Four major clades of Candida auris have been described, and all infections have clustered in these 4 clades. We identified an isolate representative of a potential fifth clade, separated from the ...other clades by >200,000 single-nucleotide polymorphisms, in a patient in Iran who had never traveled outside the country.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chondrosarcomas constitute a heterogeneous group of primary bone cancers characterized by hyaline cartilaginous neoplastic tissue. They are the second most common primary bone malignancy. The vast ...majority of chondrosarcomas are conventional chondrosarcomas, and most conventional chondrosarcomas are low- to intermediate-grade tumors (grade 1 or 2) which have indolent clinical behavior and low metastatic potential. Recurrence augurs a poor prognosis, as conventional chondrosarcomas are both radiation and chemotherapy resistant. Recent discoveries in the biology, genetics, and epigenetics of conventional chondrosarcomas have significantly advanced our understanding of the pathobiology of these tumors and offer insight into potential therapeutic targets.
Candida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely ...observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLα mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related species which may contribute to differences in drug response in this emerging fungal clade.
The release by neutrophils of DNA-based extracellular traps (NETs) is a recently recognized innate immune phenomenon that contributes significantly to control of bacterial pathogens at tissue foci of ...infection. NETs have also been implicated in the pathogenesis of non-infectious diseases such as small vessel vasculitis, lupus and cystic fibrosis lung disease. Reactive oxygen species (ROS) are important mediators of NET generation (NETosis). Neutrophils with reduced ROS production, such as those from patients with chronic granulomatous disease or myeloperoxidase (MPO) deficiency, produce fewer NETs in response to inflammatory stimuli. To better understand the roles of various ROS in NETosis, we explore the role of MPO, its substrates chloride ion (Cl(-)) and hydrogen peroxide (H(2)O(2)), and its product hypochlorite (HOCl) in NETosis.
In human peripheral blood neutrophils, pharmacologic inhibition of MPO decreased NETosis. Absence of extracellular Cl(-), a substrate for MPO, also reduced NETosis. While exogenous addition of H(2)O(2) and HOCl stimulated NETosis, only exogenous HOCl could rescue NETosis in the setting of MPO inhibition. Neither pharmacological inhibition nor genetic deletion of MPO in murine neutrophils blocked NETosis, in contrast to findings in human neutrophils.
Our results pinpoint HOCl as the key ROS involved in human NETosis. This finding has implications for understanding innate immune function in diseases in which Cl(-) homeostasis is disturbed, such as cystic fibrosis. Our results also reveal an example of significant species-specific differences in NET phenotypes, and the need for caution in extrapolation to humans from studies of murine NETosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Matrix metalloproteinases (MMPs) have been shown to play significant roles in a number of physiological as well as pathological processes. Best known to proteolyse components of the extracellular ...matrix, MMPs have recently been discovered to also target a growing list of proteins apart from these, both inside and outside the cell. MMPs have also been traditionally thought of as enzymes involved in chronic processes such as angiogenesis, remodelling and atherosclerosis on a days‐week time‐scale. However they are now understood to also act acutely in response to oxidative stress on a minutes time‐scale on non‐extracellular matrix substrates. This review focuses on the acute actions and both extracellular and intracellular targets of two prominent MMP family members, MMP‐2 and ‐9, in cardiovascular diseases including ischaemia/reperfusion injury, inflammatory heart disease, septic shock and pre‐eclampsia. Also discussed are various ways of regulating MMP activity, including post‐translational mechanisms, the endogenous tissue inhibitors of metalloproteinases and pharmacological inhibitors. A comprehensive understanding of MMP biology is necessary for the development of novel pharmacological therapies to combat the impact of cardiovascular disease.
British Journal of Pharmacology (2007) 152, 189–205; doi:10.1038/sj.bjp.0707344
With the relentless waves of coronavirus disease 2019(COVID-19), there is a need for widespread community adoption of infection prevention(IP) measures including hand hygiene, use of face masks, and ...staying at home when unwell. Understanding the profile of individuals who do not consistently practice IP can help target public health education.
We conducted a nationally-representative population survey from November 2020 to January 2021. Households were randomly selected from a proportionately stratified national census. The household member with the most recent birthday was invited to complete the survey. Three questions on a 5-point Likert-scale(never-rarely-occasionally-often-always) assessed IP behaviours(hand hygiene, face mask use when having a cough/cold, staying at home when having a cold/flu) before and during the pandemic. A multivariable logistic regression model was constructed to assess factors associated with the non- or inconsistent(“never-rarely-occasionally”) adoption of any of the three IP behaviours during the pandemic.
Mean age of 2004 respondents was 44.5(SD 15.0) years, with 52% females and 65% being highly educated (diploma/degree holders). Although 12% reported consistently(“often-always”) adopting all 3 IP behaviours pre-pandemic, the majority(n=1752, 87%) reported doing so during the pandemic. After adjusting for age, educational level, and presence of chronic illness, males(AOR 1.71 95%CI 1.30, 2.25, Chinese(AOR 1.48 1.07, 2.05), low-adopters of healthy lifestyle(AOR 1.59 1.03, 2.45) and those who did not or inconsistently adopted IP behaviours pre-pandemic(AOR 8.92 3.28, 24.27) were more likely not to or inconsistently adopt the 3 IP behaviours during the pandemic.
During the ongoing pandemic, educational messages and information channels on IP measures could be more targeted at males and Chinese. Additionally, the promotion of healthy lifestyle and consistent adoption of IP behaviours during non-pandemic times is critical for consistent adoption of IP behaviours during pandemics.
Males, Chinese, and low-adopters of healthy lifestyle and IP behaviours pre-pandemic do not consistently practice IP during the pandemic.
has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela ...revealed four populations (clades I, II, III, and IV) corresponding to these geographic regions. Since this description,
has been reported in more than 30 additional countries. To trace this global emergence, we compared the genomes of 304
isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure.
isolates from two clades with opposite mating types were detected contemporaneously in a single health care facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 360 years; outbreak-causing clusters from clades I, III, and IV originated 36 to 38 years ago. We observed high rates of antifungal resistance in clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in
as the most widespread mutation associated with azole resistance and S639P in
for echinocandin resistance. Copy number variants in
predominantly appeared in clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in
In less than a decade,
has emerged in health care settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other
species,
is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new
introductions. Through a global collaboration, we assessed genome evolution of isolates of
from 19 countries. Here, we described estimated timing of the expansion of each
clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology.
Transmission of multidrug-resistant Candida auris infection has been reported in the USA. To better understand its emergence and transmission dynamics and to guide clinical and public health ...responses, we did a molecular epidemiological investigation of C auris cases in the USA.
In this molecular epidemiological survey, we used whole-genome sequencing to assess the genetic similarity between isolates collected from patients in ten US states (California, Connecticut, Florida, Illinois, Indiana, Maryland, Massachusetts, New Jersey, New York, and Oklahoma) and those identified in several other countries (Colombia, India, Japan, Pakistan, South Africa, South Korea, and Venezuela). We worked with state health departments, who provided us with isolates for sequencing. These isolates of C auris were collected during the normal course of clinical care (clinical cases) or as part of contact investigations or point prevalence surveys (screening cases). We integrated data from standardised case report forms and contact investigations, including travel history and epidemiological links (ie, patients that had shared a room or ward with a patient with C auris). Genetic diversity of C auris within a patient, a facility, and a state were evaluated by pairwise differences in single-nucleotide polymorphisms (SNPs).
From May 11, 2013, to Aug 31, 2017, isolates that corresponded to 133 cases (73 clinical cases and 60 screening cases) were collected. Of 73 clinical cases, 66 (90%) cases involved isolates related to south Asian isolates, five (7%) cases were related to South American isolates, one (1%) case to African isolates, and one (1%) case to east Asian isolates. Most (60 82%) clinical cases were identified in New York and New Jersey; these isolates, although related to south Asian isolates, were genetically distinct. Genomic data corroborated five (7%) clinical cases in which patients probably acquired C auris through health-care exposures abroad. Among clinical and screening cases, the genetic diversity of C auris isolates within a person was similar to that within a facility during an outbreak (median SNP difference three SNPs, range 0–12).
Isolates of C auris in the USA were genetically related to those from four global regions, suggesting that C auris was introduced into the USA several times. The five travel-related cases are examples of how introductions can occur. Genetic diversity among isolates from the same patients, health-care facilities, and states indicates that there is local and ongoing transmission.
US Centers for Disease Control and Prevention
Central to anti-tumor immunity are dendritic cells (DCs), which stimulate long-lived protective T cell responses. Recent studies have demonstrated that DCs can achieve a state of hyperactivation, ...which is associated with inflammasome activities within living cells. Herein, we report that hyperactive DCs have an enhanced ability to migrate to draining lymph nodes and stimulate potent cytotoxic T lymphocyte (CTL) responses. This enhanced migratory activity is dependent on the chemokine receptor CCR7 and is associated with a unique transcriptional program that is not observed in conventionally activated or pyroptotic DCs. We show that hyperactivating stimuli are uniquely capable of inducing durable CTL-mediated anti-tumor immunity against tumors that are sensitive or resistant to PD-1 inhibition. These protective responses are intrinsic to the cDC1 subset of DCs, depend on the inflammasome-dependent cytokine IL-1β, and enable tumor lysates to serve as immunogens. If these activities are verified in humans, hyperactive DCs may impact immunotherapy.
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•Hyperactive dendritic cells display enhanced ability to migrate to lymph nodes•Hyperactive dendritic cells retain inflammasome activity in the dLN•Hyperactive cDC1s induce long-lived CD8+ T-cell-mediated anti-tumor immunity•Hyperactivating stimuli eradicate tumors that are resistant to anti-PD1 therapy
Inflammasome activation in dendritic cells (DCs) leads to pyroptosis or hyperactivation. Zhivaki et al. show that in contrast to pyroptotic DCs, hyperactive DCs stimulate durable anti-tumor immunity that eradicates established tumors. These protective responses are intrinsic to cDC1 cells and depend on DC hypermigration and on the inflammasome-dependent cytokine IL-1β.
SK-UT-1 uterine leiomyosarcomas (Ut-LMS) cells were transduced with a fatty acid synthase (FASN)-containing retroviral vector to recapitulate the "lipogenic phenotype of cancer." Consistent with this ...model, forced expression of FASN enhanced SK-UT-1 proliferation, migration, and cellular motion. Further investigation showed FASN promotes trimethylation of H3K9 (H3K9me3) and acetylation of H3K27 (H3K27ac) in SK-UT-1 cells. In contrast, siRNA targeting of FASN in high endogenous FASN expressing SK-LMS-1 Ut-LMS cells inhibits trimethylation of H3K9 and acetylation of H3K27. Palmitate, the predominant fatty acid product of FASN, increased H3K9me3, H3K27ac and H3K27me3 detection in SK-UT-1 cells. FASN promoted histone 3 methylation and acetylation through alteration of histone 3-modifying enzymatic activities (HDAC, HDM, HMT and HAT). ChIP-seq in SK-UT-1-FASN cells with anti-H3K9me3 antibody identified regions of enriched binding compared to vector-only cells. One differentially-enriched gene, CRISP1, was investigated further by ChIP-PCR. The transcriptionally repressive function of H3K9me3 was confirmed in CRISP1. Our results provide mechanistic insight into the pathobiology of the "lipogenic phenotype of cancer." Here, FASN reprograms the Ut-LMS epigenome through chromatin remodeling to promote the "malignant phenotype."
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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