Search results for "STABILITY"
showing 10 items of 3085 documents
Nonacidic Farnesoid X Receptor Modulators.
2017
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer
2018
Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CR…
Mucoadhesive solid lipid microparticles for controlled release of a corticosteroid in the chronic obstructive pulmonary disease treatment.
2017
Therapeutic efficacy of inhaled drugs is limited by rapid clearance from the site of action due to absorption into systemic circulation or metabolic degradation by alveolar macrophages. Drug delivery systems offer new solutions to clinical problems especially in the treatment of pulmonary diseases. In particular, Solid Lipid Microparticles (SLM) in the range of 3-5 µm are suggested as systems for delivery of therapeutics to the lung as, because of their size, they are able to deposit into secondary bronchi, avoiding systemic absorption typical of alveolar regions. Here, we describe two novel different SLMs prepared with chitosan and alginate for sustained release of fluticasone propionate (…
Analysis of DNA Polymerases Reveals Specific Genes Expansion in Leishmania and Trypanosoma spp.
2020
Leishmaniasis and trypanosomiasis are largely neglected diseases prevailing in tropical and subtropical conditions. These are an arthropod-borne zoonosis that affects humans and some animals and is caused by infection with protozoan of the genera Leishmania and Trypanosoma, respectively. These parasites present high genomic plasticity and are able to adapt themselves to adverse conditions like the attack of host cells or toxicity induced by drug exposure. Different mechanisms allow these adapting responses induced by stress, such as mutation, chromosomal rearrangements, establishment of mosaic ploidies, and gene expansion. Here we describe how a subset of genes encoding for DNA polymerases …
Critical amino acids for the insecticidal activity of Vip3Af from Bacillus thuringiensis: Inference on structural aspects
2018
AbstractVip3 vegetative insecticidal proteins from Bacillus thuringiensis are an important tool for crop protection against caterpillar pests in IPM strategies. While there is wide consensus on their general mode of action, the details of their mode of action are not completely elucidated and their structure remains unknown. In this work the alanine scanning technique was performed on 558 out of the total of 788 amino acids of the Vip3Af1 protein. From the 558 residue substitutions, 19 impaired protein expression and other 19 substitutions severely compromised the insecticidal activity against Spodoptera frugiperda. The latter 19 substitutions mainly clustered in two regions of the protein …
The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution
2020
The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptid…
Large Blooms of Bacillales (Firmicutes) Underlie the Response to Wetting of Cyanobacterial Biocrusts at Various Stages of Maturity.
2018
ABSTRACT Biological soil crusts (biocrusts) account for a substantial portion of primary production in dryland ecosystems. They successionally mature to deliver a suite of ecosystem services, such as carbon sequestration, water retention and nutrient cycling, and climate regulation. Biocrust assemblages are extremely well adapted to survive desiccation and to rapidly take advantage of the periodic precipitation events typical of arid ecosystems. Here we focus on the wetting response of incipient cyanobacterial crusts as they mature from “light” to “dark.” We sampled a cyanobacterial biocrust chronosequence before (dry) and temporally following a controlled wetting event and used high-throug…
Copy number variations inDCC/18q andERBB2/17q are associated with disease-free survival in microsatellite stable colon cancer
2017
We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in stage II-III microsatellite stable (MSS) colon cancer. A total of 401 patients were included from 01/2004 to 01/2009. The CNVs in 8 selected target genes, DCC/18q, EGFR/7p, TP53/17p, BLK/8p, MYC/8q, APC/5q, ERBB2/17q, and STK6/20q, were detected using a quantitative multiplex polymerase chain reaction of short fluorescent fragment (QMPSF) method. The primary end-point was the impact of the CNVs on the 4-year disease-free survival (DFS). The recurrence rate at 4 years was 20.9%, corresponding to 14% stage II patients vs 31% stage III patients (p<0.0001). The 4-year DFS was significan…
Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy
2019
[EN] Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions. Thirty-six patients diagnosed with advanced colorectal cancer from two referent public hospitals from Paraguay were recruited from May 2017 to February 2018. Sequenom Mass spectrometry, On…
Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With L…
2020
Contains fulltext : 220040.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Net…