Citations

We recently developed a fast approach for simulating shear waves generated by an acoustic radiation force. The input for these simulations is generated in FOCUS, the “Fast object-oriented C + + simulator” (www.egr.msu.edu/~fultras-web), which rapidly models the three-dimensional (3D) pressure, intensity, and acoustic radiation force on a desktop computer. The shear waves generated by the acoustic radiation force are then quickly simulated with Green's functions for viscoelastic media in a two-dimensional (2D) plane on a high-performance graphics processing unit (GPU). For these simulations, an L7-4 linear array is electronically focused at a depth of 25 mm to generate an acoustic radiation force “push” for 200 microseconds. The simulation results are compared to shear wave data measured in three viscoelastic shear wave phantoms with low, medium, and high values of the shear viscosity using a Verasonics Vantage ultrasound system. The measured and simulated shear wave data are compared for several different combinations of the simulation parameters, where these comparisons are enabled by the rapid acoustic radiation force and shear wave simulations. The results show that the shear waves simulated in 2D planes achieve good agreement with the measured shear wave data. [Work supported in part by NIH Grants EB023051 and DK092255.]

Abstract Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186–96. ©2018 AACR.

The particulate guanylyl cyclase A (pGC-A)/cGMP pathway plays important roles in regulating renal physiological function and as well as in counteracting pathophysiological conditions. Naturally occurring peptide pGC-A activators consist of atrial natriuretic peptide (ANP), b-type NP (BNP), and urodilatin (URO). These activators bind and activate pGC-A, generating the second messenger cyclic 3′,5′ guanosine monophosphate (cGMP). Cyclic GMP binds to downstream pathway effector molecules including protein kinase G (PKG), cGMP-gated ion channels, and phosphodiesterases (PDEs). These mediators result in a variety of physiological actions in the kidney, including diuresis, natriuresis, increased glomerular filtration rate (GFR) and organ protection, thus, opposing renal cellular injury and remodeling. Downstream proteins regulated by PKG include collagen 1 (Col-1), transforming growth factor beta (TGF-β) and apoptosis-related proteins. In addition to their physiological regulatory effects, pGC-A/cGMP signaling is critical for preserving renal homeostasis in different renal diseases such as acute kidney injury (AKI). Regarding therapeutic options, native pGC-A activators have short half-lives and their activity can be further enhanced by advances in innovative peptide engineering. Thus, novel designer peptide pGC-A activators with enhanced renal activity are under development.

If you haven’t measured something, you really don’t know much about it. —Karl Pearson (attributed)Gastrointestinal (GI) symptoms represent an important and often unappreciated cause of morbidity in diabetes, although the significance of this burden across the spectrum of patients and the underlying pathophysiology, including the relationship of symptoms with glycemic control, remain poorly defined. The relevance of GI symptoms and the necessity for their accurate assessment have increased with the greater focus on the gut as a therapeutic target for glucose lowering. This review addresses the prevalence, assessment, pathogenesis, and management of GI symptoms in diabetes, beginning with broad principles and then focusing on specific segments of the GI tract. We initially performed a literature search of PubMed by using synonyms and combinations of the following search terms: “gastrointestinal symptoms”, “diabetes”, “prevalence”, “pathogenesis”, “diagnosis”, and “management”. We restricted the search results to English only. Review papers and meta-analyses are presented as the highest level of evidence where possible followed by randomized controlled trials, uncontrolled trials, retrospective and observational data, and expert opinion.

Background Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change. Methods and Results Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR ‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P <5×10 −8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS 2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P =4.17×10 −8 ). G‐allele carriers of HMGCS 2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P =0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10 −8 . HMGCS 2 , a part of the HMG ‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. Conclusions These results suggest that HMGCS 2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 00246519 and NCT 01203852.

Background Quality clinical trials form an essential part of the evidence base for the treatment of headache disorders. In 1991, the International Headache Society Clinical Trials Standing Committee developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Migraine. In 2008, the Committee published the first specific guidelines on chronic migraine. Subsequent advances in drug, device, and biologicals development, as well as novel trial designs, have created a need for a revision of the chronic migraine guidelines. Objective The present update is intended to optimize the design of controlled trials of preventive treatment of chronic migraine in adults, and its recommendations do not apply to trials in children or adolescents.

Abstract Introduction: Identifying biomarkers of breast cancer risk among young women would have value in developing effective screening and prevention strategies at early ages. We have proposed that DNA methylation analysis of breast milk may provide breast cancer risk information among young women, and could possibly provide etiologic clues related to the higher rates of early onset cancers among African American as compared with White women in the US. Objective: The purpose of this project was to identify associations between genome-wide DNA methylation levels in breast milk and race adjusted for other breast cancer risk factors. Study Population: Cancer-free, lactating U.S. Black (n=57) and White (n=82) women, ages 19 to 44, provided frozen breast milk samples, as well as demographic, behavioral, and reproductive data, to the Breastmilk Laboratory at University of Massachusetts Amherst. Women were uniparous and did not have a personal history of breast cancer at the time of milk donation. Methods: DNA was extracted from breast milk samples using the phenol-chloroform method. Genome-wide methylation analysis was performed on breast milk samples using the Infinium HumanMethylation450 BeadChip. Probes with 50% or more missing data, cross-reactive probes, as well as probes with minor allelic frequency greater than 0.05 in European- or African-Americans were removed, leaving 379,042 CpG sites for analysis. Multivariate generalized linear regression models were used to examine associations between race and other breast cancer risk factors and methylation beta values, adjusting for potential confounding factors. P-values less than 1E-7 were considered statistically significant. Results: Black women in this study were more likely to be never smokers, to not have used over-the-counter pain medication in the past week, and to breastfeed longer. After adjustment by age, BMI, smoking status, and batch number, race was significantly associated with differential methylation at 1143 CpG sites, including 1024 at which Black women demonstrated increased methylation levels. Additionally, breastfeeding duration was associated with 269 CpG sites, with 268 showing a significant inverse relationship with methylation. Methylation sites significantly associated with Black race and lactation duration were located within tumor suppressor and promoter genes as well as in genes implicated in obesity and diabetes. Conclusion: This preliminarily analysis of DNA methylation in breast milk suggests that Black women have increased methylation and longer breastfeeding is associated with reduced methylation. Further research to understand how etiologic factors related to breast cancer may alter DNA methylation patterns in normal breast may lead to improved understanding of breast cancer risk at a young age and potentially causes of racial disparities in breast cancer incidence between White and Black women. Citation Format: Davis Lynn BC, Bodelon C, Pfeiffer RM, Yang HP, Yang H, Lee M, Laird PW, Campan M, Weisenberger DJ, Murphy J, Sherman ME, Browne EP, Anderton DL, Arcaro KF, Gierach GL. Differences in genome-wide DNA methylation levels in breast milk by race and lactation duration [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-10-07.