In this issue, Lyons et al. report that human mutations in the gene encoding the tyrosine kinase receptor EPH receptor B4 (EPHB4) result in venous valve disease. Further, using mouse models, they demonstrate that ephrinB2/EphB4 signaling is required for venous valve development. The cover image shows a large WT mouse venous valve in the femoral vein at postnatal day 6, with staining for smooth muscle α-actin (white), PECAM1 (blue), Foxc2 (green), and Prox1 (red).
Ozone is a highly reactive environmental pollutant with well-recognized adverse effects on lung health. Bronchial hyperactivity (BHR) is one consequence of ozone exposure, particularly for individuals with underlying lung disease. Our data demonstrate ozone induces substantial ATP release from human airway epithelia in vitro and into the airways of mice in vivo, and that ATP is a potent inducer of mast cell degranulation and BHR, acting through P2X7 receptors on mast cells. Both mast cell-deficient and P2X7 receptor-deficient (P2XT-/-) mice demonstrate markedly attenuated BHR to ozone. Re-constitution of mast cell-deficient mice with WT mast cells and P2X7-/- mast cells restores ozone-induced BHR. Despite equal numbers of mast cells in reconstituted mouse lungs, mice reconstituted with P2X7-/- mast cells demonstrated significantly less robust BHR than mice reconstituted with WT mast cells. These results support a model where P2X7 on both mast cells and other cell types contribute to ozone-induce BHR.
Xiaomei Kong, William C. Bennett, Corey M. Jania, Kelly D. Chason, Zachary German, Jennifer Adouli, Samuel D. Budney, Brandon T. Oby, Catharina van Heusden, Eduardo R. Lazarowski, Ilona Jaspers, Scott H. Randell, Barry A. Hedgespeth, Glenn Cruse, Xiaoyang Hua, Stephen A. Schworer, Gregory J. Smith, Samir N. P. Kelada, Stephen L. Tilley
The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse phase protein array (RPPA) molecular profiles from patient-derived xenograft (PDX) tumors, which revealed two PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors with 88% accuracy. Next, a support vector machine (SVM) classifier algorithm identified a minimalist biomarker signature consisting of eight proteins – Caveolin-1, Sox-2, AXL, STING, Brd4, Claudin-7, Connexin-43, and Fibronectin – whose expression strongly predicted cetuximab response in PDXs using either protein (AUC=0.95) or mRNA (AUC=0.97). A combination of Caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in HNSCC patient tumor samples with known clinical response to cetuximab. These results support further investigation into the combined use of Caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.
Mehdi Bouhaddou, Rex H. Lee, Hua Li, Neil E. Bhola, Rachel A. O'Keefe, Mohammad Naser, Tian Ran Zhu, Kelechi Nwachuku, Umamaheswar Duvvuri, Adam B. Olshen, Ritu Roy, Aaron Hechmer, Jennifer Bolen, Stephen B. Keysar, Antonio Jimeno, Gordon B. Mills, Scott Vandenberg, Danielle L. Swaney, Daniel E. Johnson, Nevan J. Krogan, Jennifer R. Grandis
BACKGROUND. Neighborhood-level socioeconomic disadvantage has wide-ranging impacts on health outcomes, particularly in older adults. Although indices of disadvantage are a widely used tool, research conducted to date has not codified a set of standard variables that should be included in these indices for the US. The objective of this study was to conduct a systematic review of literature describing the construction of geographic indices of neighborhood-level disadvantage and to summarize and distill the key variables included in these indices. We also sought to demonstrate the utility of these indices for understanding neighborhood-level disadvantage in older adults. METHODS. We conducted a systematic review of existing indices in the English-language literature. RESULTS. We identified 6,021 articles, of which 130 met final study inclusion criteria. Our review identified seven core domains that existed across the surveyed papers, including: income, education, housing, employment, neighborhood structure, demographic makeup and health. While not universally present, the most prevalent variables included in these indices were education and employment. CONCLUSION. Identifying these seven core domains is a key finding of this review. These domains should be considered for inclusion in future neighborhood-level disadvantage indices with at least 5 domains recommended to improve the strength of the resulting index. Targeting specific domains offers a path forward towards the construction of a new US-specific index of neighborhood disadvantage with health policy applications. Such an index will be especially useful for characterizing the lifecourse impact of lived disadvantage in older adults.
William R. Buckingham, Lauren Bishop, Christopher Hooper-Lane, Brittany Anderson, Jessica Wolfson, Stephanie V. Shelton, Amy J.H. Kind
Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent abscesses in the groin and flexural areas. HS is associated with a wide range of comorbidities that complicate the disease course. Although these comorbidities have been well-described, it remains unclear how these comorbidities co-associate and whether comorbidity profiles affect disease trajectory. In addition, it is unknown how comorbidity associations are modulated by race and gender. In this comprehensive analysis of 77 million patients in a large U.S. population-based cohort, we examine co-association patterns among HS comorbidities and identify clinically relevant phenotypic subtypes within HS. We demonstrate that these subtypes not only differ among races, but also influence clinical outcomes as measured by HS-related emergency department (ED) visits and cellulitis. Taken together, our findings provide key insights that elucidate the unique disease trajectories experienced by HS patients, and equip clinicians with a novel framework for risk stratification and improved targeted care in HS.
Vivian J. Hua, James M. Kilgour, Hyunje G. Cho, Shufeng Li, Kavita Y. Sarin
We recently described a previously unknown trans-tentorial venous system (TTVS) connecting venous drainage throughout the brain in humans. Prior to this finding, it was believed that the embryologic tentorial plexus regresses, resulting in a largely avascular tentorium. Our finding contradicted this understanding and necessitated further investigation into the development of the newly described TTVS. Herein we sought to investigate mice as a model to study the development of this system. First, using vascular casting and ex vivo micro-computed tomography (micro-CT), we demonstrate that this TTVS is conserved in adult mice. Next, using high-resolution magnetic resonance imaging (MRI), we found the primitive tentorial venous plexus in murine embryo at day 14.5. We also found that, at this embryologic stage, the tentorial plexus drains the choroid plexus. Finally, using vascular casting and micro-CT, we found that the TTVS is the dominant venous drainage in the early postnatal period (P8). Herein, we demonstrate that the TTVS is conserved between mice and humans and present a longitudinal study of its development. In addition, our findings establish mice as a translational model for further study of this newly described system and its relationship to intracranial physiology.
Pashayar P. Lookian, Vikram Chandrashekhar, Anthony Cappadona, Jean-Paul Bryant, Vibhu Chandrashekhar, Jessa M. Tunacao, Danielle R. Donahue, Jeeva P. Munasinghe, James G. Smirniotopoulos, John D. Heiss, Zhengping Zhuang, Jared S. Rosenblum
JCI This Month is a digest of the research, reviews, and other features published each month.