Faculty Bibliography

BACKGROUND & AIMS: Obesity-induced non-alcoholic fatty liver disease (NAFLD) develops, in part, via excess insulin-stimulated hepatic de novo lipogenesis, which increases, paradoxically, in patients with obesity-induced insulin resistance. Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) terminates insulin signaling by dephosphorylating Akt; levels of PHLPP2 are reduced in livers from obese mice. We investigated whether loss of hepatic PHLPP2 is sufficient to induce fatty liver in mice, mechanisms of PHLPP2 degradation in fatty liver, and expression of genes that regulate PHLPP2 in livers of patients with NAFLD. METHODS: C57BL/6J mice (controls), obese db/db mice and mice with liver-specific deletion of PHLPP2 (L-PHLPP2) fed either normal chow or high-fat diet (HFD) were analyzed for metabolic phenotypes including glucose tolerance and hepatic steatosis. PHLPP2-deficient primary hepatocytes or CRISPR/Cas9-mediated PHLPP2-knockout hepatoma cells were analyzed for insulin signaling and gene expression. We performed mass spectrometry analyses of livers tissues from C57BL/6J mice transduced with Ad-HA-FLAG-PHLPP2 to identify post-translational modifications to PHLPP2 and proteins that interact with PHLPP2. We measured levels of mRNAs by quantitative reverse transcription PCR in liver biopsies from patients with varying degrees of hepatic steatosis. RESULTS: PHLPP2-knockout hepatoma cells and hepatocytes from L-PHLPP2 mice showed normal initiation of insulin signaling, but prolonged insulin action. Chow-fed L-PHLPP2 mice had normal glucose tolerance but hepatic steatosis. In HFD-fed C57BL/6J or db/db obese mice, endogenous PHLPP2 was degraded by glucagon and PKA-dependent phosphorylation of PHLPP2 (at Ser1119 and Ser1210), which led to PHLPP2 binding to potassium channel tetramerization domain containing 17 (KCTD17), a substrate-adaptor for Cul3-RING ubiquitin ligases. Levels of KCTD17 mRNA were increased in livers of HFD-fed C57BL/6J or db/db obese mice and in liver biopsies patients with NAFLD, compared with liver tissues from healthy control mice or patients without steatosis. Knockdown of KCTD17 with small hairpin RNA in primary hepatocytes increased PHLPP2 protein but not Phlpp2 mRNA, indicating that KCTD17 mediates PHLPP2 degradation. KCTD17 knockdown in obese mice prevented PHLPP2 degradation and decreased expression of lipogenic genes. CONCLUSIONS: In mouse models of obesity, we found that PHLPP2 degradation induced lipogenesis without affecting gluconeogenesis. KCTD17, which is upregulated in liver tissues of obese mice and patients with NAFLD, binds to phosphorylated PHLPP2 to target it for ubiquitin-mediated degradation; this increases expression of genes that regulate lipogenesis to promote hepatic steatosis. Inhibitors of this pathway might be developed for treatment of patients with NAFLD.

Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.

Objective Compare survival outcomes between unimodality and multimodality treatments for early-stage tonsil squamous cell carcinoma (SCC). Study Design and Setting Review of the National Cancer Database. Subjects and Methods Patients were selected if they were <70 years old with clinical stage I-II SCC of the tonsil, as documented in the National Cancer Database from 1998 to 2011. Palliative and nonstandard treatments were excluded. Propensity score matching was performed, controlling for tumor stage, age, race, comorbidity, insurance status, and year of diagnosis. Overall survival (OS) was compared with the Kaplan-Meier method and log-rank test. Results We identified 3247 patients. Radiotherapy (RT) was delivered in 1295 patients (39.9%), surgery in 824 (25.4%), and surgery + RT in 1128 (34.7%). Patients treated with surgery + RT had the highest 5-year OS (81.1%), followed by surgery (67.4%) and RT (63.4%; P < .001). In a propensity score-matched subpopulation of 2378 patients, the 5-year OS was 78.8% for surgery + RT, 66.7% for surgery, and 64.5% for RT ( P < .001). Among patients who underwent surgical tonsillectomy plus elective neck dissection and/or adjuvant RT, the 5-year OS was equal ( P = .29), and all were superior to RT alone ( P < .001). Conclusion Multimodality treatment is associated with the greatest survival in early-stage tonsil cancer. The addition of tonsillectomy to RT confers a 20% increase in survival. The current guidelines might not offer the most effective treatment. An up-front surgical approach, followed by appropriately selected adjuvant therapy, may result in improved survival for early-stage tonsil SCC. These findings merit investigation in a prospective clinical trial.

Practice sharpens our perceptual judgments, a process known as perceptual learning. Although several brain regions and neural mechanisms have been proposed to support perceptual learning, formal tests of causality are lacking. Furthermore, the temporal relationship between neural and behavioral plasticity remains uncertain. To address these issues, we recorded the activity of auditory cortical neurons as gerbils trained on a sound detection task. Training led to improvements in cortical and behavioral sensitivity that were closely matched in terms of magnitude and time course. Surprisingly, the degree of neural improvement was behaviorally gated. During task performance, cortical improvements were large and predicted behavioral outcomes. In contrast, during nontask listening sessions, cortical improvements were weak and uncorrelated with perceptual performance. Targeted reduction of auditory cortical activity during training diminished perceptual learning while leaving psychometric performance largely unaffected. Collectively, our findings suggest that training facilitates perceptual learning by strengthening both bottom-up sensory encoding and top-down modulation of auditory cortex.

We propose a new mechanism of sensory modulation through cutaneous dopaminergic signalling. We hypothesize that dopaminergic signalling contributes to differential cutaneous sensitivity in darker versus lighter pigmented humans and mouse strains. We show that thermal and mechanical cutaneous sensitivity is pigmentation dependent. Meta-analyses in humans and mice, along with our own mouse behavioural studies, reveal higher thermal sensitivity in pigmented skin relative to less-pigmented or albino skin. We show that dopamine from melanocytes activates the D1-like dopamine receptor on primary sensory neurons. Dopaminergic activation increases expression of the heat-sensitive TRPV1 ion channel and reduces expression of the mechanically-sensitive Piezo2 channel; thermal threshold is lower and mechanical threshold is higher in pigmented skin.

HYPOTHESIS: A novel smartphone-based software application can facilitate self-selection of frequency allocation tables (FAT) in postlingually deaf cochlear implant (CI) users. BACKGROUND: CIs use FATs to represent the tonotopic organization of a normal cochlea. Current CI fitting methods typically use a standard FAT for all patients regardless of individual differences in cochlear size and electrode location. In postlingually deaf patients, different amounts of mismatch can result between the frequency-place function they experienced when they had normal hearing and the frequency-place function that results from the standard FAT. For some CI users, an alternative FAT may enhance sound quality or speech perception. Currently, no widely available tools exist to aid real-time selection of different FATs. This study aims to develop a new smartphone tool for this purpose and to evaluate speech perception and sound quality measures in a pilot study of CI subjects using this application. METHODS: A smartphone application for a widely available mobile platform (iOS) was developed to serve as a preprocessor of auditory input to a clinical CI speech processor and enable interactive real-time selection of FATs. The application's output was validated by measuring electrodograms for various inputs. A pilot study was conducted in six CI subjects. Speech perception was evaluated using word recognition tests. RESULTS: All subjects successfully used the portable application with their clinical speech processors to experience different FATs while listening to running speech. The users were all able to select one table that they judged provided the best sound quality. All subjects chose a FAT different from the standard FAT in their everyday clinical processor. Using the smartphone application, the mean consonant-nucleus-consonant score with the default FAT selection was 28.5% (SD 16.8) and 29.5% (SD 16.4) when using a self-selected FAT. CONCLUSION: A portable smartphone application enables CI users to self-select frequency allocation tables in real time. Even though the self-selected FATs that were deemed to have better sound quality were only tested acutely (i.e., without long-term experience with them), speech perception scores were not inferior to those obtained with the clinical FATs. This software application may be a valuable tool for improving future methods of CI fitting.

Purpose: Obesity is an established risk factor for many types of cancer. While obesity has been linked to worse long-term outcomes among patients with breast and colorectal cancer, the relationship of body mass index (BMI) and adrenocortical carcinoma (ACC) remains ill-defined. Since ACC can express adipokine and estrogen receptors, the impact of BMI on outcomes in this patient population is important. We sought to define the association of BMI on ACC clinical and biologic factors, as well as long-term survival. Methods: Data was obtained on 187 patients who underwent surgery for ACC at 13 institutions for whom BMI data were available. Patients were stratified according to the WHO classification of BMI: BMI<25, 25-29.9, 30-34.9, 35-39.9 and >=40. Demographics, tumor biology, management strategies and clinical outcomes were assessed relative to BMI category. Categorical data were analyzed by Fisher's exact test, while continuous variables were analyzed by ANOVA model; disease-free and overall survival were analyzed by Kaplan-Meier survival curves. Results: Mean BMI was 29.5, with a range of 19 to 69. Patient age was comparable among all BMI groups (p=0.9917). Patient sex (p=0.0079) and race (p=0.0373) varied by BMI category. Mean tumor size was 12.1 cm and mean tumor weight was 875 grams, which was similar in all BMI groups. AJCC stage (Stage I: n=12; Stage II: n=62; Stage III: n=47; and Stage IV: n=48) and ENSAT stage (Stage I: n=12; Stage II: n=62; Stage III: n=72; and Stage IV: n=23) did not vary by BMI. BMI tended to be associated with mean mitotic rate (BMI<25: 12.4; 25-29.9: 14.2; 30-34.9: 21.0; 35-39.9: 33.8 and >=40: 8.7; p=0.0773) and percent lymphatic invasion (BMI<25: 37%; 25-29.9: 68%; 30-34.9: 60%; 35-39.9: 67% and>=40: 44%; p=0.0818). In addition, R0 resection rate differed by BMI group (BMI<25: 68%; 25-29.9: 76%; 30-34.9: 50%; 35-39.9: 27% and >=40: 71%; p=0.0029). BMI was not associated with disease-free interval or overall survival. Conclusion: Increased BMI was associated with ACC tumor characteristics but did not affect disease-free or overall survival in our cohort. Further studies are needed to evaluate whether the endocrine effect of lipocytes influences ACC pathology

BACKGROUND: Improving the quality of healthcare is a complex and resource intensive process. To optimize the allocation of scarce resources, quality improvement (QI) should focus on high-value diseases that will produce the largest improvement in health system performance. Given the breadth and multidisciplinary nature of sinonasal disease management, the purpose of this study was to transparently develop a prioritized list of sinonasal diseases for QI from the perspective of the specialty of rhinology and the American Rhinologic Society (ARS). METHODS: The RAND modified Delphi methodology was used to rank the priority of nine sinonasal disease categories from 1 (lowest priority) to 9 (highest priority). Two rounds of ranking along with a teleconference meeting was performed by a panel of 9 experts from the ARS Quality Improvement Committee. RESULTS: The final QI-prioritized list of sinonasal diseases are as follows: chronic rhinosinusitis (CRS) (mean score = 8.9), recurrent acute rhinosinusitis (RARS) (mean score = 7.9), sinonasal neoplasms (mean score = 7.0), anatomic nasal obstruction (mean score = 5.9), refractory epistaxis (mean score = 5.2), complicated acute rhinosinusitis (mean score = 5.2), chronic nonallergic rhinitis (mean score = 4.4), orbital disease (mean score = 4.3), uncomplicated acute rhinosinusitis (mean score = 4.1), and allergy/allergic rhinitis (mean score = 3.7). CONCLUSION: The three most important disease categories for QI from the perspective of the specialty of rhinology were CRS, RARS, and sinonasal neoplasms. Future studies need to define and validate quality metrics for each of these important disease categories in order to facilitate appropriate measurement and improvement initiatives.

Importance: Research in facial aging has focused on soft-tissue changes rather than bony changes despite evidence of the importance of underlying bony structural changes. Research has also been limited by comparing different patients in separate age groups rather than the same patients over time. Objective: To longitudinally document patterns of change in the facial skeleton and determine a consistent methodology for measuring these changes. Design, Setting, and Participants: Case series study of university hospital system records using facial computed tomographic (CT) images timed at least 8 years apart in adults initially aged 40 to 55 years with no history of facial surgery who required repeated facial imaging that included the entire midface and cranium. Main Outcomes and Measures: Face CTs were analyzed for 3-dimensional constructions and 2-dimensional measurements to document changes in glabellar, piriform, and maxillary angles and piriform height and width. Results: Fourteen patients (5 men, 9 women; mean [SD] age, 51.1 [5.8] years) with mean (SD) follow-up of 9.7 (1.4) years were eligible for 2-dimensional analysis, which revealed statistically significant decreases in mean (SD) glabellar angles (from 68.8 degrees [7.6 degrees ] to 66.5 degrees [8.6 degrees ]) and maxillary angles on both the right (from 82.5 degrees [6.3 degrees ] to 81.0 degrees [7.1 degrees ]) and left (from 83.0 degrees [5.8 degrees ] to 81.0 degrees [7.0 degrees ]), as well as increases in mean (SD) piriform width (from 24.5 [1.6] mm to 25.5 [1.3] mm). Nine patients (3 men, 6 women; mean [SD] age, 51.4 [6.3] years) with mean (SD) follow-up imaging at 9.6 (1.5) years were eligible for 3-dimensional analysis, which revealed statistically significant decreases in mean (SD) maxillary angles (from 56.5 degrees [6.6 degrees ] to 51.6 degrees [7.6 degrees ]) and piriform angles (from 50.8 degrees [3.4 degrees ] to 49.1 degrees [3.4 degrees ]). Statistically significant differences between the sexes were also noted: Initial mean (SD) glabellar angle for men was 61.7 degrees (5.7 degrees ) vs 72.7 degrees (5.4 degrees ) for women, with final values of 57.9 degrees (4.9 degrees ) vs 71.2 degrees (6.0 degrees ). Mean (SD) maxillary angle initial values were 87.8 degrees (6.1 degrees ) (right) and 87.1 degrees (4.9 degrees ) (left) for men, with 79.6 degrees (4.3 degrees ) and 80.6 degrees (5.0 degrees ) for women, respectively. Final values were 87.0 degrees (4.4 degrees ) and 86.9 degrees (4.1 degrees ) for men and 77.7 degrees (6.1 degrees ) and 77.7 degrees (6.2 degrees ) for women, respectively. Mean (SD) piriform height for men was 35.0 (2.0) mm initially and 35.5 (2.1) mm finally, vs 31.3 (2.8) and 31.6 (3.0) mm for women, respectively. Conclusions and Relevance: Our pilot study of repeated CT images of patients over several years supports previous studies of bony facial aging and further characterizes these changes. This study is the first, to our knowledge, to document bony changes of the face in the same group of patients at different time points to better characterize facial aging. We also detail an improved methodology to study bony aging to contribute to additional research in the field. Level of Evidence: NA.