bluuebunny/crossref_metadata_2025_split huggingface dataset:
What is the clinical and ethical importance of incidental abnormalities found by knee MRI?
Authors: Grainger Rebecca , Stuckey Stephen , O'Sullivan Richard , Davis Susan R , Ebeling Peter R , Wluka Anita E 
Published: February 2008

Abstract
Introduction
Magnetic resonance imaging (MRI) is increasingly used to examine joints for research purposes. It may detect both suspected and unsuspected abnormalities. This raises both clinical and ethical issues, especially when incidental abnormalities are detected. The prevalence of incidental, potentially clinically significant abnormalities identified by MRI and their clinical significance in a population undergoing knee MRI in research studies are unknown.

Methods
We examined the prevalence of such lesions in healthy asymptomatic adults and those with symptomatic knee osteoarthritis (OA) undergoing knee MRI with limited sequences for the purpose of research. The MRI findings in 601 asymptomatic subjects and 132 with knee OA who underwent at least one limited knee MRI scan for cartilage volume measurement were examined by an MRI radiologist for the presence of potentially clinically significant abnormalities.

Results
These were present in 2.3% of healthy and 2.3% of OA subjects. All required further investigation to exclude non-benign disease, including four with bone marrow expansion (0.7%), requiring further investigation and management. A single potentially life-threatening lesion, a myeloma lesion, was identified in a subject with symptomatic knee OA on their second MRI scan in a longitudinal study.

Conclusion
As musculoskeletal MRI is increasingly used clinically and for research purposes, the potential for detecting unsuspected abnormalities that require further investigation should be recognized. Incorporating a system to detect these, to characterize unexpected findings, and to facilitate appropriate medical follow-up when designing studies using this technology should be considered ethical research practice.
Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer
Authors: Wu Yanyuan , Mohamed Hezla , Chillar Ram , Ali Ishrat , Clayton Sheila , Slamon Dennis , Vadgama Jaydutt V 
Published: February 2008

Abstract
Introduction
Breast cancer patients with HER2/neu overexpression have poor outcomes with a decrease in disease-free survival (DFS) and overall survival. The biology of HER2/neu overexpression in breast tumors in African-American and Latina women is poorly understood. The purpose of this study is to understand the clinical significance of activated Akt (phospho-Akt or pAkt) expression in breast tumors from African-American and Latina patients with corresponding tissue HER2/neu overexpression. Cellular and molecular studies have shown that activation of the cell signaling phosphatidylinositol-3-kinase/Akt cascade via the HER2/neu and other receptor tyrosine kinases induces cell proliferation.

Methods
A total of 234 African-American and Latina patients were selected retrospectively. From this group, 141 tumor tissue samples were analyzed for tissue pAkt by immunohistochemistry (IHC). This cohort consisted of 46 HER2/neu-positive (3+ by IHC) and 95 HER2/neu-negative tumors. The prognostic value of activated tissue Akt in relation to HER2/neu overexpression for DFS was determined.

Results
Patients with low pAkt and HER2-negative tumors had the best DFS. As expected, HER2/neu-overexpressing tumors with low pAkt had a decrease in DFS. Similarly, those with high pAkt and HER2-negative tumors also had poor DFS. However, those with an increase in both HER2 and pAkt had the worst DFS. An increase in pAkt was significantly associated with HER2/neu-positive and lymph node-positive breast tumors. Tumors with high HER2 and high pAkt were metastatic. Multivariate analysis demonstrated that, in addition to the common risk factors such as larger tumor size, lymph node involvement, estrogen receptor/progesterone receptor-negative tumors, and HER2/neu-positive tumors, overexpression of pAkt significantly was associated with a decrease in 5-year DFS. A decrease in DFS with an increase in pAkt was observed in both HER2/neu-positive and -negative groups. However, the DFS was similar between HER2/neu-positive/pAkt-negative and HER2/neu-negative/pAkt-positive groups.

Conclusion
Our data suggest that there may be differences in tumor phenotypes within the HER2/neu-overexpressing breast cancer patients. The overexpression of pAkt may be a powerful prognostic marker for predicting DFS and overall survival of breast cancer patients.
Oral Contraceptives, Postmenopausal Hormones, and Risk of Asynchronous Bilateral Breast Cancer: The WECARE Study Group
Authors: Figueiredo Jane C. , Bernstein Leslie , Capanu Marinela , Malone Kathleen E. , Lynch Charles F. , Anton-Culver Hoda , Stovall Marilyn , Bertelsen Lisbeth , Haile Robert W. , Bernstein Jonine L. 
Published: February 2008

Purpose To investigate whether oral contraceptive (OC) use and postmenopausal hormones (PMH) are associated with an increased risk of developing asynchronous bilateral breast cancer among women diagnosed with breast cancer younger than 55 years. Patients and Methods The WECARE (Women's Environment, Cancer, and Radiation Epidemiology) study is a population-based, multicenter, case-control study of 708 women with asynchronous bilateral breast cancer and 1,395 women with unilateral breast cancer. Risk factor information collected during a telephone interview focused on exposures before and after the first breast cancer diagnosis. Treatment and tumor characteristics were abstracted from medical records. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% CIs. Results OC use before the first breast cancer diagnosis was not associated with risk of asynchronous bilateral breast cancer (RR = 0.88; 95% CI, 0.67 to 1.16). OC use after breast cancer diagnosis was also not significantly associated with risk (RR = 1.56; 95% CI, 0.71 to 3.45). Risk did not increase with longer duration of use or among women who had begun using OCs at a younger age. No evidence of an increased risk of asynchronous bilateral breast cancer was observed with PMH use before (RR = 1.21; 95% CI, 0.90 to 1.61) or after breast cancer diagnosis (RR = 1.10; 95% CI, 0.67 to 1.77). Neither duration nor type of PMH were associated with risk. Age at and time since first breast cancer diagnosis did not substantially affect these results. Conclusion This study provides no strong evidence that OC or PMH use increases the risk of a second cancer in the contralateral breast.
Insulin-Like Growth Factor (IGF) Binding Protein-4 Is Both a Positive and Negative Regulator of IGF Activity in Vivo
Authors: Ning Yun , Schuller Alwin G. P. , Conover Cheryl A. , Pintar John E. 
Published: February 2008

AbstractIGFs are required for normal prenatal and postnatal growth. Although actions of IGFs can be modulated by a family of IGF-binding proteins (IGFBPs) in vitro, these studies have identified a complicated pattern of stimulatory and inhibitory IGFBP effects, so that understanding relevant aspects of IGFBP action in vivo has been limited. Here we have produced a null mutation of one specific IGFBP, IGFBP-4, which is coexpressed with IGF-II early in development. Surprisingly, mutation of IGFBP-4, believed from in vitro studies to be exclusively inhibitory, leads to a prenatal growth deficit that is apparent from the time that the IGF-II growth deficit first arises, which strongly suggests that IGFBP-4 is required for optimal IGF-II-promoted growth during fetal development. Mice encoding a mutant IGFBP-4 protease (pregnancy-associated plasma protein-A), which facilitates IGF-II release from an inactive IGF-II/IGFBP-4 complex in vitro, are even smaller than IGFBP-4 mutant mice. However, the more modest IGFBP-4 growth deficit is completely restored in double IGFBP-4/pregnancy-associated plasma protein-A-deficient mice. Taken together these results indicate not only that IGFBP-4 functions as a local reservoir to optimize IGF-II actions needed for normal embryogenesis, but also establish that IGFBP-4 proteolysis is required to activate most, if not all, IGF-II mediated growth-promoting activity.
Reduction of Indium(III) Oxide to Indium through Mechanochemical Route
Authors: Kano Junya , Kobayashi Eiko , Tongamp William , Saito Fumio 
Published: February 2008

Abstract
A nonthermal reduction of indium(III) oxide (In2O3) to metallic indium (In) was achieved through mechanochemical route in this work. A mixture of In2O3 and lithium nitride (Li3N) under ammonia (NH3) and/or nitrogen (N2) gas environments was milled in a planetary ball mill with uni-size ZrO2 balls to induce mechanochemical reaction between the starting materials. Metallic indium was obtained after milling for 120 min, and the results are confirmed by X-ray diffraction (XRD) analysis. Washing of the milled product with water to remove by-products using the planetary ball mill for a further 10 min resulted in formation of pellets which were analyzed by EPMA, results clearly show that high purity indium metal was obtained.
RANKL Inhibition with Osteoprotegerin Increases Bone Strength by Improving Cortical and Trabecular bone Architecture in Ovariectomized Rats
Authors: Ominsky Michael S , Li Xiaodong , Asuncion Frank J , Barrero Mauricio , Warmington Kelly S , Dwyer Denise , Stolina Marina , Geng Zhaopo , Grisanti Mario , Tan Hong-Lin , Corbin Timothy , McCabe James , Simonet William S , Ke Hua Z , Kostenuik Paul J 
Published: February 2008

Abstract
Introduction: Ovariectomy (OVX) results in bone loss caused by increased bone resorption. RANKL is an essential mediator of bone resorption. We examined whether the RANKL inhibitor osteoprotegerin (OPG) would preserve bone volume, density, and strength in OVX rats.
Materials and Methods: Rats were OVX or sham-operated at 3 mo of age. Sham controls were treated for 6 wk with vehicle (Veh, PBS). OVX rats were treated with Veh or human OPG-Fc (10 mg/kg, 2/wk). Serum RANKL and TRACP5b was measured by ELISA. BMD of lumbar vertebrae (L1–L5) and distal femur was measured by DXA. Right distal femurs were processed for bone histomorphometry. Left femurs and the fifth lumbar vertebra (L5) were analyzed by μCT and biomechanical testing, and L6 was analyzed for ash weight.
Results: OVX was associated with significantly greater serum RANKL and osteoclast surface and with reduced areal and volumetric BMD. OPG markedly reduced osteoclast surface and serum TRACP5b while completely preventing OVX-associated bone loss in the lumbar vertebrae, distal femur, and femur neck. Vertebrae from OPG-treated rats had increased dry and ash weight, with no significant differences in tissue mineralization versus OVX controls. μCT showed that trabecular compartments in OVX-OPG rats had significantly greater bone volume fraction, vBMD, bone area, trabecular thickness, and number, whereas their cortical compartments had significantly greater bone area (p &lt; 0.05 versus OVX-Veh). OPG improved cortical area in L5 and the femur neck to levels that were significantly greater than OVX or sham controls (p &lt; 0.05). Biomechanical testing of L5 and femur necks showed significantly greater maximum load values in the OVX-OPG group (p &lt; 0.05 versus OVX-Veh). Bone strength at both sites was linearly correlated with total bone area (r2 = 0.54–0.74, p &lt; 0.0001), which was also significantly increased by OPG (p &lt; 0.05 versus OVX).
Conclusions: OPG treatment prevented bone loss, preserved trabecular architecture, and increased cortical area and bone strength in OVX rats.
Osteoblast-Derived TGF-β1 Stimulates IL-8 Release Through AP-1 and NF-κB in Human Cancer Cells
Authors: Fong Yi-Chin , Maa Ming-Chei , Tsai Fuu-Jen , Chen Wen-Chi , Lin Jaung-Geng , Jeng Long-Bin , Yang Rong-Sen , Fu Wen-Mei , Tang Chih-Hsin 
Published: February 2008

Abstract
Introduction: The bone marrow microenvironment is further enriched by growth factors released during osteoclastic bone resorption. It has been reported that the chemokine interleukin (IL)-8 is a potent and direct activator of osteoclastic differentiation and bone resorption. However, the effect of bone-derived growth factors on the IL-8 production in human cancer cells and the promotion of osteoclastogenesis are largely unknown. The aim of this study was to investigate whether osteoblast-derived TGF-β1 is associated with osteolytic bone diseases.
Materials and Methods: IL-8 mRNA levels were measured using RT-PCR analysis. MAPK phosphorylation was examined using the Western blot method. siRNA was used to inhibit the expression of TGF-β1, BMP-2, and IGF-1. DNA affinity protein-binding assay and chromatin immunoprecipitation assays were used to study in vitro and in vivo binding of c-fos, c-jun, p65, and p50 to the IL-8 promoter. A transient transfection protocol was used to examine IL-8, NF-κB, and activator protein (AP)-1 activity.
Results: Osteoblast conditioned medium (OBCM) induced activation of IL-8, AP-1, and NF-κB promoter in human cancer cells. Osteoblasts were transfected with TGF-β1, BMP-2, or IGF-1 small interfering RNA, and the medium was collected after 48 h. TGF-β1 but not BMP-2 or IGF-1 siRNA inhibited OBCM-induced IL-8 release in human cancer cells. In addition, TGF-β1 also directly induced IL-8 release in human cancer cells. Activation of AP-1 and NF-κB DNA-protein binding and MAPKs after TGF-β1 treatment was shown, and TGF-β1–induced IL-8 promoter activity was inhibited by the specific inhibitors of MAPK cascades.
Conclusions: In this study, we provide evidence to show that the osteoblasts release growth factors, including TGF-β1, BMP-2, and IGF-1. TGF-β1 is the major contributor to the activation of extracellular signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), leading to the activation of AP-1 and NF-κB on the IL-8 promoter and initiation of IL-8 mRNA and protein release, thereby promoting osteoclastogenesis.
ALK1 Opposes ALK5/Smad3 Signaling and Expression of Extracellular Matrix Components in Human Chondrocytes
Authors: Finnson Kenneth W , Parker Wendy L , ten Dijke Peter , Thorikay Midory , Philip Anie 
Published: February 2008

Abstract
Introduction: TGF-β is a multifunctional regulator of chondrocyte proliferation, differentiation, and extracellular matrix production. Dysregulation of TGF-β action has been implicated in cartilage diseases such as osteoarthritis. TGF-β signaling is transduced through a pair of transmembrane serine/threonine kinases, known as the type I (ALK5) and type II receptors. However, recent studies on endothelial cells have identified ALK1 as a second type I TGF-β receptor and have shown that ALK1 and ALK5 have opposing functions in these cells. Here we examined ALK1 expression and its regulation of TGF-β signaling and responses in human chondrocytes.
Materials and Methods: ALK1 expression in human chondrocytes was examined by RT-PCR and Western blot. The ability of ALK1 to form complexes with other TGF-β receptors was determined by affinity labeling/immunoprecipitation and by immunoprecipitation followed by Western blot. The effect of ALK1 on TGF-β1–induced signaling and responses was determined by varying ALK1 expression levels and measuring transcriptional activity using promoter/luciferase assays, Smad1/5 and Smad3 phosphorylation, and expression of type II collagen, PAI-1, and fibronectin.
Results: Our results indicate that ALK1 is expressed in human chondrocytes and that it is a component of the TGF-β receptor system, associating with ALK5, type II TGF-β receptor, endoglin, and betaglycan. Furthermore, we show that both ALK1 and ALK5 are needed for TGF-β–induced phosphorylation of intracellular mediators Smad1/5, whereas only ALK5 is essential for TGF-β1–induced phosphorylation of Smad3. In addition, our results show that ALK1 inhibits, whereas ALK5 potentiates, TGF-β–induced Smad3-driven transcriptional activity and the expression of PAI-1, fibronectin, and type II collagen in chondrocytes.
Conclusions: Our results suggest that ALK1 and ALK5 display opposing functions in human chondrocytes, implicating an essential role for ALK1 in the regulation of TGF-β signaling and function in these cells.
Trabecular Bone Deterioration in col9a1+/− Mice Associated With Enlarged Osteoclasts Adhered to Collagen IX–Deficient Bone
Authors: Wang Chiachien Jake , Iida Keisuke , Egusa Hiroshi , Hokugo Akishige , Jewett Anahid , Nishimura Ichiro 
Published: February 2008

Abstract
Introduction: Short collagen IX, the exclusive isoform expressed by osteoblasts, is synthesized through alternative transcription of the col9a1 gene. The function of short collagen IX in bone was characterized in col9a1-null mutant mice.
Materials and Methods: Trabecular bone morphometry of lumbar bones and tibias was evaluated by μCT and nondecalcified histology. Osteoblastic and osteoclastic activities were evaluated by PCR- and microarray-based gene expression assays and TRACP-5b and C-terminal telopeptide (CTX) assays, as well as in vitro using bone marrow stromal cells and splenocytes. The effect of col9a1+/− mutation on osteoclast morphology was evaluated using RAW264.7-derived osteoclastic cells cultured on the mutant or wildtype calvarial bone substrates.
Results: Col9a1 knockout mutation caused little effects on the skeletal development; however, young adult female col9a1−/− and col9a1+/− mice exhibited significant loss of trabecular bone. The trabecular bone architecture was progressively deteriorated in both male and female heterozygous col9a1+/− mice while aging. The aged mutant mice also exhibited signs of thoracic kyphosis and weight loss, resembling the clinical signs of osteoporosis. The col9a1+/− osteoblasts synthesized short col9a1 transcripts at decreased rates. Whereas bone formation activities in vitro and in vivo were not affected, the mutant osteoblast expressed the elevated ratio of RANKL/osteoprotegerin. Increased serum TRACP-5b and CTX levels were found in col9a1+/− mice, whose bone surface was associated with osteoclastic cells that were abnormally flattened and enlarged. The mutant and wildtype splenocytes underwent similar osteoclastogenesis in vitro; however, RAW264.7-derived osteoclastic cells, when cultured on the col9a1+/− calvaria, widely spread over the bone surface and formed large resorption pits. The surface of col9a1+/− calvaria was found to lack the typical nanotopography.
Conclusions: The mineralized bone matrix deficient of short collagen IX may become susceptible to osteoclastic bone resorption, possibly through a novel non–cell-autonomous mechanism. The data suggest the involvement of bone collagen IX in the pathogenesis of osteoporosis.
Free Thyroid Hormones in Serum by Direct Equilibrium Dialysis and Online Solid-Phase Extraction–Liquid Chromatography/Tandem Mass Spectrometry
Authors: Yue Bingfang , Rockwood Alan L , Sandrock Tanya , La’ulu Sonia L , Kushnir Mark M , Meikle A Wayne 
Published: February 2008

