tbuckley/cabot-search huggingface dataset:
Use of gene expression signature to predict response to combination chemotherapy in breast cancer clinical subgroups.
Authors: K. Martin, D. Magee, M. Fournier
Journal: Journal of Clinical Oncology (2011)

e21071 Background: Accurate stratification of patients prior to treatment with combination chemotherapy would allow non-responders to receive an alternative treatment in a timely manner and potentially improve clinical outcomes. We describe a 22-gene signature that accurately predicts response to antimitotic combination chemotherapy for breast cancer. This signature was selected in a well characterized system that models a key step disrupted in tumorigenesis: the formation of spatially accurate mammary ductal units by breast epithelial cells. Hence the 22 genes represent a biological process that is independent of any specific patient set or predefined clinical classification. Methods: To determine whether genes with differential expression during human mammary acinar morphogenesis predict response to combination chemotherapy in breast cancer, we have analyzed results from two published microarray datasets (Fournier, et al., 2006; Popovici et al., 2010). Expression levels of the majority of genes that were coordinately down regulated during acini formation were significantly associated with response to combination chemotherapy treatment. A 22-gene signature representing the down regulated genes was evaluated independently in each of three breast cancer clinical subgroups, ER-positive (n=146), HER2-positive (n=41), and triple negative (n=90) using two methods of analysis, hierarchical clustering and logistic regression. Results: Hierarchical cluster analysis results showed that the 22 genes accurately stratified patients in each of the three subgroups by response (Fisher’s Exact p<0.05). Logistic regression with 3-fold cross validation demonstrated that different models accurately predicted response in these subgroups (AUC ≥0.7). We have observed that the 22-gene signature is broadly effective across independent patient clinical subgroups in its ability to stratify patients according to chemotherapy response in breast cancer. Conclusions: The 22-gene signature has the potential to provide patients, early in the care process, with accurate and personalized information to predict response to combination chemotherapy.
Abstract 3425: Overexpression of TRIM44 contributes to malignant outcome in upper GI tract cancer
Authors: Tsutomu Kawaguchi
Journal: Cancer Research (2015)

Abstract Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family, which function as important regulators for carcinogenesis. In this study, we tested whether TRIM44 (11p13) acts as a cancer-promoting gene through overexpression in gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC). We analyzed 7 GC and 14 ESCC cell lines for in vitro analysis. We also analyzed 113 GC and 68 ESCC primary tumors, which were curatively resected in our hospital between 1998 and 2008. As the results, expression of the TRIM44 protein was detected in GC and ESCC cell lines (2/7 cell lines; 29% and 8/14; 57%, respectively) and primary tumor samples of GC and ESCC (24/113 cases; 24% and 39/68; 57%, respectively). Knockdown of TRIM44 expression using several specific siRNAs inhibited cell proliferation and migration and invasion in TRIM44-overexpressing GC cell, and inhibited cell migration and invasion in TRIM44-overexpressing ESCC. Using immunohistochemical analysis, overexpression of the TRIM44 was significantly correlated with an advanced type of macroscopic appearance, lymphatic invasion, and higher recurrence rate in GC, and with the status of the lymph node metastasis in ESCC. TRIM44-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors in GC and ESCC tumors. Moreover, TRIM44 positivity was independently associated with worse outcome in multivariate analysis in GC tumors. These findings suggest that TRIM44 plays a crucial role in tumor progress through its overexpression, and highlight its usefulness as a novel predictor and potential therapeutic target in GC and ESCC. Citation Format: Tsutomu Kawaguchi. Overexpression of TRIM44 contributes to malignant outcome in upper GI tract cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3425. doi:10.1158/1538-7445.AM2015-3425
Abstract 5585: Analysis of saliva samples from healthy adults in north central Florida for human papillomavirus infection
Authors: Michelle M. Hwang, Hyun-Ji Choi, Taimour Y. Langaee, Henrietta L. Logan, Kevin P. Raisch
Journal: Cancer Research (2015)

Abstract Background: Prevalence rates of healthy adults shedding HPV in their saliva have varied depending on the socio-economical status of the subjects. We hypothesize that samples collected from high-poverty and low-education areas of North Central Florida will have a high prevalence of HPV positive subjects. From published studies, we would expect an infection rate of 2-10% with male and female rates being similar. Methods: Through health fairs in North Central Florida, we consented and collected saliva from 148 healthy adults. Of the 148 study samples, 64% were between age 18-60 and 22% were above age 60. 32% of the saliva samples were from males and 68% were from females. Dividing the saliva samples by race, we had 41% white, 51% African American. DNA was isolated from the saliva samples and PCR was used to amplify HPV-specific DNA. Degenerate PCR primers were used for the PCR and sequencing the amplicons. All DNA samples were coded so the investigators do not know the identity of the samples until completion of all experiments. Results: We optimized the degenerate primer sets, MY09/MY11 and GP5+/GP6+, for magnesium concentration and annealing temperature. In addition we optimized a nested PCR using the degenerate primers to increase the sensitivity of HPV detection. From our direct DNA sequence analysis, we identified 10/148 (7%) HPV-positive samples. HPV-types found include: 16, 12, 32, 38, 61, 83, 72, 90, and 110. The inclusion of the primer set GP5+/GP6+ with MY09/11 resulted in an increase of total HPV-positivity from 5% to 7% and the detection of high-risk HPV types 32 and 90. Of the HPV-positive saliva samples, 9% were from 18-60 year old healthy adults and 3% were from over 60-year old adults. Adult females had a similar infection rate as adult males, 7% vs. 6%. Upon comparing race, African Americans were slightly more likely to be infected than whites, 7% vs. 5%. Of the 10 adults with detectable virus in their saliva, 70% were of the high risk HPV type. Conclusion: Our sample size was small but showed an overall infection rate of healthy adults to be similar to rates found in other studies. In our study, male and females had similar infection rates. The age 60 and younger group were found to be three times more likely to be infected than the older than age 60 group. We found no significant difference between race in our study. Citation Format: Michelle M. Hwang, Hyun-Ji Choi, Taimour Y. Langaee, Henrietta L. Logan, Kevin P. Raisch. Analysis of saliva samples from healthy adults in north central Florida for human papillomavirus infection. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5585. doi:10.1158/1538-7445.AM2015-5585
202. Development of T-Cells Carrying Two Complementary Chimeric Antigen Receptors Against GPC3 and ASGR1 for the Treatment of Hepatocellular Carcinoma
Authors: Zonghai Li, Cheng Chen, Kesang Li, Hua Jiang, Huiping Gao, Fei Song, Xiaorong Pan, Bizhi Shi, Yanyu Bi, Bo Song
Journal: Molecular Therapy (2016)

Recently, we reported that GPC3-targeted CAR-T cells could eradicate hepatocellular carcinoma xenografts in mice. However, we do not know whether on-target off-tumor toxicity, a major toxicity associated with CAR-T cells will happen when using these GPC3-CAR T cells in human being. We propose that dual-targeted CAR-T cells co-expressing a GPC3- and a ASGR1 (a liver tissue-specific protein)-targeted CAR that signal using CD3ζ and 28BB (containing both CD28 and 4-1BB signaling domain) respectively might be used to reduce on-target off-tumor toxicity. We first demonstrated that GPC3 and ASGR1 were co-expressed in 54.7% of the tested HCC samples. We further demonstrated that dual-targeted CAR-T cells could exhibit no cytotoxic activities on ASGR1+GPC3− tumor cells. However, the cytotoxic activities of GPC3-targeted CAR-T cells and dual-targeted CAR-T cells have similar anti-tumor activities in vitro on ASGR1-GPC3+ or GPC3+ASGR1+HCC cells. Interestingly, dual-targeted CAR-T cells showed significantly higher cytokine secretion, proliferation and anti-apoptosis ability against tumor cells bearing both antigens in vitro than single-targeted CAR-T cells. Furthermore the dual-targeted CAR-T cells displayed potent growth suppression activity on GPC3+ASGR1+HCC tumor xenograft while no obvious growth suppression on single or double antigen-negative tumor xenografts. Additionally, the dual targeting T cells exerted superior anti-cancer activity and persistence than single targeting T cells in two GPC3+ASGR1+ HCC xenograft models. Together, T-cells carrying two complementary CARs against GPC3 and ASGR1 might reduce the risk of on-target off-tumor toxicity while remain relative potent anti-tumor activities on GPC3+ASGR1+ HCC
Abstract 5043: ERβ decreases the invasiveness of triple-negative breast cancer cells by regulating mutant p53 gain-of-function
Authors: Igor Bado, Fotis Nikolos, Gayani Rajapaksa, Jan-Ake Gustafsson, Christoforos Thomas
Journal: Cancer Research (2015)

Abstract Triple-negative breast cancers (TNBCs) display distinct metastatic potential and a poor prognosis despite a relative chemosensitivity. Most (80%) of these highly aggressive tumors express mutant p53 proteins that are known to elicit oncogenic activities that contribute to metastasis and chemoresistance. Despite the lack of estrogen receptor α (ERα), TNBCs express wild-type ERβ (ERβ1). We previously showed that ERβ1 impedes epithelial to mesenchymal transition (EMT) in TNBC cells by repressing epidermal growth factor receptor (EGFR) signaling. Our recent findings indicate that ERβ1 regulates EGFR expression and decreases the invasiveness of TNBC cells by interacting with mutant p53 and inhibiting its function. Suppression of a mutant p53 transcriptional program and induction of p63 activity are essential for the anti-migratory activity of ERβ1 in TNBC cells. These results describe an ERβ1/mutant p53 interaction that disturbs oncogenic signals to inhibit aggressiveness in TNBC. Citation Format: Igor Bado, Fotis Nikolos, Gayani Rajapaksa, Jan-Ake Gustafsson, Christoforos Thomas. ERβ decreases the invasiveness of triple-negative breast cancer cells by regulating mutant p53 gain-of-function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5043. doi:10.1158/1538-7445.AM2015-5043
166. Biophysical Characterization and Direct Delivery of S. Pyogenes Cas9 Ribonucleoprotein Complexes
Authors: William Selleck, Grant Welstead, Justin Fang, McKensie Collins, David Bumcrot, Hari Jayaram
Journal: Molecular Therapy (2015)

Several groups have demonstrated efficient genome editing in various mammalian cells by cationic lipid mediated delivery of purified Cas9 protein complexed with in-vitro translated or chemically synthesized guide-RNA (gRNA). Such "direct delivery" of the Cas9 ribonucleoprotein (RNP) complex allows for efficient gene-editing while minimizing off-target activity owing to the rapid turnover of the Cas9 protein in cells. Efficiency of gene-editing mediated by RNP delivery varies by locus, depends on the length of guide-RNA and on the amount and ratio of Cas9 protein and gRNA delivered. The Cas9 complex with gRNA has been well characterized structurally and biophysically revealing a large contact area and a high affinity. Thermal melt curves are a useful property to detect the binding and stability of complexes. We have used the large increase in the melting temperature from apo-Cas9 to the Cas9 complexed with gRNA to characterize the affinity of Cas9 for gRNA. Multiple gRNAs with differing lengths were complexed with Cas9 at differing stoichiometries and the tightness of the interaction was measured using thermal shift. These biophysically characterized complexes were then transfected into 293T cells and the efficiency of indel generated was measured. We have found that subtle differences in the gRNA length and base composition affect the binding and formation of RNP complex. Correlating binding affinity with efficiency of genome editing informs the design of an optimal composition of RNPs for cationic lipid mediated direct delivery.
The impact of sugared drink taxation and industry response
Authors: Lennert Veerman
Journal: The Lancet Public Health (2016)

In The Lancet Public Health, Adam Briggs and colleagues1 explore the possible health impact of the tiered levy on sugar-sweetened beverages (SSBs) that was proposed by the UK Government in March, 2016.2 The focus in their analysis is on the response by the food industry. Food and drink companies could pass the tax onto consumers, reduce the sugar content of their products to reduce the amount of tax due, or increase promotion of low-sugar drinks at the expense of that for high-sugar varieties. The authors find that reformulation offers the largest potential for health improvements in terms of numbers of individuals with obesity, new diabetes cases, and tooth decay.
Full Haplotype Mismatch Stem Cell Transplantation: Myeloablative with T-Cell Depletion Vs. Reduced Intensity Conditioning without T-Cell Depletion
Authors: Heeje Kim, Woo-Sung Min, Ki-Seong Eom, Byung-Sik Cho, Seung-Ah Yahng, Sung-Eun Lee, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Jong-Wook Lee, Chong-Won Park
Journal: Blood (2010)
Targeting Rac2 - Mitochondrial Respiratory Chain Complex III Signaling to Prevent Genomic Instability in Leukemia Stem and Progenitor Cells
Authors: Margaret Nieborowska-Skorska, Piotr Kopinski, Regina Ray, Grazyna Hoser, Danielle Ngaba, Sylwia Flis, Kimberly Cramer, Mamatha M. Reddy, Mateusz Koptyra, Tyrone Penserga, Eliza Glodkowska-Mrowka, Magdalena Ambrozek, Ilona Seferynska, Joanna Niesiobedzka-Krezel, Elisabeth Bolton, Artur Slupianek, Tessa L. Holyoake, Connie J. Eaves, Sabine Cerny-Reiterer, Peter Valent, Andreas Hochhaus, Timothy P. Hughes, Heiko van der Kuip, Martin Sattler, Wieslaw Wiktor-Jedrzejczak, Christine Richardson, Adrienne M. Dorrance, Tomasz Stoklosa, David A. Williams, Tomasz Skorski
Journal: Blood (2011)
Network-guided modeling allows tumor-type independent prediction of sensitivity to all-trans-retinoic acid
Authors: M. Bolis, E. Garattini, G. Paroni, A. Zanetti, M. Kurosaki, T. Castrignanò, S.K. Garattini, F. Biancardi, M.M. Barzago, M. Gianni’, M. Terao, L. Pattini, M. Fratelli
Journal: Annals of Oncology (2016)
P288 Copd patients with varying severity of airflow limitation achieve highest peak inspiratory flow rate via the breezhaler® inhaler compared to the ellipta® or the handihaler® dry powder inhalers
Authors: P Goyal, L Wehbe, J Dederichs, T Guerin, MC Moronta, AV Pino, K Kostikas, P Altman
Journal: Thorax (2016)

