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Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies. [ABSTRACT FROM AUTHOR]

Cancer, characterized by uncontrolled cell growth and metastasis, represents a significant challenge to public health. The IGF1/IGF1R axis plays a pivotal role in tumor proliferation and survival, presenting an attractive target for intervention. NT157, a small molecule tyrphostin, has emerged as a promising inhibitor of this axis, displaying potent antineoplastic effects across various cancer types. This review synthesizes the literature on NT157's mechanism of action and its impact on cellular processes in experimental cancer models. Initially identified for inducing the serine phosphorylation of IRS1 and IRS2, leading to their degradation and inhibiting the IGF1R signaling cascade, subsequent studies revealed additional targets of NT157, including STAT3, STAT5, and AXL, suggesting a multifaceted mechanism. Experimental evidence demonstrates that NT157 effectively suppresses tumor growth, metastasis, and angiogenesis in diverse cancer models. Additionally, NT157 enhances chemotherapy efficacy in combination therapy. Moreover, NT157 impacts not only tumor cells but also the tumor microenvironment, modulating inflammation and immune responses by targeting cancer-associated fibroblasts, myeloid cells, and immune cells, creating a suppressive milieu hindering tumor progression and metastasis. In conclusion, NT157 exhibits remarkable versatility in targeting multiple oncogenic pathways and hallmarks of cancer, underscoring its potential as a promising therapeutic agent. [ABSTRACT FROM AUTHOR]

Background and Aims Orchid seeds are reputed to be short lived in dry, cold storage conditions, potentially limiting the use of conventional seed banks for long-term ex situ conservation. This work explores whether Cattleya seeds are long lived or not during conventional storage (predried to ~12 % relative humidity, then stored at −18 °C). Methods We explored the possible interaction of factors influencing seed lifespan in eight species of the genus Cattleya using physiological (germination and vigour), biochemical (gas chromatography), biophysical (differential scanning calorimetry) and morphometric methods. Seeds were desiccated to ~3 % moisture content and stored at −18 °C for more than a decade, and seed quality was measured via three in vitro germination techniques. Tetrazolium staining was also used to monitor seed viability during storage. The morphometric and germination data were subjected to ANOVA and cluster analysis, and seed lifespan was subjected to probit analysis. Key Results Seeds of all Cattleya species were found to be desiccation tolerant, with predicted storage lifespans (P 50y) of ~30 years for six species and much longer for two species. Cluster analysis showed that the three species with the longest-lived seeds had smaller (9–11 %) airspaces around the embryo. The post-storage germination method impacted the quality assessment; seeds equilibrated at room temperature for 24 h or in 10 % sucrose solution had improved germination, particularly for the seeds with the smallest embryos. Chromatography revealed that the seeds of all eight species were rich in linoleic acid, and differential scanning calorimetry identified a peak that might be auxiliary to selecting long-lived seeds. Conclusions These findings show that not all orchids produce seeds that are short lived, and our trait analyses might help to strengthen prediction of seed longevity in diverse orchid species. [ABSTRACT FROM AUTHOR]

The monolayer (two-dimensional or 2D) cell culture, while widely used, lacks fidelity in replicating vital cell interactions seen in vivo, leading to a shift toward three-dimensional (3D) models. Although monolayers offer simplicity and cost-effectiveness, spheroids mimic cellular environments better. This is due to its nutrient gradients, which influence drug penetration and provide a more accurate reflection of clinical scenarios than monolayers. Consequently, 3D models are crucial in drug development, especially for anti-cancer therapeutics, enabling the screening of cell cycle inhibitors and combination therapies vital for heterogeneous tumor populations. Inhibiting processes like migration and invasion often require drugs targeting the cytoskeleton, which can exhibit dual functionality with cell cycle inhibitors. Therapeutic approaches with promising anti-cancer potential often exhibit reduced efficacy in 3D cell culture compared to their performance in monolayer settings, primarily due to the heightened complexity inherent in this system. In the face of this scenario, this review aims to survey existing knowledge on compounds utilized in both 2D and 3D cell cultures, assessing their responses across different culture types and discerning the implications for drug screening, particularly those impacting the cell cycle and cytoskeletal dynamics. [ABSTRACT FROM AUTHOR]

The use of high-grain diets in feedlots is associated with the development of acidosis and ruminitis, which can lead to the occurrence of liver abscesses (LAs). However, the effect of LA on carcass traits is not well known. This study assessed the effects of LA on the performance and carcass traits of beef cattle. Nine peer-reviewed publications with forty-seven treatment means were included in the data set. The effects of the LA were evaluated by examining the weighted mean difference (WMD) between LA (animal with LA) and control treatment (animal without LA). Heterogeneity was explored by meta-regression, followed by a subgroup analysis of the scores and percentages of liver abscess and concentrate level in the feedlot diet. Animals affected by LA showed a reduction in dry matter intake (−1.03%) and feed efficiency (−1.82%). Animals with an LA score of "A" (one or two small abscesses) exhibited a decrease in carcass weight (WMD = 3.41 kg; p = 0.034) and ribeye area (WMD = −1.37 cm2; p = 0.019). When assessing the impact of LA on carcass traits, the most reliable finding indicates a 1.21% reduction in the ribeye area, with no adverse effects observed on subcutaneous fat thickness or the marbling score in the carcass. [ABSTRACT FROM AUTHOR]

Copyright of Musica Theorica is the property of Musica Theorica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses. [ABSTRACT FROM AUTHOR]

Copyright of Revista Verde de Agroecologia e Desenvolvimento Sustentável is the property of Revista Verde de Agroecologia e Desenvolvimento Sustentavel and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The objective was to evaluate the supplementation strategy's effect on beef cattle during the growing phase and two systems during the finishing phase. One hundred and twenty young bulls were randomly divided in a 2 × 2 factorial design to receive either mineral (ad libitum) or protein + energy (3 g/kg body weight (BW)/day) during the growing phase and pasture plus concentrate supplementation (20 g/kg BW/day) or feedlot (25:75% corn silage:concentrate) during the finishing phase. Feedlot-fed bulls had meat (Longissimus thoracis—LT) with a higher content of lipids and saturated and monounsaturated fatty acids and a greater upregulation of stearoyl-CoA desaturase and sterol regulatory element-binding protein-1c than animals that fed on pasture (p < 0.05). On the other hand, pasture-fed bulls had meat with a higher content of α-linoleic acid, linolenic acid, and n6 and a greater n6:n3 ratio compared to the feedlot-fed group (p < 0.05). In addition, meat from pasture-fed bulls during the finishing phase had 17.6% more isocitrate dehydrogenase enzyme concentration than the feedlot group (p = 0.02). Mineral-fed and pasture-finished bulls showed down-regulation of peroxisome proliferator-activated receptor gamma (p < 0.05), while the bulls fed protein + energy and finished in the feedlot had higher carnitine palmitoyltransferase 2 expression (p ≤ 0.013). In conclusion, mineral or protein + energy supplementation in the growing does not affect the fatty acid composition of intramuscular fat of LT muscle. In the finishing phase, feeding bulls in the feedlot upregulates the lipogenic genes and consequently improves the intramuscular fat content in the meat. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the most lethal human neoplasms, and its therapeutic repertoire remains limited. Advances in understanding the molecular complexity involved in the biology of the disease have paved the way for new therapeutic opportunities. AD80 is a multikinase inhibitor that inhibits S6K as well as RET, RAF, and SRC and displays antineoplastic effects in hematological and solid tumors. In the present study, we report the potential of AD80 as an antineoplastic agent for pancreatic cancer and the cellular and molecular changes induced by the drug. Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced γH2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease. [ABSTRACT FROM AUTHOR]

The endogenous estradiol derivative 2-Methoxyestradiol (2-ME) has shown good and wide anticancer activity but suffers from poor oral bioavailability and extensive metabolic conjugation. However, its sulfamoylated derivative, 2-methoxyestradiol-3,17-O,O-bis-sulfamate (STX140), has superior potential as a therapeutic agent, acts by disrupting microtubule polymerization, leading to cell cycle arrest and apoptosis in cancer cells and possesses much better pharmaceutical properties. This study investigated the antiproliferative and anti-invasive activities of STX140 in both SKMEL-28 naïve melanoma (SKMEL28-P) cells and resistant melanoma cells (SKMEL-28R). STX140 inhibited cell proliferation in the nanomolar range while having a less pronounced effect on human melanocytes. Additionally, STX140 induced cell cycle arrest in the G2/M phase and sub-G1, reduced migration, and clonogenic potential in monolayer models, and inhibited invasion in a 3D human skin model with melanoma cells. Furthermore, STX140 induced senescence features in melanoma and activated the senescence machinery by upregulating the expression of senescence genes and proteins related to senescence signaling. These findings suggest that STX140 may hold potential as a therapeutic agent for melanoma treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Body and carcass weight are important economic characteristics for beef cattle production systems because the value of market cattle is based on weight. The possibility of predicting body and carcass weight through biometric measurements obtained from three-dimensional digital images favor the development of the production system. Predictive approaches, such as artificial neutral network, showed better predictive quality for body weight, while the least absolute shrinkage and selection operator and partial least square models were the most suitable for predicting carcass weight. The objective of this study was to evaluate different methods of predicting body weight (BW) and hot carcass weight (HCW) from biometric measurements obtained through three-dimensional images of Nellore cattle. We collected BW and HCW of 1350 male Nellore cattle (bulls and steers) from four different experiments. Three-dimensional images of each animal were obtained using the Kinect® model 1473 sensor (Microsoft Corporation, Redmond, WA, USA). Models were compared based on root mean square error estimation and concordance correlation coefficient. The predictive quality of the approaches used multiple linear regression (MLR); least absolute shrinkage and selection operator (LASSO); partial least square (PLS), and artificial neutral network (ANN) and was affected not only by the conditions (set) but also by the objective (BW vs. HCW). The most stable for BW was the ANN (Set 1: RMSEP = 19.68; CCC = 0.73; Set 2: RMSEP = 27.22; CCC = 0.66; Set 3: RMSEP = 27.23; CCC = 0.70; Set 4: RMSEP = 33.74; CCC = 0.74), which showed predictive quality regardless of the set analyzed. However, when evaluating predictive quality for HCW, the models obtained by LASSO and PLS showed greater quality over the different sets. Overall, the use of three-dimensional images was able to predict BW and HCW in Nellore cattle. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of hanging the carcass by the Achilles tendon (AS) versus pelvic suspension (PS) on meat quality traits. Bos indicus carcasses of two distinct biological types/sex categories comprised 10 young Brangus heifers and 10 Nellore bulls which were finished in a feedlot. Half-carcasses of each biological type/sex category were randomly hung using Achilles suspension (n = 20, AS) or pelvic suspension (n = 20, PS) for 48 h. At boning, longissimus samples were collected for evaluation by untrained consumers for tenderness, liking of flavor, juiciness and overall acceptability, after aging for 5 or 15 days. Objective samples were also tested for shear force (SF), Minolta meat colour, ultimate pH, cooking loss (CL) and purge loss (PL). There was a positive effect (p < 0.01) of PS on the sensory tenderness of Nellore bulls and Brangus heifers aged for 5 days compared to the AS method. At 15 days of aging, difference in sensory tenderness was observed (p < 0.05) in either group. Additionally, an interaction occurred between the suspension method and the aging of Nellore beef (p < 0.05) on liking of flavor, juiciness and overall acceptance, while the same effects were not observed for Brangus beef (p > 0.05). Nellore carcasses submitted to PS tended (p = 0.06) to produce more tender meat than those submitted to AS (SF = 44.62 ± 6.96 vs. 50.41 ± 8.04 N), and lower CL (p < 0.05) were found (27.7 vs. 30.9%). Carcass-suspension methods did not influence meat color, pH or PL in either group (p > 0.05). The PS contributes to improve the quality of Bos indicus bulls loins; in addition, this method allows a reduction in the aging time from 15 to 5 days, and it can be used to supply meat consumer markets which accept a certain level of eating quality. [ABSTRACT FROM AUTHOR]

Recent advances have been made in understanding molecular markers involved in cancer malignancy, resulting in better tumor staging and identifying new potential therapeutic targets. Ezrin (EZR), a member of the ezrin, radixin, moesin (ERM) protein family, is essential for linking the actin cytoskeleton to the cell membrane and participates in the signal transduction of key signaling pathways such as Rho GTPases and PI3K/AKT/mTOR. Clinical and preclinical studies in a wide variety of solid and hematological tumors indicate that (i) EZR is highly expressed and predicts an unfavorable clinical outcome, and (ii) EZR inhibition reduces proliferation, migration, and invasion in experimental models. The development of pharmacological inhibitors for EZR (or the signaling mediated by it) has opened a new round of investigation, but studies are still limited. The scope of the present review is to survey studies on the expression and clinical impact of EZR in cancer, as well as studies that perform interventions on the function of this gene/protein in cancer cells, providing proof-of-concept of its antineoplastic potential. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify differentially expressed genes, biological processes, and metabolic pathways related to adipogenesis and lipogenesis in calves receiving different diets during the cow-calf phase. Forty-eight uncastrated F1 Angus × Nellore males were randomly assigned to two treatments from thirty days of age to weaning: no creep feeding (G1) or creep feeding (G2). The creep feed offered contained ground corn (44.8%), soybean meal (40.4%), and mineral core (14.8%), with 22% crude protein and 65% total digestible nutrients in dry matter. After weaning, the animals were feedlot finished for 180 days and fed a single diet containing 12.6% forage and 87.4% corn-based concentrate. Longissimus thoracis muscle samples were collected by biopsy at weaning for transcriptome analysis and at slaughter for the measurement of intramuscular fat content (IMF) and marbling score (MS). Animals of G2 had 17.2% and 14.0% higher IMF and MS, respectively (p < 0.05). We identified 947 differentially expressed genes (log2 fold change 0.5, FDR 5%); of these, 504 were upregulated and 443 were downregulated in G2. Part of the genes upregulated in G2 were related to PPAR signaling (PPARA, SLC27A1, FABP3, and DBI), unsaturated fatty acid synthesis (FADS1, FADS2, SCD, and SCD5), and fatty acid metabolism (FASN, FADS1, FADS2, SCD, and SCD5). Regarding biological processes, the genes upregulated in G2 were related to cholesterol biosynthesis (EBP, CYP51A1, DHCR24, and LSS), unsaturated fatty acid biosynthesis (FADS2, SCD, SCD5, and FADS1), and insulin sensitivity (INSIG1 and LPIN2). Cow-calf supplementation G2 positively affected energy metabolism and lipid biosynthesis, and thus favored the deposition of marbling fat during the postweaning period, which was shown here in an unprecedented way, by analyzing the transcriptome, genes, pathways, and enriched processes due to the use of creep feeding. [ABSTRACT FROM AUTHOR]

Technological advancement in storage systems has currently stimulated their use in miscellaneous applications. The devices have gained prominence due to their increased performance and efficiency, together with the recent global appeal for reducing the environmental impacts caused by generating power or by combustion vehicles. Many technologies have been developed to allow these devices to be reused or recycled. In this sense, the use of lithium-ion batteries, especially in electric vehicles, has been the central investigative theme. However, a drawback of this process is discarding used batteries. This work provides a short review of the techniques used for the second-life batteries of electric vehicles and presents the current positioning of the field, the steps involved in the process of reuse and a discussion on important references. In conclusion, some directions and perspectives of the field are shown. [ABSTRACT FROM AUTHOR]

Simple Summary: Hematologic neoplasms comprise a heterogeneous group of diseases that interfere with normal blood production. Treating patients who fail available therapies for these diseases is an ongoing challenge. Thus, the search for new treatment options is urgent, and drug repositioning is emerging as an attractive strategy for finding new effective drugs. Eribulin is a drug that acts on microtubules, and it is used in solid tumors, and its safety is known. In the present study, we provide evidence of the effects of eribulin on hematologic cancers and identify the potential biomarkers of responsiveness. Our study indicates that eribulin is a candidate blood cancer drug for repositioning. Despite the advances in understanding the biology of hematologic neoplasms which has resulted in the approval of new drugs, the therapeutic options are still scarce for relapsed/refractory patients. Eribulin is a unique microtubule inhibitor that is currently being used in the therapy for metastatic breast cancer and soft tissue tumors. Here, we uncover eribulin's cellular and molecular effects in a molecularly heterogeneous panel of hematologic neoplasms. Eribulin reduced cell viability and clonogenicity and promoted apoptosis and cell cycle arrest. The minimal effects of eribulin observed in the normal leukocytes suggested selectivity for malignant blood cells. In the molecular scenario, eribulin induces DNA damage and apoptosis markers. The ABCB1, ABCC1, p-AKT, p-NFκB, and NFκB levels were associated with responsiveness to eribulin in blood cancer cells, and a resistance eribulin-related target score was constructed. Combining eribulin with elacridar (a P-glycoprotein inhibitor), but not with PDTC (an NFkB inhibitor), increases eribulin-induced apoptosis in leukemia cells. In conclusion, our data indicate that eribulin leads to mitotic catastrophe and cell death in blood cancer cells. The expression and activation of MDR1, PI3K/AKT, and the NFκB-related targets may be biomarkers of the eribulin response, and the combined treatment of eribulin and elacridar may overcome drug resistance in these diseases. [ABSTRACT FROM AUTHOR]

Purpose: Some first-line cytotoxic chemotherapics, e.g. doxorubicin, paclitaxel and oxaliplatin, induce activation of the immune system through immunogenic cell death (ICD). Tumor cells undergoing ICD function as a vaccine, releasing damage-associated molecular patterns (DAMPs), which act as adjuvants, and neoantigens of the tumor are recognized as antigens. ICD induction is rare, however it yields better and long-lasting antitumor responses to chemotherapy. Advanced metastatic melanoma (AMM) is incurable for more than half of patients. The discovery of ICD inducers against AMM is an interesting drug discovery strategy with high translational potential. Here we evaluated ICD induction of four highly cytotoxic chromomycins A (CA5-8). Methods: ICD features and DAMPs were evaluated using several in vitro techniques with metastatic melanoma cell line (B16-F10) exposed to chromomcins A5-8 such as flow cytometry, western blot, RT-PCR and luminescence. Additionally in vivo vaccination assays with CA5-treated cells in a syngeneic murine model (C57Bl/6) were performed to confirm ICD evaluating the immune cells activation and their antitumor activity. Results: B16-F10 treated with CA5-8 and doxorubicin exhibited ICD features such as autophagy and apoptosis, externalization of calreticulin, and releasing of HMGB1. However, CA5-treated cells had the best profile, also inducing ATP release, ERp57 externalization, phosphorylation of eIF2α and altering expression of transcription of genes related to autophagy, endoplasmic reticulum stress, and apoptosis. Bona fide ICD induction by CA5 was confirmed by vaccination of C57BL/6 mice with CA5-treated cells which activated antigen-presenting cells and T lymphocytes and stimulated antitumor activity. Conclusion: CA5 induces bona fide immunogenic cell death on melanoma. [ABSTRACT FROM AUTHOR]

The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia. [ABSTRACT FROM AUTHOR]

Combination therapies or multi-targeted drugs have been pointed out as an option to prevent the emergence of resistant clones, which could make long-term treatment more effective and translate into better clinical outcomes for cancer patients. The NT157 compound is a synthetic tyrphostin that leads to long-term inhibition of IGF1R/IRS1-2-, STAT3- and AXL-mediated signaling pathways. Given the importance of these signaling pathways for the development and progression of lung cancer, this disease becomes an interesting model for generating preclinical evidence on the cellular and molecular mechanisms underlying the antineoplastic activity of NT157. In lung cancer cells, exposure to NT157 decreased, in a dose-dependent manner, cell viability, clonogenicity, cell cycle progression and migration, and induced apoptosis (p < 0.05). In the molecular scenario, NT157 reduced expression of IRS1 and AXL and phosphorylation of p38 MAPK, AKT, and 4EBP1. Besides, NT157 decreased expression of oncogenes BCL2, CCND1, MYB, and MYC and increased genes related to cellular stress and apoptosis, JUN, BBC3, CDKN1A, CDKN1B, FOS, and EGR1 (p < 0.05), favoring a tumor-suppressive cell signaling network in the context of lung cancer. Of note, JNK was identified as a key kinase for NT157-induced IRS1 and IRS2 phosphorylation, revealing a novel axis involved in the mechanism of action of the drug. NT157 also presented potentiating effects on EGFR inhibitors in lung cancer cells. In conclusion, our preclinical findings highlight NT157 as a putative prototype of a multitarget drug that may contribute to the antineoplastic arsenal against lung cancer. [ABSTRACT FROM AUTHOR]

Mitochondria have pivotal roles in cellular physiology including energy metabolism, reactive oxygen species production, Ca2+ homeostasis, and apoptosis. Altered mitochondrial morphology and function is a common feature of cancer cells and the regulation of mitochondrial homeostasis has been identified as a key to the response to chemotherapeutic agents in human leukemias. Here, we explore the mechanistic aspects of cytotoxicity produced by thioridazine (TR), an antipsychotic drug that has been investigated for its anticancer potential in human leukemia cellular models. TR exerts selective cytotoxicity against human leukemia cells in vitro. A PCR array provided a general view of the expression of genes involved in cell death pathways. TR immediately produced a pulse of cytosolic Ca2+, followed by mitochondrial uptake, resulting in mitochondrial permeabilization, caspase 9/3 activation, endoplasmic reticulum stress, and apoptosis. Ca2+ chelators, thiol reducer dithiothreitol, or CHOP knockdown prevented TR-induced cell death. TR also exhibited potent cytotoxicity against BCL-2/BCL-xL-overexpressing leukemia cells. Additionally, previous studies have shown that TR exhibits potent antitumor activity in vivo in different solid tumor models. These findings show that TR induces a Ca2+-mediated apoptosis with involvement of mitochondrial permeabilization and ER stress in leukemia and it emphasizes the pharmacological potential of TR as an adjuvant in antitumor chemotherapy. [ABSTRACT FROM AUTHOR]

In cancer, tumor cells and their neoplastic microenvironment can sculpt the immunogenic phenotype of a developing tumor. In this context, natural killer (NK) cells are subtypes of lymphocytes of the innate immune system recognized for their potential to eliminate neoplastic cells, not only through direct cytolytic activity but also by favoring the development of an adaptive antitumor immune response. Even though the protective effect against leukemia due to NK-cell alloreactivity mediated by the absence of the KIR-ligand has already been shown, and some data on the role of NK cells inmyeloproliferative neoplasms (MPN) has been explored, their mechanisms of immune escape have not been fully investigated. It is still unclear whether NK cells can affect the biology of BCRABL1-negative MPN and which mechanisms are involved in the control of leukemic stem cell expansion. Aiming to investigate the potential contribution of NK cells to the pathogenesis of MPN, we characterized the frequency, receptor expression, maturation profile, and function of NK cells from a conditional Jak2V617F murine transgenic model, which faithfully resembles the main clinical and laboratory characteristics of human polycythemia vera, and MPN patients. Immunophenotypic analysis was performed to characterize NK frequency, their subtypes, and receptor expression in bothmutated andwildtype samples. We observed a higher frequency of total NK cells in JAK2V617F mutated MPN and a maturation arrest that resulted in low-numbered mature CD11b+ NK cells and increased immature secretory CD27+ cells in both human and murine mutated samples. In agreement, inhibitory receptors were more expressed inMPN. NK cells fromJak2V617Fmice presented a lower potential for proliferation and activation than wild-type NK cells. Colonies generated by murine hematopoietic stem cells (HSC) after mutated or wild-type NK coculture exposure demonstrated that NK cells from Jak2V617F mice were deficient in regulating differentiation and clonogenic capacity. In conclusion, our findings suggest that NK cells have an immature profile with deficient cytotoxicity that may lead to impaired tumor surveillance in MPN. These data provide a new perspective on the behavior of NK cells in the context of myeloid malignancies and can contribute to the development of new therapeutic strategies, targeting onco-inflammatory pathways that can potentially control transformed HSCs. [ABSTRACT FROM AUTHOR]

Ankyrin repeat and KH domain‐containing protein 1, ANKHD1, has been identified as a regulator of signaling pathways and cellular processes of relevance in carcinogenesis. However, the role of ANKHD1 in breast cancer remains unclear. The aim of the present study was to characterize the expression pattern and involvement of ANKHD1 in the malignant phenotype of breast cancer cell lines and to investigate the clinical relevance of ANKHD1 in a breast cancer context. Gene and protein expressions were assessed in the cell lines by quantitative reverse transcription PCR and Western blot analysis, respectively, and ANKHD1 silencing through siRNA transfection was conducted for further in vitro functional assays. The expression of ANKHD1 was identified in non‐tumorigenic breast epithelium and breast cancer cell lines, but differences in cellular localization were found among the neoplasia subtypes. ANKHD1 silencing reduced the viability, clonogenicity, and migration of triple‐negative breast cancer (TNBC) cells. Bioinformatics analyses demonstrated that patients with triple‐negative basal‐like 2 and mesenchymal breast cancer subtypes had high ANKHD1 expression associated with poor recurrence‐free survival. Therefore, these data indicate that ANKHD1 relevance in breast cancer varies among its subtypes, indicating the importance of ANKHD1 in TNBC. [ABSTRACT FROM AUTHOR]

Corn ethanol production has been growing in Brazil in the last ten years, generating by-products to feedlot diets. This study evaluates the effects of the inclusion of low-fat corn wet distillers grains (LF-WDG) on feeding behavior, ruminal health, liver abscesses and blood parameters of F1 Angus-Nellore bulls feedlot finished. Our hypothesis is that evaluation of data from feeding behavior, rumen and liver health would help to explain animal performance. In this trail, one-hundred animals were fed for 129 days with diets containing amounts of 0 (control), 15, 30 and 45% of LF-WDG replacing corn grain and soybean meal. Evaluations of fluctuation of dry matter intake (DMI) were carried out. Additionally, feeding behavior data were assessed by monitoring (24-h period) the feeding, rumination, time spent eating (TSE), and time expended on other activities (resting and number of meals per day). Blood variables such as pH, bicarbonate, total CO2 content, and base excess in extracellular fluid (Beecf) were determined. After slaughter, rumen epithelium was classified according to the incidence of lesions (rumenitis) and abnormalities (papillae clumped), and samples were collected for morphology and histology evaluations. Moreover, livers were scored for severity of abscesses as follow: as unabscessed (0), one or two small abscesses (A−), two to four small active abscesses (A) or one or more large, active abscesses (A+). The DMI (kg/day) differed (P = 0.03) among treatments and there is a tendency of 15 and 30 LF-WDG (% DM) had lower %DMI fluctuation compared to 0 or 45%. The TSE increased linearly (P < 0.01) as the amounts of inclusion of LF-WDG increased. Moreover, neutral detergent fiber (NDF) intake, NDF consumption rate and NDF rumination efficiency increased linearly (P < 0.01) in response to LF-WDG feeding. The incidence of rumenitis tended (P = 0.08) to be greater at 45% LF-WDG, while keratin thickness decreased linearly in bulls fed LF-WDG (P < 0.01). The severity of liver abscesses (score A+) increased linearly (P = 0.02). Regarding blood parameters, only Beecf decreased linearly (P < 0.01) in response to LF-WDG feeding. Therefore, the hypothesis of the current study was confirmed. We previous reported that F1 Angus-Nellore bulls fed LF-WDG show greater weight gain (1.94 ± 0.09 kg/day) and final body weight (620 ± 18.8 kg) when compare to control (1.8 ± 0.09 kg/day and 602 ± 18.8 kg, respectively). Here, we conclude that inclusion of 15 to 30% LF-WDG in feedlot diets improved feeding behavior without impairing ruminal health and blood parameters, driving performance and weigh gain of crossbred bulls. However, bulls fed 45% LF-WDG had greater severity of liver abscesses. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the most lethal human neoplasms, and despite advances in the understanding of the molecular complexity involved in the development and progression of this disease, little of this new information has been translated into improvements in therapy and prognosis. Ezrin (EZR) is a protein that regulates multiple cellular functions, including cell proliferation, survival, morphogenesis, adhesion, and motility. In pancreatic cancer, EZR is highly expressed and reflects an unfavorable prognosis, whereas EZR silencing ameliorates the malignant phenotype of pancreatic cancer cells. NSC305787 was identified as a pharmacological EZR inhibitor with favorable pharmacokinetics and antineoplastic activity. Here, we endeavored to investigate the impact of EZR expression on survival outcomes and its associations with molecular and biological characteristics in The Cancer Genome Atlas pancreatic adenocarcinoma cohort. We also assessed the potential antineoplastic effects of NSC305787 in pancreatic cancer cell lines. High EZR expression was an independent predictor of worse survival outcomes. Functional genomics analysis indicated that EZR contributes to multiple cancer-related pathways, including PI3K/AKT/mTOR signaling, NOTCH signaling, estrogen-mediated signaling, and apoptosis. In pancreatic cells, NSC305787 reduced cell viability, clonal growth, and migration. Our exploratory molecular studies identified that NSC305787 modulates the expression and activation of key regulators of the cell cycle, proliferation, DNA damage, and apoptosis, favoring a tumor-suppressive molecular network. In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Summary: Background. Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common genetic alteration found in classic MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). We and others previously demonstrated that metformin reduced splenomegaly and platelets counts in peripheral blood in JAK2V617F pre-clinical MPN models, which highlighted the antineoplastic potential of biguanides for MPN treatment. Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients. Aims. We herein aimed to investigate the effects of phenformin in MPN disease burden and stem cell function in Jak2V617F-knockin MPN mice. Results. In vitro phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2V67F cells. Long-term treatment with 40 mg/kg phenformin in Jak2V617F knockin mice increased the frequency of LSK, myeloid progenitors (MP), and multipotent progenitors (MPP) in the bone marrow. Phenformin treatment did not affect peripheral blood counts, spleen weight, megakaryocyte count, erythroid precursors frequency, or ex vivo clonogenic capacity. Ex vivo treatment of bone marrow cells from Jak2V617F knockin mice with phenformin did not affect hematologic parameters or engraftment in recipient mice. Conclusions. Phenformin increased the percentages of LSK, MP, and MPP populations, but did not reduce disease burden in Jak2V617F-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors. [ABSTRACT FROM AUTHOR]

Summary: Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML–RARα fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p < 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p < 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL. [ABSTRACT FROM AUTHOR]

Several lines of research suggest that Bcl‐xL‐mediated anti‐apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and serve as therapeutic target. Here, we used a knock‐in JAK2V617F mouse model and confirmed that Bcl‐xL was overexpressed in erythroid progenitors. The myeloproliferative neoplasm (MPN)‐induced phenotype in the peripheral blood by conditional knock‐in of JAK2V617F was abrogated by conditional knockout of Bcl2l1, which presented anemia and thrombocytopenia independently of JAK2 mutation status. Mx1‐Cre Jak2V617W/VF/Bcl2l1f/f mice presented persistent splenomegaly as a result of extramedullary hematopoiesis and pro‐apoptotic stimuli in terminally differentiated erythroid progenitors. The pan‐BH3 mimetic inhibitor obatoclax showed superior cytotoxicity in JAK2V617F cell models, and reduced clonogenic capacity in ex vivo assay using Vav‐Cre Jak2V617F bone marrow cells. Both ruxolitinib and obatoclax significantly reduced spleen weights in a murine Jak2V617F MPN model but did not show additive effect. The tumor burden reduction was observed with either ruxolitinib or obatoclax in terminal differentiation stage neoplastic cells but not in myeloid‐erythroid precursors. Therefore, disrupting the BCL2 balance is not sufficient to treat MPN at the stem cell level, but it is certainly an additional option for controlling the critical myeloid expansion of the disease. [ABSTRACT FROM AUTHOR]

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Copyright of Geopauta is the property of Edicoes UESB and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Despite great advances that have been made in the understanding of the molecular complexity of acute myeloid leukemia (AML), very little has been translated into new therapies. Here, we set out to investigate the impact of cytoskeleton regulatory genes on clinical outcomes and their potential as therapeutic targets in AML. Methods: Gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) AML study and used for survival and functional genomics analyses. For pharmacological tests, AML cells were exposed to ezrin (EZR) inhibitors and submitted to several cellular and molecular assays. Results: High EZR expression was identified as an independent marker of worse outcomes in AML patients from the TCGA cohort (p < 0.05). Functional genomics analyses suggested that EZR contributes to responses to stimuli and signal transduction pathways in leukemia cells. EZR pharmacological inhibition with NSC305787 and NSC668394 reduced viability, proliferation, autonomous clonal growth, and cell cycle progression in AML cells (p < 0.05). NSC305787 had a greater potency and efficiency than NSC668394 in leukemia models. At the molecular level, EZR inhibitors reduced EZR, S6 ribosomal protein and 4EBP1 phosphorylation, and induced PARP1 cleavage in AML cells. NSC305787, but not NSC668394, favored a gene network involving cell cycle arrest and apoptosis in Kasumi 1 AML cells. Conclusions: From our data we conclude that EZR expression may serve as a prognostic factor in AML. Our preclinical findings indicate that ezrin inhibitors may be employed as a putative novel class of AML targeting drugs. [ABSTRACT FROM AUTHOR]

Summary: Despite the great advances in the understanding of the molecular basis of acute leukemia, very little of this knowledge has been translated into new therapies. Stathmin 1 (STMN1), a phosphoprotein that regulates microtubules dynamics, is highly expressed in acute leukemia cells and promotes cell cycle progression and proliferation. GDP366 has been described as a STMN1 and survivin inhibitor in solid tumors. This study identified structural GDP366 analogs and the cellular and molecular mechanisms underlying their suppressive effects on acute leukemia cellular models. STMN1 mRNA levels were higher in AML and ALL patients, independent of risk stratification (all p < 0.001). Cheminformatics analysis identified three structural GDP366 analogs, with AD80 more potent and effective than GSK2606414 and GW768505A. In acute leukemia cells, GDP366 and AD80 reduced cell viability and autonomous clonal growth in a dose- and/or time-dependent manner (p < 0.05) and induced apoptosis and cell cycle arrest (p < 0.05). At the molecular level, GDP366 and AD80 reduced Ki-67 (a proliferation marker) expression and S6 ribosomal protein (a PI3K/AKT/mTOR effector) phosphorylation, and induced PARP1 (an apoptosis marker) cleavage and γH2AX (a DNA damage marker) expression. GDP366 induced STMN1 phosphorylation and survivin expression, while AD80 reduced survivin and STMN1 expression. GDP366 and AD80 modulated 18 of the 84 cytoskeleton regulators-related genes. These results indicated that GDP366 and AD80 reduced the PI3K/STMN1 axis and had cytotoxic effects in acute leukemia cellular models. Our findings further highlight STMN1-mediated signaling as a putative anticancer target for acute leukemia. [ABSTRACT FROM AUTHOR]

Summary: Chronic myeloid leukemia (CML) is successfully treated with BCR-ABL1 tyrosine kinase inhibitors, but a significant percentage of patients develop resistance. Insulin receptor substrate 1 (IRS1) has been shown to constitutively associate with BCR-ABL1, and IRS1-specific silencing leads to antineoplastic effects in CML cell lines. Here, we characterized the efficacy of NT157, a pharmacological inhibitor of IGF1R-IRS1/2, in CML cells and observed significantly reduced cell viability and proliferation, accompanied by induction of apoptosis. In human K562 cells and in murine Ba/F3 cells, engineered to express either wild-type BCR-ABL1 or the imatinib-resistant BCR-ABL1T315I mutant, NT157 inhibited BCR-ABL1, IGF1R, IRS1/2, PI3K/AKT/mTOR, and STAT3/5 signaling, increased CDKN1A, FOS and JUN tumor suppressor gene expression, and reduced MYC and BCL2 oncogenes. NT157 significantly reduced colony formation of human primary CML cells with minimal effect on normal hematopoietic cells. Exposure of primary CML cells harboring BCR-ABL1T315I to NT157 resulted in increased apoptosis, reduced cell proliferation and decreased phospho-CRKL levels. In conclusion, NT157 has antineoplastic effects on BCR-ABL1 leukemogenesis, independent of T315I mutational status. [ABSTRACT FROM AUTHOR]

The establishment of seed banks is essential for the conservation of cultivated and wild plant species. Cattleya species are economically important, but many of them are at risk of extinction. In this study, we aimed to evaluate the effects of storage temperature on the physiological quality of seeds of seven congeneric species of diverse biomes from the UNOESTE-OSSSU seed bank and the lipid composition. Seeds were split into sub samples, pre-conditioned to 0.03 g H2O g DW−1 for a week over a supersaturated solution of lithium chloride at 23 ± 2 °C and maintained in rubber-sealed vessels for nine months under four storage temperatures: room temperature (23 ± 2 °C), 5 °C, –18 °C and –196 °C. Germination, the germination speed index, and viability based on a tetrazolium test were evaluated at three-month intervals. Lipid profiles were determined by GC-MS in the original seed lots. Different lipid profiles were found among species. Orchid seeds with a low water content could be stored for a short period in all conditions studied and were considered orthodox short-lived seeds. Cattleya rupestris seeds were more tolerant than the congeners to deterioration under all the storage conditions. [ABSTRACT FROM AUTHOR]

The objective was to investigate gene and protein expression of myosin heavy chain (MyHC) in Nellore cattle slaughtered at different weights (BW) or degrees of meat tenderness. Ninety animals with initial BW 370 ± 37 kg, 24 months of age, were slaughtered after 95 days on feed. We evaluated shear force (SF), myofibrillar fragmentation index, ribeye area, backfat thickness, marbling, color, and cooking losses. Subsequently, 24 animals were selected and divided into four contrasting groups, in which light (BW = 504.58 ± 32.36 kg) versus heavy animals (BW = 604.83 ± 42.97 kg) and animals with tender (SF = 3.88 ± 0.57 kg) versus tough meat (SF = 7.95 ± 1.04 kg) were compared. The MYH7, MYH2 and MYH1 genes were analyzed by real-time PCR. The MyHC isoforms (MyHC-I, MyHC-IIa, and MyHC-IIx) were quantified by SDS-PAGE electrophoresis. We found lower expression of MYH2 and MYH1 genes in heavy compared to light animals and a higher amount of MyHC-I isoform in the tough meat group compared to the tender meat group. Protein expression of MyHC-IIa was higher in the tender meat group. A negative correlation was found of this protein and SF (tenderness), suggesting MyHC-IIa as a biomarker of meat quality. [ABSTRACT FROM AUTHOR]

Meat tenderness is one of the principal attribute associated with consumer preferences. This study describes tenderness measurements at three final endpoint cooking temperatures (51, 61 and 71 °C) using a mechanical Warner–Bratzler (WBSF) as the standard instrument versus digital texturometer (CT3) and penetrometer (FHT) devices. Thirty-six cross-breed heifers (Bos indicus) with initial body weight 330 ± 40 kg, 20–24 months of age, were slaughtered after 100 days on feed. Subsequently, 48 h post-slaughter, Longissimus thoracis (LT) samples were collected between the 10th and 13th ribs. Six LT samples from each animal were used to evaluate tenderness and cooking losses through analysis of variance and regression analyses. No interaction between device × temperature was observed (p = 0.57). Shear force values were greater (p < 0.05) as endpoint cooking increased and the results from CT3 were close to the ones using the WBSF (R2 = 0.76; p < 0.0001). In conclusion, the digital CT3 can replace the mechanical WBSF because these devices were strongly correlated (r = 0.85; p < 0.00). However, the results from FHT were underestimated (R2 = 0.19; p < 0.006), indicating that FHT device should not be used for the evaluation of meat tenderness. [ABSTRACT FROM AUTHOR]

Context. It is hypothesised that protein supplementation in pregnant Nellore cows during the dry season would improve reproductive performance in the next breeding season, as well as growth, myogenesis and intramuscular lipogenesis of the progeny until weaning. Aims. To evaluate the effect of maternal nutrition on cow reproductive performance, as well as on the growth, myogenesis and lipogenesis of the progeny until weaning. Methods. A total of 92 pregnant cows were fed on pasture, and half of the cows were also fed a mineral-protein supplement (36% crude protein) from 124 ± 21 days of pregnancy to calving. Therefore, two treatments were tested: non-supplemented or supplemented cows. Progeny were weighed after birth, 130 days after birth and at weaning. Six newborn calves from each treatment were slaughtered to collect muscle and jejunum samples to analyse histology and gene expression. In addition, Longissimus thoracis muscle biopsies were collected at 11 days after birth and weaning for gene expression analyses. Key results. Supplemented cows had greater bodyweight (P = 0.03) and body condition score (P = 0.05) during gestation, and the pregnancy rate in the subsequent breeding season had a tendency (P = 0.10) to be greater. The progeny from supplemented cows had greater bodyweight at birth (P = 0.05). However, no differences (P > 0.05) were found in bodyweight at weaning or in the average daily gain during this period. Non-supplemented calves had greater SLC27A4 (P = 0.04) expression and a tendency for greater expression of SLC5A1 (P = 0.08) in the jejunum. Muscle gene expression data showed that progeny from supplemented cows had greater expression of myogenic (WNT10B), adipogenic (PPARG, ZFP423, CD36) and fibrogenic (TGFb1) markers at birth and at weaning (P = 0.10). Conclusions. In conclusion, protein supplementation of pregnant Nellore cows leads to positive effects for subsequent reproductive performance and for muscle development of their progeny. In addition, the progeny from feed-restricted cows increases prenatal intestinal development for better nutrients absorption under a potentially impaired environmental condition. Implications. The use of protein supplementation in pregnant Nellore cows has a positive impact on the production system, increasing productivity in a cow/calf operation. [ABSTRACT FROM AUTHOR]

Deregulated cellular energetics is formally incorporated as an emerging hallmark of cancer, however little is known about its processes in myelodysplastic syndromes (MDS). Using transcriptomic data of CD34+ cells from 159 MDS patients and 17 healthy donors, we selected 37 genes involved in cellular energetics and interrogated about its clinical and prognostic functions. Based on the low expression of ACLY, ANPEP, and PANK1, as well as high expression of PKM and SLC25A5, we constructed our Molecular-Based Score (MBS), that efficiently discriminated patients at three risks groups: favourable risk (n = 28; 3-year overall survival (OS): 100%); intermediate (n = 60; 76% [62–93%]) and adverse (n = 71; 35% [17–61%]). Adverse MBS risk was independently associated with inferior OS (HR = 10.1 [95% CI 1.26–81]; P = 0.029) in multivariable analysis using age, gender and the revised international prognostic score system as confounders. Transcriptional signature revealed that Favourable- and intermediate-risk patients presented enriched molecular programs related to mature myeloid progenitors, cell cycle progression, and oxidative phosphorylation, indicating that this cells differs in their origin, metabolic state, and cell cycle regulation, in comparison to the adverse-risk. Our study provides the first evidence that cellular energetics is transcriptionally deregulated in MDS CD34+ cells and establishes a new useful prognostic score based on the expression of five genes. [ABSTRACT FROM AUTHOR]

RhoA and RhoC contribute to the regulation of glutamine metabolism, which is a crucial determinant of cell growth in some types of cancer. Here we investigated the participation of RhoA and RhoC in the response of prostate cancer cells to glutamine deprivation. We found that RhoA and RhoC activities were up- or downregulated by glutamine reduction in PC3 and LNCaP cell lines, which was concomitant to a reduction in cell number and proliferation. Stable overexpression of wild type RhoA or RhoC did not alter the sensitivity to glutamine deprivation. However, PC3 cells expressing dominant negative RhoAN19 or RhoCN19 mutants were more resistant to glutamine deprivation. Our results indicate that RhoA and RhoC activities could affect cancer treatments targeting the glutamine pathway. [ABSTRACT FROM AUTHOR]

Purpose: Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer with limited therapeutic options for adult patients. Aurora kinases have drawn attention as potential targets in hematological neoplasms due to their high expression and biological functions. Aurora kinase A (AURKA) and AURKB are essential for a successful mitosis, acting in spindle mitotic organization and cytokinesis. Reversine is a synthetic purine analog that acts as a multi-kinase inhibitor with anti-neoplastic activity by targeting AURKA and AURKB. Methods: ALL patient gene expression data were retrieved from the Amazonia! database. For functional assays, Jurkat (T-ALL) and Namalwa (B-ALL) cells were exposed to increasing concentrations of reversine and submitted to various cellular and molecular assays. Results: We found that AURKB expression was higher in ALL patient samples compared to normal lymphocytes (p < 0.0001). The ALL cell lines tested displayed aberrant AURKA and AURKB expression. In Jurkat and Namalwa cells, reversine reduced cell viability in a dose- and time-dependent manner (p < 0.05). Reversine also significantly reduced the viability of primary ALL cells. Reversine induced apoptosis and autophagy, and reduced cell proliferation in both cell lines (p < 0.05). Mitotic catastrophe markers, including cell cycle arrest at G2/M, increased cell size and DNA damage, were observed upon reversine exposure. Short- and long-term treatment with reversine inhibited autonomous clonogenicity (p < 0.05). At the molecular level, reversine reduced AURKB activity, induced SQSTM1/p62 consumption, and increased LC3BII and γ-H2AX levels. In Namalwa cells, reversine modulated 25 out of 84 autophagy-related genes, including BCL2, BAD, ULK1, ATG10, IRGM and MAP1LC3B, which indicates that reversine acts by initiating and sustaining autophagy signals in ALL cells. Conclusions: From our data we conclude that reversine reduces the viability of ALL cells by triggering multiple cell death mechanisms, including apoptosis, mitotic catastrophe, and autophagy. Our findings highlight reversine as a potential anticancer agent for ALL. [ABSTRACT FROM AUTHOR]

Principal component analysis (PCA) and the non-hierarchical clustering analysis (K-means) were used to characterize the most important variables from carcass and meat quality traits of crossbred cattle. Additionally, partial least square (PLS) regression analysis was applied between the carcass measurements and meat quality traits on the classes defined by the cluster analysis. Ninety-seven non-castrated F1 Angus-Nellore bulls feedlot finished were used. After slaughter, hot carcass weight, carcass yield, cold carcass weight, carcass weight losses, pH, and backfat thickness (BFT) were measured. Subsequently, samples of the longissimus thoracis were collected to analyze shear force (SF), cooking loss (CL), meat color (L*, chroma, and hue), intramuscular fat, protein, collagen, moisture, and ashes. Principal component 1 (PC1) was correlated with colorimetric variables, while PC2 was correlated with carcass weights. Afterwards, three clusters (k = 3) were formed and projected in the gradient defined by PC1 and PC2 and allowed distinguishing groups with divergent values for collagen, protein, moisture, CL, SF, and BFT. Animals from high chroma group presented meat with more attractive colors and tenderness (SF = 1.97 to 4.84 kg). Subsequently, the PLS regression on the three chroma groups revealed a good fitness and the coefficients are used to predict the chroma variable from the explanatory variables, which may have practical importance in attempts to predict meat color from carcass and meat quality traits. Thus, PCA, K-means, and PLS regression confirmed the relationship between meat color and tenderness. [ABSTRACT FROM AUTHOR]

Context: It is hypothesised that the use of processed soybean for feedlot beef cattle improves feed efficiency and produces beef with a better fatty acid profile for human health. Aims: This study aimed to evaluate average daily gain, feed efficiency, carcass traits, chemical composition, fatty acid profile and colour in the beef of young bulls fed diets with ground or extruded soybean. Methods: A total of 60 young Zebu bulls (Nellore or Nellore crossed with other Zebu breeds) with an average initial liveweight of 320 ± 8.12 kg and an average initial age of 20 ± 2 months were randomly assigned to receive one of the following diets for 84 days: dehulled and defatted soybean meal (3.22% of ether extract), ground soybean (6.51% of ether extract) or extruded soybean (6.37% of ether extract). The fatty acid profiles of these animals were analysed using high-resolution gas chromatography. The CIE L*a*b* colour space model was used to numerically describe the colour during the aging period (0, 7, 14 and 21 days). Key results: Diet had no effect on the average daily gain, feed efficiency or carcass traits of the animals (P > 0.05). Protein, ether extract and ash composition of the Longissimus lumborum (LL) muscle were not affected (P > 0.30) by the use of processed soybean grains. The ground soybean diet decreased oleic acid and C18:2 c9, t11 concentrations, but increased C18:2 t10, c12 and trans-octadecenoic acid isomer concentrations in the LL muscle compared with those in the dehulled and defatted soybean meal and extruded soybean diets (P < 0.05). Muscle from bulls fed processed soybean exhibited greater concentrations of stearic acid and saturated fatty acids, and a lower concentration of unsaturated fatty acids, as well as a decreased unsaturated fatty acids : saturated fatty acids ratio (P < 0.05). Processed soybean grains did not affect (P > 0.05) the LL muscle pH or colour. Conclusions: The use of ground or extruded soybean did not affect the performance, carcass traits, LL protein, ether extract or ash composition, and had no impact on beef colour compared with the diet containing soybean meal. Processed whole soybeans in the diet did not increase unsaturated fatty acids or conjugated linoleic acid in beef compared with a diet without soybean meal. Implications: Up to 20% of ground or extruded soybean in feedlot beef cattle can be used as a replacement for soybean meal and corn. Nutrition is a tool used in feedlots to improve beef quality. This study evaluated the performance and beef quality in young bulls fed diets with processed soybean. The results show that the use of extruded or ground soybean does not affect performance, and that most beef quality traits using this diet were comparable to those using a diet with defatted soybean meal as the protein source. Therefore, the use of processed whole soybean in feedlots is recommended, depending on the market price. [ABSTRACT FROM AUTHOR]

Summary: The main objectives of this study were to identify and functionally classify SNPs and indels by exome sequencing of animals of the racing line of Quarter Horses. Based on the individual genomic estimated breeding values (GEBVs) for maximum speed index (SImax) obtained for 349 animals, two groups of 20 extreme animals were formed. Of these individuals, 20 animals with high GEBVs for SImax and 19 with low GEBVs for SImax had their exons and 5′ and 3′ UTRs sequenced. Considering SNPs and indels, 105 182 variants were identified in the expressed regions of the Quarter Horse genome. Of these, 72 166 variants were already known and 33 016 are new variants and were deposited in a database. The analysis of the set of gene variants significantly related (Padjusted < 0.05) to extreme animals in conjunction with the predicted impact of the changes and the physiological role of protein product pointed to two candidate genes potentially related to racing performance: SLC3A1 on ECA15 and CCN6 on ECA10. [ABSTRACT FROM AUTHOR]

