Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM®. The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes. © 2012 Cárdenas et al, publisher and licensee Dove Medical Press Ltd

A multiprocessor based packet-switch: performance analysis of the communication infrastructure

The intra-chip communication infrastructures are receiving always more attention since they are becoming a crucial part in the development of current SoCs. Due to the high availability of pre-characterized hard-IP, the complexity of the design is moving toward global interconnections which are introducing always more constraints at each technology node. Power consumption, timing closure, bandwidth requirements, time to market, are some of the factors that are leading to the proposal of new solutions for next generation multi-million SoCs. The need of high programmable systems and the high gate-count availability is moving always more attention on multiprocessors systems (MP-SoC) and so an adequate solution must be found for the communication infrastructure. One of the most promising technologies is the Network-On-Chip (NoC) architecture, which seems to better fit with the new demanding complexity of such systems. Before starting to develop new solutions, it is crucial to fully understand if and when current bus architectures introduce strong limitations in the development of high speed systems. This article describes a case study of a multiprocessor based ethernet packet-switch application with a shared-bus communication infrastructure. This system aims to depict all the bottlenecks which a shared-bus introduces under heavy load. What emerges from this analysis is that, as expected, a shared-bus is not scalable and it strongly limits whole system performances. These results strengthen the hypothesis that new communication architectures (like the NoC) must be found

Unidirectional decomposition method for obtaining exact localized waves solutions totally free of backward components

In this paper we use a unidirectional decomposition capable of furnishing localized wave pulses, with luminal and superluminal peak velocities, in exact form and totally free of backward components, which have been a chronic problem for such wave solutions. This decomposition is powerful enough for yielding not only ideal nondiffracting pulses but also their finite energy versions still in exact analytical closed form. Another advantage of the present approach is that, since the backward spectral components are absent, the frequency spectra of the pulses do not need to possess ultra-widebands, as it is required by the usual localized waves (LWs) solutions obtained by other methods. Finally, the present results bring the LW theory nearer to the real experimental possibilities of usual laboratories.Comment: 28 pages, 6 figure

Attention network dysfunction underlies memory impairment in posterior cortical atrophy

Accumulating evidence suggests that memory is impaired in posterior cortical atrophy (PCA), alongside the early and defining visual disorder. The posterior parietal cortex is a key region of pathology in PCA and memory impairment may be the result of dysfunction of parietally dependent network function rather than the medial temporal lobe dependent dysfunction that defines the storage deficits in typical Alzheimer's disease. We assessed episodic memory performance and network function in16 PCA patients and 19 healthy controls who underwent structural and resting-state functional MRI and neuropsychological testing. Memory was assessed using the Free and Cued Selective Reminding Test (FCSRT), a sensitive test of episodic memory storage and retrieval. We examined correlations between memory performance and functional connectivity in the dorsal attention (DAN) and default mode network (DMN). Immediate recall on the FCSRT was relatively preserved in PCA patients. Total recall performance was impaired in patients relative to healthy controls and performance benefitted from retrieval cues. In patients only, disrupted connectivity in the DAN, but not the DMN, was associated with total recall. Memory impairment may arise from disruption to the dorsal attention network, subserved by the dorsal posterior parietal cortex, a key region of pathology in PCA, rather than classic medial temporal lobe memory circuitry.We propose that functional dysconnectivity in attentional circuits underpins memory impairment in PCA

Genetic abnormalities in pancreatic cancer

The incidence and mortality of pancreatic adenocarcinoma are nearly coincident having a five-year survival of less than 5%. Enormous advances have been made in our knowledge of the molecular alterations commonly present in ductal cancer and other pancreatic malignancies. One significant outcome of these studies is the recognition that common ductal cancers have a distinct molecular fingerprint compared to other nonductal or endocrine tumors. Ductal carcinomas typically show alteration of K-ras, p53, p16(INK4), DPC4 and FHIT, while other pancreatic tumor types show different aberrations. Among those tumors arising from the exocrine pancreas, only ampullary cancers have a molecular fingerprint that may involve some of the same genes most frequently altered in common ductal cancers. Significant molecular heterogeneity also exists among pancreatic endocrine tumors. Nonfunctioning pancreatic endocrine tumors have frequent mutations in MEN-1 and may be further subdivided into two clinically relevant subgroups based on the amount of chromosomal alterations. The present review will provide a brief overview of the genetic alterations that have been identified in the various subgroups of pancreatic tumors. These results have important implications for the development of genetic screening tests, early diagnosis, and prognostic genetic markers

Innate Immune Activation and Subversion of Mammalian Functions by Leishmania Lipophosphoglycan

Leishmania promastigotes express several prominent glycoconjugates, either secreted or anchored to the parasite surface. Of these lipophosphoglycan (LPG) is the most abundant, and along with other phosphoglycan-bearing molecules, plays important roles in parasite infectivity and pathogenesis in both the sand fly and the mammalian host. Besides its contribution for parasite survival in the sand fly vector, LPG is important for modulation the host immune responses to favor the establishment of mammalian infection. This review will summarize the current knowledge regarding the role of LPG in Leishmania infectivity, focusing on the interaction of LPG and innate immune cells and in the subversion of mammalian functions by this molecule

Superluminal Localized Solutions to Maxwell Equations propagating along a waveguide: The finite-energy case

In a previous paper of ours [Phys. Rev. E64 (2001) 066603, e-print physics/0001039] we have shown localized (non-evanescent) solutions to Maxwell equations to exist, which propagate without distortion with Superluminal speed along normal-sized waveguides, and consist in trains of "X-shaped" beams. Those solutions possessed therefore infinite energy. In this note we show how to obtain, by contrast, finite-energy solutions, with the same localization and Superluminality properties. [PACS nos.: 41.20.Jb; 03.50.De; 03.30.+p; 84.40.Az; 42.82.Et. Keywords: Wave-guides; Localized solutions to Maxwell equations; Superluminal waves; Bessel beams; Limited-dispersion beams; Finite-energy waves; Electromagnetic wavelets; X-shaped waves; Evanescent waves; Electromagnetism; Microwaves; Optics; Special relativity; Localized acoustic waves; Seismic waves; Mechanical waves; Elastic waves; Guided gravitational waves.]Comment: plain LaTeX file (12 pages), plus 10 figure

Nucleotide-Binding Oligomerization Domain-1 and -2 Play No Role in Controlling Brucella abortus Infection in Mice

Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. Further, several in vivo studies have demonstrated a role for Nod1 and Nod2 in host defense against bacterial pathogens. Here, we demonstrated that macrophages from NOD1-, NOD2-, and Rip2-deficient mice produced lower levels of TNF-α following infection with live Brucella abortus compared to wild-type mice. Similar reduction on cytokine synthesis was not observed for IL-12 and IL-6. However, NOD1, NOD2, and Rip2 knockout mice were no more susceptible to infection with virulent B. abortus than wild-type mice. Additionally, spleen cells from NOD1-, NOD2-, and Rip2-deficient mice showed unaltered production of IFN-γ compared to C57BL/6 mice. Taken together, this study demonstrates that NOD1, NOD2 and Rip2 are dispensable for the control of B. abortus during in vivo infection