Dysregulation of metabolic-associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin-15 targeting fatigue

Background Breast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down-regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin-15 (IL-15) can attenuate mammary tumourinduced muscle fatigue. Methods Early stage non-metastatic female breast cancer patients (n = 14) and female non-cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER+ /PR+ , n = 6), triple positive (ER+ /PR+ /Her2/neu+ , n = 5), or triple negative (ER/PR/Her2/neu, n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post-operative therapy. Biopsies were used for RNA-sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non-cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth. Results RNA-sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator-activated receptor signalling and activation, and IL-15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour growth for 4 weeks, and this greater muscle fatigue was attenuated in transgenic mice that overexpressed the cytokine IL-15. Conclusions Our data identify novel genes and pathways dysregulated in the muscles of breast cancer patients with early stage non-metastatic disease, with particularly aberrant expression among genes that would predispose these patients to greater muscle fatigue. Furthermore, we demonstrate that IL-15 overexpression can attenuate muscle fatigue associated with mammary tumour growth in a preclinical mouse model of breast cancer. Therefore, we propose that skeletal muscle fatigue is an inherent consequence of breast tumour growth, and this greater fatigue can be targeted therapeutically

Feasibility and Comparative Effectiveness for the Delivery of the National Diabetes Prevention Program through Cooperative Extension in Rural Communities

The U.S. Cooperative Extension Service (CE) has potential to deliver the National Diabetes Prevention Program (NDPP) to rural residents with prediabetes. However, the CE remains underutilized for the delivery of NDPP. We compared the feasibility/effectiveness of the NDPP (0–6 mos.) delivered by CE personnel to rural residents with prediabetes using Zoom® (CE-Zoom®) or by our research staff using Facebook® (FB). Adults (n = 31, age ~55 years) were enrolled (CE-Zoom® n = 16, FB n = 15). Attendance did not differ significantly between groups (CE Zoom® = 69%, FB = 83%, p = 0.15). Participant retention was similar in the CE Zoom® (88%) and FB groups (87%). CE-Zoom® and FB® groups provided weekly, self-monitoring data for 83% and 84% of the 24 potential weeks, respectively. Six-month weight loss was not different between groups (CE-Zoom® = −5.99 ± 8.0 kg, −5.4%, FB = −1.68 ± 3.3 kg, −1.6% p = 0.13). Participants achieving ≥5% weight loss was greater in the CE-Zoom® (44%) compared with the FB group (7%, p = 0.04). Participants achieving the NDPP program goal for physical activity (≥150 min/week) did not differ (CE-Zoom® = 75%, FB = 67%, p = 0.91). This pilot trial demonstrated the potential feasibility and effectiveness of the NDPP delivered by CE personnel in a group remote format (Zoom®) to adults with prediabetes living in rural areas

Nurses\u27 Alumnae Association Bulletin - Volume 6 Number 9

Remember the Relief Fund Welcome! Miss Childs Financial Report Calendar of Coming Events Lest You Forget! Attention Review of the Alumnae Association Meetings Institutional Staff Nurses\u27 Section Report of Staff Activities - 1947-1948 Private Duty Section The White Haven Division Barton Memorial Division Remember the Relief Fund Student Nurses\u27 Activities Jefferson Scores Again The Clara Melville Scholarship Fund Interesting Activities of the Nurses\u27 Home Committee of the Women\u27s Board Exclusive for Nurses Changes in the Maternity Division Gray Lady Musical Therapy Service Memorial Service Honoring Mrs. Bessie Dobson Altemus The Blood Donor Center The Hospital Pharmacy Medical College News Remember the Relief Fund Administrative Staff and Faculty of the School of Nursing Streptomycin Changes in the Staff at Jefferson Hospital Care of the Thoracic Surgical Patient Miscellaneous Items Marriages New Arrivals Deaths The Bulletin Committee Attention, Alumnae New Addresse

Influence of Inflammatory and Oxidative Stress Pathways on Longitudinal Symptom Experiences in Children With Leukemia

Purpose: The purpose of this study was to explore the influence of oxidative stress (F2-isoprostanes) and inflammatory (interleukin [IL]-8) biomarkers on symptom trajectories during the first 18 months of childhood leukemia treatment. Method: A repeated-measures design was used to evaluate symptoms experienced by 218 children during treatment. A symptom cluster (fatigue, pain, and nausea) was explored over four time periods: initiation of post-induction therapy, 4 and 8 months into post-induction therapy, and the beginning of maintenance therapy (12 months postinduction). F2-isoprostanes and IL-8 were evaluated in cerebrospinal fluid (CSF) samples collected at baseline (diagnosis) and then at the four time periods. The longitudinal relationships of these biomarkers with the symptom cluster were examined using the longitudinal parallel process. Results: Pain and fatigue levels were highest during the post-induction phases of treatment and decreased slightly during maintenance therapy, while nausea scores were relatively stable. Even in the later phases of treatment, children continued to experience symptoms. CSF levels of the biomarkers increased during the post-induction phases of treatment. Early increases in the biomarkers were associated with more severe symptoms during the same period; patients who had increased biomarkers over time also experienced more severe symptoms over time. Conclusions: Findings reveal that children experienced symptoms throughout the course of leukemia treatment and support hypothesized longitudinal relationships of oxidative stress and inflammatory biomarkers with symptom severity. Activation of the biomarker pathways during treatment may explain underlying mechanisms of symptom experiences and identify which children are at risk for severe symptoms.National Institutes of Health [R01CA1693398]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Women write the rights of woman: The sexual politics of the personal pronoun in the 1790s

This article investigates patterns of personal pronoun usage in four texts written by women about women's rights during the 1790s: Mary Wollstonecraft's A Vindication of the Rights of Woman (1792), Mary Hays' An Appeal to the Men of Great Britain (1798), Mary Robinson's Letter to the Women of England (1799) and Mary Anne Radcliffe's The Female Advocate (1799). I begin by showing that at the time these texts were written there was a widespread assumption that both writers and readers of political pamphlets were, by default, male. As such, I argue, writing to women as a woman was distinctly problematic, not least because these default assumptions meant that even apparently gender-neutral pronouns such as I, we and you were in fact covertly gendered. I use the textual analysis programme WordSmith to identify the personal pronouns in my four texts, and discuss my results both quantitatively and qualitatively. I find that while one of my texts does little to disturb gender expectations through its deployment of personal pronouns, the other three all use personal pronouns that disrupt eighteenth century expectations about default male authorship and readership. Copyright © 2007 SAGE Publications

Outcomes for paediatric Burkitt lymphoma treated with anthracycline-based therapy in Malawi

Burkitt lymphoma (BL) is the most common paediatric cancer in sub-Saharan Africa (SSA). Anthracyline-based treatment is standard in resource-rich settings, but has not been described in SSA. Children ≤ 18 years of age with newly diagnosed BL were prospectively enrolled from June 2013 to May 2015 in Malawi. Staging and supportive care were standardized, as was treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for six cycles. Among 73 children with BL, median age was 9.2 years (interquartile range 7.7–11.8), 48 (66%) were male and two were positive for human immunodeficiency virus. Twelve (16%) had stage I/II disease, 36 (49%) stage III and 25 (34%) stage IV. Grade 3/4 neutropenia occurred in 17 (25%), and grade 3/4 anaemia in 29 (42%) of 69 evaluable children. Eighteen-month overall survival was 29% (95% confidence interval [CI] 18–41%) overall. Mortality was associated with age >9 years [hazard ratio [HR] 2.13, 95% CI 1.15–3.94], female gender (HR 2.12, 95% CI 1.12–4.03), stage (HR 1.52 per unit, 95% CI 1.07–2.17), lactate dehydrogenase (HR 1.03 per 100 iu/l, 95% CI 1.01–1.05), albumin (HR 0. 96 per g/l, 95% CI 0.93–0.99) and performance status (HR 0.78 per 10-point increase, 95% CI 0.69–0.89). CHOP did not improve outcomes in paediatric BL compared to less intensive regimens in Malawi

Are ulcers a marker for invasive carcinoma in barrett's esophagus? data from a diagnostic variability study with clinical follow-up

