tbuckley/cabot-search huggingface dataset:
KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic non-squamous NSCLC
Authors: M. Cinausero, N. Laprovitera, G. De Maglio, L. Gerratana, M. Riefolo, M. Macerelli, M. Fiorentino, E. Porcellini, V. Buoro, F. Gelsomino, A. Squadrilli, G. Fasola, M. Tiseo, M. Ferracin, A. Ardizzoni
Journal: Annals of Oncology (2019)

Background: Programmed cell death -1 (PD-1) PD-ligand 1 (PD-L1) inhibitors represent a novel therapeutic option for advanced chemotherapy-pretreated non-small cell lung cancer (NSCLC) patients, leading to a significant improvement in median and long-term survival. However, about 50% patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression and tumor mutational burden (TBM) have been proposed as biomarker of benefit to anti-PD-1/PD-L1 therapy. However, PD-L1 is not an ideal biomarker and TMB calculation is hardly obtainable for all patients. Here, we planned to test specific NSCLC genetic alterations as potential predictive factors of response to immunotherapy. Methods: Tumor DNA was obtained from advanced NSCLC patients treated with anti PD-1 monoclonal antibody nivolumab (n = 44) or pembrolizumab (n = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing using Oncomine™ Solid Tumour DNA assay (Thermo Fisher). Results: The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11(9%), ERBB4 (6%), EGFR (6%), BRAF (6%) and MET (6%). We observed that KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt patients. Additionally, we observed that patients with ERBB-family, including EGFR, ERBB2 and ERBB4, mutations all failed to respond to PD-1 blockers, independently from KRAS status. Conclusions: These results suggest that the analysis of the mutational status of KRAS and ERBB-family genes is a potential molecular biomarker of response to PD-1 inhibitors that could be used in clinical practice. Legal entity responsible for the study: The authors. Funding: Associazione Italiana per la Ricerca sul Cancro (AIRC). Disclosure: M. Tiseo: Advisory boards, speakers' fee: BMS, MSD. A. Ardizzoni: Grants, personal fees: BMS; Grants: Celgene; Personal fees: MSD, Eli Lilly, Boehringer Ingelheim, Pfizer, outside the submitted work. All other authors have declared no conflicts of interest.
FRI-280-Common dietary component, wheat amylase trypsin inhibitors, driver of chronic liver disease in pre-clinical models of NASH and liver fibrosis
Authors: Muhammad Ashfaq-Khan, Misbah Aslam, Asif Qureshi, Marcel Senkowski, Shih Yeng Weng, Yong Ook Kim, Detlef Schuppan
Journal: Journal of Hepatology (2019)
TCTAP C-192 Impact of Drug-coated Balloon Angioplasty for SFA Lesions with High-resolution Angioscopy
Authors: Akinori Sumiyoshi, Atsunori Okamura, Mutsumi Iwamoto, Hiroyuki Nagai, Kota Tanaka, Kenshi Fujii
Journal: Journal of the American College of Cardiology (2019)
Blood tumor mutational burden as a predictor of clinical benefit in non-small cell lung cancer patients treated with docetaxel: Secondary analysis of the OAK and POPLAR randomized clinical trials
Authors: W. Nie, J. Qian, B.-H. Han
Journal: Annals of Oncology (2019)

Background: Blood-based tumor mutational burden (bTMB), which is measured by targeted next-generation sequencing (NGS) using cell-free DNA (cfDNA), shows a positive correlation with tissue-based TMB and is a predictive biomarker for non-small cell lung cancer (NSCLC) patients receiving atezolizumab. However, the role of bTMB in other treatment settings, such as chemotherapy, is unknown. We hypothesized that advanced NSCLC patients with low bTMB would derive more benefit from chemotherapy. Methods: The clinical and genetic data from docetaxel arm of OAK trial (n = 318, training cohort) and POPLAR trial (n = 106, validation cohort) were used. The FoundationOne CDx NGS assay was used to quantify bTMB. Efficacy was determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Durable clinical benefit (DCB) was defined as overall survival (OS) that last more than 12 months. Gene alterations and bTMB were compared among patients with DCB and no durable benefit (NDB). The cut-off value of bTMB for predicting OS was determined by time-dependent receiver operating characteristic (ROC) curve. Results: Significantly lower bTMB was observed in DCB than NDB (median, 5 vs 9 SNVs/Mb; P < 0.001) and in patients with partial response (PR) versus stable disease (SD) versus progressive disease (PD) (median, 5 vs 7 vs 10 SNVs/Mb; P = 0.007). The optimised cut-off value of bTMB for predicting OS was 7 SNVs/Mb by time-dependent ROC curve. In training cohort, the median OS of patients with low bTMB was 11.5 months and 6.4 months for those with high bTMB (HR 0.638; 95% CI 0.497-0.820; P < 0.001). The median PFS in the low bTMB group (4.3 months) was significantly longer than that in the high bTMB group (2.9 months; HR 0.588; 95% CI 0.466-0.742; P < 0.001). These results were confirmed in validation cohort. Variants in EGFR and KEAP1 associated with DCB and NDB, respectively. Conclusions: Our data showed that low bTMB (≤ 7 SNVs/Mb) was a clinically biomarker for docetaxel treatment in NSCLC. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Abstract 10544: Impact of Diabetes Mellitus on the Prediction for Pulmonary Hypertension in the Patients With Chronic Respiratory Disease
Authors: Koichi Sugimoto, Akiomi Yoshihisa, Tomoko Takahashi, Tetsuro Yokokawa, Tomofumi Misaka, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2018)

