Li Tang Research Articles

Abstract A31: Genome-wide microRNA profiling analysis of breast cancer among African American and European American women

Abstract African American (AA) women are more likely than European American (EA) women to be diagnosed with aggressive, estrogen receptor (ER) negative breast cancer. Differences in microRNA (miRNA) expression patterns have not been well studied as potential mechanisms underlying this racial disparity. In this study, we performed a whole-genome miRNA expression profiling in 58 (29 AA and 29 EA) fresh-frozen breast tumors, with clinical characteristics (e.g., ER status, histological grade, stage) comparable between AA and EA samples, and in 10 (5 AA and 5 EA) normal breast tissues obtained from women undergoing reduction mammoplasty, with pathology determined free from any abnormalities. Unsupervised hierarchical clustering showed that miRNA expression patterns clearly distinguish breast cancer from normal breast tissue. In tumors, a number of miRNAs are significantly differentially expressed between tumor subtypes and are associated with other clinicopathological factors, such as tumor grade and lymph node status. We identified 64 differentially expressed (mean fold change>2 and FDR<0.05) miRNAs between ER negative and ER positive tumors. Interestingly, we observed that there were 13 miRNAs differentially expressed between ER negative and ER positive breast tumors regardless of race, 28 miRNAs differentially expressed only in EA tumors and 23 miRNAs were differentially expressed in AA samples only. Specifically, the top most differentially expressed miRNAs from EA women include: several members of miR-17-92 cluster (miR-17, miR-18a, miR-19a, miR-20a), miR-508, miR509, and miR514a that are up-regulated, and miR-1, miR-133a, miR133b and miR206, which are down-regulated, in ER negative compared to ER positive tumors. In AA women, however, up-regulated miRNAs include miR-105, miR-106b, miR-135b, miR-520b; down-regulated ones include miR-216a, miR217, miR342, miR375, and miR378a. Further, several of these miRNAs, such as miR-17, miR-18a, miR-133a, miR-206, have been shown to regulate various target genes involved in apoptosis, cell cycle, invasion, or angiogenesis. In summary, in this genome-wide miRNA expression profiling analysis by next generation sequencing, our results suggest that miRNA expression patterns may differ by tumor subtypes between AA and EA breast samples. These initial results will provide the basis for the functional analysis of the identified miRNAs, and findings could contribute to a better understanding of the biology of breast cancer disparities and more targeted preventative and therapeutic strategies. Citation Format: Zhihong Gong, Dan Wang, Allyson Espinal, Qiang Hu, Lara Sucheston-Campbell, Li Tang, Jo Freudenheim, Peter Shields, Carl Morrison, Steven Belinsky, Song Liu, Kitaw Demissie, Michael Higgins, Christine Ambrosone. Genome-wide microRNA profiling analysis of breast cancer among African American and European American women. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A31.

Abstract B47: Methylation differences in breast tumor DNA from African American and European women are predominant in estrogen receptor (ER) negative breast cancer and are associated with childbearing

Abstract Background: Although European American (EA) women have higher incidence of breast cancer than African American (AA) women, AA women are more often diagnosed with aggressive estrogen receptor negative (ER-) tumors, the risk of which increases with parity, lack of breastfeeding, and an early age at menarche. DNA methylation could be affected by reproductive factors and may be a potential molecular mechanism driving differences in tumor etiology. In a small study using fresh frozen breast tissue (n=58 AA, 80 EA), we previously found more differentially methylated loci (DMLs) in ER- tumors from AA and EA women than in ER+ tumors. Methods: To follow up on these preliminary findings, we used the Illumina 450K platform to determine genome-wide DNA methylation profiles in formalin fixed paraffin embedded (FFPE) breast tumors from 383 AA and 350 EA women who participated in the Women's Circle of Health Study, a case control study conducted in NY and NJ. We identified DMLs by race and ER status, as well as differentially methylated regions (DMRs). DMLs in eight genes were validated using the Sequenom EpiTYPER platform. Recursively partitioned mixture modeling (RPMM) package in R was used to examine relationships between methylation clusters and reproductive factors, information available from in-person interviews. In addition, using fresh frozen tumor tissue from 50 patients treated at Roswell Park Cancer Institute, we performed RNA sequencing on samples with methylation data available from a prior study, and used Spearmen's correlation to compare methylation and gene expression of DMLs and DMRs. Results: In assessing average methylation by location relative to CpG-islands (CGIs), we found that CGIs and shores in ER- tumors were significantly hypomethylated compared to CGI and shores in ER+ tumors from AA women, but not in tumors from EA women. We also identified 410 DMLs (Δβ>0.10 & FDR<0.05) between AA and EA breast tumors (race-associated DMLs, raDMLs), the majority of which were unique to ER- tumors (n = 260) and hypomethylated in AAs. These loci were enriched for immune response genes and several cell adhesion and inflammatory pathways. RPMM showed that parity, but not breastfeeding or age at menarche, was significantly associated with methylation class of ER- breast tumors. Of the genes that had ER- specific raDMLs, FOXA1 and THSD4 DNA methylation was highly correlated with gene expression (rho=-0.80, rho=+0.87, respectively; pvalue< 2.2x10-16). Summary: ER- tumors from AA women, but not from EA women, exhibited global hypomethylation at CGI and shores compared to ER+ tumors and contained the majority of raDMLs, many of which were associated with genes involved in immune and inflammatory response. The FOXA1 gene, which encodes a pioneer factor previously implicated in suppressing the molecular phenotype of basal breast cancer cells, was found to be methylated and silenced in the majority of ER- tumors analyzed for expression, consistent with aggressiveness of these tumors. These results, and the novel finding of associations between parity and DNA methylation signature, bring us a step forward in understanding the heterogeneous population of ER- tumors and provide insight into mechanisms of racial disparities in breast cancer. Citation Format: Allyson C. Espinal, Dan Wang, Lara Sucheston-Campbell, Song Liu, Qiang Hu, Li Tang, Gary Zirpoli, Thaer Khoury, Song Yao, Kitaw Demissie, Elisa V. Bandera, Christine B. Ambrosone, Michael J. Higgins. Methylation differences in breast tumor DNA from African American and European women are predominant in estrogen receptor (ER) negative breast cancer and are associated with childbearing. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B47.

Abstract A073: Carrier-free delivery of cytokine to specifically expand adoptively transferred T cells for enhanced cancer immunotherapy

Abstract Adoptive cell transfer (ACT) with autologous tumor-reactive T cells is a promising strategy in cancer immunotherapy, but treatment of solid tumors is limited by the rapid decline in function of the transplanted T cells. In order to maintain high numbers of viable antigen-specific cytotoxic T cells in tumors, co-administration of supporting immunostimulant agents together with transferred cells is often necessary in clinical practice. However, the high systemic doses of such agents needed to enhance T cell functionality can also result in serious side effects. Here, we developed a carrier-free strategy to deliver cytokines specifically to adoptively transferred T cells for cancer immunotherapy. IL2-Fc or an IL-15 superagonist were chemically crosslinked with a disulfide linker to form protein nanogels (NGs), which were conjugated to the plasma membrane of ACT T-cells. These NGs had exceptionally high loading of cytokines (~70 wt%) and released native protein in physiological conditions in a sustained manner through breakdown of the degradable disulfide linker in response to the activated T cell surface reduction activity. Cytokine-NGs were chemically conjugated onto the plasma membrane of donor T cells, enabling continuous pseudo-autocrine release of cytokine for stimulation of transferred CD8+ T cells. Transferred pmel-1 CD8+ T cells with optimized number of NGs conjugated per cell showed enhanced expansion and long persistence in B16F10 tumor bearing mice. Quantification of transferred Thy1.1+CD8+ T cells in tumors at Day 13 showed that T cells with conjugated cytokine-NGs expanded ~80 fold more than the T cells with systemically administered free cytokine. We demonstrated that the cytokine-NG-T cell conjugation strategy could augment transferred T-cell expansion efficiently and specifically in vivo, and thus improve the therapeutic efficacy. This T cell-NG “back pack” approach provides a readily generalizable strategy to provide autocrine protein drug support to donor cells to enhance the safety and efficacy of ACT. Citation Format: Li Tang, Yiran Zheng, Llian Mabardi, Darrell J. Irvine. Carrier-free delivery of cytokine to specifically expand adoptively transferred T cells for enhanced cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A073.

Abstract 2789: Associations between insertional polymorphisms of human endogenous retrovirus K113 and K115 and breast cancer risk in African American and European American women

Abstract Background: Human endogenous retroviruses (HERVs) are remnants of ancient virus infection. The majority of them are disabled due to mutation and/or deletion. However, HERV K113 and K115 have been shown to have full-length insertion in human genome and retain the ability to encode functional virus proteins in some individuals. Considering the potential role of HERVs in carcinogenesis and a high genetic homology between HERV K and mouse mammary tumor virus, the study is designed to investigate the distribution of HERV K113 and K115 in African American (AA) and European American (EA) women, and their association with breast cancer risk. Methods: Built on a funded multi-center case-control study, the Women's Circle of Health Study, the study included 1242 cases (608 AA and 634 EA) and 1422 controls (783 AA and 639 EA). PCR followed by fragment analysis was used for insertional polymorphism assay. For each HERV, three PCRs were performed to determine whether the insertion is partial or full length. Indeed, a subset of individuals showed insertion of long terminal repeat (LTR) of HERV, instead of whole virus insertion. The distribution of insertional polymorphisms was compared between AA and EA as well as between cases and controls. Logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI) with adjustment for age at diagnosis and proportion of European ancestry. Results: For both K113 and K115, with or without including LTR insertion, the distribution was significantly different between AA and EA women. A two-fold higher prevalence of HERVs was observed in AA women, showing 51.5% of individuals with at least one copy of either K113 or K115 compared to 23.3% in EA women among controls. The prevalence of HERVs was inversely associated with proportions of European ancestry, showing a decrease from averagely 66% European ancestry in individuals without insertion to 42.9%, 23.2%, 13.3% with one, two, or more insertions of HERV K113 or K115, respectively. Between cases and controls, the prevalence of K113 was slightly higher in controls, but not for K115. Furthermore, both K113 and K115 insertion were significantly associated with the reduced risk of breast cancer in both AA and EA women. Near 50% reduction of breast cancer risk was observed in AA and EA women with homozygous insertion of K113 (combined OR, 0.45; 95% CI, 0.25-0.80). A trend of a reduction in breast cancer risk with an increase of copy number of HERV K insertion was observed in both AA and EA women. However, there was no association with breast cancer subtypes. Conclusion: This is the first study to document the prevalence of HERV K113 and K115 in AA and EA population, and to report an inverse association with breast cancer risk. Validation of the findings in a relatively large study is warranted in the future. Funded by 5R03CA156645, K07CA148888, P01151135, and R01CA100598. Citation Format: Li Tang, Steven R. Gregory, David Tritchler, Gary R. Zirpoli, Song Yao, Warren Davis, Gregory L. Ciupak, Yasmin Thanavala, Elisa V. Bandera, Christine B. Ambrosone. Associations between insertional polymorphisms of human endogenous retrovirus K113 and K115 and breast cancer risk in African American and European American women. [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 2789. doi:10.1158/1538-7445.AM2015-2789

Abstract 4126: The association of serum 25-hydroxyvitamin D with breast cancer characteristics and prognosis in the Pathways Study

Abstract Background: Vitamin D may be protective against breast cancer (BC), yet current evidence from epidemiologic studies is inconsistent. We previously reported lowest serum 25-hydyroxyvitamin D (25OHD) levels in premenopausal women with the triple-negative (TN) subtype. We aimed to validate our findings in an independent cohort and to further investigate 25OHD levels in association with breast cancer prognosis. Methods: Using a case-cohort design, 1664 invasive breast cancer patients were selected from the Pathways Study, a prospective cohort at Kaiser Permanente Northern California (KPNC). 25OHD levels were measured by immunochemiluminometric assay in blood samples collected close to diagnosis. Demographic and lifestyle information at baseline came from in-person interviews, and information on cancer characteristics, treatment, recurrence and death were obtained from KPNC cancer registries and clinical databases. We examined quartiles of 25OHD in association with BC characteristics (stage, grade, estrogen receptor status, TN subtype) using logistic regression, and with disease-free survival (DFS) and overall survival (OS) using Cox proportional hazards regression with covariate adjustment. Pending analyses will account for sampling in which biospecimens from all minorities, all non-Lum A subtypes (Lum B/TN/HER2-overexpressing), and a subset (30%) of white Lum A subtypes were selected. Results: Blood collection in winter-spring, younger age, obesity, black or Hispanic race/ethnicity, current smoking, low moderate-vigorous physical activity, no vitamin D supplement use, and low dietary vitamin D intake were associated with low serum 25OHD levels. In premenopausal women, 25OHD levels were associated inversely with cancer stage and grade, and those with the TN subtype had the lowest levels (Q4: adjusted OR vs. Lum A=0.41, 95% CI=0.19-0.86). Among white women after a median follow-up time of 5.9 y (range 2.5-7.8 y), high 25OHD levels were associated with longer DFS (Q4: adjusted HR=0.67, 95% CI=0.45-0.98), as well as OS (Q4: adjusted HR=0.58, 95% CI=0.36-0.92). Additional adjustment for stage, grade, subtype and treatment received had minimal effects on the above associations. The associations with DFS and OS appeared stronger in premenopausal women than in postmenopausal women. Conclusion: In a large prospective cohort of breast cancer patients, we validated our previous findings of 25OHD levels being associated with lower odds of TN tumor subtype in premenopausal patients. Moreover, preliminary results indicate that high 25OHD levels at the time of diagnosis were associated with longer DFS and OS, the relationships were independent of cancer characteristics and treatment, and may be stronger in premenopausal women. These findings support potential benefits of maintaining sufficient vitamin D levels for improved breast cancer prognosis. Citation Format: Song Yao, Chi-Chen Hong, Marilyn L. Kwan, Ting-Yuan Cheng, Li Tang, Susan E. McCann, Isaac J. Ergas, Janise M. Roh, Warren Davis, Christine B. Ambrosone, Lawrence H. Kushi. The association of serum 25-hydroxyvitamin D with breast cancer characteristics and prognosis in the Pathways 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 4126. doi:10.1158/1538-7445.AM2014-4126

Abstract 1266: Racial differences in the association of cruciferous vegetable intake with breast cancer hormone receptor status and tumor subtype

Abstract Background: Dietary isothiocyanates (ITCs) are chemopreventive phytochemicals from cruciferous vegetables (CV). ITCs down-regulate estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) in breast cancer cells, and inhibit development of breast cancer in animal models. CV intake was found to be inversely associated with breast cancer risk. However, the association of CV intake with breast cancer subtype is unknown. Further, racial differences exist in dietary habits and polymorphic genes in ITC-metabolizing pathway. In a prospective cohort, we examined the association of prior CV intake with breast cancer hormone receptor status and subtype by race. Methods: Among 2908 breast cancer patients diagnosed 2005-2013 at Kaiser Permanente Northern California (KPNC), data on CV intake in the past 6 months were obtained from a validated food frequency questionnaire as part of a comprehensive baseline interview about two months post-diagnosis. Breast cancer characteristics came from the KPNC Cancer Registry. CV intake and its association with hormone receptor status (ER+/-, PR+/-, and HER2+/-) and subtype (luminal A/luminal B/triple negative/HER2-overexpressing) were examined among Whites, African Americans (AA), Asians, and Hispanics. Logistic regression was used adjusting for age at diagnosis, race, menopausal status, parity, energy intake, and dietary fiber from vegetables. Results: CV intake (grams/day) differed across racial groups (p<0.01), with 46.9, 35.6, 30.7, and 27.8 for Asians, AA, Whites, and Hispanics, respectively. Except for broccoli, intake of other individual CVs differed across racial groups (p<0.01). Total CV intake was not associated with breast cancer subtypes in any racial group. However, compared with PR+ disease, coleslaw intake was associated with reduced odds of PR- disease in Asians (high vs. low: OR=0.63, 95%CI=0.41-0.97), while intake of greens including collard, kale, turnip and mustard was associated with increased odds of PR- disease in Whites (high vs. low: OR=1.34, 95%CI=1.09-1.66). Broccoli and cabbage intake were associated with reduced odds of HER2+ disease in Asians, compared with HER2- disease (high vs. low: OR=0.46, 95%CI=0.23-0.94 for broccoli, and OR=0.48, 95%CI=0.24-0.95 for cabbage). No associations were observed for Hispanics and AAs. In all racial groups combined, total CV intake, specifically broccoli intake, was associated with increased odds of luminal B, compared with luminal A subtype (OR=1.83, 95%CI= 1.19- 2.79). However, the association became null with increasing broccoli intake. Discussion: The association of CV intake with breast cancer characteristics varied by race and by individual CV. The differences may be attributable to diverse genetic background among racial groups, and specific ITCs in individual CVs. Funded by K07 CA148888 and R01 CA105274 Citation Format: Li Tang, Marilyn L. Kwan, Song Yao, Janise M. Roh, Cecile A. Laurent, Dawn L. Hershman, Schicha Kumar, Gregory E. Wilding, Christine B. Ambrosone, Lawrence H. Kushi. Racial differences in the association of cruciferous vegetable intake with breast cancer hormone receptor status and tumor subtype. [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 1266. doi:10.1158/1538-7445.AM2014-1266

Abstract 2792: Engineering T lymphocytes with protein nanogels for cancer immunotherapy

Abstract Adoptive cell transfer (ACT) with autologous tumor-reactive T-lymphocytes is a promising strategy in cancer immunotherapy, but treatment of solid tumors is limited by the rapid decline in function of the transplanted T cells. In order to maintain high numbers of viable tumor-specific cytotoxic T cells in tumors, co-administration of supporting immunostimulant agents together with transferred cells is typically necessary in clinical practice. When given systemically at high doses, these agents could enhance the in vivo viability of donor cells, improve their therapeutic function and lead to overall improved efficacy against cancer. However, high doses of such agents can also result in serious side effects. For example, the use of Interleukin-2 (IL-2) as an adjuvant drug significantly enhances the efficacy of ACT in melanoma, where IL-2 provides key adjuvant signals to donor T cells but also elicits severe dose-limiting inflammatory toxicity and expands regulatory T cells (Tregs). One approach to focus adjuvant drug action on the transferred cells and lower systemic toxicity is to genetically engineer donor cells to secrete their own supporting factors. However, the technical difficulty of engineering safe autocrine production of potent adjuvant molecules such as cytokines is a challenge. Thus, an inexpensive technology platform that would allow simple, safe and efficient delivery of adjuvant drugs specifically to therapeutic cells over a defined window of time could be broadly useful in ACT and other cell therapies for cancer. Here, we developed a novel strategy to deliver therapeutic proteins in T cell therapies, via the chemical conjugation of protein-polyethylene glycol (PEG) nanogels (NGs) directly onto the plasma membrane of donor cells, enabling continuous pseudoautocrine release of cargo proteins for stimulation of transferred T-cells. These PEG NGs loaded with IL-2 contained very high level of drug (∼80 wt% of NG was the protein cargo) and released native IL-2 in physiological conditions in a sustained manner through breakdown of a degradable linker between the IL-2 cargo and PEG chains of the NG. T-cells with optimized number of NGs conjugated per cell maintained their cellular functions and cancer targeting and killing capability. We demonstrated that this IL2-PEG NG-T cell conjugation strategy could augment T-cell expansion in vivo and result in markedly improved efficacy against metastatic B16F10 melanoma in mice. This approach provides a readily generalizable strategy to provide autocrine protein drug support to donor cells to enhance the safety and efficacy of ACT. Citation Format: Li Tang, Yiran Zheng, Darrell J. Irvine. Engineering T lymphocytes with protein nanogels for cancer immunotherapy. [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 2792. doi:10.1158/1538-7445.AM2014-2792

Abstract 4127: A prospective study of breast cancer prognosis in Kaiser Permanente Northern California: Cohort description and initial findings from the Pathways Study

Abstract Background: With over 2.8 million breast cancer survivors in the U.S. today, there is increasing interest and need to identify factors associated with recurrence and survival. The Pathways Study was designed to examine the effects of lifestyle (e.g., diet, physical activity, complementary and alternative medicine [CAM]), psychosocial (e.g., quality of life), molecular and genetic, medical care, and contextual (e.g., social and built environment characteristics) factors on breast cancer prognosis. Methods: Women newly-diagnosed with invasive breast cancer were identified daily from Kaiser Permanente Northern California (KPNC) electronic pathology records from January 2006 to April 2013; KPNC is a large, integrated health care organization. Eligibility included age at diagnosis of at least 21 y, no previous history of invasive cancer, and English, Spanish or Chinese-speaking. Women were enrolled during an in-person baseline interview that took place on average two months post-diagnosis, with collection of blood and saliva specimens. Active follow-up to update lifestyle and other factors and ascertain outcomes occurs periodically. Outcomes are also identified using KPNC electronic databases and confirmed via medical record review. Results: The final study cohort consists of 4,505 women, with blood and saliva collected from 90% and 95% of participants, respectively. The cohort has substantial racial/ethnic diversity: 64.2% White, 12.4% Hispanic, 12.8% Asian, 7.9% African American, 2.7% other. The mean age at diagnosis was 59.6 y (range: 23.6-94.8 y). Educational attainment is high, with 84.1% of the cohort having at least some college education. Most women were diagnosed with AJCC Stage I (54.0%) or II (34.6%) cancers, and receptor status was positive for estrogen in 83% of women, progesterone in 63.4%, and Her2 in 12.3%. As of December 1, 2013, 307 recurrences and 327 deaths have been confirmed, with 490 experiencing either. Initial age-adjusted results with proportional hazards regression demonstrate poorer disease-free survival (DFS) among African Americans (hazard ratio [HR]=1.84, 95% confidence interval [CI],1.39-2.45) and better DFS among Asians (HR=0.70, 95% CI, 0.49, 1.00) compared to Whites. Greater stage at diagnosis, increasing age, and negative ER status are also associated with poorer DFS. Discussion: The Pathways Study is a rich, unique resource collecting data on multiple factors that may influence breast cancer prognosis, including lifestyle, molecular, medical, and contextual factors. To date, 14 papers have been published on topics ranging from CAM use, quality of life, and physical activity during treatment, to tumor DNA methylation profiles and correlates of breast cancer molecular subtypes. With continued follow-up, it promises to provide findings on factors influencing prognosis to help guide breast cancer care. Citation Format: Lawrence H. Kushi, Marilyn L. Kwan, Isaac J. Ergas, Cecile A. Laurent, Julie R. Munneke, Janise M. Roh, Heather Greenlee, Chi-Chen Hong, Theresa H. Keegan, Dawn L. Hershman, Susan E. Kutner, Marion M. Lee, Jeanne Mandelblatt, Alfred I. Neugut, Peggy Reynolds, Salma Shariff-Marco, Li Tang, Song Yao, Janice Barlow, Scarlett Lin Gomez, John K. Wiencke, Christine B. Ambrosone. A prospective study of breast cancer prognosis in Kaiser Permanente Northern California: Cohort description and initial findings from the Pathways 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 4127. doi:10.1158/1538-7445.AM2014-4127

Abstract 2162: Prior bone health history in breast cancer patients on aromatase inhibitors

Abstract Background: Aromatase inhibitors (AIs) have been replacing tamoxifen (TAM) as adjuvant hormonal therapy (HT) for hormone receptor-positive, postmenopausal breast cancer (BC). AIs are known for their adverse effects on bone health, yet bone health history among AI users before BC diagnosis is unknown, which may impact fracture risk after AI therapy. In a cross-sectional analysis of a prospective cohort of BC patients on HT, we describe prior history of osteoporosis and fracture before BC diagnosis among AI users compared with TAM users. Methods: A total of 3280 women diagnosed with invasive BC from 2005-2013 and initially treated with AI or TAM were identified from an ongoing prospective cohort study at Kaiser Permanente Northern California (KPNC). Data on baseline demographic and lifestyle factors came from in-person interviews about two months post-diagnosis. Information on BC diagnosis and treatment, HT, and prior bone health history including bisphosphonate (BP) use was obtained from the KPNC cancer registry and clinical databases. Using age- and race-adjusted logistic regression, we examined the association of lifestyle and clinical factors at BC diagnosis with prior history of 1) osteoporosis, 2) any fracture (excluding head, face, fingers, toes), and 3) any major fracture (hip, spine, humerus, wrist). Results: Compared with initial TAM users (n=1140), initial AI users (n=2140) were more likely to be older (mean 64.5 y vs. 50.5 y) and obese (38% vs. 26%), yet less likely to have had chemotherapy (36% vs. 51%). AI users were more likely to have a prior history of osteoporosis (n=164, 7.7% vs. n=62, 5.4%, age-adjusted p<0.05), any fracture (n=356, 16.7% vs. n=92, 8.1%), and major fracture (n=104, 4.9% vs. n=22, 2.0%), yet the latter two were not significant after age adjustment. Among initial AI users, being ≥70 y (OR=5.8; 95% CI: 3.5, 9.5) and Asian (OR=1.9; 95% CI: 1.2, 3.2) were each associated with prior osteoporosis, whereas increasing BMI (obese OR=0.4; 95% CI: 0.2, 0.6) was associated with lower odds. Older age and prior osteoporosis were each related to higher odds of any prior fracture, yet the association with osteoporosis was not observed after further adjustment for prior BP use. Being Asian (OR=0.5; 95% CI: 0.3, 0.8) and light alcohol intake (≤median 0.84 g/day OR=0.7; 95% CI: 0.5, 1.0) were related to lower odds of any fracture. Odds of major fracture were similar yet attenuated with wide CIs. However, any moderate-vigorous physical activity was associated with reduced odds of major fracture (≤median 21.1 MET-hrs/wk OR=0.3; 95% CI: 0.2, 0.6; >median OR=0.4; 95% CI: 0.2, 0.7). Discussion: This descriptive analysis is one of the first to characterize AI users and risk factors for prior bone morbidity before BC diagnosis. In the future, this study will evaluate the impact of AIs on risk of subsequent bone outcomes and examine lifestyle, molecular, and genetic risk factors for AI-induced fractures. Funded by R01 CA166701 and R01 CA105274. Citation Format: Marilyn L. Kwan, Joan C. Lo, Li Tang, Cecile Laurent, Janise M. Roh, Malini Chandra, Theresa E. Hahn, Chi-Chen Hong, Lara Sucheston-Campbell, Dawn L. Hershman, Bette J. Caan, Charles P. Quesenberry, Barbara Sternfeld, Christine B. Ambrosone, Lawrence H. Kushi, Song Yao. Prior bone health history in breast cancer patients on aromatase inhibitors. [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 2162. doi:10.1158/1538-7445.AM2014-2162

The Research of Low Voltage Control at Li Tang Trunk Line in Li Jia Transformer Substation

In this paper, the rural power low-voltage of Li-Tang mains Trunk line raised the issue of secondary boost more than two groups reactive power compensation solutions, focusing on both the load power load variance method to calculate the location and placement of the regulator boost ratio, using precise moment method and reactive secondary terminal voltage rises method calculates the load side of intelligent reactive compensation on the trunk and installation location and capacity, to achieve the optimum design load tap rural power lines and intelligent var compensator configuration. The program changed in Fushun Li-Tang Trunk line in Li-Jia Transformer substation significantly after the implementation of effective, so that the end of the 31km-long line of power quality standards. Economic operation efficiency is improved.

Thermal stability of pentoxifylline: active substance and tablets

Thermal analysis is a routine method in the solution of pharmaceuticals problems such as the control of raw materials, to the determination of purity, to the qualitative and quantitative analysis of drug formulation, tests of thermal stability and compatibility, the determination of kinetic parameters, etc. The evaluation of thermal stability in the solid state is mostly made by analyzing their decomposition under isothermal and non-isothermal conditions. The present work reports the study on the thermal behavior of pentoxifylline—active substance and tablets, respectively, the determination of the kinetic parameters for the decomposition process under non-isothermal conditions and in a nitrogen atmosphere at five heating rates: 2.5, 5, 7.5, 10 and 15 °C min−1. For the determination of kinetic parameters from the TG/DTG curves, the following differential methods were utilized: Friedman isoconversional and Chang, respectively, integral methods: Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose, Li–Tang, and Starink. Thermoanalytical curves showed that the active substance is thermally more stable than the tablets. The decrease in stability was attributed to the presence of excipients.

Abstract 3641: Genome-wide methylation patterns suggest differences in breast cancer biology in American women of African and European ancestry.

Abstract European-American (EA) woman have a higher overall incidence of breast cancer than African American (AA) women, yet AA woman have poorer survival outcome, even after controlling for factors related to socioeconomic status. AA women are diagnosed at a younger age with aggressive breast tumors, more frequently ‘triple negative’ due to lack of estrogen and progesterone receptor (ER and PR) expression and negative for HER-2 amplification, as well as, high proliferative indices. These ‘triple negative’ breast cancers are most lethal since hormonal- or anti-HER2 therapy are not effective; therefore, fewer treatment options are available. Currently, the reason for racial disparities in breast cancer biology and early age of onset in AA women is largely unknown. Previous studies using a panel of 5 cancer-associated genes demonstrated a higher frequency of methylation in ER-negative tumors from younger AA women compared to EA women. We hypothesize that DNA methylation is one potential molecular mechanism that drive differences in breast cancer etiology between AA and EA women. Utilizing the Illumina Infinium Human Methylation 450K bead array, we surveyed DNA methylation at greater than 485,000 CpG sites across the genome at single-nucleotide resolution in breast tumor DNA from 138 (58 AA, 80EA) women and normal breast tissue DNA from 124 (22 AA, 102 EA) women undergoing reduction mammoplasty. Following filtering for ambiguously mapping probes and probes containing known SNPs, unsupervised hierarchical cluster analysis of the most varied CpG loci among tumor tissues distinguished three major clusters: Normal, ER-positive tumors and ER-negative tumors. We identified 157 CpG sites that are differentially methylated between tumors from AA and EA women (Δβ>0.17, FDR<0.05). Of these, 50 CpG were uniquely differentially methylated in ER-negative tumors, while 28 CpG sites were specific to ER-positive tumors. We are currently examining these loci in more depth to determine their biological significance and potential contribution to differences in breast cancer etiology between AA and EA women. Future analyses include screening a larger cohort of 1000 FFPE tumor DNAs to effectively compare differential methylation with age at onset, and a variety of tumor characteristics and risk factors. Funded by 1 R01 CA133264 to CBA, KD, and MJH, and by Cancer Center Support Grant CA16056 to RPCI. Citation Format: Allyson C. Young, Christine B. Ambrosone, Lara Sucheston, Dan Wang, Li Yan, Song Liu, Li Tang, Jo L. Freudenheim, Peter G. Shields, Carl D. Morrison, Kitwa Demissie, Saraswati Sukumar, Michael J. Higgins. Genome-wide methylation patterns suggest differences in breast cancer biology in American women of African and European ancestry. [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 3641. doi:10.1158/1538-7445.AM2013-3641

Dietmar W. Winkler, Li Tang. Hidden Treasures and Intercultural Encounters. Studies on East Syriac Christianity in China and Central Asia

Dietmar W. Winkler, Li Tang. Hidden Treasures and Intercultural Encounters. Studies on East Syriac Christianity in China and Central Asia

Hidden Treasures and Intercultural Encounters: Studies on East Syriac Christianity in China and Central Asia. Edited by Dietmar W. Winkler and Li Tang. Orientalia – Patristica – Oecumenica. Berlin: LIT, 2009. 396 pp. $39.95 paper.

Hidden Treasures and Intercultural Encounters: Studies on East Syriac Christianity in China and Central Asia. Edited by Dietmar W. Winkler and Li Tang. Orientalia – Patristica – Oecumenica. Berlin: LIT, 2009. 396 pp. $39.95 paper. - Volume 81 Issue 2

A conversation with Professors Deyi Li and Jie Tang

A conversation with Professors Deyi Li and Jie Tang

Thermal behaviour of erythromycin-active substance and tablets

The application of thermal methods is of great importance in the solution of pharmaceutical problems, such as the control of raw materials, the determination of purity, the qualitative and quantitative analysis of drug formulation, tests of thermal stability and compatibility, the determination of kinetic parameters etc. The evaluation of thermal stability in the solid state is mostly made by analyzing their decomposition under isothermal and non-isothermal conditions. This study reports the study on the thermal behaviour of erythromycin-active substance and tablets, respectively, the determination of the kinetic parameters for the decomposition process under non-isothermal conditions. For the determination of kinetic parameters from the TG/DTG curves, were utilized the following methods: Friedman isoconversional, Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose, Li–Tang, and Kissinger, respectively, a dynamic nitrogen atmosphere and different heating rates: 2.5, 5, 7.5, 10, and 15 °C min−1. Thermoanalytical curves showed that the active substance is thermally more stable than the tablets and the values of activation energy indicate a considerable thermal stability of active substance. The decrease in stability was attributed to the presence of excipients.

Hidden Treasures and Intercultural Encounters: Studies on East Syriac Christianity in China and Central Asia (review)

Reviewed by: Hidden Treasures and Intercultural Encounters: Studies on East Syriac Christianity in China and Central Asia Matteo Nicolini-Zani Hidden Treasures and Intercultural Encounters: Studies on East Syriac Christianity in China and Central Asia. Edited by Dietmar W. Winkler and Li Tang. [Orientalia—patristica—oecumenica,Vol. 1.] (Münster–Vienna: Lit Verlag. 2009. Pp. iv, 395. €39,90 paperback. ISBN 978-3-643-50045-8.) In the last twenty years, research on the commonly mistermed “Nestorian” Christianity in central and eastern Asia has grown in Eastern and Western academic circles. New publications have resulted in a new approach that is based more on sources and a broader philological foundation, which can be truly regarded as a turning point in the history of research on East Syrian Christianity in Asia. The volume under review is the outcome of the second conference on “Research on the Church of the East in China and Central Asia” in 2006. It contains papers written by scholars from disciplines such as church history, [End Page 616] philology (Syriac, Turkic, Iranic, and Chinese), archaeology, and theology. It explores the subject of East Syrian Christianity from various perspectives. The volume is organized in four parts. The first part, on “Inscriptions” (pp. 13–132), contains current research on texts carved in stone from various geographical areas (Central Asia, Inner Mongolia, China). Particularly relevant in this section are essays on Syriac and Syro-Turkic inscriptions by Mark Dickens, Wassilios Klein, Kuvatbek Tabaldiev, Li Chonglin, and Niu Ruji. They give the original text, transliteration, translation, and a commentary of Christian gravestones found in Uzbekistan, Kyrgyzistan, Inner Mongolia, and Xinjiang (China), all dating from the thirteenth and fourteenth centuries. Also worth mentioning is Li Tang’s preliminary study (text analysis, commentary, and translation) on the Chinese Christian inscription found in Luoyang in 2006 and dating from the ninth century. The second part deals briefly with “Manuscripts and Texts” (pp. 135–80). Among the three articles in this section, Max Deeg’s provocative essay invites scholars to consider the proper and improper ways to proceed in placing in their context the Chinese Christian documents of the Tang period (618–907). The third part, on “History” (pp. 183–334), is the richest and presents the evaluation and interpretation of various sources such as inscriptions, archaeological evidence, and texts coming from different regions of central and eastern Asia and dating back to various historical periods. Among the eleven essays contained in this section five concern Syriac Christianity in China and Korea during the first centuries of the second millennium: Pierre Marsone writes on the time when the Temple of the Cross at Fangshan was a “Christian Temple”; Maurizio Paolillo about King George, the thirteenth-century Christian chief of the Öngüt tribe; Li Tang on Christians of the Mongol (or, better, Mongolised Turkish) Naiman tribe and one of their princes, Küchlüg khan, as referred to in medieval sources; Yin Xiaoping on Christians in the Chinese region of Jiangnan during the Yuan dynasty (1272–1368); Alexander Toepel about Christians in Korea at the end of the thirteenth century. In addition, Matteo Nicolini-Zani shows how Jesuit missionaries in the seventeenth and eighteenth centuries referred to Tang Christianity in their writings to further their own mission, and Chen Huaiyu investigates the textual and artistic encounter between East Syrian Christianity and Tantric Buddhism in medieval China and Tibet. The last part is devoted to “Liturgy and Arts” (pp. 337–92), with three articles exploring the fields of liturgical music and religious arts. Yan Xiaojing’s article, in particular, shows the interaction between Christian, Buddhist, and Daoist artistic patterns. Photographs of historical relics are inserted in some of the contributions. Regrettably, the volume is rather carelessly edited. The two editors note in their introduction that they were aware of the challenging work of editing [End Page 617] such a collection of diverse interdisciplinary scholarship. Nevertheless, the book is a unique collection of “hidden treasures” for all those who wish to know more about those fascinating and mostly neglected interreligious and intercultural exchanges in which Christianity was involved in its diffusion along the Silk Road for about one thousand years. Matteo Nicolini-Zani Monastero di Bose Magnano...

Iso-Conversional and Isokinetic Methods of Analysis of Non-Isothermal Crystallization in Ti<sub>50</sub>Cu<sub>20</sub>Ni<sub>30</sub> Metallic Glass

The crystallization kinetics of metallic glass Ti50Cu20Ni30 has been studied using Differential Scanning Calorimetry (DSC). The DSC thermograms have been analysed using the model-free isoconversional methods and model dependent isokinetic methods. The activation energy(E) for the crystallization process has been determined utilizing; (i) various linear integral isoconversional methods, namely, Ozawa-Flynn-Wall, Kissinger-Akahira-Sunose, Li Tang method (ii) linear differential isoconversional method and (iii) different isokinetic methods. In the present work, we intend to the determination of true value of E. The above methods are found to give consistent results for E.

East Syriac Christianity in Mongol-Yuan China by Li Tang (review)

Reviewed by: East Syriac Christianity in Mongol-Yuan China by Li Tang Matteo Nicolini-Zani (bio) Li Tang. East Syriac Christianity in Mongol-Yuan China. Orientalia Biblica et Christiana, vol. 18. Wiesbaden: Harrassowitz Verlag, 2011. xvii, 169 pp. Hardcover €58.00, isbn 978-3-447-06580-1. It is a great pleasure to have in our hands a volume entirely devoted to East Syriac Christianity in Mongol-Yuan China. This subject has been quite neglected so far. Historical research on Christianity in China commonly focuses on Catholic, and mainly Jesuit, missions in the late Ming–early Qing period or the Protestant missionary endeavors in modern China. From the perspective of theological or religious studies, research on the history of East Syriac Christianity is still a small discipline in the academic world. As the author appropriately remarks in the preface to the book, “the historical and theological attention given to this subject weighs far less than the impact, which Syrian Christianity has had in history and the rich cultural-religious relics and heritage it has left behind” (p. xv). [End Page 525] In the last twenty years, however, research on East Syriac Christianity in Central and Eastern Asia has grown in academic circles both in the West and in the East (China and Japan). Quite a few publications (monographs, collections of essays, and articles) in this relatively new field of research have come out in various languages. Even more significant is the fact that these publications have resulted in a new approach, one based, to a great degree, on the sources and with a broader philological foundation. Scholars involved in this research are trying to work more concordantly through long-term collaborations. They have come to be increasingly aware of the particularly important role of fruitful interdisciplinary exchange among scholars from all over the world, which can bring together the results of different disciplines, such as religious and church history, philology, archaeology, theology, and others. With her scholarly expertise, editorial endeavors, and organizational enterprises, Li Tang, the author of the volume under review, is one of the scholars who, in the last few years, have contributed a great deal to develop this new approach in research on East Syriac Christianity in Asia. In this respect, we would like to mention at least her contribution to the organization of the second international Research on the Church of the East in China and Central Asia conference, which took place in Salzburg (Austria) in 2006. The conference proceedings were later published in a volume coedited by her and Dietmar W. Winkler.1 On the basis of her expertise in different fields—notably, her knowledge of several different ancient languages, Chinese, Syriac, Turkic, Mongolian—Li Tang with this book offers us a comprehensive reconstruction of the history of East Syriac Christianity in Mongol-Yuan China (twelfth–fourteenth centuries) within its political, social, economic, cultural, and religious environment. It deals with the relevant historical background, the ethnic Christian groups involved, philological and theological studies of the East Syriac Christian inscriptions, the migrations of Christian populations, Mongol religious policies, as well as missionary activities in the Mongolian plains and in China. In its comprehensive approach to the subject, this book can be ranged with groundbreaking works, like those by Paul Pelliot and Jean Dauvillier.2 When I first opened the book, what I appreciated very much was the effort to use the term “East Syriac” or “East Syrian” Christianity instead of the inappropriate, even though for a long time commonly used, term “Nestorian” Christianity. Although the author explicitly says that “the term ‘Nestorian’ is only used with restraint and is written in quotation marks … when the use of the term is deemed unavoidable” (preface, p. xvii), when I read the book more carefully, I nevertheless found that the term is still used several times, even when it could be avoided. In more than one case, it is not put in quotation marks. Generally speaking, I consider that the best points of the book are two. Its first merit, as said already, is that it gathers together many previously scattered materials [End Page 526] and specific studies in different disciplines; in this way it succeeds in reconstructing a...

Hidden Treasures and Intercultural Encounters: Studies on East Syriac Christianity in China and Central Asia ed. by Dietmar W. Winkler, Li Tang (review)

Hidden Treasures and Intercultural Encounters: Studies on East Syriac Christianity in China and Central Asia ed. by Dietmar W. Winkler, Li Tang (review)