AIM: We assessed the diagnostic accuracy of epidermal growth factor receptor (EGFR) mutant-specific antibodies for detecting two common activating EGFR mutations. METHODS: Immunohistochemical expression of mutation-specific antibodies against EGFR exon 19 deletion E746-A750 ((c.2235_2249del15 or c.2236_2250del15, p. Glu746_Ala750del) and exon 21 L858R point mutation (c.2573T|G, p.Leu858Arg) were assessed in a cohort of 204 resected early stage node negative lung adenocarcinomas, and protein expression was compared with DNA analysis results from mass spectrometry analysis. RESULTS: Of seven cases with L858R point mutation, six were positive by immunohistochemistry (IHC). There were three false positive cases using L858R IHC (sensitivity 85.7%, specificity 98.5%, positive predictive value 66.7%, negative predictive value 99.5%). All seven E746-A750 exon 19 deletions identified by mutation analysis were positive by IHC. Four additional cases were positive for exon 19 IHC but negative by mutation analysis.
Mitochondrial diseases, which altogether represent not so rare diseases, can be due to mutations either in the nuclear or mitochondrial genomes. Several model organisms or cell lines are usually employed to understand the mechanisms underlying diseases, yeast being one of them. However, in the case of mutations within the mitochondrial genome, yeast is a major model because it is a facultative aerobe and its mitochondrial genome can be genetically engineered and reintroduced in vivo. In this short review, I will describe how these properties can be exploited to mimic mitochondrial pathogenic mutations, as well as their limits. In particular; pathological mutations of tRNA, cytb, and ATPase genes have been successfully modeled. It is essential to stress that what has been discovered with yeast (molecular mechanisms underlying the diseases, nuclear correcting genes, import of tRNA into mitochondria or compounds from drug screening) has been successfully transferred to human patient lines, paving the way
Since Fishers (1930) development of the geometric model of the process of adaptation, it has been assumed that a mutation that affects many parts of a complex organism is less likely to be beneficial than a mutation of more restricted effect. Direct evidence supporting the generality of this supposition has been difficult to obtain, in part because of the challenge of studying high-dimensional phenotypes (Houle 2010) and because of the lack of information on the relationship between effects of pleiotropic alleles on phenotypes vs. on fitness (Paaby and Rockman 2013). By using multivariate statistical modeling of the genetic variance generated by new mutations, and of the standing genetic variance in a natural population, we have shown that selection is consistently stronger on pleiotropic mutations, supporting Fishers model of adaptation for populations in the vicinity of an adaptive optimum (Zhang 2012).. In general, we inferred strong selection acting against new mutations affecting the ...
Thesis Defense. Title: Computational Detection of Driver Mutations in Cancer Genomes. Abstract: Cancer is caused largely by the accumulation of somatic mutations during the lifetime of an individual. Recent advances in next generation sequencing (NGS) enable measurement of somatic mutations in a cohort of samples. Large-scale cancer sequencing projects like The Cancer Genome Atlas (TCGA) have generated a huge amount of somatic mutations in thousands of tumors. This thesis addresses two challenges. The first challenge is to distinguish driver mutations that are responsible for cancer development from passenger mutations, random events that do not contribute to the cancer phenotype in a cohort of samples. This is a difficult problem because most somatic mutations measured in tumor samples are passenger mutations, and only a small portion of these mutations are driver mutations. The second challenge is to accurately identify larger genomic variants, also known as structural variants (SV), one type ...
Author Summary Cancer is the consequence of an evolutionary process, which lasts several decades, is impossible to observe during most of its time, and only becomes apparent in late stages. We use mathematical modeling to shed light on the evolutionary dynamics of cancer by studying the accumulation of passenger mutations. We show that the frequencies obtained by passenger mutations depend strongly on the ratio of death and birth rates of cancer cells. We use genetic data of colorectal cancer to estimate this important quantity in vivo. We estimate the size of the cancer cell population that was present when a specific mutation first emerged. Our theory informs the analysis of cancer sequencing data and the phylogenetic reconstruction of cancer evolution.
...A specific gene mutation may be useful in predicting the level of aggr...The mutation called BRAF V600E is a genetic alteration in the BRAF o...Past studies have shown that the mutation frequently occurs in the mos...The findings come at an important time as both the incidence of thyroi...,Presence,of,gene,mutation,helps,guide,thyroid,cancer,treatment,biological,biology news articles,biology news today,latest biology news,current biology news,biology newsletters
To study the cost of chromosomal drug resistance mutations to bacteria, we investigated the fitness cost of mutations that confer resistance to different classes of antibiotics affecting bacterial protein synthesis (aminocyclitols, 2-deoxystreptamines, macrolides). We used a model system based on an in vitro competition assay with defined Mycobacterium smegmatis laboratory mutants; selected mutations were introduced by genetic techniques to address the possibility that compensatory mutations ameliorate the resistance cost. We found that the chromosomal drug resistance mutations studied often had only a small fitness cost; compensatory mutations were not involved in low-cost or no-cost resistance mutations. When drug resistance mutations found in clinical isolates were considered, selection of those mutations that have little or no fitness cost in the in vitro competition assay seems to occur. These results argue against expectations that link decreased levels of antibiotic consumption with the ...
Epidemiological evidence has long associated environmental mutagens with increased cancer risk. However, links between specific mutation-causing processes and the acquisition of individual driver mutations have remained obscure. Here we have used public cancer sequencing data to infer the independent effects of mutation and selection on driver mutation complement. First, we detect associations between a range of mutational processes, including those linked to smoking, ageing, APOBEC and DNA mismatch repair (MMR) and the presence of key driver mutations across cancer types. Second, we quantify differential selection between well-known alternative driver mutations, including differences in selection between distinct mutant residues in the same gene. These results show that while mutational processes play a large role in determining which driver mutations are present in a cancer, the role of selection frequently dominates ...
The genetic factors underpinning the development of cancers are being discovered at an increasing pace. Cancers can have an acquired or an inherited genetic aetiology. Inherited cancer predisposition caused by a single gene mutation is normally inherited in an autosomal dominant fashion. Acquired caner at the cellular level may be caused by the loss of function of both copies of the gene acting in an autosomal recessive fashion. Gene mutations may act in different ways, some drive cell growth-oncogenes, others when the gene mutates fail to stop tumour growth - tumour suppressor genes. Other genetic mutations may cause normal DNA and cellular repair mechanisms to fail. Genetic testing may be used at the level of a tumour to inform treatment decisions or in an inherited cancer susceptibility syndrome to provide information and tailor screening and prevention strategies.
Complex processes such as transcription, replication, repair, and recombination require changes in chromatin structure and the interactions of numerous trans-acting factors with DNA sequences, raising the possibility that these processes may be interrelated. Here the effect of transcription on the rate of spontaneous mutation in the yeast Saccharomyces cerevisiae was examined. With the use of a lys2 frameshift allele under the control of a highly inducible promoter, the rate of spontaneous reversion was shown to increase when the mutant gene was highly transcribed. Thus, transcriptionally active DNA and enhanced spontaneous mutation rates are associated in yeast.. ...
THE number of compensatory mutations that will affect a specific deleterious mutation is a fundamental evolutionary quantity of which little is known. A mutation is compensatory if it has a beneficial effect on fitness that is conditional on the presence of a deleterious mutation at a different site in the genome (Kimura 1985). Hence, a compensatory effect is the outcome of a strong epistatic interaction between two mutations. Each compensatory mutation represents an alternate genetic solution to adaptation; thus, fitness recovery from the accumulation of deleterious mutations becomes less likely to occur by back mutation when compensatory mutations are increasingly common (Whitlock and Otto 1999). Indeed, one must invoke a compensatory mutation to explain the rapid, stepwise recovery of fitness observed in mutationally degraded experimental populations (Burch and Chao 1999; Moore et al. 2000; Estes and Lynch 2003). Compensatory mutations are also implicated in the persistence of alleles that ...
When populations of microorganisms are exposed to nonlethal selections, mutations that relieve the selective pressure arise (7), a phenomenon called adaptive mutation (6). Although it originally seemed that only useful mutations appeared (7), it is now clear that selected mutations are accompanied by nonselected mutations, i.e., the process is not directed to useful genes (12).. Most research on adaptive mutation has focused on a strain of Escherichia coli, called FC40, that cannot utilize lactose (Lac−) but that readily reverts to lactose utilization (Lac+) when lactose is its only carbon source (6). The process that produces adaptive Lac+ mutations is not the same as that which produces Lac+ mutations during normal growth. Unlike growth-dependent mutations, almost all adaptive Lac+ mutations are dependent on recombination functions (6, 10, 24). While several different types of sequence changes revert the Lac− allele during growth, adaptive Lac+ mutations are almost all −1-bp frameshifts ...
Population included 59% of adenocarcinoma, 37% of women and 19% of non-smokers. Overall mutation rate is 46%: 31 EGFR mutations (13%) and 78 KRAS mutations (33%); 40 new mutations compared to previous study were found: 9 EGFR and 31 KRAS. In the ERMETIC 2 cohort, OS and PFS remained significantly (global test p < 0.01) better for EGFR mutated (hazard ration [HR] 0.57 [95%CI: 0.33-1.00] and 0.47 [0.28-0.78] respectively) and worse for KRAS mutated (HR 1.35 [0.97-1.88] and 1.16 respectively [0.85-1.59]) compared to wild-type (WT) NSCLC. No prognostic significant difference was found in the 177 pts common to both cohorts between pts with KRAS mutation in both cohorts (n= 28) and those with new (n = 31) mutations. In the 228 pts with several techniques, KRAS mutations detected by less sensitive technique (n = 42) have a lower OS compared to WT than those detected only by the best sensitive technique (n = 34), but are not significantly different: 1.63 (1.09-2.44) and 1.08 (0.69-1.69); results between ...
Hollander, W F., "Hydrocephalic-polydactyl, a recessive pleiotropic mutant in the mouse and its location in chromosome 6." (1976). Subject Strain Bibliography 1976. 3055 ...
A mutation in a single gene can cause endometrial cancer that is responsive to a specific drug therapy, researchers at UT Southwestern Medical Center have found in an animal study.
3799 Genomic instability involves the accumulation of mutations and is a hallmark of neoplastic development in gastrointestinal malignancies such as colorectal carcinoma. Mutations in specific cancer genes contribute to the malignant phenotype for colorectal carcinoma. For example, mutations in APC, KRAS and TP53 are critical to the development of colorectal cancer. Mutations in genes like EGFR influence the response of molecular-targeted therapies. Undoubtedly, there are other critical gene mutations to be discovered and comprehensive mutation discovery from individual cancer genomes will increase our understanding of the genetics underlying any individual tumors phenotype. This mutation profile may provide prognostic and predictive genetic biomarkers. However, current technologies are severely limited in screening large numbers of genes for mutations. As a solution, we describe the development and application of a novel resequencing strategy for point mutation discovery on a massively ...
A mutation is any change occurring in the message that a gene carries. Mutations mainly arise as copy errors when DNA is replicated at mitosis and meiosis. Darwinian evolution requires a constant supply of variation: much of it is supplied by mutation, and a mutation-selection balance can maintain a genetic polymorphism. The first major geneticist to study mutation was H.J. Muller, who demonstrated it can be induced by X-rays. He also recognized that the rate of mutation in nature is extremely low, and that they are almost always deleterious to the fitness of the organism. The accumulation of deleterious mutations places a mutational load on the population. Mutations can occur at single base level or at chromosomal level. The effects of mutation can occasionally be very dramatic: some of these fruitflies have suffered mutations which alter the number of wings that develop... Is mutation directed?. ...
Rare mutations in the switch III region of Ras can increase its nanoscale clustering, which enhances effector recruitment and downstream signaling.
|p>p53 is a tumor suppressor protein encoded by the TP53 gene that responds to DNA damage by regulating cell-cycle arrest, apoptosis and senescence. These p53 Hotspot Mutation Cell Panels are composed of select cell lines derived from tumors of various tissue origins. The p53 mutational status of these lines have been sequenced and validated by ATCC.|/p>
|p>p53 is a tumor suppressor protein encoded by the TP53 gene that responds to DNA damage by regulating cell-cycle arrest, apoptosis and senescence. These p53 Hotspot Mutation Cell Panels are composed of select cell lines derived from tumors of various tissue origins. The p53 mutational status of these lines have been sequenced and validated by ATCC.|/p>
Deletion of the I265-F268 and T271-K277 regions in the large lumenally exposed loop of the CP47 protein are known to lead to a loss of photoautotrophic growth. Here, these regions have been investigated by combinatorial mutagenesis and pseudorevertant mapping. No single amino-acid residue in the I265-F268 region was found to be critical for function, but a large hydrophobic residue at position 267 and preferentially an aromatic residue at position 268 appeared to be required for photoautotrophic growth. Starting from an obligate photoheterotrophic mutant lacking the T271-K277 region, photoautotrophic pseudorevertants were generated with short in-frame tandem repeats near the site of the original deletion, partially or fully restoring the length of the original protein. These pseudorevertants were sensitive to oxygen indicating that the T271-K277 region may provide PS II stability and/or protection against oxygen-dependent photoinactivation. Pseudorevertants with much improved photoautotrophic ...
Researchers assigned levels of risk to 25 mutations associated with breast and ovarian cancer in a large, Stanford-led study. The results may be helpful in guiding treatment and screening recommendations.
Using real-time PCR to detect HIV resistance mutations present at low levels, Jeffrey Johnson and colleagues investigate prevalence and clinical implications of minority transmitted mutations.
BioMotiv, a drug development accelerator associated with The Harrington Project, and Rutgers, the State University of New Jersey, are announcing the formation of a new biotechnology startup, Z53 Therapeutics. Z53 Therapeutics aims to develop novel anti-cancer drugs that target tumors with p53 mutations.
Most truncation or deletion mutations underlying HI are thought to lead to severe loss of ABCA12 protein function affecting important nucleotide-binding fold domains and/or transmembrane domains. Thus far, in HI patients, at least one mutation on each allele must be a truncation or deletion mutation within a conserved region to cause serious loss of ABCA12. Complete loss of ABCA12 function due to homozygous or compound heterozygous truncation mutations always results in the HI patient phenotype. ...
Scientists make a DNA breakthrough by using multi-gene test to predict the risk of five diseases.. The key to prevention is identifying people who are at higher risk for diseases early on. Since most common diseases have a genetic component, we could start classifying people based on their genetic risk.. This is where genetic variants come into play. Genetic variants are small changes in DNA that exist between people, which can contribute to disease risk. However, most common diseases of today like heart disease and diabetes, are influenced by more than one gene.. Individually each gene only makes a small contribution towards disease risk. But when found together, they play a significant role in a persons genetic predisposition to disease. Unfortunately predicting disease risk based on multiple genes isnt an easy task.. However, according to ground breaking research published in the journal of Nature Genetics, this is no longer the case. Scientist can now effectively predict the risk of ...
Vorkas, P.A.; Poumpouridou, N.; Agelaki, S.; Kroupis, C.; Georgoulias, V.; Lianidou, E.S., 2010: PIK3CA hotspot mutation scanning by a novel and highly sensitive high-resolution small amplicon melting analysis method
This report describes mutants of the zebrafish having phenotypes causing a general arrest in early morphogenesis. These mutants identify a group of loci making up about 20% of the loci identified by mutants with visible morphological phenotypes within the first day of development. There are 12 Class I mutants, which fall into 5 complementation groups and have cells that lyse before morphological defects are observed. Mutants at three loci, speed bump, ogre and zombie, display abnormal nuclei. The 8 Class II mutants, which fall into 6 complementation groups, arrest development before cell lysis is observed. These mutants seemingly stop development in the late segmentation stages, and maintain a body shape similar to a 20 hour embryo. Mutations in speed bump, ogre, zombie, specter, poltergeist and troll were tested for cell lethality by transplanting mutant cells into wild-type hosts. With poltergeist, transplanted mutant cells all survive. The remainder of the mutants tested were autonomously but ...
Genetic mutations have two major types: large mutation (deletion, insertion, duplication, and inversion) and point mutation (nonsense, missense, and frame shift). Some mutations can induce DNA transcription and translation errors eventually causing protein dysfunction that leads to disease [1, 2]. Currently, many whole genome scale association studies between disease and variation are being published [3]. However, medical researchers have had to go through mutations in patient DNA to detect mutations that may be the cause of a disease [4, 5].. There are many human disease gene databases that contain disease-causing mutation information as locus-specific databases (LSDBs). Also, large databases, such as Online Mendelian Inheritance in Man (OMIM) [6] and the Human Gene Mutation Database (HGMD) [7], collect and describe comprehensively all disease-related genes. In contrast, LSDBs usually describe variations in a small number of genes. The LSDBs aim to provide particular genetic mutation ...
Seven single gene mutations are known to cause hypertension; this article guides clinicians through identification of the relatively uncommon defects, associated laboratory findings, and treatments.
The transcription factor CCAAT-enhancer-binding protein alpha (C/EBPα) is a master regulator of granulopoiesis and regulates the switch between proliferating, uncommitted progenitors and cell-cycle-arrested, differentiated myeloid cells. Usage of two alternative translation initiation sites in the CEBPA mRNA results in expression of a full-length C/EBPα protein p42 (42 kDa) and a shorter p30 isoform (30 kDa). CEBPA mutations are found in 9-15% of Acute Myeloid Leukemia (AML) patients. N-terminal frameshift mutations in the CEBPA gene lead to selective ablation of p42 expression, while C-terminal mutations disrupt the dimerization and DNA-binding ability of C/EBPα. AML patients harbor either mono- or biallelic CEBPA mutations (CEBPAmo or CEBPAbi) and both genotypes are frequently associated with concurrent mutations in other genes. The most commonly co-occurring mutations in both groups are loss-of-function mutations in the methylcytosine dioxygenase TET2 (44.4% in CEBPAmo / 34.8% in CEBPAbi). ...
From Jules: there was quite a bit of discussion at the workshop this year about using sensitive testing to identify low-level or minority genotypic resistance. At last years Resistance Workshop the CDC and Mike Kozal from Yale reported in oral presentations that minority mutations can lead to viral failure. Concerns are how to translate these potential concerns into the clinic. There are some lingering concerns among a few that further confirmation is required before presuming that the presence of low-level mutations is a reliable test for not using a drug, despite several studies reporting that the risk for viral failure significantly increases if these mutations are present; but not everyone fails if minority mutations are present, so are you throwing out a good drug by avoiding it? Still the studies so far presented find there is a significantly increased risk of viral failure. Tests to screen for minority mutations are not clinically available yest, as far as I know. But there were several ...
Ovarian and breast cancer can be either sporadic or hereditary. Sporadic cancers make up the vast majority (85-90%) of ovarian and breast cancers and are not associated with family history of either cancer or inherited cancer-associated mutations. Sporadic cancers arise from genetic mutations acquired in some cells of the body by events part of normal metabolism and environmental factors. This type of cancer can happen to anyone. Most acquired gene mutations are not shared among relatives or passed on to children.. Hereditary (also known as inherited, or familial) cancers are those that occur due to genetic mutations that are inherited from mom or dad. Other blood relatives may also share these same gene mutations. Parents give one copy of each gene to their children. If a parent has a genetic mutation in a gene, each of their children have a 50% chance of inheriting that mutation. Therefore, even in families with hereditary cancer, not all family members inherit the mutation that is causing ...
Mutation assays can then be grouped together into PCR arrays based off common themes to enable users to profile a focused set of mutations. The mutations on an array are selected based on a commonality, such as being from the same gene, signaling pathway, or cancer type. For example, users could profile the most common 84 mutations in breast cancer or the 44 most common mutations in APC. The Custom qBiomarker Somatic Mutation PCR Arrays allow users to select the mutations that they wish to profile. Together, the qBiomarker Somatic Mutation products facilitate sensitive detection and profiling of mutations in cancer cells or tumor samples ...
Purpose: : To identify and characterize the gene mutation responsible for photoreceptor degeneration in the rd3 mouse. Methods: : We screened genes in the known rd3 (RBF/DnJ) mapped region by direct sequencing. We additionally screened other rd3 lines (RBJ/Dn, STOCK Rb(11.13)4Bnr/J and STOCK In(5)30Rk) and normal mouse strains to verify the alteration. We carried out a mutation screen of the human RD3 gene in patients with retinopathies and examined 431 patients of Caucasian ethnicity and 103 of Asian-Indian ancestry. Amino acid changes that were identified in patients but not in controls are being examined by immunoblot analysis and immunocytochemisty to determine their effect(s) on protein stability or localization. Results: : The rd3 mutation is a homozygous C to T transition, leading to a stop codon, which is predicted to result in a premature truncation of the rd3 protein. The mutation was present in all rd3 lines tested (RBF/DnJ, RBJ/Dn, 4bnr and IN-30) but not in the control lines ...
We set out to determine the feasibility of using microarray-based resequencing for cancer gene mutation screening by designing GeneChip CustomSeq Resequencing arrays (Affymetrix, Santa Clara, CA, USA) for interrogation of ARAF, BRAF, CDK4, CDK6, CDKN2A, KLF6, HRAS, KRAS, MET, NRAS, PTEN, RAF1, RB1, RET and TP53 (164 exons in total). Arrays also included four intronic bases on either side of the exons to cover splice sites, thus the arrays covered a total of 23,966 bases. Overall performance was very good, with accuracy ,99.99% and coverage ~97.5%. Twenty NSCLC samples were analyzed using the arrays, and several well-characterized somatic mutations and germline variants were found. The most significant novel finding was the detection of a transforming MET mutation (T1010I) in a NSCLC patient. ...
Understanding and predicting molecular cause of disease is one of the major challenges for biology and medicine. One particular area of interest continues to be computational analyses of disease-associated amino acid substitutions. To this end, various studies have been performed to identify molecular functions disrupted by disease-causing mutations. Here, we investigate the influence of disease- associated mutations on post-translational modifications. In particular, we study the loss of modification target sites as a consequence of disease mutation. We find that about 5% of disease-associated mutations may affect known modification sites, either partially (4%) of fully (1%), compared to about 2% of putatively neutral polymorphisms. Most of the fifteen post-translational modification types analyzed were found to be disrupted at levels higher than expected by chance. Molecular functions and physiochemical properties at sites of disease mutation were also compared to those of neutral ...
Stable disease may be annotated as a "clinical response - not further specified" where stable disease is considered by an author as a positive response to therapy and/or where stable disease has been followed by a relapse. Acquired resistance mutations will occur in tumours annotated as a resistant recurrence e.g. Imatinib clinical resistant recurrence. A recurrent tumour or a metastatic site has been screened for mutations following relapse after an initial drug response. Only those secondary mutations reported as proven to be associated with resistance or presumed by authors to be associated with resistance, e.g. based on their gene location, are annotated as acquired resistance mutations and not incidental passenger mutations detected in a recurrent tumour. Intrinsic resistance mutations will occur in tumours annotated as having a primary non response e.g. Imatinib clinical primary non response. Only those mutations reported as associated with resistance are annotated as primary resistance ...
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In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by approximately 6500-fold. Their average mutation rates per base pair vary by approximately 16,000-fold, whereas their mutation rates per genome vary by only approximately 2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs ...
Abstract Background: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next‐generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. Methods: We sent out a survey to 16 genetic centers performing SCN1A testing. Results: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation‐negative, both due to technical limitations and human errors. Conclusion: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A ...
Mutations affect organisms in two different ways. Genetic mutations are inherited DNA changes that can be passed on to the next generation. Somatic mutations are DNA changes that are acquired after...
Page 1 of 2 - Bacterial Mutations To Resist Antibiotics - posted in Creation vs Evolution: When bacteria mutates to resist antibiotics, is this witnessed evolution?
Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases this is the consequence of specific gene mutations that have the potential to be targeted and re-sensitize the tumor. The means therefore to saturate the genome with point mutations and that avoids chromosome or nucleotide sequence context bias would open the door to identify all possible drug resistance mutations in cancer models. Here we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We have developed an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower ...
Cancer arises when genetic mutations in a cell cause abnormal growth that leads to a tumour.. Some cancer drugs exploit this to attack tumour cells by targeting proteins that are mutated from their usual form because of mutations in the genes that encode them.. However, only a fraction of all the mutations that contribute significantly to cancer have been identified.. Thomas Peterson, at the University of Maryland, and colleagues developed a new statistical analysis approach that uses genetic data from cancer patients to find cancer-causing mutations.. Unlike previous studies that focused on mutations in individual genes, the new approach addresses similar mutations shared by families of related proteins.. Specifically, the new method focuses on mutations in sub-components of proteins known as protein domains.. Even though different genes encode them, different proteins can share common protein domains.. The new strategy draws on existing knowledge of protein domain structure and function to ...
Scientists believe theyve discovered a genetic mutation that may turn usually mild-mannered individuals into obnoxious, violent brutes once they get drunk. The mutation is linked to a brain abnormality... Health News Summaries. | Newser
Per bug 769207 we want to remove support for mutation events and that the reason they havent been removed already is that there is existing Web content using them. If we allow apps that use mutation events into the Marketplace, there will be a higher barrier to removing support for mutation events, since presumably we wouldnt want to break Marketplace apps. To address this problem and to make sure that we actually might have a chance of removing support for mutation events in the future, I suggest making mutation events unavailable to applications installed via the Marketplace ...
Bruce E. Johnson, MD, and Mark A. Socinski, MD, outline the evolving treatment paradigm with regard to targeted therapies and mutation testing in non–small cell lung cancer.
The Curl (Cu) and Mouse-ear (Me) mutations of tomato cause two seemingly unrelated developmental syndromes with a wide range of pleiotropic phenotypes. Yet, the distinct morphogenic alterations in shoots, leaves, and inflorescences conferred by the two mutations appear to be caused by unchecked meristematic activity that characterizes dominant mutations in Knotted1 (Kn1)-like genes of monocot plants. We have been unable to separate the two closely linked Cu and Me mutations, and they may lie in the same gene. A homeobox-containing class I Kn1-like gene, TKn2, also maps to the same location. Significantly, the dominant mutations are associated with two aberrant modes of TKn2 transcription. Overexpression of the two in-frame wild-type transcripts of TKn2 is associated with the Cu mutation, whereas misexpression of an abundant and oversized fusion mRNA is associated with the Me mutation. Available molecular evidence strongly suggests that the defective Me-TKn2 transcript is generated via a novel ...
Procaspase-3 is the dimeric precursor of the apoptosis-executioner caspase-3 that displays little activity in vitro. The interface of the procaspase-3 dimer plays a critical role in zymogen maturation, although the active sites are not located at the dimer interface. We show that replacement of valine 266, the residue at the center of the procaspase-3 dimer interface, with arginine or glutamate results in an increase in enzyme activity of about 25-60-fold, representing a pseudo-activation of the procaspase. In contrast, substitution of V266 with histidine abolishes the activity of the procaspase-3 as well as that of the mature caspase. This mutant can be activated by protein exposure at pH 5, followed by dialysis at neutral pH. While the mutations do not affect the dimeric properties of the procaspase, we show that the V266E mutation may affect the formation of a loop bundle that is important for stabilizing the active sites. In contrast, the V266H mutation affects the positioning of loop L3, ...
In a first-of-its-kind study, scientists correct a single gene mutation tied to genetic heart conditions in human embryos using CRISPR.
Health,...Unknown mutations may account for increased odds researchers say ...MONDAY Nov. 17 (HealthDay News) -- The risk of breast cancer for a wo...And in women younger than age 40 without the BRCA mutations but with ...Over a six-year period the researchers followed up nearly 1500 wome...,Family,History,Ups,Breast,Cancer,Risk,Even,Without,BRCA,Gene,medicine,medical news today,latest medical news,medical newsletters,current medical news,latest medicine news
Principal Investigator:OHTA Norio, Project Period (FY):1990 - 1991, Research Category:Grant-in-Aid for General Scientific Research (B), Research Field:Gastroenterology
View Notes - Chapter 9 from BIO SCI 325 at Wisconsin Milwaukee. 1 204-325 2 h h Chromosomal mutations are variations from Chromosomal mutations are variations from wild wild-- type condition in
Mutations . Section 12-4 This section describes and compares gene mutations and chromosomal mutations. Mutations. What are mutations? Mutations are changes in the DNA sequence that affect genetic information. Mutations. Is the following sentence true or false? Slideshow 1277847 by Patman
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (,3) unrelated cases/families with the phenotype(iii).. OR. B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (,3) unrelated cases/families with the phenotype(iii).. OR. C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.. AND. D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic ...
its that over 90% mutations in coding regions are recessive but some mutations are known to be dominant. Recessive mutation is the one that leads to loss of function but you can introduce another allele on plasmid or paralog on the chromosome to substitute phenotype. On the other hand dominant mutation has strong phenotype that is less likely be masked by supplying wildtype allele on plasmid or paralog elsewhere on the chromosome ...
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (,3) unrelated cases/families with the phenotype(iii).. OR. B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (,3) unrelated cases/families with the phenotype(iii).. OR. C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.. AND. D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic ...
