Bone marrow senescence and the microenvironment of hematological malignancies

Senescence is the irreversible arrest of cell proliferation that has now been shown to play an important role in both health and disease. With increasing age senescent cells accumulate throughout the body, including the bone marrow and this has been associated with a number of age-related pathologies including malignancies. It has been shown that the senescence associated secretory phenotype (SASP) creates a pro-tumoural environment that supports proliferation and survival of malignant cells. Understanding the role of senescent cells in tumor development better may help us to identify new treatment targets to impair tumor survival and reduce treatment resistance. In this review, we will specifically discuss the role of senescence in the aging bone marrow (BM) microenvironment. Many BM disorders are age-related diseases and highly dependent on the BM microenvironment. Despite advances in drug development the prognosis particularly for older patients remains poor and new treatment approaches are needed to improve outcomes for patients. In this review, we will focus on the relationship of senescence and hematological malignancies, how senescence promotes cancer development and how malignant cells induce senescence

Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15)

Respiratory syncytial virus (RSV) is a major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. Factors attributing to this problem are associated with an incomplete understanding of the mechanisms by which RSV modulates the host cell response to infection. In the present study, we investigate suppressor of cytokine signaling (SOCS)-1 and SOCS3 expression associated with the type I IFN and IFN-stimulated gene (ISG)-15 response following infection of mouse lung epithelial (MLE-15) cells with RSV or RSV mutant viruses lacking the G gene, or NS1 and NS2 gene deletions. Studies in MLE-15 cells are important as this cell line represents the distal bronchiolar and alveolar epithelium of mice, the most common animal model used to evaluate the host cell response to RSV infection, and exhibit morphologic characteristics of alveolar type II cells, a primary cell type targeted during RSV infection. These results show an important role for SOCS1 regulation of the antiviral host response to RSV infection, and demonstrate a novel role for RSV G protein manipulation of SOCS3 and modulation of ISG15 and IFNβ mRNA expression

Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15)

Respiratory syncytial virus (RSV) is a major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. Factors attributing to this problem are associated with an incomplete understanding of the mechanisms by which RSV modulates the host cell response to infection. In the present study, we investigate suppressor of cytokine signaling (SOCS)-1 and SOCS3 expression associated with the type I IFN and IFN-stimulated gene (ISG)-15 response following infection of mouse lung epithelial (MLE-15) cells with RSV or RSV mutant viruses lacking the G gene, or NS1 and NS2 gene deletions. Studies in MLE-15 cells are important as this cell line represents the distal bronchiolar and alveolar epithelium of mice, the most common animal model used to evaluate the host cell response to RSV infection, and exhibit morphologic characteristics of alveolar type II cells, a primary cell type targeted during RSV infection. These results show an important role for SOCS1 regulation of the antiviral host response to RSV infection, and demonstrate a novel role for RSV G protein manipulation of SOCS3 and modulation of ISG15 and IFNβ mRNA expression

LATCH usability in vehicles

This project investigated the usability of Lower Anchors and Tethers for CHildren (LATCH) hardware by measuring LATCH implementations in 98 2011 or 2010 model-year vehicles. ISO and SAE LATCH usability rating systems were used to assess all vehicles using data from the second row left position. Child restraint/vehicle interaction was assessed using both ISO and NHTSA proposed procedures. Volunteer testing was performed with 36 subjects on 12 different vehicles using 3 different child restraints, with each subject performing 8 child restraint installations. The results from the vehicle survey indicate that most vehicle manufacturers provide LATCH hardware at only the minimum number of locations required by FMVSS 225. Only 7 vehicles had three sets of LATCH hardware in the second row, while most of the remaining 91 vehicles were only equipped with LATCH in each outboard position and a tether anchor in the center position. In the 21 vehicles with a third row, four had no tether anchors and 11 had no lower anchors in the third row. The SAE child restraint fixture could not be installed in 27 vehicles, although head restraint interference was the cause of interference in only one vehicle. Fifty-nine vehicles met the SAE recommended lower attachment force of 75 N (16.9 lb) or less, while 15 vehicles required forces from 2 to 8 times this value. Only 2 vehicles met SAE recommendations for clearance angle of at least 75 degrees around the lower anchors. The depth of the lower anchors relative to the bight is less than 2 cm in 28 vehicles, 2-4 cm in 34 vehicles, and greater than 4 cm in 36 vehicles. The most common location for the tether anchor is the seatback (42) and package shelf (35). The lower anchors are marked in 77 vehicles, while the tether anchors are marked in 68 vehicles. Only Ford products clearly specify weight ranges for use of LATCH hardware in their manuals. Many vehicle manuals are not clear on how the head restraint should be positioned during child restraint installation. ISO ratings of vehicle LATCH usability ranged from 41% to 78%, while vehicles assessed using the SAE draft recommended practice met between 2 and all 10 of the recommendations. There was a slight correlation between vehicles meeting SAE recommended practices and ISO usability ratings. Twenty vehicles with a range of vehicle features were assessed using the ISO vehicle/child restraint form and 7 child restraints; ISO vehicle/child restraint interaction scores ranged from 14% to 86%. Based on these interaction scores, the Cosco Alpha Omega, the Chicco KeyFit, and Evenflo Maestro were used with a subset of 12 vehicles to perform volunteer testing and assess the quality of subject installations. No vehicle factors predicted tether use or correct use of tether. However, the correct use of lower anchors was associated with a lower anchor clearance angle greater than 54°, an attachment force of 40 lb or less, and lower anchor depth within the bight of less than 2 cm. Correct lower anchor use also had 3.3 times higher odds of tight installation compared to incorrect use.Insurance Institute for Highway Safetyhttp://deepblue.lib.umich.edu/bitstream/2027.42/90856/1/102854.pd

Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated

Exploring Expressions of Possible Selves with High School and College Students with Learning Disabilities

In this article, we explore a program designed to engage high school and college students with learning disabilities (LD) in conversations about their hopes, expectations, and fears for the future. We explore the mindset of students by focusing on their self-identified passions for life and sense of strengths and limitations. We found that males and females differed in goals related to Academics, Work Ethic, Degree Specific Statements, and Money and Finances. For example, females emphasized “Academic Goals” more frequently than males and focused on topics such as GPA and work ethic in school. However, males made more “Degree Specific Statements” than females, more often emphasizing the desire to be financially stable or have a career with a large income. These differences suggest that college transition staff may want to focus on goals identified by male and female students with LD as a way to be more responsive to student self-identified goals

PGC-1 alpha induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma

INTRODUCTION: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. METHODS: Primary melanoma cells, and MSCs derived from patients were obtained. Genes’ expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. RESULTS: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. CONCLUSION: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma

Mitochondrial oxidative phosphorylation in cutaneous melanoma

The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease

Parasite avoidance behaviours in aquatic environments

Parasites, including macroparasites, protists, fungi, bacteria and viruses, can impose a heavy burden upon host animals. However, hosts are not without defences. One aspect of host defence, behavioural avoidance, has been studied in the terrestrial realm for over 50 years, but was first reported from the aquatic environment approximately 20 years ago. Evidence has mounted on the importance of parasite avoidance behaviours and it is increasingly apparent that there are core similarities in the function and benefit of this defence mechanism between terrestrial and aquatic systems. However, there are also stark differences driven by the unique biotic and abiotic characteristics of terrestrial and aquatic (marine and freshwater) environments. Here, we review avoidance behaviours in a comparative framework and highlight the characteristics of each environment that drive differences in the suite of mechanisms and cues that animals use to avoid parasites. We then explore trade-offs, potential negative effects of avoidance behaviour and the influence of human activities on avoidance behaviours. We conclude that avoidance behaviours are understudied in aquatic environments but can have significant implications for disease ecology and epidemiology, especially considering the accelerating emergence and re-emergence of parasites.peerReviewe