This paper develops and tests a model of the determinants of information technology (IT) outsourcing by integrating both business and IT perspectives. Specifically, we attempt to explain the degree ...of IT outsourcing using business and IT competences as represented by their cost structures and economic performances. In addition, we posit that outsourcing is dependent on business governance, particularly financial leverage. Based on factor analyses and multiple regressions using data from fIfty-five major U.S. corporations, we observed that the degree of IT outsourcing is positively related to both business and IT cost structures. We also established that the degree ofIT outsourcing is negatively related to IT performance. Finally, we conclude with implications and future research directions.
It is clear that even though information technology has evolved from its traditional more strategic role within an organization, there is a glaring lack of fundamental frameworks within which to ...understand the potential of I/T for tomorrow's organizations. A model is developed for conceptualizing and directing the emerging area of strategic management of information technology. This model, termed the Strategic Alignment Model, is defined in terms of 4 fundamental domains of strategic choice: 1. business strategy, 2. information technology strategy, 3. organizational infrastructure and processes, and 4. information technology infrastructure and processes - each with its own underlying dimensions. The power of this model is illustrated in terms of two fundamental characteristics of strategic management: 1. strategic fit, and 2. functional integration. More specifically, four perspectives of alignment are derived with specific implications for guiding management practice in this important area.
The measurement of the type and number of acid sites on sulfated zirconia catalysts using the 31P NMR spectrum of adsorbed P(CH3)3 has been vexed by spectral assignment controversies. Using a ...combination of NMR experiments and theoretical methods, including chemical shift calculations at the GIAO-MP2 level, we show that a previously observed 31P resonance at +27 ppm is due to P(CH3)4 +, formed in a reaction that consumes a Brønsted site. The coproduct of this reaction, PH(CH3)2, is protonated on the surface to yield a 31P resonance in the region expected for P(CH3)3 on a Lewis site. Further complications result from a signal due to OP(CH3)3, formed by oxidizing sites on the surface, complexed to unidentified acid sites. As an alternative, we show that carefully designed 15N experiments using the less reactive and less basic probe pyridine-15N provide more easily interpreted measurements of Brønsted and Lewis sites on sulfated zirconias of diverse composition, preparation, and treatment. Quantitative studies revealed that the number of Brønsted sites capable of protonating pyridine corresponded to only ∼7% of the sulfur atoms on the catalyst we studied in the greatest depth. Additional Brønsted sites were created on this catalyst with addition of water, a reaction not observed for sulfur-free zirconia.
A two-dimensional classificatory scheme highlighting ten different approaches to the measurement of business performance in strategy research is developed. The first dimension concerns the use of ...financial versus broader operational criteria, while the second focuses on two alternate data sources (primary versus secondary). The scheme permits the classification of an exhaustive coverage of measurement approaches and is useful for discussing their relative merits and demerits. Implications for operationalizing business performance in future strategy research are discussed.
Electronic integration—a form of vertical quasi-integration achieved through the deployment of dedicated computers and communication systems between relevant actors in the adjacent stages of the ...value-chain—is an important concept to researchers in the information systems field since it focuses on the role of information technology in restructuring vertical relationships. Drawing on theoretical and empirical research on transaction costs, we develop and test a model of the determinants of the degree of electronic integration in the commercial segment of the property and casualty (P&C) industry. Based on a sample of 120 independent agencies operating under dedicated information technology-mediated conditions, we provide empirical support for three hypotheses on the determinants of electronic integration. Implications and research extensions are identified to guide further research in this important area.
Background
Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) ...has emerged as a promising therapeutic target given its isoform-specific neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood–brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age.
Methods
In three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2 J mice, spontaneously hypertensive female rats, or 11-month-old male mice within 24-h of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively.
Results
In spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (
p
< 0.05; 95% CI: 0.91–153.70 and
p
< 0.001; 95% CI: 49.54–205.62), while 0.20 mg/kg also improved neuroseverity scores (
p
< 0.05; 95% CI: 0.27–11.00) and reduced ipsilateral brain edema (
p
< 0.05; 95% CI: − 0.037 to − 0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (
p
< 0.01;
η
2
= 0.093) and neuroseverity scores (
p
< 0.05;
η
2
= 0.083), and reduced contralateral edema expansion (
p
< 0.01; 95% CI: − 1.41 to − 0.39). In 11-month-old male mice, CN-105 had a significant effect on vestibulomotor function (
p
< 0.001;
η
2
= 0.111) but not neuroseverity scores (
p
> 0.05;
η
2
= 0.034).
Conclusions
Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.
Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no ...toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of MnIIIP/MnIIP redox couple, ranged from −200 to +350mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5µM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL-100 cells. Bell-shape relationship, essentially identical to vo(Asc)oxvs E1/2, was also demonstrated between MnP/Asc-controlled cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1-relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)oxvs E1/2 relationships and cellular toxicity, MnTE-2-PyP5+ was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP5+ were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4g/kg) and MnTE-2-PyP5+ (0.2mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP5+ or ascorbate alone. About 7-fold higher accumulation of MnTE-2-PyP5+ in tumor vs normal tissue was found to contribute largely to the anticancer effect.
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•Mn porphyrins (MnPs) catalyze ascorbate (Asc) oxidation, thereby producing H2O2.•MnP-driven H2O2 production depends on the MnIII/MnII reduction potential.•MnP potency in catalyzing Asc oxidation correlates with MnP/Asc-induced cytotoxicity.•MnP/Asc suppresses tumor growth in a mouse flank model.•MnP accumulates to much higher levels in tumor than normal tissue.
Abstract
BACKGROUND
An impermeable blood–brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally ...delivered agents to treat diffuse intrinsic pontine glioma (DIPG).
OBJECTIVE
To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG.
METHODS
The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed.
RESULTS
Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305).
CONCLUSION
ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.
Presently, no pharmacological treatments have been demonstrated to improve long-term functional outcomes following intracerebral hemorrhage (ICH). Clinical evidence associates apolipoprotein E (apoE) ...genotype with ICH incidence and outcome. While apoE modifies neuroinflammatory responses through its adaptive role in glial downregulation, intact apoE holoprotein is too large to cross the blood-brain barrier (BBB). Therefore, we developed a 5-amino acid peptide - CN-105 - that mimics the polar face of the apoE helical domain involved in receptor interactions. In the current study, we investigated the therapeutic potential of CN-105 in a mouse model of ICH. Three doses of CN-105 (0.05 mg/kg) was administered by tail vein injection within 24 hours after ICH induction. Functional assessment showed durable improvement in vestibulomotor performance after CN-105 treatment, as quantified by increased Rotarod latencies on Days 1-5 post-ICH, and long-term improvement in neurocognitive performance, as quantified by reduced Morris water maze latencies on Days 29-32 post-ICH. Further, brain water content was significantly reduced, neuroinflammation was decreased and hippocampal CA3 neuronal survival was increased, although hemorrhage volume was not affected by CN-105. We concluded, therefore, that pentapeptide CN-105 improved short- and long-term neurobehavioral outcomes in a murine model of ICH, suggesting therapeutic potential for patients with acute ICH.
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