Faculty Bibliography

We developed a first-of-kind dasatinib-derivative imaging agent, ¹⁸F-SKI-249380 (¹⁸F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assess the feasibility of using ¹⁸F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min post-injection of ¹⁸F-SKI (mean: 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately post-injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of three patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of ¹⁸F-SKI. A total of 27 tumor lesions were analyzed with median SUVpeak 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min post-injection. Intratumoral drug concentrations calculated for four reference lesions ranged from 0.03-0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30-90 min post-injection. Blood radio-assay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time 1.31 ± 0.81 min, plasma 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time 285 ± 148.49 min, plasma 240 ± 84.85 min; n = 2) or a small rise to plateau (n = 2). Like dasatinib, ¹⁸F-SKI underwent extensive metabolism post-administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 (SD 0.0034) mSv/MBq. Conclusion:¹⁸F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury (TBI) and to better describe the characteristics of the condition commonly labeled Post-traumatic Amnesia, a case definition and diagnostic criteria for the Post- traumatic Confusional State (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2,466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and three rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state while upper boundary is marked by significant improvement in the four core and five associated features. Key research goals are establishment of cut-offs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery.

The aim of this study was to explore genetic and environmental contributions to laboratory-induced aggressive behavior. On a sample of 478 adult twins (316 monozygotic), the Competitive Reaction Time Task was used for aggression induction. The results showed that the initial, basic level of aggression could be explained by both shared (45%) and nonshared environmental factors (55%), while only nonshared environmental factors (100%) had a significant influence on changes in aggression as provocation increased. Genetic factors had no influence on laboratory-induced aggression. The results highlight the importance of environmental factors in shaping situation-specific aggressive responses to provocation.

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.

Our previous studies have indicated that long noncoding RNA (lncRNA) SPRY4 intronic transcript 1 (SPRY4-IT1) was highly expressed in hepatocellular carcinoma (HCC). However, it still remained unclear how SPRY4-IT1 worked in tumorgenesis in HCC. In this study, we tested the overexpression of SPRY4-IT1 in HCC tissues and cells through a quantitative real-time polymerase chain reaction. Statistical analyses showed that the upregulation had an association with the tumor node metastasis stage, thrombin time, and alkaline phosphatase. Furthermore, SPRY4-IT1 could be involved in cell proliferation, metastasis, and the epithelial-to-mesenchymal transition (EMT) process in HCC in vitro and in vivo. RNA-sequencing and transcriptome analysis were carried out to explore the mechanism of SPRY4-IT1 in HCC. With SPRY4-IT1 being knocked down or overexpressed, the level of proteins in the tumor necrosis factor (TNF) signaling pathway changed. We detected the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a SPRY4-IT1 interacting protein through RNA pull-down assay and liquid chromatography-mass spectrometry, then verified through RNA immunoprecipitation. Downregulation of HNRNPL induced the change of proteins observed on SPRY4-IT1 downregulation revealing the SPRY4-IT1: HNRNPL complex in the TNF signaling pathway and EMT process in HCC. In general, our experimental data and analysis demonstrated the role of SPRY4-IT1 in promoting progress and metastasis of HCC by the TNF signaling pathway.

We compared sudden unexpected death in epilepsy (SUDEP) diagnosis rates between North American SUDEP Registry (NASR) epileptologists and original death investigators, to determine degree and causes of discordance. In 220 SUDEP cases with post-mortem examination, we recorded the epileptologist adjudications and medical examiner- and coroner- (ME/C) listed causes of death (CODs). COD diagnosis concordance decreased with NASR's uncertainty in the SUDEP diagnosis: highest for Definite SUDEP (84%, n = 158), lower in Definite Plus (50%, n = 36), and lowest in Possible (0%, n = 18). Rates of psychiatric comorbidity, substance abuse, and toxicology findings for drugs of abuse were all higher in discordant cases than concordant cases. Possible SUDEP cases, an understudied group, were significantly older, and had higher rates of cardiac, drug, or toxicology findings than more certain SUDEP cases. With a potentially contributing or competing COD, ME/Cs favored non-epilepsy-related diagnoses, suggesting a bias toward listing CODs with structural or toxicological findings; SUDEP has no pathognomonic features. A history of epilepsy should always be listed on death certificates and autopsy reports. Even without an alternate COD, ME/Cs infrequently classified COD as "SUDEP." Improved collaboration and communication between epilepsy and ME/C communities improve diagnostic accuracy, as well as bereavement and research opportunities.

OBJECTIVE:To examine autonomic regulation of core body temperature, heart rate (HR), and breathing rate (BR) in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet syndrome (DS). METHODS:We studied video-EEG, ECG, respiration, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1a KO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise. RESULTS:Core body temperatures of WT and DS mice were similar during baseline. After 15 mins of heat exposure, the peak value was lower in DS than WT mice. In the following mins of heat exposure, the temperature slowly returned close to baseline level in WT, whereas it remained elevated in DS mice. KO of Scn1a in GABAergic neurons caused similar thermoregulatory deficits in mice. During exercise, the HR increase was less prominent in DS than WT mice. After exercise, the HR was significantly more suppressed in DS. The heart rate variability (HRV) was lower in DS than WT mice during baseline and higher in DS during exercise-recovery periods. SIGNIFICANCE/CONCLUSIONS:We found novel abnormalities that expand the spectrum of interictal, ictal, and postictal autonomic dysregulation in DS mice. During mild heat stress, there was a significantly blunted correction of body temperature, and a less suppression of both HR and respiration rate in DS than WT mice. These effects were seen in mice with selective KO of Scn1A in GABAergic neurons. During exercise stress, there was diminished increase in HR, followed by an exaggerated HR suppression and HRV elevation during recovery in DS mice compared to controls. These findings suggest that different environmental stressors can uncover distinct autonomic disturbances in DS mice. Interneurons play an important role in thermoregulation. Understanding the spectrum and mechanisms of autonomic disorders in DS may help develop more effective strategies to prevent seizures and SUDEP.