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Introduction Aim Material and method Results Conclusion Haemophilic arthropathy (HA) is the most frequent complication in people with haemophilia (PWH). MRI is the gold standard to assess HA, however, there are limitations to its use in low‐resourced areas.Primary; to compare clinical‐functional, laboratory, and ultrasonographic joint scores with MRI scores to determine a reasonable alternative to MRI. Secondary; to identify the effect of various replacement therapies on the degree of joint involvement.Fifty PWH with at least one affected joint, with or without inhibitors, and receiving either on‐demand treatment or secondary prophylaxis, were included. All participants had a joint assessment by clinical HJHS 2.1, functional FISH, HEAD‐US, and MRI DENVER scores. Also, serum COMP level was assessed by ELISA for the PWH and 50 healthy subjects as control.The HJHS 2.1 scores had a significant positive correlation with HEAD‐US and the MRI DENVER scores. The FISH score had a significant negative correlation with HJHS 2.1, HEAD‐US, and MRI DENVER Scores. The serum COMP level was comparable between the PWH and the controls. The HEAD‐US score had a significant positive correlation with the MRI score. All of the joints’ scores for the PWH on Emicizumab prophylaxis showed significantly lower HJHS 2.1 and MRI DENVER scores but higher FISH score than the joint scores of the patients receiving other types of prophylaxis.The clinical‐functional joints assessment scores (HJHS 2.1, FISH) were objective tools that correlated significantly with the HEAD‐US and the Denver MRI scores. Emicizumab prophylaxis led to better joint status. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between endoplasmic reticulum stress-related protein (CHOP), cartilage oligomeric matrix protein (COMP), tendone protein-C (TN-C) and the severity of coronary artery disease and major adverse cardiovascu- lar events (MACE) after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). Methods: 175 ACS patients admitted to our hospital from September 2020 to September 2022 were selected as observation group, and 50 healthy subjects who underwent physical examination in our hospital during the same period were selected as control group. The levels of CHOP, COMP and TN-C were detected and compared between two groups, and ACS patients were divided into mild, moderate and severe groups according to the severity of the disease, and the levels of various indicators were compared. All patients were treated with PCI, and fol- lowed up for 1 year after operation, the incidence of MACE was counted, and the levels of serum CHOP, COMP and TN-C in MACE group and non-MACE group were compared. The relationship between MACE and serum CHOP, COMP and TN-C in ACS patients after PCI were analyzed by univariate and multivariate Logistic regression models. Results: The levels of serum CHOP, COMP and TN-C in observation group were higher than those in control group (P<0.05). The levels of serum CHOP, COMP and TN-C in severe group were higher than those in moderate group and higher than those in mild group (P<0.05). 1 year after operation, the incidence of MACE was 23.43% (41/175), the levels of serum CHOP, COMP and TN-C in MACE group were higher than those in non-MACE group (P<0.05). By univariate analysis, the proportion of patients with New York Heart Association (NYHA) cardiac function grade III-IV, history of hypertension, history of diabetes and hyperlipidemia in MACE group was higher than that in non-MACE group (P<0.05). Logistic multivariate analysis showed that, high levels of CHOP, COMP, TN-C, NYHA cardiac function grade III-IV, history of hypertension, history of diabetes and hyperlipidemia were independent risk factors for MACE after PCI in ACS patients. Conclusion: Serum CHOP, COMP and TN-C show increase expression in ACS patients, and further increase with the aggravation of the patient's condition, and together with NYHA cardiac function classification and basic diseases, constitute independent risk factors for MACE after PCI in ACS patients. [ABSTRACT FROM AUTHOR]

Aims: This study aimed at investigating the efficacy of metformin as adjuvant therapy for obese knee osteoarthritis (OA) patients, considering its anti-inflammatory and cartilage-protective effects. Patients and methods: In this randomized, double-blind, placebo-controlled study, 50 obese knee OA patients were assigned randomly to two groups, the metformin group (n = 25) which was treated with metformin 500 mg orally BID plus celecoxib 200 mg orally once daily, and the placebo group (n = 25) which was treated with placebo tablets BID plus celecoxib 200 mg orally once daily for 12 weeks. Cartilage Oligomeric Matrix Protein (COMP), C-terminal cross-linked telopeptide of type I collagen (CTX-1), and Interleukin 1-beta (IL-1β) serum levels were measured, while Western Ontario and McMaster Universities Arthritis Index (WOMAC) score assessed knee pain, stiffness, and physical function at baseline and after 12 weeks. Results: Following a 12-week treatment, the metformin group exhibited significantly reduced levels of COMP, CTX-1, and IL-1β in the serum compared to the placebo group (p = 0.0081, p = 0.0106, and p = 0.0223, respectively). Furthermore, metformin group produced significant improvements in WOMAC total scale (p < 0.0001), specifically in knee pain, stiffness, and physical function compared to placebo group (p < 0.0001, p < 0.0001, and p < 0.0001, respectively). Conclusion: Metformin as an adjuvant therapy in obese knee OA patients may have beneficial effects on cartilage degradation and inflammation, as evidenced by the significant decreases in serum COMP, CTX-1, and IL-1β levels. Additionally, metformin may improve clinical outcomes, as shown by the significant improvements in WOMAC scores. Clinicaltrials.gov ID: NCT05638893/Registered December 6, 2022 — Retrospectively. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is increasing worldwide, and previous work found that OA increases systemic cartilage oligomeric matrix protein (COMP), which has also been implicated in prostate cancer (PCa). As such, we sought to investigate whether OA augments PCa progression. Cellular proliferation and migration of RM1 murine PCa cells treated with interleukin (IL)-1α, COMP, IL-1α + COMP, or conditioned media from cartilage explants treated with IL-1α (representing OA media) and with inhibitors of COMP were assessed. A validated murine model was used for tumor growth and marker expression analysis. Both proliferation and migration were greater in PCa cells treated with OA media compared to controls (p < 0.001), which was not seen with direct application of the stimulants. Migration and proliferation were not negatively affected when OA media was mixed with downstream and COMP inhibitors compared to controls (p > 0.05 for all). Mice with OA developed tumors 100% of the time, whereas mice without OA only 83.4% (p = 0.478). Tumor weight correlated with OA severity (Pearson correlation = 0.813, p = 0.002). Moreover, tumors from mice with OA demonstrated increased Ki-67 expression compared to controls (mean 24.56% vs. 6.91%, p = 0.004) but no difference in CD31, PSMA, or COMP expression (p > 0.05). OA appears to promote prostate cancer in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Multiple epiphyseal dysplasia (MED) is a heterogeneous group of inherited skeletal disorders characterized by abnormal development of the epiphyses. Patients with MED typically present with joint pain, stiffness, and a waddling gait, which often become symptomatic in child-hood or early adolescence. Radiographic features include irregular, flattened epiphyses and delayed ossification. The condition can lead to early onset of osteoarthritis. Mutations in six different genes can cause the disease; these may be inherited in an autosomal dominant or autosomal recessive manner, or occur as a “de novo” mutation. Molecular diagnostics are important for accurate prognosis and genetic counseling.

Abstract Background Cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, is vital in preserving cartilage integrity. Further, its overexpression is associated with the aggressiveness of several types of solid cancers. This study investigated COMP’s role in ovarian cancer, exploring clinicopathological links and mechanistic insights. Methods To study the association of COMP expression in cancer cells and stroma with clinicopathological features of ovarian tumor patients, we analyzed an epithelial ovarian tumor cohort by immunohistochemical analysis. Subsequently, to study the functional mechanisms played by COMP, an in vivo xenograft mouse model and several molecular biology techniques such as transwell migration and invasion assay, tumorsphere formation assay, proximity ligation assay, and RT-qPCR array were performed. Results Based on immunohistochemical analysis of epithelial ovarian tumor tissues, COMP expression in the stroma, but not in cancer cells, was linked to worse overall survival (OS) of ovarian cancer patients. A xenograft mouse model showed that carcinoma-associated fibroblasts (CAFs) expressing COMP stimulate the growth and metastasis of ovarian tumors through the secretion of COMP. The expression of COMP was upregulated in CAFs stimulated with TGF-β. Functionally, secreted COMP by CAFs enhanced the migratory capacity of ovarian cancer cells. Mechanistically, COMP activated the Notch3 receptor by enhancing the Notch3-Jagged1 interaction. The dependency of the COMP effect on Notch was confirmed when the migration and tumorsphere formation of COMP-treated ovarian cancer cells were inhibited upon incubation with Notch inhibitors. Moreover, COMP treatment induced epithelial-to-mesenchymal transition and upregulation of active β-catenin in ovarian cancer cells. Conclusion This study suggests that COMP secretion by CAFs drives ovarian cancer progression through the induction of the Notch pathway and epithelial-to-mesenchymal transition.

The diagnosis of osteoarthritis (OA) is based on radiological changes that are delayed, along with clinical symptoms. Early and very early diagnosis at the stage of molecular pathology may eventually offer an opportunity for early therapeutic intervention that may retard and prevent future damage. Cartilage oligomeric matrix protein (COMP) is a non-collagenous extracellular matrix protein that promotes the secretion and aggregation of collagen and contributes to the stability of the extracellular matrix. There are contradictory literature data and currently, the parameter is used only for scientific purposes and its significance is not well-determined. The serum level of COMP in patients with metabolic type OA of the knee has not been evaluated. The aim of the study was to analyze serum COMP levels in metabolic knee OA and controls with different BMI. Our results showed that the mean COMP values were significantly higher in the control group (1518.69 ± 232.76 ng/mL) compared to the knee OA patients (1294.58 ± 360.77 ng/mL) (p = 0.0012). This may be related to the smaller cartilage volume in OA patients. Additionally, COMP levels negatively correlated with disease duration (p = 0.04). The COMP level in knee OA with BMI below 30 kg/m2 (n = 61, 1304.50 ± 350.60 ng/mL) was higher compared to cases with BMI ≥ 30 kg/m2 (n = 76, 1286.63 ± 370.86 ng/mL), but the difference was not significant (p = 0.68). Whether this finding is related to specific features in the evolution of the metabolic type of knee OA remains to be determined. Interestingly, comparison of COMP levels in the controls with different BMI revealed significantly higher values in overweight and obese individuals (1618.36 ± 203.76 ng/mL in controls with BMI ≥ 25 kg/m2, n = 18, 1406.61 ± 216.41 ng/mL, n = 16; p = 0.0092). Whether this finding is associated with increased expression of COMP in the adipose tissue or with more intensive cartilage metabolism in relation to higher biomechanical overload in obese patients, considering the earlier development of metabolic type knee OA as an isolated finding, remains to be determined. [ABSTRACT FROM AUTHOR]

Background: Cartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment. Methods: COMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm. Results: The expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma. Conclusions: Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors. [ABSTRACT FROM AUTHOR]

Cervical cancer remains the leading cause of cancer-related mortality among female reproductive malignancies, and lymph node metastasis (LNM) represents the major reason for its poor prognosis. In this study, we aimed to identify transcriptome differences in patients with cervical squamous cell carcinoma (CSCC) who developed LNM or not and to outline the function of GLIS1 in determining metastatic fate in CSCC. In The Cancer Genome Atlas-endocervical adenocarcinoma project, patients with LNM had shorter overall survival than those without. Transcriptome data from CSCC patients with and without LNM were analyzed to screen for differentially expressed genes (DEGs). DEGs were enriched in metastasis-related pathways, such as extracellular matrix organization, cell-cell adhesion, and regulation of tissue remodeling. GLIS1 was overexpressed in tumor tissues of patients with LNM. COMP and ITGA11 were screened as downstream targets of GLIS1. GLIS1 promoted their transcription by binding to the promoter regions of COMP and ITGA11. GLIS1 enhanced the migration, invasion, and epithelial-mesenchymal transition in CSCC cells, while the knockdown of COMP or ITGA11 reversed the promotion of GLIS1 on CSCC cell malignant phenotype. Together, our results demonstrate that GLIS1 might be related to the LNM of CSCC patients via COMP and ITGA11. [ABSTRACT FROM AUTHOR]

Background: Cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, is vital in preserving cartilage integrity. Further, its overexpression is associated with the aggressiveness of several types of solid cancers. This study investigated COMP's role in ovarian cancer, exploring clinicopathological links and mechanistic insights. Methods: To study the association of COMP expression in cancer cells and stroma with clinicopathological features of ovarian tumor patients, we analyzed an epithelial ovarian tumor cohort by immunohistochemical analysis. Subsequently, to study the functional mechanisms played by COMP, an in vivo xenograft mouse model and several molecular biology techniques such as transwell migration and invasion assay, tumorsphere formation assay, proximity ligation assay, and RT-qPCR array were performed. Results: Based on immunohistochemical analysis of epithelial ovarian tumor tissues, COMP expression in the stroma, but not in cancer cells, was linked to worse overall survival (OS) of ovarian cancer patients. A xenograft mouse model showed that carcinoma-associated fibroblasts (CAFs) expressing COMP stimulate the growth and metastasis of ovarian tumors through the secretion of COMP. The expression of COMP was upregulated in CAFs stimulated with TGF-β. Functionally, secreted COMP by CAFs enhanced the migratory capacity of ovarian cancer cells. Mechanistically, COMP activated the Notch3 receptor by enhancing the Notch3-Jagged1 interaction. The dependency of the COMP effect on Notch was confirmed when the migration and tumorsphere formation of COMP-treated ovarian cancer cells were inhibited upon incubation with Notch inhibitors. Moreover, COMP treatment induced epithelial-to-mesenchymal transition and upregulation of active β-catenin in ovarian cancer cells. Conclusion: This study suggests that COMP secretion by CAFs drives ovarian cancer progression through the induction of the Notch pathway and epithelial-to-mesenchymal transition. [ABSTRACT FROM AUTHOR]

