BackgroundClinical studies have linked usage of progestins (synthetic progesterone P4) to breast cancer risk. However, little is understood regarding the role of native P4, signaling through the ...progesterone receptor (PR), in breast tumor formation. Recently, we reported a link between PR and immune signaling pathways, showing that P4/PR can repress type I interferon signaling pathways. Given these findings, we sought to investigate whether P4/PR drive immunomodulation in the mammary gland and promote tumor formation.MethodsTo determine the effect of P4 on immune cell populations in the murine mammary gland, mice were treated with P4 or placebo pellets for 21 days. Immune cell populations in the mammary gland, spleen, and inguinal lymph nodes were subsequently analyzed by flow cytometry. To assess the effect of PR overexpression on mammary gland tumor development as well as immune cell populations in the mammary gland, a transgenic mouse model was used in which PR was overexpressed throughout the entire mouse. Immune cell populations were assessed in the mammary glands, spleens, and inguinal lymph nodes of 6-month-old transgenic and control mice by flow cytometry. Transgenic mice were also monitored for mammary gland tumor development over a 2-year time span. Following development of mammary gland tumors, immune cell populations in the tumors and spleens of transgenic and control mice were analyzed by flow cytometry.ResultsWe found that mice treated with P4 exhibited changes in the mammary gland indicative of an inhibited immune response compared with placebo-treated mice. Furthermore, transgenic mice with PR overexpression demonstrated decreased numbers of immune cell populations in their mammary glands, lymph nodes, and spleens. On long-term monitoring, we determined that multiparous PR-overexpressing mice developed significantly more mammary gland tumors than control mice. Additionally, tumors from PR-overexpressing mice contained fewer infiltrating immune cells. Finally, RNA sequencing analysis of tumor samples revealed that immune-related gene signatures were lower in tumors from PR-overexpressing mice as compared with control mice.ConclusionTogether, these findings offer a novel mechanism of P4-driven mammary gland tumor development and provide rationale in investigating the usage of antiprogestin therapies to promote immune-mediated elimination of mammary gland tumors.
Babesiosis is increasing in the elderly due to an age‐related decline in immunity. Prompt diagnosis with blood smear and PCR prevent life‐threatening complications, like DIC and HLH. Studies focusing ...on pathophysiology and risk factors are needed.
Babesiosis is increasing in the elderly due to an age‐related decline in immunity. Prompt diagnosis with blood smear and PCR prevent life‐threatening complications, like DIC and HLH. Studies focusing on pathophysiology and risk factors are needed.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Voter turnout rates among survey respondents tend to exceed actual turnout by a significant margin. This note reports the results of an experiment whereby the indicated topic of a political survey ...was varied at the recruitment stage, with the goal of producing a sample with reported turnout rates that more closely mirror reality. Three experimental groups were informed that the survey was about politics, while a fourth received no indication of the nature of the study. Data from nearly 5000 respondents in Ontario, Canada suggest that this manipulation had no appreciable effect upon survey completion rates, but the level of reported turnout is lower when no topic is indicated. We theorize that this manipulation affects self-selection into (out of) surveys by voters (non-voters). By not disclosing the political nature of a survey, samples can be made to more closely reflect populations they are meant to represent in this important dimension.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
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Radiofrequency ablation devices Navaneethan, Udayakumar, MD; Thosani, Nirav, MD; Goodman, Adam, MD, FASGE ...
VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy,
10/2017, Volume:
2, Issue:
10
Journal Article
Peer reviewed
Open access
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Due to maize’s wind-driven pollination, non-target pollen contamination is problematic for producers and breeders. Maize gametophyte factors, specifically gametophyte factor 1 (ga1), have long been ...used to produce selectively pollinating phenotypes. The use of these factors is a cornerstone of commercial popcorn production, and they are used for a large range of other purposes, including preventing contamination by genetically modified pollen in organic production. However this system is at great risk from another allele at the ga1 locus, Ga1-m, which overcomes the selectively pollinating phenotypes. To further complicate this problem, the risk posed by this allele has been under-assessed. Here we reinterpret the key study on Ga1-s and report genetic resistance to the Ga1-m allele in maize lines that carry dominant gametophyte factors. We identified genetic resistance to the allele segregating in lines derived from four landraces, showed the resistance is heritable, and that it acts in full-strength and attenuated versions. Additionally, we have suggested the validity of evolutionary-based inquiry into our plant genetic resources, and provided some validation of this effort. Our results provide the first report of effective genetic resistance to pollination by the Ga1-m allele, providing an option to continue the use of genetic barriers to non-target pollination. A source of resistance to the Ga1-m allele allows research to be conducted about the allele itself, allowing for research into the possible existence of multiple versions of the allele and their distributions. We anticipate our research will be a starting point for identification of additional sources of resistance to the Ga1-m allele, specifically in popcorn production, where it is most immediately needed to prevent pollen contamination, as well as the eventual localization and mapping of the resistance alleles. We also believe the suggestion of evolutionary-based inquiry into plant genetic resources will provide a highly effective method for identification of specific traits, but will need more extensive validation.
Background The relationship between health care utilization and outcomes in patients with atrial fibrillation is unknown. The objective of this study was to investigate whether cardiologists' billing ...amounts in a fee-for-service environment are associated with better patient-level clinical outcomes. Methods and Results A retrospective cohort study was conducted using administrative claims data of cardiologists in Ontario, Canada between April 1, 2011 and March 31, 2016. The cardiologists were stratified into quintiles based on their median billing patterns per patient over the observation period. The primary outcomes were patient-level receipt of repeat visits, cardiac diagnostic tests, and medications ≤1 year of index date. The secondary clinical outcomes were death, emergency department visits, and all-cause hospitalization 1-year post-index visit. The patient cohort comprised 182 572 patients with atrial fibrillation (median age 74 years, 58% male) from 467 cardiologists. Patients with atrial fibrillation seen by higher-billing cardiologists were 26% more likely to have an echocardiogram (adjusted odds ratio aOR, 1.26 95% CI, 1.10-1.43 for quintile 5 versus 2), 28% a stress test (aOR, 1.28 1.12-1.46 for quintile 5 versus 2), 25% continuous electrocardiographic monitoring (aOR, 1.25 1.08-1.46 for quintile 4 versus 2), and 79% more likely to get a stress echocardiogram (aOR, 1.79 1.32-2.42 for quintile 5 versus 2). They also had a higher rate of all-cause hospitalization (aOR, 1.13 1.07-1.20). Mortality rates were similar across cardiologists billing quintiles (eg, aOR, 0.98 0.87-1.11 for quintile 4 versus 2). Conclusions Higher-billing cardiologists ordered more diagnostic tests per patient with atrial fibrillation but these are not associated with improvements in outcomes.
Abstract Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ...ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. Therefore we hypothesized that ENTPD-1 over expression affords myocardial protection from ischemia–reperfusion injury via specific cell signaling pathways. ENTPD-1 transgenic mice, which over express human ENTPDase-1, and wild-type (WT) littermates were subjected to either ex vivo or in vivo ischemia–reperfusion injury. Infarct size, inflammatory cell infiltrate and intracellular signaling molecule activation were evaluated. Infarct size was significantly reduced in ENTPD-1 versus WT hearts in both ex vivo and in vivo studies. Following ischemia–reperfusion injury, ENTPD-1 cardiac tissues demonstrated an increase in the phosphorylation of the cellular signaling molecule extracellular signal-regulated kinases 1/2 (ERK 1/2) and glycogen synthase kinase-3β (GSK-3β). Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A2B adenosine receptor antagonist, MRS 1754, but not the A1 selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A2B receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
ABSTRACT
Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can cure patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, many ...patients relapse or develop debilitating graft-versus-host disease. Transplant restores T-cell reactivity against tumor cells, implicating patient human leukocyte antigen (HLA)-dependent antigen presentation via the major histocompatibility complex as a determinant of response. We sought to identify characteristics of the HLA genotype that influence response in allo-HSCT patients.
Methods
We collected HLA genotype and panel-based somatic mutation profiles for 55 patients with AML and MDS and available data treated at the University of California San Diego Moores Cancer Center between May 2012 and January 2019. We evaluated characteristics of the HLA genotype relative to relapse-free time and overall survival (OS) post-allo-HSCT using univariable and multivariable regression.
Results
In multivariable regression, the presence of an autoimmune allele was significantly associated with relapse-free time (hazard ratio HR, 0.25; p = 0.01) and OS (HR, 0.16; p < 0.005). The better potential of the donor HLA type to present peptides harboring driver mutations trended toward better relapse-free survival (HR, 0.45; p = 0.07) and significantly correlated with longer OS (HR, 0.33; p = 0.01) though only a minority of cases had an HLA mismatch.
Conclusion
In this single institution retrospective study of patients receiving allo-HSCT for relapsed AML/MDS, characteristics of an individual's HLA genotype (presence of an autoimmune allele and potential of the donor HLA to better present peptides representing driver mutations) were significantly associated with better outcomes. These findings suggest that HLA type may guide the optimal application of allo-HSCT and merit evaluation in larger cohorts. ClinicalTrials.gov Identifier: NCT02478931
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