bluuebunny/crossref_metadata_2025_split huggingface dataset:
TransCent: Computational enzyme design by transferring active sites and considering constraints relevant for catalysis
Authors: Fischer André , Enkler Nils , Neudert Gerd , Bocola Marco , Sterner Reinhard , Merkl Rainer 
Published: February 2009

Abstract

Background
Computational enzyme design is far from being applicable for the general case. Due to computational complexity and limited knowledge of the structure-function interplay, heuristic methods have to be used.

Results
We have developed TransCent, a computational enzyme design method supporting the transfer of active sites from one enzyme to an alternative scaffold. In an optimization process, it balances requirements originating from four constraints. These are 1) protein stability, 2) ligand binding, 3) pKa values of active site residues, and 4) structural features of the active site. Each constraint is handled by an individual software module. Modules processing the first three constraints are based on state-of-the-art concepts, i.e. RosettaDesign, DrugScore, and PROPKA. To account for the fourth constraint, knowledge-based potentials are utilized. The contribution of modules to the performance of TransCent was evaluated by means of a recapitulation test. The redesign of oxidoreductase cytochrome P450 was analyzed in detail. As a first application, we present and discuss models for the transfer of active sites in enzymes sharing the frequently encountered triosephosphate isomerase fold.

Conclusion
A recapitulation test on native enzymes showed that TransCent proposes active sites that resemble the native enzyme more than those generated by RosettaDesign alone. Additional tests demonstrated that each module contributes to the overall performance in a statistically significant manner.
NITPICK: peak identification for mass spectrometry data
Authors: Renard Bernhard Y , Kirchner Marc , Steen Hanno , Steen Judith AJ , Hamprecht Fred A 
Published: February 2009

AbstractBackgroundThe reliable extraction of features from mass spectra is a fundamental step in the automated analysis of proteomic mass spectrometry (MS) experiments.ResultsThis contribution proposes a sparse template regression approach to peak picking called NITPICK. NITPICK is a Non-greedy, Iterative Template-based peak PICKer that deconvolves complex overlapping isotope distributions in multicomponent mass spectra. NITPICK is based onfractional averagine, a novel extension to Senko's well-known averagine model, and on a modified version of sparse, non-negative least angle regression, for which a suitable, statistically motivated early stopping criterion has been derived. The strength of NITPICK is the deconvolution of overlapping mixture mass spectra.ConclusionExtensive comparative evaluation has been carried out and results are provided for simulated and real-world data sets. NITPICK outperforms pepex, to date the only alternate, publicly available, non-greedy feature extraction routine. NITPICK is available as software package for the R programming language and can be downloaded fromhttp://hci.iwr.uni-heidelberg.de/mip/proteomics/.
Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci
Authors: Chen I-Cheng , Lin Hsuan-Yuan , Lee Ghin-Chueh , Kao Shih-Huan , Chen Chiung-Mei , Wu Yih-Ru , Hsieh-Li Hsiu-Mei , Su Ming-Tsan , Lee-Chen Guey-Jen 
Published: February 2009

Abstract

Background
Spinocerebellar ataxia type 8 (SCA8) involves the expression of an expanded CTG/CAG combined repeats (CR) from opposite strands producing CUG expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and a polyglutamine expansion protein (ataxin 8, ATXN8). The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad.

Results
Using stably induced cell models expressing 0, 23, 88 and 157 CR, we study the role of ATXN8OS transcripts in SCA8 pathogenesis. In the absence of doxycycline, the stable ATXN8OS CR cell lines exhibit low levels of ATXN8OS expression and a repeat length-related increase in staurosporine sensitivity and in the number of annexin positive cells. A repeat length-dependent repression of ATXN8OS expression was also notable. Addition of doxycycline leads to 25~50 times more ATXN8OS RNA expression with a repeat length-dependent increase in fold of ATXN8OS RNA induction. ChIP-PCR assay using anti-dimethyl-histone H3-K9 and anti-acetyl-histone H3-K14 antibodies revealed increased H3-K9 dimethylation and reduced H3-K14 acetylation around the ATXN8OS cDNA gene in 157 CR line. The repeat length-dependent increase in induction fold is probably due to the increased RNA stability as demonstrated by monitoring ATXN8OS RNA decay in cells treated with the transcriptional inhibitor, actinomycin D. In cells stably expressing ATXN8OS, RNA FISH experiments further revealed ribonuclear foci formation in cells carrying expanded 88 and 157 CR.

Conclusion
The present study demonstrates that the expanded CUG-repeat tracts are toxic to human cells and may affect ATXN8OS RNA expression and stability through epigenetic and post-transcriptional mechanisms.
Quality improvement in small office settings: an examination of successful practices
Authors: Wolfson Daniel , Bernabeo Elizabeth , Leas Brian , Sofaer Shoshanna , Pawlson Gregory , Pillittere Donna 
Published: February 2009

Abstract

Background
Physicians in small to moderate primary care practices in the United States (U.S.) (<25 physicians) face unique challenges in implementing quality improvement (QI) initiatives, including limited resources, small staffs, and inadequate information technology systems 23,36. This qualitative study sought to identify and understand the characteristics and organizational cultures of physicians working in smaller practices who are actively engaged in measurement and quality improvement initiatives.

Methods
We undertook a qualitative study, based on semi-structured, open-ended interviews conducted with practices (N = 39) that used performance data to drive quality improvement activities.

Results
Physicians indicated that benefits to performing measurement and QI included greater practice efficiency, patient and staff retention, and higher staff and clinician satisfaction with practice. Internal facilitators included the designation of a practice champion, cooperation of other physicians and staff, and the involvement of practice leaders. Time constraints, cost of activities, problems with information management and or technology, lack of motivated staff, and a lack of financial incentives were commonly reported as barriers.

Conclusion
These findings shed light on how physicians engage in quality improvement activities, and may help raise awareness of and aid in the implementation of future initiatives in small practices more generally.
Heat Shock Protein-27, -60 and -90 expression in gastric cancer: association with clinicopathological variables and patient survival
Authors: Giaginis Constantinos , Daskalopoulou Stella S , Vgenopoulou Stephanie , Sfiniadakis Ioannis , Kouraklis Gregorios , Theocharis Stamatios E 
Published: February 2009

Abstract

Background
Heat shock proteins (HSPs) are ubiquitous, highly conserved proteins across all the species and play essential roles in maintaining protein stability within the cells under normal conditions, while preventing stress-induced cellular damage. HSPs were also overexpressed in various types of cancer, being associated with tumor cell proliferation, differentiation and apoptosis. The aim of the present study was to evaluate the clinical significance of HSP -27, -60, and -90 expression in gastric carcinoma.

Methods
HSP -27, -60, and -90 proteins expression was assessed immunohistochemically in tumoral samples of 66 gastric adenocarcinoma patients and was statistically analyzed in relation to various clinicopathological characteristics, tumor proliferative capacity and patients' survival.

Results
HSP-27, -60, -90 proteins were abundantly expressed in gastric adenocarcinoma cases examined. HSP-27 expression was significantly associated with tumor size (pT, P = 0.026), the presence of organ metastases (pM, P = 0.046) and pStage (P = 0.041), while HSP-27 staining intensity with nodal status (pN, P = 0.042). HSP-60 expression was significantly associated with patients' sex (P = 0.011), while HSP-60 staining intensity with patients' age (P = 0.027) and tumor histopathological grade (P = 0.031). HSP-90 expression was not associated with any of the clinicopathological parameters examined; however, HSP-90 staining intensity was significantly associated with tumor size (pT, P = 0.020). High HSP-90 expression was significantly associated with longer overall survival times in univariate analysis (log-rank test, P = 0.033), being also identified as an independent prognostic factor in multivariate analysis (P = 0.026).

Conclusion
HSP-27, -60, and -90 were associated with certain clinicopathological parameters which are crucial for the management of gastric adenocarcinoma patient. HSP-90 expression may also be an independent prognostic indicator in gastric adenocarcinoma patients.
Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain
Authors: Quilici Sibilia , Chancellor Jeremy , Löthgren Mickael , Simon Dominique , Said Gérard , Le Trong Kim , Garcia-Cebrian Ana , Monz Brigitta 
Published: February 2009

Abstract

Background
Few direct head-to-head comparisons have been conducted between drugs for the treatment of diabetic peripheral neuropathic pain (DPNP). Approved or recommended drugs in this indication include duloxetine (DLX), pregabalin (PGB), gabapentin (GBP) and amitriptyline (AMT). We conducted an indirect meta-analysis to compare the efficacy and tolerability of DLX with PGB and GBP in DPNP, using placebo as a common comparator.

Methods
We searched PubMed, EMBASE, CENTRAL databases and regulatory websites for randomized, double-blind, placebo-controlled, parallel group or crossover clinical trials (RCTs) assessing DLX, PGB, GBP and AMT in DPNP. Study arms using approved dosages with assessments after 5–13 weeks were eligible. Efficacy criteria were: reduction in 24-hour pain severity (24 h PS) for all three drugs, and response rate (≥ 50% pain reduction) and Patient Global Impression of Improvement/Change (PGI-I/C) for DLX and PGB only. Tolerability criteria included: discontinuation, diarrhoea, dizziness, headache, nausea and somnolence. Direct comparisons versus placebo were conducted with pooled fixed – and random-effects analyses on endpoints reported in at least two studies of each drug. Indirect comparisons were performed between DLX and each of PGB and GBP using Bayesian simulation.

Results
Three studies of DLX, six of PGB, two of GBP and none of AMT met the inclusion criteria. In random-effects and fixed-effects analyses of DLX, PGB and GBP, all were superior to placebo for all efficacy parameters, with some tolerability trade-offs. Indirect comparison of DLX with PGB found no differences in 24 h PS, but significant differences in PGI-I/C, favouring PGB, and in dizziness, favouring DLX were apparent. Comparing DLX and GBP, there were no statistically significant differences.

Conclusion
From the few available studies suitable for indirect comparison, DLX shows comparable efficacy and tolerability to GBP and PGB in DPNP. Duloxetine provides an important treatment option for this disabling condition.
Perinatal outcomes in a South Asian setting with high rates of low birth weight
Authors: George Kuryan , Prasad Jasmin , Singh Daisy , Minz Shanthidani , Albert David S , Muliyil Jayaprakash , Joseph K S , Jayaraman Jyothi , Kramer Michael S 
Published: February 2009

AbstractBackgroundIt is unclear whether the high rates of low birth weight in South Asia are due to poor fetal growth or short pregnancy duration. Also, it is not known whether the traditional focus on preventing low birth weight has been successful. We addressed these and related issues by studying births in Kaniyambadi, South India, with births from Nova Scotia, Canada serving as a reference.MethodsPopulation-based data for 1986 to 2005 were obtained from the birth database of the Community Health and Development program in Kaniyambadi and from the Nova Scotia Atlee Perinatal Database. Menstrual dates were used to obtain comparable information on gestational age. Small-for-gestational age (SGA) live births were identified using both a recent Canadian and an older Indian fetal growth standard.ResultsThe low birth weight and preterm birth rates were 17.0% versus 5.5% and 12.3% versus 6.9% in Kaniyambadi and Nova Scotia, respectively. SGA rates were 46.9% in Kaniyambadi and 7.5% in Nova Scotia when the Canadian fetal growth standard was used to define SGA and 6.7% in Kaniyambadi and < 1% in Nova Scotia when the Indian standard was used. In Kaniyambadi, low birth weight, preterm birth and perinatal mortality rates did not decrease between 1990 and 2005. SGA rates in Kaniyambadi declined significantly when SGA was based on the Indian standard but not when it was based on the Canadian standard. Maternal mortality rates fell by 85% (95% confidence interval 57% to 95%) in Kaniyambadi between 1986–90 and 2001–05. Perinatal mortality rates were 11.7 and 2.6 per 1,000 total births and cesarean delivery rates were 6.0% and 20.9% among live births ≥ 2,500 g in Kaniyambadi and Nova Scotia, respectively.ConclusionHigh rates of fetal growth restriction and relatively high rates of preterm birth are responsible for the high rates of low birth weight in South Asia. Increased emphasis is required on health services that address the morbidity and mortality in all birth weight categories.
Time-frequency component analysis of somatosensory evoked potentials in rats
Authors: Zhang Zhi-Guo , Yang Jun-Lin , Chan Shing-Chow , Luk Keith Dip-Kei , Hu Yong 
Published: February 2009

AbstractBackgroundSomatosensory evoked potential (SEP) signal usually contains a set of detailed temporal components measured and identified in a time domain, giving meaningful information on physiological mechanisms of the nervous system. The purpose of this study is to measure and identify detailed time-frequency components in normal SEP using time-frequency analysis (TFA) methods and to obtain their distribution pattern in the time-frequency domain.MethodsThis paper proposes to apply a high-resolution time-frequency analysis algorithm, the matching pursuit (MP), to extract detailed time-frequency components of SEP signals. The MP algorithm decomposes a SEP signal into a number of elementary time-frequency components and provides a time-frequency parameter description of the components. A clustering by estimation of the probability density function in parameter space is followed to identify stable SEP time-frequency components.ResultsExperimental results on cortical SEP signals of 28 mature rats show that a series of stable SEP time-frequency components can be identified using the MP decomposition algorithm. Based on the statistical properties of the component parameters, an approximated distribution of these components in time-frequency domain is suggested to describe the complex SEP response.ConclusionThis study shows that there is a set of stable and minute time-frequency components in SEP signals, which are revealed by the MP decomposition and clustering. These stable SEP components have specific localizations in the time-frequency domain.
Intra-operative intra-peritoneal chemotherapy with cisplatin in patients with peritoneal carcinomatosis of ovarian cancer
Authors: Guardiola Emmanuel , Delroeux Delphine , Heyd Bruno , Combe Marielle , Lorgis Veronique , Demarchi Martin , Stein Ulrich , Royer Bernard , Chauffert Bruno , Pivot Xavier 
Published: February 2009

Abstract

Background
Intra-peritoneal (i.p.) chemotherapy is an encouraging treatment option for ovarian cancer with peritoneum involvement in addition with intravenous (i.v.) chemotherapy. Intra-operative i.p. chemotherapy is an interesting method of administration by enhancing the diffusion of chemotherapy. This study had assessed the feasibility of intra-operative i.p. chemotherapy in patients with peritoneal carcinoma of ovarian cancer.

Methods
From January 2003 to February 2006, 47 patients with stage III ovarian cancer were treated with standard paclitaxel carboplatin intravenous chemotherapy and debulking surgery with intra-operative i.p. chemotherapy. After optimal cytoreductive surgery, defined by no unresectable residual disease > 1 cm, i.p. chemotherapy was performed during surgery. The peritoneal cavity was filled by 3 litres of isotonic saline pre-heated at 37 degrees and 90 mg of cisplatin. The sequence was repeated twice during 2 hours based on previous published studies which optimized the cisplatin dosage and exposure duration. Optimal diffusion was obtained by stirring by hands during the 2 hours.

Results
Median age was 59.6 years. No severe haematological or non-haematological toxicity induced by intra operative i.p. chemotherapy was reported. No patient died due to the complications of surgery or the i.p. chemotherapy. No neurotoxicity occurred, and one patients had renal impairment.

Conclusion
This study demonstrates the feasibility of intra-operative i.p. chemotherapy with cisplatin after optimal resection of peritoneal tumor nodules. Further randomized trials are planned to investigate the clinical benefit of this therapeutic modality.
Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo
Authors: Cullen Valerie , Lindfors Maria , Ng Juliana , Paetau Anders , Swinton Erika , Kolodziej Piotr , Boston Heather , Saftig Paul , Woulfe John , Feany Mel B , Myllykangas Liisa , Schlossmacher Michael G , Tyynelä Jaana 
Published: February 2009

Abstract

Background
Elevated SNCA gene expression and intracellular accumulation of the encoded α-synuclein (aSyn) protein are associated with the development of Parkinson disease (PD). To date, few enzymes have been examined for their ability to degrade aSyn. Here, we explore the effects of CTSD gene expression, which encodes the lysosomal protease cathepsin D (CathD), on aSyn processing.

Results
Over-expression of human CTSD cDNA in dopaminergic MES23.5 cell cultures induced the marked proteolysis of exogenously expressed aSyn proteins in a dose-dependent manner. Unexpectedly, brain extractions, Western blotting and ELISA quantification revealed evidence for reduced levels of soluble endogenous aSyn in ctsd knock-out mice. However, these CathD-deficient mice also contained elevated levels of insoluble, oligomeric aSyn species, as detected by formic acid extraction. In accordance, immunohistochemical studies of ctsd-mutant brain from mice, sheep and humans revealed selective synucleinopathy-like changes that varied slightly among the three species. These changes included intracellular aSyn accumulation and formation of ubiquitin-positive inclusions. Furthermore, using an established Drosophila model of human synucleinopathy, we observed markedly enhanced retinal toxicity in ctsd-null flies.

Conclusion
We conclude from these complementary investigations that: one, CathD can effectively degrade excess aSyn in dopaminergic cells; two, ctsd gene mutations result in a lysosomal storage disorder that includes microscopic and biochemical evidence of aSyn misprocessing; and three, CathD deficiency facilitates aSyn toxicity. We therefore postulate that CathD promotes 'synucleinase' activity, and that enhancing its function may lower aSyn concentrations in vivo.
Beyond Li Fraumeni Syndrome: Clinical Characteristics of Families With p53 Germline Mutations
Authors: Gonzalez Kelly D. , Noltner Katie A. , Buzin Carolyn H. , Gu Dongqing , Wen-Fong Cindy Y. , Nguyen Vu Q. , Han Jennifer H. , Lowstuter Katrina , Longmate Jeffrey , Sommer Steve S. , Weitzel Jeffrey N. 
Published: February 2009

Purpose A clinical testing cohort was used to gain a broader understanding of the spectrum of tumors associated with germline p53 mutations to aid clinicians in identifying high-risk families. Patients and Methods Full sequencing of the coding exons (2 to 11) and associated splice junctions of the p53 gene was performed on 525 consecutive patients whose blood samples were submitted for diagnostic testing. Clinical features of p53 germline carriers in this cohort were characterized, clinical referral schemes based on reported p53-associated family phenotypes were evaluated, and practical mutation prevalence tables were generated. Results Mutations were identified in 91 (17%) of 525 patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC). Every individual with a choroid plexus tumor (eight of eight) and 14 of 21 individuals with a childhood ACC had a mutation regardless of family history. Based on reported personal and family history, 95% of patients (71 of 75) with a mutation met either classic Li Fraumeni syndrome (LFS) or Chompret criteria. A simplified prevalence table provides a concise summary of individual and family characteristics associated with p53 mutations. Conclusion This is, to our knowledge, the largest single report of diagnostic testing for germline p53 mutations, yielding practical mutation prevalence tables and suggesting clinical utility of classic LFS and Chompret criteria for identifying a subset of cancer-prone families with p53 germline mutations, with important implications for diagnosis and management.
Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms
Authors: Lai Stephen Y. , Koppikar Priya , Thomas Sufi M. , Childs Erin E. , Egloff Ann Marie , Seethala Raja R. , Branstetter Barton F. , Gooding William E. , Muthukrishnan Ashok , Mountz James M. , Lui Vivian W.Y. , Shin Dong M. , Agarwala Sanjiv S. , Johnson Rita , Couture Larry A. , Myers Eugene N. , Johnson Jonas T. , Mills Gordon , Argiris Athanassios , Grandis Jennifer R. 
Published: February 2009

Purpose Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS. Patients and Methods Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 μg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry. Results Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively). Conclusion Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects.