Jessyka G. Lighthall

Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression

TGF-beta and its signaling mediators, Smad2, -3, and -4, are involved with tumor suppression and promotion functions. Smad4-/- mouse epidermis develops spontaneous skin squamous cell carcinomas (SCCs), and Smad3-/- mice are resistant to carcinogen-induced skin cancer; however, the role of Smad2 in skin carcinogenesis has not been explored. In the present study, we found that Smad2 and Smad4, but not Smad3, were frequently lost in human SCCs. Mice with keratinocyte-specific Smad2 deletion exhibited accelerated formation and malignant progression of chemically induced skin tumors compared with WT mice. Consistent with the loss of Smad2 in poorly differentiated human SCCs, Smad2-/- tumors were poorly differentiated and underwent epithelial-mesenchymal transition (EMT) prior to spontaneous Smad4 loss. Reduced E-cadherin and activation of its transcriptional repressor Snail were also found in Smad2-/- mouse epidermis and occurred more frequently in Smad2-negative human SCCs than in Smad2-positive SCCs. Knocking down Snail abrogated Smad2 loss-associated EMT, suggesting that Snail upregulation is a major mediator of Smad2 loss-associated EMT. Furthermore, Smad2 loss led to a significant increase in Smad4 binding to the Snail promoter, and knocking down either Smad3 or Smad4 in keratinocytes abrogated Smad2 loss-associated Snail overexpression. Our data suggest that enhanced Smad3/Smad4-mediated Snail transcription contributed to Smad2 loss-associated EMT during skin carcinogenesis.

Loss of Transforming Growth Factor Beta Type II Receptor Increases Aggressive Tumor Behavior and Reduces Survival in Lung Adenocarcinoma and Squamous Cell Carcinoma

Purpose: Lung adenocarcinoma and lung squamous cell carcinoma (SCC) are the most common non–small cell lung cancer (NSCLC) subtypes. This study was designed to determine whether reduced expression of TGFβ type II receptor (TGFβRII) promotes lung adenocarcinoma and SCC carcinogenesis. Experimental Design: We examined TGFβRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFβRII expression and clinicopathologic parameters. To determine whether sporadic TGFβRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFβRII deletion alone and in combination with oncogenic KrasG12D to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase. Results: Reduced TGFβRII expression in human NSCLC is associated with male gender, smoking, SCC histology, reduced differentiation, increased tumor stage, increased nodal metastasis, and reduced survival. Homozygous or heterozygous TGFβRII deletion in mouse airway epithelia increases the size and number of KrasG12D-initiated adenocarcinoma and SCC. TGFβRII deletion increases proliferation, local inflammation, and TGFβ ligand elaboration; TGFβRII knockdown in airway epithelial cells increases migration and invasion. Conclusions: Reduced TGFβRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGFβ1 expression. TGFβRII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGFβRII loss plays a causal role in lung carcinogenesis. That TGFβRII shows haploid insufficiency suggests that a 50% TGFβRII protein reduction would negatively impact lung cancer prognosis. Clin Cancer Res; 18(8); 2173–83. ©2012 AACR.

Effect of Postoperative Aspirin on Outcomes in Microvascular Free Tissue Transfer Surgery

Objective Examine if outcomes and complication rates for free flaps vary when postoperative aspirin is used as pharmacologic thromboprophylaxis compared with no anticoagulation. Study Design Case series with chart review. Setting Oregon Health and Science University, an academic medical center. Subjects and Methods A case series with chart review was performed using a prospectively maintained microvascular reconstructive database to identify cases of free tissue transfer between February 2006 and April 2010. Outcome variables included complications, flap failure, reexploration, and salvage. Chi-square analysis was performed to identify differences based on type of postoperative antithrombotic therapy. Results A total of 390 consecutive free tissue transfer procedures were performed; 184 received no postoperative thromboprophylaxis, 142 received aspirin, 48 received low molecular weight heparin or a combination of agents, and 16 received a heparin drip. The overall complication rate was 38%, with significantly more complications in the aspirin group compared with no prophylaxis (P = .002). There was no significant difference in bleeding complications (P = .192) or flap failure (P = .839) between aspirin and no anticoagulation. There were more postoperative revisions in the aspirin group (P = .039). Conclusion Postoperative thromboprophylaxis with aspirin after microvascular free tissue transfer does not provide an improvement in free flap survival and may be associated with a higher complication rate. Prospective, randomized studies are required to elucidate the role of postoperative pharmacotherapy for prophylaxis against microvascular thrombosis.

Genetic susceptibility to chronic otitis media with effusion: Candidate gene single nucleotide polymorphisms

The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag‐single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion.

Control of Middle Ear Inflammatory and Ion Homeostasis Genes by Transtympanic Glucocorticoid and Mineralocorticoid Treatments

Hypothesis Transtympanic steroid treatment will induce changes in ion homeostasis and inflammatory gene expression to decrease middle ear inflammation due to bacterial inoculation. Background Otitis media is common, but treatment options are limited to systemic antibiotic therapy or surgical intervention. Systemic glucocorticoid treatment of mice decreases inflammation and improves fluid clearance. However, transtympanic delivery of glucocorticoids or mineralocorticoid has not been explored to determine if direct steroid application is beneficial. Methods Balb/c mice received transtympanic inoculation of heat-killed Haemophilus influenzae (H flu), followed by transtympanic treatment with either prednisolone or aldosterone. Mice given PBS instead of steroid and untreated mice were used as controls. Four hours after steroid treatment, middle ears were harvested for mRNA extraction and 24 hours after inoculation middle ears were harvested and examined for measures of inflammation. Results H flu inoculation caused the increased expression of nearly all inflammatory cytokine genes and induced changes in expression of several genes related to cellular junctions and transport channels. Both steroids generally reversed the expression of inflammatory genes and caused ion and water regulatory genes to return to normal or near normal levels. Histologic evaluation of middle ears showed improved fluid and inflammatory cell clearance. Conclusion Improvement in middle ear inflammation was noted with both the glucocorticoid prednisolone and the mineralocorticoid aldosterone. This was due to reversal of inflammation-induced changes in middle ear cytokine genes, as well as those involved in ion and water homeostasis. Because glucocorticoids bind to the mineralocorticoid receptor, but not the reverse, it is concluded that much of the reduction of fluid and other inflammation measures was due to these steroids impact on ion and water transport channels. Further research is necessary to determine if this alternative mineralocorticoid treatment for otitis media will be clinically effective with fewer side effects than glucocorticoids.

Antibiotic Use in Facial Plastic Surgery

Prophylactic antibiotic use in facial plastic surgery is a highly controversial topic primarily due to the lack of evidence in support of or against antibiotic use. In this section the authors present the available literature on the most commonly performed procedures within facial plastic surgery in an attempt to see if the data support or contradict the need for antibiotic prophylaxis in facial plastic surgery.

Genetic susceptibility to chronic otitis media with effusion: candidate gene SNPs

The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag‐single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion.

Complications of Forehead Lift

Complications and prevention of complications in brow lift are presented. A discussion of anatomic features of the brow introduces the article in keeping with the focus that a thorough understanding of the anatomy, patient variations, and potential complications is requisite for surgeons performing forehead rejuvenation. The varying approaches to brow lift are discussed. Complications reviewed are bleeding, nerve injury, scarring, alopecia, brow asymmetry, and brow elevation overcorrection or undercorrection.

Mentorship in Otolaryngology: 10 Years of Experience

Objective: The Accreditation Council for Graduate Medical Education’s (ACGME) structuring of resident education attempts to utilize mentoring relationships to augment trainee development. The purpose of the current study is to better understand the nature of the mentor-mentee relationship and find areas that should be strengthened or de-emphasized.Method: The Mentorship Program in the Department of Otolaryngology–Head and Neck Surgery at Oregon Health and Science University has existed for 10 years. Mentor-mentee pairs are assigned upon matriculation. Pairs are required to meet biannually at minimum. Guidelines for discussion topics are provided. All residents and faculty participants were surveyed online.Results: Nineteen mentors and 24 mentees completed the survey, a 100% response rate. Mentor personality traits most important to residents were honesty/integrity (93%) and supportiveness (88%), while the least important characteristics were race (100%) and gender (83%). Mentor-mentee pairs discussed a wi...

Otitis Media: Molecular Impact of Inflammation in the Middle and Inner Ear: Cytokines, Steroids, and Ion Homeostasis

An overview of recent topics under investigation in our laboratory is presented. Topics include the cytokine and ion homeostasis gene response to steroids in the middle ear in a murine model of otitis media and gene chip analysis of inner ear genes affected by trans-tympanic and systemic steroid administration to the mouse.