AbstractBackground: Measurements of free thyroxine (FT4) and free triiodothyronine (FT3) are important for the diagnosis and monitoring of thyroid diseases. Considerable differences among methods limit their clinical utility, however, and accurate methods are needed for various clinical specimens. We describe a direct equilibrium dialysis (ED)–liquid chromatography (LC)/tandem mass spectrometry (MS/MS) method for FT4 and FT3.Methods: ED was selected as the separation step. Serum samples were dialyzed 1:1 against a simple protein-free buffer for 20 h at 37 °C. Thyroid hormones in dialysates were purified by online solid-phase extraction (SPE), then chromatographically separated and quantified in positive ion and multiple reaction monitoring modes.Results: For FT4 and FT3, the lower and upper limits of quantification were 1 ng/L (pg/mL) and 400 ng/L with total imprecision &lt;10%. The method correlated well with an ED-RIA, 2 direct immunoassay methods for FT4, and 1 direct immunoassay and 1 tracer dialysis method for FT3. The adult reference intervals were 12.8–22.2 ng/L for FT4 and 3.62–6.75 ng/L for FT3. Reference intervals for the second trimester of pregnancy (14–20 weeks of gestation) were also established.Conclusions: We developed a simple protein-free buffer and ED procedure. The performance characteristics and high throughput of the LC-MS/MS method with online SPE for FT4 and FT3 (also reverse T3) are sufficient for the intended clinical use.
Epigenetics of Personality Traits: An Illustrative Study of Identical Twins Discordant for Risk-Taking Behavior
Authors: Kaminsky Zachary , Petronis Arturas , Wang Sun-Chong , Levine Brian , Ghaffar Omar , Floden Darlene , Feinstein Anthony 
Published: February 2008

AbstractDNA methylation differences between identical twins could account for phenotypic twin discordance of behavioral traits and diseases. High throughput epigenomic microarray profiling can be a strategy of choice for identification of epigenetic differences in phenotypically different monozygotic (MZ) twins. Epigenomic profiling of a pair of MZ twins with quantified measures of psychometric discordance identified several DNA methylation differences, some of which may have developmental and behavioral implications and are consistent with the contrasting psychometric profiles of the twins. In particular, differential methylation of CpG islands proximal to the homeobox DLX1 gene could modulate stress responses and risk taking behavior, and deserve further attention as a potential marker of aversion to danger. The epigenetic difference detected at DLX1 of ∼1.2 fold change was used to evaluate experimental design issues such as the required numbers of technical replicates. It also enabled us to estimate the power this technique would have to detect a functionally relevant epigenetic difference given a range of 1 to 50 twin pairs. We found that use of epigenomic microarray profiling in a relatively small number (15–25) of phenotypically discordant twin pairs has sufficient power to detect 1.2 fold epigenetic changes.
Genetic and Environmental Contributions to Humor Styles: A Replication Study
Authors: Vernon Philip A. , Martin Rod A. , Schermer Julie Aitken , Cherkas Lynn F. , Spector Tim D. 
Published: February 2008

AbstractOne thousand and seventy three pairs of adult monozygotic (MZ) twins and 895 pairs of same sex adult dizygotic (DZ) twins from the United Kingdom (UK) completed the Humor Styles Questionnaire: a 32-item measure which assesses two positive and two negative styles of humor. MZ correlations were approximately twice as large as DZ correlations for all four humor styles, and univariate behavioral genetic model fitting indicated that individual differences in all of them can be accounted for entirely by genetic and nonshared environmental factors, with heritabilities ranging from .34 to .49. These results, while perhaps not surprising, are somewhat at odds with a previous study that we conducted in North America (Vernon et al., in press) in which genetic factors contributed significantly to individual differences in the two positive humor styles, but contributed far less to the two negative styles, variance in which was instead largely due to shared and nonshared environmental factors. We suggest that differences between North American and UK citizens in their appreciation of different kinds of humor may be responsible for the different results obtained in these two studies.