Interaction between menopausal status and obesity in affecting breast cancer risk.

Obesity has a complex relationship to breast cancer risk that differs in premenopausal and postmenopausal women. Before the menopause, the level of adiposity is inversely related to risk, indicative of a protective effect, whereas in postmenopausal women, particularly the elderly, the association is a positive one, consistent with obesity being a risk factor. The importance of high estrogen production in adipose tissue, with consequent elevation of circulating biologically available estradiol, in the promotional effect of obesity on postmenopausal breast carcinogenesis is well established; the resulting tumors express both estrogen and progesterone receptors.

Synthesis and biological evaluation of heteroanalogues of kotalanol and de-O-sulfonated kotalanol.

The synthesis of nitrogen and selenium analogues of kotalanol and de-O-sulfonated kotalanol, naturally occurring sulfonium-ion glucosidase inhibitors isolated from Salacia reticulata, and their evaluation as glucosidase inhibitors against the N-terminal catalytic domain of human maltase glucoamylase (ntMGAM) are described.

A small molecule that inhibits the interaction of paxillin and alpha 4 integrin inhibits accumulation of mononuclear leukocytes at a site of inflammation.

Extracellular antagonists of alpha 4 integrin are an effective therapy for several autoimmune and inflammatory diseases; however, these agents that directly block ligand binding may exhibit mechanism-based toxicities. Inhibition of alpha 4 integrin signaling by mutations of alpha 4 that block paxillin binding inhibits inflammation while limiting mechanism-based toxicities. Here, we test a pharmacological approach by identifying small molecules that inhibit the alpha 4 integrin-paxillin interaction.

The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma.

The proteasomal pathway of protein degradation involves 2 discrete steps: ubiquitination and degradation. Here, we evaluated the effects of inhibiting the ubiquitination pathway at the level of the ubiquitin-activating enzyme UBA1 (E1). By immunoblotting, leukemia cell lines and primary patient samples had increased protein ubiquitination.

New glucosidase inhibitors from an ayurvedic herbal treatment for type 2 diabetes: structures and inhibition of human intestinal maltase-glucoamylase with compounds from Salacia reticulata.

An approach to controlling blood glucose levels in individuals with type 2 diabetes is to target alpha-amylases and intestinal glucosidases using alpha-glucosidase inhibitors acarbose and miglitol. One of the intestinal glucosidases targeted is the N-terminal catalytic domain of maltase-glucoamylase (ntMGAM), one of the four intestinal glycoside hydrolase 31 enzyme activities responsible for the hydrolysis of terminal starch products into glucose. Here we present the X-ray crystallographic studies of ntMGAM in complex with a new class of alpha-glucosidase inhibitors derived from natural extracts of Salacia reticulata, a plant used traditionally in Ayuverdic medicine for the treatment of type 2 diabetes.

A long-wavelength fluorescent substrate for continuous fluorometric determination of alpha-mannosidase activity: resorufin alpha-D-mannopyranoside.

A simple and reliable continuous assay for measurement of alpha-mannosidase activity is described and demonstrated for analysis with two recombinant human enzymes using the new substrate resorufin alpha-d-mannopyranoside (Res-Man). The product of enzyme reaction, resorufin, exhibits fluorescence emission at 585 nm with excitation at 571 nm and has a pK(a) of 5.8, allowing continuous measurement of fluorescence turnover at or near physiological pH values for human lysosomal and Drosophila Golgi alpha-mannosidases.

Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer.

Chromosomal translocations are a hallmark of leukemia/lymphoma and also appear in solid tumors, but the underlying mechanism remains elusive. By establishing a cellular model that mimics the relative frequency of authentic translocation events without proliferation selection, we report mechanisms of nuclear receptor-dependent tumor translocations. Intronic binding of liganded androgen receptor (AR) first juxtaposes translocation loci by triggering intra- and interchromosomal interactions.

Stroke volume variation during acute normovolemic hemodilution.

