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INTRODUCTION Few African American (AA) donors have been included in post mortem Alzheimer's disease (AD) studies compared to European‐ancestry (EA) individuals. METHODS We generated transcriptome‐wide bulk pre‐frontal cortex (PFC) gene expression data from 125 AA donors with neuropathologically determined AD and 82 AA controls. RESULTS Transcriptome‐wide significant differential expression was observed with 482 genes. The most significant, ADAMTS2, showed 1.52 times higher expression in AD cases (p = 2.96x10−8). Comparison of findings with those from a recent gene expression study of EA brain donors revealed substantial concordance, including ADAMTS2. Other associations not observed in EA results may be especially relevant to AD risk in the AA population. Examination of AA AD GWAS‐implicated variants identified several expression quantitative trait loci. CONCLUSION This first large‐scale AA brain AD gene expression study identified many differentially expressed genes, including ADAMTS2, and supports gene expression as a molecular pathway underlying the impact of several AA AD risk variants. Highlights We performed the largest African American brain tissue Alzheimer's disease (AD) gene expression study. Expression differences for 482 genes, notably ADAMTS2, were study‐wide significant. Many significant differentially expressed genes are involved in energy metabolism. Several previously known AD‐associated variants in African Americans are eQTLs. These results advance knowledge of the genetic basis of AD in the AA population.

Collagen type VIII alpha 1 chain (COL8A1) is a part of the collagen family and has been involved in tumor progression in numerous cancers. Nevertheless, its expression pattern, functional role, and underlying mechanisms in prostate cancer (PCa) remain largely unexplored. COL8A1 expression was analyzed using public datasets and clinical samples. Functional roles of COL8A1 in PCa cells were assessed via CCK-8, Transwell, wound healing, and flow cytometry assays. Protein interactions were assessed by co-immunoprecipitation and pull-down assays. The underlying mechanism was explored using Western blot (WB), bioinformatics analysis, and in vivo xenograft models. COL8A1 was significantly increased in PCa tissues and cell lines, and its expression related to advanced clinicopathological features and poor progression-free survival. Functional studies showed that COL8A1 promotes cell proliferation, invasion, and migration while inhibiting apoptosis. Mechanistically, COL8A1 interacts with ADAMTS2, and its modulation affects ADAMTS2 protein expression. This interaction results in stimulation of the FAK/PI3K/AKT pathway. ADAMTS2 suppression partially reversed the oncogenic effects of COL8A1 overexpression. Moreover, COL8A1 expression was positively linked to immune cell infiltration in the tumor microenvironment. In vivo experiments confirmed that COL8A1 knockdown suppresses tumor growth. Our findings identify COL8A1 as an innovative oncogenic driver in PCa that promotes tumor progression via modulation of the ADAMTS2-FAK/PI3K/AKT axis and immune infiltration. COL8A1 may be a potential prognostic biomarker and therapeutic target for PCa.

Background The importance of epithelial‒mesenchymal transition (EMT) in tumour invasion and metastasis in high-grade serous ovarian cancer (HGSOC) has been highlighted in numerous studies, but genetic biomarkers for predicting EMT in HGSOC are still lacking. Methods The role of EMT hallmarks and the relationship between EMT and the tumour microenvironment in HGSOC were examined based on transcriptomic data from 366 HGSOC patients in the TCGA dataset via the GSVA algorithm, the ESTIMATE method and Pearson correlation analyses. Furthermore, machine learning was applied to determine key EMT signatures and classify EMT subtypes. Moreover, the role of the key EMT signature ADAMTS2 in the behaviour and EMT process of HGSOC cells was detected via western blot, CCK8, transwell, wound healing and immunofluorescence assays. Results The expression of EMT hallmarks (EMT score) was significantly associated with the progression, immune microenvironment and prognosis of HGSOC patients. Different machine learning algorithms identified MMP2 , ADAMTS2 , FN1 , THBS2 , C3ORF80 , FAP and POSTN as key EMT-related signatures in HGSOC. Finally, qPCR, western blotting and IHC staining consistently revealed elevated expression of ADAMTS2 in five ovarian cancer tissues from HGSOC patients and five normal ovarian epithelial tissues from five uterine prolapse patients. Further in vitro experiments revealed that ADAMTS2 knockdown inhibited cell proliferation, migration, and invasion as well as the expression of TNF-α, IL-1β and EMT markers (E-cadherin, N-cadherin, SLUG, and TWIST1), whereas ADAMTS2 overexpression promoted the above cellular behaviours and increased the expression of TNF-α, IL-1β and EMT markers. Conclusion Our study presents a new classifier to predict EMT and the immune microenvironment in HGSOC and identifies ADAMTS2 as a novel regulator of the EMT process. These findings might promote the development of EMT-related immunotherapeutic strategies for HGSOC patients.

