bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing
Authors: Sokolenko Anna P , Voskresenskiy Dmitry A , Iyevleva Aglaya G , Bit-Sava Elena M , Gutkina Nadezhda I , Anisimenko Maxim S , Yu Sherina Nathalia , Mitiushkina Nathalia V , Ulibina Yulia M , Yatsuk Olga S , Zaitseva Olga A , Suspitsin Evgeny N , Togo Alexandr V , Pospelov Valery A , Kovalenko Sergey P , Semiglazov Vladimir F , Imyanitov Evgeny N 
Published: January 2009

AbstractAlthough the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.
Genetic variants in MUTYH are not associated with endometrial cancer risk
Authors: Ashton Katie A , Proietto Anthony , Otton Geoffrey , Symonds Ian , Scott Rodney J 
Published: January 2009

Abstract
Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant inherited predisposition to a number of epithelial cancers, most notably colorectal and endometrial cancer. Outside of the context of Lynch syndrome there is little evidence for an autosomal dominant or recessive condition that predisposes to endometrial cancer. Recently, genetic variants in MUTYH have been associated with a recessive form of colorectal cancer, known as MUTYH associated polyposis or MAP. MUTYH is involved in base excision repair of DNA lesions and as such a breakdown in the fidelity of this process would necessarily not be predicted to result in a specific disease. At present there is little information about the role of MUTYH in other types of cancer and only one report indicating a possible relationship with endometrial cancer.
Similar to a previous study, we investigated a series of endometrial cancer patients to determine if MUTYH variants were over-represented compared to a series of healthy control subjects and to assess whether or not endometrial cancer risk could be explained by an autosomal recessive model of inheritance.
Two MUTYH mutations, Y165C and G382D, and three common MUTYH polymorphisms, V22M, Q324H and S501F, were genotyped in 213 endometrial cancer patients and 226 controls from Australia using real time PCR. Differences in genotype frequencies were compared using Chi-squared analysis and by calculating odds ratios and 95% confidence intervals.
Three endometrial cancer patients were identified with heterozygous MUTYH mutations (two G382D and one Y165C). No bi-allelic mutation carriers were identified. Two of the three patients' clinical characteristics were similar to those commonly identified in HNPCC and lend support to the notion that MUTYH mutations increase the risk of developing HNPCC related diseases. There was no difference in the five genotype frequencies of the endometrial cancer patients compared to the controls. The results of our study suggest that MUTYH is unlikely to be involved in the genetic basis of endometrial cancer but a possible association of MUTYH variants with HNPCC related diseases cannot be excluded.
Selective amplification of glucocorticoid anti-inflammatory activity through synergistic multi-target action of a combination drug
Authors: Zimmermann Grant R , Avery William , Finelli Alyce L , Farwell Melissa , Fraser Christopher C , Borisy Alexis A 
Published: January 2009

Abstract
Introduction
Glucocorticoids are a mainstay of anti-inflammatory therapy, but significant adverse effects ultimately limit their utility. Previous efforts to design glucocorticoid structures with an increased therapeutic window have focused on dissociating anti-inflammatory transcriptional repression from adverse effects primarily driven by transcriptional activation. An alternative to this medicinal chemistry approach is a systems biology based strategy that seeks to amplify selectively the anti-inflammatory activity of very low dose glucocorticoid in immune cells without modulating alternative cellular networks that mediate glucocorticoid toxicity.

Methods
The combination of prednisolone and the antithrombotic drug dipyridamole was profiled using in vitro and in vivo models of anti-inflammatory activity and glucocorticoid-induced adverse effects to demonstrate a dissociated activity profile.

Results
The combination synergistically suppresses release of proinflammatory mediators, including tumour necrosis factor-α, IL-6, chemokine (C-C motif) ligand 5 (RANTES), matrix metalloproteinase-9, and others, from human peripheral blood mononuclear cells and mouse macrophages. In rat models of acute lipopolysaccharide-induced endotoxemia and delayed-type hypersensitivity, and in chronic models of collagen-induced and adjuvant-induced arthritis, the combination produced anti-inflammatory activity that required only a subtherapeutic dose of prednisolone. The immune-specific amplification of prednisolone anti-inflammatory activity by dipyridamole did not extend to glucocorticoid-mediated adverse effects, including corticosterone suppression or increased expression of tyrosine aminotransferase, in vivo after repeat dosing in rats. After 8 weeks of oral dosing in mice, treatment with the combination did not alter prednisolone-induced reduction in osteocalcin and mid-femur bone density, which are markers of steroid-induced osteoporosis. Additionally, amplification was not observed in the cellular network of corticotroph AtT-20/D16v-F2 cells in vitro, as measured by pro-opiomelanocortin expression and adrenocorticotropic hormone secretion.

Conclusions
These data suggest that the multi-target mechanism of low-dose prednisolone and dipyridamole creates a dissociated activity profile with an increased therapeutic window through cellular network selective amplification of glucocorticoid-mediated anti-inflammatory signaling.
Automatic versus manual pressure support reduction in the weaning of post-operative patients: a randomised controlled trial
Authors: Taniguchi Corinne , Eid Raquel C , Saghabi Cilene , Souza Rogério , Silva Eliezer , Knobel Elias , Paes Ângela T , Barbas Carmen S 
Published: January 2009

Abstract
Introduction
Reduction of automatic pressure support based on a target respiratory frequency or mandatory rate ventilation (MRV) is available in the Taema-Horus ventilator for the weaning process in the intensive care unit (ICU) setting. We hypothesised that MRV is as effective as manual weaning in post-operative ICU patients.

Methods
There were 106 patients selected in the post-operative period in a prospective, randomised, controlled protocol. When the patients arrived at the ICU after surgery, they were randomly assigned to either: traditional weaning, consisting of the manual reduction of pressure support every 30 minutes, keeping the respiratory rate/tidal volume (RR/TV) below 80 L until 5 to 7 cmH2O of pressure support ventilation (PSV); or automatic weaning, referring to MRV set with a respiratory frequency target of 15 breaths per minute (the ventilator automatically decreased the PSV level by 1 cmH2O every four respiratory cycles, if the patient's RR was less than 15 per minute). The primary endpoint of the study was the duration of the weaning process. Secondary endpoints were levels of pressure support, RR, TV (mL), RR/TV, positive end expiratory pressure levels, FiO2 and SpO2 required during the weaning process, the need for reintubation and the need for non-invasive ventilation in the 48 hours after extubation.

Results
In the intention to treat analysis there were no statistically significant differences between the 53 patients selected for each group regarding gender (p = 0.541), age (p = 0.585) and type of surgery (p = 0.172). Nineteen patients presented complications during the trial (4 in the PSV manual group and 15 in the MRV automatic group, p < 0.05). Nine patients in the automatic group did not adapt to the MRV mode. The mean ± sd (standard deviation) duration of the weaning process was 221 ± 192 for the manual group, and 271 ± 369 minutes for the automatic group (p = 0.375). PSV levels were significantly higher in MRV compared with that of the PSV manual reduction (p < 0.05). Reintubation was not required in either group. Non-invasive ventilation was necessary for two patients, in the manual group after cardiac surgery (p = 0.51).

Conclusions
The duration of the automatic reduction of pressure support was similar to the manual one in the post-operative period in the ICU, but presented more complications, especially no adaptation to the MRV algorithm.

Trial Registration
Trial registration number: ISRCTN37456640
The effect of glutamine infusion on the inflammatory response and HSP70 during human experimental endotoxaemia
Authors: Andreasen Anne Sofie , Pedersen-Skovsgaard Theis , Mortensen Ole Hartvig , van Hall Gerrit , Moseley Pope Lloyd , Pedersen Bente Klarlund 
Published: January 2009

Abstract
Introduction
Glutamine supplementation has beneficial effects on morbidity and mortality in critically ill patients, possibly in part through an attenuation of the proinflammatory cytokine response and a stimulation of heat shock protein (HSP)70. We infused either alanine-glutamine or saline during endotoxin challenge and measured plasma cytokines and HSP70 protein expression.

Methods
This crossover study, conducted in eight healthy young men, was double-blind, randomized and placebo-controlled. It was performed on 2 trial days, separated by a 4-week washout period. The volunteers received an infusion of alanine-glutamine at a rate of 0.025 g/(kg body weight × hour) or saline for 10 hours. After 2 hours, an intravenous bolus of Escherichia coli endotoxin (0.3 ng/kg) was administered. Blood samples were collected hourly for the following 8 hours. HSP70 protein content in isolated blood mononuclear cells (BMNCs) was measured by Western blotting.

Results
Plasma glutamine increased during alanine-glutamine infusion. Endotoxin reduced plasma glutamine during both trials, but plasma glutamine levels remained above baseline with alanine-glutamine supplementation. Endotoxin injection was associated with alterations in white blood cell and differential counts, tumour necrosis factor-α, IL-6, temperature and heart rate, but glutamine affected neither the endotoxin-induced change in these variables nor the expression of HSP70 in BMNCs.

Conclusions
Endotoxin reduced plasma glutamine independently of alanine-glutamine infusion, but supplementation allows plasma levels to be maintained above baseline. Glutamine alters neither endotoxin-induced systemic inflammation nor early expression of HSP70 in BMNCs.

Trial Registration
ClinicalTrials.gov ID: NCT 00780520.
Excellent Outcome With Reduced Treatment for Infants With Disseminated Neuroblastoma Without MYCN Gene Amplification
Authors: De Bernardi Bruno , Gerrard Mary , Boni Luca , Rubie Hervé , Cañete Adela , Di Cataldo Andrea , Castel Victoria , Forjaz de Lacerda Ana , Ladenstein Ruth , Ruud Ellen , Brichard Benédicte , Couturier Jerome , Ellershaw Caroline , Munzer Caroline , Bruzzi Paolo , Michon Jean , Pearson Andrew D.J. 
Published: January 2009

Purpose On the assumption that most infants with disseminated neuroblastoma without MYCN amplification (MYCNA) have a favorable prognosis, two concomitant prospective trials were started in which chemotherapy was limited to patients presenting life- or organ-threatening symptoms or overt metastases to skeleton, lung, or CNS. Surgery was to be performed only in the absence of surgical risk factors. Patients and Methods One hundred seventy infants with disseminated neuroblastoma without MYCNA, diagnosed between June 1999 and June 2004 in nine European countries were eligible for either of the two studies. Trial 99.2 included all stage 4S infants and those with stage 4 with a primary tumor infiltrating across the midline or positive skeletal scintigraphy who were to be observed in absence of symptoms. Trial 99.3 included infants with overt metastases to the skeleton, lung, and CNS to be treated with a minimum of four chemotherapy courses. Results The 125 infants treated on trial 99.2 had a 2-year overall survival (OS) of 97.6% with no difference between asymptomatic and symptomatic patients (97.7% v 97.3%), patients without or with unresectable primary tumors (96.8% v 100%), and patients without or with positive skeletal scintigraphy without radiologic abnormalities (97.2% v 100%). The 45 infants treated on trial 99.3 had a 2-year OS of 95.6%. No patients died of surgery- or chemotherapy-related complications. Conclusion Infants with disseminated disease without MYCNA have excellent survival with minimal or no treatment. Asymptomatic infants with an unresectable primary tumor or positive skeletal scintigraphy without radiologic abnormalities may undergo observation alone.
Sensitivity of Surveillance Studies for Detecting Asymptomatic and Unsuspected Relapse of High-Risk Neuroblastoma
Authors: Kushner Brian H. , Kramer Kim , Modak Shakeel , Cheung Nai-KongV. 
Published: January 2009

Purpose Relapse-free survival (RFS) is a powerful measure of treatment efficacy. We describe the sensitivity of standard surveillance studies for detecting relapse of neuroblastoma (NB). Patients and Methods The patients were in complete/very good partial remission of high-risk NB; routine monitoring revealed asymptomatic and, therefore, unsuspected relapses in 113 patients, whereas 41 patients had symptoms prompting urgent evaluations. Assessments every 2 to 4 months included computed tomography, iodine-131–metaiodobenzylguanidine 131I-MIBG; through November 1999) or iodine-123–metaiodobenzylguanidine (123I-MIBG) scan, urine catecholamines, and bone marrow (BM) histology. Bone scan was routine through 2002. Results 123I-MIBG scan was the most reliable study for revealing unsuspected relapse; it had an 82% detection rate, which was superior to the rates with 131I-MIBG scan (64%; P = .1), bone scan (36%; P < .001), and BM histology (34%; P < .001). Among asymptomatic patients, 123I-MIBG scan was the sole positive study indicating relapse in 25 (27%) of 91 patients compared with one (4.5%) of 22 patients for 131I-MIBG scan (P = .04) and 0% to 6% of patients for each of the other studies (P < .001). Patients whose monitoring included 123I-MIBG scan were significantly less likely than patients monitored by 131I-MIBG scan to have an extensive osteomedullary relapse and had a significantly longer survival from relapse (P < .001) and from diagnosis (P = .002). They also had significantly longer survival than patients with symptomatic relapses (P = .002). Conclusion 123I-MIBG scan is essential for valid estimation of the duration of RFS of patients with high-risk NB. Without monitoring that includes 123I-MIBG scan, caution should be used when comparing RFS between institutions and protocols.
Randomized Phase II Trial of First-Line Treatment With Sorafenib Versus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma
Authors: Escudier Bernard , Szczylik Cezary , Hutson Thomas E. , Demkow Tomasz , Staehler Michael , Rolland Frédéric , Negrier Sylvie , Laferriere Nicole , Scheuring Urban J. , Cella David , Shah Sonalee , Bukowski Ronald M. 
Published: January 2009

Purpose An open-label, phase II study to evaluate progression-free survival (PFS), overall best response, adverse events (AEs), and patient-reported outcomes with sorafenib versus interferon alfa-2a (IFN-α-2a) in patients with untreated, advanced renal cancer. Patients and Methods A total of 189 patients were randomly assigned to oral sorafenib 400 mg twice daily or to subcutaneous IFN-α-2a 9 million U three times weekly (period 1). Sorafenib patients who progressed were dose-escalated to 600 mg twice daily; IFN-α-2a patients who progressed were switched to sorafenib 400 mg twice daily (period 2). Results In period 1 PFS was similar for sorafenib-treated (n = 97; 5.7 months) and IFN-α-2a–treated patients (n = 92; 5.6 months); more sorafenib-treated patients had tumor shrinkage (68.2% v 39.0%). Common drug-related AEs (Grades ≥ 3) for sorafenib were hand-foot skin reaction (11.3%), diarrhea (6.2%), and rash/desquamation (6.2%); for IFN-α-2a, these were fatigue (10.0%), nausea (3.3%), flu-like syndrome (2.2%), and anorexia (2.2%). Sorafenib-treated patients reported fewer symptoms, better quality of life (QOL), and greater treatment satisfaction. In period 2, 41.9% of patients who received sorafenib 600 mg twice daily (n = 43) experienced tumor reduction (median PFS, 3.6 months). After the switch to sorafenib 400 mg twice daily, tumors were reduced in 76.2% of 50 patients (median PFS, 5.3 months). AEs were mostly grade 1 to 2; no increase in AEs of grades ≥ 3 occurred after sorafenib dose escalation. Conclusion In this study, sorafenib resulted in similar PFS as IFN-α-2a in patients with untreated RCC. However, sorafenib-treated patients experienced greater rates of tumor size reduction, better QOL, and improved tolerability. Both dose escalation of sorafenib after progression and a switch to sorafenib after progression on IFN-α-2a resulted in clinical benefit.
Peripheral Administration of Nesfatin-1 Reduces Food Intake in Mice: The Leptin-Independent Mechanism
Authors: Shimizu H. , Oh-I S. , Hashimoto K. , Nakata M. , Yamamoto S. , Yoshida N. , Eguchi H. , Kato I. , Inoue K. , Satoh T. , Okada S. , Yamada M. , Yada T. , Mori M. 
Published: January 2009

Nesfatin-1 is a novel satiety molecule in the hypothalamus and is also present in peripheral tissues. Here we sought to identify the active segment of nesfatin-1 and to determine the mechanisms of its action after peripheral administration in mice. Intraperitoneal injection of nesfatin-1 suppressed food intake in a dose-dependent manner. Nesfatin-1 has three distinct segments; we tested the effect of each segment on food intake. Injection of the midsegment decreased food intake under leptin-resistant conditions such as db/db mice and mice fed a high-fat diet. After injection of the midsegment, expression of c-Fos was significantly activated in the brainstem nucleus tractus solitarius (NTS) but not in the hypothalamic arcuate nucleus; the nicotinic cholinergic pathway to the NTS contributed to midsegment-induced anorexia. Midsegment injection significantly increased expression of proopiomelanocortin and cocaine- and amphetamine-regulated transcript genes in the NTS but not in the arcuate nucleus. Investigation of mutant midsegments demonstrated that a region with amino acid sequence similarity to the active site of agouti-related peptide was indispensable for anorexigenic induction. Our findings indicate that the midsegment of nesfatin-1 causes anorexia, possibly by activating POMC and CART neurons in the NTS via a leptin-independent mechanism after peripheral stimulation.
Peripherally administered nesfatin-1 and its mid-segment suppress food intake in mice. The nicotinic cholinergic pathway to the nucleus tractus solitarius contributes to the anorexigenic action of the mid-segment.
A unified manufacturing resource model for representation of computerized numerically controlled machine tools
Authors: Vichare P , Nassehi A , Newman S 
Published: January 2009

The capability of any manufacturing system primarily depends on its available machine tools. Thus machine tool representation is a vital part of modelling any manufacturing system. With the rapid advances in computerized numerically controlled (CNC) machines, machine tool representation has become a more challenging task than ever before. Today's CNC machine tools are more than just automated manufacturing machines, as they can be considered multi-purpose, multi-tasking, and hybrid machining centres. This paper presents a versatile methodology for representing such state-of-the-art CNC machining system resources. A machine tool model is a conceptual representation of the real machine tool and provides a logical framework for representing its functionality in the manufacturing system. There are several commercial modelling tools available in the market for modelling machine tools. However, there is no common methodology among them to represent the wide diversity of machine tool configurations. These modelling tools are either machine vendor specific or limited in their scope to represent machine tool capability. In addition, the current information models of STEP-NC, namely ISO 14649, can only describe machining operations, technologies, cutting tools, and product geometries. However, they do not support the representation of machine tools. The proposed unified manufacturing resource model (UMRM) has a data model which can fill this gap by providing machine specific data in the form of an EXPRESS schema and act as a complementary part to the STEP-NC standard to represent various machine tools in a standardized form. UMRM is flexible enough to represent any type of CNC machining centre. This machine tool representation can be utilized to represent machine tool functionality and consequential process capabilities for allocating resources for process planning and machining.
The protection motivation theory within the stages of the transtheoretical model – Stage‐specific interplay of variables and prediction of exercise stage transitions
Authors: Lippke Sonia , Plotnikoff Ronald C. 
Published: January 2009

Objective Two different theories of health behaviour have been chosen with the aim of theory integration: a continuous theory (protection motivation theory, PMT) and a stage model (transtheoretical model, TTM). This is the first study to test whether the stages of the TTM moderate the interrelation of PMT‐variables and the mediation of motivation, as well as PMT‐variables' interactions in predicting stage transitions.Design Hypotheses were tested regarding (1) mean patterns, stage pair‐comparisons and nonlinear trends using ANOVAs; (2) prediction‐patterns for the different stage groups employing multi‐group structural equation modelling (MSEM) and nested model analyses; and (3) stage transitions using binary logistic regression analyses.Method Adults (N=1,602) were assessed over a 6 month period on their physical activity stages, PMT‐variables and subsequent behaviour.Results (1) Particular mean differences and nonlinear trends in all test variables were found. (2) The PMT adequately fitted the five stage groups. The MSEM revealed that covariances within threat appraisal and coping appraisal were invariant and all other constrains were stage‐specific, i.e. stage was a moderator. Except for self‐efficacy, motivation fully mediated the relationship between the social‐cognitive variables and behaviour. (3) Predicting stage transitions with the PMT‐variables underscored the importance of self‐efficacy. Only when threat appraisal and coping appraisal were high, stage movement was more likely in the preparation stage.Conclusions Results emphasize stage‐specific differences of the PMT mechanisms, and hence, support the stage construct. The findings may guide further theory building and research integrating different theoretical approaches.