tbuckley/cabot-search huggingface dataset:
Patient-reported outcomes in a multicenter randomized study of in-person versus telephone disclosure of genetic test results for cancer susceptibility.
Authors: Angela R. Bradbury, Linda J. Patrick-Miller, Brian L. Egleston, Olufunmilayo I. Olopade, Michael J. Hall, Mary Beryl Daly, Linda Fleisher, Generosa Grana, Pamela Ganschow, Dominique Fetzer, Susan M. Domchek
Journal: Journal of Clinical Oncology (2016)

1502 Background: Genetic testing for cancer predisposition traditionally includes in-person pre- and post-test genetic counseling. Outcomes of telephone delivery of a range of cancer genetic test results, including multi-gene panel testing, are unknown. Methods: 984 patients at 5 centers undergoing cancer genetic testing (after in-person pre-test counseling) enrolled. 819 were randomly assigned to in-person (IPD; n=418) or telephone disclosure (TD; n=401) of results. 17% (n=165) declined randomization given a preference for IPD. Primary outcomes were knowledge, state anxiety and general anxiety. We used non-inferiority tests for primary analyses, and T-tests for secondary analyses. Results: TD was not worse than IPD for general and state anxiety, but did not reach the non-inferiority threshold for knowledge. In secondary analyses examining change scores between arms, there were no significant differences in knowledge, anxiety, depression, or cancer worry between arms. Those in the TD arm had greater increases in satisfaction (+3.26 v. -0.26, p=0.008), greater reductions in access burdens (-1.5 v. 0.10, p<0.001) and less increase in uncertainty (-0.26 v. + 0.76, p=0.04) compared to IPD. Among several subgroups (169 participants who had multi-gene testing; 88 who received a positive result, 54 who received a variant of uncertain significance), there were no significant differences between randomized arms in knowledge, depression, cancer worry or uncertainty, and TD was associated with greater increases in satisfaction and decreases in access burdens compared to IPD. Among those with a positive result, those in the TD arm had less increase in general anxiety compared to IPD (5.85 v. 6.77, p=0.02). Conclusions: Short-term patient reported distress is not worse in telephone communication of results than in-person disclosure, but knowledge failed the test for non-inferiority. Although there are patient reported advantages to phone disclosure, longitudinal data and evaluation of the impact on health behaviors is needed before widespread adoption of phone communication for disclosure of genetic test results, particularly in the era of multi-gene testing. Clinical trial information: NCT01736345.
A Systems Biology Approach to Molecular Diagnostics in the ErbB-3/HER2 System
Authors: Yosef Yarden
Journal: Clinical Cancer Research (2007)

PL03-03   Growth factors and their transmembrane receptors contribute to all steps of tumor progression, from the initial phase of clonal expansion, through angiogenesis to metastasis. Hence, the information relay system involved in growth factor signaling provides potential sites for signal interception and tumor inhibition. A relevant example comprises the epidermal growth factor (EGF) and the respective receptor tyrosine kinase, namely ErbB-1/EGFR, which belongs to a prototype signaling module that drives carcinoma development. The extended module includes two autonomous receptor, EGFR and ErbB-4, and two non-autonomous receptors, namely: a ligand-less oncogenic receptor, HER2/ErbB-2, and a kinase-dead receptor (ErbB-3). This signaling module is richly involved in human cancer and already serves as a target for several cancer drugs. Due to inherent complexity and a large amount of experimental data, we propose a systems approach to understanding ErbB signaling. EGF-to-ErbB signaling is envisioned as a bow-tie configured, evolvable network, sharing modularity, redundancy and control circuits with robust biological and engineered systems. My presentation will concentrate on system controls, a plethora of negative feedback loops, which include E3 ubiquitin ligases, receptor endocytosis and newly transcribed genes. Because network fragility is an inevitable tradeoff of robustness, systems level understanding is expected to identify therapeutic opportunities for targeting aberrant activation of the network in human pathologies. Specific examples will be discussed with an emphasis on gene expression and the control of metastsis.
Phase 1 study of triweekly nab-paclitaxel combined with S-1 in patients with HER2 negative metastatic breast cancer.
Authors: Katsuhiko Nakatsukasa, Tetsuya Taguchi, Kouichi Sakaguchi, Yoshihumi Hujita
Journal: Journal of Clinical Oncology (2016)

e12510 Background: Combination chemotherapy regimens show a significant advantage for overall survival, tumor response and time to progression in patients with metastatic breast cancer (MBC), but they also appear more toxicities. Previous reports revealed that S-1 and paclitaxel repressed synergistically tumor progression in a xenograft mouse model, so we conducted a phase I study of nab-paclitaxel and S-1 to evaluate the efficacy and safety. Methods: From 2012 to 2015, nine patients were enrolled. This study was done “3+3 design” from level 1 (triweekly nab-paclitaxel 220 mg/m2 on day1, S-1 65 mg for 14 days followed by one week rest). The median age was 56 years. Five patients diagnosis stage IV. Four patients had previously received two to six regimens, including anthracycline and taxane. The primary endpoints of this study were to estimate the maximum tolerated dose (MTD) and recommended dose (RD) of the combination therapy of nab-paclitaxel and S-1 in patients with MBC. The secondary endpoints were to evaluate response rate (RR), clinical benefit rate (CBR), and safety. Results: RD was determined at 260 mg/m2 nab-paclitaxel intravenously injected on day 1 combination with 65 mg/m2 oral S-1 for 14 days followed by one week of rest. Of the nine patients, six patients were partial response, one was stable disease, one was progression disease, and one was not evaluate. The RR and CBR were 66.7 % (95% confidence interval [CI], 29.9-92.5) and 77.8 % (95% CI, 45.0-95.9), respectively. The most frequent reasons for discontinuation of chemotherapy were disease progression (four [44.4%]), peripheral neuropathy (two [22.2%]), watering eyes (one [11.1%]). Conclusions: We demonstrated a feasibility of combination chemotherapy with nab-paclitaxel and S-1. In addition, the present results showed the high response rates in MBC patients with previous regimens. The establishment of effective countermeasures against nab-paclitaxel invoked peripheral neuropathy is needed. Clinical trial information: UMIN000016377.
Modulation of apoptosis and apoptosis related genes in oesophageal adenocarcinoma following neoadjuvant chemoradiotherapy
Authors: AA Raouf, DA Evoy, MM Griffin, JV Reynolds
Journal: Endoscopy (2005)

Aims: To assess frequency of spontaneous apoptosis and cell proliferation in oesophageal adenocarcinoma prior to and after neoadjuvant chemoradiotherapy.
Anion gap and cancer mortality: Insight from NHANES database.
Authors: Ashish Verma, Rehan Qayyum
Journal: Journal of Clinical Oncology (2017)

e13068 Background: The serum anion gap is an effective tool to analyze acid- base disorders for the past 40 years. Anion gap and non-anion gap acidosis is prevalent in cancer patients and contributes to morbidity and mortality The aim of the present study was to investigate the independent association of serum anion gap with cancer mortality. Methods: We examined the 34,370 participants ( ≥ 20years of age) using National Health and Nutrition Examination survey data (1999-2010) combined with National Death Index for mortality status through December 2011.The serum anion gap was calculated by subtracting sum of chloride and bicarbonate from sodium concentrations in meq/l. We divided the data set in to four quartiles of serum anion gap. Cox proportional hazard models were made to estimate the hazard ratios for cancer mortality for each unit increase in serum anion gap. The models were adjusted from demographic and confoundig variables. Results: The mean age of participants was 49.59±18.42 years. Out of total population 33,717(98.1%) were alive and 651 (1.9%) were dead secondary to cancer. The mean period of follow up was 5.55±3.53 years. In univariate regression model using serum anion gap as continuous variable, we found 6% (HR-1.06;95%CI,1.0-1.1), increase in cancer mortality with each unit increase in serum anion gap. After adjusting for potential confounders using multivariate regression model we found 8%(HR-1.08;95%CI,1.03-1.14), increase in cancer mortality with each unit increase in serum anion gap. In univariate regression model using quartiles, we found 47% (HR-1.47;95%CI,1.04-1.93), increase in cancer mortality with each unit increase in serum anion gap in highest quartile compared to the lowest quartile. After adjusting to the potential confounders the risk for cancer mortality increases to 60% in highest quartile comparison to lowest quartile (HR-1.60;95%CI,1.12-2.26). Conclusions: We found a linear association between serum anion gap and cancer mortality. A high serum anion gap is associated with increase in cancer mortality and may be the prognostic indicator of cancer mortality in general population. This should be validated by performing further investigation.
Prognostic significance of interferon regulating factor 4 (IRF4) in node-negative breast cancer.
Authors: Marcus Schmidt, Leonie van de Sandt, Karolina Edlund, Isabel Sicking, Marco Johannes Battista, Antje Lebrecht, Gerald Hoffmann, Joerg Rahnenfuehrer, Jan G Hengstler
Journal: Journal of Clinical Oncology (2014)

