Faculty Bibliography

Melanoma brain metastasis is the largest cause of melanoma morbidity and mortality, and melanoma has the highest rate of brain metastasis of any cancer. The mechanisms that mediate melanoma brain metastasis remain poorly understood. We characterized patient-derived Short-Term Cultures (STCs) as a novel model system for the study of melanoma brain metastasis. Unbiased proteomics analysis of STCs revealed striking alterations in brain metastasis vs non-brain metastasis derived STCs in proteins related to neurodegeneration. Through in-vivo assays, we show that loss of Amyloid Precursor Protein (APP) in melanoma cells dramatically inhibits melanoma brain metastasis formation without affecting metastasis to other organs and that amyloid beta is the form of APP critically required for melanoma brain metastasis. Additionally, we demonstrate that APP is required for late growth and survival of melanoma cells in the brain parenchyma. Furthermore, we demonstrate that melanoma-derived amyloid beta polarizes astrocytes to an anti-inflammatory secretory phenotype that inhibits microglial phagocytosis of melanoma cells. Finally, we show that treatment of mice with a beta secretase inhibitor (LY2886721), which prevents amyloid beta production, decreases brain metastatic burden. Our results demonstrate a critical role for amyloid beta in melanoma brain metastasis, establish a novel connection between brain metastasis and neurodegenerative pathologies, and show that amyloid beta is a promising therapeutic target for brain metastasis treatment. Studies to further characterize how amyloid beta acts in the melanoma brain metastasis microenvironment are currently underway

Spike-and-wave discharges (SWDs) of absence epilepsy are considered as pathologic alterations of sleep spindles; however, their network-level relationship has never been convincingly revealed. In order to observe the development and generalization of the thalamocortical SWDs and the concomitant alterations of sleep related oscillations, we performed local field potential (LFP) and single unit recordings in rats for three months during their maturation. We found that while SWDs and spindles look similar in young, they become different with maturation and shift to appear in different brain states. Thus, despite being generated by the same network, they are likely two distinct manifestations of the thalamocortical activity. We show that while spindles are already mainly global oscillations, SWDs appear mainly only focally in young. They become capable to generalize later with maturation, when the out-of-focus brain regions develop a decreased inhibitory/excitatory balance. These results suggest that a hyperexcitable focus is not sufficient alone to drive generalized absence seizures. Importantly, we also found the gradual age dependent disappearance of sleep spindles coinciding with the simultaneous gradual emergence of spike and waves, which both could be reversed by the proper dosing of ethosuximide (ETX). Based on these observations we conclude that the absence seizure development might be a multi-step process, which might involve the functional impairment of cortical interneurons and network-level changes that negatively affect sleep quality.

Regulating gene expression at the protein level is becoming increasingly important for answering basic questions in neurobiology. Several techniques using destabilizing domains (DD) on transgenes, which can be activated or deactivated by specific drugs, have been developed to achieve this goal. A DD from bacterial dihydrofolate reductase bound and stabilized by trimethoprim (TMP) represents such a tool. To control transgenic protein levels in the brain, the DD-regulating drugs need to have sufficient penetration into the central nervous system (CNS). Yet, very limited information is available on TMP pharmacokinetics in the CNS following systemic injection. Here, we performed a pharmacokinetic study on the penetration of TMP into different CNS compartments in the rat. We used mass spectrometry to measure TMP concentrations in serum, cerebrospinal fluid (CSF) and tissue samples of different CNS regions upon intraperitoneal TMP injection. We show that TMP quickly (within 10 min) penetrates from serum to CSF through the blood-CSF barrier. TMP also shows quick penetration into brain tissue but concentrations were an order of magnitude lower compared to serum or CSF. TMP concentration in spinal cord was lower than in any other analyzed CNS area. Nevertheless, effective levels of TMP to stabilize DDs can be reached in the CNS with half-lives around 2 h. These data show that TMP has good and fast penetration properties into the CNS and is therefore a valuable ligand for precisely controlling protein expression in the CNS in rodents.

The piriform cortex is the first area of integration for all peripheral odor information and it is believed to generate a unique and wholistic representation of behavioral relevance, sensory object. However, what properties of the cortical neural population activity define odor objects remains unknown. To address this question, we recorded cortical spiking responses to synthetic odors made of fully parameterized optogenetic activity patterns in the olfactory bulb, enabling independent and precise control of the incoming neural responses unattainable with natural odorants. Then, we measured changes in the neural response to a range of controlled spatial and temporal perturbations of the pattern for which we previously established their behavioral relevance. We developed an experimental approach to systematically probe cortical neural activity and found features of the population code which represent behaviorally relevant information

Background: Our previous study showed that PH without a transplant (tx) had worse HRQoL compared to the US Standard Population and worsened with increased stone frequency. We now show the first longitudinal HRQoL profiles for PH patients with transplants.
Method(s): PH participants were enrolled from the Rare Kidney Stone Consortium registry. HRQoL was measured with a generic non-disease specific instrument (SF-36v2). Results were calculated as norm-based scores (NBS) based on US Standard Population (Mean domain score = 50). We created three groups based on the time of last stone event (<= 30 days, 31 - 365 days, >;366 days). The study compared HRQoL for participants with a kidney and/or liver transplant over 5 different time points.
Result(s): This sub-sample included 100 surveys of 32 PH participants (16 males and 16 females) with a tx. The mean age was 47 years for both males and females. This subsample includes 24 participants with liver/kidney tx (75%) and 8 with kidney tx only (25%). Participants with only a kidney tx reported significantly more stone events within a year (26% vs 13%, X2 =0.028). Two way ANOVA did not find a change in HRQoL profiles over time for PH participants with kidney or kidney/liver tx (figure). Most mean domain scores are 50 or above, except for the domain of General Health which was less. Participants with only a kidney tx scored significantly lower in role physical, bodily pain, general health, social function, and physical component score (data not shown) than participants with kidney/liver tx. There was no difference between male and female participants over time.
Conclusion(s): PH participants with kidney/liver tx achieve better HRQoL, measured with a non-disease specific generic instrument, than those with kidney alone; both are better when compared to the US Standard Population. The majority of PH participants with a tx are stone-free, with a direct beneficial impact on their HRQoL

The acceptance of students to a medical school places a considerable emphasis on performance in standardized tests and undergraduate grade point average (uGPA). Traditionally, applicants may be judged as a homogeneous population according to simple quantitative thresholds that implicitly assume a linear relationship between scores and academic success. This 'one-size-fits-all' approach ignores the notion that individuals may show distinct patterns of achievement and follow diverse paths to success. In this study, we examined a dataset composed of 53 variables extracted from the admissions application records of 1,088 students matriculating to NYU School of Medicine between the years 2006-2014. We defined training and test groups and applied K-means clustering to search for distinct groups of applicants. Building an optimized logistic regression model, we then tested the predictive value of this clustering for estimating the success of applicants in medical school, aggregating eight performance measures during the subsequent medical school training as a success factor. We found evidence for four distinct clusters of students-we termed 'signatures'-which differ most substantially according to the absolute level of the applicant's uGPA and its trajectory over the course of undergraduate education. The 'risers' signature showed a relatively higher uGPA and also steeper trajectory; the other signatures showed each remaining combination of these two main factors: 'improvers' relatively lower uGPA, steeper trajectory; 'solids' higher uGPA, flatter trajectory; 'statics' both lower uGPA and flatter trajectory. Examining the success index across signatures, we found that the risers and the statics have significantly higher and lower likelihood of quantifiable success in medical school, respectively. We also found that each signature has a unique set of features that correlate with its success in medical school. The big data approach presented here can more sensitively uncover success potential since it takes into account the inherent heterogeneity within the student population.

Background: Albuminuria is a risk factor for kidney disease progression and CV disease. We examined the relative and absolute effects of CANA by baseline albuminuria among CREDENCE participants.
Method(s): CREDENCE was a double-blind, randomized study of 4401 participants with eGFR 30-<90mL/min/1.73m2 and uACR >300-5000mg/g who demonstrated that CANA significantly reduced renal and CV outcomes, including the primary composite of end-stage kidney disease, doubling serum creatinine, or renal or CV death. We analyzed the effect of CANA on renal, CV, and safety outcomes by baseline uACR.
Result(s): At baseline, 2348 (53.4%), 1547 (35.2%), and 506 (11.5%) participants had uACR <=1000, >1000-<3000, >=3000mg/g. Higher uACR was associated with higher event rates (Figure). CANA reduced renal and CV endpoints, with no statistical variation by uACR (all p heterogeneity >0.17). CANA led to a greater absolute reduction in renal events in those with higher uACR (number needed to treat to prevent 1 episode of the primary composite: 22 and 8 for uACR >1000-<3000 and >=3000mg/g). Rates of renalrelated adverse events were lower with CANA, and the relative reduction was greater with higher uACR (p heterogeneity=0.003). CANA had no significant effect on acute kidney injury, volume depletion, hyperkalemia, urinary tract infections or hypoglycemia, with no differences by uACR (all p heterogeneity >0.12).
Conclusion(s): CANA safely reduces renal and CV events in people with type 2 diabetes and substantial albuminuria, with the greatest absolute renal benefit in those with uACR of 3000-5000mg/g