bluuebunny/crossref_metadata_2025_split huggingface dataset:
PHOTOADDITION OF ALCOHOLS TO PURINE*
Authors: CONNOLLY JOHN S. , LINSCHITZ HENRY 
Published: January 2008

Abstract— A new photoreaction is described, in which alcohols add to purine. The adducts of methanol, ethanol (two isomers), and isopropanol have been isolated and characterized by chemical analysis, and their u.v., i.r., NMR and mass spectra. Mainly on the basis of the NMR data and using deuterated‐purine adducts, it is shown that the addition involves bonding between the α‐carbon of the alcohol and the 6‐carbon of the purine ring. The quantum yield of the reaction, at 254 ran, is about 0·2 in dry, deoxygenated methanol, ethanol or isopropanol. The reaction appears to be rather general, as shown by experiments on pyrimidine and several other simple nitrogen heteroaromatic molecules.RESUMENSe describe una fotorreacción de adición de alcoholes a purinas. Los productos obtenidos por la adición de metanol, dos isómeros del etanol e isopropanol se han aislado y caracterizado mediante analisis químico, además de sus espectros de masa, UV, 1R y NMR. Fundamentalmente sobre la base de datos de NMR y usando purinas deuteradas, se ha demostrado que la adición involucra unión entre el carbono α del alcohol y el carbono‐6 del anillo de la base. El rendimiento cuántico de la reacción, a 254 nm es aproximadamente 0·2 en metanol, etanol o isopropanol deoxigenados y secos. La reacción parece ser algo general, como lo demuestran los experimentos realizados en pirimidina y algunas otras moléculas heteroaromáticas.
Thromboxane A2 Receptors in Prostate Carcinoma: Expression and Its Role in Regulating Cell Motility via Small GTPase Rho
Authors: Nie Daotai , Guo Yande , Yang Dianer , Tang Yong , Chen Yakun , Wang Man-Tzu , Zacharek Alex , Qiao Yan , Che Mingxin , Honn Kenneth V. 
Published: January 2008

Abstract
Thromboxane A2 (TxA2) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product prostaglandin H2 as the substrate. Previously, increased expression of thromboxane synthase was found in prostate tumors, and tumor cell motility was attenuated by inhibitors of thromboxane synthase. This study was undertaken to elucidate how tumor motility is regulated by TxA2. Here, we report that human prostate cancer cells express functional receptors for TxA2 (TP). Ligand binding assay found that PC-3 cells binded to SQ29548, a high-affinity TP antagonist, in a saturable manner with Kd of 3.64 nmol/L and Bmax of 120.4 fmol per million cells. Treatment of PC-3 cells by U46619, a TP agonist, induced PC-3 cell contraction, which was blocked by pretreatment with the TP antagonist SQ29548 or pinane TxA2. The migration of prostate cancer cells was significantly inhibited either by sustained activation of TP or by blockade of TP activation, suggesting that TP activation must be tightly controlled during cell migration. Further studies found that small GTPase RhoA was activated by TP activation, and pretreatment of PC-3 cells with Y27632, a Rho kinase (ROCK) inhibitor, blocked U46619-induced cell contraction. A dominant-negative mutant of RhoA also blocked U46619-induced cell contraction. Taken together, the data suggest that TPs are expressed in prostate cancer and activation of TPs regulates prostate cancer cell motility and cytoskeleton reorganization through activation of Rho. [Cancer Res 2008;68(1):115–21]
Crucial Role of Phospholipase Cε in Skin Inflammation Induced by Tumor-Promoting Phorbol Ester
Authors: Ikuta Shuzo , Edamatsu Hironori , Li Mingzhen , Hu Lizhi , Kataoka Tohru 
Published: January 2008

Abstract
In two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase Cε (PLCε−/− mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLCε−/− mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLCε in tumor promotion. Here, we show that PLCε−/− mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-1α (IL-1α). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLCε background, suggesting that the PLCε's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLCε lipase activity, which leads to the induction of IL-1α expression. Experiments using small interfering RNA–mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLCε is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLCε. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLCε activation, leading to tumor promotion. [Cancer Res 2008;68(1):64–72]
Allelic Imbalance at rs6983267 Suggests Selection of the Risk Allele in Somatic Colorectal Tumor Evolution
Authors: Tuupanen Sari , Niittymäki Iina , Nousiainen Kari , Vanharanta Sakari , Mecklin Jukka-Pekka , Nuorva Kyösti , Järvinen Heikki , Hautaniemi Sampsa , Karhu Auli , Aaltonen Lauri A. 
Published: January 2008

Abstract
A common single nucleotide polymorphism (SNP), rs6983267, at 8q24.21 has recently been shown to associate with colorectal cancer (CRC). Three independent SNP association studies showed that rs6983267 contributes to CRC with odds ratios (OR) of 1.17 to 1.22. Here, we genotyped a population-based series of 1,042 patients with CRC and 1,012 healthy controls for rs6983267 and determined the contribution of SNP to CRC in Finland, using germ line DNA, as well as the respective cancer DNA in heterozygous patients. The comprehensive clinical data available from the 1,042 patients and their first-degree relatives enabled us to thoroughly examine the possible association of this variant with different clinical features. As expected, a significant association between the G allele of rs6983267 and CRC [OR, 1.22; 95% confidence interval (CI), 1.08–1.38; P = 0.0018] was found, confirming the previous observations. A trend towards association of the G allele with microsatellite-stable cancer (OR, 1.37; 95% CI, 1.02–1.85; P = 0.04) and family history of cancers other than CRC was seen (OR, 1.20; 95% CI, 1–1.43; P = 0.05). Four hundred and sixty-six GT heterozygotes identified in this study were analyzed for allelic imbalance at rs6983267 in the respective cancer DNA. One hundred and one tumors showed allelic imbalance (22%). The risk allele G was favored in 67 versus 34 tumors (P = 0.0007). This finding implicates that the underlying germ line genetic defect in 8q24.21 is a target in the somatic evolution of CRC. [Cancer Res 2008;68(1):14–7]
Both Germ Line and Somatic Genetics of the p53 Pathway Affect Ovarian Cancer Incidence and Survival
Authors: Bartel Frank , Jung Juliane , Böhnke Anja , Gradhand Elise , Zeng Katharina , Thomssen Christoph , Hauptmann Steffen 
Published: January 2008

Abstract
Purpose: Although p53 is one of the most studied genes/proteins in ovarian carcinomas, the predictive value of p53 alterations is still ambiguous.
Experimental Design: We performed analyses of the TP53 mutational status and its protein expression using immunohistochemistry. Moreover, the single nucleotide polymorphism SNP309 in the P2 promoter of the MDM2 gene was investigated. We correlated the results with age of onset and outcome from 107 patients with ovarian carcinoma.
Results: In our study, we identified a large group of patients with p53 overexpression despite having a wild-type gene (49% of all patients with wild-type TP53). This was associated with a significantly shortened overall survival time (P = 0.019). Patients with p53 alterations (especially those with overexpression of wild-type TP53) were also more refractory to chemotherapy compared with patients with normal p53 (P = 0.027). The G-allele of SNP309 is associated with an earlier age of onset in patients with estrogen receptor–overexpressing FIGO stage III disease (P = 0.048). In contrast, in patients with FIGO stage III disease, a weakened p53 pathway (either the G-allele of SNP309 or a TP53 mutation) was correlated with increased overall survival compared with patients whose tumors were wild-type for both TP53 and SNP309 (P = 0.0035).
Conclusion: Our study provides evidence that both germ line and somatic alterations of the p53 pathway influence the incidence and survival of ovarian carcinoma, and it underscores the importance of assessing the functionality of p53 in order to predict the sensitivity of platinum-based chemotherapies and patient outcome.
The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor AZD6244 (ARRY-142886) Induces Growth Arrest in Melanoma Cells and Tumor Regression When Combined with Docetaxel
Authors: Haass Nikolas K. , Sproesser Katrin , Nguyen Thiennga K. , Contractor Rooha , Medina C. Angelica , Nathanson Katherine L. , Herlyn Meenhard , Smalley Keiran S.M. 
Published: January 2008

Abstract
Purpose: Disseminated melanoma is highly therapy resistant. The finding that 66% of melanomas harbor the activating BRAFV600E mutation has raised expectations for targeting the Ras/RAF/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway in melanoma. This study addresses the anti-melanoma activity of the MEK inhibitor AZD6244 (ARRY-142886).
Experimental Design: We recently have shown that growing melanoma cells as three-dimensional collagen-implanted spheroids enhances resistance to the MEK inhibitor U0126. Here, we investigated the anti-melanoma activity of AZD6244 in two-dimensional cell culture, the three-dimensional spheroid model, and an in vivo model.
Results: In two-dimensional cell culture, AZD6244 was cytostatic and reduced the growth of melanoma cells in a concentration-dependent fashion through the induction of G1-phase cell cycle arrest. In our three-dimensional spheroid model, the effects of AZD6244 were largely cytostatic and reversible, with drug washout leading to spheroid regrowth. Finally, 1205Lu cells were grown as tumor xenografts in severe combined immunodeficient mice. After tumor establishment, mice were dosed twice daily with 0, 10, or 30 mg/kg AZD6244 p.o. AZD6244 treatment decreased phospho-ERK in the tumors and significantly suppressed tumor growth. The original tumors remained viable, suggesting that AZD6244 monotherapy was largely cytostatic, and not proapoptotic in this model. Further studies showed that co-administration of AZD6244 (30 mg/kg) with docetaxel (15 mg/kg) led to tumor regression, indicating the potential for MEK inhibitor/chemotherapy drug combinations.
Conclusions: Inhibition of MEK is cytostatic as a monotherapy in melanoma, but cytotoxic when combined with docetaxel.
Identification of Patients with (Atypical) MUTYH-Associated Polyposis by KRAS2 c.34G &gt; T Prescreening Followed by MUTYH Hotspot Analysis in Formalin-Fixed Paraffin-Embedded Tissue
Authors: van Puijenbroek Marjo , Nielsen Maartje , Tops Carli M.J. , Halfwerk Hans , Vasen Hans F.A. , Weiss Marjan M. , van Wezel Tom , Hes Frederik J. , Morreau Hans 
Published: January 2008

Abstract
Purpose: To assess the feasibility of identifying patients with (atypical) MUTYH-associated polyposis (MAP) by KRAS2 c.34G &gt; T prescreening followed by MUTYH hotspot mutation analysis in formalin-fixed paraffin-embedded tissue (FFPE).
Methods: We collected 210 colorectal FFPE tumors from 192 individuals who presented with &lt;10 adenomas or familial mismatch repair proficient colorectal carcinomas with &lt;10 concomitant adenomas. The tissues were tested for somatic KRAS2 mutations and for three Dutch hotspot MUTYH germ line mutations (p.Tyr165Cys, p.Gly382Asp, and p.Pro391Leu) by sequencing analysis.
Results: The c.34G &gt; T, KRAS2 transversion was detected in 10 of 210 tumors. In one of these 10 cases, a monoallelic p.Gly382Asp MUTYH mutation was found and a full MUTYH analysis in leukocyte DNA revealed an unclassified variant p.Met269Val. This was in a 61-year-old patient with a cecum carcinoma and three adenomas. After further requests, her family case history revealed that her brother had had between 10 and 15 adenomas and turned out to carry both MUTYH germ line mutations. MUTYH hotspot mutation screening in 182 patients without the somatic c.34G &gt; T KRAS2 mutation led to the detection of three monoallelic germ line MUTYH mutation carriers.
Conclusion: KRAS2 c.34G &gt; T somatic prescreening, followed by MUTYH hotspot mutation analysis when positive, can identify patients with (atypical) MAP. If heterozygous hotspot MUTYH mutations are identified, a complete germ line MUTYH mutation screening should be carried out if possible. Immediate MUTYH hotspot mutation analysis is a practical alternative in patients with &gt;10 adenomas or in cases of multiple colorectal carcinomas in one generation for which only FFPE tissue is available.
Induction of Tumor-Specific CD4+ and CD8+ T-Cell Immunity in Cervical Cancer Patients by a Human Papillomavirus Type 16 E6 and E7 Long Peptides Vaccine
Authors: Welters Marij J.P. , Kenter Gemma G. , Piersma Sytse J. , Vloon Annelies P.G. , Löwik Margriet J.G. , Berends-van der Meer Dorien M.A. , Drijfhout Jan W. , Valentijn A. Rob P.M. , Wafelman Amon R. , Oostendorp Jaap , Fleuren Gert Jan , Offringa Rienk , Melief Cornelis J.M. , van der Burg Sjoerd H. 
Published: January 2008

AbstractPurpose: The study aims to evaluate the effect of a human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides vaccine on the antigen-specific T-cell response in cervical cancer patients.Experimental Design: Patients with resected HPV16-positive cervical cancer were vaccinated with an overlapping set of long peptides comprising the sequences of the HPV16 E6 and E7 oncoproteins emulsified in Montanide ISA-51. HPV16-specific T-cell immune responses were analyzed by evaluating the magnitude, breadth, type, and polarization by proliferation assays, IFNγ-ELISPOT, and cytokine production and phenotyped by the T-cell markers CD4, CD8, CD25, and Foxp3.Results: Vaccine-induced T-cell responses against HPV16 E6 and E7 were detected in six of six and five of six patients, respectively. These responses were broad, involved both CD4+ and CD8+ T cells, and could be detected up to 12 months after the last vaccination. The vaccine-induced responses were dominated by effector type CD4+CD25+Foxp3− type 1 cytokine IFNγ-producing T cells but also included the expansion of T cells with a CD4+CD25+Foxp3+ phenotype.Conclusions: The HPV16 E6 and E7 synthetic long peptides vaccine is highly immunogenic, in that it increases the number and activity of HPV16-specific CD4+ and CD8+ T cells to a broad array of epitopes in all patients. The expansion of CD4+ and CD8+ tumor-specific T cells, both considered to be important in the antitumor response, indicates the immunotherapeutic potential of this vaccine. Notably, part of the vaccine-induced T cells display a CD4+CD25+Foxp3+ phenotype that is frequently associated with regulatory T-cell function, suggesting that strategies to disarm this subset of T cells should be considered as components of immunotherapeutic modalities against HPV-induced cancers.
Prognostic Significance of Cyclooxygenase-2 Overexpression in Glottic Cancer
Authors: Sackett Melanie K. , Bairati Isabelle , Meyer François , Jobin Édith , Lussier Sébastien , Fortin André , Gélinas Michel , Nabid Abdenour , Brochet François , Têtu Bernard 
Published: January 2008

AbstractPurpose: Cyclooxygenase-2 (COX-2) overexpression has been associated with a poor prognosis in many cancers. However, the role of COX-2 overexpression in head and neck cancers remains undetermined. The objective of this study was to evaluate whether COX-2 is a prognostic factor in glottic cancer.Experimental Design: This study was part of a phase III placebo-controlled randomized trial evaluating the efficacy of α-tocopherol in reducing second primary cancers (SPC) in head and neck cancer patients. Immunohistochemical analyses were conducted on pretreatment biopsies of 301 patients with early-stage glottic cancer treated by radiotherapy. The median value of 50% of positive tumor cells was the cutoff point used to define COX-2 overexpression. Outcomes considered in the statistical analysis were recurrence, SPC, and death. The Cox proportional hazards model was used to estimate the hazard ratios (HR) and their 95% confidence intervals (95% CI).Results: The HR associated with COX-2 overexpression was 0.94 (95% CI, 0.55-1.62) for recurrence. The HR associated with SPC was 2.63 (95% CI, 1.32-5.23) for the first 3.5 years of follow-up and 0.55 (95% CI, 0.22-1.32) for the following 3.5 years. The HR associated with COX-2 overexpression was 1.57 (95% CI, 1.01-2.45) for overall mortality.Conclusions: COX-2 overexpression in glottic cancer was associated with increased overall mortality and an increased risk of SPC during the early follow-up period. Future studies are needed to explain observed effects on SPC. COX-2 expression may prove helpful in defining an individual patient's prognosis.
Decadal Trends in Sea Level Patterns: 1993–2004
Authors: Wunsch Carl , Ponte Rui M. , Heimbach Patrick 
Published: January 2008

AbstractEstimates of regional patterns of global sea level change are obtained from a 1° horizontal resolution general circulation model constrained by least squares to about 100 million ocean observations and many more meteorological estimates during the period 1993–2004. The data include not only altimetric variability, but most of the modern hydrography, Argo float profiles, sea surface temperature, and other observations. Spatial-mean trends in altimetric data are explicitly suppressed to isolate global average long-term changes required by the in situ data alone. On large scales, some regions display strong signals although few individual points have statistically significant trends. In the regional patterns, thermal, salinity, and mass redistribution contributions are all important, showing that regional sea level change is tied directly to the general circulation. Contributions below about 900 m are significant, but not dominant, and are expected to grow with time as the abyssal ocean shifts. Estimates made here produce a global mean of about 1.6 mm yr−1, or about 60% of the pure altimetric estimate, of which about 70% is from the addition of freshwater. Interannual global variations may be dominated by the freshwater changes rather than by heating changes. The widely quoted altimetric global average values may well be correct, but the accuracies being inferred in the literature are not testable by existing in situ observations. Useful estimation of the global averages is extremely difficult given the realities of space–time sampling and model approximations. Systematic errors are likely to dominate most estimates of global average change: published values and error bars should be used very cautiously.
Bioinformatic analysis of the CLE signaling peptide family
Authors: Oelkers Karsten , Goffard Nicolas , Weiller Georg F , Gresshoff Peter M , Mathesius Ulrike , Frickey Tancred 
Published: January 2008

Abstract

Background
Plants encode a large number of leucine-rich repeat receptor-like kinases. Legumes encode several LRR-RLK linked to the process of root nodule formation, the ligands of which are unknown. To identify ligands for these receptors, we used a combination of profile hidden Markov models and position-specific iterative BLAST, allowing us to detect new members of the CLV3/ESR (CLE) protein family from publicly available sequence databases.

Results
We identified 114 new members of the CLE protein family from various plant species, as well as five protein sequences containing multiple CLE domains. We were able to cluster the CLE domain proteins into 13 distinct groups based on their pairwise similarities in the primary CLE motif. In addition, we identified secondary motifs that coincide with our sequence clusters. The groupings based on the CLE motifs correlate with known biological functions of CLE signaling peptides and are analogous to groupings based on phylogenetic analysis and ectopic overexpression studies. We tested the biological function of two of the predicted CLE signaling peptides in the legume Medicago truncatula. These peptides inhibit the activity of the root apical and lateral root meristems in a manner consistent with our functional predictions based on other CLE signaling peptides clustering in the same groups.

Conclusion
Our analysis provides an identification and classification of a large number of novel potential CLE signaling peptides. The additional motifs we found could lead to future discovery of recognition sites for processing peptidases as well as predictions for receptor binding specificity.
Sepsis: rethinking the approach to clinical research
Authors: Marshall John C 
Published: January 2008

AbstractThe clinical syndrome of sepsis encompasses a highly heterogeneous group of clinical disorders, varying with respect to the site, bacteriology, and even presence of infection and with the clinical syndrome evolving in the host. Clinical trials of strategies to modulate the host response that mediates sepsis were first initiated 25 years ago. A continuing record of disappointment has characterized subsequent work, and only a single new therapy has been licensed for clinical use. Yet, these commercial disappointments obscure a vibrant body of new knowledge that has clarified the biology of the innate immune response whose deranged expression is responsible for sepsis and that has provided important new insights into the failings of the traditional model of clinical research in sepsis. This review highlights advances in basic biology and underlines insights from clinical research that may point to new and more effective ways of translating an understanding of innate immunity into effective treatments for a leading cause of global morbidity and mortality.
Development and reliability of a structured interview guide for
the Montgomery-Åsberg Depression Rating Scale (SIGMA)
Authors: Williams Janet B. W. , Kobak Kenneth A. 
Published: January 2008

BackgroundThe Montgomery-Åsberg Depression Rating Scale (MADRS) is often used in
clinical trials to select patients and to assess treatment efficacy. The
scale was originally published without suggested questions for clinicians
to use in gathering the information necessary to rate the items.
Structured and semi-structured interview guides have been found to
improve reliability with other scales.AimsTo describe the development and test-retest reliability of a structured
interview guide for the MADRS (SIGMA).MethodA total of 162 test-retest interviews were conducted by 81 rater pairs.
Each patient was interviewed twice, once by each rater conducting an
independent interview.ResultsThe intraclass correlation for total score between raters using the SIGMA
was r = 0.93, P < 0.0001. All ten
items had good to excellent interrater reliability.ConclusionsUse of the SIGMA can result in high reliability of MADRS scores in
evaluating patients with depression.