FRA1:c-JUN:HDAC1 complex down-regulates filaggrin expression upon TNFα and IFNγ stimulation in keratinocytes.

Filaggrin (FLG), an essential structural protein for skin barrier function, is down-regulated under chronic inflammatory conditions, leading to disruption of the skin barrier. However, the detailed molecular mechanisms of how FLG changes in the context of chronic inflammation are poorly understood. Here, we identified the molecular mechanisms by which inflammatory cytokines inhibit FLG expression in the skin. We found that the AP1 response element within the -343/+25 of the FLG promoter was necessary for TNFα + IFNγ-induced down-regulation of FLG promoter activity. Using DNA affinity precipitation assay, we observed that AP1 subunit composition binding to the FLG promoter was altered from c-FOS:c-JUN (at the early time) to FRA1:c-JUN (at the late time) in response to TNFα + IFNγ stimulation. Knockdown of FRA1 or c-JUN abrogated TNFα + IFNγ-induced FLG suppression. Histone deacetylase (HDAC) 1 interacted with FRA1:c-JUN under TNFα + IFNγ stimulation. Knockdown of HDAC1 abrogated the inhibitory effect of TNFα + IFNγ on FLG expression. The altered expression of FLG, FRA1, c-JUN, and HDAC1 was confirmed in mouse models of 2,4-dinitrochlorobenzene-induced atopic dermatitis and imiquimod-induced psoriasis. Thus, the current study demonstrates that TNFα + IFNγ stimulation suppresses FLG expression by promoting the FRA1:c-JUN:HDAC1 complex. This study provides insight into future therapeutic strategies targeting the FRA1:c-JUN:HDAC1 complex to restore impaired FLG expression in chronic skin inflammation.

Clinical Applications, Challenges, and Recommendations for Artificial Intelligence in Musculoskeletal and Soft-Tissue Ultrasound: AJR Expert Panel Narrative Review.

Artificial intelligence (AI) is increasingly used in clinical practice for musculoskeletal imaging tasks, such as disease diagnosis and image reconstruction. AI applications in musculoskeletal imaging have focused primarily on radiography, CT, and MRI. Although musculoskeletal ultrasound stands to benefit from AI in similar ways, such applications have been relatively underdeveloped. In comparison with other modalities, ultrasound has unique advantages and disadvantages that must be considered in AI algorithm development and clinical translation. Challenges in developing AI for musculoskeletal ultrasound involve both clinical aspects of image acquisition and practical limitations in image processing and annotation. Solutions from other radiology subspecialties (e.g., crowdsourced annotations coordinated by professional societies), along with use cases (most commonly rotator cuff tendon tears and palpable soft-tissue masses), can be applied to musculoskeletal ultrasound to help develop AI. To facilitate creation of high-quality imaging datasets for AI model development, technologists and radiologists should focus on increasing uniformity in musculoskeletal ultrasound performance and increasing annotations of images for specific anatomic regions. This Expert Panel Narrative Review summarizes available evidence regarding AI's potential utility in musculoskeletal ultrasound and challenges facing its development. Recommendations for future AI advancement and clinical translation in musculoskeletal ultrasound are discussed.

Effect of Corticosteroid Use on the Occurrence and Progression of Osteonecrosis of the Femoral Head: A nationwide Nested Case-Control Study.

BACKGROUND: Although it is very well known that corticosteroids cause osteonecrosis of the femoral head (ONFH), it is unclear as to which patients develop ONFH. Additionally, there are no studies on the association between corticosteroid use and femoral head collapse in ONFH patients. We aimed to investigate the association between corticosteroid use and the risk of ONFH among the general population and what factors affect ONFH occurrence. Additionally, we aimed to demonstrate which factors affect femoral head collapse and total hip arthroplasty (THA) after ONFH occurrence. METHODS: A nationwide, nested case-control study was conducted with data from the National Health Insurance Service Physical Health Examination Cohort (2002 to 2019) in the Republic of Korea. We defined ONFH (N = 3,500) using diagnosis and treatment codes. Patients who had ONFH were matched 1:5 to form a control group based on the variables of birth year, sex, and follow-up duration. Additionally, in patients who have ONFH, we looked for risk factors for progression to THA. RESULTS: Compared with the control group, ONFH patients had a low household income and had more diabetes, hypertension, dyslipidemia, and heavy alcohol use (drinking more than 3 to 7 drinks per week). Systemic corticosteroid use (≥ 1,800 mg) was significantly associated with an increased risk of ONFH incidence. However, lipid profiles, corticosteroid prescription, and cumulative doses of corticosteroid did not affect the progression to THA. CONCLUSION: The ONFH risk increased rapidly when cumulative prednisolone use was ≥ 1,800 mg. However, oral or high-dose intravenous corticosteroid use and cumulative dose did not affect the prognosis of ONFH. Since the occurrence and prognosis of ONFH are complex and multifactorial processes, further study is needed.

Preliminary study for prediction of benign vertebral compression fracture age by quantitative water fraction using modified Dixon sequences: an imaging biomarker of fracture age.

PURPOSE: This study aimed to evaluate whether quantitative water fraction parameters could predict fracture age in patients with benign vertebral compression fractures (VCFs). METHODS: A total of 38 thoracolumbar VCFs in 27 patients imaged using modified Dixon sequences for water fraction quantification on 3-T MRI were retrospectively reviewed. To calculate quantitative parameters, a radiologist independently measured the regions of interest in the bone marrow edema (BME) of the fractures. Furthermore, five features (BME, trabecular fracture line, condensation band, cortical or end plate fracture line, and paravertebral soft-tissue change) were analyzed. The fracture age was evaluated based on clear-onset symptoms and previously available images. A correlation analysis between the fracture age and water fraction was evaluated using a linear regression model, and a multivariable analysis of the dichotomized fracture age model was performed. RESULTS: The water fraction ratio was the only significant factor and was negatively correlated with the fracture age of VCFs in multiple linear regression (p = 0.047), whereas the water fraction was not significantly correlated (p = 0.052). Water fraction and water fraction ratio were significant factors in differentiating the fracture age of 1 year in multiple logistic regression (odds ratio 0.894, p = 0.003 and odds ratio 0.986, p = 0.019, respectively). Using a cutoff of 0.524 for the water fraction, the area under the curve, sensitivity, and specificity were 0.857, 85.7%, and 87.1%, respectively. CONCLUSIONS: Water fraction is a good imaging biomarker for the fracture healing process. The water fraction ratio of the compression fractures can be used to predict the fracture age of benign VCFs.

EGR1 Regulation of Vasculogenic Mimicry in the MDA-MB-231 Triple-Negative Breast Cancer Cell Line through the Upregulation of KLF4 Expression.

Vasculogenic mimicry (VM) is an intriguing phenomenon observed in tumor masses, in which cancer cells organize themselves into capillary-like channels that closely resemble the structure and function of blood vessels. Although VM is believed to contribute to alternative tumor vascularization, the detailed regulatory mechanisms controlling these cellular processes remain poorly understood. Our study aimed to investigate the role of Early Growth Response 1 (EGR1) in regulating VM in aggressive cancer cells, specifically MDA-MB-231 triple-negative breast cancer cells. Our study revealed that EGR1 promotes the formation of capillary-like tubes by MDA-MB-231 cells in a 3-dimensional Matrigel matrix. EGR1 was observed to upregulate Kruppel-like factor 4 (KLF4) expression, which regulates the formation of the capillary-like tube structure. Additionally, our findings highlight the involvement of the ERK1/2 and p38 mitogen-activated protein kinase pathways in mediating the expression of EGR1 and KLF4, underscoring their crucial role in VM in MDA-MB-231 cells. Understanding these regulatory mechanisms will provide valuable insights into potential therapeutic targets for preventing VM during the treatment of triple-negative breast cancer.

Detection of Pacemaker and Identification of MRI-conditional Pacemaker Based on Deep-learning Convolutional Neural Networks to Improve Patient Safety.

With the increased availability of magnetic resonance imaging (MRI) and a progressive rise in the frequency of cardiac device implantation, there is an increased chance that patients with implanted cardiac devices require MRI examination during their lifetime. Though MRI is generally contraindicated in patients who have undergone pacemaker implantation with electronic circuits, the recent introduction of MR Conditional pacemaker allows physicians to take advantage of MRI to assess these patients during diagnosis and treatment. When MRI examinations of patients with pacemaker are requested, physicians must confirm whether the device is a conventional pacemaker or an MR Conditional pacemaker by reviewing chest radiographs or the electronic medical records (EMRs). The purpose of this study was to evaluate the utility of a deep convolutional neural network (DCNN) trained to detect pacemakers on chest radiographs and to determine the device's subclassification. The DCNN perfectly detected pacemakers on chest radiographs and the accuracy of the subclassification of pacemakers using the internal and external test datasets were 100.0% (n = 106/106) and 90.1% (n = 279/308). The DCNN can be applied to the radiologic workflow for double-checking purposes, thereby improving patient safety during MRI and preventing busy physicians from making errors.

AI musculoskeletal clinical applications: how can AI increase my day-to-day efficiency?

Artificial intelligence (AI) is expected to bring greater efficiency in radiology by performing tasks that would otherwise require human intelligence, also at a much faster rate than human performance. In recent years, milestone deep learning models with unprecedented low error rates and high computational efficiency have shown remarkable performance for lesion detection, classification, and segmentation tasks. However, the growing field of AI has significant implications for radiology that are not limited to visual tasks. These are essential applications for optimizing imaging workflows and improving noninterpretive tasks. This article offers an overview of the recent literature on AI, focusing on the musculoskeletal imaging chain, including initial patient scheduling, optimized protocoling, magnetic resonance imaging reconstruction, image enhancement, medical image-to-image translation, and AI-aided image interpretation. The substantial developments of advanced algorithms, the emergence of massive quantities of medical data, and the interest of researchers and clinicians reveal the potential for the growing applications of AI to augment the day-to-day efficiency of musculoskeletal radiologists.

Fabrication and evaluation of bilateral Helmholtz radiofrequency coil for thermo-stable breast image with reduced artifacts.

PURPOSE: The positron emission tomography (PET)-magnetic resonance (MR) system is a newly emerging technique that yields hybrid images with high-resolution anatomical and metabolic information. With PET-MR imaging, a definitive diagnosis of breast abnormalities will be possible with high spatial accuracy and images will be acquired for the optimal fusion of anatomic locations. Therefore, we propose a PET-compatible two-channel breast MR coil with minimal disturbance to image acquisition which can be used for simultaneous PET-MR imaging in patients with breast cancer. MATERIALS AND METHODS: For coil design and construction, the conductor loops of the Helmholtz coil were tuned, matched, and subdivided with nonmagnetic components. Element values were optimized with an electromagnetic field simulation. Images were acquired on a GE 600 PET-computed tomography (CT) and GE 3.0 T MR system. For this study, we used the T1-weighted image (volunteer; repetition time (TR), 694 ms; echo time (TE), 9.6 ms) and T2-weighted image (phantom; TR, 8742 ms; TE, 104 ms) with the fast spin-echo sequence. RESULTS: The results of measuring image factors with the proposed radiofrequency (RF) coil and standard conventional RF coil were as follows: signal-to-noise ratio (breast; 207.7 vs. 175.2), percent image uniformity (phantom; 89.22%-91.27% vs. 94.63%-94.77%), and Hounsfield units (phantom; -4.51 vs. 2.38). CONCLUSIONS: Our study focused on the feasibility of proposed two-channel Helmholtz loops (by minimizing metallic components and soldering) for PET-MR imaging and found the comparable image quality to the standard conventional coil. We believe our work will help significantly to improve image quality with the development of a less metallic breast MR coil.

Saikosaponin A and Saikosaponin C Reduce TNF-α-Induced TSLP Expression through Inhibition of MAPK-Mediated EGR1 Expression in HaCaT Keratinocytes.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide, characterized by intense pruritus and eczematous lesions. Aberrant expression of thymic stromal lymphopoietin (TSLP) in keratinocytes is associated with the pathogenesis of AD and is considered a therapeutic target for the treatment of this disease. Saikosaponin A (SSA) and saikosaponin C (SSC), identified from Radix Bupleuri, exert anti-inflammatory effects. However, the topical effects of SSA and SSC on chronic inflammatory skin diseases are unclear. In this study, we investigated the effects of SSA and SSC on TSLP suppression in an AD-like inflammatory environment. We observed that SSA and SSC suppressed tumor necrosis factor-α-induced TSLP expression by downregulating the expression of the transcription factor early growth response 1 (EGR1) via inhibition of the extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, and p38 mitogen-activated protein kinase pathways. We also confirmed that topical application of SSA or SSC reduced AD-like skin lesions in BALB/c mice challenged with 2,4-dinitrochlorobenzene. Our findings suggest that suppression of EGR1-regulated TSLP expression in keratinocytes might be attributable to the anti-inflammatory effects of SSA and SSC in AD-like skin lesions.

ß-Caryophyllene Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis through the Downregulation of Mitogen-Activated Protein Kinase/EGR1/TSLP Signaling Axis.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases accompanied by severe itching. ß-caryophyllene (BCP), which displays anti-inflammatory activity, is a natural agonist of cannabinoid receptor 2. However, the therapeutic effects of BCP on atopic dermatitis (AD) remain poorly understood. The current study aimed to evaluate the topical therapeutic efficacy of BCP in an AD-like mouse model. Thymic Stromal Lymphopoietin (TSLP) is a keratinocyte-derived cytokine that drives AD pathogenesis. This study also investigated the effect of BCP on the interleukin 4 (IL-4)-induced expression of TSLP in HaCaT keratinocytes. We found that the topical application of BCP alleviated AD-like skin inflammation and inhibited the infiltration of proinflammatory cells into skin lesions. Moreover, the topical application of BCP reduced EGR1 (Early Growth Response 1) and TSLP expression in AD-like skin lesions. We also found that BCP inhibited IL-4-induced TSLP expression by downregulating mitogen-activated protein kinase (MAPK)-mediated EGR1 expression in HaCaT keratinocytes. These findings demonstrate that BCP ameliorates DNCB-induced AD-like skin lesions through the downregulation of the MAPK/EGR1/TSLP signaling axis. BCP may be applicable for developing topical therapeutic agents for chronic skin inflammatory diseases, such as AD.

The Natural Janus Kinase Inhibitor Agerarin Downregulates Interleukin-4-Induced PER2 Expression in HaCaT Keratinocytes.

The circadian clock system is closely associated with inflammatory responses. Dysregulation of the circadian clock genes in the skin impairs the skin barrier function and affects the pathophysiology of atopic dermatitis. Interleukin 4 (IL-4) is a proinflammatory cytokine derived from T-helper type 2 cells; it plays a critical role in the pathogenesis of atopic dermatitis. Agerarin (6,7-dimethoxy-2,2-dimethyl-2H-chromene) is a natural JAK1/2/3 inhibitor isolated from Ageratum houstonianum that has a protective effect on the epidermal skin barrier. However, it remains unclear whether agerarin affects the circadian clock system. The aim of this study is to investigate the effect of agerarin on IL-4-induced PER2 gene expression in human keratinocytes through reverse transcription (RT)-PCR, quantitative real-time PCR (qPCR), immunoblotting, immunofluorescence microscopic analysis, and real-time bioluminescence analysis. We found that agerarin reduced IL-4-induced PER2 mRNA expression by suppressing the JAK-STAT3 pathway. In addition, real-time bioluminescence analysis in PER2:luc2p promoter-reporter cells revealed that agerarin restored the oscillatory rhythmicity of PER2 promoter activity altered by IL-4. These findings suggest that agerarin may be useful as a cosmeceutical agent against inflammatory skin conditions associated with disrupted circadian rhythms, such as atopic dermatitis.

PD-L1 tumour expression is predictive of pazopanib response in soft tissue sarcoma.

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. METHODS: Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. RESULTS: Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8-5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1-9% (n = 3, 4.5%), 10-49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45-5.56, P = 0.006). CONCLUSION: We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.

Inhibition of EGR-1-dependent MMP1 transcription by ethanol extract of Ageratum houstonianum in HaCaT keratinocytes.

Matrix metalloproteinase 1 (MMP-1) initiates the breakdown of matrix networks by cleaving fibrillar collagen during the pathophysiological progression of skin aging. Ageratum houstonianum ethanol extract (AHE) has been used as a traditional herbal medicine to treat external wounds and skin diseases. However, the mechanism of action underlying A. houstonianum-mediated modulation of skin aging has not been investigated. In this study, we evaluated the effect of AHE on MMP-1 expression in HaCaT keratinocytes. Gene expression was analyzed by Reverse transcription-PCR (RT-PCR), Quantitative real-time PCR (Q-PCR), gene promoter-reporter assay, and immunoblotting. We found that AHE abrogated TNFα-induced MMP1 expression at the transcriptional level via the suppression of ERK1/2 mitogen-activated protein kinase (MAPK)-mediated Early Growth Response 1 (EGR1) expression. We also demonstrated that ß-caryophyllene, a cannabinoid receptor 2 (CB2) agonist, is a functional component of the AHE that inhibits TNFα-induced EGR-1 and MMP1 expression. AHE exerts inhibitory activity on TNFα-induced MMP1 expression at the transcription level through EGR-1 downregulation in keratinocytes. ß-Caryophyllene is a bioactive ingredient of AHE that is responsible for the inhibition of TNFα-induced EGR1 expression. ß-Caryophyllene can be used as a potential agent to prevent inflammation-induced skin aging.

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood. In this study, we investigated the mode of action of chrysin in TSLP suppression in an AD-like inflammatory environment. We observed that the transcription factor early growth response (EGR1) contributed to the tumor necrosis factor alpha (TNFα)-induced transcription of TSLP. Chrysin attenuated TNFα-induced TSLP expression by downregulating EGR1 expression in HaCaT keratinocytes. We also showed that the oral administration of chrysin improved AD-like skin lesions in the ear and neck of BALB/c mice challenged with 2,4-dinitrochlorobenzene. We also showed that chrysin suppressed the expression of EGR1 and TSLP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 mitogen-activated protein kinase pathways. Collectively, the findings of this study suggest that chrysin improves AD-like skin lesions, at least in part, through the downregulation of the ERK1/2 or JNK1/2-EGR1-TSLP signaling axis in keratinocytes.

Deep-learned short tau inversion recovery imaging using multi-contrast MR images.

PURPOSE: To generate short tau, or short inversion time (TI), inversion recovery (STIR) images from three multi-contrast MR images, without additional scanning, using a deep neural network. METHODS: For simulation studies, we used multi-contrast simulation images. For in-vivo studies, we acquired knee MR images including 288 slices of T1 -weighted (T1 -w), T2 -weighted (T2 -w), gradient-recalled echo (GRE), and STIR images taken from 12 healthy volunteers. Our MR image synthesis method generates a new contrast MR image from multi-contrast MR images. We used a deep neural network to identify the complex relationships between MR images that show various contrasts for the same tissues. Our contrast-conversion deep neural network (CC-DNN) is an end-to-end architecture that trains the model to create one image from three (T1 -w, T2 -w, and GRE images). We propose a new loss function to take into account intensity differences, misregistration, and local intensity variations. The CC-DNN-generated STIR images were evaluated with four quantitative evaluation metrics, including mean squared error, peak signal-to-noise ratio (PSNR), structural similarity (SSIM), and multi-scale SSIM (MS-SSIM). Furthermore, a subjective evaluation was performed by musculoskeletal radiologists. RESULTS: Our method showed improved results in all quantitative evaluations compared with other methods and received the highest scores in subjective evaluations by musculoskeletal radiologists. CONCLUSION: This study suggests the feasibility of our method for generating STIR sequence images without additional scanning that offered a potential alternative to the STIR pulse sequence when additional scanning is limited or STIR artifacts are severe.

Comprehensive Immuno-Molecular Profiles for Liposarcoma: Roles of Programmed Death Ligand 1, Microsatellite Instability, and PIK3CA.

BACKGROUND: Developing personalized strategies for cancer has shown good efficacies. METHODS: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. RESULTS: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL- tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). CONCLUSIONS: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.

Regulation of pro-opiomelanocortin (POMC) gene transcription by interleukin-31 via early growth response 1 (EGR-1) in HaCaT keratinocytes.

Pro-opiomelanocortin (POMC) is a large precursor protein of and ß-endorphin. POMC expressed in keratinocytes regulates various pathophysiological responses, such as pruritus in atopic dermatitis. Interleukin (IL)-31 is a T helper 2 (Th2)-derived cytokine that functions as a pruritogen, stimulating the sensory neurons in the skin. However, the regulatory mechanism underlying IL-31-induced POMC expression in keratinocytes remains largely unknown. Herein, using a 5'-serial deletion and site-specific mutation constructs of the regulatory region of POMC, we demonstrated that a putative EGR1-binding sequence (EBS) motif in POMC is required for its upregulation by IL-31 in HaCaT keratinocytes. Notably, EGR-1 directly interacted with the EBS motif in POMC. The ectopic expression of EGR-1 stimulated the POMC promoter activity, whereas the knockdown of EGR-1 expression by RNA interference reduced IL-31-induced POMC expression. Furthermore, we observed that three major mitogen-activated protein kinases, ERK, JNK, and p38 kinase, mediated IL-31-induced EGR-1 expression. In summary, our results suggest that EGR-1 trans-activates POMC in response to IL-31 stimulation in HaCaT keratinocytes.

Adequate protection rather than knee flexion prevents popliteal vascular injury during high tibial osteotomy: analysis of three-dimensional knee models in relation to knee flexion and osteotomy techniques.

PURPOSE: (1) To analyse popliteal artery (PA) movement in a three-dimensional (3D) coordinate system in relation to knee flexion and high tibial osteotomy (HTO) techniques (lateral closed wedge HTO [LCHTO], uniplane medial open wedge HTO [UP-MOHTO], biplane medial open wedge HTO [BP-MOHTO]) and (2) to identify safe zones of the PA in each osteotomy plane. METHODS: Sixteen knees of patients who underwent magnetic resonance imaging with extension and 90° flexion were used to develop subject-specific 3D knee flexion models. Displacement of the PA during knee flexion was measured along the X- and Y-axis, as was the distance between the posterior tibial cortex and PA parallel to the Y-axis (d-PCA). Frontal plane safety index (FPSI) and maximal axial safe angles (MASA) of osteotomy, which represented safe zones for the osteotomy from the PA injury, were analysed. All measurements were performed along virtual osteotomy planes. Differences among the three osteotomy methods were analysed for each flexion angle using a linear mixed model. RESULTS: The average increments in d-PCA during knee flexion were 1.3 ± 2.3 mm in LCHTO (n.s.), 1.4 ± 1.2 mm in UP-MOHTO (P < 0.0001), and 1.7 ± 2.0 mm in BP-MOHTO (P = 0.015). The mean FPSIs in knee extension were 37.6 ± 5.9%, 46.4 ± 5.8%, and 45.1 ± 8.1% for LCHTO, UP-MOHTO, and BP-MOHTO, respectively. The mean MASA values in knee extension were 45.8° ± 4.4°, 37.3° ± 6.1°, and 38.9° ± 6.5° for LCHTO, UP-MOHTO, and BP-MOHTO, respectively. CONCLUSION: Although the PA moved posteriorly during knee flexion, the small (1.7 mm) increment thereof and inconsistent movements in subjects would not be of clinical relevance to PA safety during HTO. LEVEL OF EVIDENCE: Diagnostic study, Level II.

Arthroscopic gel-type autologous chondrocyte implantation presents histologic evidence of regenerating hyaline-like cartilage in the knee with articular cartilage defect.

PURPOSE: To investigate the clinical, radiological, and histological results of arthroscopic gel-type autologous chondrocyte implantation (GACI) in treating chondral defects of the knee. METHODS: This study prospectively examined five males and five females with a mean age of 40.3 ± 10.3 years who underwent arthroscopic GACI between March 2012 and February 2013. The gel comprised a mixture of 1 ml of fibrinogen plus 0.1-0.2 ml of thrombin. The mean size of chondral defect was 2.9 ± 1.2 cm2 (range 1.2-5.4 cm2). International knee documentation committee (IKDC) subjective score, knee injury and osteoarthritis outcome score (KOOS), knee society score, and visual analog scale (VAS) for pain were assessed preoperatively and during regular follow-up examinations performed for up to 5 years postoperatively. Serial magnetic resonance imaging was performed for up to 2 years after the surgery to observe healing, using the modified magnetic resonance observation of cartilage repair tissue (MOCART) score. In eight patients, second-look arthroscopy was performed at 1 year after the implantation to assess the status of treated cartilage, and a portion of regenerated cartilage was harvested for histologic evaluation. RESULTS: The mean VAS score (p = 0.045), IKDC subjective score (p = 0.041), KOOS pain (p = 0.025), KOOS activities of daily living (p = 0.048), and KOOS quality of life (p = 0.029) showed significant improvement at 5 years after the surgery. The modified MOCART evaluation showed that the scores were 59.5 ± 29.4 and 85.0 ± 8.0 at 12 weeks and 2 years after the operation, respectively. Histologic examination demonstrated a mean regenerated cartilage thickness of 3.5 ± 0.8 mm and a mean Oswestry score of 8.2 ± 1.8. Immunohistochemistry analysis showed that the expression of collagen type II was more evident and more evenly distributed than collagen type I in regenerated cartilage. There was a significant correlation between Oswestry score and change in VAS scale from postoperative 2-5 years. CONCLUSIONS: Arthroscopic GACI produces satisfactory clinical and radiologic outcomes, and histologic evaluation confirms sufficient regeneration of hyaline-like cartilage that correlates with improved symptoms. Therefore, it is an acceptable, minimally invasive, and technically simple option for the restoration of cartilage defects of the knee. LEVEL OF EVIDENCE: IV.

Chrysin Inhibits NF-κB-Dependent CCL5 Transcription by Targeting IκB Kinase in the Atopic Dermatitis-Like Inflammatory Microenvironment.

Chrysin (5,7-dihydroxyflavone) is a natural polyphenolic compound that induces an anti-inflammatory response. In this study, we investigated the molecular mechanism underlying the chrysin-induced suppression of C-C motif chemokine ligand 5 (CCL5) gene expression in atopic dermatitis (AD)-like inflammatory microenvironment. We showed that chrysin inhibited CCL5 expression at the transcriptional level through the suppression of nuclear factor kappa B (NF-κB) in the inflammatory environment. Chrysin could bind to the ATP-binding pocket of the inhibitor of κB (IκB) kinase (IKK) and, subsequently, prevent IκB degradation and NF-κB activation. The clinical efficacy of chrysin in targeting IKK was evaluated in 2,4-dinitrochlorobenzene-induced skin lesions in BALB/c mice. Our results suggested that chrysin prevented CCL5 expression by targeting IKK to reduce the infiltration of mast cells to the inflammatory sites and at least partially attenuate the inflammatory responses. These findings suggested that chrysin might be useful as a platform for the design and synthesis of small-molecule IKK-targeting drugs for the treatment of chronic inflammatory diseases, such as AD.