Cancer-Associated Mutations in Endometriosis without Cancer Anglesio, Michael S; Papadopoulos, Nickolas; Ayhan, Ayse ...
New England journal of medicine/The New England journal of medicine,
05/2017, Letnik:
376, Številka:
19
Journal Article
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Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic ...lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis.
We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations.
Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions.
We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.
Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor ...cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.
A defining feature of mitochondria is their maternal mode of inheritance. However, little is understood about the cellular mechanism through which paternal mitochondria, delivered from sperm, are ...eliminated from early mammalian embryos. Autophagy has been implicated in nematodes, but whether this mechanism is conserved in mammals has been disputed. Here, we show that cultured mouse fibroblasts and pre-implantation embryos use a common pathway for elimination of mitochondria. Both situations utilize mitophagy, in which mitochondria are sequestered by autophagosomes and delivered to lysosomes for degradation. The E3 ubiquitin ligases PARKIN and MUL1 play redundant roles in elimination of paternal mitochondria. The process is associated with depolarization of paternal mitochondria and additionally requires the mitochondrial outer membrane protein FIS1, the autophagy adaptor P62, and PINK1 kinase. Our results indicate that strict maternal transmission of mitochondria relies on mitophagy and uncover a collaboration between MUL1 and PARKIN in this process.
Summary
This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients ...encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well‐established registry.
Since our first report in 2013, the number of patients entered into the UKPID registry has more than doubled to 4758 encompassing 97% of immunology centers within the United Kingdom. We believe this registry now represents virtually all patients with primary immunodeficiency within the UK. As such, this dataset continues to provide valuable information to clinicians, researchers, service commissioners and industry alike on PID within the UK, which may not otherwise be available without the existence of a well‐established registry.
Antibiotic resistance is a global health crisis linked to increased, and often unrestricted, antibiotic use in humans and animals. As one of the world's largest producers and consumers of ...antibiotics, China is witness to some of the most acute symptoms of this crisis. Antibiotics and antibiotic resistance genes (ARGs) are widely distributed in surface water, sewage treatment plant effluent, soils and animal wastes. The emergence and increased prevalence of ARGs in the clinic/hospitals, especially carbapenem-resistant gram negative bacteria, has raised the concern of public health officials. It is important to understand the current state of antibiotic use in China and its relationship to ARG prevalence and diversity in the environment. Here we review these relationships and their relevance to antimicrobial resistance (AMR) trends witnessed in the clinical setting. This review highlights the issues of enrichment and dissemination of ARGs in the environment, and also future needs in mitigating the spread of antibiotic resistance in the environment, particularly under the ‘planetary health’ perspective, i.e., the systems that sustain or threaten human health.
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•Antibiotics and ARGs are widely distributed in environment media in China.•Antibiotic resistance varies geographically in China.•Strategies to mitigate the spread of antibiotic resistance are suggested.
We engineered three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: ...N501Y from UK and SA; 69/70-deletion + N501Y + D614G from UK; and E484K + N501Y + D614G from SA. Neutralization geometric mean titers (GMTs) of 20 BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.
Neutralizing Activity of BNT162b2-Elicited Serum Liu, Yang; Liu, Jianying; Xia, Hongjie ...
New England journal of medicine/The New England journal of medicine,
04/2021, Letnik:
384, Številka:
15
Journal Article
Mesoporous silica nanoparticles (MSNs), one of the important porous materials, have garnered interest owing to their highly attractive physicochemical features and advantageous morphological ...attributes. They are of particular importance for use in diverse fields including, but not limited to, adsorption, catalysis, and medicine. Despite their intrinsic stable siliceous frameworks, excellent mechanical strength, and optimal morphological attributes, pristine MSNs suffer from poor drug loading efficiency, as well as compatibility and degradability issues for therapeutic, diagnostic, and tissue engineering purposes. Collectively, the desirable and beneficial properties of MSNs have been harnessed by modifying the surface of the siliceous frameworks through incorporating supramolecular assemblies and various metal species, and through incorporating supramolecular assemblies and various metal species and their conjugates. Substantial advancements of these innovative colloidal inorganic nanocontainers drive researchers in promoting them toward innovative applications like stimuli (light/ultrasound/magnetic)‐responsive delivery‐associated therapies with exceptional performance in vivo. Here, a brief overview of the fabrication of siliceous frameworks, along with discussions on the significant advances in engineering of MSNs, is provided. The scope of the advancement in terms of structural and physicochemical attributes and their effects on biomedical applications with a particular focus on recent studies is emphasized. Finally, interesting perspectives are recapitulated, along with the scope toward clinical translation.
Mesoporous silica nanoparticles (MSNs) have garnered enormous interest owing to their highly advantageous physicochemical and morphological attributes. Collectively, progression has been made by modifying the surface of the siliceous frameworks through incorporating diverse supramolecular assemblies. An overview of the fabrication of MSNs and discussions on significant advances in engineering of MSNs, along with their scope toward clinical translation, is provided.
Recent development in proton-exchange membrane fuel cell technology has stimulated research in fuel processing for hydrogen production. Hydrogen can be produced from four different types of methanol ...reforming processes, namely methanol decomposition, partial oxidation of methanol, steam reforming of methanol and oxidative steam reforming of methanol. This review paper discusses commonly used Cu-based catalysts including their kinetic, compositional, and morphological characteristics in methanol reforming reactions. Although research exploring surface reaction mechanism over various Cu-based catalysts was first attempted about three decades ago, the scheme remains controversial. This technical discussion will focus on the commonly reported surface intermediate species, which are methoxy, formaldehyde, dioxymethylene, formate and methyl formate. The surface reaction mechanism could be complicated by the introduction of reactants such as oxygen and steam, into the system as they would subsequently initiate secondary reactions. Different reaction schemes of methanol reforming are presented.
•All four systems of methanol reforming to produce hydrogen were considered.•Cu-based catalysts, Cu sintering and modifications were discussed.•Surface reaction mechanisms involving common intermediate species were outlined.•Reaction schemes were complicated by secondary reactions.
The vital role that nitrogenase plays in sustaining life is examined from a biomolecular perspective. Nitrogen fixation is shown to occur in lightning and the Haber-Bosch process.
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