Recent Hits Acquired by BLAST (ReHAB): A tool to identify new hits in sequence similarity searches

BACKGROUND: Sequence similarity searching is a powerful tool to help develop hypotheses in the quest to assign functional, structural and evolutionary information to DNA and protein sequences. As sequence databases continue to grow exponentially, it becomes increasingly important to repeat searches at frequent intervals, and similarity searches retrieve larger and larger sets of results. New and potentially significant results may be buried in a long list of previously obtained sequence hits from past searches. RESULTS: ReHAB (Recent Hits Acquired from BLAST) is a tool for finding new protein hits in repeated PSI-BLAST searches. ReHAB compares results from PSI-BLAST searches performed with two versions of a protein sequence database and highlights hits that are present only in the updated database. Results are presented in an easily comprehended table, or in a BLAST-like report, using colors to highlight the new hits. ReHAB is designed to handle large numbers of query sequences, such as whole genomes or sets of genomes. Advanced computer skills are not needed to use ReHAB; the graphics interface is simple to use and was designed with the bench biologist in mind. CONCLUSIONS: This software greatly simplifies the problem of evaluating the output of large numbers of protein database searches

Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.

Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery

Spring 1984 Department Newsletter

Newsletter spotlights the department\u27s recent, successful NASAD (National Association of Schools of Art and Design) review

To play or not to play: Can an instrument really impact lip and tongue performance?

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. (1) Background: Increasing tongue and lip strength may help improve various speech and swallowing disorders, but it is unclear if instrumentalists who use these muscle groups for long periods of time have greater strength and endurance compared to controls. It is also unclear if instrumentalists can more accurately estimate various exercise intensities. The purpose of this study was to determine differences in lip and tongue strength and endurance between instrumentalists and non-instrumentalists (controls). A secondary purpose was to assess differences in ability to estimate various exercise intensities between the two groups. (2) Methods: Instrumentalists and controls’ maximum strength and endurance were measured using the IOPI Pro medical device. In addition, 40%, 60% and 80% of maximum strength were estimated in a randomized order. (3) Results: No significant differences were found between instrumentalists and controls in strength or endurance or the ability to estimate various intensities. Overall, participants were better at estimating tongue strength at moderate intensities and lip strength at higher intensities. (4) Conclusion: Tongue and lip strength and endurance and the ability to estimate exercise intensities are not impacted by years of instrumentalist training compared to healthy controls

Comparative Toxicity of Gasoline and Diesel Engine Emissions

Better information on the comparative toxicity of airborne emissions from different types of engines is needed to guide the development of heavy vehicle engine, fuel, lubricant, and exhaust after-treatment technologies, and to place the health hazards of current heavy vehicle emissions in their proper perspective. To help fill this information gap, samples of vehicle exhaust particles and semi-volatile organic compounds (SVOC) were collected and analyzed. The biological activity of the combined particle-SVOC samples is being tested using standardized toxicity assays. This report provides an update on the design of experiments to test the relative toxicity of engine emissions from various sources

Dust Production and Mass Loss in the Galactic Globular Cluster NGC 362

We investigate dust production and stellar mass loss in the Galactic globular cluster NGC 362. Due to its close proximity to the Small Magellanic Cloud (SMC), NGC 362 was imaged with the IRAC and MIPS cameras onboard the Spitzer Space Telescope as part of the Surveying the Agents of Galaxy Evolution (SAGE-SMC) Spitzer Legacy program. We detect several cluster members near the tip of the Red Giant Branch that exhibit infrared excesses indicative of circumstellar dust and find that dust is not present in measurable quantities in stars below the tip of the Red Giant Branch. We modeled the spectral energy distribution (SED) of the stars with the strongest IR excess and find a total cluster dust mass-loss rate of 3.0(+2.0/-1.2) x 10^-9 solar masses per year, corresponding to a gas mass-loss rate of 8.6(+5.6/-3.4) x 10^-6 solar masses per year, assuming [Fe/H] = -1.16. This mass loss is in addition to any dust-less mass loss that is certainly occurring within the cluster. The two most extreme stars, variables V2 and V16, contribute up to 45% of the total cluster dust-traced mass loss. The SEDs of the more moderate stars indicate the presence of silicate dust, as expected for low-mass, low-metallicity stars. Surprisingly, the SED shapes of the stars with the strongest mass-loss rates appear to require the presence of amorphous carbon dust, possibly in combination with silicate dust, despite their oxygen-rich nature. These results corroborate our previous findings in omega Centauri.Comment: 13 pages, 11 figures. Accepted to Ap

Baseline Results:The Association between Cardiovascular Risk and Preclinical Alzheimer's Disease Pathology (ASCEND) Study

BACKGROUND: The rate of AD for African Americans (AAs) is 64% higher than for non-Hispanic White Americans (Whites). It is hypothesized that poor peripheral vascular function, in combination with genetics, stress, and inflammation may directly contribute to the accumulation of AD pathologic biomarkers. These risk factors may disproportionately affect AAs. OBJECTIVE: Our objective was to determine if in a healthy middle-aged cohort at risk for AD (1) AD biomarkers in CSF differ by race, (2) peripheral vascular dysfunction and cognition are related to a higher burden of CSF AD biomarkers, and (3) these relationships differ by race. METHODS: We enrolled 82 cognitively normal, middle-aged (45 and older) adults including AAs and Whites at high risk for AD due to parental history. Study procedures included lumbar puncture, vascular ultrasound, and cognitive testing. RESULTS: While participants were in overall good health, AAs exhibited poorer indices of preclinical vascular health, including higher central SBP, central MAP, and EndoPAT AI, a marker of arterial stiffness. AAs also had significantly less cerebrospinal fluid tau burden than Whites. After polynomial regression analysis, adjusted for age, gender, education, and ApoE4 status, race significantly modified the relationship between total tau, phospho-tau, and Trails B, a marker of executive function. Small differences in tau correlated with poorer cognition in AAs. CONCLUSION: In a healthy middle-aged cohort at risk for AD, AAs had worse peripheral vascular health and worse cognition than Whites. Despite lower tau burden overall, race modified the relationship between tau and cognition, such that small differences in tau between AAs was related to worse cognition when compared to Whites

Decreased expression of RNA interference machinery, Dicer and Drosha, is associated with poor outcome in ovarian cancer patients

The clinical and functional significance of RNA interference (RNAi) machinery, Dicer and Drosha, in ovarian cancer is not known and was examined. Dicer and Drosha expression was measured in ovarian cancer cell lines (n=8) and invasive epithelial ovarian cancer specimens (n=111) and correlated with clinical outcome. Validation was performed with previously published cohorts of ovarian, breast, and lung cancer patients. Anti-Galectin-3 siRNA and shRNA transfections were used for in vitro functional studies. Dicer and Drosha mRNA and protein levels were decreased in 37% to 63% of ovarian cancer cell lines and in 60% and 51% of human ovarian cancer specimens, respectively. Low Dicer was significantly associated with advanced tumor stage (p=0.007), and low Drosha with suboptimal surgical cytoreduction (p=0.02). Tumors with both high Dicer and Drosha were associated with increased median patient survival (>11 years vs. 2.66 years for other groups; p<0.001). In multivariate analysis, high Dicer (HR=0.48; p=0.02), high-grade histology (HR=2.46; p=0.03), and poor chemoresponse (HR=3.95; p<0.001) were identified as independent predictors of disease-specific survival. Findings of poor clinical outcome with low Dicer expression were validated in separate cohorts of cancer patients. Galectin-3 silencing with siRNA transfection was superior to shRNA in cell lines with low Dicer (78-95% vs. 4-8% compared to non-targeting sequences), and similar in cell lines with high Dicer. Our findings demonstrate the clinical and functional impact of RNAi machinery alterations in ovarian carcinoma and support the use of siRNA constructs that do not require endogenous Dicer and Drosha for therapeutic applications

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival