scholarly journals The origins and genetic interactions of KRAS mutations are allele- and tissue-specific

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joshua H. Cook ◽  
Giorgio E. M. Melloni ◽  
Doga C. Gulhan ◽  
Peter J. Park ◽  
Kevin M. Haigis
Keyword(s):  
Experimental Studies ◽  
Epidemiological Studies ◽  
Genetic Interactions ◽  
Mutant Form ◽  
Missense Mutations ◽  
Kras Mutations ◽  
Tissue Specific ◽  
Activating Mutations ◽  
Clinical Consequences ◽  
Mutational Activation

AbstractMutational activation of KRAS promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of specific activating missense mutations. Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear. Here, we analyze 13,492 samples from these four tumor types to examine allele- and tissue-specific genetic properties associated with oncogenic KRAS mutations. The prevalence of known mutagenic mechanisms partially explains the observed spectrum of KRAS activating mutations. However, there are substantial differences between the observed and predicted frequencies for many alleles, suggesting that biological selection underlies the tissue-specific frequencies of mutant alleles. Consistent with experimental studies that have identified distinct signaling properties associated with each mutant form of KRAS, our genetic analysis reveals that each KRAS allele is associated with a distinct tissue-specific comutation network. Moreover, we identify tissue-specific genetic dependencies associated with specific mutant KRAS alleles. Overall, this analysis demonstrates that the genetic interactions of oncogenic KRAS mutations are allele- and tissue-specific, underscoring the complexity that drives their clinical consequences.

Potential Role of Inflammation in Associations between Particulate Matter and Heart Failure

2018 ◽  
Vol 24 (3) ◽  
pp. 341-358 ◽  
Author(s):  
Xiaotong Ji ◽  
Yingying Zhang ◽  
Guangke Li ◽  
Nan Sang
Keyword(s):  
Heart Failure ◽  
Particulate Matter ◽  
Inflammatory Response ◽  
Heart Diseases ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Inflammatory Mechanism ◽  
High Concentrations ◽  
Future Work ◽  
The Relationship

Recently, numerous studies have found that particulate matter (PM) exposure is correlated with increased hospitalization and mortality from heart failure (HF). In addition to problems with circulation, HF patients often display high expression of cytokines in the failing heart. Thus, as a recurring heart problem, HF is thought to be a disorder characterized in part by the inflammatory response. In this review, we intend to discuss the relationship between PM exposure and HF that is based on inflammatory mechanism and to provide a comprehensive, updated evaluation of the related studies. Epidemiological studies on PM-induced heart diseases are focused on high concentrations of PM, high pollutant load exposure in winter, or susceptible groups with heart diseases, etc. Furthermore, it appears that the relationship between fine or ultrafine PM and HF is stronger than that between HF and coarse PM. However, fewer studies paid attention to PM components. As for experimental studies, it is worth noting that coarse PM may indirectly promote the inflammatory response in the heart through systematic circulation of cytokines produced primarily in the lungs, while ultrafine PM and its components can enter circulation and further induce inflammation directly in the heart. In terms of PM exposure and enhanced inflammation during the pathogenesis of HF, this article reviews the following mechanisms: hemodynamics, oxidative stress, Toll-like receptors (TLRs) and epigenetic regulation. However, many problems are still unsolved, and future work will be needed to clarify the complex biologic mechanisms and to identify the specific components of PM responsible for adverse effects on heart health.

scholarly journals Relationship between Autism Spectrum Disorder and Pesticides: A Systematic Review of Human and Preclinical Models

2021 ◽  
Vol 18 (10) ◽  
pp. 5190
Author(s):  
Judit Biosca-Brull ◽  
Cristian Pérez-Fernández ◽  
Santiago Mora ◽  
Beatriz Carrillo ◽  
Helena Pinos ◽  
...  
Keyword(s):  
Systematic Review ◽  
Autism Spectrum Disorder ◽  
Experimental Studies ◽  
Clinical Signs ◽  
Epidemiological Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Preclinical Studies ◽  
Preclinical Models ◽  
Gestational Exposure

