bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving the Search Performance of Extended Connectivity Fingerprints through Activity‐Oriented Feature Filtering and Application of a Bit‐Density‐Dependent Similarity Function
Authors: Hu Ye , Lounkine Eugen , Bajorath Jürgen
Published: March 2009

Improving fingerprint search performance: An activity‐oriented feature‐ filtering procedure and a corresponding similarity function were developed for molecule‐specific fingerprints, recording ensembles of structural patterns such as the popular extended connectivity fingerprints. Shown are comparisons of search calculations for cyclooxygenase inhibitors based on k nearest neighbor (1NN, 10NN) and Tanimoto coefficient (Tc) calculations, and the ACF BDM approach introduced herein.

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The Pipeline Pilot extended connectivity fingerprints (ECFPs) are currently among the most popular similarity search tools in drug discovery settings. ECFPs do not have a fixed bit string format but generate variable numbers of structural features for individual test molecules. This variable string design makes ECFP representations amenable to compound‐class‐directed modification. We have devised an intuitive feature‐filtering technique that focuses ECFP search calculations on feature string ensembles of given compound activity classes. In combination with a simple bit‐density‐dependent similarity function, feature filtering consistently improved the search performance of ECFP calculations based on Tanimoto similarity and state‐of‐the‐art data fusion techniques on a diverse array of activity classes. Feature filtering and the bit density similarity metric are easily implemented in the Pipeline Pilot environment. The approach provides a viable alternative to conventional similarity searching and should be of general interest to further improve the success rate of practical ECFP applications.
Discovery of Riociguat (BAY 63‐2521): A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension
Authors: Mittendorf Joachim , Weigand Stefan , Alonso‐Alija Cristina , Bischoff Erwin , Feurer Achim , Gerisch Michael , Kern Armin , Knorr Andreas , Lang Dieter , Muenter Klaus , Radtke Martin , Schirok Hartmut , Schlemmer Karl‐Heinz , Stahl Elke , Straub Alexander , Wunder Frank , Stasch Johannes‐Peter
Published: March 2009

Direct stimulation of soluble guanylate cyclase (sGC) represents a promising therapeutic strategy for the treatment of a range of diseases, including the severely disabling pulmonary hypertension (PH). Optimization of the unfavorable DMPK profile of previous sGC stimulators provided riociguat, which is currently being investigated in phase III clinical trials for the oral treatment of PH.

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Soluble guanylate cyclase (sGC) is a key signal‐transduction enzyme activated by nitric oxide (NO). Impairments of the NO–sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41‐2272 and BAY 41‐8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat is currently being investigated in phase III clinical trials for the oral treatment of PH.
Properties and mechanisms of spontaneous activity in the embryonic chick hindbrain
Authors: Hughes Sean M. , Easton Curtis R. , Bosma Martha M.
Published: March 2009

Spontaneous activity regulates many aspects of central nervous system development. We demonstrate that in the embryonic chick hindbrain, spontaneous activity is expressed between embryonic days (E) 6–9. Over this period the frequency of activity decreases significantly, although the events maintain a consistent rhythm on the timescale of minutes. At E6, the activity is pharmacologically dependent on serotonin, nACh, GABAA, and glycine input, but not on muscarinic, glutamatergic, or GABAB receptor activation. It also depends on gap junctions, t‐type calcium channels and TTX‐sensitive ion channels. In intact spinal cord‐hindbrain preparations, E6 spontaneous events originate in the spinal cord and propagate into lateral hindbrain tissue; midline activity follows the appearance of lateral activity. However, the spinal cord is not required for hindbrain activity. There are two invariant points of origin of activity along the midline, both within the caudal group of serotonin‐expressing cell bodies; one point is caudal to the nV exit point while the other is caudal to the nVII exit point. Additional caudal midline points of origin are seen in a minority of cases. Using immunohistochemistry, we show robust differentiation of the serotonergic raphe near the midline at E6, and extensive fiber tracts expressing GAD65/67 and the nAChR in lateral areas; this suggests that the medial activity is dependent on serotonergic neuron activation, while lateral activity requires other transmitters. Although there are differences between species, this activity is highly conserved between mouse and chick, suggesting that developmental event(s) within the hindbrain are dependent on expression of this spontaneous activity. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009
A tetracycline‐inducible and skeletal muscle‐specific Cre recombinase transgenic mouse
Authors: Rao Pengcheng , Monks D. Ashley
Published: March 2009

We have generated a transgenic mouse that expresses Cre recombinase only in skeletal muscle and only following tetracycline treatment. This spatiotemporal specificity is achieved using two transgenes. The first transgene uses the human skeletal actin (HSA) promoter to drive expression of the reverse tetracycline‐controlled transactivator (rtTA). The second transgene uses a tetracycline responsive promoter to drive the expression of Cre recombinase. We monitored transgene expression in these mice by crossing them with ROSA26 loxP‐LacZ reporter mice, which express β‐galactosidase when activated by Cre. We find that the expression of this transgene is only detectable within skeletal muscle and that Cre expression in the absence of tetracycline is negligible. Cre is readily induced in this model with tetracycline analogs at a range of embryonic and postnatal ages and in a pattern consistent with other HSA transgenic mice. This mouse improves upon existing transgenic mice in which skeletal muscle Cre is expressed throughout development by allowing Cre expression to begin at later developmental stages. This temporal control of transgene expression has several applications, including overcoming embryonic or perinatal lethality due to transgene expression. This mouse is especially suited for studies of steroid hormone action, as it uses tetracycline, rather than tamoxifen, to activate Cre expression. In summary, we find that this transgenic induction system is suitable for studies of gene function in the context of hormonal regulation of skeletal muscle or interactions between muscle and motoneurons in mice. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009
Female emotional eaters show abnormalities in consummatory and anticipatory food reward: A functional magnetic resonance imaging study
Authors: Bohon Cara , Stice Eric , Spoor Sonja
Published: March 2009

Objective:

To test the hypothesis that emotional eaters show greater neural activation in response to food intake and anticipated food intake than nonemotional eaters and whether these differences are amplified during a negative versus neutral mood state.

Method:

Female emotional eaters and nonemotional eaters (N = 21) underwent functional magnetic resonance imaging (fMRI) during receipt and anticipated receipt of chocolate milkshake and a tasteless control solution while in a negative and neutral mood.

Results:

Emotional eaters showed greater activation in the parahippocampal gyrus and anterior cingulate (ACC) in response to anticipated receipt of milkshake and greater activation in the pallidum, thalamus, and ACC in response to receipt of milkshake during a negative relative to a neutral mood. In contrast, nonemotional eaters showed decreased activation in reward regions during a negative versus a neutral mood.

Discussion:

Results suggest that emotional eating is related to increased anticipatory and consummatory food reward, but only during negative mood. © 2008 by Wiley Periodicals, Inc. Int J Eat Disord 2009
New Concise Route to 2‐Amino‐3‐hydroxycycloalkanecarboxylic Acids by Imidate‐Mediated Intramolecular Conjugate Addition
Authors: Matsushima Yoshitaka , Kino Jun
Published: March 2009

Trichloroacetimidates, generated either in situ or prepared and isolated from methyl 3‐hydroxycycloalk‐1‐enecarboxylates, undergo stereoselective intramolecular conjugate addition reactions to produce oxazolines. These oxazolines lead, in a novel, simple way, to 2‐amino‐3‐hydroxycycloalkanecarboxylic acids and their derivatives. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Personal project commitment in adolescence: The role of relatedness, competence and integrity
Authors: Harré Niki , Bullen Pat
Published: March 2009

University (n = 175) and high school (n = 162) students rated their commitment to three personal projects self‐identified as central to their lives, the extent to which each project generated experiences of relatedness, competence and integrity, and how much approval it received from significant others. This study compared the ‘life’ (hobbies, fitness, church, life transitions, intrapersonal, etc.) and education projects of participants who spontaneously generated an example of each (98 university and 70 high school participants). Integrity and competence received higher ratings than relatedness and were the most important predictors of commitment to both types of project. For both groups, education projects received more family/adult approval than life projects and there was much greater variation in approval ratings for the latter. The results suggest that, at least for young people in New Zealand, feeling that you are good at a project and it fits with your values, is almost a proxy for commitment. It is possible that social factors play a less direct role, perhaps by influencing the choice of interpersonal settings in which to carry out important projects. Copyright © 2009 John Wiley & Sons, Ltd.
Elevation adjustments of paired natural levees during flooding of the Saskatchewan River
Authors: Smith Norman D. , Pérez‐Arlucea Marta , Edmonds Douglas A. , Slingerland Rudy L.
Published: March 2009

Natural levees control the exchange of water between an alluvial channel and its floodplain, but little is known about the spatial distribution and evolution of levee heights. The summer 2005 flood of the Saskatchewan River (Cumberland Marshes, east‐central Saskatchewan) inundated large areas of floodplain for up to seven weeks, forming prominent new deposits on natural levees along main‐stem channels. Measurements of flood‐deposit thickness and crest heights of 61 levee pairs show that the thickest deposits occur on the lower pre‐flood levee in 80% of the sites, though no clear relationship exists between deposit thickness and magnitude of height difference. Only 16% of the pairs displayed thicker deposits on the higher levee, half of which occurred at sites where relatively clear floodbasin waters re‐entered turbid channels during general flooding. Difference in crest elevation (ΔE) between paired levees is approximately log‐normally distributed, both before and after the flood, though with different mean values. Supplemental observations from tank experiments indicate that during near‐bankfull flows, temporally and spatially variable deposition and erosion occur on levees due to backwater effects associated with nearby channel bars and irregular rises of the channel bed forced by channel extension. During floods, preferential deposition in lows tends to even out crest heights. Copyright © 2009 John Wiley & Sons, Ltd.
Agricultural soil erosion and global carbon cycle: controversy over?
Authors: Kuhn Nikolaus J. , Hoffmann Thomas , Schwanghart Wolfgang , Dotterweich Markus
Published: March 2009

Recent research on the contribution of soil erosion on agricultural land to atmospheric carbon dioxide (CO2) emphasizes either the contribution of soil organic matter (SOM) mineralization during transport as source for atmospheric CO2, or the deep burial of SOM‐rich sediment in agricultural landscapes as a sink. The contribution of either process is subject to a controversial debate. In this letter, we present preliminary results on our research on interrill carbon (C) erosion, SOM transport by rill erosion and the stationarity of C erosion during the Holocene. None of those issues has been incorporated comprehensively and with global coverage in the debate on the role of C erosion in the global C cycle. Therefore, we argue that only an eco‐geomorphologic perspective on organic C movement through landscapes can reconcile the two positions. Copyright © 2009 John Wiley & Sons, Ltd.
Sternohyoid muscle flap interposition in the treatment of an acquired tracheoesophageal fistula
Authors: Pisanu Adolfo , Reccia Isabella , Nieddu Riccardo , Uccheddu Alessandro
Published: March 2009

Background.

Tracheoesophageal fistula caused by prolonged intubation is a rare clinical entity. We report the case of a patient successfully treated by interposition of a sternohyoid muscle flap.

Methods.

Tracheoesophageal fistula secondary to prolonged ventilatory assistance developed in a 61‐year‐old woman who had a septic shock related to fecal peritonitis. Fistula was located at the decubitus point of the cuffed tracheostomy tube on the posterior tracheal wall. Esophageal and tracheal defects were separately sutured and protected by interposition of a left inferiorly based sternohyoid muscle flap.

Results.

There were neither local wound complications nor suture release and the procedure resulted in resolution of the fistula allowing a full oral diet. Sixty days after the operation, tracheal stoma was finally closed.

Conclusion.

The described approach has to be retained as an alternative to other surgical methods such as tracheal resection and major flap mobilization. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
Prognostic impact of tumor volume in patients with stage III–IVA hypopharyngeal cancer without bulky lymph nodes treated with definitive concurrent chemoradiotherapy
Authors: Chen Shang‐Wen , Yang Shih‐Neng , Liang Ji‐An , Lin Fang‐Jen , Tsai Ming‐Hsui
Published: March 2009

Background.

To investigate the prognostic value of volumetric analysis in patients with stage III–IVA hypopharyngeal cancer treated with concurrent chemoradiotherapy (CCRT).

Methods.

Seventy‐six stage III–IVA hypopharyngeal cancer patients without bulky lymph nodes were enrolled for a volumetric analysis. The pyriform sinus was the principal site of involvement in the 63 cases. All patients were allocated a course of CCRT. Tumor volume measurement was derived using separate calculations for the primary tumor volume (pGTV) and the nodal tumor volume (nGTV).

Results.

The pGTV ranged from 3.8 to 152.4 mL (mean, 33.4 mL). The 3‐year cause‐specific survival (CSS) was 75% for those with a pGTV <30 mL and 20% when the pGTV was ≥30 mL (p = .0001). Furthermore, the 3‐year primary tumor relapse‐free survival (PRFS) was 72% for those with a pGTV <30 mL and 23% when the pGTV were ≥30 mL (p = .0001). The 3‐year PRFSs for <30 mL and ≥30 mL were 74% and 25% for stage III disease (p = .01) and 65% and 22% for stage IVA tumors (p = .01), respectively. Multivariate analyses of the CSS revealed a single prognostic factor, namely pGTV <30 mL versus ≥30 mL (p = .0001, hazard ratio 2.84). Multivariate analyses of the PRFS gave a similar finding, with a pGTV ≥30 mL (p = .0001, hazard ratio 2.55) being significant.

Conclusion.

A patient's pGTV is a strong outcome predictor for hypopharyngeal cancer treatment using CCRT. Therefore, a selected group of patients, mainly those with tumor volumes <30 mL should be considered for laryngeal preservation. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
Morbidity and functional outcomes following gastro‐omental free flap reconstruction of circumferential pharyngeal defects
Authors: Patel Rajan S. , Makitie Antti A. , Goldstein David P. , Gullane Patrick J. , Brown Dale , Irish Jonathan , Gilbert Ralph W.
Published: March 2009

Background.

In patients with extensive soft tissue fibrosis requiring circumferential pharyngeal reconstruction following definitive radiotherapy and/or chemotherapy, we take advantage of abundant omental progenitor factors in the tubed gastro‐omental free flap. This study reviews our experience with this flap.

Methods.

Review of 11 patients (median follow‐up, 2.8 years) undergoing total pharyngolaryngectomy following organ preservation protocols for recurrent squamous cell carcinoma (n = 9) and stricture (n = 2).

Results.

Operative morbidity and mortality rates were 54% and 9%, respectively. One patient died following carotid rupture. Complications included: chyle leak (18%), pharyngocutaneous fistula (9%), and late stricture (27%). Ten patients (91%) achieved oral diet, and all 7 patients (100%) considered suitable for tracheoesophageal speech rehabilitation achieved functional speech. Seven patients remain alive without disease at a median of 41 months following surgery.

Conclusions.

The gastro‐omental flap provides a viable option in high‐risk patients undergoing circumferential pharyngeal reconstruction. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
miRNA expression profiles in head and neck squamous cell carcinoma and adjacent normal tissue
Authors: Ramdas Latha , Giri Uma , Ashorn Cheryl L. , Coombes Kevin R. , El‐Naggar Adel , Ang K. Kian , Story Michael D.
Published: March 2009

Background.

The expression of miRNA in head and neck squamous cell carcinomas (HNSCCs) that had been classified as high risk by surgical pathologic features and validated by trial outcome for disease recurrence was determined and compared with matched adjacent normal tissues.

Methods.

miRNA and corresponding gene expression were determined using miRNA bioarrays and gene expression arrays.

Results.

Twenty miRNAs were determined to be differentially regulated in the HNSCC samples when compared with their normal tissue counterparts. Quantitative reverse transcriptase‐polymerase chain reaction confirmed differential regulation of miRNA expression, and gene expression analysis on these same‐paired samples confirmed the loss of putative mRNA targets including genes such as adenomatous polyposis coli, programmed cell death protein 4, and TGF beta receptor 3 in the tumor samples.

Conclusions.

These data suggest a role for the upregulation of specific miRNAs in high‐risk HNSCC. Furthermore, upregulation of these miRNAs may be responsible for the elimination of mRNAs that lead to the growth and progression of HNSCC. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
Upper limb dysfunction following selective neck dissection: A retrospective questionnaire study
Authors: Carr Simon D. , Bowyer Duncan , Cox Graham
Published: March 2009

Background.

To determine total upper limb function following selective neck dissection over a mean follow‐up of 1.6 years.

Methods.

A retrospective questionnaire study in a tertiary head and neck surgical unit. One hundred forty‐eight patients who underwent selective neck dissection for head and neck cancer from January 2000 to December 2005 were invited to participate. The main outcome measure was ipsilateral upper limb dysfunction as measured by the Disability of Arm, Shoulder and Hand (DASH) questionnaire.

Results.

Sixty‐five patients responded to the invitation to join the study from 148 invited. Despite accessory nerve conserving surgery for all the selective neck dissections studied, 23% reported no upper limb dysfunction, 54% reported mild upper limb dysfunction, 15% reported moderate, and 8% reported a severe dysfunction.

Conclusions.

Long‐term upper limb dysfunction is common following nerve preserving surgery. The DASH questionnaire is a useful preoperative and postoperative clinical tool for those patients undergoing selective neck dissections. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
Analysis of thrombosis on postoperative day 5 or later after microvascular reconstruction for head and neck cancers
Authors: Kadota Hideki , Sakuraba Minoru , Kimata Yoshihiro , Yano Tomoyuki , Hayashi Ryuichi
Published: March 2009

Background.

Because of the low incidence of late thrombosis in free flaps used for head and neck reconstruction, the risk factors, prognosis, and the optimal method of treatment are unclear.

Methods.

The timing of thrombosis, types of flaps, occluded vessels, causative factors, previous irradiation, and salvage rates were reviewed and compared between 79 patients who had thrombosis on postoperative day 4 or earlier (early‐thrombosis group) and 24 patients who had thrombosis on postoperative day 5 or later (late‐thrombosis group).

Results.

The main causative factor for thrombosis in the late‐thrombosis group was wound infection (54%), whereas wound infection was present in only 1% of cases of thrombosis in the early‐thrombosis group. None of the flaps could be salvaged in the late‐thrombosis group.

Conclusion.

Poor salvage rate in the late‐thrombosis group is the most serious problem. Prevention, early detection, and appropriate management of wound infection are essential for avoiding late thrombosis. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
Development and validation of the functional assessment of cancer therapy nasopharyngeal cancer subscale
Authors: Tong Michael C. F. , Lo Phoebe S. Y. , Wong Kam Hung , Yeung Rebecca M. W. , van Hasselt C. Andrew , Eremenco Sonya , Cella David
Published: March 2009

Background.

We aimed to develop a quality‐of‐life subscale for nasopharyngeal carcinoma (NPC) and validate the functional assessment of cancer therapy‐nasopharyngeal (FACT‐NP).

Methods.

The FACT‐NP was tested cross‐sectionally in survivors of postirradiated NPC (n = 357) and was administered to newly diagnosed patients (n = 160) before, at the end of, and 3 months after radiotherapy (RT).

Results.

Each FACT‐NP domain was internally consistent (Cronbach's alpha = 0.87–0.90). The test–retest reliability for each subscale was satisfactory (intraclass correlation coefficient = .73–.88). Concurrent validity was suggested by the moderate to strong correlations between the FACT‐NP and the Quality of Life‐Radiation Therapy Instrument‐Head and Neck (QOL‐RTI‐H&N) subscales (Pearson r = .39–.84). The FACT‐NP was responsive to clinical changes from pretreatment to 3 months after RT (effect sizes > 0.6 for clinically relevant subscales). The pooled data for multitrait scaling analysis showed satisfactory item internal consistency and item discriminant validity (100% and 90% scaling success, respectively).

Conclusion.

The FACT‐NP is a reliable and valid instrument for measuring QOL in patients with NPC. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
Identification of the maximum acceptable frequencies of upper‐extremity motions in the sagittal plane
Authors: Kwon Ochae , You Heecheon , Jung Kihyo
Published: March 2009

The present study examined the maximum acceptable frequencies (MAFs; motions/min) of upper‐extremity motions in the sagittal plane at different forces. A dumbbell of 9.8 or 39.2 N was rotated by the arm about the shoulder, the forearm about the elbow, and the hand about the wrist; a dynamometer was pressed to 2.45 or 9.8 N by the index finger. Seventeen right‐handed Korean men in their 20s without any history of musculoskeletal disorders received 1 hour of individual training and conducted each upper‐extremity task for 30 minutes a day, assuming they were on an incentive basis. The participants determined their MAFs for 8 hours of work by the self‐adjustment method, and work pulse (change in heart rate; beats per minute [bpm]) and rating of perceived exertion (RPE) were measured. For a limited set of conditions, the reproducibility of the MAF experimental protocol was found satisfactory (r = 0.97; interclass correlation coefficient > 0.95). The average MAFs of arm, forearm, hand, and index finger motions were 24, 45, 56, and 128 at their low force level and 9, 20, 30, and 66 at their high force level. The average work pulses of arm, forearm, and hand motions were 3.0, 2.1, and 1.5 times that of index finger motion (4.2 bpm at their low force level and 5.7 bpm at their high force level). The maximum average RPEs at the upper‐extremity regions ranged from 2.1 (weak) to 3.1 (moderate) in Borg's CR‐10 scale. © 2009 Wiley Periodicals, Inc.
Screening and adenocarcinoma of the cervix
Authors: Sasieni Peter , Castanon Alejandra , Cuzick Jack
Published: March 2009

Screening has had a major impact on cervical cancer in many countries. Although there can be no doubt about its effectiveness in preventing squamous‐cell carcinoma, there is little evidence of any benefit on adenocarcinoma and adenosquamous carcinoma of the cervix, and many authors have concluded that it is ineffective. A population‐based case–control design was used in women aged 20–69 in the United Kingdom, with information on screening obtained from routine databases. Among 3,305 cases with known histology, 641 had adenocarcinoma and 133 adenosquamous carcinoma. The risk reduction associated with 3‐yearly screening was greater for squamous carcinoma (75%, 95%CI 71–79%) and adenosquamous carcinoma (83%, 95%CI 68–91%) than for adenocarcinoma (43%, 95%CI 24–58%). Among stage 1B+ cases, 83% (335/406) of women with adenocarcinoma had been screened within 10 years of diagnosis. This is very similar to controls (82%, 3,292/3,965), but much higher than in women with squamous carcinoma (57%, 852/1,493). Incidence of adenocarcinoma was low within 2.5 years of a negative smear (OR 2.3, 95%CI 0.15–0.34), but was no different from the background rates 4.5–5.5 years after a negative smear. We conclude that screening has reduced the incidence of adenocarcinoma of the cervix, but the prognostic value of cytology is less (in both magnitude and duration) for adenocarcinoma than for squamous carcinoma. The impact of screening on adenosquamous carcinoma is similar to its impact on squamous carcinoma. © 2009 UICC
Accumulation of lipid peroxidation‐derived DNA lesions in iron‐overloaded thalassemic mouse livers: Comparison with levels in the lymphocytes of thalassemia patients
Authors: Meerang Mayura , Nair Jagadeesan , Sirankapracha Pornpan , Thephinlap Chonthida , Srichairatanakool Somdet , Arab Khelifa , Kalpravidh Ruchaneekorn , Vadolas Jim , Fucharoen Suthat , Bartsch Helmut
Published: March 2009

In thalassemia patients, iron overload can stimulate lipid peroxidation (LPO), thereby generating miscoding DNA adducts. Adducted DNA was measured in the lymphocytes of β‐Thal/Hb E patients and healthy controls and in the organs of thalassemic mice. εdA, εdC and M1dG residues were quantified by 32P‐postlabeling‐TLC/HPLC. M1dG levels in lymphocyte DNA from patients were 4 times as high as in controls, while the increase in εdA and εdC was not significant. Adducted DNA accumulated in the liver of thalassemic mice having >2.7 mg Fe/g tissue dry weight; DNA adducts and iron were highly correlated. εdA was not specifically generated in certain mouse liver cell types as revealed by immunohistochemical staining. We found elevated LPO‐induced DNA damage in the liver of thalassemic mouse and in lymphocytes, implicating that massive DNA damage occurs in the liver of thalassemia patients. We conclude that promutagenic LPO‐derived DNA lesions are involved in the onset of hepatocellular carcinoma in these patients. © 2009 UICC
Allorestricted T lymphocytes with a high avidity T‐cell receptor towards NY‐ESO‐1 have potent anti‐tumor activity
Authors: Krönig Holger , Hofer Kathrin , Conrad Heinke , Guilaume Philippe , Müller Julia , Schiemann Matthias , Lennerz Volker , Cosma Antonio , Peschel Christian , Busch Dirk H. , Romero Pedro , Bernhard Helga
Published: March 2009

The cancer‐testis antigen NY‐ESO‐1 has been targeted as a tumor‐associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T‐cell‐based therapy is the induction of T cells capable of recognizing the NY‐ESO‐1‐expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY‐ESO‐1157–165 epitope known to be naturally presented with HLA‐A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY‐ESO‐1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA‐A2‐positive, NY‐ESO‐1‐expressing tumor cell lines derived from different origins, e.g. melanoma and myeloma. The allorestricted NY‐ESO‐1‐specific T lymphocytes displayed TCRs with the highest avidity and best anti‐tumor recognition activity. TCRs derived from allorestricted, NY‐ESO‐1‐specific T cells may be useful reagents for redirecting primary T cells by TCR gene transfer and, therefore, may facilitate the development of adoptive transfer regimens based on TCR‐transduced T cells for the treatment of NY‐ESO‐1‐expressing hematological malignancies and solid tumors. © 2009 UICC
Effect of chondroitin sulfate modification on rhBMP‐2 release kinetics from collagen delivery system
Authors: Wang Yan , Zhang Lihai , Hu Min , Wen Weisheng , Xiao Hongxi , Niu Yu
Published: March 2009

Protein delivery systems focus on protecting the protein that directly affects release kinetics. This study was carried out to determine the effect of surface polar group and fiber structure in a recombinant human bone morphogenetic protein‐2 (rhBMP‐2) protecting system based on a collagen matrix on its pharmacokinetics (PK) and osteoinductive activity In this study, two types of collagen carriers were made for rhBMP‐2 protecting system. The PKs of rhBMPs within collagen (Col) and collagen‐chondroitin sulfate (Col‐CS) carriers were determined using 125I‐labeled proteins in rat ectopic assay. The two carriers were characterized with surface energy and hydrophilicity. We observed that the osteoinductivity of these two scaffolds seemed to depend on two parameters: the nature of the carrier material and the release kinetics of the carriers. Results indicated that with CS modification, the initial burst release of rhBMP‐2 from Col‐CS scaffold was much higher than collagen scaffold. The subsequent PKs at longer times were not strongly dependent on the carriers. These differences were expected to affect the osteoinductive activity of the implants. It was concluded that surface energy played a significant role in the release PK of implanted rhBMP and higher initial burst is favorable to bone regeneration near the matrix. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2010
Amide–π interactions between formamide and benzene
Authors: Imai Yumi N. , Inoue Yoshihisa , Nakanishi Isao , Kitaura Kazuo
Published: March 2009

High‐level ab initio calculations have been carried out using a formamide–benzene model system to evaluate amide–π interactions. The interaction energies were estimated as a sum of the CCSD(T) correlation contribution and the HF energy at the complete basis set limit, for the geometries of the model structures at the energy minimum obtained by potential energy surface (PES) scans. NH/π geometry in a face‐on configuration was found to be the most attractive among the various geometries considered, with interaction energy of −3.75 kcal/mol. An interaction energy of −2.08 kcal/mol was calculated for the stacked N/Center type geometry, where the nitrogen atom of formamide points directly toward the center of the aromatic ring. The weakest CO/π geometry, where a carbonyl oxygen atom points toward the plane of the aromatic ring, was found to have energy minimum at an intermolecular distance of 3.67 Å from the PES, with a repulsive interaction energy less than 1 kcal/mol. However, if there are simultaneous attractive interactions with other parts of the molecule besides the amide group, the weak repulsion could be easily overcome, to give a CO/π geometry interaction. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009
Mammalian sperm quality and aromatase expression
Authors: Carreau Serge , Delalande Christelle , Galeraud‐Denis Isabelle
Published: March 2009

In most mammalian species the aromatase is encoded by a single gene (cyp19), which contains 18 exons, 9 of them being translated. In adult rats, together with Leydig cells germ cells represent an additional source of estrogens. The amount of P450arom transcript is threefold higher in pachytene spermatocytes compared to younger cells (spermatogonia‐preleptotene spermatocyte) or round spermatids; conversely, aromatase activity is more intense in haploid cells. In man besides Leydig cells, we have shown the presence of a biologically active aromatase and of estrogen receptors (ERα and ERß) in immature germ cells and ejaculated spermatozoa. Concerning aromatase, a 30% decrease of the amount of mRNA is observed in immotile compared to motile sperm fraction from the same sample; moreover, the aromatase activity is diminished. We have amplified aromatase mRNA by RT‐real time PCR in spermatozoa from asthenospermic, teratospermic, and asthenoteratospermic men and recorded respectively 44, 52, and 67% decreases of the amount of transcripts as compared to controls. Statistical analyses between the sperm morphology and the aromatase/GAPDH ratio have revealed a high degree of correlation (r = −0.64) with the percentage of abnormal spermatozoa (especially microcephaly and acrosome malformations). Alterations of sperm number and motility have been described in men genetically deficient in aromatase, which together with our data, suggest a likely role for aromatase/estrogens in the acquisition of sperm motility. Therefore besides gonadotrophins and testosterone, estrogens produced locally should be considered as a physiologically relevant hormone involved in the regulation of mammalian spermatogenesis. Microsc. Res. Tech., 2009. © 2009 Wiley‐Liss, Inc.
Cytokines and chemokines in testicular inflammation: A brief review
Authors: Guazzone Vanesa Anabella , Jacobo Patricia , Theas María Susana , Lustig Livia
Published: March 2009

A wide spectrum of data in the literature shows the relevance of cytokines as paracrine regulators of spermatogenesis and steroidogenesis in the normal testis. In this brief review, we highlight the relevance of cytokines in the testis during inflammation. This phenomenon involves complex and multiple interactions among immune and germ cells generally resulting in the alteration of spermatogenesis. The complexity of these cell interactions is multiplied because Sertoli and Leydig cells are also producers of pro‐ and anti‐inflammatory cytokines and chemokines. Also, cytokines are pleiotropic and they exert opposite and/or redundant effects in different conditions. However, in spite of this bidirectional immunoregulatory function of cytokines, the mass of the data, reported from experiments of acute testicular inflammation, shows upregulation of interleukin (IL)‐1β, IL‐1α, IL‐6, and tumor necrosis factor alpha (TNF‐α), which induce adverse effects on germ cells. In autoimmune orchitis, a chronic testicular inflammation, chemokines such as CCL2, CCL3, and CCL4 induce attraction and extravasation of immune cells within the testicular interstitium. These cells alter the normal immunosuppressor microenvironment principally through the secretion of proinflammatory cytokines, interferon‐γ initially, and IL‐6 and TNF‐α thereafter. Germ cells expressing TNFR1, IL‐6R, and Fas increase in number and undergo apoptosis, through the TNF‐α/TNFR1, IL‐6/IL‐6R, and Fas/Fas L systems. The knowledge of immune‐germ and somatic testicular cell interactions will contribute to the understanding of the mechanisms by which chronic inflammatory conditions of the testis can disrupt the process of spermatogenesis. Microsc. Res. Tech. 2009. © 2009 Wiley‐Liss, Inc.
Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of α‐glucosidase in Pompe disease
Authors: Douillard‐Guilloux Gaëlle , Richard Emmanuel , Batista Lionel , Caillaud Catherine
Published: March 2009

Background

Glycogen storage disease type II (GSDII) or Pompe disease is an inherited disease of glycogen metabolism caused by a lack of functional lysosomal acid α‐glucosidase (GAA). Affected individuals store glycogen in lysosomes resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe form. Even if enzyme replacement therapy (ERT) has already proven some efficacy, its results remain heterogeneous in skeletal muscle, especially in cross reactive immunological material (CRIM)‐negative patients. We investigated for the first time the use of hematopoietic stem cell (HSC) gene therapy in a murine model of GSDII.

Methods

Deficient HSC were transduced with a lentiviral vector expressing human GAA or enhanced green fluorescent protein (GFP) under the control of the retroviral MND promoter and transplanted into lethally irradiated GSDII mice. Animals were then subjected to an ERT protocol for 5 weeks and monitored for metabolic correction and GAA‐induced immune reaction.

Results

GAA was expressed as a correctly processed protein, allowing a complete enzymatic correction in transduced deficient cells without toxicity. Seventeen weeks after transplantation, a partial restoration of the GAA enzymatic activity was observed in bone marrow and peripheral blood cells of GSDII mice, allowing a significant glycogen clearance in skeletal muscle. ERT induced a robust antibody response in GFP‐transplanted mice, whereas no immune reaction could be detected in GAA‐transplanted mice.

Conclusions

Lentiviral vector‐mediated HSC gene therapy leads to a partial metabolic correction and induces a tolerance to ERT in GSDII mice. This strategy could enhance the efficacy of ERT in CRIM‐negative Pompe patients. Copyright © 2009 John Wiley & Sons, Ltd.
Sinonasal Wegener granulomatosis: A single‐institution experience with 120 cases
Authors: Cannady Steven B. , Batra Pete S. , Koening Curry , Lorenz Robert R. , Citardi Martin J. , Langford Carol , Hoffman Gary S.
Published: March 2009

Objectives/Hypothesis:

Wegener granulomatosis (WG) is intimately associated with the sinonasal tract, with involvement reported in 85% of patients during the course of the disease process. The objectives of the study were: 1) to describe sinonasal symptoms and signs at the time of initial otolaryngologic evaluation; and 2) to review indications and outcomes for rhinologic surgery in WG at our institution.

Methods:

A retrospective analysis of 120 patients presenting with WG and referred for otolaryngology consultation at a tertiary care center was performed.

Results:

Eighty‐nine percent of patients exhibited sinonasal involvement including nasal crusting (69%), chronic rhinosinusitis (CRS) (61%), nasal obstruction (58%), bloody nasal discharge (52%), septal perforation (33%), saddle‐nose deformity (23%), epiphora (13%), and mucocele formation (3.3%). Thirty‐nine (33%) patients underwent primary functional endoscopic sinus surgery or dacryocystorhinotomy (DCR) prior to referral. Nineteen (16%) patients underwent noncosmetic, functional sinonasal procedures at our institution. These included endoscopic sinus surgery for CRS or mucocele decompression in 14 patients, DCR for chronic epiphora in seven patients, and orbital decompression for pseudotumor in three patients. Individual symptom recurrence within the first year was greatest for visual impairment from pseudotumor (50%), followed by CRS (14%) and nasolacrimal duct obstruction (11%).

Conclusions:

The majority of patients with WG are referred to otolaryngology because of involvement of the sinonasal tract. Noncosmetic functional sinonasal procedures are indicated in a minority of patients. Sinonasal morbidity remains significant even after surgery. It is greatest for orbital pseudotumor, but also common for CRS and nasolacrimal duct obstruction. Laryngoscope, 2009
Phonation threshold flow measurements in normal and pathological phonation
Authors: Zhuang Peiyun , Sprecher Alicia J. , Hoffman Matthew R. , Zhang Yi , Fourakis Marios , Jiang Jack J. , Wei Chun Sheng
Published: March 2009

Objectives/Hypothesis:

Phonation threshold flow (PTF) may provide a tool to assess laryngeal function and could differentiate between normal and pathological voices. Both polyps and nodules contribute to an increased PTF by creating an incomplete glottal closure and increased vocal fold mass and thickness.

Study Design:

Prospective study.

Methods:

The Kay Elemetrics Phonatory Aerodynamic System (PAS) (Kay Elemetrics Corp., Lincoln Park, NJ) was used to collect mean flow rate (MFR) and PTF measurements from 40 normal subjects, 21 patients with vocal fold nodules, and 23 patients with vocal fold polyps. Gender‐based differences were assessed using a t test. The effect of vocal pathology on PTF and MFR was determined with an ANOVA. Diagnostic potential was evaluated using a receiver operation characteristics (ROC) analysis.

Results:

Both PTF (P = .047) and MFR (P = .008) were significantly affected by gender. Using a two‐way ANOVA and correcting for gender differences, the influence of pathology on PTF was determined to be significant (P < .001). Post hoc tests found a significant difference between normal and polyp subjects (P < .001) but not normal and nodule subjects (P = .177) or nodule and polyp subjects (P = .246). ROC analysis found that PTF (area under the curve [AUC] = 0.691) and MFR (AUC = 0.684) had a similar diagnostic utility.

Conclusions:

PTF can be used to differentiate between normal and pathological voices. As a parameter that is experimentally sensitive to the biomechanical parameters providing its theoretical basis, it could be used clinically to analyze laryngeal functionality. Future research could focus on measuring PTF in other pathologies, such as paralysis or scarring, which would also affect the effort required to produce voice. Laryngoscope, 2009
Arytenoid adduction with medialization laryngoplasty versus injection or medialization laryngoplasty: The role of the arytenoidopexy
Authors: Mortensen Melissa , Carroll Linda , Woo Peak
Published: March 2009

Objectives/Hypothesis:

There continues to be controversy about the added role of arytenoid adduction (AA) in the rehabilitation of unilateral vocal cord paralysis (UVCP). Some authors feel that the added morbidity of AA is not warranted in UVCP rehabilitation. Objective analysis of acoustic and aerodynamic measures were performed before and after surgery to try to resolve this controversy.

Methods:

This is an institutional review board–approved retrospective study of 85 patients with UVCP undergoing surgical rehabilitation by injection laryngoplasty (n = 45), medialization laryngoplasty (n = 14), or medialization laryngoplasty with arytenoid adduction (n = 26). Acoustic and aerodynamic parameters were studied before and after surgery. The medialization laryngoplasty (ML) group (medialization alone, injection laryngoplasty ML/IL) data were compared to the AA‐ML group using a paired t test for the individual measures and analysis of variance (ANOVA) for the multivariate analysis of acoustic and aerodynamic measures.

Results:

In all treatment arms there were statistically significant improvements in all acoustic and aerodynamic measures after intervention (P < .05). For ML and IL, the mean difference between preoperative from postoperative jitter was 1.504%, shimmer 3.265%, noise to harmonic ratio (NHR) 0.036, mean phonation time 4.523 seconds, transglottic flow 0.130 L/s, and subglottic pressure 0.616 cm H2O. For AA‐ML the mean difference between preoperative and postoperative jitter was 2.431%, shimmer 6.068%, NHR 0.082, mean phonation time 6.74 seconds, flow 0.181 L/s, and subglottic pressure 0.611 cm H2. Preoperatively, the average phonatory function of the AA‐ML group was worse than the ML group. Comparison between the two treatment arms, individual acoustic and aerodynamic measures, were not different (paired t test, P < .05). However, mulitvariate analysis (ANOVA, P < .05) of acoustic and aerodynamic measures, showed a statistically significant difference between the two groups. The degree of change was significantly better in the AA‐ML group.

Conclusions:

AA‐ML and IL/ML improve phonatory function, but not to normal. We were unable to demonstrate a statistical difference between groups using a single measure, but using mutlivariate analysis, there is a statistical significance between the groups. AA‐ML patients had worse preoperative function and had better postoperative function. When clinically indicated, AA‐ML procedure does appear to correct the physiology of the incompetent larynx better than ML alone. Laryngoscope, 2009
An EPR Study of the V(IV) Species Formed Upon Activation of a Vanadyl Phenoxyimine Polymerization Catalyst with AlR3 and AlR2Cl (R = Me, Et)
Authors: Soshnikov Igor E. , Semikolenova Nina V. , Bryliakov Konstantin P. , Shubin Alexander A. , Zakharov Vladimir A. , Redshaw Carl , Talsi Evgenii P.
Published: March 2009

Vanadium(IV) complexes formed in the systems L2VIVO/AlR3, L2VIVO/AlR3/ETA, L2VIVO/AlR2Cl, and L2VIVO/AlR2Cl/ETA, where L is a phenoxyimine ligand (Scheme 1), R = Me or Et, and ETA is ethyltrichloroacetate, were monitored by EPR. It was shown, that at 20 °C, V(IV) complexes with proposed structures (L′)VIV(O)(R)(AlR3) are formed in the systems L2VIVO/AlR3 and L2VIVO/AlR3/ETA, whereas complexes with proposed structures (L′)VIV(O)(R)(AlR2Cl) are formed in the systems L2VIVO/AlR2Cl and L2VIVO/AlR2Cl/ETA (L′ is the modified initial ligand). The systems L2VIVO/AlR3/ETA are inert towards polymerization of ethylene, whereas the systems L2VIVO/AlR2Cl/ETA are moderately active in this reaction. The polymerization activity of the systems L2VIVO/AlR2Cl/ETA correlates with the concentration of V(IV) species present in the reaction solution. V(IV) complexes of the type (L′)VIV(O)(R)(AlR2Cl) can be precursors of the active species of polymerization.

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Enforced expression of PPP1R13L increases tumorigenesis and invasion through p53‐dependent and p53‐independent mechanisms
Authors: Laska Magdalena J. , Lowe Scott W. , Zender Lars , Hearn Stephen , Vogel Ulla , Jensen Uffe B. , Bric Anka , Nexø Bjørn A.
Published: March 2009

PPP1R13L was initially identified as a protein that binds to the NF‐κB subunit p65/RelA and inhibits its transcriptional activity. It also binds p53 and inhibits its action. One set of experimental findings based on overexpression of PPP1R13L indicates that PPP1R13L blocks apoptosis. Another set of experiments, based on endogenous production of PPP1R13L, suggests that the protein may sometimes be pro‐apoptotic. We have used primary mouse embryonic fibroblasts (MEFs), dually transformed by HRAS and adenovirus E1A and differing in their p53 status, to explore the effects of PPP1R13L overexpression, thus examining the ability of PPP1R13L to act as an oncoprotein. We found that overexpression of PPP1R13L strongly accelerated tumor formation by RAS/E1A. PPP1R13L overexpressing cells were depleted for both p53 and active p65/RelA and we found that both p53‐dependent and ‐independent apoptosis pathways were modulated by PPP1R13L. Finally, studies with the proteasome inhibitor MG132 revealed that overexpression of PPP1R13L causes faster p53 degradation, a likely explanation for the depletion of p53. Taken together, our results show that increased levels of PPP1R13L can increase tumorigenesis and furthermore suggest that PPP1R13L can influence metastasis. © 2009 Wiley‐Liss, Inc.