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Biomedical subjects

S Briggs

Publications and source records attributed to S Briggs.

At least 19 recordsLinked to original sources
PubMed2000

Structure-based design of potent, amidine-derived inhibitors of factor Xa: evaluation of selectivity, anticoagulant activity, and antithrombotic activity.

To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

Amidines↗
PubMed1997

Acute idiopathic gastric dilation with gastric necrosis in individuals with Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) have excessive appetite with the ability to consume large quantities of food. Absence of vomiting and a high pain threshold are considered manifestations of the disorder. We present 6 patients with PWS with acute dramatic gastric distention. In 3 young adult women with vomiting and apparent gastroenteritis, clinical course progressed rapidly to massive gastric dilatation with subsequent gastric necrosis. One individual died of overwhelming sepsis and disseminated intravascular coagulation. In 2 children, gastric dilatation resolved spontaneously. Gastrectomy specimens--in 2 cases subtotal and distal, in the other with accompanying partial duodenectomy and pancreatectomy--showed similar changes. All cases demonstrated signs of ischaemic gastroenteritis. All specimens showed diffuse mucosal infarction with multifocal transmural necrosis. Vascular dilatation and small bifrin thrombi were apparent within the infarcted areas. These 6 women with PWS had acute idiopathic gastric dilatation. It is possible that a predisposition to acute gastric dilatation may be related to abnormal gastric homeostasis on a genetic basis. Understanding the mechanisms responsible for this event could increase the understanding of gastrointestinal and appetite regulation in individuals with PWS.

Adult↗
PubMed1995

Two SH2 domains of p120 Ras GTPase-activating protein bind synergistically to tyrosine phosphorylated p190 Rho GTPase-activating protein.

p120 GTPase-activating protein (GAP) is a negative regulator of Ras that functions at a key relay point in signal transduction pathways that control cell proliferation. Among other proteins, p120 GAP associates with p190, a GAP for the Ras-related protein, Rho. To characterize the p120.p190 interaction further, we used bacterially expressed glutathione S-transferase fusion polypeptides to map the regions of p120 necessary for its interactions with p190. Our results show that both the N-terminal and the C-terminal SH2 domains of p120 are individually capable of binding p190 expressed in a baculovirus/insect cell system. Moreover, the two SH2 domains together on one polypeptide bind synergistically to p190, and this interaction is dependent on tyrosine phosphorylation of p190. In addition, mutation of the highly conserved Arg residues in the critical FLVR sequences of both SH2 domains of full-length p120 reduces binding to tyrosine-phosphorylated p190. The dependence on p190 phosphorylation for complex formation with p120 SH2 domains observed in vitro is consistent with analysis of the native p120.p190 complexes formed in vivo. These findings suggest that SH2-phosphotyrosine interaction is one mechanism by which the cell regulates p120.p190 association and thus may be a means for coordinating the Ras- and Rho-mediated signaling pathways.

Animals↗
PubMed1995

Exercise intensity dependent inhibition of 1-methyl-1-nitrosourea induced mammary carcinogenesis in female F-344 rats.

The objective of this experiment was to evaluate the effects of treadmill exercise on tumor induction in an experimental model for breast cancer. Female F-344 rats were injected i.p. with 50 mg MNU/kg body wt at 50 and 57 days of age. Animals were assigned to one of five groups: sham exercise or 35% or 70% maximal treadmill running intensity for 20 or 40 min/day, 5 days per week. These work rates represent an exercise intensity level generally considered insufficient to improve cardiovascular fitness (35% maximal intensity) or an aerobic level of exercise sufficient to improve cardiovascular fitness in humans (70% maximal intensity). Rats were exercised for 3 months following carcinogen administration at which time the experiment was terminated. Mammary cancer incidence was reduced by as much as 37% and cancer multiplicity by < 60% at the highest exercise intensity. Unexpectedly, the degree of protection against cancer was proportional to the intensity but not to the duration of exercise.

Animals↗
PubMed1993

Alkaline elution analysis of DNA fragmentation induced during apoptosis.

We report that alkaline elution analysis fails to provide a complete profile of DNA fragmentation induced by some genotoxic agents, particularly if these agents induce apoptotic cell death resulting in fragmentation of DNA into oligonucleosomal length multimers. It was questioned whether these oligonucleosome fragments are responsible for the more rapidly eluting component of DNA that is observed as a biphasic elution profile when cells treated with certain genotoxic agents are subjected to alkaline elution. The results of this study indicate that DNA fragmented during apoptotic cell death is eluted in fractions before alkaline denaturation that are normally discarded. Collection of fractions prior to alkaline denaturation is recommended for complete evaluation of the total spectrum of damage induced by genotoxic agents, especially when the compound is suspected of inducing cell death by apoptosis.

Alkalies↗
PubMed1993

Fine specificity of antibody recognition of carcinoma-associated epithelial mucins: antibody binding to synthetic peptide epitopes.

The protein core of polymorphic epithelial mucins consists predominantly of a repeating 20 amino acid peptide motif. Many monoclonal antibodies reactive with breast carcinomas recognise determinants located within the mucin protein core, and epitope mapping techniques have demonstrated that these antibodies bind to epitopes of three, four or five amino acids within the hydrophilic sequence, P D T R P A P. Each of these mucin core-reactive antibodies map to epitopes containing the central arginine residue. The fine specificity of a panel of anti-mucin antibodies binding to the tetrameric peptides P D T R or R P A P (synthesised on the heads of polyethylene pins) was examined by systematically replacing each amino acid in turn with all other 19 natural amino acids, and then testing these analogues for antibody binding. We have (i) identified those amino acids in epitopes which are essential for antibody binding, (ii) shown that for each epitope there is a hierarchy of residues required for immune recognition--certain amino acids may be replaced with little or no loss of antibody binding, while the presence of others is essential, and (iii) concluded that antibody specificity is further regulated by the residue(s) flanking an epitope motif which may impose conformational constraints upon the presentation of the epitope to an antibody.

Amino Acid Sequence↗
PubMed1993

Construction of a reshaped HMFG1 antibody and comparison of its fine specificity with that of the parent mouse antibody.

A human antibody with milk mucin specificity was obtained by transferring the complementarity determining regions (CDR) of the mouse antibody HMFG1 onto carefully selected human framework regions. The resulting reshaped human antibody, HuHMFG1, showed no difference in relative affinity for its antigen compared with the parent mouse HMFG1. The minimum epitope recognized by both the mouse and reshaped antibodies was demonstrated by epitope mapping to be identical, and consists of the tetramer PDTR. In a replacement net analysis, in which each of the amino acids was replaced in turn with the 19 other residues, it was determined that mouse HMFG1 and HuHMFG1 reacted with this series of synthetic peptides in an equivalent manner, indicating retention of identical fine specificity in the HuHMFG1 antibody. In contrast to other published reports, this was achieved without involvement of any framework residues in the binding site transfer. These data demonstrate that if well-matching human framework regions are employed grafting the CDR only can be sufficient to confer desired specificities to human antibodies and can, indeed, provide human analogues of mouse antibodies with virtually indistinguishable affinities and fine specificities relative to the mouse parent antibodies.

Amino Acid Sequence↗
PubMed1992

Crack hands: a dermatologic effect of smoking crack cocaine.

We have seen multiple cases of a characteristic skin lesion produced by smoking crack cocaine. We describe a typical case with photographs demonstrating multiple blackened hyperkeratotic lesions of the palmar aspects of the fingers and palm, some linear, some circular. These involve mostly the dominant hand and are caused by the heat of the glass cocaine pipe.

Adult↗
PubMed1991

Immune recognition of linear epitopes in peptide fragments of epithelial mucins.

Anti-human milk fat globule membrane monoclonal antibodies HMFG-1 and HMFG-2 recognize epitopes within the protein core of human polymorphic epithelial mucin (PEM). These have been identified as PDTR and DTR, respectively. Using the solid phase synthesis of immobilized tetrameric peptides, we have systematically investigated the contribution of each amino acid in the immune recognition of the PDTR domain by the antibodies HMFG-1 and HMFG-2. The findings obtained have been interpreted with respect to the presence of, and requirements for elements of secondary structure, which have been identified in this region of the PEM protein core.

Antibodies, Monoclonal↗
PubMed1990

Emergency intraosseous infusion in severely burned children.

Severely burned patients require rapid administration of large volumes of isotonic fluids. Obtaining adequate intravenous (IV) access in children with greater than 70% total body surface area burns may be difficult, time-consuming, and sometimes impossible. This report describes the use of intraosseous infusion technique as a life-saving means of establishing IV access in two severely burned children.

Bone and Bones↗