Characterization and Potential Applications of Dog Natural Killer Cells in Cancer Immunotherapy.

Natural killer (NK) cells of the innate immune system are a key focus of research within the field of immuno-oncology based on their ability to recognize and eliminate malignant cells without prior sensitization or priming. However, barriers have arisen in the effective translation of NK cells to the clinic, in part because of critical species differences between mice and humans. Companion animals, especially dogs, are valuable species for overcoming many of these barriers, as dogs develop spontaneous tumors in the setting of an intact immune system, and the genetic and epigenetic factors that underlie oncogenesis appear to be similar between dogs and humans. Here, we summarize the current state of knowledge for dog NK cells, including cell surface marker phenotype, key NK genes and genetic regulation, similarities and differences of dog NK cells to other mammals, especially human and mouse, expression of canonical inhibitory and activating receptors, ex vivo expansion techniques, and current and future clinical applications. While dog NK cells are not as well described as those in humans and mice, the knowledge of the field is increasing and clinical applications in dogs can potentially advance the field of human NK biology and therapy. Better characterization is needed to truly understand the similarities and differences of dog NK cells with mouse and human. This will allow for the canine model to speed clinical translation of NK immunotherapy studies and overcome key barriers in the optimization of NK cancer immunotherapy, including trafficking, longevity, and maximal in vivo support

Assessing the effect of geographically correlated failures on interconnected power-communication networks

We study the reliability of power transmission networks under regional disasters. Initially, we quantify the effect of large-scale non-targeted disasters and their resulting cascade effects on power networks. We then model the dependence of data networks on the power systems and consider network reliability in this dependent network setting. Our novel approach provides a promising new direction for modeling and designing networks to lessen the effects of geographical disasters.National Science Foundation (U.S.). (grant CNS-1017800)National Science Foundation (U.S.). (grant CNS-0830961)United States. Defense Threat Reduction Agency (HDTRA-09-1-005 )United States. Defense Threat Reduction Agency (HDTRA-1-13-10021

Network Reliability under Random Circular Cuts

Optical fiber networks consist of fibers that are laid out along physical terrestrial paths. As such, they are vulnerable to geographical physical failures, such as earthquakes and Electromagnetic Pulse (EMP) attacks. Moreover, such disasters can lead to multiple, geographically correlated, failures on the fiber network. Thus, the geographical layout of the fiber infrastructure has a critical impact on the robustness of the network in the face of such geographical physical failures. In this paper, we develop tools to analyze network connectivity after a `random' geographic disaster. The random location of the disaster allows us to model situations where the physical failures are not targeted attacks. In particular, we consider disasters that take the form of a `randomly' located disk in a plane. Using results from geometric probability, we are able to approximate some network performance metrics to such a disaster in polynomial time. We present some numerical results that make clear geographically correlated failures are fundamentally different from independent failures and then discuss network design in the context of random disk-cuts.National Science Foundation (U.S.) (Grant CNS-0830961)National Science Foundation (U.S.) (Grant CNS-1017800)United States. Defense Threat Reduction Agency (Grant HDTRA1-07-1-0004)United States. Defense Threat Reduction Agency (Grant HDTRA-09-1-005

Haemoglobin S and haemoglobin C: 'quick but costly' versus 'slow but gratis' genetic adaptations to Plasmodium falciparum malaria

Haemoglobin S (HbS; beta 6Glu -> Val) and HbC (beta 6Glu -> Lys) strongly protect against clinical Plasmodium falciparum malaria. HbS, which is lethal in homozygosity, has a multi-foci origin and a widespread geographic distribution in sub-Saharan Africa and Asia whereas HbC, which has no obvious CC segregational load, occurs only in a small area of central West-Africa. To address this apparent paradox, we adopted two partially independent haplotypic approaches in the Mossi population of Burkina Faso where both the local S (S-Benin) and the C alleles are common (0.05 and 0.13). Here we show that: both C and S-Benin are monophyletic; C has accumulated a 4-fold higher recombinational and DNA slippage haplotypic variability than the S-Benin allele (P = 0.003) implying higher antiquity; for a long initial lag period, the C alleles did apparently remain very few. These results, consistent with epidemiological evidences, imply that the C allele has been accumulated mainly through a recessive rather than a semidominant mechanism of selection. This evidence explains the apparent paradox of the uni-epicentric geographic distribution of HbC, representing a 'slow but gratis' genetic adaptation to malaria through a transient polymorphism, compared to the polycentric 'quick but costly' adaptation through balanced polymorphism of HbS

Assessing the Vulnerability of the Fiber Infrastructure to Disasters

Communication networks are vulnerable to natural disasters, such as earthquakes or floods, as well as to physical attacks, such as an electromagnetic pulse (EMP) attack. Such real-world events happen in specific geographical locations and disrupt specific parts of the network. Therefore, the geographical layout of the network determines the impact of such events on the network's connectivity. In this paper, we focus on assessing the vulnerability of (geographical) networks to such disasters. In particular, we aim to identify the most vulnerable parts of the network. That is, the locations of disasters that would have the maximum disruptive effect on the network in terms of capacity and connectivity. We consider graph models in which nodes and links are geographically located on a plane. First, we consider a simplistic bipartite graph model and present a polynomial-time algorithm for finding a worst-case vertical line segment cut. We then generalize the network model to graphs with nodes at arbitrary locations. We model the disaster event as a line segment or a disk and develop polynomial-time algorithms that find a worst-case line segment cut and a worst-case circular cut. Finally, we obtain numerical results for a specific backbone network, thereby demonstrating the applicability of our algorithms to real-world networks. Our novel approach provides a promising new direction for network design to avert geographical disasters or attacks.United States. Defense Threat Reduction Agency (Grant HDTRA1-07-1-0004)United States. Defense Threat Reduction Agency (Grant HDTRA09-1-005)United States. Defense Threat Reduction Agency (Grant HDTRA1-09-1-0057)National Science Foundation (U.S.) (Grant CNS-1017800)National Science Foundation (U.S.) (Grant CNS0830961)National Science Foundation (U.S.) (Grant CNS-1018379)National Science Foundation (U.S.) (Grant CNS-1054856)National Science Foundation (U.S.) (Grant CNS-0626781)American Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipNational Science Foundation (U.S.) (Grant EEC-0812072

Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer.

We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival. Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17-19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P = 0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta). Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance

Assessement of Malaria Transmission in an Area with Very Low Mosquito Density

The increase in world travel in recent years, especially to and from areas where vector-borne diseases are endemic, has resulted in a substantial rise in imported cases of those diseases. In particular, malaria is a cause of concern. In those countries at the edge of its distribution, it can be difficult to distinguish between autochthonous and imported cases. However, distinguishing between the two is important because of the different allocation of resources to combat the disease that each requires. In general, observation of the various stages of parasite development in wild-caught female mosquitoes is considered evidence of autochthonous transmission. Observation of oocysts in the mosquito mid-gut testifies that mosquitoes are susceptible to infection but conclusions cannot be reached about their ability to complete the transmission cycle. Perhaps the best indication of autochthonous transmission is microscopic observation of sporozoites in mosquito salivary glands, since this detects parasites ready to be inoculated (BELER et al., 1990). Detection of circumsporozoite protein (CSP)(BURKOT, WILLIAMS & SCHNEIDER, 1984) in dry mosquito thoraxes, by Enzyme Linked Immunosorbent Assay (ELISA) is also widely used to determine transmission, especially when large numbers of mosquitoes need to be processed. Such assays provide information about the parasite species infecting the mosquito (BURKOT & WIRTZ, 1986; WIRTZ et al., 1987; BELER et al., 1990)

A cartesian grid embedded boundary method for hyperbolic conservation laws

We present a second-order Godunov algorithm to solve time-dependent hyperbolic systems of conservation laws on irregular domains. Our approach is based on a formally consistent discretization of the conservation laws on a finite-volume grid obtained from intersecting the domain with a Cartesian grid. We address the small-cell stability problem associated with such methods by hybridizing our conservative discretization with a stable, nonconservative discretization at irregular control volumes, and redistributing the difference in the mass increments to nearby cells in a way that preserves stability and local conservation. The resulting method is second-order accurate in L{sup 1} for smooth problems, and is robust in the presence of large-amplitude discontinuities intersecting the irregular boundary

A clonal Plasmodium falciparum population in an isolated outbreak of malaria in the Republic of Cabo Verde

We present the first parasitological, molecular and longitudinal analysis of an isolated outbreak of malaria. This outbreak occurred on Santiago Island (Republic of Cabo Verde), a region where malaria is hypoendemic and controlled, and thus the population is considered non-immune. Blood samples were collected from the inhabitants over 1 month and during cross-sectional surveys in the following year. The presence and nature of the parasites was determined by PCR. Plasmodium falciparum was the only species detected. Genetic analysis revealed that the circulating parasites were genetically homogeneous, and probably clonal. Gametocytes were found throughout this period. Our data suggest that this represented a focal outbreak, resulting in the infection of at least 40% of the villagers with a clonal parasite line. Thus, P. falciparum infections can persist for at least 1 year in a substantial proportion (10%) of the hosts. Implications for malaria control and the interpretation of epidemiological data are discussed