T1rho MR properties of human patellar cartilage: correlation with indentation stiffness and biochemical contents.

OBJECTIVE: Cartilage degeneration involves structural, compositional, and biomechanical alterations that may be detected non-invasively using quantitative MRI. The goal of this study was to determine if topographical variation in T1rho values correlates with indentation stiffness and biochemical contents of human patellar cartilage. DESIGN: Cadaveric patellae from unilateral knees of 5 donors with moderate degeneration were imaged at 3-Telsa with spiral chopped magnetization preparation T1rho sequence. Indentation testing was performed, followed by biochemical analyses to determine water and sulfated glycosaminoglycan contents. T1rho values were compared to indentation stiffness, using semi-circular regions of interest (ROIs) of varying sizes at each indentation site. ROIs matching the resected tissues were analyzed, and univariate and multivariate regression analyses were performed to compare T1rho values to biochemical contents. RESULTS: Grossly, superficial degenerative change of the cartilage (i.e., roughened texture and erosion) corresponded with regions of high T1rho values. High T1rho values correlated with low indentation stiffness, and the strength of correlation varied slightly with the ROI size. Spatial variations in T1rho values correlated positively with that of the water content (R2 = 0.10, p < 0.05) and negatively with the variations in the GAG content (R2 = 0.13, p < 0.01). Multivariate correlation (R2 = 0.23, p < 0.01) was stronger than either of the univariate correlations. CONCLUSION: These results demonstrate the sensitivity of T1rho values to spatially varying function and composition of cartilage and that the strength of correlation depends on the method of data analysis and consideration of multiple variables.

Lung T2 * mapping using 3D ultrashort TE with tight intervals δTE.

PURPOSE: To develop 3D ultrashort-TE (UTE) sequences with tight TE intervals (δTE), allowing for accurate T 2 * $$ {\mathrm{T}}_2^{\ast } $$ mapping of lungs under free breathing. METHODS: We have implemented a four-echo UTE sequence with δTE (< 0.5 ms). A Monte-Carlo simulation was performed to identify an optimal number of echoes that would result in a significant improvement in the accuracy of the T 2 * $$ {\mathrm{T}}_2^{\ast } $$ fit within an acceptable scan time. A validation study was conducted on a phantom with known short T 2 * $$ {\mathrm{T}}_2^{\ast } $$ values (< 5 ms). The scanning protocol included a combination of a standard multi-echo UTE with six echoes (2.2-ms intervals) and a new four-echo UTE (TE < 2 ms) with tight TE intervals δTE. The human imaging was performed at 3 T on 6 adult volunteers. T 2 * $$ {\mathrm{T}}_2^{\ast } $$ mapping was performed with mono-exponential and bi-exponential models. RESULTS: The simulation for the proposed 10-echo acquisition predicted over 2-fold improvement in the accuracy of estimating the short T 2 * $$ {\mathrm{T}}_2^{\ast } $$ compared with the regular six-echo acquisition. In the phantom study, the T 2 * $$ {\mathrm{T}}_2^{\ast } $$ was measured up to three times more accurately compared with standard six-echo UTE. In human lungs, T 2 * $$ {\mathrm{T}}_2^{\ast } $$ maps were successfully obtained from 10 echoes, yielding average values T 2 * $$ {\mathrm{T}}_2^{\ast } $$ = 1.62 ± 0.48 ms for mono-exponential and T 2 s * $$ {\mathrm{T}}_{2s}^{\ast } $$ = 1.00 ± 0.53 ms for bi-exponential models. CONCLUSION: A UTE sequence using δTE was implemented and validated on short T 2 * $$ {\mathrm{T}}_2^{\ast } $$ phantoms. The sequence was successfully applied for lung imaging; the bi-exponential signal model fit for human lung imaging may provide valuable insights into the diseased human lungs.

Estrogen-responsive cancer-associated fibroblasts promote invasive property of gastric cancer in a paracrine manner via CD147 production.

Estrogen signaling has been extensively studied, especially in cancers that express estrogen receptor alpha (ERα). However, little is known regarding the effect of estrogen on cancer-associated fibroblasts (CAFs). Here, we explored the role of estrogen signaling of CAFs in gastric cancer (GC) progression. We investigated the phenotypic changes in CAFs upon 17ß-estradiol (E2) treatment using ERα-negative/positive CAFs, and the conditioned media (CM) collected from these were compared with regard to cancer cell proliferation, migration, and invasion. A paracrine factor was found using a cytokine array and was confirmed using qRT-PCR, western blotting, and enzyme-linked immunosorbent assays. ERα-CD147-matrix metalloproteinase (MMP) axis was confirmed by knockdown experiments using specific siRNAs. We found that a subset of CAFs expressed ERα. ERα-positive CAFs were responsive to E2, inducing ERα expression in a dose-dependent manner. Although E2 did not induce the proliferation of ERα-positive CAFs, the CM from E2-bound ERα-positive CAFs significantly promoted cancer cell migration and invasion. Cytokine array revealed that CD147 was induced in ERα-positive CAFs upon E2 treatment; this was mediated via ERα. Increased CD147 upregulated MMP2 and MMP9 in CAFs, and also influenced cancer cells in a paracrine manner to increase MMPs and CD147 in cancer cells. High CD147 expression in tumor tissue was associated with a worse prognosis in GC patients. Our data suggest that estrogen signaling activation in CAFs and the byproduct CD147 are among the critical mediators between the interplay of CAFs and cancer cells to facilitate cancer progression.

Ultrashort time-to-echo MR morphology of cartilaginous endplate correlates with disc degeneration in the lumbar spine.

PURPOSE: Using ultrashort echo time (UTE) MRI, we determined prevalence of abnormal cartilaginous endplate (CEP), and the relationship between CEP and disc degeneration in human lumbar spines. MATERIALS AND METHODS: Lumbar spines from 71 cadavers (age 14-74 years) were imaged at 3 T using sagittal UTE and spin echo T2 map sequences. On UTE images, CEP morphology was defined as "normal" with linear high signal intensity or "abnormal" with focal signal loss and/or irregularity. On spin echo images, disc grade and T2 values of the nucleus pulposus (NP) and annulus fibrosus (AF) were determined. 547 CEPs and 284 discs were analysed. Effects of age, sex, and level on CEP morphology, disc grade, and T2 values were determined. Effects of CEP abnormality on disc grade, T2 of NP, and T2 of AF were also determined. RESULTS: Overall prevalence of CEP abnormality was 33% and it tended to increase with older ages (p = 0.08) and at lower spinal levels of L5 than L2 or L3 (p = 0.001). Disc grades were higher and T2 values of the NP were lower in older spines (p < 0.001) and at lower disc level of L4-5 (p < 0.05). We found significant association between CEP and disc degeneration; discs adjacent to abnormal CEPs had high grades (p < 0.01) and lower T2 values of the NP (p < 0.05). CONCLUSION: These results suggest that abnormal CEPs are frequently found, and it associates significantly with disc degeneration, suggesting an insight into pathoetiology of disc degeneration.

Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand.

Interleukin-6 (IL-6) family cytokines signal through multimeric receptor complexes, providing unique opportunities to create novel ligand-based therapeutics. The cardiotrophin-like cytokine factor 1 (CLCF1) ligand has been shown to play a role in cancer, osteoporosis, and atherosclerosis. Once bound to ciliary neurotrophic factor receptor (CNTFR), CLCF1 mediates interactions to coreceptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). By increasing CNTFR-mediated binding to these coreceptors we generated a receptor superagonist which surpassed the potency of natural CNTFR ligands in neuronal signaling. Through additional mutations, we generated a receptor antagonist with increased binding to CNTFR but lack of binding to the coreceptors that inhibited tumor progression in murine xenograft models of nonsmall cell lung cancer. These studies further validate the CLCF1-CNTFR signaling axis as a therapeutic target and highlight an approach of engineering cytokine activity through a small number of mutations.

Deep-Learning-Aided Evaluation of Spondylolysis Imaged with Ultrashort Echo Time Magnetic Resonance Imaging.

Isthmic spondylolysis results in fracture of pars interarticularis of the lumbar spine, found in as many as half of adolescent athletes with persistent low back pain. While computed tomography (CT) is the gold standard for the diagnosis of spondylolysis, the use of ionizing radiation near reproductive organs in young subjects is undesirable. While magnetic resonance imaging (MRI) is preferable, it has lowered sensitivity for detecting the condition. Recently, it has been shown that ultrashort echo time (UTE) MRI can provide markedly improved bone contrast compared to conventional MRI. To take UTE MRI further, we developed supervised deep learning tools to generate (1) CT-like images and (2) saliency maps of fracture probability from UTE MRI, using ex vivo preparation of cadaveric spines. We further compared quantitative metrics of the contrast-to-noise ratio (CNR), mean squared error (MSE), peak signal-to-noise ratio (PSNR), and structural similarity index (SSIM) between UTE MRI (inverted to make the appearance similar to CT) and CT and between CT-like images and CT. Qualitative results demonstrated the feasibility of successfully generating CT-like images from UTE MRI to provide easier interpretability for bone fractures thanks to improved image contrast and CNR. Quantitatively, the mean CNR of bone against defect-filled tissue was 35, 97, and 146 for UTE MRI, CT-like, and CT images, respectively, being significantly higher for CT-like than UTE MRI images. For the image similarity metrics using the CT image as the reference, CT-like images provided a significantly lower mean MSE (0.038 vs. 0.0528), higher mean PSNR (28.6 vs. 16.5), and higher SSIM (0.73 vs. 0.68) compared to UTE MRI images. Additionally, the saliency maps enabled quick detection of the location with probable pars fracture by providing visual cues to the reader. This proof-of-concept study is limited to the data from ex vivo samples, and additional work in human subjects with spondylolysis would be necessary to refine the models for clinical use. Nonetheless, this study shows that the utilization of UTE MRI and deep learning tools could be highly useful for the evaluation of isthmic spondylolysis.

Impact of smoking on the development of idiopathic pulmonary fibrosis: results from a nationwide population-based cohort study.

BACKGROUND: Smoking has been considered an important risk factor for idiopathic pulmonary fibrosis (IPF) incidence. However, there are no population-based large-scale studies demonstrating the effects of smoking on the development of IPF. We aimed to evaluate the effect of smoking on IPF development using a nationwide population-based cohort. METHODS: Using the Korean National Health Information Database, we enrolled individuals who had participated in the health check-up service between 2009 and 2012. Participants having a prior diagnosis of IPF were excluded. The history of smoking status and quantity was collected by a questionnaire. We identified all cases of incident IPF through 2016 on the basis of ICD-10 codes for IPF and medical claims. Cox proportional hazards models were used to calculate the adjusted HR (aHR) of the development of IPF. RESULTS: A total of 25 113 individuals (0.11%) with incident IPF were identified out of 23 242 836 participants registered in the database. The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively. Current smokers had a higher risk of IPF than former smokers (aHR 1.17, 95% CI 1.13 to 1.21). The risk of IPF development increased as the smoking intensity and duration increased. CONCLUSION: Smoking significantly increased the risk of IPF development. Current smokers had a higher risk of IPF than former smokers. A dose-response relationship was observed between smoking and the development of IPF.

miR-4742-5p promotes invasiveness of gastric cancer via targeting Rab43: An in vitro study.

miRNA (miR)-4742-5p is a recently identified microRNA regarding progression and metastasis in gastric cancer (GC). However, the biological function of this novel miRNA is largely unknown. We identified that the miR-4742-5p expression level was variably increased in GC cell lines. Suppression of miR-4742-5p using miR-inhibitor reduced the proliferation, migration, and invasion of GC cells with high miR-4742-5p expression, whereas overexpression of miR-4742-5p-mimic enhanced the aforementioned properties in GC cells with low miR-4742-5p expression. miR-4742-5p expression induced the decreases of Zo-1 and E-cadherin expression as well as the increases of vimentin and N-cadherin expression, leading to epithelial-mesenchymal transition (EMT) of cancer cells. RNA sequencing results indicated Ras-related GTP-binding protein 43 (Rab43) as a potential target gene. We identified that the expression of Rab43 is associated with activation of AKT and nuclear factor-kappa B (NF-κB) which are key oncogenic pathways in cancer cells. Our results demonstrate a new component in GC progression, promising a potential therapeutic strategy.

Time-Resolved Noncontrast Magnetic Resonance Perfusion Imaging of Paraspinal Muscles.

BACKGROUND: While evaluation of blood perfusion in lumbar paraspinal muscles is of interest in low back pain, it has not been performed using noncontrast magnetic resonance (MR) techniques. PURPOSE: To introduce a novel application of a time-resolved, noncontrast MR perfusion technique for paraspinal muscles and demonstrate effect of exercise on perfusion parameters. STUDY TYPE: Longitudinal. SUBJECTS: Six healthy subjects (27-48 years old, two females) and two subjects with acute low back pain (46 and 65 years old females, one with diabetes/obesity). FIELD STRENGTH/SEQUENCE: 3-T, MR perfusion sequence. ASSESSMENT: Lumbar spines of healthy subjects were imaged axially at L3 level with a tag-on and tag-off alternating inversion recovery arterial spin labeling technique that suppresses background signal and acquires signal increase ratio (SIR) from the in-flow blood at varying inversion times (TI) from 0.12 seconds to 3.5 seconds. SIR vs. TI data were fit to determine the perfusion metrics of peak height (PH), time to peak (TTP), mean transit time, apparent muscle blood volume (MBV), and apparent muscle blood flow (MBF) in iliocostal, longissimus, and multifidus. Imaging was repeated immediately after healthy subjects performed a 20-minute walk, to determine the effect of exercise. STATISTICAL TESTS: Repeated measures analysis of variance. RESULTS: SIR vs. TI data showed well-defined leading and trailing edges, with sharply increasing SIR to TI of approximately 500 msec subsiding quickly to near zero around TI of 1500 msec. After exercise, the mean SIR at every TI increased markedly, resulting in significantly higher PH, MBV, and MBF (each P < 0.001 and F > 28.9), and a lower TTP (P < 0.05, F = 4.5), regardless of the muscle. MBF increased 2- to 2.5-fold after exercise, similar to the expected increase in cardiac output, given the intensity of the exercise. DATA CONCLUSIONS: Feasibility of an MR perfusion technique for muscle perfusion imaging was demonstrated, successfully detecting significantly increased perfusion after exercise. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Intrinsically stretchable and healable semiconducting polymer for organic transistors.

Thin-film field-effect transistors are essential elements of stretchable electronic devices for wearable electronics. All of the materials and components of such transistors need to be stretchable and mechanically robust. Although there has been recent progress towards stretchable conductors, the realization of stretchable semiconductors has focused mainly on strain-accommodating engineering of materials, or blending of nanofibres or nanowires into elastomers. An alternative approach relies on using semiconductors that are intrinsically stretchable, so that they can be fabricated using standard processing methods. Molecular stretchability can be enhanced when conjugated polymers, containing modified side-chains and segmented backbones, are infused with more flexible molecular building blocks. Here we present a design concept for stretchable semiconducting polymers, which involves introducing chemical moieties to promote dynamic non-covalent crosslinking of the conjugated polymers. These non-covalent crosslinking moieties are able to undergo an energy dissipation mechanism through breakage of bonds when strain is applied, while retaining high charge transport abilities. As a result, our polymer is able to recover its high field-effect mobility performance (more than 1 square centimetre per volt per second) even after a hundred cycles at 100 per cent applied strain. Organic thin-film field-effect transistors fabricated from these materials exhibited mobility as high as 1.3 square centimetres per volt per second and a high on/off current ratio exceeding a million. The field-effect mobility remained as high as 1.12 square centimetres per volt per second at 100 per cent strain along the direction perpendicular to the strain. The field-effect mobility of damaged devices can be almost fully recovered after a solvent and thermal healing treatment. Finally, we successfully fabricated a skin-inspired stretchable organic transistor operating under deformations that might be expected in a wearable device.

Bone Marrow Aspirate Concentrate Augmentation May Accelerate Allograft Ligamentization in Anterior Cruciate Ligament Reconstruction: A Double-Blinded Randomized Controlled Trial.

PURPOSE: To assess the effect of bone marrow aspiration concentrate (BMAC) augmentation on clinical outcomes and magnetic resonance imaging (MRI) findings in anterior cruciate ligament (ACL) reconstruction (ACLR) with bone-patellar tendon-bone (BTB) allografts. METHODS: A double-blinded, randomized controlled trial was conducted on 80 patients undergoing ACL reconstruction using BTB allografts. Patients were randomized to 2 groups: (1) bone marrow aspirate was collected from the iliac crest, concentrated, and approximately 2.5 mL was injected into the BTB allograft, or (2) a small sham incision was made at the iliac crest (control). MRI was performed at 3 months and 9 months postoperatively to determine the signal intensity ratio of the ACL graft. RESULTS: Seventy-three patients were available for follow-up at 1-year postoperatively (36 BMAC, 37 control). International Knee Documentation Committee (IKDC) scores were significantly greater in the BMAC group versus the control at the 9-month postoperative period (81.6 ± 10.5 vs 74.6 ± 14.2, P = .048). There was no significant difference in the proportion of patients who met the minimal clinically important difference for IKDC between the BMAC and control groups at 9 months (89% vs 85%; P = .7). Three months postoperatively, signal intensity ratio of the inferior third of the ACL graft was significantly greater in the BMAC group versus the control group (3.2 ± 2.2 vs 2.1 ± 1.5; P = .02). CONCLUSIONS: Patients who received BMAC augmentation of the BTB allograft during ACL reconstruction demonstrated greater signal intensity scores on MRI at 3 months, suggesting increased metabolic activity and remodeling, and potentially accelerated ligamentization. Additionally, patients in the BMAC group had greater patient-reported outcomes (IKDC) at 9 months postoperatively when compared with those who underwent a standard surgical procedure. There was no significant difference in the proportion of patients who met the minimal clinically important difference for IKDC between the BMAC and control groups at 9 months, suggesting limited clinical significance at this time point. LEVEL OF EVIDENCE: I, randomized control trial.

MicroRNA signatures associated with lymph node metastasis in intramucosal gastric cancer.

Although a certain proportion of intramucosal carcinomas (IMCs) of the stomach does metastasize, the majority of patients are currently treated with endoscopic resection without lymph node dissection, and this potentially veils any existing metastasis and may put some patients in danger. In this regard, biological markers from the resected IMC that can predict metastasis are warranted. Here, we discovered unique miRNA expression profiles that consist of 21 distinct miRNAs that are specifically upregulated (miR-628-5p, miR-1587, miR-3175, miR-3620-5p, miR-4459, miR-4505, miR-4507, miR-4720-5p, miR-4742-5p, and miR-6779-5p) or downregulated (miR-106b-3p, miR-125a-5p, miR-151b, miR-181d-5p, miR-486-5p, miR-500a-3p, miR-502-3p, miR-1231, miR-3609, and miR-6831-5p) in metastatic (M)-IMC compared to nonmetastatic (N)-IMC, or nonneoplastic gastric mucosa. Intriguingly, most of these selected miRNAs showed stepwise increased or decreased expression from nonneoplastic tissue to N-IMC to M-IMC. This suggests that common oncogenic mechanisms are gradually intensified during the metastatic process. Using a machine-learning algorithm, we demonstrated that such miRNA signatures could distinguish M-IMC from N-IMC. Gene ontology and pathway analysis revealed that TGF-ß signaling was enriched from upregulated miRNAs, whereas E2F targets, apoptosis-related, hypoxia-related, and PI3K/AKT/mTOR signaling pathways, were enriched from downregulated miRNAs. Immunohistochemical staining of samples from multiple institutions indicated that PI3K/AKT/mTOR pathway components, MAPK1, phospho-p44/42 MAPK, and pS6 were highly expressed and the expression of SMAD7, a TGF-ß pathway component, was decreased in M-IMC, which could aid in distinguishing M-IMC from N-IMC. The miRNA signature discovered in this study is a valuable biological marker for identifying metastatic potential of IMCs, and provides novel insights regarding the metastatic progression of IMC.

Quantitation of ligand is critical for ligand-dependent MET signalling activation and determines MET-targeted therapeutic response in gastric cancer.

BACKGROUND: Despite the promising preclinical antitumor activity of MET-targeting therapies, most clinical trials have failed. We introduced a new concept of quantitation of stroma-induced hepatocyte growth factor (HGF) to assess the actual MET signalling activity in gastric cancer (GC). METHODS: We treated serially diluted HGF and conditioned media (CM) from cancer-associated fibroblasts (CAFs) on low MET-expressing cancer cells and investigated the phenotypical and signalling changes. Stromal proportion and MET expression in GC samples were assessed, and gene set enrichment analysis (GSEA) from the public database was performed. The antitumor effect of anti-MET treatment was examined, especially when cancer cells were activated in a ligand-dependent manner. RESULTS: Relatively high doses of HGF or high-concentrated CM fully activated MET signalling cascades and promoted cell proliferation/invasion. High stromal proportion denoted worse patient survival in MET-positive GCs than in MET-negative ones. GSEA showed that the gene sets regarding proliferation, migration, and CAF as well as MET pathway signature were enriched in simultaneously MET- and HGF-positive samples. Sufficient ligand-dependent MET signalling activation increased the sensitivity to crizotinib. CONCLUSIONS: We conclude that patients whose tumours have a high stromal proportion and at least low MET expression may benefit more from MET-targeted therapies.

Quantitative magnetic resonance imaging of meniscal pathology ex vivo.

OBJECTIVE: To determine the ability of conventional spin echo (SE) T2 and ultrashort echo time (UTE) T2* relaxation times to characterize pathology in cadaveric meniscus samples. MATERIALS AND METHODS: From 10 human donors, 54 triangular (radially cut) meniscus samples were harvested. Meniscal pathology was classified as normal (n = 17), intrasubstance degenerated (n = 33), or torn (n = 4) using a modified arthroscopic grading system. Using a 3-T MR system, SE T2 and UTE T2* values of the menisci were determined, followed by histopathology. Effect of meniscal pathology on relaxation times and histology scores were determined, along with correlation between relaxation times and histology scores. RESULTS: Mean ± standard deviation UTE T2* values for normal, degenerated, and torn menisci were 3.6 ± 1.3 ms, 7.4 ± 2.5 ms, and 9.8 ± 5.7 ms, respectively, being significantly higher in degenerated (p < 0.0001) and torn (p = 0.0002) menisci compared to that in normal. In contrast, the respective mean SE T2 values were 27.7 ± 9.5 ms, 25.9 ± 7.0 ms, and 35.7 ± 10.4 ms, without significant differences between groups (all p > 0.14). In terms of histology, we found significant group-wise differences (each p < 0.05) in fiber organization and inner-tip surface integrity sub-scores, as well as the total score. Finally, we found a significant weak correlation between UTE T2* and histology total score (p = 0.007, Rs2 = 0.19), unlike the correlation between SE T2 and histology (p = 0.09, Rs2 = 0.05). CONCLUSION: UTE T2* values were found to distinguish normal from both degenerated and torn menisci and correlated significantly with histopathology.

MR imaging pattern of tibial subchondral bone structure: considerations of meniscal coverage and integrity.

OBJECTIVES: To compare regional differences in subchondral trabecular structure using high-resolution MRI in meniscus-covered/meniscus-uncovered tibia in cadaveric knees with intact/torn menisci. MATERIALS AND METHODS: 3D proton density CUBE MRI of 6 cadaveric knees without significant osteoarthritis (OA) was acquired, 0.25-mm resolution. Menisci were evaluated and classified intact or torn. MR data were transferred to ImageJ program to segment tibial 3D volume of interest (VOI). Data was subdivided into meniscus-covered/meniscus-uncovered regions. Segmented VOI was classified into binary data, trabeculae/bone marrow. The trabecular bone data was used to measure MR biomarkers (apparent subchondral plate-connected bone density (adapted from spine MR), apparent trabecular bone volume fraction, apparent mean trabecular thickness, apparent connectivity density, and structure model index (SMI)). Mean value of parameters was analyzed for the effects of meniscal tear/tibial coverage. RESULTS: Nine torn menisci and 3 intact menisci were present. MR measures of bone varied significantly due to meniscal coverage/tear. Subchondral plate-connected bone density under covered meniscus regions increased from 10.9 to 23.5% with meniscal tear. Values increased in uncovered regions, 19.3% (intact) and 32.4% (torn). This reflects higher density when uncovered (p = 0.048) with meniscal tear (p = 0.007). Similar patterns were found for trabecular bone fraction (coverage p < 0.001, tear p = 0.047), trabecular thickness (coverage p = 0.03), connectivity density (coverage p = 0.002), and SMI (coverage p = 0.015). CONCLUSION: Quantitative trabecular bone evaluation emphasizes intrinsic structural differences between meniscus-covered/meniscus-uncovered tibias. Results offer insight into bone adaptation with meniscal tear and support the hypothesis that subchondral bone plate-connected bone density could be important in early subchondral bone adaptation.

Functional loss of ARID1A is tightly associated with high PD-L1 expression in gastric cancer.

Notwithstanding remarkable treatment success with anti-PD-1 monoclonal antibody, oncogenic mechanism of PD-L1 regulation in gastric cancer (GC) remains poorly understood. We hypothesized that ARID1A might be related to tumor PD-L1 expression in GC. We found that tumor PD-L1 positivity was associated with loss of ARID1A and showed trend toward better survival of patients with various molecular subtypes of GC (experimental set, n = 273). Considering heterogeneous ARID1A expression, we validated this using whole tissue sections (n = 159) and found that loss of ARID1A was correlated with microsatellite instability-high (MSI-H), Epstein-Barr virus (EBV), and PD-L1 positivity. Furthermore, for patients with MSI-H tumors, the degree of PD-L1 expression was significantly higher in ARID1A-deficient tumors. After ARID1A knockdown in GC cell lines, total and membranous PD-L1 protein, and PD-L1 mRNA levels were increased based on Western blot, flow cytometry, and qRT-PCR, respectively. With IFN-γ treatment, PD-L1 expression was significantly increased both in ARID1A-deficient cancer cells and controls, but the increase was not more pronounced in the former. Loss of ARID1A increased PD-L1 via activating AKT signaling, while LY294002 (PI3K inhibitor) decreased PD-L1 levels. Furthermore, we found that 3 MSI-H tumors showing highest expression of PD-L1 had simultaneous KRAS mutation and loss of ARID1A, suggesting a possible synergistic role boosting PD-L1. Our results strongly indicate that loss of ARID1A is tightly associated with high PD-L1 expression in GC. These results would increase our understanding of the oncogenic mechanism of PD-L1 regulation in GC, and also help to find the optimal candidates for immunotherapy.

Improved in vitro antioxidant properties and hepatoprotective effects of a fermented Inula britannica extract on ethanol-damaged HepG2 cells.

This study aimed to improve antioxidant effect and hepatoprotective effect of Inula britannica using fermentation. Epigallocatechin gallate (EGCG) in an I. britannica extract was found to be upregulated from 2.06 to 10.28 µg/mg during fermentation (p < 0.001). After fermentation, DPPH radical-scavenging ABTS radical-scavenging, and superoxide anion-scavenging abilities increased to 92.65%, 694.25 µM Trolox/mL, and 86.38%, respectively, at 500 µg/mL (p < 0.05). Cupric-ion-reducing capacity with formation of the Cu+-neocuproine complex increased by 5.88%, 6.38%, 3.24%, and 8.55% at 62.5 to 500 µg/mL. Ferric-ion-reducing capacity of the fermented extract increased by 20%, 7.16%, 3.85%, and 5.45% at each concentration (p < 0.05). Unfermented extracts yielded cell viability of 91.42%, 90.59%, 88.38%, and 79.17%, whereas the fermented extract yielded 100.28%, 99.66%, 96.15%, and 89.90%, respectively, at each concentration in ethanol-damaged HepG2 cells (p < 0.05). Additionally, the fermented extract decreased alanine transaminase activity from 117.2 to 61.7 U/mL in the ethanol-damaged HepG2 cell line (p < 0.01). Overall, both antioxidant and hepatoprotective effect increased by fermentation in I. britannica extract. These properties are expected to lead to new antioxidant agents via production of EGCG by fermentation.

Correction to: ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

The author "Ashish D. Diwan" receives educational consultant fees from Nuvasive Inc.

Patterns of cartilage degeneration in knees with medial tibiofemoral offset.

OBJECTIVE: To determine if radiographic medial tibiofemoral offset (MTFO) is associated with: (1) magnetic resonance imaging (MRI) pathology of cartilage, meniscus, and ligament; and (2) a distinct pattern of lateral cartilage degeneration on MRI. MATERIALS AND METHODS: Three hundred consecutive adult knee MRIs with anteroposterior (AP) radiographs were retrospectively reviewed, and 145 studies were included. MTFO was defined as a medial extension of the medial femoral condyle beyond the articular surface of the medial tibial plateau on weight-bearing AP radiographs. The patients were then divided into the MTFO (n = 61) or no-offset (n = 84) groups. On MRI data obtained on a 1.5-Tesla system, articular cartilage of the femoral condyle and tibial plateau were graded using a modified Outerbridge classification (36 sub-regions similar to whole-organ MRI Score (WORMS) system). In addition, MR pathology of the ACL, MCL, LCL, medial and lateral menisci, were determined. RESULTS: Significantly increased (ANOVA p < 0.007) MR grade of the ligaments, menisci, and cartilage in the MTFO group (ranging from 0.3 to 2.5) compared to the control group (0.2 to 1.1). Color maps of the cartilage grades suggested a marked difference in both severity of degeneration and regional variations between the groups. MTFO group exhibited focally increased cartilage grades in the central, non-weight regions of lateral compartment (region p = 0.07 to 0.12, interaction p = 0.05 to 0.1). CONCLUSIONS: MTFO is associated with overall degeneration of the knee and features a distinct lateral cartilage degeneration pattern, which may reflect non-physiologic contact of the cartilage between the lateral tibial eminence and lateral central femoral condyle.

Investigation of Brassica juncea, Forsythia suspensa, and Inula britannica: phytochemical properties, antiviral effects, and safety.

BACKGROUND: General antiviral agents such as oseltamivir are associated with certain adverse effects and the emergence of resistance. This study investigated the phytochemical properties, antiviral activities, and safety of three herbs used in traditional Korean medicine. METHODS: Extracts of three medicinal herbs (Brassica juncea, Forsythia suspensa, and Inula britannica) were prepared using ethanol or water. The total phenolic, flavonoid, and saponin content, condensed tannin content, and reducing sugar content of the herb extracts were determined via phytochemical screening. Tandem mass analysis was performed using an ultra-performance liquid chromatography (UPLC)-electrospray ionization (ESI)-Q/Orbitrap instrument. Virus titrations were determined via tissue culture infective dose (TCID50) and cytotoxicity assays. Hemolysis and hepatotoxicity were measured to determine safety. RESULTS: Among the three medicinal herbs, F. suspensa showed the highest concentration of phenolic compounds, flavonoids, and saponins. The number of phytochemical compounds detected via tandem mass analysis of B. juncea, F. suspensa, and I. britannica was 5 (including sinigrin, m/z [M-H] = 358.02), 14 (including forsythoside A, m/z [M-H] = 623.19), and 18 (including chlorogenic acid, m/z [M-H] = 353.20), respectively. The antiviral effects of the B. juncea extracts (ethanol and water) and I. britannica extract (ethanol) were further investigated. The ethanol extract of B. juncea showed a 3 Log TCID50/25 µL virus titration reduction and the water extract showed a selectivity index of 13.668 against infected influenza H1N1 virus A/NWS/33. The B. juncea extracts did not show hemolysis activities and hepatotoxicity (< 20%). The ethanol extract of I. britannica showed the most effective virus titration decrease, whereas its hemolytic and hepatotoxicity values were the most significantly different compared to the control. Despite the high concentration of phytochemicals detected in F. suspensa, the extract showed approximately 1 Log TCID50/25 µL at the highest concentration. CONCLUSION: B. juncea may show antiviral effects against H1N1 in a host. In addition, B. juncea may also show decreased disadvantages compared to other antiviral agents.