Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of ...small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2).
We present the largest CCL sensitivity dataset yet available, and an analysis method integrating information from multiple CCLs and multiple small molecules to identify CCL response predictors robustly. We updated the CTRP to enable the cancer research community to leverage these data and analyses.
This study aimed to ascertain the effects of astaxanthin (ASX) in an experimental necrotizing enterocolitis (NEC) model using rat pups.
Forty-two pups born from five Wistar albino rats were randomly ...divided into three groups as the control group, NEC + placebo (saline), and NEC + ASX. Pups in the NEC + ASX group were given 100 mg/kg/day oral ASX from day 1 to day 4 of the study. Saline of 2 mL/kg was given to the NEC + placebo group. Histopathological, immunohistochemical (caspase-3), and biochemical evaluations including the total antioxidant status (TAS), total oxidant status (TOS), superoxide dismutase (SOD), glutathione (GSH), lipid hydroperoxide (LPO), 8-hydroxydeoxyguanosine (8-OHdG), advanced oxidation protein products (AOPP), myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nuclear factor erythroid 2-related factor 2 (Nfr-2) activities were all performed.
A better survival rate and weight gain were demonstrated in the NEC + ASX group (
< 0.05). In the histopathological evaluation, the severity of intestinal damage was significantly reduced in the NEC + ASX group, as well as decreased apoptosis (enzyme-linked immunosorbent assay ELISA for caspase-3;
= 0.001). The biochemical analyses of intestinal tissue TOS, oxidative stress index (OSI; TOS/TAS), IL-1β, LPO, 8-OHdG, AOPP, caspase-3 (
< 0.001 for all), and TNF-α and MPO (
= 0.001 for both parameters) levels were lower in the NEC + ASX group than in the NEC + placebo group. Nrf-2, TAS, GSH, and SOD levels were higher in the NEC + ASX group than in the NEC + placebo group (
= 0.001, 0.001, <0.001, and 0.01, respectively).
ASX treatment has been shown to effectively reduce the severity of intestinal damage in NEC due to its antioxidant, anti-inflammatory, and antiapoptotic properties.
· NEC causes extremely high morbidity and mortality, as well as many complications.. · We investigated the effectiveness of ASX in the experimental NEC model created in rat pups.. · First study examining the effect of ASX on the experimental NEC rat model..
The Rhipicephalus sanguineus complex is a group of closely related tick species distributed all around the world. In this study, using mitochondrial 16S ribosomal DNA, new specimens of R sanguineus ...sensu lato from Turkey and Rhipicephalus camicasi from Kenya, were evaluated together with available sequences of this complex in GenBank. Our objectives were to delimit the complex, re-evaluate its global phylogeny and develop a reconstruction of its biogeographic history. Given Turkey's geographical location and its neighboring status within Africa, Asia and Europe, molecular information of R. sanguineus s.l. species from this region could have important implications both on a regional and global scale. Phylogenetic trees obtained with three methods (Bayesian, Maximum Likelihood and Maximum Parsimony) were highly similar and consensus trees gave the same branching patterns and similar node support values. A total of four different clades with up to 9 Operational Taxonomic Units formed strong monophyletic groups. Biogeographic reconstructions demonstrated the importance of populations in Middle East (Turkey) in the spread of the group from Europe to Africa and Asia. Data supported previous conclusions on the existence of two species of R. sanguineus s.l. in South America and the strong molecular similarity between R. camicasi and the so-called tropical lineage of R. sanguineus s.l. These results point to the need of a re-evaluation of most specimens designated as R. sanguineus s.l. in East Europe, Middle East, Africa and Asia after an adequate re-description of this taxon.
Laccase activity was monitored in synthetic media supplemented with various phenolics. Phenol was the most effective inducer. The white rot basidiomycete
Trametes versicolor, grown in non-induced and ...phenol induced conditions, was tested for production of laccase (TvLac), lignin peroxidase (LiP), manganese peroxidase (MnP), arylalcohol oxidase (AAO) and polyphenol oxidase (PPO). Although no PPO, LiP and AAO were observed in the culture filtrates, TvLac and MnP activities were detected at the fourth and fifth day of incubation, respectively. In phenol induced cultures, the maximum enzyme activity was enhanced about 20-fold with regard to control cultures. Laccase production at optimum phenol concentration was investigated by monitoring enzyme activity, protein content, glucose consumption and biomass and it was determined that laccase production is non-growth associated. The optimum pH of the enzyme was 4.5. Kinetic constants of TvLac was determined as
K
m value 0.6
1mM and a
V
max of 8264
U/L (
R
2 = 0.99). Laccase, isolated from
T.versicolor, was also used for denim washing without a mediator. TvLac was more effective than commercial laccase with a mediator.
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•Heat shock proteins (HSPs) are molecular chaperones assisting with the folding, transport, and degradation of proteins.•Hsp72 is a classic, stress-inducible, cytoplasmic Hsp with ...broad cytoprotective functions.•Patients with non-alcoholic steatohepatitis and chronic hepatitis C displayed elevated HSP72 expression.•Hsp72 overexpression protects the liver against a variety of stress situations.•Future studies should explore the therapeutic potential of drugs inducing Hsp72 production and/or mimicking its function.
Heat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals.
Double transgenic mice overexpressing Hsp72 (gene Hspa1a) under the control of a tissue-specific tetracycline-inducible system (Hsp72-LAP mice) were produced. Acute liver injury was induced by a single injection of acetaminophen (APAP). Feeding with either a methionine choline-deficient (MCD; 8 weeks) or a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC; 12 weeks) was used to induce lipotoxic injury and Mallory–Denk body (MDB) formation, respectively. Primary hepatocytes were treated with palmitic acid.
Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1β or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation.
Our results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions.
HSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various forms of liver stress.
Modern trends in the development of pasta production are based on the use of starch-containing raw materials for the production of medicinal and preventive pasta products. In this connection, an ...important observation is the state of protein and starch in pasta flour, which can be achieved by electron microscopy of the microstructure of macaroni products. Therefore, the study of microstructures and microbiological indicators of pasta from non-traditional raw materials will be relevant. The practical value of the research is characterized by improved consumer properties of pasta made from non-traditional raw materials. The novelty of the research is the development of scientific and technological bases for the production of pasta from non-traditional polycereal raw materials. The results obtained: the analysis of the obtained electronic micro-drawings showed that the microstructure of pasta from non-traditional raw materials corresponds to the standards in comparison with the control sample. The following types of mycotoxins were found in pasta from non-traditional raw materials in permitted quantities: aflatoxin B1, aflatoxin M1, zearalenone, deoxynivalenol, ochratoxin A, fumonisin, patulin, T-2. For example, the amount of zearalenone (mg/kg): in pasta according to recipe No. 1 – 0.0637, according to recipe No. 2 – 0.0251 and according to recipe No. 3 – 0.0758; in flour raw materials – according to recipe No. 1 – 0.1485, according to recipe No. 2 – 0.0261 and according to recipe No. 3 – 0.2.
In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus ...(EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8
T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro-generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8
T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.
Pseudomonas putida was acclimized to phenol by increase in concentration and the degradation rate was calculated as approximately 0.042
g
l
−1
h
−1 in batch shake flask cultures. Phenol degradation ...by
P. putida immobilized on several silica based support materials was investigated. Pumice was chosen as a support material and then partially characterized physically and chemically. The cell adsorption ratio was 91% with Zr-activated pumice. The biocatalyst completely degraded 1.0
g
l
−1 phenol in the batch shaking system in 22
h and it was also used in recycled and continuous mode packed bed bioreactors for phenol degradation. The performance of the bioreactor was tested by running five times and it was observed that the degradation rates did not change for the first four runs. The biodegradation rate becomes high and concentration-independent in recycled packed bed bioreactors for phenol degradation. The reactor performance at high phenol concentration for the reactor tolerance was 1.25
g phenol
l
−1. Continuous degradation of phenol in a packed bed bioreactor was also studied. The phenol concentrations in the feed tank was increased with a constant dilution rate (2.27
h
−1) from 0.065 to 0.820
g
l
−1. The maximum phenol degradation level of 99% was reached at a phenol loading rate of 0.001–0.002
g
l
−1. The biocatalyst could be stored at 4
°C for 6 months without significant decrease in activity.
Immobilization of a commercial cellulase (C) onto chemically modified pumice (P) particles has been studied. ZrOCl
2 activated pumice was used as a carrier for the cellulase immobilization and some ...operational properties of this carrier were determined. Denim washing performance of immobilized cellulase (MP) was also investigated comparing with free enzymes (FE) and traditional denim washing procedure. Immobilized acid cellulases can efficiently abrade indigo dyed denim fabrics.
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