Reluplex: An Efficient SMT Solver for Verifying Deep Neural Networks

Deep neural networks have emerged as a widely used and effective means for tackling complex, real-world problems. However, a major obstacle in applying them to safety-critical systems is the great difficulty in providing formal guarantees about their behavior. We present a novel, scalable, and efficient technique for verifying properties of deep neural networks (or providing counter-examples). The technique is based on the simplex method, extended to handle the non-convex Rectified Linear Unit (ReLU) activation function, which is a crucial ingredient in many modern neural networks. The verification procedure tackles neural networks as a whole, without making any simplifying assumptions. We evaluated our technique on a prototype deep neural network implementation of the next-generation airborne collision avoidance system for unmanned aircraft (ACAS Xu). Results show that our technique can successfully prove properties of networks that are an order of magnitude larger than the largest networks verified using existing methods.Comment: This is the extended version of a paper with the same title that appeared at CAV 201

Backward Reachability Analysis of Neural Feedback Loops: Techniques for Linear and Nonlinear Systems

As neural networks (NNs) become more prevalent in safety-critical applications such as control of vehicles, there is a growing need to certify that systems with NN components are safe. This paper presents a set of backward reachability approaches for safety certification of neural feedback loops (NFLs), i.e., closed-loop systems with NN control policies. While backward reachability strategies have been developed for systems without NN components, the nonlinearities in NN activation functions and general noninvertibility of NN weight matrices make backward reachability for NFLs a challenging problem. To avoid the difficulties associated with propagating sets backward through NNs, we introduce a framework that leverages standard forward NN analysis tools to efficiently find over-approximations to backprojection (BP) sets, i.e., sets of states for which an NN policy will lead a system to a given target set. We present frameworks for calculating BP over approximations for both linear and nonlinear systems with control policies represented by feedforward NNs and propose computationally efficient strategies. We use numerical results from a variety of models to showcase the proposed algorithms, including a demonstration of safety certification for a 6D system.Comment: 17 pages, 15 figures. Journal extension of arXiv:2204.0831

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies

Inter-cultural differences in response to a computer-based anti-bullying intervention

Background and purpose: Many holistic anti-bullying interventions have been attempted, with mixed success, while little work has been done to promote a 'self-help' approach to victimisation. The rise of the ICT curriculum and computer support in schools now allows for approaches that benefit from technology to be implemented. This study evaluates the cross-cultural effects of a computer-based anti-bullying intervention on primary school-aged children's knowledge about bullying and relevant coping strategies. Programme description: FearNot! is an interactive computer-based virtual learning environment designed for use as an anti-bullying intervention. It includes interactive virtual agents who assume the most common participant roles found in episodes of bullying. FearNot! was used by children over three consecutive weeks to allow its effectiveness to be evaluated in a longitudinal in situ programme. Sample: Two comparable samples were drawn from the UK and Germany. In the UK, 651 participants (aged 8-11) were recruited from primary schools in Hertfordshire, Coventry and Warwickshire, whereas the 535 German participants (aged 7-10) were sourced from Grundschulen in the Bayern and Hessen regions. Because of lack of parental consent, late joiners and absences/missing responses, data from 908 participants (UK 493; Germany 415) were analysed. Design and methods: A quasi-experimental, pre/post-tests control group design employed pre-published and bespoke questionnaires to collect data. Descriptive and inferential analyses were conducted. Results: UK students possessed higher coping strategy knowledge scores than German participants, but German children's scores improved over time and as a result of the FearNot! intervention. Conclusions: Overall, while not effective at increasing children's coping strategy knowledge in this study, the FearNot! intervention could prove a useful classroom tool to approach the issue of bullying as part of a wider initiative. Cultural differences at baseline and reactions to the intervention are discussed

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Stability in Bullying and Victimization and its Association with Social Adjustment in Childhood and Adolescence

This study examined the concurrent and longitudinal associations between stability in bullying and victimization, and social adjustment in childhood and adolescence. Participants were 189 girls and 328 boys who were studied in primary school and in secondary school. The mean age of the participants was 11.1 years in primary school and 14.1 years in secondary school. The measures consisted of peer reported social and personal characteristics. Children who bullied in childhood and adolescence were less liked and more disliked in childhood, and more aggressive and disruptive both in childhood and adolescence, than children who bullied only in childhood or adolescence. Children who bullied or who were victimized only in childhood did not differ largely in adolescence from the children that were never bullies or victims. Children who were victimized in adolescence closely resembled those who were victimized in childhood and adolescence in terms of being liked or disliked, being nominated as a friend, and shyness. The study stresses the need to distinguish between stable and transient bullies and victims

Children’s coping with in vivo peer rejection: An experimental investigation

We examined children's behavioral coping in response to an in vivo peer rejection manipulation. Participants (N=186) ranging between 10 and 13 years of age, played a computer game based on the television show Survivor and were randomized to either peer rejection (i.e., being voted out of the game) or non-rejection control. During a five-min. post-feedback waiting period children's use of several behavioral coping strategies was assessed. Rejection elicited a marked shift toward more negative affect, but higher levels of perceived social competence attenuated the negative mood shift. Children higher in depressive symptoms were more likely to engage in passive and avoidant coping behavior. Types of coping were largely unaffected by gender and perceived social competence. Implications are discussed. © 2006 Springer Science+Business Media, LLC

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy