• Targeting Invasive Glioblastoma via the TROY-JAK1 Signaling Pathway

      Kahn, Allon; The University of Arizona College of Medicine - Phoenix; Tran, Nhan (The University of Arizona., 2013-03)
      Objective and Hypothesis: Glioblastoma multiforme, the most common and lethal primary brain neoplasm in adults, has been historically difficult to treat, as its invasion into contiguous brain tissue mitigates the benefit of surgical resection. Furthermore, its unique ability to evade apoptosis and selectively induce proliferation promotes chemotherapeutic resistance and explains the lack of substantial survival improvement despite decades of research. The orphan transmembrane receptor, TROY, has been shown to influence glioma cell migration and survival. While TROY downstream signaling presents a potential therapeutic target, the detailed pathway has yet to be fully elucidated. We identified the non-receptor tyrosine kinase, JAK1,as a candidate binding partner and hypothesized that JAK1 is a downstream mediator of TROY-induced glioma invasion, ultimately seeking to validate the potential therapeutic potential of this interaction. Methods: TROY-JAK1 binding was assessed by co-immunoprecipitation of JAK1 with immunoblotting for TROY. The mechanism of this JAK1-TROY interaction was assessed by western blottingfor phosphorylated JAK1 and STAT3 in wild type vs. TROY-overexpressing glioma cells. Finally, an in-vitro radial migration assay was performed under siRNA depletion of JAK1 to assess functional validation. Results: JAK1 was confirmedas a TROY binding partner by co-immunoprecipitation, with immunoblotting demonstrating that TROY-overexpression induces JAK1 phosphorylation. siRNA-mediated depletion of JAK1 also resulted in decreasedphosphorylated STAT3 level. Finally, a radial migration assay performed on wild-type and TROY-overexpressing T98G cells with and without JAK1 depletion demonstrated statistically significant reductions in migration rate in both JAK1-depleted groups compared to controls. Significance: This study identified and confirmed JAK1 as a downstream mediator of TROY signaling and demonstrated that JAK1 depletion results in mitigation of the pro-migratory effect of TROY overexpression. Thus, JAK1 provides a potential novel therapeutic target for disruption of glioblastoma TROY signaling in vivo andmay contribute to the development of more efficacious chemotherapeutic agents.
    • TDP-43 Deposition in Prospectively Followed, Cognitively Normal Elderly Individuals: A Correlative Study

      Arnold, Stacy J.; The University of Arizona College of Medicine - Phoenix; Beach, Thomas; Dugger, Brittany (The University of Arizona., 2013-03)
      TAR DNA-binding protein 43 (TDP-43) has been heavily researched in recent years due to its involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Numerous studies have also sought to investigate the frequency of TDP-43 deposition in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, with very few studies focusing on the relationship of TDP-43 to pathological and clinical parameters within cognitively normal subjects. We sought to explore the deposition of TDP-43 and its relation to pathological and clinical parameters in a series of prospectively followed, cognitively normal, elderly individuals whom have come to autopsy. We screened thick, coronal sections of mesial temporal lobe; containing hippocampus and/or amygdalar regions from a series of 110 cognitively normal subjects (age range 71-100 years) using immunohistochemical methods for phosphorylated TDP-43. Consistent with previous results, we found a 36.4% incidence of pathologic TDP-43. Deposition was detected in the form of dendritic neurites, intranuclear inclusions, and perikaryal cytoplasmic neuronal inclusions. With respect to other concomitant pathologies commonly found in elderly individuals, cases with TDP-43 had a greater proportion of cases with argyrophilic grains (ARG) (40% vs. 18.6%). There was not greater prevalence or densities of other concomitant pathologies, including cerebral white matter rarefaction, incidental Lewy bodies, neurofibrillary tangles or amyloid plaques in TDP-43 positive cases. These results indicate deposition of TDP-43 occurs in a substantial subset of cognitively normal elderly subjects and is more common in those with argyrophilic grains.
    • Valproic Acid-Induced Gait Disturbance and Cognitive Impairment that was Reversible

      Evans, Matt; The University of Arizona College of Medicine - Phoenix; Yaari, Roy (The University of Arizona., 2013-03)
      Clinicians should be aware that treating patients with Valproic Acid (VPA) can cause cognitive and neurological decline in a small percentage of patients. A 67-year-old female with urinary incontinence, who had taken VPA without major complaints for 15 years to control her seizures, presented with abnormal gait and cognitive impairment that was significantly impacting her day-to-day level of functioning. Initially normal pressure hydrocephalus was suspected, but large volume LP did not show significant improvements in gait or cognition. Discontinuation of VPA reversed her symptoms over the next two months. The hypothesis of this project was that clinical judgment combined with objective criteria could be used to support the argument that this patient’s symptoms were likely an adverse drug reaction to VPA. The Naranjo adverse drug reaction scale was used as an objective measure and indicated that this patient’s likelihood of an adverse drug reaction to VPA was “probable”. Imaging findings consistent with the literature demonstrated reversible cortical pseudoatrophy and enlargement of the lateral ventricles, although changes in ventricular size did not reach statistical significance by two-tailed t-test. This case exemplifies the adverse effects of VPA, which can cause reversible neurological symptoms even in long-term treated patients and can present as parkinsonism or other dementia syndromes such as normal pressure hydrocephalus.
    • What’s in your sample closet? A cross-sectional study to quantify the number of expired samples and to evaluate novelty and usefulness of sample closet medications

      Evans, Kari; The University of Arizona College of Medicine - Phoenix; Brown, Steven (The University of Arizona., 2013-03)
      Background Many physicians dispense drug samples in their offices. In general, evidence suggests that drug samples provide minimal benefit to patients. Objective and Hypothesis To quantify the number of expired sample closet medications and to analyze the medications most commonly found for their novelty and usefulness. We hypothesized that the medications found in local sample closets will often be expired and will not be novel or useful. Methods We inventoried ten sample closets in primary care clinics. We quantified the number of expired medications and analyzed the 23 medications found in seven or more closets. To assess novelty, we determined if the sample medication: had a new mechanism of action, had a generic on market with same mechanism of action, and had a generic medication on market for the same indication. To assess usefulness, we determined if the sample medication had improved patient oriented outcomes, safety, and tolerability. We noted the cost of a one-month supply for the typical starting dose of each sample medication. Results Of the 12,581 drug packages and boxes we inventoried, 14% of were expired. Ninety-six percent (n=22) of sample closet medications had a generic medication on the market for the same indication and 74% (n=17) had a generic medication on the market with the same mechanism. Only 3 medications (13%) had evidence of superior patient oriented outcomes when compared to other medications for the same indication. Six medications (26%) demonstrated superior safety and tolerability. Only one medication (4%) was recommended as first line therapy in an evidence-based guideline. The mean cost for a one month supply of a typical starting dose was 178 dollars. Significance and Conclusions. Sample closet medications are often expired, have limited novelty and usefulness, and are expensive. The widespread use of sample medications should be re-examined.