Many mutations in cancer are of unknown functional significance. Standard methods use statistically significant recurrence of mutations in tumor samples as an indicator of functional impact. We extend such analyses into the long tail of rare mutations by considering recurrence of mutations in clusters of spatially close residues in protein structures. Analyzing 10,000 tumor exomes, we identify more than 3000 rarely mutated residues in proteins as potentially functional and experimentally validate several in RAC1 and MAP2K1. These potential driver mutations (web resources: 3dhotspots.org and cBioPortal.org) can extend the scope of genomically informed clinical trials and of personalized choice of therapy.
Because ppGpp influences the expression of many genes including those also controlled by cAMP-CRP (32), it is impossible to elucidate the precise physiological basis for the advantage of the spoT mutation. However, at least two possibilities can be suggested. First, the array data show that the spoT mutation lowers expression of the flagella-encoding flg operons (Table 1). The ancestral strain used in the evolution experiment was nonmotile, the selective environment lacked physical structure, and the production of flagella is known to be costly (34). Hence, reducing the expression of these genes could be beneficial (35). Second, a reduction in the concentration of ppGpp, shown to result from mutations in the regulatory region of spoT (32, 36), might increase the rate of transcription from tRNA and rRNA promoters (37). This increased transcription raises the maximal growth rate (38), presumably via an increased speed of translation during growth in minimal medium (39). Although tRNA and rRNA ...
The much-vaunted medical benefits of sequencing the human genome itself have just received some vindication from the results of clinical trials of the anti-cancer drug PLX4032. The dramatic potential of the drug for shrinking skin-cancer tumours was reported in August, and is confirmed by a recent paper in Nature. But the real excitement stems from the approach: the drug was developed to target a specific carcinogenic mutation of a gene called BRAF, involved in cell growth. The problem is that there are several dangerous mutations of BRAF alone, and thousands of other genetic mutations that also cause cancer. But the new results show that targeting a particular mutation can be highly effective, hitting only those cancer cells that possess it instead of employing the scattershot attack of current cancer chemotherapies. If many mutant-specific drugs come online, rapid gene profiling of patients could enable them to be given precisely the right treatment, without the debilitating side-effects. ...
FREDERICK, Md-Mutations in two genes that produce chemokine receptors-CCR5 and CCR2-account for about 30% of long-term survivors of HIV infection, that is, patients whose disease has not progressed to AIDS within 10 to 20 years of infection, said Stephen J. O Brien, PhD, of the NCIs Laboratory of Genomic Diversity. 1
Maturity-onset diabetes of the young (MODY) is a subtype of diabetes characterized by early age of onset (usually ,25 years), autosomal dominant inheritance, and a progressive defect in β-cell function (1). In U.K. populations, mutations in the hepatocyte nuclear factor-1α (HNF-1α) gene account for ∼65% of cases (2). Over 120 different HNF-1α mutations have been reported (3), of which ∼30% are nonsense or frameshift and lead to the production of premature termination codons (PTCs) (4). The most common HNF-1α mutation results from the insertion of a C nucleotide in a polyC tract in exon 4 (2,5-7). This mutation, P291fsinsC, accounts for ∼20% of families with HNF-1α mutations (4,8,9).. HNF-1α mutations might produce the MODY phenotype by haploinsufficiency or a dominant-negative mutational mechanism. There is considerable support for haploinsufficiency; a mutation in the HNF-1α promoter that disrupts the HNF-4α binding site results in a phenotype indistinguishable from mutations in ...
Chen G, Kong J, Tucker-Burden C, Anand M, Rong Y, Rahman F, Moreno CS, Van Meir EG, Hadjipanayis CG, Brat DJ. (2014) Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. Cancer Res. 74:4536-48. Zerrouqi A, Pyrzynska B, Brat DJ, Van Meir EG. (2014) p14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway. Cancer Res 74:1371-8.. The Cancer Genome Research Network (2015). Comprehensive and Integrative Genomic Characterization of Diffuse Lower Grade Gliomas. N Eng J Med 372:2481-98. *Corresponding Author. Chen K, Yang D, Li X, Sun B, Song F, Cao W, Brat D, Gao Z, Li H, Liang H,Zhao Y, Zheng H, Li M, Buckner J, Patterson SD, Ye X, Reinhard C, Bhathena A, Joshi D, Mischel PS, Croce C, Wang YM, Kaimal S, Li H, Lu X, Pan Y, Chang H, Ba S, Luo L, Cavenee W, Zhang W, Xishan Hao X. (2015) Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy. Proc Natl Acad Sci. 112:1107-12.. Lin R, Elf ...
As tumors can harbor thousands of mutations, it is technically challenging to sort out the most relevant mutations of potential functional and biologic significance in exceptional responders to chemotherapy. Al-Ahmadie and colleagues (2) provide valuable insights into delineating tumor genome sequencing data. First, they sequenced the recurrent tumor specimen obtained after standard chemotherapy, but before trial enrollment. They then confirmed the mutations in the diagnostic tumor samples collected before chemotherapy. By comparing treated and treatment-naïve tumors, the authors selected mutations that arose early in molecular time, which were more likely to exert biologic driving effects on tumor development. Second, they performed an integrated analysis using the mutation, DNA copy number, and tumor clonality data with pathway analysis relevant to the mechanism of drug action to prioritize genomic aberrations. Third, considering heterogeneity of tumor cells, they confirmed whether the ...
R. Marty, S. Kaabinejadian, D. Rossell, M.J. Slifker, J. van de Haar, H.B. Engin, N. de Prisco, T. Ideker, W.H. Hildebrand, J. Font-Burgada, H. Carter, "MHC-I genotype restricts the oncogenic mutational landscape," Cell, 2017 (In Press).. H. Carter*, R. Marty, M. Hofree, A. Gross, J. Jensen, K. Fisch, X. Wu, C. DeBoever, E. Van Nostrand, Y. Song, E. Wheeler, J. Kreisberg, S. Lippman, G. Yeo, S. Gutkind, T. Ideker, "Widespread interacion of inherited polymorphisms with somatic events in cancer," Cancer Discovery Apr 1;7(4):410-23, 2017. PMID: 28188128 * Corresponding author. B. Engin, J. Kreisberg, H. Carter, "Structure-based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces," PLoS One Apr 4;11(4):e0152929, 2016. PMID: 27043210. B. Engin, M. Hofree, H. Carter, "Identifying Mutation-Specific Cancer Pathways Using a Structurally Resolved Protein Interaction Network," Pac Symp Biocomput. 84-95, 2015. PMID: 25592571. H. Carter, A. Chen, L. Isik, S. Tyekucheva, V.E. ...
Using molecular genetic techniques, we have generated and characterized six temperature sensitive (ts) alleles of nop2. All failed to support growth at 37 degrees C and one was also formamide sensitive (fs) and failed to grow on media containing 3% formamide. Conditional lethality is not due to rapid turnover of mutant Nop2p proteins at 37 degrees C. Each allele contains between seven and 14 amino acid substitutions and one possesses a nonsense mutation near the C-terminus. Mapping experiments with one allele, nop2-4, revealed that a subset of the amino acid substitutions conferred the ts phenotype and that these mutations have an additive effect. All six mutants exhibited dramatic reductions in levels of 60S ribosome subunits under non-permissive conditions as well as some reduction at permissive temperature. Processing of 27S pre-rRNA to mature 25S rRNA was defective in all six mutants grown under non-permissive conditions. Levels of the 40S ribosomal subunit and 18S rRNA were not ...
Although KRAS is one of the major oncogenes associated with aggressive cancers, drugs designed to block KRAS function have not been able to halt cancer progression in a clinical setting. Until now, KRAS has remained infamously "undruggable.". In a new study, published this month in Cancer Discovery, University of California San Diego School of Medicine researchers report that approximately half of lung and pancreatic cancers that originate with a KRAS mutation become addicted to the gene as they progress. By understanding the mechanism that causes these cancers to remain dependent on KRAS for survival, they were able to identify a drug capable of targeting it.. "Certain tumors use mutant KRAS to boost their survival by helping them take up nutrients and process toxins, causing them to become addicted to KRAS," said David Cheresh, PhD, UC San Diego School of Medicine Distinguished Professor of Pathology and senior author of the paper. "Other tumors that do not use KRAS in this way can do without ...
G3: Genes,Genomes,Genetics is pleased to offer a new format for quickly and easily publishing mutant screen reports.. The Mutant Screen Report provides a useful format for describing the results of mutant screens. The format is succinct, and follows a structured template designed to make it fast and easy for authors to submit, for reviewers to rapidly assess, and for readers to easily understand the screen and its results. The Reports fulfill one of G3s goals: to make data from useful genetic screens available to the community in a timely fashion. Guidelines here.. So find those lab notebooks and submit your Mutant Screen Reports today to G3!. ...
The basic principle behind the data analysis is that we compare the Ct value of a mutation assay in a test sample with the Ct value of the same assay in a wildtype sample. When there is a significant difference (a preset value of 4 Cts) between the Ct values, the test sample is concluded to contain the mutation. The Ct values used for comparison can either be raw Ct (in average Ct method) or normalized Ct (in delta delta Ct case). When the Ct difference falls between 3 and 4, we give a borderline mutation call, which means that the mutation may be present at low percentage. When the Ct difference is smaller than 3, we give a negative mutation call (i.e. the mutation percentage is beyond the detection limit of the array). The wildtype sample can be either a genuine wildtype sample that is tested in the same experiment, or it could be a "virtual" wildtype sample that is computed from all test samples. For detailed description of the data analysis principle, refer to (link to white paper ...
Chromosomal mutations occur inside the chromosome. There are 23 pairs of chromosomes in each human cell. Mutation occurs in the genes DNA base sequence. There are several factors associated with gene mutation. Some mutations are hereditary while others occur due to environmental factors in an individuals lifetime. Learn more facts about chromosomal mutations.
Several different single-gene mutations are known to cause varying degrees of diabetes and obesity in mice. The severity of the diabetes produced depends on both the mutation itself and the interaction of the mutant gene with the inbred background. Establishing the nature of these gene-background interactions should aid us in our understanding of similar interactions that occur in human diabetes. The documentation of several different genes that produce similar, if not identical, diabetes-obesity syndromes suggests that lesions in many pathways can cause diabetes. An understanding of these defects in mice should help us to understand similar defects involved in the human disease. The developmental stages in each mutant are similar. The early symptoms include hyperphagia, hyperinsulinemia, and hypertrophy and hyperplasia of the beta cells of the islets of Langerhans. Hyperglycemia, obesity, and severe diabetes are secondary features that result from insulin resistance and the failure to
There are many disease-related gene mutants and the mutant cDNA clones are critical for disease models in biomedical research. OriGene offers both kinase-dead ORF clones and naturally occurred disease-related mutants. The mutant and variant ORF clones are all provided in a mammalian expression vector.
The phenomenon of mutation, therefore, is a most important component of the evolution model. The evolution model must postulate some mechanism to produce the required upward progress in complexity which characterizes the model in its broadcast dimension. Mutation is supposedly that mechanism.. The basic evolution model would predict, therefore, that mutations must be primarily beneficial, generating a vertical change upward toward higher degrees of order. Each such change must be positively helpful in the environment if it is to be preserved by natural selection and contribute to evolutionary progress.. The creation model, on the other hand, would predict that, if there are any such things as real mutations, causing vertical changes in complexity and order of the kings, they will be harmful, not beneficial.. With these two models in mind, let us now consider some of the actual experimental facts relative to mutations.. 1. Mutations are random, not directed.. ...
4IJT: Structural studies of p53 inactivation by DNA-contact mutations and its rescue by suppressor mutations via alternative protein-DNA interactions.
4IBQ: Structural studies of p53 inactivation by DNA-contact mutations and its rescue by suppressor mutations via alternative protein-DNA interactions.
Using a database of human tumor genomic data, researchers at the University of California San Diego, School of Medicine and Moores Cancer Center discovered that mutation hotspots known as kataegis are a positive marker in breast cancer - patients with kataegis have less invasive tumors and better prognoses. The study, published June 30 in Cell Reports, also suggests kataegis status could help doctors determine treatment options that might work best for patients with the mutation pattern.
Activating mutations in K-Ras are among the most common lesions found in human cancer, and such mutations are generally associated with poor prognosis. Despite numerous efforts in academia and industry, small molecule inhibitors that directly target K-Ras remain elusive. Even more highly desired are molecules that selectively target mutant K-Ras while sparing the wild type protein. We have used a fragment-based screen to discover oncogenic mutant-specific inhibitors of K-Ras. Crystallographic studies with multiple inhibitors in complex with K-Ras reveal that the compounds bind in a novel hydrophobic pocket that is not apparent in any published crystal structure of Ras. These inhibitors disrupt the conformations of Switch I and Switch II, domains that are essential for the association and activation of downstream signaling partners. Our medicinal chemistry effort has greatly improved potency, showing that this pocket is particularly amenable to chemical optimization. In vitro biochemical ...
Thought you all might be interested in this video on whether or not mutations are random. It covers both why we originally thought mutations were random plus
A new study provides some of the first links between relatively common mutations in the blood cells of the elderly and atherosclerosis.. Though cardiovascular disease, which is characterized in part by atherosclerosis, or plaque build-up, is a leading cause of death in the elderly, almost 60 percent of elderly patients with atherosclerotic cardiovascular disease (CVD) exhibit no conventional risk factors, or just one. This and other data suggest that age-dependent risk factors that havent yet been identified may contribute to CVD.. Scientists know that accumulation of somatic DNA mutations is a feature of aging, though little data exists on the role of such mutations in age-associated disorders beyond cancer. Meanwhile, recent human studies indicate that aging is associated with an increase in somatic mutations in the hematopoietic system, which gives rise to blood cells; these mutations provide a competitive growth advantage to the mutant hematopoietic cells, allowing for their clonal ...
Ok i was under the impression that exon skipping would work for nonsense mutations, but I was told that it could require multiple skips to get the desired resu…
My research is focused on understanding the molecular pathways that lead to inherited Parkinsons disease linked to mutations in Leucine rich repeat kinase 2 (LRRK2). Mutations in this gene are the single most common genetic cause of Parkinsons disease, affecting 5-10,000 people in the UK alone. LRRK2 itself is a multidomain enzyme, possessing both kinase and GTPase activities, and much of my work over the past 8 years has been directed at dissecting how mutations impact on these activities, and how they regulate one another. To do this, my group uses a combination of cellular and biochemical approaches, including cellular models for LRRK2 function and in vitro enzymatic assays. We have a particular interest in investigating proteins closely related to LRRK2 as a means to achieving a greater understanding of how LRRK2 itself functions. Our research has highlighted a putative role for LRRK2 in the regulation of autophagy ...
In the last two decades, according to the National Institute of Allergy and Infectious Diseases, nearly half of the new pathogens that affect human and animal health have been viruses. As with the influenza A (H1N1) pandemic in 2009, most of these diseases can quickly adapt and morph into nastier strains that resist attacks by vaccines and immune systems.. The Defense Advanced Research Projects Agency (DARPA), through a program called DARPA Prophecy, has tapped Harvard University and APL to develop methods to predict how, and how fast, these viral agents might mutate.. The current approach to dealing with viruses is reactive, explains Andrew Feldman, DARPA Prophecy project manager and principal investigator in the Research and Exploratory Development Department. Existing vaccines and therapies are designed to protect against viruses that are already out there, and new vaccines take years to develop. But we are trying to get out in front of emerging diseases by predicting how viruses ...
While the findings could have implications for other common diseases, in particular neurological disorders such as autism or schizophrenia, several scientists say it is unlikely that rare mutations play an equally large role in common diseases with late onset, where natural selection has had a different effect.
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The following mutations are based on material from earlier editions of Gamma World, adapted for the Alternity edition. The gamemaster can extend the mutation tables or allow the new mutations to be substituted for some existing mutations, if they are being determined randomly. Physical Mutations Burning Hands Good, Activated, WIL The mutant can emit heat from his hands…
Mutations in the promoter region and the three exons of CYP1B1 were analyzed by direct PCR sequencing in a total 109 people, which consisted of 39 affected by PCG and 70 unaffected relatives of the patients. No mutations segregating with the disease were found in the promoter region. We identified a total of 16 distinct DNA mutations in 13 (34.2%) of the 38 unrelated index cases: six transitions (2 G,A and 4 C,T), six transversions (3 C,A, 1 T,A and 2 G,T), three small deletions, and one small duplication (Table 2 and Figure 1). The transitions and transversions predicted nine missense (P52L, G61E, Y81N, A106D, F261L, R390S, P400S, P437L, and R469W) and three nonsense (E262X, W341X, and E173X) amino acid substitutions (Table 2 and Figure 1). On the other hand, the conceptual translation of one nucleotide long and 13 nucleotide long deletions (c.906delG and c.1435_1447delGAGTGCAGGCAGA, respectively) as well as one 10 nucleotide long duplication (c.1571_1580dupTCATGCCACC) resulted in three ...
Contrary to what was thought previously, bacteria seem to be, not merely spectators to their own evolution, but, through a variety of mechanisms, able to increase the rate at which mutations occur and, consequently, to increase their chances of becoming resistant to antibiotics. Laboratory studies and mathematical models suggest that, under stressful conditions, such as antibiotic challenge, selective pressure favors mutator strains of bacteria over nonmutator strains. These hypermutable strains have been found in natural bacterial populations at higher frequencies than expected. The presence of mutator strains in the clinical setting may indicate an enhanced risk of acquiring antibiotic resistance through mutational and recombinational events. In addition, some antibiotics are inducers of mechanisms that transiently increase the mutation rate, and thus probably act, not only as mere selectors of antibiotic resistant clones, but also as resistance-promoters ...
In accordance with the latest scientific findings, we are updating our somatic tumor panel. The total number of genes on this panel is now 710, up from 649. The panel now includes mutational load analysis of the tumor and also supports the examination of leukemia and lymphoma.. The current update was designed to enable personalized therapy decisions, determined by an interdisciplinary tumor board, addressing solid tumors, leukemia and lymphoma. Weve added additional genes that, according to the latest scientific findings, are linked to the development, growth, disease outlook, drug metabolism, and tumor therapy outcome. The examination of selected translocations is now performed in 29 genes.. In addition to the reporting of these treatment-relevant gene changes, we are also expanding our medical reports by reporting the mutation load of the tumor. Data increasingly suggests that tumors with very high mutation load have increased numbers of neo-antigens on the cell surface, and may therefore ...
A mathematical model that combines stochasticity and spatial structure describes the dynamics of the viral population during an infection cycle, and fitting the model to RNA and virus abundances over time shows that poliovirus follows a geometric replication mode.
A gene mutation in the brain can trigger irregular heart beat and sudden death in people with epilepsy, revealed a study released Tuesday.
The enteric pathogen S. typhimurium has a phage-type known as DT104, which is associated with an epidemiology that is extensive and virulent. It was characterised about 30 years ago, and has spread to nearly all areas of the earth since then (2). S. typhimurium DT104 was found to have become resistant to multiple antibiotics in 1972 (2). This strain, now known as MDR-DT104, acquired the relevant mutation through the integration of an additional 43-kilobase genomic island (SGI1) into its genetic profile (3). In 1975, an alternative strain of DT104 also acquired multi-drug resistance in Thailand via different mechanisms (2). SGI1 confers resistance to a specific subset of antibiotics: sulphonamide-types, as well as tetracycline, streptomycin, chloramphenicol and ampicillin (3). However, some MDR-DT104 strains isolated in Britain were found to have added resistance to trimethoprim, (13%) ciprofloxacin (16%) or both (2%) to their anti-drug arsenal (1). In addition, some studies have reported ...
To defeat current commercial antivirus software, the virus developers are employing obfuscation techniques to create mutating viruses. The current antiviru
More recently, another analysis (Ohno, 1984) added further evidence that at least one of the proteins was formed from an essentially random sequence of amino acids. This evidence is a little bit more difficult to understand since its comprehension involves some understanding of how the genetic code works. Ill just have to refer readers who do not have this background to an explanation such as Suzuki, et. al, 1976. It appears that the DNA that formed the gene was somewhat unusual since it could be "read" without finding a "stop" word in any of the three "reading frames." It can be shown that such DNA sequences could easily occur through the well-known process of duplication. The DNA sequence suggests that a simple "frame-shift" mutation could have brought about the chance formation of at least this one enzyme. "Frame-shift" mutations are known for forming totally new and essentially random arrays of amino acids since the code is "read" in a new reading frame. Usually the proteins that are formed ...
Independent mutations in Ad2ts111 cause degradation of cellular DNA and defective viral DNA replication.: An adenovirus mutant, Ad2ts111, has previously been sh
Potential energy (kJ/mol) of native and mutant type SHV β-lactamases.Native is shown in black; S130G mutant form of SHV β-lactamases is shown in red.
On Thu, Jul 7, 2011 at 3:43 PM, John J Barton ,[email protected],wrote: , , On Thu, Jul 7, 2011 at 1:58 PM, Ryosuke Niwa ,[email protected], wrote: ,, ,, ,,, On Thu, Jul 7, 2011 at 12:18 PM, Jonas Sicking ,[email protected], wrote: ,,, ,,, ,,,, I dont think John J Bartons proposal to fire before mutation ,,,, notifications is doable. ,,,, ,,,, ,,, I concur. Being synchronous was one of the reasons why the existing DOM ,,, mutation events dont work. We shouldnt adding yet-another synchronous ,,, event here. ,,, ,,, ,, However, my proposal need not be synchronous in the sense that is , important here: before mutation listeners need not able to mutate, only , cancel. So its not yet another synchronous event. Developers would use , their handler to build a new mutation event and fire it on the next turn: , it s essentially asynchronous. Being able to cancel is dangerous enough for me. There are lots of reasons why before events may not be practical, , including lack of enthusiasm ...
holds that natural selection in combination with random mutation is the directive or creative force of evolution. How do we falsify this?" To answer the question you have to think about the two variables that are acting on the population, natural selection, through environmental changes (this includes physical as well as chemical changes), and random mutation. Random mutation first, not all mutations can pass down to off spring so we can not accept these (the mutations that will not pass) as leading to an evolutary adaptation. Second the mutation has to be one that does not reduce the chance of the organisms survival, thus we study the mutation that can be passed to offspring and does not reduce survivability of the organism. Now to natural selection, this would be a change in environment that would lead to either the reduced reproduction of the population or a change where the reproduction rate slows. Now when combined, the mutation must provide some benefit to allow for the organism to have ...
In this presentation from the 18th European Congress: Perspectives in Lung Cancer, Dr. Céline Mascaux discusses treatment strategies in both the front line and relapse settings of EGFR+ tumors. Earn CME Credit for a related activity: http://elc.imedex.com/ELC/S... © 2017 Imedex, LLC.
TY - JOUR. T1 - Modeling post-translational modifications and cancer-associated mutations that impact the heterochromatin protein 1α-importin α heterodimers. AU - Zimmermann, Michael T.. AU - Williams, Monique M.. AU - Klee, Eric W. AU - Lomberk, Gwen A.. AU - Urrutia, Raul. PY - 2019/1/1. Y1 - 2019/1/1. N2 - Heterochromatin protein 1α (HP1α) is a protein that mediates cancer-associated processes in the cell nucleus. Proteomic experiments, reported here, demonstrate that HP1α complexes with importin α (IMPα), a protein necessary for its nuclear transport. This data is congruent with Simple Linear Motif (SLiM) analyses that identify an IMPα-binding motif within the linker that joins the two globular domains of this protein. Using molecular modeling and dynamics simulations, we develop a model of the IMPα-HP1α complex and investigate the impact of phosphorylation and genomic variants on their interaction. We demonstrate that phosphorylation of the HP1α linker likely regulates its ...
BACKGROUND: In lung adenocarcinoma, molecular profiling of actionable genes has become essential to set up targeted therapies. However, the feasibility and the relevance of molecular profiling from the cerebrospinal fluid (CSF) in the context of meningeal metastasis have been poorly assessed. METHODS: We selected patients with stage IV lung adenocarcinoma harbouring metastatic cells in the CSF after cytological analysis. Seven samples from six patients were eligible for molecular testing of epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS), v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) and human epidermal growth factor receptor 2 (HER2) mutations using quantitative polymerase chain reaction (PCR) high-resolution melting curve analysis and Sanger sequencing after DNA extraction from the cell pellets of the CSF ...
The aim of the present study was to investigate the mutation rate of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients and to apply logistic regression analysis to investigate the factors associated with EGFR gene mutation to provide data for the treatment of NSCLC. Paraffin tissue, bronchoscopy or pleural effusion specimens were collected from 176 NSCLC patients following pathological diagnosis. The EGFR gene exon 19 delL747-S75linss and delL747-S752ins deletion mutations, and the exon 20 T790M and exon 21 L858R mutations were identified using amplification refractory mutation system analysis. The clinical data and laboratory results of the patients were collected, and the total mutation rate of the EGFR gene in exons 19, 20 and 21 in the 176 NSCLC patients was found to be 48.3% (85/176). In addition, the EGFR gene mutation rate in adenocarcinoma was found to be significantly higher than that in squamous cell and large cell carcinoma (χ²=12.454; ...
We have isolated three independent Chinese hamster ovary cell mutants (B3853, I223, and M311) with temperature-sensitive, pleiotropic defects in receptor-mediated endocytosis. Activities affected at 41 degrees C include uptake via the D-mannose 6-phosphate receptor, accumulation of Fe from diferric transferrin, uptake of alpha 2-macroglobulin, compartmentalization of newly synthesized acid hydrolases, resistance to ricin, and sensitivity to diphtheria and Pseudomonas toxins and modeccin. The three mutants also displayed decreased sialylation of some secreted glycoproteins at 41 degrees C, reminiscent of the nonconditional mutant DTG1-5-4 that showed both endocytic and Golgi-associated defects (Robbins, A.R., C. Oliver, J.L. Bateman, S.S. Krag, C.J. Galloway, and I. Mellman, 1984, J. Cell Biol., 99:1296-1308). Phenotypic changes were detectable within 30 min after transfer of the mutants to 41 degrees C; maximal alteration of most susceptible functions was obtained 4 h after temperature shift. At ...
Looking for online definition of cystic fibrosis transmembrane conductance regulator gene in the Medical Dictionary? cystic fibrosis transmembrane conductance regulator gene explanation free. What is cystic fibrosis transmembrane conductance regulator gene? Meaning of cystic fibrosis transmembrane conductance regulator gene medical term. What does cystic fibrosis transmembrane conductance regulator gene mean?
Objective: Familial hemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin (PRF1), syntaxin-11 (STX11), and Munc13-4 (UNC13D). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well-defined patient cohort. Methods: Sequencing of UNC13D was performed in 38 FHL patients from 34 families where mutations in the PRF1 and STX11 had been excluded. Results: We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11-negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in ...
TY - JOUR. T1 - Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome. T2 - A prospective, open-label, dose-escalation study. AU - Bulua, Ariel C.. AU - Mogul, Douglas Bradford. AU - Aksentijevich, Ivona. AU - Singh, Harjot. AU - He, David Y.. AU - Muenz, Larry R.. AU - Ward, Michael M.. AU - Yarboro, Cheryl H.. AU - Kastner, Daniel L.. AU - Siegel, Richard M.. AU - Hull, Keith M.. PY - 2012/3. Y1 - 2012/3. N2 - Objective To investigate the efficacy of etanercept in improving the symptoms and underlying inflammation in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Methods Fifteen patients with TRAPS were enrolled in a prospective, open-label, dose-escalation study. Patients recorded attacks, symptom severity, and use of ancillary medications in a daily diary. Blood samples were collected during each period and measured for levels of acute-phase reactants. Between 7 years and 9 years after the conclusion of the initial ...
American Journal of Pathology, Vol. 164, No. 1, January 2004 Copyright © American Society for Investigative Pathology KIT Mutations Are Common in Testicular Seminomas Kathleen Kemmer,* Christopher L. Corless, † Jonathan A. Fletcher, ‡ Laura McGreevey,* Andrea Haley, † Diana Griffith,* Oscar W. Cummings, § Cecily Wait,* Ajia Town,* and Michael C. Heinrich* From the Division of Hematology and Oncology,* Department of Pathology, † Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, Oregon; the Department of Pathology, † Brigham and Womens Hospital, Boston, Massachusetts; and the Department of Pathology, § Indiana University, Indianapolis, Indiana Expression of KIT tyrosine kinase is critical for normal germ cell development and is observed in the majority of seminomas. Activating mutations in KIT are common in gastrointestinal stromal tumors and mastocytosis. In this study we examined the frequency and spectrum of KIT mutations ...
The Online Mendelian Inheritance in Man (OMIM) compendium of human genes and genetic phenotypes includes three types of congenital dyserythropoietic anemia as reported in Table 1. A comprehensive overview of these disorders has been published recently.1. Congenital dyserythropoietic anemia type II is the most common of these inherited disorders. Typical morphological abnormalities of this condition are shown in Figure 1: these abnormalities clearly indicate that incomplete cytokinesis is one of the key features of erythroid cells in this condition.. More than 30 years ago, we investigated the pathophysiology of anemia in patients with congenital dyserythropoietic anemia type II in studies of iron kinetics.2 A wide variation in effectiveness of erythroid activity was observed, and a significant inverse relationship was found between ineffective erythropoiesis and peripheral hemolysis. In 4 patients with prominent peripheral hemolysis, splenectomy was carried out. Marked improvement in their ...