Rick J. Koch

Bio: Rick J. Koch is an academic researcher from Icahn School of Medicine at Mount Sinai. The author has contributed to research in topics: Striatum & Dopamine. The author has an hindex of 12, co-authored 17 publications receiving 1059 citations. Previous affiliations of Rick J. Koch include University of Wisconsin-Madison & Veterans Health Administration.

Patterns of cytokine gene expression by CD4+ T cells from young and old mice.

Abstract: We have analyzed the patterns of induced cytokine gene expression and cell cycle activity by CD4+ cells from mice, and have examined how these response patterns change during the aging process. CD4+ cells were isolated from spleens of young adult and old C57BL/6NNia mice and were stimulated in vitro with plate-bound anti-CD3 epsilon mAb. The cells were then assessed over time for the capacity to accumulate transcripts for IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta; to secrete IL-2, IL-3, IL-4, IL-5, IL-6, and IFN-gamma; and to progress through S phase. Before the first major cell division in culture (< 32 h), stimulated CD4+ cells of the old group contained similar peak levels of IL-2, TNF-alpha, and TNF-beta transcripts relative to young adult controls, whereas IL-3, IL-4, IL-5, and IFN-gamma transcripts accumulated to significantly higher peak levels in the old group. These findings were consistent with the patterns of cytokine secretion later in culture (24 to 72 h): the peak IL-2 levels were similar between age groups, but the old group exhibited an enhanced capacity to release IL-3, IL-4, IL-5, and IFN-gamma. In contrast, CD4+ cells of the young group were superior in the hyper-expression of the housekeeping gene, rpL32, before cell division and in the levels of S phase activity throughout 3-day cultures. Similar analyses of CD4+ cells from mice of intermediate ages showed that the alterations in cytokine profiles occurred gradually from young adulthood to old age, whereas the reductions in proliferative capacity were late life changes. Consistent with previous reports, we found that the splenic CD4+ cell group also underwent a progressive, age-dependent increase in the proportions of cells expressing high levels of membrane CD44 (a phenotype associated with memory or effector cells). Moreover, the analysis of IL-3, IL-5, and IFN-gamma production by isolated CD4+CD44lo and CD4+CD44hi cells revealed that the capacity to produce these cytokines segregated predominantly with the CD44hi subset, regardless of donor age. Taken together, our data suggest that gradual age-associated shifts in the subset composition of the splenic CD4+ cell pool underlie progressive changes in the patterns of cytokine gene expression by this cell group.

The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations

Abstract: The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.

Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol

Abstract: The phenolic lignans enterolactone and enterodiol appear periodically in women's urine, dependent upon synthesis from plant-derived lignans by the intestinal microflora. The phytoestrogen equol is also present in women's urine, and is also derived from a vegetarian diet. Antiestrogenic or antiproliferative actions of these compounds have been postulated and related to the observation that there is a reduced incidence of breast cancer associated with diet. We evaluated the estrogenic and antiestrogenic activity of these compounds using four sensitive assays in tissue culture, including the use of human breast cancer cell lines T47D and MCF-7. Unexpectedly, we found that enterolactone and enterodiol, as well as equol, are weak estrogens, and that enterolactone and equol could stimulate the growth of estrogen-dependent breast cancer cell lines. We suggest that these environmental agents can promote the growth of breast cancer, particularly hormone-dependent metastases that may be located near the gut or in the mesenteries or liver, where the concentration of these intestinally produced compounds would be highest. Treatment with an antiestrogen such as tamoxifen blocks the estrogenic activity of these compounds. In the absence of treatment with an antiestrogen such as tamoxifen, hormonal therapy to block steroidal estrogen synthesis in a patient with breast cancer could conceivably be circumvented by a vegeterian diet rich in the precursors to estrogenic compounds such as enterolactone and equol.

Structural requirements for the pharmacological activity of nonsteroidal antiestrogens in vitro.

Abstract: The structure-activity relationships of a tamoxifen (TAM) (Z-1-(4- beta-dimethylaminoethoxyphenyl)1,2-diphenylbut-1-ene) series have been investigated. The tamoxifen derivatives were assayed in vitro by their modulation of estradiol (E2)-stimulated prolactin synthesis in primary cultures of dispersed rat pituitary gland cells. Monohydroxylation of TAM in position 4 of the stilbene ring system was found to be the optimal substitution for binding to the estrogen receptor [relative binding affinity (RBA) = 234] and to inhibit E2 (1 nM)-stimulated prolactin synthesis (IC50 7 nM) by pituitary cells in primary culture. Substitution in positions 3 and 4 to form a catechol did not decrease affinity for the estrogen receptor (RBA = 252), and potency as an antiestrogen was maintained in the prolactin assay (IC50 20 nM) as long as oxidation of the catechol was prevented. All of the hydroxylated derivatives of tamoxifen tested were estrogen antagonists; however, removal of the alkylaminoethoxy side chain from TAM produced a full estrogen agonist with low potency (20 nM). In contrast, removal of the side chain from 4-hydroxytamoxifen (4-OH TAM) produced a partial agonist. A structural analogue of 4-OH TAM, 3-[beta-dimethylaminoethoxy]-11-ethyl-12-(4-hydroxyphenyl)5,6- dihydrodibenzo[a,e]-cyclooctene (7c) had a decreased potency (IC50 16 nM) compared with 4-OH TAM (IC50 4 nM in the same experiment) as an estrogen antagonist. If the side chain was changed from a dimethylaminoethoxy to glyceryl, antagonist activity was reduced (IC50 0.8 microM). An allyl side chain produced a compound with no antiestrogenic activity at concentrations up to 1 microM. An adaptation of Belleau's macromolecular perturbation theory is suggested to explain the interaction of agonists, antagonists, and partial agonists at the ligand binding site of the estrogen receptor.

Ligand interaction at the estrogen receptor to program antiestrogen action: a study with nonsteroidal compounds in vitro.

Abstract: The estrogenic and antiestrogenic actions of the geometric isomers of tamoxifen and 4-hydroxytamoxifen were determined in a PRL synthesis assay using primary cultures of dispersed immature rat pituitary gland cells. 4-Hydroxytamoxifen was 100 times more potent as an antiestrogen than tamoxifen. The cis isomer of tamoxifen was a weak estrogen, but the cis isomer of 4-hydroxytamoxifen was converted to the trans isomer during the 6-day assay. This made an accurate determination of the properties of cis-(E)4-hydroxytamoxifen impossible. A series of fixed ring derivatives of the compounds were evaluated in the PRL synthesis assay in vitro to determine their estrogenic and antiestrogenic activities. The fixed ring derivatives of tamoxifen, cis-tamoxifen and trans-(Z)4-hydroxytamoxifen all had properties that were the same as those of the original triphenylethylenes. The fixed ring derivative of the cis-(E) isomer of 4-hydroxytamoxifen was a weak competitive antagonist of estrogen action with only very slight es...

Phyto-oestrogens and Western Diseases

Abstract: Incidences of breast, colorectal and prostate cancer are high in the Western world compared to countries in Asia. We have postulated that the Western diet compared to the semivegetarian diet in some Asian countries may alter hormone production, metabolism or action at the cellular level by some biochemical mechanisms. Our interest has been focused on two groups of hormone-like diphenolic phyto-oestrogens of dietary origin, the lignans and isoflavonoids abundant in plasma of subjects living in areas with low cancer incidence. The precursors of the biologically active compounds detected in man are found in soybean products, whole-grain cereal food, seeds, and berries. The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormone-like compounds. The weakly oestrogenic diphenols formed influence sex-hormone production, metabolism and biological activity, intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, cell adhesion and angiogenesis in such a way as to make them strong candidates for a role as natural cancer-protective compounds. Their effect on some of the most important steroid biosynthetic enzymes may result in beneficial modulation of hormone concentrations and action in the cells preventing development of cancer. Owing to their oestrogenic activity they reduce hot flushes and vaginal dryness in postmenopausal women and may to some degree inhibit osteoporosis, but alone they may be insufficient for complete protection. Soy intake prevents oxidation of the low-density lipoproteins in vitro when isolated from soy-treated individuals and affect favourably plasma lipid concentrations. Animal experiments provide evidence suggesting that both lignans and isoflavonoids may prevent the development of cancer as well as atherosclerosis. However, in some of these experiments it has not been possible to separate the phyto-oestrogen effect from the effect of other components in the food. The isoflavonoids and lignans may play a significant inhibitory role in cancer development particularly in the promotional phase of the disease, but recent evidence points also to a role in the initiation stage of carcinogenesis. At present, however, no definite recommendations can be made as to the dietary amounts needed for prevention of disease. This review deals with all the above-mentioned aspects of phyto-oestrogens.

The BioGRID interaction database: 2019 update

Abstract: The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the curation and archival storage of protein, genetic and chemical interactions for all major model organism species and humans. As of September 2018 (build 3.4.164), BioGRID contains records for 1 598 688 biological interactions manually annotated from 55 809 publications for 71 species, as classified by an updated set of controlled vocabularies for experimental detection methods. BioGRID also houses records for >700 000 post-translational modification sites. BioGRID now captures chemical interaction data, including chemical-protein interactions for human drug targets drawn from the DrugBank database and manually curated bioactive compounds reported in the literature. A new dedicated aspect of BioGRID annotates genome-wide CRISPR/Cas9-based screens that report gene-phenotype and gene-gene relationships. An extension of the BioGRID resource called the Open Repository for CRISPR Screens (ORCS) database (https://orcs.thebiogrid.org) currently contains over 500 genome-wide screens carried out in human or mouse cell lines. All data in BioGRID is made freely available without restriction, is directly downloadable in standard formats and can be readily incorporated into existing applications via our web service platforms. BioGRID data are also freely distributed through partner model organism databases and meta-databases.

Therapeutic inhibitor of vascular smooth muscle cells

Abstract: Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent.