Faculty Bibliography

Although generally regarded as degradatory enzymes, certain proteases are also signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation, from immune, inflammatory epithelial and cancer cells, as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.

Head and neck squamous cell carcinoma (HNSCC) causes more severe pain and psychological stress than other types of cancer. Despite clinical evidence linking pain, stress, and cancer progression, the underlying relationship between pain and sympathetic neurotransmission in oral cancer is unknown. We found that human HNSCC tumors and mouse tumor tissue are innervated by peripheral sympathetic and sensory nerves. Moreover, [beta]-adrenergic 1 and 2 receptors ([beta]-AR) are overexpressed in human oral cancer cell lines, and norepinephrine treatment increased [beta]-AR2 protein expression as well as cancer cell proliferation in vitro. We have recently demonstrated that inhibition of tumor necrosis factor alpha (TNF[alpha]) signaling reduces oral cancer-induced nociceptive behavior. Norepinephrine-treated cancer cell lines secrete more TNF[alpha] which, when applied to tongue-innervating trigeminal neurons, evoked a larger Ca2+ transient; TNF-TNFR inhibitor blocked the increase in the evoked Ca2+ transient. Using an orthotopic xenograft oral cancer model, we found that mice demonstrated significantly less orofacial cancer-induced nociceptive behavior during systemic [beta]-adrenergic inhibitory treatment with propranolol. Furthermore, chemical sympathectomy via guanethidine led to a significant reduction in tumor size and nociceptive behavior. We infer from these results that sympathetic signaling modulates oral cancer pain via TNF[alpha] secretion and tumorigenesis. Further investigation of the role of neuro-cancer communication in cancer progression and pain is warranted.

Background and Objectives: Perioperative ketamine has been shown to reduce opioid consumption and pain after surgery. Ketamine is most often given as an infusion, but an alternative is single-dose ketamine. Single-dose ketamine at up to 1 mg/kg has been shown to reduce symptoms of depression, and a wide range of dosages has been used for pain in the emergency department. However, limited data exists on the tolerability and efficacy of a single-dose of ketamine at 0.6 mg/kg for pain when administered immediately after surgery. We conducted a pilot study of single-dose ketamine in patients undergoing mastectomy with reconstruction, hypothesizing that a single-dose of ketamine is well tolerated and can relieve postoperative pain and improve mood and recovery. Methods: This is a randomized, single-blind, placebo-controlled, two-arm parallel, single-center study. Thirty adult women undergoing mastectomy with reconstruction for oncologic indication received a single-dose of ketamine (0.6mg/kg) or placebo after surgery in the post-anesthesia care unit (PACU). Patients were followed through postoperative day (POD) 7. The primary outcome was postoperative pain measured by the Brief Pain Inventory (BPI) pain subscale on POD 1 and 2. Secondary outcomes include effects on opioid use, PROMIS fatigue and sleep, mood, Quality of Recovery-15, and the Breast Cancer Pain Questionnaire. Results: Side effects were minor and not significantly different in frequency between groups. The ketamine group reported lower scores on the BPI pain severity subscale, especially at POD 7; however, the difference was not statistically significant. There were no statistically significant differences between ketamine and placebo groups for the secondary outcomes. Conclusion: A single-dose of ketamine at 0.6mg/kg administered postoperatively in the PACU is well tolerated in women undergoing mastectomy and may confer better pain control up to one week after surgery. Future studies with larger sample sizes are necessary to adequately characterize the effect of postoperative single-dose ketamine on pain control in this population.

PURPOSE OF REVIEW/OBJECTIVE:The persistent rise in kidney stone prevalence in recent decades has prompted much speculation as to the causes. There has been some discussion about the effect of heat on nephrolithiasis. Here, we review recent data and postulate that heat may play a role in stone formation on a large scale and among African-Americans in particular. RECENT FINDINGS/RESULTS:African-Americans are the race/ancestry group with faster rates of increasing incidence and prevalence of kidney stones. We make the observation that urban heat islands in the United States have resulted in part from the effects of redlining, a practice of systematic segregation and racism in housing that led to the development of neighborhoods with substantial disparities in environmental conditions. SUMMARY/CONCLUSIONS:In this thought experiment, we propose that the disproportionate rise in the prevalence of nephrolithiasis in minoritized populations correlates with increased temperatures specifically in neighborhoods adversely affected by the practice of redlining. We discuss phenomena in support of this hypothesis and ongoing work to test this theory.

In neonatal brain development there is a period of normal apoptotic cell death that regulates adult neuron number. At approximately the same period, ethanol exposure can cause a dramatic spike in apoptotic cell death. While ethanol-induced apoptosis has been shown to reduce adult neuron number, questions remain about the regional selectivity of the ethanol effect, and whether the brain might have some capacity to overcome the initial neuron loss. The present study used stereological cell counting to compare cumulative neuron loss 8 h after postnatal day 7 (P7) ethanol treatment to that of animals left to mature to adulthood (P70). Across several brain regions we found that the reduction of total neuron number after 8 h was as large as that of adult animals. Comparison between regions revealed that some areas are more vulnerable, with neuron loss in the anterior thalamic nuclei > the medial septum/vertical diagonal band, dorsal subiculum, and dorsal lateral geniculate nucleus > the mammillary bodies and cingulate cortex > whole neocortex. In contrast to estimates of total neuron number, estimates of apoptotic cell number in Nissl-stained sections at 8 h after ethanol treatment provided a less reliable predictor of adult neuron loss. The findings show that ethanol-induced neonatal apoptosis often causes immediate neuron deficits that persist in adulthood, and furthermore suggests that the brain may have limited capacity to compensate for ethanol-induced neuron loss.

Studies of the choroid plexuses lag behind those of, the more widely known, blood brain barrier in spite of a much longer history. This review has two overall aims. The first is to outline longstanding areas of research where there are unanswered questions, such as control of cerebrospinal fluid (CSF) secretion and blood flow. The second part reviews research over the past ten years where the focus has shifted to the idea that the choroid plexuses make specific contributions to brain development and function through molecules they generate and circulate throughout the CSF; these appear to be particularly important for aspects of normal brain growth. Most research in the 20^th Century dealt with the choroid plexuses as one of the brain barrier interfaces that make an important contribution to the composition and stability of the internal environment of the brain in the adult and during its development. More recent research has shown the importance of choroid plexus generated CSF in neurogenesis, influence of sex and other hormones on plexus function, and their role in circadian rhythms and sleep. Of clinical importance are attempts to develop methods to deliver brain-specific drugs via the CSF and understanding the implications of drug entry into developing brain when administered to pregnant women.

Modern medical imaging techniques, such as ultrasound (US) and cardiac magnetic resonance (MR) imaging, have enabled the evaluation of myocardial deformation directly from an image sequence. While many traditional cardiac motion tracking methods have been developed for the automated estimation of the myocardial wall deformation, they are not widely used in clinical diagnosis, due to their lack of accuracy and efficiency. In this paper, we propose a novel deep learning-based fully unsupervised method, SequenceMorph, for in vivo motion tracking in cardiac image sequences. In our method, we introduce the concept of motion decomposition and recomposition. We first estimate the inter-frame (INF) motion field between any two consecutive frames, by a bi-directional generative diffeomorphic registration neural network. Using this result, we then estimate the Lagrangian motion field between the reference frame and any other frame, through a differentiable composition layer. Our framework can be extended to incorporate another registration network, to further reduce the accumulated errors introduced in the INF motion tracking step, and to refine the Lagrangian motion estimation. By utilizing temporal information to perform reasonable estimations of spatio-temporal motion fields, this novel method provides a useful solution for image sequence motion tracking. Our method has been applied to US (echocardiographic) and cardiac MR (untagged and tagged cine) image sequences; the results show that SequenceMorph is significantly superior to conventional motion tracking methods, in terms of the cardiac motion tracking accuracy and inference efficiency. Code will be available at <uri>https://github.com/DeepTag/SequenceMorph</uri>.