To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of ...BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.
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Black tunnels and hammocks Biggs, William D.; Santos, Jorge E.
The journal of high energy physics,
11/2022, Volume:
2022, Issue:
11
Journal Article
Peer reviewed
Open access
A
bstract
We construct the holographic duals to a large
N
, strongly coupled
N
= 4 super Yang-Mills conformal field theory defined on a four-dimensional de Sitter-Schwarzschild background. There are ...two distinct five-dimensional bulk solutions. One, named the black tunnel, is static and possesses two disconnected horizons. The other, the black hammock, contains only one horizon in the bulk. The hammock horizon is not a Killing horizon, and hence possesses interesting properties, such as non-vanishing expansion and shear, as well as allowing classical flow along it. The DeTurck method was used in order to attain the black tunnel solutions, whilst the black hammocks were found in Bondi-Sachs gauge.
The presence of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is the most important predictor of liver mortality. There are limited data on the diagnostic accuracy of gut ...microbiota-derived signature for predicting the presence of advanced fibrosis. In this prospective study, we characterized the gut microbiome compositions using whole-genome shotgun sequencing of DNA extracted from stool samples. This study included 86 uniquely well-characterized patients with biopsy-proven NAFLD, of which 72 had mild/moderate (stage 0–2 fibrosis) NAFLD, and 14 had advanced fibrosis (stage 3 or 4 fibrosis). We identified a set of 40 features (p < 0.006), which included 37 bacterial species that were used to construct a Random Forest classifier model to distinguish mild/moderate NAFLD from advanced fibrosis. The model had a robust diagnostic accuracy (AUC 0.936) for detecting advanced fibrosis. This study provides preliminary evidence for a fecal-microbiome-derived metagenomic signature to detect advanced fibrosis in NAFLD.
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•Gut microbiota is associated with advanced fibrosis in human NAFLD•Metagenome-based gut microbiome panel can accurately diagnose advanced fibrosis
Loomba et al. reveal how a panel of gut microbiome biomarkers can be used as a non-invasive test to accurately diagnose advanced fibrosis in patients with non-alcoholic fatty liver disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Deep sequencing of 10,000 human genomes Telenti, Amalio; Pierce, Levi C. T.; Biggs, William H. ...
Proceedings of the National Academy of Sciences - PNAS,
10/2016, Volume:
113, Issue:
42
Journal Article
Peer reviewed
Open access
We report on the sequencing of 10,545 human genomes at 30×–40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome ...can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.
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We find rotating black hole solutions in the Randall-Sundrum II (RSII) model, by numerically solving a three-dimensional PDE problem using pseudospectral collocation methods. We compute the area and ...equatorial innermost stable orbits of these solutions. For large black holes compared with the AdS length scale ℓ the black hole exhibits four-dimensional behavior, approaching the Kerr metric on the brane, while for small black holes, the solution tends instead towards a five-dimensional Myers-Perry black hole with a single nonzero rotation parameter aligned with the brane. This departure from exact four-dimensional gravity may lead to different phenomenological predictions for rotating black holes in the RSII model to those in standard four-dimensional general relativity. This Letter provides a stepping stone for studying such modifications.
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We present a high-resolution (2.0 A) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. ...The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His(396)Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position.
Short tandem repeats (STRs) are hyper-mutable sequences in the human genome. They are often used in forensics and population genetics and are also the underlying cause of many genetic diseases. There ...are challenges associated with accurately determining the length polymorphism of STR loci in the genome by next-generation sequencing (NGS). In particular, accurate detection of pathological STR expansion is limited by the sequence read length during whole-genome analysis. We developed TREDPARSE, a software package that incorporates various cues from read alignment and paired-end distance distribution, as well as a sequence stutter model, in a probabilistic framework to infer repeat sizes for genetic loci, and we used this software to infer repeat sizes for 30 known disease loci. Using simulated data, we show that TREDPARSE outperforms other available software. We sampled the full genome sequences of 12,632 individuals to an average read depth of approximately 30× to 40× with Illumina HiSeq X. We identified 138 individuals with risk alleles at 15 STR disease loci. We validated a representative subset of the samples (n = 19) by Sanger and by Oxford Nanopore sequencing. Additionally, we validated the STR calls against known allele sizes in a set of GeT-RM reference cell-line materials (n = 6). Several STR loci that are entirely guanine or cytosines (G or C) have insufficient read evidence for inference and therefore could not be assayed precisely by TREDPARSE. TREDPARSE extends the limit of STR size detection beyond the physical sequence read length. This extension is critical because many of the disease risk cutoffs are close to or beyond the short sequence read length of 100 to 150 bases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The blood DNA virome in 8,000 humans Moustafa, Ahmed; Xie, Chao; Kirkness, Ewen ...
PLOS pathogens,
03/2017, Volume:
13, Issue:
3
Journal Article
Peer reviewed
Open access
The characterization of the blood virome is important for the safety of blood-derived transfusion products, and for the identification of emerging pathogens. We explored non-human sequence data from ...whole-genome sequencing of blood from 8,240 individuals, none of whom were ascertained for any infectious disease. Viral sequences were extracted from the pool of sequence reads that did not map to the human reference genome. Analyses sifted through close to 1 Petabyte of sequence data and performed 0.5 trillion similarity searches. With a lower bound for identification of 2 viral genomes/100,000 cells, we mapped sequences to 94 different viruses, including sequences from 19 human DNA viruses, proviruses and RNA viruses (herpesviruses, anelloviruses, papillomaviruses, three polyomaviruses, adenovirus, HIV, HTLV, hepatitis B, hepatitis C, parvovirus B19, and influenza virus) in 42% of the study participants. Of possible relevance to transfusion medicine, we identified Merkel cell polyomavirus in 49 individuals, papillomavirus in blood of 13 individuals, parvovirus B19 in 6 individuals, and the presence of herpesvirus 8 in 3 individuals. The presence of DNA sequences from two RNA viruses was unexpected: Hepatitis C virus is revealing of an integration event, while the influenza virus sequence resulted from immunization with a DNA vaccine. Age, sex and ancestry contributed significantly to the prevalence of infection. The remaining 75 viruses mostly reflect extensive contamination of commercial reagents and from the environment. These technical problems represent a major challenge for the identification of novel human pathogens. Increasing availability of human whole-genome sequences will contribute substantial amounts of data on the composition of the normal and pathogenic human blood virome. Distinguishing contaminants from real human viruses is challenging.
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An outstanding question in adipocyte biology is how hormonal cues are relayed to the nucleus to activate the transcriptional program that promotes adipogenesis. The forkhead transcription factor ...Foxo1 is regulated by insulin via Akt-dependent phosphorylation and nuclear exclusion. We show that Foxo1 is induced in the early stages of adipocyte differentiation but that its activation is delayed until the end of the clonal expansion phase. Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. Further,
Foxo1 haploinsufficiency protects from diet-induced diabetes in mice. We propose that Foxo1 plays an important role in the integration of hormone-activated signaling pathways with the complex transcriptional cascade that promotes adipocyte differentiation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP ...site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
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