Faculty Bibliography

Background/UNASSIGNED:Harmony is an important part of tonal music that conveys context, form and emotion. Two notes sounded simultaneously form a harmonic interval. In normal-hearing (NH) listeners, some harmonic intervals (e.g., minor 2nd, tritone, major 7th) typically sound more dissonant than others (e.g., octave, major 3rd, 4th). Because of the limited spectro-temporal resolution afforded by cochlear implants (CIs), music perception is generally poor. However, CI users may still be sensitive to relative dissonance across intervals. In this study, dissonance ratings for harmonic intervals were measured in 11 unilaterally deaf CI patients, in whom ratings from the CI could be compared to those from the normal ear. Methods/UNASSIGNED:Stimuli consisted of pairs of equal amplitude MIDI piano tones. Intervals spanned a range of two octaves relative to two root notes (F3 or C4). Dissonance was assessed in terms of subjective pleasantness ratings for intervals presented to the NH ear alone, the CI ear alone, and both ears together (NH + CI). Ratings were collected for both root notes for within- and across-octave intervals (1-12 and 13-24 semitones). Participants rated the pleasantness of each interval by clicking on a line anchored with "least pleasant" and "most pleasant." A follow-up experiment repeated the task with a smaller stimulus set. Results/UNASSIGNED:< 0.001). Ratings were similar between NH-only and NH + CI listening, with no significant binaural enhancement/interference. The follow-up tests showed that ratings were reliable for the least and most pleasant intervals. Discussion/UNASSIGNED:Although pleasantness ratings were less differentiated for the CI ear than the NH ear, there were similarities between the two listening modes. Given the lack of spectro-temporal detail needed for harmonicity-based distinctions, temporal envelope interactions (within and across channels) associated with a perception of roughness may contribute to dissonance perception for harmonic intervals with CI-only listening.

Medical innovators and regulators have increasingly recognized the importance of working with patients to design medical therapies and clinical trials that meet the needs of specific patient populations. For diseases such as Parkinson's disease (PD), a progressive, degenerative disease with few effective treatment options, traditional randomized clinical trials with a fixed statistical threshold may not reflect patients' perspectives on the trade-off between the risk of endorsing an ineffective therapy (false positive) and the risk of rejecting an effective therapy (false negative). This collaborative project, which involved academia, industry, FDA, patient-scientists and MJFF, developed and tested methods for incorporating patient preference information as explicit means to set significance levels in clinical trial design.
Method(s): With direct input from patients with PD, we developed a patient preference survey and deployed it online through Fox Insight for 6-weeks and received 2,752 complete responses (24.4%), allowing us to analyze differences in outcome priorities among various demographic groups. We then assigned weights to the consequences of errors based on identified patient preferences, and proposed a hypothetical clinical trial design optimized to maximize the values identified by patients.
Result(s): Movement symptoms, which are common endpoints in PD clinical trials, were ranked as most important, and psychological and cognitive symptoms, which are less commonly studied, were ranked as the next most important. Differences emerged from different groups within the patient population, depending upon how the disease manifested itself. Preferences from respondents with mild PD symptoms and no prior experience with deep brains stimulation (

Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G⁺ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G⁺ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G⁺ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G⁺ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G⁺ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.

Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m² per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for MDM4 and MDM2, respectively, and chromosome 17, where the gene for TP53 is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the JAK2V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of MDM4 In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in MDM2/MDM4 transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of TP53, had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.

Observational learning occurs when an animal capitalizes on the experience of another to change its own behavior in a given context. This form of learning is an efficient strategy for adapting to changes in environmental conditions, but little is known about the underlying neural mechanisms. There is an abundance of literature supporting observational learning in humans and other primates, and more recent studies have begun documenting observational learning in other species such as birds and rodents. The neural mechanisms for observational learning depend on the species' brain organization and on the specific behavior being acquired. However, as a general rule, it appears that social information impinges on neural circuits for direct learning, mimicking or enhancing neuronal activity patterns that function during pavlovian, spatial or instrumental learning. Understanding the biological mechanisms for social learning could boost translational studies into behavioral interventions for a wide range of learning disorders.

Measuring how the brain encodes and processes an animal's own motion presents major technical challenges. New approaches demonstrate the viability and merit of measuring vestibular responses throughout the entire brain.

BACKGROUND:Frailty is defined as a disability in those of advanced age, often with comorbidities, poor nutritional status, cognitive decline, and reduced functional status. OBJECTIVES/OBJECTIVE:The purpose of this article is to discuss the concept of frailty, assess the use of a comprehensive geriatric assessment (CGA), and understand the implications for treatment to maintain or enhance physical, functional, and cognitive health of older adult patients with cancer. METHODS:Literature about frailty in older adult patients diagnosed with cancer was reviewed to determine evidence-based assessment and treatment options. FINDINGS/RESULTS:About half of all older adult patients with cancer experience some degree of frailty. CGA is a useful way to evaluate frailty and the extent of limitations. Many frailty-specific tools have been developed. Evidence-based strategies are available to address limitations associated with frailty in older adult patients with cancer.

Current consensus on optimal treatment of vestibular schwannoma remains poorly established; treatment options include observation, stereotactic radiosurgery, microsurgical resection, medical therapy, or a combination of these. Treatment should be individualized and incorporate the multitude of patient- and tumor-specific characteristics known to affect outcome. Treatment paradigms for sporadic and neurofibromatosis type 2-related tumors are distinct and decision-making in neurofibromatosis type 2 is uniquely challenging. In all cases, treatment should maximize tumor control and minimize functional deficit.

Most animals orient their bodies with respect to gravity to facilitate locomotion and perception. The neural circuits responsible for these orienting movements have long served as a model to address fundamental questions in systems neuroscience. Though postural control is vital, we know little about development of either balance reflexes or the neural circuitry that produces them. Recent work in a genetically and optically accessible vertebrate, the larval zebrafish, has begun to reveal the mechanisms by which such vestibular behaviors and circuits come to function. Here we highlight recent work that leverages the particular advantages of the larval zebrafish to illuminate mechanisms of postural development, the role of sensation for balance circuit development, and the organization of developing vestibular circuits. Further, we frame open questions regarding the developmental mechanisms for functional circuit assembly and maturation where studying the zebrafish vestibular system is likely to open new frontiers.