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Marina A Costa,1 Layane M Teodoro,1 Gustavo H Bahia-de-Oliveira,2 Ana Paula N Nunes,3 Ricardo A Barata1 1Laboratório de Parasitologia, Departamento de Ciências Biológicas, Universidade Federal dos Vales dos Jequitinhonha e Mucuri, Diamantina, MG, Brazil; 2Laboratório de Doenças Parasitárias, Departamento de Farmácia, Universidade Federal dos Vales dos Jequitinhonha e Mucuri, Diamantina, MG, Brazil; 3Laboratório de Bioestatística e Epidemiologia, Departamento de Ciências Básicas, Universidade Federal dos Vales dos Jequitinhonha e Mucuri, Diamantina, MG, Brazil Background: Banknotes are objects of great turnover and diffusion among the population, and can be efficient mechanisms in the dissemination of several intestinal parasites. This study investigated the presence of biological forms of intestinal parasites present in circulating cash banknotes in the city of Diamantina, Minas Gerais, Brazil, aiming to propose interventions aimed at improving local public health. Materials and methods: Between February and April 2017, samples of banknotes collected in five commercial establishments of the city were analyzed, namely: 1) gas station, 2) supermarket, 3) butchery, 4) pharmacy and 5) free fair. Ten circulating banknotes of each value (R$2.00, R$5.00, R$10.00, R$20.00, R$50.00 and R$100.00) were exchanged for new banknotes, washed with Tween 80 and, after spontaneous sedimentation, analyzed under an optical microscope with a magnification of 10× and 40×. Results: Cysts of Entamoeba coli (74.60%), cysts of Endolimax nana (16.94%), Giardia lamblia cysts (4.44%), unidentified nematode larvae (2.02%), Hymenolepis sp. (0.81%), Taenia sp. (0.81%) and Ancylostomidae larvae (0.40%) were found. Conclusions: The results revealed the need for improvements in basic sanitation, health and education activities that emphasized the importance of proper hand hygiene. Keywords: intestinal parasites, banknotes, Diamantina

Water scarcity is one of the main abiotic factors that limit agricultural production. In this sense, the identification of genotypes tolerant to water deficit associated with irrigation management strategies is extremely important. In this context, the objective of this study was to evaluate the morphology, production, water consumption, and water use efficiency of colored fiber cotton genotypes submitted to irrigation strategies with a water deficit in the phenological phases. Two experiments were conducted in succession. In the first experiment, a randomized block design was used in a 3 × 7 factorial scheme, corresponding to three colored cotton genotypes (BRS Rubi, BRS Jade, and BRS Safira) in seven irrigation management strategies with 40% of the real evapotranspiration (ETr) varying the phenological stages. In the second experiment, the same design was used in a 3 × 10 factorial arrangement (genotypes × irrigation management strategies). The water deficit in the vegetative phase can be used in the first year of cotton cultivation. Among the genotypes, 'BRS Jade' is the most tolerant to water deficit in terms of phytomass accumulation and fiber production.

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms (MPN); in this pathway, IRS2 is involved in the malignant transformation induced by JAK2 V617F , and upregulation of IGF1R signaling induces the MPN phenotype. NT157, a synthetic compound designed as an IGF1R-IRS1/2 inhibitor, has been shown to induce antineoplastic effects in solid tumors. Herein, we aimed to characterize the molecular and cellular effects of NT157 in JAK2 V617F -positive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2 V617F cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G 2 /M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NFκB signaling, and it activated the AP-1 complex, downregulated four oncogenes (CCND1, MYB, WT1, and NFKB1), and upregulated three apoptotic-related genes (CDKN1A, FOS, and JUN) (p < 0.05). NT157 induced genotoxic stress in a JAK2/STAT-independent manner. NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients (p < 0.05). These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.

The insulin receptor substrate (IRS) proteins are a family of cytoplasmic proteins that integrate and coordinate the transmission of signals from the extracellular to the intracellular environment via transmembrane receptors, thus regulating cell growth, metabolism, survival and proliferation. The PI3K/AKT/mTOR and MAPK signaling pathways are the best-characterized downstream signaling pathways activated by IRS signaling (canonical pathways). However, novel signaling axes involving IRS proteins (noncanonical pathways) have recently been identified in solid tumor and hematologic neoplasm models. Insulin receptor substrate-1 (IRS1) and insulin receptor substrate-2 (IRS2) are the best-characterized IRS proteins in hematologic-related processes. IRS2 binds to important cellular receptors involved in normal hematopoiesis (EPOR, MPL and IGF1R). Moreover, the identification of IRS1/ABL1 and IRS2/JAK2V617F interactions and their functional consequences has opened a new frontier for investigating the roles of the IRS protein family in malignant hematopoiesis. Insulin receptor substrate-4 (IRS4) is absent in normal hematopoietic tissues but may be expressed under abnormal conditions. Moreover, insulin receptor substrate-5 (DOK4) and insulin receptor substrate-6 (DOK5) are linked to lymphocyte regulation. An improved understanding of the signaling pathways mediated by IRS proteins in hematopoiesis-related processes, along with the increased development of agonists and antagonists of these signaling axes, may generate new therapeutic approaches for hematological diseases. The scope of this review is to recapitulate and review the evidence for the functions of IRS proteins in normal and malignant hematopoiesis.

The recurrent gain-of-function JAK2 V617F mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, we investigate and compare effects of metformin and ruxolitinib alone and in combination on cell signaling and cellular functions in JAK2 V617F -positive cells. In JAK2 V617F -expressing cell lines, metformin treatment significantly reduced cell viability, cell proliferation, clonogenicity, and cellular oxygen consumption and delayed cell cycle progression. Metformin reduced cyclin D1 expression and RB, STAT3, STAT5, ERK1/2 and p70S6K phosphorylation. Metformin plus ruxolitinib demonstrated more intense reduction of cell viability and induction of apoptosis compared to monotherapy. Notably, metformin reduced Ba/F3 JAK2 V617F tumor burden and splenomegaly in Jak2 V617F knock-in-induced MPN mice and spontaneous erythroid colony formation in primary cells from polycythemia vera patients. In conclusion, metformin exerts multitarget antileukemia activity in MPN: downregulation of JAK2/STAT signaling and mitochondrial activity. Our exploratory study establishes novel molecular mechanisms of metformin and ruxolitinib action and provides insights for development of alternative/complementary therapeutic strategies for MPN.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by abnormal proliferation and accumulation of lymphoblasts in the hematopoietic system. Stathmin 1 is a proliferation marker for normal lymphocytes, which has been described as highly expressed in ALL patients and functionally important for leukemia phenotype. In the present study, we expand our previous observations and aim to investigate Stathmin 1 expression and its impact on laboratory features and clinical outcomes in an independent cohort of ALL patients, and to verify the effects of paclitaxel treatment on Stathmin 1 phosphorylation and cell viability in ALL cell lines. In ALL patients, Stathmin 1 expression was significantly increased, associated with lower age onset and positively correlated with white blood cell counts, but did not impact on clinical outcomes. Functional assays revealed that paclitaxel induces Stathmin 1 phosphorylation at serine 16 (an inhibitory site), microtubule stability and apoptosis in Jurkat and Namalwa cell lines. Paclitaxel treatment did not modulate cell viability of normal peripheral blood leukocytes. In conclusion, our data confirm increased levels of Stathmin 1 in ALL patients and that therapeutic doses of paclitaxel inhibits Stathmin 1 function and promote microtubule stability and apoptosis in ALL cells.