bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative analysis of RNA regulatory elements of amino acid metabolism genes in Actinobacteria
Authors: Seliverstov Alexander V , Putzer Harald , Gelfand Mikhail S , Lyubetsky Vassily A
Published: October 2005

Background

Formation of alternative structures in mRNA in response to external stimuli, either direct or mediated by proteins or other RNAs, is a major mechanism of regulation of gene expression in bacteria. This mechanism has been studied in detail using experimental and computational approaches in proteobacteria and Firmicutes, but not in other groups of bacteria.

Results

Comparative analysis of amino acid biosynthesis operons in Actinobacteria resulted in identification of conserved regions upstream of several operons. Classical attenuators were predicted upstream of trp operons in Corynebacterium spp. and Streptomyces spp., and trpS and leuS genes in some Streptomyces spp. Candidate leader peptides with terminators were observed upstream of ilvB genes in Corynebacterium spp., Mycobacterium spp. and Streptomyces spp. Candidate leader peptides without obvious terminators were found upstream of cys operons in Mycobacterium spp. and several other species. A conserved pseudoknot (named LEU element) was identified upstream of leuA operons in most Actinobacteria. Finally, T-boxes likely involved in the regulation of translation initiation were observed upstream of ileS genes from several Actinobacteria.

Conclusion

The metabolism of tryptophan, cysteine and leucine in Actinobacteria seems to be regulated on the RNA level. In some cases the mechanism is classical attenuation, but in many cases some components of attenuators are missing. The most interesting case seems to be the leuA operon preceded by the LEU element that may fold into a conserved pseudoknot or an alternative structure. A LEU element has been observed in a transposase gene from Bifidobacterium longum, but it is not conserved in genes encoding closely related transposases despite a very high level of protein similarity. One possibility is that the regulatory region of the leuA has been co-opted from some element involved in transposition. Analysis of phylogenetic patterns allowed for identification of ML1624 of M. leprae and its orthologs as the candidate regulatory proteins that may bind to the LEU element. T-boxes upstream of the ileS genes are unusual, as their regulatory mechanism seems to be inhibition of translation initiation via a hairpin sequestering the Shine-Dalgarno box.
A gonococcal homologue of meningococcal γ-glutamyl transpeptidase gene is a new type of bacterial pseudogene that is transcriptionally active but phenotypically silent
Authors: Takahashi Hideyuki , Watanabe Haruo
Published: October 2005

Background

It has been speculated that the γ-glutamyl transpeptidase (ggt) gene is present only in Neisseria meningitidis and not among related species such as Neisseria gonorrhoeae and Neisseria lactamica, because N. meningitidis is the only bacterium with GGT activity. However, nucleotide sequences highly homologous to the meningococcal ggt gene were found in the genomes of N. gonorrhoeae isolates.

Results

The gonococcal homologue (
g

gt
g onococcal h omologue;
g

gh) was analyzed. The nucleotide sequence of the ggh gene was approximately 95 % identical to that of the meningococcal ggt gene. An open reading frame in the ggh gene was disrupted by an ochre mutation and frameshift mutations induced by a 7-base deletion, but the amino acid sequences deduced from the artificially corrected ggh nucleotide sequences were approximately 97 % identical to that of the meningococcal ggt gene. The analyses of the sequences flanking the ggt and ggh genes revealed that both genes were localized in a common DNA region containing the fbp-ggt (or ggh)-glyA-opcA-dedA-abcZ gene cluster. The expression of the ggh RNA could be detected by dot blot, RT-PCR and primer extension analyses. Moreover, the truncated form of ggh- translational product was also found in some of the gonococcal isolates.

Conclusion

This study has shown that the gonococcal ggh gene is a pseudogene of the meningococcal ggt gene, which can also be designated as Ψggt. The gonococcal ggh (Ψggt) gene is the first identified bacterial pseudogene that is transcriptionally active but phenotypically silent.
Combining RNA interference and kinase inhibitors against cell signalling components involved in cancer
Authors: O'Grady Michael , Raha Debasish , Hanson Bonnie J , Bunting Michaeline , Hanson George T
Published: October 2005

Background

The transcription factor activator protein-1 (AP-1) has been implicated in a large variety of biological processes including oncogenic transformation. The tyrosine kinases of the epidermal growth factor receptor (EGFR) constitute the beginning of one signal transduction cascade leading to AP-1 activation and are known to control cell proliferation and differentiation. Drug discovery efforts targeting this receptor and other pathway components have centred on monoclonal antibodies and small molecule inhibitors. Resistance to such inhibitors has already been observed, guiding the prediction of their use in combination therapies with other targeted agents such as RNA interference (RNAi). This study examines the use of RNAi and kinase inhibitors for qualification of components involved in the EGFR/AP-1 pathway of ME180 cells, and their inhibitory effects when evaluated individually or in tandem against multiple components of this important disease-related pathway.

Methods

AP-1 activation was assessed using an ME180 cell line stably transfected with a beta-lactamase reporter gene under the control of AP-1 response element following epidermal growth factor (EGF) stimulation. Immunocytochemistry allowed for further quantification of small molecule inhibition on a cellular protein level. RNAi and RT-qPCR experiments were performed to assess the amount of knockdown on an mRNA level, and immunocytochemistry was used to reveal cellular protein levels for the targeted pathway components.

Results

Increased potency of kinase inhibitors was shown by combining RNAi directed towards EGFR and small molecule inhibitors acting at proximal or distal points in the pathway. After cellular stimulation with EGF and analysis at the level of AP-1 activation using a β-lactamase reporter gene, a 10–12 fold shift or 2.5–3 fold shift toward greater potency in the IC50 was observed for EGFR and MEK-1 inhibitors, respectively, in the presence of RNAi targeting EGFR.

Conclusion

EGFR pathway components were qualified as targets for inhibition of AP-1 activation using RNAi and small molecule inhibitors. The combination of these two targeted agents was shown to increase the efficacy of EGFR and MEK-1 kinase inhibitors, leading to possible implications for overcoming or preventing drug resistance, lowering effective drug doses, and providing new strategies for interrogating cellular signalling pathways.
Numbers of mutations to different types of colorectal cancer
Authors: Calabrese Peter , Mecklin Jukka-Pekka , Järvinen Heikki J , Aaltonen Lauri A , Tavaré Simon , Shibata Darryl
Published: October 2005

Background

The numbers of oncogenic mutations required for transformation are uncertain but may be inferred from how cancer frequencies increase with aging. Cancers requiring more mutations will tend to appear later in life. This type of approach may be confounded by biologic heterogeneity because different cancer subtypes may require different numbers of mutations. For example, a sporadic cancer should require at least one more somatic mutation relative to its hereditary counterpart.

Methods

To better estimate numbers of mutations before transformation, 1,022 colorectal cancers were classified with respect to microsatellite instability (MSI) and germline DNA mismatch repair mutations characteristic of hereditary nonpolyposis colorectal cancer (HNPCC). MSI- cancers were also classified with respect to clinical stage. Ages at cancer and a Bayesian algorithm were used to estimate the numbers of oncogenic mutations required for transformation for each cancer subtype.

Results

Ages at MSI+ cancers were consistent with five or six oncogenic mutations for hereditary (HNPCC) cancers, and seven or eight mutations for its sporadic counterpart. Ages at cancer were consistent with seven mutations for sporadic MSI- cancers, and were similar (six to eight mutations) regardless of clinical cancer stage.

Conclusion

Different biologic subtypes of colorectal cancer appear to require different numbers of oncogenic mutations before transformation. Sporadic MSI+ cancers may require more than a single additional somatic alteration compared to hereditary MSI+ cancers because the epigenetic inactivation of MLH1 commonly observed in sporadic MSI+ cancers may be a multistep process. Interestingly, estimated numbers of MSI- cancer mutations were similar (six to eight mutations) regardless of clinical cancer stage, suggesting a propensity to spread or metastasize does not require additional mutations after transformation. Estimates of oncogenic mutation numbers may help explain some of the biology underlying different cancer subtypes.
Inter-individual variations of human mercury exposure biomarkers: a cross-sectional assessment
Authors: Berglund Marika , Lind Birger , Björnberg Karolin Ask , Palm Brita , Einarsson Östen , Vahter Marie
Published: October 2005

Background

Biomarkers for mercury (Hg) exposure have frequently been used to assess exposure and risk in various groups of the general population. We have evaluated the most frequently used biomarkers and the physiology on which they are based, to explore the inter-individual variations and their suitability for exposure assessment.

Methods

Concentrations of total Hg (THg), inorganic Hg (IHg) and organic Hg (OHg, assumed to be methylmercury; MeHg) were determined in whole blood, red blood cells, plasma, hair and urine from Swedish men and women. An automated multiple injection cold vapour atomic fluorescence spectrophotometry analytical system for Hg analysis was developed, which provided high sensitivity, accuracy, and precision. The distribution of the various mercury forms in the different biological media was explored.

Results

About 90% of the mercury found in the red blood cells was in the form of MeHg with small inter-individual variations, and part of the IHg found in the red blood cells could be attributed to demethylated MeHg. THg in plasma was associated with both IHg and MeHg, with large inter-individual variations in the distribution between red blood cells and plasma. THg in hair reflects MeHg exposure at all exposure levels, and not IHg exposure. The small fraction of IHg in hair is most probably emanating from demethylated MeHg. The inter-individual variation in the blood to hair ratio was very large. The variability seemed to decrease with increasing OHg in blood, most probably due to more frequent fish consumption and thereby blood concentrations approaching steady state. THg in urine reflected IHg exposure, also at very low IHg exposure levels.

Conclusion

The use of THg concentration in whole blood as a proxy for MeHg exposure will give rise to an overestimation of the MeHg exposure depending on the degree of IHg exposure, why speciation of mercury forms is needed. THg in RBC and hair are suitable proxies for MeHg exposure. Using THg concentration in plasma as a measure of IHg exposure can lead to significant exposure misclassification. THg in urine is a suitable proxy for IHg exposure.
Infection with Anaplasma phagocytophilum in a seronegative patient in Sicily, Italy: Case Report
Authors: de la Fuente J , Torina A , Naranjo V , Caracappa S , Di Marco V , Alongi A , Russo M , Maggio AR , Kocan KM
Published: October 2005

Background

Anaplasma phagocytophilum causes human granulocytic anaplasmosis (HGA) in humans, which has been recognized as an emerging tick-borne disease in the United States and Europe. Although about 65 cases of HGA have been reported in Europe, some of them do not fulfill the criteria for confirmed HGA. Confirmation of HGA requires A. phagocytophilum isolation from blood, and/or identification of morulae in granulocytes and/or positive PCR results with subsequent sequencing of the amplicons to demonstrate specific rickettsial DNA. Seroconversion or at least fourfold increase in antibody titers to A. phagocytophilum has been used as criteria for confirmed HGA also.

Case presentation

Infection with A. phagocytophilum was confirmed by PCR in a patient in Sicily, Italy, who had negative serology for A. phagocytophilum. A fragment of A. phagocytophilum 16S rDNA was amplified by two independent laboratories and sequenced from two separate patient's blood samples. The 16S rDNA sequence was identical in both samples and identical to the sequence of the A. phagocytophilum strain USG3 originally obtained from a dog.

Conclusion

Infection with A. phagocytophilum was confirmed in a patient without a detectable antibody response against the pathogen. The results reported herein documented the first case of confirmed HGA in Sicily, Italy. These results suggested the possibility of human infections with A. phagocytophilum strains that result in clinical symptoms and laboratory findings confirmatory of HGA but without detectable antibodies against the pathogen.
An unusual clinical presentation resembling superior vena cava syndrome post heart surgery
Authors: López-Candales Angel , Kaczorowski David , Pellegrini Ronald
Published: October 2005

Background

An unusual sequence of post operative events heralded by hemodynamic deterioration followed by dyspnea and rapidly progressive dilatation of superficial neck and facial veins, resembling a superior vena cava syndrome, two days post surgical resection of filamentous aortic valve masses, closure of a patent foramen ovale, and performance of a modified Maze procedure for atrial fibrillation in a patient that presented with transient neurologic findings is presented.

Case Presentation

Although both clinical findings and hemodynamic derangements completely resolved following tricuspid valve repair aimed to correct the new onset severe tricuspid regurgitation noted post operatively; a clear mechanism was not readily obvious and diagnostic testing data somewhat conflictive. We present a careful retrospective examination of all clinical data and review possible clinical entities that could have been implicated in this particular case and recognize that transesophageal echocardiographic findings were most useful in identifying the best course of action.

Conclusion

After reviewing all clinical data and despite the inconclusive nature of test results; the retrospective examination of transesophageal echocardiographic findings proved to be most useful in identifying the best course of action. We postulate that in our case, resolution of the suspected pulmonary embolism with anticoagulation and reestablishment of a normal right ventricular geometry with tricuspid valve repair worked in unison in restoring normal hemodynamics and resolving both dyspnea and venous dilatation.
Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts
Authors: Pawitan Yudi , Bjöhle Judith , Amler Lukas , Borg Anna-Lena , Egyhazi Suzanne , Hall Per , Han Xia , Holmberg Lars , Huang Fei , Klaar Sigrid , Liu Edison T , Miller Lance , Nordgren Hans , Ploner Alexander , Sandelin Kerstin , Shaw Peter M , Smeds Johanna , Skoog Lambert , Wedrén Sara , Bergh Jonas
Published: October 2005

Introduction

Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction.

Methods

We obtained the gene expression profiles of 159 population-derived breast cancer patients, and used hierarchical clustering to identify the signature associated with prognosis and impact of adjuvant therapies, defined as distant metastasis or death within 5 years. Independent datasets of 76 treated population-derived Swedish patients, 135 untreated population-derived Swedish patients and 78 Dutch patients were used for validation. The inclusion and exclusion criteria for the studies of population-derived Swedish patients were defined.

Results

Among the 159 patients, a subset of 64 genes was found to give an optimal separation of patients with good and poor outcomes. Hierarchical clustering revealed three subgroups: patients who did well with therapy, patients who did well without therapy, and patients that failed to benefit from given therapy. The expression profile gave significantly better prognostication (odds ratio, 4.19; P = 0.007) (breast cancer end-points odds ratio, 10.64) compared with the Elston–Ellis histological grading (odds ratio of grade 2 vs 1 and grade 3 vs 1, 2.81 and 3.32 respectively; P = 0.24 and 0.16), tumor stage (odds ratio of stage 2 vs 1 and stage 3 vs 1, 1.11 and 1.28; P = 0.83 and 0.68) and age (odds ratio, 0.11; P = 0.55). The risk groups were consistent and validated in the independent Swedish and Dutch data sets used with 211 and 78 patients, respectively.

Conclusion

We have identified discriminatory gene expression signatures working both on untreated and systematically treated primary breast cancer patients with the potential to spare them from adjuvant therapy.
18F-Fluorodeoxyglucose Positron Emission Tomography Contributes to the Diagnosis and Management of Infections in Patients With Multiple Myeloma: A Study of 165 Infectious Episodes
Authors: Mahfouz T. , Miceli M.H. , Saghafifar F. , Stroud S. , Jones-Jackson L. , Walker R. , Grazziutti M.L. , Purnell G. , Fassas A. , Tricot G. , Barlogie B. , Anaissie E.
Published: October 2005

Purpose

Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM).

Patients and Methods

The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome.

Results

One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET.

Conclusion

In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.
Antitumor Activity in Melanoma and Anti-Self Responses in a Phase I Trial With the Anti-Cytotoxic T Lymphocyte–Associated Antigen 4 Monoclonal Antibody CP-675,206
Authors: Ribas Antoni , Camacho Luis H. , Lopez-Berestein Gabriel , Pavlov Dmitri , Bulanhagui Cecile A. , Millham Robert , Comin-Anduix Begoña , Reuben James M. , Seja Elisabeth , Parker Charla A. , Sharma Amarnath , Glaspy John A. , Gomez-Navarro Jesus
Published: October 2005

Purpose

Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206.

Patients and Methods

Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose.

Results

Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response.

Conclusion

CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.
Treatment of Metastatic Renal Cell Carcinoma With a Combination of Bevacizumab and Erlotinib
Authors: Hainsworth John D. , Sosman Jeffrey A. , Spigel David R. , Edwards Donna L. , Baughman Cara , Greco Anthony
Published: October 2005

Purpose

To evaluate the efficacy and toxicity of combined treatment with two targeted agents, an antibody against vascular endothelial growth factor (bevacizumab) and an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib), in the treatment of patients with metastatic clear-cell renal carcinoma.

Patients and Methods

Sixty-three patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients who responded continued treatment until they experienced tumor progression.

Results

Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses to treatment, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Only eight patients' (14%) disease had progressed at this time point. The median and 1-year progression-free survivals were 11 months and 43%, respectively. After a median follow-up of 15 months, median survival has not been reached; survival at 18 months was 60%. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities.

Conclusion

The combination of bevacizumab and erlotinib is an effective and well-tolerated treatment for patients with advanced renal cell carcinoma. The efficacy of these two drugs in combination suggests that targeting of separate pathways critical to tumor growth and dissemination may achieve results superior to either drug as a single agent. Additional development of this and other combinations of targeted agents is warranted.
Long-Term Follow-Up of Gastric MALT Lymphoma After Helicobacter Pylori Eradication
Authors: Wündisch Thomas , Thiede Christian , Morgner Andrea , Dempfle Astrid , Günther Annette , Liu Hongxiang , Ye Hongtao , Du Ming-Qing , Kim Theo D. , Bayerdörffer Ekkehard , Stolte Manfred , Neubauer Andreas
Published: October 2005

Purpose

Cure of infection induces remissions in most patients with early stage Helicobacter pylori- (Hp) positive gastric MALT (mucosa-associated lymphoid tissue) lymphoma (GML). We tracked the long-term stability of remissions in this prospective, multicenter trial.

Patients and Methods

In 120 patients with stage I1E disease, we performed sequential endoscopic-bioptic follow-up after Hp eradication and polymerase chain reaction of the rearranged immunoglobulin heavy chain gene. The status of t(11;18) was assessed in 65 patients.

Results

Median follow-up was 75 months (range, one to 116). Five-year survival was 90%. Eighty percent of patients (96 of 120) achieved complete histologic remission (CR). Eighty percent of CRs are in continuous complete histologic remission (CCR). Three percent of CR patients (three of 96) relapsed and were referred for alternative treatment. Seventeen percent of CR patients (16 of 96) showed histologic residual disease (RD) during follow-up; a watch-and-wait strategy was applied, and all entered into a second CR. After a median follow-up of 63 months, 14 of 52 analyzed patients reaching CR showed ongoing B-cell monoclonality. Fifteen percent of GMLs were t(11;18) positive. Both t(11;18) and ongoing monoclonality were associated with a significantly higher risk for no response or relapse (P =.004, P =.007), but also present in patients in CCR. Early gastric cancer was diagnosed in three cases during follow-up.

Conclusion

Cure of Hp infection results in CCR in most patients. Histologic RD, B-cell monoclonality, and t(11;18) were present in a considerable number of CR patients. A watch-and-wait strategy is justified when close follow-up is guaranteed.
Geographic and Socioeconomic Variation in the Treatment of Prostate Cancer
Authors: Krupski Tracey L. , Kwan Lorna , Afifi Abdelmonem A. , Litwin Mark S.
Published: October 2005

Purpose

Within a framework of quality assessment, primary treatment choice constitutes an indicator of quality of care. This study examines geographic and socioeconomic variation in the primary treatment of men with prostate cancer during the era of prostate-specific antigen testing.

Methods

Using the National Cancer Institute's Surveillance, Epidemiology, and End Results public use data files, we identified men with localized/regional prostate cancer who underwent surgery, radiation therapy, or watchful waiting. We used the year 2000 US Census information to ascribe education and income levels to these men based on their county of residence and ethnicity.

Results

Among the 96,769 men with localized/regional prostate cancer (during 1995 to 1999) who had sufficient information for analysis, we observed significant geographic variation nationwide in surgical, radiation, and watchful waiting treatment rates (P <.0015). Patterns noted 10 years ago, such as higher surgical rates in western regions, persisted. Ethnicity, income, and grade were all independently associated with primary treatment, or lack thereof. Blacks and low-income patients had the lowest rates of surgery and radiation. Grade was the best predictor of aggressive treatment.

Conclusion

Nonclinical factors, such as ethnicity and income, were associated with the use of watchful waiting rather than surgery or radiation in men with early-stage prostate cancer. These findings have implications for quality of care.
Determination of the Reaction Rate Constants of Antioxidants with the Hydroxyl Radical by a Rapid-Flow ESR Method
Authors: Ohashi Yasunori , Takeuchi Yuya , Hirama Mutsumi , Yoshioka Hisashi , Yoshioka Hiroe
Published: October 2005

The reaction rate constants of antioxidants with the hydroxyl radical (HO•) were determined by a rapid-flow ESR method. ESR spectra of the antioxidant radical formed by a reaction with HO• generated from the Ti3+ + H2O2 system were measured. When an antioxidant and ethanol were mixed with HO•, a superposed spectrum of the 1-hydroxyethyl radical and antioxidant radical was obtained. The intensity ratio of the signals of these radicals was calculated from the doubly integrated curve, and then the ratio of the reaction-rate constant of the antioxidant with HO• to that of ethanol was obtained. The ratios of pyrogallol, gallic acid, catechol, phloroglucinol, resorcinol, and methanol were 19, 17, 11, 1.5, 1.2, and 0.56, respectively. The dissociation energies of the bonds in antioxidant molecules were obtained by MO calculations, which demonstrated that phenoxy, hydroxymethyl, and 1-hydroxylethyl radicals were formed by the reactions with HO•, as expected from their spectra. The relationship between the relative activation energies obtained from the rate constants and the bond-dissociation energies showed that the Evans–Polanyi equation holds in polyphenol series, but the line was shifted from that of alcohols. This suggested that the structures of the transition state of alcohols were stabilized by a polar effect.
Proton NMR Investigation of the Stoichiometry, Stability, and Exchange Kinetics of Tl+ Complexes with Hexacyclen and Hexamethylhexacyclen in N,N-Dimethylformamide Solutions. Observation of a Three-Site Exchange Process
Authors: Alizadeh Naader , Bordbar Maryam , Shamsipur Mojtaba
Published: October 2005

1H NMR spectroscopy was used to investigate the stoichiometry, stability, and exchange kinetics and mechanism of ligand interchange for Tl+ complexes with hexacyclen (HCY) and hexamethylhexacyclen (HMHCY) in dimethylformamide (DMF) solution. In both cases, a stable complex with a 1:1 stoichiometry was formed in solution. A complete line-shape analysis was used to evaluate the mean exchange times and exchange rates. The two-site chemical exchange between Tl+ and HCY proceeded via a dissociative ligand-interchange mechanism in the temperature range 250–310 K. However, the 1H NMR spectra of the Tl+–HMHCY complex system in DMF, in about the same temperature range, revealed the predominance of a three-site exchange process in the system. The type of exchange was dependent on the Tl+/HMHCY mole ratio, ρ. At ρ < 1, ligand exchange occurs via a dissociative mechanism, while at ρ > 1, a bimolecular metal exchange is the predominate mechanism. In this case, the main factors controlling the exchange rates are the conformational rearrangement of the ligand during a concerted partial decomplexation of a Tl+ cation and partial complexation of a second one. The activation parameters (Ea, ΔH‡, ΔS‡, and ΔG‡) for the exchange processes (i.e. the ligand exchange, metal exchange, and the conformational change of the complex) were determined and compared with those for a two-site exchange for the Tl+–HCY system.
Remarkable Enhancement Effect of 2,2,2-Trifluoroethanol on the Solubility of Tris(pentane-2,4-dionato)chromium(III) in Supercritical Carbon Dioxide by Outer-Sphere Complexation through Hydrogen Bonding
Authors: Ohashi Akira , Hoshino Hirobumi , Niida Junichi , Imura Hisanori , Ohashi Kousaburo
Published: October 2005

The solubility of tris(pentane-2,4-dionato)chromium(III) (Cr(acac)3) in supercritical carbon dioxide (SC-CO2) with and without modifiers was investigated by UV–vis spectrophotometry. The influence of some polar and nonpolar modifiers, such as methanol, ethanol, 2,2,2-trifluoroethanol (TFE), acetone, chloroform, and benzene, was studied by changing the temperature, pressure, and concentration of the modifiers. Alcohols, particularly TFE, demonstrated a large solubility enhancement of Cr(acac)3 among these modifiers. In contrast, acetone having a relatively larger polarity gave a lower enhancement effect than chloroform and benzene. The measurement of the IR absorption spectra of TFE in the presence of Cr(acac)3 in SC-CO2 suggested that a drastic solubility enhancement of Cr(acac)3 upon the addition of TFE could be ascribed to the formation of the stable Cr(acac)3–TFE complex through hydrogen bonding. The association constants of Cr(acac)3 with TFE in SC-CO2 could be determined from the relationship of the solubility enhancement against the TFE concentration.
Cholesterol-Appended β-(1 → 3)-d-Glucan Schizophyllan for Antisense Oligonucleotides Delivery to Enhance the Cellular Uptake
Authors: Koumoto Kazuya , Mizu Masami , Anada Takahisa , Nagasaki Takeshi , Shinkai Seiji , Sakurai Kazuo
Published: October 2005

Schizophyllan is a natural β-(1 → 3)-d-glucan existing as a triple helix in water and as a single chain in dimethyl sulfoxide (DMSO), respectively. As we already reported, when a homo-polynucleotide is added to a schizophyllan solution, the single chain of schizophyllan forms a complex with the polynucleotide. One of the potential applications of this novel complex is an antisense-oligonucleotide (AS ODN) carrier. The present paper describes a modification technique that enables us to introduce a cholesterol group only to the side chain of schizophyllan. We prepared four cholesterol-appended schizophyllans with different modification levels. Using these compounds, we made complexes and carried out an in vitro antisense assay, administrating a phosphorothioate AS ODN to the several cell lines to depress their c-myb mRNA. When we used 2.2–2.3 mol % modified schizophyllan as the carrier, the antisense effect was most enhanced among others. The addition of β-cyclodextrin improved the complexation ability as well as the up-take for highly modified samples. Furthermore, the cytotoxicity for these modified schizophyllan samples was negligibly as small as the natural (unmodified) schizophyllan. The present work has thus clarified that schizophyllan can act as a new potential candidate for AS ODN carriers.
Unique Reactivity of α-Alkoxy Ginkgolide Lactones to Nucleophilic Reagents: Preparation of New Lactol Derivatives
Authors: Tanaka Katsunori , Pimentel Marc , Berova Nina , Nakanishi Koji
Published: October 2005

It has been found that nucleophilic reagents, i.e., NaBH4, Grignard reagents, and alkyl lithium, uniquely react with the α-alkoxy- or acyloxy-lactone moieties in ginkgolide and F-seco-ginkgolides to give rise to lactol derivatives. The reaction is rapid and stops at the lactol stage; the strong coordination of Na, Mg, and Li metals to the conformationally rigid cage structure is involved in both the initiation and termination stages. The NaBH4 reduction of F-seco-ginkgolides gives rise to an equilibrium mixture of α- and β-lactols, the separation of which becomes only possible after acylation by p-phenylbenzoic acid. The resulting acyl-lactol stereogenic centers were elucidated by both NOE and the CD/FDCD exciton chirality method utilizing the sterically hindered 7-hydroxyl. On the other hand, the alkylation of ginkgolide B derivatives proceeds regio- and stereoselectively at the C-11 lactone group, resulting from the approach of Grignard and alkyl lithium reagents to the convex face of the cage-shaped ginkgolide molecule. The additional new stereogenic centers of the quaternary lactol hydroxyls have been determined by NOE. This facile alkylation protocol gives rise to a deep-seated skeletal transformation of ginkgolides, resulting in a new class of ball-shaped heptacyclic ginkgolide derivatives via “olefin/olefin” and “olefin/alkyne” ring-closing metathesis.
Reduction of Carboxylic Acid Derivatives Using Diphenylsilane in the Presence of a Rh–PPh3 Complex
Authors: Ohta Tetsuo , Kamiya Masahiro , Nobutomo Mami , Kusui Keisuke , Furukawa Isao
Published: October 2005

Reductions of carboxylic acid derivatives by silanes in the presence of rhodium complexes were studied. Carboxylic esters were reduced to alcohols by diphenylsilane catalyzed by [RhCl(cod)]2/4PPh3 or [RhCl(PPh3)3] at room temperature in up to 99% yields. For example, ethyl decanoate and ethyl phenylacetate were converted to decanol and 2-phenylethanol in 98 and 92% yields, respectively. Carboxylic acids were also reduced by this reducing system to the corresponding alcohols in high yields. Furthermore, N-monosubstituted amides were reduced to secondary amines in moderate to good yields. For sterically hindered amides, the yields were moderate, and imines were produced in competitive yields.
Thermal-Degradation Process Analysis of Mesoporous Silica in Different Atmospheres
Authors: Zhang Cunman , Liu Qian , Xu Zheng , Wan Keshu
Published: October 2005

The thermal-degradation process of the mesoporous structure in silica MCM-41 was investigated in the present research via a series of thermal-stability experiments in different atmospheres with varied technique analysis (N2-sorption, XRD, IR, and NMR spectra). The research showed that the atmosphere was also a very important factor to affect the thermal stability of mesoporous silica as well as the temperature and time; the oxygen atmosphere obviously accelerated the degradation process of the ordered pore structure in mesoporous silica. We considered that the thermal vibration of atom groups, silanol condensation, and the reconstruction of bridge oxygen bonds between SiO4 tetrahedra in the mesopore wall can be the main causes resulting in the contraction of the inorganic networks and the degradation of the pore structure in mesoporous silica. The oxygen molecule could play an important role during the heat treatment. The oxygen can not only promote silanol condensation, but also make some original bridge oxygen bonds rupture more easily, and then the ruptured units immediately reconstruct more stable bonds with other ruptured units, SiO4, which results in the contraction of inorganic networks and degradation of the mesoporous structure.
Rapid, Accurate and Precise Quantitative Drug Analysis: Comparing Liquid Chromatography Tandem Mass Spectrometry and Chip-Based Nanoelectrospray Ionisation Mass Spectrometry
Authors: Alfazema Louisa N. , Richards Don S. , Gélébart Sylvie , Mitchell John C. , Snowden Martin J.
Published: October 2005

We have developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) system capable of achieving better than 2% accuracy, routinely over a wide concentration range of 1–800 ng mL−1. We demonstrate that the necessary high precision, high accuracy and rapid analysis can be achieved using LC-MS/MS technology. Automated nanoelectrospray ionisation tandem mass spectrometry (nanoESI-MS/MS) technology can be employed to eliminate the chromatographic step completely. In this paper, nanoESI-MS/MS is evaluated and compared directly with LC-MS/MS for the quantitative analysis of two-test analytes, amitriptyline (ATT) and 5-methoxytryptamine (5-MTT), in aqueous/organic mixture. Calibration curves were found to be linear over a wide concentration range of 1–800 ng mL−1 for both analytes using LC-MS/MS. Using nanoESI-MS/MS ATT gave a linear response while 5-MTT gave a non-linear response using nanoESI-MS/MS over the same concentration range as in LC-MS/MS. Accuracy and precision values of quality control samples (QCs) at four concentration levels were analysed in replicates of six at each level using 5-MTT and ATT as test analytes for both techniques. The LC-MS/MS system was capable of achieving accuracy levels of 99.50–101.96% for ATT and 100.17–100.40% for 5-MTT. Accuracy levels using nanoESI-MS/MS were not comparable to LC-MS/MS, they ranged from 90.09–100.18% for ATT and 95.95–113.55% for 5-MTT. The precision values obtained for nanoESI-MS/MS were in good agreement with those obtained by LC-MS/MS.
Differentiation of Ionised Benzimidazole from its Isomeric α-Distonic Ion by Collision-Induced Dissociation and Neutralisation—Reionisation Mass Spectrometry
Authors: Fox Athan , Bowen Richard D.
Published: October 2005

Ionised benzimidazole and its isomeric α-distonic ion (or ionised ylid) have been examined by recording their metastable ion, collision-induced dissociation and neutralisation–reionisation mass spectra. These tautomers may be distinguished by careful consideration of key features of the collision-induced dissociation spectra, with or without prior neutralisation and reionisation. Formation of doubly-charged ions by charge stripping occurs preferentially when the α-distonic ion is subjected to collision. This α-distonic ion survives neutralisation and reionisation, thus establishing that the corresponding ylid is stable on the microsecond time frame. The effects of benzannulation on the ease of differentiation of classical and distonic radical cations derived from biologically important heterocycles are considered.
Delegating Pricing Decisions in Competitive Markets with Symmetric and Asymmetric Information
Authors: Mishra Birendra K. , Prasad Ashutosh
Published: October 2005

Delegating pricing decisions to the salesforce has been a salient issue for marketing academics and practitioners. We examine this issue in a competitive market using standard agency theory with symmetric and asymmetric information. Under symmetric information we find that the optimal contracts have a nice property that allows managers to reach the upper bound on firms’ profit by using either centralized or delegated pricing, and hence there are no incentive-based reasons to prefer centralized versus delegated contract types. Thus, managers can focus on the design of the optimal incentive scheme without worrying about the contract type. Under asymmetric information we find that there always exists an equilibrium where all firms use centralized pricing that is either unique or payoff equivalent to equilibria that have a combination of contract types. These results are robust to a large class of agent and market parameters. However, if restrictions are exogenously imposed on contract form or observability, the above results are no longer true, as in earlier work. We demonstrate our results by providing explicit solutions under the Holmstrom and Milgrom (1987) framework.
Conditioning Prices on Purchase History
Authors: Acquisti Alessandro , Varian Hal R.
Published: October 2005

The rapid advance in information technology now makes it feasible for sellers to condition their price offers on consumers’ prior purchase behavior. In this paper we examine when it is profitable to engage in this form of price discrimination when consumers can adopt strategies to protect their privacy.

Our baseline model involves rational consumers with constant valuations for the goods being sold and a monopoly merchant who can commit to a pricing policy. Applying results from the prior literature, we show that although it is feasible to price so as to distinguish high-value and low-value consumers, the merchant will never find it optimal to do so.

We then consider various generalizations of this model, such as allowing the seller to offer enhanced services to previous customers, making the merchant unable to commit to a pricing policy, and allowing competition in the marketplace. In these cases we show that sellers will, in general, find it profitable to condition prices on purchase history.
Optimizing the Marketing Interventions Mix in Intermediate-Term CRM
Authors: Rust Roland T. , Verhoef Peter C.
Published: October 2005

We provide a fully personalized model for optimizing multiple marketing interventions in intermediate-term customer relationship management (CRM). We derive theoretically based propositions on the moderating effects of past customer behavior and conduct a longitudinal validation test to compare the performance of our model with that of commonly used segmentation models in predicting intermediate-term, customer-specific gross profit change. Our findings show that response to marketing interventions is highly heterogeneous, that heterogeneity of response varies across different marketing interventions, and that the heterogeneity of response to marketing interventions may be partially explained by customer-specific variables related to customer characteristics and the customer’s past interactions with the company. One important result from these moderating effects is that relationship-oriented interventions are more effective with loyal customers, while action-oriented interventions are more effective with nonloyal customers. We show that our proposed model outperformed models based on demographics, recency-frequency-monetary value (RFM), or finite mixture segmentation in predicting the effectiveness of intermediate-term CRM. The empirical results project a significant increase in intermediate-term profitability over all of the competing segmentation approaches and a significant increase in intermediate-term profitability over current practice.
The Impact of Utility Balance and Endogeneity in Conjoint Analysis
Authors: Hauser John R. , Toubia Olivier
Published: October 2005

Adaptive metric utility balance is at the heart of one of the most widely used and studied methods for conjoint analysis. We use formal models, simulations, and empirical data to suggest that adaptive metric utility balance leads to partworth estimates that are relatively biased—smaller partworths are upwardly biased relative to larger partworths. Such relative biases could lead to erroneous managerial decisions. Metric utility-balanced questions are also more likely to be inefficient and, in one empirical example, contrary to popular wisdom, lead to response errors that are at least as large as nonadaptive orthogonal questions. We demonstrate that this bias is because of endogeneity caused by a “winner’s curse.” Shrinkage estimates do not mitigate these biases. Combined with adaptive metric utility balance, shrinkage estimates of heterogeneous partworths are biased downward relative to homogeneous partworths. Although biases can affect managerial decisions, our data suggest that, empirically, biases and inefficiencies are of the order of response errors. We examine viable alternatives to metric utility balance that researchers can use without biases or inefficiencies to retain the desired properties of (1) individual-level adaptation and (2) challenging questions.
Promotion Effect on Endogenous Consumption
Authors: Sun Baohong
Published: October 2005

Over the years, researchers have found that promotion makes consumers switch brands and purchase earlier or more. However, it is unclear how promotion affects consumption, especially for product categories that are perceived to be versatile and substitutable. In this paper, we propose a dynamic structural model with endogenous consumption under promotion uncertainty to analyze the promotion effect on consumption. This model recognizes consumers as rational decision makers who form promotion expectations and plan their purchase and consumption decisions in light of promotion schedule. Applying the proposed model to packaged tuna and yogurt, we find that endogenous consumption responds to promotion as a result of forward-looking and stockpiling behavior. This is the first empirical paper that recognizes consumption as an endogenous decision variable and proposes a structural model to offer behavioral explanations on whether, how, and why promotion encourages consumption for product categories with flexible consumption.
The 2004 ISMS Practice Prize Competition
Authors: Lilien Gary L.
Published: October 2005

The two reports and two articles (as well as a Commentary) that follow are the finalists from the 2004 ISMS Practice Prize Competition, representing the best examples of rigor plus relevance that our profession produces.