bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers
Authors: Neuhausen Susan L , Brummel Sean , Ding Yuan Chun , Singer Christian F , Pfeiler Georg , Lynch Henry T , Nathanson Katherine L , Rebbeck Timothy R , Garber Judy E , Couch Fergus , Weitzel Jeffrey , Narod Steven A , Ganz Patricia A , Daly Mary B , Godwin Andrew K , Isaacs Claudine , Olopade Olufunmilayo I , Tomlinson Gail , Rubinstein Wendy S , Tung Nadine , Blum Joanne L , Gillen Daniel L 
Published: October 2009

Abstract
Introduction
Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.

Methods
A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.

Results
Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.

Conclusions
This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.
Gastroesophageal reflux in mechanically ventilated pediatric patients and its relation to ventilator-associated pneumonia
Authors: Abdel-Gawad Tarek A , El-Hodhod Mostafa A , Ibrahim Hanan M , Michael Yousef W 
Published: October 2009

Abstract
Introduction
The objective was to determine the frequency of gastroesophageal reflux (GER) in mechanically ventilated pediatric patients and its role as a risk factor for ventilator-associated pneumonia (VAP), which may be enhanced among those patients.

Methods
The study is a prospective cohort study of mechanically ventilated pediatric patients in the pediatric intensive care unit (PICU) of Ain Shams University Children's Hospital. It was conducted in 24 mechanically ventilated patients (16 of them developed VAP and 8 did not, with mean age of 16.6 +/- 20.5 and 18.6 +/- 22.4 months respectively). Esophageal 24-hour pH-metry beside clinical and laboratory evaluation of their underlying problem and severity of their condition were carried out.

Results
All VAP patients had GER (50% alkaline reflux, 12.5% acidic reflux and 37.5% combined reflux) compared to 75% of non-VAP ones (100% alkaline reflux). The mean total reflux time was significantly longer among VAP (50 minutes) versus non-VAP (3 minutes) patients. There was significant increase in acidic reflux parameters among non-survivors versus survivors (P < 0.001). For VAP mortality, total acidic reflux at a cut-off value of 28.6 minutes is found to be a mortality predictor with a sensitivity of 100% and a specificity of 100%.

Conclusions
GER is a constant incident in mechanically ventilated pediatric patients, with alkaline reflux being more common than acidic reflux. Both acidic and alkaline refluxes were found to be associated with the development of VAP and total reflux time was found to be a reliable predictor of VAP. Moreover, acidic reflux was found to be more related to mortality than alkaline reflux.
Preventing Future Cancers by Testing Women With Ovarian Cancer forBRCAMutations
Authors: Kwon Janice S. , Daniels Molly S. , Sun Charlotte C. , Lu Karen H. 
Published: October 2009

PurposeWomen with ovarian cancer have a 10% probability of carrying a BRCA mutation. If a mutation is identified, unaffected family members can undergo genetic testing and cancer risk-reducing strategies. We estimated the net health benefits and cost-effectiveness of different criteria for BRCA mutation testing in women with ovarian cancer, and the downstream benefits for their first-degree relatives (FDRs).MethodsWe developed a Markov Monte Carlo simulation model to compare four criteria for BRCA testing in women with ovarian cancer: no testing (reference); only if personal history of breast cancer, family history of breast/ovarian cancer, or Ashkenazi Jewish ancestry; only if invasive serous cancer; any invasive nonmucinous epithelial cancer. Net health benefit was life expectancy for FDRs and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of future breast and ovarian cancer cases in FDRs.ResultsBRCA testing based on personal/family history and ancestry could prevent future cases in FDRs with an ICER of $32,018 per year of life (LY) gained compared with the reference strategy. BRCA testing based on serous or any nonmucinous epithelial ovarian cancer could prevent more cancer cases, but at ICERs of $128,465 and $148,363 per LY gained, respectively.ConclusionBRCA testing of women with ovarian cancer based on personal/family history of cancer or Ashkenazi Jewish ancestry is a cost-effective strategy to prevent future breast and ovarian cancers among FDRs. More inclusive testing strategies prevent additional cancer cases but at significant cost.
Cancer During Pregnancy: An Analysis of 215 Patients Emphasizing the Obstetrical and the Neonatal Outcomes
Authors: Van Calsteren Kristel , Heyns Liesbeth , De Smet Frank , Van Eycken Liesbet , Gziri Mina Mhallem , Van Gemert Willemijn , Halaska Michael , Vergote Ignace , Ottevanger Nelleke , Amant Frédéric 
Published: October 2009