Autism spectrum disorder (ASD) is a complex set of neurodevelopmental pathologies characterized by impoverished social and communicative abilities and stereotyped behaviors. Although its genetic basis is unquestionable, the involvement of environmental factors such as exposure to pesticides has also been proposed. Despite the systematic analyses of this relationship in humans, there are no specific reviews including both human and preclinical models. The present systematic review summarizes, analyzes, and discusses recent advances in preclinical and epidemiological studies. We included 45 human and 16 preclinical studies. These studies focused on Organophosphates (OP), Organochlorine (OC), Pyrethroid (PT), Neonicotinoid (NN), Carbamate (CM), and mixed exposures. Preclinical studies, where the OP Chlorpyrifos (CPF) compound is the one most studied, pointed to an association between gestational exposure and increased ASD-like behaviors, although the data are inconclusive with regard to other ages or pesticides. Studies in humans focused on prenatal exposure to OP and OC agents, and report cognitive and behavioral alterations related to ASD symptomatology. The results of both suggest that gestational exposure to certain OP agents could be linked to the clinical signs of ASD. Future experimental studies should focus on extending the analysis of ASD-like behaviors in preclinical models and include exposure patterns similar to those observed in human studies.

scholarly journals Mutations in the Bacillus subtilis β Clamp That Separate Its Roles in DNA Replication from Mismatch Repair

2010 ◽  
Vol 192 (13) ◽  
pp. 3452-3463 ◽  
Author(s):  
Nicole M. Dupes ◽  
Brian W. Walsh ◽  
Andrew D. Klocko ◽  
Justin S. Lenhart ◽  
Heather L. Peterson ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Dna Replication ◽  
Mismatch Repair ◽  
Mutation Frequency ◽  
Elevated Temperatures ◽  
Temperature Sensitive ◽  
Mutant Form ◽  
Appreciable Effect ◽  
Missense Mutations ◽  
Dna Mismatch

ABSTRACT The β clamp is an essential replication sliding clamp required for processive DNA synthesis. The β clamp is also critical for several additional aspects of DNA metabolism, including DNA mismatch repair (MMR). The dnaN5 allele of Bacillus subtilis encodes a mutant form of β clamp containing the G73R substitution. Cells with the dnaN5 allele are temperature sensitive for growth due to a defect in DNA replication at 49°C, and they show an increase in mutation frequency caused by a partial defect in MMR at permissive temperatures. We selected for intragenic suppressors of dnaN5 that rescued viability at 49°C to determine if the DNA replication defect could be separated from the MMR defect. We isolated three intragenic suppressors of dnaN5 that restored growth at the nonpermissive temperature while maintaining an increase in mutation frequency. All three dnaN alleles encoded the G73R substitution along with one of three novel missense mutations. The missense mutations isolated were S22P, S181G, and E346K. Of these, S181G and E346K are located near the hydrophobic cleft of the β clamp, a common site occupied by proteins that bind the β clamp. Using several methods, we show that the increase in mutation frequency resulting from each dnaN allele is linked to a defect in MMR. Moreover, we found that S181G and E346K allowed growth at elevated temperatures and did not have an appreciable effect on mutation frequency when separated from G73R. Thus, we found that specific residue changes in the B. subtilis β clamp separate the role of the β clamp in DNA replication from its role in MMR.

Hypoxic mechanisms in primary headaches

Cephalalgia ◽  
2016 ◽  
Vol 37 (4) ◽  
pp. 372-384 ◽  
Author(s):  
Josefine Britze ◽  
Nanna Arngrim ◽  
Henrik Winther Schytz ◽  
Messoud Ashina
Keyword(s):  
Cluster Headache ◽  
High Altitude ◽  
Acute Mountain Sickness ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Primary Headaches ◽  
Secondary Headaches ◽  
Novel Approach ◽  
Calcitonin Gene ◽  
Level Of Knowledge

Background Hypoxia causes secondary headaches such as high-altitude headache (HAH) and headache due to acute mountain sickness. These secondary headaches mimic primary headaches such as migraine, which suggests a common link. We review and discuss the possible role of hypoxia in migraine and cluster headache. Methods This narrative review investigates the current level of knowledge on the relation of hypoxia in migraine and cluster headache based on epidemiological and experimental studies. Findings Epidemiological studies suggest that living in high-altitude areas increases the risk of migraine and especially migraine with aura. Human provocation models show that hypoxia provokes migraine with and without aura, whereas cluster headache has not been reliably induced by hypoxia. Possible pathophysiological mechanisms include hypoxia-induced release of nitric oxide and calcitonin gene-related peptide, cortical spreading depression and leakage of the blood-brain barrier. Conclusion There is a possible link between hypoxia and migraine and maybe cluster headache, but the exact mechanism is currently unknown. Provocation models of hypoxia have yielded interesting results suggesting a novel approach to study in depth the mechanism underlying hypoxia and primary headaches.

A simple approach to manage dosages in drug-epidemiology research

2008 ◽  
Vol 17 (3) ◽  
pp. 186-187 ◽  
Author(s):  
Michela Nosè ◽  
Corrado Barbui
Keyword(s):  
Psychotropic Drugs ◽  
Experimental Studies ◽  
International Comparisons ◽  
Health Impact ◽  
Epidemiological Studies ◽  
Drug Consumption ◽  
Specific Drug ◽  
Second Generation Antipsychotics ◽  
Drug Utilization Studies ◽  
Drug Epidemiology

In the study of the beneficial and adverse effects of psychotropic drugs, in addition to experimental studies (Barbui et al., 2007), epidemiological studies may provide interesting insights. A key methodological aspect in drug utilization studies is how drug consumption should be measured. Specifically, the need is to end up with a single variable that may be reliably used to indicate the overall consumption, for each patient included in a certain survey, of one specific drug (for example one antipsychotic, say haloperidol) or a specific drug class (for example second-generation antipsychotics) or a group of drugs (for example psychotropic drugs, including antipsychotics plus antidepressants plus benzodiazepines). Not only such a variable has to accommodate the problem that actual doses cannot be directly compared, but also that many patients often receive more than one drug, belonging to different or to the same pharmacological class. A methodology is therefore needed to convert each medication dosage into a standardised measure that allows to calculate, for each patient, a cumulative index of drug consumption. Standardised measures of drug consumption are also beneficial for national and international comparisons, for the evaluation of time trends in drug use, and for assessing the public health impact of specific events (for example a change in reimbursement status).

Exposure to environmental chemicals and type 1 diabetes: an update

2019 ◽  
Vol 73 (6) ◽  
pp. 483-488 ◽  
Author(s):  
Sarah G Howard
Keyword(s):  
Type 1 Diabetes ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Environmental Chemicals ◽  
Exposure Level ◽  
Environmental Chemical ◽  
Timing Of Exposure

This narrative review summarises recently published epidemiological and in vivo experimental studies on exposure to environmental chemicals and their potential role in the development of type 1 diabetes mellitus (T1DM). These studies focus on a variety of environmental chemical exposures, including to air pollution, arsenic, some persistent organic pollutants, pesticides, bisphenol A and phthalates. Of the 15 epidemiological studies identified, 14 include measurements of exposures during childhood, 2 include prenatal exposures and 1 includes adults over age 21. Together, they illustrate that the role of chemicals in T1DM may be complex and may depend on a variety of factors, such as exposure level, timing of exposure, nutritional status and chemical metabolism. While the evidence that these exposures may increase the risk of T1DM is still preliminary, it is critical to investigate this possibility further as a means of preventing T1DM.

scholarly journals The Pathophysiology of Post-Traumatic Glioma

2018 ◽  
Vol 19 (8) ◽  
pp. 2445 ◽  
Author(s):  
Donata Simińska ◽  
Klaudyna Kojder ◽  
Dariusz Jeżewski ◽  
Ireneusz Kojder ◽  
Marta Skórka ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Immune System ◽  
Experimental Studies ◽  
Epidemiological Studies ◽  
Detection Rates ◽  
Expression Of Genes ◽  
Specific Morphology ◽  
Post Traumatic ◽  
The Brain ◽  
Very High

Malignant glioma is a brain tumor with a very high mortality rate resulting from the specific morphology of its infiltrative growth and poor early detection rates. The causes of one of its very specific types, i.e., post-traumatic glioma, have been discussed for many years, with some studies providing evidence for mechanisms where the reaction to an injury may in some cases lead to the onset of carcinogenesis in the brain. In this review of the available literature, we discuss the consequences of breaking the blood–brain barrier and consequences of the influx of immune-system cells to the site of injury. We also analyze the influence of inflammatory mediators on the expression of genes controlling the process of apoptosis and the effect of chemical mutagenic factors on glial cells in the brain. We present the results of experimental studies indicating a relationship between injury and glioma development. However, epidemiological studies on post-traumatic glioma, of which only a few confirm the conclusions of experimental research, indicate that any potential relationship between injury and glioma, if any, is indirect.

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