Publications by authors named "David H Wang"

73 Publications

A "Clue" to Improving Liquid Biopsies for Cancer: Microfluidic Multiparametric Exosome Analysis.

Clin Chem 2021 Jan;67(2):335-337

Esophageal Diseases Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

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http://dx.doi.org/10.1093/clinchem/hvaa209DOI Listing
January 2021

Colitis-induced IL11 promotes colon carcinogenesis.

Carcinogenesis 2021 Apr;42(4):557-569

Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

Colitis increases the risk of colorectal cancer; however, the mechanism of the association between colitis and cancer remains largely unknown. To identify colitis-associated cancer promoting factors, we investigated gene expression changes caused by dextran sulfate sodium (DSS)-induced colitis in mice. By analyzing gene expression profiles, we found that IL11 was upregulated in DSS-induced colitis tissue and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP)/DSS-induced colon tumours in mice as well as in human colorectal cancer. By characterizing the activation/phosphorylation of STAT3 (pSTAT3), we found that pSTAT3 was induced transiently in colitis, but maintained at higher levels from hyper-proliferative dysplastic lesions to tumours. Using the IL11 receptor (IL11Rα1) knockout mice, we found that pSTAT3 in the newly regenerated crypt epithelial cells in colitis is abolished in IL11Rα1+/- and -/- mice, suggesting that colitis-induced IL11 activates STAT3 in colon crypt epithelial cells. Moreover, colitis-promoted colon carcinogenesis was significantly reduced in IL11Rα1+/- and -/- mice. To determine the roles of the IL11 in colitis, we found that the inhibition of IL11 signalling by recombinant IL11 antagonist mutein during colitis was sufficient to attenuate colitis-promoted carcinogenesis. Together, our results demonstrated that colitis-induced IL11 plays critical roles in creating cancer promoting microenvironment to facilitate the development of colon cancer from dormant premalignant cells.
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http://dx.doi.org/10.1093/carcin/bgaa122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086771PMC
April 2021

Emergency Department Admission Triggers for Palliative Consultation May Decrease Length of Stay and Costs.

J Palliat Med 2021 04 8;24(4):554-560. Epub 2020 Sep 8.

Division of Palliative Medicine, Scripps Health, San Diego, California, USA.

Emergency department (ED) initiated palliative consultation impacts downstream care utilization. Various admission consult triggers have been proposed without clear best practice or outcomes. This 18-month single-center study evaluated the clinical, operational, and financial impact of simplified admission triggers for ED-initiated palliative consults as compared to downstream Floor and intensive care unit (ICU) palliative consults initiated per usual practice. We distilled ED admission triggers into three criteria to ensure bedside actionability and sustainability: (1) end-stage illness, (2) functional limitation, and (3) clinician would not be surprised if the patient died this hospitalization. Eligible patients met all criteria, and received consultation within 24 hours of admission. We compared ED-initiated consults against Floor and ICU consults from March 1, 2018, to September 30, 2019, with matched cohort analysis to evaluate financial outcomes. While overall palliative consult volume remained intentionally steady, the proportion of ED-initiated consults significantly increased (7% vs. 19%,  < 0.001). ED consistently comprised 15-25% of all monthly palliative consults. Compared with Floor, ED had similar ED length of stay (LOS) and inpatient mortality. Among live discharges, ED were more likely to be referred to hospice than Floor (59% vs. 47%,  = 0.24) or ICU (59% vs. 34%,  = 0.02). In a matched cohort analysis, ED demonstrated median cost avoidance of $9,082 per patient versus Floor ($5,578 vs. $14,660,  < 0.001) and $15,138 per patient versus ICU ($5,578 vs. $20,716,  < 0.001). ED had significantly shorter median LOS before consult than Floor (0 vs. 3 days,  < 0.001) or ICU (0 vs. 3 days,  < 0.001), which did not differ between live discharges or inpatient deaths. Overall hospital LOS was disproportionately shorter for ED, with a net difference-in-differences of 1-3.5 days compared to Floor and ICU. Simple ED admission triggers to expedite palliative engagement are associated with a 50-75% reduction in both hospital LOS and costs when compared against usual palliative consultation practice. ED initiation reduces both lead time before consultation and subsequent downstream hospitalization length.
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http://dx.doi.org/10.1089/jpm.2020.0082DOI Listing
April 2021

Gastrointestinal pharmacology: practical tips for the esophagologist.

Ann N Y Acad Sci 2020 12 21;1481(1):90-107. Epub 2020 Aug 21.

Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Gastroesophageal reflux disease (GERD) is primarily a motor disorder, and its pathogenesis is multifactorial. As a consequence, treatment should be able to address the underlying pathophysiology. Proton pump inhibitors (PPIs) are the mainstay of medical therapy for GERD, but these drugs only provide the control of symptoms and lesions without curing the disease. However, continuous acid suppression with PPIs is recommended for patients with Barrett's esophagus because of their potential chemopreventive effects. In addition to the antisecretory activity, these compounds display several pharmacological properties, often overlooked in clinical practice. PPIs can indeed affect gastric motility, exert a mucosal protective effect, and an antioxidant, anti-inflammatory, and antineoplastic activity, also protecting cancer cells from developing chemo- or radiotherapeutic resistance. Even in the third millennium, current pharmacologic approaches to address GERD are limited. Reflux inhibitors represent a promise unfulfilled, effective and safe prokinetics are lacking, and antidepressants, despite being effective in selected patients, give rise to adverse events in a large proportion of them. While waiting for new drug classes (like potassium-competitive acid blockers), reassessing old drugs (namely alginate-containing formulations), and paving the new avenue of esophageal mucosal protection are, at the present time, the only reliable alternatives to acid suppression.
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http://dx.doi.org/10.1111/nyas.14447DOI Listing
December 2020

Recent insights into the biology of Barrett's esophagus.

Ann N Y Acad Sci 2020 12 17;1481(1):198-209. Epub 2020 Jul 17.

Department of Upper Gastrointestinal Surgery, St Vincent's Hospital, Melbourne, Victoria, Australia.

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), an aggressive cancer with a poor prognosis. Our understanding of the pathogenesis and Barrett's metaplasia is incomplete, and this has limited the development of new therapeutic targets and agents, risk stratification ability, and management strategies. This review outlines current insights into the biology of BE and addresses controversies surrounding cell of origin, cellular reprogramming theories, updates on esophageal epithelial barrier function, and the significance of goblet cell metaplasia and its association with malignant change. Further research into the basic biology of BE is vital as it will underpin novel therapies and improve our ability to predict malignant progression and help identify the minority of patients who will develop EAC.
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http://dx.doi.org/10.1111/nyas.14432DOI Listing
December 2020

Top Ten Tips Palliative Care Clinicians Should Know About Caring for Patients in the Emergency Department.

J Palliat Med 2019 12 29;22(12):1597-1602. Epub 2019 Jul 29.

Department of Emergency Medicine and Emory University School of Medicine, Atlanta, Georgia.

Palliative principles are increasingly within the scope of emergency medicine (EM). In EM, there remain untapped opportunities to improve primary palliative care (PC) and integrate patients earlier into the palliative continuum. However, the emergency department (ED) differs from other practice environments with its unique systemic pressures, priorities, and expectations. To build effective, efficient, and sustainable partnerships, palliative clinicians are best served by understanding the ED's practice priorities. The authors, each EM and Hospice and Palliative Medicine board certified and in active practice, present these 10 high-yield tips to optimize the ED consultation by PC teams.
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http://dx.doi.org/10.1089/jpm.2019.0251DOI Listing
December 2019

GEAMP, a novel gastroesophageal junction carcinoma cell line derived from a malignant pleural effusion.

Lab Invest 2020 01 10;100(1):16-26. Epub 2019 Jul 10.

Esophageal Diseases Center and Division of Hematology-Oncology, Department of Internal Medicine and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Gastroesophageal junction (GEJ) cancer remains a clinically significant disease in Western countries due to its increasing incidence, which mirrors that of esophageal cancer, and poor prognosis. To develop novel and effective approaches for prevention, early detection, and treatment of patients with GEJ cancer, a better understanding of the mechanisms driving pathogenesis and malignant progression of this disease is required. These efforts have been limited by the small number of available cell lines and appropriate preclinical animal models for in vitro and in vivo studies. We have established and characterized a novel GEJ cancer cell line, GEAMP, derived from the malignant pleural effusion of a previously treated GEJ cancer patient. Comprehensive genetic analyses confirmed a clonal relationship between GEAMP cells and the primary tumor. Targeted next-generation sequencing identified 56 nonsynonymous alterations in 51 genes including TP53 and APC, which are commonly altered in GEJ cancer. In addition, multiple copy-number alterations were found including EGFR and K-RAS gene amplifications and loss of CDKN2A and CDKN2B. Histological examination of subcutaneous flank xenografts in nude and NOD-SCID mice showed a carcinoma with mixed squamous and glandular differentiation, suggesting GEAMP cells contain a subpopulation with multipotent potential. Finally, pharmacologic inhibition of the EGFR signaling pathway led to downregulation of key downstream kinases and inhibition of cell proliferation in vitro. Thus, GEAMP represents a valuable addition to the limited number of bona fide GEJ cancer cell lines.
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http://dx.doi.org/10.1038/s41374-019-0278-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920545PMC
January 2020

Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing.

Nat Commun 2018 11 21;9(1):4903. Epub 2018 Nov 21.

The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA.

Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. Fibrosis and regeneration are currently considered the opposite end of wound healing. This study sought to determine if scar could be remodeled to promote healing with HF regeneration. Here, we identify that activation of the Sonic hedgehog (Shh) pathway reinstalls a regenerative dermal niche, called dermal papilla, which is required and sufficient for HF neogenesis (HFN). Epidermal Shh overexpression or constitutive Smoothened dermal activation results in extensive HFN in wounds that otherwise end in scarring. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. These studies demonstrate that mechanisms of scarring and regeneration are not distant from one another and that wound repair can be redirected to promote regeneration following injury by modifying a key dermal signal.
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http://dx.doi.org/10.1038/s41467-018-07142-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249328PMC
November 2018

Increasing Safe Outpatient Management of Emergency Department Patients With Pulmonary Embolism: A Controlled Pragmatic Trial.

Ann Intern Med 2018 12 13;169(12):855-865. Epub 2018 Nov 13.

The Permanente Medical Group and Kaiser Permanente Northern California, Oakland, and Kaiser Permanente San Rafael Medical Center, San Rafael, California (D.W.B.).

Background: Many low-risk patients with acute pulmonary embolism (PE) in the emergency department (ED) are eligible for outpatient care but are hospitalized nonetheless. One impediment to home discharge is the difficulty of identifying which patients can safely forgo hospitalization.

Objective: To evaluate the effect of an integrated electronic clinical decision support system (CDSS) to facilitate risk stratification and decision making at the site of care for patients with acute PE.

Design: Controlled pragmatic trial. (ClinicalTrials.gov: NCT03601676).

Setting: All 21 community EDs of an integrated health care delivery system (Kaiser Permanente Northern California).

Patients: Adult ED patients with acute PE.

Intervention: Ten intervention sites selected by convenience received a multidimensional technology and education intervention at month 9 of a 16-month study period (January 2014 to April 2015); the remaining 11 sites served as concurrent controls.

Measurements: The primary outcome was discharge to home from either the ED or a short-term (<24-hour) outpatient observation unit based in the ED. Adverse outcomes included return visits for PE-related symptoms within 5 days and recurrent venous thromboembolism, major hemorrhage, and all-cause mortality within 30 days. A difference-in-differences approach was used to compare pre-post changes at intervention versus control sites, with adjustment for demographic and clinical characteristics.

Results: Among 881 eligible patients diagnosed with PE at intervention sites and 822 at control sites, adjusted home discharge increased at intervention sites (17.4% pre- to 28.0% postintervention) without a concurrent increase at control sites (15.1% pre- and 14.5% postintervention). The difference-in-differences comparison was 11.3 percentage points (95% CI, 3.0 to 19.5 percentage points; P = 0.007). No increases were seen in 5-day return visits related to PE or in 30-day major adverse outcomes associated with CDSS implementation.

Limitation: Lack of random allocation.

Conclusion: Implementation and structured promotion of a CDSS to aid physicians in site-of-care decision making for ED patients with acute PE safely increased outpatient management.

Primary Funding Source: Garfield Memorial National Research Fund and The Permanente Medical Group Delivery Science and Physician Researcher Programs.
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http://dx.doi.org/10.7326/M18-1206DOI Listing
December 2018

Sex differences in concussion: a review of brain anatomy, function, and biomechanical response to impact.

Brain Inj 2019 7;33(2):105-110. Epub 2018 Nov 7.

a Elite Sports Medicine , Connecticut Children's Medical Center , Farmington , Connecticut , USA.

Objective: Provide a potential explanation for sex differences associated with concussions.

Research Design: Review of current literature from complementary disciplines to synthesize a theory to explains sex differences in individuals with concussion.

Methods: Systematic review focusing on sex-related differences in individuals with concussion. Articles published in peer-reviewed journals after 2000 were reviewed and discussed among the authors to determine common themes across the different disciplines represented in the literature review.

Results: There are differences in brain structure between sexes. The male corpus callosum has larger fibers and cross-sectional area compared to females. Females tend to utilize both hemispheres of the brain for most tasks, while males are more lateralized. Computation models of concussive impacts indicate that the greater strains occur at the corpus callosum. The corpus callosum is the conduit for interhemispheric connections within the brain; therefore, it stands to reason that increased strain in this area may affect interhemispheric communications resulting in a difference in perceived symptoms between males and females.

Conclusions: Strain injury of the corpus callosum may affect females to a greater extent since their ability to process information may become more disrupted than males.
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http://dx.doi.org/10.1080/02699052.2018.1542507DOI Listing
January 2020

Cellular Origins of Barrett's Esophagus: the Search Continues.

Curr Gastroenterol Rep 2018 Sep 26;20(11):51. Epub 2018 Sep 26.

Division of Hematology and Oncology, Esophageal Diseases Center, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8584, USA.

Purpose Of Review: The cellular origins of Barrett's esophagus remain elusive. In this review, we discuss the potential cellular mechanisms behind squamous to columnar metaplasia as well as the limitations of these proposed mechanisms.

Recent Findings: Several theories have been proposed, including the reprogramming of native squamous cells, repopulation from submucosal glands, contributions from circulating bone marrow-derived cells, and direct extension of gastric cells. Most recent data support an innate progenitor cell unique to the squamocolumnar junction that can expand into metaplastic glands. Active investigation to clarify each of these potential cells of origin is being pursued, but ultimately each could contribute to the pathogenesis of Barrett's esophagus depending on the clinical context. Nonetheless, identifying cells of origin is critical to understand the molecular mechanisms behind Barrett's esophagus and developing strategies to better treat (and possibly prevent) this increasingly significant premalignant disease.
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http://dx.doi.org/10.1007/s11894-018-0657-2DOI Listing
September 2018

Serum Albumin at Diagnosis is an Independent Predictor of Early Mortality in Veteran Patients with Esophageal Cancer.

Nutr Cancer 2018 Nov-Dec;70(8):1246-1253. Epub 2018 Sep 20.

a Gastrointestinal Section, Department of Internal Medicine , VA North Texas Healthcare System , Dallas , Texas , USA.

Aims: To identify independent factors that could predict mortality within 6 months in a cohort of patients with esophageal cancer.

Methods: Esophageal cancer patients were grouped into early (≤6 months, n = 41) and late (>6 months, n = 81) mortality groups. 52 variables were analyzed by univariable analysis (UA). A multivariable (MVA) regression model was created to identify predictors of early mortality.

Results: When comparing early and late mortality groups, there was no difference in age, BMI, race, histology, or anatomic location between the two groups. UA demonstrated that the early mortality group had a lower mean albumin level (3.3 ± 0.1 g/dl vs. 3.8 ± 0.1 g/dl; P < 0.001), poorer ECOG performance status (1.9 ± 0.2 vs. 1.1 ± 0.1, P = 0.02), higher WBC count (9.6 ± 0.7 K/µL vs. 8.2 ± 0.3 K/µL, P = 0.04), and were less likely to receive surgery (2.4% vs. 22.2%; P = 0.003), neoadjuvant treatment (4.9% vs. 28.4%; P = 0.009) and definitive chemoradiation (7.3% vs. 27.2%; P = 0.01). MVA revealed that only low albumin at diagnosis was an independent predictor of survival (P = 0.016).

Conclusion: Albumin level at diagnosis is an independent predictor of early mortality and might be used with other variables to provide prognostic information for patients and to guide treatment.
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http://dx.doi.org/10.1080/01635581.2018.1512639DOI Listing
September 2019

Columnar-Lined Esophagus Develops via Wound Repair in a Surgical Model of Reflux Esophagitis.

Cell Mol Gastroenterol Hepatol 2018 27;6(4):389-404. Epub 2018 Jun 27.

Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center, Center for Esophageal Research, Baylor Scott and White Research Institute, Dallas, Texas.

Background & Aims: After esophagojejunostomy, rodents develop reflux esophagitis and a columnar-lined esophagus with features of Barrett's metaplasia. This rodent columnar-lined esophagus has been proposed to develop from cellular reprogramming of progenitor cells, but studies on early columnar-lined esophagus development are lacking. We performed a systematic, histologic, and immunophenotypic analysis of columnar-lined esophagus development in rats after esophagojejunostomy.

Methods: At various times after esophagojejunostomy in 52 rats, the esophagus was removed and tissue sections were evaluated for type, location, and length of columnar lining. Molecular characteristics were evaluated by immunohistochemistry and immunofluorescence.

Results: At week 2, ulceration was seen in esophageal squamous epithelium, starting distally at the esophagojejunostomy anastomosis. Re-epithelialization of the distal ulcer segment occurred via proliferation and expansion of immature-appearing glands budding directly off jejunal crypts, characteristic of wound healing. The columnar-lined esophagus's immunoprofile was similar to jejunal crypt epithelium, and columnar-lined esophagus length increased significantly from 0.15 mm (±0.1 SEM) at 2 weeks to 5.22 mm (±0.37) at 32 weeks. Neoglands were found within esophageal ulcer beds, and spindle-shaped cells expressing epithelial-mesenchymal transition markers were found at the columnar-lined esophagus's leading edge. Only proliferative squamous epithelium was found at the proximal ulcer border.

Conclusions: After esophagojejunostomy in rats, metaplastic columnar-lined esophagus develops via a wound healing process that does not appear to involve cellular reprogramming of progenitor cells. This process involves EMT-associated migration of jejunal cells into the esophagus, where they likely have a competitive advantage over squamous cells in the setting of ongoing gastroesophageal reflux disease.
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http://dx.doi.org/10.1016/j.jcmgh.2018.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122432PMC
April 2019

Recent advances in Barrett's esophagus.

Ann N Y Acad Sci 2018 12 5;1434(1):227-238. Epub 2018 Jul 5.

Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.

Barrett's esophagus (BE) is the only known precursor of esophageal adenocarcinoma, one of the few cancers with increasing incidence in developed countries. The pathogenesis of BE is unclear with regard to either the cellular origin of this metaplastic epithelium or the manner in which malignant transformation occurs, although recent data indicate a possible junctional origin of stem cells for BE. Treatment of BE may be achieved using endoscopic eradication therapy; however, there is a lack of discriminatory tools to identify individuals at sufficient risk for cancer development in whom intervention is warranted. Reduction in gastroesophageal reflux of gastric contents including acid is mandatory to achieve remission from BE after endoscopic ablation, and can be achieved using medical or nonmedical interventions. Research topics of greatest interest include the mechanism of BE development and transformation to cancer, risk stratification methods to identify individuals who may benefit from ablation of BE, optimization of eradication therapy, and surveillance methods to ensure that remission is maintained after eradication is achieved.
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http://dx.doi.org/10.1111/nyas.13909DOI Listing
December 2018

Near infrared fluorescent peptide nanoparticles for enhancing esophageal cancer therapeutic efficacy.

Nat Commun 2018 07 4;9(1):2605. Epub 2018 Jul 4.

Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, 43210, USA.

Various types of nanoparticles have been proposed for targeted drug delivering, imaging, and tracking of therapeutic agents. However, highly biocompatible nanoparticles with structure-induced fluorescence and capability to conjugate with biomarkers and drugs remain lacking. This research proposes and synthesizes fluorescent nanoparticles (f-PNPs) assembled by cyclic peptides to combine imaging and drug delivering for esophageal cancer (EC). To achieve tumor targeting, f-PNPs are first conjugated with RGD moieties to selectively target EC cells via αβ integrin; the nanoparticles are then embedded with epirubicin (EPI). Cell viability assays and analysis of tissue histology reveal that EPI-loaded RGD-f-PNPs (RGD-f-PNPs/EPI) led to significantly reduced cardiotoxicity and improved anti-tumor activity compared to EPI alone. Moreover, the drug delivery to tumor sites and therapeutic responses could be monitored with near-infrared fluorescence using RGD-f-PNPs/EPI. This unique nanoparticle system may lead to potential approaches for bioorganic fluorescence-based delivering, imaging, and drug release tracking.
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http://dx.doi.org/10.1038/s41467-018-04763-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031624PMC
July 2018

Origins of Metaplasia in Barrett's Esophagus: Is this an Esophageal Stem or Progenitor Cell Disease?

Dig Dis Sci 2018 08;63(8):2005-2012

Division of Hematology-Oncology, Department of Internal Medicine and the Simmons Comprehensive Cancer Center, Esophageal Diseases Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, MC 8584, Dallas, TX, 75390-8584, USA.

The incidence of esophageal adenocarcinoma has been increasing in Western countries over the past several decades. Though Barrett's esophagus, in which the normal esophageal squamous epithelium is replaced with metaplastic intestinalized columnar cells due to chronic damage from gastroesophageal reflux, is accepted as the requisite precursor lesion for esophageal adenocarcinoma, the Barrett's esophagus cell of origin and the molecular mechanism underlying esophageal epithelial metaplasia remain controversial. Much effort has been dedicated towards identifying the Barrett's esophagus cell of origin since this could lead to more effective prevention and treatment strategies for both Barrett's esophagus and esophageal adenocarcinoma. Previously, it was hypothesized that terminally differentiated esophageal squamous cells might undergo direct conversion into specialized intestinal columnar cells via the process of transdifferentiation. However, there is increasing evidence that stem and/or progenitor cells are molecularly reprogrammed through the process of transcommitment to differentiate into the columnar cell lineages that characterize Barrett's esophagus. Given that Barrett's esophagus originates at the gastroesophageal junction, the boundary between the distal esophagus and gastric cardia, potential sources of these stem and/or progenitor cells include columnar cells from the squamocolumnar junction or neighboring gastric cardia, native esophageal squamous cells, native esophageal cuboidal or columnar cells from submucosal glands or ducts, or circulating bone marrow-derived cells. In this review, we focus on native esophageal specific stem and/or progenitor cells and detail molecular mediators of transcommitment based on recent insights gained from novel mouse models and clinical observations from patients.
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http://dx.doi.org/10.1007/s10620-018-5069-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783253PMC
August 2018

Response to the Letter to the Editor.

Curr Sports Med Rep 2018 03;17(3):105

Drexel University 10 Shurs Lane Philadelphia, PA University at Buffalo Sports Medicine Institute, University Sports Medicine, Buffalo, NY Department of Orthopaedics, Elite Sports Medicine, Connecticut Children's Medical Center, Hartford, CT.

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http://dx.doi.org/10.1249/JSR.0000000000000466DOI Listing
March 2018

High-Temperature and High-Energy-Density Dipolar Glass Polymers Based on Sulfonylated Poly(2,6-dimethyl-1,4-phenylene oxide).

Angew Chem Int Ed Engl 2018 02 16;57(6):1528-1531. Epub 2018 Jan 16.

Department of Macromolecular Science and Engineering and Department of Chemistry, Case Western Reserve University, 2100 Adelbert Road, Cleveland, OH, 44106-7202, USA.

A new class of high-temperature dipolar polymers based on sulfonylated poly(2,6-dimethyl-1,4-phenylene oxide) (SO -PPO) was synthesized by post-polymer functionalization. Owing to the efficient rotation of highly polar methylsulfonyl side groups below the glass transition temperature (T ≈220 °C), the dipolar polarization of these SO -PPOs was enhanced, and thus the dielectric constant was high. Consequently, the discharge energy density reached up to 22 J cm . Owing to its high T  , the SO -PPO sample also exhibited a low dielectric loss. For example, the dissipation factor (tan δ) was 0.003, and the discharge efficiency at 800 MV m was 92 %. Therefore, these dipolar glass polymers are promising for high-temperature, high-energy-density, and low-loss electrical energy storage applications.
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http://dx.doi.org/10.1002/anie.201710474DOI Listing
February 2018

Outpatient Management of Emergency Department Patients With Acute Pulmonary Embolism: Variation, Patient Characteristics, and Outcomes.

Ann Emerg Med 2018 07 13;72(1):62-72.e3. Epub 2017 Dec 13.

Permanente Medical Group, Oakland, CA; Kaiser Permanente Division of Research, Oakland, CA; Department of Emergency Medicine, Kaiser Permanente Oakland Medical Center, Oakland, CA; Department of Critical Care, Kaiser Permanente Oakland Medical Center, Oakland, CA.

Study Objective: Outpatient management of emergency department (ED) patients with acute pulmonary embolism is uncommon. We seek to evaluate the facility-level variation of outpatient pulmonary embolism management and to describe patient characteristics and outcomes associated with home discharge.

Methods: The Management of Acute Pulmonary Embolism (MAPLE) study is a retrospective cohort study of patients with acute pulmonary embolism undertaken in 21 community EDs from January 2013 to April 2015. We gathered demographic and clinical variables from comprehensive electronic health records and structured manual chart review. We used multivariable logistic regression to assess the association between patient characteristics and home discharge. We report ED length of stay, consultations, 5-day pulmonary embolism-related return visits and 30-day major hemorrhage, recurrent venous thromboembolism, and all-cause mortality.

Results: Of 2,387 patients, 179 were discharged home (7.5%). Home discharge varied significantly between EDs, from 0% to 14.3% (median 7.0%; interquartile range 4.2% to 10.9%). Median length of stay for home discharge patients (excluding those who arrived with a new pulmonary embolism diagnosis) was 6.0 hours (interquartile range 4.6 to 7.2 hours) and 81% received consultations. On adjusted analysis, ambulance arrival, abnormal vital signs, syncope or presyncope, deep venous thrombosis, elevated cardiac biomarker levels, and more proximal emboli were inversely associated with home discharge. Thirteen patients (7.2%) who were discharged home had a 5-day pulmonary embolism-related return visit. Thirty-day major hemorrhage and recurrent venous thromboembolism were uncommon and similar between patients hospitalized and those discharged home. All-cause 30-day mortality was lower in the home discharge group (1.1% versus 4.4%).

Conclusion: Home discharge of ED patients with acute pulmonary embolism was uncommon and varied significantly between facilities. Patients selected for outpatient management had a low incidence of adverse outcomes.
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http://dx.doi.org/10.1016/j.annemergmed.2017.10.022DOI Listing
July 2018

No Easy Way Out: A Case of Physician-Assisted Dying in the Emergency Department.

Authors:
David H Wang

Ann Emerg Med 2018 08 13;72(2):206-210. Epub 2017 Oct 13.

Division of Palliative Medicine, University of California San Francisco, San Francisco, CA, and the Department of Emergency Medicine, Kaiser Permanente, San Francisco, CA. Electronic address:

Currently, 1 out of 6 Americans lives within a jurisdiction in which physician-assisted dying is legally authorized. In most cases, patients ingest lethal physician-assisted dying medications at home without involvement of emergency medical services (EMS) or the emergency department (ED). However, occasionally the dying process is interrupted as a result of incomplete ingestion or vomiting of medications, confusion about timing of dying trajectory, familial emotional distress, and other variables. A case is presented here of a patient who arrived by ambulance to an urban ED after ingesting physician-assisted dying medication. Stepwise analysis of communication and actions between providers (paramedics, emergency physician, and admitting physician), risk management, and family are described chronologically. This case highlights the significant distress experienced by each party, as well as key challenges and learning points. Guidance is provided to emergency providers about expectations and communication. In states with limited physician-assisted dying experience, many EMS agencies, EDs, and hospitals require comprehensive protocols to handle the complex ethical and psychosocial issues surrounding physician-assisted dying in the ED.
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http://dx.doi.org/10.1016/j.annemergmed.2017.08.056DOI Listing
August 2018

The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation.

Ann Surg 2018 12;268(6):992-999

Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, United States.

Objective: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials.

Summary Background Data: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients.

Methods: To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation.

Results: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure.

Conclusions: Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors.
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http://dx.doi.org/10.1097/SLA.0000000000002410DOI Listing
December 2018

"Futile Care"-An Emergency Medicine Approach: Ethical and Legal Considerations.

Ann Emerg Med 2017 Nov 26;70(5):707-713. Epub 2017 Jul 26.

Center for Bioethics and Medical Humanities, Institute for Health and Society, and Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee, WI.

Futility often serves as a proposed reason for withholding or withdrawing medical treatment, even in the face of patient and family requests. Although there is substantial literature describing the meaning and use of futility, little of it is specific to emergency medicine. Furthermore, the literature does not provide a widely accepted definition of futility, and thus is difficult if not impossible to apply. Some argue that even a clear concept of futility would be inappropriate to use. This article will review the origins of and meanings suggested for futility, specific challenges such cases create in the emergency department (ED), and the relevant legal background. It will then propose an approach to cases of perceived futility that is applicable in the ED and does not rely on unilateral decisions to withhold treatment, but rather on avoiding and resolving the conflicts that lead to physicians' believing that patients are asking them to provide "futile" care.
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http://dx.doi.org/10.1016/j.annemergmed.2017.06.005DOI Listing
November 2017

Nutritional Supplements for the Treatment and Prevention of Sports-Related Concussion-Evidence Still Lacking.

Curr Sports Med Rep 2017 Jul/Aug;16(4):247-255

1Division of Sports Medicine, Department of Family, Community & Preventative Medicine, Drexel University, College of Medicine, Philadelphia, PA 19127; 2Connecticut Children's Medical Center, Elite Sports Medicine, Farmington, CT; and 3UBMD Department of Orthopaedics and Sports Medicine, SUNY Buffalo Buffalo, NY.

Concussions are common neurologic events that affect many athletes. Very little has been studied on the treatment of concussions with supplements and medications. The U.S. Food and Drug Administration (FDA) reminds us that no supplement has been proven to treat concussions. Many animal studies show that supplements have potential for improving the effects of a brain injury but none have been shown to be of consistent benefit in human studies. Animal studies on severe traumatic brain injury (TBI) may not therefore be applicable transfer to sports-related concussions (SRC).Of the many supplements reviewed in this article, omega-3 fatty acids (Ω-3 FA) have potential for SRC treatment but in the one human trial those taking higher dosages preinjury had more concussions. In animal studies, postinjury administration was as effective as pretreatment. N-acetyl-cysteine has demonstrated a positive short-term effect on blast injuries in soldiers if administered within 24 h, but there are no studies in SRC. Caffeine, conversely, may be detrimental if taken after SRC. Lower serum levels of vitamins D, C, or E preinjury have worse outcomes in animal studies. Preinjury correction of deficiencies may be of benefit. Current human trials for nicotinamide ribose, melatonin, and branched chain amino acids (BCAA) may soon provide more evidence for the use of these supplements to reduce the impact of SRC in athletes.
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http://dx.doi.org/10.1249/JSR.0000000000000387DOI Listing
March 2018

A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma.

Nat Neurosci 2017 Aug 12;20(8):1074-1084. Epub 2017 Jun 12.

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Aberrant epidermal growth factor receptor (EGFR) signaling is widespread in cancer, making the EGFR an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition has not been effective in treating this tumor. Here we propose that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. We show that in glioma cells expressing either EGFR wild type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased tumor necrosis factor (TNF) secretion, which leads to activation in turn of c-Jun N-terminal kinase (JNK), the Axl receptor tyrosine kinase and extracellular signal-regulated kinases (ERK). Inhibition of this adaptive axis at multiple nodes rendered glioma cells with primary resistance sensitive to EGFR inhibition. Our findings provide a possible explanation for the failures of anti-EGFR therapy in GBM and suggest a new approach to the treatment of EGFR-expressing GBM using a combination of EGFR and TNF inhibition.
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http://dx.doi.org/10.1038/nn.4584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529219PMC
August 2017

The Esophageal Squamous Epithelial Cell-Still a Reasonable Candidate for the Barrett's Esophagus Cell of Origin?

Authors:
David H Wang

Cell Mol Gastroenterol Hepatol 2017 Jul 6;4(1):157-160. Epub 2017 Mar 6.

Esophageal Diseases Center, Department of Internal Medicine and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, Medical Service, Dallas VA Medical Center, Dallas, Texas.

Barrett's esophagus is the metaplastic change of the squamous epithelium lining the distal esophagus into an intestinalized columnar epithelium that predisposes to esophageal adenocarcinoma development. The cell that gives rise to Barrett's esophagus has not been identified definitively, although several sources for the Barrett's esophagus cell of origin have been postulated. One possible source is a fully differentiated squamous epithelial cell or a squamous epithelial progenitor or stem cell native to the esophagus that, through molecular reprogramming, either transdifferentiation or transcommitment, could give rise to an intestinalized columnar cell. Multilayered epithelium found in human patients and rodents with Barrett's esophagus and direct phenotypic conversion of mouse embryonic esophageal epithelium provide support for this. Limitations in current experimental approaches may explain why it has been difficult to fully change an esophageal squamous epithelial cell into an intestinalized columnar cell in vitro.
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http://dx.doi.org/10.1016/j.jcmgh.2017.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453881PMC
July 2017

Laparoscopic ischemic conditioning of the stomach increases neovascularization of the gastric conduit in patients undergoing esophagectomy for cancer.

J Surg Oncol 2017 Sep 29;116(3):391-397. Epub 2017 May 29.

Division of Gastrointestinal and General Surgery and the Digestive Health Center, Department of Surgery, Oregon Health & Science University Medical Center, Portland, Oregon.

Background And Objectives: Gastric ischemic preconditioning has been proposed to improve blood flow and reduce the incidence of anastomotic complications following esophagectomy with gastric pull-up. This study aimed to evaluate the effect of prolonged ischemic preconditioning on the degree of neovascularization in the distal gastric conduit at the time of esophagectomy.

Methods: A retrospective review of a prospectively maintained database identified 30 patients who underwent esophagectomy. The patients were divided into three groups: control (no preconditioning, n = 9), partial (short gastric vessel ligation only, n = 8), and complete ischemic preconditioning (left and short gastric vessel ligation, n = 13). Microvessel counts were assessed, using immunohistologic analysis to determine the degree of neovascularization at the distal gastric margin.

Results: The groups did not differ in age, gender, BMI, pathologic stage, or cancer subtype. Ischemic preconditioning durations were 163 ± 156 days for partial ischemic preconditioning, compared to 95 ± 50 days for complete ischemic preconditioning (P = 0.2). Immunohistologic analysis demonstrated an increase in microvessel counts of 29% following partial ischemic preconditioning (P = 0.3) and 67% after complete ischemic preconditioning (P < 0.0001), compared to controls.

Conclusions: Our study indicates that prolonged ischemic preconditioning is safe and does not interfere with subsequent esophagectomy. Complete ischemic preconditioning increased neovascularization in the distal gastric conduit.
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http://dx.doi.org/10.1002/jso.24668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533617PMC
September 2017

Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus.

Gut 2018 04 25;67(4):606-615. Epub 2017 Apr 25.

Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Objective: In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression.

Design: We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression.

Results: In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate HO, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells.

Conclusions: Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.
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http://dx.doi.org/10.1136/gutjnl-2016-313584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656558PMC
April 2018

Beyond Code Status: Palliative Care Begins in the Emergency Department.

Authors:
David H Wang

Ann Emerg Med 2017 Apr 26;69(4):437-443. Epub 2017 Jan 26.

Department of Emergency Medicine, Stanford University, Stanford, CA; Division of Palliative Medicine, University of California-San Francisco, San Francisco, CA. Electronic address:

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http://dx.doi.org/10.1016/j.annemergmed.2016.10.027DOI Listing
April 2017

NOD-Like Receptor Protein 3 Inflammasome Priming and Activation in Barrett's Epithelial Cells.

Cell Mol Gastroenterol Hepatol 2016 Jul 19;2(4):439-453. Epub 2016 Mar 19.

Esophageal Diseases Center, VA North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas; Department of Medicine, VA North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Background & Aims: Microbial molecular products incite intestinal inflammation by activating Toll-like receptors (TLRs) and inflammasomes of the innate immune system. This system's contribution to esophageal inflammation is not known. Gram-negative bacteria, which dominate the esophageal microbiome in reflux esophagitis, produce lipopolysaccharide (LPS), a TLR4 ligand. TLR4 signaling produces pro-interleukin (IL)1β, pro-IL18, and NOD-like receptor protein 3 (NLRP3), which prime the NLRP3 inflammasome. Subsequent NLRP3 inflammasome activation cleaves caspase-1, inducing secretion of proinflammatory cytokines and pyroptosis (inflammatory cell death). We explored LPS effects on NLRP3 inflammasome priming and activation in esophageal cells.

Methods: We exposed esophageal squamous and Barrett's epithelial cells to LPS and measured the following: (1) TLR4, pro-IL1β, pro-IL18, and NLRP3 expression; (2) caspase-1 activity; (3) tumor necrosis factor-α, IL8, IL1β, and IL18 secretion; (4) lactate dehydrogenase (LDH) release (a pyroptosis marker); and (5) mitochondrial reactive oxygen species (ROS). As inhibitors, we used acetyl-Tyr-Val-Ala-Asp-CHO for caspase-1, small interfering RNA for NLRP3, and (2-(2,2,6,6,-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride for mitochondrial ROS.

Results: Squamous and Barrett's cells expressed similar levels of TLR4, but LPS induced TLR4 signaling that increased tumor necrosis factor-α and IL8 secretion only in Barrett's cells. Barrett's cells treated with LPS showed increased expression of pro-IL18, pro-IL1β, and NLRP3, and increased mitochondrial ROS levels, caspase-1 activity, IL1β and IL18 secretion, and LDH release. Acetyl-Tyr-Val-Ala-Asp-CHO, NLRP3 small interfering RNA, and Mito-TEMPO all blocked LPS-induced IL1β and IL18 secretion and LDH release.

Conclusions: In Barrett's cells, LPS both primes and activates the NLRP3 inflammasome, causing secretion of proinflammatory cytokines and pyroptosis. By triggering molecular events promoting inflammation, the esophageal microbiome might contribute to inflammation-mediated carcinogenesis in Barrett's esophagus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042564PMC
http://dx.doi.org/10.1016/j.jcmgh.2016.03.006DOI Listing
July 2016
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