tbuckley/cabot-search huggingface dataset:
Abstract 211: The mitochondrial protein MTP18 enhances chemosensitivity by promoting mitochondrial fission
Authors: Lynn Htet Htet Aung, Peifeng Li
Journal: Cancer Research (2016)

Abstract Background: Chemotherapy plays a major role in cancer therapy. Yet, one of its greatest obstacles is the development of chemotherapy resistance. Hence, understanding the molecular basis of chemoresistance is crucial to improve its therapeutic outcome. A close relationship between mitochondrial dynamic and cellular apoptosis has recently been identified. Mitochondrial fission is necessary for initiation of cellular apoptosis, whereas mitochondrial fusion is able to inhibit apoptosis. However, the association of mitochondrial fission and chemo-sensitivity has not been widely explored. Recently, mitochondrial protein MTP18 has been shown to promote mitochondrial fragmentation in various cancer cell lines. However, its role in apoptosis and chemotherapeutic resistance remains elusive. Here, we aimed to detect 1) whether MTP18 is able to regulate mitochondrial fission and apoptosis in gastric cancer cells, and 2) by which mechanism it regulates these events. Methods and Results: Doxorubicin is one of the most widely used chemotherapeutic agents in variety of cancers. Mitochondrial staining with MitoTracker Red CMXRos revealed doxorubicin was able to induce mitochondrial fission both in vitro and in vivo gastric cancer models. We observed doxorubicin led to a decreasing level of MTP18 expression in gastric cancer cell lines, and this effect was concentration- and time-dependent. To understand the role of MTP18 in doxorubicin-induced mitochondrial fission and apoptosis, endogenous MTP18 expression was knockdown using MTP18-shRNA. Strikingly, doxorubicin could not induce mitochondrial fission in gastric cancer cells transfected with MTP18-shRNA. On the other hand, upon enforced expression of MTP18, the same concentration of doxorubicin sensitized a significantly higher number of gastric cancer cells to undergo mitochondrial fission and apoptosis. These findings suggest that MTP18 is required for doxorubicin-induced mitochondrial fission and apoptosis. In exploring the molecular mechanism of MTP18, we found that MTP18 enriched dynamin-related protein Drp1 accumulation in mitochondria and mediated the signal of doxorubicin to induce mitochondrial fission. Drp1 accumulation in mitochondria caused the release of cytochrome-c to cytosol and subsequently promoted apoptosis. Conclusion: Taken together, our findings suggest that MTP18 induces mitochondrial fission and enhances apoptosis in gastric cancer cells, by promoting Drp1 accumulation in mitochondria. Thus, it is compelling us to conclude that MTP18 enhances doxorubicin sensitivity of gastric cancer cells by targeting mitochondrial fission machinery. Citation Format: Lynn Htet Htet Aung, Peifeng Li. The mitochondrial protein MTP18 enhances chemosensitivity by promoting mitochondrial fission. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 211.
Unpacking the Bundle to Lower Rates of Ventilation-Associated Pneumonia
Authors: Andrew Auerbach, Peter Lindenauer
Journal: JAMA Internal Medicine (2016)

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Into the Wild of long non-coding RNAs in Gastrointestinal Stromal Tumors (GISTs) to explore new prognostic/predictive biomarkers
Authors: N. Barraco, A. Listì, R. Maragliano, V. Bazan, G. Badalamenti, F. Fulfaro, L. Incorvaia, V. Calò, M. Castiglia, G. Bronte, A. Cangemi, A. Perez, L. Insalaco, E. Bronte, A. Russo
Journal: Annals of Oncology (2015)
Abstract 2259: Comprehensive evaluation of promising biomarkers for lung cancer risk prediction
Authors: Mattias A. Johansson, Ayumu Taguchi, David Muller, Samir Hanash, Paul Brennan
Journal: Cancer Research (2016)

Abstract Introductory sentence indicating the purposes of the study: Lung cancer will remain the number one cancer killer worldwide for the foreseeable future (Globocan 2012). Although low-dose CT screening has been shown to reduce mortality, there is an urgent need to improve risk prediction models to identify those subjects at high risk and most likely to benefit from screening in order its improve the screening efficacy (PMID: 23697514, 25372087). Brief description of pertinent experimental procedures: We have assembled a compendium of promising blood-based risk biomarkers for lung cancer that are currently being validated in order to identify a panel of validated risk markers for use in lung cancer risk assessment. Using pre-diagnostic serum samples from CARET cohort participants (current or former heavy smokers) we have recently validated pro-surfactant protein B (Pro-SFTPB) and Diacetyl spermine (DAS) as risk markers for non-small cell lung cancer (PMID: 26282655). Validation of additional markers from the compendium using Pro-SFTPB and DAS as anchor markers with further refinement of the risk prediction models is currently being performed in two large independent cohort studies (EPIC and NSHDS). Biospecimens from these cohorts include pre-diagnostic plasma from 550 former and current smoking lung cancer cases that were diagnosed within 5 years of blood draw, along with 1,100 matched controls. Summary of the new, unpublished data and conclusion: Preliminary data indicate that blood-based biomarkers of lung cancer risk have a strong potential to improve on questionnaire-based risk prediction models for lung cancer (PMID: 26282655). During the meeting we will present detailed results of the individual risk biomarkers and their associations with lung cancer risk up to 2 years prior to diagnosis, as well as an assessment of the extent to which they can improve traditional risk prediction models. Citation Format: Mattias A. Johansson, Ayumu Taguchi, David Muller, Samir Hanash, Paul Brennan. Comprehensive evaluation of promising biomarkers for lung cancer risk prediction. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2259.
Unintentional Pediatric Exposures to Marijuana in Colorado, 2009-2015
Authors: George Sam Wang, Marie-Claire Le Lait, Sara J. Deakyne, Alvin C. Bronstein, Lalit Bajaj, Genie Roosevelt
Journal: JAMA Pediatrics (2016)

As of 2015, almost half of US states allow medical marijuana, and 4 states allow recreational marijuana. To our knowledge, the effect of recreational marijuana on the pediatric population has not been evaluated.To compare the incidence of pediatric marijuana exposures evaluated at a children's hospital and regional poison center (RPC) in Colorado before and after recreational marijuana legalization and to compare population rate trends of RPC cases for marijuana exposures with the rest of the United States.Retrospective cohort study of hospital admissions and RPC cases between January 1, 2009, and December 31, 2015, at Children's Hospital Colorado, Aurora, a tertiary care children's hospital. Participants included patients 0 to 9 years of age evaluated at the hospital's emergency department, urgent care centers, or inpatient unit and RPC cases from Colorado for single-substance marijuana exposures.Marijuana.Marijuana exposure visits and RPC cases, marijuana source and type, clinical effects, scenarios, disposition, and length of stay.Eighty-one patients were evaluated at the children's hospital, and Colorado's RPC received 163 marijuana exposure cases between January 1, 2009, and December 31, 2015, for children younger than 10 years of age. The median age of children's hospital visits was 2.4 years (IQR, 1.4-3.4); 25 were girls (40%) . The median age of RPC marijuana exposures was 2 years (IQR, 1.3-4.0), and 85 patients were girls (52%). The mean rate of marijuana-related visits to the children's hospital increased from 1.2 per 100 000 population 2 years prior to legalization to 2.3 per 100,000 population 2 years after legalization (P = .02). Known marijuana products involved in the exposure included 30 infused edibles (48%). Median length of stay was 11 hours (interquartile range [IQR], 6-19) and 26 hours (IQR, 19-38) for admitted patients. Annual RPC pediatric marijuana cases increased more than 5-fold from 2009 (9) to 2015 (47). Colorado had an average increase in RPC cases of 34% (P < .001) per year while the remainder of the United States had an increase of 19% (P < .001). For 10 exposure scenarios (9%), the product was not in a child-resistant container; for an additional 40 scenarios (34%), poor child supervision or product storage was reported. Edible products were responsible for 51 exposures (52%).Colorado RPC cases for pediatric marijuana increased significantly and at a higher rate than the rest of the United States. The number of children's hospital visits and RPC case rates for marijuana exposures increased between the 2 years prior to and the 2 years after legalization. Almost half of the patients seen in the children's hospital in the 2 years after legalization had exposures from recreational marijuana, suggesting that legalization did affect the incidence of exposures.
Abstract 3703: MDM2 regulation of MYC and MYCN in pediatric neural cancers
Authors: Hung N. Tran, Donglai Qi, David Cobrinik
Journal: Cancer Research (2016)

