ABSTRACT
Ruxolitinib (RUX) is a Janus kinase 1/2 inhibitor (JAKi) approved in the EU for treating diseaserelated splenomegaly or symptoms in adults patients with myelofibrosis (MF). This is an interim analysis of JAKoMo, a prospective, noninterventional, phase IV study in MF. Between 2012-2019 (cutoff March 2021), 928 patients (JAKi-naïve and -pretreated) enrolled from 122 German centers. This analysis focuses on JAKi-naïve patients. RUX was administered according to the Summary of Product Characteristics. Compared to the COMFORT-I, -II, and JUMP trials, patients in JAKoMo were older (median 73 years), had poorer Eastern Cooperative Oncology Group (ECOG) performance statuses (16.5% had ECOG ≥ 2), and were more transfusion dependent (48.5%). JAKoMo represents the more challenging patients with MF encountered outside of interventional studies. However, patients with low-risk International Prognostic Scoring System (IPSS) scores or without palpable splenomegaly were also included. Following RUX treatment, 82.5% of patients experienced rapid (≤ 1 month), significant decreases in palpable spleen size, which remained durable for 24 months (60% patients). Symptom assessment scores improved significantly in Month 1 (median -5.2) up to Month 12 (-6.2). Common adverse events (AEs) were anemia (31.2%) and thrombocytopenia (28.6%). At cutoff, 54.3% of patients had terminated the study due to, death, AEs, or deterioration of health. No new safety signals were observed. Interim analysis of the JAKoMo study confirms RUX safety and efficacy in a representative cohort of real-world, elderly, JAKi-naïve patients with MF. Risk scores were used in less than half of the patients to initiate RUX treatment.Trial registration: NCT05044026; September 14, 2021.
Subject(s)
Janus Kinase Inhibitors , Primary Myelofibrosis , Adult , Humans , Aged , Splenomegaly/drug therapy , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/drug therapy , Prospective Studies , Nitriles , Treatment OutcomeABSTRACT
DUSP4 (MKP-2), a member of the mitogen-activated protein kinase phosphatase (MKP) family and potential tumor suppressor, negatively regulates the MAPKs (mitogen-activated protein kinases) ERK, p38 and JNK. MAPKs play a crucial role in cancer development and progression. Previously, using microarray analyses we found a conspicuously frequent overexpression of DUSP4 in colorectal cancer (CRC) with high frequent microsatellite instability (MSI-H) compared to microsatellite stable (MSS) CRC. Here we studied DUSP4 expression on mRNA level in 38 CRC (19 MSI-H and 19 MSS) compared to matched normal tissue as well as in CRC cell lines by RT-qPCR. DUSP4 was overexpressed in all 19 MSI-H tumors and in 14 MSS tumors. Median expression levels in MSI-H tumors were significantly higher than in MSS-tumors (p < 0.001). Consistently, MSI-H CRC cell lines showed 6.8-fold higher DUSP4 mRNA levels than MSS cell lines. DUSP4 expression was not regulated by promoter methylation since no methylation was found by quantitative methylation analysis of DUSP4 promoter in CRC cell lines neither in tumor samples. Furthermore, no DUSP4 mutation was found on genomic DNA level in four CRC cell lines. DUSP4 overexpression in CRC cell lines through DUSP4 transfection caused upregulated expression of MAPK targets CDC25A, CCND1, EGR1, FOS, MYC and CDKN1A in HCT116 as well as downregulation of mismatch repair gene MSH2 in SW480. Furthermore, DUSP4 overexpression led to increased proliferation in CRC cell lines. Our findings suggest that DUSP4 acts as an important regulator of cell growth within the MAPK pathway and causes enhanced cell growth in MSI-H CRC.
Subject(s)
Cell Proliferation , Colorectal Neoplasms/genetics , DNA Methylation , Dual-Specificity Phosphatases/genetics , Microsatellite Instability , Mitogen-Activated Protein Kinase Phosphatases/genetics , Apoptosis , Blotting, Western , Colon/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Dual-Specificity Phosphatases/metabolism , Humans , Immunoenzyme Techniques , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Mutation/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Rectum/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , ras Proteins/geneticsABSTRACT
Aldehyde oxidase 1 (AOX1) is highly abundant in the liver and oxidizes aldehydes thereby generating reactive oxygen species. Enzymes involved in detoxification of aldehydes are expressed in adipocytes and alter adipogenesis, therefore the functional role of AOX1 in adipocytes was analyzed. AOX1 mRNA was higher in visceral compared to subcutaneous human adipose tissue but AOX1 protein was detected in both fat depots. AOX1 expression in adipocytes was confirmed by immunohistochemistry and immunoblot. AOX1 was induced during adipocytic differentiation and was downregulated by fenofibrate in differentiated cells. Knock-down of AOX1 in preadipocytes led to impaired lipid storage and adiponectin release in the differentiated cells. These data indicate that AOX1 is essential for adipogenesis and may link energy and drug metabolism.