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

Lipid Rafts: Linking Alzheimer's Amyloid-β Production, Aggregation, and Toxicity at Neuronal Membranes

Lipid rafts are membrane microdomains, enriched in cholesterol and sphingolipids, into which specific subsets of proteins and lipids partition, creating cell-signalling platforms that are vital for neuronal functions. Lipid rafts play at least three crucial roles in Alzheimer's Disease (AD), namely, in promoting the generation of the amyloid-β (Aβ) peptide, facilitating its aggregation upon neuronal membranes to form toxic oligomers and hosting specific neuronal receptors through which the AD-related neurotoxicity and memory impairments of the Aβ oligomers are transduced. Recent evidence suggests that Aβ oligomers may exert their deleterious effects through binding to, and causing the aberrant clustering of, lipid raft proteins including the cellular prion protein and glutamate receptors. The formation of these pathogenic lipid raft-based platforms may be critical for the toxic signalling mechanisms that underlie synaptic dysfunction and neuropathology in AD

Rushworth M. Kidder: 10-13-1978

In an interview recorded October 13, 1978, Rushworth M. Kidder discusses the poetry and painting of E. E. Cummings. The video includes paintings donated to the College at Brockport by James Sibley Watson, Jr. Images Discussed: Sound #5 Masked Female Nudes Seated Red-Headed Nude Dance Hall Scofield Thayer The Paris Rooftops Mount Chocorua Sunset Flowers and Hat: Patchin Placehttps://digitalcommons.brockport.edu/writers_videos/1029/thumbnail.jp

Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients

The Role of PI3K Isoforms in Regulating Bone Marrow Microenvironment Signaling Focusing on Acute Myeloid Leukemia and Multiple Myeloma

Despite the development of novel treatments in the past 15 years, many blood cancers still remain ultimately fatal and difficult to treat, particularly acute myeloid leukaemia (AML) and multiple myeloma (MM). While significant progress has been made characterising small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of various blood cancers, less is understood about the complex microenvironment of the bone marrow (BM), which is known to be a key player in the pathogenesis of chronic lymphocytic leukaemia (CLL), AML and MM. This niche acts as a sanctuary for the cancerous cells, protecting them from chemotherapeutics and encouraging clonal cell survival. It does this by upregulating a plethora of signalling cascades within the malignant cell, with the phosphatidylinositol-3-kinase (PI3K) pathway taking a critical role. This review will focus on how the PI3K pathway influences disease progression and the individualised role of the PI3K subunits. We will also summarise the current clinical trials for PI3K inhibitors and how these trials impact the treatment of blood cancers

Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL

Flexible regression for river systems

Maintaining river health is of vital importance to the human populations that depend on them for drinking water, and for the income generated from industry and leisure activities. The key to a clear understanding of the current state of the river environment lies in assimilating the various data that are available for a particular river catchment. As a result of the large expense involved in extensive data collection programmes, measurements are often only taken at a handful of monitoring locations, resulting in large portions of a river network remaining unmonitored and rendering it difficult to assess the health of the river as a whole. Interpreting observations associated with a particular response variable pivots on understanding many other variables whose underlying relationships are often highly complex and which may not be routinely measured. Cutting-edge statistical methods can play a crucial role in the interpretation of such data, particularly when faced with small sample sizes and the presence of latent processes. In particular, developing models for environmental data that relax the assumption of simple linear dependencies between response and covariate is a core theme of this thesis, which can enable powerful descriptions of such complex systems. This approach adopts and promotes modern flexible regression techniques based on penalised splines, which are motivated and summarised in Chapter 2; these permit regression relationships to assume a wide variety of non-linear shapes, without requiring the modeller to impose a priori structure. This thesis aims to address two related, but distinct regression problems for data collected within a river catchment. Firstly, the relationship between rainfall data collected at a rain gauge and subsequent river flow rates collected at a point downstream is tackled in Chapter 3. In this application, it is of particular interest to understand the degree, duration and time-lag of the influence of a rainfall event on a measurable increase in river flow rates at a downstream location. This relationship is complex because it is governed by attributes of the surrounding river environment that may not be readily available, such as soil composition, land use and ground strata. However, rainfall and flow data are frequently collected at a high temporal resolution, and Chapter 3 develops models that exploits this feature that are able to express complex lagged dependence structures between a sequence of flow rates and a rainfall time series. The chapter illustrates how the resulting model enables insight into the sensitivity of the river to additional rainfall, and provides a mechanism for obtaining predictions of future flow rates, without recourse to traditional computationally intensive deterministic modelling. This thesis also tackles the problem of constructing appropriate models for the spatial structure of variables that are carried by water along the channels of the river network. This problem cannot be approached using traditional spatial modelling tools due to the presence of the different volumes of water that mix at confluence points, often causing sudden changes in the levels of the measured variable. Very little literature is available for this type of spatial problem, and none has been developed that is appropriate for the large data sets that are becoming increasingly common in many environmental settings. Chapters 4 and 5 develop new regression models that can incorporate spatial variation on a stream network that respects the presence of confluences, flow rates and direction, while including non-linear functional representations for the influence of covariates. These different model components are constructed using the same modern flexible regression framework as used in Chapter 3, and the computational benefits of adopting this approach are highlighted. Chapter 4 illustrates the utility of the new models by applying them to a large set of dissolved nitrate concentrations collected over a Scottish river network. The application reveals strong trends in both space and time, and evidence of a subtle interaction between temporal trend and the location in space; both conclusions would have been difficult to reach using other techniques

Research in Special Education: Implications for Practice

Identifying How to Better Support Parents of Children with Autism by Sarah Rushworth Autism Spectrum Disorder (ASD) is collection of neurological disorders affecting communication, social, and behavioral development (Nealy, 2012). More and more children are being diagnosed as having ASD each year in America. Today, 1 in every 110 children in the United States has autism (Nealy, 2012). The families of these children with autism must learn how to cope with the challenges that come along with the disorder. These challenges include lacking social and communication skills, which can lead to difficult behaviors. Raising a child with autism is associated with increased family stress and depression. This impacts family functioning and can lead to families being isolated from friends and family, as well as leave families with a feeling of stress and helplessness; parents need more support with how to cope with having a family member with autism in order to help improve these families overall quality of life (Russa, 2015). The purpose of this research was to examine how parents of children with autism could be better supported, using interview data. Families of children with autism need to have a variety of supports in place and overall feel as though they are not receiving enough (Nealy, 2012). The intention of this study is to obtain more knowledge of what parents of children with autism need in order to feel better supported, more confident, and less stressed. The Use of Project Based Learning to Empower Latino Students by Shannon Ward Today, the high school graduation rate for Latino males is 50% (Huerta, 2015). Additionally, Latino males often compose a disproportionate amount of suspensions, and the Latino population makes up a disproportionate amount of the students in special education. There has been much research done on the history of the Latino experience in the American school system, and how it has affected their current performance (Conchas, 2015), cultural factors that have impeded Latino student performance, as well as ways in which school counselors, and more developed college access programs can help mitigate this issue (Huerta, 2015). However, there has been little or no research done as to what teachers, in the classroom, can do to support Latino students to help them feel more part of the school community and graduate from high school. Therefore, the goal for this research is to identify learning strategies that can be successful in empowering Latino students in their education. The Common Core State Standards (CCSS) aim to provide young men and women with the skills necessary to be successful in their future college and career endeavors. The incorporation of Project Based Learning (PBL) is one method educators use to achieve this purpose. PBL may be very beneficial to the Latino community as its focus on group work will ensure that they interact with their peers, and become more involved in their own learning. Currently, there is significant research on PBL project ideas, group dynamics, and cooperative learning strategies. However, there is very limited empirical research on the effect PBL has on the education of struggling learners. Therefore, the goal of this study is to determine how to use PBL to empower students of the Latino community. Behavior Interventions for the Classroom by Anna Veelman Behavior challenges and Urban Education are two terms that unfortunately go hand and hand. Students from urban communities are more likely to experience trauma due to violence, death, neglect, and abuse. Children may respond to these traumatic experiences in the form of behaviors in the classroom. Students with trauma or behavior disorders are likely exhibit severe behaviors such as violence, disruption, self-harm, and defiance with in the classroom (Gregory, Skiba, & Noguera, 2010). Students who exhibit these types of behaviors may be put on a behavior plan or be referred for an Individualized Education Program for Emotional Disturbance or miss academics due to being sent out of the classroom. With a high amount of these students being boys of color, this increases the over-representation of this demographic within special education but also aids in the continuation of systems like the school to prison pipeline and achievement gap (Wilson, 2014). This project will be looking deeper into trauma-based behaviors and strategies for teachers to use within the classroom to best support students who exhibit these severe behaviors. The Role of Trauma in Special Education and Early Interventions for Educators by Kristen Wimpee Children\u27s brains develop within the context of their earliest environments and experiences. Their neural and social development can be affected as consequences of complex trauma, disorganized attachment, maltreatment, and abuse. During early childhood, children\u27s nervous systems are in their most vulnerable period of maturation and organizational development. Early life traumas and stresses can lead to structural and physiological differences, which can have long-term consequences on emotional, behavioral, cognitive, and social development. These students often have trouble interacting with others, communicating, playing, and learning. Research shows that students with trauma have difficulty with self-regulation and self-soothing; they tend to struggle with aggressive tendencies, attention, disassociation, and physical and motor delays (Bath, 2008). Children with adverse childhood experiences, including complex trauma, are more likely to be suspended, expelled, and have lower academic achievement. They are at a higher risk of failing, dropping out, and are usually assigned to special education. This puts students with early trauma histories at greater risk of behavioral challenges, suspension, expulsion, low academic achievement, drop out, and difficulty in peer relationships. Many of these children are assigned to special education. Early interventions and creating trauma- sensitive classrooms through multi-modal methods can significantly impact brain development for students who have experienced complex trauma by helping students to self-soothe and self-regulate. Therefore, this presentation will report on the complex link between trauma, diagnosed behavioral disabilities, and behavioral difficulties in the classroom that affect student learning. Trauma-informed teaching methods can help build strong relationships with trauma-affected children, who often have disrupted attachments. These methods can help students develop a resiliency mindset and develop the skills and motivation to successfully engage with the world around them

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

Validation and comparison of geostatistical and spline models for spatial stream networks

Scientists need appropriate spatial-statistical models to account for the unique features of stream network data. Recent advances provide a growing methodological toolbox for modelling these data, but general-purpose statistical software has only recently emerged, with little information about when to use different approaches. We implemented a simulation study to evaluate and validate geostatistical models that use continuous distances, and penalised spline models that use a finite discrete approximation for stream networks. Data were simulated from the geostatistical model, with performance measured by empirical prediction and fixed effects estimation. We found that both models were comparable in terms of squared error, with a slight advantage for the geostatistical models. Generally, both methods were unbiased and had valid confidence intervals. The most marked differences were found for confidence intervals on fixed-effect parameter estimates, where, for small sample sizes, the spline models underestimated variance. However, the penalised spline models were always more computationally efficient, which may be important for real-time prediction and estimation. Thus, decisions about which method to use must be influenced by the size and format of the data set, in addition to the characteristics of the environmental process and the modelling goals