We correlated follow-up information from 138 patients with Barrett's esophagus and varying degrees of dysplasia with the presence of ulcers. Methods A group of pathologist participants were asked to contribute patients’ initial biopsy slides showing Barrett's esophagus (BE) without dysplasia and with epithelial changes indefinite for dysplasia, low grade dysplasia (LGD), high grade dysplasia (HGD), and adenocarcinoma. From the initial 250 cases used for a diagnostic reproducibility study, follow-up information was available for 138 patients. Results There were 44 cases submitted as BE, 22 as BE with epithelial changes indefinite for dysplasia, 26 as BE with LGD, 33 as BE with HGD, and 13 as BE with adenocarcinoma. Ulcers were present in 35/138 cases (25%), including 3/44 cases of BE without dysplasia (7%), 2/22 cases of BE with epithelial changes indefinite for dysplasia (9%), 0/26 cases of BE with LGD (0%), 10/33 cases of BE with HGD (30%), and 7/13 cases of BE with adenocarcinoma (54%). On follow-up, there were no invasive carcinomas detected among the BE without dysplasia group (median follow-up = 38.5 months). Adenocarcinomas were detected in 4/22 cases (18%) submitted as BE with epithelial changes indefinite for dysplasia at 19, 55, 60, and 62 months and in 4/26 cases (15%) of BE with LGD at 9, 9, 11, and 60 months. None of these carcinomas occurred in cases in which an ulcer was present in the initial biopsy specimen. Among the 33 HGD cases, 20 (60%) were found to have adenocarcinoma on subsequent resection specimens. The presence of an ulcer with HGD increased the likelihood of finding carcinoma in the resection specimen, as 8/10 biopsies (80%) of HGD patients with ulcers had carcinoma, compared to 12/23 biopsies (52%) of HGD patients without ulcers. All of the cases interpreted as adenocarcinomas on biopsy were found either to have invasive carcinoma on esophageal resection or to have metastases that were demonstrated in unresectable patients. Conclusion If an ulcer accompanies HGD in a biopsy specimen from a patient with BE, it is likely that invasive carcinoma is also present at that time.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75186/1/j.1572-0241.2002.05420.x.pd

Trans-Ethnic Mapping of BANK1 Identifies Two Independent SLE-Risk Linkage Groups Enriched for Co-Transcriptional Splicing Marks

BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combinedwith a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomicmarks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways.The work presented in this paper has been supported by the Ministerio de Economía y Competitividad, Spain (SAF2016-78631-P), partly co-financed by FEDER funds of the European Union, the Gustaf den V:e-80-års Fond and the Swedish Association against Rheumatism to M.E.A-R. In addition, this work was financed by the NIH P01 grant P01-AI-083194 to C.D.L., J.B.H., R.K., and M.E.A-R. JBH: NIH grants: R01 AI024717, U01 HG00866, P30 AR070549 and U01 AI130830 and the US Department of Veterans Affairs: I01 BX001834.C.D.L.: Center for Public Health Genomics. R.K.: NIH grant R01-AR33062. J.A.J.: NIH grants U54GM104938, P30AR053483

Optimizing Critical Illness Recovery: Perspectives and Solutions from the Caregivers of ICU Survivors

Objectives: To understand the unmet needs of caregivers of ICU survivors, how they accessed support post ICU, and the key components of beneficial ICU recovery support systems as identified from a caregiver perspective. Design: International, qualitative study. Subjects: We conducted 20 semistructured interviews with a diverse group of caregivers in the United States, the United Kingdom, and Australia, 11 of whom had interacted with an ICU recovery program. Setting: Seven hospitals in the United States, United Kingdom, and Australia. Interventions: None. Measurements and Main Results: Content analysis was used to explore prevalent themes related to unmet needs, as well as perceived strategies to improve ICU outcomes. Post-ICU care was perceived to be generally inadequate. Desired caregiver support fell into two main categories: practical support and emotional support. Successful care delivery initiatives included structured programs, such as post discharge telephone calls, home health programs, post-ICU clinics, and peer support groups, and standing information resources, such as written educational materials and online resources. Conclusions: This qualitative, multicenter, international study of caregivers of critical illness survivors identified consistently unmet needs, means by which caregivers accessed support post ICU, and several care mechanisms identified by caregivers as supporting optimal ICU recovery