tbuckley/cabot-search huggingface dataset:
Development of nationwide genomic screening project (LC-SCRUM-Japan) contributing to the establishment of precision medicine in Japan.
Authors: Takuma Yokoyama, Shingo Matsumoto, Kiyotaka Yoh, Takashi Seto, Haruyasu Murakami, Eiji Iwama, Yuichiro Ohe, Masato Shingyoji, Kadoaki Ohashi, Koji Takeda, Yoshihiro Hattori, Shunichi Sugawara, Sho Saeki, Tomoya Fukui, Makoto Nishio, Masahiro Kodani, Takashi Kohno, Koji Tsuta, Katsuya Tsuchihara, Koichi Goto
Journal: Journal of Clinical Oncology (2016)

9089 Background: Most of targetable gene alterations are found only in 1-5% of non-small cell lung cancer (NSCLC) cases. Large scale screening systems for these rare populations are necessary for the development of molecular targeted therapies. Thus, a nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) has been operated since February 2013. Methods: Non-squamous NSCLCs without EGFR mutations were eligible for inclusion in this study. The tumors were analyzed for ALK/RET/ROS1 fusions using RT-PCR, and detected fusions were confirmed by FISH. Since March 2015, this nationwide project has been amended to an academic-industrial collaboration project with 14 pharmaceutical companies, and the samples were further subjected to a next-generation sequencing (NGS) system, Oncomine Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: As of December 31, 2015, 195 institutions across Japan were participating and 2161 patients had been enrolled. Among 1988 available samples, including 497 for the NGS analysis, ALK/RET/ROS1 fusions were detected in 37 (2%)/51 (3%)/86 (4%), respectively. The NGS analysis also showed that 269 cases (54%) had targetable gene alterations, including 82 KRAS mutations (17%), 36 ERBB2 mutations (7%), 28 BRAF mutations (6%), 22 PIK3CA mutations (4%), 6 NRAS mutations (1%), 6 MAP2K1 mutations (1%) and 2 FGFR2 fusions (0.4%). MET/ERBB2/FGFR1 amplifications were also detected by the NGS in 13 (3%)/11 (2%)/3 (1%) cases, respectively. Through this screening, the preplanned numbers of patient with RET and ROS1 fusions (n = 19 and 26, respectively) were successfully enrolled in clinical trials of vandetanib (LURET study in Japan) and of crizotinib (OO12-01 study in East Asia), respectively. Three patients with ERBB2 alterations and 2 with MET amplifications were also enrolled in genotype-matched ongoing trials. Conclusions: This nationwide screening system enables efficiently and successfully detecting various targetable gene alterations in NSCLC, thereby contributing to promote cancer precision medicine through the development of targeted therapies.
Array Based Comparative Genomic Hybridization Detects Copy Number Alterations in 80.3% of Adult Acute Lymphoblastic Leukemia (ALL) with Normal Karyotype or Failed Chromosome Banding Analysis and Identifies a Subset with Only Submicroscopic Alterations Associated with Favorable Outcome
Authors: Claudia Haferlach, Melanie Zenger, Torsten Haferlach, Wolfgang Kern, Susanne Schnittger
Journal: Blood (2014)
AMP-Activated Protein Kinase Alpha 2 Deletion Induces VSMC Phenotypic Switching and Reduces Features of Atherosclerotic Plaque Stability
Authors: Ye Ding, Miao Zhang, Wencheng Zhang, Qiulun Lu, Zhejun Cai, Ping Song, Imoh Sunday Okon, Lei Xiao, Ming-Hui Zou
Journal: Circulation Research (2016)

AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether AMPKα2 controls atherosclerotic plaque stability remains unknown.The aim of this study was to evaluate the impact of AMPKα2 deletion on atherosclerotic plaque stability in advanced atherosclerosis at the brachiocephalic arteries and to elucidate the underlying mechanisms.Features of atherosclerotic plaque stability and the markers for contractile or synthetic vascular smooth muscle cell (VSMC) phenotypes were monitored in the brachiocephalic arteries from Apoe(-/-)AMPKα2(-/-) mice or VSMC-specific AMPKα2(-/-) mice in an Apoe(-/-) background (Apoe(-/-)AMPKα2(sm-/-)) fed Western diet for 10 weeks. We identified that Apoe(-/-)AMPKα2(-/-) mice and Apoe(-/-)AMPKα2(sm-/-) mice exhibited similar unstable plaque features, aggravated VSMC phenotypic switching, and significant upregulation of Kruppel-like factor 4 (KLF4) in the plaques located in the brachiocephalic arteries compared with those found in Apoe(-/-) and Apoe(-/-)AMPKα2(sm+/+) control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in Apoe(-/-)AMPKα2(sm+/+) mice, but not in Apoe(-/-)AMPKα2(sm-/-) mice. VSMC isolated from AMPKα2(-/-) mice displayed a significant reduction of contractile proteins(smooth muscle actin-α, calponin, and SM-MHC [smooth muscle-mysion heavy chain]) in parallel with increased detection of synthetic proteins (vimentin and osteopontin) and KLF4, as observed in vivo. KLF4-specific siRNA abolished AMPKα2 deletion-induced VSMC phenotypic switching. Furthermore, pharmacological or genetic inhibition of nuclear factor-κB significantly decreased KLF4 upregulation in VSMC from AMPKα2(-/-) mice. Finally, we found that AMPKα2 deletion markedly promoted the binding of nuclear factor-κBp65 to KLF4 promoter.This study demonstrated that AMPKα2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in nuclear factor-κB-KLF4-dependent manner.
Abstract 1385: Patient-derived xenografts as validation material for NGS assays: Analysis of genetic homogeneity
Authors: Yves Konigshofer, Bharathi Anekella, Russell Garlick
Journal: Cancer Research (2016)

Abstract Full process controls and validation materials for next generation sequencing (NGS)-based molecular diagnostics in Oncology that mimic a biopsy sample and are renewable and scalable have been elusive. Patient-derived Xenografts (PDXs), which are similar in morphology and somatic mutations to original tumors, may present a solution to this pressing need. In order to evaluate the abilities of PDXs to serve as full process controls and validation materials, we had PDXs that contained established driver mutations KRAS G12C analyzed by clinical laboratories using a variety of different NGS-based assays. The resulting data was analyzed for genetic homogeneity as well as for the presence of mouse-derived variants. PDXs were found to be generally compatible with NGS-based assays and similar variant frequencies of driver mutations were reported. High concordance was also observed in variant frequencies of PDXs at passage 5 that were derived from the same tumor but grown in different mice. For example, the observed differences in over 90% of variants and all driver mutations were not statistically significant. In amplicon-based assays, which represent the majority of current assays that look at mutational hotspots, mouse-derived variants were rare. Typically, variant data was usable without any further processing. In hybrid/capture-based assays, mouse-derived variants were common because of the lower binding stringency used by these assays. Without further processing, this manifested in slightly lowered variant frequencies for driver mutations - where wild-type “reference” sequences are often conserved between species and thus inflate the number of reference sequences - and greatly elevated numbers of total variants. However, by processing the data at the FASTQ stage using in-house developed software, it was possible to effectively remove mouse-derived variants in a manner that would be compatible with patient testing as well. In conclusion, we show that PDXs are compatible with NGS-based assays and can be used to control the full process from the point where the Pathologist first fixes the tissue. Those containing driver mutations that have been previously characterized in cancer also enable laboratories to control and validate their assays by showing that they can consistently detect these mutations. Citation Format: Yves Konigshofer, Bharathi Anekella, Russell Garlick. Patient-derived xenografts as validation material for NGS assays: Analysis of genetic homogeneity. [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 1385.
Seizures in patients with glioma treated with phenytoin and levetiracetam
Authors: R. T. Merrell, D. H. Lachance, S. K. Anderson
Journal: Journal of Clinical Oncology (2009)

