Jennifer L. Carey

Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer

BTG2, a p53-inducible antiproliferative gene, is stimulated in breast cancer cells by activation of nuclear factor kappa B (NF-κB). In rat mammary glands, BTG2 is expressed in epithelial cells and levels decreased during pregnancy and lactation but recovered during involution. Estrogen and progestin suppress BTG2 expression, suggesting that these steroids, which stimulate proliferation and lobuloalveolar development of mammary epithelial cells, may downregulate BTG2 in the mammary gland during pregnancy. Consistent with the report that BTG2 inhibits cyclin D1 expression, suppression of BTG2 mRNA in the mammary gland during gestation, and by estrogen and progestin, correlated with stimulation of cyclin D1. Ectopic expression of BTG2 inhibited breast cancer cell growth by arresting cells in the G1u2009phase, an effect reversed by cyclin D1. BTG2 expression was very low or undetectable in human breast cancer cell lines compared with nontumorigenic mammary epithelial cells, and nuclear expression of BTG2 was absent in 65% of human breast tumors compared with adjacent matched normal glands. Spontaneous mammary tumors arising in a mouse model with targeted expression of the early region of the SV40 large tumor Ag demonstrated loss of BTG2 protein very early during the tumorigenic process. Thus deregulation of BTG2 may be an important step in the development of mammary tumors.

Mullerian-inhibiting substance regulates NF–κB signaling in the prostate in vitro and in vivo

Mullerian-inhibiting substance (MIS) is a member of the transforming growth factor β superfamily, a class of molecules that regulates growth, differentiation, and apoptosis in many cells. MIS type II receptor in the Mullerian duct is temporally and spatially regulated during development and becomes restricted to the most caudal ends that fuse to form the prostatic utricle. In this article, we have demonstrated MIS type II receptor expression in the normal prostate, human prostate cancer cell lines, and tissue derived from patients with prostate adenocarcinomas. MIS induced NF–κB DNA binding activity and selectively up-regulated the immediate early gene IEX-1S in both androgen-dependent and independent human prostate cancer cells in vitro. Dominant negative IκBα expression ablated both MIS-induced increase of IEX-1S mRNA and inhibition of growth, indicating that activation of NF–κB signaling was required for these processes. Androgen also induced NF–κB DNA binding activity in prostate cancer cells but without induction of IEX-1S mRNA, suggesting that MIS-mediated increase in IEX-1S was independent of androgen-mediated signaling. Administration of MIS to male mice induced IEX-1S mRNA in the prostate in vivo, suggesting that MIS may function as an endogenous hormonal regulator of NF–κB signaling and growth in the prostate gland.

Mullerian Inhibiting Substance induces NFkB signaling in breast and prostate cancer cells

The MIS type II receptor is expressed at high levels in the Mullerian duct and in Sertoli cells and granulosa cells of the embryonic and adult gonads. The presence of MIS type II and type I receptors in tissues and cell lines derived from breast and prostate suggests that the prostate and mammary glands may be additional targets for MIS action. In both breast and prostate cancer cells, MIS activated NFkB DNA binding activity and induced IEX-1, an immediate early gene which regulates cell growth and apoptosis. Exposure of cells to MIS inhibited growth by increasing the fraction of cells in the G1 phase of the cell cycle and by inducing apoptosis. These results suggest that MIS may be a putative mediator of growth regulatory signals in the breast and prostate.

Central respiratory failure during acute organophosphate poisoning

Organophosphate (OP) pesticide poisoning is a global health problem with over 250,000 deaths per year. OPs affect neuronal signaling through acetylcholine (Ach) neurotransmission via inhibition of acetylcholinesterase (AChE), leading to accumulation of Ach at the synaptic cleft and excessive stimulation at post-synaptic receptors. Mortality due to OP agents is attributed to respiratory dysfunction, including central apnea. Cholinergic circuits are integral to many aspects of the central control of respiration, however it is unclear which mechanisms predominate during acute OP intoxication. A more complete understanding of the cholinergic aspects of both respiratory control as well as neural modification of pulmonary function is needed to better understand OP-induced respiratory dysfunction. In this article, we review the physiologic mechanisms of acute OP exposure in the context of the known cholinergic contributions to the central control of respiration. We also discuss the potential central cholinergic contributions to the known peripheral physiologic effects of OP intoxication.

Mullerian Inhibiting Substance Promotes Interferon γ-induced Gene Expression and Apoptosis in Breast Cancer Cells

This report demonstrates that in addition to interferons and cytokines, members of the TGFβ superfamily such as Mullerian inhibiting substance (MIS) and activin A also regulate IRF-1 expression. MIS induced IRF-1 expression in the mammary glands of mice in vivo and in breast cancer cells in vitro and stimulation of IRF-1 by MIS was dependent on activation of the NFκB pathway. In the rat mammary gland, IRF-1 expression gradually decreased during pregnancy and lactation but increased at involution. In breast cancer, the IRF-1 protein was absent in 13% of tumors tested compared with matched normal glands. Consistent with its growth suppressive activity, expression of IRF-1 in breast cancer cells induced apoptosis. Treatment of breast cancer cells with MIS and interferon γ (IFN-γ) co-stimulated IRF-1 and CEACAM1 expression and synergistic induction of CEACAM1 by a combination of MIS and IFN-γ was impaired by antisense IRF-1 expression. Furthermore, a combination of IFN-γ and MIS inhibited the growth of breast cancer cells to a greater extent than either one alone. Both reagents alone significantly decreased the fraction of cells in the S-phase of the cell cycle, an effect not enhanced when they were used in combination. However, MIS promoted IFN-γ-induced apoptosis demonstrating a functional interaction between these two classes of signaling molecules in regulation of breast cancer cell growth.

Methods for Evaluating the Content, Usability, and Efficacy of Commercial Mobile Health Apps

Commercial mobile apps for health behavior change are flourishing in the marketplace, but little evidence exists to support their use. This paper summarizes methods for evaluating the content, usability, and efficacy of commercially available health apps. Content analyses can be used to compare app features with clinical guidelines, evidence-based protocols, and behavior change techniques. Usability testing can establish how well an app functions and serves its intended purpose for a target population. Observational studies can explore the association between use and clinical and behavioral outcomes. Finally, efficacy testing can establish whether a commercial app impacts an outcome of interest via a variety of study designs, including randomized trials, multiphase optimization studies, and N-of-1 studies. Evidence in all these forms would increase adoption of commercial apps in clinical practice, inform the development of the next generation of apps, and ultimately increase the impact of commercial apps.

Integrating Personalized Technology in Toxicology: Sensors, Smart Glass, and Social Media Applications in Toxicology Research

Rapid proliferation of mobile technologies in social and healthcare spaces create an opportunity for advancement in research and clinical practice. The application of mobile, personalized technology in healthcare, referred to as mHealth, has not yet become routine in toxicology. However, key features of our practice environment, such as frequent need for remote evaluation, unreliable historical data from patients, and sensitive subject matter, make mHealth tools appealing solutions in comparison to traditional methods that collect retrospective or indirect data. This manuscript describes the features, uses, and costs associated with several of common sectors of mHealth research including wearable biosensors, ingestible biosensors, head-mounted devices, and social media applications. The benefits and novel challenges associated with the study and use of these applications are then discussed. Finally, opportunities for further research and integration are explored with a particular focus on toxicology-based applications.

Drugs and Medical Devices: Adverse Events and the Impact on Women’s Health

A large number of medications and medical devices removed from the market by the US Food and Drug Administration over the past 4 decades specifically posed greater health risks to women. This article reviews the historical background of sex and gender in clinical research policy and describes several approved drugs and devices targeted for use in women that have caused major morbidity and mortality. The intended population for the medications and devices, population affected, approval process, and the basic and legal actions taken against the medication/drug company are also discussed. It is recognized that women are still at risk for harm from unsafe medications and devices, and continued improvements in legislation that promotes inclusion of sex and gender into the design and analysis of research will improve safety for both men and women.

Tension pneumoperitoneum during routine colonoscopy.

Colonoscopy is generally a safe and effective means to detect, diagnose, and treat colonic abnormalities. Although the overall complication rate is low, the morbidity and mortality following perforation approach 50%. Here we present a case of a 49-year-old woman undergoing routine colonoscopy when she suffered bowel perforation and tension pneumoperitoneum. This is a seldom occurrence and may result following bowel perforation with the rapid accumulation of free air into the peritoneal cavity. It is a life-threatening complication and a surgical emergency.

mHealth for the Detection and Intervention in Adolescent and Young Adult Substance Use Disorder

Purpose of ReviewThe goal of this review is to highlight recent research in mHealth-based approaches to the detection and treatment of substance use disorders in adolescents and young adults.Recent FindingsThe main methods for mHealth-based detection include mobile phone-based self-report tools, GPS tracking, and wearable sensors. Wearables can be used to detect physiologic changes (e.g., heart rate, electrodermal activity) or biochemical contents of analytes (i.e., alcohol in sweat) with reasonable accuracy, but larger studies are needed. Detection methods have been combined with interventions based on mindfulness, education, incentives/goals, and motivation. Few studies have focused specifically on the young adult population, although those that did indicate high rates of utilization and acceptance.SummaryResearch that explores the pairing of advanced detection methods such as wearables with real-time intervention strategies is crucial to realizing the full potential of mHealth in this population.