bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A02: Comparative analysis of breast density among Black, White, and Hispanic women presenting for screening mammography
Authors: Oppong Bridget A. , Dash Chiranjeev , Oneill Suzanne , Makambi Kepher , Coleman Tesha , Adams-Campbell Lucile L.
Published: December 2017

Background: Data on ethnic variations in breast density are limited and often not inclusive of underrepresented minorities, including Black and Hispanic women. As breast density is associated with elevated breast cancer risk, investigating racial and ethnic difference may elucidate the observed differences in breast cancer risk among different populations.

Methods: We reviewed breast density recorded at the initial mammographic screening study in women presenting to the Capital Breast Care Center (CBCC) and Georgetown University Hospital (GUH) from 2010 to 2014. Patient demographics including race, age at screening, education and menopausal status were abstracted in addition to body mass index (BMI). From imaging reports, we recorded the BI-RADS density categories: 1-fatty, 2-scattered fibroglandular densities, 3-heterogeneously dense and 4-extremely dense. Multivariable unconditional logistic regression was used to identify predictors of breast density.

Results: Density categorization was recorded for 2,146 women over the five-year period, with 940 (43.8%) Black, 893 (41.6%), Hispanic and 314 (14.6%) White. Analysis of subject characteristics by low density (categories 1 and 2) and high density (categories 3 and 4) show that high category is observed in younger, Hispanic, nulliparous, premenopausal and non-obese women (P-values <.0001). Obese women are 70% less likely to have high breast density compared to non-obese women. Being Hispanic, premenopausal, and non-obese were predictive of high mammographic density on logistic regression.

Conclusion: In this analysis of density distribution in a diverse sample of women presenting for mammography, Hispanic women have the highest breast density, followed by Black women with Whites having the lowest. Unique in our findings is women who identify as Hispanic having the highest breast density and lower rates of obesity. Further investigation of the impact of obesity on breast density in minority women, especially in the understudied Hispanic group is needed.

Citation Format: Bridget A. Oppong, Chiranjeev Dash, Suzanne Oneill, Kepher Makambi, Tesha Coleman, Lucile L. Adams-Campbell. Comparative analysis of breast density among Black, White, and Hispanic women presenting for screening mammography [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A02.
Abstract A07: Hyperthermia plus radiotherapy in triple-negative breast cancer; before or after?
Authors: Joveini Zahra , Behrouzkia Zhaleh , Aghdam Reza Zohdi
Published: December 2017

Introduction: Breast Cancer (BC) is the most common cancer among women. Hyperthermia is a new cancer treatment modality which is used in addition to other treatments to improve patient's survival. The clinical use of Hyperthermia in the combination of radiotherapy is debatable and shows important technical challenges. But the most challenge in this case is the order of this combination. We aimed to explore that in Triple-negative breast cancer applying hyperthermia before radiotherapy is better or after it.

Methods and Material: The anti-proliferative activity of Hyperthermia alone and in combination with Radiotherapy in 4T1 balb/c triple negative breast cancer cell line was assessed by the standard 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium bromide (MTT) method. We also used Acridine Orange/ Propidium Iodide fluorescent staining for approving the inhibitory effect. We exposed the cells to 43±0.2°C for 30 minutes in a regular incubator, as Hyperthermia treatment and also exposing into 4Gy Gamma irradiation as Radiotherapy. In two modality treatments the time interval was two hours. Then the viability rates of cells were determined after 24, 48 and 72 hours.

Statistical analysis used: All data are expressed as the mean ± standard deviation. We used Kruskal-Wallis and Mann-Whitney for statistical analysis. P-values of less than 0/05 were considered to be statistically significant.

Results: The findings indicated that adding hyperthermia before Radiotherapy showed 58 ± 4.06, 60.6±2.03 and 62.4±2.5 viability rate after 24,48 and 72 hours, respectively; while applying it after Radiotherapy showed 63.4 ± 1.81, 67.2±2.2 and 62.4±2.5 viability rate after 24,48 and 72 hours.

Conclusions: It was concluded that in Triple negative breast cancer applying hyperthermia before radiotherapy is more efficient.

Note: This abstract was not presented at the conference.

Citation Format: Zahra Joveini, Zhaleh Behrouzkia, Reza Zohdi Aghdam. Hyperthermia plus radiotherapy in triple-negative breast cancer; before or after? [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A07.
Abstract A17: Molecular and clinicopathological features of native Nigerian colorectal cancer
Authors: Irabor David O. , Melas Marilena , Gruber Stephen B. , Shi Chanjuan , Raskin Leon
Published: December 2017

Colorectal cancer (CRC) needs no introduction in Africa; once a rare cancer type, it is now the 3rd or 4th most common cancer. However, there are significant differences in the incidence rates, tumor biology, and clinical behavior in comparison to other populations. While the total incidence rates are about one-tenth of those in the developed world, Nigerian CRC occurs at a younger age and rapidly metastasizes. Molecular pathology and genetics of African CRC have not been comprehensively studied. In addition to better understanding of the biology of African CRC, analysis of genetic and molecular biomarkers, including microsatellite instability (MSI), is aimed at improving CRC diagnosis, treatment, and prognosis in Africa. We obtained 83 CRC paraffin-embedded blocks from the University of Ibadan and private pathology laboratories in Ibadan collected in the period from 2007 to 2014. Median age of the cases was 56±14.6 years with equal number of males and females. More than 60% of the patients had stage III and IV CRC. The majority were adenocarcinomas (76%) with a relatively high prevalence of mucinous adenocarcinoma (10%) and signet ring carcinoma (4%). Of all patients, 66% had rectal cancer. Poorly differentiated tumors were observed in 34% of all cases. We found a high prevalence of MSI CRC (43%, 15/35) in the tested Nigerian samples. There were no significant differences in clinicopathological features, including tumor location, between MSI and microsatellite stable (MSS) CRC. Our results are in line with our previous report that found a high prevalence (41%) of MSI CRC in Ghanaian patients. These findings raise important questions about the role of genetic and environmental factors in CRC development in West Africa.

Citation Format: David O. Irabor, Marilena Melas, Stephen B. Gruber, Chanjuan Shi, Leon Raskin. Molecular and clinicopathological features of native Nigerian colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A17.
Abstract A18: Association of anthropometric factors with risk of colorectal neoplasia in the Black Women's Health Study
Authors: Dash Chiranjeev , Rosenberg Lynn , Yu Jeffrey , Nomura Sarah , Palmer Julie , Adams-Campbell Lucile L.
Published: December 2017

Evidence for the association of anthropometric factors with colorectal neoplasms is limited for African Americans. Association of 6 anthropometric measures with the risk of both colorectal adenomas and colorectal cancer (CRC) in the ongoing Black Women's Health Study cohort was examined. Using a nested case-control design for the adenoma analyses, 954 cases of colorectal adenoma were compared with 3,816 controls without a colorectal polyp, matched on age and follow-up time. For the CRC analyses, 413 incident CRC cases were identified over a 16-year follow up (802,783 person-years). Cases of adenoma and CRC were verified by medical record review. We used multivariable logistic regression analyses (for adenoma) and Cox proportional hazards analyses (for CRC) that included anthropometric exposures and selected confounders. Among postmenopausal women, risk of adenoma increased by 10% (95% CI: 1.00, 1.22), 11% (95% CI: 1.01, 1.29), and 9% (1.00, 1.19) with 1 standard deviation increase in body mass index, waist circumference, and weight change since age 18 , respectively. Anthropometric factors were not associated with adenoma risk among premenopausal women. None of the anthropometric factors were associated with CRC risk among either pre- or postmenopausal women. Future research should attempt to replicate the modest association of obesity with colon adenoma risk but not CRC risk among postmenopausal African American women.

Citation Format: Chiranjeev Dash, Lynn Rosenberg, Jeffrey Yu, Sarah Nomura, Julie Palmer, Lucile L. Adams-Campbell. Association of anthropometric factors with risk of colorectal neoplasia in the Black Women's Health Study [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A18.
Abstract B01: Association of cholangiocarcinoma and hepatocellular carcinoma: Which one should be treated?
Authors: Mazouzi Khaoula
Published: December 2017

Introduction: The combination of cholangiocarcinoma and hepatocellular carcinoma is a rare entity.

Methods: We will present a clinical case involving a combination of cholangiocarcinoma and hepatocellular carcinoma in a patient with post-viral C cirrhosis.

Results: A 60 Y.O male know with a personal history of hepatitis treated in 1969 by an unknown injectable treatment for two years, was presented at the consultation for evolving abdominal bloating.

CT-scan revealed ascites with a total portal vein thrombosis and a heterogeneous tumor occupying the right liver without “wash-out” sign. The patient was put under anticoagulation with LMWH. After a week, liver MRI found that the ascites has totally dried, the thrombosis disappeared, and revealed that the tumor had a typical aspect of cholangiocarcinoma. Alfa-fetal protein test was to 1156 IU / ml. Liver biopsy was contradictory; on some pieces hepatocellular carcinoma was found and on others cholangiocarcinoma. Because Sorafenib is a multikinase inhibitor with anti-angiogenic and anti-proliferative action it can be effective on many tumors as they use the same ligands and signaling pathways similar to proliferate, it was chosen instead of chemotherapy at 400 mg/day. Sure enough, after two weeks of treatment, alfa fetoprotein decreased to 834 IU/ml and after two months biology and imaging found a satisfactory partial response. Currently, after six months of treatment, the patient is in complete clinical, biological and radiological remission except that the treatment cannot be interrupted for the time. Surgeons are discussing a partial surgery to the residual liver retraction.

Conclusion: This association is rare and needs deep research especially molecular testing for patients who have a spectacular response.

Citation Format: Khaoula Mazouzi. Association of cholangiocarcinoma and hepatocellular carcinoma: Which one should be treated? [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B01.
Abstract B03: The EWS/FLI oncogene exerts pro-migratory and anti-apoptotic effects via dysregulation of focal adhesion kinase (FAK) signaling in Ewing sarcoma
Authors: Steinestel Konrad , Trautmann Marcel , Rehkaemper Jan , Wardelmann Eva , Dirksen Uta , Hartmann Wolfgang
Published: December 2017

Ewing sarcoma (ES), an aggressive bone tumor of childhood and adolescence, is one of the most genetically normal tumors. The oncogenic potential is derived from chimeric fusions of EWS and ETS family transcription factors, with EWS-FLI1 rearrangements in 85% of cases. (Micro-) metastatic dissemination is the major threat for patients, and earlier studies have shown that cytoskeletal rearrangements upon EWS/FLI oncoprotein expression contribute to a migratory phenotype in ES cells.

Using a patient-derived ES cell line with a stable EWS/FLI knockdown (A673-iEF), we show here that key tumorigenic effects of EWS/FLI are mediated via autophosphorylation of FAK on tyrosine 397, resulting in enhanced formation of focal adhesions and actin stress fibers as well as tumor cell migration, but impaired caspase-3-mediated anoikis (detachment-induced cell death) in vitro. This effect was not limited to A673 cells, but could also be observed in TC-32 and CADO-ES1 ES cells. Application of the FAK inhibitor 1, 2, 4, 5-Benzenetetraamine tetrahydrochloride (Y15) impaired cell migration and enhanced caspase-mediated apoptosis. Taken together, our results show that key oncogenic effects of EWS rearrangements are mediated via FAK autophosphorylation in ES and provide a rationale for the use of FAK inhibitors to impair metastatic dissemination of ES.

Citation Format: Konrad Steinestel, Marcel Trautmann, Jan Rehkaemper, Eva Wardelmann, Uta Dirksen, Wolfgang Hartmann. The EWS/FLI oncogene exerts pro-migratory and anti-apoptotic effects via dysregulation of focal adhesion kinase (FAK) signaling in Ewing sarcoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B03.
Abstract B12: Investigating the specificity of the small molecule inhibitor INI-43 for Kpnβ1 in cancer cells
Authors: Carden Sarah , Watt Pauline van der , Lavia Patrizia , Leaner Virna
Published: December 2017

Karyopherin β1 (Kpnβ1) is the major nuclear import protein involved in the shuttling of cargo proteins and mRNAs into the cell nucleus. Recent studies have found that Kpnβ1 levels are significantly upregulated in cancer cells, and that targeted inhibition of Kpnβ1 with siRNA results in reduced proliferation and the induction of apoptosis, suggesting that Kpnβ1 is important for cancer cell survival. Inhibitor of Nuclear Import-43 (INI-43) is a small molecule inhibitor identified in our laboratory as having the potential to interfere with the nuclear import function of Kpnβ1. It has been shown to inhibit the nuclear localization of both Kpnβ1 and known Kpnβ1 cargoes such as NFκB and NFAT, as well as inhibit the proliferation of cancer cells of different tissue origins. This study aimed to investigate the specificity of INI-43 for Kpnβ1 by performing experiments to determine whether expression of exogenous Kpnβ1-GFP was able to rescue cells from the effects of INI-43 treatment. Results show that Kpnβ1 overexpression rescues cell viability, as well as the inhibitory effects that INI-43 has on the nuclear import of NFκB/p65 and NFAT. Overexpression of Kpnβ1 also rescues cells from an INI-43 induced G2/M cell cycle block. In addition, treatment of cells with INI-43 enhances degradation of Kpnβ1, but not of other members of the Karyopherin family. These results suggest that the small molecule inhibitor INI-43 is acting, at least in part, by targeting Kpnβ1.

Citation Format: Sarah Carden, Pauline van der Watt, Patrizia Lavia, Virna Leaner. Investigating the specificity of the small molecule inhibitor INI-43 for Kpnβ1 in cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B12.
Abstract B13: A growth of human choriocarcinoma cells was selectively inhibited by therapeutic neural stem cells expressing cytosine deaminase and interferon-β in cellular and xenograft models
Authors: Kim Gyu-Sik , Choi Kyung-Chul
Published: December 2017

