Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection

Background: An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099) Methods: Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17–23 weeks after treatment discontinuation. Results: Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log[sub]10 HIV-1 RNA copies/mL, respectively. Conclusions: The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group. Trial Registration: Clinicaltrials.gov NCT0012509

Broadband Multi-wavelength Properties of M87 during the 2017 Event Horizon Telescope Campaign

Abstract: In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109 M ⊙. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87’s spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded

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

Unresolved Issues in the Forensic Use of DNA Profiling

The enormous amount of genetic diversity in humans allows for a powerful form of individual identification. This “DNA profiling”; is based on the fact that sites within the human genome have variable numbers of tandem repeats (VNTRs) and has been hailed in forensic sciences as the greatest discovery since fingerprinting. The techniques involved are virtually the same as those used in all molecular biology laboratories. A major difference however is that in forensic science DNA samples can be less than ideal in both quality and quantity. Furthermore, in basic molecular biology the origin of the sample is known while in forensic testing it is not. Thus, the challenge is to reconcile a “match”; between a crime scene DNA sample and one from a suspect(s). Presently, a debate exists regarding the use of the unmodified product rule versus a more conservative ceiling principle approach to calculate the probability of a coincidentally matching DNA profiles. The latter was endorsed in a recently published report by the prestigious National Research Council but has not received widespread support from testing laboratories. Further exacerbating the debate over how much weight should be attached to DNA profile evidence is a lack of widely accepted standards for forensic laboratories especially in the areas of proficiency testing, publication of error rates and laboratory personnel certification

Unresolved Issues in the Forensic Use of DNA Profiling

The enormous amount of genetic diversity in humans allows for a powerful form of individual identification. This “DNA profiling”; is based on the fact that sites within the human genome have variable numbers of tandem repeats (VNTRs) and has been hailed in forensic sciences as the greatest discovery since fingerprinting. The techniques involved are virtually the same as those used in all molecular biology laboratories. A major difference however is that in forensic science DNA samples can be less than ideal in both quality and quantity. Furthermore, in basic molecular biology the origin of the sample is known while in forensic testing it is not. Thus, the challenge is to reconcile a “match”; between a crime scene DNA sample and one from a suspect(s). Presently, a debate exists regarding the use of the unmodified product rule versus a more conservative ceiling principle approach to calculate the probability of a coincidentally matching DNA profiles. The latter was endorsed in a recently published report by the prestigious National Research Council but has not received widespread support from testing laboratories. Further exacerbating the debate over how much weight should be attached to DNA profile evidence is a lack of widely accepted standards for forensic laboratories especially in the areas of proficiency testing, publication of error rates and laboratory personnel certification

Delta power robustly predicts cognitive function in Angelman syndrome.

ObjectiveAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A gene in neurons. Promising disease-modifying treatments to reinstate UBE3A expression are under development and an early measure of treatment response is critical to their deployment in clinical trials. Increased delta power in EEG recordings, reflecting abnormal neuronal synchrony, occurs in AS across species and correlates with genotype. Whether delta power provides a reliable biomarker for clinical symptoms remains unknown.MethodsWe analyzed combined EEG recordings and developmental assessments in a large cohort of individuals with AS (N&nbsp;=&nbsp;82 subjects, 133 combined EEG and cognitive assessments, 1.08-28.16&nbsp;years; 32F) and evaluated delta power as a biomarker for cognitive function, as measured by the Bayley Cognitive Score. We examined the robustness of this biomarker to varying states of consciousness, recording techniques and analysis procedures.ResultsDelta power predicted the Bayley Scale cognitive score (P&nbsp;&lt;&nbsp;10-5 , R2 &nbsp;=&nbsp;0.9374) after controlling for age (P&nbsp;&lt;&nbsp;10-24 ), genotype:age (P&nbsp;&lt;&nbsp;10-11 ), and repeat assessments (P&nbsp;&lt;&nbsp;10-8 ), with the excellent fit on cross validation (R2 &nbsp;=&nbsp;0.95). There were no differences in model performance across states of consciousness or bipolar versus average montages (ΔAIC&nbsp;&lt;&nbsp;2). Models using raw data excluding frontal channels outperformed other models (ΔAIC&nbsp;&gt;&nbsp;4) and predicted performance in expressive (P&nbsp;=&nbsp;0.0209) and receptive communication (P&nbsp;&lt;&nbsp;10-3 ) and fine motor skills (P&nbsp;&lt;&nbsp;10-4 ).InterpretationDelta power is a simple, direct measure of neuronal activity that reliably correlates with cognitive function in AS. This electrophysiological biomarker offers an objective, clinically relevant endpoint for treatment response in emerging clinical trials

Delta power robustly predicts cognitive function in Angelman syndrome.

ObjectiveAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A gene in neurons. Promising disease-modifying treatments to reinstate UBE3A expression are under development and an early measure of treatment response is critical to their deployment in clinical trials. Increased delta power in EEG recordings, reflecting abnormal neuronal synchrony, occurs in AS across species and correlates with genotype. Whether delta power provides a reliable biomarker for clinical symptoms remains unknown.MethodsWe analyzed combined EEG recordings and developmental assessments in a large cohort of individuals with AS (N&nbsp;=&nbsp;82 subjects, 133 combined EEG and cognitive assessments, 1.08-28.16&nbsp;years; 32F) and evaluated delta power as a biomarker for cognitive function, as measured by the Bayley Cognitive Score. We examined the robustness of this biomarker to varying states of consciousness, recording techniques and analysis procedures.ResultsDelta power predicted the Bayley Scale cognitive score (P&nbsp;&lt;&nbsp;10-5 , R2 &nbsp;=&nbsp;0.9374) after controlling for age (P&nbsp;&lt;&nbsp;10-24 ), genotype:age (P&nbsp;&lt;&nbsp;10-11 ), and repeat assessments (P&nbsp;&lt;&nbsp;10-8 ), with the excellent fit on cross validation (R2 &nbsp;=&nbsp;0.95). There were no differences in model performance across states of consciousness or bipolar versus average montages (ΔAIC&nbsp;&lt;&nbsp;2). Models using raw data excluding frontal channels outperformed other models (ΔAIC&nbsp;&gt;&nbsp;4) and predicted performance in expressive (P&nbsp;=&nbsp;0.0209) and receptive communication (P&nbsp;&lt;&nbsp;10-3 ) and fine motor skills (P&nbsp;&lt;&nbsp;10-4 ).InterpretationDelta power is a simple, direct measure of neuronal activity that reliably correlates with cognitive function in AS. This electrophysiological biomarker offers an objective, clinically relevant endpoint for treatment response in emerging clinical trials