Introduction: Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft‐tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed. Aim: The aim of this project was to assess plasmatic biomolecules indicative of osteo‐cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. Methods: In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score. Results: Two biomarkers were identified, respectively SDF‐1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. Conclusion: Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors of the small intestine (SI‐NETs) often develop lymph node metastasis (LNM)‐induced mesenteric fibrosis (MF). MF can cause intestinal obstruction as well as ischemia and render surgical resection technically challenging. The underlying pathomechanisms of MF are still not well understood. We examined mesenteric LNM and the surrounding stroma compartment from 24 SI‐NET patients, including 11 with in situ presentation of strong MF (MF+) and 13 without MF (MF−). Differential gene expression was assessed with the HTG EdgeSeq Oncology Biomarker Panel comparing MF+ with MF− within LNM and paired stromal samples, respectively. Most interesting differentially expressed genes were validated by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) in combination with validation of associated protein levels utilizing immunohistochemistry (IHC) staining of MF+ and MF– formalin‐fixed, paraffin‐embedded (FFPE) patient samples. Overall, 14 genes measured with a 2549‐gene expression panel were differentially expressed in MF+ patients compared to MF−. Of those, nine were differentially expressed genes in LNM and five genes in the stromal tissue (>2‐fold change, p <.05). The top hits included increased COMP and COL11A1 expression in the stroma of MF+ patients compared to MF−, as well as decreased HMGA2, COL6A6, and SLC22A3 expression in LNM of MF+ patients compared to LNM of MF− patients. RT‐qPCR confirmed high levels of COMP and COL11A1 in stroma samples of MF+ compared to MF− patients. IHC staining confirmed the enrichment of α‐smooth muscle actin‐positive fibrosis in MF+ compared to MF− patients with corresponding increase of COMP‐expressing stromal cells in MF+. Since COMP is associated with the known driver for fibrosis development transforming growth factor beta and with a cancer‐associated fibroblasts enriched environment, it seems to be a promising new target for MF research. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH) is a rare, dominant genetic disorder affecting bone and cartilage development, characterized by short-limb short stature, brachydactyly, loose joints, joint stiffness, and pain. The disorder is caused by mutations in the COMP gene, which encodes a protein that plays a role in the formation of collagen fibers. In this study, we present the clinical and genetic characteristics of PSACH in two Chinese families. Whole-exome sequencing (WES) analysis revealed two novel missense variants in the COMP gene: NM_000095.3: c.1319G>T (p.G440V, maternal) and NM_000095.3: c.1304A>T (p.D435V, paternal-mosaic). Strikingly, both the G440V and D435V mutations were located in the same T3 repeat motif and exhibited the potential to form hydrogen bonds with each other. Upon further analysis using Missense3D and PyMOL, we ascertained that thesemutations showed the propensity to disrupt the protein structure of COMP, thus hampering its functioning. Our findings expand the existing knowledge of the genetic etiology underlying PSACH. The identification of new variants in theCOMP gene can broaden the range of mutations linked with the condition. This information can contribute to the diagnosis and genetic counseling of patients with PSACH. [ABSTRACT FROM AUTHOR]

Introduction. Juvenile idiopathic arthritis (JIA) is a common multifactorial disease characterized by the presence of chronic inflammation in the joints, entheses and other structures of the musculoskeletal system in combination with a certain range of extraskeletal disorders. Vast variety of JIA clinical variants and the variability of the disease course make primary and differential diagnosis difficult, which often leads to a delayed start of treatment and an inadequate choice of medical therapy or, conversely, an excess of medication. In the range of differential diagnostic conditions that have similar symptoms and are manifested by severe arthralgia, gait disturbance, joint stiffness, as well as the presence of effusion and gradual progression of bone destruction mainly in the epiphyseal plate, one should remember about hereditary skeletal dysplasias, primarily from a genetically heterogeneous group of multiple epiphyseal dysplasias (MED). The aim of the study – description of the clinical and genetic characteristics of three patients with various genetic variants of MED and defining approaches for their differential diagnosis with JIA. Materials and methods. There were three patients from three unrelated families aged from 7 to 13 years old under our supervision. To clarify the diagnosis, a genealogical analysis, a clinical examination of patients and first-degree relatives, as well as an assessment of X-ray images of long tubular bones were carried out. Molecular genetic confirmation of the MED diagnosis types 1 and 2 was based on the results of custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. To clarify the molecular genetic diagnosis of MED type 4, an analysis of the SLC26A2 gene was performed using automated Sanger sequencing. Results. Anamnestic, clinical, radiological, and molecular genetic characteristics of three unrelated patients with different genetic types of MED caused by variants in the COMP, SLC26A2, and COL9A2 genes were analyzed. The first symptoms of the disease in observed patients with three different genetic variants of MED occurred at the age of 2–3 years old and were characterized by gait disturbance and climbing stairs difficulties. Gradually, these symptoms were accompanied by pain in large joints. According to the ultrasound examination of the joints, signs of synovitis were noted, as a result they were diagnosed with JIA (polyarticular variant, seronegative for rheumatoid and antinuclear factor) and immunosuppressive therapy were prescribed without significant effect. The atypical course of the JIA was the reason for additional examination of patients by an orthopedist and geneticist. Careful analysis of the large joints radiographs made it possible to suspect one of the variants of MED in our patients based on the detection of distinctive signs, which were characterized by abnormal ossification (diminished size and flattening) of the epiphyses and abnormal shape and structure of the femoral head epiphysis. Molecular genetic analysis was performed to confirm the diagnosis. As a result, a pathogenic variant of the nucleotide sequence in the COMP gene was detected in one of the patients, two pathogenic variants in the SLC26A2 gene in another patient, and one pathogenic variant in the COL9A2 gene in the third patient, which made it possible to confirm the final diagnosis of MED type 1 with an autosomal dominant type of inheritance, MED type 4 with an autosomal recessive type of inheritance and MED type 2 with an autosomal dominant type of inheritance, respectively. Based on the results of our own research and analysis of the literature data, key directions for the differential diagnosis of MED and JIA were formulated. It is shown that the analysis of the X-ray images of patients is essential in differential diagnosis. Conclusion. Despite the significant overlap of the clinical symptoms between JIA and MED, the key to the early diagnosis of MED is a comprehensive examination, which included genealogical analysis, features of clinical manifestations and disease course in combination with distinctive radiological signs including delayed ossification of the epiphyses of tubular bones typical for MED. However, the question remains about the probability of a combined nature of osteoarticular disorders, i. e., the possible development of JIA in patients with hereditary skeletal dysplasias which requires in-depth study in the future.

Summary: Skeletal muscle is a highly plastic organ that adapts to different metabolic states or functional demands. This study explored the impact of permanent glucose restriction (GR) on skeletal muscle composition and metabolism. Using Glut4m mice with defective glucose transporter 4, we conducted multi-omics analyses at different ages and after low-intensity treadmill training. The oxidative fibers were significantly increased in Glut4m muscles. Mechanistically, GR activated AMPK pathway, promoting mitochondrial function and beneficial myokine expression, and facilitated slow fiber formation via CaMK2 pathway. Phosphorylation-activated Perm1 may synergize AMPK and CaMK2 signaling. Besides, MAPK and CDK kinases were also implicated in skeletal muscle protein phosphorylation during GR response. This study provides a comprehensive signaling network demonstrating how GR influences muscle fiber types and metabolic patterns. These insights offer valuable data for understanding oxidative fiber formation mechanisms and identifying clinical targets for metabolic diseases.

With the increase in user density, it is a challenging problem to achieve higher energy efficiency in vehicle-to-everything (V2X) networks, where frequent handovers occur as users continuously pass through dense cell boundaries. In this paper, we investigate this energy efficiency problem in a highly dense V2X network. To alleviate inter-cell interference and reduce unnecessary handovers, we propose a user-centric network architecture and utilize the coordinated multiple point (CoMP) transmission scheme to enable multiple roadside access points (APs) simultaneously to service one mobile vehicle. Moreover, non-orthogonal multiple access (NOMA) is adopted to enable multiple users to multiplex within one sub-channel and improve system spectrum reuse. Accordingly, the energy efficiency optimization problem is formulated as system achievable rate per joule, with the constraints of the AP transmit power budget, vehicle minimum rate requirements, and the maximum number of CoMP APs serving each vehicle. To solve the optimization problem, a semi-dynamic CoMP AP clustering algorithm is proposed to select a group of CoMP APs to serve a vehicle user by considering the vehicle–AP channel coefficients and the vehicle user's achievable energy efficiency. Then, with the selected CoMP AP clusters, a bidirectional selection algorithm is applied via NOMA to select multiple vehicle users multiplexing within one sub-channel and perform sub-channel power allocation. Numerical simulations are presented to verify the effectiveness of the proposed algorithms, and the results show the improvements offered by the proposed algorithms compared to current benchmarks. [ABSTRACT FROM AUTHOR]

Purpose: To determine associations between immediate and delayed response of serum cartilage oligomeric matrix protein (sCOMP) to loading (i.e., 3000 walking steps) and femoral cartilage interlimb T1ρ relaxation times in individual's post-anterior cruciate ligament reconstruction (ACLR). Methods: This cross-sectional study included 20 individuals 6–12 months following primary ACLR (65% female, 20.5 ± 4.0 years old, 24.9 ± 3.0 kg/m2, 7.3 ± 1.5 months post-ACLR). Serum samples were collected prior to, immediately following, and 3.5 h following walking 3000 steps on a treadmill at habitual walking speed. sCOMP concentrations were processed using enzyme-linked immunosorbent assays. Immediate and delayed absolute sCOMP responses to loading were evaluated immediately and 3.5 h post-walking, respectively. Participants underwent bilateral magnetic resonance imaging with T1ρ sequences to calculate resting femoral cartilage interlimb T1ρ relaxation time ratios between limbs (i.e., ACLR/Uninjured limb). Linear regression models were fitted to determine associations between sCOMP response to loading and femoral cartilage T1ρ outcomes controlling for pre-loading sCOMP concentrations. Results: Greater increases in delayed sCOMP response to loading were associated with greater lateral (∆R2 = 0.29, p = 0.02) but not medial (∆R2 < 0.01, p = 0.99) femoral cartilage interlimb T1ρ ratios. Associations between immediate sCOMP response to loading with femoral cartilage interlimb T1ρ ratios were weak and non-significant (∆R2 range = 0.02–0.09, p range = 0.21–0.58). Conclusion: Greater delayed sCOMP response to loading, a biomarker of cartilage breakdown, is associated with worse lateral femoral cartilage composition in the ACLR limb compared to the uninjured limb. Delayed sCOMP response to loading may be a more indicative metabolic indicator linked to deleterious changes in composition than immediate sCOMP response. [ABSTRACT FROM AUTHOR]

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol's therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented. [ABSTRACT FROM AUTHOR]

Cartilage oligomeric matrix protein (COMP) regulates transforming growth factor-β (TGF-β) signaling pathway, which has been proved to be associated with skin fibrosis and pulmonary fibrosis. Atrial fibrosis is a major factor of atrial fibrillation (AF). Nevertheless, the interaction between COMP and TGF-β as well as their role in AF remains undefined. The purpose of this study is to clarify the role of COMP in AF and explore its potential mechanism. The hub gene of AF was identified from two datasets using bioinformatics. Furthermore, it was verified by the downregulation of COMP in angiotensin-II (Ang-II)-induced AF in mice. Moreover, the effect on AF was examined using CCK8 assay, ELISA, and western blot. The involvement of TGF-β pathway was further discussed. The expression of COMP was the most significant among all these hub genes. Our experimental results revealed that the protein levels of TGF-β1, phosphorylated Smad2 (P-Smad2), and phosphorylated Smad3 (P-Smad3) were decreased after silencing COMP, which indicated that COMP knockdown could inhibit the activation of TGF-β pathway in AF cells. However, the phenomenon was reversed when the activator SRI was added. COMP acts as a major factor and can improve Ang-II-induced AF via TGF-β signaling pathway. Thus, our research enriches the understanding of the interaction between COMP and TGF-β in AF, and provides reference for the pathogenesis and diagnosis of AF. [ABSTRACT FROM AUTHOR]

This article presents a quick overview of conventional precoding and beamforming techniques in the cellular networks and proposes a novel coordinated beamforming technique for coordinated multipoint (CoMP) networks, which is based upon signal-to-leakage-plus-noise ratio (SLNR) metric. The proposed scheme has reduced computational cost and offers improved performance compared to the conventional multi-cell precoding schemes in the noise-dominated environments. Simulation results reveal that proposed scheme offers a spectrally efficient, low complexity solution with improved average user throughput and sum rate in the CoMP enabled networks.

Tumor necrosis factor α inhibitor (TNFαI) therapy is associated with a significant inhibition of radiographic progression, resulting in improved physical function and quality of life among patients with rheumatoid arthritis (RA). The mechanism by which TNFαI prevent joint destruction is still unknown. In this study, the effect of 15-month anti-TNF-α therapy in combination with methotrexate on circulating levels of biochemical markers of cartilage turnover in female RA patients was assessed. Serum levels of collagen type II C-terminal cleavage neoepitope (C2C), C-terminal propeptide of type II collagen (PIICP), cartilage oligomeric matrix protein (COMP), and matrix metalloproteinase-3 (MMP-3) were evaluated using immunoassays at baseline and 15 months after the start of TNFαI treatment. Baseline COMP, C2C, and MMP-3 levels and C2C/PIICP ratios were significantly higher in women with RA compared with those observed in the healthy subjects. No differences in PIICP levels between the controls and the women with RA were observed. After 15 months of TNFαI treatment, serum levels of C2C, COMP, and MMP-3 decreased, whereas the levels of PIICP increased but were still not different from those of the controls. These changes were accompanied by significantly reduced C2C/PIICP ratios. Before the start of TNFαI therapy, serum levels of COMP significantly correlated with the patients' ages (p < 0.05) and their 28-joint disease activity score values based on their erythrocyte sedimentation rates (DAS28-ESR; p < 0.05). Moreover, multiple linear regression analysis showed that baseline COMP levels retained a significant association with DAS28-ESR value (β = 287.74, p = 0.022, R2 model = 0.25) after model adjustments. The largest area under the ROC curve was obtained for C2C/PIICP ratios (AUC: 0.830, 95% CI: 0.727–0.932, p < 0.001). Our results suggest that long-term anti-TNF-α therapy combined with MTX has a beneficial effect on cartilage remodeling that is associated with clinical improvement among RA patients. Serum C2C/PIICP ratios may help to monitor the effectiveness of anti-TNF-α treatment among RA patients. [ABSTRACT FROM AUTHOR]

Subchondral bone that has intense communication with the articular cartilage might be a potential target for pharmacological treatment in the early stages of osteoarthritis (OA). Considering the emerging data about the role of adipokines in the pathogenesis of OA, the administration of drugs that influence their level is also intriguing. Metformin and alendronate were administered in mice with collagenase-induced OA (CIOA) as a monotherapy and in combination. Safranin O staining was used for the assessment of changes in subchondral bone and articular cartilage. Before and after treatment, serum levels of visfatin and biomarkers of cartilage turnover (CTX-II, MMP-13, and COMP) were assessed. In the current study, the combined administration of alendronate and metformin in mice with CIOA led to the protection against cartilage and subchondral bone damage. In mice with CIOA, metformin led to a decrease in visfatin level. In addition, treatment with metformin, alendronate, or their combination lowered the level of cartilage biomarkers (CTX-II and COMP), while the level of MMP-13 was not influenced. In conclusion, personalized combination treatment in OA according to clinical phenotype, especially in the early stages of the disease, might lead to the identification of a successful disease-modifying therapeutic protocol in OA. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a pathological process associated with various forms of heart failure. This study identified latent transforming growth factor-β binding protein 2, cartilage oligomeric matrix protein, and cartilage intermediate layer protein 1 as potential biomarkers for cardiac fibrosis. All 3 encoded proteins showed increased expression in fibroblasts after transforming growth factor-β stimulation in vitro and localized specifically to fibrotic regions in vivo. Of the 3, only the full-length cartilage intermediate layer protein 1 showed a significant decrease in circulating levels in patients with heart failure compared with healthy volunteers. Further studies on these 3 proteins will lead to a better understanding of their biomarker potential for cardiac fibrosis.

Cardiac fibrosis is a pathological process associated with various forms of heart failure. This study identified latent transforming growth factor-β binding protein 2, cartilage oligomeric matrix protein, and cartilage intermediate layer protein 1 as potential biomarkers for cardiac fibrosis. All 3 encoded proteins showed increased expression in fibroblasts after transforming growth factor-β stimulation in vitro and localized specifically to fibrotic regions in vivo. Of the 3, only the full-length cartilage intermediate layer protein 1 showed a significant decrease in circulating levels in patients with heart failure compared with healthy volunteers. Further studies on these 3 proteins will lead to a better understanding of their biomarker potential for cardiac fibrosis.

The generation of cartilage from progenitor cells for the purpose of cartilage repair is often hampered by hypertrophic differentiation of the engineered cartilaginous tissue caused by endochondral ossification. Since a healthy cartilage matrix contains high amounts of Aggrecan and COMP, we hypothesized that their supplementation in the biogel used in the generation of subperiosteal cartilage mimics the composition of the cartilage extracellular matrix environment, with beneficial properties for the engineered cartilage. Supplementation of COMP or Aggrecan was studied in vitro during chondrogenic differentiation of rabbit periosteum cells and periosteum-derived chondrocytes. Low melting agarose was supplemented with bovine Aggrecan, human recombinant COMP or vehicle and was injected between the bone and periosteum at the upper medial side of the tibia of New Zealand white rabbits. Generated subperiosteal cartilage tissue was analyzed for weight, GAG and DNA content and ALP activity. Key markers of different phases of endochondral ossification were measured by RT-qPCR. For the in vitro experiments, no significant differences in chondrogenic marker expression were detected following COMP or Aggrecan supplementation, while in vivo favorable chondrogenic marker expression was detected. Gene expression levels of hypertrophic markers as well as ALP activity were significantly decreased in the Aggrecan and COMP supplemented conditions compared to controls. The wet weight and GAG content of the in vivo generated subperiosteal cartilage tissue was not significantly different between groups. Data demonstrate the potential of Aggrecan and COMP to favorably influence the subperiosteal microenvironment for the in vivo generation of cartilage for the optimization of cartilage regenerative approaches.

Background: We attempted to examine the clinical characteristics in patients with breast cancer (BC) and thyroid cancer (TC); explore the potential mechanisms of tumorigenesis and progression. Methods: Using the Surveillance, Epidemiology, and End Result Program-9 (SEER-9) database, a retrospective study (1975-2017) was conducted on patients with BC and TC. We identified the common differentially expressed genes involved in BC and TC using the Gene ExpressionOmnibus database (GEO). Immunohistochemical staining (IHC) was performed to verify the expression of the hit gene in patients with co-occurrence of BC and TC. Using The Cancer Genome Atlas (TCGA) database, the relationship between gene expression and clinicopathological characters was determined. Gene set enrichment analysis (GSEA) was used to identify the pathways enriched in BC and TC. Results: BC patients had a higher predisposition to develop TC (standardized incidence ratio, SIR: 1.29) and vice-versa (SIR: 1.12). Most of these patients were differentiated thyroid carcinoma (DTC) and hormone receptor (HR) - positive BC. The mRNA expression of COMP (Cartilage oligomeric matrix protein) was significantly overexpressed in BC and TC by analyzing the GEO database. The protein expression of COMP was increased in both BC and TC tissues obtained from the same patients validated by IHC. COMP was correlated with worse OS in BC (stage II-IV) and TC; it was the independent factor for prognosis of BC. GSEA indicated that the estrogen response and epithelial-mesenchymal transition (EMT) pathways were significantly enriched in both TC-and BC- COMP overexpressed groups. Conclusion: The co-occurrence risk of BC and TC in the same individual is higher than in the general population. Overexpression of COMP could promote oncogenesis and progression in patients with BC and TC through estrogen signaling and EMT pathways. [ABSTRACT FROM AUTHOR]

Cartilage oligomeric matrix protein (COMP), an extracellular matrix protein, has been shown to enhance proliferation and mechanical integrity in the matrix, supporting functions of the growth plate and articular cartilage. Mutations in COMP cause pseudoachondroplasia (PSACH), a severe dwarfing condition associated with premature joint degeneration and significant lifelong joint pain. The MT (mutant)-COMP mouse mimics PSACH with decreased limb growth, early joint degeneration and pain. Ablation of endoplasmic reticulum stress CHOP signaling eliminated pain and prevented joint degeneration. The health effects of mutant COMP are discussed in relation to cellular/chondrocyte stress in the growth plate, articular cartilage and nearby tissues, and the implications for therapeutic approaches. There are many similarities between osteoarthritis and mutant-COMP protein-induced joint degeneration, suggesting that the relevance of findings in the joints may extend beyond PSACH to idiopathic primary OA. [Display omitted] • Our MT-COMP mouse mimics pseudoachondroplasia with decreased limb growth, early joint degeneration, and pain. • Interrupting CHOP ER stress signaling (genetic ablation of CHOP) in MT-COMP eliminated pain, prevented joint degeneration, and dampened chondrocyte stress. • Osteoarthritis (OA) and mutant-COMP-induced joint degeneration share many stress processes including ER stress, inflammation, oxidative stress, dysregulated autophagy, and senescence suggesting our findings may extend to primary OA. [ABSTRACT FROM AUTHOR]

Abstract—Nowadays the possible influence of the coronavirus infection on cartilage degeneration and synovial membrane inflammation during chronic joint pathology—osteoarthritis—remains largely unelucidated. The aim of the presented work is to analyze the TGFB1, FOXO1, and COMP gene expression and free radical generation intensity in blood of patients suffering from osteoarthritis after beating the SARS-CoV2 infection. The work was carried out using molecular genetics and biochemistry methods. The decrease of the TGFB1 and FOXO1 expression level was shown to be more evident in the osteoarthritis patients after COVID-19 if compared to the group with knee osteoarthritis during simultaneous and more prominent diminishing of both superoxide dismutase and catalase activity (possibly indicating cell redox state disruption and TGF- P1-FOXO1 signaling attenuation) in patients with osteoarthritis after SARS-CoV2 disease. At the same time, the more prominent decrease of COMP gene expression level was demonstrated in patients with osteoarthritis after COVID-19 compared to the group with knee osteoarthritis and more intense increase of the COMP concentration in patients with osteoarthritis after the SARS-CoV2 infection was revealed. These data indicate more significant activation of cell destructive processes after the infection as well as further pathology progression. [ABSTRACT FROM AUTHOR]

Multiple epiphyseal dysplasia type 1 is one of the most common autosomal dominant types of the genetically heterogeneous group of skeletal dysplasias characterized by impaired ossification of the epiphyses of long bones. To date, it is known that the disease is caused by heterozygous variants in the COMP gene and is characterized by a significant variability in the clinical manifestations. We report the first case of a patient with MED 1 caused by novel homozygous single nucleotide variant c.2170dupG (p.Val724Glyfs*20) in the COMP gene identified by whole-exome sequencing. The following segregation analysis in the family found a detected variant in heterozygous state in healthy consanguineous parents of the proband. Clinical and radiological examination revealed the atypical signs of epiphyseal dysplasia including limited range of extension and supination of both forearms, severe bilateral ulnar clubhand, plano-valgus deformity of the feet and generalized muscle weakness with gait disturbances. Among the clinical features, myopathic signs were the most prominent. The radiological and neurophysiological data can be helpful in the differential diagnostics with the congenital myopathies. The novel homozygous variant in the COMP gene that caused multiple epiphyseal dysplasia 1 with autosomal recessive inheritance can contribute to the more detailed description of genotype–phenotype correlations, which will allow research to understand better the role of the C-terminal domain of COMP.

Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable formulation of curcumin, was tested in MT-COMP mice at doses of 82.3 (1X) and 164.6 mg/kg (2X). CurQ+ treatment of MT-COMP mice from 1 to 4 weeks postnatally decreased mutant COMP intracellular retention, inflammation, restoring both autophagy and chondrocyte proliferation. CurQ+ reduction of cellular stress in growth plate chondrocytes dramatically reduced chondrocyte death, normalized femur length at 2X 164.6 mg/kg and recovered 60% of lost limb growth at 1X 82.3 mg/kg. These results indicate that CurQ+ is a potential therapy for COMPopathy-associated lost limb growth, joint degeneration, and other conditions involving persistent inflammation, oxidative stress, and a block of autophagy. [ABSTRACT FROM AUTHOR]

In a multi cell scenario, co channel and adjacent channel interferences occur and degrade the performance of cellular networks particularly of the edge users. In this paper, a fusion algorithm is proposed for cancellation of Inter cell Interference and resource allocation. This algorithm is based on Energy Efficiency and capacity. The main objective of this algorithm is considering the edge user equal to center user. Due to transmission through relay node, energy efficiency will be high for edge users. Energy efficient algorithm is proposed for users and it provides better cell edge efficiency and fairness. In this method, inter cell interference (ICI) is cancelled by modified frequency reuse (MFR) technique. After cancellation of ICI, the resources are allocated to the user equipment based on scheduling metric and transmitted energy per bit. The proposed method is compared with the previous techniques like maximum carrier to interference ratio (MCI) and round robin technique (RR). Performance metrics like spectral efficiency, SINR, cell energy efficiency, capacity and fairness are analyzed. [ABSTRACT FROM AUTHOR]

Background: Colon cancer is characterized by a sophisticated tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which make up the majority of the stromal cells in TME, participate in tumor development and immune regulation. Further investigations of CAFs would facilitate an in-depth understanding of its role in colon cancer TME. Methods: In this study, we estimated CAF abundance based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases using the Microenvironment Cell Populations-counter (MCP-counter) algorithm. CAF-related genes were identified by differential gene expression analysis combined with weighted gene coexpression network analysis. For further selection, the least absolute shrinkage and selection operator (LASSO)-Cox regression was used, and the prognostic value of the selected gene was confirmed in numerous external cohorts. The function enrichment, immunological characteristics, tumor mutation signature, immunotherapy response, and drug sensitivity of the selected gene were subsequently explored. The bioinformatics analysis results were validated using immunohistochemistry on clinical samples from our institution. Results: According to our findings, cartilage oligomeric matrix protein (COMP) was uncovered as a candidate CAFs-driven biomarker in colon cancer and plays an important role in predicting prognosis in colon cancer. COMP upregulation was associated with enhanced stromal and immune activation, and immune cell infiltration, especially M2 macrophages. Genes that mutated differently between the high- and low-COMP expression subgroups may be correlated with TME change. Following verification, COMP reliably predicted the immunotherapy response and drug response. In addition, our experimental validation demonstrated that COMP overexpression is associated with colon cancer carcinogenesis and is strongly associated with CAFs and M2 macrophage infiltration. Conclusion: Our study uncovered that COMP was a key CAFs-driven gene associated with M2 macrophage infiltration and acted as a convincing predictor for prognosis and immunotherapy response in colon cancer patients. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancers (CRCs) continue to be the leading cause of cancer-related deaths worldwide. The exact landscape of the molecular features of TGF-β pathway-inducing CRCs remains uncharacterized. Methods: Unsupervised hierarchical clustering was performed to stratify samples into two clusters based on the differences in TGF-β pathways. Weighted gene co-expression network analysis was applied to identify the key gene modules mediating the different characteristics between two subtypes. An algorithm integrating the least absolute shrinkage and selection operator (LASSO), XGBoost, and random forest regression was performed to narrow down the candidate genes. Further bioinformatic analyses were performed focusing on COMP-related immune infiltration and functions. Results: The integrated machine learning algorithm identified COMP as the hub gene, which exhibited a significant predictive value for two subtypes with an area under the curve (AUC) value equaling 0.91. Further bioinformatic analysis revealed that COMP was significantly upregulated in various cancers, especially in advanced CRCs, and regulated the immune infiltration, especially M2 macrophages and cancer-associated fibroblasts in CRCs. Conclusions: Comprehensive immune analysis and experimental validation demonstrate that COMP is a reliable signature for subtype prediction. Our results could provide a new point for TGFβ-targeted anticancer drugs and contribute to guiding clinical decision making for CRC patients. [ABSTRACT FROM AUTHOR]

Abstract Background Specific serum biomarkers of cartilage metabolism such as cartilage oligomeric matrix protein (sCOMP) and procollagen type II C-terminal propeptide (sPIICP) as well as hyaluronan (sHA), a biomarker of synovitis, have been implicated in the pathophysiology of knee osteoarthritis (OA). However, the associations of these biomarkers with the severity of the disease and OA risk factors, including age and obesity remain inconclusive. This analysis examines the associations between these serum biomarkers and the radiographic severity of OA and knee pain, as wells as obesity, the age and gender of the participants, and other OA risk factors. Methods From 44 patients with early knee OA and 130 patients with late knee OA we analyzed the radiographic severity of the disease using the Kellgren and Lawrence (KL) grading system. Moreover, 38 overweight healthy individuals were used as a control group. Specific information was collected from all participants during their recruitment. The levels of the three serum biomarkers were quantified using commercially available ELISA kits. Serum biomarkers were analyzed for associations with the average KL scores and pain in both knees, as well as with specific OA risk factors. Results The levels of sCOMP were elevated in patients with severe late OA and knee pain and correlated weakly with OA severity. A weakly correlation of sHA levels and OA severity OA was observed. We demonstrated that only sPIICP levels were markedly decreased in patients with late knee OA suggesting the alterations of cartilage metabolism in this arthritic disease. Moreover, we found that sPIICP has the strongest correlation with obesity and the severity of OA, as well as with the knee pain at rest and during walking regardless of the severity of the disease. ROC analysis showed that the area under the ROC curve (AUC) was 0.980 (95% CI: 0.945–0.995; p

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol’s therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.

Cartilage oligomeric matrix protein (COMP) is an emerging regulator of tumor progression. The aim of this study was to evaluate the expression of COMP in periampullary adenocarcinoma with respect to prognostic value for survival and relapse, levels of fibrosis and infiltrating immune cells. COMP expression was evaluated using immunohistochemistry in primary tumors and subsets of paired lymph node metastases in tissue microarrays including 175 patients with periampullary adenocarcinoma. Collagen content was assessed with Sirius Red-Fast Green staining. High COMP levels were detected in cancer cells and in stroma, in 46% and 57% of the patients, respectively. High COMP expression was strongly associated with more aggressive pancreatobiliary-type (PB-type) compared to intestinal-type tumors (p

In this paper, we consider unmanned aerial vehicles (UAVs) equipped with a visible light communication (VLC) access point and coordinated multipoint (CoMP) capability that allows users to connect to more than one UAV. UAVs can move in 3-dimensional (3D) at a constant acceleration, where a central server is responsible for synchronization and cooperation among UAVs. The effect of accelerated movement in UAV is necessary to be considered. Unlike most existing works, we examine the effects of variable speed on kinetics and radio resource allocations. For the proposed system model, we define two different time scales. In the frame, the acceleration of each UAV is specified, and in each slot, radio resources are allocated. Our goal is to formulate a multi-objective optimization problem where the total data rate is maximized, and the total communication power consumption is minimized simultaneously. To handle this multi-objective optimization, we first apply the scalarization method and then apply multi-agent deep deterministic policy gradient (MADDPG). We improve this solution method by adding two critic networks together with two-stage resource allocation. [ABSTRACT FROM AUTHOR]

Coordinated multipoint joint transmission (JT) is one of the critical downlink transmission technologies to improve network throughput. However, multiple cells in a JT group should have the same user data to transmit simultaneously, resulting in a considerable backhaul burden. Even when cells are already equipped with caches in fifth-generation networks, JT groups, without effectively utilizing the caching data, still cause unnecessary backhaul data traffic. In this article, we investigate the JT grouping problem with the consideration of caches at cells. Then, we propose a genetic approach to solve the above problem with the objective of minimizing the amount of backhaul data traffic subject to the data-rate requirement of each user. The simulation results show that our proposed generic algorithm can significantly decrease the backhaul bandwidth consumption compared to the two baselines. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of Alphacalcidol supplementation on pain based on WOMAC pain index and joint cartilage condition based on cartilage oligomeric matrix protein (COMP) serum markers in knee osteoarthritis (OA) elderly patients. Materials andMethods: This is a randomized, double-blind, and placebo-controlled trial. Symptomatic knee OA elderly subjects visited our clinic in Jakarta July-December 2017 were recruited. History taking, physical examinations, and knee radiology were performed. Serum Vitamin D (25(OH)D) and COMP were analysed using chemiluminescent immunoassay and enzyme-linked immunosorbent assay, respectively. Body mass index, physical activity, sun exposure frequency, and dietary vitamin D were assessed. Subjects were randomly allocated to either intervention group to be given 1 µg Alphacalcidol or control group to be given placebo for 12 weeks. Comparation analysis of WOMAC pain index and serum COMP concentration between both groups was performed. Results: There were 146 subjects participated this study. Increases of 25(OH)D were found in intervention group (2.63 ±11.24 nmol/L, p=0.05) and control groups (1.09±9.42 nmol/L, p=0.28). Alphacalcidol significantly reduced pain based on WOMAC indicator with mean reduction differences of intervention group compared to control group was 2.174±1.060 (p=0.00). COMP serum level was reduced with mean reduction differences of intervention group compared to control group was 38.15±87.553 ng/ml (p=0.39). Alphacalcidol and gender were the determinants of WOMAC pain index reduction (p=0.00 and p=0.06, respectively) while Alphacalcidol was the only serum COMP level change determinant (p=0.39). Conclusions: Alphacalcidol administration reduced pain based on WOMAC indicator and COMP serum in knee OA elderly subjects. [ABSTRACT FROM AUTHOR]

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In this letter, a novel and flexible hybrid guard duration (HGD) based on zero tail (ZT) and cyclic prefix (CP) concepts is proposed for facilitating timing synchronization (TS) in coordinated multi-point (COMP) networks. The proposed HGD harmoniously provides enough guard duration for mitigating the channel’s delay spread and facilitating TS without extending the total symbol duration while supporting both COMP and non-COMP users. That is, unlike the traditional extended CP (E-CP) approach that degrades the system’s spectral efficiency (SE) and elevates the transmission latency due to the extended symbol duration, HGD maintains the usage of the normal CP size and the total symbol duration, thereby ensuring better SE performance and relatively low latency. The proposed HGD is evaluated and compared with the traditional E-CP in terms of bit error rate, SE, and latency. [ABSTRACT FROM AUTHOR]

Following the roadmap of carbon neutrality, wireless communication systems are upgrading to use green energy that comes from renewable sources, e.g., sun, tide, and wind. Due to the volatile arrival of green energy, the on-grid energy is used as a backup for a green coordinated multiple point system. In this work, a weighted sum-rate maximization problem in the green coordinated multiple point system is investigated by expecting non-positive consumption of the on-grid energy in the long term. Motivated by the capacity-achieving property and simple implementation, an online zero-forcing dirty paper precoder is proposed to update the precoding matrices by combining statistical learning with the Lyapunov learning technique. A tradeoff relation is theoretically established to show that the long-term weighted sum rate approaches the ${\mathcal{ O}}(V)$ -neighbor of optimal value while the long-term on-grid energy increases at a rate of ${\mathcal{ O}}({\scriptstyle {}^{\scriptstyle \log ^{2}(V)}}\hspace {-0.224em}/\hspace {-0.112em}{\scriptstyle \sqrt {V}})$ , where $V$ is an introduced control parameter. Numerical results are used to verify the performance of the proposed online adaptive precoder. [ABSTRACT FROM AUTHOR]

The huge traffic demand envisioned in 5G requires radical changes in mobile network architecture. A Centralized Radio Access Network (C-RAN) was introduced as a novel mobile network architecture, designed to effectively support the challenging requirements of future 5G networks. Coordinated Multi-point (CoMP) is one of the technologies aiming to increase user traffic by transforming inter-cell interference into useful signals to maximize cell-edge users throughput. Intra-CoMP means that cooperating RRHs are assigned to the same Base Band Unit (BBU). On the other hand, in inter-CoMP, the cooperating RRHs are assigned to different BBUs, which introduce overhead signalling over an X2 interface. This paper proposes a model for BBU placement in C-RAN deployment over a 5G optical aggregation network. The model aims to minimize the number of users undergoing inter-CoMP, therefore reducing X2 signalling overhead. First, we solve the BBU placement problem using Integer Linear Programming (ILP), which minimizes the number of BBUs and the number of used links. Second, given the output of the ILP model (i.e., BBU locations and routes), we propose a heuristic algorithm to reconfigure the BBUs (i.e., the assignment of the RRHs to their corresponding BBUs), which aims at minimizing the number of users undergoing inter-CoMP. The proposed heuristic algorithm considers minimizing end-to-end delay, the number of used wavelengths, and maximizing multiplexing gain. The results show that up to 97% of inter-CoMP users migrated to intra-CoMP users. This results in a decrease in the X2 traffic, which is mainly used for the coordination between the BBUs. [ABSTRACT FROM AUTHOR]

With the rapid evolution of Internet of things (IoT), many edge devices require simultaneous connection in 5G communication era. To afford massive data of IoT devices, multiple input multiple output non-orthogonal multiple access (MIMO-NOMA) method has been considered as a promising technology. However, there are numerous drawbacks due to error propagation and inter-user interferences. Therefore, proposed scheme aims to improve the reliability of the MIMO-NOMA system with digital beamforming and intra-cluster cooperative multi point (CoMP) to efficiently support IoT system. In the conventional MIMO-NOMA system, user entities are grouped into clusters. Block diagonalization (BD) is applied to efficiently eliminate the inter-cluster interference of the MIMO-NOMA system. However, since the channel path of the data stream from a single antenna to a single cluster doesn't hold other cluster's data, the system can't fully utilize the selective subcarrier channel states. It indicates that there can be better channel paths for a data stream at a certain subcarrier index. Therefore, proposed scheme allocates data streams to antennas adaptively considering selective channel states. Additionally, intra-cluster CoMP method is adjusted to enhance the reliability of the system in the clusters. The simulation results show that the proposed scheme improves BER and throughput performance compared to the conventional MIMO-NOMA system. [ABSTRACT FROM AUTHOR]