Wei Lu Research Articles

Naphthalimide‐Based Aggregation‐Induced Emissive Polymeric Hydrogels for Fluorescent Pattern Switch and Biomimetic Actuators

Front Cover: In article 2000123, Wei Lu, Tao Chen and co-workers prepare a robust aggregation-induced emissive polymeric hydrogel by copolymerization of N-isopropylacrylamide and a specially designed 4-phenoxy-N-allyl-1,8-naphthalimide (PhAN) monomer. The hydrogel is characterized with thermally controlled emission/transmittance response, and its potential applications as a fluorescence pattern switch and biomimetic actuator are demonstrated.

Permission to Narrate a Pandemic in Palestine

Permission to Narrate a Pandemic in Palestine

Erratum: Association of 3 Common Polymorphisms of IL-27 Gene with Susceptibility to Cancer in Chinese People: Evidence from an Updated Meta-Analysis of 27 Studies.

The authors informed the journal that an error occurred in their manuscript.Figure 3C was mistakenly merged by the authors.The new version of the Figure 3C is as below.Reference:1. Meng Zhang, Xiuxiu Tan, Junjie Huang, Zekai Ke, Yukun Ge, Hu Xiong, Wei Lu, Lu Fang, Zhiming Cai, Song Wu: Association of 3 Common Polymorphisms of IL-27 Gene with Susceptibility to Cancer in Chinese: Evidence From an Updated Meta-Analysis of 27 Studies. Med Sci Monit 2015; 21: 2505-2513. DOI: 10.12659/MSM.895032.

Abstract 2741: Comprehensive molecular profiling of primary tumors and paired distant metastases in non-small cell lung cancer

Abstract Despite complete resection, many non-small cell lung cancer (NSCLC) patients still develop and succumb to distant metastases, which is a major cause of cancer-related death worldwide. However, our understanding of the molecular mechanisms driving metastasis is rudimentary. We performed whole exome sequencing, RNA sequencing (RNA-seq), methylation microarray, and immunohistochemistry using multiple immune markers on 8 pairs of NSCLC primary tumors and matched distant metastases including 7 metachronous brain and 1 synchronous liver metastases. On average, 60% of all somatic mutations (22% to 90%) and 86% of canonical cancer gene mutations were shared between primary tumors and paired distant metastases. Metastases also resembled paired primary tumors closely in regard to their mutational spectrum, copy number aberrations, allelic imbalance, and methylation profiles. Genomic aberrations unique to metastases were rather patient-specific than commonly observed across multiple patients. Of particular interest, subclonal architecture analysis suggested that monoclonal metastatic seeding is a prevalent mode of metastasis in NSCLC. We validated these findings in a large published dataset consisting of 38 pairs of primary lung tumors and matched distant metastases. RNA-seq showed gene expression profiles in metastases were similar to those of paired primary tumors. Metastases commonly up-regulated metabolism-associated pathways and down-regulated immune-related pathways, consistent with the immunohistochemical staining data for CD3, CD4, CD8, CD20, CD68, PD1, and PD-L1. Our data suggest that distant metastasis is a late event during carcinogenesis and that a majority of genomic and epigenetic aberrations occur before metastatic outgrowth. While molecular mechanisms underlying postsurgical distant metastasis seem to be variable among NSCLC patients, immune suppression may be a common characteristic of cancer cells with metastatic plasticity. Citation Format: Won-Chul Lee, Daniel Gomez, Jianhua Zhang, Alexandre Reuben, Ali Jalali, Whijae Roh, Chia Chin Wu, Wei Lu, Chi-Wan Chow, Junya Fujimoto, Mara Antonoff, Cesar Moran, Erik Sulman, Ganesh Rao, Stephen Swisher, John Heymach, Ignacio I. Wistuba, Andrew Futreal, Jianjun Zhang. Comprehensive molecular profiling of primary tumors and paired distant metastases in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2741.

RETRACTED ARTICLE: Expression tendency and prognostic value of TCF21 in hepatocellular carcinoma

We, the Editors and Publisher of the journal Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article: Wei Lu, Chao Yang, Peng Du, Jun-Li Zhang & Jia-Cheng Zhang (2019) Expression tendency and prognostic value of TCF21 in hepatocellular carcinoma. Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 1466–1470, DOI: https://doi.org/10.1080/21691401.2019.1601102 It has come to our attention that the full authorship list and affiliations for this manuscript were changed after the article was submitted. We have contacted the authors for an explanation, but we have not received a response within the requested timeframe. In addition, the article content significantly overlaps with a manuscript previously submitted to the journal, with a different authorship team listed. As determining authorship is core to the integrity of published work, we are retracting the article. All authors listed in this publication have been sent notification. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Correction to Self-Assembly Growth of In-Rich InGaAs Core-Shell Structured Nanowires with Remarkable Near-Infrared Photoresponsivity.

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Self-Assembly Growth of In-Rich InGaAs Core–Shell Structured Nanowires with Remarkable Near-Infrared PhotoresponsivityChen ZhouChen ZhouMore by Chen Zhouhttp://orcid.org/0000-0002-4619-9014, Xu-Tao ZhangXu-Tao ZhangMore by Xu-Tao Zhanghttp://orcid.org/0000-0001-5259-5745, Kun Zheng*Kun ZhengMore by Kun Zheng, Ping-Ping ChenPing-Ping ChenMore by Ping-Ping Chen, Wei LuWei LuMore by Wei Lu, and Jin Zou*Jin ZouMore by Jin Zouhttp://orcid.org/0000-0001-9435-8043Cite this: Nano Lett. 2019, 19, 3, 2188Publication Date (Web):February 27, 2019Publication History Published online27 February 2019Published inissue 13 March 2019https://doi.org/10.1021/acs.nanolett.9b00803Copyright © 2019 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1049Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (214 KB) Get e-Alerts Get e-Alerts

Abstract 634: SOX11 is a potential clinical marker for hormone receptor negative ductal carcinoma in situ

Abstract Background: Ductal carcinoma in situ (DCIS) comprises 20-25% of screen-detected breast cancer and, like invasive ductal carcinoma (IDC), is heterogeneous in terms of underlying biology, presentation and outcome. There are limited potential biomarkers of outcome for DCIS, although estrogen receptor (ER)-positive (pos), progesterone receptor (PgR)-pos, and HER2-negative (neg) DCIS appears to have a better outlook than DCIS neg for ER and PgR but pos for HER2. The aim of this study was to identify markers for DCIS to develop a panel to stratify DCIS into DCIS at low or high risk of further DCIS. Methods and results: To identify genes driving DCIS evolution followed by the progression to IDC, we first used transcriptional data sets (GSE788, GSE16873) which had data from both normal mammary glands (NMG) and DCIS and performed class comparison (NMG vs DCIS). For both GSE7882 and GSE16883, the number of over- and under-expressed genes was 297 and 187. Over-expressed genes in DCIS represented a mitotic/proliferative feature annotated as mitotic spindle and condensed chromosome. Under-expressed genes represented loss of epithelial features annotated as epithelial cell differentiation and development. A total of 484 differentially expressed genes in DCIS were further correlated with recurrence events of IDC using Kessler's breast cancer data set to identify genes contributing aggressive feature across DCIS and IDC. Genes correlating to recurrence events were selected. From 484 genes, 99 were significantly associated with recurrence events of IDC (with P<0.003). Among these 99 genes, proliferation-related genes were depleted but component genes of the Oncotype DCIS score and genes reported as relevant to DCIS biology, such as SOX11, were included for Nanostring transcriptional analysis. The final number of genes-of-interest was 58 including 5 housekeeping genes. 40 DCIS and 8 NMG lesions were macro-dissected from formalin-fix paraffin-embedded blocks (FFPE) and extracted transcripts were subjected for Nanostring analysis. Gene expression data was clustered in an unsupervised manner using R software. Two sample clusters were identified: an ER/PgR-neg cluster and an ER/PgR-pos cluster. Over-expression of SOX11 and HER2 were exclusively seen in the ER/PgR-neg cluster within which samples were further subcategorized into HER2low/SOX11+ and HER2high/SOX11+. These RNA expression findings are undergoing confirmation by immunohistochemistry of FFPE sections. A further independent series of DCIS which has recurred as DCIS or IDC is currently under investigation for validation of an ER/PgR/HER2/SOX11 signature of poor prognosis DCIS. Conclusion: SOX11 is exclusively overexpressed in ER/PgR-neg DCIS and is a candidate clinical marker for recurrence of DCIS or progression of ER/PgR-neg DCIS to IDC. Citation Format: Kazuharu Kai, Wei Lu, Fei Yang, Ximing Tang, Ignacio I. Wistuba, Subrata Sen, Alastair Thompson. SOX11 is a potential clinical marker for hormone receptor negative ductal carcinoma in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 634.

Abstract 1105: Tumor cells of the early metastatic process show up regulation of cytokine genes involved in migration of inflammatory cells

Abstract Background: Patients with metastatic breast cancer have poorer prognosis and distant metastasis is the main cause of breast cancer (BC) deaths. Hence, better understanding of the early metastatic process is needed. Most BC metastasize primarily lymphogenic and tumor cells within the lympho-vascular space are the first clear visible step in the metastatic process. However, these cells are hardly investigated since the tumor area is very small and therefore difficult to analyze. In this study we wanted to show that tumor cells within the lympho-vascular space can be analyzed for gene expression and that differences compared between main tumor mass and lympho vascular invasion (LVI) occur. Methods: We included 20 BCs diagnosed at UT MD Anderson Cancer Center between 2010 and 2015. The cohort showed the following characteristics: Invasive ductal (n=18), lobular (n=1), ductulo-lobular (n=1), ER positive (n=18), ER negative (n=2), PgR positive (n=15), PgR negative (n=5), Her2 negative (n=16), and Her2 positive (n=4). Suitable FFPE tissue blocks were identified for all BCs. Ten µm sections were performed, air-dried and stained with methyl-green for visualization of the morphology. Macro-dissection and measurement of the tumor area (LVI) was done under a stereo microscope. Afterwards, HTG Seq quantitative assay of the oncology biomarker panel (2,560genes) was performed with some modifications to the standard protocol. Results: The macro-dissection was successful for both, LVI and main tumor mass, in 19 BCs. The dissected areas were between 11-60mm2. Eighteen samples could be included for RNA expression analysis. The main tumor mass and LVI showed clearly different expression patterns (clustering). LVI showed down regulation of genes coding for collagens (COL3A1, COL5A1), or genes involved in the interaction with the extracellular matrix (SPARC, VCAN). Up regulation was seen for genes coding for chemotactic factors involved in migration of inflammatory cells such as CCL18 for B-lymphocytes, CCL27 that seems to play a role in homing of lymphocytes to the skin, or CCL2 that is involved in recruiting monocytes and basophils. Conclusion: We showed that RNA expression analysis is feasible on small amount of tumor cells dissected from LVI that were stained with methyl green. Additionally, we could show that tumor cells from the main tumor mass and LVI have different gene expression levels and show clear clustering. Down regulation was seen in genes interacting with the extracellular matrix may indicating that these interactions are not needed when floating in lymphatic vessels. Interestingly, LVI showed upregulation of genes involved in the migration of white blood cells what could be an indication that tumor cells might relay on the same cytokines for migration in lymphatic vessels as inflammatory cells. Citation Format: Coya Tapia, Xiaoping Su, Ximing Tang, Lakshmi Kakaral, Aysegul Sahin, Wei Lu, Ignacio I. Wistuba. Tumor cells of the early metastatic process show up regulation of cytokine genes involved in migration of inflammatory cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1105.

Abstract 4054: Gene expression difference (GED) revealed immune function gene down-regulation as tumor-associated inflammatory cell (TAIC) infiltration in microenvironment in non-small cell lung cancer (NSCLC)

Abstract Background Advances in molecular analyses of tumor tissues based on high-throughput technologies can contribute to a better prediction of disease prognosis and the efficacy of immunotherapies. We investigated the GED related to immune response in a large cohort of NSCLC. Methods Using low-input, high-throughput HTG EdgeSeq assay, we examined expression of a panel of 549 immune response-related genes (28 are categorized as immune function genes) in FFPE tumor tissues of 226 surgically resected, stage I to III NSCLCs (137 adenocarcinomas [ADC] and 89 squamous cell carcinomas [SqCC]) with annotated clinical, pathological characteristics. Molecular data were available on mutations of EGFR and KRAS (cases=126), STK11, PIK3CA and TP53 by whole exome sequencing (n=180), and TAICs density detected by IHC (CD3, CD4, CD68, CD8, FOXP3, GZB, PD-L1 and PD-1) (n=145). We associated GED to 12 clinical, pathological or molecular characteristics including age, gender, smoking history, histology, stage, size, lymph node status and gene mutations of tumors and to patients' outcome (recurrence free survival [RFS] and overall survival [OS]). Results Univariate analysis showed upregulations of 82 genes in ADC and 89 in SqCC by comparing each other (P≤0.001). In ADC, 23 GEDs [FDR (false discover rate) ≤5%] associated with ever smoking history (8 up- and 15 down-regulated). Some genes were identified to be associated with mutations of EGFR, KRAS, STK11, PIK3CA and P53 genes. GEDs were identified in the tumors with TAIC high density by IHC. In ADC, 192 genes were down- and 191 up-regulated; while among the 28 immune function genes 21 down- and, only the gene APP (in all 8 high density TAICs) up-regulated. In SqCC, 121 genes down- and 112 up-regulated; while in the 28 genes 17 were down- and only the gene CAP up-regulated slightly in the high FOXP3 tumors. Cox proportional hazard model using FDR 5% in multi-testing showed that in ADC treated with adjuvant chemotherapy high-expression in 10 genes such as CD52, CD74 and HLA-DRA having a beneficial and 5 genes such as HRT2 and SERPINB2 having worse effect on OS; in the ADC patients who did not receive adjuvant therapy, high-expression of PIK3CD showed beneficial and, TTK and CXCL8 showed detrimental effect on OS; no gene was found to be associated with RFS in ADC and with OS and RFS in SqCC. Conclusion Gene expression profiling analysis of a panel of immune-related genes using low-input mRNA from FFPE tumor tissues revealed a number of genes associating to tumor characteristics, gene mutation patterns and TAIC infiltration in NSCLC. Interestingly, almost of immune function genes were down-regulated in the tumor with TAIC high density in NSCLC. (Supported in part by grant CPRIT RP160668) Citation Format: Ximing Tang, Wei Lu, Jiexin Zhang, Carmen Berhens, Edwin R. Parra, John Wineman, Jianjun Zhang, Don Lynn Gibbons, Mark Koeppel, BJ Kerns, Mark Stern, Boris Sepesi, Jack J. Lee, Ignacio I. Wistuba. Gene expression difference (GED) revealed immune function gene down-regulation as tumor-associated inflammatory cell (TAIC) infiltration in microenvironment in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4054.

Combined transplantation of neural precursor cells and olfactory ensheathing cells for the treatment of X-linked adrenoleukodystrophy in children

Combined transplantation of neural precursor cells and olfactory ensheathing cells for the treatment of X-linked adrenoleukodystrophy in children Hui Yang,1,* Yu Zhang,1,* Zhaoyan Wang,1 Wei Lu,1 Fang Liu,1 Xin Yu,2 Xiaoyan Zheng,1 Yinxiang Yang,1 Zuo Luan,1 Suqing Qu1 1Department of Pediatrics, 2Department of Neurological Surgery, Navy General Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work. Abstract: Hematopoietic stem cell transplantation is only suitable for early-stage adrenoleukodystrophy (ALD). In this study, we observed the therapeutic efficacy of combined transplantation of neural precursor cells (NPCs) and olfactory ensheathing cells (OECs) on late-stage X-linked ALD in nine children who were admitted in our hospital between June 2009 and January 2014. Related patient information included onset time 3 months to 1 year, magnetic resonance imaging (MRI) score 11.02±0.90, and neurologic function score 2–3. All patients received combined transplantation of NPCs and OECs by injection around the lateral angle of the frontotemporal–occipital lesion under MRI guidance. It was found that the visual function, sleep, and communication obstacles were improved significantly without evidence of disease progression in six (66.7%) of the nine patients within 1 month after transplantation. In two of the six patients, the lesions became significantly smaller than before, although their MRI scores remained unchanged significantly. In addition, cell therapy did not induce any irreversible adverse event during the study period, indicating that combined transplantation of NPCs and OECs was safe and reliable, and could improve the clinical manifestations of ALD in children within a short time. Although this cell therapy was not able to halt the progression of the disease 1–3 months after transplantation, it could still be used as an early treatment and provide patients with more opportunities for hematopoietic stem cell transplantation, which is the only effective long-term treatment for X-linked ALD at present. The preliminary results from this study suggest that a comprehensive prevention strategy of serial and combined transplantation may improve some functions for ALD patients in the short-term, however, long-term effects need further study. Keywords: X-linked adrenoleukodystrophy, combined transplantation, neural precursor cells, olfactory ensheathing cells

Abstract 2413: Cell type-specific deconvolution of heterogeneous tumor samples with immune infiltration using expression data

Abstract Tumor tissue samples comprise a mixture of cancerous and surrounding stromal cells. Understanding tumor heterogeneity is crucial to analyzing gene signatures associated with cancer prognosis and treatment decisions. Compared with the experimental approach of using laser micro-dissection to isolate different tissue components, in silico dissection of mixed cell samples is faster and cheaper. Numerous computational approaches previously developed have limited ability to deconvolute heterogeneous tumor samples. We have developed a deconvolution model, DeMix-T, that can explicitly account for a third component such as infiltrating immune cells, and address this challenging problem when the observed signals are assumed to come from a mixture of three cell compartments, infiltrating immune cells, the tumor microenvironment and cancerous tissues. The optimization-based algorithm for DeMix-T finds a local optimum for our estimation problem and is computationally feasible when it needs to compute high-dimensional integrals. DeMix-T therefore involves a novel two-stage filtering method that yields accurate estimates of cell purities and compartment-specific expression profiles. Simulations and real data analyses have demonstrated the good performance of our method. Compared with other deconvolution tools, DeMix-T can be applied more widely and provides deeper insight for cancer biomarker studies. It allows for a further understanding of immune cell infiltration in cancer and assists in the development of novel prognostic markers and therapeutic strategies. Citation Format: Zeya Wang, Jeffrey S. Morris, Chris C. Holmes, Jaeil Ahn, Bo Li, Wei Lu, Ximing Tang, Ignacio I. Wistuba, Wenyi Wang. Cell type-specific deconvolution of heterogeneous tumor samples with immune infiltration using expression data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2413.

Abstract 2993: The landscape of DNA allelic imbalance in the normal-appearing airway field of cancerization

Abstract The phenomenon of field cancerization has been previously postulated and observed in various cancers, including those of the lung. We have recently demonstrated that normal-appearing airway cells carry expression profiles that are often characteristic of the adjacent tumor. A better understanding of the molecular mechanisms that drive these field changes may provide important biological insights into lung cancer pathogenesis. Loss-of-heterozygosity (LOH) and other forms of acquired chromosomal alterations (allelic imbalance; AI) have an established and profound role in oncogenesis. However, the relationship between AI and field cancerization has not been studied comprehensively across the genome. Here we address this void by interrogating a rich collection of normal-appearing airways from non-small cell lung cancer (NSCLC) patients. We applied Illumina 1M SNP arrays to characterize whole genome copy number alterations in 435 samples from 45 early-stage NSCLC patients [31 adenocarcinomas (ADCs), 14 squamous cell carcinomas (SCCs)]. Each patient set comprised samples from the primary tumor and adjacent normal-appearing airways paired with blood cells and/or uninvolved normal lung tissue. A subset of these included brushings from ipsilateral large airways (mainstem bronchi) and from the nasal cavities as well as multi-region tumor biopsies for intra-tumoral analysis (on 22, 27, and 20 patients, respectively). To characterize the field in normal-appearing airways at a genome-wide scale, we applied a haplotype-based computational program, hapLOH, to profile AI events (loss, gain, copy neutral LOH) in a paired mode contrasting signals in the blood or normal lung. We detected 198 AI events in normal-appearing airways of 24 of 45 patients; 92% of these events were represented in the paired tumor. Of the 24 patients, 23 had events in the adjacent airway, 3 had events in the large airway, and no events were observed in nasal brushings, indicating a pronounced AI field gradient. We detected AI in the airways of approximately 43% of ADCs regardless of smoking status (3 of 7 smokers, 10 of 24 non-smokers), and 79% (11 of 14) of SCCs, clearly indicating squamous histology as a greater predictor of observing a genomic field effect (P < 0.03). The most frequently observed airway alterations were in 9p and 9q, affecting 13 smoker patients; interestingly, these were not observed in the non-smokers. Finally, we note that AI events were present in the adjacent airways of 4/5 (80%) of patients with recurrence and only in 20/40 patients without recurrence, signaling a profound prognostic value in studying the field of cancerization in NSCLC. Although preliminary, our findings suggest that chromosomal aberrations are common in the normal-appearing airway field of cancerization and can potentially provide insights into the biology of lung cancer pathogenesis and progression. Citation Format: Yasminka Jakubek, Wenhua Lang, Selina Vattathil, Melinda Garcia, Lili Huang, Wei Lu, Chi-Wan Chow, Zachary Weber, Gareth E. Davies, Carmen Behrens, Neda Kalhor, Cesar Moran, Junya Fujimoto, Reza J. Mehran, Jerry Fowler, Erik A. Ehli, Ignacio I. Wistuba, Paul Scheet, Humam Kadara. The landscape of DNA allelic imbalance in the normal-appearing airway field of cancerization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2993. doi:10.1158/1538-7445.AM2015-2993

TU‐CD‐BRA‐12: Coupling PET Image Restoration and Segmentation Using Variational Method with Multiple Regularizations

Purpose:To propose a new variational method which couples image restoration with tumor segmentation for PET images using multiple regularizations.Methods:Partial volume effect (PVE) is a major degrading factor impacting tumor segmentation accuracy in PET imaging. The existing segmentation methods usually need to take prior calibrations to compensate PVE and they are highly system‐dependent. Taking into account that image restoration and segmentation can promote each other and they are tightly coupled, we proposed a variational method to solve the two problems together. Our method integrated total variation (TV) semi‐blind deconvolution and Mumford‐Shah (MS) segmentation. The TV norm was used on edges to protect the edge information, and the L₂ norm was used to avoid staircase effect in the no‐edge area. The blur kernel was constrained to the Gaussian model parameterized by its variance and we assumed that the variances in the X‐Y and Z directions are different. The energy functional was iteratively optimized by an alternate minimization algorithm. Segmentation performance was tested on eleven patients with non‐Hodgkin's lymphoma, and evaluated by Dice similarity index (DSI) and classification error (CE). For comparison, seven other widely used methods were also tested and evaluated.Results:The combination of TV and L₂ regularizations effectively improved the segmentation accuracy. The average DSI increased by around 0.1 than using either the TV or the L₂ norm. The proposed method was obviously superior to other tested methods. It has an average DSI and CE of 0.80 and 0.41, while the FCM method — the second best one — has only an average DSI and CE of 0.66 and 0.64.Conclusion:Coupling image restoration and segmentation can handle PVE and thus improves tumor segmentation accuracy in PET. Alternate use of TV and L2 regularizations can further improve the performance of the algorithm.This work was supported in part by National Natural Science Foundation of China (NNSFC), under Grant No.61375018, and Fundamental Research Funds for the Central Universities, under Grant No. 2012QN086. Wei Lu was supported in part by the National Institutes of Health (NIH) Grant No. R01 CA172638.

Abstract 4140: Secular trends in incidence and mortality of female cancers in Shanghai, China (1973-2009)

Abstract Socioeconomic development and urbanization have resulted in dramatic changes in cancer incidence and mortality in China. As one of the largest and most developed cities in China, Shanghai's cancer rates reflect the changing burden of cancer in China. This study was undertaken to evaluate trends and quantify changes in the incidence and mortality of breast, ovarian, endometrial, and cervical cancers among female residents of urban Shanghai from 1973 to 2009. Data on cancer incidence and mortality were collected by the Shanghai Cancer Registry. International Classification of Disease version 10 codes for breast (C50), cervical (C53), endometrial (corpus uteri and uterus unspecified; C54 and C55), and ovarian cancer (C56) were included in the current analysis. Annual population data was provided by the Department of Vital Statistics, Shanghai Municipal Center for Disease Control and Prevention. A total of 73,755 female cancers and 28,274 related deaths were documented between 1973 and 2009. Age-standardized incidence and mortality rates were calculated using the Segi/Doll 1960 world standard. Joinpoint regression models were used to fit joined straight lines on a log-scale for annual age-standardized rates and to calculate annual percent changes (APC). Between 1973 and 2009, the incidence of breast, ovarian, and endometrial cancers increased, with overall APCs of 2.93, 2.20, and 1.66, respectively. Significant trends were found for breast cancer between 1979 and 1998 (APC 3.07) and for ovarian cancer between 1983 and 2009 (APC 2.83). For endometrial cancer a significant decrease occurred from 1973 to 1983 (APC -4.27), followed by a significant increase from 1983 to 1996 (APC 2.58). The incidence of cervical cancer decreased, with an overall APC of -3.91; this included three significant decreasing trends between 1973 and 1996, followed by a significant increase through 2009 (APC 8.49). The mortality of breast and ovarian cancers increased, with overall APCs of 0.70 and 0.58, respectively. Significant trends were found for breast cancer between 1982 and 2004 (APC 1.55) and for ovarian cancer during the entire time period. The mortality of cervical and endometrial cancers decreased, with overall APCs of -5.36 and -2.33, respectively. For cervical cancer, this included a significant decrease between 1973 and 1999 (APC -7.34), followed by a significant increase through 2009 (APC 3.24). For endometrial cancer, this included a significant decrease between 1973 and 1988 (APC -5.59). In summary, increasing trends were found for breast, ovarian and endometrial cancer incidence, and for breast and ovarian cancer mortality, while decreasing trends were found for cervical cancer incidence and cervical and endometrial cancer mortality among women in urban Shanghai. Additional analyses to identify age-period-cohort effects in this data are underway. This study lays the ground work for the establishment of cancer prevention and control priorities in China. Citation Format: Zhezhou Huang, Alicia C. Beeghly-Fadiel, Ying Zheng, Wanqing Wen, Yutang Gao, Chunxiao Wu, Pingping Bao, Weijian Zhong, Fan Jin, Yongbing Xiang, Wei Zheng, Xiao Ou Shu, Wei Lu. Secular trends in incidence and mortality of female cancers in Shanghai, China (1973-2009). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4140. doi:10.1158/1538-7445.AM2014-4140

Abstract 3281: TGFβ pathway alteration, body mass index, physical activity and breast cancer outcomes: The Shanghai Breast Cancer Survival Study

Abstract Background: Cumulative evidence suggests that the transforming growth factor-beta (TGF-β) pathway may have prognostic significance in human breast cancer. It also has been shown that the TGF-β pathway may play a role in glucose regulation and energy homeostasis. However, no previous study has examined the potential modifying effects of obesity and physical activity on associations between TGF-β pathway biomarkers, such as TGFβRII and pSmad2, and breast cancer outcomes. Methods: Breast cancer patients aged 20 to 75 years were recruited 6 months after diagnosis between 2002 and 2005 and participated in in-person baseline and follow-up surveys that collected information on cancer diagnosis, treatment, lifestyle exposures, anthropometrics, and physical activity. The expression of TGFβRII and nuclear pSmad2 in breast cancer cells and breast stromal tissue cells was evaluated immunohistochemically. Five-year disease-free survival (DFS) and overall survival (OS) rates were estimated by Kaplan Meier method. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) with adjustment for other prognostic variables and further stratified by body mass index (BMI) or physical activity. Results: Breast cancer cells exhibited either a membranous or a cytoplasmic expression pattern of TGFβRII. Compared with the membranous pattern, the cytoplasmic pattern was more prevalent among patients with low BMI (P<0.01) and was associated with lower five-year DFS (91% vs. 83%, P=0.04; adjusted HR=1.66, 95% CI: 1.03-2.68). Compared with lower nuclear pSmad2 expression intensity, higher expression intensity of nuclear pSmad2 in breast cancer cells was associated with lower five-year DFS (87% vs. 82%, P=0.02; adjusted HR=1.31, 95%CI: 0.96-1.79). This association was predominantly seen among participants with moderate physical activity levels (<9.4 MET-hr/wk; adjusted HR=2.05, 95% CI: 1.11-3.79 for five-year DFS) and lower BMI (<25; adjusted HR=1.80, 95% CI: 1.17-2.77 for five-year DFS), although the test for multiplicative interaction was only significant for BMI (Pinteraction=0.02). Analyses of OS showed similar patterns of association with a significant interaction between BMI and pSmad2 (adjusted HR=2.09, 95% CI: 1.38-3.15 for patients with low BMI, Pinteraction<0.001). The expression of TGFβRII and nuclear pSmad2 in stromal cells was unrelated to breast cancer outcomes. Conclusion: Expression levels of TGFβRII and nuclear pSmad2 in cancer cells were associated with breast cancer outcomes. These associations may be modified by BMI. Citation Format: Yinghao Su, Wei Zheng, Hui Cai, Ying Zheng, Qingchao Qiu, Wei Lu, Xiao-Ou Shu, Qiuyin Cai. TGFβ pathway alteration, body mass index, physical activity and breast cancer outcomes: The Shanghai Breast Cancer Survival Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3281. doi:10.1158/1538-7445.AM2014-3281

Abstract LB-296: Tumor tissue microRNA expression in association with triple negative breast cancer recurrence and mortality

Abstract Background Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers in the United States1. Compared with other breast cancer patients, TNBC displays high rates of metastasis, has poorer prognosis, and has no targeted therapies. microRNAs are small non-coding RNAs that function in transcriptional and post-transcriptional regulation of gene expression. Recent studies, primarily based on cell-line and animal studies, suggest that miRNA expression may be related to cancer metastasis and prognosis1-5. Purpose To systematically investigate associations of tumor expression of 38 miRNAs that have been previously implicated in breast cancer prognosis with TNBC recurrence and cancer-specific mortality. Method Included in the study were 456 TNBC cases recruited by the Shanghai Breast Cancer Survival Study between March 2002 and April 2006 and aged 20 to 75 years at diagnosis. Information on breast cancer diagnosis, treatment, demographics, lifestyle factors, and disease progression was collected approximately 6 months after diagnosis and reassessed at 18, 36, and 60 months after diagnosis in follow-up interviews. Information on disease recurrence and mortality was collected via in-person follow-up surveys and linkages with population-based cancer registry and vital statistics databases. miRNA expression levels in formalin-fixed, paraffin-embedded breast cancer tissue sections were measured using the NanoString nCounter assay. The association of miRNA expression with breast cancer recurrence and mortality was evaluated by Cox regression analysis with adjustment for age at diagnosis and TNM stage (I-IV). Results Of the 38 miRNAs evaluated, expression levels of miR-374b (P=0.0022), miR-148a (P=0.0029), miR-126 (P=0.0059), and miR-218 (P=0.0087) were significantly and inversely associated with recurrence and breast cancer mortality among TNBC patients independent of age and TNM stage. The directions of association were consistent with those previously reported in the literature. A composite score derived from the expression levels of these four miRNAs was more significantly associated with breast cancer recurrence and mortality (P=0.0001), with hazard ratios (95% confidence interval) of 1.2 (0.77-2.0), 0.53 (0.30-0.94), and 0.23 (0.11-0.48) for the second to fourth quartiles compared with the lowest quartile of scores. Conclusion In this, the largest study to date of tumor miRNA expression and TNBC outcomes, we found that miR-374b, miR-148a, miR-126, and miR-218, were individually and jointly associated with TNBC prognosis. 1. Cascione L, Gasparini P, Lovat F et al., Integrated MicroRNA and mRNA Signatures Associated with Survival in Triple Negative Breast Cancer. PLoS ONE 2013 8(2): e55910 2. Voliniaa S, Galassoa M, Sanaa M, et al., Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA, PNAS 2012 109, 3024-3029 3. Png K, Halberg N, Yoshida M et al. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells, Nature 2012 481:190-194 4. Zhang Y, Yang P, Sun T et al., miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nature Cell Biology 2013 15, 284-294 5. Pencheva N & Tavazoie S Control of metastatic progression by microRNA regulatory networks. Nature Cell Biology 2013 15, 546-554 Citation Format: Yan Liu, Qiuyin Cai, Fei Ye, Ying Zheng, Jie Wu, Yinghao Su, Hui Cai, Ping-Ping Bao, Wei Zheng, Wei Lu, Xiao-Ou Shu. Tumor tissue microRNA expression in association with triple negative breast cancer recurrence and mortality. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-296. doi:10.1158/1538-7445.AM2014-LB-296

Abstract 3265: Dual specificity phosphatase 4 gene expression in triple negative breast cancer

Abstract Background Triple negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. A recent report suggested that dual specificity phosphatase 4 (DUSP4) may be a potential marker of chemotherapy resistance for TNBC. Methods We measured the DUSP4 gene expression levels in breast cancer tissue from 469 TNBC patients who participated in the Shanghai Breast Cancer Survival Study and evaluated their association with breast cancer recurrence/breast cancer mortality and total mortality. Study participants were diagnosed with incident breast cancer between March 2002 and April 2006 and aged between 20 and 75 years. Information on breast cancer diagnosis and treatment, as well as demographic, lifestyle, and disease progression information, were collected approximately 6 months after cancer diagnosis and reassessed at 18, 36, and 60 months after diagnosis in follow-up interviews. Expression levels of transcript variant 1 (NM_001394) and transcript variant 2 (NM_057158) of DUSP4 gene were measured by the NanoString nCounter assay using RNA obtained from formalin-fixed, paraffin-embedded tissue sections. Cox regression analysis was applied in the data analyses with adjustment for clinical and demographic factors. Results Of the 469 TNBC participants in this study, 100 deaths and 92 recurrences/breast cancer deaths were documented over a median follow-up of 5.3 years (range, 0.7-8.9 years). The expression of the two DUSP4 isoforms were highly correlated (r=0.76). Low DUSP4, particularly variant 1 (NM_001394), expression levels were associated with increased recurrence/breast cancer mortality and overall mortality. After adjustment for age at diagnosis and TNM stage, the hazard ratios comparing those with DUSP4 (variant 1) expression levels below the median to those above the median were 1.97 (95% confidence interval (CI): 1.27, 3.05) for recurrence/breast cancer mortality and 2.09 (95% CI: 1.38, 3.17) for overall mortality. Adjustment for expression levels of MKI67 and TP53, common treatment types, breast cancer subtype, or grade did not materially alter the observed association. Conclusion Low DUSP4 expression levels predict recurrence and mortality in TNBC patients independently from known clinical and molecular predictors. Citation Format: Michelle L. Baglia, Qiuyin Cai, Ying Zheng, Jie Wu, Yinghao Su, Fei Ye, Ping-Ping Bao, Hui Cai, Zhiguo Zhao, Wei Zheng, Wei Lu, Xiao-Ou Shu. Dual specificity phosphatase 4 gene expression in triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3265. doi:10.1158/1538-7445.AM2014-3265

SU‐E‐I‐96: A Study About the Influence of ROI Variation On Tumor Segmentation in PET

Purpose:To study the influence of different regions of interest (ROI) on tumor segmentation in PET.Methods:The experiments were conducted on a cylindrical phantom. Six spheres with different volumes (0.5ml, 1ml, 6ml, 12ml, 16ml and 20 ml) were placed inside a cylindrical container to mimic tumors of different sizes. The spheres were filled with 11C solution as sources and the cylindrical container was filled with 18F‐FDG solution as the background. The phantom was continuously scanned in a Biograph‐40 True Point/True View PET/CT scanner, and 42 images were reconstructed with source‐to‐background ratio (SBR) ranging from 16:1 to 1.8:1. We took a large and a small ROI for each sphere, both of which contain the whole sphere and does not contain any other spheres. Six other ROIs of different sizes were then taken between the large and the small ROI. For each ROI, all images were segmented by eitht thresholding methods and eight advanced methods, respectively. The segmentation results were evaluated by dice similarity index (DSI), classification error (CE) and volume error (VE). The robustness of different methods to ROI variation was quantified using the interrun variation and a generalized Cohen's kappa.Results:With the change of ROI, the segmentation results of all tested methods changed more or less. Compared with all advanced methods, thresholding methods were less affected by the ROI change. In addition, most of the thresholding methods got more accurate segmentation results for all sphere sizes.Conclusion:The results showed that the segmentation performance of all tested methods was affected by the change of ROI. Thresholding methods were more robust to this change and they can segment the PET image more accurately.This work was supported in part by National Natural Science Foundation of China (NNSFC), under Grant Nos. 60971112 and 61375018, and Fundamental Research Funds for the Central Universities, under Grant No. 2012QN086. Wei Lu was supported in part by the National Institutes of Health (NIH) Grant No. R01 CA172638.

SU-C-9A-03: Simultaneous Deconvolution and Segmentation for PET Tumor Delineation Using a Variational Method

Purpose: To implement a new method that integrates deconvolution with segmentation under the variational framework for PET tumor delineation. Methods: Deconvolution and segmentation are both challenging problems in image processing. The partial volume effect (PVE) makes tumor boundaries in PET image blurred which affects the accuracy of tumor segmentation. Deconvolution aims to obtain a PVE-free image, which can help to improve the segmentation accuracy. Conversely, a correct localization of the object boundaries is helpful to estimate the blur kernel, and thus assist in the deconvolution. In this study, we proposed to solve the two problems simultaneously using a variaional method so that they can benefit each other. The energy functional consists of a fidelity term and a regularization term, and the blur kernel was limited to be the isotropic Gaussian kernel. We minimized the energy functional by solving the associated Euler-Lagrange equations and taking the derivative with respect to the parameters of the kernel function. An alternate minimization method was used to iterate between segmentation, deconvolution and blur-kernel recovery. The performance of the proposed method was tested on clinic PET images of patients with non-Hodgkin's lymphoma, and compared with seven other segmentation methods using the dice similarity index (DSI) and volume error (VE). Results: Among all segmentation methods, the proposed one (DSI=0.81, VE=0.05) has the highest accuracy, followed by the active contours without edges (DSI=0.81, VE=0.25), while other methods including the Graph Cut and the Mumford-Shah (MS) method have lower accuracy. A visual inspection shows that the proposed method localizes the real tumor contour very well. Conclusion: The result showed that deconvolution and segmentation can contribute to each other. The proposed variational method solve the two problems simultaneously, and leads to a high performance for tumor segmentation in PET. This work was supported in part by National Natural Science Foundation of China (NNSFC), under Grant Nos. 60971112 and 61375018, and Fundamental Research Funds for the Central Universities, under Grant No. 2012QN086. Wei Lu was supported in part by the National Institutes of Health (NIH) Grant No. R01 CA172638.

Abstract 2557: Genetic variants in microRNA genes and breast cancer risk.

Abstract microRNA (miRNA) are small noncoding molecules that function as regulators of the genome. Genetic variants in miRNA binding sites and miRNA genes have begun to be evaluated in relation to disease risk; however, no studies have yet comprehensively evaluated miRNA variants in relation to breast cancer risk. Using a two stage study design, and genome-wide association study (GWAS) data, we evaluated genetic variants within 1,425 miRNA genes (±5kb). In Stage 1, a total of 2,213 common genetic variants were evaluated among 2,876 breast cancer cases and 2,285 controls using data from the Shanghai Breast Cancer Genetics Study. Nominally significant associations (P value ≤0.05) were found for 108 variants in 96 genetic loci (r²≥0.6). In Stage 2, 94 variants in 84 loci were evaluated among 2,225 cases and 2,052 controls from the Seoul Breast Cancer Study; nine variants in eight loci had nominally significant associations. In analyses of the two study stages combined, 14 loci had highly significant associations (P value ≤0.01) and 19 additional loci had significant associations (P value ≤0.05) with breast cancer risk, all with consistent directions of association between the two study stages. These 36 variants in 33 loci have been mapped to 16 miRNA genes, many in the promoter regions. Based on our findings, genetic variants in miRNA genes are likely to contribute to breast cancer susceptibility. Citation Format: Alicia C. Beeghly-Fadiel, Hyuna Sung, Ben Zhang, Ji-Yeob Choi, Ryan J. Delahanty, Jirong Long, Yu-Tang Gao, Wei Lu, Qiuyin Cai, Xiao Ou Shu, Daehee King, Wei Zheng. Genetic variants in microRNA genes and breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2557. doi:10.1158/1538-7445.AM2013-2557