Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Evaluation of a multi-scale enhancement protocol for digital mammography

We have carried out a receiver operating characteristics (ROC) study for the enhancement of mammographic features in digitized mammograms. The study evaluated the benefits of multi-scale enhancement methods in terms of diagnostic performance of radiologists. The enhancement protocol relied on multi-scale expansions and non-linear enhancement functions. Dyadic spline wavelet functions were used together with a sigmoidal non-linear enhancement function. We designed a computer interface ona softcopy display and performed an ROC study with three radiologists, who specialized in mammography. Clinical cases were obtained from a national mammography database of digitized radiographs prepared by the University of South Florida and Harvard Medical School. Our study focused on dense mammograms, i.e. mammograms of density 3 and 4 on the American College of Radiology breast density rating, which are the most difficult cases in screening, were selected. To compare the performance of radiologists with an without using multi-scale enhancement, two groups of 30 cases each were diagnosed. Each group contained 15 cases of cancerous and 15 cases of normal mammograms. Conventional ROC analysis was applied, and the resulting ROC curves indicated improved diagnostic performance when radiologists used multi-scale non-linear enhancement

Women in accounting in Great Britain and in the United States -- Some historical parallels

The public accounting profession in the United States has its roots in Great Britain. Chartered accountants from England and Scotland came to this country to account for the capital coming into the States from the Old World [Stevens, 1981, p. 3]. Hence, a history of women in accounting in the United States would be expected to have many parallels with a history of women in accounting in Great Britain

Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Genes Suggest Ancestral Colour Polymorphisms Are Shared across Morphologically Cryptic Species in Arctic Bumblebees

email Suzanne orcd idCopyright: © 2015 Williams et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Mnt modulates Myc-driven lymphomagenesis

The transcriptional represser Mnt is a functional antagonist of the proto-oncoprotein Myc. Both Mnt and Myc utilise Max as an obligate partner for DNA binding, and Myc/Max and Mnt/Max complexes compete for occupancy at E-box DNA sequences in promoter regions. We have previously shown in transgenic mouse models that the phenotype and kinetics of onset of haemopoietic tumours varies with the level of Myc expression. We reasoned that a decrease in the level of Mnt would increase the functional level of Myc and accelerate Myc-driven tumorigenesis. We tested the impact of reduced Mnt in three models of myc transgenic mice and in p53+/− mice. To our surprise, mnt heterozygosity actually slowed Myc-driven tumorigenesis in vavP-MYC10 and Eμ-myc mice, suggesting that Mnt facilitates Myc-driven oncogenesis. To explore the underlying cause of the delay in tumour development, we enumerated Myc-driven cell populations in healthy young vavP-MYC10 and Eμ-myc mice, expecting that the reduced rate of leukaemogenesis in mnt heterozygous mice would be reflected in a reduced number of preleukaemic cells, due to increased apoptosis or reduced proliferation or both. However, no differences were apparent. Furthermore, when mnt+/+ and mnt+/− pre-B cells from healthy young Eμ-myc mice were compared in vitro, no differences were seen in their sensitivity to apoptosis or in cell size or cell cycling. Moreover, the frequencies of apoptotic, senescent and proliferating cells were comparable in vivo in mnt+/− and mnt+/+ Eμ-myc lymphomas. Thus, although mnt heterozygosity clearly slowed lymphomagenesis in vavP-MYC10 and Eμ-myc mice, the change(s) in cellular properties responsible for this effect remain to be identified

Multidimensional kinships : Black and Indigenous environmental thought

Multidimensional Kinships examines work by six Black and Indigenous women authors (Sarah Winnemucca, Hannah Crafts, Natasha Trethewey, Linda Hogan, Tiana Clark, and Lehua Taitano), paying particular attention to how the authors theorize interpersonal and environmental relationships. Multidimensional Kinships builds on the foundational understanding that Black and Indigenous kinships have long been a threat to the state and thus targeted for extermination and yet these women continue building kinships with one another and the land despite state interventions and violences. This project redefines the environment as relationship, as demonstrated through the chosen texts. These works’ Indigenous and Black women writers theorize the environment as a kinship formation, that is, a type of relationality encompassing environmental, economic, familial, and spiritual modes of Black and Indigenous ways of knowing and being. Further, these writers establish environmental relationalities by exploring how being in and of a place or separated from it affect family structures, land ownership and tenure, spiritual relationships and many other aspects of Black and Indigenous women’s lives. This project illustrates how Black and Native women’s texts use kinship-building in multidimensional ways, such as (re)mapping space and engaging in actions unseen by the colonial gaze, to work toward goals of Black liberation and Indigenous resurgence

MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature

Sensitivity to temozolomide is restricted to a subset of glioblastoma patients, with the major determinant of resistance being a lack of promoter methylation of the gene encoding the repair protein DNA methyltransferase MGMT, although other mechanisms are thought to be active. There are, however, limited preclinical data in model systems derived from pediatric glioma patients. We screened a series of cell lines for temozolomide efficacy in vitro, and investigated the differential mechanisms of resistance involved. In the majority of cell lines, a lack of MGMT promoter methylation and subsequent protein overexpression were linked to temozolomide resistance. An exception was the pediatric glioblastoma line KNS42. Expression profiling data revealed a coordinated upregulation of HOX gene expression in resistant lines, especially KNS42, which was reversed by phosphoinositide 3-kinase pathway inhibition. High levels of HOXA9/HOXA10 gene expression were associated with a shorter survival in pediatric high-grade glioma patient samples. Combination treatment in vitro of pathway inhibition and temozolomide resulted in a highly synergistic interaction in KNS42 cells. The resistance gene signature further included contiguous genes within the 12q13-q14 amplicon, including the Akt enhancer PIKE, significantly overexpressed in the KNS42 line. These cells were also highly enriched for CD133 and other stem cell markers. We have thus shown an in vitro link between phosphoinositide 3-kinase-mediated HOXA9/HOXA10 expression, and a drug-resistant, progenitor cell phenotype in MGMT-independent pediatric glioblastoma.Cancer Research UK (C1178/A10294, C309/A2187, C309/A8274), the Oak Foundation (L. Marshall), and La Fondation de France (N. Gaspar). We acknowledge NHS funding to the NIHR Biomedical Research Centre. P. Workman is a Cancer Research UK Life Fello

Real-world treatment outcomes of systemic treatments for moderate-to-severe atopic dermatitis in children aged less than 12 years:2-year results from PEDIatric STudy in Atopic Dermatitis

Background:The arrival of biologics and small-molecule therapies (eg Janus kinase inhibitors) changed atopic dermatitis treatment, but older systemic treatments continue to be prescribed. Objective: To provide real-world effectiveness, safety, and adherence data for dupilumab, cyclosporine, and methotrexate. Methods: PEDIatric STudy in Atopic Dermatitis (NCT03687359) is a real-world, prospective, observational, 10-year study of children (&lt;12 years) with inadequately controlled moderate-to-severe atopic dermatitis. We report 2-year interim results. Results: Median treatment durations were 8.1, 13.0, and 10.7 months for dupilumab (n = 144), methotrexate (n = 114), and cyclosporine (n = 121), respectively. Dupilumab had numerically greater within-group improvements than methotrexate and cyclosporine in Eczema Area and Severity Index (−12.4∗ vs −5.7∗ and −3.3); body surface area affected (−19.9%∗ vs −11.8%∗ and −8.8%∗); itching (night-time: −2.1∗ vs −0.4 and + 0.1; daytime: −1.5∗ vs +0.1 and + 0.2; ≥6 years); itching/scratching (−3.6∗ vs −1.4∗ and −0.2; &lt;6 years); and Patient-Oriented Eczema Measure (−7.0∗ vs −4.7∗ and −1.5) (∗P &lt; .05 within-group improvements from baseline). Dupilumab had less discontinuations (8.3% vs 28.9% and 43.0%) and adverse event(s) (18.1% vs 29.8% and 31.4%). Limitations: No randomization, placebo, or specified dosages. Conclusion: Dupilumab was associated with numerically greater outcomes and higher adherence than cyclosporine or methotrexate.</p