Single variable domain antibody as a versatile building block for the construction of IgG-like bispecific antibodies.

Bispecific antibodies (BsAb) have been traditionally utilized to redirect cytotoxic effector cells and agents to kill tumor cells expressing the target antigens. Recently a new concept is emerging to develop BsAb that simultaneously block the functions of two tumor-associated targets, eg., growth factor receptors, for enhanced antitumor efficacies.

Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer.

Purpose: Vascular endothelial growth factor receptor-1 (VEGFR-1) plays important roles in promotion of tumor growth by mediating cellular functions in tumor vascular endothelium and cancer cells. Blockade of VEGFR-1 activation has been shown to inhibit pathologic angiogenesis and tumor growth, implicating VEGFR-1 as a potential therapeutic target for the treatment of cancer. We have thus developed a VEGFR-1 antagonist human monoclonal antibody designated as IMC-18F1 and evaluated its antitumor activity in preclinical experimental models to show the therapeutic potential of the antibody for cancer treatment in clinic.

Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors.

Purpose: A human type 1 insulin-like growth factor receptor antibody (A12) has been shown to effectively inhibit human xenograft tumor growth, including androgen-dependent and androgen-independent prostate tumors. Docetaxel, either as a single agent or combined with others, has shown a survival benefit in prostate cancer patients. Based on these data, we investigated the combined in vivo effect of A12 and docetaxel on human androgen-independent and osseous prostate tumor growth.

Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member.

RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target.

R-wave amplitude in lead II of an electrocardiograph correlates with central hypovolemia in human beings.

Objectives: Previous animal and human experiments have suggested that reduction in central blood volume either increases or decreases the amplitude of R waves in various electrocardiograph (ECG) leads depending on underlying pathophysiology. In this investigation, we used graded central hypovolemia in adult volunteer subjects to test the hypothesis that moderate reductions in central blood volume increases R-wave amplitude in lead II of an ECG.

Methods: A four-lead ECG tracing, heart rate (HR), estimated stroke volume (SV), systolic blood pressure, diastolic blood pressure, and mean arterial pressure were measured during baseline supine rest and during progressive reductions of central blood volume to an estimated volume loss of >1,000 mL with application of lower-body negative pressure (LBNP) in 13 healthy human volunteer subjects.

Oesophageal dysmotility in systemic sclerosis: comparison of HRCT and scintigraphy.

The aim of this study was to compare oesophageal abnormalities observed in high-resolution CT with radionuclide transit in patients with systemic sclerosis. 76 patients with systemic sclerosis were evaluated by high-resolution CT and oesophageal transit scintigraphy. Residual activity > or =20% (in relation to peak activity) at 15 s after the beginning of the swallow of the labelled liquid (in supine position) was considered indicative of oesophageal dysfunction.

Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis.

Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro.

Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2.

Compelling evidence suggest that vascular endothelial growth factor (VEGF) and its receptors, especially receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in angiogenesis under both physiological and pathological conditions, including cancer and angiogenic retinopathies such as age-related macular degeneration (AMD). To this end, inhibition of angiogenesis with antagonists to either VEGF or KDR has yielded significant therapeutic efficacy both in preclinical studies in animal models and in clinical trials in patients with cancer and AMD. We previously reported the identification of a high affinity, fully human anti-KDR antibody fragment, 1121B Fab, through a highly stringent affinity maturation process with a Fab originally isolated from a naïve human antibody phage display library.

Inflammation and changes in metabolic syndrome abnormalities in US adolescents: findings from the 1988-1994 and 1999-2000 National Health and Nutrition Examination Surveys.

Background: Understanding of C-reactive protein (CRP) in adult metabolic syndrome is increasing; however, this relationship in children is less clear.

Methods: We compared the prevalence of metabolic abnormalities and metabolic syndrome in fasting 12- to 19-year-olds from the 1999-2000 and 1988-1994 National Health and Nutrition Examination Survey (NHANES). In the more recent dataset we explored the relationship between metabolic abnormalities and CRP as measured by a high-sensitivity assay.

Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells.

The Insulin-like growth factor-1 receptor (IGF-1R) is overexpressed in a variety of tumors including breast, prostate and myeloma. Thus, IGF-1R and its downstream signaling effectors are good candidates for molecular-based targeted antitumor therapies. Indeed, protein inhibitors of IGF-1R signaling and IGF-1R blocking antibodies are undergoing clinical trials.

Incremental ecological exposure risks from contaminated sediments in an urban estuarine river.

Estuaries in urban regions present unique environmental management challenges. Ecosystems in urban estuaries are typically impacted by habitat loss and degradation, watershed modification, and nonpoint and point sources of many chemicals. Restoring such systems requires an understanding of the relative contribution of various stressors to overall ecological conditions and an understanding of shifting patterns of stress over time.

When children eat what they watch: impact of television viewing on dietary intake in youth.

Objectives: To test whether increased television viewing is associated with increased total energy intake and with increased consumption of foods commonly advertised on television, and to test whether increased consumption of these foods mediates the relationship between television viewing and total energy intake.

Design: Prospective observational study with baseline (fall 1995) and follow-up (spring 1997) measures of youth diet, physical activity, and television viewing. We used food advertising data to identify 6 food groups for study (sweet baked snacks, candy, fried potatoes, main courses commonly served as fast food, salty snacks, and sugar-sweetened beverages).

Screening for type 2 diabetes mellitus in children and adolescents: attitudes, barriers, and practices among pediatric clinicians.

Objective: The American Diabetes Association (ADA) recommends screening children at risk for type 2 diabetes with a fasting plasma glucose test or an oral glucose tolerance test. The purpose of this study was to describe attitudes, barriers, and practices related to type 2 diabetes screening in children among pediatric clinicians.

Methods: Pediatricians, nurse practitioners and physician assistants from a multispecialty, group practice in Eastern Massachusetts completed a mailed survey.

Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.

Background & Aims: The p38 mitogen-activated protein kinase (MAPK) regulates the expression of proinflammatory cytokines, which play a critical role in the pathophysiology of Crohn's disease (CD). This study investigated the efficacy and safety of BIRB 796, a highly potent inhibitor of p38 MAPK, in chronic active CD.

Methods: In a multicenter, multinational trial, 284 patients with moderate to severe CD were randomized to receive placebo, or 10, 20, 30, or 60 mg of BIRB 796 twice daily for 8 weeks.

Effects of decreasing sugar-sweetened beverage consumption on body weight in adolescents: a randomized, controlled pilot study.

Objective: The role of sugar-sweetened beverages (SSBs) in promoting obesity is controversial. Observational data link SSB consumption with excessive weight gain; however, randomized, controlled trials are lacking and necessary to resolve the debate. We conducted a pilot study to examine the effect of decreasing SSB consumption on body weight.

Heart rate variability and its association with mortality in prehospital trauma patients.

Background: Accurate prehospital triage of trauma patients is difficult, especially in mass casualty situations. Accordingly, the U.S.

mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.

Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity.

Tumor cell lines expressing the proteasome subunit isoform LMP7E1 exhibit immunoproteasome deficiency.

The immune system can recognize antigenic peptides derived from tumors by their presentation on MHC class I complexes to CTLs. Immunoproteasomes (i20S) can substantially enhance the MHC class I peptide repertoire, making down-regulation of i20S an important strategy of tumor cells in manipulating immune surveillance. Here, we report that human cancer cells express the nonfunctional immunosubunit-variant LMP7E1, in addition to, or instead of LMP7E2, in response to IFN-gamma.

Antigen targeting to MHC class II-enriched late endosomes in colonic epithelial cells: trafficking of luminal antigens studied in vivo in Crohn's colitis patients.

In Crohn's disease (CD), colonic epithelial cells (CECs) are suggested to stimulate pro-inflammatory CD4+ T cells. However, the endocytic pathways of luminal antigens involved in underlying MHC class II presentation by CECs remain unknown. Our aim was to elucidate antigen trafficking and associated MHC class II expression in CECs of CD patients in vivo.

Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers.

Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH) has been implicated in the pathogenesis. The allele ADH1C*1 of ADH1C encodes for an enzyme with a high capacity to generate acetaldehyde.

Radial pulse character relationships to systolic blood pressure and trauma outcomes.

Background: Patient measurements that do not require monitoring equipment may be the only way to evaluate casualties in austere conditions to determine treatment and transport priority. Objective. To test the hypothesis that palpable pulse characteristics in the radial artery would estimate systolic blood pressure (SBP) and predict outcome in trauma patients.

Association of consumption of fried food away from home with body mass index and diet quality in older children and adolescents.

Objectives: Rates of overweight have increased dramatically among children in the United States. Although an increase in consumption of food prepared away from home has paralleled overweight trends, few data exist relating food prepared away from home to change in BMI in children. The goals of this study were to (1) examine the cross-sectional and longitudinal associations between consumption of fried foods away from home (FFA) and BMI and (2) examine the cross-sectional associations between intake of FFA and several measures of diet quality.

Interactive effects of anger expression and ET-1 Lys198Asn polymorphism on vasoconstriction reactivity to behavioral stress.

Background: Ineffective anger expression has been associated with essential hypertension (EH) and with blood pressure (BP) reactivity to stress. The ET-1/Lys198Asn polymorphism has been associated with increased resting BP and exaggerated vasoconstrictive mediated BP reactivity. African Americans (AAs) are at particular risk for development of EH, report greater anger difficulties, and exhibit greater vasoconstrictive reactivity than their European American (EA) counterparts.