This study examined the magnitude of work-related disability in postmenopausal women with breast cancer compared with healthy controls. It also examined demographic and clinical correlates of ...work-related disability in postmenopausal women with breast cancer.
This was an exploratory secondary analysis of longitudinal study.
The Work Limitations Questionnaire measured the percentage of at-work productivity loss.
The analysis revealed a significant group-by-time interaction effect (F1,40 = 4.705, P = 0.036, partial η = .105) on work-related disability. Participants with breast cancer (mean = 2.364, SE = 0.374) had significantly higher percentage of at-work productivity loss compared with the healthy control group (mean = 1.263, SE = 0.392). At baseline, cognitive-emotional symptoms were moderately to strongly associated with work-related disability. At 6 months, physical symptoms were moderately associated with work-related disability.
Women with newly diagnosed breast cancer are likely to experience higher rates of work-related disability compared with health counterparts. Health care providers should provide intervention to parallel the shift in symptoms that lead to higher work-related disability and job cessation.
About the Authors: Carolyn B. Coyne * E-mail: coynec2@pitt.edu Affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America ...Citation: Coyne CB (2018) Horsepox: Framing a dual use research of concern debate. The four author groups represented in these Opinions include Drs. Ryan S. Noyce and David H. Evans, two authors of a recent PLOS ONE study on Horsepox virus 1, Dr. Volker Thiel, who served as Academic Editor for the article describing the study, and Dr. Thomas Inglesby, Jr. and Dr. Kevin M. Esvelt, both of whom have advocated for changes in the peer reviewing and publishing of DURC-related research. The publishing of this study led to intense debate among the public and scientific community as to whether this type of study should be permissible given that the methods described could be used to synthesize any poxvirus, particularly variola virus, which was declared eradicated in 1980 and is the infectious agent responsible for smallpox.
Objective: Weight gain occurs frequently in men aged 25–40. This study compared the effectiveness of a clinic‐based and a home‐based intervention with a no‐treatment control group in preventing this ...weight gain.
Research Methods and Procedures: Men (n = 67)—aged 25 to 40, sedentary, with a body mass index of 22 to 30, recruited from the University of Pittsburgh—were randomly assigned to 4‐month treatments focused on increasing aerobic exercise and reducing fat intake through a clinic‐based (CB) or a home‐based (HB) program, or to a de‐layed‐treatment control group. Subjects were reassessed at 4 months.
Results: Adherence and outcome did not differ significantly between the CB and HB programs, except that CB subjects recorded their food intake more frequently, and a greater number of CB subjects achieved a total of 120 miles of exercise over the 4 months. Subjects in the two intervention conditions combined lost significantly more weight (‐1.6 ± 2.5 kg) than control subjects, who gained 0.2 ±1.9 kg (p<0.01); this effect of treatment was seen primarily in men with a body mass index of 27 to 30 (‐2.7 kg for CB and HB combined vs. +1.5 kg for control). Treated subjects also had somewhat greater improvements in body composition, aerobic fitness, and weekly energy expenditure than controls, although these differences did not reach significance. Discussions: Both CB and HB intervention show promise in preventing weight gain in young men, especially in those who are slightly overweight. Larger studies, using more representative samples of young men, appear warranted.
Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ ...that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.
