Regulation of 92-kD gelatinase release in HL-60 leukemia cells

Matrix metalloproteinase 9 (MMP-9), also known as 92-kD type IV collagenase/gelatinase, is believed to play a critical role in tumor invasion and metastasis. Here, we report that MMP-9 was constitutively released from the human promyelocytic cell line HL-60 as determined by zymographic analysis. Tumor necrosis factor-alpha (TNF-alpha) enhanced the enzyme release threefold to fourfold and the protein kinase C (PKC) activator and differentiation inducer 12-O-tetradecanoylphorbol-13- acetate (TPA) eightfold to ninefold. Gelatinase induction by TNF-alpha and TPA was inhibited by actinomycin D or cycloheximide, indicating that de novo protein synthesis was required. Neutralizing monoclonal antibodies to TNF-alpha (anti-TNF-alpha) decreased the basal MMP-9 release of these cells. In addition, these antibodies also significantly interfered with the TPA-induced enzyme release. Agents that inhibit TNF-alpha expression in HL-60 cells, such as pentoxifylline and dexamethasone, completely abrogated both the constitutive and TPA-evoked MMP-9 release. Diethyldithiocarbamate, which is known to stimulate TNF-alpha production in HL-60 cells, exerted a positive effect on MMP-9 release in untreated cells but was inhibitory in TPA-treated HL-60 cells. The PKC inhibitor staurosporine at low concentrations (100 ng/mL) caused a significant augmentation of MMP-9 release in untreated cultures that was blocked by the addition of anti-TNF-alpha. High concentrations (2 mumol/L) of staurosporine completely abolished the extracellular enzyme activity both in untreated and TPA-stimulated cells. These results suggest, that TNF- alpha is required for basal and PKC-mediated MMP-9 release in HL-60 leukemia cells. Thus, MMP-9 secretion may be regulated by TNF-alpha not only in a paracrine but also in an autocrine fashion. This may potentiate the matrix degradative capacity of immature leukemic cells in the processes of bone marrow egress and the evasion of these cells into peripheral tissue

Orthogonal invariant sets of the diffusion tensor and the development of a curvilinear set suitable for low-anisotropy tissues.

We develop a curvilinear invariant set of the diffusion tensor which may be applied to Diffusion Tensor Imaging measurements on tissues and porous media. This new set is an alternative to the more common invariants such as fractional anisotropy and the diffusion mode. The alternative invariant set possesses a different structure to the other known invariant sets; the second and third members of the curvilinear set measure the degree of orthotropy and oblateness/prolateness, respectively. The proposed advantage of these invariants is that they may work well in situations of low diffusion anisotropy and isotropy, as is often observed in tissues such as cartilage. We also explore the other orthogonal invariant sets in terms of their geometry in relation to eigenvalue space; a cylindrical set, a spherical set (including fractional anisotropy and the mode), and a log-Euclidean set. These three sets have a common structure. The first invariant measures the magnitude of the diffusion, the second and third invariants capture aspects of the anisotropy; the magnitude of the anisotropy and the shape of the diffusion ellipsoid (the manner in which the anisotropy is realised). We also show a simple method to prove the orthogonality of the invariants within a set

SUSTAINABILITY OF A LONG TERM PROFESSIONAL DEVELOPMENT PROGRAM

Currently, in most school districts, the main form of teacher education comes from professional development (PD) that claims to improve teaching and student achievement. School districts and teachers spend time and money trying to make sure that they are providing the best quality education for their students. Yet, educators are looking for what the most effective form of PD should look like. Utilizing the methodology of a descriptive case study a long-term PD grant, called Science Alliance was evaluated to add to the research on PD and grant program efficacy. Twelve teachers that participated in the Science Alliance grant were interviewed, observed, and given a survey to see how and to what degree they were implementing the inquiry methodology three years after the grant ended. The results were compared with previously existing data that were collected by a company that Science Alliance hired to complete external research on the effects of the PD. The findings suggest that the teachers that participated have sustained the utilization and implementation of the methodology learned during the training. School administrators and/or staff developers could utilize the findings from this study to see what effective PD may entail. Future researchers may use findings from this study when reporting about grant program evaluations and/or PD

Elder abuse: The role of general practitioners in community-based screening and multidisciplinary action

BACKGROUND:There are growing calls for elder abuse screening to be conducted by a range of community-based service providers, including general practitioners (GPs), practice nurses, home care workers and lawyers. Improved screening may be a valuable first step towards improving elder abuse detection and response; however, practitioners need evidence-based strategies for screening and follow-up. OBJECTIVE:This article summarises several brief screening tools for various forms of elder abuse. Screening tool properties and evidence gaps are noted. As elder abuse often requires multidisciplinary responses, initiatives to connect health, legal and other service providers are highlighted. DISCUSSION:GPs are trusted professionals who are well placed to identify older patients at risk of, or experiencing, various forms of abuse. They should be aware of available screening tools and consider how best to incorporate them into their own practice. They also play an important role in multidisciplinary action to address elder abuse.  

Endometrial Histology of Depomedroxyprogesterone Acetate Users: A Pilot Study

Objective. To obtain pilot data on the endometrial histology of Depomedroxyprogesterone acetate (Depo-Provera, DMPA) users experiencing breakthrough bleeding (BTB) versus users with amenorrhea. To compare the endometrial histology of patients who used DMPA continuously for 3–12 months versus those who used it for 13 months or more. Methods. Cross-sectional study. Endometrial biopsy was obtained fromall consenting patients who used DMPA for at least 3 months. Patients were divided into those with BTB in the last 3 months versus those with amenorrhea for at least 3 months. Histology results and duration of therapy were compared. Results. The proportion of women with chronic endometritis, uterine polyps, atrophic, proliferative, or progesteronedominant endometrium did not differ between those DMPA users with BTB versus those with amenorrhea. Duration of therapy did not correlate with symptoms of BTB or endometrial histology. Chronic endometritis was the most common histologic finding (10/40, 25%) and occurred more often in women experiencing BTB (35% versus 15%) (RR 1.62 CI 0.91–2.87). Moreover, 45% of women with BTB had received DMPA for more than 12 months. Conclusions. BTB was more common than previously reported in women using DMPA for more than 12 months. Chronic endometritis, which may indicate an underlying infectious or intracavitary anatomic etiology, has not been previously reported as a frequent finding in DMPA users, and may be related to ethnic or other sociodemographic characteristics of our patient population. Further study to elucidate the etiology of chronic endometritis in these patients is warranted

Ethical and legal aspects of research involving older people with cognitive impairment: A survey of dementia researchers in Australia

© 2019 Elsevier Ltd People with dementia are under-represented in clinical research, in part due to the ethical and legal complexities of involving people in studies who may lack capacity to consent. Excluding this population from research limits the evidence to inform care. The attitudes and practices of researchers are key to the inclusion of people with dementia in research, however, there are few empirical studies on researchers' perspectives in this area. A cross-sectional study involved researchers in Australia who had experience in the ethical aspects of conducting dementia-related studies with human participants (n = 70). Data were collected via an online survey from November 2017 to January 2018. Most respondents (97%) agreed with the importance of including people at all stages of dementia in research, yet around three-quarters of respondents perceived ethical and legal rules and processes as unduly restrictive or time-consuming. Researchers reported variable practices in assessing prospective participants' capacity to consent to their studies. Various tools are used for this purpose, ranging from tools designed for research (eg, MacArthur Competence Assessment Tool for Clinical Research) to more general cognitive function screens (eg, Mini Mental State Exam). Few respondents (14%) routinely exclude people from studies who are unable to give their own consent, but instead seek permission from proxy decision-makers, such as legally appointed guardians or family carers. Respondents reported positive and negative outcomes of ethics review processes. Positive outcomes included strengthening the protections for participants with cognitive impairment while negative outcomes included delays and inconsistent decisions from different ethics committees. The findings suggest a need for improved strategies in the research context to assess and enhance the decision-making capacity of people with dementia to support appropriate opportunities for inclusion. Education for ethics committees, proxy decision-makers and other gatekeepers is also needed to reduce barriers to participation in research

An improved model for the Earth's gravity field

An improved model for the Earth's gravity field, TEG-1, was determined using data sets from fourteen satellites, spanning the inclination ranges from 15 to 115 deg, and global surface gravity anomaly data. The satellite measurements include laser ranging data, Doppler range-rate data, and satellite-to-ocean radar altimeter data measurements, which include the direct height measurement and the differenced measurements at ground track crossings (crossover measurements). Also determined was another gravity field model, TEG-1S, which included all the data sets in TEG-1 with the exception of direct altimeter data. The effort has included an intense scrutiny of the gravity field solution methodology. The estimated parameters included geopotential coefficients complete to degree and order 50 with selected higher order coefficients, ocean and solid Earth tide parameters, Doppler tracking station coordinates and the quasi-stationary sea surface topography. Extensive error analysis and calibration of the formal covariance matrix indicate that the gravity field model is a significant improvement over previous models and can be used for general applications in geodesy

The calpastatin-derived calpain inhibitor CP1B reduces mRNA expression of matrix metalloproteinase-2 and-9 and invasion by leukemic THP-1 cells

The ubiquitous proteases μ- and m-calpain are Ca2+-dependent cysteine endopeptidases. Besides involvement in a variety of physio(patho)logical processes, recent studies suggest a pivotal role of calpains in differentiation of hematopoietic cells and tumor cell invasion. However, the precise actions of calpains and their endogenous inhibitor, calpastatin, in these processes are only partially understood. Here we have studied the role of the calpain/calpastatin system in the invasion of leukemic cells under basal and differentiationstimulating conditions. To further differentiate the human leukaemic cell line THP-1 (monocytic), the cells were treated for 24 hours with the differentiationstimulating reagents phorbol 12-myristate 13-acetate (PMA) and dimethyl sulfoxide (DMSO). Macrophage and granulocytelike differentiation was confirmed by induction of vimentin expression as well as by microscopic and fluorescence assisted cytometric analysis. Extracellular matrix (ECM) invasion of both the basal and differentiation stimulated cells in a Matrigel assay was inhibited by preincubation of the cells with the specific calpain inhibitor CP1B for 24 hours. Inhibition of invasiveness correlated with decreased mRNA expression and secretion of the matrix metalloproteinases MMP-2 and MMP-9. In contrast, addition of CP1B only during the invasion process did neither influence transmigration nor MMP release. This is the first report showing that the calpain/calpastatin system mediates MMPmRNA expression of the leukemic THP-1 cells and as a consequence their invasiveness