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Biomedical subjects

William M Brown

Publications and source records attributed to William M Brown.

12 recordsLinked to original sources

rAAt (dermatological) Arriva/ProMetic.

Arriva Pharmaceuticals Inc and ProMetic Life Sciences Inc are developing a gel formulation of recombinant alpha1-antitrypsin (rAAT). The therapy, as a topical formulation, is in phase II clinical trials for the potential treatment of atopic dermatitis and severe dermatological disorders. rAAT is also under preclinical investigation for the potential treatment of other inflammatory skin conditions, including psoriasis, as well as for otitis media.

Administration, Topical↗

rAAt (inhaled) Arriva/Hyland Immuno.

Arriva Pharmaceuticals Inc and Hyland Immuno are developing a nebulized formulation of the recombinant alpha1-antitrypsin (rAAT) for the potential treatment of respiratory disorders, including emphysema, asthma and chronic obstructive pulmonary disease. The therapy, as a nebulized formulation, is currently undergoing phase II clinical trials.

Clinical Trials, Phase I as Topic↗

TRX-4 (TolerRx Inc).

TolerRx Inc, under license from BTG plc, is developing TRX-4, an anti-CD3 humanized monoclonal antibody for the potential treatment of type 1 diabetes and psoriasis. Phase II trials of the therapeutic antibody in type 1 diabetes have been completed and the company is planning a pivotal phase III trial for this indication. TolerRx is also enrolling psoriasis patients in a phase Ib clinical study of TRX-4. TRX-4 has been awarded Orphan Drug status for recent-onset type 1 diabetes.

Antibodies, Monoclonal↗

Anti-CD3 antibody MacroGenics Inc.

A non-FcR-binding anti-CD3 monoclonal antibody, hOKT3gamma1 (Ala-Ala), originally developed by Columbia University, is being developed by MacroGenics for the potential treatment of type 1 diabetes and autoimmune diseases. Phase I/II trials in patients with diabetes have been completed, and a phase II clinical trial in psoriatic arthritis was initiated in October 2005. A Phase II trial that will evaluate a multi-course study of the drug in patients with new-onset diabetes began in March 2006. MacroGenics is currently seeking to outlicense the project to a strategic partner.

Animals↗

Dance reveals symmetry especially in young men.

Dance is believed to be important in the courtship of a variety of species, including humans, but nothing is known about what dance reveals about the underlying phenotypic--or genotypic--quality of the dancer. One measure of quality in evolutionary studies is the degree of bodily symmetry (fluctuating asymmetry, FA), because it measures developmental stability. Does dance quality reveal FA to the observer and is the effect stronger for male dancers than female? To answer these questions, we chose a population that has been measured twice for FA since 1996 (ref. 9) in a society (Jamaican) in which dancing is important in the lives of both sexes. Motion-capture cameras created controlled stimuli (in the form of videos) that isolated dance movements from all other aspects of visual appearance (including FA), and the same population evaluated these videos for dancing ability. Here we report that there are strong positive associations between symmetry and dancing ability, and these associations were stronger in men than in women. In addition, women rate dances by symmetrical men relatively more positively than do men, and more-symmetrical men value symmetry in women dancers more than do less-symmetrical men. In summary, dance in Jamaica seems to show evidence of sexual selection and to reveal important information about the dancer.

Adolescent↗

Cilomilast GlaxoSmithKline.

GlaxoSmithKline is developing cilomilast, a phosphodiesterase 4 inhibitor, for the potential treatment of chronic obstructive pulmonary disease. The compound has been assessed in phase III clinical trials.

Animals↗

Just how happy is the happy puppet? An emotion signaling and kinship theory perspective on the behavioral phenotype of children with Angelman syndrome.

The favored level of parental investment in a child may differ for genes of maternal and paternal origin in the child. This conflict can be expressed in the phenomenon of genomic imprinting that refers to situations in which the same gene is differentially expressed depending on its parent of origin. Two disorders that show the effects of genomic imprinting--both at 15q11-q13--are Angelman Syndrome (AS) which is due to the absence of expression of maternally-inherited genes and Prader-Willi syndromes (PWS) which is due to the absence of expression of paternally-inherited genes. However, although both disorders can arise from the deletion of the same genetic region, the gustatory, behavioral, and affective characteristics of AS and PWS children are remarkably distinct. Recent research inspired by kinship theory has suggested the origins of these phenotypic differences may lie in the differential investment of each parent's genome in the AS or PWS child. Specifically, it is thought that each set of parental genes have different 'ideas' regarding how the child should behave towards the mother and how much investment they should look to extract. In normal cases, the trade-off between the competing parental genomes produces a behavioral equilibrium in the child. However, in pathological instances, particularly where gene expression is one-sided, the evolved behavioral strategies favored by the contributing genome will dominate the child's behavior. To date, research in the area of genomic conflict in AS and PWS children has primarily focusing on differences in post-natal nutrition-related behaviors. The current paper extends this framework by offering an emotion and evolutionary signaling interpretation of the affective characteristics of AS children. A review of the affective characteristics of the two syndromes (PWS and AS) is presented before kinship and emotions theory are used to examine the functions that differential affect expression may serve in altering maternal investment. We expected that because the ultimate goal of paternal genes is to increase the child rearing burden of mothers, the Angelman behavioral phenotype should exhibit the emotion signaling characteristics that elicit levels of investment more consistent with paternal genetic interests. AS children display more positive, relative to negative, affect expressions (i.e. AS children laugh and smile more frequently than PWS children). In affect signaling theories, positive affect signals (i.e., smiling, laughing) have evolved to manipulate the sensory systems of receivers to increase social resources. In contrast, because the expression of some negative affects may indicate to the mother that the infant is not viable, negative affect expression is characteristically low among AS children. However, AS children may nonetheless have high levels of non-expressed anxiety because of its role in assisting the child (and its paternal genome) to maintain vigilance for changes in investment on the part of the mother. Overall, our kinship and emotion signaling analysis of AS children suggests that their global pattern of affect signaling represents one manifestation of an array of possible evolved strategies within the parental genome. Specifically, because AS exhibits the effects of paternally-inherited genes unhindered by the expression of maternally-inherited genes, the AS infant manifests a pattern of expression and non-expression that maximize maternal investment and thus paternal fitness. This theory is a significant departure from the standard but erroneous conjecture that a mother and child's inclusive fitness interests are one and the same.

Adult↗

17-beta-Hydroxysteroid dehydrogenase type 1: computational design of active site inhibitors targeted to the Rossmann fold.

17-beta-Hydroxysteroid dehydrogenase type 1 (17betaHSD1), also called estradiol dehydrogenase, catalyzes the NADPH-dependent reduction of the weak estrogen, estrone, into the more potent estrogen, 17-beta-estradiol. 17betaHSD1 is an attractive drug target in hormone-sensitive breast cancer. Past efforts to develop selective inhibitors of 17betaHSD1 have focused on design of substrate analogs. It is challenging to develop steroid analogs that are devoid of any undesired biological activity. 17betaHSD1 is a member of the short-chain dehydrogenase/reductase (SDR) superfamily that includes many hydroxysteroid dehydrogenases. Members of the SDR family bind NAD(P)(H) in a motif that is a modified Rossmann fold. We demonstrated previously that the Rossmann folds of classical dehydrogenases can be selectively inhibited by derivatives and analogs of the natural product gossypol. In this study, we have addressed the question whether the modified Rossmann fold in 17betaHSD1 is a target for identification of lead compounds for structure-based drug design. 17betaHSD1 was purified from human placenta. 17betaHSD1 is inhibited by derivatives of gossypol with dissociation constants as low as 2 microM. Inhibition is competitive with the binding of cofactor. Molecular modeling studies using the published coordinates of human 17betaHSD1 suggest that these inhibitors occupy the modified Rossmann fold at the nicotinamide end of the dinucleotide-binding site, extending towards the substrate site. A computational approach was used to design potential new inhibitors of 17betaHSD1. The results suggest not only that derivatives of gossypol represent attractive lead compounds for structure-based drug design but also suggest that appropriate incorporation of a substrate analog into the design of these Rossmann fold inhibitors may provide pan-active site inhibitors that span the cofactor and substrate site, potentially offering specificity and increased potency.

17-Hydroxysteroid Dehydrogenases↗

Intellectual property law: a primer for scientists.

Intellectual property (IP) is a generic legal term for patents, copyrights, and trademarks, which provide legal rights to protect ideas, the expression of ideas, and the inventors and creators of such ideas. A patent provides legal protection for a new invention, an application of a new idea, discovery, or concept that is useful. Copyright provides legal protection from copying for any creative work, as well as business and scientific publications, computer software, and compilations of information. A trademark provides rights to use symbols, particular words, logos, or other markings that indicate the source of a product or service. A further method of benefiting from an invention is simply to keep it secret, rather than to disclose it a trade secret. IP impinges on almost everything scientists do. As scientists are paid to come up with ideas and aspire to patent and/or publish their work, the protection of ideas and of written works especially should be of interest and concern to all.

Biochemistry↗

Inhibition of yeast lipase (CRL1) and cholesterol esterase (CRL3) by 6-chloro-2-pyrones: comparison with porcine cholesterol esterase.

Previously, it was demonstrated that pancreatic cholesterol esterase is selectively inhibited by 6-chloro-2-pyrones with cyclic aliphatic substituents in the 3-position. Inhibition is reversible and is competitive with substrate. Pancreatic cholesterol esterase is a potential target for treatment of hypercholesterolemia. In the present study, yeast cholesterol esterase from Candida cylindracea (also called C. rugosa CRL3) was compared to porcine pancreatic cholesterol esterase for inhibition by a series of 3-alkyl- or 5-alkyl-6-chloro-2-pyrones. In addition, CRL3 was compared with the related yeast lipase CRL1. Inhibition of CRL3 by substituted 6-chloro-2-pyrones was competitive with binding of the substrate p-nitrophenyl butyrate. Inhibition constants ranged from 0.2 microM to >90 microM. Small changes in the alkyl group had profound effects on binding. The pattern of inhibition of CRL3 is quite distinct from that observed with porcine cholesterol esterase. Molecular modeling studies suggest that the orientation of binding of these inhibitors at the active site of CRL3 can vary but that the pyrone ring consistently occupies a position close to the active site serine. CRL1 is highly homologous to CRL3. Nevertheless, patterns of inhibition of CRL1 by substituted 6-chloro-2-pyrones differ markedly from patterns observed with CRL3. The substituted 6-chloro-2-pyrones are slowly hydrolyzed in the presence of CRL1 and are pseudosubstrates of CRL3, but are simple reversible inhibitors of pancreatic cholesterol esterase

Animals↗

Barriers to drug discovery and development for Alzheimer disease.

Alzheimer disease (AD) is a neurodegenerative condition leading to progressive, irreversible loss of cognitive and behavioral function. Despite considerable investments in neuroscience research, only four drugs, all cholinesterase inhibitors, have been approved for the symptomatic management of AD in the United States. Although basically safe and modestly effective, these drugs are far from ideal, being neither universally efficacious nor disease modifying. AD exacts a considerable toll in direct medical costs, quality of life, and caregiver burden for persons and society. In addition to the obvious clinical benefit, therapeutic agents for AD and related dementias represent a considerable market opportunity for the pharmaceutical and biotechnology industries. There are currently 8-10 million AD sufferers in the seven major pharmaceutical markets. The market will grow rapidly in coming decades, as the developed world experiences an enormous increase in its elderly population. Given the great need for new therapeutic agents to manage and prevent AD, the Institute for the Study of Aging and the Fidelity Foundation organized a workshop, "Barriers to the Discovery and Development of Drugs for Alzheimer's Disease," to examine ways to expedite drug discovery and development. The identified barriers and potential solutions will be discussed here and in the accompanying articles in more detail.

Alzheimer Disease↗