The prognostic impact of WT1 expression levels, mutations, and SNP rs16754 in AML patients: A retrospective cohort study

Background & Objective: The clinical outcomes and treatment options for acute myeloid leukemia (AML) patients are highly dependent upon molecular markers. In this study, Wilms tumor 1 (WT1) (exons 7 and 9) mutations, single-nucleotide polymorphism (SNP) rs16754, and WT1 expression levels in 130 random AML patients were screened; FMs-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD), nucleophosmin (NPM1), and CCAAT/enhancer-binding protein alpha (CEBPA) mutations were also evaluated. Materials & Methods: Overall, 130 AML patients were recruited for this study. WT1 mutations were determined by Sanger sequencing, and expression levels were determined by real-time polymerase chain reaction (PCR). The Kaplan-Meier method was used to calculate overall survival (OS) and disease-free survival (DFS). Results: The frequency of WT1 mutations in the study population was 5.4, and it did not affect OS (P=0.98), DFS (P=0.97), or complete remission (CR) rates in AML patients. The major allele of SNP rs16754 in the current study was A. No significant differences were found for OS (P=0.52), DFS (P=0.42), or CR rates among all SNP rs16754 genotypes. The overexpression of WT1 was observed in 83 of patients at diagnosis. No significant difference was found for OS (P=0.84), DFS (P=0.82), or CR rates between AML patients with high and low WT1 expression levels. Conclusion: The results of the current study do not support WT1 mutation, SNP rs16754, or WT1 overexpression at diagnosis, as they were found to be poor prognostic markers in AML patients. © 2021, Zanjan University of Medical Sciences and Health Services. All rights reserved

FLT3-ITD compared with DNMT3A R882 mutation is a more powerful independent inferior prognostic factor in adult acute myeloid leukemia patients after allogeneic hematopoietic stem cell transplantation: A retrospective cohort study Allojenik hematopoetik kök hücre nakli sonrası yeti�kin akut myeloid lösemi hastalarında, FLT3-ITD, DNMT3A R882 mutasyonu ile kar�ıla�tırıldı�ında daha güçlü bir ba�ımsız kötü prognostik faktördür: Retrospektif kohort çalı�ması

Objective: This study aimed to evaluate DNMT3A exon 23 mutations and their prognostic impacts in the presence of NPM1 and FLT3 mutations in acute myeloid leukemia (AML) patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Materials and Methods: This study comprised 128 adult AML patients referred to the Hematology-Oncology and Stem Cell Research Center of Shariati Hospital. NPM1 and FLT3-ITD mutations were detected by fragment analysis. For DNMT3A exon 23 mutation analysis, we used Sanger sequencing. Overall survival (OS) and relapse-free survival (RFS) curves were estimated by the Kaplan-Meier method and the log-rank test was used to calculate differences between groups. Results: The prevalence of DNMT3A exon 23 mutations was 15.6 and hotspot region R882 mutations were prominent. RFS and OS were compared in patients with and without DNMT3A exon 23 mutations using univariate analysis and there was no significant difference between these groups of patients. On the contrary, the FLT3-ITD mutation significantly reduced the OS (p=0.009) and RFS (p=0.006) in AML patients after allogeneic HSCT. In the next step, patients with AML were divided into four groups regarding FLT3-ITD and DNMT3A mutations. Patients with DNMT3A R882mut/FLT3-ITDpos had the worst OS and RFS. These results indicate that DNMT3A mutations alone do not affect the clinical outcomes of AML patients undergoing allogeneic HSCT, but when accompanied by FLT3-ITD mutations, the OS was significantly reduced (5-year OS 0 for DNMT3A R882mut/ FLT3-ITDpos patients vs. 62 DNMT3A R882wt/FLT3-ITDneg, p=0.025) and the relapse rate increased. Conclusion: It can be deduced that DNMT3A R882mut/FLT3-ITDpos is an unfavorable prognostic factor in AML patients even after allogeneic HSCT. © 2018 by Turkish Society of Hematology

Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

Earlier we have established a carbazole alkaloid (mahanine) isolated from an Indian edible medicinal plant as an anticancer agent with minimal effect on normal cells. Here we report for the first time that mahanine-treated drug resistant and sensitive virulent Leishmania donovani promastigotes underwent apoptosis through phosphatidylserine externalization, DNA fragmentation and cell cycle arrest. An early induction of reactive oxygen species (ROS) suggests that the mahanine-induced apoptosis was mediated by oxidative stress. Additionally, mahanine-treated Leishmania-infected macrophages exhibited anti-amastigote activity by nitric oxide (NO)/ROS generation along with suppression of uncoupling protein 2 and Th1-biased cytokines response through modulating STAT pathway. Moreover, we have demonstrated the interaction of a few antioxidant enzymes present in parasite with mahanine through molecular modeling. Reduced genetic and protein level expression of one such enzyme namely ascorbate peroxidase was also observed in mahanine-treated promastigotes. Furthermore, oral administration of mahanine in acute murine model exhibited almost complete reduction of parasite burden, upregulation of NO/iNOS/ROS/IL-12 and T cell proliferation. Taken together, we have established a new function of mahanine as a potent antileishmanial molecule, capable of inducing ROS and exploit antioxidant enzymes in parasite along with modulation of host’s immune response which could be developed as an inexpensive and nontoxic therapeutics either alone or in combination

Neratinib protects pancreatic beta cells in diabetes

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes

Clone-specific expression, transcriptional regulation, and action of interleukin-6 in human colon carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Many cancer cells produce interleukin-6 (IL-6), a cytokine that plays a role in growth stimulation, metastasis, and angiogenesis of secondary tumours in a variety of malignancies, including colorectal cancer. Effectiveness of IL-6 in this respect may depend on the quantity of basal and inducible IL-6 expressed as the tumour progresses through stages of malignancy. We therefore have evaluated the effect of <it>IL-6 </it>modulators, i.e. IL-1β, prostaglandin E₂, 17β-estradiol, and 1,25-dihydroxyvitamin D₃, on expression and synthesis of the cytokine at different stages of tumour progression.</p> <p>Methods</p> <p>We utilized cultures of the human colon carcinoma cell clones Caco-2/AQ, COGA-1A and COGA-13, all of which expressed differentiation and proliferation markers typical of distinct stages of tumour progression. IL-6 mRNA and protein levels were assayed by RT-PCR and ELISA, respectively. DNA sequencing was utilized to detect polymorphisms in the <it>IL-6 </it>gene promoter.</p> <p>Results</p> <p><it>IL-6 </it>mRNA and protein concentrations were low in well and moderately differentiated Caco-2/AQ and COGA-1A cells, but were high in poorly differentiated COGA-13 cells. Addition of IL-1β (5 ng/ml) to a COGA-13 culture raised IL-6 production approximately thousandfold via a prostaglandin-independent mechanism. Addition of 17β-estradiol (10^-7M) reduced basal IL-6 production by one-third, but IL-1β-inducible IL-6 was unaffected. Search for polymorphisms in the <it>IL-6 </it>promoter revealed the presence of a single haplotype, i.e., -597A/-572G/-174C, in COGA-13 cells, which is associated with a high degree of transcriptional activity of the <it>IL-6 </it>gene. IL-6 blocked differentiation only in Caco-2/AQ cells and stimulated mitosis through up-regulation of c-<it>myc </it>proto-oncogene expression. These effects were inhibited by 10^-8M 1,25-dihydroxyvitamin D₃.</p> <p>Conclusion</p> <p>In human colon carcinoma cells derived from well and moderately differentiated tumours, IL-6 expression is low and only marginally affected, if at all, by PGE₂, 1,25-dihydroxyvitamin D₃, and 17β-estradiol. However, IL-6 is highly abundant in undifferentiated tumour cells and is effectively stimulated by IL-1β. In case of overexpression of an <it>IL-6 </it>gene variant with extreme sensitivity to IL-1β, massive release of the cytokine from undifferentiated tumour cells may accelerate progression towards malignancy by paracrine action on more differentiated tumour cells with a still functioning proliferative IL-6 signalling pathway.</p

Regular dorsal dimples and damaged mites of Varroa destructor in some Iranian honey bees (Apis mellifera)

The frequency of damaged Varroadestructor Anderson and Trueman (Mesostigmata: Varroidae) found on the bottom board of hives of the honey bee, Apis mellifera L. (Hymenoptera: Apidae) has been used as an indicator of the degree of tolerance or resistance of honey bee colonies against mites. However, it is not clear that this measure is adequate. These injuries should be separated from regular dorsal dimples that have a developmental origin. To investigate damage to Varroa mites and regular dorsal dimples, 32 honey bee (A. mellifera) colonies were selected from four Iranian provinces: Isfahan, Markazi, Qazvin, and Tehran. These colonies were part of the National Honey bee Breeding Program that resulted in province-specific races. In April, Varroa mites were collected from heavily infested colonies and used to infest the 32 experimental colonies. In August, 20 of these colonies were selected (five colonies from each province). Adult bees from these colonies were placed in cages and after introducing mites, damaged mites were collected from each cage every day. The average percentage of injured mites ranged from 0.6 to 3.0% in four provinces. The results did not show any statistical differences between the colonies within provinces for injuries to mites, but there were some differences among province-specific lines. Two kinds of injuries to the mites were observed: injuries to legs and pedipalps, and injuries to other parts of the body. There were also some regular dorsal dimples on dorsal idiosoma of the mites that were placed in categories separate from mites damaged by bees. This type of classification helps identifying damage to mites and comparing them with developmental origin symptoms, and may provide criteria for selecting bees tolerant or resistant to this mite

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin