bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive Model for Survival in Patients With Advanced Cancer
Authors: Chow Edward , Abdolell Mohamed , Panzarella Tony , Harris Kristin , Bezjak Andrea , Warde Padraig , Tannock Ian 
Published: November 2008

Purpose To derive and validate a simple predictive model for survival of patients with metastatic cancer attending a palliative radiotherapy clinic. Patients and Methods We described previously a model predicting survival of patients referred for palliative radiotherapy using six prognostic factors: primary cancer site, site of metastases, Karnofsky performance score (KPS), and the fatigue, appetite, and shortness of breath subscales from the Edmonton Symptom Assessment Scale. Here we simplified the model to include only three factors: primary cancer site, site of metastases, and KPS. Each factor was assigned a value proportional to its prognostic weight, and the weighted scores for each patient were summed to obtain a survival prediction score (SPS). Patients were also grouped according to their number of risk factors (NRF): nonbreast cancer, metastases other than bone, and KPS ≤ 60. The three- and six- variable models were evaluated for their ability to predict survival in patients referred during a different time period and of those referred to a different cancer center. Results A training set of 395 patients, a temporal validation set of 445 patients, and an external validation set of 467 patients were used. The ability of the three- and six-variable models to separate patients into three prognostic groups and to predict their survival was similar using both SPS and NRF methods in the training, temporal, and external validation data sets. There was no statistically significant difference in the performance of the models. Conclusion The three-variable NRF model is preferred because of its relative simplicity.
American Society of Clinical Oncology 2008 Clinical Practice Guideline Update: Use of Chemotherapy and Radiation Therapy Protectants
Authors: Hensley Martee L. , Hagerty Karen L. , Kewalramani Tarun , Green Daniel M. , Meropol Neal J. , Wasserman Todd H. , Cohen Gary I. , Emami Bahman , Gradishar William J. , Mitchell R. Brian , Thigpen J. Tate , Trotti Andy , von Hoff Daniel , Schuchter Lynn M. 
Published: November 2008

Purpose To update a clinical practice guideline on the use of chemotherapy and radiation therapy protectants for patients with cancer. Methods An update committee reviewed literature published since the last guideline update in 2002. Results Thirty-nine reports met the inclusion criteria: palifermin and dexrazoxane, three reports (two studies) each; amifostine, 33 reports (31 studies); and mesna, no published randomized trials identified since 2002. Recommendations Dexrazoxane is not recommended for routine use in breast cancer (BC) in adjuvant setting, or metastatic setting with initial doxorubicin-based chemotherapy. Consider use with metastatic BC and other malignancies, for patients who have received more than 300 mg/m2 doxorubicin who may benefit from continued doxorubicin-containing therapy. Cardiac monitoring should continue in patients receiving doxorubicin. Amifostine may be considered for prevention of cisplatin-associated nephrotoxicity, reduction of grade 3 to 4 neutropenia (alternative strategies are reasonable), and to decrease acute and late xerostomia with fractionated radiation therapy alone for head and neck cancer. It is not recommended for protection against thrombocytopenia, prevention of platinum-associated neurotoxicity or ototoxicity or paclitaxel-associated neuropathy, prevention of radiation therapy–associated mucositis in head and neck cancer, or prevention of esophagitis during concurrent chemoradiotherapy for non–small-cell lung cancer. Palifermin is recommended to decrease severe mucositis in autologous stem-cell transplantation (SCT) for hematologic malignancies with total-body irradiation (TBI) conditioning regimens, and considered for patients undergoing myeloablative allogeneic SCT with TBI-based conditioning regimens. Data are insufficient to recommend use in the non-SCT setting.
Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system
Authors: Musse Abdiwahab A. , Li Zhen , Ackerley Cameron A. , Bienzle Dorothee , Lei Helena , Poma Roberto , Harauz George , Moscarello Mario A. , Mastronardi Fabrizio G. 
Published: November 2008

SUMMARYDemyelination in the central nervous system is the hallmark feature in multiple sclerosis (MS). The mechanism resulting in destabilization of myelin is a complex multi-faceted process, part of which involves deimination of myelin basic protein (MBP). Deimination, the conversion of protein-bound arginine to citrulline, is mediated by the peptidylarginine deiminase (PAD) family of enzymes, of which the PAD2 and PAD4 isoforms are present in myelin. To test the hypothesis that PAD contributes to destabilization of myelin in MS, we developed a transgenic mouse line (PD2) containing multiple copies of the cDNA encoding PAD2, under the control of the MBP promoter. Using previously established criteria, clinical signs were more severe in PD2 mice than in their normal littermates. The increase in PAD2 expression and activity in white matter was demonstrated by immunohistochemistry, reverse transcriptase-PCR, enzyme activity assays, and increased deimination of MBP. Light and electron microscopy revealed more severe focal demyelination and thinner myelin in the PD2 homozygous mice compared with heterozygous PD2 mice. Quantitation of the disease-associated molecules GFAP and CD68, as measured by immunoslot blots, were indicative of astrocytosis and macrophage activation. Concurrently, elevated levels of the pro-inflammatory cytokine TNF-α and nuclear histone deimination support initiation of demyelination by increased PAD activity. These data support the hypothesis that elevated PAD levels in white matter represents an early change that precedes demyelination.
Conceptions of learning, approaches to studying and personal development in UK higher education
Authors: Edmunds Robert , Richardson John T. E. 
Published: November 2008

Background Students in higher education are known to vary in their conceptions of learning, their approaches to studying, and the personal development and personal change that result.Aims This study aimed to explore the relationships among these four aspects of students' experience; to examine whether there were variations across academic subjects and across departments in each subject; and to explore whether there were changes from first year to after graduation.Sample Students in the first year and the final year of the undergraduate programmes at 15 departments, five offering each of three subjects: bioscience, business studies, and sociology.Method Participants completed a questionnaire containing four instruments and were given a similar questionnaire roughly two years later (when the entering students were in their third year, and when the exiting students were in their second year after graduation).Results The students' conceptions of learning showed a clear relationship with their approaches to studying, but the relationships with their personal development and personal change were much weaker. The students' scores were significantly related to age and gender and showed some significant differences across academic subjects and departments. However, there was little change in their scores over time.Conclusion Students' approaches to studying are influenced by their conceptions of learning and are relatively consistent across different contexts. In contrast, their reports of personal change and development seem to be determined by their implicit theories on entering higher education.
Inhibiting Dickkopf-1 (Dkk1) Removes Suppression of Bone Formation and Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma
Authors: Heath Deborah J , Chantry Andrew D , Buckle Clive H , Coulton Les , Shaughnessy John D , Evans Holly R , Snowden John A , Stover David R , Vanderkerken Karin , Croucher Peter I 
Published: November 2008

Abstract
Multiple myeloma (MM) is associated with the development of osteolytic bone disease, mediated by increased osteoclastic bone resorption and impaired osteoblastic bone formation. Dickkopf-1 (Dkk1), a soluble inhibitor of wingless/int (Wnt) signaling and osteoblastogenesis, is elevated in patients with MM and correlates with osteolytic bone disease. In this study, we investigated the effect of inhibiting Dkk1 on the development of osteolytic lesions in the 5T2MM murine model of myeloma. We showed that Dkk1 is expressed by murine 5T2MM myeloma cells. Injection of 5T2MM cells into C57BL/KaLwRij mice resulted in the development of osteolytic bone lesions (p &lt; 0.05), mediated by increased osteoclast numbers (p &lt; 0.001) and a decrease in osteoblast numbers (p &lt; 0.001) and mineralizing surface (p &lt; 0.05). Mice bearing 5T2MM cells were treated with an anti-Dkk1 antibody (BHQ880, 10 mg/kg, IV, twice weekly for 4 wk) from time of paraprotein detection. Anti-Dkk1 treatment prevented 5T2MM-induced suppression of osteoblast numbers (p &lt; 0.001) and surface (p &lt; 0.001). Treatment increased mineralizing surface by 28% and bone formation rate by 25%; however, there was no change in mineral apposition rate. Inhibiting Dkk1 had no effect on osteoclast numbers. μCT analysis showed that anti-Dkk1 treatment significantly protected against 5T2MM-induced trabecular bone loss (p &lt; 0.05) and reduced the development of osteolytic bone lesions (p &lt; 0.05). Treatment had no significant effect on tumor burden. These data suggest that inhibiting Dkk1 prevents the suppression of bone formation and in doing so is effective in preventing the development of osteolytic bone disease in myeloma, offering an effective therapeutic approach to treating this clinically important aspect of myeloma.
Somatic Mutations in SQSTM1 Detected in Affected Tissues From Patients With Sporadic Paget's Disease of Bone
Authors: Merchant Anand , Smielewska Magda , Patel Nimit , Akunowicz Jennifer D , Saria Elizabeth A , Delaney John D , Leach Robin J , Seton Margaret , Hansen Marc F 
Published: November 2008

Abstract
Paget's disease of bone (PDB) is a focal disorder of bone remodeling that leads to overgrowth of affected bone, with rare progression to osteosarcoma. Extensive studies of familial PDB showed that a majority of cases harbor germline mutations in the Sequestosome1 gene (SQSTM1). In contrast, little is known about the mutational status of SQSTM1 in sporadic PDB. We hypothesized that somatic SQSTM1 mutations might occur in the affected tissues of sporadic PDB and pagetic osteosarcoma. We used laser capture microdissection to capture homogeneous populations of cells from the affected bone or tumor of patients with sporadic PDB or pagetic osteosarcoma, respectively. DNA from these samples and appropriate controls was used for sequence analysis and allelic discrimination analysis. Two of five patients with sporadic PDB had SQSTM1C1215T mutations detected in their affected bone but not in their blood samples, indicating a somatic origin of the mutations. Samples from three of five sporadic pagetic osteosarcoma patients had the SQSTM1C1215T mutation, whereas the normal adjacent tissue from two of these tumors clearly lacked the mutation, again indicating an occurrence of somatic events. No SQSTM1 mutations were found in primary adolescent osteosarcomas. The discovery of somatic SQSTM1 mutations in sporadic PDB and pagetic osteosarcoma shows a role for SQSTM1 in both sporadic and inherited PDB. The discovery of somatically acquired mutations in both the diseased bone and tumor samples suggests a paradigm shift in our understanding of this disease.
Association Analysis of WNT10B With Bone Mass and Structure Among Individuals of African Ancestry
Authors: Zmuda Joseph M , Yerges Laura M , Kammerer Candace M , Cauley Jane A , Wang Xiaojing , Nestlerode Cara S , Wheeler Victor W , Patrick Alan L , Bunker ClareAnn H , Moffett Susan P , Ferrell Robert E 
Published: November 2008

Abstract
Wnts comprise a family of secreted growth factors that regulate the development and maintenance of many organs. Recently, Wnt10b was shown to stimulate osteoblastogenesis and bone formation in mice. To evaluate further the role of Wnt10b in bone health in humans, we performed bidirectional sequencing of ∼8 kb of the WNT10B gene region in 192 individuals (96 African, 96 white) to identify single nucleotide polymorphisms (SNPs). We identified 19 SNPs with minor allele frequency (MAF) ≥0.01. Ten of these SNPs were not present in the NCBI dbSNP database (build 127), whereas 10 of the 20 SNPs (50%) reported in dbSNP were not verified. We initially genotyped seven tagging SNPs that captured common (MAF ≥ 0.05) variation in the region with r2 &gt; 0.80 and a potentially functional SNP in exon 5 in 1035 Afro-Caribbean men ≥40 yr of age. Association analysis showed three SNPs in a 3′ region of linkage disequilibrium that were associated with DXA measures of hip BMD. Associations between two of these three SNPs (rs1051886, rs3741627) with hip BMD were replicated in an additional 980 Afro-Caribbean men (p &lt; 0.05), in the combined sample of 2015 men (p ≤ 0.006), and in 416 individuals ≥18 yr of age (mean, 44 yr) belonging to eight extended, multigenerational Afro-Caribbean families with mean family size &gt;50 (3535 relative pairs; p &lt; 0.05). Further analysis showed that rs1051886 and rs3741627 were associated with cortical cross-sectional area, periosteal circumference, and BMC in the radius, such that individuals with the minor alleles had lower biomechanical indices of long-bone bending strength. This analysis implicates the WNT10B locus as a genetic element in the regulation of bone mass and structural geometry.
How Does Body Fat Influence Bone Mass in Childhood? A Mendelian Randomization Approach
Authors: Timpson Nicholas J , Sayers Adrian , Davey-Smith George , Tobias Jonathan H 
Published: November 2008

Abstract
Fat mass may be a causal determinant of bone mass, but the evidence is conflicting, possibly reflecting the influence of confounding factors. The recent identification of common genetic variants related to obesity in children provides an opportunity to implement a Mendelian randomization study of obesity and bone outcomes, which is less subject to confounding and several biases than conventional approaches. Genotyping was retrieved for variants of two loci reliably associated with adiposity (the fat mass and obesity-related gene FTO and that upstream of the MC4R locus) within 7470 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had undergone total body DXA scans at a mean of 9.9 yr. Relationships between both fat mass/genotypes and bone measures were assessed in efforts to determine evidence of causality between adiposity and bone mass. In conventional tests of association, both with and without height adjustment, total fat mass was strongly related to total body, spinal, and upper and lower limb BMC (ratio of geometric means [RGM]: 1.118 [95% CI: 1.112, 1.123], 1.110 [95% CI: 1.102, 1.119], 1.101 [95% CI: 1.093, 1.108], 1.146 [95% CI: 1.143, 1.155]; p &lt; 10−10 [adjusted for sex, height, and sitting height]). Equivalent or larger effects were obtained from instrumental variable (IV) regression including the same covariates (1.139 [95% CI: 1.064, 1.220], 1.090 [95% CI: 1.010, 1.177], 1.142 [95% CI: 1.049, 1.243], 1.176 [95% CI: 1.099, 1.257]; p = 0.0002, 0.03, 0.002, and 2.3−6 respectively). Similar results were obtained after adjusting for puberty, when truncal fat mass was used in place of total fat, and when bone area was used instead of bone mass. In analyses where total body BMC adjusted for bone area (BA) was the outcome (reflecting volumetric BMD), linear regression with fat mass showed evidence for association (1.004 [95% CI: 1.002, 1.007], p = 0.0001). IV regression also showed a positive effect (1.031 [95% CI: 1.000, 1.062], p = 0.05). When MC4R and FTO markers were used as instruments for fat mass, similar associations with BMC were seen to those with fat mass as measured by DXA. This suggests that fat mass is on the causal pathway for bone mass in children. In addition, both directly assessed and IV-assessed relationships between fat mass and volumetric density showed evidence for positive effects, supporting a hypothesis that fat effects on bone mass are not entirely accounted for by association with overall bone size.
A Rare Haplotype in the Upstream Regulatory Region of COL1A1 Is Associated With Reduced Bone Quality and Hip Fracture
Authors: Jin Huilin , Stewart Tracy L , Van't Hof Rob , Reid David M , Aspden Richard M , Ralston Stuart 
Published: November 2008

Abstract
Three polymorphisms have been identified in the 5′ regulatory region of the COL1A1 gene at positions −1997 (rs1107946), −1663 (rs2412298), and +1245G/T (rs1800012), which combine to form haplotypes that have been associated with BMD in several populations. These polymorphisms and haplotypes have not thus far been studied in relation to biomechanical properties of bone or fracture risk. Genotypes and haplotypes of the COL1A1 gene were related to the biomechanical properties of bone ex vivo in samples of bone tissue obtained from the femoral head of 98 consecutive patients undergoing surgery for low-trauma hip fractures. Genotype and haplotype frequencies in the hip fracture cases were compared with 3418 population-based controls recruited from the same region. All three polymorphisms were associated with material density of the bone core, yield strength, and toughness. The association between −1663InsdelT and +1245G/T alleles, yield strength, and toughness remained significant after adjusting for material density of the core and other confounding factors. A haplotype comprising the unfavorable allele at all three polymorphic sites (−1997T/−1663delT/+1245T) was also associated with yield strength, modulus, and toughness after adjusting for confounding factors. This haplotype was carried by 19/94 (20.2%) patients with hip fracture compared with only 2/3399 (0.06%) female controls drawn from the general population (p &lt; 0.0001). In contrast, there was no significant difference between cases and controls in genotype distribution for the individual polymorphisms. This study shows that common genetic variants in the 5′ regulatory region of COL1A1 are associated with biomechanical properties of bone and reduced bone quality by mechanisms independent of their effects on BMD. The biomechanically unfavorable allele at each polymorphic site defines a haplotype that is extremely rare in the general population but that is ∼400-fold enriched in hip fracture patients. This haplotype may have clinical value as a genetic marker for susceptibility to hip fracture, and further studies to investigate this possibility would be of interest.
Comparison of Effects of the Bisphosphonate Alendronate Versus the RANKL Inhibitor Denosumab on Murine Fracture Healing
Authors: Gerstenfeld Louis C , Sacks Daniel J , Pelis Megan , Mason Zachary D , Graves Dana T , Barrero Mauricio , Ominsky Michael S , Kostenuik Paul J , Morgan Elise F , Einhorn Thomas A 
Published: November 2008

Abstract
The role of osteoclast-mediated resorption during fracture healing was assessed. The impact of two osteoclast inhibitors with different mechanisms of action, alendronate (ALN) and denosumab (DMAB), were examined during fracture healing. Male human RANKL knock-in mice that express a chimeric (human/murine) form of RANKL received unilateral transverse femur fractures. Mice were treated biweekly with ALN 0.1 mg/kg, DMAB 10 mg/kg, or PBS (control) 0.1 ml until death at 21 and 42 days after fracture. Treatment efficacy assessed by serum levels of TRACP 5b showed almost a complete elimination of TRACP 5b levels in the DMAB-treated animals but only ∼25% reduction of serum levels in the ALN-treated mice. Mechanical testing showed that fractured femurs from both ALN and DMAB groups had significantly increased mechanical properties at day 42 compared with controls. μCT analysis showed that callus tissues from DMAB-treated mice had significantly greater percent bone volume and BMD than did both control and ALN-treated tissues at both 21 and 42 days, whereas ALN-treated bones only had greater percent bone volume and BMC than control at 42 days. Qualitative histological analysis showed that the 21-and 42-day ALN and DMAB groups had greater amounts of unresorbed cartilage or mineralized cartilage matrix compared with the controls, whereas unresorbed cartilage could still be seen in the DMAB groups at 42 days after fracture. Although ALN and DMAB delayed the removal of cartilage and the remodeling of the fracture callus, this did not diminish the mechanical integrity of the healing fractures in mice receiving these treatments. In contrast, strength and stiffness were enhanced in these treatment groups compared with control bones.
Genetic Influences on Thought Problems in 7-Year-Olds: A Twin-Study of Genetic, Environmental and Rater Effects
Authors: Abdellaoui Abdel , Bartels Meike , Hudziak James J. , Rizzu Patrizia , van Beijsterveldt Toos CEM , Boomsma Dorret I. 
Published: November 2008

AbstractThe Thought–Problem scale (TP) of the CBCL assesses symptoms such as hallucinations and strange thoughts/behaviors and has been associated with other behavioral disorders. This study uses parental reports to examine the etiology of variation in TP, about which relatively little is known, in 7-year-old twins. Parental ratings on TP were collected in 8,962 7-year-old twin pairs. Because the distribution of TP scores was highly skewed scores were categorized into 3 classes. The data were analyzed under a threshold liability model with genetic structural equation modeling. Ratings from both parents were simultaneously analyzed to determine the rater agreement phenotype (or common phenotype [TPc]) and the rater specific phenotype [TPs] that represents rater disagreement caused by rater bias, measurement error and/or a unique view of the parents on the child's behavior. Scores on the TP-scale varied as a function of rater (fathers rated fewer problems), sex (boys scored higher) and zygosity (DZ twins scored higher). The TPc explained 67% of the total variance in the parental ratings. Variation in TPc was influenced mainly by the children's genotype (76%). Variance in TPs also showed a contribution of genetic factors (maternal reports: 61%, paternal reports: 65%), indicating that TPs does not only represent rater bias. Shared environmental influences were only found in the TPs. No sex differences in genetic architecture were observed. These results indicate an important contribution of genetic factors to thought problems in children as young as 7 years.