Deglycosylation of anti-beta amyloid antibodies inhibits microglia activation in BV-2 cellular model.

Immunotherapy has become a strategy for treatment of Alzheimer's disease, by inducing antibody response to amyloid-beta peptide (AbetaP) or by passive administration of anti-AbetaP antibodies. Clearance of amyloid plaques involves interaction of immunoglobulin Fc receptor (FcR)-expressing microglia and antibodyopsonized Abeta deposits, stimulating phagocytosis but may promote neuroinflammation. Carbohydrate moiety of Fc of the immunoglobulin G molecule plays a significant role in modulating binding to FcR and its effector functions.

A phase I trial of high-dose palliative radiotherapy plus concurrent weekly Vinorelbine and Cisplatin in patients with locally advanced and metastatic NSCLC.

The role of concurrent chemoradiotherapy (CRT) in patients with non-small-cell lung cancer (NSCLC) unsuitable for radical therapy but who require locoregional treatment has not been defined. The aims of this phase I trial were thus to develop a novel regimen of weekly chemotherapy concurrent with high-dose palliative RT (40 Gy/20 fractions) and assess its tolerability, objective and symptomatic response rates. Eligible patients had stage I-IIIB NSCLC unsuitable for radical RT or limited stage IV disease, ECOG PS View Article and Find Full Text PDF

Single chain antibody against the common epitope of mutant p53 restores wild-type activity to mutant p53 protein.

Here, we describe the biological activity of ME1, a mouse single chain Fv fragment (scFv) against the common epitope of mutant p53, which is efficiently expressed in mammalian cells. We found that in vivo interaction of the conformational p53 mutant R175H protein with the scFv resulted in the acquisition of wild-type p53 characteristics, manifested in trans-activation of p21, as well as induction of apoptosis. Moreover, antibody binding leads to abrogation of the mutant p53 mediated "gain of function" as estimated by downregulation of EGR-1, a transcriptional target of mutant p53.

Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging.

Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [(18)F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.

Evaluation of kiosk-based tailoring to promote household safety behaviors in an urban pediatric primary care practice.

We tested a kiosk-based tailoring intervention with a sample of 144 parents of young children using a two-group randomized controlled design to evaluate the kiosk. Intervention group parents (n = 70) answered 50 questions at a practice-based kiosk and they and their child's physician received immediate feedback reports of their injury prevention needs. Four weeks later, both control (n = 74) and intervention parents completed a telephone interview.

Alzheimer's disease and immunotherapy.

Site-directed antibodies which modulate conformation of beta-amyloid peptide became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3-6 of the N-terminal region of Alzheimer's AbetaP, found to be a key position in protein conformation modulation, suppress formation of beta-amyloid and dissolve already formed fibrillar amyloid. The performance of anti-beta-amyloid antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and dissolving beta-amyloid plaques.

Inhibition of amyloid precursor protein processing by beta-secretase through site-directed antibodies.

Amyloid-beta peptide (AbetaP) that accumulates in the Alzheimer's diseased brain is derived from proteolytic processing of the amyloid precursor protein (APP) by means of beta- and gamma-secretases. The beta-secretase APP cleaving enzyme (BACE), which generates the N terminus of AbetaP, has become a target of intense research aimed at blocking the enzyme activity, thus reducing AbetaP and, subsequently, plaque formation. The search for specific inhibitors of beta-secretase activity as a possible treatment for Alzheimer's disease intensified with the discovery that BACE may be involved in processing other non-APP substrates.

Generation of anti-beta-amyloid antibodies via phage display technology towards Alzheimer's disease vaccination.

The pathology of Alzheimer's disease (AD) shows a significant correlation between beta-amyloid peptide (betaAP) deposition and the clinical severity of dementia. The ability of site-directed antibodies towards the N-terminal region of beta-amyloid peptide to suppress in vitro formation of toxic beta-amyloid serves as a factual basis for in vivo investigations. We localized the epitope of these anti-aggregating antibodies, and injection of phage displaying this epitope induced antibodies against the whole anti-beta-amyloid peptide.

An in vivo evaluation of the diagnostic quality ultra-speed versus insight intraoral dental film.

Twelve sets of FMS (full mouth survey) radiographs were taken by California licensed radiology technicians. Ten of the sets of FMS radiographs were taken using Ultra-Speed "D" film on the left side of the patient and Insight "F" speed film on the right side of the patient. The remaining two sets of films were taken using Insight Film on both sides of the patient to act as a control.

Training in community pediatrics: a national survey of program directors.

Objective: To describe the spectrum of residency training in community-based settings, assess the extent of resident education on community pediatrics topics, and determine whether educational activities vary by program size or availability of primary care tracks.

Methods: Survey of US pediatric residency program directors from May-September 2002. A 10-item self-administered questionnaire assessed the programs' extent of resident involvement in 15 selected community-based settings and inclusion of didactic or practical education regarding 13 community health topics.

EFRH-phage immunization of Alzheimer's disease animal model improves behavioral performance in Morris water maze trials.

We have developed an immunization procedure for the production of effective anti-beta-amyloid (anti-Abeta) antibodies, using filamentous phage displaying only 4 amino acids. The EFRH sequence, encompassing amino acids 3-6 of the 42 residues of Abeta peptide, was found previously to be the main regulatory site for amyloid modulation and the epitope of anti-aggregating antibodies. Engineered filamentous phage enable the display of various numbers of EFRH copies on the phage and serve as potent carriers of antigens.

Generation of anti-beta-amyloid antibodies via phage display technology.

The EFRH sequence, found to be the main anti-aggregating epitope corresponding to amino acids 3-6 of beta-amyloid peptide (AbetaP), was displayed on a phage and used as an antigen for immunization of mice, guinea pigs and rabbits. The generated antibodies recognize the full-length AbetaP (1-40) and exhibit similar biological properties to antibodies raised against whole soluble peptide and/or fibrillar beta-amyloid. EFRH-phage immunization of a transgenic mouse model of Alzheimer's disease evokes antibodies able to dissolve already formed beta-amyloid plaques, suggesting that they could become a therapeutic approach in treatment of the disease.

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure.

Objective: The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure.

Summary Background Data: In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL.

Familial immunodeficiency with cutaneous vasculitis, myoclonus, and cognitive impairment.

We report a family with five of six siblings (including identical male twins) with a novel constellation of immunologic and neurologic impairments. Affected subjects experienced severe dermatitis starting around 9 months of age, Stevens-Johnson syndrome in early childhood, and extreme elevations of IgE (9,400-43,000 IU/ml). The oldest sibling died at age 27 of respiratory failure following recurrent, severe pneumonias.

Generation of antibodies against prion protein in wild-type mice via helix 1 peptide immunization.

We present here the development of antibodies against prion protein in BALB/C mice using as antigen human helix 1 of PrP. This sequence is suggested to be involved in protein pathological conformational changes, and is distinguished from that of mice by one amino acid. The immune tolerance to an 'almost-self' epitope and the poor immunogenicity of short peptides was overcome by using Multiple Antigen Peptide displaying eight copies of helix 1.

Immunological approach for the treatment of Alzheimer's disease.

Formation of amyloid beta (Abeta) is a complex kinetic and thermodynamic process, dependent on peptidepeptide interactions that may be modulated by other proteins. We found that site-directed antibodies toward peptide (glutamic acid, phenyl alanine, arginine, histidine) EFRH sequences 3-6 of the N-terminal region of beta-amyloid peptide (AbetaP) suppress in vitro formation of Abeta and dissolve already formed fibrillar amyloid. These so-called chaperone-like properties of monoclonal antibodies led to the development of a new immunological approach toward Alzheimer's disease (AD) treatment.

Applications of positron emission tomography in the development of molecular targeted cancer therapeutics.

For molecular targeted cancer therapies to fulfill their promise in cancer treatment, innovative approaches are required to overcome significant obstacles that exist in the clinical development of these agents. Positron emission tomography (PET) is a functional imaging technology that allows rapid, repeated, noninvasive, in vivo assessment and quantification of many biological processes and in some cases molecular pathways targeted by these therapies. It is highly sensitive, with the capacity to detect subnanomolar concentrations of radiotracer and provides superior image resolution to conventional nuclear medicine imaging with gamma cameras.

Phase I/II study of concurrent twice-weekly paclitaxel and weekly cisplatin with radiation therapy for stage III non-small cell lung cancer.

The optimal chemoradiation regimen for stage III non-small cell lung cancer (NSCLC) has not been determined. In this phase I/II study, the use of twice-weekly paclitaxel concomitant with weekly cisplatin and thoracic radiotherapy (RT) was evaluated. Patients with stage III NSCLC (without pleural effusion or cervical lymphadenopathy) were treated with thoracic RT (60 Gy in 30 fractions over 6 weeks) with concurrent weekly cisplatin 20 mg/m(2) and escalating doses of twice-weekly paclitaxel (starting dose of paclitaxel of 20 mg/m(2) increased in increments of 5 mg/m(2)) in successive cohorts of three to six patients until two or more patients experienced dose limiting toxicities (DLTs) at a particular dose level.

Quality care at the end of life in Africa.

Each year about 0.5% of the total population in Botswana, Ethiopia, Tanzania, Uganda, and Zimbabwe die from HIV/AIDS or cancer. The members of a WHO project to improve palliative care in these countries discuss their work.

Vaccination for the prevention and treatment of Alzheimer's disease.

In vitro studies showed that beta-amyloid peptide neurotoxicity correlates with the formation of fibrillar beta-amyloid and the variation in neurotoxic potency is related to the extent of peptide aggregation. Many efforts are being focused on the development of potent and selective inhibitors of amyloid formation in order to reduce the extent of their deposition and related neurotoxic effects. In our laboratory we are pioneering the idea that site-directed monoclonal antibodies (MAbs) can solubilize synthetic beta-amyloid aggregates.

Protective Molecules in Alzheimer's Disease: Therapeutic Antibodies.

Treatment of Alzheimer's disease by recruiting an immune response against beta-amyloid was suggested by the findings that monoclonal antibodies against beta-amyloid peptide can keep the peptides from aggregating into neurotoxic fibrils and dissolve already formed amyloid. Subsequent beta-amyloid vaccination studies in transgenic mice models of Alzheimer's disease have shown a significant reduction in the number of amyloid plaques and overall amyloid burden and even some improvement in cognitive performance. It is not yet clear if immunization with soluble or fibrillar forms of beta-amyloid peptide will end up being a treatment to prevent or treat Alzheimer's disease.

EGFR blockade with ZD1839 ("Iressa") potentiates the antitumor effects of single and multiple fractions of ionizing radiation in human A431 squamous cell carcinoma. Epidermal growth factor receptor.

Purpose: Signaling pathways initiated by the epidermal growth factor receptor (EGFR) play important roles in the response to ionizing radiation. In this study the consequences of inhibiting the EGFR on the response of A431 cells (human vulvar squamous cell carcinoma cells that overexpress EGFR) to radiation, were investigated in vitro and in vivo, using the selective EGFR-tyrosine kinase inhibitor, ZD1839 ("Iressa").

Methods And Materials: The effect of ZD1839 on proliferation, apoptosis, and clonogenic survival after radiation was determined in vitro.

Reduction of beta-amyloid plaques in brain of transgenic mouse model of Alzheimer's disease by EFRH-phage immunization.

Antibodies to the epitope EFRH, representing residues 3-6 within the beta-amyloid (Abeta) sequence, were previously shown to affect the solubility and disaggregation of Abeta fibrils in vitro. Here, we describe a novel method of immunization, using as antigen the EFRH peptide displayed on the surface of the filamentous phage. The EFRH phage evoked effective auto-immune antibodies in amyloid precursor protein [V717I] (APP[V717I]) transgenic mice that recapitulate the amyloid plaques and vascular pathology of Alzheimer's disease (AD).