bluuebunny/crossref_metadata_2025 huggingface dataset:
Infections Requiring Hospitalization as Predictors of Pediatric-Onset Crohn’s Disease and Ulcerative Colitis
Authors: Hutfless Susan , Abramson Oren , Heyman Melvin B. , Bayless Theodore M. , Li De-Kun , Winthrop Kevin , Herrinton Lisa J.
Published: May 2015

Objectives.To assess the relationship between infections and the risk of pediatric-onset inflammatory bowel disease (IBD).Methods.We conducted a nested case-control study of 501 incident cases aged ≤17 years and 9,442 controls who were members of Kaiser Permanente Northern California for at least one consecutive year between 1996 and 2006. IBD was confirmed and the incidence date was adjudicated by pediatric gastroenterologists. Hospitalized infections were identified from the principal diagnosis code of electronic inpatient records. Medications to treat infections were identified during the hospitalization. Conditional logistic regression was used to assess the associations between hospitalized infections, medications, and Crohn’s disease and ulcerative colitis.Results.In the year prior to diagnosis, both hospitalized infection of any system (OR 6.3; 95% CI 1.6–23.9) and hospitalized intestinal infection (OR 19.4; 95% CI 2.6–143.2) were associated with CD. Hospitalized infections of any system were inversely associated with UC after excluding the year prior to diagnosis (OR 0.4; 95% CI 0.2–0.9). No UC case had a hospitalized gastrointestinal infection prior to diagnosis.Conclusion.Infections appear to play opposite roles prior to the diagnosis of CD and UC. Infections may be associated with an increased risk of CD and a decreased risk of UC.
Efficient Scheduling of Scientific Workflows with Energy Reduction Using Novel Discrete Particle Swarm Optimization and Dynamic Voltage Scaling for Computational Grids
Authors: Christobel M. , Tamil Selvi S. , Benedict Shajulin
Published: May 2015

One of the most significant and the topmost parameters in the real world computing environment is energy. Minimizing energy imposes benefits like reduction in power consumption, decrease in cooling rates of the computing processors, provision of a green environment, and so forth. In fact, computation time and energy are directly proportional to each other and the minimization of computation time may yield a cost effective energy consumption. Proficient scheduling of Bag‐of‐Tasks in the grid environment ravages in minimum computation time. In this paper, a novel discrete particle swarm optimization (DPSO) algorithm based on the particle’s best position (pbDPSO) and global best position (gbDPSO) is adopted to find the global optimal solution for higher dimensions. This novel DPSO yields better schedule with minimum computation time compared to Earliest Deadline First (EDF) and First Come First Serve (FCFS) algorithms which comparably reduces energy. Other scheduling parameters, such as job completion ratio and lateness, are also calculated and compared with EDF and FCFS. An energy improvement of up to 28% was obtained when Makespan Conservative Energy Reduction (MCER) and Dynamic Voltage Scaling (DVS) were used in the proposed DPSO algorithm.
Disinfection of Needleless Connector Hubs: Clinical Evidence Systematic Review
Authors: Moureau Nancy L. , Flynn Julie
Published: May 2015

Background. Needleless connectors (NC) are used on virtually all intravascular devices, providing an easy access point for infusion connection. Colonization of NC is considered the cause of 50% of postinsertion catheter-related infections. Breaks in aseptic technique, from failure to disinfect, result in contamination and subsequent biofilm formation within NC and catheters increasing the potential for infection of central and peripheral catheters.Methods. This systematic review evaluated 140 studies and 34 abstracts on NC disinfection practices, the impact of hub contamination on infection, and measures of education and compliance.Results. The greatest risk for contamination of the catheter after insertion is the NC with 33–45% contaminated, and compliance with disinfection as low as 10%. The optimal technique or disinfection time has not been identified, although scrubbing with 70% alcohol for 5–60 seconds is recommended. Studies have reported statistically significant results in infection reduction when passive alcohol disinfection caps are used (48–86% reduction).Clinical Implications. It is critical for healthcare facilities and clinicians to take responsibility for compliance with basic principles of asepsis compliance, to involve frontline staff in strategies, to facilitate education that promotes understanding of the consequences of failure, and to comply with the standard of care for hub disinfection.
Inhibitory Effect of Various Breads on DMH-Induced Aberrant Crypt Foci and Colorectal Tumours in Rats
Authors: Qi Guangying , Zeng Sien , Takashima Tiri , Nozoe Koichiro , Shobayashi Megumi , Kakugawa Koji , Murakami Kaori , Jikihara Hiroshi , Zhou Lihua , Shimamoto Fumio
Published: May 2015

Bread is rich in dietary fibre and many phytochemical compounds, which may influence chemoprevention of colon cancer. In the present study, we evaluated the effect of three kinds of bread on DMH-induced colorectal tumours in F344 rats. F344 rats were divided into four groups (Steinmetz Three-Grain bread, Steinmetz Country bread, White bread, and MF). All groups were injected with 1,2-dimethylhydrazine (DMH, 20 mg/kg body weight) once a week for 8 consecutive weeks from 5 weeks of age. To investigate the antioxidant effect of bread, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging rate of bread and the serum levels of 8-hydroxy-deoxyguanosine (8-OHdG) in rats were examined. The number of colorectal aberrant crypt foci (ACF) and the incidence of colorectal tumours were studied after 34 weeks of DMH treatment. The Steinmetz Three-Grain and Steinmetz Country bread groups had higher scavenging rates of the DPPH free radical and lower serum levels of 8-OHdG and incidence of ACF, adenomas, and adenocarcinomas of colon than the White bread and MF group. Steinmetz Three-Grain bread and Steinmetz Country bread have various ingredient combinations that may inhibit colorectal cancer progression.
Extraction Optimization for ObtainingArtemisia capillarisExtract with High Anti-Inflammatory Activity in RAW 264.7 Macrophage Cells
Authors: Jang Mi , Jeong Seung-Weon , Kim Bum-Keun , Kim Jong-Chan
Published: May 2015

Plant extracts have been used as herbal medicines to treat a wide variety of human diseases. We used response surface methodology (RSM) to optimize theArtemisia capillarisThunb. extraction parameters (extraction temperature, extraction time, and ethanol concentration) for obtaining an extract with high anti-inflammatory activity at the cellular level. The optimum ranges for the extraction parameters were predicted by superimposing 4-dimensional response surface plots of the lipopolysaccharide- (LPS-) induced PGE2and NO production and by cytotoxicity ofA. capillarisThunb. extracts. The ranges of extraction conditions used for determining the optimal conditions were extraction temperatures of 57–65°C, ethanol concentrations of 45–57%, and extraction times of 5.5–6.8 h. On the basis of the results, a model with a central composite design was considered to be accurate and reliable for predicting the anti-inflammation activity of extracts at the cellular level. These approaches can provide a logical starting point for developing novel anti-inflammatory substances from natural products and will be helpful for the full utilization ofA. capillarisThunb. The crude extract obtained can be used in someA. capillarisThunb.-related health care products.
Good Linear Operators and Meromorphic Solutions of Functional Equations
Authors: Li Nan , Korhonen Risto , Yang Lianzhong
Published: May 2015

Nevanlinna theory provides us with many tools applicable to the study of value distribution of meromorphic solutions of differential equations. Analogues of some of these tools have been recently developed for difference, q-difference, and ultradiscrete equations. In many cases, the methodologies used in the study of meromorphic solutions of differential, difference, and q-difference equations are largely similar. The purpose of this paper is to collect some of these tools in a common toolbox for the study of general classes of functional equations by introducing notion of a good linear operator, which satisfies certain regularity conditions in terms of value distribution theory. As an example case, we apply our methods to study the growth of meromorphic solutions of the functional equation M(z,f)+P(z,f)=h(z), where M(z,f) is a linear polynomial in f and L(f), where L is good linear operator, P(z,f) is a polynomial in f with degree deg P≥2, both with small meromorphic coefficients, and h(z) is a meromorphic function.
Feature Reduction Based on Genetic Algorithm and Hybrid Model for Opinion Mining
Authors: Kalaivani P. , Shunmuganathan K. L.
Published: May 2015

With the rapid growth of websites and web form the number of product reviews is available on the sites. An opinion mining system is needed to help the people to evaluate emotions, opinions, attitude, and behavior of others, which is used to make decisions based on the user preference. In this paper, we proposed an optimized feature reduction that incorporates an ensemble method of machine learning approaches that uses information gain and genetic algorithm as feature reduction techniques. We conducted comparative study experiments on multidomain review dataset and movie review dataset in opinion mining. The effectiveness of single classifiers Naïve Bayes, logistic regression, support vector machine, and ensemble technique for opinion mining are compared on five datasets. The proposed hybrid method is evaluated and experimental results using information gain and genetic algorithm with ensemble technique perform better in terms of various measures for multidomain review and movie reviews. Classification algorithms are evaluated using McNemar’s test to compare the level of significance of the classifiers.
Minimally Invasive Technique for PMMA Augmentation of Fenestrated Screws
Authors: Klingler Jan-Helge , Scholz Christoph , Kogias Evangelos , Sircar Ronen , Krüger Marie T. , Volz Florian , Scheiwe Christian , Hubbe Ulrich
Published: May 2015

Purpose. To describe the minimally invasive technique for cement augmentation of cannulated and fenestrated screws using an injection cannula as well as to report its safety and efficacy. Methods. A total of 157 cannulated and fenestrated pedicle screws had been cement‐augmented during minimally invasive posterior screw‐rod spondylodesis in 35 patients from January to December 2012. Retrospective evaluation of cement extravasation and screw loosening was carried out in postoperative plain radiographs and thin‐sliced triplanar computed tomography scans. Results. Twenty‐seven, largely prevertebral cement extravasations were detected in 157 screws (17.2%). None of the cement extravasations was causing a clinical sequela like a new neurological deficit. One screw loosening was noted (0.6%) after a mean follow‐up of 12.8 months. We observed no cementation‐associated complication like pulmonary embolism or hemodynamic insufficiency. Conclusions. The presented minimally invasive cement augmentation technique using an injection cannula facilitates convenient and safe cement delivery through polyaxial cannulated and fenestrated screws during minimally invasive screw‐rod spondylodesis. Nevertheless, the optimal injection technique and design of fenestrated screws have yet to be identified. This trial is registered with German Clinical Trials DRKS00006726.
Enhanced MET Translation and Signaling Sustains K-Ras–Driven Proliferation under Anchorage-Independent Growth Conditions
Authors: Fujita-Sato Saori , Galeas Jacqueline , Truitt Morgan , Pitt Cameron , Urisman Anatoly , Bandyopadhyay Sourav , Ruggero Davide , McCormick Frank
Published: May 2015

Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage-independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage-independent culture conditions, we discovered the involvement of Met in K-Ras–dependent, anchorage-independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage-independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global downregulation of mRNA translation during anchorage-independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras–mediated Met expression drives “K-Ras addiction” in anchorage-independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage-independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients. Cancer Res; 75(14); 2851–62. ©2015 AACR.
Mitochondrial DNA Copy Number in Peripheral Blood Cells and Risk of Developing Breast Cancer
Authors: Lemnrau Alina , Brook Mark N. , Fletcher Olivia , Coulson Penny , Tomczyk Katarzyna , Jones Michael , Ashworth Alan , Swerdlow Anthony , Orr Nick , Garcia-Closas Montserrat
Published: May 2015

Increased mitochondrial DNA (mtDNA) copy number in peripheral blood cells (PBC) has been associated with the risk of developing several tumor types. Here we evaluate sources of variation of this biomarker and its association with breast cancer risk in a prospective cohort study. mtDNA copy number was measured using quantitative real-time PCR on PBC DNA samples from participants in the UK-based Breakthrough Generations Study. Temporal and assay variation was evaluated in a serial study of 91 women, with two blood samples collected approximately 6-years apart. Then, associations with breast cancer risk factors and risk were evaluated in 1,108 cases and 1,099 controls using a nested case–control design. In the serial study, mtDNA copy number showed low assay variation but large temporal variation [assay intraclass correlation coefficient (ICC), 79.3%–87.9%; temporal ICC, 38.3%). Higher mtDNA copy number was significantly associated with younger age at blood collection, being premenopausal, having an older age at menopause, and never taking HRT, both in cases and controls. Based on measurements in a single blood sample taken on average 6 years before diagnosis, higher mtDNA copy number was associated with increased breast cancer risk [OR (95% CI) for highest versus lowest quartile, 1.37 (1.02–1.83); P trend = 0.007]. In conclusion, mtDNA copy number is associated with breast cancer risk and represents a promising biomarker for risk assessment. The relatively large temporal variation should be taken into account in future analyses. Cancer Res; 75(14); 2844–50. ©2015 AACR.
Breast Cancer Cell–Derived GM-CSF Licenses Regulatory Th2 Induction by Plasmacytoid Predendritic Cells in Aggressive Disease Subtypes
Authors: Ghirelli Cristina , Reyal Fabien , Jeanmougin Marine , Zollinger Raphaël , Sirven Philémon , Michea Paula , Caux Christophe , Bendriss-Vermare Nathalie , Donnadieu Marie-Hélène , Caly Martial , Fourchotte Virginie , Vincent-Salomon Anne , Sigal-Zafrani Brigitte , Sastre-Garau Xavier , Soumelis Vassili
Published: May 2015

Reciprocal interactions between tumor cells and their microenvironment vitally impact tumor progression. In this study, we show that GM-CSF produced by primary breast tumor cells induced the activation of plasmacytoid predendritic cells (pDC), a cell type critical to anti-viral immunity. pDC that expressed the GM-CSF receptor were increased in breast tumors compared with noninvolved adjacent breast tissue. Tumor-activated pDC acquired naïve CD4+ T-cell stimulatory capacity and promoted a regulatory Th2 response. Finally, the concomitant increase of GM-CSF and pDC was significantly associated with relatively more aggressive breast cancer subtypes. Our results characterize the first tumor-derived factor that can activate pDC to promote a regulatory Th2 response, with implications for therapeutic targeting of a tumor-immune axis of growing recognition in its significance to cancer. Cancer Res; 75(14); 2775–87. ©2015 AACR.
Targeting Pancreatic Cancer Metastasis by Inhibition of Vav1, a Driver of Tumor Cell Invasion
Authors: Razidlo Gina L. , Magnine Christopher , Sletten Arthur C. , Hurley Rachel M. , Almada Luciana L. , Fernandez-Zapico Martin E. , Ji Baoan , McNiven Mark A.
Published: May 2015

Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48Cre/+, KrasG12D/+, p53F/+ mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors. Cancer Res; 75(14); 2907–15. ©2015 AACR.
Pharmacological Inhibition of β3 Integrin Reduces the Inflammatory Toxicities Caused by Oncolytic Adenovirus without Compromising Anticancer Activity
Authors: Browne Ashley , Tookman Laura A. , Ingemarsdotter Carin K. , Bouwman Russell D. , Pirlo Katrina , Wang Yaohe , McNeish Iain A. , Lockley Michelle
Published: May 2015

Adenoviruses have been clinically tested as anticancer therapies but their utility has been severely limited by rapid, systemic cytokine release and consequent inflammatory toxicity. Here, we describe a new approach to tackling these dangerous side effects. Using human ovarian cancer cell lines as well as malignant epithelial cells harvested from the ascites of women with ovarian cancer, we show that tumor cells do not produce cytokines in the first 24 hours following in vitro infection with the oncolytic adenovirus dl922-947. In contrast, dl922-947 does induce inflammatory cytokines at early time points following intraperitoneal delivery in mice with human ovarian cancer intraperitoneal xenografts. In these animals, cytokines originate predominantly in murine tissues, especially in macrophage-rich organs such as the spleen. We use a nonreplicating adenovirus to confirm that early cytokine production is independent of adenoviral replication. Using β3 integrin knockout mice injected intraperitoneally with dl922-947 and β3 null murine peritoneal macrophages, we confirm a role for macrophage cell surface β3 integrin in this dl922-947–induced inflammation. We present new evidence that co-administration of a cyclic RGD-mimetic–specific inhibitor of β3 integrin significantly attenuates the cytokine release and inflammatory hepatic toxicity induced by dl922-947 in an intraperitoneal murine model of ovarian cancer. Importantly, we find no evidence that β3 inhibition compromises viral infectivity and oncolysis in vitro or anticancer efficacy in vivo. By enabling safe, systemic delivery of replicating adenoviruses, this novel approach could have a major impact on the future development of these effective anticancer agents. Cancer Res; 75(14); 2811–21. ©2015 AACR.
Therapeutic Targeting of Anaplastic Lymphoma Kinase in Lung Cancer: A Paradigm for Precision Cancer Medicine
Authors: Katayama Ryohei , Lovly Christine M. , Shaw Alice T.
Published: May 2015

The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase was initially discovered as a component of the fusion protein nucleophosmin (NPM)–ALK in anaplastic large-cell lymphoma (ALCL). Genomic alterations in ALK, including rearrangements, point mutations, and genomic amplification, have now been identified in several malignancies, including lymphoma, non–small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, and others. Importantly, ALK serves as a validated therapeutic target in these diseases. Several ALK tyrosine kinase inhibitors (TKI), including crizotinib, ceritinib, and alectinib, have been developed, and some of them have already been approved for clinical use. These ALK inhibitors have all shown remarkable clinical outcomes in ALK-rearranged NSCLC. Unfortunately, as is the case for other kinase inhibitors in clinical use, sensitive tumors inevitably relapse due to acquired resistance. This review focuses on the discovery, function, and therapeutic targeting of ALK, with a particular focus on ALK-rearranged NSCLC. Clin Cancer Res; 21(10); 2227–35. ©2015 AACR.

See all articles in this CCR Focus section, “Progress in Lung Cancer.”
PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure
Authors: Huang Haishan , Pan Xiaofu , Jin Honglei , Li Yang , Zhang Lin , Yang Caili , Liu Pei , Liu Ya , Chen Lili , Li Jingxia , Zhu Junlan , Zeng Xingruo , Fu Kai , Chen Guorong , Gao Jimin , Huang Chuanshu
Published: May 2015

Purpose: The carcinogenic capacity of B[a]P/B[a]PDE is supported by epidemiologic studies. However, the molecular mechanisms responsible for B[a]P/B[a]PDE-caused lung cancer have not been well investigated. We evaluated here the role of novel target PHLPP2 in lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure.

Experimental Design: We used the Western blotting, RT-PCR, [35S]methionine pulse and immunohistochemistry staining to determine PHLPP2 downregulation following B[a]P/B[a]PDE exposure. Both B[a]PDE-induced Beas-2B cell transformation model and B[a]P-caused mouse lung cancer model were used to elucidate the mechanisms leading to PHLPP2 downregulation and lung carcinogenesis. The important findings were also extended to in vivo human studies.

Results: We found that B[a]P/B[a]PDE exposure downregulated PHLPP2 expression in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The ectopic expression of PHLPP2 dramatically inhibited cell transformation upon B[a]PDE exposure. Mechanistic studies showed that miR-205 induction was crucial for inhibition of PHLPP2 protein translation by targeting PHLPP2-3′-UTR. Interestingly, PHLPP2 expression was inversely associated with tumor necrosis factor alpha (TNFα) expression, with low PHLPP2 and high TNFα expression in lung cancer tissues compared with the paired adjacent normal lung tissues. Additional studies revealed that PHLPP2 exhibited its antitumorigenic effect of B[a]P/B[a]PDE through the repression of inflammatory TNFα transcription.

Conclusions: Our studies not only first time identify PHLPP2 downregulation by lung carcinogen B[a]P/B[a]PDE, but also elucidate a novel molecular mechanisms underlying lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. Clin Cancer Res; 21(16); 3783–93. ©2015 AACR.
Small Cell Lung Cancer: Will Recent Progress Lead to Improved Outcomes?
Authors: Pietanza M. Catherine , Byers Lauren Averett , Minna John D. , Rudin Charles M.
Published: May 2015

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: Nearly four decades after the introduction of a platinum–etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here. Clin Cancer Res; 21(10); 2244–55. ©2015 AACR.

See all articles in this CCR Focus section, “Progress in Lung Cancer.”
EGFR: The Paradigm of an Oncogene-Driven Lung Cancer
Authors: Riely Gregory J. , Yu Helena A.
Published: May 2015

Somatic, activating mutations in EGFR identify a significant minority of patients with non–small cell lung cancer (NSCLC). Although these mutations are associated with an approximately 70% response rate to some EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, and afatinib), patients develop resistance (i.e., “acquired resistance”) after a median of 9 to 12 months. In patients with clinical acquired resistance, repeat biopsy of tumors has identified a number of relevant mechanisms of resistance, but by far the most frequent event is the acquisition of EGFR T790M, a mutation in the “gatekeeper” residue that confers resistance to gefitinib, erlotinib, and afatinib. This emphasizes the critical dependence upon EGFR signaling for some tumors, a property that has been exploited therapeutically. Dual EGFR blockade using afatinib and cetuximab led to a 29% radiographic response rate. More recently, drugs that target EGFR T790M (e.g., rociletinib, AZD9291, and others) have entered clinical trials, with impressive results observed in phase I clinical trials. The development of these newer drugs, with efficacy after resistance to first-line EGFR tyrosine kinase inhibitor, has led to exploration of these strategies in multiple disease settings: at resistance, in the first line, and in adjuvant treatment of those with completely resected early-stage disease who would otherwise die of recurrent/metastatic disease. This example of translational research that identifies mechanisms of resistance to first-generation drugs, and then targets those mechanisms yielding clinical benefit, is a paradigm for how targeted therapies can be developed. Clin Cancer Res; 21(10); 2221–6. ©2015 AACR.

See all articles in this CCR Focus section, “Progress in Lung Cancer.”
Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells
Authors: Shen Kaikai , Xie Jianling , Wang Hua , Zhang Hong , Yu Mengyuan , Lu Fangfang , Tan Hongsheng , Xu Hongxi
Published: May 2015

Cambogin is a polycyclic polyprenylated acylphoroglucinol (PPAP) from the Garcinia genus, which has been used traditionally for cancer treatment across Southeastern Asia. In this study, we found that cambogin inhibited breast cancer cell proliferation and induced cell apoptosis in vitro. Cambogin induced the activation of the caspase-independent mitochondrial apoptotic pathway, as indicated by an increase in the ratio of Bax/Bcl-2 and the nuclear translocation of apoptosis inducing factor (AIF). Two-dimensional gel electrophoresis and mass spectrometry revealed that the expression of proteins involving in the radical oxygen species (ROS) pathway was among the most affected upon cambogin treatment. Cambogin enhanced cellular ROS production, and induced the activation of the ASK1–MKK4/MKK7–JNK/SAPK signaling pathway. Pretreatment with ROS scavenger N-acetylcysteine (NAC), an antioxidant, or the JNK inhibitor SP600125 was able to restore cell viability in the presence of cambogin. Importantly, cambogin treatment led to the activation of activating transcription factor-2 (ATF-2) and the trimethylation of histone H3K9 in the activator protein 1 (AP-1) binding region of the Bcl-2 gene promoter. Finally, cambogin exhibited a potential antitumor effect in MCF-7 breast cancer xenografts without apparent toxicity. Taken in conjunction, the present study indicates that cambogin can induce breast adenocarcinoma cell apoptosis and therefore represents therapeutic potential for cancer treatment. Mol Cancer Ther; 14(7); 1738–49. ©2015 AACR.
Abstract A23: Development and initial feedback about a human papillomavirus (HPV) vaccine comic book for adolescents
Authors: Katz Mira L. , Goodwin Jennifer , Reiter Paul L. , Ruffin Mack T. , Paskett Electra D.
Published: May 2015

Purpose. Adolescent human papillomavirus (HPV) vaccination rates do not meet the Healthy People 2020 goal of 80%, thus interventions to improve vaccination rates are needed. Focus groups of parents assisting in the development of an intervention to improve HPV vaccination rates suggested that an educational tool for young adolescents be included in the intervention. Parents recommended a comic book format, and provided input into the development of a theoretically-based story.

Methods. We conducted a pilot study to obtain initial feedback about a HPV vaccine comic book among parents (n=20) and their adolescents (ages 9 to 14) recruited from a community-based organization. Three adolescents did not participate because of lack of time, difficulty reading, and parental refusal. Parents completed a pre-post test including items addressing HPV knowledge, HPV vaccine attitudes, and about the content of the comic book. Adolescents (n=17) completed a brief interview after reading the comic book.

Results. After reading the comic book, HPV knowledge improved (2.7 to 4.6 correct answers on a 0-5 scale; p<0.01) and more positive attitudes toward HPV vaccination (p<0.05) were reported among parents. Most parents confirmed that the comic book's content was acceptable. Adolescents liked the story, found it easy to read, and thought the comic book was a good way to learn about being healthy.

Conclusions. Parents provided valuable information in the development of a theoretically-based comic book and the comic book appears to be an acceptable format for providing HPV vaccine information to young adolescents. A comic book format as an educational tool may provide important health information to adolescents. Future research will include the comic book in a study of an intervention to improve HPV vaccination rates among adolescents.

Citation Format: Mira L. Katz, Jennifer Goodwin, Paul L. Reiter, Mack T. Ruffin, IV, Electra D. Paskett. Development and initial feedback about a human papillomavirus (HPV) vaccine comic book for adolescents. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A23. doi:10.1158/1538-7755.DISP13-A23
Abstract A36: Community involvement in prevention research: A model for reducing cancer disparities
Authors: Parker Dorothy F. , Kelley Tracy , Thompson Eric , Kobetz Erin N.
Published: May 2015

This presentation describes a campus-community partnership established to address cancer disparities in a medically-underserved neighborhood within a large metropolitan urban area. Over the past several decades, the historically African American area has become increasingly isolated and disenfranchised due to demographic changes in surrounding communities. Pilot studies we conducted show higher than expected mortality rates from certain cancers, a high rate of behaviors that increase their risk for cancer (e.g., tobacco use), and a low rate of routine cancer screening and timely access to cancer treatment. As part of our university cancer center's cancer control and community research initiative to decrease local disparities, we created a network of Community Advisory Boards (CAB) throughout our catchment area. The CAB described here was developed to address documented cancer disparities in an area in close proximity to the university's medical campus. We identified community leaders and conducted 20 key informant interviews. With guidance from the CAB, we conducted a door-to-door survey of 250 randomly-selected households in a public housing development to assess community needs related to cancer and barriers to accessing services. A community-based participatory research (CBPR) model was used to engage the community and establish an economic partnership that benefits the community. Benefits include services and employment opportunities. Employing residents as research assistants has been found to maximize recruitment and community acceptance. To date, funded investigations have been conducted on the following: reducing the high prevalence of tobacco use, early detection of oral cancers using biomarkers, stress management for cancer survivors, and screening for conditions related to other chronic diseases such as diabetes. In addition, the university responded to request for services by conducting free annual health screening and education fairs and offering ongoing smoking cessation resources. We will discuss the successes and challenges of this partnership with a community that has minimal infrastructure but is motivated to improve the health of its residents. We will also describe how CAB members are taking ownership of the process and bringing additional resources to the table.

Citation Format: Dorothy F. Parker, Tracy Kelley, Eric Thompson, Erin N. Kobetz. Community involvement in prevention research: A model for reducing cancer disparities. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A36. doi:10.1158/1538-7755.DISP13-A36
Abstract A76: Poverty as a carcinogen
Authors: Osian Sarah Rausch , Samiian Laila , Kraemer Dale , Butterfield Ryan
Published: May 2015

Background: The breast cancer mortality rate for black women in Duval County, FL (greater Jacksonville, FL) is the highest in the state of Florida, and is 38% higher for black women (36.7 per 100,000), than for white women (24.0 per 100,000). We sought to evaluate county specific breast cancer data, in an effort to better understand the disparities, and to begin designing effective targeted interventions to reduce these disparities.

Methods: Data on female breast cancer cases from 2004-2010 were extracted using the Florida Cancer Data System (FCDS). This data was analyzed using traditional descriptive statistics. Additional classification included residence, race, insurance, and age. The primary outcomes were Stage at diagnosis, and time from diagnosis to treatment.

Results: Using the FCDS, 6,579 new breast cancers were identified in Duval County from 2004 – 2010. Of these women, 73% were white, 24% black, 5% Hispanic, 2% Asian, and 2% unknown/other. Initially, univariate analyses identified black race, living in the urban core, being uninsured or having Medicaid insurance as having the worst outcomes in percentage of Stage IV disease at diagnosis and longer times from diagnosis to treatment (p<.01). However, using advanced multivariate analyses, race was no longer significant, and living in the urban core, being uninsured or having Medicaid insurance became predictors for higher percentage of Stage IV disease at diagnosis, and longer times from diagnosis to treatment (p<.001).

Conclusion: Although initially black race was included as a significant predictor of poorer outcomes, advanced multivariate analyses revealed that living in the urban core, and lack of insurance or Medicaid funding was significantly associated with advanced stage at diagnosis and longer time from diagnosis to treatment in Duval County, Florida. Therefore, it seems that markers of poverty in Duval County, FL are better predictors of breast cancer disparities. These findings can inform targeted interventions to reduce the disparities in Duval County, FL.

Citation Format: Sarah Rausch Osian, Laila Samiian, Dale Kraemer, Ryan Butterfield. Poverty as a carcinogen. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A76. doi:10.1158/1538-7755.DISP13-A76
Abstract B60: Enhancing the chemopreventive effect by combining arctigenin and green tea polyphenol with curcumin in prostate and breast cancer cell
Authors: Wang Piwen , Wang Bin , Wu Yanyuan , Chung Seyung , Henning Susanne M. , Vadgama Jaydutt V.
Published: May 2015

The incidence and mortality rates of both prostate and breast cancer are much higher in African-American population compared to other races. Both cancers are typically diagnosed at a later age and subject to dietary factors and obesity. Therefore natural products may be an ideal option for chemoprevention to reduce cancer incidence particularly in the high-risk populations. However, the low bioavailability of most flavonoids limits their application as anti-carcinogenic agents in humans. A novel approach of treatment with a mixture of bioactive compounds in low physiologically achievable concentrations may resolve the limitations of reduced bioavailability. We therefore investigate whether a combination of three natural products arctigenin (Arc), a novel anti-inflammatory lignan from the seeds of Arctium lappa, green tea polyphenol (-)-epigallocatechin gallate (EGCG) and curcumin (Cur) increases the chemopreventive potency at low concentrations of individual compounds. LNCaP prostate cancer cells and MCF-7 breast cancer cells were treated with 2μg/mL Cur, 1μM Arc and 40μM EGCG alone or in combination for 48h. In both cell lines treatment with the mixture of Cur, Arc and EGCG increased the antiproliferative effect by 40% compared to Cur alone. In LNCaP cells both Arc and EGCG increased the pro-apoptotic effect of curcumin. Whereas in MCF-7 cells Arc increased the cell apoptosis of Cur while EGCG enhanced cell cycle arrest at G0/G1 phase. The strongest effects on cell cycle arrest and apoptosis in both cell lines were achieved by combining all three bioactive compounds. The combination treatments significantly increased the ratio of Bax to Bcl-2 proteins, decreased the activation of NFkB, PI3K/Akt and Stat3 pathways and cell migration compared to individual treatments. This study is anticipated to provide a novel, culturally acceptable, and cost-effective regimen to enhance chemoprevention of both prostate and breast cancer particularly in minority populations.

Citation Format: Piwen Wang, Bin Wang, Yanyuan Wu, Seyung Chung, Susanne M. Henning, Jaydutt V. Vadgama. Enhancing the chemopreventive effect by combining arctigenin and green tea polyphenol with curcumin in prostate and breast cancer cell. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B60. doi:10.1158/1538-7755.DISP13-B60
Abstract B79: Colonoscopy screening in a community sample of African Americans
Authors: Jefferson Melanie S. , Briggs Vanessa , Delmoor Ernestine , Johnson Jerry C. , Hughes-Halbert Chanita
Published: May 2015

Background: Colonoscopy is an efficacious strategy for reducing morbidity and mortality from colorectal cancer. Low utilization of colonoscopy contributes to racial disparities in colorectal cancer outcomes. Predictors of colonoscopy have been examined in clinical samples, but decisions about cancer screening are made in a multidimensional context that includes social, psychological, socioeconomic factors. Evaluating the association between colonoscopy utilization and multidimensional factors in a community-based sample is needed to understand how screening decisions are made in a community context.

Objectives: To evaluate the independent associations between social, psychological, socioeconomic, and clinical factors on colonoscopy use in a community-based sample of urban African American adults.

Methods: Participants were 236 African American men and women ages 50-75 who were enrolled in a community-based navigation program for cancer control. Data on colonoscopy use and socioeconomic (e.g., income), clinical (e.g., provider communication about colonoscopy), social (e.g., neighborhood satisfaction), and psychological factors (e.g., self-efficacy) were obtained by self-report during a baseline telephone interview that was completed prior to navigation.

Results: Overall, 58% of participants reported having a colonoscopy. Factors having significant independent associations with colonoscopy included older age (OR=1.15, 95% CI=1.07, 1.24, p=0.0002), greater neighborhood satisfaction (OR=1.86, 95% CI=1.05, 3.30, p=0.03), physician recommendation (OR=12.69, 95% CI=5.33, 30.20, p=0.0001), greater self-efficacy (OR=2.60, 95% CI=1.29, 5.24, p=0.01) and higher income (OR=2.70, 95% CI=1.35, 5.37, p=0.005). Participants with greater levels of present temporal orientation were also more likely to report having a colonoscopy compared to those with lower levels (OR=1.18, 95% CI=0.99, 1.41, p=0.06)

Conclusions: Colonoscopy is sub-optimal in a community-based sample of African Americans. In addition to psychological factors, participants who were more satisfied with their neighborhood conditions and those who had greater levels of present temporal orientation were likely to have a colonoscopy. Social and cultural factors may need to be addressed to enhance colonoscopy use among African Americans.

Citation Format: Melanie S. Jefferson, Vanessa Briggs, Ernestine Delmoor, Jerry C. Johnson, Chanita Hughes-Halbert. Colonoscopy screening in a community sample of African Americans. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B79. doi:10.1158/1538-7755.DISP13-B79
Abstract B89: Timeliness in follow-up after abnormal mammography screening among Asian groups
Authors: Nguyen Kim H. , Karliner Leah , Pasick Rena J.
Published: May 2015

Background: Treatment of breast cancer at the earliest possible stage results from a combination of screening for non-palpable abnormalities and timely and appropriate follow-up of abnormal test results. Studies have addressed Black-White differences in follow-up of abnormal mammograms but little is known about other groups including Asian Americans, a population composed of distinct ethnic sub-groups with substantial heterogeneity in risk factors that correspond with important to differences in breast cancer rates. In this study we aimed to assess completion and timeliness of diagnostic follow-up after an abnormal mammogram between White and Asian women and among disaggregated Asian ethnic subgroups. Methods: Using data from the San Francisco Mammography Registry, we identified women with an index abnormal screening mammogram result of BIRADS 0/3+ between the years 2000-2010. Our study sample included women who self-report White or Asian race/ ethnicity, ages 40 and older. Our outcomes were: 1) proportion of women without diagnostic follow-up within a year of their index mammogram, and 2) median days to diagnostic follow-up. Results: We identified 54028 White and Asian women between 2000 and 2010 in the SFMR data. Seventy percent of women were White and 30% were Asians. Among Asians, 16.2% were Chinese, 6.7% Filipina, 1.8% Japanese, 1.1% Vietnamese, 2.4% Other Asian, and 1.4% Mixed Asian. The majority of women were between the ages of 40-59 (67%). A total of 6023 (11.1%) of women did not receive follow-up within one year after an index abnormal mammogram. A higher proportion of Asian women did not receive follow-up compared to Whites (15% vs 10%). Among Asian groups, Filipinas had the highest percentage of women not receiving follow-up (18%) while Japanese women had the lowest (10.4%). In comparisons of individuals who received follow-up to those who did not, a higher proportion of women with no follow-up had lower education levels (24% vs 15%). Median time to diagnostic follow-up for White and Asian women combined was 18 days. The median follow-up time was 15 days for Whites, and 26 days for Asians. Among Asians, the median follow-up time differed significantly among ethnic groups: Japanese women had the lowest (19 days) and Vietnamese women the longest (30 days) followed by Filipinas (28 days). Conclusion: We observed disparities in timeliness to follow-up between White and Asian women and among Asian ethnic groups. Disaggregation of ethnicity can identify subpopulations most in need of breast cancer control, and to provide more specific information on breast cancer patterns.

Citation Format: Kim H. Nguyen, Leah Karliner, Rena J. Pasick. Timeliness in follow-up after abnormal mammography screening among Asian groups. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B89. doi:10.1158/1538-7755.DISP13-B89