Purpose The aim of this study was to assess the management and the obstetrical and neonatal outcomes of pregnancies complicated by cancer. Patients and Methods In an international collaborative setting, patients with invasive cancer diagnosed during pregnancy between 1998 and 2008 were identified. Clinical data regarding the cancer diagnosis and treatment and the obstetric and neonatal outcomes were collected and analyzed. Results Of 215 patients, five (2.3%) had a pregnancy that ended in a spontaneous miscarriage and 30 (14.0%) pregnancies were interrupted. Treatment was initiated during pregnancy in 122 (56.7%) patients and postpartum in 58 (27.0%) patients. The most frequently encountered cancer types were breast cancer (46%), hematologic malignancies (18%), and dermatologic malignancies (10%). The mean gestational age at delivery was 36.3 ± 2.9 weeks. Delivery was induced in 71.7% of pregnancies, and 54.2% of children were born preterm. In the group of patients prenatally exposed to cytotoxic treatment, the prevalence of preterm labor was increased (11.8%; P = .012). Furthermore, in this group a higher proportion of small-for-gestational-age children (birth weight below 10th percentile) was observed (24.2%; P = .001). Of all neonates, 51.2% were admitted to a neonatal intensive care unit, mainly (85.2%) because of prematurity. There was no increased incidence of congenital malformations. Conclusion Pregnant cancer patients should be treated in a multidisciplinary setting with access to maternal and neonatal intensive care units. Prevention of iatrogenic prematurity appears to be an important part of the treatment strategy.
Phase II Trial of Pemetrexed Plus Bevacizumab for Second-Line Therapy of Patients With Advanced Non–Small-Cell Lung Cancer: NCCTG and SWOG Study N0426
Authors: Adjei Alex A. , Mandrekar Sumithra J. , Dy Grace K. , Molina Julian R. , Adjei Araba A. , Gandara David R. , Ziegler Katie L. Allen , Stella Philip J. , Rowland Kendrith M. , Schild Steven E. , Zinner Ralph G. 
Published: October 2009

Purpose To evaluate the efficacy and toxicity of pemetrexed combined with bevacizumab as second-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes with clinical outcome. Patients and Methods Patients with previously treated NSCLC received pemetrexed (500 mg/m2 intravenous) combined with bevacizumab (15 mg/kg intravenous) every 3 weeks. The primary end point, evaluated using a one-stage Fleming design for detecting a true success rate of at least 70%, was the proportion of patients who were progression free and on treatment at 3 months. Polymorphisms in genes responsible for pemetrexed transport (reduced folate carrier [SLC19A1]) and metabolism (folylpolyglutamate synthase [FPGS] and gamma-glutamyl hydrolase [GGH]) evaluated in germline DNA (blood) were correlated with treatment outcome. Results Forty-eight evaluable patients (14 females and 34 males) received a median of four cycles (range, one to 20 cycles). The most common grade 3 or 4 nonhematologic adverse events (AEs) were fatigue (13%), dyspnea (10%), and thrombosis (10%). Grade 3 or 4 hematologic AEs were neutropenia (19%) and lymphopenia (13%). Twenty-four (57%; 95% CI, 41% to 72%) of the first 42 patients met the success criteria. Median overall survival (OS) and progression-free survival (PFS) times were 8.6 and 4.0 months, respectively. The exon 6 (2522)C→T polymorphism in SLC19A1 correlated with 3-month progression-free status (P = .01) and with PFS (P = .05). The IVS1(1307)C→T polymorphism in GGH correlated with OS (P = .04). Conclusion The study did not meet its primary end point. However, the median PFS time of 4 months is promising. Pharmacogenetic studies in larger cohorts are needed to definitively identify polymorphisms that predict for survival and toxicity of pemetrexed.
A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells
Authors: Budiu Raluca A. , Diaconu Iulia , Chrissluis Rachel , Dricu Anica , Edwards Robert P. , Vlad Anda M. 
Published: October 2009

SUMMARYEndometriosis is defined by the presence of tissue implants resembling endometrial glands outside of the uterus, at ectopic sites, frequently on the ovarian surface. The ectopic lesions are often invasive, resistant to therapy, and may predispose to endometrioid and clear cell ovarian tumors. The complex mechanisms leading to chronic endometriosis are mediated partly by impaired immune surveillance in the host. Although innate immunity has been addressed previously, the response of adaptive immune effectors to specific antigens has not been characterized, mostly because very few endometriosis antigens have been defined to date. We postulated that the mucin 1 (MUC1) glycoprotein, which is normally present on eutopic human endometrial glands and overexpressed in endometrioid and clear cell ovarian tumors, is also present in ectopic lesions of ovarian endometriosis. Furthermore, changes in MUC1 expression in endometriosis could promote adaptive anti-MUC1 immunity that might play a role in the malignant progression. To test our hypothesis, we crossed MUC1 transgenic mice, which express human MUC1 under the endogenous promoter, with the loxP-Stop-loxP-KrasG12D/+ (Kras) mice, in which endometriosis can be induced through Cre-loxP recombination. The double transgenic MUC1Kras mice develop benign, MUC1-positive ovarian lesions, closely resembling human endometriosis. Subsequent to disease induction, the mice generate high titers of IgM and IgG antibodies that are specific for MUC1. Antibodies appear early in disease and the predominance of the IgG1 subclass suggests Th2-driven immunity. Immune phenotyping revealed an accumulation of Foxp3+ CD4 regulatory T cells (Tregs) in the draining lymph nodes at late-stage disease. Furthermore, our observations in human endometriosis showed a similar recruitment of FOXP3+ CD4 T cells. Overall, our results reveal a Th2/Treg-dominant natural immunity in endometriosis with potential implications for cancer progression.
Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes
Authors: Meznikova Marie , Erdmann Natalie , Allsopp Rich , Harrington Lea A. 
Published: October 2009

SUMMARY
Autosomal dominant mutations in telomere-associated factors elicit a disease known as dyskeratosis congenita (DKC), and patients suffer proliferative abnormalities associated with telomere erosion. Mice that are heterozygous for telomerase genes (Tert or Terc, hereafter referred to as mTert and mTerc) are useful models of telomerase haploinsufficiency, but do not strictly mimic DKC. In strains with long telomeres (&gt;60 kbp), animals that are heterozygous for mTert undergo telomere erosion for nine generations and remain phenotypically normal. In an mTerc heterozygous strain with short telomeres (&lt;15 kbp), early mortality arises after five to six generations, but dyskeratosis occurs only upon the further loss of mPot1b. We show that prolonged mTert heterozygosity (for greater than ten generations) did not elicit disease, even upon heterozygote interbreeding, and that telomeres reset to wild-type lengths. This lengthening did not occur in nullizygotes, and short telomeres inherited from mTert null parents were rescued only in heterozygous progeny. In the bone marrow, nullizygotes remained competent for radioprotection for three generations. Thus, gradual telomere erosion in the presence of telomerase may enable subsequent telomere extension, similar to that described in budding yeast. We speculate whether such adaptation occurs in normal human cells (or whether it could be induced in DKC-derived cells), and whether it might mitigate the impact of telomerase inhibition upon stem cells during cancer therapy.
Circulating ghrelin exists in both lipoprotein bound and free forms
Authors: Holmes E , Davies I , Lowe G , Ranganath L R 
Published: October 2009

Introduction Ghrelin is a gastric peptide that has been implicated in the development of obesity and cardiovascular disease. It has been reported that ghrelin binds to lipoproteins, although the different binding patterns of acylated ghrelin (AG) and unacylated ghrelin (UAG) are still to be determined. Methods Lipoprotein fractions were generated using a self-generating iodixanol gradient. AG and UAG were measured using specific enzyme immunoassays. Results AG bound to all lipoproteins in approximately equal concentrations (VLDL 26%, LDL 22%, HDL 23%) and was present as a plasma protein (27%). UAG bound more specifically to HDL (49%) and was present as a plasma protein (48%). Conclusions The different binding patterns of AG and UAG may have significant implications for their biological effects, including roles in energy metabolism, the development of obesity and potentially in the modulation of cardiovascular disease.
Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: Findings from the women's health initiative (WHI)
Authors: Carbone Laura D , Johnson Karen C , Robbins John , Larson Joseph C , Curb J David , Watson Kathleen , Gass Margery , LaCroix Andrea Z 
Published: October 2009

Abstract
Antiepileptic drugs (AEDs) are used increasingly in clinical practice to treat a number of conditions. However, the relationship between the use of these medications, particularly the newer AEDs, and fracture risk has not been well characterized. We used data from the Women's Health Initiative (WHI) to determine the relationship bewteen the use of AEDs and falls, fractures, and bone mineral density (BMD) over an average of 7.7 years of follow-up. We included 138,667 women (1,385 users of AEDs and 137,282 nonusers) aged 50 to 79 years in this longitudinal cohort analyses. After adjustment for covariates, use of AEDs was positively associated with total fractures [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.30–1.61], all site-specific fractures including the hip (HR = 1.51, 95% CI 1.05–2.17), clinical vertebral fractures (HR = 1.60, 95% CI 1.20–2.12), lower arm or wrist fractures (HR = 1.40, 95% CI 1.11–1.76), and other clinical fractures (HR = 1.46, 95% CI 1.29–1.65) and two or more falls (HR = 1.62, 95% CI 1.50–1.74) but not with baseline BMD or changes in BMD (p ≥ .064 for all sites). Use of more than one and use of enzyme-inducing AEDs were significantly associated with total fractures (HR = 1.55, 95% CI 1.15–2.09 and HR = 1.36, 95% CI 1.09–1.69, respectively). We conclude that in clinical practice, postmenopausal women who use AEDs should be considered at increased risk for fracture, and attention to fall prevention may be particularly important in these women. © 2010 American Society for Bone and Mineral Research.
Bone material quality in transiliac bone biopsies of postmenopausal osteoporotic women after 3 years of strontium ranelate treatment
Authors: Roschger Paul , Manjubala Inderchand , Zoeger Norbert , Meirer Florian , Simon Rolf , Li Chenghao , Fratzl-Zelman Nadja , Misof Barbara M , Paschalis Eleftherios P , Streli Christina , Fratzl Peter , Klaushofer Klaus 
Published: October 2009