BackgroundChimeric antigen receptors (CAR) have demonstrated remarkable efficacy in licensing T cells for antitumor responses against hematopoietic malignancies but have had limited success against ...solid tumors. Macrophages, both archetypic phagocytes and professional antigen presenting cells, may exert profound effector functions which complement adaptive cellular immunity.1 Recently, it was shown that human macrophages engineered to express CARs (CAR-Ms) demonstrated antigen-specific phagocytosis, inhibited solid xenograph tumors, and induced an inflammatory tumor microenvironment boosting antitumor T cell responses.2 Kimura et al. previously completed the first prophylactic cancer vaccine trial based on a non-viral antigen, tumor-associated hypoglycosylated Mucin 1 (MUC1).3 A panel of fully-human affinity-matured MUC1-specific antibodies raised in healthy subjects following immunization was identified from these patients.4 Using these MUC1-specific scFv domains for CAR generation, we have now engineered MUC1-targeting CAR-Ms that may potentially possess reduced off-target specificities.MethodsLentiviral CAR expression vectors containing the scFv domains of three unique hypoglycosylated MUC1-specific antibodies or a CD20-specific antibody, the CD3zeta signaling domain, and CD28 and OX40 co-stimulatory domains were constructed. The human monocyte/macrophage U937, SC, and THP-1 lines were stably transduced and flow-sort purified to generate MUC1- or CD20-specific CAR-Ms. CAR-Ms were differentiated into macrophages via 48 hour PMA treatment, and subsequently evaluated for antigen-specific function against MUC1- and/or CD20-expressing K562, ZR-75-1, and Raji cells or cancer cells isolated from solid lung tumors or malignant pleural effusions. CAR-M phenotype was evaluated by flow cytometry following in vitro differentiation and polarization with conventional ‘M1’ and ‘M2’ stimuli. Phagocytosis and lysosomal processing of phagocytosed cargo were evaluated by fluorescence microscopy of GFP/CellTrace labeled targets or detection of pH-sensitive pHrodo expression following CAR-M and tumor cell co-culture, respectively. Antigen-specific cytokine production was determined via cytometric bead array following co-culture of CAR-Ms with MUC1- or CD20-expressing tumor cells or 100mer MUC1 peptide.ResultsDifferentiated CAR-Ms possessed an inflammatory phenotype expressing IL-8 and CD86 which was further enhanced by IFNgamma or LPS treatment and was resistant to ‘M2’ polarization with conventional stimuli. CAR-Ms exhibited phagocytosis and subsequent lysosomal processing in an antigen-specific manner, with minimal reactivity against tumor cell targets in the absence of the corresponding MUC1 or CD20 antigen. MUC1-specific CAR-Ms stimulated with MUC1 peptide or MUC1+ tumor cells secreted robust levels of pro-inflammatory IL-8, TNFa, and IL-1beta, but not immunosuppressive IL-10.ConclusionsMUC1-targeting CAR-Ms exert potent tumor-restricted effector function in vitro and may provide a novel treatment strategy either alone or in potential synergistic combination with T cell-mediated immunotherapies.AcknowledgementsThe authors would like to thank Dr. Olivera J. Finn for generously providing reagents and guidance and Dr. Michael T. Lotze for his mentorship. This study was supported by funding from the University of Pittsburgh’s Department of Cardiothoracic Surgery to ACS and RD.ReferencesWilliams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. Npj Breast Cancer Internet. Breast Cancer Research Foundation/Macmillan Publishers Limited; 2016;2:15025. Available from: http://dx.doi.org/10.1038/npjbcancer.2015.25Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38:947–53.Kimura T, McKolanis JR, Dzubinski LA, Islam K, Potter DM, Salazar AM, et al. MUC1 Vaccine for Individuals with Advanced Adenoma of the Colon: A Cancer Immunoprevention Feasibility Study. Cancer Prev Res Internet 2013;6:18–26. Available from: http://cancerpreventionresearch.aacrjournals.org/content/6/1/18.abstractLohmueller JJ, Sato S, Popova L, Chu IM, Tucker MA, Barberena R, et al. Antibodies elicited by the first non-viral prophylactic cancer vaccine show tumor-specificity and immunotherapeutic potential. Sci Rep 2016;6:31740.Ethics ApprovalThe study was approved by the University of Pittsburgh’s Institutional Review Board approval number CR19120172-005.
Research over the past few years has demonstrated the central role of protein phosphorylation in regulating mitosis and the cell cycle. However, little is known about how the mechanisms regulating ...the entry into mitosis contribute to the positional and temporal regulation of the actomyosin-based contractile ring formed during cytokinesis. Recent studies implicate p34cdc2 as a negative regulator of myosin II activity, suggesting a link between the mitotic cycle and cytokinesis. In an effort to study the relationship between protein phosphorylation and cytokinesis, we examined the in vivo and in vitro phosphorylation of actin-associated cortical cytoskeletal (CSK) proteins in an isolated model of the sea urchin egg cortex. Examination of cortices derived from eggs or zygotes labeled with 32P-orthophosphate reveals a number of cortex-associated phosphorylated proteins, including polypeptides of 20, 43 and 66 kDa. These three major phosphoproteins are also detected when isolated cortices are incubated with 32PATP in vitro, suggesting that the kinases that phosphorylate these substrates are also specifically associated with the cortex. The kinase activities in vivo and in vitro are stimulated by fertilization and display cell cycle-dependent activities. Gel autophosphorylation assays, kinase assays and immunoblot analysis reveal the presence of p34cdc2 as well as members of the mitogen-activated protein kinase family, whose activities in the CSK peak at cell division. Nocodazole, which inhibits microtubule formation and thus blocks cytokinesis, significantly delays the time of peak cortical protein phosphorylation as well as the peak in whole-cell histone H1 kinase activity. These results suggest that a key element regulating cortical contraction during cytokinesis is the timing of protein kinase activities associated with the cortical cytoskeleton that is in turn regulated by the mitotic apparatus.
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