Cancer modelling: Getting to the heart of the problem

Paradoxically, improvements in healthcare that have enhanced the life expectancy of humans in the Western world have, indirectly, increased the prevalence of certain types of cancer such as prostate and breast. It remains unclear whether this phenomenon should be attributed to the ageing process itself or the cumulative effect of prolonged exposure to harmful environmental stimuli such as ultraviolet light, radiation and carcinogens (Franks and Teich, 1988). Equally, there is also compelling evidence that certain genetic abnormalities can predispose individuals to specific cancers (Ilyas et al., 1999). The variety of factors that have been implicated in the development of solid tumours stems, to a large extent, from the fact that ‘cancer’ is a generic term, often used to characterize a series of disorders that share common features. At this generic level of description, cancer may be viewed as a cellular disease in which controls that usually regulate growth and maintain homeostasis are disrupted. Cancer is typically initiated by genetic mutations that lead to enhanced mitosis of a cell lineage and the formation of an avascular tumour. Since it receives nutrients by diffusion from the surrounding tissue, the size of an avascular tumour is limited to several millimeters in diameter. Further growth relies on the tumour acquiring the ability to stimulate the ingrowth of a new, circulating blood supply from the host vasculature via a process termed angiogenesis (Folkman, 1974). Once vascularised, the tumour has access to a vast nutrient source and rapid growth ensues. Further, tumour fragments that break away from the primary tumour, on entering the vasculature, may be transported to other organs in which they may establish secondary tumours or metastases that further compromise the host. Invasion is another key feature of solid tumours whereby contact with the tissue stimulates the production of enzymes that digest the tissue, liberating space into which the tumour cells migrate. Thus, cancer is a complex, multiscale process. The spatial scales of interest range from the subcellular level, to the cellular and macroscopic (or tissue) levels while the timescales may vary from seconds (or less) for signal transduction pathways to months for tumour doubling times The variety of phenomena involved, the range of spatial and temporal scales over which they act and the complex way in which they are inter-related mean that the development of realistic theoretical models of solid tumour growth is extremely challenging. While there is now a large literature focused on modelling solid tumour growth (for a review, see, for example, Preziosi, 2003), existing models typically focus on a single spatial scale and, as a result, are unable to address the fundamental problem of how phenomena at different scales are coupled or to combine, in a systematic manner, data from the various scales. In this article, a theoretical framework will be presented that is capable of integrating a hierarchy of processes occurring at different scales into a detailed model of solid tumour growth (Alarcon et al., 2004). The model is formulated as a hybrid cellular automaton and contains interlinked elements that describe processes at each spatial scale: progress through the cell cycle and the production of proteins that stimulate angiogenesis are accounted for at the subcellular level; cell-cell interactions are treated at the cellular level; and, at the tissue scale, attention focuses on the vascular network whose structure adapts in response to blood flow and angiogenic factors produced at the subcellular level. Further coupling between the different spatial scales arises from the transport of blood-borne oxygen into the tissue and its uptake at the cellular level. Model simulations will be presented to illustrate the effect that spatial heterogeneity induced by blood flow through the vascular network has on the tumour’s growth dynamics and explain how the model may be used to compare the efficacy of different anti-cancer treatment protocols

miRNAs link metabolic reprogramming to oncogenesis

The most profound biochemical phenotype of cancer cells is their ability to metabolize glucose to lactate, even under aerobic conditions. This alternative metabolic circuitry is sufficient to support the biosynthetic and energy requirements for cancer cell proliferation and metastasis. Alterations in oncogenes and tumor suppressor genes are involved in the metabolic switch of cancer cells to aerobic glycolysis, increased glutaminolysis and fatty acid biosynthesis. MiRNAs mediate fine-tuning of genes involved directly or indirectly in cancer metabolism. In this review, we discuss the regulatory role of miRNAs on enzymes, signaling pathways and transcription factors involved in glucose and lipid metabolism. We further consider the therapeutic potential of metabolism-related miRNAs in cancer

Clinical applications of microRNAs

MicroRNAs represent a class of small RNAs derived from polymerase II controlled transcriptional regions. The primary transcript forms one or several bulging double stranded hairpins which are processed by Drosha and Dicer into hetero-duplexes. The targeting microRNA strand of the duplex is incorporated into the RNA Induced Silencing Complex from where it silences up to hundreds of mRNA transcript by inducing mRNA degradation or blocking protein translation. Apart from involvement in a variety of biological processes, microRNAs were early recognized for their potential in disease diagnostics and therapeutics. Due to their stability, microRNAs could be used as biomarkers. Currently, there are microRNA panels helping physicians determining the origins of cancer in disseminated tumors. The development of microRNA therapeutics has proved more challenging mainly due to delivery issues. However, one drug is already in clinical trials and several more await entering clinical phases. This review summarizes what has been recognized pre-clinically and clinically on diagnostic microRNAs. In addition, it highlights individual microRNA drugs in running platforms driven by four leading microRNA-therapeutic companies

Digital Signal Processing Research Program

Contains table of contents for Section 2, an introduction, reports on twenty research projects and a list of publications.Lockheed Sanders, Inc. Contract BZ4962U.S. Army Research Laboratory Grant QK-8819U.S. Navy - Office of Naval Research Grant N00014-93-1-0686National Science Foundation Grant MIP 95-02885U.S. Navy - Office of Naval Research Grant N00014-95-1-0834U.S. Navy - Office of Naval Research Grant N00014-96-1-0930U.S. Navy - Office of Naval Research Grant N00014-95-1-0362National Defense Science and Engineering FellowshipU.S. Air Force - Office of Scientific Research Grant F49620-96-1-0072National Science Foundation Graduate Research Fellowship Grant MIP 95-02885Lockheed Sanders, Inc. Grant N00014-93-1-0686National Science Foundation Graduate FellowshipU.S. Army Research Laboratory/ARL Advanced Sensors Federated Lab Program Contract DAAL01-96-2-000

SoK: Inference Attacks and Defenses in Human-Centered Wireless Sensing

Human-centered wireless sensing aims to understand the fine-grained environment and activities of a human using the diverse wireless signals around her. The wireless sensing community has demonstrated the superiority of such techniques in many applications such as smart homes, human-computer interactions, and smart cities. Like many other technologies, wireless sensing is also a double-edged sword. While the sensed information about a human can be used for many good purposes such as enhancing life quality, an adversary can also abuse it to steal private information about the human (e.g., location, living habits, and behavioral biometric characteristics). However, the literature lacks a systematic understanding of the privacy vulnerabilities of wireless sensing and the defenses against them. In this work, we aim to bridge this gap. First, we propose a framework to systematize wireless sensing-based inference attacks. Our framework consists of three key steps: deploying a sniffing device, sniffing wireless signals, and inferring private information. Our framework can be used to guide the design of new inference attacks since different attacks can instantiate these three steps differently. Second, we propose a defense-in-depth framework to systematize defenses against such inference attacks. The prevention component of our framework aims to prevent inference attacks via obfuscating the wireless signals around a human, while the detection component aims to detect and respond to attacks. Third, based on our attack and defense frameworks, we identify gaps in the existing literature and discuss future research directions

From variome to phenome : pathogenesis, diagnosis and management of ectopic mineralization disorders

Ectopic mineralization - inappropriate biomineralization in soft tissues - is a frequent finding in physiological aging processes and several common disorders, which can be associated with significant morbidity and mortality. Further, pathologic mineralization is seen in several rare genetic disorders, which often present life-threatening phenotypes. These disorders are classified based on the mechanisms through which the mineralization occurs: metastatic or dystrophic calcification or ectopic ossification. Underlying mechanisms have been extensively studied, which resulted in several hypotheses regarding the etiology of mineralization in the extracellular matrix of soft tissue. These hypotheses include intracellular and extracellular mechanisms, such as the formation of matrix vesicles, aberrant osteogenic and chondrogenic signaling, apoptosis and oxidative stress. Though coherence between the different findings is not always clear, current insights have led to improvement of the diagnosis and management of ectopic mineralization patients, thus translating pathogenetic knowledge (variome) to the phenotype (phenome). In this review, we will focus on the clinical presentation, pathogenesis and management of primary genetic soft tissue mineralization disorders. As examples of dystrophic calcification disorders Pseudoxanthoma elasticum, Generalized arterial calcification of infancy, Keutel syndrome, Idiopathic basal ganglia calcification and Arterial calcification due to CD73 (NT5E) deficiency will be discussed. Hyperphosphatemic familial tumoral calcinosis will be reviewed as an example of mineralization disorders caused by metastatic calcification