ADAMTS Proteases: Their Multifaceted Role in the Regulation of Cancer Metastasis.

Cancer leads to nearly 10 million deaths worldwide per year. The tumour microenvironment (TME) is fundamental for tumour growth and progression. A key component of the TME, the extracellular matrix (ECM) has recently become a focus of interest in cancer research. Dysregulation of ECM synthesis and proteolysis leads to uncontrolled tumour growth and metastasis. Matrix remodelling enzymes, secreted by cancer cells and stromal cells, modify the overall structure and organisation of ECM proteins, therefore influencing biochemical interactions, tissue integrity and tissue turnover. While A Disintegrin and Metalloproteinases (ADAMs)' and matrix metalloproteinases' role in cancer has been deeply investigated, other proteolytic enzymes, like ADAMs with thrombospondin(-like) motifs (ADAMTSs) have been gaining interest due to their roles in modulating cancer cell-ECM interactions and oncogenic signalling pathways. In this review, we will discuss the dysregulation of ADAMTSs in cancer and their roles in regulating cancer development and progression, via ECM remodelling and cell signalling modulation.

Imbalance in the vWF - ADAMTS13 axis exists early in acute pancreatitis and predicts persistent organ failure and pancreatic necrosis-a prospective study.

BACKGROUND: The pathophysiology of Acute Pancreatitis (AP) may be complicated by endothelial activation. von Willebrand Factor (vWF)- ADAMTS13 axis is a marker of endothelial activation. The study aimed to investigate the axis in AP, comparing it in patients with and without persistent organ failure (OF), with and without pancreatic necrosis, and correlating it with the standard severity scores (CRP, APACHE II, BISAP, SOFA, and qSOFA) METHODS: vWF-Antigen (vWF:Ag), vWF-Collagen-Binding-Assay (vWF:CBA), and ADAMTS13 activity (ADAMTS13:act) levels were measured within 5 days of symptom onset in consecutive patients (n = 98), who were admitted with a first episode of AP (Dec 2021-May 2023). RESULTS: Of the 98 patients admitted with AP, 78(79.6 %) had no or transient OF; 20(20.4 %) had persistent OF. Age was comparable (43.73 ± 15.36 vs 38.65 ± 13.69) [mean ± SD](years), and males were predominant in both groups (70.5 % vs 80 %). Patientswith persistent OF had higher vWF:CBA(%)[323(279-486.5) vs 199.5(159.1-295.75)] and lower ADAMTS13:act(%)[35.4(23.8-56.85) vs 56.35(44.1-71.9)][median (25th - 75th percentile)](P = 0.001) than those with no or transient OF. Patients with pancreatic necrosis (n = 19) had lower ADAMTS13:act(%)[42.79 ± 18.69] than those without pancreatic necrosis (n = 18) [62.49 ± 22.64] (P < 0.01). ADAMTS13:act had a negative correlation(r = -0.2), whereas vWF:Ag and vWF:CBA had a positive correlation (r = 0.2) with the standard severity scores (P < 0.05). ADAMTS13:act could predict pancreatic necrosis [AUROC-0.737, P < 0.05] and persistent OF [AUROC-0.746, P < 0.001], while vWF:CBA could predict persistent OF [AUROC- 0.73, P < 0.001]. CONCLUSION: vWF-ADAMTS13 axis helps to predict severe disease and is associated with poor outcomes in acute pancreatitis.

von Willebrand factor antigen, von Willebrand factor propeptide and ADAMTS13 activity in TIA or ischaemic stroke patients changing antiplatelet therapy.

Data are limited on the impact of commencing antiplatelet therapy on von Willebrand Factor Antigen (VWF:Ag) or von Willebrand Factor propeptide (VWFpp) levels and ADAMTS13 activity, and their relationship with platelet reactivity following TIA/ischaemic stroke. In this pilot, observational study, VWF:Ag and VWFpp levels and ADAMTS13 activity were quantified in 48 patients ≤4 weeks of TIA/ischaemic stroke (baseline), and 14 days (14d) and 90 days (90d) after commencing aspirin, clopidogrel or aspirin+dipyridamole. Platelet reactivity was assessed at moderately-high shear stress (PFA-100® Collagen-Epinephrine / Collagen-ADP / INNOVANCE PFA P2Y assays), and low shear stress (VerifyNow® Aspirin / P2Y12, and Multiplate® Aspirin / ADP assays). VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d in the overall population (P ≤ 0.03). In the clopidogrel subgroup, VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d (P ≤ 0.01), with an increase in ADAMTS13 activity between baseline vs. 90d (P ≤ 0.03). In the aspirin+dipyridamole subgroup, there was an inverse relationship between VWF:Ag and VWFpp levels with both PFA-100 C-ADP and INNOVANCE PFA P2Y closure times (CTs) at baseline (P ≤ 0.02), with PFA-100 C-ADP, INNOVANCE PFA P2Y and C-EPI CTs at 14d (P ≤ 0.05), and between VWF:Ag levels and PFA-100 INNOVANCE PFA P2Y CTs at 90d (P = 0.03). There was a positive relationship between ADAMTS13 activity and PFA-100 C-ADP CTs at baseline (R2 = 0.254; P = 0.04). Commencing/altering antiplatelet therapy, mainly attributed to commencing clopidogrel in this study, was associated with decreasing endothelial activation following TIA/ischaemic stroke. These data enhance our understanding of the impact of VWF:Ag and VWFpp especially on ex-vivo platelet reactivity status at high shear stress after TIA/ischaemic stroke.

Inhibition of neutrophil rolling and migration by caADAMTS13 in vitro and in mouse models of thrombosis and inflammation.

Recent investigation of a constitutively active ADAMTS13 variant (caADAMTS13) in murine models of acute ischaemic stroke (AIS) have revealed a potential anti-inflammatory mechanism of action contributing to its protective effect. However, it remains unclear whether these observations are a direct result of VWF proteolysis by caADAMTS13. We have implemented state of the art in vitro assays of neutrophil rolling and transmigration to quantify the impact of caADAMTS13 on these processes. Moreover, we have tested caADAMTS13 in two in vivo assays of neutrophil migration to confirm the impact of the treatment on the neutrophil response to sterile inflammation. Neutrophil rolling, over an interleukin-1ß stimulated hCMEC/D3 monolayer, is directly inhibited by caADAMTS13, reducing the proportion of neutrophils rolling to 9.5 ± 3.8 % compared to 18.0 ± 4.5 % in untreated controls. Similarly, neutrophil transmigration recorded in real-time, was significantly suppressed in the presence of caADAMTS13 which reduced the number of migration events to a level like that in unstimulated controls (18.0 ± 4.5 and 15.8 ± 7.5 cells/mm2/h, respectively). Brain tissue from mice undergoing experimental focal cerebral ischaemia has indicated the inhibition of this process by caADAMTS13. This is supported by caADAMTS13's ability to reduce neutrophil migration into the peritoneal cavity in an ischaemia-independent model of sterile inflammation, with the VWF-dependent mechanism by which this occurs being confirmed using a second experimental stroke model. These findings will be an important consideration in the further development of caADAMTS13 as a potential therapy for AIS and other thromboinflammatory pathologies, including cardiovascular disease.

Protease Expression in the Human and Rat Cumulus Oocyte Complex (COC) During the Periovulatory Period: A Role in COC Migration.

The migratory and matrix-invading capacities of the cumulus oocyte complex (COC) have been shown to be important for the ovulatory process. In metastatic cancers, these capacities are due to increased expression of proteases, however, there is limited information on protease expression in the COCs. The present study examined COC expression of plasmins, matrix metalloproteases (MMP) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family members in the rat and human. In the rat, hCG administration increased COC expression of Mmp2, Mmp9, Mmp13, Mmp14, Mmp16, Adamts1, and the protease inhibitors Timp1, Timp3 and Serpine1 by 8-12 hours. This ovulatory induction of proteases in vivo could be mimicked by forskolin and ampiregulin treatment of cultured rat COCs with increases observed in Mmp2, Mmp13, Mmp14, Mmp16, Mmp19, Plat, and the protease inhibitors Timp1, Timp3 and Serpine1. Comparison of expression between rat COCs and granulosa cells at the time of ovulation showed decreased Mmp9 and increased Mmp13, Mmp14, Mmp16, Adamts1, Timp1 and Timp3 expression in the COCs. In human, comparison of expression between cumulus and granulosa cells at the time of IVF retrieval showed decreased MMP1, MMP2, MMP9, and ADAMTS1, while expression of MMP16, TIMP1, and TIMP3 were increased. Treatment of expanding rat COCs with a broad spectrum MMP inhibitor, GM6001, significantly reduced the migration of cumulus cells in vitro. These data provide evidence that multiple proteases and their inhibitors are expressed in the COCs and play an important role in imparting the migratory phenotype of the COCs at the time of ovulation.

Navigating the Nexus: Lenalidomide-Associated Thrombotic Thrombocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) marked by thrombocytopenia, microangiopathic hemolytic anemia, and microvascular thrombosis leading to end-organ damage. While TTP commonly results from hereditary or acquired ADAMTS13 deficiency, its association with lenalidomide is notably rare. The link between lenalidomide and TMA is unclear and requires more studies, given the high mortality risk associated with TTP. The underlying mechanism may involve immunomodulatory effects leading to ADAMTS13 inhibitory antibody formation. Herein, we present a case of a 56-year-old male with a history of multiple myeloma status post autologous stem cell transplant, on lenalidomide maintenance therapy for over five years, who presented with progressive weakness, jaundice, palpitations, and paraesthesia in his extremities. On arrival, the patient was afebrile and was neurologically intact except for the subjective paraesthesia. He was found to have critically low ADAMTS13 activity at <0.03 IU/mL and detectable ADAMTS13 inhibitors, with other findings of TTP, requiring discontinuation of lenalidomide, in addition to receiving treatment for this life-threatening TMA.

Practical approach to thrombocytopenia in patients with sepsis: a narrative review.

Thrombocytopenia frequently occurs in patients with sepsis. Disseminated intravascular coagulation (DIC) may be a possible cause of thrombocytopenia owing to its high prevalence and association with poor outcomes; however, it is important to keep the presence of other diseases in mind in sepsis practice. Thrombotic microangiopathy (TMA), which is characterized by thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (HUS), and complement-mediated HUS, is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage. TMA has become widely recognized in recent years because of the development of specific treatments. Previous studies have reported a remarkably lower prevalence of TMA than DIC; however, its epidemiology is not well defined, and there may be cases in which TMA is not correctly diagnosed, resulting in poor outcomes. Therefore, it is important to differentiate DIC from TMA. Nevertheless, differentiating between DIC and TMA remains a challenge as indicated by previous reports that most patients with TMA can be diagnosed as DIC using the universal coagulation scoring system. Several algorithms to differentiate sepsis-related DIC from TMA have been suggested, contributing to improving the care of septic patients with thrombocytopenia; however, it may be difficult to apply these algorithms to patients with coexisting DIC and TMA, which has recently been reported. This review describes the disease characteristics, including epidemiology, pathophysiology, and treatment, of DIC, TMA, and other diseases with thrombocytopenia and proposes a novel practical approach flow, which is characterized by the initiation of the diagnosis of TMA in parallel with the diagnosis of DIC. This practical flow also refers to the longitudinal diagnosis and treatment flow with TMA in mind and real clinical timeframes. In conclusion, we aim to widely disseminate the results of this review that emphasize the importance of incorporating consideration of TMA in the management of septic DIC. We anticipate that this practical new approach for the diagnostic and treatment flow will lead to the appropriate diagnosis and treatment of complex cases, improve patient outcomes, and generate new epidemiological evidence regarding TMA.

FTO-mediated RNA m6A methylation regulates synovial aggression and inflammation in rheumatoid arthritis.

Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (m6A) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in FLS and synovium from RA patients. Functionally, FTO knockdown or treatment with FB23-2, an inhibitor of the mRNA m6A demethylase FTO, inhibited the migration, invasion and inflammatory response of RA FLS, however, FTO-overexpressed RA FLS exhibited increased migration, invasion and inflammatory response. We further demonstrated that FTO promoted ADAMTS15 mRNA stability in an m6A-IGF2BP1 dependent manner. Notably, the severity of arthritis was significantly reduced in CIA mice with FB23-2 administration or CIA rats with intra-articular injection of FTO shRNA. Our results illustrate the contribution of FTO-mediated m6A modification to joint damage and inflammation in RA and suggest that FTO might be a potential therapeutic target in RA.