Purpose: The Ehlers–Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility. Methods: We report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition. Results: We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients. Conclusion: This study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS. Genet Med 18 9, 882–891.

Background Excessive inflammation and alveolar barrier dysfunction are commonly observed in acute respiratory distress syndrome (ARDS). ADAMTS2 is an ECM‐remodeling metalloproteinase with emerging immunomodulatory roles and may influence inflammatory injury and epithelial barrier stability via PI3K/AKT/mTOR signaling. Methods Transcriptome sequencing of peripheral blood samples from ARDS patients revealed elevated ADAMTS2 expression. An in vitro ARDS model was established by stimulating human type II alveolar epithelial cells with LPS. The impact of ADAMTS2 silencing on inflammatory response, autophagic activity, tight junction proteins, and PI3K/AKT/mTOR signaling was examined through qRT‐PCR, Western blot, immunofluorescence, ELISA, and flow cytometry analyses. A rescue experiment was performed using the PI3K activator 740 Y‐P. Results ADAMTS2 was significantly upregulated in ARDS transcriptomic analysis, with functional enrichment highlighting ECM‐related processes and PI3K/AKT/mTOR signaling. In LPS‐stimulated alveolar epithelial cells, ADAMTS2 expression was 2.5–3.0‐fold higher than that in control cells. ADAMTS2 silencing reduced TNF‐α and IL‐1β release by 55%–60% and decreased apoptosis by 30%, while improving barrier integrity (increased ZO‐1/Occludin levels and TEER). Autophagy‐related changes were observed upon ADAMTS2 knockdown, including increased Beclin‐1 and LC3B‐II levels with reduced p62/SQSTM1 accumulation. Mechanistically, ADAMTS2 knockdown attenuated PI3K/AKT/mTOR phosphorylation, and these protective effects were partially reversed by the PI3K agonist 740 Y‐P. Conclusion ADAMTS2 knockdown mitigated LPS‐induced epithelial injury and barrier dysfunction, in association with PI3K/AKT/mTOR signaling and autophagy‐related changes, suggesting ADAMTS2 as a potential therapeutic target for ARDS pending further in vivo validation.

Ehlers–Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC. Three different alterations were detected in the two patients with typical EDS type VIIC. The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3–5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an in-frame skipping of exons 14–16 at the mRNA level. Although the exons 3–5 or 14–16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function. The three other patients with a phenotype with some resemblance to EDS type VIIC only had silent and functionally neutral variations also frequently found in a normal population.

Background Mixed phenotype acute leukemias (MPAL) include acute leukemias with blasts that express antigens of more than one lineage, with no clear evidence of myeloid or lymphoid lineage differentiation. T/myeloid (T/My) MPAL not otherwise specified (NOS) is a rare leukemia that expresses both T and myeloid antigens, accounting for less than 1% of all leukemias but 89% of T/My MPAL. From a molecular point of view, very limited data are available on T/My MPAL NOS. Case presentation In this report we describe a T/My MPAL NOS case with a complex rearrangement involving chromosomes 5 and 14, resulting in overexpression of the ADAM metallopeptidase with thrombospondin type 1 motif, 2 ( ADAMTS2 ) gene due to its juxtaposition to the T cell receptor delta ( TRD ) gene segment. Conclusion Detailed molecular cytogenetic characterization of the complex rearrangement in the reported T/My MPAL case allowed us to observe ADAMTS2 gene overexpression, identifying a molecular marker that may be useful for monitoring minimal residual disease. To our knowledge, this is the first evidence of gene dysregulation due to a chromosomal rearrangement in T/My MPAL NOS.

Ascorbic acid (vitamin C) is a cofactor required for the function of several hydroxylases and monooxygenases. It is not synthesized in humans and some other animal species and has to be provided by diet or pharmacologic means. Its absence is responsible for scurvy, a condition related in its initial phases to a defective synthesis of collagen by the reduced function of prolylhydroxylase and production of collagen polypeptides lacking hydroxyproline, therefore, they are unable to assemble into stable triple-helical collagen molecules. In fibroblast cultures, vitamin C also stimulates collagen production by increasing the steady-state level of mRNA of collagen types I and III through enhanced transcription and prolonged half-life of the transcripts. The aim of the experimental work has been to evaluate the effect on dermal cells of a preparation of vitamin C topically applied on one side vs placebo on the other side of the dorsal face of the upper forearm of postmenopausal women. Biopsies were collected on both sides and the level of mRNA measured by non competitive reverse transcription-polymerase chain reaction made quantitative by the simultaneous transcription and amplification of synthetic RNA used as internal standards. The mRNA of collagen type I and type III were increased to a similar extent by vitamin C and that of three post-translational enzymes, the carboxy- and amino-procollagen proteinases and lysyloxidase similarly increased. The mRNA of decorin was also stimulated, but elastin, and fibrillin 1 and 2 were not modified by the vitamin. The expression of matrix metalloproteinases 1, 2, and 9 was not significantly changed, but an increased level of tissue inhibitor of matrix metalloproteinase 1 mRNA was observed without modification of tissue inhibitor of matrix metalloproteinase 2 mRNA. The stimulating activity of topical vitamin C was most conspicuous in the women with the lowest dietary intake of the vitamin and unrelated to the level of actinic damage. The results indicate that the functional activity of the dermal cells is not maximal in postmenopausal women and can be increased.

Chondrosarcoma is one of the most common bone tumors, and at present, there is no non-invasive treatment option for this cancer. The chondrosarcoma OUMS-27 cell line produces proteoglycan and type II, IX, and XI collagens, which constitutes cartilage tissue. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteases are a group of secreted proteases, which include the procollagen N-proteinases ADAMTS-2, -3 and -14. These procollagen N-proteinases perform a role in the processing of procollagens to collagen and the maturation of type I collagen. The present study aimed to improve the understanding of the causes of metastasis, local invasion and resistance to chemo- and radiotherapy in chondrosarcoma, as well as the effect of insulin on cancer cells. The present study was designed to reveal the effects of insulin on procollagen N-proteinases in chondrosarcoma OUMS-27 cells. The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) alone or in DMEM containing 10 µg/ml insulin. The medium was changed every other day for 11 days. The cells were harvested on days 1, 3, 7 and 11, and total RNA isolation was performed immediately following harvesting. The expression levels of ADAMTS2, ADAMTS3 and ADAMTS14 mRNA were estimated by reverse transcription-quantitative polymerase chain reaction using appropriate primers. ADAMTS2 mRNA expression was found to be decreased on day 7 (P=0.028) and increased at day 11 compared with the control group (P=0.016). The increase in mRNA concentration at day 11 was significantly different compared to the concentrations on days 3 (P=0.047) and 7 (P=0.008). The expression of ADAMTS3 mRNA decreased immediately subsequent to insulin induction on day 1 compared with the control group (P=0.008). The most evident decrease in mRNA concentration was seen at day 7 subsequent to insulin induction (P=0.008). The present results demonstrated that ADAMTS2 and ADAMTS3 may perform a role in the invasion and metastasis of tumors, and may also possess proteolytic activity that results in the breakdown of the extracellular matrix (ECM). Insulin itself can modulate the biosynthesis of ECM macromolecules that are altered in diabetes through various pathways.

The regulated expression of ADAMTS2 ( a d isintegrin a nd m etalloproteinase with t hrombo s pondin motifs), a secreted metalloproteinase involved in the processing of procollagen to collagen, was studied in peripheral blood mononuclear cells (PBMC). Stimulation with glucocorticoids (GC) resulted in a pronounced dose- and time-dependent increase of ADAMTS2 mRNA levels in PBMC. The increase of ADAMTS2 expression was specific for CD14++ monocytes (440-fold) and alveolar macrophages (200-fold), whereas CD3+ (T lymphocytes), phytohemagglutinin-activated CD3+ (T lymphocytes), and CD19+ (B lymphocytes) showed no significant changes in ADAMTS2 mRNA after GC treatment. Treatment of monocyte-derived macrophages (MDM) with GC also resulted in an increase of ADAMTS2 protein in the culture tissue media. Using the GC analog RU486, GC-mediated induction of ADAMTS2 mRNA was blocked, implicating that GC acts specifically via the GC-receptor. In agreement with findings in blood monocytes, cell lines of the monocytic lineage (MM6, THP-1) showed significant GC-induced significant increases in ADAMTS2 mRNA, while in epithelial cells (A549, Calu-3, Colo320, BT-20) and fibroblast (MRC-5, WI-38, and two NHDF-c cell types from adult cheek and upper arm), they showed no or little responsiveness to GC. As macrophages have important functions in immune defense and tissue homeostasis, these findings suggest that GC-mediated specific induction of ADAMTS2 in these cells may play a crucial role in the resolution of inflammation and wound repair.