Abstract Background MYC and MYCN have critical roles in a wide range of cancers and can be deregulated through diverse transcriptional and post-transcriptional mechanisms. Recent studies have shown that the high-level MYCN expression needed to drive retinoblastoma and MYCN-amplified neuroblastoma proliferation depends upon efficient MYCN translation mediated by highly expressed MDM2 and acting via a p53-independent mechanism. Here, we assessed MDM2-mediated regulation of MYC as well as MYCN in other pediatric neural tumors, specifically in Group 3 medulloblastoma and in MYC-overexpressing neuroblastoma. We also assessed MDM2-mediated regulation of MYCN in small cell lung cancer (SCLC), which has genetic and morphologic features in common with retinoblastoma. Methods MDM2, MYCN, and MYC expression were defined in Group 3 medulloblastoma lines D283, D425, D341; in MYC-overexpressing neuroblastoma lines CHLA 255 and SY-5Y; and in p53-wild type and p53-mutant SCLC lines H69 and H526 by western blotting. Cells were infected with shMDM2 and scrambled control lentivirus and effects on MDM2, MYC, and MYCN protein expression defined using western blot and effects on cell growth defined using Cell Titer-Glo. In neuroblastoma cells, MDM2 knockdown effects were defined with or without p53 co-knockdown. Results Group 3 medulloblastoma lines D283, D341, D425 highly expressed MYC but not MYCN. MDM2 knockdown did not decrease MYC expression in these cells. MDM2 knockdown decreased MYC expression In CHLA 255 and SY5Y neuroblastoma cells, along with p53 induction and cell death, and MYC down-regulation and cell death were mitigated by co-knockdown of p53. MDM2 knockdown decreased MYCN expression and impaired viability in p53-wild type H69 SCLC cells and in p53-mutant H526 SCLC cells. Conclusions MDM2 is not needed to sustain high-level MYC expression in three Group 3 medulloblastoma cell lines. MDM2 sustains high-level MYC in two MYC-overexpressing neuroblastoma cell lines via a p53-dependent mechanism distinct from the p53-independent MYCN regulation in MYCN-amplified neuroblastomas. In SCLC, MDM2 sustains high-level MYCN expression and viability in a p53-independent manner, similar to MDM2 effects in retinoblastoma and in MYCN-amplified neuroblastoma. These findings suggest that MDM2 selectively sustains MYCN but not MYC expression through a p53-independent mechanism and raise the possibility that cis-acting elements specific to MYCN-RNA mediate MDM2 regulation. Citation Format: Hung N. Tran, Donglai Qi, David Cobrinik. MDM2 regulation of MYC and MYCN in pediatric neural cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3703.
Genetic Predispositions to Myeloid Neoplasms Caused By Germline DDX41 Mutations
Authors: June Takeda, Kenichi Yoshida, Hideki Makishima, Tetsuichi Yoshizato, Yusuke Shiozawa, Yuichi Shiraishi, Yusuke Okuno, Ayana Kon, Yasunobu Nagata, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Mamiko Sakata-Yanagimoto, Naoshi Obara, Tsuyoshi Nakamaki, Ken Ishiyama, Akira Haigaishi, Shigeru Chiba, Hiraku Mori, Norio Asou, Hitoshi Kiyoi, Chikara Hirase, Kiyotoshi Imai, Nobuaki Dobashi, Toru Kiguchi, Yasushi Miyazaki, Tomoki Naoe, Satoru Miyano, Kensuke Usuki, Shuichi Miyawaki, Yoichiro Kamatani, Yukihide Momozawa, Michiaki Kubo, Chantana Polprasert, Jaroslaw P. Maciejewski, Seishi Ogawa
Journal: Blood (2015)
A multi-centric randomized phase II trial evaluating dual targeting of the EGFR with cetuximab and afatinib versus cetuximab alone in patients with chemotherapy refractory wtKRAS metastatic colorectal cancer (UCGI 25: A UNICANCER trial).
Authors: Helene Senellart, Emmanuelle Samalin, Florence Castan, Christophe Borg, Antoine Adenis, Christelle De La Fouchardiere, David Malka, Veronique Guerin-Meyer, Eric Francois, Meher Ben Abdelghani, Eveline Boucher, Thierry Andre, Francois Ghiringhelli, Astrid Lievre, Trevor Stanbury, Jaafar Bennouna
Journal: Journal of Clinical Oncology (2016)

3537 Background: Promising results using cetuximab and erlotinib to treat wtKRAS metastatic colorectal cancer (mCRC) were reported by Weickhardt (J Clin Oncol 2012; 30:1505-12). Combining a monoclonal antibody and a tyrosine kinase inhibitor may be a treatment option for mCRC patients (pts). We investigated dual targeting with cetuximab and afatinib in chemotherapy refractory wtKRAS mCRC. Methods: wtKRAS mCRC pts (ECOG ≤ 1) who failed chemotherapy with irinotecan and oxaliplatin were eligible. Due to low accrual and the frequent use of an anti-EGFR antibody in the first- or second-line, the study was amended, after 19 inclusions, to allow pre-treatment with anti-EGFRs. This multicenter, prospective, open phase II trial randomized pts (2:1) to cetuximab (500mg/m2/two weeks) and oral afatinib (40mg/day) (Arm A) or cetuximab alone (500mg/m2/two weeks) (Arm B). Treatment continued until progression (evaluated every six weeks using RECIST 1.1) or limiting toxicity. At progression (Arm B) afatinib could be added to cetuximab. The primary objective was the non-progression rate at six months (Fleming’s one-step design, one-sided a = 5%, b = 10%, H0: 30%; H1: 50%; 75 pts needed, 49 in Arm A). Results: 75 pts were included between November 2012 and May 2015 in 14 French sites. We randomized 51 pts in Arm A and 24 in Arm B. The non-progression rate (CI95%) at six months was 17.0% in Arm A [7.7-30.8] and 20.8% in Arm B [7.1-42.2]. Median PFS (CI95%) and OS (CI95%) were 4.1 months [2.7; 5.4] and 13.6 months [7.7; 19.9] in Arm A; and 2.7 months [1.4; 4.7] and 13.4 months [4.7; 20.4] in Arm B. The objective response was 26.0% in Arm A and 8.3% in Arm B. 38 pts (76%) in Arm A vs 14 (58%) in Arm B had AEs of grade 3 or 4. Conclusions: ORR results are encouraging with cetuximab and afatinib. The median PFS has to be interpreted considering the criterion allowing pre-treatment with anti-EGFRs. Cross-over in Arm A could explain the similar median OS in both arms. Additional data will be presented (NRAS, subgroup of pts not pre-treated with anti-EGFRs, pts treated with cross-over). Clinical trial information: NCT01919879.
Abstract 3629: Gene fusion detection in sarcoma using TRAC technology
Authors: Laura Mattinen, Jari Rautio, Jani Salmivaara, jussi Halleen, Marko Sirkiä
Journal: Cancer Research (2016)

Abstract Genomic rearrangements are a defining feature of cancer, and can lead to gene fusions and chimeric transcripts with respective fusion proteins that have oncogenic properties. The fusion transcripts can have diagnostic, prognostic and therapeutic implications. However, the fusion partners and the exact breakpoints vary from patient to patient and from cancer type to another. This can result in significant sequence variation, and together with the large number of potential genes able to participate in fusion events makes reliable detection of fusion events challenging for many traditional methods. The TRAC (Transcript Analysis with aid of Affinity Capture) method solves a number of these issues by a combination of specific capture and detection probes. By capturing all known 5’ fusion partners and detecting potential 3’ partners for a given cancer type, only a very limited set of positive signals are detected from an individual sample, enabling high-level of multiplexing. In practice, dozens of different fusion events can be detected per sample by using an easily modifiable pool of capture/detection probes. This effectively enables detection of all known fusion types in sarcomas from one sample without the prerequisite of knowing the exact cancer type. TRAC is a direct hybridization based assay that enables rapid quantification of multiple mRNA targets simultaneously from large number of samples. Transcript levels can be measured directly from cell or tissue lysates without the need for RNA extraction, cDNA conversion or PCR-amplification. The TRAC protocol is straightforward and enables sample analysis in a high-throughput format with little hands-on time. In this analysis, TRAC was used to detect the fusion transcripts COL1A1-PDGFB, FUS-DDIT3, and SS18-SSX1/2 from three types of sarcoma tissue biopsies. All fusion types were detected for the respective targets. In addition, twenty Ewing sarcoma cell lines were analyzed for the EWSR1-FLI1 fusion, identifying 12 cell lines positive for the chimeric transcript. Sarcoma tissue lysate was found applicable for direct TRAC analysis. These results demonstrate that the TRAC Fusion Transcript Assay is functional and capable of discriminating sarcomas based on fusion transcript expression. The assay is easy to set up and it can be run using standard laboratory equipment with little hands-on time. Citation Format: Laura Mattinen, Jari Rautio, Jani Salmivaara, jussi Halleen, Marko Sirkiä. Gene fusion detection in sarcoma using TRAC technology. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3629.
Abstract 5037: Upregulated superoxide dismutase 2 by specificity protein 1 mediates temozolomide resistance in glioma stem cells
Authors: Jian-Ying Chuang, Jr-Jiun Liu, Shao-Wen Chou, Wen-Chang Chang, Kwang-Yu Chang
Journal: Cancer Research (2016)

Abstract The resisitant mechanism of glioblastoma mutliforme (GBM) to the standard chemotherapy temozolomide (TMZ) can be attributed to methylguanine methyltransferase (MGMT) expression in only half of the clinical cases. For the other half, it is not fully understood. To elucidate the mechanism, MGMT-negative GBM cell lines, U87MG and A172, were used to develop the TMZ-resistant variants. The variants showed reduced reactive oxygen species (ROS) accumulation by TMZ treatment comparing to the parental one. Further analysis of the cells revealed enhanced expression of superoxide dismutases 2 (SOD2), an antioxidative enzyme, as well as the stem cell-like properties. The protein was shown to associate with glioma stem cells (GSC). Notably, inhibition of SOD2 by diethyldithiocarbamate attenuated the stemness properties and the viability of the resistant variants. Further investigation of the promotor binding study suggested specificity protein 1 (Sp1) as the key factor of the SOD2 response. Moreover, Sp1 expression was even enhanced in the spheroid cells and the TMZ-resistant U87MG cell line. Conversely, treatment with Sp1 inhibitor mithramycin A attenuates SOD2 expression and the stemness properties of the resistant variants. In summary, our results suggested a novel role of SOD2 in TMZ resistant mechanism of GBM. Further study of Sp1-SOD2 pathway as a therapeutic target to restore susceptibility of chemotherapy is therefore warranted. Citation Format: Jian-Ying Chuang, Jr-Jiun Liu, Shao-Wen Chou, Wen-Chang Chang, Kwang-Yu Chang. Upregulated superoxide dismutase 2 by specificity protein 1 mediates temozolomide resistance in glioma stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5037.
Invasive melanoma<i>in vivo</i>can be distinguished from basal cell carcinoma, benign naevi and healthy skin by canine olfaction: a proof-of-principle study of differential volatile organic compound emission
Authors: C.M. Willis, L.E. Britton, M.A. Swindells, E.M. Jones, A.E. Kemp, N.L. Muirhead, A. Gul, R.N. Matin, L. Knutsson, M. Ali
Journal: British Journal of Dermatology (2016)

Volatile organic compounds (VOCs) are continuously released by the body during normal metabolic processes, but their profiles change in the presence of cancer. Robust evidence that invasive melanoma in vivo emits a characteristic VOC signature is lacking.To conduct a canine olfactory, proof-of-principle study to investigate whether VOCs from invasive melanoma are distinguishable from those of basal cell carcinoma (BCC), benign naevi and healthy skin in vivo.After a 13-month training period, the dog's ability to discriminate melanoma was evaluated in 20 double-blind tests, each requiring selection of one melanoma sample from nine controls (three each of BCC, naevi and healthy skin; all samples new to the dog).The dog correctly selected the melanoma sample on nine (45%) occasions (95% confidence interval 0·23-0·68) vs. 10% expected by chance alone. A one-sided exact binomial test gave a P-value of < 0·01, supporting the hypothesis that samples were not chosen at random but that some degree of VOC signal from the melanoma samples significantly increased the probability of their detection. Use of a discrete-choice model confirmed melanoma as the most influential of the recorded medical/personal covariates in determining the dog's choice of sample. Accuracy rates based on familiar samples during training were not a reliable indicator of the dog's ability to distinguish melanoma, when confronted with new, unknown samples.Invasive melanoma in vivo releases odorous VOCs distinct from those of BCC, benign naevi and healthy skin, adding to the evidence that the volatile metabolome of melanoma contains diagnostically useful biomarkers.