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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.techfore.2007.05.009 Byline: J. Roland Ortt (a), David J. Langley (b), Nico Pals (b) Keywords: Market potential; Breakthrough technology; Futures research; Market research Abstract: In this article, the gap between futures research (long term) and market research (short term) is closed in two ways. Firstly, by describing methods of market exploration that can be used earlier on in the process of development and diffusion of breakthrough technologies, so market research can be applied along with futures research. Secondly, the gap is closed by actually combining futures research and market research. We start the article from the perspective of the market research discipline and describe the problems in market research that require new approaches. The validity of market research results is often low when breakthrough technologies enter the market. To investigate this problem, assumptions for valid market research results are presented. In some cases, when breakthrough technologies first enter the market, these assumptions do not hold and market research becomes problematic whereas in other cases customers' needs and preferences are not an issue at all and attention focuses on technological issues. Potential solutions to explore the market in the former cases are suggested. Four approaches are distinguished: (1) adapting existing methods; (2) combining consumer research with market structure analysis or futures research; (3) using theoretic models; and (4) probe and learn approaches. These approaches require different subsets of assumptions and are therefore applicable in different situations. Author Affiliation: (a) Associate professor of Management of Technology at Delft University of Technology, faculty of Technology, Policy, and Management, Jaffalaan 5, 2628 BZ Delft, The Netherlands (b) TNO ICT, PO Box 1416, 9701 BK Groningen, The Netherlands Article History: Received 15 October 2006; Revised 27 April 2007; Accepted 1 May 2007

Summary The archetypal T cell-dependent antigen is sheep red blood cells (SRBCs), which have defined much of what we know about humoral immunity. Early studies using solubilized or sonicated SRBCs argued that the intact structure of SRBCs was important for optimal antibody responses. However, the reason for the requirement of intact SRBCs for the response to polyvalent protein antigen remained unknown. Here, we report that the immune response to SRBCs is driven by cytosolic recognition of SRBC RNA through the RIG-I-like receptor (RLR)-mitochondrial anti-viral signaling adaptor (MAVS) pathway. Following the uptake of SRBCs by antigen-presenting cells, the MAVS signaling complex governs the differentiation of both T follicular cells and antibody-producing B cells. Importantly, the involvement of the RLR-MAVS pathway precedes that of endosomal Toll-like receptor pathways, yet both are required for optimal effect. [ABSTRACT FROM AUTHOR]

Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) form the evolutionarily conserved pancreatic polypeptide family. While the fold is widely utilized in nature, crystal structures remain elusive, particularly for the human forms, with only the structure of a distant avian form of PP reported. Here we utilize a crystallization chaperone (antibody Fab fragment), specifically recognizing the amidated peptide termini, to solve the structures of human NPY and human PYY. Intriguingly, and despite limited sequence identity (~50%), the structure of human PYY closely resembles that of avian PP, highlighting the broad structural conservation of the fold throughout evolution. Specifically, the PYY structure is characterized by a C-terminal amidated α-helix, preceded by a backfolded poly-proline N-terminus, with the termini in close proximity to each other. In contrast, in the structure of human NPY the N-terminal component is disordered, while the helical component of the peptide is observed in a four-helix bundle type arrangement, consistent with a propensity for multimerization suggested by NMR studies. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to evaluate the impact of the STAT-MI (ST-Segment Analysis Using Wireless Technology in Acute Myocardial Infarction) network on outcomes in the treatment of patients presenting with ST-segment elevation myocardial infarction (STEMI). Background: Shortening door-to-balloon (D2B) time remains a national priority for the treatment of STEMI. We previously reported a fully automated wireless network (STAT-MI) for transmission of electrocardiograms (ECGs) for suspected STEMI from the field to offsite cardiologists, allowing early triage with shortening of subsequent D2B times. We now report the impact of the STAT-MI wireless network on infarct size, length of hospital stay (LOS), and mortality. Methods: A fully automated wireless network (STAT-MI) was developed to enable automatic 12-lead ECG transmission and direct communication between emergency medical services personnel and offsite cardiologists that facilitated direct triage of patients to the cardiac catheterization laboratory. Demographic, laboratory, and time interval data of STAT-MI network patients were prospectively collected over a 33-month period and compared with concurrent control patients who presented with STEMI through non–STAT-MI pathways. Results: From June 2006 through February 2009, 92 patients presented via the STAT-MI network, and 50 patients presented through non–STAT-MI pathways (control group). Baseline clinical and demographic variables were similar in both groups. Overall, compared with control subjects, STAT-MI patients had significantly shorter D2B times (63 [42 to 87] min vs. 119 [96 to 178] min, U = 779.5, p < 0.00004), significantly lower peak troponin I (39.5 [11 to 120.5] ng/ml vs. 87.6 [38.4 to 227] ng/ml, U = 889.5, p = 0.005) and creatine phosphokinase-MB (126.1 [37.2 to 280.5] ng/ml vs. 290.3 [102.4 to 484] ng/ml, U = 883, p = 0.001), higher left ventricular ejection fractions (50% [35 to 55] vs. 35% [25 to 52], U = 1,075, p = 0.004), and shorter LOS (3 [2 to 4] days vs. 5.5 [3.5 to 10.5] days, U = 378, p < 0.001). Conclusions: A fully automated, field-based, wireless network that transmits ECGs automatically to offsite cardiologists for the early evaluation and triage of patients with STEMI shortens D2B times, reduces infarct size, limits ejection fraction reduction, and shortens LOS. [Copyright &y& Elsevier]

Abstract: In this article, the gap between futures research (long term) and market research (short term) is closed in two ways. Firstly, by describing methods of market exploration that can be used earlier on in the process of development and diffusion of breakthrough technologies, so market research can be applied along with futures research. Secondly, the gap is closed by actually combining futures research and market research. We start the article from the perspective of the market research discipline and describe the problems in market research that require new approaches. The validity of market research results is often low when breakthrough technologies enter the market. To investigate this problem, assumptions for valid market research results are presented. In some cases, when breakthrough technologies first enter the market, these assumptions do not hold and market research becomes problematic whereas in other cases customers'' needs and preferences are not an issue at all and attention focuses on technological issues. Potential solutions to explore the market in the former cases are suggested. Four approaches are distinguished: (1) adapting existing methods; (2) combining consumer research with market structure analysis or futures research; (3) using theoretic models; and (4) probe and learn approaches. These approaches require different subsets of assumptions and are therefore applicable in different situations. [Copyright &y& Elsevier]

The vertical variation of particle number distributions (PNDs) and concentrations in a street canyon is the result of the competing influences of meteorology, traffic and transformation processes overall and for various particle size ranges. A recently developed instrument, the ‘fast-response differential mobility spectrometer DMS500’, measured PNDs in the 5–2738nm range, pseudo-simultaneously, at four different heights (z/H=0.09, 0.19, 0.40 and 0.64) on the leeward side of an 11.6-m-deep street canyon which had a height-to-width ratio of near unity. Measurements were made in Cambridge, UK, between 20 and 21 March 2007. The PNDs were bimodal with the same shape at each height, and with similar values of both the peak and geometric mean particle diameters in each mode. This suggested that transformation processes were not important. Coagulation and condensation time scales were comparable and large, and these processes should have had a negligible effect on the PNDs. The particle number concentrations (PNCs) changed significantly with height from a maximum at z/H=0.19 and decreasing towards both the lowest (z/H=0.09) and highest (z/H=0.64) sampling points. The decrease in PNCs with height in the upper part of the canyon was attributed to the removal of particles as a result of mass exchange between street canyon and the wind above while the reduction in the PNC towards street level was thought to be due to dilution and dry deposition. Over 99% of the PNCs were found in 10–300nm range whereas the particle mass concentrations were almost equally distributed between the 10–1000nm and 1000–2738nm size range at each height. The PNCs in the 10–30nm and the 30–300nm size range were linearly correlated with the traffic volume but poorly correlated with the rooftop wind speed. [Copyright &y& Elsevier]

Interactions between N-methylacetamide (NMA) and N-methylated derivatives of uracil, isocyanurate and barbituric acid have been studied using ab initio methods at the local MP2/6-31G** level of theory. The results were compared to similar interactions between the oxygen atom of NMA and the π-clouds of perfluorobenzene, quinone and trimethyltriazine. The π-acidic amides of isocyanurate and barbituric acid were found to interact with a hydrogen bond acceptor primarily through electrostatic attractions. These groups may be used as alternatives of a hydrogen bond donor to complement a hydrogen bond acceptor or an anion in molecular recognition and drug design. Examples of such interactions were identified through a search of the CSD database. [Copyright &y& Elsevier]

Healthcare users and providers increasingly utilize social media to interact with one another. For a future understanding of when and how these interactions supplement or replace offline doctor-patient interactions, it is essential to understand who interacts, about what, and how these interactions can be categorized in a taxonomy. We draw on affordance theory and employ a mixed-methods approach to study social media interactions among healthcare users and providers. We first engage in qualitative content analysis, which is followed by cluster analysis. We identify five archetypal interactions and categorize these in a taxonomy that adds to current literature on how social media is utilized in the healthcare context. We also provide a clear and systematic overview of the interactions in different social media categories that can stimulate future research regarding doctor-patient interactions. Furthermore, we identify a new and distinct type of social media enabled interaction in healthcare, namely lifestyle support, focusing on prevention. • We identify archetypical interactions and categorize them into a taxonomy. • We challenge the traditional view on types of interactions between healthcare users and providers. • Informational support consists of three distinct subtypes. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso - 13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy. [ABSTRACT FROM AUTHOR]

Human VH single domains represent a promising class of antibody fragments with applications as therapeutic modalities. Unfortunately, isolated human VH domains also generally display poor biophysical properties and a propensity to aggregate. This has encouraged the development of non-human antibody domains as alternative means of antigen recognition and, in particular, camelid (VHH) domains. Naturally devoid of light chain partners, these domains are characterized by favorable biophysical properties and propensity for cleft binding, a highly desirable characteristic, allowing the targeting of cryptic epitopes. In contrast, previously reported structures of human VH single domains had failed to recapitulate this property. Here we report the engineering and characterization of phage display libraries of stable human VH domains and the selection of binders against a diverse set of antigens. Unlike "camelized" human domains, the domains do not rely on potentially immunogenic framework mutations and maintain the structure of the VH/VH interface. Structure determination in complex with hen egg white lysozyme revealed an extended VH binding interface, with complementarity- determining region 3 deeply penetrating into the active site cleft, highly reminiscent of what has been observed for camelid domains. Taken together, our results demonstrate that fully human VH domains can be constructed that are not only stable and well expressed but also rival the cleft binding properties of camelid antibodies. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer’s disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses. [ABSTRACT FROM AUTHOR]

Abstract: Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0nM), as 5-HT6 selective antagonists. Activity was improved some 2–4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure–activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability. [Copyright &y& Elsevier]

Combinations of LIM homeodomain proteins form a transcriptional "LIM code" to direct the specification of neural cell types. Two paralogous pairs of LIM homeodomain proteins, LIM homeobox protein 3/4 (Lhx3/Lhx4) and Islet-1/2 (Isl1/Isl2), are expressed in developing ventral motor neurons. Lhx3 and Isl1 interact within a well characterized transcriptional complex that triggers motor neuron development, but it was not known whether Lhx4 and Isl2 could participate in equivalent complexes. We have identified an Lhx3-binding domain (LBD) in Isl2 based on sequence homology with the Isl1LBD and show that both Isl2LBD and Isl1LBD can bind each of Lhx3 and Lhx4. X-ray crystal- and small-angle x-ray scattering-derived solution structures of an Lhx4·Isl2 complex exhibit many similarities with that of Lhx3·Isl1; however, structural differences supported by mutagenic studies reveal differences in the mechanisms of binding. Differences in binding have implications for the mode of exchange of protein partners in transcriptional complexes and indicate a divergence in functions of Lhx3/4 and Isl1/2. The formation of weaker Lhx·Isl complexes would likely be masked by the availability of the other Lhx·Isl complexes in postmitotic motor neurons. [ABSTRACT FROM AUTHOR]

Pathogens must steal iron from their hosts to establish infection. In mammals, hemoglobin (Hb) represents the largest reservoir of iron, and pathogens express Hb-binding proteins to access this source. Here, we show how one of the commonest and most significant human pathogens, Staphylococcus aureus, captures Hb as the first step of an iron-scavenging pathway. The x-ray crystal structure of Hb bound to a domain from the Isd (iron-regulated surface determinant) protein, IsdH, is the first structure of a Hb capture complex to be determined. Surface mutations in Hb that reduce binding to the Hb-receptor limit the capacity of S. aureus to utilize Hb as an iron source, suggesting that Hb sequence is a factor in host susceptibility to infection. The demonstration that pathogens make highly specific recognition complexes with Hb raises the possibility of developing inhibitors of Hb binding as antibacterial agents. [ABSTRACT FROM AUTHOR]

Abstract: Direct oximation of 2-oxo-2-phenylacetate (3) gave the (Z)-methyl 2-(methoxyimino)-2-phenylacetate (1) in 71% yield, while the E oxime 2 was prepared from 3 in 65% yield via oxime isomerization of 2-(methoxyimino)-2-phenylacetic acid (5). Computational studies suggest that the isomerization of 5 is thermodynamically driven, while the direct oximation of ketoester 3 is kinetically controlled. [Copyright &y& Elsevier]

Abstract: 3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via SNAr reaction and double decarboxylation under mild conditions is demonstrated. [Copyright &y& Elsevier]

Abstract: A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f. [Copyright &y& Elsevier]

Human immunodeficiency virus (HIV) integrase enzyme is required for the integration of viral DNA into the host cell chromosome. Integrase complex assembly and subsequent strand transfer catalysis are mediated by specific interactions between integrase and bases at the end of the viral long terminal repeat (LTR). The strand transfer reaction can be blocked by the action of small molecule inhibitors, thought to bind in the vicinity of the viral LTR termini. This study examines the contributions of the terminal four bases of the nonprocessed strand (G²T¹C-1A-2) of the HIV LTR on complex assembly, specific strand transfer activity, and inhibitor binding. Base substitutions and abasic replacements at the LTR terminus provided a means to probe the importance of each nucleotide on the different functions. An approach is described wherein the specific strand transfer activity for each integrase/LTR variant is derived by normalizing strand transfer activity to the concentration of active sites. The key findings of this study are as follows. 1) The G²:C² base pair is necessary for efficient assembly of the complex and for maintenance of an active site architecture, which has high affinity for strand transfer inhibitors. 2) Inhibitor-resistant enzymes exhibit greatly increased sensitivity to LTR changes. 3) The strand transfer and inhibitor binding defects of a Q148R mutant are due to a decreased affinity of the complex for magnesium. 4) GIn148 interacts with G², T¹, and C-1 at the 5′ end of the viral LTR, with these four determinants playing important and overlapping roles in assembly, strand transfer catalysis and high affinity inhibitor binding. [ABSTRACT FROM AUTHOR]

Abstract: Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor. [Copyright &y& Elsevier]

Abstract: The effect of structural variation of the benzimidazol-2-one ring of RSV fusion inhibitors related to BMS-433771 (1) was examined in conjunction with side chain modifications and the introduction of an aminomethyl substituent at the 5-position of the core benzimidazole moiety. Replacement of the benzimidazol-2-one moiety with benzoxazole, oxindole, quinoline-2-one, quinazolin-2,4-dione and benzothiazine derivatives provided a series of potent RSV fusion inhibitors 4. However, the intrinsic potency of 6,6-fused ring systems was generally less than that of comparably substituted 5,6-fused heterocycles of the type found in BMS-433771 (1). The introduction of an aminomethyl substituent to the benzimidazole ring enhanced antiviral activity in the 6,6-fused ring systems. [Copyright &y& Elsevier]

Abstract: Extensive SAR studies and optimization of ADME properties of benzimidazol-2-one derivatives led to the identification of BMS-433771 (3) as an orally active RSV fusion inhibitor. In order to extend the structure–activity relationships for this compound series, substitution of the benzimidazole ring was examined with a view to establishing additional productive interactions between the inhibitor and functionality present in the proposed binding pocket. Amongst the compounds synthesized, the 5-aminomethyl analogue 10aa demonstrated potent antiviral activity towards wild-type RSV and retained excellent inhibitory activity towards a virus that had been developed to express resistance to BMS-433771 (3), data consistent with an additional productive interaction between the inhibitor and the fusion protein target. [Copyright &y& Elsevier]

Abstract: Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose–phosphate portion of the ATP binding pocket. [Copyright &y& Elsevier]

Abstract: The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented. [Copyright &y& Elsevier]

Abstract: Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket. [Copyright &y& Elsevier]

Abstract: A novel series of 2-anilino-3-phenylsulfonyl-6-methylpyridines was synthesized and evaluated as corticotropin-releasing factor receptor ligands. Structure–activity relationship studies focused primarily on optimization of the 3-phenylsulfonyl group. Compounds within this series were identified which showed potent binding affinity for the CRF1 receptor. Selected compounds were examined in a rat pharmacokinetic study and were found to have oral bioavailabilities ranging from 16 to 35%. [Copyright &y& Elsevier]

Previous studies have identified a series of imidazo[1,2- a pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)- 1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested. [ABSTRACT FROM AUTHOR]

A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure. [ABSTRACT FROM AUTHOR]