Citations

Biomimetic biomaterials require good biocompatibility and bioactivity to serve as appropriate scaffolds for tissue engineering applications.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Elevated levels of follistatin‐like protein 1 (FSTL1) have been found both in mouse models for human rheumatoid arthritis (RA) and collagen‐induced arthritis (CIA). In this study, we elucidated the potential mechanisms by which FSTL1 contributes to the pathogenesis of RA. Fibroblast‐like synoviocytes (FLSs) were established from synovial tissues of RA patients and stimulated with human recombinant FSTL1. Protein and mRNA expression levels of select matrix metalloproteinases (i.e., MMP1, MMP3, MMP13) in FLS were measured by, respectively, real‐time RT‐qPCR and ELISA. Activation of MAPK and other pathways that affect MMPs were evaluated by Western blotting. We also compared concentrations of MMPs in plasma in RA patients versus healthy controls (HC). Expression levels of MMP1, MMP3, and MMP13 were clearly stimulated by FSTL1 in vitro. FSTL1 activated the inflammation‐related NF‐κB signaling pathway, as well as all three mitogen‐activated protein kinase (MAPK) pathways and the JAK/STAT3 pathway. Moreover, select chemical inhibitors that target p38 (SB203580), Erk1/2 (SP600125), JNK (SCH772984), STAT3 (AG490), and NF‐κB (BAY 11–7082) significantly attenuated MMP expression. Inhibition of Toll‐like receptor 4 by compound TAK‐242 significantly abolished those effects of FSTL1. Importantly, elevated plasma concentrations of MMP3 were found to correlate with plasma FSTL1 levels in RA patients. These findings suggest that FSTL1 accelerates RA progression by activating MAPK, JAK/STAT3, and NF‐κB pathways to enhance secretion of different MMPs and this enhancement is via TLR4. Targeting FSTL1 may provide a promising pharmacological drug therapy to ameliorate RA symptoms and perhaps reverse disease progression.

Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

Background: Trials suggest that bronchoscopic lung volume reduction (BLVR) with endobronchial valve (EBV) implantation may produce similar effects as lung volume reduction surgery, by inducing atelectasis and reducing hyperinflation through a minimally invasive procedure. This study sought to investigate the efficacy and safety of BLVR with EBV for advanced emphysema. Methods: We searched PubMed, EMBASE, Web of Science, CINAHL, ClinicalTrials.gov, and Cochrane Library databases for randomized controlled trials comparing EBV implantation versus standard medical treatment or sham bronchoscopy. The main outcome of interest was the percentage change of forced expiratory volume in 1 second. Results: Data analyzed from 5 randomized controlled trials with 703 patients revealed improvement in percentage change of forced expiratory volume in 1 second in EBV group compared with control group [weighted mean difference (WMD)=11.43; 95% confidence interval (CI), 6.05-16.80; P<0.0001] and improvement in the St. George’s Respiratory Questionnaire score (WMD=−5.69; 95% CI, −8.67 to −2.70; P=0.0002). There is no difference shown in the 6-minute walking test (WMD=14.12; 95% CI, −4.71 to 32.95; P=0.14). The overall complication rate of EBV was not significantly different except for an increased rate of pneumothorax [relative risk (RR)=8.16; 95% CI, 2.21-30.11; P=0.002), any hemoptysis (RR=5.01; 95% CI, 1.12-22.49; P=0.04)] and valve migration (RR=8.64; 95% CI, 2.01-37.13; P=0.004). Conclusion: BLVR using EBV shows short-term improvement in lung function and quality of life, but with increased risk of minor hemoptysis, pneumothorax, and valve migration. Follow-up data on the studies are needed to determine its long-term efficacy.

Background and Objectives Patients with colorectal cancer with synchronous liver metastases may undergo a staged or a simultaneous resection. This study aimed to determine whether the time to adjuvant chemotherapy was delayed in patients undergoing a simultaneous resection. Methods A retrospective cohort study was conducted between 2005 and 2016. The primary outcome was time to adjuvant chemotherapy. A multivariate linear regression was conducted to ascertain the adjusted effect of a simultaneous versus a staged approach on time to adjuvant chemotherapy. Results A total of 155 patients were included. A total of 127 patients underwent a staged resection, whereas 28 patients underwent a simultaneous resection. Age, sex, and American Society of Anesthesiologists class as well tumor, node, metastasis stage, tumor location, and number and size of metastases were not significantly different between the groups. The median time to adjuvant chemotherapy was 70 and 63 days for the staged and simultaneous groups, respectively ( P = .27). Multivariate analysis did not demonstrate an increased propensity for prolonged time to chemotherapy after simultaneous resection (rate ratio: 0.97, 95% CI: 0.71‐1.32, P = .84). There were no significant differences in the length of stay, complications, overall survival, and disease‐free survival between the groups ( P > .05). Conclusions This study demonstrated that simultaneous resection does not result in significant delay of adjuvant chemotherapy compared with a staged approach.

Objective The aims of this study were to quantitatively assess two new scan modes on a photon-counting detector computed tomography system, each designed to maximize spatial resolution, and to qualitatively demonstrate potential clinical impact using patient data. Materials and Methods This Health Insurance Portability Act–compliant study was approved by our institutional review board. Two high–spatial-resolution scan modes (Sharp and UHR) were evaluated using phantoms to quantify spatial resolution and image noise, and results were compared with the standard mode (Macro). Patients were scanned using a conventional energy-integrating detector scanner and the photon-counting detector scanner using the same radiation dose. In first patient images, anatomic details were qualitatively evaluated to demonstrate potential clinical impact. Results Sharp and UHR modes had a 69% and 87% improvement in in-plane spatial resolution, respectively, compared with Macro mode (10% modulation-translation-function values of 16.05, 17.69, and 9.48 lp/cm, respectively). The cutoff spatial frequency of the UHR mode (32.4 lp/cm) corresponded to a limiting spatial resolution of 150 μm. The full-width-at-half-maximum values of the section sensitivity profiles were 0.41, 0.44, and 0.67 mm for the thinnest image thickness for each mode (0.25, 0.25, and 0.5 mm, respectively). At the same in-plane spatial resolution, Sharp and UHR images had up to 15% lower noise than Macro images. Patient images acquired in Sharp mode demonstrated better delineation of fine anatomic structures compared with Macro mode images. Conclusions Phantom studies demonstrated superior resolution and noise properties for the Sharp and UHR modes relative to the standard Macro mode and patient images demonstrated the potential benefit of these scan modes for clinical practice.