Distribution of horseradish peroxidase (HRP)- anti-HRP immune complexes in mouse spleen with special reference to follicular dendritic cells

The distribution of immune complexes has been studied in mouse spleen stimulated to contain many germinal centers (GC′s). Horseradish peroxidase (HRP)-anti-HRP complexes were used as an appropriately precise and sensitive model. We were primarily interested in the relative abilities of three cell types to interact with complexes: lymphocytes, macrophages, and follicular dendritic cells (FDC′s). The latter are distinctive, nonendocytic, stellate cells located primarily at the transition of mantle and GC zones of 2° lymphoid follicles (Chen, L. L., J. C. Adams, and R. M. Steinman, 1978, J. Cell Biol. 77: 148). Binding of immune complexes to lymphocytes could not be visualized in situ. Macrophages avidly interiorized complexes into lysosomes, but did not retain them extracellularly. In contrast, FDC′s could retain HRP-anti-HRP extracellularly under appropriate conditions, but did not endocytose them. Cytochemical reactivity accumulated progressively on FDC′s 1-6 h after administration of complexes i.v., remained stable in amount and location for 1 day, and then was progressively lost over a 1- to 5-day period. Several variables in the association of complexes with macrophages and FDC′s were pursued. Only 1 /xg of complexed HRP had to be administered to visualize binding to both cell types. Macrophages interiorized complexes formed in a wide range of HRP/anti-HRP ratios, while FDC′s associated with complexes formed in HRP excess only. Quantitative studies with [125I]HRP-anti-HRP demonstrated that 20 of the splenic load of HRP associated with FDC′s. Complexes formed with an F(ab′)2 anti-HRP were distributed primarily in macrophages. When the levels of the third component of serum complement were depleted by prior treatment with cobra venom factor, uptake of complexes by macrophages was reduced some 50 whereas association with FDC′s was abolished. The fact that antigen excess complexes are retained extracellularly strengthens the idea that they are immunogenic. Finally, the association of complexes with FDC′s seems to retard the entry of antigen into the GC proper

Genome-wide RAD sequencing resolves the evolutionary history of serrate leaf Juniperus and reveals discordance with chloroplast phylogeny

Juniper (Juniperus) is an ecologically important conifer genus of the Northern Hemisphere, the members of which are often foundational tree species of arid regions. The serrate leaf margin clade is native to topologically variable regions in North America, where hybridization has likely played a prominent role in their diversification. Here we use a reduced-representation sequencing approach (ddRADseq) to generate a phylogenomic data set for 68 accessions representing all 22 species in the serrate leaf margin clade, as well as a number of close and distant relatives, to improve understanding of diversification in this group. Phylogenetic analyses using three methods (SVDquartets, maximum likelihood, and Bayesian) yielded highly congruent and well-resolved topologies. These phylogenies provided improved resolution relative to past analyses based on Sanger sequencing of nuclear and chloroplast DNA, and were largely consistent with taxonomic expectations based on geography and morphology. Calibration of a Bayesian phylogeny with fossil evidence produced divergence time estimates for the clade consistent with a late Oligocene origin in North America, followed by a period of elevated diversification between 12 and 5 Mya. Comparison of the ddRADseq phylogenies with a phylogeny based on Sanger-sequenced chloroplast DNA revealed five instances of pronounced discordance, illustrating the potential for chloroplast introgression, chloroplast transfer, or incomplete lineage sorting to influence organellar phylogeny. Our results improve understanding of the pattern and tempo of diversification in Juniperus, and highlight the utility of reduced-representation sequencing for resolving phylogenetic relationships in non-model organisms with reticulation and recent divergence

Exhaust All Measures: Ethical Issues in Pediatric End-of-Life Care

The death of a child may have a profound impact on parents, family members, and health care providers who provided care for the child. Unique challenges are faced by parents of seriously ill children as they must serve as the legal authority for health care decisions of children under age 18, although the child’s wishes must also be considered. Social workers must balance core social work values, bioethical values, and psychosocial issues presented by such situations. While studies have been conducted with physicians and nurses regarding ethical issues in pediatric end-of-life care settings, little is known about how social workers experience these conflicts. This article utilizes two vignettes to illustrate potential ethical issues in this setting and applies the National Association of Social Workers Standards for Palliative and End of Life Care (NASW, Citation2004) to explore options for their resolution. These vignettes provide descriptions of possible reactions in this setting and can be used as a basis for further exploration of ethics in pediatric end-of-life care from a social work perspective

Ethics at the End of Life: A Teaching Tool

Social workers rarely receive education and training in the areas of grief, bereavement, and death and dying, which may lead to difficulties in compassionately and ethically addressing concerns in end-of-life or grief-related contexts. This article presents actual and potential outcomes from three challenging end-of-life case studies using Mattison’s ethical decision-making model as a framework. The case studies were drawn from student interviews with experienced master’s-level social workers. This pedagogical article helps to promote self-reflection and consideration of ethical issues in grief and death-related situations as well as supplement death education and ethics curricula to include end-of-life content

The Relationship Between Depressive Symptoms and Social Cognitive Processing in Partners of Long-Term Breast Cancer Survivors

Purpose/Objectives: To determine 1) if depressive symptoms in partners of long-term breast cancer survivors (BCS) could be predicted by social cognitive processing theory, and 2) if partners of younger and older breast cancer survivors were differentially affected by the cancer experience. Design: A cross-sectional, descriptive study utilizing self-report questionnaires. Setting: Indiana University and 97 ECOG-ACRIN sites. Sample: Partners of breast cancer survivors (n=508) diagnosed 3-8 years prior. Methods: Secondary data mediation analyses were conducted to determine if cognitive processing mediated the relationship between social constraints and depressive symptoms. Age-related differences on all scales were tested. Main Research Variables: Depressive symptoms; secondary variables included social constraints, cognitive processing (avoidance and intrusive thoughts), and potentially confounding variables. Findings: Cognitive processing mediated the relationship between social constraints and depressive symptoms for partners (F(5,498)= 19.911, R2=.167, p<.001). Partners of young BCS reported worse outcomes on all measures than partners of older breast cancer survivors Conclusions: As predicted by the social cognitive processing theory, cognitive processing mediated the relationship between social constraints and depressive symptoms. Furthermore, partners of younger BCS fared worse on social constraints, intrusive thoughts and depressive symptoms than partners of older BCS. Implications for Nursing: Results provide support for using the social cognitive processing theory in intervention design with partners of long-term BCS to decrease depressive symptoms. Knowledge Translation: • Partners of long-term BCS report clinically significant depression. • Partners of younger BCS report higher levels of depressive symptoms than the national average and than partners of older survivors. • Addressing social constraints within the dyad may improve depressive symptoms.This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA189828, CA180795, CA37403, CA35199, CA17145 and CA49883, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Number F31NR013822, and by the National Cancer Institute of the National Institutes of Health under Award Numbers K05CA175048 and R25CA117865. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, including the National Cancer Institute or the National Institute of Nursing Research

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression

Local and Global Well-Posedness for Aggregation Equations and Patlak-Keller-Segel Models with Degenerate Diffusion

Recently, there has been a wide interest in the study of aggregation equations and Patlak-Keller-Segel (PKS) models for chemotaxis with degenerate diffusion. The focus of this paper is the unification and generalization of the well-posedness theory of these models. We prove local well-posedness on bounded domains for dimensions $d\geq 2$ and in all of space for $d\geq 3$, the uniqueness being a result previously not known for PKS with degenerate diffusion. We generalize the notion of criticality for PKS and show that subcritical problems are globally well-posed. For a fairly general class of problems, we prove the existence of a critical mass which sharply divides the possibility of finite time blow up and global existence. Moreover, we compute the critical mass for fully general problems and show that solutions with smaller mass exists globally. For a class of supercritical problems we prove finite time blow up is possible for initial data of arbitrary mass.Comment: 31 page

Avoidant Coping and Self-efficacy Mediate Relationships between Perceived Social Constraints and Symptoms among Long-term Breast Cancer Survivors

Objective Many breast cancer survivors feel constrained in discussing their cancer experience with others. Limited evidence suggests that social constraints (e.g., avoidance and criticism) from loved ones may negatively impact breast cancer survivors' global health, but research has yet to examine relationships between social constraints and common physical symptoms. Informed by social cognitive processing theory, this study examined whether perceived social constraints from partners and healthcare providers (HCPs) were associated with fatigue, sleep disturbance, and attentional functioning among long-term breast cancer survivors (N = 1052). In addition, avoidant coping and self-efficacy for symptom management were examined as potential mediators of these relationships. Methods Long-term breast cancer survivors (mean years since diagnosis = 6) completed questionnaires assessing social constraints from partners and HCPs, avoidant coping, self-efficacy for symptom management, and symptoms (i.e., fatigue, sleep disturbance, and attentional functioning). Structural equation modeling was used to evaluate the hypothesized relationships among variables in two models: one focused on social constraints from partners and one focused on social constraints from HCPs. Results Both models demonstrated good fit. Consistent with theory and prior research, greater social constraints from both partners and HCPs were associated with greater symptom burden (i.e., greater fatigue and sleep disturbance, poorer attentional functioning). In addition, all relationships were mediated by avoidant coping and self-efficacy for symptom management. Conclusions Findings are consistent with social cognitive processing theory and suggest that symptom management interventions may be enhanced by addressing the impact of social constraints from survivors' partners and HCPs on their coping and self-efficacy

Long-Term Fear of Recurrence in Young Breast Cancer Survivors and Partners

Background Fear of a breast cancer recurrence is the most prevalent and disruptive source of distress for long-term survivors and their partners. However, few studies have focused on predictors of fear of recurrence. The aim of this study is to test the efficacy of the Social Cognitive Processing Theory (SCPT) in predicting fear of recurrence in long-term breast cancer survivors diagnosed at age 45 years or younger and their partners. Methods In a large cross-sectional study, breast cancer survivors (n = 222) 3–8 years from diagnosis and their partners completed a survey assessing demographic characteristics, fear of recurrence, social constraints, and cognitive processing (intrusive thoughts and cognitive avoidance). Mediation analyses were conducted for survivors and partners separately to determine if cognitive processing would mediate the relationship between social constraints and fear of recurrence. Results Cognitive processing mediated the relationship between social constraints and fear of recurrence both for survivors [F(3,213) = 47.541, R2 = 0.401, p < 0.001] and partners [F(3,215) = 27.917, R2 = 0.280, p < 0.001). Demographic variables were not significant predictors of fear of recurrence. Conclusions As predicted, cognitive processing mediated the relationship between social constraints and fear of recurrence. Results expand the utility of the SCPT in long-term survivors and their partners by supporting its use in intervention design.Acknowledgement: This research was supported by an American Cancer Society grant: RSGPB-04-089-01-PBP. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA189828, CA180795 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Number F31NR013822. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number K05CA175048. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Factors associated with depressive symptoms in young long-term breast cancer survivors

Purpose Long-term breast cancer survivors frequently report distress (i.e., depressive symptoms) that impacts their quality of life. Previous studies have found that negative social interactions (“social constraints”) from partners contribute to long-term, unresolved cycling of intrusive thoughts and cognitive avoidance, resulting in psychological distress. However, these relationships have not been tested in long-term breast cancer survivors. Furthermore, the effect of partners’ depressive symptoms on the survivors’ depressive symptoms has not been tested within the context of these relationships. Therefore, the purpose of this study was to test relationships between breast cancer survivors’ depressive symptoms and (1) social constraints, cognitive avoidance, and intrusive thoughts, and (2) partners’ depressive symptoms. Methods Data were from a cross-sectional descriptive study of breast cancer survivors (N = 222) 3–8 years post-diagnosis and their partners, who completed surveys assessing demographic characteristics, social constraints, intrusive thoughts, cognitive avoidance, and depressive symptoms. Structural equation modeling confirmatory path analyses were conducted to determine significant relationships between survivors’ depressive symptoms and all other variables. Results Our model fits the data well. Breast cancer survivors’ depressive symptoms were predicted by social constraints and intrusive thoughts. The relationship between survivors’ depressive symptoms and partners’ depressive symptoms was close but not significant. Conclusions As hypothesized, depressive symptoms were predicted by social constraints and intrusive thoughts. Further research is needed to understand the possible relationship between survivors’ long-term depressive symptoms and cognitive avoidance and partners’ depressive symptoms. Our findings highlight the negative impact of social constraints from partners on psychological outcomes in long-term breast cancer survivors