<h3>Background and aim</h3> Chronic and progressive nature of COPD necessitates the patients to regularly self-administer inhaled medication. Inhalation effort required and flow rates achieved through DPIs, are some of the important considerations while selecting dry power inhalers (DPIs). Here, we present the comparison of the peak inspiratory flow (PIF) rates achieved by COPD patients, with varying degrees of airflow limitation, through three types of DPIs (Breezhaler®, Ellipta® and HandiHaler®). We also assessed the effect of severity of airflow limitation on PIF rates. <h3>Methods</h3> This randomised, open-label, multicentre and cross-over study recruited patients with moderate-to-very severe airflow limitation (GOLD 2014) aged ≥40 years with a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. After training the patients on correct use, inhalation flow profiles of patients were recorded using pressure tapped inhalers attached to a pressure transducer. For each patient, the inhalation profile with the highest PIF rate, out of three replicate inhalations per device, was selected for analysis. The primary analysis was based on the per-protocol set comprising 93 patients who completed all three inhalations per device. A paired t-test was performed to compare PIF means between each combination of devices. <h3>Results</h3> In total, 97 COPD patients were randomised, of whom 96 completed the study and 93 patients (per-protocol set) were included in the analysis. The highest mean PIF rate (L/min ± SE) was observed with the Breezhaler® (107.5 ± 2.4), followed by the Ellipta® (80.0 ± 2.2) and the HandiHaler® (53.6 ± 2.1), in all patients (patients with moderate-to-very severe airflow limitation). The mean PIF rate (L/min) achieved via the Breezhaler® was higher vs the Ellipta® (mean difference[Δ] = 27.7; p &lt; 0.0001) and also vs the HandiHaler® (Δ = 53.9; p &lt; 0.0001). Also, when assessed by severity of airflow limitation, the Breezhaler® device exhibited significantly higher PIF rate vs the Ellipta® and vs the HandiHaler® (Table). <h3>Conclusions</h3> COPD patients with varying degree of airflow limitation (moderate-to-very severe COPD) achieved the highest PIF rates via the Breezhaler® compared with the Ellipta® or the HandiHaler® inhaler.
Abstract 4332: Evaluation of arachidonic acid pathways with prognosis in patients with surgically resected non-small cell lung cancer
Authors: Yinghao Su, Ming-Zhi Zhang, Wanqing Wen, Wei Zheng, Rosana Eisenberg, Pierre P. Massion, Qiuyin Cai
Journal: Cancer Research (2015)

Abstract Background: Arachidonic acid (ARA) is a polyunsaturated fatty acid present in the phospholipids of cell membranes. ARA is metabolized through two major pathways, cyclooxygenase (COX) and lipoxygenase (LOX), resulting in various biologically active eicosanoids, such as prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids. Cumulative evidence from both in vitro and animal studies suggests that COX and LOX pathways may be involved in the development and progression of lung cancer by regulating multiple biological processes. However, no direct evidence exists to connect key enzymes of COX and LOX pathways with prognosis of non-small cell lung cancer (NSCLC). We conducted a study to evaluate the association of protein expression of major enzymes in the COX and LOX pathways with prognosis of NSCLC. Materials and Methods: Included in the study are 98 patients with surgically resected NSCLC. The archived paraffin-embedded tumor tissue blocks were retrieved, and tissue microarray were constructed with at least two cores for most cases. Clinical data were obtained from medical records. Expression levels of COX-2, 12-LOX, 15-LOX-1, 15-LOX-2, 5-LOX activating protein (FLAP), and 11β-hydroxysteroid dehydrogenase type I (11βHSD1) and type II (11βHSD2) were evaluated immunohistochemically. Odds ratios (OR) of death were estimated using logistic regression models with adjustment for age at diagnosis, BMI, smoking status, and tumor stage. Results: All seven assayed markers were significantly correlated with one another (r = 0.299 - 0.658, P &amp;lt; 0.01). We observed that a higher level of COX-2 protein expression was associated with advanced tumor stage (P = 0.026). A higher level of 15-LOX-1 protein expression was associated with significantly increased risk of death (OR = 3.27, 95% CI 1.01 - 10.5, P = 0.048) and a higher level of 11βHSD1 protein expression was associated with a marginally significant increased risk of death (OR = 2.67, 95% CI 0.86 - 8.31, P = 0.089). No association of other markers with lung cancer death was found. Conclusions: 15-LOX-1 and 11βHSD1 may be prognostic markers for NSCLC. Validation of the findings in an independent patient cohort is warranted. Citation Format: Yinghao Su, Ming-Zhi Zhang, Wanqing Wen, Wei Zheng, Rosana Eisenberg, Pierre P. Massion, Qiuyin Cai. Evaluation of arachidonic acid pathways with prognosis in patients with surgically resected non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4332. doi:10.1158/1538-7445.AM2015-4332
Abstract 2604: Preclinical anti-tumor efficacy and mode of action of a novel, orally available, selective MKNK1 inhibitor [BAY 1143269]
Authors: Susann Santag, Franziska Siegel, Antje Margret Wegner, Claudia Schneider, Ulf Boemer, Knut Eis, Florian Puehler, Martin Michels, Franz von Nussbaum, Karl Ziegelbauer, Dominik Mumberg, Kirstin Petersen
Journal: Cancer Research (2015)

Abstract MKNK1 (MAP kinase-interacting serine/threonine-protein kinase, also known as Mnk1) is activated by the mitogen-activated protein kinases ERK1/2 and p38. Thus, MKNK1 signaling is involved in the cellular response to environmental stress factors and cytokines. Of particular interest, MKNK1 kinase was shown to regulate mRNA translation by phosphorylating the translation initiation factor eIF4E (eukaryotic translation initiation factor 4E), known to be critical for malignant transformation but dispensable for translation in normal cells. In addition, MKNK is involved in resistance mechanisms to cancer therapeutics. Thus, the inhibition of MKNK1 activity may provide an innovative approach for anti-cancer therapy. BAY 1143269 was identified as a potent and selective inhibitor of MKNK1 activity with an unprecedented mode of action. It inhibits the phosphorylation of eIF4E in various cancer cell lines in vitro and leads to reduced expression of MKNK-regulated translational downstream targets, including survivin, Cdc25C and cyclin B1. In addition, BAY 1143269 potently inhibits cytokine release in LPS stimulated human blood. In vivo, BAY 1143269 shows a significant monotherapy efficacy in non-small cell lung cancer (NSCLC), colorectal cancer and melanoma xenograft models after an once daily, oral application of 200 mg/kg in mice and 70 mg/kg in rats. Furthermore, combination treatment with chemotherapy and BAY 1143269 gives additive efficacy in several NSCLC cell lines and patient-derived xenograft models leading to partial response (Lu7558, A549), stable disease (Lu7187, Lu7166) or significant delay in tumor re-growth versus chemotherapy alone after stop of treatment (Lu7558). In summary, BAY 1143269 is a selective, orally available MKNK1 inhibitor that demonstrates preclinical in vivo efficacy in mono- and combination therapy and may provide therapeutic benefit for patients with solid tumors. Citation Format: Susann Santag, Franziska Siegel, Antje Margret Wegner, Claudia Schneider, Ulf Boemer, Knut Eis, Florian Puehler, Martin Michels, Franz von Nussbaum, Karl Ziegelbauer, Dominik Mumberg, Kirstin Petersen. Preclinical anti-tumor efficacy and mode of action of a novel, orally available, selective MKNK1 inhibitor [BAY 1143269]. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2604. doi:10.1158/1538-7445.AM2015-2604