Abstract
Strontium ranelate (SrR) is a relatively new treatment for osteoporosis. In this study we investigated its potential impact on human bone material quality in transiliac bone biopsies from postmenopausal osteoporotic women treated 3 years with calcium and vitamin D plus either 2 g SrR per day or placebo. Bone mineralization density distribution (BMDD), strontium (Sr) concentration, collagen cross-link ratio, and indentation modulus were analyzed by quantitative backscattered electron imaging, electron-induced X-ray fluorescence analysis, synchrotron radiation induced micro X-ray fluorescence elemental mapping, Fourier transform infrared imaging, and nanoindentation, respectively. The BMDD of SrR-treated patients was shifted to higher atomic numbers (Zmean +1.5%, p &lt; .05 versus placebo). We observed Sr being preferentially incorporated in bone packets formed during SrR treatment up to 6% atom fraction [Sr/(Sr + Ca)] depending on the SrR serum levels of the individuals (correlation r = 0.84, p = .018). Collagen cross-link ratio was preserved in SR-treated bone. The indentation modulus was significantly decreased in younger versus older bone packets for both placebo- (−20.5%, p &lt; .0001) and SrR-treated individuals (−24.3%, p &lt; .001), whereas no differences were found between the treatment groups. In conclusion, our findings indicate that after SrR treatment, Sr is heterogeneously distributed in bone and preferentially present in bone packets formed during treatment. The effect of SrR on BMDD seems to be due mainly to the uptake of Sr and not to changes in bone calcium content. Taken together, these data provide evidence that the investigated bone quality determinants at tissue level were preserved in postmenopausal osteoporotic women after 3-year treatment with 2 g SrR per day plus calcium and vitamin D. © 2010 American Society for Bone and Mineral Research
Hip fracture causes excess mortality owing to cardiovascular and infectious disease in institutionalized older people: A prospective 5-year study
Authors: Cameron Ian D , Chen Jian Sheng , March Lyn M , Simpson Judy M , Cumming Robert G , Seibel Markus J , Sambrook Philip N 
Published: October 2009

Abstract
An increasing risk of death after hip fracture has been well documented, but the duration and causes remain unclear, especially in very frail older people. This is a nested case-control study of 229 hip fracture cases and 229 controls matched by age, gender, institution type, and follow-up period from a cohort of 2005 institutionalized older people. The residents were assessed at baseline and followed up for hip fracture and death for at least 5 years. Time to death was measured from the same time for each case (time of the hip fracture) and the matched control. The study sample consisted of 90 males and 368 females with a mean age of 86 years (range 67 to 102 years). The hazard ratio (HR) of death for the cases compared with the controls was 3.09 [95% confidence interval (CI) 1.83–5.22, p &lt; .001] for the first 3 months, 1.99 (95% CI 1.13–3.51, p = .02) for the period of 3 to 9 months, and 0.88 (95% CI 0.64–1.22, p = .46) for the period beyond 9 months following a fracture, after adjusting for age, gender, institution type, weight, immobility, cognitive function, comorbidities, and number of medications. The main causes of the excess mortality in the first 9 months were infections (HR = 6.66, 95% CI 1.95–22.77, p = .002) for females and cardiac disease (HR = 2.68, 95% CI 1.39–5.15, p = .003) for both males and females. Bisphosphonate use was associated with a reduction in mortality after hip fracture (p = .002). Intensive medical supervision to reduce cardiovascular and infective complications should be provided for frail older people with recent hip fracture to reduce mortality. © 2010 American Society for Bone and Mineral Research.
Neutron powder diffraction study and DFT calculations on the structure of Zr10Sc4O26
Authors: Meyer Stefanie , Schweda Eberhard , Martinez Meta Neil Jesus , Boysen Hans , Hoelzel Markus , Bredow Thomas 
Published: October 2009

Abstract
Powder neutron diffraction was used to investigate Zr10Sc4O26, the so called γ-phase in the zirconia scandia system. This fluorite related anion deficient compound with composition MX1.86 crystallizes in space group R-3 and lattice constants a = 952.7(3) pm and c = 1745.3(4) pm. Anion vacancies are inserted on the 6c sites in R-3. The neutron data as well as the periodic density-functional calculations performed count for a divacancy model. The paired defect is more stable by 29 kJ/mol than any model with unpaired vacancies including the model with the 1/2[111]F (index F = fluorite) vacancy separation along an empty anion cube.