In Vivo RNAi Screening Identifies Regulators of Actin Dynamics as Key Determinants of Lymphoma Progression

April 1, 2010Mouse models have markedly improved our understanding of cancer development and tumor biology. However, these models have shown limited efficacy as tractable systems for unbiased genetic experimentation. Here, we report the adaptation of loss-of-function screening to mouse models of cancer. Specifically, we have been able to introduce a library of shRNAs into individual mice using transplantable Eμ-myc lymphoma cells. This approach has allowed us to screen nearly 1,000 genetic alterations in the context of a single tumor-bearing mouse. These experiments have identified a central role for regulators of actin dynamics and cell motility in lymphoma cell homeostasis in vivo. Validation experiments confirmed that these proteins represent bona fide lymphoma drug targets. Additionally, suppression of two of these targets, Rac2 and twinfilin, potentiated the action of the front-line chemotherapeutic vincristine, suggesting a critical relationship between cell motility and tumor relapse in hematopoietic malignancies.National Institutes of Health (U.S.) (RO1 CA128803-01)Massachusetts Institute of Technology. Dept. of Biology (Training Grant)Massachusetts Institute of Technology. Undergraduate Research Opportunities ProgramNational Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant 1-U54-CA112967

Building a Systematic Online Living Evidence Summary of COVID-19 Research

Throughout the global coronavirus pandemic, we have seen an unprecedented volume of COVID-19 researchpublications. This vast body of evidence continues to grow, making it difficult for research users to keep up with the pace of evolving research findings. To enable the synthesis of this evidence for timely use by researchers, policymakers, and other stakeholders, we developed an automated workflow to collect, categorise, and visualise the evidence from primary COVID-19 research studies. We trained a crowd of volunteer reviewers to annotate studies by relevance to COVID-19, study objectives, and methodological approaches. Using these human decisions, we are training machine learning classifiers and applying text-mining tools to continually categorise the findings and evaluate the quality of COVID-19 evidence

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

A randomized controlled trial of an oral probiotic to reduce antepartum group B Streptococcus colonization and gastrointestinal symptoms

Background: Probiotics have been suggested as a strategy to reduce antenatal Group B Streptococcus (GBS) colonization. While probiotics are known to improve gastrointestinal symptoms, this has not been studied during pregnancy. Objectives: To evaluate the efficacy of a probiotic to reduce: 1) Standard of Care (SOC) antenatal GBS colonization and colony counts and 2) gastrointestinal symptoms of pregnancy. Study: In a double-blind fashion, 109 healthy adult pregnant people were randomized to Florajen3 probiotic or placebo capsules once daily from 28-weeks gestation until labor onset. Baseline vaginal and rectal study swabs for GBS colony forming units (CFU) and microbiome analysis were collected at 28- and 36-weeks gestation. SOC vaginal to rectal GBS swabs were collected on all participants at 36-weeks gestation and determined the need for intrapartum antibiotic prophylaxis. Data collection included solicitation of adverse events, demographic information, Antepartum Gastrointestinal Symptom Assessment (AP-GI-SA) score, yogurt ingestion, sexual activity, and vaginal cleaning practices. Results: 83 participants completed the study to 36 weeks gestation with no adverse events. Standard of care GBS colonization in the control group was 20.4% and 15.4% in probiotic group participants (-5%; P=.73). The relative risk for positive SOC GBS was 1.33 (95% CI 0.5 to 3.40) times more in control group than in probiotic group (p =0.55). There were no differences in median vaginal (P=0.16) or rectal (P=0.20) GBS CFUs at baseline or at 36 weeks (Vaginal P\u3e0.999; Rectal P=0.56). AP-GI-SA scores were similar at baseline (P=0.19), but significantly decreased in probiotic group participants at 36 weeks (P=0.02). No covariates significantly altered GBS colonization. Significantly more Florajen3 bacteria components in the were recovered in the vaginal/rectal samples of probiotic group participants (32%; P=.04) compared to controls. Conclusions: The findings of this study provided insufficient evidence for the clinical application of the Florajen3 probiotic intervention to reduce SOC GBS. The prevalence of GBS was lower than expected in the study population and intervention adherence was poor. Probiotic bacteria colonized the genitourinary tract of intervention group participants more than controls and significantly reduced GI symptoms of pregnancy

Predicting outcomes in traumatic out-of-hospital cardiac arrest: The relevance of Utstein factors

Background: Given low survival rates in cases of traumatic out-of-hospital cardiac arrest (OHCA), there is a need to identify factors associated with outcomes. We aimed to investigate Utstein factors associated with achieving return of spontaneous circulation (ROSC) and survival to hospital in traumatic OHCA. Methods: The Victorian Ambulance Cardiac Arrest Registry (VACAR) was used to identify cases of traumatic OHCA that received attempted resuscitation and occurred between July 2008 and June 2014. We excluded cases aged < 16 years or with a mechanism of hanging or drowning. Results: Of the 660 traumatic OHCA patients who received attempted resuscitation, ROSC was achieved in 159 patients (24%) and 95 patients (14%) survived to hospital (ROSC on hospital handover). Factors that were positively associated with achieving ROSC in multivariable logistic regression models were age =65 years (adjusted OR (AOR)=1.56, 95% CI: 1.01 to 2.43) and arresting rhythm (shockable (AOR=3.65, 95% CI: 1.64 to 8.11) and pulseless electrical activity (AOR=2.15, 95% CI: 1.36 to 3.39) relative to asystole). Similarly, factors positively associated with survival to hospital were arresting rhythm (shockable (AOR=3.92, 95% CI: 1.64 to 9.41) relative to asystole), and the mechanism of injury (falls (AOR=2.16, 95% CI: 1.03 to 4.54) relative to motor vehicle collisions), while trauma type (penetrating (AOR=0.27, 95% CI: 0.08 to 0.91) relative to blunt trauma) and event region (rural (AOR=0.39, 95% CI: 0.19 to 0.80) relative to urban) were negatively associated with survival to hospital. Conclusions: Few patient and arrest characteristics were associated with outcomes in traumatic OHCA. These findings suggest there is a need to incorporate additional information into cardiac arrest registries to assist prognostication and the development of novel interventions in these trauma patients

How similar was the 1983 Mw 6.9 Borah Peak earthquake rupture to its surface-faulting predecessors along the northern Lost River fault zone (Idaho, USA)?

We excavated trenches at two paleoseismic sites bounding a trans-basin bedrock ridge (the Willow Creek Hills) along the northern Lost River fault zone to explore the uniqueness of the 1983 Mw 6.9 Borah Peak earthquake compared to its prehistoric predecessors. At the Sheep Creek site on the southernmost Warm Springs section, two earthquakes occurred at 9.8–14.0 ka (95% confidence) and 6.5–7.1 ka; each had ~1.9 m of vertical displacement. About 4 km to the southeast, across the Willow Creek Hills, two ruptures at the Arentson Gulch site on the northernmost Thousand Springs section occurred at 9.0–14.7 ka and 6.1–7.5 ka with ~1.9 m of vertical displacement each. We synthesize these and previous paleoseismic results into a model of five postglacial (<15 ka) ruptures along a ~65 km reach of the northern Lost River fault zone. Our results show that the Borah Peak earthquake (34 km; 0.9 m mean displacement) was unique compared to previous ruptures that had both longer and shorter rupture lengths (~25–38 km), more displacement (mean of ~1.3–1.4 m), and equal or greater magnitude (Mw 6.9–7.1) than that in the 1983 earthquake. These ruptures support a hypothesis of variable rupture length and displacement on the northern Lost River fault zone and show that predecessors to the 1983 rupture have passed unimpeded through the Willow Creek Hills. Our work demonstrates that normal faults are capable of producing variable spatial-temporal patterns of rupture that, together with comparisons of fault geometry and historical rupture length, improve our understanding of fault segmentation and help inform models of earthquake rupture probability.This project was supported by the U.S. Geological Survey Earthquake Hazards Program