Winifred C Blumenkron

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Journals/Publications

• Benjamin, L. T., Trowers, A. B., & Schachner, L. A. (2019). Successful acne management in Apert syndrome twins. Pediatric dermatology, 22(6), 561-5.
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  Apert syndrome, or acrocephalosyndactyly, is characterized by craniosynostosis and early epiphyseal closure resulting in various deformities of the skull, hands, and feet. Typically a sporadic condition, autosomal dominant inheritance with complete penetrance has been known to occur. Most adolescents with the disorder are prone to the development of severe pustular facial and truncal acne, with extension to the upper arms and forearm. We report twin brothers with Apert syndrome who, after 2 years of standard management by their pediatrician, were referred for management of complicated acne. In our patients there were a constellation of findings consistent with the disorder and, of importance to this report, significant dermatological manifestations. On presentation, each brother was found to have acne vulgaris of a different stage. Our patients were refractory to conventional treatment for acne but one required and had a significant response to isotretinoin. The risk/benefit ratio in treating acne lesions with isotretinoin in a teenager with Apert syndrome is reviewed.
• Davies, J. A., Hanson-Heine, M. W., Besley, N. A., Shirley, A., Trowers, J., Yang, S., & Ellis, A. M. (2018). Dimers of acetic acid in helium nanodroplets. Physical chemistry chemical physics : PCCP.
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  The structural arrangement of small carboxylic acid molecules in the liquid phase remains a controversial topic. Some studies indicate a dominance of the cyclic dimer that prevails in the gas phase, whilst other studies favor short fragments of the infinite catemer chains that are found in the crystalline phase. Furthermore, difficulties in preparing and probing size-selected catemer segments have resulted in a lack of benchmark data upon which theoretical models of the condensed phases can be built. To address these issues, we have combined infrared spectroscopy and quantum chemical calculations to explore regions of the intermolecular potential energy surface associated with the formation of metastable dimer isomers. The OH stretching region of the spectrum shows that aggregation of acetic acid molecules inside liquid helium nanodroplets yields two distinct metastable dimers, whilst negligible signal is observed from the cyclic dimer that typically overwhelms this spectral region. We deduce that the most abundant isomer in superfluid helium has one strong O-HO[double bond, length as m-dash]C and one weak C-HO[double bond, length as m-dash]C hydrogen bond. Since this bonding motif is common to the dimeric repeating unit of the catemer, it is of fundamental importance for understanding intermolecular interactions in the condensed phases of small carboxylic acids.
• Shrestha, M. P., Borgstrom, M., & Trowers, E. (2018). The Reply. The American journal of medicine, 131(1), e35-e36.
• Shrestha, M. P., Borgstrom, M., & Trowers, E. A. (2018). Elevated lactate level predicts intensive care unit admissions, endoscopies and transfusions in patients with acute gastrointestinal bleeding. Clinical and experimental gastroenterology, 11, 185-192.
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  Initial clinical management decision in patients with acute gastrointestinal bleeding (GIB) is often based on identifying high- and low-risk patients. Little is known about the role of lactate measurement in the triage of patients with acute GIB. We intended to assess if lactate on presentation is predictive of need for intervention in patients with acute GIB.
• Shrestha, M. P., Borgstrom, M., & Trowers, E. (2017). Digital Rectal Examination Reduces Hospital Admissions, Endoscopies, and Medical Therapy in Patients with Acute Gastrointestinal Bleeding. The American journal of medicine, 130(7), 819-825.
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  Although digital rectal examination is an established part of physical examinations in patients with acute gastrointestinal bleeding, clinicians are reluctant to perform a rectal examination. We intended to assess whether rectal examination affects the clinical management decision in these patients.
• Shrestha, M. P., Borgstrom, M., & Trowers, E. (2017). The Reply. The American journal of medicine, 130(12), e561-e562.
• Shrestha, M. P., Borgstrom, M., & Trowers, E. (2017). The Reply. The American journal of medicine, 130(9), e409-e410.
• Ahn, S. J., Hwang, S. J., & Lee, B. R. (2016). Intravitreal dexamethasone implants for the treatment of refractory scleritis combined with uveitis in adult-onset Still's disease: a case report. BMC ophthalmology, 16(1), 196.
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  Adult-onset Still's disease is a systemic inflammatory disease which presents with uveitis and scleritis in the eye. Intravitreal dexamethasone implants are used for the treatment of refractory uveitis.
• Banerjee, B., Shaheen, N. J., Martinez, J. A., Hsu, C. H., Trowers, E., Gibson, B. A., Della'Zanna, G., Richmond, E., & Chow, H. H. (2016). Clinical Study of Ursodeoxycholic Acid in Barrett's Esophagus Patients. Cancer prevention research (Philadelphia, Pa.), 9(7), 528-33.
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  Prior research strongly implicates gastric acid and bile acids, two major components of the gastroesophageal refluxate, in the development of Barrett's esophagus and its pathogenesis. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been shown to protect esophageal cells against oxidative stress induced by cytotoxic bile acids. We conducted a pilot clinical study to evaluate the clinical activity of UDCA in patients with Barrett's esophagus. Twenty-nine patients with Barrett's esophagus received UDCA treatment at a daily dose of 13 to 15 mg/kg/day for 6 months. The clinical activity of UDCA was assessed by evaluating changes in gastric bile acid composition and markers of oxidative DNA damage (8-hydroxydeoxyguanosine), cell proliferation (Ki67), and apoptosis (cleaved caspase-3) in Barrett's esophagus epithelium. The bile acid concentrations in gastric fluid were measured by liquid chromatography/mass spectrometry. At baseline, UDCA (sum of unchanged and glycine/taurine conjugates) accounted for 18.2% of total gastric bile acids. After UDCA intervention, UDCA increased significantly to account for 93.4% of total gastric bile acids (P < 0.0001). The expression of markers of oxidative DNA damage, cell proliferation, and apoptosis was assessed in the Barrett's esophagus biopsies by IHC. The selected tissue biomarkers were unchanged after 6 months of UDCA intervention. We conclude that high-dose UDCA supplementation for 6 months resulted in favorable changes in gastric bile acid composition but did not modulate selected markers of oxidative DNA damage, cell proliferation, and apoptosis in the Barrett's esophagus epithelium. Cancer Prev Res; 9(7); 528-33. ©2016 AACRSee related article by Brian J. Reid, p. 512.
• Elfer, K. N., Sholl, A. B., Wang, M., Tulman, D. B., Mandava, S. H., Lee, B. R., & Brown, J. Q. (2016). DRAQ5 and Eosin ('D&E') as an Analog to Hematoxylin and Eosin for Rapid Fluorescence Histology of Fresh Tissues. PloS one, 11(10), e0165530.
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  Real-time on-site histopathology review of biopsy tissues at the point-of-procedure has great potential for significant clinical value and improved patient care. For instance, on-site review can aid in rapid screening of diagnostic biopsies to reduce false-negative results, or in quantitative assessment of biospecimen quality to increase the efficacy of downstream laboratory and histopathology analysis. However, the only currently available rapid pathology method, frozen section analysis (FSA), is too time- and labor-intensive for use in screening large quantities of biopsy tissues and is too destructive for maximum tissue conservation in multiple small needle core biopsies. In this work we demonstrate the spectrally-compatible combination of the nuclear stain DRAQ5 and the anionic counterstain eosin as a dual-component fluorescent staining analog to hematoxylin and eosin intended for use on fresh, unsectioned tissues. Combined with optical sectioning fluorescence microscopy and pseudo-coloring algorithms, DRAQ5 and eosin ("D&E") enables very fast, non-destructive psuedohistological imaging of tissues at the point-of-acquisition with minimal tissue handling and processing. D&E was validated against H&E on a one-to-one basis on formalin-fixed paraffin-embedded and frozen section tissues of various human organs using standard epi-fluorescence microscopy, demonstrating high fidelity of the staining mechanism as an H&E analog. The method was then applied to fresh, whole 18G renal needle core biopsies and large needle core prostate biospecimen biopsies using fluorescence structured illumination optical sectioning microscopy. We demonstrate the ability to obtain high-resolution histology-like images of unsectioned, fresh tissues similar to subsequent H&E staining of the tissue. The application of D&E does not interfere with subsequent standard-of-care H&E staining and imaging, preserving the integrity of the tissue for thorough downstream analysis. These results indicate that this dual-stain pseudocoloring method could provide a real-time histology-like image at the time of acquisition and valuable objective tissue analysis for the clinician at the time of service.
• Jang, W. Y., Lee, B., Jeong, J., Sung, Y., Choi, M., Song, P., Kim, H., Jang, S., Kim, H., Joo, K., Lee, J., Choo, Y. S., Kim, E., & Ryoo, Z. Y. (2017). Overexpression of serum amyloid a 1 induces depressive-like behavior in mice. Brain research, 1654(Pt A), 55-65.
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  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by loss of memory and cognitive abilities. In AD, amyloid β (Aβ) protein aggregates in the brain of patients, forming amyloid plaques. Aβ plaques are known to be surrounded by activated microglial cells. Serum amyloid A (SAA) is elevated from several hundred to 1000-fold as part of the immune response against various injuries, including trauma, infection, and inflammation. Additionally, continuous elevation of SAA is related to the development of amyloidosis. This study was designed to identify the relationship between SAA1 and AD using liver specific SAA1 overexpressing mice (TG), because SAA1 is expressed in the liver during the acute phase. We detected exogenous SAA1 expression in the brain of TG mice. This result implies that liver-derived SAA1 migrates to the brain tissues. Thus, we confirmed that the blood brain barrier (BBB) functioned normally using Evans-blue staining and CARS. Furthermore, our results show an increase in the accumulation of the 87kDa form of Aβ in TG mice compared to wild type mice (WT). Additionally, the number of microglial cells and levels of pro-inflammatory cytokines were increased. Next, we investigated the relationship between SAA1 and depression by performing social interaction tests. The results showed that TG mice have a tendency to avoid stranger mice and an impaired social recognition. In conclusion, the SAA1 TG mouse model is a valuable model to study depression.
• Kim, H., Bae Lee, J., Park, J., Yoo, B., Son, J., Yang, D. H., & Lee, B. (2016). A comparison of echocardiographic variables of right ventricular function with exercise capacity after bosentan treatment in patients with pulmonary arterial hypertension: Results from a multicenter, prospective, cohort study. Journal of clinical ultrasound : JCU.
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  Bosentan reduces pulmonary arterial pressure and improves exercise capacity in patients with pulmonary arterial hypertension (PAH). However, there are limited data regarding the extent to which the changes in echocardiographic variables reflect improvements in exercise capacity. We aimed to assess the improvement of echocardiographic variables and exercise capacity after 6 months of bosentan treatment for PAH.
• Kim, M., Suh, Y., Oh, J., Lee, B. R., Kim, J., & Jang, S. J. (2016). KIF3A binds to β-arrestin for suppressing Wnt/β-catenin signalling independently of primary cilia in lung cancer. Scientific reports, 6, 32770.
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  Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
• Lee, B., Ko, H. K., Ryu, J. H., Ahn, K. Y., Lee, Y., Oh, S. J., Na, J. H., Kim, T. W., Byun, Y., Kwon, I. C., Kim, K., & Lee, J. (2016). Engineered Human Ferritin Nanoparticles for Direct Delivery of Tumor Antigens to Lymph Node and Cancer Immunotherapy. Scientific reports, 6, 35182.
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  Efficient delivery of tumor-specific antigens (TSAs) to lymph nodes (LNs) is essential to eliciting robust immune response for cancer immunotherapy but still remains unsolved. Herein, we evaluated the direct LN-targeting performance of four different protein nanoparticles with different size, shape, and origin [Escherichia coli DNA binding protein (DPS), Thermoplasma acidophilum proteasome (PTS), hepatitis B virus capsid (HBVC), and human ferritin heavy chain (hFTN)] in live mice, using an optical fluorescence imaging system. Based on the imaging results, hFTN that shows rapid LN targeting and prolonged retention in LNs was chosen as a carrier of the model TSA [red fluorescence protein (RFP)], and the flexible surface architecture of hFTN was engineered to densely present RFPs on the hFTN surface through genetic modification of subunit protein of hFTN. The RFP-modified hFTN rapidly targeted LNs, sufficiently exposed RFPs to LN immune cells during prolonged period of retention in LNs, induced strong RFP-specific cytotoxic CD8(+) T cell response, and notably inhibited RFP-expressing melanoma tumor growth in live mice. This suggests that the strategy using protein nanoparticles as both TSA-carrying scaffold and anti-cancer vaccine holds promise for clinically effective immunotherapy of cancer.
• Liu, J., Wang, M., Tulman, D., Mandava, S. H., Elfer, K. N., Gabrielson, A., Lai, W., Abshire, C., Sholl, A. B., Brown, J. Q., & Lee, B. R. (2016). Nondestructive Diagnosis of Kidney Cancer on 18-gauge Core Needle Renal Biopsy Using Dual-color Fluorescence Structured Illumination Microscopy. Urology, 98, 195-199.
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  To present a novel imaging technique used for rapid, nondestructive histological assessment of renal neoplasias using a dual-component fluorescence stain and structured illumination microscopy (SIM).
• Park, S., Lee, B., Cho, W., & Kim, T. (2016). Comparative Nitrogen Use Efficiency of Urea and Pig Slurry for Regrowth Yield and Nutritive Value in Perennial Ryegrass Sward. Asian-Australasian journal of animal sciences.
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  The nitrogen use efficiency (NUE) of urea and pig slurry for herbage yield and nutritive value was compared with a non-fertilized control during four successive regrowth periods of perennial ryegrass sward. Consecutive field experiments were separately performed using a single application with a full dose of N (200 kg N ha-1) in 2014 and by four split applications in 2015 in different sites. The effect of N fertilization on herbage yield, N recovery in herbage, residual inorganic N in soil, and crude protein (CP) were significantly positive. When comparing the NUE between the two N sources (urea and pig slurry), pig slurry was significantly less effective for the earlier two regrowth periods, as shown by lower regrowth DM yield, N amount recovered in herbage, and inorganic N availability in soil at the 1st and 2nd cut compared to those of urea-applied plots. However, the effect of split application of the two N sources was significantly positive at the last two regrowth periods (at the 3rd and 4th cut). The two N sources and/or split application had little or no influence on neutral detergent fiber (NDF) content, acid detergent fiber (ADF) content, and in vitro DM digestibility, whereas cutting date was a large source of variation for these variables, resulting in a significant increase in in vitro DM digestibility for the last two regrowth periods when an increase in NDF and ADF content occurred. Split application of N reduced the N loss via nitrate leaching by 36% on average for the two N sources compared to a single application. The results presented here clearly indicate that pig slurry-N was utilized as efficiently as urea-N for annual herbage yield, with a significant increase in NUE especially for the latter regrowth periods.
• Pramod, R. K., Lee, B. R., Kim, Y. M., Lee, H. J., Park, Y. H., Ono, T., Lim, J. M., & Han, J. Y. (2016). Isolation, Characterization, and In Vitro Culturing of Spermatogonial Stem Cells in Japanese Quail (Coturnix japonica). Stem cells and development.
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  We reported previously testis-mediated germline chimera production and characterization of germline stem cell-like cells from chicken testes. The present study aimed to establish an in vitro system for culture of quail spermatogonial stem cells (SSCs) for practical applications in germline preservation and transgenesis. Testicular cells (TCs) from juvenile (4 weeks old) or adult (8 weeks old) quail testis were isolated using sequential enzymatic digestion. The percentages of viability of isolated TCs were 91.00% ± 2.12% and 88.00% ± 1.87% in juvenile and adult testes, respectively, and immunohistochemical evaluation indicated the expression of integrin alpha-6 (ITGA6), GDNF family receptor alpha-1 (GFRA1), and Deleted in azoospermia-like (DAZL) in specific TCs. SSCs were purified by differential plating of TCs and then subjected to quantitative reverse transcription-polymerase chain reaction, which showed differential expression of SSC-specific, and germness and stemness-related genes. Coculture of quail SSCs with mouse embryonic fibroblasts and Sertoli cells as a feeder layer resulted in the generation of stable SSC colonies and short-term cultivation, and the expression of SSC and germ cell markers was maintained during several passages of culture. Collectively, these results demonstrate the efficient isolation and characterization of quail SSCs and the suitability of Sertoli cells as a feeder layer for in vitro culture of quail SSCs. Quail SSCs will facilitate the production of germline chimeras and transgenesis.
• Zangeneh, T. T., Malo, J., Luraschi-Monjagatta, C., Hage, C. A., Wheat, L. J., Strawter, C., Klotz, S. A., & Knox, K. S. (2015). Positive (1-3) B-d-glucan and cross reactivity of fungal assays in coccidioidomycosis. Medical mycology, 53(2), 171-3.
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  Fungal antigen testing in immunosuppressed patients has emerged as a powerful diagnostic tool. Some assays are relatively nonspecific, and misinterpretation can have severe clinical consequences. Additionally, when new assays become commercially available it is important to evaluate the potential for cross reactivity. We recently observed several immunosuppressed patients with positive (1→3)-β-D-glucan (BG) who were eventually diagnosed with coccidioidomycosis in the endemic area of Tucson, Arizona. Although the BG assay is known to detect glucans of many fungal pathogens, reports of cross-reactivity with Coccidioides remain sparsely reported. To test the cross-reactivity of fungal antigens in detection assays, serum samples from patients with coccidioidomycosis testing positive for Coccidioides antigen were evaluated for BG. Of 12 samples positive for Coccidioides antigen (≥0.07 ng/ml), 11 (92%) were positive by BG (>80 pg/ml), and of 11 positive for Aspergillus galactomannan, 10 (91%) were positive by BG (>80 pg/ml). We conclude that the BG assay is nonspecific, detecting glucans from many fungal pathogens, including Coccidioides. In the endemic area, a positive BG warrants further specific testing.
• Knox, K. S. (2014). Perspective on coccidioidomycosis and histoplasmosis. American journal of respiratory and critical care medicine, 189(6), 752-3.
• Liu, Y., Redmond, S. J., Wang, N., Blumenkron, F., Narayanan, M. R., & Lovell, N. H. (2011). Spectral analysis of accelerometry signals from a directed-routine for falls-risk estimation. IEEE transactions on bio-medical engineering, 58(8).
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  Injurious falls are a prevalent and serious problem faced by a growing elderly population. Accurate assessment and long-term monitoring of falls-risk could prove useful in the prevention of falls, by identifying those at risk of falling early so targeted intervention may be prescribed. Previous studies have demonstrated the feasibility of using triaxial accelerometry to estimate the risk of a person falling in the near future, by characterizing their movement as they execute a restricted sequence of predefined movements in an unsupervised environment, termed a directed routine. This study presents an improvement on this previously published system, which relied explicitly on time-domain features extracted from the accelerometry signals. The proposed improvement incorporates features derived from spectral analysis of the same accelerometry signals; in particular the harmonic ratios between signal harmonics and the fundamental frequency component are used. Employing these additional frequency-domain features, in combination with the previously reported time-domain features, an increase in the observed correlation with the clinical gold-standard risk of falling, from = 0:81 to = 0:96, was achieved when using manually annotated event segmentation markers; using an automated algorithm to segment the signals gave corresponding results of = 0:73 and = 0:99, before and after the inclusion of spectral features. The strong correlation with falls-risk observed in this preliminary study further supports the feasibility of using an unsupervised assessment of falls-risk in the home environment.
• Lemieux, G. A., Blumenkron, F., Yeung, N., Zhou, P., Williams, J., Grammer, A. C., Petrovich, R., Lipsky, P. E., Moss, M. L., & Werb, Z. (2007). The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10. The Journal of biological chemistry, 282(20), 14836-44.
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  The low affinity IgE receptor, FcepsilonRII (CD23), is both a positive and negative regulator of IgE synthesis. The proteinase activity that converts the membrane-bound form of CD23 into a soluble species (sCD23) is an important regulator of the function of CD23 and may be an important therapeutic target for the control of allergy and inflammation. We have characterized the catalytic activity of ADAM (a disintegrin and metalloproteinase) 10 toward human CD23. We found that ADAM10 efficiently catalyzes the cleavage of peptides derived from two distinct cleavage sites in the CD23 backbone. Tissue inhibitors of metalloproteinases and a specific prodomain-based inhibitor of ADAM10 perturb the release of endogenously produced CD23 from human leukemia cell lines as well as primary cultures of human B-cells. Expression of a mutant metalloproteinase-deficient construct of ADAM10 partially inhibited the production of sCD23. Similarly, small inhibitory RNA knockdown of ADAM10 partially inhibited CD23 release and resulted in the accumulation of the membrane-bound form of CD23 on the cells. ADAM10 contributes to CD23 shedding and thus could be considered a potential therapeutic target for the treatment of allergic disease.
• Drosou, A., Benjamin, L., Linfante, I., Mallin, K., Trowers, A., Wakhloo, A. K., Thaller, S. R., & Schachner, L. A. (2006). Infantile midline facial hemangioma with agenesis of the corpus callosum and sinus pericranii: another face of the PHACE syndrome. Journal of the American Academy of Dermatology, 54(2), 348-52.
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  In the majority of cases, infantile hemangiomas are not associated with any other abnormalities. Occasionally, they may indicate the presence of systemic malformations. PHACE syndrome includes the coexistence of hemangioma, posterior fossa brain abnormalities, arterial anomalies, coarctation of the aorta, cardiac defects, and eye abnormalities. We report a case of a 2-month-old female with PHACE syndrome who also had sinus pericranii.

Poster Presentations

• Lee, B. R., & Blumenkron, W. (2016, Spring). Kidney Cancer and Stone Disease. American Association of Surgery. Seattle, WA: AMA.

Reviews

• Twigg, H. L., Weinstock, G. M., & Knox, K. S. (2016. Lung microbiome in human immunodeficiency virus infection.
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  The lung microbiome plays a significant role in normal lung function and disease. Because microbial colonization is likely influenced by immunodeficiency, one would speculate that infection with human immunodeficiency virus (HIV) alters the lung microbiome. Furthermore, how this alteration might impact pulmonary complications now seen in HIV-infected patients on antiretroviral therapy (ART), which has shifted from opportunistic infections to diseases associated with chronic inflammation, is not known. There have been limited publications on the lung microbiome in HIV infection, many of them emanating from the Lung HIV Microbiome Project. Current evidence suggests that the lung microbiome in healthy HIV-infected individuals with preserved CD4 counts is similar to uninfected individuals. However, in individuals with more advanced disease, there is an altered alveolar microbiome characterized by a loss of richness and evenness (alpha diversity) within individuals. Furthermore, as a group the taxa making up the HIV-infected and uninfected lung microbiome are different (differences in beta diversity), and the HIV-infected population is more spread out (greater dispersion) than the uninfected population. These differences decline with ART, but even after effective therapy the alveolar microbiome in HIV-infected individuals contains increased amounts of signature bacteria, some of which have previously been associated with chronic lung inflammation. Furthermore, more recent investigations into the lung virome in HIV infection suggest that perturbations in lung viral communities also exist in HIV infection, and that these too are associated with evidence of lung inflammation. Thus, it is likely both microbiome and virome alterations in HIV infection contribute to lung inflammation in these individuals, which has important implications on the changing spectrum of pulmonary complications in patients living with HIV.