Clinical and economic burden of suspected thrombotic thrombocytopenic purpura in US hospitals.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Severe ADAMTS13 deficiency (activity <10%) is the diagnostic threshold for thrombotic thrombocytopenic purpura (TTP) and is associated with various clinical symptoms, abnormal laboratory results, and long-term complications. METHODS: This retrospective, noninterventional cohort study used the Premier Healthcare Database to identify patients with ADAMTS13 activity of <10% in US hospitals from January 1, 2016, through March 31, 2020. The objective was to describe patient characteristics, laboratory results, comorbidities (as measured by the Elixhauser comorbidity index), symptoms, length of stay, treatment patterns, mortality, inpatient costs, and readmission rates (summarized descriptively). Inpatient costs were calculated as total cost to the hospital. RESULTS: There were 211 patients with severe ADAMTS13 deficiency; 89% of patients had a TTP-related diagnosis, of whom 62% had a primary diagnosis of thrombotic microangiopathy. Over 80% of patients with available data had a decreased platelet count and elevated lactate dehydrogenase; schistocytes were detected in 99%. The most prevalent symptoms/complications were neurological, bleeding, and pain. Most patients (86%) had 2 or more Elixhauser comorbidities. Over 80% of patients received 1 or more TTP-related treatments, mostly plasma exchange. The mean length of stay was 11.5 days; 5% of patients died during their stay. Readmission rates at 30, 60, and 90 days were 20%, 26%, and 28%, respectively. The median (interquartile range) total inpatient cost to the hospital throughout the index admission was $33,221 ($19,431-$64,901). CONCLUSION: Patients with severe ADAMTS13 deficiency have substantial clinical burden, have high mortality and readmission rates, and generate high costs for hospitals. There is a high need for a therapy that replaces ADAMTS13, thus addressing the root cause of the symptoms and complications caused by this deficiency.

ADAMTS16 Suppression by MicroRNA-25 Leads to Oncogenic Properties in Renal Cell Carcinoma.

INTRODUCTION: Increasing evidence indicates that microRNAs (miRNAs) play a crucial role in modulating tumor growth. This study is centered on investigating the contribution of miR-25 to the progression of Renal Cell Carcinoma (RCC). METHODS: The investigators examined the expression levels of miR-25 and ADAMTS16 in RCC samples and cell lines. The association between miR-25 and ADAMTS16 was validated via a luciferase reporter assay. Cell viability, apoptosis, migration, and invasion were evaluated utilizing CCK-8 and flow cytometry techniques, while the expression levels of ADAMTS16, ß-catenin, GSK-3ß, and p-GSK-3ß were assessed through western blot analysis. RESULTS: The investigation revealed elevated expression levels of miR-25 in RCC tissues. Subsequently, ADAMTS16 was identified as a target of miR-25. Increased miR-25 levels were associated with decreased expression of ADAMTS16, resulting in enhanced cell viability and diminished apoptosis. Conversely, inhibition of miR-25 led to decreased cell viability, proliferation, and migration. Additionally, the researchers observed that miR-25 triggered the phosphorylation of GSK-3ß and ß-catenin while leaving the total GSK-3ß level unaffected. CONCLUSION: This study suggests that miR-25 regulates the expression of ADAMTS16 through the Wnt/ß-catenin signaling pathway, providing new insights into the cause and potential treatment of RCC.

The effect of ADAMTS13 on graft-versus-host disease.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) can potentially cure malignant blood disorders and benign conditions such as haemoglobinopathies and immunologic diseases. However, allo-HSCT is associated with significant complications. The most common and debilitating among them is graft-versus-host disease (GVHD). In GVHD, donor-derived T cells mount an alloimmune response against the recipient. The alloimmune response involves several steps, including recognition of recipient antigens, activation and proliferation of T cells in secondary lymphoid organs, and homing into GVHD-targeted organs. Adhesion molecules on T cells and endothelial cells mediate homing of T cells into lymphoid and non-lymphoid tissues. In this study, we showed that Von Willebrand factor (VWF), an adhesion molecule secreted by activated endothelial cells, plays an important role in mouse models of GVHD. We investigated the effect of the VWF-cleaving protease ADAMTS13 on GVHD. We found that ADAMTS13 reduced the severity of GVHD after bone marrow transplantation from C57BL6 donor to BALB/C recipient mice. A recombinant VWF-A2 domain peptide also reduced GVHD in mice. We showed that ADAMTS13 and recombinant VWF-A2 reduced the binding of T cells to endothelial cells and VWF in vitro, and reduced the number of T cells in lymph nodes, Peyer's patches and GVHD-targeted organs in vivo. We identified LFA-1 (αLß2) as the binding site of VWF on T cells. Our results showed that blocking T-cell homing by ADAMTS13 or VWF-A2 peptide reduced the severity of the GVHD after allo-HSCT, a potentially novel method for treating and preventing GVHD.

