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941.
Renata Ferrarotto Vasudha Mishra Elad Herz Adar Yaacov Oz Solomon Rami Rauch Adi Mondshine Maria Motin Tal Leibovich-Rivkin Matti Davis Joel Kaye Christopher R. Weber Le Shen Alexander T. Pearson Ari J. Rosenberg Xiangying Chen Alka Singh Jon C. Aster Nishant Agrawal Evgeny Izumchenko 《Cell death & disease》2022,13(8)
Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.Subject terms: Head and neck cancer, Targeted therapies 相似文献
942.
Leslie Chvez‐Galn Jhacqueline Illescas‐Eugenio Magaly Alvarez‐Sekely Renata Baez‐Saldaa Raúl Chvez Ricardo Lascurain 《Microbiology and immunology》2019,63(8):316-327
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major cause of morbidity and mortality worldwide. In the host's immune response system, T cells play a critical role in mediating protection against Mtb infection, but the role of CD8+ T cells is still controversial. We evaluated the phenotypical characterization and cytotoxic ability of CD8+ T cells by flow cytometry‐based assay. Cytokine levels in serum were measured by multiplex cytokine assay. Our data show that cells from TB patients have an increased percentage of peripheral blood CD8+αβ+ T (p = 0.02) and CD56+CD8+ T (p = 0.02) and a decreased frequency of NKG2D+CD8+ T (p = 0.02) compared with healthy donors. Unlike CD8+ T cells from healthy donors, CD8+ T cells from TB patients exhibit greater cytotoxicity, mediated by HLA class I molecules, on autologous monocytes in the presence of mycobacterial antigens (p = 0.005). Finally, TB patients have a proinflammatory profile characterized by serum high level of TNF‐α (p = 0.02) and IL‐8 (p = 0.0001), but, interestingly, IL‐4 (p = 0.002) was also increased compared with healthy donors. Our data show evidence regarding the highly cytotoxic status of CD8+ T cells in Mtb infection. These cytotoxic cells restricted to HLA‐A, B, and C could be used to optimize strategies for designing new TB vaccines or for identifying markers of disease progression. 相似文献
943.
Despite recent developments in analyzing RNA secondary structures, relatively few RNA structures have been determined. To date, many investigators have relied on the traditional method of using structure-specific RNAse enzymes to probe RNA secondary structures. However, if these data were combined with novel computational approaches, investigators would have an informative and valuable tool for RNA structural analysis. To this end, we created the web server “RNAdigest.” RNAdigest uses mfold RNA structural models in order to predict the results of RNAse digestion experiments. Furthermore, RNAdigest also utilizes both RNA sequence and the experimental digestion patterns to formulate the constraints for predicting secondary structures of the RNA. Thus, RNAdigest allows for the structural interpretation of RNAse digestion experiments. Overall, RNAdigest simplifies RNAse digestion result analyses while allowing for the identification of unique fragments. These unique fragments can then be used for testing predicted mfold structures and for designing structural-specific DNA/RNA probes. 相似文献
944.
Caio Maximino Annanda Waneza Batista da Silva Juliana Araújo Monica Gomes Lima Vanessa Miranda Bruna Puty Rancés Benzecry Domingos Luiz Wanderley Pican?o-Diniz Amauri Gouveia Jr Karen Renata Matos Oliveira Anderson Manoel Herculano 《PloS one》2014,9(7)
A major hindrance for the development of psychiatric drugs is the prediction of how treatments can alter complex behaviors in assays which have good throughput and physiological complexity. Here we report the development of a medium-throughput screen for drugs which alter anxiety-like behavior in adult zebrafish. The observed phenotypes were clustered according to shared behavioral effects. This barcoding procedure revealed conserved functions of anxiolytic, anxiogenic and psychomotor stimulating drugs and predicted effects of poorly characterized compounds on anxiety. Moreover, anxiolytic drugs all decreased, while anxiogenic drugs increased, serotonin turnover. These results underscore the power of behavioral profiling in adult zebrafish as an approach which combines throughput and physiological complexity in the pharmacological dissection of complex behaviors. 相似文献
945.
Pete Chandrangsu Renata Dusi Chris J. Hamilton John D. Helmann 《Molecular microbiology》2014,91(4):706-715
Methylglyoxal (MG) is a toxic by‐product of glycolysis that damages DNA and proteins ultimately leading to cell death. Protection from MG is often conferred by a glutathione‐dependent glyoxalase pathway. However, glutathione is absent from the low‐GC Gram‐positive Firmicutes, such as Bacillus subtilis. The identification of bacillithiol (BSH) as the major low‐molecular‐weight thiol in the Firmicutes raises the possibility that BSH is involved in MG detoxification. Here, we demonstrate that MG can rapidly and specifically deplete BSH in cells, and we identify both BSH‐dependent and BSH‐independent MG resistance pathways. The BSH‐dependent pathway utilizes glyoxalase I (GlxA, formerly YwbC) and glyoxalase II (GlxB, formerly YurT) to convert MG to d ‐lactate. The critical step in this pathway is the activation of the KhtSTU K+ efflux pump by the S‐lactoyl‐BSH intermediate, which leads to cytoplasmic acidification. We show that cytoplasmic acidification is both necessary and sufficient for maximal protection from MG. Two additional MG detoxification pathways operate independent of BSH. The first involves three enzymes (YdeA, YraA and YfkM) which are predicted to be homologues of glyoxalase III that converts MG to d ‐lactate, and the second involves YhdN, previously shown to be a broad specificity aldo‐keto reductase that converts MG to acetol. 相似文献
946.
947.
Ramona Cabiddu Renata Trimer Audrey Borghi-Silva Matteo Migliorini Renata G. Mendes Antonio D. Oliveira Jr. Fernando S. M. Costa Anna M. Bianchi 《PloS one》2015,10(4)
Obesity is associated with cardiovascular mortality. Linear methods, including time domain and frequency domain analysis, are normally applied on the heart rate variability (HRV) signal to investigate autonomic cardiovascular control, whose imbalance might promote cardiovascular disease in these patients. However, given the cardiac activity non-linearities, non-linear methods might provide better insight. HRV complexity was hereby analyzed during wakefulness and different sleep stages in healthy and obese subjects. Given the short duration of each sleep stage, complexity measures, normally extracted from long-period signals, needed be calculated on short-term signals. Sample entropy, Lempel-Ziv complexity and detrended fluctuation analysis were evaluated and results showed no significant differences among the values calculated over ten-minute signals and longer durations, confirming the reliability of such analysis when performed on short-term signals. Complexity parameters were extracted from ten-minute signal portions selected during wakefulness and different sleep stages on HRV signals obtained from eighteen obese patients and twenty controls. The obese group presented significantly reduced complexity during light and deep sleep, suggesting a deficiency in the control mechanisms integration during these sleep stages. To our knowledge, this study reports for the first time on how the HRV complexity changes in obesity during wakefulness and sleep. Further investigation is needed to quantify altered HRV impact on cardiovascular mortality in obesity. 相似文献
948.
Vania Vilas-Boas Renata Silva Andreia Palmeira Emília Sousa Luísa Maria Ferreira Paula Sério Branco Félix Carvalho Maria de Lourdes Bastos Fernando Remi?o 《PloS one》2013,8(8)
P-glycoprotein (P-gp) is a 170 kDa transmembrane protein involved in the outward transport of many structurally unrelated substrates. P-gp activation/induction may function as an antidotal pathway to prevent the cytotoxicity of these substrates. In the present study we aimed at testing rifampicin (Rif) and three newly synthesized Rif derivatives (a mono-methoxylated derivative, MeORif, a peracetylated derivative, PerAcRif, and a reduced derivative, RedRif) to establish their ability to modulate P-gp expression and activity in a cellular model of the rat’s blood–brain barrier, the RBE4 cell line P-gp expression was assessed by western blot using C219 anti-P-gp antibody. P-gp function was evaluated by flow cytometry measuring the accumulation of rhodamine123. Whenever P-gp activation/induction ability was detected in a tested compound, its antidotal effect was further tested using paraquat as cytotoxicity model. Interactions between Rif or its derivatives and P-gp were also investigated by computational analysis. Rif led to a significant increase in P-gp expression at 72 h and RedRif significantly increased both P-gp expression and activity. No significant differences were observed for the other derivatives. Pre- or simultaneous treatment with RedRif protected cells against paraquat-induced cytotoxicity, an effect reverted by GF120918, a P-gp inhibitor, corroborating the observed P-gp activation ability. Interaction of RedRif with P-gp drug-binding pocket was consistent with an activation mechanism of action, which was confirmed with docking studies. Therefore, RedRif protection against paraquat-induced cytotoxicity in RBE4 cells, through P-gp activation/induction, suggests that it may be useful as an antidote for cytotoxic substrates of P-gp. 相似文献
949.
Luciana Dalcin Renata C. Silva Fernanda Paulini Bianca D.M. Silva Jairo P. Neves Carolina M. Lucci 《Cryobiology》2013
Even though sheep embryo cryopreservation is a commonly used procedure the survival and pregnancy outcomes can vary greatly. This study investigated whether cryopreservation was causing subtle changes in ultrastructure, mitochondrial activity or cytoskeletal integrity. Sheep embryos were either slow cooled in 1.5 M EG (n = 22), or vitrified in 20% EG + 20% DMSO with 0.5 M sucrose in Open Pulled Straws (OPS) (n = 24). One hour after warming the cryopreserved embryos differed from control embryos in that they had no mitochondrial activity combined with cytoskeletal disorganization and large vesicles. Vitrified embryos also showed many points of cytoskeleton disruption. Ultrastructural alterations resulting from actin filaments disorganization were observed in both cryopreserved groups. This includes areas presenting no cytoplasmic organelles, Golgi complex located far from the nucleus and a decrease of specialized intercellular junctions. Additionally, large vesicles were observed in vitrified morulae and early blastocysts. The alterations after cryopreservation were proportional to embryo quality as assessed using the stereomicroscope. Even in the absence of mitochondrial activity, grade I and II cryopreserved embryos contained mitochondria with normal ultrastructure. Embryos classified as grade I or II in the stereomicroscope revealed mild ultrastructural alterations, meaning that this tool is efficient to evaluate embryos after cryopreservation. 相似文献
950.
Renata Velozo Timbó Marcelo Hermes-Lima Luciano Paulino Silva Angela Mehta Maria Carolina Blassioli Moraes Débora Pires Paula 《PloS one》2014,9(10)
Plant defense response is an elaborate biochemical process shown to depend on the plant genetic background and on the biological stressor. This work evaluated the soybean biochemical foliar response to brown stink bug herbivory injury through an analysis of redox metabolism and proteomic 2DE profiles of susceptible (BRS Silvania RR) and resistant (IAC-100) varieties. The activity of lipoxygenase-3, guaiacol peroxidase, catalase and ascorbate peroxidase was monitored every 24 h up to 96 h. In the susceptible variety, injury caused an increase in the activities of lipoxygenase 3 and guaiacol peroxidase, no change in ascorbate peroxidase, and a decrease in catalase. In the resistant variety, injury did not cause an alteration of any of these enzymes. The proteomic profiles were evaluated after 24 h of injury and revealed to have a similar proportion (4–5%) of differential protein expression in both varieties. The differential proteins, identified by mass spectrometry, in the susceptible variety were related to general stress responses, to plant defense, and to fungal infections. However, in the resistant variety, the identified change in protein profile was related to Calvin cycle enzymes. While the susceptible variety showed adaptive changes in redox metabolism and expression of stress-responsive proteins, the resistant showed a defense response to circumvent the biological stressor. 相似文献