Background: Chronic respiratory disease is often complicated by pulmonary hypertension (PH). However, clinical risk factors for predicting PH have not been identified. Recent studies reported that ...
BRB-seq: ultra-affordable high-throughput transcriptomics enabled by bulk RNA barcoding and sequencing
Authors: Daniel Alpern, Vincent Gardeux, Julie Russeil, Bastien Mangeat, Antonio C. A. Meireles-Filho, Romane Breysse, David Hacker, Bart Deplancke
Journal: Genome biology (2019)

Despite its widespread use, RNA-seq is still too laborious and expensive to replace RT-qPCR as the default gene expression analysis method. We present a novel approach, BRB-seq, which uses early multiplexing to produce 3' cDNA libraries for dozens of samples, requiring just 2 hours of hands-on time. BRB-seq has a comparable performance to the standard TruSeq approach while showing greater tolerance for lower RNA quality and being up to 25 times cheaper. We anticipate that BRB-seq will transform basic laboratory practice given its capacity to generate genome-wide transcriptomic data at a similar cost as profiling four genes using RT-qPCR.
18F-FDG PET/CT in a Case of Metastatic Breast Cancer to the Vulva
Authors: Priscilla Guglielmo, Mariachiara Paderno, Federica Elisei, Luca Guerra, Claudio Landoni, Alessandro Buda, Cinzia Crivellaro
Journal: Clinical Nuclear Medicine (2019)

Abstract A 56-year-old woman, previously treated for breast cancer, presented to gynecologists with a lump of the left labium major of the vulva. The FDG pattern resembled as a cIV stage vulvar cancer, whereas biopsy indicated metastases from breast cancer. Metastatic disease to the vulva is particularly uncommon, representing 5% to 8% of all vulvar cancer lesions. However, gynecological uptakes, including vulvar site, have to be kept in mind as a possible site of metastatic lesions from breast cancer.
TCTAP A-133 Domestic New-generation Drug-eluting Stents Versus Imported New-generation Drug-eluting Stents in China
Authors: Ru Liu, Zhan Gao, Ma Yuanliang, Ying Song, Huanhuan Wang, Lin Jiang, Lijian Gao, Shubin Qiao, Yuejin Yang, Runlin Gao, Bo Xu, Jinqing Yuan
Journal: Journal of the American College of Cardiology (2019)
TCTAP C-073 When Antegrade Wire Escalation and Retrograde Lost Their Way, "Knuckle" Found the Way
Authors: Chee Sin Khaw, Nee Hooi Tan, Mohd Faiz Faizul Fauzi, Chong Aik Goh, Muhamad Ali SK Abdul Kader, Omar Ismail
Journal: Journal of the American College of Cardiology (2019)
Exosome transcriptome analysis to provide novel tools for CLL patient stratification.
Authors: Raffaele Calogero, Maddalena Arigoni, Federica Riccardo, Ana Rodriguez-Vicente, Jesus Maria Hernandez, Francesca Zolezzi
Journal: Journal of Clinical Oncology (2015)

7038 Background: Routine diagnostic techniques can detect very low levels of CLL phenotype cells. Monoclonal B-cell lymphocytosis (MBL) is a diagnostic category encapsulating individuals with an abnormal B-cell population but not meeting the diagnostic criteria for a B-cell malignancy. MBL and CLL show similar karyotypes and mRNA/miRNA expression data were shown not to be suitable for a molecular discrimination between the two diseases. Exosomes are vesicles secreted into the extracellular environment. A growing body of evidence suggests that exosome-contained coding and non-coding RNAs may be used as biomarkers for the diagnosis and prognosis of malignant tumors. Methods: We analyzed the exosome transcriptome of 14 CLL patients and 13 MBL patients, characterized by similar karyotypes. We collected data for coding genes, fusion transcripts, long non-coding RNAs, snRNA, snoRNA, miRNA precursors and mature transcripts, using whole-transcriptome and small RNA sequencing analyses. Results: A subset of 8 CLL patients was characterized by a reduced expression of four miRNAs (miR-146a-5p, miR-151a-3p, miR-22-3p, miR-584-5p), which act as tumor suppressors in various solid cancers. Six of the above mentioned patients were also characterized by an up-modulation of TPT1, which is a predictor of poor prognosis in breast cancer. It is notable that TPT1 is located on q13-14.11, however, six out of eight samples with high TPT1 expression are characterized by 63% to 95% deletion of the long arm of chromosome 13, which suggests that TPT1 exosome expression is associated to the sub-population of CLL still retaining at least part of the long arm of chromosome 13. Furthermore, using a signature based on miR-6813 and two snRNA U2 pseudogenes we managed to stratify CLL patients in 4 groups, which are independent by the patient karyotype. MBL patients clustered all in the same group together with 3 CLL patients (21%). Conclusions: Our work describes an exhaustive analysis of the transcriptome of exosomes circulating in the peripheral blood of CLL/MBL patients. Our data suggest that the exosome transcriptome of CLL and MBL patients carries an important amount of non-coding RNAs, which might be instrumental for CLL patients’ stratification.
Immunogenic neoantigens derived from gene fusions stimulate T cell responses
Authors: Wei Yang, Ken-Wing Lee, Raghvendra M. Srivastava, Fengshen Kuo, Chirag Krishna, Diego Chowell, Vladimir Makarov, Douglas Hoen, Martin G. Dalin, Leonard Wexler, Ronald Ghossein, Nora Katabi, Zaineb Nadeem, Marc A. Cohen, S. Ken Tian, Nicolas Robine, Kanika Arora, Heather Geiger, Phaedra Agius, Nancy Bouvier, Kety Huberman, Katelynd Vanness, Jonathan J. Havel, Jennifer S. Sims, Robert M. Samstein, Rajarsi Mandal, Justin Tepe, Ian Ganly, Alan L. Ho, Nadeem Riaz, Richard J. Wong, Neerav Shukla, Timothy A. Chan, Luc G. T. Morris
Journal: Nature Medicine (2019)
THU-244-Virological and clinical characteristics of chronic hepatitis delta patients of Mongolia
Authors: Delgersaikhan Zulkhuu, Bekhbold Dashtseren, Myagmarjav Budeebazar, Maralmaa Enkhbat, Miriam Eichner, Purevjargal Bat-Ulzii, Zulkhuu Genden, Altankhuu Mordorjyn, Dahgwahdorj Yagaanbuyant, Naranbaatar Dashdorj, Andreas Bungert, Naranjargal Dashdorj
Journal: Journal of Hepatology (2019)
Dynamic changes of circulating tumor cells during chemotherapy as a prognostic factor in patients with advanced lung cancer.
Authors: Jie Zhang, Jian Fang, Jun Nie, Ling Dai, Weiheng Hu, Xiaoling Chen, Jindi Han, Xiangjuan Ma, Guangming Tian, Di Wu
Journal: Journal of Clinical Oncology (2015)

e22024 Background: The detection of circulating tumor cells (CTCs) in peripheral blood is currently an important field of studies. The aim of the study is to evaluate whether CTC count is associated with prognosis and the correlation between CTC appearance and clinical characteristics. Then detect inherited characters on CTCs. Methods: We evaluated the clinical significance of CTCs in 43 patients with advanced lung cancer in this study. Detection of CTCs was performed using epithelial cell adhesion molecule independent enrichment and CD45 combined fluorescence in situ hybridization (imFISH) identified methods. CTCs ≥2/3.2ml was considered as positive. To detect inherited characters of positive patients, EGFR probes were hybridized on them. Results: CTCs were identified in 95.3% (41/43) of patients at baseline, in which CTC count ranged from 0 to 15. Numbers after two cycles ranged from 0 to 21. Change of CTCs count after two cycles of chemotherapy was consistent with chemotherapy response (p= 0.043). The median overall survival in patients whose post-treatment CTCs count increased was shorter than those decreased (9.9 versus 13.7 months, p= 0.008). The results of a multivariate analysis failed to demonstrate a significant prognostic relevance for the change of CTC count in patients, although trends have been detected (p= 0.06). Three EGFR amplification cells were found in 1 PD patient, one at baseline, two after chemotherapy. Conclusions: Dynamic changes of CTCs in the peripheral blood may indicate a poor prognosis in patients with lung cancer. EGFR amplifications may be a predictive factor in target therapy, but further study with large number needs to be performed.
TCTAP C-078 The Novel Use of PCI Technique to Cross the CTO Lesion
Authors: Pei-Heng Kao, Chun-Yuan Chu, Wen-Hsien Lee, Po-Chao Hsu, Hung-Hao Lee, Cheng-An Chiu, Ho-Ming Su, Tsung-Hsien Lin, Chee-Siong Lee, Hsueh-Wei Yen, Wen-Chol Voon, Wen-Ter Lai
Journal: Journal of the American College of Cardiology (2019)
MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma
Authors: Jennifer Hüllein, Mikołaj Słabicki, Maciej Rosolowski, Alexander Jethwa, Stefan Habringer, Katarzyna Tomska, Roma Kurilov, Junyan Lu, Sebastian Scheinost, Rabea Wagener, Zhiqin Huang, Marina Lukas, Olena Yavorska, Hanne Helfrich, René Scholtysik, Kyle Bonneau, Donato Tedesco, Ralf Küppers, Wolfram Klapper, Christiane Pott, Stephan Stilgenbauer, Birgit Burkhardt, Markus Löffler, Lorenz H. Trümper, Michael Hummel, Benedikt Brors, Marc Zapatka, Reiner Siebert, Markus Kreuz, Ulrich Keller, Wolfgang Huber, Thorsten Zenz
Journal: Cancer Research (2019)

Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation (FLI1, BCL11A) or B-cell development and activation (PAX5, CDKN1B, JAK2, CARD11) and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype-phenotype association was seen for TP53. MDM4, a negative regulator of TP53, was essential in TP53 wild-type (TP53wt) Burkitt lymphoma cell lines. MDM4 knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4-p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the MDM4 locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable. SIGNIFICANCE: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.
P‐Glycoprotein Antibody Decorated Porous Hydrogel Particles for Capture and Release of Drug‐Resistant Tumor Cells
Authors: Xiaoyan Ma, Ze Zhao, Huan Wang, Yuxiao Liu, Yueshuang Xu, Jing Zhang, Baoan Chen, Ling Li, Yuanjin Zhao
Journal: Advanced Healthcare Materials (2019)

Multidrug resistance is one of the leading causes of chemotherapy failure in cancer patients. Early detection and capture of drug-resistant tumor cells can facilitate the monitoring of the therapy process and improve the prognosis of patients. In this study, novel P-glycoprotein (P-gp) antibody modified porous hydrogel particles are proposed for drug-resistant tumor cells capture. The hydrogel particles employ a highly biocompatible hydrogel, methacrylate gelatin (GelMA), as the carrier and replicate from the silica colloidal crystal beads. By the modification of P-gp antibody probes on their surfaces, the hydrogel particles are endowed with the ability to capture drug-resistant tumor cells, which overexpress specific components of P-gp on their membranes. Additionally, the acquired ordered porous nanostructure of the particles can provide not only more surface area for antibody immobilization but also a nanopatterned platform for highly efficient target cell capture. The above advantages make the porous hydrogel particles ideal for efficient capture and detection of the drug-resistant tumor cells, which can be expected to facilitate the point-of-care pharmacotherapy and promisingly improve the patient outcomes.
Effect of the combination of imatinib mesylate (Glivec) and curcumin in chronic myeloid leukemia cell line
Authors: Eun Kyung Bae, Young-Ju Kim, Jong-Seok Lee, Seonyang Park, Byoung Kook Kim, Sung-Soo Yoon, Myung Ju Ahn
Journal: Cancer Research (2005)

5117  Curcumin, a natural, biologically active compound extracted from rhizomes of Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor and anti-oxidative properties. To investigate whether this agent was shown to decrease the proliferative potential and induce the apoptosis potential of cancer cells, first, the in vitro growth characteristics of K562 were examined after treating with various concentrations of curcumin. The results demonstrated that curcumin causes dose-dependent apoptosis of K562, which is preceded by the activation of caspase 3. Recently we reported that curcumin induced apoptosis via repression of p-AKT and activation of caspase-3. Despite high rates of hematologic and cytogenetic responses to Glivec therapy, the emergence of resistance to Glivec has been recognized as a major problem in the treatment of CML. To investigate whether combination of curcumin with Glivec is more effective than Glivec alone, the expression of apoptosis related genes were examined by western analysis in K562 chronic myeloid leukemia cell line. Our results showed that Bcl-2, -XL, and Bid were more down-regulated with combined treatment compared with control groups. And the expression levels of STATs, Cyclin D1 and A were dramatically down-regulated in combined treatment. Also, the activity of caspase 3 was 2-fold higher than compared with control groups. For further investigation of the genes affected by combination therapy, DNA chip analysis was performed. The expression of candidate genes, which we selected in chip analysis, was confirmed using real-time PCR. Our result indicated that apoptosis related genes were up-regulated and cyclin D1 and cyclin A were down-regulated. Also, several genes (protein phosphatase 2C, ZNF272, protein-tyrosine phosphatase nonreceptor 7 (PTPN7), SOCS2) were more down-regulated in combined treatment, showing 2-fold difference. Those genes may be associated with the progression of chronic myeloid leukemia. We suggest that their down-regulation by combined treatment was effective mainly via the induction of apoptosis. Taken together, our data suggested that combined treatment with curcumin could be effective to overcome the problems of Imatinib mesylate (Glivec, STI571) therapy.
Effect of ten-valent pneumococcal conjugate vaccine on invasive pneumococcal disease and nasopharyngeal carriage in Kenya: a longitudinal surveillance study
Authors: Laura L Hammitt, Anthony O Etyang, Susan C Morpeth, John Ojal, Alex Mutuku, Neema Mturi, Jennifer C Moisi, Ifedayo M Adetifa, Angela Karani, Donald O Akech, Mark Otiende, Tahreni Bwanaali, Jackline Wafula, Christine Mataza, Edward Mumbo, Collins Tabu, Maria Deloria Knoll, Evasius Bauni, Kevin Marsh, Thomas N Williams, Tatu Kamau, Shahnaaz K Sharif, Orin S Levine, J Anthony G Scott
Journal: The Lancet (2019)

Ten-valent pneumococcal conjugate vaccine (PCV10), delivered at 6, 10, and 14 weeks of age was introduced in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. Coverage with at least two PCV10 doses in children aged 2-11 months was 80% in 2011 and 84% in 2016; coverage with at least one dose in children aged 12-59 months was 66% in 2011 and 87% in 2016. We aimed to assess PCV10 effect against nasopharyngeal carriage and invasive pneumococcal disease (IPD) in children and adults in Kilifi County.
Abstract 4: Regulation of Mitochondrial Complex I Assembly
Authors: Edward Owusu-Ansah
Journal: Circulation Research (2017)

Mitochondrial CI (NADH: ubiquinone oxidoreductase) is the first and largest of the electron transport chain (ETC) complexes involved in oxidative phosphorylation, and has a molecular mass approaching 1 MDa. Mitochondrial Complex I (CI) is composed of 44 distinct subunits, but only 14 of these subunits are directly required for catalysis. A fundamental question in mitochondrial biology is to elucidate the roles of the additional 30 or so accessory subunits. In addition, CI can form different supercomplexes with other ETC complexes. It is unclear how these supercomplexes are assembled in the human heart, or any organism. We have established Drosophila flight muscles as a suitable system for studying CI assembly as well as the assembly of CI-containing supercomplexes. We show that many of the 30 accessory subunits regulate specific steps of CI assembly in vivo ; and that CI biogenesis in flight muscles proceeds via the formation of ~315-, ~370-, ~550-, and ~815 kDa CI assembly intermediates as has been reported in mammalian systems. A specific accessory subunit (dNDUFA5) is required for the formation or stabilization of the ~315 kDa assembly intermediate. Additionally, we define a specific role for the CX 9 C-containing accessory subunit (dNDUFS5); by showing that it is required for converting a transient CI assembly intermediate (an ~700 kDa assembly intermediate) into the ~815 kDa assembly intermediate. Finally, we are performing genetic screens to identify genes that specifically regulate supercomplex assembly. Our findings highlight the potential of studies of CI biogenesis in Drosophila to uncover novel mechanisms of CI assembly in a living organism, and establish Drosophila as a suitable model organism for addressing questions relevant to CI biogenesis in humans.
SAT-021-How to use platelets and liver stiffness to rule out esophageal varices needing treatment?
Authors: Arthur Berger, Federico Ravaioli, Oana Farcau, Davide Festi, Horia Stefanescu, Bureau christophe, Nathalie Ganne-Carrié, Annalisa Berzigotti, Victor De Ledinghen, Paul Cales
Journal: Journal of Hepatology (2019)