Ariel - Volume 9 Number 6

Executive Editor Seth B. Paul Associate Editor Warren J. Ventriglia Business Manager Fredric Jay Matlin University News John Patrick Welch World News George Robert Coar Editorials Editor Steve Levine Features Mark Rubin Sports Editor Eli Saleeby Photo Editor Ken Buckwalter Circulation Victor Onufreiczuk Lee Wugofski Graphics and Art Steve Hulkower Commons Editor Brenda Peterso

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors

INTRODUCTION: Of the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors. METHODS: ER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors. RESULTS: Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues. CONCLUSIONS: The studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites

NAFTA: capstone and cornerstone

North American Free Trade Agreement

Identification of Insertion Deletion Mutations from Deep Targeted Resequencing

Taking advantage of the deep targeted sequencing capabilities of next generation sequencers, we have developed a novel two step insertion deletion (indel) detection algorithm (IDA) that can determine indels from single read sequences with high computational efficiency and sensitivity when indels are fractionally less compared to wild type reference sequence. First, it identifies candidate indel positions utilizing specific sequence alignment artifacts produced by rapid alignment programs. Second, it confirms the location of the candidate indel by using the Smith-Waterman (SW) algorithm on a restricted subset of Sequence reads. We demonstrate that IDA is applicable to indels of varying sizes from deep targeted sequencing data at low fractions where the indel is diluted by wild type sequence. Our algorithm is useful in detecting indel variants present at variable allelic frequencies such as may occur in heterozygotes and mixed normal-tumor tissue

The genetics of speciation: Insights from Fisher's geometric model.

Research in speciation genetics has uncovered many robust patterns in intrinsic reproductive isolation, and fitness landscape models have been useful in interpreting these patterns. Here, we examine fitness landscapes based on Fisher's geometric model. Such landscapes are analogous to models of optimizing selection acting on quantitative traits, and have been widely used to study adaptation and the distribution of mutational effects. We show that, with a few modifications, Fisher's model can generate all of the major findings of introgression studies (including "speciation genes" with strong deleterious effects, complex epistasis and asymmetry), and the major patterns in overall hybrid fitnesses (including Haldane's Rule, the speciation clock, heterosis, hybrid breakdown, and male-female asymmetry in the F1). We compare our approach to alternative modeling frameworks that assign fitnesses to genotypes by identifying combinations of incompatible alleles. In some cases, the predictions are importantly different. For example, Fisher's model can explain conflicting empirical results about the rate at which incompatibilities accumulate with genetic divergence. In other cases, the predictions are identical. For example, the quality of reproductive isolation is little affected by the manner in which populations diverge.Agence Nationale de la Recherche (HYSEA project, ANR-12-BSV7- 0011)This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/evo.1296

Ariel - Volume 9 Number 4

Executive Editor Emily Wofford Business Manager Fredric Jay Matlin University News John Patrick Welch World News George Robert Coar Editorials Editor Steve Levine Features Mark Rubin Brad Feldstein Sports Editor EIi Saleeby Circulation Victor Onufreiczuk Lee Wugofski Graphics and Art Steve Hulkower Commons Editor Brenda Peterso

Centrifugal Compressor Performance Enhancement Through The Use Of A Single Stage Development Rig.

LecturePg. 101-112Despite recent advances in computation fluid dynamics, the complex flows through centrifugal compressor components are still not totally understood. These uncertainties detract from the designer's ability to accurately predict component performance. Consequently, design verification remains largely dependent on performance testing. Some data can be gathered during testing of production units. However, this information can be somewhat limited, i.e., only overall or stage data, no component data. A more direct approach is to gather the required data in a single stage research vehicle. Recent experiences in the use of such a rig are presented. The advantages of rig production testing are described. Also included is a description of the test rig facilities used: the rig itself; the instrumentation; and the data acquisition system. A recent performance comparison of two three-dimensional impellers is discussed. A stage containing the first wheel exhibited an undesirable droop in pressure rise toward surge. Therefore, a new arbitrary bladed, inducer-style impeller was developed and validated in the rig. Test results for both wheels are presented. Tests being conducted using a variable geometry low solidity vaned diffuser (LSO) are also cited. Included are comments on the advantages/disadvantages of LSOs, prior experience, and the factors which prompted the test program. Recent test results are submitted which show the effect of LSD setting angle on stage performance. The authors conclude that single stage rig testing is essential to: acquire a better understanding of existing stages; verify new stage or component designs; validate design procedures; and develop the technology necessary to achieve enhanced compressor performance

Specifications of Futures and Options Contracts

4 pp., 3 tablesTo use futures and options, you must understand how such contracts are specified. This publication features complete descriptions of the contract specifications for both futures and options as they are used for agricultural commodities

Trusted CI Experiences in Cybersecurity and Service to Open Science

This article describes experiences and lessons learned from the Trusted CI project, funded by the US National Science Foundation to serve the community as the NSF Cybersecurity Center of Excellence. Trusted CI is an effort to address cybersecurity for the open science community through a single organization that provides leadership, training, consulting, and knowledge to that community. The article describes the experiences and lessons learned of Trusted CI regarding both cybersecurity for open science and managing the process of providing centralized services to a broad and diverse community.Comment: 8 pages, PEARC '19: Practice and Experience in Advanced Research Computing, July 28-August 1, 2019, Chicago, IL, US