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Nasopharyngeal carcinoma (NPC) is one of the most predominant cancers occurring in China with high morbidity. Lately, large quantities of long non-coding RNAs (lncRNAs) have been highlighted to regulate the biological activities in multiple tumors, including NPC. Our study centered on whether TTN-AS1 was involved in NPC and how it modulated the progression of NPC. Here, RT-qPCR data uncovered that TTN-AS1 expression was conspicuously high in NPC cells. Based on the results of functional assays, TTN-AS1 silence hampered the proliferative, migratory and invasive abilities but stimulated apoptotic capability of NPC cells. After a series of mechanism assays, TTN-AS1 was found to competitively bind with miR-876-5p and recruit UPF1 to enhance NETO2 expression. In addition, TTN-AS1 could be transcriptionally activated by YY1 in NPC cells. It was also found miR-876-5p overexpression or NETO2 down-regulation had inhibitory effects on cell proliferation, migration and invasion in NPC. Moreover, NETO2 up-regulation could restore the suppressive impacts of TTN-AS1 depletion on NPC cell and tumor growth. In conclusion, YY1-activated TTN-AS1 interacted with both miR-876-5p and UPF1 to up-regulate NETO2, thus strengthening NPC cell malignant behaviors, which might provide more useful information for people to develop effective NPC treatments.

Uterine rupture and postterm pregnancy pose a number of life-threatening complications to both mother and child, including severe intra-abdominal bleeding and peritonitis, birth injury, hypoxia, and fetal loss. This report presents a rare case of a 20-year-old female experiencing fetal demise at 60 weeks of pregnancy, with uterine rupture and bone tissue discharge from her vagina without severe intra-abdominal bleeding and peritonitis. The mild clinical course despite complete uterine rupture was due to the firm adhesion of the amniotic sac to the uterus caused by inflammation. The adhesion of the intestines to the rupture site prevented dehiscence of the ruptured wound. Suppuration and bone tissue discharge relieved the pressure on the patient's abdominal cavity and prevented subsequent occurrence of severe peritonitis. Radiologists mistakenly regarded the thick amniotic sac wall on the right side of the uterine wall as a right cornual pregnancy with uterine rupture caused by chronic inflammation. This report aims to bring awareness of this rare condition to medical students and radiologists.

Context FSH may have independent actions on bone remodeling and body fat regulation. Cross-sectionally, we have shown that serum FSH is associated with bone mineral density (BMD) and body fat in older postmenopausal women, but it remains unknown whether FSH predicts bone and fat changes. Objective We examined whether baseline FSH level is associated with subsequent bone loss or body composition changes in older adults. Setting, Design, Participants We studied 162 women and 158 men (mean age 82 ± 4 years) from the Age, Gene/Environment Susceptibility (AGES)-Bone Marrow Adiposity cohort, a substudy of the AGES-Reykjavik Study of community-dwelling older adults. Skeletal health and body composition were characterized at baseline and 3 years later. Main Outcomes Annualized change in BMD and body composition by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Models were adjusted for serum estradiol and testosterone levels. Results There was no evidence for an association between baseline FSH level and change in BMD or body composition by DXA or QCT. For femoral neck areal BMD, adjusted mean difference (95% CI) per SD increase in FSH was 1.3 (-0.7 to 3.3) mg/cm2/y in women, and -0.2 (-2.6 to 2.2) mg/cm2/y in men. For visceral fat, adjusted mean difference (95% CI) per SD increase in FSH was 1.80 (-0.03 to 3.62) cm2/y in women, and -0.33 (-3.73 to 3.06) cm2/y in men. Conclusions Although cross-sectional studies and studies in perimenopausal women have demonstrated associations between FSH and BMD and body composition, in older adults, FSH level is not associated with bone mass or body composition changes.

Excessive tissue deformation near cartilage lesions and acute inflammation within the knee joint after anterior cruciate ligament (ACL) rupture and reconstruction surgery accelerate the loss of fixed charge density (FCD) and subsequent cartilage tissue degeneration. Here, we show how biomechanical and biochemical degradation pathways can predict FCD loss using a patient-specific finite element model of an ACL reconstructed knee joint exhibiting a chondral lesion. Biomechanical degradation was based on the excessive maximum shear strains that may result in cell apoptosis, while biochemical degradation was driven by the diffusion of pro-inflammatory cytokines. We found that the biomechanical model was able to predict substantial localized FCD loss near the lesion and on the medial areas of the lateral tibial cartilage. In turn, the biochemical model predicted FCD loss all around the lesion and at intact areas; the highest FCD loss was at the cartilage-synovial fluid-interface and decreased towards the deeper zones. Interestingly, simulating a downturn of an acute inflammatory response by reducing the cytokine concentration exponentially over time in synovial fluid led to a recovery of FCD content in the cartilage. Our novel numerical approach suggests that in vivo FCD loss can be estimated in injured cartilage following ACL injury and reconstruction. Significance: Our novel modeling platform can benefit the prediction of PTOA progression and the development of treatment interventions such as disease-modifying drug testing and rehabilitation strategies. This article is protected by copyright. All rights reserved.

Human blood cells (HBCs) play essential roles in multiple biological processes but their roles in development of uterine polyps are unknown. Here we implemented a Mendelian randomization (MR) analysis to investigate the effects of 36 HBC traits on endometrial polyps (EPs) and cervical polyps (CPs). The random-effect inverse-variance weighted method was adopted as standard MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Genetic instruments of HBC traits was extracted from a large genome-wide association study of 173,480 individuals, while data for EPs and CPs were obtained from the UK Biobank. All samples were Europeans. Using genetic variants as instrumental variables, our study found that both eosinophil count (OR 0.85, 95% CI 0.79–0.93, P = 1.06 × 10−4) and eosinophil percentage of white cells (OR 0.84, 95% CI 0.77–0.91, P = 2.43 × 10−5) were associated with decreased risk of EPs. The results were robust in sensitivity analyses and no evidences of horizontal pleiotropy were observed. While we found no significant associations between HBC traits and CPs. Our findings suggested eosinophils might play important roles in the pathogenesis of EPs. Besides, out study provided novel insight into detecting uterine polyps biomarkers using genetic epidemiology approaches.

Robert's uterus is a rare Müllerian malformation first characterized by a French gynecologist Héléne Robert in 1969. It represents an asymmetric division of the uterine cavity. A 45-year-old female patient presented with vaginal bleeding and vague abdominal pain for the course of 20 days, with a blood human chorionic gonadotropin level of 10331.00 mIU/mL, and a gestational sac in the right uterine horn without a fetal heart beat revealed by the ultrasound. Ectopic pregnancy in the right uterine horn seemed to be the most likely diagnosis. Laparoscopic and hysteroscopic attempts to terminate the pregnancy failed. A pelvic magnetic resonance imaging (MRI) performed after the surgery demonstrated Robert's uterus with pregnancy in the blind hemicavity. When a pregnancy sac has been revealed by an ultrasound but nothing has been found by a hysteroscopy, a possibility of uterine malformation should be considered. Radiologists and gynecologists should consider the application of MRI for diagnosis of congenital Müllerian uterine anomalies.

Background: The association between activity level after anterior cruciate ligament (ACL) reconstruction (ACLR) and development of posttraumatic osteoarthritis (PTOA) remains unclear. This study investigated the relationship of patient-reported outcomes and progressive cartilage degenerative changes at 3 years after ACLR. Hypothesis: Higher activity levels, as measured by Marx scores, are significantly correlated with early cartilage degeneration after ACLR. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 35 patients (16 women; mean age, 31.0 ± 7.6 years) with isolated ACLR and without pre-existing arthritis were prospectively enrolled. Patients reported Marx activity scores and Knee injury and Osteoarthritis Outcome Score (KOOS) scores and underwent T1ρ magnetic resonance imaging (MRI) preoperatively, 6 months, 1 year, 2 years, and 3 years after ACLR with soft tissue graft (22 autograft). The change in cartilage relaxation times between preoperative and 3-year imaging was used to identify cartilage degeneration, defined as an increase in T1ρ values by 14.3%. Correlation between Marx activity levels, KOOS scores, and T1ρ degeneration was performed with the Spearman rank test. The Fisher exact test was used to test for association between Marx activity score cutoffs and degeneration. The Student t test was used to compare Whole-Organ Magnetic Resonance Imaging Score (WORMS) and T1ρ relaxation times. Significance was defined as P < .05. Results: Sixteen patients (45.7%) showed evidence of cartilage degeneration at 3 years, most frequently in the medial compartment (n = 12; 34%). Higher Marx activity scores at 3 years correlated with cartilage degeneration in the medial femur (rho = 0.34; P = .045), and medial tibia (rho = 0.43; P = .01). A Marx score of 11 or greater at 3 years was significantly associated with medial compartment degeneration ( P = .03), with a positive predictive value of 52.6%. No Marx score cutoff at years 1 or 2 predicted future cartilage degeneration. The KOOS Quality of Life score was inversely correlated with cartilage degeneration (rho = 0.38; P = .02). WORMS did not correlate with degeneration of the medial compartment. Conclusion: Increased activity at 3 years after ACLR was significantly associated with increased risk of medial compartment PTOA. While further research is needed to fully define these relationships, patients may be counseled that return to Marx activity levels of greater than 11 may be associated with a higher risk of medial compartment cartilage degeneration.

The transition of alveolar type II epithelial cells into fibroblasts has been reported to cause and/or aggravate pulmonary fibrosis (PF), which is characterized by fibroblast proliferation, an enhanced production and accumulation of ECM (extracellular matrix), alveolar wall damage and functional capillary unit loss. Traditional Chinese medicine Emodin has been reported to inhibit TGF‐β‐induced epithelial‐mesenchymal transition (EMT) in alveolar epithelial cells through Notch signalling. In the present study, neutrophil elastase (NE, also known as ELA2) treatment promoted EMT, Notch1 cleavage (NICD/Notch1 ratio increase) and NICD nuclear translocation in RLE‐6TN cells and A549 cells. The promotive roles of NE treatment in these events were significantly reversed by Notch1 knockdown. Traditional Chinese medicine Emodin treatment remarkably inhibited the enzyme activity of NE, suppressed EMT, Notch1 cleavage and NICD nuclear translocation within RLE‐6TN and A549 cells, while NE treatment significantly reversed the effects of Emodin. Moreover, in RLE‐6TN, the effects of NE on EMT, Notch1 cleavage and NICD nuclear translocation were remarkably attenuated by Emodin treatment and more attenuated by the combination of Emodin and neutrophil elastase inhibitor Sivelestat or notch signal pathway inhibitor DAPT. In conclusion, we revealed the involvement of NE‐induced Notch1 cleavage in the functions of Emodin suppressing NE‐caused EMT in RLE‐6TN cells and A549 cells. This novel mechanism of Emodin inhibiting EMT might extend the application of Emodin in PF treatment.

Objective.The aim of this multireader exercise was to assess the reliability and change over time of erosion measurements in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT).Methods.HR-pQCT scans of 23 patients with RA were assessed at baseline and 12 months. Four experienced readers examined the dorsal, palmar, radial, and ulnar surfaces of the metacarpal head (MH) and phalangeal base (PB) of the second and third digits, blinded to time order. In total, 368 surfaces (23 patients´ 16 surfaces) were evaluated per timepoint to characterize cortical breaks as pathological (erosion) or physiological, and to quantify erosion width and depth. Reliability was evaluated by intraclass correlation coefficients (ICC), percentage agreement, and Light k; change over time was defined by means ± SD of erosion numbers and dimensions.Results.ICC for the mean measurements of width and depth of the pathological breaks ranged between 0.819–0.883, and 0.771–0.907, respectively. Most physiological cortical breaks were found at the palmar PB, whereas most pathological cortical breaks were located at the radial MH. There was a significant increase in both the numbers and the dimensions of erosions between baseline and follow-up (P= 0.0001 for erosion numbers, width, and depth in axial plane;P= 0.001 for depth in perpendicular plane).Conclusion.This exercise confirmed good reliability of HR-pQCT erosion measurements and their ability to detect change over time.

The purpose of this proof-of-concept study was to develop three-dimensional patient-specific mechanobiological knee joint models to simulate alterations in the fixed charged density (FCD) around cartilage lesions during the stance phase of the walking gait. Two patients with anterior cruciate ligament (ACL) reconstructed knees were imaged at 1 and 3 years after surgery. The magnetic resonance imaging (MRI) data were used for segmenting the knee geometries, including the cartilage lesions. Based on these geometries, finite element (FE) models were developed. The gait of the patients was obtained using a motion capture system. Musculoskeletal modeling was utilized to calculate knee joint contact and lower extremity muscle forces for the FE models. Finally, a cartilage adaptation algorithm was implemented in both FE models. In the algorithm, it was assumed that excessive maximum shear and deviatoric strains (calculated as the combination of principal strains), and fluid velocity, are responsible for the FCD loss. Changes in the longitudinal T1ρ and T2 relaxation times were postulated to be related to changes in the cartilage composition and were compared with the numerical predictions. In patient 1 model, both the excessive fluid velocity and strain caused the FCD loss primarily near the cartilage lesion. T1ρ and T2 relaxation times increased during the follow-up in the same location. In contrast, in patient 2 model, only the excessive fluid velocity led to a slight FCD loss near the lesion, where MRI parameters did not show evidence of alterations. Significance: This novel proof-of-concept study suggests mechanisms through which a local FCD loss might occur near cartilage lesions. In order to obtain statistical evidence for these findings, the method should be investigated with a larger cohort of subjects.

Background: There is growing evidence suggesting a link between patellofemoral joint (PFJ) osteoarthritis in anterior cruciate ligament (ACL)–reconstructed knees and altered joint alignment. Purpose: To determine whether patellar alignment differs between participants with and without ACL reconstruction (ACLR) and to identify possible associations between patellar alignment and PFJ osteoarthritis features over 3 years. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 37 participants with ACLR (sex, 23 male; mean ± SD age, 28.1 ± 7.4 years) and 20 healthy controls (13 male; 30.4 ± 4.8 years) participated. Patients underwent magnetic resonance imaging: (1) sagittal T2-weighted fat-saturated fast spin echo images to calculate patellar alignment, (2) sagittal 3-dimensional intermediate-weighted fast spin echo Cube sequence for clinical morphological grading (modified Whole-Organ Magnetic Resonance Imaging Score [WORMS]), and (3) sagittal combined T1ρ/T2 mapping sequence for performing voxel-based relaxometry. Patellar alignment of the ACLR knees were assessed at 6 months (baseline). One-way analysis of variance was used to compare patellar alignment among the ACLR (at 6 months), contralateral, and control knees. Within the ACLR group, a logistic regression model was used to identify if patellar alignment measures at baseline were risk factors for worsening of PFJ structural changes over 3 years. Statistical parametric mapping was used to evaluate the longitudinal associations between patellar alignment and cartilage relaxation times at 3 years. Results: When compared with control knees, ACLR knees exhibited a laterally and anteriorly displaced patella ( P = .045 and P = .041), less flexion ( P = .031), and less lateral spin ( P = .012). Furthermore, excessive lateral displacement was a significant predictor of worsening of WORMS ( P = .050). Lateral displacement was positively correlated with increased T1ρ and T2 in the patellar and trochlear cartilage at 3 years. Patellar lateral spin revealed similar negative findings. Conclusion: Participants with ACLR exhibited a laterally and anteriorly displaced patella, less flexion, and less lateral spin when compared with healthy controls. Excessive patellar lateral displacement was the strongest predictor to the development of PFJ osteoarthritis features longitudinally.

The purpose of this study was to analyze the relationship between postsurgical tibial translation (TT) and tibial rotation (TR) with cartilage matrix changes using quantitative magnetic resonance imaging, specifically voxel-based relaxometry with T1ρ and T2 mapping sequences. Knee magnetic resonance imaging's (MRI's) of 51 patients with unilateral anterior cruciate ligament injury, no concomitant ligamentous injury, history of osteoarthritis (OA), and previous knee surgery were scanned prior to surgery. Thirty-four patients completed follow-up MRI scans at 6-month, 1- and 2-year post-reconstruction and were included in this study. Knee biomechanics, T1ρ, and T2 were calculated using an in-house Matlab program. Compared to the contralateral knee, the injured knee demonstrated significantly increased anterior TT at baseline (P < .001), 6-month (P < .001), 1- (P = .001), and 2-year (P < .001). Furthermore, patients were divided into groups based on TT at 6-month. When compared to patients with normal TT, those with increased anterior TT at 6-month displayed significantly longer T1ρ and T2 relaxation times in 10.4% and 7.4% of the voxels in the injured medial tibia at 1-year, respectively, as well as 12.4% and 9.8% of the voxels in the injured medial tibia at 2-year, respectively. Our results demonstrate an association between abnormal tibiofemoral position and early degradative changes to the articular cartilage matrix of the injured knee. Clinical significance: These findings suggest that altered tibiofemoral position following ACL reconstruction is associated with early degeneration of knee cartilage. Future prospective studies employing longer follow-up times are warranted to evaluate the relationship between abnormal tibiofemoral position and the early onset of posttraumatic OA.

Background: Joint space assessment for rheumatoid arthritis (RA) by ordinal conventional radiographic scales is susceptible to floor and ceiling effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides superior resolution, and may detect earlier changes. The goal of this work was to compare existing 3D methods to calculate joint space width (JSW) metrics in human metacarpophalangeal (MCP) joints with HR-pQCT and reach consensus for future studies. Using the consensus method, we established reproducibility with repositioning as well as feasibility for use in second-generation HR-pQCT scanners.Methods: Three published JSW methods were compared using datasets from individuals with RA from three research centers. A SPECTRA consensus method was developed to take advantage of strengths of the individual methods. Using the SPECTRA method, reproducibility after repositioning was tested and agreement between scanner generations was also established.Results: When comparing existing JSW methods, excellent agreement was shown for JSW minimum and mean (ICC 0.987-0.996) but not maximum and volume (ICC 0.000-0.897). Differences were identified as variations in volume definitions and algorithmic differences that generated high sensitivity to boundary conditions. The SPECTRA consensus method reduced this sensitivity, demonstrating good scan-rescan reliability (ICC >0.911) except for minimum JSW (ICC 0.656). There was strong agreement between results from first- and second-generation HR-pQCT (ICC >0.833).Conclusions: The SPECTRA consensus method combines unique strengths of three independently-developed algorithms and leverages underlying software updates to provide a mature analysis to measure 3D JSW. This method is robust with respect to repositioning and scanner generations, suggesting its suitability for detecting change.

Intrauterine growth restriction (IUGR) is a common fetal development disorder which has great impact on neonatal health. Insulin-like growth factor-1 (IGF1) has an important role in regulating fetal growth. Whether IGF1 DNA methylation was associated with IUGR has not been studied. Placenta samples from IUGR (n = 27) and normal delivery (n = 29) were collected whereas basic information of mothers and infants were also collected. RT-PCR was performed to examine IGF1 transcriptions and bisulfite sequencing PCR was used for DNA methylation analysis. Gene expression analysis found IUGR had significantly lower IGF1 transcription compared to control group (IUGR: 0.330 ± 0.351; control group: 1.001 ± 0.800, t = 3.995, P IGF1 were all highly methylated and there is no difference on DNA methylation rate between IUGR and control group (IUGR: 75%; control group: 81%; P = 0.09). Interestingly, in both IUGR and control groups, male fetus had significantly higher methylation rate than female fetus (IUGR: male: 87%; female: 74%, P = 0.016; control: male: 82%; female: 69%, P = 0.012). There was no correlation between IGF1gene expression and DNA methylation rate (r = 0.095, P = 0.063). Intrauterine fetal growth restriction placenta had significantly lower IGF1gene expression; however, IGF1 DNA methylation level was similar. A potential fetus gender difference was also found in IGF1 DNA methylation rate.

Purpose Fully automatic tissue segmentation is an essential step to translate quantitative MRI techniques to clinical setting. The goal of this study was to develop a novel approach based on the generative adversarial networks for fully automatic segmentation of knee cartilage and meniscus. Theory and methods Defining proper loss function for semantic segmentation to enforce the learning of multiscale spatial constraints in an end-to-end training process is an open problem. In this work, we have used the conditional generative adversarial networks to improve segmentation performance of convolutional neural network, such as UNet alone by overcoming the problems caused by pixel-wise mapping based objective functions, and to capture cartilage features during the training of the network. Furthermore, the Dice coefficient and cross entropy losses were incorporated to the loss functions to improve the model performance. The model was trained and tested on 176, 3D DESS (double-echo steady-state) knee images from the Osteoarthritis Initiative data set. Results The proposed model provided excellent segmentation performance for cartilages with Dice coefficients ranging from 0.84 in patellar cartilage to 0.91 in lateral tibial cartilage, with an average Dice coefficient of 0.88. For meniscus segmentation, the model achieves 0.89 Dice coefficient for lateral meniscus and 0.87 Dice coefficient for medial meniscus. The results are superior to previously published automatic cartilage and meniscus segmentation methods based on deep learning models such as convolutional neural network. Conclusion The proposed UNet-conditional generative adversarial networks based model demonstrated a fully automated segmentation method with high accuracy for knee cartilage and meniscus.

MRI-based cartilage compositional analysis shows biochemical and microstructural changes at early stages of osteoarthritis before changes become visible with structural MRI sequences and arthroscopy. This could help with early diagnosis, risk assessment, and treatment monitoring of osteoarthritis. Spin-lattice relaxation time constant in rotating frame (T1ρ) and T2 mapping are the MRI techniques best established for assessing cartilage composition. Only T2 mapping is currently commercially available, which is sensitive to water, collagen content, and orientation of collagen fibers, whereas T1ρ is more sensitive to proteoglycan content. Clinical application of cartilage compositional imaging is limited by high variability and suboptimal reproducibility of the biomarkers, which was the motivation for creating the Quantitative Imaging Biomarkers Alliance (QIBA) Profile for cartilage compositional imaging by the Musculoskeletal Biomarkers Committee of the QIBA. The profile aims at providing recommendations to improve reproducibility and to standardize cartilage compositional imaging. The QIBA Profile provides two complementary claims (summary statements of the technical performance of the quantitative imaging biomarkers that are being profiled) regarding the reproducibility of biomarkers. First, cartilage T1ρ and T2 values are measurable at 3.0-T MRI with a within-subject coefficient of variation of 4%–5%. Second, a measured increase or decrease in T1ρ and T2 of 14% or more indicates a minimum detectable change with 95% confidence. If only an increase in T1ρ and T2 values is expected (progressive cartilage degeneration), then an increase of 12% represents a minimum detectable change over time. The QIBA Profile provides recommendations for clinical researchers, clinicians, and industry scientists pertaining to image data acquisition, analysis, and interpretation and assessment procedures for T1ρ and T2 cartilage imaging and test-retest conformance. This special report aims to provide the rationale for the proposed claims, explain the content of the QIBA Profile, and highlight the future needs and developments for MRI-based cartilage compositional imaging for risk prediction, early diagnosis, and treatment monitoring of osteoarthritis. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Kijowski in this issue.

The extravagant osteoclast formation and resorption is the main cause of osteoporosis. Inhibiting the hyperactive osteoclastic resorption is considered as an efficient treatment for osteoporosis. Rhaponticin (RH) is a small molecule that has been reported to possess anti-inflammatory, anti-allergic, anti-fibrotic, and anti-diabetic activities. However, the influence of RH on osteoclasts differentiation and function is still unclear. To this end, an array of assays including receptor activator of nuclear factor kappa-Β (NF-κB) ligand (RANKL) induced osteoclastogenesis, tartrate-resistant acidic phosphatase (TRAcP) staining, immunofluorescence, and hydroxyapatite resorption were performed in this study. It was found that RH had significant anti-catabolic effects by inhibiting osteoclastogenesis and bone resorption without cytotoxicity. Mechanistically, the expression of NADPH oxidase 1 (Nox1) was found to be suppressed and antioxidant enzymes including catalase, superoxide dismutase 2 (SOD-2), and heme oxygenase-1(HO-1) were enhanced following RH treatment, suggesting RH exhibited antioxidant activity by reducing the generation of reactive oxygen species (ROS) as well as enhancing the depletion of ROS. In addition, MAPKs, NF-κB, and intracellular Ca2+ oscillation pathways were significantly inhibited by RH. These changes led to the deactivation of osteoclast master transcriptional factor-nuclear factor of activated T cells 1 (NFATc1), as examined by qPCR and Western blot assay, which led to the decreased expression of downstream integrin β3, c-Fos, cathepsin K, and Atp6v0d2. These results suggested that RH could effectively suppress RANKL-regulated osteoclast formation and bone resorption. Therefore, we propose that RH can represent a novel natural small molecule for the treatment of osteoporosis by inhibiting excessive osteoclast activity.

The aims of this case-control study were to: (1) Identify cartilage locations and volumes at risk of osteoarthritis (OA) using subject-specific finite element (FE) models; (2) Quantify the relationships between the simulated biomechanical parameters and T2 and T1ρ relaxation times of magnetic resonance imaging (MRI). We created subject-specific FE models for seven patients with anterior cruciate ligament (ACL) reconstruction and six controls based on a previous proof-of-concept study. We identified locations and cartilage volumes susceptible to OA, based on maximum principal stresses and absolute maximum shear strains in cartilage exceeding thresholds of 7 MPa and 32%, respectively. The locations and volumes susceptible to OA were compared qualitatively and quantitatively against 2-year longitudinal changes in T2 and T1ρ relaxation times. The degeneration volumes predicted by the FE models, based on excessive maximum principal stresses, were significantly correlated (r = 0.711, p < 0.001) with the degeneration volumes determined from T2 relaxation times. There was also a significant correlation between the predicted stress values and changes in T2 relaxation time (r = 0.649, p < 0.001). Absolute maximum shear strains and changes in T1ρ relaxation time were not significantly correlated. Five out of seven patients with ACL reconstruction showed excessive maximum principal stresses in either one or both tibial cartilage compartments, in agreement with follow-up information from MRI. Expectedly, for controls, the FE models and follow-up information showed no degenerative signs. Our results suggest that the presented modelling methodology could be applied to prospectively identify ACL reconstructed patients at risk of biomechanically driven OA, particularly by the analysis of maximum principal stresses of cartilage.

Background Osteolytic diseases share symptoms such as bone loss, fracture and pain, which are caused by over-activated osteoclasts. Targeting osteoclast differentiation has emerged as a therapeutic strategy clinically. Dendrobine is an alkaloid isolated from Chinese herb Dendrobium nobile, with knowing effects of analgesia and anti-inflammation. The roles of dendrobine on osteoclasts and osteolysis remain unclear. Purpose Herein, the possible roles of dendrobine in osteoclastogenesis, inflammatory osteolysis and the underlying mechanism were explored. Methods Bone marrow-derived macrophages (BMMs) and RAW264.7 cells were employed to evaluate the roles of dendrobine on osteoclastogenesis, bone absorption and the underlying mechanism in vitro. LPS injection was used to cause inflammatory osteolysis in vivo. Results Dendrobine repressed osteoclastogenesis, bone resorption induced by receptor activator of nuclear factor kappa B ligand (RANKL) in vitro. Mechanistically, dendrobine inhibited RANKL-upregulated intracellular (ROS), p-p38, c-Fos expression and nuclear factor of activated T cells (NFATc1) nuclear translocation. Osteoclastic genes were reduced, and among them matrix metalloproteinase 9 (MMP9) mRNA was dramatically blocked by dendrobine. Moreover, it substantially suppressed MMP9 protein expression during osteoclastogenesis in vitro. Accordingly, oral 20 mg/kg/day dendrobine was capable of preventing LPS-induced osteolysis with decreased osteoclasts in vivo. Conclusion Taken together, dendrobine suppresses osteoclastogenesis through restraining ROS, p38-c-Fos and NFATc1-MMP9 in vitro, thus attenuates inflammatory osteolysis in vivo. This finding supports the discover of dendrobine as a novel osteoclast inhibitor for impeding bone erosion in the future.

Adoptive chimeric antigen receptor (CAR)-modified T or NK cells (CAR-T/NK) have emerged as a novel form of disease treatment. Lentiviral vectors (LVs) are commonly employed to engineer T/NK cells for the efficient expression of CARs. This study reported for the first time the influence of single-promoter and dual-promoter LVs on the CAR expression and cytotoxicity of engineered NK cells. Our results demonstrated that the selected CAR exhibits both a higher expression level and a higher coexpression concordance with the GFP reporter in HEK-293T or NK92 cells by utilizing the optimized single-promoter pCDHsp rather than the original dual-promoter pCDHdp. After puromycin selection, the pCDHsp produces robust CAR expression and enhanced in vitro cytotoxicity of engineered NK cells. Therefore, infection with a single-promoter pCDHsp lentivector is recommended to prepare CAR-engineered cells. This research will help to optimize the production of CAR-NK cells and improve their functional activity, to provide CAR-NK cell products with better and more uniform quality.

Symptoms of coronavirus disease 2019 (COVID-19) range from asymptomatic to severe pneumonia and death. A deep understanding of the variation of biological characteristics in severe COVID-19 patients is crucial for the detection of individuals at high risk of critical condition for the clinical management of the disease. Herein, by profiling the gene expression spectrum deduced from DNA coverage in regions surrounding transcriptional start site in plasma cell-free DNA (cfDNA) of COVID-19 patients, we deciphered the altered biological processes in the severe cases and demonstrated the feasibility of cfDNA in measuring the COVID-19 progression. The up- and downregulated genes in the plasma of severe patient were found to be closely related to the biological processes and functions affected by COVID-19 progression. More importantly, with the analysis of transcriptome data of blood cells and lung cells from control group and cases with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, we revealed that the upregulated genes were predominantly involved in the viral and antiviral activity in blood cells, reflecting the intense viral replication and the active reaction of immune system in the severe patients. Pathway analysis of downregulated genes in plasma DNA and lung cells also demonstrated the diminished adenosine triphosphate synthesis function in lung cells, which was evidenced to correlate with the severe COVID-19 symptoms, such as a cytokine storm and acute respiratory distress. Overall, this study revealed tissue involvement, provided insights into the mechanism of COVID-19 progression, and highlighted the utility of cfDNA as a noninvasive biomarker for disease severity inspections.

Prostate cancer (PCa) remains the second leading cause of cancer-related death among men in the United States, and its molecular mechanism remains to be elucidated. Recent studies have suggested that microRNAs may play an important role in cancer development and progression. By analyzing the Gene Expression Omnibus dataset, we found lower expression for miR-488 in PCa than in normal tissues. Moreover, CCK-8, EdU, glucose uptake, and lactate secrete assays revealed that overexpression of miR-488 in PCa cell lines PC3 and DU145 resulted in inhibition of proliferation and glycolysis. In contrast, downregulation of miR-488 expression promoted proliferation and glycolysis in PCa cells. Using a bioinformatic approach and dual-luciferase reporter assays, we identified 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform3 (PFKFB3), as a direct target of miR-488. Inhibition of PFKFB3 also suppressed PCa cell glycolysis and proliferation. Our study suggests that miR-488 inhibits PCa cell proliferation and glycolysis by targeting PFKFB3, and thus, miR-488 may be a novel therapeutic candidate for PCa.

Background Current chemotherapy for acute myeloid leukemia (AML) mainly involves cytotoxic agents such as doxorubicin (DNR), mitoxantrone (Mito) or 2‐aminopurine‐6‐thiol (6‐TG). However, because these agents are relatively ineffective, discovering other more effective drugs for AML treatment would be valuable. Methods The in vitro antitumor effect of lenvatinib on AML cells was examined using the colorimetric MTT assay for assessing cell metabolic activity. AML cells mixed with Poloxamer 407 were injected into nude mice to form subcutaneous tumors. Tumor‐bearing mice received lenvatinib by oral administration. The antitumor effect of lenvatinib was established by measuring tumor volumes and weights. Results Lenvatinib inhibited the growth of AML cells in a dose‐dependent manner. We used AML cells to establish subcutaneous tumor tissues by mixing the cell suspension with Poloxamer 407. Poloxamer 407 alone did not influence the subcutaneous growth of AML cells. Treatment of lenvatinib inhibited in vivo tumor growth of AML cells. Conclusion The multiple‐kinase inhibitor lenvatinib inhibits the in vitro proliferation of AML cells, and restricts the in vivo growth of AML tumors.

In chronic infectious diseases caused by gram-negative bacteria, such as osteomyelitis, septic arthritis, and periodontitis, osteoclastic activity is enhanced with elevated inflammation, which disturbs the bone homeostasis and results in osteolysis. Lipopolysaccharide (LPS), as a bacteria product, plays an important role in this process. Recent evidence shows that an antimalarial drug artesunate attenuates LPS-induced osteolysis independent of RANKL. In this study we evaluated the effects of artesunate on LPS-induced osteoclastogenesis in vitro and femur osteolysis in vivo, and explored the mechanisms underlying the effects of artesunate on LPS-induced osteoclast differentiation independent of RANKL. In preosteoclastic RAW264.7 cells, we found that artesunate (1.56−12.5 μM) dose dependently inhibited LPS-induced osteoclast formation accompanied by suppressing LPS-stimulated osteoclast-related gene expression (Fra-2, TRAP, Cathepsin K, β3-integrin, DC-STAMP, and Atp6v0d2). We showed that artesunate (3.125−12.5 µM) inhibited LPS-stimulated nuclear factor of activated T cells c1 (NFATc1) but not NF-κB transcriptional activity; artesunate (6.25, 12.5 μM) significantly inhibited LPS-stimulated NFATc1 protein expression. Furthermore, artesunate treatment markedly suppressed LPS-induced Ca 2+ influx, and decreased the expression of PP2B-Aα (calcineurin) and pPLCγ1 in the cells. In addition, artesunate treatment significantly decreased the expression of upstream signals TLR4 and TRAF6 during LPS-induced osteoclastogenesis. Administration of artesunate (10 mg/kg, ip) for 8 days effectively inhibited serum TNF-α levels and ameliorated LPS (5 mg/kg, ip)-induced inflammatory bone loss in vivo. Taken together, artesunate attenuates LPS-induced inflammatory osteoclastogenesis by inhibiting the expression of TLR4/TRAF6 and the downstream PLCγ1-Ca 2+ -NFATc1 signaling pathway. Artesunate is a valuable choice to treat bone loss induced by gram-negative bacteria infection or inflammation in RANKL-independent pathway.

Sinomenine (SIN) is an anti-inflammatory and antiarthritic alkaloid derived from Sinomenium acutum, and the product Zhengqing Fengtongning produced from SIN has been marketed in China for treating rheumatoid arthritis (RA). Interestingly, we recently found that SIN could significantly ameliorate bone destruction induced by breast cancer cells in mice. Micro-CT examination showed that bone loss of the trabecular bones in tumor-bearing mice was markedly decreased by i.p. treatment of SIN at 150 mg/kg body weight. A mechanistic study demonstrated that SIN could suppress osteoclast formation and bone absorption induced by both MDA-MB-231 cells and MDA-MB-231 cell-conditioned medium (MDA-MB-231 CM) in preosteoclastic RAW264.7 cells. The MDA-MB-231 CM-induced osteoclast-related genes TRAP and OSCAR were obviously downregulated by SIN. In addition, mRNA expression of c-Fos and NFATc1 and nuclear translocation of c-Fos and NFATc1 protein were inhibited by SIN during MDA-MB-231 CM-induced osteoclastogenesis, while NF-κB signaling was not impacted by SIN. More interestingly, SIN was demonstrated to decrease hIL-8 mRNA expression in cultured MDA-MB-231 cells and to inhibit hIL-8 protein expression in MDA-MB-231 cells cocultured with preosteoclastic RAW264.7 cells while simultaneously downregulating CXCR1, the ligand of IL-8 related to bone destruction, during MDA-MB-231 CM-induced osteoclastogenesis. Previously, IL-8/CXCR1 was reported to be associated with the pathogenesis and progression of RA, and SIN was observed to markedly ameliorate bone erosion of RA patients. Our current findings may extend the utilization of SIN to preventing osteoclastogenesis and bone destruction in breast cancer patients and may enable IL-8/CXCR1 to serve as new targets for both anticancer and antiarthritic drug discovery.

The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) contributes to cartilage and bone destruction in rheumatoid arthritis (RA). Betulinic acid has been demonstrated to have a positive therapeutic effect on tumor, inflammation and immune disorder, however, the effects of betulinic acid on RA FLSs have not been verified. Therefore, in the present study, we observed the effect of betulinic acid on the migration and invasion of RA FLSs and explored its underlying signal mechanisms. Our results showed that betulinic acid treatment suppressed the migration, invasion and reorganization of the actin cytoskeleton of RA FLSs. In addition, we found that the mRNA expression of IL-1β, IL-6, IL-8 and IL-17A were markedly down-regulated by treatment with betulinic acid in TNF-α-induced RA FLSs. To gain insight into the molecular mechanisms, we evaluated the effect of betulinic acid on NF-κB activation in RA FLSs. The results indicated that betulinic acid treatment reduced the TNF-α-induced activation of NF-κB signal pathway and the NF-κB nuclear accumulation. We also observed that treatment with betulinic acid attenuated synovial inflammation and joint destruction in mice with CIA. Taken together, these results suggest that betulinic acid inhibits the migration and invasion of RA FLSs by blocking NF-κB signal pathway activation.

Background Mogroside V, the main ingredient of Siraitia grosvenorii, has been proved to have therapeutic effects on pulmonary diseases. The specific mechanism still remains to be clarified, which hinders the potence of its medicinal value. Purpose Serum and lung metabolomics based on LC-MS analysis were applied to explore the mechanism of mogroside V against lung inflammation. Method In this study, balb/c mice were divided into control, model, mogeoside V and SH groups. We evaluated the protective effects of mogroside V on lung inflammation in asthmatic mice. Suhuang Zhike Jiaonang was used as positive drug. Metabolic profiles of serum and lung samples of mice in control, model and mogroside V groups were analyzed by LC-MS. Results Administration of mogroside V effectively relieved the expression of biochemical cytokines and lung inflammatory infiltration of asthmatic mice caused by ovalbumin (OVA). And visceral index of mice treated with mogroside V was close to control group. These results indicated that mogroside V ameliorated OVA-induced lung inflammation. LC-MS based metabolomics analysis demonstrated 6 main pathways in asthmatic mice including Vitamin B6 metabolism, Taurine and hypotaurine metabolism, Ascorbate and aldarate metabolism, Histidine metabolism, Pentose and glucuronate interconversions, Citrate cycle (TCA cycle) were regulated after using mogroside V. Conclusion The study firstly elucidates the metabolic pathways regulated by mogroside V on lung inflammation through metabolomics, providing a theoretical basis for more sufficient utilization and compatibility of mogroside V.

Haiyan Jiao,1 Hongjun Yang,1 Zhiyi Yan,1 Jianbei Chen,1 Mengbai Xu,1 Youming Jiang,1 Yueyun Liu,1 Zhe Xue,1 Qingyu Ma,2 Xiaojuan Li,2 Jiaxu Chen1,2 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Formula-Pattern Research center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, Guangdong, People’s Republic of ChinaCorrespondence: Jiaxu Chen Tel +86 1064286656Email chenjiaxu@hotmail.comBackground: At present, the pathogenesis of depression is not fully understood, and nearly half of depression patients experience no obvious effects during treatment. This study aimed to establish a depression mouse model to explore the possible role of ferroptosis in the pathogenesis of depression, and observe the effects of Xiaoyaosan on PEBP1-GPX4-mediated ferroptosis in the hippocampus.Methods: Forty-eight male C57BL/6 mice were randomly divided into a control group, CUMS group, Xiaoyaosan group and fluoxetine group, and the model was established by chronic unpredictable mild stress (CUMS) for a successive 6 weeks. The medication procedure was performed from the 4th to the 6th week of modeling. The behavioral evaluations were measured to evaluate depressive-like behaviors. The expressions of GPX4, FTH1, ACSL4 and COX2 were detected as ferroptosis-related indicators. Then, the total iron and ferrous content in the hippocampus were measured. The levels of PEBP1 and ERK1/2 were observed, and the expressions of GFAP and IBA1 were also detected to measure the functions of astrocytes and microglia in the hippocampus.Results: Eight herbs of Xiaoyaosan had 133 active ingredients which could regulate the 43 ferroptosis-related genes in depression. After 6 weeks of modeling, the data showed that mice in the CUMS group had obvious depressive-like behaviors, and medication with Xiaoyaosan or fluoxetine could significantly improve the behavioral changes. The expressions of GPX4, FTH1, ACSL4, COX2, PEBP1, ERK1/2, GFAP and IBA1 changed in the CUMS group mice, while the total iron and ferrous content also changed. Xiaoyaosan and fluoxetine had obvious curative effects that could significantly alleviate the above changes in the hippocampus.Conclusion: Our results revealed that the activation of ferroptosis might exist in the hippocampi of CUMS-induced mice. The PEBP1-GPX4-mediated ferroptosis could be involved in the antidepressant mechanism of Xiaoyaosan. It also implied that ferroptosis could become a new target for research into the depression mechanism and antidepressant drugs.Keywords: chronic unpredictable mild stress, depression, Xiaoyaosan, ferroptosis, GPX4, PEBP1

Micro (mi)RNAs are crucial participants in the progression of cervical cancer (CC). Growing evidence indicates that miRNA (miR)‑34c‑5p is a pivotal tumor suppressor in numerous types of cancer and its functions in CC require further investigating. The present study demonstrated that there was a decreased level of miR‑34c‑5p in CC‑associated cell lines compared with healthy control samples. It also demonstrated that miR‑34c‑5p targeted Notch1 and suppressed CC progression. Dual‑luciferase reporter assays verified the targeted relationship of miR‑34c‑5p and Notch1. The expression of Notch1 in HeLa cells was markedly reduced following miR‑34c‑5p overexpression and the proliferation, migration and invasion of HeLa cells were reduced although apoptosis was accelerated. However, overexpression of miR‑34c‑5p was reversed following the addition of Notch1, which supported the finding of the targeted relationship between miR‑34c‑5p and Notch1. Flow cytometry demonstrated that miR‑34c‑5p inhibited the proliferation of HeLa cells while accelerating apoptosis. The present study concluded that miR‑34c‑5p was a tumor suppressor in CC and may be a novel measure for the future treatment of CC.

PKC-δ is an important molecule for B-cell proliferation and tolerance. B cells have long been recognized to play a part in osteoimmunology and pathological bone loss. However, the role of B cells with PKC-δ deficiency in bone homeostasis and the underlying mechanisms are unknown. We generated mice with PKC-δ deletion selectively in B cells by crossing PKC-δ-loxP mice with CD19-Cre mice. We studied their bone phenotype using micro-CT and histology. Next, immune organs were obtained and analyzed. Western blotting was used to determine the RANKL/OPG ratio in vitro in B-cell cultures, ELISA assay and immunohistochemistry were used to analyze in vivo RANKL/OPG balance in serum and bone sections respectively. Finally, we utilized osteoclastogenesis to study osteoclast function via hydroxyapatite resorption assay, and isolated primary calvaria osteoblasts to investigate osteoblast proliferation and differentiation. We also investigated osteoclast and osteoblast biology in co-culture with B-cell supernatants. We found that mice with PKC-δ deficiency in B cells displayed an osteopenia phenotype in the trabecular and cortical compartment of long bones. In addition, PKC-δ deletion resulted in changes of trabecular bone structure in association with activation of osteoclast bone resorption and decrease in osteoblast parameters. As expected, inactivation of PKC-δ in B cells resulted in changes in spleen B-cell number, function, and distribution. Consistently, the RANKL/OPG ratio was elevated remarkably in B-cell culture, in the serum and in bone specimens after loss of PKC-δ in B cells. Finally, in vitro analysis revealed that PKC-δ ablation suppressed osteoclast differentiation and function but co-culture with B-cell supernatant reversed the suppression effect, as well as impaired osteoblast proliferation and function, indicative of osteoclast–osteoblast uncoupling. In conclusion, PKC-δ plays an important role in the interplay between B cells in the immune system and bone cells in the pathogenesis of bone lytic diseases.

Hepatocellular carcinoma (HCC) remains a challenge in the medical field due to its high malignancy and mortality rates particularly for HCC, which has developed multidrug resistance. Therefore, the identification of efficient chemotherapeutic drugs for multidrug resistant HCC has become an urgent issue. Natural products have always been of significance in drug discovery. In the present study, a cell-based method was used to screen a natural compound library, which consisted of 78 compounds, and the doxorubicin-resistant cancer cell line, HepG2/ADM, as screening tools. The findings of the present study led to the shortlisting of one of the compounds, digitoxin, which displayed an inhibitory effect on HepG2/ADM cells, with 50% inhibitory concentration values of 132.65±3.83, 52.29±6.26, and 9.13±3.67 nM for 24, 48, and 72 h, respectively. Immunofluorescence, western blotting and cell cycle analyses revealed that digitoxin induced G2/M cell cycle arrest via the serine/threonine-protein kinase ATR (ATR)-serine/threonine-protein kinase Chk2 (CHK2)-M-phase inducer phosphatase 3 (CDC25C) signaling pathway in HepG2/ADM cells, which may have resulted from a DNA double-stranded break. Digitoxin also induced mitochondrial apoptosis, which was characterized by changes in the interaction between Bcl-2 and Bax, the release of cytochrome c, as well as the activation of the caspase-3 and -9. To the best of our knowledge, the present study is the first report that digitoxin displays an anti-HCC effect on HepG2/ADM cells through G2/M cell cycle arrest, which was mediated by the ATR-CHK2-CDC25C signaling pathway and mitochondrial apoptosis. Therefore, digitoxin could be a promising chemotherapeutic agent for the treatment of patients with HCC.

Objectives: The prevalence of patellofemoral joint (PFJ) osteoarthritis (OA) ranges from 8-47% 7-10 years after anterior cruciate ligament reconstructions (ACLR) using bone-patellar tendon-bone (BTB) autograft. In performing BTB ACLR, some hypothesize that either trauma caused by harvest of the patellar bone autograft or altered biomechanics lead to PFJ post traumatic osteoarthritis (PTOA). Our objective was to evaluate by 3T MRI whether the ACLR knees had more signs of early PTOA compared to the contralateral knee within the MOON nested cohort. We hypothesize that a BTB autograft harvested using a minimally traumatic technique will not increase the risk of PFJ OA. Methods: MRIs of operative and contralateral uninjured knees were collected in 60 patients (28 males, mean age 21 years) from a single site in the Multicenter Orthopaedic Outcomes Network (MOON) nested cohort at minimum 2 years post BTB ACLR. Harvesting the patellar block for the BTB autograft was performed using an oscillating saw with a narrow blade, being careful not to extend the cut into the posterior cortex of the patella, and with gentle elevation of the bone block with an osteotome. MRI was performed at 3T (Philips, Achieva) and the imaging protocol included intermediate-weighted sagittal turbo spin-echo (TSE) imaging, axial and coronal fat-saturated TSE imaging, and 3D coronal gradient echo imaging. Structural MRI assessment of the knees was performed using the MRI Osteoarthritis Knee Score (MOAKS) semi-quantitative scoring system by a board-certified musculoskeletal radiologist. The prevalence of cartilage defects in each knee compartment (medial, lateral, patellofemoral), meniscal tears (medial, lateral; yes/no), bone marrow edema-like lesions (BMEL; medial, lateral, patellofemoral; yes/no), effusion (yes/no) and Hoffa synovitis (yes/no) were compared between the reconstructed and contralateral uninjured knees. Hypothesis testing was performed for the PF joint using a logistic regression model where the dependent variable was presence/absence of cartilage loss and the independent variable was knee status (surgical or contralateral). Results: There were no significant differences in the prevalence of cartilage defects (any lesions or full thickness loss) in the PFJ between the surgical BTB ACLR knees and the uninjured non-operative contralateral control knees. 38.3% of BTB ACLR knees had PFJ cartilage defects versus 31.7% of contralateral control knees with PFJ cartilage defects (p>0.05) (Table 1). The BTB ACLR knees had more cartilage defects in the medial and lateral tibiofemoral compartments, more meniscal tears, BMEL, effusion and Hoffa synovitis, than the contralateral knees. Figure 1 shows examples of PFJ cartilage defects on MRI for the reconstructed and contralateral uninjured knees. At 2 years follow-up, KOOS symptoms, sports, pain, and activities of daily living scores were maintained at a high level ranging from 88-98. Conclusion: Although prior studies suggest BTB ACLR increases the risk of PFJ OA, the current study shows no difference in MRI signs of early PTOA in the PFJ. Cartilage defects comparing reconstructed vs. contralateral uninjured knees 2 years after surgery based on MRI were not different. These results should be used in shared decision making with athletes in choosing the appropriate autograft during reconstruction. Future studies will investigate the influence of cartilage defects found in the medial and lateral compartments further.

PURPOSE: To investigate (i) the frequency and natural evolution of meniscal ramp lesions (MRLs) on MRI in subjects with acute ACL-tear and (ii) to compare knee cartilage compositional degeneration between subjects with MRLs and subjects without meniscal pathology over 2 years. MATERIALS AND METHODS: Fifty-seven subjects with ACL tears (32 females; age 32.6±8.3y; BMI 24.5±3.5kg/m(2)) from a prospective study were screened for the presence of MRLs. Morphological (high-resolution 3D fast spin-echo) and compositional (T1ρ and T2-mapping) MRI was performed prior to and 2-years after ACL-reconstruction. Follow-up MR images were assessed for changes in the signal-intensity of the MRLs and the presence of meniscal tears. Differences of compositional parameters were compared between subjects with MRLs and without meniscal lesions using an Independent Samples t Tests. RESULTS: MRLs were found in 16% (9/56) of the subjects with ACL tears at baseline. Only one subject with MRLs developed a posterior horn meniscal tear over 2 years. In 12 knees no meniscal tears were found, which were defined as controls. Most interestingly, cartilage ΔT1ρ of the medial femur and medial tibia increased significantly more in subjects with MRLs compared to controls (mean difference, MF=6.0±0.8 vs. 2.3±0.6, p=0.004 and MT=4.4±1.4 vs. 0.4±0.6, p=0.027) and medial femur ΔT2 over 2 years increased significantly more in MRL than in control knees (5.1±2.5 ms vs. 2.2±1.9 ms, p=0.012). CONCLUSION: Subjects with ACL-tear presented MRLs in 16% of cases. Compared to controls without meniscal lesions knees with MRLs demonstrated accelerated degeneration of cartilage composition in the medial knee compartment over 2-years.

Clinical symptoms of coronavirus disease 2019 (COVID-19) range from asymptomatic to severe pneumonia and death. Detection of individuals at high risk for critical condition is crucial for control of the disease. Herein, for the first time, we profiled and analyzed plasma cell-free DNA (cfDNA) of mild and severe COVID-19 patients. We found that in comparison between mild and severe COVID-19 patients, Interleukin-37 signaling was one of the most relevant pathways; top significantly altered genes included POTEH, FAM27C, SPATA48, which were mostly expressed in prostate and testis; adrenal glands, small intestines and liver were tissues presenting most differentially expressed genes. Our data thus revealed potential tissue involvement, provided insights into mechanism on COVID-19 progression, and highlighted utility of cfDNA as a noninvasive biomarker for disease severity inspections.One Sentence SummaryCfDNA analysis in COVID-19 patients reveals severity-related tissue damage.

T1 ρ and T2 magnetic resonance imaging (MRI) may allow for a noninvasive assessment of ligamentization after anterior cruciate ligament (ACL) reconstruction. We hypothesized that ACL graft T1 ρ and T2 relaxation times would decrease over time, that T1 ρ and T2 relaxation times would be inversely correlated with Knee Osteoarthritis Outcome Scores (KOOS), and that T1 ρ and T2 values would be lower for autograft relative to allograft reconstruction. Thirty-nine patients (age: 30.5 ± 8.2 years) were followed prospectively after ACL reconstruction with hamstring autograft (N = 27) or soft-tissue allograft (N = 12). Magnetic resonance (MR) imaging and KOOS surveys were completed at 6, 12, 24, and 36 months after surgery. ACL graft was segmented to define T1 ρ and T2 relaxation times. Relaxation times were compared between time points with ANOVA tests. Log-transformed autograft and allograft relaxation times were compared with the Student t tests. The relationship between KOOS and relaxation times at 24 months was investigated with Spearman's rank correlation. ACL graft T1 ρ relaxation times were significantly higher at 6 months relative to 12 months (P = .042), 24 months (P

ATP6V1s participate in the biological process of transporting hydrogen ions and are associated with various cancers in expression and clinicopathological features, while its role in kidney renal clear cell carcinoma is unknown. We aimed to demonstrate the relationship between ATP6V1s and kidney renal clear cell carcinoma. This study investigated the expression and roles of ATP6V1s in KIRC using Oncomine, The Cancer Genome Atlas, UALCAN, Human Protein Atlas, Clinical Proteomics Tumor Analysis Consortium, GeneMANIA, Tumor IMmune Estimation Resource, GEPIA databases. Low mRNA and protein expression of ATP6V1s members were found to be significantly associated with clinical cancer stages, nodal metastasis status, and patient's gender in KIRC patients. Besides, lower mRNA expression of ATP6V1A, ATP6V1B2, ATP6V1C1, ATP6V1C2, ATP6V1D, ATP6V1E1, ATP6V1E2, ATP6V1F, ATP6V1G1, and ATP6V1H have shorter OS. Taken together, these results indicated that ATP6V1s family members could be a potential target in the development of anti-KIRC therapeutics and an efficient marker of the prognostic value of KIRC.

SummaryPreeclampsia, a life-threatening pregnancy complication characterized by hypertension and multiorgan damage, affects 2-5% of pregnancies and causes 76,000 deaths per year. Most preeclampsia associated syndromes immediately dispel after removal of placenta, indicating a casual role of placenta in the pathogenesis. Failed transformation of spiral artery due to insufficient invasion and excessive apoptosis of trophoblast suggested developmental defects in preeclampsia placenta. However, the underlying molecular mechanisms that affected placenta development in preeclampsia remained elusive. Here we show that, in preeclampsia placenta, the epigenetic landscape formed during extraembryonic tissue differentiation was disrupted: dramatic chromatin accessibility shift affected known and novel genes implicated in preeclampsia. DNA methylation defects in preeclampsia affected lineage-defining PcG-controlled loci in trophectoderm. LTR12 retrotransposons associated with VCT/SCT-specific genes were hypermethylated. Meanwhile, hundreds of PcG-regulated EVT-specific gene promoters, which otherwise undergone post-ZGA extraembryonic-tissue-specific de novo methylation, were hypomethylated and hyper-activated. Together, these epigenetic defects resulted in placenta developmental delay in preeclampsia. The defective methylation pattern could be detected in serum cfDNA, and could be used to accurately predict preeclampsia at early pregnancy weeks in independent validation cohorts. Our data suggests that the preeclampsia placenta represents a stalled state of epigenetic reprogramming en route of development from trophectoderm to normal placenta.

Currently, dendritic cell-specific transmembrane protein (DC-STAMP), a multipass transmembrane protein, is considered as the master regulator of cell–cell fusion, which underlies the formation of functional multinucleated osteoclasts. Thus, DC-STAMP has become a promising target for osteoclast-associated osteolytic diseases. In this study, we investigated the effects of oridonin (ORI), a natural tetracyclic diterpenoid compound isolated from the traditional Chinese herb Rabdosia rubescens, on osteoclastogenesis in vivo and ex vivo. ICR mice were injected with LPS (5 mg/kg, ip, on day 0 and day 4) to induce inflammatory bone destruction. Administration of ORI (2, 10 mg·kg(−1)·d(−1), ig, for 8 days) dose dependently ameliorated inflammatory bone destruction and dramatically decreased DC-STAMP protein expression in BMMs isolated from LPS-treated mice. Treatment of preosteoclast RAW264.7 cells with ORI (0.78–3.125 μM) dose dependently inhibited both mRNA and protein levels of DC-STAMP, and suppressed the following activation of NFATc1 during osteoclastogenesis. Knockdown of DC-STAMP in RAW264.7 cells abolished the inhibitory effects of ORI on RANKL-induced NFATc1 activity and osteoclast formation. In conclusion, we show for the first time that ORI effectively attenuates inflammation-induced bone loss by suppressing DC-STAMP expression, suggesting that ORI is a potential agent against inflammatory bone diseases.

BackgroundAs a secure vehicle of probiotics, breast milk can provide babies with the Lactobacillus which can not only colonize and inhibit the pathogenic bacterial infection in infant's intestines. The purpose of this study was to assess the occurrence and probiotic properties of Lactobacillus spp. of maternal breast milk in the Uyghur population, Xinjiang China, by using culture method. Results Based on repetitive genomic fingerprinting PCR (rep-PCR), a total of 198 isolates of L actobacill us from 31 different lactation of breast milk samples of Uighur in kashi region of Xinjiang were classified into 11 genotypes, which were identified as Lactobacillus fermentum (82 isolates, prevalence: 61.3%, mean relative abundance: 45.4%, genotype: 3), Lactobacillus brevis (75, 41.9%, 38.1%, 4), Lactobacillus oris (37, 32.3%, 15.1%, 3) and rare Lactobacillus vaginalis (4, 9.7%, 1.4%, 1). From colostrum to mature milk, the number and species of Lactobacillus showed an uptrend, from mature milk to late milk, a downside was found in Lactobacillus. The relative abundance of L. fermentum decreased throughout lactation, while L . brevis showed an opposite trend. Three isolates were randomly selected for each genotype to estimate antimicrobial activity (33 isolates in total). Among the isolates, 20 isolates exhibited broad antibacterial spectrum with inhibition halos >10 mm against most indicator pathogens, which were selected for assessing probiotic properties. Nineteen isolates showed the resistance to vancomycin and co-trimoxazole, and KM66 ( L . brevis ) was resistant up to 5/8 antibiotics. KM147 ( L. brevis ) and Y3 ( L. fermentum ) strains were selected as potential probiotics by combining lysozyme, acid and bile salt tolerance. Conclusion Species composition and prevalence of Lactobacillus varied with the study subjects throughout lactation phase. The deliberately selected Lactobacillus strains from breast milk may have a great potential as probiotics to inhibit pathogen infection in infants.

PURPOSE OF REVIEW: To provide an overview on recent technical development for quantifying marrow composition using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques, as well as a summary on recent findings of interrelationship between marrow adipose tissue (MAT) and skeletal health in the context of osteoporosis. RECENT FINDINGS: There have been significant technical advances in reliable quantification of marrow composition using MR techniques. Cross-sectional studies have demonstrated a negative correlation between MAT and bone, with trabecular bone associating more strongly with MAT than cortical bone. However, longitudinal studies of MAT and bone are limited. MAT contents and composition have been associated with prevalent vertebral fracture. The evidence between MAT and clinical fracture is more limited, and, to date, no studies have reported on the relationship between MAT and incident fracture. SUMMARY: Increasing evidence suggests a dynamic role of marrow fat in skeletal health. Reliable non-invasive quantification of marrow composition will facilitate developing novel treatment strategies for osteoporosis.

Background: Several reports have shown that altered biomechanics after anterior cruciate ligament reconstruction (ACLR) are associated with the development of posttraumatic osteoarthritis. However, it is not fully understood whether altered biomechanics are associated with meniscal changes after ACLR. Purpose: To investigate changes in gait and landing biomechanics over a 3-year period and their correlation with meniscal matrix alterations present before and after ACLR through use of magnetic resonance T1ρ/T2 mapping, which can allow detection of early meniscal degeneration. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 36 patients with ACLR and 14 healthy controls were included in this study. All patients underwent magnetic resonance imaging and biomechanical analysis during gait of the injured knee and contralateral knee preoperatively and at 6 months, 1 year, 2 years, and 3 years after ACLR, as well as biomechanical analysis during drop-landing from 6 months to 3 years postoperatively. To evaluate biochemical changes of the mensical matrix, T1ρ/T2 relaxation times of the meniscus were calculated. Results: Mean T1ρ/T2 values of ACLR knees were significantly higher than values in the contralateral and control knees in the posterior lateral and medial horns up to 1 year after surgery; however, the differences were not seen at 3 years after surgery. The ACLR knee exhibited significantly lower peak knee flexion moment and angle during gait at 6 months compared with baseline and continued to decrease until 3 years. The ACLR knee exhibited significantly lower peak vertical ground-reaction force and peak knee flexion moment and angle during landing at 6 months. However, the differences were no longer present at 3 years. Biomechanics at 6 months had significant correlations with changes of mean T1ρ/T2 values in the medial posterior horn from 6 months to 3 years after ACLR. Conclusion: Although mean T1ρ/T2 values of meniscus seen before ACLR improved after 3 years, approximately 30% of patients with ACLR did not show decreases from 6 months to 3 years. Patients with abnormal lower limb kinetics of the ACLR knee at 6 months showed less recovery in the medial posterior horn from 6 months to 3 years, suggesting that biomechanical parameters during the early stage of recovery might be potential biomarkers for predicting persistent medial meniscal abnormality after ACLR.

The Hippo‑yes‑associated protein (YAP) signaling pathway was previously identified to serve an important role in controlling chondrocyte differentiation and post‑natal growth. Growth plate cartilage tissue is avascular, and hypoxia‑inducible factor (HIF)‑1α is essential for chondrocytes to maintain their chondrogenic phenotype in a hypoxic environment. In the present study, the role of hypoxia and HIF‑1α in the regulation of YAP in chondrocytes was investigated. The data demonstrated that hypoxia promoted the maintenance of the chondrogenic phenotype, HIF‑1α expression and YAP activation in chondrocytes in a time‑dependent manner. Hypoxia promoted YAP activation in a Hippo‑independent manner. Inhibiting the expression of HIF‑1α decreased the activation of YAP and downregulated the expression of sex‑determining region‑box 9 protein (SOX9) under hypoxic conditions, while the upregulation of HIF‑1α by cobalt chloride promoted the expression and nuclear translocation of YAP and upregulated the expression of SOX9 and collagen II chain under normoxic conditions. In addition, inhibition of YAP expression under hypoxia did not affect the expression of the HIF‑1α signaling pathway, but inhibited the up‑regulation of SOX9 expression caused by hypoxia. In addition, reoxygenation following hypoxia inhibited the activation of YAP caused by hypoxia in chondrocytes, whereas the upregulation of SOX9 and collagen II chain also appeared to be inhibited. In conclusion, the results of the present study demonstrated that hypoxia promoted YAP activation via HIF‑1α. Therefore, the HIF‑1α/YAP signaling axis may serve an important role in controlling growth plate chondrocyte differentiation and the maintenance of the chondrogenic phenotype in growth plate chondrocytes.

Bone marrow adiposity is associated with aging, osteoporosis, and reduced hematopoiesis, as well as anorexia nervosa, but little is known about the underlying mechanisms that affect marrow adiposity. Chronic kidney disease (CKD) may influence bone marrow adipose tissue (BMAT), possibly through loss of lean mass or higher circulating levels of sclerostin. To test these hypotheses, we investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) as a measure of kidney function and 1 H-MRS-based measurement of vertebral BMAT (L1 to L4) in 475 older adults from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. Mean BMAT was compared in those with eGFR >60 (n = 297) versus those with eGFR 45 to 60 (n = 120) or eGFR 60 (adjusted mean 53.8%; 95% CI, 52.8 to 54.8) (p = 0.0002). BMAT did not differ in those with eGFR 45 to 60 (adjusted mean 54.3%; 95% CI, 52.8 to 55.9) compared with those with eGFR >60 (p = 0.58). In a subgroup of participants with serum sclerostin available (n = 253), additional adjustment for sclerostin attenuated the difference in adjusted mean vertebral BMAT between those with eGFR 60 from 3.7% (p = 0.04) to 2.4% (p = 0.20). CKD stage 3b or worse was associated with greater bone marrow adiposity; this association may be partially mediated by sclerostin. © 2018 American Society for Bone and Mineral Research.

Patients who have suffered ACL injury are more likely to develop early onset post-traumatic osteoarthritis despite reconstruction. The purpose of our study was to evaluate the longitudinal changes in the tibiofemoral cartilage contact area size and location after ACL injury and reconstruction. Thirty-one patients with isolated unilateral ACL injury were followed with T2 weighted Fast Spin Echo, T1ρ and T2 MRI at baseline prior to reconstruction, and 6 months, 1 year, and 2 years after surgery. Areas were delineated in FSE images with an in-house Matlab program using a spline-based semi-automated segmentation algorithm. Tibiofemoral contact area and centroid position along the anterior-posterior axis were calculated along with T1ρ and T2 relaxation times on both the injured and non-injured knees. At baseline, the injured knees had significantly smaller and more posteriorly positioned contact areas on the medial tibial surface compared to corresponding healthy knees. These differences persisted 6 months after reconstruction. Moreover, subjects with more anterior medial centroid positions at 6 months had elevated T1ρ and T2 measures in the posterior medial tibial plateau at 1 year. Changes in contact area and centroid position after ACL injury and reconstruction may characterize some of the mechanical factors contributing to post-traumatic osteoarthritis. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2718-2727, 2018.

Cell sheet techniques offer a promising future for myocardial infarction (MI) therapy; however, insufficient nutrition supply remains the major limitation in maintaining stem cell bioactivity in vitro. In order to enhance cell sheet mechanical strength and bioactivity, a decellularized porcine pericardium (DPP) scaffold was prepared by the phospholipase A2 method, and aspartic acid was used as a spacer arm to improve the vascular endothelial growth factor crosslink efficiency on the DPP scaffold. Based on this scaffold, multilayered bone marrow mesenchymal stem cell sheets were rapidly constructed, using RAD16-I peptide hydrogel as a temporary 3D scaffold, and cell sheets were cultured in either the 3D-dynamic system (DCcs) or the traditional static condition (SCcs). The multilayered structure, stem cell bioactivity, and ultrastructure of DCcs and SCcs were assessed. The DCcs exhibited lower apoptosis, lower differentiation, and an improved paracrine effect after a 48 h culture in vitro compared to the SCcs. Four groups were set to evaluate the cell sheet effect in rat MI model: sham group, MI control group, DCcs group, and SCcs group. The DCcs group improved cardiac function and decreased the infarcted area compared to the MI control group, while no significant improvements were observed in the SCcs group. Improved cell survival, angiogenesis, and Sca-1+ cell and c-kit+ cell amounts were observed in the DCcs group. In conclusion, the DCcs maintained higher stem cell bioactivity by using the 3D-dynamic system to provide sufficient nutrition, and transplanting DCcs significantly improved the cardiac function and angiogenesis. Statement of Significance This study provides an efficient method to prepare vascular endothelial growth factor covalent decellularized pericardium scaffold with aspartic acid, and a multilayered bone marrow mesenchymal stem cell (BMSC) sheet is constructed on it using a 3D-dynamic system. The dynamic nutrition supply showed a significant benefit on BMSC bioactivity in vitro, including decreasing cell apoptosis, reducing stem cell differentiation, and improving growth factor secretion. These favorable bioactivity improved BMSC survival, angiogenesis, and cardiac function of the infarcted myocardium. The study highlights the importance of dynamic nutrition supply on maintaining stem cell bioactivity within cell sheet, and it stresses the necessity and significance of setting a standard for assessing cell sheet products before transplantation in the future application.

ObjectivesTo assess (i) normal imaging anatomy of the popliteomeniscal fascicles, (ii) prevalence and natural evolution of popliteomeniscal fascicle tears (PMFT) in subjects with traumatic anterior cruciate ligament (ACL) tears over 2 years and (iii) compare knee cartilage degeneration in subjects with and without PMFT longitudinally.Methods57 subjects with ACL tears were screened for PMFT. Morphological (high-resolution 3D fast spin-echo) and compositional (T1ρ and T2 mapping) MR imaging was performed prior to and 2 years after ACL reconstruction. Differences of morphological and compositional parameters were compared between subjects with and without PMFT using logistic regression, adjusting for age, sex and BMI.ResultsIn 24% (n = 14) of the subjects with ACL tear a PMFT was detected on baseline MRI. One subject with PMFT developed a meniscal tear over 2 years. Cartilage ∆T1ρ of the lateral femur increased significantly more in subjects with isolated PMFT compared to controls (mean difference, 2.0 ± 2.9 vs. -1.3 ± 1.6, p = 0.027).ConclusionPMFT detected by MRI are a common finding in subjects with ACL tears. Subjects with these defects showed higher compositional cartilage deterioration compared to controls, over 2 years in the lateral femoral compartment, indicating accelerated cartilage degeneration.Key points• Popliteomeniscal fascicle lesions are a common finding in subjects with ACL tears. • Progression to a meniscal tear over 2 years is not frequent. • Anteroinferior popliteomeniscal fascicle is injured most frequently. • Patients with popliteomeniscal fascicle lesions showed accelerated cartilage degeneration.

Background: Abnormal frontal plane gait mechanics are known risk factors for knee osteoarthritis, but their role in early cartilage degeneration after anterior cruciate ligament reconstruction (ACLR) is not well understood. Hypothesis/Purpose: The objective was to evaluate the association of frontal plane gait mechanics with medial knee cartilage magnetic resonance (MR) relaxation times over 1 year in patients with ACLR and controls. It was hypothesized that (1) there will be an increase in frontal plane medial knee loading and medial knee MR relaxation times over time in the patients with ACLR, and (2) increases in frontal plane medial knee loading will be associated with an increase in medial knee MR relaxation times. Study Design: Case-control study; Level of evidence, 3. Methods: Patients with ACLR (n = 37) underwent walking gait analyses and bilateral quantitative MR imaging (MRI) before surgery and at 6 and 12 months after ACLR. Healthy control participants (n = 13) were evaluated at baseline and 12 months. Gait variables included peak knee adduction moment (KAM), KAM impulse, and peak knee adduction angle. MRI variables included medial femur and medial tibia whole compartment and subregional T1ρ and T2 relaxation times. Statistical analyses included a comparison of changes over time for gait and MRI variables, correlations between changes in gait and MRI variables over time, and differences in change in MRI variables in patients who showed an increase versus decrease in KAM impulse. Results: There were significant increases in medial T1ρ (Δ 4%-11%) and T2 (Δ 2%-10%) relaxation times from baseline to 6 months for both knees in the ACLR group and in KAM (Δ 13%) for the injured knee. From baseline to 6 months, patients who had an increase in KAM impulse in the injured knee had a greater increase in medial T1ρ and T2 relaxation times as compared with those who did not have an increase in KAM impulse. Longitudinal changes for the control group were not significant. Conclusion: There is an increase in medial knee relaxation times over the first 6 months after ACLR. People with an increase in medial knee loading show an increase in medial knee relaxation times when compared with those who do not have an increase in medial knee loading over the first 6 months.

BackgroundThe factors that contribute to the abnormal knee kinematics after anterior cruciate ligament (ACL) injury and ACL reconstruction remain unclear. Bone shape has been implicated in the development of hip and knee osteoarthritis, although there is little knowledge about the effects of bone shape on knee kinematics after ACL injury and after ACL reconstruction. QUESTIONS/QUESTIONS: (1) What is the relationship between bony morphology with alterations in knee kinematics after ACL injury? (2) Are baseline bone shape features related to abnormal knee kinematics at 12 months after ACL reconstruction?MethodsThirty-eight patients (29 ± 8 years, 21 men) were prospectively followed after acute ACL injury and before ligamentous reconstruction. Patients were excluded if there was a history of prior knee ligamentous injury, a history of inflammatory arthritis, associated meniscal tears that would require repair, or any prior knee surgery on either the injured or contralateral side. In total, 54 patients were recruited with 42 (78%) patients completing 1-year followup and four patients excluded as a result of incomplete or unusable imaging data. MR images were obtained for the bilateral knees at two time points 1 year apart for both the injured (after injury but before reconstruction and 1 year after reconstruction) and contralateral uninjured knees. Kinematic MRI was performed with the knee loaded with 25% of total body weight, and static images were obtained in full extension and in 30° of flexion. The side-to-side difference (SSD) between tibial position in the extended and flexed positions was determined for each patient. Twenty shape features, referred to as modes, for the tibia and femur each were extracted independently from presurgery scans with the principal component analysis-based statistical shape modeling algorithm. Spearman rank correlations were used to evaluate the relationship between the SSD in tibial position and bone shape features with significance defined as p < 0.05. Each of the shape features (referred to as the bone and mode number such as Femur 18 for the 18th unique femoral bone shape) associated with differences in tibial position was then investigated by modeling the mean shape ± 3 SDs.ResultsTwo of the 20 specific femur bone shape features (Femur 10, Femur 18) and two of the 20 specific tibial bone shape features (Tibia 19, Tibia 20) were associated with an increasingly anterior SSD in the tibial position for the patients with ACL injury before surgical treatment. The shape features described by these modes include the superoinferior height of the medial femoral condyle (Femur 18; ρ = 0.33, p = 0.040); the length of the anterior aspect of the lateral tibial plateau (Tibia 20; ρ = -0.35, p = 0.034); the sphericity of the medial femoral condyle (Femur 10; ρ = -0.52, p < 0.001); and tibial slope (Tibia 19; ρ = 0.34; p = 0.036). One year after surgical treatment, there were two of 20 femoral shape features that were associated with SSD in the tibial position in extension (Femur 10, Femur 18), one of 20 femoral shape features associated with SSD in the tibial position in flexion (Femur 10), and three of 20 tibial shape features associated with SSD in the tibial position in flexion (Tibia 2, Tibia 4, Tibia 19). The shape features described by these modes include the sphericity of the medial femoral condyle (Femur 10; ρ = -0.38, p = 0.020); the superoinferior height of the medial femoral condyle (Femur 18; ρ = 0.34, p = 0.035); the height of the medial tibial plateau (Tibia 2; ρ = -0.32, p = 0.048); the AP length of the lateral tibial plateau (Tibia 4; ρ = -0.37, p = 0.021); and tibial slope (Tibia 19; ρ = 0.34, p = 0.038).ConclusionsWe have observed multiple bone shape features in the tibia and the femur that may be associated with abnormal knee kinematics after ACL injury and ACL reconstruction. Future directions of research will include the influence of bony morphology on clinical symptoms of instability in patients with and without ACL reconstruction and the long-term evaluation of these shape factors to better determine specific contributions to posttraumatic arthritis and graft failure.Level of evidenceLevel II, therapeutic study.

Background: Osteoarthritis of the medial tibiofemoral joint (MTFJ) is prevalent among patients undergoing anterior cruciate ligament reconstruction (ACLR). Magnetic resonance T1ρ and T2 relaxation times provide noninvasive methods to quantify early cartilage degeneration. Altered sagittal-plane gait biomechanics have been observed after ACLR, but their associations with longitudinal changes in MTFJ cartilage T1ρ and T2 remain unclear. Hypothesis/Purpose: To examine whether the peak knee flexion moment (KFM), knee flexion angle (KFA), and vertical ground-reaction force (vGRF) during gait are associated with prospective changes in medial tibiofemoral cartilage T1ρ and T2 in ACL-reconstructed knees and to compare these gait characteristics between patients undergoing ACLR and healthy control participants. We hypothesized that a higher KFM, KFA, and vGRF would be associated with greater increases in cartilage relaxation times and that patients undergoing ACLR would demonstrate altered gait characteristics compared with healthy controls. Study Design: Controlled laboratory study. Methods: Thirty-three patients undergoing ACLR underwent gait analysis before and 6 months and 1 year after ACLR and knee magnetic resonance imaging (MRI) before and 6 months, 1 year, and 2 years after ACLR. Twelve healthy controls underwent knee MRI and gait analysis at baseline and 1 year. Cartilage T1ρ and T2 were calculated for the medial tibia and medial femoral condyle. Linear regressions were used to evaluate associations between gait characteristics and changes in cartilage relaxation times from before ACLR to follow-up time points. Independent t tests were used to compare differences in gait between patients undergoing ACLR and control participants. Results: A higher KFM and KFA before ACLR were related to greater increases in medial femoral condyle T1ρ and T2 at 6 months after ACLR. Similarly, a higher KFM, KFA, and vGRF at 6 months were associated with greater increases in medial tibia and medial femoral condyle T1ρ and T2 at 1 and 2 years after ACLR. Gait characteristics at 1 year were not associated with changes in cartilage relaxation times at 2 years after ACLR. Compared with healthy controls, patients undergoing ACLR demonstrated a lower KFM at 6 months after ACLR. Conclusion/Clinical Relevance: The findings of this study revealed that a higher KFM, KFA, and vGRF during gait, especially at 6 months after ACLR, were associated with greater deterioration of MTFJ cartilage health at later time points.