Ryan S Sprissler

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Journals/Publications

• Romine, J. K., Li, H., Coughlin, M. M., Jones, J. M., Britton, A., Tyner, H. L., Fuller, S. B., Bloodworth, R., Edwards, L. J., Etoule, J. N., Morrill, T. C., Newes-Adeyi, G., Olsho, L. E., Gaglani, M., Fowlkes, A., Hollister, J., Bedrick, E. J., Uhrlaub, J. L., Beitel, S., , Sprissler, R. S., et al. (2024). Hybrid immunity and SARS-CoV-2 antibodies: results of the HEROES-RECOVER prospective cohort study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.
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  There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels.
• Sprissler, R., Hammer, M., Labiner, D., Joshi, N., Alan, A., & Weinand, M. (2024). Leukocyte differential gene expression prognostic value for high versus low seizure frequency in temporal lobe epilepsy. BMC neurology, 24(1), 16.
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  This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE).
• Herring, M. K., Romine, J. K., Wesley, M. G., Ellingson, K. D., Yoon, S. K., Caban-Martinez, A. J., Meece, J., Gaglani, M., Grant, L., Olsho, L. E., Tyner, H. L., Naleway, A. L., Khan, S. M., Phillips, A. L., Solle, N. S., Rose, S., Mak, J., Fuller, S. B., Hunt, A., , Kuntz, J. L., et al. (2023). Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 76(10), 1822-1831.
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  Data on antibody kinetics are limited among individuals previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From a cohort of healthcare personnel and other frontline workers in 6 US states, we assessed antibody waning after messenger RNA (mRNA) dose 2 and response to dose 3 according to SARS-CoV-2 infection history.
• Hollister, J., Caban-Martinez, A. J., Ellingson, K. D., Beitel, S., Fowlkes, A. L., Lutrick, K., Tyner, H. L., Naleway, A. L., Yoon, S. K., Gaglani, M., Hunt, D., Meece, J., Mayo Lamberte, J., Schaefer Solle, N., Rose, S., Dunnigan, K., Khan, S. M., Kuntz, J. L., Fisher, J. M., , Coleman, A., et al. (2023). Serum per- and polyfluoroalkyl substance concentrations and longitudinal change in post-infection and post-vaccination SARS-CoV-2 antibodies. Environmental research, 239(Pt 1), 117297.
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  Per- and polyfluoroalkyl substances (PFAS) are ubiquitous throughout the United States. Previous studies have shown PFAS exposure to be associated with a reduced immune response. However, the relationship between serum PFAS and antibody levels following SARS-CoV-2 infection or COVID-19 vaccination has not been examined. We examined differences in peak immune response and the longitudinal decline of antibodies following SARS-CoV-2 infection and COVID-19 vaccination by serum PFAS levels in a cohort of essential workers in the United States. We measured serum antibodies using an in-house semi-quantitative enzyme-linked immunosorbent assay (ELISA). Two cohorts contributed blood samples following SARS-CoV-2 infection or COVID-19 vaccination. We used linear mixed regression models, adjusting for age, race/ethnicity, gender, presence of chronic conditions, location, and occupation, to estimate differences in immune response with respect to serum PFAS levels. Our study populations included 153 unvaccinated participants that contributed 316 blood draws over a 14-month period following infection, and 860 participants and 2451 blood draws over a 12-month period following vaccination. Higher perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) concentrations were associated with a lower peak antibody response after infection (p = 0.009, 0.031, 0.015). Higher PFOS, perfluorooctanoic acid (PFOA), PFHxS, and PFNA concentrations were associated with slower declines in antibodies over time after infection (p = 0.003, 0.014, 0.026, 0.025). PFOA, PFOS, PFHxS, and PFNA serum concentrations prior to vaccination were not associated with differences in peak antibody response after vaccination or with differences in decline of antibodies over time after vaccination. These results suggest that elevated PFAS may impede potential immune response to SARS-CoV-2 infection by blunting peak antibody levels following infection; the same finding was not observed for immune response to vaccination.
• Lafleur, B. J., White, L., Dake, M. D., Nikolich, J. Z., Sprissler, R., & Bhattacharya, D. (2023). No Evidence That Analgesic Use after COVID-19 Vaccination Negatively Impacts Antibody Responses. ImmunoHorizons, 7(12), 834-841.
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  Uptake of mRNA vaccines, especially booster immunizations, against COVID-19 has been lower than hoped, perhaps in part due to their reactogenicity. Analgesics might alleviate symptoms associated with vaccination, but they might also impact immune responses. We semiquantitatively measured Ab responses following COVID-19 vaccination in 2354 human participants surveyed about analgesic use after vaccination. Participants who used nonsteroidal anti-inflammatory drugs or acetaminophen after vaccination showed elevated Ab levels against the receptor-binding domain of Spike protein relative to those who did not use analgesics. This pattern was observed for both mRNA-1273 and BNT162b2 and across age groups. Participants who used analgesics more frequently reported fatigue, muscle aches, and headaches than did those who did not use painkillers. Among participants who reported these symptoms, we observed no statistically significant differences in Ab levels irrespective of analgesic use. These data suggest that elevated Ab levels are associated with symptoms and inflammatory processes rather than painkiller use per se. Taken together, we find no evidence that analgesic use reduces Ab responses after COVID-19 vaccination. Recommendation of their use to alleviate symptoms might improve uptake of booster immunizations.
• Lyski, Z. L., Porter, C., Uhrlaub, J. L., Ellingson, K. D., Jeddy, Z., Gwynn, L., Rivers, P., Sprissler, R., Hegmann, K. T., Coughlin, M., Fowlkes, A., Hollister, J., LeClair, L., Mak, J., Beitel, S. C., Fuller, S., Grant, L., Newes-Adeyi, G., Yoo, Y. M., , Olsho, L., et al. (2023).

  Humoral Immune Response to Messenger RNA Coronavirus Disease 2019 Vaccination Among Children Aged 5–11 Years in a Multisite Prospective Cohort Study, September 2021–September 2022

  . Open Forum Infectious Diseases, 10(8). doi:10.1093/ofid/ofad431
• Lyski, Z. L., Porter, C., Uhrlaub, J. L., Ellingson, K. D., Jeddy, Z., Gwynn, L., Rivers, P., Sprissler, R., Hegmann, K. T., Coughlin, M., Fowlkes, A., Hollister, J., LeClair, L., Mak, J., Beitel, S. C., Fuller, S., Grant, L., Newes-Adeyi, G., Yoo, Y. M., , Olsho, L., et al. (2023). Humoral Immune Response to Messenger RNA Coronavirus Disease 2019 Vaccination Among Children Aged 5-11 Years in a Multisite Prospective Cohort Study, September 2021-September 2022. Open forum infectious diseases, 10(8), ofad431.
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  The PROTECT study is a longitudinal cohort study initiated in July 2021 with weekly testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 4 states: Arizona, Florida, exas, and Utah. This study aims to examine vaccine-elicited antibody response against postvaccination SARS-CoV-2 infections.
• Quirk, G. E., Schoenle, M. V., Peyton, K. L., Uhrlaub, J. L., Lau, B., Burgess, J. L., Ellingson, K., Beitel, S., Romine, J., Lutrick, K., Fowlkes, A., Britton, A., Tyner, H. L., Caban-Martinez, A. J., Naleway, A., Gaglani, M., Yoon, S., Edwards, L., Olsho, L., , Dake, M., et al. (2023). Determinants of B cell responses to drifted epitopes in post-vaccination SARS-CoV-2 infections. medRxiv : the preprint server for health sciences.
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  Vaccine-induced immunity may impact subsequent responses to drifted epitopes in SARS-CoV-2 variants, but this has been difficult to quantify due to the challenges in recruiting unvaccinated control groups whose first exposure to SARS-CoV-2 is a primary infection. Through local, statewide, and national SARS-CoV-2 testing programs, we were able to recruit cohorts of individuals who had recovered from either primary or post-vaccination infections by either the Delta or Omicron BA.1 variants. Regardless of variant, we observed greater Spike-specific and neutralizing antibody responses in post-vaccination infections than in those who were infected without prior vaccination. Through analysis of variant-specific memory B cells as markers of responses, we observed that Delta and Omicron BA.1 infections led to a marked shift in immunodominance in which some drifted epitopes elicited minimal responses, even in primary infections. Prior immunity through vaccination had a small negative impact on these responses, but this did not correlate with cross-reactive memory B cells, arguing against competitive inhibition of naïve B cells. We conclude that dampened B cell responses against drifted epitopes are mostly a function of altered immunodominance hierarchies that are apparent even in primary infections, with a more modest contribution from pre-existing immunity, perhaps due to accelerated antigen clearance.
• Arani, G., Beitel, S., Burgess, J. L., Caban-Martinez, A. J., Edwards, T., Ellingson, K. D., Fowlkes, A. L., Fuller, S. B., Gaglani, M., Grant, L., Herring, M. K., Hunt, A., Khan, S. M., Kuntz, J. L., Lamberte, J. M., Lowe, A. A., Lutrick, K., Mak, J., Meece, J., , Naleway, A. L., et al. (2022).

  Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses

  . Clinical Infectious Diseases, 76(10), 1822-1831. doi:10.1093/cid/ciac976
• Jergović, M., Uhrlaub, J. L., Watanabe, M., Bradshaw, C. M., White, L. M., LaFleur, B. J., Edwards, T., Sprissler, R., Worobey, M., Bhattacharya, D., & Nikolich-Žugich, J. (2022). Competent immune responses to SARS-CoV-2 variants in older adults following two doses of mRNA vaccination. Nature communications, 13(1), 2891.
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  Aging is associated with a reduced magnitude of primary immune responses to vaccination. mRNA-based SARS-CoV-2 vaccines have shown efficacy in older adults but virus variant escape is still unclear. Here we analyze humoral and cellular immunity against an early-pandemic viral isolate and compare that to the P.1 (Gamma) and B.1.617.2 (Delta) variants in two cohorts (55 age) of mRNA vaccine recipients. We further measure neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595, with the latter SARS-CoV-2 isolate bearing the spike mutation E484Q. Robust humoral immunity is measured following second vaccination, and older vaccinees manifest cellular immunity comparable to the adult group against early-pandemic SARS-CoV-2 and more recent variants. More specifically, the older cohort has lower neutralizing capacity at 7-14 days following the second dose but equilibrates with the younger cohort after 2-3 months. While long-term vaccination responses remain to be determined, our results implicate vaccine-induced protection in older adults against SARS-CoV-2 variants and inform thinking about boost vaccination.
• Kang, H., Allison, S., Spangenberg, A., Carr, T., Sprissler, R., Halonen, M., & Cusanovich, D. A. (2022). Evaluation of Swab-Seq as a scalable, sensitive assay for community surveillance of SARS-CoV-2 infection. Scientific reports, 12(1), 3047.
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  The ongoing SARS-CoV-2 pandemic and subsequent demand for viral testing has led to issues in scaling diagnostic lab efforts and in securing basic supplies for collection and processing of samples. This has motivated efforts by the scientific community to establish improved protocols that are more scalable, less resource intensive, and less expensive. One such developmental effort has resulted in an assay called "Swab-Seq", so named because it was originally developed to work with dry nasal swab samples. The existing gold standard test consists of RNA extracted from a nasopharyngeal (NP) swab that is subjected to quantitative reverse transcription polymerase chain reaction (qRT-PCR). Swab-Seq adapts this method to a next-generation sequencing readout. By pairing this modification with extraction-free sampling techniques, Swab-Seq achieves high scalability, low cost per sample, and a reasonable turnaround time. We evaluated the effectiveness of this assay in a community surveillance setting by testing samples collected from both symptomatic and asymptomatic individuals using the traditional NP swab. In addition, we evaluated extraction-free sampling techniques (both saliva and saline mouth gargle samples). We found the assay to be as clinically sensitive as the qRT-PCR assay, adaptable to multiple sample types, and able to easily accommodate hundreds of samples at a time. We thus provide independent validation of Swab-Seq and extend its utility regarding sample type and sample stability. Assays of this type greatly expand the possibility of routine, noninvasive, repeated testing of asymptomatic individuals suitable for current and potential future needs.
• Snyder, E. M., Sprissler, R., & Olson, T. P. (2022). Data at 36 months for the Symplicity SPYRAL HTN-ON MED pilot. Lancet (London, England), 400(10351), 491-492.
• Betancourt, W. Q., Schmitz, B. W., Innes, G. K., Prasek, S. M., Pogreba Brown, K. M., Stark, E. R., Foster, A. R., Sprissler, R. S., Harris, D. T., Sherchan, S. P., Gerba, C. P., & Pepper, I. L. (2021). COVID-19 containment on a college campus via wastewater-based epidemiology, targeted clinical testing and an intervention. The Science of the total environment, 779, 146408.
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  Wastewater-based epidemiology has potential as an early-warning tool for determining the presence of COVID-19 in a community. The University of Arizona (UArizona) utilized WBE paired with clinical testing as a surveillance tool to monitor the UArizona community for SARS-CoV-2 in near real-time, as students re-entered campus in the fall. Positive detection of virus RNA in wastewater lead to selected clinical testing, identification, and isolation of three infected individuals (one symptomatic and two asymptomatic) that averted potential disease transmission. This case study demonstrated the value of WBE as a tool to efficiently utilize resources for COVID-19 prevention and response. Thus, WBE coupled with targeted clinical testing was further conducted on 13 dorms during the course of the Fall semester (Table 3). In total, 91 wastewater samples resulted in positive detection of SARS-CoV-2 RNA that successfully provided an early-warning for at least a single new reported case of infection (positive clinical test) among the residents living in the dorm. Overall, WBE proved to be an accurate diagnostic for new cases of COVID-19 with an 82.0% positive predictive value and an 88.9% negative predictive value. Increases in positive wastewater samples and clinical tests were noted following holiday-related activities. However, shelter-in-place policies proved to be effective in reducing the number of daily reported positive wastewater and clinical tests. This case study provides evidence for WBE paired with clinical testing and public health interventions to effectively contain potential outbreaks of COVID-19 in defined communities.
• Harris, D. T., Badowski, M., Jernigan, B., Sprissler, R., Edwards, T., Cohen, R., Paul, S., Merchant, N., Weinkauf, C. C., Bime, C., Erickson, H. E., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., Campion, J., , Chopra, M., et al. (2021). SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus. Biomedicines, 9(5).
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Shroff, R. T., Chalasani, P., Wei, R., Pennington, D., Quirk, G., Schoenle, M. V., Peyton, K. L., Uhrlaub, J. L., Ripperger, T. J., Jergović, M., Dalgai, S., Wolf, A., Whitmer, R., Hammad, H., Carrier, A., Scott, A. J., Nikolich-Žugich, J., Worobey, M., Sprissler, R., , Dake, M., et al. (2021). Immune responses to two and three doses of the BNT162b2 mRNA vaccine in adults with solid tumors. Nature medicine, 27(11), 2002-2011.
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  Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. In this study, we compared immune responses to the BNT162b2 mRNA Coronavirus Disease 2019 vaccine in patients with solid tumors (n = 53) who were on active cytotoxic anti-cancer therapy to a control cohort of participants without cancer (n = 50). Neutralizing antibodies were detected in 67% of patients with cancer after the first immunization, followed by a threefold increase in median titers after the second dose. Similar patterns were observed for spike protein-specific serum antibodies and T cells, but the magnitude of each of these responses was diminished relative to the control cohort. In most patients with cancer, we detected spike receptor-binding domain and other S1-specific memory B cell subsets as potential predictors of anamnestic responses to additional immunizations. We therefore initiated a phase 1 trial for 20 cancer cohort participants of a third vaccine dose of BNT162b2 ( NCT04936997 ); primary outcomes were immune responses, with a secondary outcome of safety. At 1 week after a third immunization, 16 participants demonstrated a median threefold increase in neutralizing antibody responses, but no improvement was observed in T cell responses. Adverse events were mild. These results suggest that a third dose of BNT162b2 is safe, improves humoral immunity against SARS-CoV-2 and could be immunologically beneficial for patients with cancer on active chemotherapy.
• Snider, J. M., You, J. K., Wang, X., Snider, A. J., Hallmark, B., Zec, M. M., Seeds, M. C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Carr, T. F., Lutrick, K., Parthasarathy, S., Bime, C., Zhang, H. H., Luberto, C., Kew, R. R., Hannun, Y. A., , Guerra, S., et al. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. The Journal of clinical investigation, 131(19).
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  There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., Aini, T. E., Rischard, F., , Campion, J., et al. (2020). Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure. medRxiv : the preprint server for health sciences.
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  We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., , Campion, J., et al. (2020). Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity. Immunity, 53(5), 925-933.e4.
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  We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
• Sprissler, R. S., Perkins, B., Babiker, H. M., Chalasani, P., Johnstone, L., Lau, B., Ramos, K., Placencia, C., Gutenkunst, R. N., Mannakee, B. K., Hammer, M. F., & Mahadevan, D. (2020). Whole exome sequencing of rare tumor and matched germline DNA identifies somatic and inherited variants of clinical significance. Cancers.
• Sprissler, R., Perkins, B., Johnstone, L., Babiker, H. M., Chalasani, P., Lau, B., Hammer, M., & Mahadevan, D. (2020). Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations. Cancers, 12(6).
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  Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants-1670 in oncogenes and 1673 in tumor suppressor genes-generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.
• Babiker, H. M., Chalasani, P., Gutenkunst, R., Hammer, M., Johnstone, L., Lau, B., Mahadevan, D., Perkins, B., Placencia, C., Ramos, K., & Sprissler, R. (2019).

  Rare tumor with matched germline whole exome sequencing to identify somatic and inherited variants of clinical significance.

  . Journal of Clinical Oncology, 37(15_suppl), 1523-1523. doi:10.1200/jco.2019.37.15_suppl.1523
• Curry, T. B., Kelley, E. F., Olson, T. P., Snyder, E. M., & Sprissler, R. (2019).

  The Effect of Genetically Guided Mathematical Prediction and the Blood Pressure Response to Pharmacotherapy in Hypertension Patients

  . Clinical Medicine Insights: Cardiology, 13, 117954681984588. doi:10.1177/1179546819845883
• Hammer, M. F., Sprissler, R., Bina, R. W., Lau, B., Johnstone, L., Walter, C. M., Labiner, D. M., & Weinand, M. E. (2019). Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency. Epilepsy research, 155, 106145.
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  Despite recent advances in our understanding of synaptic transmission associated with epileptogenesis, the molecular mechanisms that control seizure frequency in patients with temporal lobe epilepsy (TLE) remain obscure. RNA-Seq was performed on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. Differential expression (DE) analysis of individuals with low (LSF, mean = 4 seizure/month) versus high (HSF, mean = 60 seizures/month) seizure frequency identified 979 genes with ≥2-fold change in transcript abundance (FDR-adjusted p-value ö0.05). Comparisons with post-mortem controls revealed a large number of downregulated genes in the HSF (1676) versus LSF (399) groups. More than 50 signaling pathways were inferred to be deactivated or activated, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both groups, key neuronal system pathways were systematically deactivated in the HSF group, including calcium, CREB and Opioid signaling. We also infer that enhanced expression of a signaling cascade promoting synaptic downscaling may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE.
• Kelley, E. F., Olson, T. P., Snyder, E. M., & Sprissler, R. (2019).

  The importance and challenges of developing a pharmacogenetics test for hypertension

  . Pharmacogenomics, 20(8), 563-566. doi:10.2217/pgs-2019-0056
• Abraham, I., Akre, M. K., Alkhatib, N. S., Kelley, E. F., Olson, T. P., Snyder, S. C., Snyder, E. M., & Sprissler, R. (2018).

  Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study

  . Journal of Medical Economics, 21(12), 1246-1253. doi:10.1080/13696998.2018.1531011
• Bina, R. W., Kasoff, W., Sprissler, R. S., Witte, M. H., Bernas, M. J., Walter, C. M., Labiner, D. M., Hammer, M., & Weinand, M. E. (2018). Leukocyte RNA expression: Prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy. Neurosurgery, 65(1), 94.
• Kelley, E., Snyder, E., Alkhatib, N., Snyder, S., Sprissler, R. S., Olson, T., & Abraham, I. L. (2018). Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study.. Journal of Medical Economics, 21, 1246-1253.
• Herrell, A., Lyons, E., Miller, S., Pivniouk, V., Pivniouk, O., Rosenbaum, D., Sprissler, R., & Vercelli, D. (2014).

  DNA methylation profiles at the human Th2 locus in BAC transgenic mice point to novel putative regulatory elements (IRM6P.720)

  . The Journal of Immunology, 192(1_Supplement), 63.12-63.12. doi:10.4049/jimmunol.192.supp.63.12
• Barth-Maron, A., Erickson, R. P., Greenberg, M. E., Hammer, M. F., Jentsch, T. J., Johnstone, L., Karafet, T. M., Pazzi, M., Restifo, L. L., Salogiannis, J., Sprissler, R., Stuhlmann, T., Talwar, D., Veeramah, K. R., Weinert, S., & Wolf, D. (2013).

  Exome sequencing reveals new causal mutations in children with epileptic encephalopathies

  . Epilepsia, 54(7), 1270-1281. doi:10.1111/epi.12201

Presentations

• Whitaker, M. E., Nai, V., Gupta, A., Sweitzer, N. K., Khalpey, Z. I., Tardiff, J. C., Granzier, H. L., Sotak, S., Sprissler, R. S., & Desai, A. (2015, November). dult Onset Non-Ischemic Dilated Cardiomyopathy: A Novel Titin Mutation and a Case of Complex Inheritance. American College of Physicians (Arizona Chapter) Scientific Meeting. Phoenix, AZ: American College of Physicians (Arizona Chapter).