Hematological features and alternate diagnoses in critically ill thrombotic antiphospholipid syndrome patients.

OBJECTIVES: Severe thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome. METHODS: This French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers' ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied. RESULTS: One hundred and thirty-four patients, female 72%, median [IQR] age 45 [34-56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3-8.8] g/dL and 38 [21-60] g/L, respectively. The lowest platelet count below 20 g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27-74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients. CONCLUSION: Thrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients. Key Points • Thrombocytopenia is the hallmark laboratory finding in CAPS. • A complete thrombotic microangiopathy pattern is infrequent in CAPS patients. • Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated.

Ratio of von Willebrand factor to ADAMTS13 is a useful predictor of esophagogastric varices progression after sustained virologic response in patients with hepatitis C virus-related liver cirrhosis.

AIM: Esophagogastric varices (EGV) are a serious complication of hepatitis C virus (HCV)-related liver cirrhosis (HCV-LC). In most cases, portal hypertension improves after a sustained virologic response (SVR) is achieved with direct-acting antiviral (DAA) treatment; however, in some cases, EGV exacerbation occurs after HCV elimination. We investigated whether von Willebrand factor (VWF) and a disintegrin-like metalloproteinase with thrombospondin type-1 motif 13 (ADAMTS13) can predict EGV progression with HCV-LC after SVR achievement. METHODS: This retrospective study enrolled 47 patients with HCV-LC who achieved an SVR after DAA treatment. Eighteen patients experienced EGV progression after the SVR was achieved (EGV progression group). Twenty-nine patients did not experience EGV progression after the SVR was achieved (non-EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity were measured the day before DAA treatment. RESULTS: The EGV progression group had significantly higher plasma VWF antigen levels (p = 0.00331) and VWF-to-ADAMTS13 ratios (p = 0.000249) than the non-EGV progression group. Multivariate logistic regression models found that a VWF-to-ADAMTS13 ratio >2.3 was the only risk factor for EGV progression after the SVR was achieved (hazard ratio [HR], 18.4; 95% confidence interval [CI], 3.08-109; p = 0.00138). During the observation period, patients with a VWF-to-ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after SVR achievement than patients with a VWF-to-ADAMTS13 ratio ≤2.3 (HR, 6.4; 95% CI, 1.78-22.96; p = 0.0044). CONCLUSIONS: The VWF-to-ADAMTS13 ratio before DAA treatment for HCV could predict EGV progression after SVR achievement.

Thrombotic Thrombocytopenic Purpura in the Setting of Cirrhosis and Baseline Thrombocytopenia.

The management of immune thrombotic thrombocytopenic purpura (iTTP) has evolved significantly over the past several years. However, despite recent advances, there are limited tools available for patients with comorbidities that preclude either the utilization of available treatment modalities or evidence-based laboratory target levels. Literature to guide the management of such patients is sparse at best, and many complications associated with pre-existing comorbidities in the context of iTTP have not been reported. Here we describe the case of a patient with severe thrombocytopenia at baseline due to liver cirrhosis who developed iTTP. The challenges of the case in terms of pursuing disease-directed treatment, defining laboratory parameters to guide treatment, and mitigating the risks of bleeding and disease exacerbation are discussed. We offer our perspective in treating iTTP in the setting of severe baseline thrombocytopenia and high bleeding risk.

Serum ARGS-aggrecan in a phase 2 clinical trial targeting osteoarthritis.

OBJECTIVE: To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function. DESIGN: ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by magnetic resonance imaging, function and pain by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression. RESULTS: S201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post-treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope -0.8×10-6 [-2.9×10-6, 1.3×10-6]) or change in WOMAC pain and function (slopes -30×10-6 [-64×10-6, 5.2×10-6] and -97×10-6 [-214×10-6, 20×10-6], respectively) at week 52. CONCLUSION: Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function.

Imbalance of the von Willebrand Factor - ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S).

BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an ultra-rare, autosomal-dominant small vessel disease caused by loss-of-function variants in the gene TREX1. Recently, elevated serum levels of von Willebrand Factor Antigen (vWF-Ag) pointed to an underlying endotheliopathy, and microvascular ischemia was suggested to contribute to the neurodegeneration in RVCL-S. Aim of this study was to further elucidate the endotheliopathy in RVCL-S. METHODS: vWF-Ag and ADAMTS-13 activity were repeatedly measured in two patients with genetically confirmed RVCL-S. Renal biopsy of both RVCL-S patients and autoptic brain, renal, hepatic, and pulmonary specimen of one patient with RVCL-S were examined immunohistochemically in comparison to matched controls. In addition, cerebral methylome analysis was performed in the autoptic brain specimen calculating differentially methylated positions compared to controls. RESULTS: While vWF-Ag and activity was strongly elevated, ADAMTS-13 activity was low in RVCL-S and further decreased over the course of the disease. Autoptic brain specimen showed signs of thromboinflammation in cerebral small vessels, and vWF-Ag staining was strongly positive in cerebral and renal small vessels in RVCL-S, while only a light to moderate vWF-Ag staining was found in controls. Cerebral methylome analysis yielded 115 differentially methylated CpGs (p < 0.05) in the deceased RVCL-S patient compared to the eight controls without brain pathology. One of the hypomethylated genes coded for ADAMTS-13 (p = 0.00056). CONCLUSIONS: These findings point to an imbalance of the vWF - ADAMTS-13 axis in patients with RVCL-S, that may finally lead to an accumulation of vWF-Ag in renal and cerebral small vessels. Elevated vWF-Ag levels may serve as an early serum marker reflecting disease activity. If confirmed, therapeutic approaches might aim at an inhibition of vWF-Ag or increase of ADAMTS-13 activity in the future.

Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks.

To elucidate the molecular genetic mechanisms underpinning feather color in Muscovy ducks. A cohort of 100 Muscovy ducks was meticulously selected for this research. Follicular tissues from ducks exhibiting black and white plumage served as the experimental samples. From these tissues, RNA and proteins were extracted for further analysis. The RNA underwent reverse transcription polymerase chain reaction amplification, followed by validation through western blot assays. The data revealed a significant upregulation in the expression of FN domain-containing protein 1 (FNDC1) and ADAMTS12 genes in Muscovy ducks with white plumage traits as opposed to those with black plumage traits. Specifically, individuals with pure white plumage demonstrated a markedly elevated expression of the FNDC1 gene in comparison to their pure black counterparts. Conversely, expression levels of the ADAMTS12 gene were found to be reduced in ducks with pure black plumage relative to those with pure white plumage. Notably, the expression patterns of FNDC1 and ADAMTS12 genes exhibited inconsistencies between mRNA and protein levels. This study offers significant insights into the molecular genetic mechanisms underlying feather color variation in Muscovy ducks. FNDC1 and ADAMTS12 could be considered potential targets for genetic manipulation or selective breeding strategies aimed at achieving specific feather color phenotypes in Muscovy ducks.

Histological Structure and Immunohistochemical Properties of the Ligamentum Teres in Patients With Developmental Dysplasia of the Hip.

Introduction This study aims to evaluate the histology of the ligamentum teres and its relationship with matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which are involved in the destruction of extracellular matrix proteins in patients with developmental dysplasia of the hip (DDH). Methodology The patients who underwent open reduction and pelvic osteotomy due to DDH were included in the study. Patient groups were formed according to Tönnis stages, positive family history, consanguineous marriage, age, and bilateral involvement. The histology and immunohistochemical properties (MMP-2, MMP-9, and ADAMTS-7) of ligamentum teres tissue obtained from the patients were evaluated according to these groups. Results Thirty-five patients (female 30, 85.7%; male 5, 14.3%) with DDH between the ages of 14 and 99 months were included in the study. Preoperative and postoperative Tönnis stages, positive family history, consanguineous marriage, age, and bilaterality did not cause a significant difference between histological parameters. A significant correlation was found between MMP-2, MMP-9, and ADAMTS-7 and all histological parameters. Conclusions The histological structure of ligamentum teres in patients with DDH shows moderate inflammation, fibrosis, neovascularization, hyalinization, and fatty infiltration regardless of age and radiological stage. ADAMTS-7, MMP-2, and MMP-9 correlate positively with the histological parameters of the ligamentum teres in patients with DDH.