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

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

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 and talin: Who is taking whom to the integrin engagement party?

In this issue, Lawson et al. provide new insight into the relationship between FAK and talin during assembly of integrin adhesions on fibronectin. They show that FAK is upstream of talin, and that talin is not required for FAK recruitment or for integrin activation at nascent adhesions. However, FAK-talin binding is required for adhesion turnover and cell motility. The findings question the view that talin is always upstream of focal adhesion protein recruitment to clustered integrin sites

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

Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells

Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish. When investigating the therapeutic potential of combining inhibitors of mutant BRAF and TGFBR1, we noted that unexpectedly, low-dose PLX-4720 (a vemurafenib analogue) promoted proliferation of drug-naïve melanoma cells. Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. Importantly, vemurafenib-resistant patient derived cells retained sensitivity to TGFBR1 inhibition, suggesting that TGFBR1 could be targeted therapeutically to combat the development of vemurafenib drug-resistance

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours