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1.  Clonal Evolution in Breast Cancer Revealed by Single Nucleus Genome Sequencing 
Nature  2014;512(7513):155-160.
SUMMARY
Sequencing studies of breast tumor cohorts have identified many prevalent mutations, but provide limited insight into the genomic diversity within tumors. Here, we developed a whole-genome and exome single cell sequencing approach called Nuc-Seq that utilizes G2/M nuclei to achieve 91% mean coverage breadth. We applied this method to sequence single normal and tumor nuclei from an estrogen-receptor positive breast cancer and a triple-negative ductal carcinoma. In parallel, we performed single nuclei copy number profiling. Our data show that aneuploid rearrangements occurred early in tumor evolution and remained highly stable as the tumor masses clonally expanded. In contrast, point mutations evolved gradually, generating extensive clonal diversity. Many of the diverse mutations were shown to occur at low frequencies (<10%) in the tumor mass by targeted single-molecule sequencing. Using mathematical modeling we found that the triple-negative tumor cells had an increased mutation rate (13.3X) while the ER+ tumor cells did not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.
doi:10.1038/nature13600
PMCID: PMC4158312  PMID: 25079324
2.  Treatment of acute lung injury by targeting MG53-mediated cell membrane repair 
Nature communications  2014;5:4387.
Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischemia-reperfusion and over-ventilation induced injury to the lung when compared with wild type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases.
doi:10.1038/ncomms5387
PMCID: PMC4109002  PMID: 25034454
3.  Estimating Anatomically-Correct Reference Model for Craniomaxillofacial Deformity via Sparse Representation 
The success of craniomaxillofacial (CMF) surgery depends not only on the surgical techniques, but also upon an accurate surgical planning. However, surgical planning for CMF surgery is challenging due to the absence of a patient-specific reference model. In this paper, we present a method to automatically estimate an anatomically correct reference shape of jaws for the patient requiring orthognathic surgery, a common type of CMF surgery. We employ the sparse representation technique to represent the normal regions of the patient with respect to the normal subjects. The estimated representation is then used to reconstruct a patient-specific reference model with “restored” normal anatomy of the jaws. We validate our method on both synthetic subjects and patients. Experimental results show that our method can effectively reconstruct the normal shape of jaw for patients. Also, a new quantitative measurement is introduced to quantify the CMF deformity and validate the method in a quantitative approach, which is rarely used before.
doi:10.1007/978-3-319-10470-6_10
PMCID: PMC4197838  PMID: 25328919
4.  Reaching Spanish-speaking smokers online: a 10-year worldwide research program 
Objective
To describe a 10-year proof-of-concept smoking cessation research program evaluating the reach of online health interventions throughout the Americas.
Methods
Recruitment occurred from 2002–2011, primarily using Google.com AdWords. Over 6 million smokers from the Americas entered keywords related to smoking cessation; 57 882 smokers (15 912 English speakers and 41 970 Spanish speakers) were recruited into online self-help automated intervention studies. To examine disparities in utilization of methods to quit smoking, cessation aids used by English speakers and Spanish speakers were compared. To determine whether online interventions reduce disparities, abstinence rates were also compared. Finally, the reach of the intervention was illustrated for three large Spanish-speaking countries of the Americas—Argentina, Mexico, and Peru—and the United States of America.
Results
Few participants had utilized other methods to stop smoking before coming to the Internet site; most reported using no previous smoking cessation aids: 69.2% of Spanish speakers versus 51.8% of English speakers (P < 0.01). The most used method was nicotine gum, 13.9%. Nicotine dependence levels were similar to those reported for in-person smoking cessation trials. Overall observed quit rate for English speakers was 38.1% and for Spanish speakers, 37.0%; quit rates in which participants with missing data were considered to be smoking were 11.1% and 10.6%, respectively. Neither comparison was significantly different.
Conclusions
The systematic use of evidence-based Internet interventions for health problems could have a broad impact throughout the Americas, at little or no cost to individuals or to ministries of health.
PMCID: PMC4171061  PMID: 25211569
Internet; smoking cessation; outcome assessment (health care); healthcare disparities; Latin America
5.  Implementation of Biomarker-Driven Cancer Therapy: Existing Tools and Remaining Gaps 
Discovery medicine  2014;17(92):101-114.
There has been growing interest in biomarker-driven personalized cancer therapy, also known as precision medicine. Recently, dozens of molecular tests, including next generation sequencing, have been developed to detect biomarkers that have the potential to predict response of cancers to particular targeted therapies. However, detection of cancer-related biomarkers is only the first step in the battle. Deciding what therapy options to pursue can also be daunting, especially when tumors harbor more than one potentially actionable aberration. Further, different mutations/variants in a single gene may have different functional consequences, and response to targeted agents may be context dependent. However, early clinical trials with new molecular entities are increasingly conducted in a biomarker-selected fashion, and even when trials are not biomarker-selected, much effort is placed on enrolling patients onto clinical trials where they have the highest probability of response. We review available molecular tests and therapy discerning tools, including tools available for assessing functional consequences of molecular alterations and tools for finding applicable clinical trials, which exist to help bridge the gap between detection of cancer-related biomarker to the initiation of biomarker-matched targeted therapies.
PMCID: PMC4160907  PMID: 24534473
6.  Towards accurate characterization of clonal heterogeneity based on structural variation 
BMC Bioinformatics  2014;15(1):299.
Background
Recent advances in deep digital sequencing have unveiled an unprecedented degree of clonal heterogeneity within a single tumor DNA sample. Resolving such heterogeneity depends on accurate estimation of fractions of alleles that harbor somatic mutations. Unlike substitutions or small indels, structural variants such as deletions, duplications, inversions and translocations involve segments of DNAs and are potentially more accurate for allele fraction estimations. However, no systematic method exists that can support such analysis.
Results
In this paper, we present a novel maximum-likelihood method that estimates allele fractions of structural variants integratively from various forms of alignment signals. We develop a tool, BreakDown, to estimate the allele fractions of most structural variants including medium size (from 1 kilobase to 1 megabase) deletions and duplications, and balanced inversions and translocations.
Conclusions
Evaluation based on both simulated and real data indicates that our method systematically enables structural variants for clonal heterogeneity analysis and can greatly enhance the characterization of genomically instable tumors.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-299) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2105-15-299
PMCID: PMC4165998  PMID: 25201439
Structural variation; Clonal heterogeneity; Variant allele fraction
7.  Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors 
Oncotarget  2014;5(18):8544-8557.
We tested the antitumor efficacy of mTOR catalytic site inhibitor MLN0128 in models with intrinsic or acquired rapamycin-resistance. Cell lines that were intrinsically rapamycin-resistant as well as those that were intrinsically rapamycinsensitive were sensitive to MLN0128 in vitro. MLN0128 inhibited both mTORC1 and mTORC2 signaling, with more robust inhibition of downstream 4E-BP1 phosphorylation and cap-dependent translation compared to rapamycin in vitro. Rapamycin-sensitive BT474 cell line acquired rapamycin resistance (BT474 RR) with prolonged rapamycin treatment in vitro. This cell line acquired an mTOR mutation (S2035F) in the FKBP12-rapamycin binding domain; mTORC1 signaling was not inhibited by rapalogs but was inhibited by MLN0128. In BT474 RR cells, MLN0128 had significantly higher growth inhibition compared to rapamycin in vitro and in vivo. Our results demonstrate that MLN0128 may be effective in tumors with intrinsic as well as acquired rapalog resistance. mTOR mutations are a mechanism of acquired resistance in vitro; the clinical relevance of this observation needs to be further evaluated.
PMCID: PMC4226703  PMID: 25261369
mTOR; Akt; rapamycin; everolimus; breast cancer
8.  Tea Consumption and Risk of Head and Neck Cancer 
PLoS ONE  2014;9(5):e96507.
Background
The current study evaluated the association between tea consumption and head and neck cancer (HNC) in Taiwan, where tea is a major agricultural product and a popular beverage.
Methods
Interviews regarding tea consumption (frequency, duration, and types) were conducted with 396 HNC cases and 413 controls. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with tea drinking, adjusted for sex, age, education, cigarette smoking, betel quid chewing, and alcohol drinking.
Results
A reduced HNC risk associated with tea drinking (OR for every cup per day = 0.96, 95% CI: 0.93–0.99; OR for ≧5 cups per day = 0.60, 95% CI: 0.39–0.94) was observed. The association was especially significant for pharyngeal cancer (OR for every cup per day = 0.93, 95% CI: 0.88–0.98; OR for ≧5 cups per day = 0.32, 95% CI: 0.16–0.66). A significant inverse association between HNC and tea consumption was observed particularly for green tea.
Conclusions
This study suggests that tea drinking may reduce the risk of HNC. The anticancer property of tea, if proven, may offer a natural chemopreventive measure to reduce the occurrence of HNC.
doi:10.1371/journal.pone.0096507
PMCID: PMC4010481  PMID: 24796481
9.  Automated Segmentation of CBCT Image using Spiral CT Atlases and Convex Optimization 
Cone-beam computed tomography (CBCT) is an increasingly utilized imaging modality for the diagnosis and treatment planning of the patients with craniomaxillofacial (CMF) deformities. CBCT scans have relatively low cost and low radiation dose in comparison to conventional spiral CT scans. However, a major limitation of CBCT scans is the widespread image artifacts such as noise, beam hardening and inhomogeneity, causing great difficulties for accurate segmentation of bony structures from soft tissues, as well as separating mandible from maxilla. In this paper, we presented a novel fully automated method for CBCT image segmentation. In this method, we first estimated a patient-specific atlas using a sparse label fusion strategy from predefined spiral CT atlases. This patient-specific atlas was then integrated into a convex segmentation framework based on maximum a posteriori probability for accurate segmentation. Finally, the performance of our method was validated via comparisons with manual ground-truth segmentations.
PMCID: PMC3918683  PMID: 24505768
10.  CanDrA: Cancer-Specific Driver Missense Mutation Annotation with Optimized Features 
PLoS ONE  2013;8(10):e77945.
Driver mutations are somatic mutations that provide growth advantage to tumor cells, while passenger mutations are those not functionally related to oncogenesis. Distinguishing drivers from passengers is challenging because drivers occur much less frequently than passengers, they tend to have low prevalence, their functions are multifactorial and not intuitively obvious. Missense mutations are excellent candidates as drivers, as they occur more frequently and are potentially easier to identify than other types of mutations. Although several methods have been developed for predicting the functional impact of missense mutations, only a few have been specifically designed for identifying driver mutations. As more mutations are being discovered, more accurate predictive models can be developed using machine learning approaches that systematically characterize the commonality and peculiarity of missense mutations under the background of specific cancer types. Here, we present a cancer driver annotation (CanDrA) tool that predicts missense driver mutations based on a set of 95 structural and evolutionary features computed by over 10 functional prediction algorithms such as CHASM, SIFT, and MutationAssessor. Through feature optimization and supervised training, CanDrA outperforms existing tools in analyzing the glioblastoma multiforme and ovarian carcinoma data sets in The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia project.
doi:10.1371/journal.pone.0077945
PMCID: PMC3813554  PMID: 24205039
11.  GENOMIC LANDSCAPE OF NON-SMALL CELL LUNG CANCER IN SMOKERS AND NEVER SMOKERS 
Cell  2012;150(6):1121-1134.
Summary
We report the results of whole genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and over 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatic modification and DNA repair pathways were identified along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions including ROS1 and ALK as well as novel metabolic enzymes. Cell cycle and JAK-STAT pathways are significantly altered in lung cancer along with perturbations in 54 genes that are potentially targetable with currently available drugs.
doi:10.1016/j.cell.2012.08.024
PMCID: PMC3656590  PMID: 22980976
12.  BreakTrans: uncovering the genomic architecture of gene fusions 
Genome Biology  2013;14(8):R87.
Producing gene fusions through genomic structural rearrangements is a major mechanism for tumor evolution. Therefore, accurately detecting gene fusions and the originating rearrangements is of great importance for personalized cancer diagnosis and targeted therapy. We present a tool, BreakTrans, that systematically maps predicted gene fusions to structural rearrangements. Thus, BreakTrans not only validates both types of predictions, but also provides mechanistic interpretations. BreakTrans effectively validates known fusions and discovers novel events in a breast cancer cell line. Applying BreakTrans to 43 breast cancer samples in The Cancer Genome Atlas identifies 90 genomically validated gene fusions. BreakTrans is available at http://bioinformatics.mdanderson.org/main/BreakTrans
doi:10.1186/gb-2013-14-8-r87
PMCID: PMC4054677  PMID: 23972288
13.  Aliskiren and Amlodipine in the Management of Essential Hypertension: Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(7):e70111.
Background
Aliskiren is a novel renin-angiotensin aldosterone system (RAAS) inhibitor, the combination therapy of aliskiren and amlodipine for blood pressure control have been reported recently. The primary objective of this analysis is to review recently reported randomized controlled trials (RCTs) to compare antihypertensive effects and adverse events between mono (amlodipine or aliskiren alone) and combination therapy of both medicines.
Methods
Databases for the search included Pubmed, Embase and the Cochrane Central Register of Controlled Trials. Revman v5.0 statistical program was used to analyze the data. Weighted mean differences (WMD) with a 95% confidence interval (CI) were used for the calculation of continuous data, and relative risk (RR) with a 95% CI was used for dichotomous data.
Results
We analyzed the data from 7 RCTs for a total of 6074 participants in this meta-analysis. We found that the aliskiren/amlodipine combination therapy had a stronger effect in lowering blood pressure as compared with the monotherapy using aliskiren (SBP: WMD = −10.42, 95% CI −13.03∼−7.82, P<0.00001; DBP: WMD = −6.60, 95% CI −7.22∼−5.97, P<0.00001) or amlodipine (SBP: WMD = −4.85, 95% CI −6.88∼−2.81, P<0.00001; DBP: WMD = −2.91, 95% CI −3.85∼−1.97, P<0.00001). No differences were found in terms of adverse events between combination therapy and monotherapy, except for the rates of peripheral edema and hypokalaemia which were significantly lower in the combination therapy than in the amlodipine monotherapy (RR = 0.78, 0.66∼0.92, P = 0.004; RR = 0.51, 0.27∼0.97, P = 0.04). Similar antihypertensive effects were found in both obese (body mass index > = 30 kg/m2) hypertensive and non-obese (body mass index <30 kg/m2) hypertensive patients. Moreover, there was no difference with the blood pressure lowering or adverse effects with regards to the combination therapy in both subgroups.
Conclusion
We found that aliskiren/amlodipine combination therapy provided a more effective blood pressure reduction than monotherapy with either drug without increase in the occurrence of adverse events.
doi:10.1371/journal.pone.0070111
PMCID: PMC3726495  PMID: 23922924
14.  The origin and evolution of mutations in Acute Myeloid Leukemia 
Cell  2012;150(2):264-278.
Summary
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability, driving clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of AML samples with a known initiating event (PML-RARA) vs. normal karyotype AML samples, and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.
doi:10.1016/j.cell.2012.06.023
PMCID: PMC3407563  PMID: 22817890
15.  BreakFusion: targeted assembly-based identification of gene fusions in whole transcriptome paired-end sequencing data 
Bioinformatics  2012;28(14):1923-1924.
Summary: Despite recent progress, computational tools that identify gene fusions from next-generation whole transcriptome sequencing data are often limited in accuracy and scalability. Here, we present a software package, BreakFusion that combines the strength of reference alignment followed by read-pair analysis and de novo assembly to achieve a good balance in sensitivity, specificity and computational efficiency.
Availability: http://bioinformatics.mdanderson.org/main/BreakFusion
Contact: kchen3@mdanderson.org; lding@genome.wustl.edu
Supplementary information: Supplementary data are available at Bioinformatics online
doi:10.1093/bioinformatics/bts272
PMCID: PMC3389765  PMID: 22563071
16.  Massively Parallel Sequencing Approaches for Characterization of Structural Variation 
The emergence of next-generation sequencing (NGS) technologies offers an incredible opportunity to comprehensively study DNA sequence variation in human genomes. Commercially available platforms from Roche (454), Illumina (Genome Analyzer and Hiseq 2000), and Applied Biosystems (SOLiD) have the capability to completely sequence individual genomes to high levels of coverage. NGS data is particularly advantageous for the study of structural variation (SV) because it offers the sensitivity to detect variants of various sizes and types, as well as the precision to characterize their breakpoints at base pair resolution. In this chapter, we present methods and software algorithms that have been developed to detect SVs and copy number changes using massively parallel sequencing data. We describe visualization and de novo assembly strategies for characterizing SV breakpoints and removing false positives.
doi:10.1007/978-1-61779-507-7_18
PMCID: PMC3679911  PMID: 22228022
Next-generation sequencing; Paired-end sequencing; 454; Illumina; Solexa; Abi solid; Insertions; Deletions; Duplications; Inversions; Translocations; Indels; Copy number variants
17.  Value of circulating cell-free DNA in diagnosis of hepatocelluar carcinoma 
AIM: To investigate the value of combined detection of circulating cell-free DNA (cfDNA), α-fetal protein (AFP) and α L-fucosidase (AFU) for diagnosis of hepatocellular carcinoma (HCC).
METHODS: Serum samples from 39 HCC patients and 45 normal controls were collected. Branched DNA (bDNA) was used to detect the level of cfDNA, and a receiver operating characteristic curve was employed to evaluate the diagnostic sensitivity, specificity, accuracy, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and Youden index, and to assess the diagnostic efficiency and their correlations with the clinicopathological features. AFP and AFU were detected by chemiluminescence and colorimetry, respectively. The significance of combined detection of the three biomarkers was discussed.
RESULTS: cfDNA level was increased in 22 of the 39 HCC samples and in 2 of the 45 normal controls. cfDNA level in HCC samples was significantly higher than that in normal controls (P < 0.05). There were significant differences in sex and extra- and intrahepatic metastasis (P < 0.05). There was no significant correlation between cfDNA, AFP and AFU in the detection of HCC. The sensitivity of combined detection of cfDNA with one marker (AFP or AFU) and cfDNA with two markers (AFP and AFU) was 71.8%, 87.2% and 89.7% vs 56.4%, 53.8% and 66.7% for cfDNA, AFP and AFU used alone, respectively, the difference being statistically significant (P < 0.05).
CONCLUSION: Quantitative analysis of cfDNA is sensitive and feasible, and the combined detection of cfDNA with AFP or AFU or both could improve the diagnostic sensitivity for HCC.
doi:10.3748/wjg.v19.i20.3143
PMCID: PMC3662956  PMID: 23716996
Alu; Branched DNA; Circulating cell free DNA; Diagnosis; Hepatocellular carcinoma
18.  An optical tracker based robot registration and servoing method for ultrasound guided percutaneous renal access 
Background
Robot-assisted needle steering facilitates the percutaneous renal access (PRA) for their accuracy and consistency over manual operation. However, inaccurate image-robot correspondence and uncertainties in robot parameters make the needle track deviate from the intrarenal target. This paper aims to simplify the image-tracker-robot registration procedure and improves the accuracy of needle alignment for robot assisted ultrasound-guided PRA.
Methods
First, a semi-automatic rigid registration is used for the alignment of the preoperative MR volume and the intraoperative orthogonal US slices. Passive markers are mounted both on US probe and robot end-effector, the planned puncture path is transferred from the MR volume frame into optical tracker frame. Tracker-robot correspondence and robot calibration are performed iteratively using a simplified scheme, both position and orientation information are incorporated to estimate the transformation matrix, only several key structural robot parameters and joint zero-positions are calibrated for simplicity in solving the inverse kinematic. Furthermore, an optical tracker feedback control is designed for compensating inaccuracies in robot parameters and tracker-robot correspondence, and improving the accuracy of needle alignment. The intervention procedure was implemented by a telemanipulated 5R1P robot, two experiments were conducted to validate the efficiency of robot-tracker registration method and the optical tracker feedback control, robot assisted needle insertion experiment was conducted on kidney phantom to evaluate the system performance.
Results
The relative positioning accuracy of needle alignment is 0.24 ± 0.08 mm, the directional accuracy is 6.78 ± 1.65 × 10-4rad; the needle-target distance of needle insertion is 2.15 ± 0. 17 mm. The optical tracker feedback control method performs stable against wide range of angular disturbance over (0 ~ 0.4) radians, and the length disturbance over (0 ~ 100) mm.
Conclusions
The proposed optical tracker based robot registration and servoing method is capable of accurate three dimension needle operation for PRA procedure with improved precision and shortened time.
doi:10.1186/1475-925X-12-47
PMCID: PMC3679870  PMID: 23705678
19.  BreakDancer: An algorithm for high resolution mapping of genomic structural variation 
Nature methods  2009;6(9):677-681.
Detection and characterization of genomic structural variation are important for understanding the landscape of genetic variation in human populations and in complex diseases such as cancer. Recent studies demonstrate the feasibility of detecting structural variation using next-generation, short-insert, paired-end sequencing reads. However, the utility of these reads is not entirely clear, nor are the analysis methods under which accurate detection can be achieved. The algorithm BreakDancer predicts a wide variety of structural variants including indels, inversions, and translocations. We examined BreakDancer's performance in simulation, comparison with other methods, analysis of an acute myeloid leukemia sample, and the 1,000 Genomes trio individuals. We found that it substantially improved the detection of small and intermediate size indels from 10 bp to 1 Mbp that are difficult to detect via a single conventional approach.
doi:10.1038/nmeth.1363
PMCID: PMC3661775  PMID: 19668202
20.  Mice Transgenic for CD4-Specific Human CD4, CCR5 and Cyclin T1 Expression: A New Model for Investigating HIV-1 Transmission and Treatment Efficacy 
PLoS ONE  2013;8(5):e63537.
Mice cannot be used to evaluate HIV-1 therapeutics and vaccines because they are not infectible by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 entry and replication including CD4, CCR5 and cyclin T1. We overcame this limitation by constructing mice with CD4 enhancer/promoter-regulated human CD4, CCR5 and cyclin T1 genes integrated as tightly linked transgenes (hCD4/R5/cT1 mice) promoting their efficient co-transmission and enabling the murine CD4-expressing cells to support HIV-1 entry and Tat-mediated LTR transcription. All of the hCD4/R5/cT1 mice developed disseminated infection of tissues that included the spleen, small intestine, lymph nodes and lungs after intravenous injection with an HIV-1 infectious molecular clone (HIV-IMC) expressing Renilla reniformis luciferase (LucR). Furthermore, localized infection of cervical-vaginal mucosal leukocytes developed after intravaginal inoculation of hCD4/R5/cT1 mice with the LucR-expressing HIV-IMC. hCD4/R5/cT1 mice reproducibly developed in vivo infection after inoculation with LucR-expressing HIV-IMC which could be bioluminescently quantified and visualized with a high sensitivity and specificity which enabled them to be used to evaluate the efficacy of HIV-1 therapeutics. Treatment with highly active anti-retroviral therapy or one dose of VRC01, a broadly neutralizing anti-HIV-1 antibody, almost completed inhibited acute systemic HIV-1 infection of the hCD4/R5/cT1 mice. hCD4/R5/cT1 mice could also be used to evaluate the capacity of therapies delivered by gene therapy to inhibit in vivo HIV infection. VRC01 secreted in vivo by primary B cells transduced with a VRC01-encoding lentivirus transplanted into hCD4/R5/cT1 mice markedly inhibited infection after intravenous challenge with LucR-expressing HIV-IMC. The reproducible infection of CD4/R5/cT1 mice with LucR-expressing HIV-IMC after intravenous or mucosal inoculation combined with the availability of LucR-expressing HIV-IMC expressing transmitted/founder and clade A/E and C Envs will provide researchers with a highly accessible pre-clinical in vivo HIV-1-infection model to study HIV-1 acquisition, treatment, and prevention.
doi:10.1371/journal.pone.0063537
PMCID: PMC3655194  PMID: 23691059
21.  Background mutations in parental cells account for most of the genetic heterogeneity of Induced Pluripotent Stem Cells 
Cell Stem Cell  2012;10(5):570-582.
Summary
To assess the genetic consequences of induced Pluripotent Stem Cell (iPSC) reprogramming, we sequenced the genomes of ten murine iPSC clones derived from three independent reprogramming experiments, and compared them to their parental cell genomes. We detected hundreds of single nucleotide variants (SNVs) in every clone, with an average of 11 in coding regions. In two experiments, all SNVs were unique for each clone and did not cluster in pathways, but in the third, all four iPSC clones contained 157 shared genetic variants, which could also be detected in rare cells (<1 in 500) within the parental MEF pool. This data suggests that most of the genetic variation in iPSC clones is not caused by reprogramming per se, but is rather a consequence of cloning individual cells, which “captures” their mutational history. These findings have implications for the development and therapeutic use of cells that are reprogrammed by any method.
doi:10.1016/j.stem.2012.03.002
PMCID: PMC3348423  PMID: 22542160
22.  SomaticSniper: identification of somatic point mutations in whole genome sequencing data 
Bioinformatics  2011;28(3):311-317.
Motivation: The sequencing of tumors and their matched normals is frequently used to study the genetic composition of cancer. Despite this fact, there remains a dearth of available software tools designed to compare sequences in pairs of samples and identify sites that are likely to be unique to one sample.
Results: In this article, we describe the mathematical basis of our SomaticSniper software for comparing tumor and normal pairs. We estimate its sensitivity and precision, and present several common sources of error resulting in miscalls.
Availability and implementation: Binaries are freely available for download at http://gmt.genome.wustl.edu/somatic-sniper/current/, implemented in C and supported on Linux and Mac OS X.
Contact: delarson@wustl.edu; lding@wustl.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr665
PMCID: PMC3268238  PMID: 22155872
23.  Allergies and Risk of Head and Neck Cancer: An Original Study plus Meta-Analysis 
PLoS ONE  2013;8(2):e55138.
Background
Although the relationship between allergy and cancer has been investigated extensively, the role of allergy in head and neck cancer (HNC) appears less consistent. It is not clear whether allergies can independently influence the risk of HNC in the presence of known strong environmental risk factors, including consumption of alcohol, betel quid, and cigarette.
Methods
The current paper reports results from: 1) an original hospital-based case-control study, which included 252 incident cases of HNC and 236 controls frequency-matched to cases on sex and age; and 2) a meta-analysis combining the results of the current case-control study and 13 previously published studies (9 cohort studies with 727,569 subjects and 550 HNC outcomes and 5 case-control studies with 4,017 HNC cases and 10,928 controls).
Results
In the original case-control study, we observed a strong inverse association between allergies and HNC [odds ratio = 0.41, 95% confidence interval (CI): 0.27–0.62]. The meta-analysis also indicated a statistically significant inverse association between HNC and allergies [meta-relative risk (RR) = 0.76, 95% CI: 0.63–0.91], particularly strong for allergic rhinitis (meta-RR = 0.55, 95% CI: 0.40–0.76). In addition, the inverse association between allergies and HNC was observed only among men (meta-RR = 0.67, 95% CI: 0.54–0.84) but not among women (meta-RR = 0.98, 95% CI: 0.81–1.18).
Conclusions
These findings suggest that immunity plays an influential role in the risk of HNC. Future studies investigating immune biomarkers, including cytokine profiles and genetic polymorphisms, are warranted to further delineate the relationship between allergies and HNC. Understanding the relationship between allergies and HNC may help devise effective strategies to reduce and treat HNC.
doi:10.1371/journal.pone.0055138
PMCID: PMC3562357  PMID: 23383309
24.  Whole Genome Analysis Informs Breast Cancer Response to Aromatase Inhibition 
Nature  2012;486(7403):353-360.
Summary
To correlate the variable clinical features of estrogen receptor positive (ER+) breast cancer with somatic alterations, we studied pre-treatment tumour biopsies accrued from patients in a study of neoadjuvant aromatase inhibitor (AI) therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to hematopoietic disorders. Mutant MAP3K1 was associated with Luminal A status, low grade histology and low proliferation rates whereas mutant TP53 associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon AI treatment. Pathway analysis demonstrated mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in ER+ breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
doi:10.1038/nature11143
PMCID: PMC3383766  PMID: 22722193
25.  CREST maps somatic structural variation in cancer genomes with base-pair resolution 
Nature methods  2011;8(8):652-654.
We developed CREST (Clipping REveals STructure), an algorithm that uses next-generation sequencing reads with partial alignments to a reference genome to directly map structural variations at the nucleotide level of resolution. Application of CREST to whole-genome sequencing data from five pediatric T-lineage acute lymphoblastic leukemias (T-ALLs) and a human melanoma cell line, COLO-829, identified 160 somatic structural variations. Experimental validation exceeded 80% demonstrating that CREST had a high predictive accuracy.
doi:10.1038/nmeth.1628
PMCID: PMC3527068  PMID: 21666668

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