Nutraceuticals have been evaluated for their ability to protect and heal the gastrointestinal mucosa, especially in adverse conditions. Thus, the present study evaluated the effect of a nutraceutical diet composed of bovine first milk secretion in the intestinal health of juvenile Piaractus mesopotamicus subjected to high stocking density. Juveniles (140 ± 10 g) distributed into 16 cages and stocked at 50 kg m−3 were fed twice daily with a pelleted and semi-purified diet containing nutraceutical food (NF) in increasing levels, being 0, 10, 20, and 30% of inclusion (n = 4). Quantification of goblet cells containing neutral, acidic (including sialo and sulfomucins) and acidic-neutral mucins, volume (Vv), and surface density (Sv) of the mucosa and thickness of the internal circular muscle layer was determined after 28 experimental days in the middle gut and rectum (RT). The apoptotic rate was analyzed qualitatively according to the intensity (high, medium, and low) of caspase-3 immunostaining in epithelial cells. Performance parameters were not affected by the inclusion of NF in the diets. Juveniles fed 20% and 30% of NF showed a lower number of goblet cells containing sulfomucins than juveniles fed 0% and 10% of NF (P = 0.01) in the RT. In the last segment of the middle gut (S2) and RT, the intensity of caspase-3 immunostaining in enterocytes was inversely related to the concentration of NF added in the diet. The inclusion of 20% and 30% of nutraceutical food in the diet of P. mesopotamicus reduced the rate of apoptosis and the number of goblet cells containing sulfomucin in the last intestinal segments of juveniles subjected to high stocking density, mitigating the effects caused by the adverse condition and being, therefore, beneficial for intestinal health. [ABSTRACT FROM AUTHOR]

Orchid pollinia have the potential to make a valuable contribution to current techniques of germplasm storage and assisted reproduction, yet information regarding their preservation and their ability to remain viable over time is currently limited. Dactylorhiza fuchsii and Disa uniflora were used as models for investigating potential techniques for storing orchid pollinia. Initially, freshly harvested pollinia of Dact. fuchsii were incubated at 25 °C and 100% RH (relative humidity) for up to 7 days and germinated in vitro. For pollinia from both species, moisture sorption isotherms were constructed and thermal fingerprints generated using differential scanning calorimetry (DSC). Pollinia were stored at three temperatures (5, − 18 and − 196 °C) after equilibration at four different RHs (5, 33, 50 and 75%) and germinated. The isotherms and DSC results varied between species. Compared with D. uniflora, pollinia of Dact. fuchsii consistently equilibrated at higher moisture content (MC) for each RH, had less detectable lipids by DSC and had shorter lifespans, remaining viable after 3–4 months only at − 20 and − 196 °C and at low RH (5 and 33%). Both species' pollinia stored well at − 20 °C and − 196 °C, although there was some evidence of a small loss of viability under cryopreservation. In conclusion, pollen of these two species can be stored successfully for at least 3–4 months, and to maximize the pre-storage quality, it is recommended that fresh pollen is collected from flowers just prior to anthesis. [ABSTRACT FROM AUTHOR]

Antioxidant components of colostrum prevent oxidative cell damage caused by free radicals that could harm the calf's development. The relationship of antioxidant potential of colostrum with parity is not well defined and could enlighten the importance of these components for the neonate and for the protection of the intestinal epithelium. The purpose of this work was to determine the antioxidant potential of colostrum from primiparous and multiparous Holstein cows in a commercial dairy farm. Samples from the first milk secretion from primiparous (first lactation, n = 8) and multiparous (second and third lactations, n = 8) Holstein cows were collected after birth of calves for determination of immune and antioxidant factors. The cows sampled in this study were vaccinated during pregnancy in order to improve colostrum quality. Colostrum from primiparous cows showed higher values of ceruloplasmin activity, oxygen radical absorbance capacity (ORAC) and transferrin saturation index (TSI) than colostrum from multiparous cows (P < 0.05). The total iron binding capacity (TIBC) and transferrin concentration in the colostrum of primiparous cows showed a non-significant numerical decrease (P = 0.06) in relation to the value in the colostrum of multiparous cows. Concentration of proteins, immunoglobulin G, and activity of lactoperoxidase, lysozyme, glutathione peroxidase and catalase, in turn, did not differ (P > 0.05). Metabolic differences between primiparous and multiparous cows may have affected the antioxidative status of colostrum, since ORAC values were twice higher in first lactation cows. Lower values of transferrin and TIBC and higher TSI in colostrum from primiparous cows suggests a relationship between lower iron stock and higher antioxidant activity. Thus, this work indicates an important role of the antioxidant potential of colostrum for neonates from first-lactation cows. Additionally, the iron stock may be directly related to the higher antioxidant potential of the colostrum from primiparous cows, and further investigations are required. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with few molecular predictors of malignancy and survival, especially in paediatric patients. Stathmin 1 (STMN1) regulates microtubule dynamics and has been involved in the malignant phenotype of cancer cells. Recently, it was reported that STMN1 is highly expressed in ACC patients, and STMN1 silencing reduces the clonogenicity and migration of ACC cell lines. However, the prognostic significance of STMN1 and its therapeutic potential remain undefined in ACC. In the present study, STMN1 mRNA levels were significantly higher (p < 0.05) in ACC patients, especially in an advanced stage, and correlated with BUB1B and PINK1 expression, the prognostic-related genes in ACC. In paediatric tumours, high STMN1 expression was observed in both adrenocortical carcinoma and adrenocortical adenoma patients. Among the adult malignant tumours, STMN1 level was an independent predictor of survival outcomes (overall survival: hazard ratio = 6.08, p = 0.002; disease-free survival: hazard ratio = 4.65, p < 0.0001). Paclitaxel, a microtubule-stabilizing drug, reduces the activation of STMN1 and significantly decreases cell migration and invasion in ACC cell lines and ACC cells from secondary cell culture (all p < 0.0001). In summary, STMN1 expression may be of great value to clinical and pathological findings in therapeutic trials and deserves future studies in ACC. [ABSTRACT FROM AUTHOR]

Summary: JAK2V617F can mimic growth factor signaling, leading to PI3K/AKT/mTOR activation and inhibition of autophagy. We hypothesized that selective inhibition of JAK1/2 by ruxolitinib could induce autophagy and limit drug efficacy in myeloproliferative neoplasms (MPN). Therefore, we investigated the effects of ruxolitinib treatment on autophagy-related genes and cellular processes, to determine the potential benefit of autophagy inhibitors plus ruxolitinib in JAK2V617F cells, and to verify the frequency and clinical impact of autophagy-related gene mutations in patients with MPNs. In SET2 JAK2V617F cells, ruxolitinib treatment induced autophagy and modulated 26 out of 79 autophagy-related genes. Ruxolitinib treatment reduced the expressions of important autophagy regulators, including mTOR/p70S6K/4EBP1 and the STAT/BCL2 axis, in a dose- and time-dependent manner. Pharmacological inhibition of autophagy was able to significantly suppress ruxolitinib-induced autophagy and increased ruxolitinib-induced apoptosis. Mutations in autophagy-related genes were found in 15.5% of MPN patients and were associated with increased age and a trend towards worse survival. In conclusion, ruxolitinib induces autophagy in JAK2V617F cells, potentially by modulation of mTOR-, STAT- and BCL2-mediated signaling. This may lead to inhibition of apoptosis. Our results suggest that the combination of ruxolitinib with pharmacological inhibitors of autophagy, such as chloroquine, may be a promising strategy to treat patients with JAK2V617F-mutated MPNs. [ABSTRACT FROM AUTHOR]