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Acute myeloid leukemia (AML) is a malignancy characterized by differentiation arrest of hematopoietic precursor cells. Differentiation therapy is effective for patients with acute promyelocytic leukemia; however, only a few effective differentiation therapies have been established for patients with other AML subtypes. In this study, seven benzimidazole anthelmintics were examined to determine the effects of differentiation on AML cells. The expression of monocyte markers (CD11b and CD14) was elevated after treatment with most benzimidazole anthelmintics. Among these drugs, parbendazole (PBZ) induced AML cell differentiation at low concentration. PBZ induced the monocyte marker expression, KLF4/DPYSL2A gene expression, and apoptosis for 21 AML cell lines with various subtypes and a primary AML sample. Finally, an in vivo analysis using an AML patient-derived xenograft mouse model showed a significant decrease in the chimerism level and prolonged survival in PBZ-treated mice. These findings could lead to a more effective differentiation therapy for AML. Low concentrations of the anthelmintic parbendazole (PBZ) induces monocytic differentiation in AML cells and PBZ could be a candidate for drug repositioning. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma. Interfering with RUNX family proteins reduces glioblastoma growth in mice and reveals pathways involved in the maintenance of tumour growth. [ABSTRACT FROM AUTHOR]

Recent effective therapies enable most rheumatoid arthritis (RA) patients to achieve remission; however, some patients experience relapse. We aimed to predict relapse in RA patients through machine learning (ML) using data on ultrasound (US) examination and blood test. Overall, 210 patients with RA in remission at baseline were dichotomized into remission (n = 150) and relapse (n = 60) based on the disease activity at 2-year follow-up. Three ML classifiers [Logistic Regression, Random Forest, and extreme gradient boosting (XGBoost)] and data on 73 features (14 US examination data, 54 blood test data, and five data on patient information) at baseline were used for predicting relapse. The best performance was obtained using the XGBoost classifier (area under the receiver operator characteristic curve (AUC) = 0.747), compared with Random Forest and Logistic Regression (AUC = 0.719 and 0.701, respectively). In the XGBoost classifier prediction, ten important features, including wrist/metatarsophalangeal superb microvascular imaging scores, were selected using the recursive feature elimination method. The performance was superior to that predicted by researcher-selected features, which are conventional prognostic markers. These results suggest that ML can provide an accurate prediction of relapse in RA patients, and the use of predictive algorithms may facilitate personalized treatment options. [ABSTRACT FROM AUTHOR]

APL with I ZBTB16-RARA i is reported to be resistant to treatment with ATRA and ATO and exhibits a low response to conventional chemotherapy [[7], [9]]. APL is usually sensitive to all-trans retinoic acid (ATRA) therapy in combination with anthracyclines or arsenic trioxide (ATO), resulting in favorable rates of complete remission and superior overall survival. Dear Editor, Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia characterized by reciprocal chromosome translocation t(15;17)(q24;q21), resulting in the production of the I PML-RARA i fusion gene [[1]]. Notably, I ZBTB16-RARA i APL is resistant to ATO and exhibits impaired sensitivity to ATRA, leading to a significantly poorer clinical outcome than patients with I PML-RARA i [[5]-[7]]. [Extracted from the article]

Purpose: This study aimed to evaluate the positive rate and prognostic significance of superb microvascular imaging (SMI) in rheumatoid arthritis (RA) patients in remission with normal C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESR). Methods: The study enrolled 112 RA patients, and ultrasound (US) assessment was performed on 28 joints of each patient. Results: The SMI signal-positive rates for each joint were: metacarpophalangeal (MCP) joints: 20.5%, wrist joints: 43.8%, metatarsophalangeal (MTP) joints: 17.0%, and other foot joints: 25.0%. Investigation of the prognostic significance of the SMI signal in each joint revealed that only in the MTP joints was the total score of the SMI signal in the patients with relapse significantly higher than that in the patients with remission (P = 0.01). Comparison of the receiver operating characteristics curves for predicting relapse showed that the area under the curve (AUC) of the MTP joints was the highest (AUC = 0.66) of the investigated joints. The optimal threshold for the total MTP SMI score was 1 (accuracy = 83.3%). Positive/negative data of the SMI signal in the MTP joints were not significantly associated with the values of conventional disease activity markers. Conclusion: In RA patients in remission with normal CRP and ESR levels, the percentage of positive SMI signal was highest in the wrist joints. However, the accuracy of the SMI signal for predicting relapse was greatest for the MTP joints, suggesting that US assessment of the MTP joints by SMI is useful for predicting relapse in these patients. [ABSTRACT FROM AUTHOR]

The t(8;21) translocation is the most common cytogenetic abnormality in acute myeloid leukemia (AML). Although t(8;21) AML patients have a relatively favorable prognosis, relapse is a frequent occurrence, underscoring the need to develop novel therapeutic approaches. Here, we showed that t(8;21) AML is characterized by frequent mutation and overexpression of CCND2. Analysis of 19 AML cell lines showed that t(8;21) AML cells had lower IC50 values for the selective CDK4/6 inhibitors palbociclib and abemaciclib than non-t(8;21) AML cells. CDK4/6 inhibitors caused cell cycle arrest at G1 phase and impaired cell proliferation in t(8;21) AML cells. CDK4/6 inhibition decreased MAP-ERK and PI3K-AKT-mTOR signaling pathway activity, induced LC3B-I to LC3B-II conversion, and enhanced autophagosome formation, suggesting autophagy induction. Treatment of t(8;21) AML cells with the autophagy inhibitors chloroquine (CQ) or LY294002 in combination with the CDK4/6 inhibitor abemaciclib significantly increased the percentage of apoptotic (Annexin V positive) cells, whereas CQ or LY294002 single treatment had no significant effects. The effectiveness of co-inhibiting CDK4/6 and autophagy was confirmed in primary t(8;21) AML cells. The results suggest that the combination of CDK4/6 and autophagy inhibitors had a synergistic effect on inducing apoptosis, suggesting a novel therapeutic approach for the treatment of t(8;21) AML. [ABSTRACT FROM AUTHOR]

Although the biological importance of Krüppel-like factor 4 (KLF4) transcription factor in the terminal differentiation of hematopoietic cells to the monocytes has been well established, the underlying mechanisms remain elusive. To clarify the molecular basis of KLF4-mediated monocytic differentiation, we performed detailed genetic studies in acute myeloid leukemia (AML) cells. Here, we report that dihydropyrimidinase like 2 (DPYSL2), also known as CRMP2, is a novel key differentiation mediator downstream of KLF4 in AML cells. Interestingly, we discovered that KLF4-mediated monocytic differentiation is selectively dependent on one specific isoform, DPYSL2A, but not on other DPYSL family genes. Terminal differentiation to the monocytes and proliferation arrest in AML cells induced by genetic or pharmacological upregulation of KLF4 were significantly reversed by short hairpin RNA (shRNA)-mediated selective depletion of DPYSL2A. Chromatin immunoprecipitation assay revealed that KLF4 associates with the proximal gene promoter of DPYSL2A and directly transactivates its expression. Together with the unique expression patterns of KLF4 and DPYSL2 limited to the differentiated monocytes in the hematopoietic system both in human and mouse, the identified KLF4-DPYSL2 axis in leukemia cells may serve as a potential therapeutic target for the development of novel differentiation therapies for patients with AML. [ABSTRACT FROM AUTHOR]

Purpose: Ultrasound is commonly used to assess the degree of synovitis in patients with rheumatoid arthritis (RA); however, it is unclear which joints are optimal for evaluating and predicting recurrence and remission. Patients and methods: In 293 RA patients enrolled in the KURAMA cohort, 28 joints were assessed by ultrasound. Results: Results from patients in remission in both 2015 and 2017 (Group 1, n = 152) were compared with those from patients in remission in 2015 and non-remission in 2017 (Group 2, n = 60). The SMI scores for total (3.1 vs. 6.3, P = 0.004), MCP2-5 (1.1 vs. 2.4, P = 0.03), wrist (0.9 vs. 2.1, P = 0.0003), MTP2-5 (0.4 vs. 1.0, P = 0.03), and Lisfranc joints (0.07 vs. 0.25, P = 0.04) were significantly higher for Group 2. When those in non-remission in 2015 and remission in 2017 (Group 3, n = 27) were compared with those in remission in 2015 and non-remission in both 2015 and 2017 (Group 4, n = 54), the GS–SMI combined score (3.0 vs. 5.0, P = 0.04) and SMI score (1.5 vs. 2.9, P = 0.04) for MCP2-5 joints were significantly higher for Group 4. Multivariate logistic regression analysis identified "wrist SMI score ≧ 1" as an independent prognostic factor for recurrence (odds ratio 3.08, P = 0.001) and "MCP2-5 GS–SMI combined score ≦ 4" as an independent prognostic factor for remission (odds ratio 3.25, P = 0.048). Conclusion: We identified the optimal joint cut-off scores for predicting recurrence and remission in RA patients. Risk-stratification therapy based on the ultrasound scores may improve outcome and quality of life for patients with RA. [ABSTRACT FROM AUTHOR]

In treatment of acute myeloid leukemia (AML), prognostic factors, including gene mutation and abnormal gene expression, enable risk stratification of patients. However, in the case of a small proportion of leukemic blast cells, such as AML associated with Down syndrome (AML-DS), it is not possible to examine prognostic factors precisely due to the large proportion of normal cells. Here, we present a novel method for examining prognostic factors by making a smear on a membrane slide glass from a small amount of diagnostic specimen and collecting highly pure leukemic blast cells by laser microdissection (LMD). We verified the effectiveness of this method using 10% KPAM1 cell line suspension and peripheral blood containing 20% blast cells obtained from a patient with transient abnormal myelopoiesis (TAM). After making blood smears, approximately 100 cells were collected and analyzed by direct sequencing. Frameshift mutations (2 bp deletion and 17 bp duplication, respectively) in GATA-1 were detected in each sample, suggesting KPAM1 and TAM blast cells were accurately purified. This novel method enables us to precisely examine prognostic factors in many cases, even in cases with a small proportion of leukemic blast cells or small specimens to preserve. [ABSTRACT FROM AUTHOR]