bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4304: Prevalence and triggers of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a cancer patient cohort
Authors: Gillis Nancy K. , Bell Gillian C. , McLeod Howard L. , Brandt Amy J. 
Published: July 2016

Abstract
SJS and TEN are extremely rare (approximately 2-7 cases per million per year) hypersensitivity reactions most commonly attributed to medications. The life-threatening nature of SJS/TEN necessitates early diagnosis and immediate identification and withdrawal of causative agents. Some of the most commonly associated culprits include sulfonamide antibiotics, aromatic anticonvulsants (phenytoin, carbamazepine, lamotrigine), -oxicam NSAIDs (e.g., meloxicam), allopurinol, and nevirapine. Individual case reports of SJS/TEN have been associated with anti-cancer agents, but a comprehensive assessment has not been performed. A large-scale retrospective analysis of the prevalence of SJS/TEN in cancer patients treated at Moffitt Cancer Center (MCC) between Jan 1, 2002 - Dec 31, 2014 was conducted. A total of 104,917 cancer patients were screened for SJS/TEN-related ICD-9 codes in the MCC health research informatics database. SJS/TEN diagnoses were identified in 121 patients. Manual chart review of physician, dermatology, and pathology notes confirmed SJS/TEN in 47 patients (in-patient + historical) and possible SJS/TEN in an additional 17 patients, corresponding to an overall prevalence of 0.06%. Confirmed in-patient cases of SJS/TEN were more common in hematologic malignancies compared to solid tumors (n = 12 vs. n = 7, respectively). Notably, 5 of the 19 (26.3%) confirmed cases were observed in patients with acute myeloid leukemia. Physician-reported culprits for SJS/TEN diagnoses included antibiotics, immunomodulators, anticonvulsants, and anti-cancer agents. The observed prevalence of SJS/TEN was higher in cancer patients than previous reports from the general USA population. There were 19 confirmed in-patient diagnoses of SJS/TEN and an additional 45 historical and possible cases of SJS/TEN in 104,917 cancer patients, corresponding to an overall prevalence of 0.018% to 0.06%, an approximately 90-fold increase when compared to the general population. Possible explanations for increased risk in cancer patients include increased exposure to culprit medications, cancer disease process, immunocompromised state, or synergy between risk factors. A thorough understanding of the factors that increase risk to SJS/TEN in cancer patients is critical to facilitate culprit withdrawal and maximize patient outcomes and survival.
Citation Format: Nancy K. Gillis, Gillian C. Bell, Howard L. McLeod, Amy J. Brandt. Prevalence and triggers of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a cancer patient cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4304.
Abstract 4315: Effects of increased dietary fat consumption on prostate cancer progression in genetically engineered mice
Authors: De Velasco Marco A. , Kura Yurie , Hatanaka Yuji , Oki Takashi , Yamamoto Yutaka , Sugimoto Koichi , Mori Yasunori , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: July 2016

Abstract
Prostate cancer is a highly heterogeneous disease and evidence indicates that lifestyle and environmental factors can contribute to cancer-related deaths. Accumulating data also suggests that increased dietary fat consumption may promote and increase the risk of prostate cancer-related morbidity and mortality. However, data between studies is inconsistent and a direct link between increased consumption of dietary fat and the promotion of prostate cancer remains unclear. Here, we present our findings from a preclinical study of increased dietary fat consumption and its effects on prostate tumor growth and progression using genetically engineered mouse models of prostate cancer. We determined the effects of a high fat diet on tumor cell proliferation and apoptosis in vivo using a well-established mouse model of prostate cancer. Twenty-week-old mice, with conditional biallelic deletion of PTEN, harboring castration-naïve or castration-resistant prostate tumors were randomized and assigned to a standard laboratory diet (4% fat) or a high-fat diet (HFD, 13.6% fat) for 8 weeks. In both tumor models, mice fed a HFD had increased expression levels of proteins associated with proliferation and decreased levels of apoptosis markers. To determine the long term effects of a HFD, we used a mouse model of advanced prostate cancer. Mice with concomitant inactivation of PTEN and p53 develop tumors that progress quickly and are characterized with increased metastatic development and decreased survival compared to PTEN knockout mice. PTEN/p53 double knockout mice were randomized and assigned to control or HFD experimental groups after weaning. Our findings revealed that mice fed a HFD resulted in obesity that led to decreased progression-free survival and overall survival rates compared to mice fed a standard diet. Our results provide evidence to support the effects of high dietary fat consumption and increased prostate cancer risk, and provide a platform to investigate chemoprevention strategies.
Citation Format: Marco A. De Velasco, Yurie Kura, Yuji Hatanaka, Takashi Oki, Yutaka Yamamoto, Koichi Sugimoto, Yasunori Mori, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Effects of increased dietary fat consumption on prostate cancer progression in genetically engineered mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4315.
Abstract 4319: Associations of dietary inflammation scores with incident, sporadic adenoma
Authors: Holmes Ashley C. , Bostick Roberd M. 
Published: July 2016

