Computer Security Breaches A Threat To Credit Sales

Business security has progressed from the wooden cash box to the cash register and now the nightmare of the computer. Control has progressively slipped from the control of the instrument operator to a little understood collection of networked instruments. This evolution of difficulty has created numerous protection problems for the business operator. Not only does the cash and other payment means need collection and protection, but now the payment instrument itself has fallen under the responsibility of the vendor. Business owners are as much at risk from cyber security as from physical security. Thieves don’t have to rush the store with guns blazing to steal money in fact they don’t have to steal money from the store at all. Information and data are the sources of new gold. The information collected from customers’ credit cards contains enough data to secure riches for any enterprising evil doer. In addition to normal data growth, regulatory compliance (Sarbanes/Oxley (SOX), SEC17a, HIPAA, Patriot Act, Freedom of Information etc.) is contributing exponentially to data growth, as more records are generated; more regulations are created in more industries. This creates a big fat target as much a target as any “old west” bank, and businesses are responsible for the protection and security of customers’ data

Modular Nucleic Acid Scaffolds for Synthesizing Monodisperse and Sequence-Encoded Antibody Oligomers.

Synthesizing protein oligomers that contain exact numbers of multiple different proteins in defined architectures is challenging. DNA-DNA interactions can be used to program protein assembly into oligomers; however, existing methods require changes to DNA design to achieve different numbers and oligomeric sequences of proteins. Herein, we develop a modular DNA scaffold that uses only six synthetic oligonucleotides to organize proteins into defined oligomers. As a proof-of-concept, model proteins (antibodies) are oligomerized into dimers and trimers, where antibody function is retained. Illustrating the modularity of this technique, dimer and trimer building blocks are then assembled into pentamers containing three different antibodies in an exact stoichiometry and oligomeric sequence. In sum, this report describes a generalizable method for organizing proteins into monodisperse, sequence-encoded oligomers using DNA. This advance will enable studies into how oligomeric protein sequences affect material properties in areas spanning pharmaceutical development, cascade catalysis, synthetic photosynthesis, and membrane transport

DNA-Directed Protein Packing within Single Crystals.

Designed DNA-DNA interactions are investigated for their ability to modulate protein packing within single crystals of mutant green fluorescent proteins (mGFPs) functionalized with a single DNA strand (mGFP-DNA). We probe the effects of DNA sequence, length, and protein-attachment position on the formation and protein packing of mGFP-DNA crystals. Notably, when complementary mGFP-DNA conjugates are introduced to one another, crystals form with nearly identical packing parameters, regardless of sequence if the number of bases is equivalent. DNA complementarity is essential, because experiments with non-complementary sequences produce crystals with different protein arrangements. Importantly, the DNA length and its position of attachment on the protein markedly influence the formation of and protein packing within single crystals. This work shows how designed DNA interactions can be used to influence the growth and packing in X-ray diffraction quality protein single crystals and is thus an important step forward in protein crystal engineering

Angiogenesis in Spontaneous Tumors and Implications for Comparative Tumor Biology.

Blood supply is essential for development and growth of tumors and angiogenesis is the fundamental process of new blood vessel formation from preexisting ones. Angiogenesis is a prognostic indicator for a variety of tumors, and it coincides with increased shedding of neoplastic cells into the circulation and metastasis. Several molecules such as cell surface receptors, growth factors, and enzymes are involved in this process. While antiangiogenic therapy for cancer has been proposed over 20 years ago, it has garnered much controversy in recent years within the scientific community. The complex relationships between the angiogenic signaling cascade and antiangiogenic substances have indicated the angiogenic pathway as a valid target for anticancer drug development and VEGF has become the primary antiangiogenic drug target. This review discusses the basic and clinical perspectives of angiogenesis highlighting the importance of comparative biology in understanding tumor angiogenesis and the integration of these model systems for future drug development

Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor

Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5-fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally up-regulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic. © 1999 Cancer Research Campaig

Polymerization-induced thermal self-assembly (PITSA)

Polymerization-induced self-assembly (PISA) is a versatile technique to achieve a wide range of polymeric nanoparticle morphologies. Most previous examples of self-assembled soft nanoparticle synthesis by PISA rely on a growing solvophobic polymer block that leads to changes in nanoparticle architecture during polymerization in a selective solvent. However, synthesis of block copolymers with a growing stimuli-responsive block to form various nanoparticle shapes has yet to be reported. This new concept using thermoresponsive polymers is termed polymerization-induced thermal self-assembly (PITSA). A reversible addition-fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide from a hydrophilic chain transfer agent composed of N,N-dimethylacrylamide and acrylic acid was carried out in water above the known lower critical solution temperature (LCST) of poly(N-isopropylacrylamide) (PNIPAm). After reaching a certain chain length, the growing PNIPAm self-assembled, as induced by the LCST, into block copolymer aggregates within which dispersion polymerization continued. To characterize the nanoparticles at ambient temperatures without their dissolution, the particles were crosslinked immediately following polymerization at elevated temperatures via the reaction of the acid groups with a diamine in the presence of a carbodiimide. Size exclusion chromatography was used to evaluate the unimer molecular weight distributions and reaction kinetics. Dynamic light scattering and transmission electron microscopy provided insight into the size and morphologies of the nanoparticles. The resulting block copolymers formed polymeric nanoparticles with a range of morphologies (e.g., micelles, worms, and vesicles), which were a function of the PNIPAm block length

Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib

BACKGROUND: Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes. METHODS: Toxicities (≥ grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes. RESULTS: Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136). CONCLUSIONS: This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib

Bibliometrics of systematic reviews : analysis of citation rates and journal impact factors

Background: Systematic reviews are important for informing clinical practice and health policy. The aim of this study was to examine the bibliometrics of systematic reviews and to determine the amount of variance in citations predicted by the journal impact factor (JIF) alone and combined with several other characteristics. Methods: We conducted a bibliometric analysis of 1,261 systematic reviews published in 2008 and the citations to them in the Scopus database from 2008 to June 2012. Potential predictors of the citation impact of the reviews were examined using descriptive, univariate and multiple regression analysis. Results: The mean number of citations per review over four years was 26.5 (SD +/-29.9) or 6.6 citations per review per year. The mean JIF of the journals in which the reviews were published was 4.3 (SD +/-4.2). We found that 17% of the reviews accounted for 50% of the total citations and 1.6% of the reviews were not cited. The number of authors was correlated with the number of citations (r = 0.215, P =5.16) received citations in the bottom quartile (eight or fewer), whereas 9% of reviews published in the lowest JIF quartile (<=2.06) received citations in the top quartile (34 or more). Six percent of reviews in journals with no JIF were also in the first quartile of citations. Conclusions: The JIF predicted over half of the variation in citations to the systematic reviews. However, the distribution of citations was markedly skewed. Some reviews in journals with low JIFs were well-cited and others in higher JIF journals received relatively few citations; hence the JIF did not accurately represent the number of citations to individual systematic reviews

Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia

This is the final version of the article. Available from the publisher via the DOI in this record.Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases.This work was supported by the British Heart Foundation (a PhD studentship to KS and PG 13 89 30577), Medical Research Council, and an ERC Starting Investigator Grant (to TK), as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Janssen Pharmaceutica and Pfizer). The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre

Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs

Funding: This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (ZIA SC006538); in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E; the Intramural Research Program of the National Institute on Aging, National Institutes of Health; and a Wellcome Trust-NIH PhD Studentship to SB, WDF, and NV (Grant number 098252/Z/12/Z). Acknowledgments: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.Peer reviewedPublisher PD