bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal competition with alternating dominance in multiple myeloma
Authors: Keats Jonathan J. , Chesi Marta , Egan Jan B. , Garbitt Victoria M. , Palmer Stephen E. , Braggio Esteban , Van Wier Scott , Blackburn Patrick R. , Baker Angela S. , Dispenzieri Angela , Kumar Shaji , Rajkumar S. Vincent , Carpten John D. , Barrett Michael , Fonseca Rafael , Stewart A. Keith , Bergsagel P. Leif 
Published: April 2012

Abstract
Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection.
Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial
Authors: Kumar Shaji K. , Hayman Suzanne R. , Buadi Francis K. , Roy Vivek , Lacy Martha Q. , Gertz Morie A. , Allred Jacob , Laumann Kristina M. , Bergsagel Leif P. , Dingli David , Mikhael Joseph R. , Reeder Craig B. , Stewart A. Keith , Zeldenrust Steven R. , Greipp Philip R. , Lust John A. , Fonseca Rafael , Russell Stephen J. , Rajkumar S. Vincent , Dispenzieri Angela 
Published: April 2012

Abstract
Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).
The ARIC predictive model reliably predicted risk of type II diabetes in Asian populations
Authors: Chin Calvin Woon-Loong , Chia Elian Hui San , Ma Stefan , Heng Derrick , Tan Maudrene , Lee Jeanette , Tai E Shyong , Salim Agus 
Published: April 2012

Abstract

Background
Identification of high-risk individuals is crucial for effective implementation of type 2 diabetes mellitus prevention programs. Several studies have shown that multivariable predictive functions perform as well as the 2-hour post-challenge glucose in identifying these high-risk individuals. The performance of these functions in Asian populations, where the rise in prevalence of type 2 diabetes mellitus is expected to be the greatest in the next several decades, is relatively unknown.

Methods
Using data from three Asian populations in Singapore, we compared the performance of three multivariate predictive models in terms of their discriminatory power and calibration quality: the San Antonio Health Study model, Atherosclerosis Risk in Communities model and the Framingham model.

Results
The San Antonio Health Study and Atherosclerosis Risk in Communities models had better discriminative powers than using only fasting plasma glucose or the 2-hour post-challenge glucose. However, the Framingham model did not perform significantly better than fasting glucose or the 2-hour post-challenge glucose. All
published
models suffered from poor calibration. After recalibration, the Atherosclerosis Risk in Communities model achieved good calibration, the San Antonio Health Study model showed a significant lack of fit in females and the Framingham model showed a significant lack of fit in both females and males.

Conclusions
We conclude that adoption of the ARIC model for Asian populations is feasible and highly recommended when local prospective data is unavailable.
Longitudinal seroepidemiologic study of the 2009 pandemic influenza A (H1N1) infection among health care workers in a children's hospital
Authors: Yen Ting-Yu , Lu Chun-Yi , Chang Luan-Yin , Tsai Yi-Ting , Huang Li-Min 
Published: April 2012

Abstract

Background
To probe seroepidemiology of the 2009 pandemic influenza A (H1N1) among health care workers (HCWs) in a children's hospital.

Methods
From August 2009 to March 2010, serum samples were drawn from 150 HCWs in a children's hospital in Taipei before the 2009 influenza A (H1N1) pandemic, before H1N1 vaccination, and after the pandemic. HCWs who had come into direct contact with 2009 influenza A (H1N1) patients or their clinical respiratory samples during their daily work were designated as a high-risk group. Antibody levels were determined by hemagglutination inhibition (HAI) assay. A four-fold or greater increase in HAI titers between any successive paired sera was defined as seroconversion, and factors associated with seroconversion were analyzed.

Results
Among the 150 HCWs, 18 (12.0%) showed either virological or serological evidence of 2009 pandemic influenza A (H1N1) infection. Of the 90 unvaccinated HCWs, baseline and post-pandemic seroprotective rates were 5.6% and 20.0%. Seroconversion rates among unvaccinated HCWs were 14.4% (13/90), 22.5% (9/40), and 8.0% (4/50) for total, high-risk group, and low-risk group, respectively. Multivariate analysis revealed being in the high-risk group is an independent risk factor associated with seroconversion.

Conclusion
The infection rate of 2009 pandemic influenza A (H1N1) in HCWs was moderate and not higher than that for the general population. The majority of unvaccinated HCWs remained susceptible. Direct contact of influenza patients and their respiratory samples increased the risk of infection.
A novel single nucleotide polymorphism within the NOD2 gene is associated with pulmonary tuberculosis in the Chinese Han, Uygur and Kazak populations
Authors: Zhao Mengyuan , Jiang Feng , Zhang Wanjiang , Li Fujian , Wei Liliang , Liu Jiyan , Xue Yun , Deng Xiling , Wu Fang , Zhang Le , Zhang Xing , Zhang Yuxiang , Fan Dapeng , Sun Xiaojun , Jiang Tingting , Li Ji-Cheng 
Published: April 2012

Abstract

Background
The present study aimed to investigate the genetic polymorphisms in exon 4 of the NOD2 gene in tuberculosis patients and healthy controls, in order to clarify whether polymorphisms in the NOD2 gene is associated with tuberculosis.

Methods
A case-control study was performed on the Chinese Han, Uygur and Kazak populations. Exon 4 of the NOD2 gene was sequenced in 425 TB patients and 380 healthy controls to identify SNPs.

Results
The frequency of T/G genotypes for the Arg587Arg (CGT → CGG) single nucleotide polymorphism (SNP) in NOD2 was found to be significantly higher in the Uygur (34.9%) and Kazak (37.1%) populations than the Han population (18.6%). Also, the frequency of G/G genotypes for the Arg587Arg SNP was significantly higher in the Uyghur (8.3%) and Kazak (5.4%) populations than the Han population (0.9%). Meanwhile, no significant difference was found in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Uyghur and Kazak populations (P > 0.05) whereas, a significant difference was observed in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Han population (P < 0.01). The odd ratio of 2.16 (95% CI = 1.31-3.58; P < 0.01) indicated that the Arg587Arg SNP in NOD2 may be associated with susceptibility to tuberculosis in the Chinese Han population.

Conclusions
Our study is the first to demonstrate that the Arg587Arg SNP in NOD2 is a new possible risk factor for tuberculosis in the Chinese Han population, but not in the Uyghur and Kazak populations. Our results may reflect racial differences in genetic susceptibility to tuberculosis.
Novel optoelectronic devices based on single semiconductor nanowires (nanobelts)
Authors: Ye Yu , Dai Lun , Gan Lin , Meng Hu , Dai Yu , Guo Xuefeng , Qin Guogang 
Published: April 2012

Abstract
Semiconductor nanowires (NWs) or nanobelts (NBs) have attracted more and more attention due to their potential application in novel optoelectronic devices. In this review, we present our recent work on novel NB photodetectors, where a three-terminal metal–semiconductor field-effect transistor (MESFET) device structure was exploited. In contrast to the common two-terminal NB (NW) photodetectors, the MESFET-based photodetector can make a balance among overall performance parameters, which is desired for practical device applications. We also present our recent work on graphene nanoribbon/semiconductor NW (SNW) heterojunction light-emitting diodes (LEDs). Herein, by taking advantage of both graphene and SNWs, we have fabricated, for the first time, the graphene-based nano-LEDs. This achievement opens a new avenue for developing graphene-based nano-electroluminescence devices. Moreover, the novel graphene/SNW hybrid devices can also find use in other applications, such as high-sensitivity sensor and transparent flexible devices in the future.
An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs
Authors: Wang Shuo , Wang Hua , Liang Wenquan , Huang Yongzhuo 
Published: April 2012

Abstract
Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short-term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs.
Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced
Authors: Hellevik Turid , Pettersen Ingvild , Berg Vivian , Winberg Jan Olof , Moe Bjørn T , Bartnes Kristian , Paulssen Ruth H , Busund Lill-Tove , Bremnes Roy , Chalmers Anthony , Martinez-Zubiaurre Iñigo 
Published: April 2012

Abstract

Background
Cancer-Associated Fibroblasts (CAFs) are significant components of solid malignancies and play central roles in cancer sustainability, invasion and metastasis. In this study we have investigated the invasive capacity and matrix remodelling properties of human lung CAFs after exposure to ablative doses of ionizing radiation (AIR), equivalent to single fractions delivered by stereotactic ablative radiotherapy (SART) for medically inoperable stage-I/II non-small-cell lung cancers.

Methods
CAFs were isolated from lung tumour specimens from 16 donors. Initially, intrinsic radiosensitivity was evaluated by checking viability and extent of DNA-damage response (DDR) at different radiation doses. The migrative and invasive capacities of CAFs were thereafter determined after a sub-lethal single radiation dose of 18 Gy. To ascertain the mechanisms behind the altered invasive capacity of cells, expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) were measured in the conditioned media several days post-irradiation, along with expression of cell surface integrins and dynamics of focal contacts by vinculin-staining.

Results
Exposing CAFs to 1 × 18 Gy resulted in a potent induction of multiple nuclear DDR foci (> 9/cell) with little resolution after 120 h, induced premature cellular senescence and inhibition of the proliferative, migrative and invasive capacity. AIR promoted MMP-3 and inhibited MMP-1 appearance to some extent, but did not affect expression of other major MMPs. Furthermore, surface expression of integrins α2, β1 and α5 was consistently enhanced, and a dramatic augmentation and redistribution of focal contacts was observed.

Conclusions
Our data indicate that ablative doses of radiation exert advantageous inhibitory effects on the proliferative, migratory and invasive capacity of lung CAFs. The reduced motility of irradiated CAFs might be a consequence of stabilized focal contacts via integrins.
Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract
Authors: Marois Isabelle , Cloutier Alexandre , Garneau Émilie , Richter Martin V 
Published: April 2012

Abstract
Infectious dose of influenza determines inflammatory, innate, and adaptive CD8+ T cell responses, and modulates central and effector protective immunity to heterologous infection.
Factors from the virus and the host contribute to influenza virus pathogenicity and to the development of immunity. This study thoroughly examined the effects of an initial infectious dose of virus and unveiled new findings concerning the antiviral and inflammatory responses, innate and adaptive immunity, memory responses, and protection against secondary heterologous infection. Our results demonstrated that the initial infectious dose significantly affects the gene expression of antiviral (IFN-β) and inflammatory (TNF-α, IL-6, IL-1β) cytokines and of enzymes involved in nitrosative/oxidative stress (iNOS, HO-1, NQO1) early in the response to influenza. This response correlated with significantly increased recruitment of innate immune cells into the lungs of infected mice. We showed that this response also alters the subsequent accumulation of activated IFN-γ+ CD44hi CD62Llo influenza-specific CD8+ T cells into the lungs of infected mice through increased T cell-recruiting chemokine gene expression (CCL3, CCL4, CCL5, CXCL10). Furthermore, we demonstrated that the initial infectious dose determines the generation and the distribution of memory CD8+ T cell subsets without affecting trafficking mechanisms. This impacted on immune protection against heterologous infection. Lastly, we showed that the effects on innate and adaptive immunity were not dependent on influenza strain or on the genetic background of the host. Collectively, our data show for the first time and in detail that the initial infectious dose of influenza determines the development of several aspects of antiviral immunity. This study provides new insights on virus-host interaction in the generation of the global immune response to influenza.
Evidence for an alternate molecular progression in prostate cancer
Authors: Vinall Ruth L. , Chen Jane Q. , Hubbard Neil E. , Sulaimon Shola S. , DeVere White Ralph W. , Borowsky Alexander D. 
Published: April 2012

Summary
Tp53 mutations are common in prostate cancer (CaP), occurring with a frequency of ~30% and ~70% in localized and metastatic disease respectively. In vitro studies have determined several common mutations of Tp53 that have specific gain of function properties in addition to loss of function, including the ability to promote castrate resistant growth of CaP cells in some contexts. To date, a lack of suitable mouse models has prohibited investigation of the role played by p53 mutations in mediating CaP progression in vivo. Here we describe the effects of conditional expression of a mutant p53 that is equivalent to the human hotspot R273H into the prostate epithelium of mice. Heterozygous 'p53LSL.R270H/+' (129S4(Trp53tm3Tyj);Nkx3.1cre' (129S(Nkx3-1tm3CreMms) mice with prostate-specific expression of the p53.R270H mutation (p53R270H/+ Nkx3.1cre mice) bred on to a FVB/N background via speed congenesis to produce strain FVB.129S4(Trp53tm3Tyj/wt);FVB.129S(Nkx3-1tm3CreMms/wt) and littermate genotype negative control mice. These mice had significantly increased incidences of prostatic intraepithelial neoplasia (PIN) lesions that appeared earlier compared to the Nkx3.1 haploinsufficient (Nkx3.1cre het) littermate mice that did not express the Tp53 mutation. PIN lesions in these mice showed consistent progression, and invasive adenocarcinoma that evolved into a high grade, sarcomatoid or epithelial-mesenchymal transition (EMT) phenotype. PIN lesions were similar to those seen in PTEN conditional knockout mice, with evidence of AKT activation concomitant with neoplastic proliferation. Meanwhile, the invasive tumor phenotype was unlike any previously described mouse model of prostatic neoplasia. These data indicate the p53R270H mutation plays a role in CaP initiation. This finding has not previously been reported. Further characterization of this model, particularly in a setting of androgen deprivation, should allow further insights into the mechanisms by which the p53R270H mutation mediates CaP progression.
Evidence for a Natural Allelic Series at the Maize Domestication Locus teosinte branched1
Authors: Studer Anthony J , Doebley John F 
Published: April 2012

Abstract
Despite numerous quantitative trait loci and association mapping studies, our understanding of the extent to which natural allelic series contribute to the variation for complex traits is limited. In this study, we investigate the occurrence of a natural allelic series for complex traits at the teosinte branched1 (tb1) gene in natural populations of teosinte (Zea mays ssp. parviglumis, Z. mays ssp. mexicana, and Z. diploperennis). Previously, tb1 was shown to confer large effects on both plant architecture and ear morphology between domesticated maize and teosinte; however, the effect of tb1 on trait variation in natural populations of teosinte has not been investigated. We compare the effects of nine teosinte alleles of tb1 that were introgressed into an isogenic maize inbred background. Our results provide evidence for a natural allelic series at tb1 for several complex morphological traits. The teosinte introgressions separate into three distinct phenotypic classes, which correspond to the taxonomic origin of the alleles. The effects of the three allelic classes also correspond to known morphological differences between the teosinte taxa. Our results suggest that tb1 contributed to the morphological diversification of teosinte taxa as well as to the domestication of maize.
Improved Models for Transcription Factor Binding Site Identification Using Nonindependent Interactions
Authors: Zhao Yue , Ruan Shuxiang , Pandey Manishi , Stormo Gary D 
Published: April 2012

AbstractIdentifying transcription factor (TF) binding sites is essential for understanding regulatory networks. The specificity of most TFs is currently modeled using position weight matrices (PWMs) that assume the positions within a binding site contribute independently to binding affinity for any site. Extensive, high-throughput quantitative binding assays let us examine, for the first time, the independence assumption for many TFs. We find that the specificity of most TFs is well fit with the simple PWM model, but in some cases more complex models are required. We introduce a binding energy model (BEM) that can include energy parameters for nonindependent contributions to binding affinity. We show that in most cases where a PWM is not sufficient, a BEM that includes energy parameters for adjacent dinucleotide contributions models the specificity very well. Having more accurate models of specificity greatly improves the interpretation of in vivo TF localization data, such as from chromatin immunoprecipitation followed by sequencing (ChIP-seq) experiments.
Increasing Association Mapping Power and Resolution in Mouse Genetic Studies Through the Use of Meta-Analysis for Structured Populations
Authors: Furlotte Nicholas A , Kang Eun Yong , Van Nas Atila , Farber Charles R , Lusis Aldons J , Eskin Eleazar 
Published: April 2012

AbstractGenetic studies in mouse models have played an integral role in the discovery of the mechanisms underlying many human diseases. The primary mode of discovery has been the application of linkage analysis to mouse crosses. This approach results in high power to identify regions that affect traits, but in low resolution, making it difficult to identify the precise genomic location harboring the causal variant. Recently, a panel of mice referred to as the hybrid mouse diversity panel (HMDP) has been developed to overcome this problem. However, power in this panel is limited by the availability of inbred strains. Previous studies have suggested combining results across multiple panels as a means to increase power, but the methods employed may not be well suited to structured populations, such as the HMDP. In this article, we introduce a meta-analysis-based method that may be used to combine HMDP studies with F2 cross studies to gain power, while increasing resolution. Due to the drastically different genetic structure of F2s and the HMDP, the best way to combine two studies for a given SNP depends on the strain distribution pattern in each study. We show that combining results, while accounting for these patterns, leads to increased power and resolution. Using our method to map bone mineral density, we find that two previously implicated loci are replicated with increased significance and that the size of the associated is decreased. We also map HDL cholesterol and show a dramatic increase in the significance of a previously identified result.