Faculty Bibliography

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n=5) compared to N0 cancers (n=10) and normal tissue (n=5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

Sexual and aggressive behaviors are fundamental to animal survival and reproduction. The medial preoptic nucleus (MPN) and ventrolateral part of the ventromedial hypothalamus (VMHvl) are essential regions for male sexual and aggressive behaviors, respectively. While key inhibitory inputs to the VMHvl and MPN have been identified, the extrahypothalamic excitatory inputs essential for social behaviors remain elusive. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the posterior amygdala (PA) as a main source of excitatory inputs to the hypothalamus and key mediators for mating and fighting in male mice. We find two largely distinct PA subpopulations that differ in connectivity, gene expression, in vivo responses and social behavior relevance. MPN-projecting PA^Esr1+ cells are activated during mating and are necessary and sufficient for male sexual behaviors, while VMHvl-projecting PA^Esr1+ cells are excited during intermale aggression and promote attacks. These findings place the PA as a key node in both male aggression and reproduction circuits.

Objective: To study the rate of progression of multiple system atrophy (MSA) and assess for a potential ceiling effect of the Unified Multiple System Atrophy Rating Scale (UMSARS).
Background(s): Disease progression of MSA as measured by UMSARS varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2 respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): Three hundred and forty nine patients (61.4+/-7.9 years old) with MSA were enrolled. Disease duration was 4.5+/-5.1 years. 143 patients completed 1-year evaluations and 61 completed the 2-year evaluation. The 12-month progression rates were 5.4+/-5.1 for the UMSARS-I, 5.9+/-5.3 for the UMSARS-II, and 11.8+/-9.6 for the total score. The 24-month progression rates were 10.8+/-7.3 for the UMSARS-I, 12.2+/-7.9 for the UMSARSII, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p = 0.0153) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A possible ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

Objective: To develop a clinical score to distinguish between the parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD).
Background(s): The differential diagnosis between MSA-P and PD is often difficult, particularly early in the disease course.
Method(s): We compared patients with probable MSA-P and with PD with a disease duration of <3 years, selected from those who were enrolled in the Natural History Study of the Synucleinopathies, an international prospective observational study. Detailed clinical neurological, and autonomic parameters were assessed at enrollment using UMSARS part I, II and IV; Schrag quality of life (QoL) scale; burden of autonomic dysfunction by COMPASS-31 scale; smell function using the UPSIT; cardiovascular autonomic function using heart rate variability during deep-breathing, analysis of the Valsalva maneuver, orthostatic stress test, plasma catecholamine levels during supine rest and after head-up tilt; and cognitive evaluation using MoCA. Positive and negative likelihood ratios (LR) were obtained for each variable assessed. Multiple iterations of a composite score based on sequential addition of variables with the highest diagnostic accuracy were created by multiplying each variable's LR and applying a logarithmic function.
Result(s): Fifty-eight MSA-P and 53 PD patients had a disease duration of less than 3 years. The vast majority of patients had been diagnosed within the last 12 months (81% MSA-P and 66% PD patients). MSA-P patients were more frequently female (53% vs. 30% p<0.05) and younger at diagnosis (63+/-8 years vs. 71+/-8 years, p<0.001). A 7-item score comprising the bladder weighted subscore of the COMPASS-31, UMSARS's part 1, UPSIT, hyperreflexia, the motor subscore of Schrag's MSA quality of life scale, falls within 3 years of diagnosis, and new or increased snoring resulted in a ROC curve AUC of 0.983, with excellent 93% sensitivity and 98% specificity to distinguish early MSA-P from PD.
Conclusion(s): We propose a scale of 7 clinical items to distinguish early stage MSA-P from PD. It considers urinary function, olfactory function, corticospinal signs, performance of activities of daily living, motor symptoms burden on quality of life, frequent early falls and sleep disordered breathing. We are now prospectively validating the scale to determine its predictive value in our prodromal cohort. (Figure Presented)

People with chronic kidney disease (CKD) are at increased risk of hyperkalemia, an electrolyte abnormality that can cause serious, sometimes fatal, cardiac arrhythmias. Muscle contraction causes potassium to be released from cells, increasing serum potassium concentrations. However, these effects are transient, and the long-term impact of exercise training on hyperkalemia risk in CKD patients is largely unknown. In this review, we examine the effects of exercise on factors affecting potassium balance in people with CKD, highlighting the potential benefits of regular exercise on hyperkalemia risk in this population. Although regular exercise is already recommended for people with CKD, research examining this hypothesis may lead to novel therapeutic treatments for this life-threatening condition.

Objective: To confirm: 1) clinical efficacy and safety of once-daily oral ampreloxetine in a 4-week double-blind (

The current coronavirus disease 2019 (COVID-19) crisis continues to grow and has resulted in marked changes to clinical operations. In parallel with clinical preparedness, universities have shut down most scientific research activities. Radiology researchers are currently grappling with these challenges that will continue to affect current and future imaging research. The purpose of this article is to describe the collective experiences of a diverse international group of academic radiology research programs in managing their response to the COVID-19 pandemic. The acute response at six distinct institutions will be described first, exploring common themes, challenges, priorities, and practices. This will be followed by reflections about the future of radiology research in the wake of the COVID-19 pandemic.