Kirkegaardabildgaard0397

Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R (P = 0.047; P = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (P = 0.047; P = 0.0002). pT1b microstaging was associated with a genomic cluster (P = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. SIGNIFICANCE Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.Obesity enhances breast cancer risk in postmenopausal women and premenopausal women with genetic or familial risk factors. We have shown previously that within breast tissue, obesity increases macrophage-driven inflammation and promotes expansion of luminal epithelial cell populations that are hypothesized to be the cells of origin for the most common subtypes of breast cancer. However, it is not clear how these changes within the microenvironment of the breast alter cancer risk and tumor growth. Using a high-fat diet to induce obesity, we examined preneoplastic changes associated with epithelial cell-specific loss of Trp53. Obesity significantly enhanced the incidence of tumors of diverse histotypes and increased stromal cells within the tumor microenvironment. Obesity also promoted the growth of preneoplastic lesions containing elevated numbers of luminal epithelial progenitor cells, which were surrounded by macrophages. To understand how macrophage-driven inflammation due to obesity enhances tumor formation, mice were treated with IgG or anti-F4/80 antibodies to deplete macrophages during preneoplastic growth. Unexpectedly, depletion of macrophages in obese mice enhanced mammary epithelial cell stem/progenitor activity, elevated expression of estrogen receptor alpha, and increased DNA damage in cells. Together, these results suggest that in obesity, macrophages reduce epithelial cells with DNA damage, which may limit the progression of preneoplastic breast lesions, and uncovers complex macrophage function within the evolving tumor microenvironment. Understanding how obesity alters the function of macrophages during tumor formation may lead to chemoprevention options for at-risk obese women. SIGNIFICANCE Understanding how obesity impacts early tumor growth and response to macrophage-targeted therapies may improve therapeutics for obese patients with breast cancer and identify patient populations that would benefit from macrophage-targeted therapies.Cardiac damage from chemotherapy is a known phenomenon leading to significant morbidity and mortality in the cancer surviving population, and identifying high-risk pediatric patients early is challenging. The purpose of this pilot study was to evaluate whether echo strain, cardiac MRI (CMR), and serum biomarkers are more sensitive methods for detecting cardiac toxicity than standard echo and to examine the relationship between biomarkers in patients without decreased systolic function as determined by standard echo. In this pilot study, we prospectively enrolled pediatric subjects after completion of anthracycline inclusive chemotherapy. Each subject underwent a post-treatment echocardiogram (standard with strain), serum biomarkers (N-terminal brain natriuretic peptide (NT-pro-BNP) and interleukin 1 receptor-like 1 protein (ST2)), and CMR (standard and extracellular volumes (ECVs)). We correlated the markers using Pearson correlation. We enrolled 30 subjects, 11F/19M, aged 8-21 years. selleck products Cumulative anthracycline dose (CAD) correlated with BNP (p=0.06), CMR ECV 4-chamber (p=0.05) and sagittal (p=0.01), and mitral valve E/A (p=0.02). BNP correlated with CMR ECV 4-chamber (p=0.001) and sagittal (p=0.001) and with echo average longitudinal strain (ALS) (p=0.05). This study demonstrated a significant correlation of CAD with BNP and CMR ECV. There was also a significant correlation of NT-pro-BNP with CMR ECV and ALS. Combining these parameters with standard echo has the potential to identify high-risk patients early. Further studies are needed for long-term follow-up and management in this vulnerable population.

To determine the time to positivity for bacterial pathogens and contaminants in blood and cerebrospinal fluid (CSF) cultures in a cohort of febrile infants ≤60 days of age.

This was a secondary analysis of prospective observational multicenter study of noncritically ill infants ≤60 days of age with temperatures ≥38°C and blood cultures (December 2008 to May 2013). The main outcome was time to positivity for bacterial pathogens and contaminants.

A total of 256 of 303 (84.49%) patients with positive blood cultures, and 73 of 88 (82.95%) with positive CSF cultures met inclusion criteria. Median time (interquartile range [IQR]) to positivity for blood cultures was 16.6 hours (IQR 12.6-21.9) for bacterial pathogens (

= 74) and 25.1 hours (IQR 19.8-33.0) for contaminants (

= 182);

< .001. Time to bacterial pathogen positivity was similar in infants 0 to 28 days of age (15.8 hours [IQR 12.6-21.0]) and 29 to 60 days of age (17.2 [IQR 12.9-24.3];

= .328). Median time to positivity for CSF was 14.0 hours (IQR 1.5-21.0) for bacterial pathogens (

= 22) and 40.5 hours (IQR 21.2-62.6) for contaminants (

= 51);

< .001. A total of 82.4% (95% confidence interval, 71.8-90.3) and 81.8% (95% confidence interval, 59.7%-94.8%) of blood and CSF cultures showed bacterial pathogen positivity within 24 hours.

Among febrile infants ≤60 days of age, time to blood and CSF positivity was significantly shorter for bacterial pathogens than contaminants. Most blood and CSF cultures for bacterial pathogens were positive within 24 hours. With our findings, there is potential to reduce duration of hospitalization and avoid unnecessary antibiotics.

Among febrile infants ≤60 days of age, time to blood and CSF positivity was significantly shorter for bacterial pathogens than contaminants. Most blood and CSF cultures for bacterial pathogens were positive within 24 hours. With our findings, there is potential to reduce duration of hospitalization and avoid unnecessary antibiotics.Studies in the yeast Saccharomyces cerevisiae have helped define mechanisms underlying the activity of the ubiquitin-proteasome system (UPS), uncover the proteasome assembly pathway, and link the UPS to the maintenance of cellular homeostasis. However, the spectrum of UPS substrates is incompletely defined, even though multiple techniques-including MS-have been used. Therefore, we developed a substrate trapping proteomics workflow to identify previously unknown UPS substrates. We first generated a yeast strain with an epitope tagged proteasome subunit to which a proteasome inhibitor could be applied. Parallel experiments utilized inhibitor insensitive strains or strains lacking the tagged subunit. After affinity isolation, enriched proteins were resolved, in-gel digested, and analyzed by high resolution liquid chromatography-tandem MS. A total of 149 proteasome partners were identified, including all 33 proteasome subunits. When we next compared data between inhibitor sensitive and resistant cells, 27 proteases via manipulations of our engineered strain.Stroke remains a leading cause of death and disability worldwide. Despite continuous advances, the identification of key molecular signatures in the hyper-acute phase of ischemic stroke is still a primary interest for translational research on stroke diagnosis, prognosis, and treatment. Data integration from high-throughput -omics techniques has become crucial to unraveling key interactions among different molecular elements in complex biological contexts, such as ischemic stroke. Thus, we used advanced data integration methods for a multi-level joint analysis of transcriptomics and proteomics data sets obtained from mouse brains at 2 h after cerebral ischemia. By modeling net-like correlation structures, we identified an integrated network of genes and proteins that are differentially expressed at a very early stage after stroke. We validated 10 of these deregulated elements in acute stroke, and changes in their expression pattern over time after cerebral ischemia were described. Of these, CLDN20, GADD45G, RGS2, BAG5, and CTNND2 were next evaluated as blood biomarkers of cerebral ischemia in mice and human blood samples, which were obtained from stroke patients and patients presenting stroke-mimicking conditions. Our findings indicate that CTNND2 levels in blood might potentially be useful for distinguishing ischemic strokes from stroke-mimicking conditions in the hyper-acute phase of the disease. Furthermore, circulating GADD45G content within the first 6 h after stroke could also play a key role in predicting poor outcomes in stroke patients. For the first time, we have used an integrative biostatistical approach to elucidate key molecules in the initial stages of stroke pathophysiology and highlight new notable molecules that might be further considered as blood biomarkers of ischemic stroke.

To assess the impact of describing an antibody-positive test result using the terms Immunity and Passport or Certificate, alone or in combination, on perceived risk of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and protective behaviours.

2×3 experimental design.

Online.

1204 adults from a UK research panel.

Participants were randomised to receive one of six descriptions of an antibody test and results showing SARS-CoV-2 antibodies, differing in the terms describing the type of test (Immunity vs Antibody) and the test result (Passport vs Certificate vs Test).

Primary outcome proportion of participants perceiving no risk of infection with SARS-CoV-2 given an antibody-positive test result. Other outcomes include intended changes to frequency of hand washing and physical distancing.

When using the term Immunity (vs Antibody), 19.1% of participants (95% CI 16.1% to 22.5%) (vs 9.8% (95% CI 7.5% to 12.4%)) perceived no risk of catching coronavirus given an antibody-positive test result (adjusted OR (AOR) 2.91 (95% CI 1.52 to 5.55)). Using the terms Passport or Certificate-as opposed to Test-had no significant effect (AOR 1.24 (95% CI 0.62 to 2.48) and AOR 0.96 (95% CI 0.47 to 1.99) respectively). There was no significant interaction between the effects of the test and result terminology. Across groups, perceiving no risk of infection was associated with an intention to wash hands less frequently (AOR 2.32 (95% CI 1.25 to 4.28)); there was no significant association with intended avoidance of physical contact (AOR 1.37 (95% CI 0.93 to 2.03)).

Using the term Immunity (vs Antibody) to describe antibody tests for SARS-CoV-2 increases the proportion of people believing that an antibody-positive result means they have no risk of catching coronavirus in the future, a perception that may be associated with less frequent hand washing.

Open Science Framework https//osf.io/tjwz8/files/.

Open Science Framework https//osf.io/tjwz8/files/.