The Influence of Birth Weight on Body Mass Index in Young Children in Northwest Arkansas

Body Mass Index (BMI) is a screening tool to measure body fat that is calculated based on the height, weight, age, and gender of a child. Being overweight as a child is defined as having a BMI between the 85th and 95th percentiles. Obesity is defined as having a BMI at or above the 95th percentile (“Basics About Childhood Obesity,” 2012). Having a high BMI comes with an increased risk of multiple co-morbidities, both physical and psychosocial (Pulgarón, 2013). Birth weight has been presumed to play a role in the prevalence of obesity in children. The purpose of this study was to determine the correlation of birth weight and obesity. A retrospective chart review from patients Harvey Pediatric evaluated weight at birth, two years, four years, and seven years of age to determine if there was a correlation between BMI and birth weight in NWA. 53 chart reviews were completed, and although there were small positive correlations between birth weight and body mass index at ages two and four, there was no statistically significant correlation. Therefore the hypothesis, there is no statistically significant difference between birth weight and BMI measurements in children at the ages of birth, 2, 5, and 7 years, was accepted

Antibacterial Host Defence Mechanisms in Rheumatoid Arthritis

The present in vitro studies employed a radioassay, incorporating tritiated [3H] thymidine, to measure phagocytic uptake of Staphylococcus aureus (S. aureus) by polymorphonuclear leucocytes (PMNs) of patients with rheumatoid arthritis (RA) and healthy controls. An intrinsic defect was detected in the phagocytic capacity of peripheral blood (PB) PMNs from patients with RA. Serum from RA patients and normals had a similar inhibitory effect on PMN phagocytosis. However, synovial fluid (SF) from RA patients was found to impair phagocytic ability by acting directly on the PMN. Furthermore, these SF significantly impaired PMN uptake as compared to SF from patients with various other arthritides. No correlation was found between defective phagocytosis and age, disease activity, drug therapy, the amount of circulating immune complexes (ICs) or rheumatoid factor (RF). Also, the lack of correlation between clinical parameters such as titres of RF and complement components, suggests factors other than ICs may be involved in this inhibitory activity. Complement levels and heat-labile opsonic activity were lower in SF from RA patients than SF from other forms of arthritis or normal serum. Nevertheless, none of the RA sera or SF tested lacked opsonic activity. Interleukin 1 (IL-1) production by monocytes of RA patients and normal subjects were studied both spontaneously and after lipopolysaccharide (LPS) and S. aureus stimulation. Interleukin 1 activity was measured using the LBRM TG-6/HT2 bioassay system. Rheumatoid arthritis monocytes spontaneously produced more IL-1 than the controls and this difference was maintained after stimulation. When paired PB and SF monocytes were compared, SF cells produced less IL-1 than corresponding PB monocytes, but more than normal PB monocytes. This was similarly observed after stimulation. These findings suggest that this line of host defence is not impaired in RA patients. However, a high concentration of IL-1 may be detrimental to the PMNs migrating into the SF from the PB. Hydrocortisone sodium phosphate was found to inhibit IL-1 production. This is not true for the other anti-rheumatic drugs studied. Thus, the findings of these studies suggest that the increased incidence of bacterial infection in RA patients is the consequence of impaired PMN phagocytosis. The mechanism underlying this defect could be intrinsic to the cell, and amplified by extracellular inhibitory factors present in SF, as yet to be characterised

FAK goes nuclear to control anti-tumor immunity – a new target in cancer immuno-therapy

Evading the antitumor immune response is important for the survival and progression of cancer. Recently, we identified an unexpected role for nuclear Focal Adhesion Kinase (FAK) activity in the control of tumor Treg levels and immune evasion by regulating chemokine and cytokine transcription in cancer cells. We proposed a potentially new purpose for FAK kinase inhibitors, which can cause immune-mediated tumor regression

Phenotypic manipulation of normal and malignant brain cells

In this investigation several questions were posed about expression of differentiated and malignancy-associated properties in cell cultures derived from grades III and IV anaplastic astrocytomas. For comparison, cells derived from normal adult post-mortem brain and foetal brain, were also investigated. Characterisation studies were complicated by the absence of the astrocyte-specific protein, GFAP from the normal adult cultures and many of the gliomas. Other groups of workers have demonstrated that both normal glia-(278) and glioma-(110) derived cultures can lose GFAP as a result of in vitro growth. In the case of the malignant cells, the loss of cellular differentiation could also be the result of in vitro neoplasia. GFAP positive glioma cultures were presumed to contain highly differentiated astrocytoma cells, whereas GFAP negative cultures probably contained less well differentiated or more anaplastic cells. Biochemical investigation led to the hypothesis that the flat polygonal cells obtained in cultures from normal adult brain tissue were percursor glial cells or glioblasts. The malignant cell lines represented a gradation in states of biochemical, astroglial differentiation. The degree of differentiation exhibited by a particular cell line was not related to the pathological state of the tumour from which it was derived. The foetal cultures contained apparently mature, highly differentiated astroglia and were found to be pheno-typically stable, relative to the normal adult and malignant cultures, in response to environmental changes. The accumulation of immunological and biochemical data for many cell lines led to the postulation of a possible astroglial precursor pathway. Investigating the relationship between differentiated and malignancy-associated properties, required the development of assays to represent marker properties. GFAP, high affinity GABA uptake and glutamine synthetase were chosen to represent expression of the differentiated astroglial phenotype and plasminogen activator and tumour angiogenesis factor (or endothelial cell mitogenesis), the malignancy associated phenotype. The effects of varying the microenvironment of the cells in culture were investigated in a number of ways. Increasing cell density, dramatically increased the expression of GFAP in C6 cultures and high affinity GABA uptake in many cell lines, at the onset of confluence. As these differentiated properties were stimulated, the production of PA in malignant cell lines was dramatically reduced; possible explanations for the observed effects with changing cell density were put forward in terms of the proliferative state of cells and the formation of cell-cell contacts. Experiments with heterologous co-cultures and high density perfusion cultures, further demonstrated the importance of cell-cell contacts in the expression of differentiation. The effects of exposing neoplastic cells to various chemical agents were also investigated. Some of the agents upset the balance between differentiated and malignancy-associated properties. In particular dexamethasone, pig brain extract and interferon pushed the phenotypic expression of malignant cells in the direction of more mature, differentiated astroglia, at the same time reducing expression of the malignancy- associated properties. The tumour promoting phorbol ester, TPA, effectively pushed the balance of phenotypic expression in the direction of malignancy, as determined by in vitro criteria. The differentiated properties were unaffected by this agent. The DNA-alkylating carcinogens,mitomycin C and methylnitrosourea, both used clinically in the treatment of cancer, stimulated expression of both differentiated and malignancy-associated properties. The relevance of these findings in considering the growth and spread of tumours after chemotherapy, and possible new treatment procedures for malignant disease, are discussed

Src/FAK-mediated regulation of E-cadherin as a mechanism for controlling collective cell movement Insights from in vivo imaging

Recent advances in confocal and multi-photon microscopy, together with fluorescent probe development, have enabled cancer biology studies to go beyond the culture dish and interrogate cancer-associated processes in the complex in vivo environment. Regulation of the tumor suppressor protein E-cadherin plays an important role in cancer development and progression, and may contribute to the decision between ‘single cell’ and ‘collective invasion’ in vivo. Mounting evidence from in vitro and in vivo experiments places the two nonreceptor protein tyrosine kinases Src and Focal Adhesion Kinase at the heart of E-cadherin regulation and the crosstalk between integrins and cadherins. Here we discuss recent insights, attained using high-resolution fluorescent in vivo imaging, into the regulation of E-cadherin and collective invasion. We focus on the regulatory crosstalk between the Src/FAK signaling axis and E-cadherin in vivo

c-Src drives intestinal regeneration and transformation

The non‐receptor tyrosine kinase c‐Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult <i>Drosophila</i> and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage‐induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self‐renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non‐redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation <i>in vivo.</i&gt

FAK Deletion Promotes p53-Mediated Induction of p21, DNA-Damage Responses and Radio-Resistance in Advanced Squamous Cancer Cells

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is elevated in a variety of human cancers. While FAK is implicated in many cellular processes that are perturbed in cancer, including proliferation, actin and adhesion dynamics, polarisation and invasion, there is only some limited information regarding the role of FAK in radiation survival. We have evaluated whether FAK is a general radio-sensitising target, as has been suggested by previous reports. We used a clean genetic system in which FAK was deleted from mouse squamous cell carcinoma (SCC) cells (FAK −/−), and reconstituted with exogenous FAK wild type (wt). Surprisingly, the absence of FAK was associated with increased radio-resistance in advanced SCC cells. FAK re-expression inhibited p53-mediated transcriptional up-regulation of p21, and a sub-set of other p53 target genes involved in DNA repair, after treatment with ionizing radiation. Moreover, p21 depletion promoted radio-sensitisation, implying that FAK-mediated inhibition of p21 induction is responsible for the relative radio-sensitivity of FAK-proficient SCC cells. Our work adds to a growing body of evidence that there is a close functional relationship between integrin/FAK signalling and the p53/p21 pathway, but demonstrates that FAK's role in survival after stress is context-dependent, at least in cancer cells. We suggest that there should be caution when considering inhibiting FAK in combination with radiation, as this may not always be clinically advantageous

Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal. In this review we describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets. We detail how they are implementing more physiologically relevant phenotypic assays which better recapitulate key areas of disease biology coupled with more focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer target-annotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.Peer reviewe