Background: The intravascular volume of surgical patients should be optimized to avoid complications associated with both overhydration and underresuscitation. In patients undergoing intraoperative acute normovolemic hemodilution, we investigated whether stroke volume variation (SVV) derived from an arterial pressure-based cardiac output (CO) monitor system (FloTrac/Vigileo, Edwards Lifesciences, Irvine, CA) tracked the changes associated with blood removal and replacement. We further evaluated the correlations between SVV and 3-dimensional (3D) transesophageal echocardiographic (TEE) left ventricular (LV) volume measurements.

Paris Lesbos.

This article recounts something of the history of the lesbian world of Paris at the fin de siècle. It tells of the public visibility of lesbian women and the recognition of their place in Paris society whether in the salons of the upper crust, in the theatre, or in the brothels. It touches on the idea of Paris as a city where multiple and transgressive identities played within an unstable ambience where all was masks and mirrors, and little was what it seemed; this itself contributed to the concept of Paris both as a place of decadence and a place of tolerance: "gay Paree.

Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils.

LL-37, derived from human cathelicidin, stimulates immune responses in neutrophils. Although FPR2 and P2X7 were proposed as LL-37 receptors, we have shown that among 21 neutrophil receptors only CXCR2 was down-regulated by LL-37. LL-37 functions similarly to CXCR2-specific chemokines CXCL1 and CXCL7 in terms of receptor down-regulation and intracellular calcium mobilization on freshly isolated neutrophils.

The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects.

Kidney organogenesis depends on reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (MM) to form the UB-derived collecting system and MM-derived nephron. With the advent of in vitro systems, it is clear that UB branching can occur independently of MM contact; however, little has been done to detail the role of MM cellular contact in this process. Here, a model system in which the cultured isolated UB is recombined with uninduced MM is used to isolate the effects of the MM progenitor tissue on the development and maturation of the collecting system.

Human lysosomal alpha-mannosidases exhibit different inhibition and metal binding properties.

Two structurally-related members of the lysosomal mannosidase family, the broad substrate specificity enzyme human lysosomal alpha-mannosidase (hLM, MAN2B1) and the human core alpha-1, 6-specific mannosidase (hEpman, MAN2B2) act in a complementary fashion on different glycosidic linkages, to effect glycan degradation in the lysosome. We have successfully expressed these enzymes in Drosophila S2 cells and functionally characterized them. hLM and hEpman were significantly inhibited by the class II alpha-mannosidase inhibitors, swainsonine and mannostatin A.

Influence of obesity on breast cancer receptor status and prognosis.

Pre-existing obesity and postoperative weight gain are related to a poor prognosis in breast cancer regardless of menopausal status. Delayed diagnosis may be one cause, but of more biological significance, especially in younger women, is the association of adiposity with estrogen receptor-negative tumors with a propensity for distant metastasis. After the menopause, the major mechanism for the relationship is the elevated estrogen synthesis by adipose tissue; these hormone-dependent tumors are estrogen receptor-positive.

Angiogenesis, adipokines and breast cancer.

The prevalence of overweight and obesity is rapidly increasing world wide. Numerous epidemiological studies have shown that obesity is a risk factor for postmenopausal breast cancer and relapse. However, the biological factors that drive the growth and progression of these tumors and how obesity contributes to the tumor microenvironment are poorly understood.

The influence of socioeconomic disparities on breast cancer tumor biology and prognosis: a review.

Objective: Socioeconomic deprivation is associated with an increased risk of breast cancer mortality. This article summarizes the relationships between socioeconomic status (SES) and breast cancer in white European women compared with racial and ethnic groups in the United States. Furthermore, we examine the association between obesity and breast cancer within socioeconomic disparities.

Look who's talking: visual detection of speech from whole-body biological motion cues during emotive interpersonal conversation.

Biological motion stimuli contain a great deal of information about the person and action depicted. Here, we extend the known range by showing that viewers can see which member of a pair of conversing actors is talking. Moreover, the ability varies with the emotional content of the conversation.

Total syntheses of casuarine and its 6-O-alpha-glucoside: complementary inhibition towards glycoside hydrolases of the GH31 and GH37 families.

Total synthesis of naturally occurring casuarine (1) and the first total synthesis of casuarine 6-O-alpha-glucoside (2) were achieved through complete stereoselective nitrone cycloaddition, Tamao-Fleming oxidation and selective alpha-glucosylation as key steps. Biological assays of the two compounds proved their strong and selective inhibitory properties towards glucoamylase NtMGAM and trehalase Tre37A, respectively, which place them among the most powerful inhibitors of these enzymes. The structural determination of the complexes of NtMGAM with 1 and of Tre37A with 2 revealed interesting similarities in the catalytic sites of these two enzymes which belong to different families and clans.

The molecular basis of inhibition of Golgi alpha-mannosidase II by mannostatin A.

Mannostatin A is a potent inhibitor of the mannose-trimming enzyme, Golgi alpha-mannosidase II (GMII), which acts late in the N-glycan processing pathway. Inhibition of this enzyme provides a route to blocking the transformation-associated changes in cancer cell surface oligosaccharide structures. Here, we report on the synthesis of new Mannostatin derivatives and analyze their binding in the active site of Drosophila GMII by X-ray crystallography.

Triple-negative breast cancer and obesity in a rural Appalachian population.

Background: Our objective was to determine the clinicopathologic features of triple-negative (estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor negative) breast cancer and their relationship to obesity in women drawn from a population with one of the highest obesity rates in the United States.

Methods: This retrospective study involved 620 White patients with invasive breast cancer in West Virginia. Hospital tumor registry, charts, and pathology records provided age at diagnosis, tumor histologic type, size, nodal status, and receptor status.

Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules.

Although the role of liganded nuclear receptors in mediating coactivator/corepressor exchange is well-established, little is known about the potential regulation of chromosomal organization in the 3-dimensional space of the nucleus in achieving integrated transcriptional responses to diverse signaling events. Here, we report that ligand induces rapid interchromosomal interactions among specific subsets of estrogen receptor alpha-bound transcription units, with a dramatic reorganization of nuclear territories, which depends on the actions of nuclear actin/myosin-I machinery and dynein light chain 1. The histone lysine demethylase, LSD1, is required for these ligand-induced interactive loci to associate with distinct interchromatin granules, long thought to serve as "storage" sites for the splicing machinery, some critical transcription elongation factors, and various chromatin remodeling complexes.

Structural analysis of Golgi alpha-mannosidase II inhibitors identified from a focused glycosidase inhibitor screen.

The N-glycosylation pathway is a target for pharmaceutical intervention in a number of pathological conditions including cancer. Golgi alpha-mannosidase II (GMII) is the final glycoside hydrolase in the pathway and has been the target for a number of synthetic efforts aimed at providing more selective and effective inhibitors. Drosophila GMII (dGMII) has been extensively studied due to the ease of obtaining high resolution structural data, allowing the observation of substrate distortion upon binding and after formation of a trapped covalent reaction intermediate.

Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function.

Aberrant N-linked glycans promote the malignant potential of cells by enhancing the epithelial-to-mesenchymal transition and the invasive phenotype. To identify small molecule inhibitors of N-glycan biosynthesis, we developed a chemical screen based on the ability of the tetravalent plant lectin L-phytohemagglutinin (L-PHA) to bind and crosslink surface glycoproteins with beta1,6GlcNAc-branched complex type N-glycans and thereby induce agglutination and cell death. In this screen, Jurkat cells were treated with a library of off-patent chemicals (n = 1,280) to identify molecules that blocked L-PHA-induced death.

Studies directed toward the stereochemical structure determination of the naturally occurring glucosidase inhibitor, kotalanol: synthesis and inhibitory activities against human maltase glucoamylase of seven-carbon, chain-extended homologues of salacinol.

The synthesis of new seven-carbon, chain-extended sulfonium salts of 1,4-anhydro-4-thio- d-arabinitol, analogues of the naturally occurring glycosidase inhibitor salacinol, are described. These compounds were designed on the basis of the structure activity data of chain-extended analogues of salacinol, with the intention of determining the hitherto unknown stereochemical structure of kotalanol, the naturally occurring seven-carbon chain-extended analogue of salacinol. The target zwitterionic compounds were synthesized by means of nucleophilic attack of the PMB-protected 1,4-anhydro-4-thio- d-arabinitols at the least hindered carbon atom of two 1,3-cyclic sulfates differing in stereochemistry at only one stereogenic center.