The investigation of serum levels of ADAMTS 5 and 8 (the A disintegrin and metalloproteinase with thrombospondin motifs) in the etiology of endometrial cancer.

The aim of this study was to investigate the serum levels of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 and 8 in patients diagnosed with endometrial cancer. Our study included 41 patients diagnosed with endometrial cancer. The control group consisted of 41 patients diagnosed with benign endometrial pathology. The serum samples were centrifuged and stored at -80 °C. The serum levels of ADAMTS were significantly higher (p<.001), whereas the levels of ADAMTS 8 were significantly lower in patients diagnosed with cancer (p<.001). In addition to the presence of known factors in the aetiology of endometrial cancer, the effect of inflammatory factors and some new proteins has centred on the causes of tumourigenesis in recent years. In this sense, these proteins, called the ADAMTS, are the source of new studies.Impact StatementWhat is already known on this subject? When the recent studies about endometrial cancer are evaluated, it is seen that the effects of chronic inflammation and cytokines have gained importance in its aetiology. The A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) gene family consist of 19 proteases that play essential role in the formation of the extracellular matrix (ECM) and interact with inflammatory cytokines. These proteases and their substrates provide a wide range of functions in different tissues, including ECM remodelling, angiogenesis, fibrosis and coagulation.What the results of this study add? ADAMTS 5, which causes the degradation of the ECM with Aggrecanase activity, was found to be significantly higher in patients diagnosed with cancer and ADAMTS 8 with anti-angiogenesis activity was significantly lower in patients diagnosed with endometrial cancer.What the implications are of these findings for clinical practice and/or further research? In this study, it is understood that the effect of inflammatory mediators is remarkably important in the aetiology of endometrial cancer, as in many types of organ specific cancer.

Decreased ADAMTS-1, -9 and -20 levels in women with endometrial polyps: a possible link between extracellular matrix proteases and endometrial pathologies.

A disintegrin-like and metalloproteinase domain with thrombospondin-type 1 motifs (ADAMTS) protein superfamily includes 19 secreted metalloproteases. Proteolytic substrates of ADAMTS enzymes have been linked to female reproductive function. Herein, we aimed to investigate serum ADAMTS-1, -9 and -20 levels in women with and without endometrial polyps (EPs). The study group (n = 40) consisted of women who had hysteroscopically detected and histologically confirmed EPs whereas control group (n = 40) was recruited from those women without any endometrial pathology. Data recorded for every woman were as follows: age, body mass index, gravidity and parity, number of miscarriages, smoking status and serum ADAMTS-1, -9 and -20 levels. ADAMTS-1, -9 and -20 values were measured by commercially available ELISA kits. No statistically significant differences between the groups were observed in terms of demographics. There were also no statistically significant differences between the groups with regard to ADAMTS-1 and -20 levels, although both of them were lower in the study group. However, ADAMTS-9 was significantly lower in the study group compared to the controls (p = .010). The optimal cut off value of ADAMTS-9 in predicting EPs was found to be 163.2 ng/mL with 100% sensitivity and 35% specificity. In conclusion, ADAMTS-9 protein is decreased in women with EPs. Impact statement What is already known on this subject? Endometrial polyps (EPs) are common and are generally benign gynaecologic disorders. ADAMTS enzymes comprise a zinc metalloproteinase gene family that has roles in vascular biology, inflammation and especially in the control of the function and structure of the extracellular matrix (ECM). ECM plays an important role in the pathogenesis of myomas, adenomyosis and abnormal uterine bleeding, as well as EPs. There is an interest in these proteases, especially with regard to the physiology of ovulation and implantation. They are also associated with carcinogenesis and metastasis. One of the most feared consequences of EPs is the risk of malignancy. Therefore, it is important in gynaecology practice to diagnose these endometrial abnormalities. What do the results of this study add? This is the first study performed to investigate the relationship between some ADAMTS (-1, -9 and -20) proteases and uterine polyps. Our results demonstrate novel molecular mediators contributing to EPs physiopathology. What are the implications of these findings for clinical practice and/or further research? ADAMTS-9 is defined as a tumour suppressor gene in various malignancies. Decreased ADAMTS-9 protein, which is the product of this gene, may have a role in the pathogenesis of EPs. There is a need for further research that should be done with benign-malign EPs.

ADAMTSL4, a Secreted Glycoprotein, Is a Novel Immune-Related Biomarker for Primary Glioblastoma Multiforme.

BACKGROUND: Researches on immunotherapy of glioblastoma multiforme (GBM, WHO grade IV) have increased exponentially in recent years. As a targeted therapy, a series of biomarkers have been identified in local tumor tissue, while circulating marker which could be detected in the body fluids is still lacking. ADAMTSL4, a secreted glycoprotein, was earlier found to play a critical role in a prognostic signature for primary GBM (pGBM). We aimed to investigate the role of ADAMTSL4 at transcriptome level and its relationship with clinical practice in pGBM. METHODS: A cohort of 88 pGBM patients with RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) was analyzed, and 168 pGBM patients from TCGA were included as validation. Several bioinformatic methods and predictive tools were applied to investigate the ADAMTSL4-associated immune microenvironment status. RESULTS: We found that ADAMTSL4 was enriched in GBM (WHO grade IV), especially for those with IDH1/2 wild-type and MGMT unmethylated groups. According to the TCGA classification scheme, ADAMTSL4 can act as a potential marker for subtypes with poorer prognosis. Bioinformatic analyses revealed that ADAMTSL4 was significantly correlated to the immune-related processes in GBM (WHO grade IV), especially representing the infiltration of immune cells and complicated tumor microenvironment. Clinically, high expression of ADAMTSL4 was an independent indicator for poor prognosis. CONCLUSION: The expression of ADAMTSL4 is closely related to the clinicopathologic characteristics of pGBM. Meanwhile, it may play a critical role in immune-related processes. As a secreted glycoprotein, ADAMTSL4 is a promising circulating biomarker for pGBM, deserving further investigations.

Comparison of Serum A Disintegrin and Metalloproteinase with Thrombospondin Motifs-19 Levels in Different Fertility Situations: Could It Be a Serum Marker of Ovarian Function and Oocyte Pool?

BACKGROUND/AIMS: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) enzymes take part in extracellular matrix (ECM) remodeling which has been shown to contribute to the ovulation and follicular functions. We aimed to compare serum levels of ADAMTS-19 in patients with different fertility situations. METHODS: A total of 86 women were enrolled to this cross sectional and case-control study. Four groups were constituted with respect to women's clinical and hormonal status: group 1, women with premature ovarian failure (POF; n = 21); group 2, women with natural menopause (n = 21); group 3, women with polycystic ovary syndrome (PCOS; n = 22); and group 4, healthy fertile controls. Serum ADAMTS-19 levels and individual characteristics were compared among groups. RESULTS: -ADAMTS-19 levels were found as 36.7 ± 10.2, 40.1 ± 12.6, 46.7 ± 16.1, and 51.0 ± 18.8 ng/mL in POF, fertile, natural menopause, and PCOS groups, respectively (p = 0.012). Especially, ADAMTS-19 levels in the PCOS group were significantly higher than the POF group, as found in dual comparisons (p = 0.010). CONCLUSIONS: ADAMTS-19 was found to be higher in PCOS patients than in POF patients. This work provides a novel vantage point for function of ECM within the ovary. ADAMTS-19 may have a potential for being an important marker of ovarian function and oocyte pool.

Relationship between ADAMTS14/rs4747096 gene polymorphism and knee osteoarthritis in Chinese population.

To investigate the association between single nucleotide polymorphisms (SNPs) of A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 14 (ADAMTS14) gene and susceptibility to knee osteoarthritis (KOA) in Chinese Han population. Using a case-control design, we enrolled 346 KOA patients and 480 healthy controls. Peripheral blood samples were extracted from each subject. Genotype was determined by sequencing PCR products. The genotype frequencies between cases and controls were compared. The genotype distribution was in accordance with Hardy-Weinberg equilibrium. The minor G allele in case group was significantly higher than in the control group (21.4 compared with 8.8%, P=0.000, odds ratio (OR) = 1.71 (95% confidence interval (CI): 1.39-2.11). The GG genotype and the GG/AG combination were more common in the osteoarthritis (OA) group than in the control group. Compared with AA genotype, the GG (OR = 3.09, 95%CI: 2.01-4.75), AG (OR = 2.55, 95%CI: 1.64-3.96), and GG/AG (OR = 1.57, 95%CI: 1.19-2.07) increased the risk of OA. Multiple logistic confirmed the findings by adjusting some potential factors. Subgroup analysis indicated that the ras4747096 was still significantly associated with KOA. There were no significant differences in allele frequency or genotypes frequency for erythrocyte sedimentation rate and C-reaction protein in OA patients (P>0.05). ADAMTS14 gene polymorphism was associated with KOA, and the GG genotype increased the risk of KOA in Chinese Han population. The ADAMTS14 may be a diagnostic marker and therapeutic target for KOA treatment. The future study should explore the specific molecular mechanism.

Comparative analysis of gene expression in maternal peripheral blood and monocytes during spontaneous preterm labor.

BACKGROUND: Preterm birth is the leading cause of newborn death worldwide, and is associated with significant cognitive and physiological challenges in later life. There is a pressing need to define the mechanisms that initiate spontaneous preterm labor, and for development of novel clinical biomarkers to identify high-risk pregnancies. Most preterm birth studies utilize fetal tissues, and there is limited understanding of the transcriptional changes that occur in mothers undergoing spontaneous preterm labor. Earlier work revealed that a specific population of maternal peripheral leukocytes (macrophages/monocytes) play an active role in the initiation of labor. Thus, we hypothesized that there are dynamic gene expression changes in maternal blood leukocytes during preterm labor. OBJECTIVE: Using next-generation sequencing we aim to characterize the transcriptome in whole blood leukocytes and peripheral monocytes of women undergoing spontaneous preterm labor compared to healthy pregnant women who subsequently delivered at full term. STUDY DESIGN: RNA sequencing was performed in both whole blood and peripheral monocytes from women who underwent preterm labor (24-34 weeks of gestation, N = 20) matched for gestational age to healthy pregnant controls (N = 30). All participants were a part of the Ontario Birth Study cohort (Toronto, Ontario, Canada). RESULTS: We identified significant differences in expression of 262 genes in peripheral monocytes and 184 genes in whole blood of women who were in active spontaneous preterm labor compared to pregnant women of the same gestational age not undergoing labor, with 43 of these genes differentially expressed in both whole blood and peripheral monocytes. ADAMTS2 expression was significantly increased in women actively undergoing spontaneous preterm labor, which we validated through digital droplet reverse transcriptase polymerase chain reaction. Intriguingly, we have also identified a number of gene sets including signaling by stem cell factor-KIT, nucleotide metabolism, and trans-Golgi network vesicle budding, which exhibited changes in relative gene expression that was predictive of preterm labor status in both maternal whole blood and peripheral monocytes. CONCLUSION: This study is the first to investigate changes in both whole blood leukocytes and peripheral monocytes of women actively undergoing spontaneous preterm labor through robust transcript measurements from RNA sequencing. Our unique study design overcame confounding based on gestational age by collecting blood samples from women matched by gestational age, allowing us to study transcriptomic changes directly related to the active preterm parturition. We performed RNA profiling using whole genome sequencing, which is highly sensitive and allowed us to identify subtle changes in specific genes. ADAMTS2 expression emerged as a marker of prematurity within peripheral blood leukocytes, an accessible tissue that plays a functional role in signaling during the onset of labor. We identified changes in relative gene expression in a number of gene sets related to signaling in monocytes and whole blood of women undergoing spontaneous preterm labor compared to controls. These genes and pathways may help identify potential targets for the development of novel drugs for preterm birth prevention.

ADAMTS 1, 4, 12, and 13 levels in maternal blood, cord blood, and placenta in preeclampsia.

The aim of this study is to compare ADAMTS (A Disintegrin and Metalloprotease Domains with Thrombospondins motifs) 1, 4, 12, and 13 levels in maternal and cord blood and placental tissue between preeclampsia and uncomplicated pregnancies. The enzyme-linked immunosorbent assay (ELISA) results showed that ADAMTS 1, 4, 12, and 13 levels in the maternal and cord blood were lower in the preeclampsia group than in the control group. Based on the immunohistochemistry (IHC) results, ADAMTS 1, 4, and 12 levels in placental tissues were higher in the preeclampsia group. According to the polymerase chain reaction (PCR) results, ADAMTS 1, 4, and 12 were higher, whereas ADAMTS 13 was lower in the preeclampsia group than in the control group.

ADAMTS-3, -13, -16, and -19 levels in patients with habitual abortion.

A disintegrin-like and metalloproteinase domain with thrombospondin-type 1 motifs (ADAMTS) protein superfamily includes 19 secreted metalloproteases. Proteolytic substrates of ADAMTS enzymes have been linked to reproductive function. The aim of this study was to investigate serum ADAMTS-3, -13, -16, and -19 levels in women with habitual abortions compared with those in healthy controls. A total of 86 women were enrolled in this prospective case-control study. ADAMTS-3, -13, -16, and -19 values were recorded and analyzed in association with demographic and clinical parameters. There were no statistically significant differences between the two groups in terms of demographics. No statistically significant differences were observed between the groups with regard to ADAMTS-13 and -19 levels (p>0.05). However, ADAMTS-3 and -16 were significantly higher in the study group than in the control group (p=0.004 and p=0.005, respectively). To estimate habitual abortions using an area under receiver operating characteristic curve analysis, the cutoff values for ADAMTS-3 and -16 were found to be 87.28 ng/mL (sensitivity, 64.44%; specificity 68.29%) and 15.75 ng/mL (sensitivity, 66.67%; specificity 68.29%), respectively. In conclusion, the pregnancy-loss rate seems to be affected by both ADAMTS-3 and -16.

Total oxidative and anti-oxidative status, and ADAMTS-12 levels in placenta previa and early-onset severe preeclampsia.

AIM: This study was carried out due to the discussions in the literature stating that the inverse association between placenta previa (PP) and preeclampsia (PE). The aim of this study was to determine whether total antioxidant status (TAS), and total oxidant status (TOS) and ADAMTS-12 levels differ among early-onset (<34th gestational week) severe PE (EOS-PE), PP and uncomplicated pregnancies. METHODS: In this case-control study, serum samples obtained from 26 pregnant with EOS-PE, 31 pregnant with PP, and 32 healthy patients with uncomplicated pregnancies (control group). RESULTS: TOS levels were significantly higher in the EOS-PE than in the control group and PP groups (p=0.002, p=0.05, respectively). TAS levels were significantly lower in the EOS-PE than in the control (p<0.001). Although TAS levels were lower in the EOS-PE group than in the PP group, the differences were not statistically significant (p=0.09). There were no significant differences in the ADAMTS-12 levels of the groups. DISCUSSION: The data in this study suggested that the balance between oxidative and anti-oxidative substances were comparable and normal in pregnancies complicated by PP when compared to normal pregnancies without placentation abnormality. In support of this, we encountered no case with PE and fetal growth restriction in our study groups suggesting normal placental angiogenesis. Contrarily, EOS-PE was associated with decreased TAS and increased TOS levels in the maternal serum.

Evaluation of ADAMTS12, ADAMTS16, ADAMTS18 and IL-33 serum levels in pre-eclampsia.

OBJECTIVE: Pre-eclampsia is the result of impaired trophoblast invasion and spiral artery remodeling managed by inflammatory response in its etiology and physiopathology. The aim of this study was to compare serum molecules including IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels between pre-eclampsia and control groups and to investigate the role of these molecules in pre-eclampsia. METHODS: Forty-one women diagnosed as pre-eclampsia between 30 and 40 weeks of gestation and 41 non-complicated pregnant women were enrolled in this cross-sectional, case-control prospective study. ELISA method was used to determine IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels within serums in two groups. RESULTS: Serum ADAMTS12 and IL-33 levels were significantly lower in pre-eclampsia group (p < 0.001 and p: 0.028, respectively), however, in sub-group analysis, no significant difference was observed (p > 0.05). The cut-off value of ADAMTS12 levels to discriminate pre-eclampsia with %73.17 sensitivity and %92.68 specificity was 8.27 ng/ml while the cut-off value for IL-33 was 0.23 pg/ml with 82.93% sensitivity and 53.66% specificity. CONCLUSION: Pre-eclampsia is associated with lower serum IL-33 and ADAMTS12 levels.