e13020 Background: Seizures are common in patients with glioma. Phenytoin, traditionally used for these patients, can be associated with intolerable side effects and potentially alters the metabolism of chemotherapeutic agents. Levetiracetam has more favorable pharmacokinetics facilitating ease of use with fewer side effects and is nonenzyme inducing. We compare seizure outcomes and side effects in patients with glioma treated with phenytoin and levetiracetam monotherapy. Methods: Retrospective analysis of consecutive patients with glioma. Subjects had at least one clinical seizure and had to be followed for 6 months. Seizure outcomes and side effects were compared between cohorts treated with phenytoin or levetiracetam. Seizure outcomes were measured by time to second seizure and seizure frequency. Results: 76 patients (34 female) with pathologically proven glioma and seizures were identified, 25 treated with phenytoin and 51 with levetiracetam. 64% had grade 4 astrocytoma. There was no difference in seizure outcome between the phenytoin and levetiracetam groups when comparing time to second seizure (p = 0.584), second seizure rates (p = 0.462), and average seizures per month (p = 0.776). When adjusting for age, gender, type of seizure, type of glioma, and dosage using univariate and multivariate models there were no differences between the treatment groups and none of these covariates were statistically significant for explaining the second seizure rates between treatment groups (all p values &gt;0.05). The incidence of side effects in the levetiracetam group was 5.9% versus 20% in the phenytoin group (p = 0.106). Additionally, 36.0% of the patients in the phenytoin group had dose adjustments not related to breakthrough seizures compared to only 9.8% in the levetiracetam group (p = 0.010). Conclusions: In this study, glioma patients treated with levetiracetam had similar seizure control as patients treated with phenytoin. Patients treated with levetiracetam experienced fewer side effects and required fewer non seizure related dose adjustments than patients treated with phenytoin. Levetiracetam is a safe, effective, and preferred alternative for seizure management in patients with glioma. No significant financial relationships to disclose.
Prolonged Overall Survival with Lenalidomide Plus Dexamethasone Compared with Dexamethasone Alone in Patients with Relapsed or Refractory Multiple Myeloma.
Authors: Donna Weber, Robert Knight, Christine Chen, Andrew Spencer, Zhinuan Yu, Jerome Zeldis, Marta Olesnyckyj, Meletios Dimopoulos
Journal: Blood (2007)
Predictive factors for pneumonia development and progression to respiratory failure in MERS-CoV infected patients
Authors: Jae-Hoon Ko, Ga Eun Park, Ji Yeon Lee, Ji Yong Lee, Sun Young Cho, Young Eun Ha, Cheol-In Kang, Ji-Man Kang, Yae-Jean Kim, Hee Jae Huh, Chang-Seok Ki, Byeong-Ho Jeong, Jinkyeong Park, Chi Ryang Chung, Doo Ryeon Chung, Jae-Hoon Song, Kyong Ran Peck
Journal: Journal of Infection (2016)

BackgroundAfter the 2015 Middle East respiratory syndrome (MERS) outbreak in Korea, prediction of pneumonia development and progression to respiratory failure was emphasized in control of MERS outbreak.MethodsMERS-CoV infected patients who were managed in a tertiary care center during the 2015 Korean MERS outbreak were reviewed. To analyze predictive factors for pneumonia development and progression to respiratory failure, we evaluated clinical variables measured within three days from symptom onset.ResultsA total of 45 patients were included in the study: 13 patients (28.9%) did not develop pneumonia, 19 developed pneumonia without respiratory failure (42.2%), and 13 progressed to respiratory failures (28.9%). The identified predictive factors for pneumonia development included age ≥45 years, fever ≥37.5 °C, thrombocytopenia, lymphopenia, CRP ≥ 2 mg/dL, and a threshold cycle value of PCR less than 28.5. For respiratory failure, the indicators included male, hypertension, low albumin concentration, thrombocytopenia, lymphopenia, and CRP ≥ 4 mg/dL (all P < 0.05). With ≥ two predictive factors for pneumonia development, 100% of patients developed pneumonia. Patients lacking the predictive factors did not progress to respiratory failure.ConclusionFor successful control of MERS outbreak, MERS-CoV infected patients with ≥ two predictive factors should be intensively managed from the initial presentation.
Efficacy and safety of eribulin in Japanese patients (pts) with advanced breast cancer.
Authors: H. Iwata, K. Aogi, N. Masuda, H. Mukai, M. Yoshida, Y. Rai, K. Taguchi, Y. Sasaki, S. Takashima
Journal: Journal of Clinical Oncology (2010)

1081 Background: Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor with a novel mechanism of action currently in development for the treatment of advanced breast cancer and other solid tumors. This study evaluated the efficacy and safety of eribulin in Japanese pts with advanced breast cancer. Methods: This was a single-arm, open-label phase 2 study in pts with metastatic breast cancer (MBC) or locally advanced disease (RECIST measurable disease), ECOG performance status 0-2, previously treated with an anthracycline and a taxane. Pts had received ≤3 prior chemotherapy (CT) regimens in the metastatic setting, and either progressed within 6 months of their last CT or relapsed within 12 months of adjuvant or neoadjuvant CT. Eribulin mesylate (1.4 mg/m2) was administered as a 2-5 minute intravenous (IV) infusion on days 1 and 8 of a 21-day cycle. The primary efficacy endpoint was objective response rate (ORR; number of pts with complete response [CR] or partial response [PR] divided by the number of pts in the analysis population) as assessed by independent review (IR) using RECIST criteria. Results: Of the 84 pts enrolled, 81 received eribulin and had the following characteristics: median age 54 (range: 31-72) yrs; ER-positive or PgR- positive (65%); HER2/neu-positive (11.3%); triple ER, PgR, HER2-negative (27.5%). The median of number of prior CT regimens was 3. The median number of treatment cycles with eribulin was 5 (range 1-20). ORR was 21.3% (CR 0, PR 17 pts; 95% CI 12.9, 31.8%). SD was 37.5% and the clinical benefit rate (CR + PR + SD>6 months) was 27.5% (95% CI 18.1, 38.6%). The median duration of response was 119.0 days (95% CI 85.0, 148.0 days). Median progression-free survival (PFS) was 112.0 days (95% CI 61.0, 133.0 days) and median overall survival (OS) was 331.0 days (95% CI 234.0, - days [upper CI not determined due to shortage of events]). Six-month PFS and OS rates were 20.1% and 72.3%, respectively. The most frequent treatment-related grade 3/4 toxicities were neutropenia (95.1%), leukopenia (74.1%), febrile neutropenia 13.6%, and lymphopenia (12.3%). Grade 3 peripheral neuropathy occurred in 3.7% of pts (no grade 4). Conclusions: Eribulin was effective and tolerable treatment for heavily pretreated pts with MBC or locally advanced disease. No significant financial relationships to disclose.
Abstract 199: Evaluation of multiple EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants using in vitro modeling
Authors: Hanako Hasegawa
Journal: Cancer Research (2016)

Abstract Purpose: We are able to use multiple EGFR-TKIs to treat patients with lung cancer harboring EGFR mutations. However, there is no clear guideline regarding which EGFR-TKIs should be used for which mutations. The purpose of this study is to establish an in vitro model to determine the “therapeutic window” of EGFR-TKIs against various types of EGFR mutations, including several EGFR exon 20 insertion mutations. Experimental design: We evaluated drug sensitivity and downstream signaling of human lung cancer cell lines harboring EGFR mutations (PC9, H3255, PC9-ER, BID007 and H1975) and Ba/F3 cells exogenously expressing mutated or wild type EGFR for the 1st (erlotinib), 2nd (afatinib), and 3rd (osimertinib and rociletinib) generation EGFR-TKIs using MTS assay, apoptosis assay and western blotting, simultaneously. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFRs. Results: The model of mutation specificity identified wide therapeutic windows of afatinib for exon 19 deletions and L858R and those of osimertinib and rociletinib for T790M positive mutations in human cell lines and Ba/F3 cells. In human cell lines and Ba/F3 cells harboring exon 19 deletions or L858R, afatinib showed the lowest IC50 and most potently inhibited the phosphorylation of EGFR, AKT, and ERK. Afatinib and 3rd generation EGFR-TKIs (osimertinib and rociletinib), effectively inhibited the cell growth and the phosphorylation of downstream signaling of EGFR in T790M positive cells. For EGFR exon 20 insertion mutations, osimertinib was potent and presented the most wide therapeutic window. Conclusion: This model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations including EGFR exon 20 insertions. Citation Format: Hanako Hasegawa. Evaluation of multiple EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants using in vitro modeling. [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 199.
The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: Independent validation in a prospective cohort of early stage patients
Authors: Stefano Molica, Tait D. Shanafelt, Diana Giannarelli, Massimo Gentile, Rosanna Mirabelli, Giovanna Cutrona, Luciano Levato, Nicola Di Renzo, Francesco Di Raimondo, Caterina Musolino, Francesco Angrilli, Angelo Famà, Anna Grazia Recchia, Kari G. Chaffee, Antonino Neri, Neil E. Kay, Manlio Ferrarini, Fortunato Morabito
Journal: American Journal of Hematology (2016)

The chronic lymphocytic leukemia International Prognostic Index (CLL‐IPI) combines 5 parameters (age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], IGHV mutational status, serum β2‐microglobulin) to predict survival and time‐to‐first‐treatment (TTFT) in CLL patients. We performed an observational study in 337 prospectively collected, Binet stage A patients to validate the ability of the CLL‐IPI to predict TTFT in an independent cohort of early stage CLL patients. The CLL‐IPI score stratified Binet stage A patients into three subgroups with different outcome. Since the CLL‐IPI was originally developed to predict survival, we next investigated the optimal cut‐off score to predict TTFT in Binet stage A patients. Recursive partitioning analysis identified three subsets with scores of 0 ( n = 139), 1 ( n = 90), and ≥ 2( n = 108). The probability of remaining free from therapy 5 years after diagnosis was 85%, 67% and 46% in these three categories ( P &lt; 0.0001.; C ‐statistic:c = 0.72; 95% CI:0.58‐0.81). This optimized CLL‐IPI scoring for TTFT was subsequently validated in an independent cohort of Binet A patients from the Mayo Clinic ( n = 525). The ability of either original or optimized CLL‐IPI to predict TTFT was equivalent to other prognostic models specifically designed for this endpoint (2011 MDACC score and O‐CLL1 score). Although originally developed to predict suvival, the CLL‐IPI is useful for predicting TTFT in early stage CLL patients. Am. J. Hematol. 91:1090–1095, 2016. © 2016 Wiley Periodicals, Inc.
Are IPSS-R and IPSS Cytogenetic Risk Stratification Informative At the Time of Allogeneic Hematopoietic Cell Transplantation?
Authors: Zohar Sachs, Michelle Dollan, Todd E De For, Leyla Shune, Sarah Cooley, Daniel J. Weisdorf, Erica D. Warlick, Celalettin Ustun
Journal: Blood (2012)
Optimization of porcine hepatocyte cryopreservation
Authors: Jana Smržová, Jana Ulrichová, Vilím Šimánek, Jan Lata, Petr Dítě, Jiří Adler
Journal: Gut (2000)

In this study , we sought the optimal procedure for
cryopreservativation of prrcine hapatocytes for both laboratory
and clinical purposes. This would ensure the accessibility of
cells for laboratory use, permit the standardisatin of
experiments and animals lives. Hepatocytes were isolated from
the liver lobe of a mini-pig and frozen with foetal calf serum
and DMSO in two different media in four different
concentrations, 1.8 ml cryotubes and 120 ml Baxter bags were
used for this purpose. Cells were cryopreseved either in a
controlled freezer Sylab or step by step in a styrofoan box and
stored at -196 C. The quality of fresh and cryopreserved
hepatocytes were assessed by trypan blue exclusion test and by
evaluation of cytochrome P450 isoenzymes and
glutathiones-S-transferase activities, primary cultures were
evaluated morphologically and by MTT test.
The emerging role of epigenetics in pulmonary hypertension
Authors: Elisabetta Gamen, Werner Seeger, Soni Savai Pullamsetti
Journal: European Respiratory Journal (2016)

Epigenetics is usually defined as the study of changes in phenotype and gene expression not related to sequence alterations, but rather the chemical modifications of DNA and of its associated chromatin proteins. These modifications can be acquired de novo, being inherited, and represent the way in which genome and environment interact. Recent evidence points to the involvement of epigenetic changes in the pathogenesis of pulmonary hypertension, as they can partly explain how environmental and lifestyle factors can impose susceptibility to pulmonary hypertension and can explain the phenotypic alteration and maintenance of the disease state.In this article, we review the epigenetic regulatory mechanisms that are mediated by DNA methylation, the post-translational modifications of histone tails and noncoding RNAs in the pathogenesis of pulmonary hypertension. Furthermore, pharmacological interventions aimed at epigenetic regulators/modifiers and their outcomes in different cellular and preclinical rodent models are discussed. Lastly, the remaining challenges and future directions in which to explore epigenetic-based therapies in pulmonary hypertension are discussed.