In this study, human neural stem cells (hNSCs) expressing Escherichia coli cytosine deaminase (CD) and human interferon-β (IFN-β) was used to cancer treatment strategy for human choriocarcinoma cancer. Prodrug 5-fluorocytosine (5-FC) is converted to 5-fluorouacil (5-FU) by CD, which induces an effect of killing the tumor cells through DNA synthesis inhibition. Also, IFN-β suppresses tumor growth through the apoptotic process. To manufacture animal models xenografted with choriocarcinoma, CMFDA pre-labeled JEG-3 cells (2×106) were injected intravenously (i.v.) into the tail vein of athymic nude mice (group A) and injected subcutaneously (s.c.) into the back of the mice (group B). Subcutaneously injected cancer cells were mixed with Matrigel (BD Biosciences, Bedford, MA, USA) at 1:1 volume ratio of Matrigel to PBS in 100 μl. On group A, CM-dil pre-labeled hNSCs (2×106) were injected intravenously after a week. On group B, when the tumor volume reached at 100mm3, CM-Dil pre-labeled hNSCs (2×106) were injected subcutaneously adjacent to the tumor mass. Every mice received i.p. injections of 5-FC (500 mg/kg/day) every day for 21 days. In a modified trans-well migration assay, NSCs selectively migrated to JEG-3 choriocarcinoma cells. It was revealed that the tumor-tropic properties of engineered NSCs were attributed to chemoattractant factors (CXCR4, SCF, SDF-1a, VEGF) secreted by JEG-3 cells. When JEG-3 cells co-cultured with engineered NSCs in the presence of 5-FC, the viability of JEG-3 cells was markedly decreased. The present results suggested that NSCs expressing CD gene and IFN-β gene have a potential therapeutic effect against choriocarcinoma. Consequently, hNSC therapy may be a clinically effective tool for the treatment of human choriocarcinoma cancer. In addition, we are currently studying on an in vivo model to demonstrate that selective anti-tumor effect of NSCs.

Note: This abstract was not presented at the conference.

Citation Format: Gyu-Sik Kim, Kyung-Chul Choi. A growth of human choriocarcinoma cells was selectively inhibited by therapeutic neural stem cells expressing cytosine deaminase and interferon-β in cellular and xenograft models [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B13.
Abstract B14: Injection of therapeutic stem cells expressing cytosine deaminase and interferon-beta resulted in the inhibition of K562 human chronic myeloid leukemia cells in a xenograft model
Authors: Park Geon-Tae , Choi Kyung-Chul
Published: December 2017

Gene-directed enzyme/prodrug therapies have been found to be more advantageous compared to conventional cancer treatment method. One of these, a cytosine deaminase (CD)/5-fluorocytosine (5-FC) system, is known to induce apoptosis of cancer cells by converting 5-FC, a prodrug, to its metabolically active form, 5-fluorouracil. In this study, human neural stem cells (hNSCs) derived enzyme/prodrug therapy was used to treat leukemia. The parental hNSCs, HB1.F3, were engineered to express E. coli CD and/or human interferon-β. To manufacture animal models xenografted with leukemia, K-562 cells (1×106) were mixed with Matrigel (BD Biosciences, Bedford, MA, USA) at 1:1 volume ratio of Matrigel to PBS in 100 μl and injected subcutaneously (s.c.) into the back of athymic nude mice. This animal study was performed for 24 days after hNSCs injections. When tumor volume reached 500 mm3, CM-Dil pre-labeled hNSCs (4 x 106 cells per mouse) were injected subcutaneously adjacent to the tumor mass. Another group, CM-dil pre-labeled hNSCs (4 x 106 cells per mouse) was injected intravenously. hNSCs were injected on the first day of each week. Two days after the injection of hNSCs, all mice received i.p. injections of 5-FC (500 mg/kg/day in 100 μl PBS) every day for 24 days. At 24 h after the last 5-FC treatment, the mice were euthanized and tumor masses were harvested for molecular analysis. In a xenografted mouse model administered with hNSCs intravenously or subcutaneously, hNSC significantly inhibits the growth of tumor mass and extends survival date in the presence of a prodrug. In addition, HB1.F3.CD.IFN-β treatment group showed more antitumor effect compared with HB1.F3.CD treatment group, indicating that IFN- β may have a synergistic effect for directly killing leukemia tumors. The present results represent that engineered hNSCs and prodrug treatment inhibited the proliferation of leukemia. These results suggest that gene therapy employing genetically engineered stem cells expressing CD and IFN-β may be effective for treating leukemia.

Note: This abstract was not presented at the conference.

Citation Format: Geon-Tae Park, Kyung-Chul Choi. Injection of therapeutic stem cells expressing cytosine deaminase and interferon-beta resulted in the inhibition of K562 human chronic myeloid leukemia cells in a xenograft model [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B14.
Abstract B16: Two kills with one shot: A biomarker with therapeutic implications in poor prognosis gastric cancers
Authors: Sato Ko
Published: December 2017

Bioinformatic approaches are useful to predict significance of gene expression in clinical outcome. Utilizing these non-biased approaches, we now identify that upregulation of aldosterone-regulated sodium reabsorption (ARSR) is seen in a subset of gastric cancers with poor prognosis. Our analysis of a clinical cohort of gastric cancers shows a subunit component of ARSR, SCNNIG, is indeed often overexpressed and is linked to poor survival. To understand this mechanism of the poor survival, overexpression of SCNNIG causes rapid growth of tumors in a xenograft model. Inhibition of aldosterone by spironolactone, a traditional diuretic, specifically kills cancer cells with overexpression of SCNNIG in vitro and in vivo, suggesting a clinical and therapeutic benefit for evaluating patients for this biomarker.

Citation Format: Ko Sato. Two kills with one shot: A biomarker with therapeutic implications in poor prognosis gastric cancers [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B16.
Abstract B17: Targeting the oncogenic TBX3 and its co-factors in anti-cancer drug development
Authors: Willmer Tarryn , Smyly Shannon , Smuts Danica , Prince Sharon
Published: December 2017

Sarcomas are heterogeneous neoplasms of mesenchymal origin whose clinical management is compromised due to inadequate diagnostic markers and limited therapeutic options. While the incidence rates for sarcomas in Africa remain uncertain, there is a widely held view that they are common in black African children and adolescents. Indeed, according to a Nigerian study, soft tissue sarcomas make up as much as 11.3% of all childhood cancers. We recently reported that the transcription factor, TBX3, is overexpressed in a diverse range of sarcoma subtypes where it plays a direct oncogenic role and it has been proposed as a novel target for their treatments. Direct targeting of transcription factors for therapies however continues to represent a serious challenge and therefore the molecular mechanisms that mediate its biological activity may be more amenable as anti-cancer drug targets. To address this, affinity purifications coupled with mass spectrometry was performed to identify TBX3 protein co-factors that regulate its oncogenic activity in sarcomas. Here we describe the validation of nucleolin as TBX3 co-factor by co-immunoprecipitation assays and confocal microscopy/co-localization analysis. The effect of nucleolin on TBX3 function was determined using RNAi rescue experiments coupled with growth curve and scratch motility assays to assess cell proliferation and migration respectively. Finally, the effect of the nucleolin targeting aptamer, AS1411, on the cell viability of a range of sarcoma subtypes was tested. Results show that the overexpression of TBX3 and nucleolin are common in a number of sarcoma subtypes. We provide compelling evidence that nucleolin interacts with and co-operates with TBX3 to promote proliferation and migration of chondrosarcoma, liposarcoma and rhabdomyosarcoma cells. Furthermore, AS1411 exhibits potent anti-cancer activity in these sarcomas whilst it has no effect on normal cells. In conclusion, we propose that TBX3 and nucleolin can be used in combination as biomarkers for the diagnosis and targeted therapy of a diverse range of sarcomas which are highly aggressive and treatment resistant cancers.

Citation Format: Tarryn Willmer, Shannon Smyly, Danica Smuts, Sharon Prince. Targeting the oncogenic TBX3 and its co-factors in anti-cancer drug development [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B17.
Abstract B21: Potassium dichromate and sodium arsenite toxicities: Modification by methanol extract of Rauvolfia vomitoria in albino mice
Authors: Akinwumi Kazeem Akinyinka , Osifeso Olabode Olatunbosun , Aboyewa Olajumoke Jumoke , Odunola Oyeronke Aduni
Published: December 2017

Exposure to arsenic and hexavalent chromium is a major public health concern especially in the developing part of the world and there is still no reliable treatment. This study evaluates the effect of combined exposure to potassium heptaoxochromate VI (K2Cr2O7) and sodium arsenite (NaAsO2) in mice as well as the effect of methanol leaf extracts of Rauvolfia vomitoria (MRV) on the toxicity of both toxicants. Test mice were pre-treated with 275mg/kg body weight MRV before being challenged with either NaAsO2 and/ or K2Cr2O7 on the seventh day. The control animals were exposed to distilled water or a single dose of 2.5 mg/kg body weight NaAsO2 or 12mg/kg of K2Cr2O7 a day before the animals were sacrificed. The frequency of micronucleated polychromatic erythrocytes (mPCEs) was monitored in bone marrow cells, while aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were assessed in the plasma. Hepatic glutathione (GSH) and malondialdehyde (MDA) levels as well as catalase (CAT) and glutathione-S-transferase (GST) activities were also monitored. The NaAsO2 and K2Cr2O7 significantly (P<0.05) increased the frequency of mPCE formation, AST, ALT, CAT and GST activities when compared with the control. Simultaneous exposure to NaAsO2 and K2Cr2O7 further increased (p<0.05) the levels of the markers. In addition, GSH and GST were significantly (p<0.05) reduced in mice exposed to NaAsO2 or K2Cr2O7 or their combination. However, MRV reversed the markers towards that of the control. Our study therefore suggests that MRV ameliorates NaAsO2 and K2Cr2O7 induced toxicities via reduction of oxidative stress and fortification of anti-oxidant system

Note: This abstract was not presented at the conference.

Citation Format: Kazeem Akinyinka Akinwumi, Olabode Olatunbosun Osifeso, Olajumoke Jumoke Aboyewa, Oyeronke Aduni Odunola. Potassium dichromate and sodium arsenite toxicities: Modification by methanol extract of Rauvolfia vomitoria in albino mice [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B21.
Abstract B23: The anticancer properties of South African herbal teas utilizing an in vitro pre-exposure anti-inflammatory UVB/keratinocyte model
Authors: Keet Lana , Riedel Sylvia , Swart Amanda C. , Joubert E , Gelderblom WCA
Published: December 2017

The incidence of skin cancer, resulting from exposure to UVB irradiation, has become a global concern as it continues to rise rapidly with the non-melanoma skin cancers, comprised of basal cell carcinoma and squamous cell carcinoma, being the most frequently diagnosed in Caucasian populations. Chronic inflammation is suggested to contribute to cancer development and therefore poses a potential target for chemoprevention. In the skin, keratinocytes and macrophages play an integral part in acute and chronic inflammation, with interleukin 1-α (IL-1α) and tumor necrosis factor α (TNF-α) as key cytokines governing this process. Green tea (Camellia sinensis) and the South African herbal teas, rooibos (Aspalathus linearis) and honeybush (Cyclopia spp.) displayed anti-inflammatory effects in mouse and human skin. To further investigate the anti-inflammatory properties of green tea and the herbal teas, rooibos and honeybush (C. subternata and C. maculata) herbal teas, a pre-exposure UVB-irradiated/keratinocytes cell culture model was developed and validated utilizing human keratinocytes (HaCaT) utilizing the intracellular accumulation of IL-1α as endpoint. Aqueous extracts of the green tea and unfermented herbal teas were prepared, their polyphenolic composition determined by high performance liquid chromatography (HPLC) and their antioxidant activity characterized utilizing different antioxidant assays. Green tea and rooibos exhibited similar antioxidant activities while C. maculata displayed the lowest overall antioxidant activity mainly due to a high mangiferin level, the major polyphenol in honeybush. UVB-induced IL-1α was decreased by pre-exposing the keratinocytes to the green tea extract for 16 hrs prior to UVB-irradiation while a far weaker response was obtained with the rooibos extract. Both the honeybush extracts displayed a significant anti-inflammatory effect in the reduction of IL-1α with C. subternata exhibiting a slightly increased protection at a lower extract concentration. Flavonoid diversity of the teas is likely to explain the differential effects regarding their antioxidant and anti-inflammatory activities. Proposed mechanisms for the anti-inflammatory effects include the modulation of UVB-induced oxidative stress via various pathways and the subsequent down regulation of nuclear factor kappa β (NFκB) and activated protein-1 (AP-1) which are key regulators of cytokine production governing the inflammatory response.

Citation Format: Lana Keet, Sylvia Riedel, Amanda C. Swart, E Joubert, WCA Gelderblom. The anticancer properties of South African herbal teas utilizing an in vitro pre-exposure anti-inflammatory UVB/keratinocyte model [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B23.
Abstract B26: iNOS expression and lethal prostate cancer in patients with localized disease
Authors: Rider Jennifer R. , Erlandsson Ann , Vyas Chirag , Davidsson Sabina , Carlsson Jessica , Andersson Swen-Olof , Andren Ove
Published: December 2017

Inducible nitric oxide synthase (iNOS) has demonstrated both tumor-promoting and tumor-inhibiting effects in prostate cancer. However, the relationship between iNOS protein expression and long-term prostate cancer outcomes is unclear. We evaluated iNOS expression in tumor epithelia and stroma in 300 men with localized tumors diagnosed incidentally by transurethral resection of the prostate (TURP) in Sweden. In this extreme case-control design, cases (N=132) died of prostate cancer and controls (N=168) survived at least 8 years following diagnosis without death from prostate cancer or a competing cause. Immunohistochemistry was undertaken with a polyclonal rabbit anti-human NOS2 antibody (Abcam) and the Ventana (Roche) semi-automated staining system. Two observers individually scored the staining according to intensity and number of positive cells from 0-3. The median value across cores in each patient were then categorized as <1, >1-<2, and >2, separately for epithelial and stromal compartments. Odds ratios for lethal prostate cancer were estimated with logistic regression controlling for the matching factors (age, calendar year of diagnosis), as well as tumor stage, Gleason score, and percent tumor. iNOS was expressed by stromal-associated M1 macrophages and fibroblasts, as well as tumor cells. Gleason score was positively associated with both stromal and epithelial iNOS staining. In the stroma, there was no statistically significant association between iNOS expression and lethal prostate cancer after adjustment for clinical covariates. However, the odds of lethal prostate cancer increased with tumor expression of iNOS in the fully adjusted model. Compared to patients with the lowest category of iNOS expression, the odds ratios for lethal prostate cancer were 2.96 (95% CI: 1.26-6.96) for patients in the second category and 3.80 (95% CI: 1.45-9.97) for patients in the top category. These results suggest that iNOS may help to identify patients with aggressive prostate cancer at the time of diagnosis, or may be a therapeutic target. Given previously reported in vitro data suggesting that iNOS promotes proliferation of androgen-independent prostate tumors, future analyses will investigate association between iNOS expression and time to castration-resistant prostate cancer in this patient population.

Citation Format: Jennifer R. Rider, Ann Erlandsson, Chirag Vyas, Sabina Davidsson, Jessica Carlsson, Swen-Olof Andersson, Ove Andren. iNOS expression and lethal prostate cancer in patients with localized disease [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B26.
Abstract B30: Development of robust in vitro 3D models of human tumors for the identification and evaluation of anti-cancer drugs
Authors: Harvey Amanda Carys , Place Graham , Baggott Kathryn , Samra Satinder , Freathy Caroline , Cross Neil
Published: December 2017

Currently in vivo testing of animals is still the gold standard for drug development and testing of cytotoxic compounds. With the demand for non-animal alternatives raising here we compared the development and functionality of two 3D culture models for tumor spheroids.

Firstly 3D tumor spheroids were generated from lung cancer cell lines (NCI-H1650, NCI-H2170, NCI-H1975 and HCC-827) with known EGFR pathway mutations, and also primary isolated lung cancer epithelial cells, by encapsulation within an Alginate matrix to produced isogenic cell populations. Additionally, spheroids were co-cultured alongside primary Cancer-Associated Fibroblasts (CAFs). Following generation (7 days), spheroids (up to 500µm diameter) were treated with cytotoxic agents. The presence of CAFs attenuated the growth of smaller tumor spheroids (<100μm) although drug responses were not markedly changed in larger spheroids. Secondly, 3D tumor spheroids were generated using the OrganDot system (Asterand Biosciences) for the same lung and primary cell lines. Consistent responses were achieved between OrganDOT cultures and 3D alginate spheroids. Both systems allowed long-term viability of cultures allowing sequential or chronic compound testing.

Both systems produced responses consistent with known genotypes for those cell lines. Ongoing studies using these models are focused at assessing whether anti-EGFR responses may predict the presence or absence of EGFR-pathway mutations in freshly isolated primary lung tumor cultures mutations.

Citation Format: Amanda Carys Harvey, Graham Place, Kathryn Baggott, Satinder Samra, Caroline Freathy, Neil Cross. Development of robust in vitro 3D models of human tumors for the identification and evaluation of anti-cancer drugs [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B30.
Abstract B34: Investigating disruptions in the circadian clock in cancer cells
Authors: Lexow Waldo , Silva Sian-Ailin Da , Leaner Virna D. , Watt Pauline J. van der
Published: December 2017

The circadian clock is man's internal time-keeping mechanism; it synchronizes human physiology with the external cycle of day and night. At the molecular level, all cells display a circadian clock driven by core clock proteins that constitute transcription-translation feedback loops, generating oscillating patterns of circadian clock gene expression over time. It is becoming increasingly apparent that disruptions in the circadian clock may contribute to cancer development. This study aimed to investigate the molecular components of the circadian clock in two cancer types prevalent in South Africa: cervical and oesophageal cancer. To our knowledge the circadian clock has not previously been investigated in these cancer types. Microarray and real-time RT-PCR analyses revealed significantly decreased expression of Period 2 (Per2) mRNA in cervical and oesophageal cancer patient tissue compared to normal tissue. Cervical and oesophageal cancer cell lines similarly displayed significantly reduced mRNA and protein levels of certain circadian clock genes, including positive and negative regulators of the circadian clock. Nuclear transport of circadian clock proteins was investigated, since cancer cells display increased nuclear transport rates and circadian clock proteins rely on nucleocytoplasmic shuttling to maintain the correct pace of the circadian clock. Fluorescence recovery after photobleaching (FRAP) analysis was performed and revealed increased nuclear import rates of Bmal1 in cancer compared to normal cells. Altered expression and nuclear import rates of circadian clock proteins in cancer cells suggest these cells might harbor an impaired circadian clock. Luminescence assays are thus currently being employed to determine whether cancer cells display rhythmic expression of core clock genes, as an indication of a functioning circadian clock. A real-time bioluminescence imager is being used to measure Bmal1 and Per2 promoter-luciferase activities in cancer cells over time, after synchronization of circadian oscillators with the glucocorticoid analogue, Dexamethasone. This type of study is relevant to the field of chronotherapy, where elucidating differences in circadian clock functioning in normal and cancer cells could yield better insights into the timing of administration of chemotherapy, ultimately ensuring a better patient response.

Citation Format: Waldo Lexow, Sian-Ailin Da Silva, Virna D. Leaner, Pauline J. van der Watt. Investigating disruptions in the circadian clock in cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B34.
Abstract B35: Runx3 contributes for the defense against endogenous level of oncogenic K-Ras-induced tumorigenesis
Authors: Chi Xin-Zi , Lee You-Soub , Bae Suk-Chul
Published: December 2017

Recent studies demonstrated that p53 affects only adenocarcinomas in K-RasG12V knockin mice leaving untouched adenomas which are likely to progress into adenocarcinomas (1, 2). These observations raised a fundamental question regarding whether cells can defend against endogenous level of oncogenic signal (3). Runx3, which plays pivotal roles in lineage determination and functions as a tumor suppressor, is frequently inactivated by promoter hypermethylation in various types of human tumors (4). Previously, we showed that deletion of Runx3 markedly enhanced K-Ras-G12V-induced lung tumorigenesis and led to early death (5). In this study, we found that immortalized Runx3-/- mouse embryonic fibroblast cells (MEFs) were tumorigenic. In addition, Runx3 was silenced by promoter hypermethylation in K-Ras-G12V-knockin MEFs. Expression of Runx3 in the K-Ras-G12V MEFs abolished their tumorigenesity. In mice, knockin of K-Ras-G12V in limited number of cells failed to induce tumor, but combination of K-Ras-G12V-knockin and Runx3-knockout by the same targeting method rapidly induced severe lung adenocarcinomas, lymphomas and skin carcinomas (median survival, 48 days). RUNX3 was silenced in all cases of K-Ras-activated human non-small cell lung cancers (n=20). Our results demonstrate that mammalian cells can defend against endogenous oncogenic K-Ras and Runx3 plays a key role in the defense mechanism.

References

1. Feldser et al. (2010). Nature 468, 572-575.

2. Junttila et al. (2010). Nature 468, 567-571.

3. Berns A. (2010). Nature 468:519-20

4. Ito Y, Bae S-C, Chuang LS. (2015). Nat Rev Cancer. 15:81-95.

5. Lee et al., (2013). Cancer Cell. 24(5):603-16.

Citation Format: Xin-Zi Chi, You-Soub Lee, Suk-Chul Bae. Runx3 contributes for the defense against endogenous level of oncogenic K-Ras-induced tumorigenesis [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B35.
Abstract B37: Value of penetrated NIR spectroscopy in the diagnostic process of lung cancer
Authors: Bruha Tomas , Votruba Jiri , Cech Vladimír , Skvarek Josef
Published: December 2017

Background: Recently due to advances in biological therapy and immunotherapy there is an increased need for precise morphological and mutational verification of lung cancer. We have been testing the possibilities of NIR (near infrared) n spectroscopy in the process lung cancer detection.

Methods: For the analyses, we used a custom-made endoscopic lensed microprobe consisting of one excitation and one collection optical fibers that were coupled to a NIR spectrometer. In 55 patients with lung cancer diagnosis undergoing bronchoscopy we carried on 110 measurements of NIR penetrated spectra from both normal and malignant lung tissues. Detected spectral curves of absolute transmittance for normal tissue and pathological tissue were further analyzed utilizing two chosen parameters which are corresponding to important characteristics of the curves. First parameter was statical moment of area under spectral curve referenced to vertical axis of maximal wavelength whose value reflected average intensity of detected signal as well as rate of shifting higher intensities to shorter wavelengths of spectral band (that means how much is investigated tissue permeable on shortest possible wavelengths). As the second parameter serve horizontal coordinates of the centrum of gravity of the area under spectral curve referenced to vertical axis of maximal wavelength whose value reflected just the rate of shifting signal to shorter wavelengths of spectral band regardless absolute intensity (this parameter compared shifting to shorter wavelengths for spectral curves as if were normalized to its maximal intensity value). Finally ratio of pathological to normal value for both parameters was calculated.

Results: Resulting values of these ratios for both above mentioned parameters were higher than 1 for all types of pathologies. Moreover ratio for second parameter is significantly higher for adenocarcinoma than for any type of pathologies.

Conclusion: NIR spectroscopy showed a potential for a reliable discrimination between normal and pathological lung tissue. We observed spectral differences between adenocarcinoma and all other types of lung pathologies.

Acknowledgement:

PROGRAM MPO-TRIO

PROJECT: FV 10657, OPROX, a.s.

Research and development of technologies and methods for optical penetrating spectroscopy of atypical lung tissue nodules.

Note: This abstract was not presented at the conference.

Citation Format: Tomas Bruha, Jiri Votruba, Vladimír Cech, Josef Skvarek. Value of penetrated NIR spectroscopy in the diagnostic process of lung cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B37.
Abstract B40: A novel activating I1171T ALK mutation in neuroblastoma responds better to ceritinib compare to the first generation inhibitor crizotinib
Authors: Siaw Joachim T. , Guan Jikui , Martinsson Tommy , Hansson Magnus , Kogner Per , Palmer Ruth
Published: December 2017

Mutations in the kinase domain of Anaplastic Lymphoma Kinase (ALK) have been suggested to be important players in the genetics and progression of the childhood tumor neuroblastoma. Here we report the appearance of a novel ALK mutation in neuroblastoma together with other chromosomal aberrations that mediate neuroblastoma initiation and progression. Analyses of genomic tumor DNA from biopsy samples initially showed an 11q minus, 17q gain with a mutation of the ALK gene at protein position 1171, which mediate an amino acid change from isoleucine to threonine. We show that mutation of I1171 to threonine generates a potent gain-of-function mutant, as observed in two independent systems. Firstly, in PC12 cell lines expressing ALKI1171T display ligand independent activation of ALK, neurite outgrowth and further downstream signaling activation. Secondly, ALKI1171T meditate foci formation in a NIH3T3 transformation analysis. Finally, pharmacological inhibition of ALKI1171T employing ceritinib, an FDA approved ALK inhibitor show 14-fold better ability to abrogate ALKI1171T compared with crizotinib.

Citation Format: Joachim T. Siaw, Jikui Guan, Tommy Martinsson, Magnus Hansson, Per Kogner, Ruth Palmer. A novel activating I1171T ALK mutation in neuroblastoma responds better to ceritinib compare to the first generation inhibitor crizotinib [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B40.