Abstract
It is now well-accepted that inflammation is causal in colorectal carcinogenesis and that reducing inflammation reduces risk for colorectal neoplasms. The ability to characterize specific dietary components as having pro- or anti-inflammatory effects is a promising area of cancer prevention. To assess associations of diet with inflammation and diet-associated inflammation with cancer risk, we created a new food-based inflammation (FBI) score based on associations of whole food dietary components (processed meats, red meat, white meat, fish, nuts, coffee, tea, high- and low-fat dairy products, refined and whole grains, and 10 botanical categories) with a panel of biomarkers of inflammation (plasma C-reactive protein [CRP] and interleukins-6, -8, and -10) among 590 chronic disease diagnosis-free participants (47% male, 53% female, 57% white, 43% black) in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study. A previously reported Dietary Inflammation Index (DII) is a primarily nutrient-based score developed for the same purposes. We investigated associations of our new FBI score, a DII that includes contributions from foods and nutritional supplements (Food + Supplements DII), and a DII that includes contributions only from foods (Food-only DII) with incident, sporadic adenoma in a case-control study (CPRU; n = 2,195) conducted in the Twin Cities area of Minnesota from 1990 - 1994. Diet was assessed using a Willett food frequency questionnaire. Associations of the scores with adenoma were estimated using unconditional logistic regression models adjusted for age, sex, hormone replacement therapy use, family history of colorectal cancer, regular non-steroidal anti-inflammatory drug (NSAID) use, total energy intake, smoking, physical activity level, alcohol consumption, and body mass index (BMI). The multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for those in the highest relative to those in the lowest score quartiles were 1.28 (95% CI 0.95, 1.72) for the FBI, 1.23 (95% CI 0.82, 1.85) for the Food + Supplements DII, and 1.14 (95% CI 0.85, 1.53) for the Foods-only DII. These results suggest that 1) a more pro-inflammatory diet may be associated with higher risk of colorectal adenoma, and 2) support further development and investigation of a food-based inflammation score for investigating associations of diet-related contributions to systemic inflammation with colorectal and other cancers and chronic diseases.
Citation Format: Ashley C. Holmes, Roberd M. Bostick. Associations of dietary inflammation scores with incident, sporadic adenoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4319.
Abstract 4369: Genome-wide copy number dependency analysis identifies partial copy loss of SF3B1 as a novel cancer vulnerability
Authors: Paolella Brenton R. , Gibson William J. , Urbanski Laura M. , Alberta John A. , Zack Travis I. , Bandopadhayay Pratiti , Nichols Caitlin A. , Agarwalla Pankaj K. , Brown Meredith S. , Lamothe Rebecca , Yu Yong , Choi Peter S. , Obeng Esther A. , Heckl Dirk , Ebert Benjamin L. , Wei Guo , Wang Belinda , Hahn William C. , Vazquez Francisca , Weir Barbara A. , Stiles Charles D. , Reed Robin , Beroukhim Rameen 
Published: July 2016

Abstract
Genomic instability is a hallmark of cancer resulting in widespread somatic copy number alterations. We integrated a genome-scale shRNA viability screen and copy number profiles from 179 cancer cell lines to perform an unbiased analysis of copy-number associated gene-dependency interactions. We found most copy-number associated gene dependencies result from losses of genetic material rather than gains. Strikingly, the most enriched class of these dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes. Hemizygous loss of CYCLOPS genes sensitizes cancer cells to their further suppression. One of the “top hits” from the analysis was the pre-mRNA splicing factor SF3B1, which is also frequently mutated in cancer. We then sought to evaluate SF3B1 as a CYCLOPS gene. Cancer cells with hemizygous SF3B1 copy-loss were uniquely sensitive to partial SF3B1 suppression by RNAi compared to cells with normal SF3B1 gene dosage. Mechanistically, cancer cells harboring partial SF3B1 copy-loss lack a reservoir of excess SF3b complex, a precursor complex of the U2 snRNP, which protects cells with normal SF3B1 copy number from cell death upon SF3B1 suppression. Our data highlight the prevalence of CYCLOPS dependencies in cancer and establish the spliceosome as a frequent CYCLOPS target. Further, these data indicate targeting wild-type SF3B1 as a novel cancer dependency in cells with hemizygous SF3B1 copy-loss.
Citation Format: Brenton R. Paolella, William J. Gibson, Laura M. Urbanski, John A. Alberta, Travis I. Zack, Pratiti Bandopadhayay, Caitlin A. Nichols, Pankaj K. Agarwalla, Meredith S. Brown, Rebecca Lamothe, Yong Yu, Peter S. Choi, Esther A. Obeng, Dirk Heckl, Benjamin L. Ebert, Guo Wei, Belinda Wang, William C. Hahn, Francisca Vazquez, Barbara A. Weir, Charles D. Stiles, Robin Reed, Rameen Beroukhim. Genome-wide copy number dependency analysis identifies partial copy loss of SF3B1 as a novel cancer vulnerability. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4369.
Abstract 4373: Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ
Authors: Dharmaiah Sathiya , Bindu Lakshman , Frank Peter , Gillette William , Esposito Dominic , Nissley Dwight , McCormick Frank , Stephen Andrew , Simanshu Dhirendra 
Published: July 2016

Abstract
KRAS is the most frequently mutated member of RAS superfamily in all human cancers. Post-translational farnesylation and methylation of KRAS at its C-terminal end plays an important role in its trafficking to proper subcellular compartments for cell signaling events. PDEδ acts as a chaperone for farnesylated members of the RAS superfamily and plays a key role in their trafficking from the place of biosynthesis or post-translational modification to a transport vesicle or plasma membrane. We solved the structures of wild-type full-length KRAS4b (farnesylated and methylated) in complex with PDEδ in two different crystal forms at 2 Ang resolution. Our structure showed that only the last six amino acids of hypervariable region (and not the G-domain) of KRAS4b interact with PDEδ. Farnesyl and methyl groups present on Cys185 bind tightly in the central hydrophobic pocket present in PDEδ. In crystal form II, we could see all amino acids present in the hypervariable region of KRAS4b, thus providing atomic details of hypervariable region of KRAS4b for the first time. Comparison of the two crystal forms suggests how PDEδ could bind to both farnesylated as well as geranylgeranylated KRAS4b. The structure provides the rationale for nucleotide-independent binding of KRAS4b to PDEδ and its interaction with other farnesylated but not palmitoylated members of RAS superfamily.
Citation Format: Sathiya Dharmaiah, Lakshman Bindu, Peter Frank, William Gillette, Dominic Esposito, Dwight Nissley, Frank McCormick, Andrew Stephen, Dhirendra Simanshu. Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4373.
Abstract 4383: SOCRATES: integrating ex vivo and in silico analysis to identify optimal drug combinations for patients
Authors: Coker Elizabeth A. , Stewart Adam , Minchom Anna , O’Brien Mary , Yap Timothy , Workman Paul , Banerji Udai , Al-Lazikani Bissan 
Published: July 2016

Abstract
Recent work on cancer heterogeneity and evolution has greatly enhanced our understanding of drivers of drug resistance, but this has also highlighted the need to move away from generic, “one-size-fits-all” treatment regimes. It is clear that we should tailor therapy to individual patients at different stages of disease based on the current behaviour of their tumour cells, yet detailed experimental characterisation and analysis of patient tissue is impractical and costly. Predictive computational models that can produce patient-specific recommendations of drug combinations would therefore be of great value to the field of personalised medicine. In silico modelling has already been used to successfully predict synergistic drug combinations in single cell lines in the lab, but such approaches have not yet been translated to dynamic, real patient data in the clinic.
The SOCRATES project (Signalling output to rationalise combinations of targeted anticancer therapies) integrates experimental data and computational analysis to predict context-specific synergistic drug combinations. Here we present ambitious computational modelling of dynamic signalling network changes in response to ex vivo exposure of seven targeted drugs used singly at clinically appropriate concentrations. We also apply our adaptive modelling to genomics and proteomics data from 54 proteins in over 30 non small-cell lung cancer cell lines and ten patient samples to predict and experimentally validate personalised, context specific drug combinations. We will describe our adaptive, in silico modelling for predicting response to drug combinations, including novel methods utilizing network topology. We have predicted over 50 synergistic drug combinations and will present our predictions alongside initial results of experimental validation in the lab. We will also illustrate the differences observed in various cell lines and patient derived cells depending on genetic context.
SOCRATES is, to our knowledge, the first project of its kind and is a prototype for the future of adaptive, individualised cancer treatment.
Citation Format: Elizabeth A. Coker, Adam Stewart, Anna Minchom, Mary O’Brien, Timothy Yap, Paul Workman, Udai Banerji, Bissan Al-Lazikani. SOCRATES: integrating ex vivo and in silico analysis to identify optimal drug combinations for patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4383.
Abstract 4392: Yes1 is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance
Authors: Yamamoto Hiromasa , Takeda Tatsuaki , Kanzaki Hirotaka , Suzawa Ken , Namba Kei , Sato Hiroki , Torigoe Hidejiro , Watanabe Mototsugu , Maki Yuho , Soh Junichi , Asano Hiroaki , Tsukuda Kazunori , Miyoshi Shinichiro , Kitamura Yoshihisa , Sendo Toshiaki , Toyooka Shinichi 
Published: July 2016

Abstract
Background: Overexpression of human epidermal growth factor receptor 2 (HER2) was observed in approximately 15-23% of breast cancers and they are classified as HER2-positive breast cancer. Trastuzumab is a therapeutic drug for the first choice for HER2-positive breast cancer, showing good response. However, acquired resistance to trastuzumab is one of the critical clinical issues in breast cancer treatment, especially in the patients with recurrent breast cancer. Therefore, it is necessary to develop the effective therapy to overcome the resistance. In this study, we established a trastuzumab-resistant breast cancer cell line from a trastuzumab-sensitive cell line with HER2 amplification (BT-474). We analyzed the mechanisms of resistance to trastuzumab and demonstrated the anti-tumor effect of dasatinib.
Methods: Trastuzumab-resistant breast cancer cell line (BT-474-R) was established by treating BT-474 cells for long-term exposure with increasing doses of trastuzumab (from 0.1 μg/mL up to 40 μg/mL). Expression and activation of HER2 and its related molecules were investigated using western blotting and real-time PCR. Cell viability was evaluated using MTS assay. Cell cycle was analyzed using flow cytometry.
Results: Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R. HER2 and Akt were also activated. Silencing of Yes1 by siRNA induced BT-474-R to recover sensitivity to trastuzumab. Pharmaceutical inhibition of Yes1 by Src inhibitor dasatinib was also effective to recovery sensitivity to trastuzumab in BT-474-R. Combination treatment of dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, these combination treatments induced G1-phase cell-cycle arrest and apoptosis.
Conclusion: Yes1 plays an important role in acquired resistance to trastuzumab in HER2-positive breast cancer. Our data also suggest that pharmacological inhibition of Yes1 may become the new strategy to overcome resistance to trastuzumab.
Citation Format: Hiromasa Yamamoto, Tatsuaki Takeda, Hirotaka Kanzaki, Ken Suzawa, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka. Yes1 is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4392.
Abstract 4395: Tissue stiffness and hypoxia regulate breast cancer stem cells through ILK
Authors: Pang Mei-Fong , Stallings-Mann Melody , Siedlik Michael J. , Varner Victor D. , Han Siyang , Radisky Derek C. , Nelson Celeste M. 
Published: July 2016

Abstract
The mechanical and chemical properties of the cellular microenvironment can influence the phenotype of cancer cells. The hypoxic conditions within solid breast tumors can contribute to invasiveness and the formation of breast cancer stem cells (CSCs). Integrin-linked kinase (ILK) is a critical mediator for mechanotransduction, a process that converts exogenous mechanical stimuli into biochemical signals. Yet, it is unclear how the physical properties of the tumor microenvironment, including matrix stiffness and hypoxia, integrate to direct the formation of the breast CSC niche.
Using an innovative engineered culture model, we found that stiff and hypoxic microenvironments activate integrin signaling and a stem-like gene signature in breast cancer cells, suggesting that integrin signaling, matrix mechanics and oxygen tension cooperatively promote the formation of breast CSCs. Stiff and hypoxic microenvironments promote integrin signaling and the expression of CSC markers including CD44 and Nanog. Knocking down ILK reverts the CSC phenotype of invasive breast cancer cells on stiff matrix, and abrogates their ability to form mammospheres and colonies in soft agar. In contrast, ectopic expression of ILK enhances CSC properties. ILK promotes integrin signaling and the CSC phenotype through the PI3K/Akt pathway. Stiff microenvironments promote tumor formation and metastasis in ovo. ILK depletion significantly abrogates the tumorigenenic and metastatic potential of invasive breast cancer cells in ovo. Importantly, we found that breast cancer cells expressing ILK and the CSC marker CD44 were only present in the regions of tumors predicted to be stiff in breast cancer patient samples.
Our data suggest that ILK act as an essential mechanosensor that regulates breast CSC phenotype in response to matrix mechanics and oxygen tension to regulate the formation of breast CSCs.
Citation Format: Mei-Fong Pang, Melody Stallings-Mann, Michael J. Siedlik, Victor D. Varner, Siyang Han, Derek C. Radisky, Celeste M. Nelson. Tissue stiffness and hypoxia regulate breast cancer stem cells through ILK. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4395.