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Background. Upadacitinib (UPA), demonstrated efficacy and safety in the treatment of Rheumatoid Arthritis (RA) in several randomized clinical trials (RCTs) and in long-term extension (LTE) studies. However, it is well known that experiences in real world evidence (RWE) play a pivotal and complementary role to RCTs. On this basis, Calabrian rheumatologists has decided to collect data aiming at providing futher evidences on the efficacy and safety of UPA in RA patients.   Materials and Methods. To evaluate efficacy and safety, 87 RA patients (>18 years old) were enrolled retrospectively from January 2021 to December 2023 from 11 different Rheumatology Units in Calabria. Data were collected at baseline and the at 3, 6, 12 and 24 months from the start of therapy, including demographic features, prior therapies, comorbidities, RA features, clinimetric data and adverse events (AEs). Of the 87 enrolled patients, 80.5% are women. The mean age is 61.4 ± 10.9 years. The median disease duration is 96 months. The mean BMI is 26.07± 5.23. Eight patients (9.3%) had a history of previous cardiovascular events, ten patients (11.6%) were smokers and two patients (2.3%) ex smokers. Ten patients (11.8%) had a concomitant diagnosis of diabetes, thirty patients (34.9%) had hypertension, two (6.9%) hyperuricemia, thirteen patients (36.1%) had dyslipidemia, three patients (3.5%) had recurrent infections and five patients (5.8%) had a family history of neoplasm. No patients had a history of thromboembolism and four patients (4.6%) had previous events of herpes zoster (HZ), only 6 patients receveid vaccine anti-HZ virus. Twenty-five patients (71.4%) had a positivity for rheumatoid factor (RF) and twenty-two (61.6%) were positive to anti-citrullinated protein antibodies (ACPA). Ninenty-three percent of patients were previously treated with at least one bDMARDs and only one patient with another tsDMARD. During the follow-up, four patients discontinued UPA for lack of efficacy (n=1) or for adverse events (n=3).   Results. We observed a significant reduction of pain, number of tender/swollen joints and a significant reduction of inflammatory parameters was observed at T3, T6, T12 and T24. A significant percentage of patients reached remission (DAS28, CDAI and SDAI) at T3 and a significant steroid-sparing was observed at T3. This Calabrian cohort is a picture on the use of UPA in clinical practice including 87 patients. Among these, 53 patients (60.9%) had at least one risk factors identified by EMA and almost all patients showed an inadeguate response to bDMARDs. Only six patients were vaccinated for HZ. Although this cohort was at high risk to develop HZ and MACE, only 4 patients discontinued therapy for adverse events, no CV events were observed. At T24, only two patients developed a Zoster infection.   Conclusions. Our data confirmed the good safety profile of UPA reported in RCT and in RWE studies. Regarding efficacy, these results confirmed data reported in RCT on the reduction of pain, inflammation and in the improvement of clinical parameters, especially in the so-called difficult-to-treat patients.

Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine that acts on various epithelial cells to regulate cell growth, movement and morphogenesis, and tissue regeneration of injured organs. HGF is sequestered by heparin-like protein in its inactive form and is widespread in the extracellular matrix of most tissues. When the liver loses its average mass, volume, or physiological and biochemical functions due to various reasons, HGF binds to its specific receptor c-Met (cellular mesenchymal-epithelial transition) and transmits the signals into the cells, and triggers the intrinsic kinase activity of c-Met. The downstream cascades of HGF/c-Met include JAK/STAT3, PI3K/Akt/NF-κB, and Ras/Raf pathways, affecting cell proliferation, growth, and survival. HGF has important clinical significance for liver fibrosis, hepatocyte regeneration after inflammation, and liver regeneration after transplantation. And the development of HGF as a biological drug for regenerative therapy of diseases, that is, using recombinant human HGF protein to treat disorders in clinical trials, is underway. This review summarizes the recent findings of the HGF/c-Met signaling functions in liver regeneration.

Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological and pathophysiological conditions and is controlled by a wide range of proangiogenic and antiangiogenic molecules. The plasminogen activator–plasmin system plays a major role in the extracellular matrix remodeling process necessary for angiogenesis. Urokinase/tissue-type plasminogen activators (uPA/tPA) convert plasminogen into the active enzyme plasmin, which in turn activates matrix metalloproteinases and degrades the extracellular matrix releasing growth factors and proangiogenic molecules such as the vascular endothelial growth factor (VEGF-A). The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of uPA and tPA, thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively. Paradoxically, PAI-1, which is expressed by EC during angiogenesis, is elevated in several cancers and is found to promote angiogenesis by regulating plasmin-mediated proteolysis and by promoting cellular migration through vitronectin. The urokinase-type plasminogen activator receptor (uPAR) also induces EC cellular migration during angiogenesis via interacting with signaling partners. Understanding the molecular functions of the plasminogen activator plasmin system and targeting angiogenesis via blocking serine proteases or their interactions with other molecules is one of the major therapeutic strategies scientists have been attracted to in controlling tumor growth and other pathological conditions characterized by neovascularization.

Plant pathogenic bacteria of the genus Xanthomonas inject transcription activator-like effector (TALe) proteins that bind to and activate host promoters, thereby promoting disease or inducing plant defense. TALes bind to corresponding UPT (up-regulated by TALe) promoter boxes via tandemly arranged 34/35-amino acid repeats. Recent studies uncovered the TALe code in which two amino acid residues of each repeat define specific pairing to UPT boxes. Here we employed the TALe code to predict potential UPT boxes in TALe-induced host promoters and analyzed these via β-glucuronidase (GUS) reporter and electrophoretic mobility shift assays (EMSA). We demonstrate that the Xa13, OsTFX1 and Os11N3 promoters from rice are induced directly by the Xanthomonas oryzae pv. oryzae TALes PthXo1, PthXo6 and AvrXa7, respectively. We identified and functionally validated a UPT box in the corresponding rice target promoter for each TALe and show that box mutations suppress TALe-mediated promoter activation. Finally, EMSA demonstrate that code-predicted UPT boxes interact specifically with corresponding TALes. Our findings show that variations in the UPT boxes of different rice accessions correlate with susceptibility or resistance of these accessions to the bacterial blight pathogen.

Fibrotic diseases, such as systemic sclerosis (SSc), idiopathic pulmonary fibrosis, renal fibrosis and liver cirrhosis are characterized by tissue overgrowth due to excessive extracellular matrix (ECM) deposition. Fibrosis progression is caused by ECM overproduction and the inhibition of ECM degradation due to several events, including inflammation, vascular endothelial dysfunction, and immune abnormalities. Recently, it has been reported that urokinase plasminogen activator (uPA) and its receptor (uPAR), known to be fibrinolytic factors, orchestrate the inflammatory response, vascular homeostasis, and immune homeostasis system. The uPA/uPAR system may show promise as a potential therapeutic target for fibrotic diseases. This review considers the role of the uPA/uPAR system in the progression of fibrotic diseases.

Simultaneous ablation of the two known activators of plasminogen (Plg), urokinase‐type (uPA) and the tissue‐type (tPA), results in a substantial delay in skin wound healing. However, wound closure and epidermal re‐epithelialization are significantly less impaired in uPA;tPA double‐deficient mice than in Plg ‐deficient mice. Skin wounds in uPA;tPA ‐deficient mice treated with the broad‐spectrum matrix metalloproteinase (MMP) inhibitor galardin ( N ‐[(2 R )‐2‐(hydroxamido‐carbonylmethyl)‐4‐methylpentanoyl]‐ L ‐tryptophan methylamide) eventually heal, whereas skin wounds in galardin‐treated Plg ‐deficient mice do not heal. Furthermore, plasmin is biochemically detectable in wound extracts from uPA;tPA double‐deficient mice. In vivo administration of a plasma kallikrein (pKal)‐selective form of the serine protease inhibitor ecotin exacerbates the healing impairment of uPA;tPA double‐deficient wounds to a degree indistinguishable from that observed in Plg ‐deficient mice, and completely blocks the activity of pKal, but not uPA and tPA in wound extracts. These findings demonstrate that an additional plasminogen activator provides sufficient plasmin activity to sustain the healing process albeit at decreased speed in the absence of uPA, tPA and galardin‐sensitive MMPs and suggest that pKal plays a role in plasmin generation.

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.

Exosomes (Exos) have been reported to promote pre-metastatic niche formation, proliferation, angiogenesis and metastasis. We have investigated the role of uPAR in melanoma cell lines-derived Exos and their pro-angiogenic effects on human microvascular endothelial cells (HMVECs) and endothelial colony-forming cells (ECFCs). Melanoma Exos were isolated from conditioned media of A375 and M6 cells by differential centrifugation and filtration. Tunable Resistive Pulse Sensing (TRPS) and Nanoparticle tracking analysis were performed to analyze dimension and concentration of Exos. The CRISPR–Cas 9 technology was exploited to obtain a robust uPAR knockout. uPAR is expressed in melanoma Exos that are internalized by HMVECs and ECFCs, enhancing VE-Cadherin, EGFR and uPAR expression in endothelial cells that undergo a complete angiogenic program, including proliferation, migration and tube formation. uPAR loss reduced the pro-angiogenic effects of melanoma Exos in vitro and in vivo by inhibition of VE-Cadherin, EGFR and uPAR expression and of ERK1,2 signaling in endothelial cells. A similar effect was obtained with a peptide that inhibits uPAR–EGFR interaction and with the EGFR inhibitor Gefitinib, which also inhibited melanoma Exos-dependent EGFR phosphorylation. This study suggests that uPAR is required for the pro-angiogenic activity of melanoma Exos. We propose the identification of uPAR-expressing Exos as a potentially useful biomarker for assessing pro-angiogenic propensity and eventually monitoring the response to treatment in metastatic melanoma patients.

Urban and Peri-urban Agriculture (UPA) has recently come into sharp focus as a valuable source of food for urban populations. High population density and competing land use demands lend a spatiotemporally dynamic and heterogeneous nature to urban and peri-urban croplands. For the provision of information to stakeholders in agriculture and urban planning and management, it is necessary to characterize UPA by means of regular mapping. In this study, partially cloudy, intermittent moderate resolution Landsat images were acquired for an area adjacent to the Tokyo Metropolis, and their Normalized Difference Vegetation Index (NDVI) was computed. Daily MODIS 250 m NDVI and intermittent Landsat NDVI images were then fused, to generate a high temporal frequency synthetic NDVI data set. The identification and distinction of upland croplands from other classes (including paddy rice fields), within the year, was evaluated on the temporally dense synthetic NDVI image time-series, using Random Forest classification. An overall classification accuracy of 91.7% was achieved, with user’s and producer’s accuracies of 86.4% and 79.8%, respectively, for the cropland class. Cropping patterns were also estimated, and classification of peanut cultivation based on post-harvest practices was assessed. Image spatiotemporal fusion provides a means for frequent mapping and continuous monitoring of complex UPA in a dynamic landscape.