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This study was performed to provide evidence, albeit indirectly, as to which matrix metalloproteinases (MMPs), among the gelatinases MMP-2 and MMP-9 and the collagenases MMP-1 and MMP-13, play a more proactive role in the angiogenic process in arthritic joint. Joint fluid was collected from 33 patients with rhuematoid arthritis (RA) and osteoarthritis (OA), and protein (MMPs and vascular endothelial growth factor (VEGF)) levels were measured by ELISA, and the association of MMPs with VEGF was evaluated in joint fluid of patients with RA or OA. The levels of collagenases (total MMP-1 and total MMP-13) and gelatinases (total MMP-2 and total MMP-9) in RA joint fluid were significantly higher than those in OA fluid. Total MMP-9 levels were significantly associated with VEGF levels in RA fluids, but not in OA fluid, while total MMP-13 levels were strongly associated with VEGF levels in both RA and OA fluid. However, total MMP-2 and total MMP-1 levels were not associated with VEGF levels in either RA or OA joint fluid. Our results indirectly suggest that in RA and OA, MMP-9 and MMP-13 may play a more important role in angiogenesis than MMP-2 and MMP-1.

Background and Aims:In addition to its crucial role in dampening tissue-damaging immune responses in the gut, transforming growth factor β (TGFβ) is a potent profibrogenic agent inducing collagen synthesis and regulating the balance between matrix-degrading matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). TGFβ signalling was investigated by analysis of Smad proteins and MMPs/TIMPs in the mucosa overlying strictures in patients with Crohn’s disease (CD).Methods:Specimens were collected from macroscopically normal mucosa overlying strictured and non-strictured gut of patients with fibrostenosing CD. Isolated myofibroblasts were cultured with anti-TGFβ blocking antibody or TGFβ1. TGFβ transcripts were analysed by quantitative reverse transcription-PCR (RT-PCR). Smad proteins and MMPs were determined by immunoblotting. MMP-12 activity was measured by a real-time MMP-12 activity assay. An in vitro wound-healing scratch assay was used to assess myofibroblast migration.Results:TGFβ transcripts, phosphorylated Smad2–Smad3 (pSmad2–3) and TIMP-1 proteins were higher in mucosa overlying strictures than in mucosa overlying non-strictured areas. In contrast, mucosa overlying strictured gut had lower expression of Smad7, MMP-12 and MMP-3. Myofibroblasts from mucosa overlying strictured gut showed higher TGFβ transcripts, a greater pSmad2–3 response to TGFβ, increased TIMP-1, lower Smad7, increased collagen production and reduced migration ability compared with myofibroblasts from mucosa overlying non-strictured gut. TGFβ blockade increased myofibroblast MMP-12 production and migration, more obviously in myofibroblasts isolated from mucosa overlying non-strictured compared with strictured gut.Conclusions:Changes in TGF-β signalling and MMP production were identified in the mucosa overlying strictures in CD which may give a window into the process of fibrosis.

Three members of the SIBLING family of integrin-binding phosphoglycoproteins (bone sialoprotein, BSP; osteopontin, OPN; and dentin matrix protein-1, DMP1) were recently shown to bind with high affinity (nM) and to activate 3 different matrix metalloproteinases (MMP-2, MMP-3, and MMP-9, respectively) in vitro. The current study was designed to document the possible biological relevance of the SIBLING-MMP activation pathway in vivo by showing that these 3 SIBLINGs and their known MMP partners are co-expressed in normal adult tissue. BSP, OPN, and DMP1 were invariably co-expressed with their partner MMPs in salivary glands of humans and mice. The 2 SIBLING proteins without known MMP partners, dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE), were also expressed in salivary glands. Expression of all SIBLINGs in this normal, non-mineralizing epithelial tissue suggests that they serve at least one function in vivo other than directly promoting matrix mineralization—a function we hypothesize involves local activation of MMPs.

Aims. Matrix metalloproteinases (MMPs) are a group of calcium-dependent zinc-containing proteinases acting both physiologically and in pathological conditions. The aim of this study was to evaluate the concentration of MMP-2, MMP-8, and MMP-9 and their inhibitors TIMP-1 and TIMP-2 of unstimulated whole saliva (UWS) in correlation with the oral health in juvenile idiopathic arthritis (JIA) children. Methods. The study population comprised 34 JIA patients and 34 age- and sex-matched controls (C). They were divided into two groups: with mixed dentition (MD) and with permanent dentition (PD). Dental caries (DMFT/dmft), unstimulated salivary flow rate (SF), and gingival inflammation (Gingival Index (GI) and Papilla Bleeding Index (PBI)) and oral hygiene (Simplified Oral Hygiene Index (OHI-S)) indices were evaluated. Saliva samples were tested with the enzyme-linked immunosorbent assay (ELISA) for MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2. Data were statistically analysed with the Mann–Whitney U test and Spearman’s rank correlation (p<0.05). Results. There were no differences in dental hygiene or dental and periodontal status between the JIA and C groups. The MMP-9 concentration was higher in the whole JIA group compared with C (p=0.005) and JIA MD groups (p=0.038). A positive correlation of MMP-2 with the OHI-S index and a negative correlation of MMP-2 with SF were found in JIA. MMP-9 and its tissue inhibitor TIMP-1 had a positive mean correlation with the GI. A high correlation of MMP-8 with the number of decayed teeth (D) in JIA MD patients (p=0.037) was revealed. In the JIA-PD patients, there was a positive correlation of MMP-2, -8, and -9 levels with gingival inflammation indices and a negative correlation of MMP-2 and 8 with the SF. Conclusions. Despite a comparable clinical oral status of affected and unaffected children, in the JIA patients, a statistically significantly increased level of MMP-9 was found. In reference to the periodontal status, the role of MMPs increased in children with permanent dentition, whereas in reference to dental caries, the period of mixed dentition (MD) was critical.

Examination of spatial variation in demography among or within populations of the same species is a topic of growing interest in ecology. We examined whether spatial variation in demography of a tropical megaherbivore followed the “temporal paradigm” or the “adult survival paradigm” of ungulate population dynamics formulated from temperate-zone studies. We quantified spatial variation in demographic rates for giraffes (Giraffa camelopardalis) at regional and continental scales. Regionally, we used photographic capture-mark-recapture data from 860 adult females and 449 calves to estimate adult female survival, calf survival, and reproduction at 5 sites in the Tarangire ecosystem of Tanzania. We examined potential mechanisms for spatial variation in regional demographic rates. At the continental scale, we synthesized demographic estimates from published studies across the range of the species. We created matrix population models for all sites at both scales and used prospective and retrospective analyses to determine which vital rate was most important to variation in population growth rate. Spatial variability of demographic parameters at the continental scale was in agreement with the temporal paradigm of low variability in adult survival and more highly variable reproduction and calf survival. In contrast, at the regional scale, adult female survival had higher spatial variation, in agreement with the adult survival paradigm. At both scales, variation in adult female survival made the greatest contribution to variation in local population growth rates. Our work documented contrasting patterns of spatial variation in demographic rates of giraffes at 2 spatial scales, but at both scales, we found the same vital rate was most important. We also found anthropogenic impacts on adult females are the most likely mechanism of regional population trajectories.

We examined whether the expression and activation of pro-matrix metalloproteinase (MMP)-1 varies from that of pro-MMP-13 in the joint fluid of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. To do this, joint fluid was collected from 34 RA and 34 OA patients. The collagenase (pro-MMP-1 and MMP-13, total MMP-1, and MMP-13), gelatinase (total MMP-2 and MMP-9), stromelysin (total MMP-3), matrilysin (total MMP-7), uPA, and tissue inhibitor of MMP (TIMP) levels were measured by ELISA. The level of total MMP-1 in RA joint fluids was similar to that of the OA joint fluid. In contrast, the level of total MMP-13 in the RA group was significantly higher than that of the OA group. Among various MMPs (MMP-2, MMP-3, MMP-7, and MMP-9), only MMP-9 was strongly associated with total MMP-13 in both RA and OA. The level of uPA was also strongly associated with MMP-13 in RA but not OA, while the level of TIMP-1 and TIMP-2 was not significantly different between RA and OA. In conclusion, MMP-9 and uPA might be involved in the activation of pro-MMP-13 through unknown mechanisms in arthritic diseases.

Background The biological mechanisms driving orthodontic tooth movement (OTM) remain incompletely understood. Gingival crevicular fluid (GCF) is an important indicator of the periodontal bioprocess, providing valuable cues for probing the molecular mechanisms of OTM. Methods A rigorous review of the clinical studies over the past decade was conducted after registering the protocol with PROSPERO and adhering to inclusion criteria comprising human subjects, specified force magnitudes and force application modes. The thorough screening investigated differentially expressed proteins (DEPs) in GCF associated with OTM. Protein-protein interaction (PPI) analysis was carried out using the STRING database, followed by further refinement through Cytoscape to isolate top hub proteins. Results A comprehensive summarization of the OTM-related GCF studies was conducted, followed by an in-depth exploration of biomarkers within the GCF. We identified 13 DEPs, including ALP, IL-1β, IL-6, Leptin, MMP-1, MMP-3, MMP-8, MMP-9, PGE 2 , TGF-β1, TNF-α, OPG, RANKL. Bioinformatic analysis spotlighted the top 10 hub proteins and their interactions involved in OTM. Based on these findings, we have proposed a hypothetic diagram for the time-course bioprocess in OTM, which involves three phases containing sequential cellular and molecular components and their interplay network. Conclusions This work has further improved our understanding to the bioprocess of OTM, suggesting biomarkers as potential modulating targets to enhance OTM, mitigate adverse effects and support real-time monitoring and personalized orthodontic cycles.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumor invasion, but their prognostic significance is still under discussion. We set out to analyze the epithelial and stromal expression of MMP-2, MMP-7, MMP-9, MT1-MMP, TIMP-1 and TIMP-2 in advanced epithelial ovarian cancers and to assess their prognostic value. A tissue microarray of malignant ovarian tumors from 69 patients was constructed. Immunostaining results were scored using the HSCORE and assessed by univariate analysis with Bonferroni correction and classical multidimensional scaling (CMDS). Kaplan-Meier survival curves calculated with regard to patient and tumor characteristics were compared by the log-rank test. Patients treated by primary surgery (n=43) had a higher tumor size and a trend toward higher epithelial MMP and TIMP expression than those treated by interval surgery (n=26). Optimal cytoreduction (residue ≤1 cm) was obtained in 27 and 18 patients, respectively. Clinical and histological characteristics were not different in patients with optimal cytoreduction and those with suboptimal cytoreduction. The expression of epithelial MMP-9 (P=0.002) and TIMP-2 (P=0.026) were higher in the latter group. CMDS failed to demonstrate any influence of MMP and TIMP expression with regard to cytoreduction outcome. MMP and TIMP expression did not influence survival. Their prognostic values were outweighed by histological type, lymph node involvement and cytoreduction. Standard statistical analysis adjusted after Bonferroni correction and CMDS reduced the relevance of MMPs and TIMPs in the prognosis of patients with advanced ovarian cancer.

Encapsulated papillary carcinoma (EPC) of the breast is a distinct histological subtype characterised by malignant epithelial proliferation supported by fibrovascular stalks. Although EPC typically lacks myoepithelial cells, it shows indolent clinical course. The classification of EPC as an in situ, or invasive disease, remains a matter of debate. Methods In this study, the authors investigated a panel of invasion-associated markers in a series of EPC and compared their expression with control groups of non-papillary ductal carcinoma in situ (DCIS) and conventional invasive carcinomas. The expression pattern of four matrix metalloproteinases (MMP-1, MMP-2, MMP-7 and MMP-9), transforming growth factor receptor beta, vascular endothelial growth factor (VEGF) and E-cadherin were assessed in the tumour cell and/or stromal tissue, and the results were analysed. Results EPC showed higher expression levels of both MMP-1 and MMP-9 compared with DCIS, and no significant differences were observed between EPC and invasive carcinoma. Expression of MMP-2 and MMP-7 levels were similar in EPC and DCIS, but both showed lower levels compared with invasive tumours. EPC showed higher expression of E-cadherin and transforming growth factor receptor ß1 compared with both DCIS and invasive cancer. No difference in the stromal expression of MMPs or tumour expression of VEGF was detected. Conclusion EPC exhibits an expression pattern of invasion-associated markers, which is intermediate in nature between DCIS and invasive cancer, providing further support of the unique biological features of EPC, and which may explain its clinically indolent behaviour.

Background Grayscale image attributes of computed tomography (CT) of pulmonary scans contain valuable information relating to patients with respiratory ailments. These attributes are used to evaluate the severity of lung conditions of patients confirmed to be with and without COVID‐19. Method Five hundred thirteen CT images relating to 57 patients (49 with COVID‐19; 8 free of COVID‐19) were collected at Namazi Medical Centre (Shiraz, Iran) in 2020 and 2021. Five visual scores (VS: 0, 1, 2, 3, or 4) are clinically assigned to these images with the score increasing with the severity of COVID‐19‐related lung conditions. Eleven deep learning and machine learning techniques (DL/ML) are used to distinguish the VS class based on 12 grayscale image attributes. Results The convolutional neural network achieves 96.49% VS accuracy (18 errors from 513 images) successfully distinguishing VS Classes 0 and 1, outperforming clinicians’ visual inspections. An algorithmic score (AS), involving just five grayscale image attributes, is developed independently of clinicians’ assessments (99.81% AS accuracy; 1 error from 513 images). Conclusion Grayscale CT image attributes can be successfully used to distinguish the severity of COVID‐19 lung damage. The AS technique developed provides a suitable basis for an automated system using ML/DL methods and 12 image attributes. Grayscale CT image statistics accurately distinguish the severity of COVID‐19‐related lung conditions Highlights Grayscale image statistics of CT scans can effectively classify lung abnormalities Graphical trends of grayscale statistics distinguish visual assessments COVID‐19 classes Machine/deep learning algorithms predict severity from image grayscale attributes Algorithmic class systems can be established using just five grayscale attributes Confusion matrices provide detailed insight to algorithm prediction capabilities