Background/Aim: Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disease, and a major challenge for the eradication of CML is to understand the cause of the permanence of minimal residual disease (DRM). This work aimed to induce the maturation of leukemic stem cells with All-trans-retinoic acid (ATRA), making them sensitive to treatment with Imatinib (IM). Materials and Methods: K562 cells were treated with IM and with the combined therapy of ATRA together with IM for 48 and 72 h. The expression of BCR-ABL gene and multidrug resistance gene ABCB1 were evaluated using RT-qPCR. Results: The combined ATRA and IM therapy showed a discreet cell differentiation pattern, evidenced by the panoptic morphology analysis at 48 and 72 h of treatment. The BCR-ABL expression showed no statistical difference when treated alone with IM, however in combination with ATRA, the expression was statistically significant in 48 and 72 h (p≤0.0001) and when the treatment groups were compared to each other (p≤0.001). The ABCB1 gene expression showed a decrease in isolated IM therapy (p≤0.05) and in the combination in 48 and 72 h (p≤0.0001). Conclusion: Combined ATRA and IM therapy was shown to be effective in decreasing BCR-ABL and ABCB1 genes, possibly through the differentiation of blast cells, demonstrating that the therapy could be potentially effective in the blast crisis of the disease and for those patients who develop resistance to available CML treatments.

Artesunate (ARS) is a semi‐synthetic derivative of artemisinin, used as an outstanding antimalarial drug, which also displays antitumor, anti‐inflammatory and immunosuppressive effects. In spite of the numerous reports showing the antitumor activity of ARS, the particular mechanisms associated with its cytotoxicity and genotoxicity in non‐neoplastic human cells remain unclear. Here we aimed to verify the specific chromosome damages and the changes in markers of oxidative‐nitrosative stress and apoptosis triggered by ARS exposure in human peripheral blood lymphocytes. Cultures were incubated in the presence of ARS and the number of binucleated cells was determined. To discriminate between micronuclei (MN) containing a whole chromosome or an acentric chromosome, the MN test was employed in combination with the fluorescence in situ hybridization assay. Alterations in the levels of superoxide anion (O2−) and nitric oxide (NO) were measured by the nitroblue tetrazolium and Griess assay, respectively. Changes in the expression of the apoptotic markers were assessed by immunocytochemistry. We found that ARS induced a significant formation of both centromere‐positive MN (C+ MN) and centromere‐negative MN (C– MN). These alterations were accompanied by an increase in both cellular levels of O2− and total NO production, and a remarkable enhancement in the expression of the apoptotic markers cytochrome c and caspases 8 and 9. Together these findings reveal that ARS induces changes in the oxidative‐nitrosative status of human lymphocytes, which are followed by apoptosis and clastogenic and aneugenic effects.

No abstract

Gastric cancer is one of the most common cancers and the third cause of cancer-related death worldwide. The treatment of GC patients improved due to advancements in surgery, radiotherapy and chemotherapy. However, the long-term survival rate of patients with gastric cancer remains around 20%. Thus, development of novel therapeutic approaches is of great interest, in order to reduce the need for mutilating surgeries and morbid adjuvant therapies. For many years, it was believed that the RNA was a mere intermediate molecule in the genetic information flow. However, during the past decades, with the advent of new sequencing technologies, it was revealed that non-coding RNAs play important roles in many different biological processes. The Wnt/β-catenin signaling pathway has been reported to regulate crucial events during neoplasic development, such as cell differentiation, proliferation, invasion, migration, apoptosis, and angiogenesis. In this review, we will focus on microRNAs and long non-coding RNAs that have been implicated in gastric cancer tumorigenesis via modulation of the Wnt/β-catenin signaling pathway, which provided some biomarkers to prognosis, diagnosis, and therapy.

Gastric cancer (GC) is one of the most common cancers and one of the leading causes of cancer related death worldwide. Although the treatment of GC patients has improved during the last decades, thanks to advancements in surgery, radiotherapy and chemotherapy, the long-term survival rates of patients with GC remains around 20%. In addition, late diagnosis usually occurs due to the absence of symptoms or the presence of non-specific symptoms in early stages of the disease. Thus, the continuous study of new strategies for early diagnosis and identification of novel therapeutic approaches is of great interest, to reduce the need for mutilating surgeries and morbid adjuvant therapies. Next-generation sequencing technologies unveiled new roles and functions of RNAs, particularly, non-coding RNAs. Among the most studied molecules, microRNAs (miRNAs) have been reported to play important roles in different physiological and pathological processes, including cancer. Therefore, the goals of this project are (1) to determine the miRNA profile of patients with GC using tumor tissue samples using next-generation sequencing; and (2) to validate the expression profile of differentially expressed (DE) miRNAs in serum from patients with GC. To identify DE microRNAs between GC tissues and gastric tissues from individuals without cancer, 24 samples (17 cancer and 7 controls) were sequenced using the Ion Torrent PGM (Thermo Fisher Scientific) sequencing equipment. Preliminary results indicate that there are 54 DE miRNAs among the 269 known human miRNAs identified, where 44 were upregulated, while 10 were downregulated in samples from GC patients when compared to samples from individuals without cancer. As expected, Over-Representation Analysis (ORA) revealed that the disease most frequently associated with these DE miRNAs is the digestive system neoplasm. Moreover, Gene Set Enrichment Analysis (GSEA) showed that neoplasm metastasis is the phenotype most associated with this subset of DE miRNAs, indicating that these miRNAs possibly contribute to cell invasion and migration in gastric tumors. To confirm these findings, further experiments are now being performed, such as validation of the DE miRNAs by qRT-PCR in tissue and serum of GC samples, as well as functional studies. Thereby, the identification of a circulating signature of miRNAs will allow a better understanding of physiopathology of gastric carcinogenesis and the identification of possible biomarkers, which may help in early diagnosis, prognosis, and development of novel anticancer therapies.Funding: MACS, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grant # 2016/25562-0; MACS, Conselho Nacional de Pesquisa (CNPq) grant # 2018/301127-2; MACS, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) 23038051640/2009-01; BTRK, Postdoctoral Fellowship, FAPESP 2019/20592-6; CAP, CAPES Doctoral Fellowship 88882.430351/2019-01. Citation Format: Bruno Takao Real Karia, Camila Albuquerque Pinto, Leonardo Caires, Yeda Beatriz Louredo dos Santos, Fernanda Wisnieski, Carolina Gigek, Marilia de Arruda Cardoso Smith. Investigation of differentially expressed miRNAs in patients with gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1491.