925 research outputs found
Focused Ion Microbeam Irradiation Induces Clustering of DNA Double-Strand Breaks in Heterochromatin Visualized by Nanoscale-Resolution Electron Microscopy
Background: Charged-particle radiotherapy is an emerging treatment modality for radioresistant tumors. The enhanced effectiveness of high-energy particles (such as heavy ions) has been
related to the spatial clustering of DNA lesions due to highly localized energy deposition. Here, DNA
damage patterns induced by single and multiple carbon ions were analyzed in the nuclear chromatin
environment by different high-resolution microscopy approaches. Material and Methods: Using the
heavy-ion microbeam SNAKE, fibroblast monolayers were irradiated with defined numbers of carbon
ions (1/10/100 ions per pulse, ipp) focused to micrometer-sized stripes or spots. Radiation-induced
lesions were visualized as DNA damage foci (γH2AX, 53BP1) by conventional fluorescence and stimulated emission depletion (STED) microscopy. At micro- and nanoscale level, DNA double-strand
breaks (DSBs) were visualized within their chromatin context by labeling the Ku heterodimer. Single
and clustered pKu70-labeled DSBs were quantified in euchromatic and heterochromatic regions at
0.1 h, 5 h and 24 h post-IR by transmission electron microscopy (TEM). Results: Increasing numbers
of carbon ions per beam spot enhanced spatial clustering of DNA lesions and increased damage
complexity with two or more DSBs in close proximity. This effect was detectable in euchromatin, but
was much more pronounced in heterochromatin. Analyzing the dynamics of damage processing, our
findings indicate that euchromatic DSBs were processed efficiently and repaired in a timely manner.
In heterochromatin, by contrast, the number of clustered DSBs continuously increased further over
the first hours following IR exposure, indicating the challenging task for the cell to process highly
clustered DSBs appropriately. Conclusion: Increasing numbers of carbon ions applied to sub-nuclear
chromatin regions enhanced the spatial clustering of DSBs and increased damage complexity, this
being more pronounced in heterochromatic regions. Inefficient processing of clustered DSBs may
explain the enhanced therapeutic efficacy of particle-based radiotherapy in cancer treatment
Estimation versus measurement of the glomerular filtration rate for kidney function assessment in patients with cancer undergoing cisplatin-based chemotherapy
Children diagnosed with presymptomatic type 1 diabetes through public health screening have milder diabetes at clinical manifestation
Distinct chemokine receptor expression profiles in de novo DLBCL, transformed follicular lymphoma, Richter’s trans-formed DLBCL and germinal center B-cells
The role of the tissue microenvironment in the regulation of cancer cell motility and invasion
During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion
Impact of sex and gender on post-COVID-19 syndrome, Switzerland, 2020
Background: Women are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender) differences between women and men might account for this imbalance, yet their impact on PASC is unknown. Aim: We assessed the impact of sex and gender on PASC in a Swiss population. Method: Our multicentre prospective cohort study included 2,856 (46% women, mean age 44.2 ± 16.8 years) outpatients and hospitalised patients with PCR-confirmed SARS-CoV-2 infection.ResultsAmong those who remained outpatients during their first infection, women reported persisting symptoms more often than men (40.5% vs 25.5% of men; p < 0.001). This sex difference was absent in hospitalised patients. In a crude analysis, both female biological sex (RR = 1.59; 95% CI: 1.41-1.79; p < 0.001) and a score summarising gendered sociocultural variables (RR = 1.05; 95% CI: 1.03-1.07; p < 0.001) were significantly associated with PASC. Following multivariable adjustment, biological female sex (RR = 0.96; 95% CI: 0.74-1.25; p = 0.763) was outperformed by feminine gender-related factors such as a higher stress level (RR = 1.04; 95% CI: 1.01-1.06; p = 0.003), lower education (RR = 1.16; 95% CI: 1.03-1.30; p = 0.011), being female and living alone (RR = 1.91; 95% CI: 1.29-2.83; p = 0.001) or being male and earning the highest income in the household (RR = 0.76; 95% CI: 0.60-0.97; p = 0.030). Conclusion: Specific sociocultural parameters that differ in prevalence between women and men, or imply a unique risk for women, are predictors of PASC and may explain, at least in part, the higher incidence of PASC in women. Once patients are hospitalised during acute infection, sex differences in PASC are no longer evident
Human Papillomavirus-16 E7 Interacts with Glutathione S-Transferase P1 and Enhances Its Role in Cell Survival
Background:Human Papillomavirus (HPV)-16 is a paradigm for "high-risk" HPVs, the causative agents of virtually all cervical carcinomas. HPV E6 and E7 viral genes are usually expressed in these tumors, suggesting key roles for their gene products, the E6 and E7 oncoproteins, in inducing malignant transformation.Methodology/Principal Findings:By protein-protein interaction analysis, using mass spectrometry, we identified glutathione S-transferase P1-1 (GSTP1) as a novel cellular partner of the HPV-16 E7 oncoprotein. Following mapping of the region in the HPV-16 E7 sequence that is involved in the interaction, we generated a three-dimensional molecular model of the complex between HPV-16 E7 and GSTP1, and used this to engineer a mutant molecule of HPV-16 E7 with strongly reduced affinity for GSTP1.When expressed in HaCaT human keratinocytes, HPV-16 E7 modified the equilibrium between the oxidized and reduced forms of GSTP1, thereby inhibiting JNK phosphorylation and its ability to induce apoptosis. Using GSTP1-deficient MCF-7 cancer cells and siRNA interference targeting GSTP1 in HaCaT keratinocytes expressing either wild-type or mutant HPV-16 E7, we uncovered a pivotal role for GSTP1 in the pro-survival program elicited by its binding with HPV-16 E7.Conclusions/Significance:This study provides further evidence of the transforming abilities of this oncoprotein, setting the groundwork for devising unique molecular tools that can both interfere with the interaction between HPV-16 E7 and GSTP1 and minimize the survival of HPV-16 E7-expressing cancer cells. © 2009 Mileo et al
Identification of heavy-flavour jets with the CMS detector in pp collisions at 13 TeV
Many measurements and searches for physics beyond the standard model at the LHC rely on the efficient identification of heavy-flavour jets, i.e. jets originating from bottom or charm quarks. In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented. Heavy-flavour jet identification algorithms have been improved compared to those used previously at centre-of-mass energies of 7 and 8 TeV. For jets with transverse momenta in the range expected in simulated events, these new developments result in an efficiency of 68% for the correct identification of a b jet for a probability of 1% of misidentifying a light-flavour jet. The improvement in relative efficiency at this misidentification probability is about 15%, compared to previous CMS algorithms. In addition, for the first time algorithms have been developed to identify jets containing two b hadrons in Lorentz-boosted event topologies, as well as to tag c jets. The large data sample recorded in 2016 at a centre-of-mass energy of 13 TeV has also allowed the development of new methods to measure the efficiency and misidentification probability of heavy-flavour jet identification algorithms. The heavy-flavour jet identification efficiency is measured with a precision of a few per cent at moderate jet transverse momenta (between 30 and 300 GeV) and about 5% at the highest jet transverse momenta (between 500 and 1000 GeV)
Search for heavy resonances decaying to a top quark and a bottom quark in the lepton+jets final state in proton–proton collisions at 13 TeV
info:eu-repo/semantics/publishe
Evidence for the Higgs boson decay to a bottom quark–antiquark pair
info:eu-repo/semantics/publishe
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