tbuckley/cabot-search huggingface dataset:
Abstract 896: miR-198 silencing is a mechanism of gemcitabine resistance in human pancreatic adenocarcinoma.
Authors: Olorunseun O. Ogunwobi, Jian Li, Xiangxuan Zhao, Jose Trevino, Thomas George, Chen Liu
Journal: Cancer Research (2013)

Abstract Pancreatic adenocarcinoma (PAC) is a very aggressive disease with extremely high mortality rate. Chemotherapy with gemcitabine (G) is a standard of care for advanced disease, but chemotherapy resistance is commonly noted. Human PAC is characterized by overexpression of the proto-oncogene c-met. Increased activation of c-met has been reported in G-resistant PAC cells. Also, aberrant expression of microRNAs (miRNAs) has been linked to cancer progression. Furthermore, a recent study showed that miR-198 regulates c-met expression by binding to the 3′-untranslated region of c-met mRNA. However, the role of miR-198 in chemotherapy resistance in PAC has not previously been studied. Consequently, in this study we used the G-sensitive and G-resistant subclones of the L3.6pl human PAC cell line to examine the role of miR-198 in G-resistant PAC. We observed that the G-resistant subclone had increased expression of c-met (using qPCR and western blotting) and phosphorylated c-met (using western blotting), but not hepatocyte growth factor (HGF). Furthermore, using qPCR we observed significant silencing of miR-198 expression in the G-resistant subclone in comparison to the G-sensitive subclone (P &amp;lt; 0.01). To determine the functional significance of miR-198 silencing in G resistance, we silenced miR-198 expression in the G-sensitive subclone by transfection of a specific oligonucleotide inhibitor of miR-198. We observed that miR-198 silencing resulted in increased expression of c-met and phosphorylated c-met. Further, miR-198 silencing on its own increased total RNA concentration significantly by 146% (P &amp;lt; 0.05) and cell viability by 14.3% (P &amp;lt; 0.05; using MTT assay), both suggestive of a proliferative effect. However, significant effects on apoptosis were undetectable (using Hoechst nuclear staining). Furthermore, miR-198 silencing significantly abrogated G-induced apoptosis (P &amp;lt; 0.05) and G-induced reduction of cell viability (P &amp;lt; 0.05). We conclude that G-resistant human PAC cells have silencing of miR-198. Moreover, miR-198 silencing in PAC cells induces increased expression and phosphorylation of c-met, increased cell proliferation and abrogation of G-induced apoptosis and induction of proliferation. Therefore, miR-198 silencing is a mechanism of G-resistance in PAC. Furthermore, therapeutic strategies to enhance miR-198 expression may be beneficial in PAC. Citation Format: Olorunseun O. Ogunwobi, Jian Li, Xiangxuan Zhao, Jose Trevino, Thomas George, Chen Liu. miR-198 silencing is a mechanism of gemcitabine resistance in human pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 896. doi:10.1158/1538-7445.AM2013-896
AB0300 Efficacy of rituximab in the treatment of rheumatoid arthritis in moroccan patients tnf alpha inhibitor-naive: a prospective study
Authors: A. Watik, W. Rachidi, S. Janani, O. Mkinsi
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The emergence of publications about the role of B cells in the immunopathogenesis of rheumatoid arthritis (RA) has generated interest in the use of rituximab to treat RA. Several studies have demonstrated the efficacy of rituximab in the treatment of RA after the failure of the TNFα inhibitor. <h3>Objectives</h3> The purpose of this study was to evaluate the response to this treatment in rheumatoid arthritis Moroccan patients TNFα inhibitors-naive. <h3>Methods</h3> We prospectively studied in our rheumatology Clinic in Morocco the outcome of thirty-one patients with RA TNFα inhibitors-naive confirmed on ACR / EULAR new criteria. One thousand milligrams (1000 mg) of rituximab was administered twice at an interval of 15 days. Therapeutic response was determined at mean 20 weeks after the infusion on the basis of DAS28 scores and EULAR response criteria. <h3>Results</h3> Thirty-one patients were included in the study, a mean age of 49.1(± SD 8.27) years, 85% were EULAR responders. There was no significant difference in EULAR response between patients treated with rituximab and MTX (71.8%) and those who had received rituximab alone (76.5%). The mean of interval to retreatment is 34.3 weeks; However, interval to retreatment was significantly shorter in TNF inhibitor-naive patients treated with rituximab alone (<i>P</i> = 0.01). Lastly, a significant difference (<i>P</i> = 0.02) in EULAR response rate was observed between rheumatoid factor(RF)-positive patients (81.8%) and RF-negative patients (63.9%). Interval to retreatment was also significantly shorter in RF-negative patients. <h3>Conclusions</h3> Our results of efficacy of rituximab appear to be consistent with those published in the literature. Even if the number of patients is small, our study is original because is the first in Morocco to evaluate the response to rituximab in patients with RA TNFα inhibitor-naive. <h3>Disclosure of Interest</h3> None Declared
The Role of Tonsils in Predisposing to Streptococcal Infections and Recurrences of Rheumatic Fever
Authors: Alvan R. Feinstein, Muriel Levitt
Journal: New England Journal of Medicine (1970)

The size of tonsils in 532 children and adolescents, all with previous attacks of rheumatic fever, was correlated with the subsequent development of streptococcal infections and rheumatic recurrences, as noted in monthly or bimonthly examinations. The size of tonsils did not significantly affect the incidence of infections or of rheumatic recurrences in patients who maintained good continuity of antistreptococcal prophylaxis. In patients who did not maintain good prophylaxis (an analogue of the situation in the preantibiotic era), an increasing size of tonsils was associated with significant increases in the rates of streptococcal infection and of rheumatic recurrence. The rising gradient in attack rates for increasing size of tonsils persisted even when patients were stratified according to age and cardiac status. The size of the tonsils did not affect the types of symptoms produced by streptococcal infections. These data support both the old and the new beliefs about the role of tonsils, and of prophylactic medication in preventing streptococcal infections in patients who have had rheumatic fever.
P979 NEUTROPHIL-TO-LYMPHOCYTE RATIO IS A PREDICTOR OF ONE-YEAR SURVIVAL IN PATIENTS WITH HEPATOCELLULAR CARCINOMA RECEIVING SORAFENIB
Authors: A. Luè, F.J. Bustamante, M. Iñarrairaegui, J.I. Arenas, M.T. Serrano, M. Testillano, S. Lorente, C. Gil, M. De la Torre, A. Gómez, B. Sangro
Journal: Journal of Hepatology (2014)
Abstract 891: Association of genetic polymorphisms of SIPA1 with breast cancer risk and survival among Chinese women
Authors: Shimian Qu, Hui Cai, Jirong Long, Qiuyin Cai, Regina Courtney, Xiao-Ou Shu, Yu-Tang Gao, Wei Zheng
Journal: Cancer Research (2010)

Abstract Signal-induced proliferation-associated gene 1 (Sipa1), encodes a GTPase-activating protein (GAP), was identified as a candidate host metastasis-regulatory factor in mice. Several epidemiological studies have shown that SIPA1 may play an important role in breast cancer risk and metastasis with inconsistent results. We evaluated functional single nucleotide polymorphisms (SNPs) in SIPA1 in relation to breast cancer risk and survival in Chinese women. Included in the study were 1,134 cases and 1,234 age frequency-matched community controls that participated in the Shanghai Breast Cancer Study, a large scale population-basd case-control study. Breast cancer patients were followed to determine intervals of overall survival and disease-free survival. Functional SNPs were genotyped using TaqMan assays. Additional SNPs in this gene region, both genotyped and imputed from a genome-wide association study, were also included in the analyses. The SIPA1 polymorphisms were not associated with breast cancer risk. We found SIPA1 polymorphisms were associated with breast cancer overall survival. Patients carrying the GA/AA genotypes in the synonymous exonic SNP rs746429 were associated with a marginally significant poor overall survival (HR =1.2, 95% CI, 0.9-1.6) as compared with the common GG genotype. Furthermore, this association was more evident among patients with an early stage cancer (HR =1.4, 95% CI, 1.0-1.9) than those with a late stage cancer (HR=1.2, 95% CI, 0.7-2.1). Patients carrying the AA genotype of rs3741378, a nonsynonymous exonic SNP, were associated with a better overall survival (HR =0.6, 95% CI, 0.4-1.0) as compared to those with the common GG genotype. We found that the SIPA1 polymorphisms were not associated with disease-free survival. Our findings suggested that common SIPA1 genetic polymorphisms may be associated with breast cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 891.
Abstract LB-28: RAF inhibitors activate MAPK pathway through relief of RAF auto-inhibition
Authors: Matthew Holderfield, Hanne Merritt, John Chan, Marco Wallroth, Laura Tandeske, Steve Hardy, Mohammad Hekmat-Nejad, Frank McCormick, Tobi Nagel
Journal: Cancer Research (2011)

Abstract Mutations in the RAS/RAF/MEK/ERK pathway are among the most common in human cancers, and RAF small molecule kinase inhibitors are now being tested for the treatment of BRAFV600E tumors, with promising initial results. However, both clinical and pre-clinical data indicate that selective RAF inhibitors have poor efficacy in wildtype BRAF tumors. Moreover, these inhibitors actually promote phosphorylation of downstream targets, MEK and ERK when wildtype RAF is activated by upstream components of the pathway. Here, we show that biochemical activation of wildtype BRAF and CRAF by selective RAF inhibitors is exquisitely sensitive to ATP concentrations in an in vitro kinase assay. While BRAFV600E kinase activity remains high at ATP concentrations in excess of 1mM, wildtype BRAF and CRAF reach maximum kinase velocity at ∼1–10 mM ATP and are inhibited by more than 80% in the presence of 1mM ATP. Selective small molecule RAF inhibitors block the ATP concentration dependent inhibition of wildtype RAF, demonstrating that inhibition requires RAF kinase activity and suggests RAF auto-phosphorylation. Furthermore, while in its auto-inhibited state, wildtype RAF kinase activity cannot be increased by RAF inhibitors, but is rather decreased in a dose dependent manner consistent with ATP competitive inhibition kinetics, demonstrating that binding compound does not reverse RAF auto-inhibition. Together, these results suggest a novel mechanism that can account for the paradoxical activation of MAPK pathway due to wildtype RAF inhibition whereby wildtype RAF exists in an auto-inhibited state at physiological conditions through auto-phosphorylation. In the presence of a RAF inhibitor wildtype RAF auto-phosphorylation and consequential auto-inhibition of RAF is therefore relieved to activate the MAPK pathway leading to enhanced proliferation. This study offers new insight into RAF biochemistry and enzyme kinetics with significant implications for drug development strategies and therapeutic use of RAF inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-28. doi:10.1158/1538-7445.AM2011-LB-28
Abstract P5-10-09: Prediction of Trastuzumab treatment response for HER2-positive breast cancer by microRNA profiling
Authors: F Sato, Z Wang, T Ueno, A Myomoto, S Takizawa, N Masuda, Y Mikami, K Shimizu, G Tsujimoto, M Toi
Journal: Cancer Research (2012)

Abstract [Background and Aim] Although Trastuzumab has been used for HER2(+) breast cancer, the treatment response of Trastuzumab therapy depends on unknown mechanisms among individual cases. In order to avoid unnecessary adverse events and to lighten financial burden for patients, pre-treatment prediction of trastuzumab treatment response would be beneficial for patients. Thus, in this study, we develop a prediction algorithm using microRNA expression profile of breast cancer tissues. [Materials and Methods] Eighty-three breast cancer patients who underwent trastuzumab-chemo combined therapy before operations were enrolled with written informed consent. FFPE specimens of pre-treatment core needle biopsy samples were collected, and regions containing cancer and adjacent stromal cells were laser-microdissected. Total RNA samples extracted from the microdissected specimens were subjected for microRNA microarray (3D-Gene®, Toray, Japan) analysis. Among these 83 patients, 39 cases had pCR (complete response in IDC regions regardless presense of DCIS without lymphnode metastasis), and the other 44 cases did not. According to the pCR/non-pCR information, we develop a prediction model using 35 signature microRNAs by a SVM technique. Prediction accuracy assessed by Leave-one-out validation was AUROC=0.889. The 35 signature microRNAs for trastuzumab treatment response included 7 out of 8 let-7 family members and miR-125a-5p/b-5p. [Conclusion] microRNA profile could predict treatment response of trastuzumab-chemo combined therapy for HER2(+) breast cancer, and the developed prediction algorithm might be a useful tool for clinical decision making. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-09.
Abstract LB-185: Cytokinesis-blocked micronuclei Assay (CBMN) as a biological cancer risk assessment tool
Authors: Stacy M. Lloyd, M Lopez, Randa El-Zein
Journal: Cancer Research (2012)

Abstract Lung cancer is the leading cause of all cancer-related deaths in the US. Given the lack of effective of screening modalities, the need to develop more accurate cancer risk assessment tools is imperative to improve the ability to identify individuals that are at greatest risk of developing this disease. The Cytokinesis-Blocked Micronuclei Assay (CBMN) presents a sensitive, specific, and rapid method of assessing DNA damage, a hallmark of cancer. We have previously reported that this assay is extremely sensitive to genetic damage caused by the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and that the binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds in lymphocytes (chromosome damage endpoints measured by the assay) are strong predictors of lung cancer risk. To further identify the specific chromosomes involved in lung carcinogenesis, we conducted Spectral Karyotyping (SKY) on a population of n=116 cases and n=126 controls on whom CBMN data are available. SKY was performed on both baseline and NNK-treated blood lymphocytes. After adjusting for age, gender, race/ethnicity, smoking status, pack years (intensity), and smoke years (duration), we observed consistent significant results for damage on chromosomes 1, 3, 4, 9, 13, 16, 17, 19, 22, and X (all p's ≤ 0.05) and lung cancer risk. Several of these identified chromosomes are well known to harbor critical genes involved in lung carcinogenesis, such as the FHIT gene (chromosome 3), p16/CDKN2A (chromosome 9), PADPRP (chromosome 13) and TP53 (chromosome 17). Our results support the utilization of CBMN as a cancer risk assessment tool, and when used in conjunction with other cytogenetic methodologies can increase our ability to identify specific regions of DNA damage, thereby improving our understanding of the underlying mechanisms involved in individual cancer predisposition. This work was supported by the following: Kellogg Health Scholars Program (W.K. Kellogg Foundation P0117943) NIMHS P60 MD000503 CA129050 NIHS P30 ES007784 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-185. doi:1538-7445.AM2012-LB-185
Chikungunya outbreak in the Caribbean region, December 2013 to March 2014, and the significance for Europe
Authors: W Van Bortel, F Dorleans, J Rosine, A Blateau, D Rousset, S Matheus, I Leparc-Goffart, O Flusin, C M Prat, R Césaire, F Najioullah, V Ardillon, E Balleydier, L Carvalho, A Lemaître, H Noël, V Servas, C Six, M Zurbaran, L Léon, A Guinard, J van den Kerkhof, M Henry, E Fanoy, M Braks, J Reimerink, C Swaan, R Georges, L Brooks, J Freedman, B Sudre, H Zeller
Journal: Eurosurveillance (2014)

On 6 December 2013, two laboratory-confirmed cases of chikungunya without a travel history were reported on the French part of the Caribbean island of Saint Martin, indicating the start of the first documented outbreak of chikungunya in the Americas. Since this report, the virus spread to several Caribbean islands and French Guiana, and between 6 December 2013 and 27 March 2014 more than 17,000 suspected and confirmed cases have been reported. Further spread and establishment of the disease in the Americas is likely, given the high number of people travelling between the affected and non-affected areas and the widespread occurrence of efficient vectors. Also, the likelihood of the introduction of the virus into Europe from the Americas and subsequent transmission should be considered especially in the context of the next mosquito season in Europe. Clinicians should be aware that, besides dengue, chikungunya should be carefully considered among travellers currently returning from the Caribbean region.
AT-56 * TREATMENT OF LARGE LOW-GRADE OLIGODENDROGLIAL TUMORS WITH UPFRONT PROCARBAZINE, LOMUSTINE, AND VINCRISTINE CHEMOTHERAPY WITH LONG FOLLOW-UP: A RETROSPECTIVE COHORT STUDY WITH GROWTH KINETICS
Authors: W. Taal, K. van der Rijt, W. Dinjens, P. S. Smitt, A. Wertenbroek, J. Bromberg, I. van Heuvel, J. Kros, M. van den Bent
Journal: Neuro-Oncology (2014)

PURPOSE: We treated patients with newly diagnosed and large low-grade oligodendroglial tumors with upfront procarbazine, lomustine (CCNU) and vincristine (PCV) in our institution in order to delay RT. We now report long term follow-up on a cohort of patients treated between 1998 and 2006. METHODS: Patients were treated with PCV in cycles of 6 weeks, for a maximum of 6 cycles. Central pathology review, genotyping on 1p/19q loss and immunohistochemistry on the IDH1 mutational status and MIB-1 labeling was performed. The response to treatment was defined according to the RANO criteria; in addition change over time of mean tumor diameters (growth kinetics) was calculated. RESULTS: Thirty-two patients were treated, 18 of which were diagnosed with 1p/19q co-deleted tumors. Median follow-up duration was 8 years. The median overall survival (OS) was 120 months and the median progression-free survival (PFS) was 46 months. Growth kinetics showed an ongoing decrease of the mean tumor diameter after completion of chemotherapy, during a median time of 35 months (range 5-136 months), but an increase of the mean tumor diameter did not herald progression as detected by RANO criteria. 1p/19q co-deletion was associated with a significant increase in OS (median OS 83 months versus not reached for codeleted tumors; p = 0.003)) and PFS (median PFS 35 months versus 67 months for codeleted tumors; p = 0.024). Patients with combined 1p/19q loss had a 10 year PFS of 34% and the radiotherapy in these patients was postponed for a median period of more than 6 years. CONCLUSION: This long-term follow-up study indicates that upfront PCV chemotherapy is associated with long PFS and OS and delays radiotherapy for a considerable period of time in patients with low-grade oligodendroglial tumors, in particular with combined 1p/19q loss.
Abstract 5096: Targeted genome sequencing of 184 cancer-related genes for molecular targeted therapy in gastric cancer
Authors: Hwang-Phill Kim, Geuna Cho, Jong-Yeon Shin, Won-Cheol Lee, Young-Kwang Yoon, Sae-Won Han, Jong-Il Kim, Jeong-Sun Seo, Tae-You Kim
Journal: Cancer Research (2012)

Abstract Cancer is a result of complex genetic alterations including mutations, copy number alterations, and gene fusions. Recent advance in sequencing technology enables comprehensive genome-wide study of the complex genetic alterations. Better understanding of the genetic alteration of cancer will ultimately lead to better treatment options and improved survival of the patients. We have established a set of cancer-related genes comprised of 184 genes for targeted sequencing using next generation sequencing technology. Targeted genome sequencing of the coding regions in the gene set was performed using the Illumina Genome Analyzer IIx. We analyzed the gene set in 13 gastric cancer cell lines. Average coverage depth was 140X. A total of 237 somatic sequence variations were found in 111 genes. The frequently mutated genes were ATM in 7, MSH6 in 6, TP53 in 5, and KRAS in 4 gastic cancer cells. Using the coverage data, we could also analyze copy number variations. Copy number gain (&amp;gt;2.0 fold) was found in 5 genes, whereas copy number loss (&amp;lt;2.0 fold) was found in 17 genes in gastric cancer cell lines. Moreover, the association between the genetic alterations and in vitro sensitivity to various targeted agents is being analyzed. The analyses are aimed at identifying sensitive/resistant mechanisms of the targeted agents and identification of novel therapeutic target. Validation and detailed analysis is currently underway. Targeted genome sequencing of cancer-related genes using NGS can be an accurate and efficient method for studying mutations and copy number variations with a single analysis. Moreover, investigational therapies with their molecular characteristics will reveal biomarkers that can be used to guide clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5096. doi:1538-7445.AM2012-5096
Closing the gap in POEM
Authors: D. Yang, P. Draganov
Journal: Endoscopy (2013)

We have read with interest the paper from Saxena et al., reporting their experience with over-the-scope clips (OTSCs) as an alternative technique for mucosal entry closure during peroral endoscopic myotomy (POEM) in two cases [1]. We concur with their assessment that given the larger mouth and higher compressive force of OTSCs compared with standard clips [2] [3] [4], the OTSC may be a more suitable tool for the management of difficult mucosal closures in POEM.