Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to ...provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Postbloom fruit drop disease (PFD) has caused serious impacts on citrus production in the Americas, occurring sporadically and suddenly during rain in the flowering period. In São Paulo State, ...Brazil, Colletotrichum abscissum is the causal agent responsible for over 80% of the disease incidence. Pathogen dispersal over long distances and the origin of primary inoculum are still unclear for PFD epidemics. We tested the hypothesis that citrus propagation material can harbour C. abscissum DNA by quantifying it in leaves of budwood increase block trees (BIB) and young citrus plants (YP) using multiplex quantitative PCR (qPCR). C. abscissum DNA was detected in all citrus nurseries, regardless of the type of propagative material, the sweet orange variety, or the nursery location. Overall, 73.4% of all samples from citrus nurseries have DNA from the pathogen, with a detection limit of 10 conidia. The average of 155 conidia found in YP was higher than the conidia observed on leaf samples from BIB (p = 0.03), although leaf samples from cultivars Valencia and Pera did not differ significantly, with means around 127 and 118 conidia, respectively (p = 0.75). This is the first molecular detection of C. abscissum in citrus propagative material. The multiplex qPCR assay may be used as a protocol for an accurate diagnosis of C. abscissum in citrus propagative material, may assist a better understanding of the pathogen dispersal over long distances, and may be used for further studies involving the quantification of C. abscissum in citrus orchards.
Colletotrichum abscissum, causal agent of citrus postbloom fruit drop, was detected by quantitative PCR (qPCR) in all tested nurseries, regardless of the type of propagative material, the sweet orange variety and the nursery location
Cellular senescence is a tumor suppressive mechanism that can paradoxically contribute to aging pathologies. Despite evidence of immune clearance in mouse models, it is not known how senescent cells ...(SnCs) persist and accumulate with age or in tumors in individuals. Here, we identify cooperative mechanisms that orchestrate the immunoevasion and persistence of normal and cancer human SnCs through extracellular targeting of natural killer receptor signaling. Damaged SnCs avoid immune recognition through MMPs-dependent shedding of NKG2D-ligands reinforced via paracrine suppression of NKG2D receptor-mediated immunosurveillance. These coordinated immunoediting processes are evident in residual, drug-resistant tumors from cohorts of >700 prostate and breast cancer patients treated with senescence-inducing genotoxic chemotherapies. Unlike in mice, these reversible senescence-subversion mechanisms are independent of p53/p16 and exacerbated in oncogenic RAS-induced senescence. Critically, the p16INK4A tumor suppressor can disengage the senescence growth arrest from the damage-associated immune senescence program, which is manifest in benign nevi lesions where indolent SnCs accumulate over time and preserve a non-pro-inflammatory tissue microenvironment maintaining NKG2D-mediated immunosurveillance. Our study shows how subpopulations of SnCs elude immunosurveillance, and reveals secretome-targeted therapeutic strategies to selectively eliminate -and restore the clearance of- the detrimental SnCs that actively persist after chemotherapy and accumulate at sites of aging pathologies.
Criegee Intermediates (CI), formed in the ozonolysis of alkenes, play a central role in tropospheric chemistry as an important source of radicals, with stabilised CI (SCI) able to participate in ...bimolecular reactions, affecting climate through the formation of inorganic and organic aerosol. However, total SCI yields have only been determined for a few alkene systems, while speciated SCI yields from asymmetrical alkenes are almost entirely unknown. Here we report for the first time a systematic experimental exploration of the stabilisation of CH
2
OO and (CH
3
)
2
COO CI, formed from ten alkene-ozone systems with a range of different sizes and structures, under atmospherically relevant conditions in the EUPHORE chamber. Experiments in the presence of excess SO
2
(an SCI scavenger) determined total SCI yields from each alkene-ozone system. Comparison of primary carbonyl yields in the presence/absence of SO
2
determined the stabilisation fraction of a given CI. The results show that the stabilisation of a given CI increases as the size of the carbonyl co-product increases. This is interpreted in terms of the nascent population of CI formed following decomposition of the primary ozonide (POZ) having a lower mean energy distribution when formed with a larger carbonyl co-product, as more of the energy from the POZ is taken by the carbonyl. These findings have significant implications for atmospheric modelling of alkene ozonolysis. Higher stabilisation of small CI formed from large alkenes is expected to lead to lower radical yields from CI decomposition, and higher SCI concentrations, increasing the importance of SCI bimolecular reactions.
Stabilisation of CI produced in alkene ozonolysis increases with co-product size, due to lower energy of the nascent CI population.
Ascariosis is a parasitic disease caused by Ascaris lumbricoides, a large geohelmint endemic in our country. At present, ascariosis is a rare infection in Chile. We present a case of an adult, ...resident of the Villa Alemana municipality, Valparaiso Region, who spontaneously expelled two juvenile nematodes by mouth. We review the manifestations produced by the larval and adult stages of this parasite including their diagnosis, treatment, and epidemiological considerations.
Isosporosis is an infection caused by parasitic protozoa of the genus Isospora, coccidia affecting various different vertebrate species, including humans. It is an uncommon infection in our country ...and it is not a zoonosis. We present two cases of Isospora belli infection in HIV positive patients from the Valparaiso region. We discuss the clinical events caused by this agent, its epidemiology, cases published in the local and foreign literature, as well as its treatment and prevention measures.
Genetical characterization of human Cryptosporidium isolates to determine species diversity.
A cross-sectional study in Valparaiso, Chile, was performed. A total of 458 patients participated in the ...study: 259 immunodeficient (HIV, cancer, renal transplant hyper-IgM syndrome, HIV and unintended pregnancy) and 178 immunocompetent individuals provided stool samples and 21 patients bile samples.
We obtained 29 (6.3%) positive samples. 25 (9.7%) derived from immunodeficient patients: 18 (7.3%) from HIV patients and 7 from patients with other immunodeficiencies. The remaining 4 (2.2%) samples originated from immunocompetent individuals. Cryptosporidium genotyping was performed by nested polymerase chain reaction (PCR) and restriction fragments length polymorphism and/or PCR followed by sequencing of the SSU rRNA from oocysts in stool samples. 4 species were identified: C. parvum, C. hominis, C. muris, and C. meleagridis. In immunodeficient patients, 16 C. parvum, 8 C. hominis, and 1 C. muris strain were identified. In immunocompetent participants, 3 C. hominis and 1 C. meleagridis isolate were found.
The results indicate that zoonotic and anthroponotic transmission occurs and that C. parvum is the predominant species in our study population. Cryptosporidium species of zoonotic transmission accounted for 62% of the human infections detected in this study.
Cryptosporidium sp oocysts were detected in snails (Helix aspersa Miller) and slug (Deroceras reticulatum Miller) from the Valparaiso Region, Chile. Snails and slug were collected from public squares ...and private domestic gardens. Cryptosporidium sp oocysts were recovered from faeces of both species. Ziehl Neelsen stain, nested PCR, and sequencing analysis demonstrated a profile similar to that described for genotype C or 2 of the parasite. These results demonstrate that snails and slug could act as a reservoir and mechanic vector of C. parvum infection for humans and animals. Moreover, gastropods could serve as bioindicators of fecal soil contamination.
Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular ...carcinoma in whom previous sorafenib therapy had failed.
We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m
doxorubicin-loaded nanoparticles (30 mg/m
group), 20 mg/m
doxorubicin-loaded nanoparticles (20 mg/m
group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693.
Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m
group; 130 to the 20 mg/m
group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 95% CI 0·78-1·28, two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 10% of 242 treated with doxorubicin-loaded nanoparticles and eight 6% of 134 in the control group), asthenia (six 2% and four 3%), and thrombocytopenia (three 1% and ten 7%). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group.
Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed.
Onxeo.
Dipylidiasis is a zoonotic parasitic infection caused by the dog tapeworm Dipylidium caninum; it affects both feline and canine species and accidentally, humans. In Chile, as well as in other ...countries, it is an uncommon infection. A case of a 2 year old child from Casablanca, (a city located in the Valparaíso Region), with an infection by D. caninum, is presented. Clinical manifestations are reviewed, as well as epidemiology in domestic and wild animals, cases among the published national literature and its treatment and prevention strategies.
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