SPIN is an efficient verification system for models of distributed software systems. It has been used to detect design errors in applications ranging from high-level descriptions of distributed algorithms to detailed code for controlling telephone exchanges. The paper gives an overview of the design and structure of the verifier, reviews its theoretical foundation, and gives an overview of significant practical applications.

/pdf/the-model-checker-spin-1bgo4jtefp.pdf

The model checker SPIN

Leukocytes respond to lipopolysaccharide (LPS) at nanogram per milliliter concentrations with secretion of cytokines such as tumor necrosis factor-alpha (TNF-alpha). Excess secretion of TNF-alpha causes endotoxic shock, an often fatal complication of infection. LPS in the bloodstream rapidly binds to the serum protein, lipopolysaccharide binding protein (LBP), and cellular responses to physiological levels of LPS are dependent on LBP. CD14, a differentiation antigen of monocytes, was found to bind complexes of LPS and LBP, and blockade of CD14 with monoclonal antibodies prevented synthesis of TNF-alpha by whole blood incubated with LPS. Thus, LPS may induce responses by interacting with a soluble binding protein in serum that then binds the cell surface protein CD14.

https://science.sciencemag.org/content/sci/249/4975/1431.full.pdf

CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.

Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can
show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we
highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for
therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

Nanoparticle therapeutics: an emerging treatment modality for cancer

Six monoclonal antibodies have been isolated from mice immunized with synthetic peptide immunogens whose sequences are derived from that of the human c-myc gene product. Five of these antibodies precipitate p62c-myc from human cells, and three of these five also recognize the mouse c-myc gene product. None of the antibodies sees the chicken p110gag-myc protein. All six antibodies recognize immunoblotted p62c-myc. These reagents also provide the basis for an immunoblotting assay by which to quantitate p62c-myc in cells.

Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product.

Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.

/pdf/evidence-of-rnai-in-humans-from-systemically-administered-3pba6uirdb.pdf

Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles

Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis.

The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron.

https://jcp.bmj.com/content/jclinpath/36/5/539.full.pdf

Transferrin receptors in human tissues: their distribution and possible clinical relevance.

Antisera to acute lymphoblastic leukemia cells.

Analysis of immune responses involving distinctive cell types has been greatly facilitated by the development of technology for separating and purifying different lymphocyte populations (1–5) In conjugation with the use of markers which identify selective expression of cell surface components (6, 7) this approach provides an efficient means of studying multi-component immune responses Marker systems identifying human thymus derived 2 (T) and bone marrow-derived (B) lymphocytes are now well advanced (reviewed in 8–10) and we report here the application of various markers to determine the efficacy of separation techniques aimed at providing a simple and reproducible protocol for the preparation of effectively pure human T and B lymphocytes for functional studies Materials and Methods All cell separations were performed on human tonsil cell suspensions since these were available daily from University College Hospital ENT Theatre and provided a convenient source of over 2 × 10 8 viable lymphocytes per tonsil

Purification of Human T and B Lymphocytes

Lx is a scalable and customizable VLIW processor technology platform designed by Hewlett-Packard and STMicroelectronics that allows variations in instruction issue width, the number and capabilities of structures and the processor instruction set. For Lx we developed the architecture and software from the beginning to support both scalability (variable numbers of identical processing resources) and customizability (special purpose resources).In this paper we consider the following issues. When is customization or scaling beneficial? How can one determine the right degree of customization or scaling for a particular application domain? What architectural compromises were made in the Lx project to contain the complexity inherent in a customizable and scalable processor family?The experiments described in the paper show that specialization for an application domain is effective, yielding large gains in price/performance ratio. We also show how scaling machine resources scales performance, although not uniformly across all applications. Finally we show that customization on an application-by-application basis is today still very dangerous and much remains to be done for it to become a viable solution.

/pdf/lx-a-technology-platform-for-customizable-vliw-embedded-4mbjg5dzf7.pdf

Geoffrey Brown

Papers

Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis.

Transferrin receptors in human tissues: their distribution and possible clinical relevance.

Antisera to acute lymphoblastic leukemia cells.

Purification of Human T and B Lymphocytes

Lx: a technology platform for customizable VLIW embedded processing