Citations

Key Points ALK-negative ALCLs have chromosomal rearrangements of DUSP22 or TP63 in 30% and 8% of cases, respectively. DUSP22-rearranged cases have favorable outcomes similar to ALK-positive ALCLs, whereas other genetic subtypes have inferior outcomes.

Understanding the mechanisms that sustain pluripotency in human embryonic stem cells (hESCs) is an active area of research that may prove useful in regenerative medicine and will provide fundamental information relevant to development and cancer. hESCs and cancer cells share the unique ability to proliferate indefinitely and rapidly. Because the protein survivin is uniquely overexpressed in virtually all human cancers and in hESCs, we sought to investigate its role in supporting the distinctive capabilities of these cell types. Results presented here suggest that survivin contributes to the maintenance of pluripotency and that post‐transcriptional control of survivin isoform expression is selectively regulated by microRNAs. miR‐203 has been extensively studied in human tumors, but has not been characterized in hESCs. We show that miR‐203 expression and activity is consistent with the expression and subcellular localization of survivin isoforms that in turn modulate expression of the Oct4 and Nanog transcription factors to sustain pluripotency. This study contributes to understanding of the complex regulatory mechanisms that govern whether hESCs proliferate or commit to lineages. J. Cell. Physiol. 230: 63–70, 2015. © 2014 Wiley Periodicals, Inc.

Abstract Motivation: Exome sequencing (exome-seq) data, which are typically used for calling exonic mutations, have also been utilized in detecting DNA copy number variations (CNVs). Despite the existence of several CNV detection tools, there is still a great need for a sensitive and an accurate CNV-calling algorithm with built-in QC steps, and does not require a paired reference for each sample. Results: We developed a novel method named PatternCNV, which (i) accounts for the read coverage variations between exons while leveraging the consistencies of this variability across different samples; (ii) reduces alignment BAM files to WIG format and therefore greatly accelerates computation; (iii) incorporates multiple QC measures designed to identify outlier samples and batch effects; and (iv) provides a variety of visualization options including chromosome, gene and exon-level views of CNVs, along with a tabular summarization of the exon-level CNVs. Compared with other CNV-calling algorithms using data from a lymphoma exome-seq study, PatternCNV has higher sensitivity and specificity. Availability and implementation: The software for PatternCNV is implemented using Perl and R, and can be used in Mac or Linux environments. Software and user manual are available at http://bioinformaticstools.mayo.edu/research/patterncnv/ , and R package at https://github.com/topsoil/patternCNV/ . Contact: Asmann.Yan@mayo.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Hartsfield syndrome has been recently reported to be associated with mutations in FGFR1 however, to this date; no familial cases have been reported. In this report, we describe two siblings with Hartsfield syndrome and a novel de novo FGFR1 mutation suggesting gonadal mosaicism. The proband presented at our institution at age 6 years with a clinical diagnosis of Hartsfield syndrome and requesting further genetic evaluation. Previous studies included a normal karyotype, oligonucleotide array, and single gene testing for nonsyndromic holoprosencephaly (SHH, SIX3, ZIC2, TGIF). At the age of 6 years, exome sequencing was performed and a de novo novel missense variant was identified in FGFR1 (coding for fibroblast growth factor‐1) on chromosome 8p12: c.1880G>C (p.R627T). Subsequently, a younger sibling was born with the same phenotype (holoprosencephaly, ectrodactyly of bilateral hands and feet and bilateral cleft lip and palate). Targeted sequencing of FGFR1 revealed the identical variant that was previously identified in the proband. To our knowledge this observation is the first documentation of familial recurrence of Hartsfield syndrome. As both parents were negative for the sequence variant in FGFR1 gene by testing peripheral blood samples, this suggests gonadal mosaicism. The frequency of gonadal mosaicism in Hartsfield syndrome is not known however given our case, this possibility should be taken in to consideration for recurrence risk estimation in children of clinically unaffected parents. © 2014 Wiley Periodicals, Inc.

The Green's function approach describes propagating shear waves generated by an acoustic radiation force in elastic and viscoelastic soft tissue. Calculations with the Green's function approach are evaluated in elastic and viscoelastic soft tissue models for a line source and for a simulated focused beam. The results for the line source input are evaluated at 200 time samples in a 101 by 101 point grid that is perpendicular to the line source. For a shear wave speed of 1.4832 m/s and a compressional wave speed of 1500 m/s, shear wave simulations for a line source input in elastic and viscoelastic soft tissue models are completed in 431 and 2487 s with Matlab scripts, respectively, where the shear viscosity is 0.1 Pa.s in the viscoelastic model. Simulations are evaluated at a single point for an acoustic radiation force generated by a 128 element linear array operating at 4.09 MHz, and these simulations require 228 s and 1327 s for elastic and viscoelastic soft tissue models, respectively. The results show that these are effective models for simulating shear wave propagation in soft tissue, and plans to accelerate these simulations will also be discussed. [Supported in part by NIH Grants R01 EB012079 and R01 DK092255.]

Elasticity imaging has emerged as a viable clinical tool for assisting in diagnosis of certain diseases such as liver fibrosis and cancer. Many methods have been developed for generating and measuring shear waves in soft tissues. The advantage of using shear waves is that the shear wave velocity is proportional to the mechanical material properties of the tissues under investigation. Soft tissues are inherently viscoelastic and considerable effort has been made to quantify the dispersion, or variation of frequency, of the velocity and attenuation of shear waves. This is accomplished by measuring the shear wave motion and using Fourier-based techniques to extract the shear wave velocity and attenuation. Additional considerations are made in tissues where geometric dispersion is also present such as in the heart. Viscoelastic characterization of the shear viscoelasticity of soft tissues in vivo such as human liver, human kidney, and swine heart will be shown. We will also demonstrate parameterization of the results by using a model-free approach or by fitting the shear wave velocity dispersion to rheological models. The diagnostic value of the viscoelastic parameters will be discussed for each particular application. [This work was supported in part by NIH Grant Nos. DK092255, DK082408, and EB002167.]

BACKGROUNDThe authors evaluated sarcopenia as a predictor of cancer‐specific survival (CSS) and overall survival (OS) among patients with urothelial cancer of the bladder undergoing radical cystectomy (RC).METHODSThe lumbar skeletal muscle index (SMI) of 205 patients treated with RC for urothelial cancer between 2000 and 2007 was measured. Sarcopenia was classified according to international consensus definitions (SMI of < 55 cm2/m2 for men and < 39 cm2/m2 for women). The CSS and OS were estimated using the Kaplan‐Meier method and compared with the log‐rank test. Variables associated with CSS and all‐cause mortality were summarized with hazard ratios (HRs).RESULTSOf 205 patients, 141 (68.8%) were sarcopenic. Patients with sarcopenia were older, but were otherwise similar to patients without sarcopenia with respect to sex, Charlson comorbidity index, American Society of Anesthesiologists score, Eastern Cooperative Oncology Group performance status, receipt of neoadjuvant chemotherapy, TNM stage of disease, and tumor grade (P > .05 for all). The median follow‐up was 6.7 years, during which time 135 patients died, including 91 who died of bladder cancer. Sarcopenic patients had significantly worse 5‐year CSS (49% vs 72%; P = .003) and OS (39% vs 70%; P = .003) compared with patients without sarcopenia. Moreover, sarcopenia was found to be independently associated with both increased CSS (HR, 2.14; P = .007) and all‐cause mortality (HR, 1.93; P = .004) on multivariable analysis.CONCLUSIONSThe presence of sarcopenia was found to significantly increase a patient's risk of CSS and all‐cause mortality after undergoing RC for bladder cancer. Cancer 2014;120:2910–2918. © 2014 American Cancer Society.

Objective— To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC). Approach and Results— We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the ≤50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 ( P =0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 ( P =0.001), and for CAC, it was 1.9, P =0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results. Conclusions— AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality.