Cluster-Based Strategy for Maximizing the Sum-Rate of a Distributed Reconfigurable Intelligent Surface (RIS)-Assisted Coordinated Multi-Point Non-Orthogonal Multiple-Access (CoMP-NOMA) System.

This article proposes a distributed intelligent Coordinated Multi-Point Non-Orthogonal Multiple-Access (CoMP-NOMA) collaborative transmission model with the assistance of reconfigurable intelligent surfaces (RISs) to address the issues of poor communication quality, low fairness, and high system power consumption for edge users in multi-cellular networks. By analyzing the interaction mechanisms and influencing factors among RIS signal enhancement, NOMA user scheduling, and multi-point collaborative transmission, the model establishes RIS-enhanced edge user grouping and coordinates NOMA user clusters based on this. In the multi-cell RIS-assisted JT-CoMP NOMA downlink transmission, joint optimization of the power allocation (PA), user clustering (UC), and RIS phase-shift matrix design (PS) poses a challenging Mixed-Integer Non-Linear Programming (MINLP) problem. The original problem is decomposed by optimizing the formulas into joint sub-problems of PA, UC, and PA and PS, and solved using an alternating optimization approach. Simulation results demonstrate that the proposed scheme effectively reduces the system's power consumption while significantly improving the system's throughput and rates.

Metformin as adjuvant therapy in obese knee osteoarthritis patients.

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-1ß) 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-1ß 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-1ß levels. Additionally, metformin may improve clinical outcomes, as shown by the significant improvements in WOMAC scores. GOV ID: NCT05638893/Registered December 6, 2022 - Retrospectively.

Osteoarthritis as a Systemic Disease Promoted Prostate Cancer In Vivo and In Vitro.

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.

Proteomic, single-cell and bulk transcriptomic analysis of plasma and tumor tissues unveil core proteins in response to anti-PD-L1 immunotherapy in triple negative breast cancer.

BACKGROUND: Anti-PD-1/PD-L1 treatment has achieved durable responses in TNBC patients, whereas a fraction of them showed non-sensitivity to the treatment and the mechanism is still unclear. METHODS: Pre- and post-treatment plasma samples from triple negative breast cancer (TNBC) patients treated with immunotherapy were measured by tandem mass tag (TMT) mass spectrometry. Public proteome data of lung cancer and melanoma treated with immunotherapy were employed to validate the findings. Blood and tissue single-cell RNA sequencing (scRNA-seq) data of TNBC patients treated with or without immunotherapy were analyzed to identify the derivations of plasma proteins. RNA-seq data from IMvigor210 and other cancer types were used to validate plasma proteins in predicting response to immunotherapy. RESULTS: A random forest model constructed by FAP, LRG1, LBP and COMP could well predict the response to immunotherapy. The activation of complement cascade was observed in responders, whereas FAP and COMP showed a higher abundance in non-responders and negative correlated with the activation of complements. scRNA-seq and bulk RNA-seq analysis suggested that FAP, COMP and complements were derived from fibroblasts of tumor tissues. CONCLUSIONS: We constructe an effective plasma proteomic model in predicting response to immunotherapy, and find that FAP+ and COMP+ fibroblasts are potential targets for reversing immunotherapy resistance.

Cartilage Oligomeric Matrix Protein in Osteoarthritis and Obesity-Do New Considerations Emerge?

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.

Stromal cartilage oligomeric matrix protein as a tumorigenic driver in ovarian cancer via Notch3 signaling and epithelial-to-mesenchymal transition.

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-ß. 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 ß-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 prognostic and potentially immunomodulatory role of cartilage oligomeric matrix protein in patients with gastric and esophageal adenocarcinoma.

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.

Stromal cell-derived factor 1 alpha (SDF-1alfa) and cartilage oligomeric matrix protein (COMP): Two potential signature biomarkers of radiological detectable hemophilic arthropathy.

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.

Diagnostic value of serum COMP and ADAMTS7 for intervertebral disc degeneration.

OBJECTIVE: Intervertebral disc degeneration (IVDD) is a major cause of morbidity and disability. Our study aimed to investigate the potential of cartilage oligomeric matrix protein (COMP) and ADAMTS7 (A disintegrin and metalloproteinases with thrombospondin motifs 7) as biomarkers for IVDD together with their functional relationship. METHODS: IVD tissues and peripheral blood samples were collected from IVDD rabbit models over 1-4 weeks. Tissues and blood samples were also collected from clinical patients those were stratified into four equal groups according to Pfirrmann IVDD grading (I-V) with baseline data collected for each participant. COMP and ADAMTS7 expression were analyzed and biomarker characteristics were assessed using linear regression and receiver operating curve (ROC) analyses. RESULTS: COMP and ADAMTS7 expression increased in tissues and serum during IVDD progression. Serum COMP (sCOMP) and serum ADAMTS7 (sADAMTS7) levels increased in a time-dependent manner following IVD damage in the rabbit model while significant positive correlations were detected between sCOMP and sADAMTS7 and Pfirrmann grade in human subjects. ROC analysis showed that combining sCOMP and sADAMTS7 assay results produced an improved diagnostic measure for IVDD compared to individual sCOMP or sADAMTS7 tests. In vitro assays conducted on human cell isolates revealed that COMP prevented extracellular matrix degradation and antagonized ADAMTS7 expression although this protective role was uncoupled under microenvironmental conditions mimicking IVDD. CONCLUSIONS: Increases in circulating COMP and ADAMTS7 correlate with IVDD progression and may play regulatory roles. Assays for sCOMP and/or sADAMTS7 levels can discriminate between healthy subjects and IVDD patients, warranting further clinical assessment.

Shiga toxin type 2 B subunit protects mice against toxin challenge when leashed and bundled by a stable pentameric coiled-coil molecule.

Vaccines against Shiga toxin (Stx)-producing Escherichia coli (STEC) have not yet been developed. Two immunologically distinct serotypes of Stx (Stx1 and Stx2) are the main virulence factors of STEC. Thus, blocking their B subunits (StxB) from binding to the cell surface receptor globotriaosylceramide (Gb3) efficiently prevents the action of these toxins. We expressed Stx1B and Stx2B in E. coli inclusion bodies and reassembled them into pentamers by a stepwise dialysis. Stx1B pentamer fully protected mice against Stx1 challenge, but Stx2B pentamer failed to protect mice against Stx2 challenge. To explain those observations, we proposed that the pentamer of Stx2B readily dissociates into its constituent monomers, especially under in vivo conditions, thus being unable to induce pentamer-specific immunity. To increase pentamer stability, we fused the B subunit to a pentameric coiled-coil domain of the cartilage oligomeric matrix protein (COMP). This "five-to-five" fusion hybrid molecule (Stx2B-COMP) was shown to be protective against Stx2 challenge, demonstrating that the Stx2B subunit when leashed and bundled by a rigid pentameric coiled-coil domain mount a pentamer-specific immune response and efficiently neutralize the toxin both in vitro and in vivo. Our data strongly suggest that the Stx2B subunit moiety fluctuates between a pentameric and monomeric state within the fusion protein, which may increase the likelihood of the immune system recognizing the pentameric conformation for toxin neutralization.

Glucose restriction enhances oxidative fiber formation: A multi-omic signal network involving AMPK and CaMK2.

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.

Mesenteric fibrosis in patients with small intestinal neuroendocrine tumors is associated with enrichment of alpha-smooth muscle actin-positive fibrosis and COMP-expressing stromal cells.

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.

N-phenyl and N-benzyl substituted succinimides: Preclinical evaluation for their antihypertensive effect and underlying mechanism.

The study was designed to investigate the antihypertensive potential of 2-(2, 5-dioxo-1-phenylpyrrolidin-3-yl)-3-(4-isopropylphenyl)-2-methylpropanal (Comp-1) and 2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-3-(4-isopropylphenyl)-2-methylpropanal (Succ-5) in rats. The study results showed that, just like nifedipine (the standard reference drug), the test compounds, Comp-1 (at doses of 15 and 20 mg/kg) and Succ-5 (at a dose of 20 mg/kg) had significant antihypertensive effect against deoxycorticosterone acetate-salted rats. The test compounds maintained the level of cardiac markers troponin I and creatinine kinase myocardial bands (CK-MB) in serum, and modulate the oxidative stress markers Glutathione s-transferase (GST) activity, reduced glutathione (GSH), catalase levels, and lipid peroxidation (LPO). These compounds also reduced the expression of inflammatory markers, including cyclooxygenase-2 (COX-2) and tumor necrosis factor alpha (TNF-α) in heart tissues. Furthermore, in the ex-vivo study, the test substances relaxed the contractions induced by phenylephrine (PE) and potassium (K+). Vasodilation was endothelium-independent because the test substances showed nearly the same effect in aortic rings with intact endothelium, denuded endothelium, and with L-NAME pretreatment. The test compounds shifted the calcium curve to the right, i.e., contraction was inhibited and decreased the maximal response. This study demonstrated the antihypertensive, anti-inflammatory, antioxidant, and vasodilate effects of the test compounds. In addition, the results supported the phenomenon of calcium channel blockades responsible for vasodilation.

Effect of GLIS1 on the Lymph Node Metastasis of Cervical Squamous Carcinoma Based on Transcriptome Analysis.

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.

Case Report: Whole-exome sequencing identified two novel COMP variants causing pseudoachondroplasia.

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 these mutations 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 the COMP 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.

Active anterior rhinomanometry: A study on nasal airway resistance, paradoxical reactions to decongestion, and repeatability in healthy subjects.

Objectives: Anterior active rhinomanometry (AAR) is widely used in Swedish routine clinical practice to decide if septoplasty is necessary. The scientific basis for the method needs to be strengthened. Therefore, the aims were to evaluate nasal airway resistance (NAR), paradoxical reactions to pharmacological decongestion, and test-retest characteristics of the Rhino-Comp® AAR in healthy subjects. Methods: A prospective longitudinal design was used. AAR was performed before and after decongestion at baseline and after ≥6 months on 60 healthy volunteers. The relationships between NAR, height, weight, BMI, sex, and allergic rhinitis were evaluated by regression analyses. Descriptive statistics were used to evaluate paradoxical reactions. Test-retest and repeatability characteristics were evaluated with intra-class coefficients (ICC), Cronbach's α, and standard error of measurement. Results: No statistically significant differences were found between genders or nasal cavity sides. NAR was statistically significantly related to height. Short- and long-term test-retest characteristics were good with ICC and Cronbach's α > .75. The minimal significant difference in NAR Log10V2 values between the two measurements was 0.11 and 0.09 (long- and short-term). Paradoxical reactions to pharmacological decongestion were rare, mostly weak, and not evidently reproducible. Conclusion: In this study, we report reference data for healthy subjects, test-retest capabilities, and the minimal relevant difference between two measurements for the Rhino-Comp® AAR, information that is vital and necessary for the appropriate use of AAR in clinical practice. An effective method for pharmacological decongestion is described and recommended for future studies and clinical practice. Paradoxical reactions to pharmacological decongestants exist but maybe without clinical significance. Level of Evidence: NA.

The European landscape for gene therapies in orphan diseases: 6-year experience with the EMA Committee for Orphan Medicinal Products.

In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.

Unveiling genetic diversity and forensic utility of SureID® human DNA identification kits: a comprehensive analysis of 44 autosomal STR loci in English and Irish populations.

Background: Human identification and kinship testing in forensic science rely on Short Tandem Repeat (STR) multiplex kits, typically containing loci recommended by standard sets. However, complementary kits with additional STR loci can be valuable in complex cases. Allele frequency databases specific to the population are essential for accurate forensic analysis.Aim: This study aimed to generate allele frequencies and population genetic data for 44 autosomal STR loci from SureID® PanGlobal and 27comp kits in English and Irish populations for forensic casework, human identification, and kinship testing.Subjects and methods: Buccal swab samples from 645 White Caucasians (365 English, 280 Irish) were collected. DNA was extracted and amplified using the mentioned kits. Quality control, statistical analysis, and genetic distance calculations were performed.Results: Both kits demonstrated robustness with no significant deviations from Hardy-Weinberg Equilibrium (HWE). Variant alleles and minor discordances between kits were observed. Syntenic STR pairs were identified but showed no significant linkage. A close genetic relationship was found between English and Irish populations, allowing for combined databases.Conclusions: The SureID® PanGlobal and 27comp kits showed high discriminatory power and reliability in the English and Irish populations. Care is needed when handling variant alleles, discordances, and syntenic loci. Combining data from both populations is feasible for a comprehensive database. Further studies are required to explore their effectiveness in diverse populations.

A novel high-risk aortic root anatomy for right coronary artery occlusion during TAVI.

Acute coronary occlusion during transcatheter aortic valve implantation (TAVI) is a rare but potentially lethal complication. Main mechanisms are sinus insufficiency or sinus sequestration with well-described risk factors. We present two cases of acute right coronary artery occlusion during TAVI with a self-expanding valve in the absence of classical risk factors and propose a novel mechanism.

Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH).

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.