57.0% versus 51.3%;
P
<0.001 in
HF
r
EF
and
HF
p
EF
). Prevalence of
WRF
increased as creatinine clearance decreased in both heart failure subgroups. Among various predictors of
WRF
, chronic renal failure was the strongest predictor.
WRF
was an independent predictor of adverse in‐hospital outcomes (
HF
r
EF
: odds ratio; 2.75; 95% confidence interval, 1.50–5.02;
P
=0.001;
HF
p
EF
: odds ratio, 9.48; 95% confidence interval, 1.19–75.89;
P
=0.034) and 1‐year mortality (
HF
r
EF
: hazard ratio, 1.41; 95% confidence interval
,
1.12–1.78;
P
=0.004 versus
HF
p
EF
: hazard ratio, 1.72; 95% confidence interval, 1.23–2.42;
P
=0.002). Transient
WRF
was a risk factor for 1‐year mortality, whereas persistent
WRF
had no additive risk compared to transient
WRF
.

Conclusions

In patients with acute heart failure patients,
WRF
is an independent predictor of adverse in‐hospital and follow‐up outcomes in both
HF
r
EF
and
HF
p
EF
, though with a different effect size.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
01389843.
Elevated Circulating Fibrocytes Is a Marker of Left Atrial Fibrosis and Recurrence of Persistent Atrial Fibrillation
Authors: Liu Yang , Niu Xiao‐Hui , Yin Xiaomeng , Liu Yue‐Jian , Han Chao , Yang Jie , Huang Xin , Yu Xiaohong , Gao Lianjun , Yang Yan‐Zong , Xia Yun‐Long , Li Hui‐Hua
Published: March 2018

Background

In atrial fibrillation (
AF
), a more extensively fibrotic left atrium (
LA
) provides a substrate for arrhythmias and increases risk of relapse following ablation. Fibrocytes are bone marrow–derived circulating mesenchymal progenitors that have been identified in the atrium of patients with AF who have valvular diseases. The present study investigates the associations between circulating fibrocytes and
LA
fibrosis or the prevalence of recurrence after ablation in patients with persistent
AF
.

Methods and Results

We measured the proportion, differentiation, and migration of circulating fibrocytes from patients with persistent
AF
(n=40), those with paroxysmal
AF
(n=30), and sinus rhythm controls (n=30).
LA
low‐voltage (fibrosis) area was identified by an electroanatomic mapping system, and patients were followed up for 1 year after ablation. The relationship between circulating fibrocyte percentage and
LA
low‐voltage area or recurrence was assessed by multivariate regression analysis. Circulating fibrocyte percentage positively associated with
LA
low‐voltage area in the persistent
AF
group, and circulating fibrocyte (≥4.05%) was a significant predictor of 1‐year recurrence after ablation. Cultured fibrocytes exhibited enhanced potential of differentiation in the persistent
AF
group (67.58±1.54%) versus the paroxysmal
AF
group (56.67±1.52%) and sinus rhythm controls (48.43±1.79%). Furthermore, expression of fibroblast activation markers and cell migratory ability were also elevated in differentiated fibrocytes from patients with persistent
AF
. Transforming growth factor β1 and stromal cell–derived factor 1 were elevated in the plasma of patients with persistent AF and were shown to promote fibrocyte differentiation and migration, respectively.

Conclusions

In patients with persistent
AF
, increased circulating fibrocytes served as a marker of
LA
fibrosis and recurrence.