620 Background: The transcription factor IRF4 (interferon regulating factor 4) regulates immunoglobulin class switch recombination as well as plasma cell differentiation. We examined the prognostic significance of IRF4 mRNA expression in node-negative breast cancer. Methods: Microarray based gene-expression data for IRF4 (204562_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of IRF4 on metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes: luminal A (ER+/HER2-/aurora kinase A [AURKA]low, luminal B (ER+/HER2-/AURKAhigh), basal-like (ER-/HER2-), HER2+. Independent prognostic relevance was analysed using multivariate Cox regression. Results: Higher RNA expression of IRF4 was related to better MFS in a meta-analysis of the whole cohort (HR 0.49, 95% CI 0.35-0.69, P<0.0001). Prognostic significance was most pronounced in the HER2+ positive molecular subtype (HR 0.18, 95% CI 0.06-0.55, P=0.0008) as compared to luminal A (HR 0.75, 95% CI 0.36-1.53, P=0.425), luminal B (HR 0.39, 95% CI 0.20-0.76, P=0.0044) and basal-like (HR 0.55, 95% CI 0.32-0.94), P=0.0279) carcinomas of the breast. IRF4 showed independent prognostic significance (HR 0.394, 95% CI 0.249-0.621, P<0.0001) in multivariate analysis. In addition to IRF4, only histological grade of differentiation (HR 2.591, 95% CI 1.604-4.187, P<0.0001) and tumor size (HR 1.791, 95% CI 1.135-2.825, P=0.012), but neither age nor HER2 status nor hormone receptor status retained an independent prognostic association with MFS. Conclusions: The transcription factor IRF4 has independent prognostic significance in node-negative breast cancer. Higher expression of IRF4 is associated with improved outcome. The prognostic impact differs between diverse molecular subtypes and is most pronounced in HER2+ breast cancer.
Whole exome sequencing and copy-number variation analysis of 20 NF2-associated spinal and cranial meningiomas.
Authors: Ramita Dewan, Alexander Pemov, Nancy F Hansen, Settara C Chandrasekharappa, Jim Mullikin, Joseph F Boland, Ashok R Asthagiri, Douglas Stewart
Journal: Journal of Clinical Oncology (2017)

2051 Background: Neurofibromatosis type 2 is a heritable tumor predisposition syndrome characterized by the growth of multiple tumor types in the nervous system, including bilateral vestibular schwannomas, meningiomas and ependymomas. Recent genomic sequencing studies have revealed that NF2 inactivation is the most frequent genetic event in sporadic meningiomas. In line with Knudson’s hypothesis, it is accepted that somatic inactivation of the wildtype NF2 allele initiates tumor growth in NF2 patients, but little is known of what other genes or pathways influence meningioma tumorigenesis. Methods: To investigate this question, we performed whole exome sequencing (WES) (Illumina Hi-Seq 2500 platform, 96 Mb SeqCap EZ Exome + UTR Library, NimbleGen) and SNP-array analysis (HumanOmniExpressExome-8, v1.2 arrays, Illumina) of twenty spinal and cranial meningioma samples from seven NF2 patients. Mutation validation was completed via orthogonal sequencing (IonTorrent, ThermoFisher). Results: We identified NF2 germline mutations in all patients, including five nonsense, one splice site and one likely pathogenic intronic mutation. We found that the predominant mechanism of somatic NF2 inactivation in the tumors was loss of heterozygosity (LOH): we identified large chromosome 22 deletions containing NF2 in nineteen out of twenty meningiomas. The second most frequent chromosomal aberration was a deletion within chromosome 1p, followed by entire chromosome X deletion and rearrangements in chromosome 17q. The remaining samples exhibited normal diploid genomic architecture. Somatic mutations included about twenty point substitutions and small indels. Conclusions: Our study revealed that somatic inactivation of NF2 is the most frequent and only recurrent genetic event in NF2-associated meningiomas. Large LOH events are the most prevalent second hit mechanism and may also represent a common path of meningioma progression. Somatic single nucleotide substitutions and small indels are rare in these tumors. Interestingly, we did not identify mutations in TRAF7, KLF4, AKT1, or SMO, which have been found to be critical for non-NF2 meningioma growth.
Large scale adverse event data mining for targeted therapies development.
Authors: Mayur Sarangdhar, Bruce Aronow, Anil Goud Jegga, Brian Turpin, Erin Haag Breese, John Peter Perentesis
Journal: Journal of Clinical Oncology (2017)

2538 Background: Targeted anti-cancer small molecule drugs &amp; immune therapies have had a dramatic impact in improving outcomes &amp; the approach to clinical trials. Increasingly, regulatory approvals are expedited with small studies designed to identify strong efficacy signals. However, this may limit the extent of safety profiling. The use of large scale/big data meta-analyses can identify novel safety &amp; efficacy signals in "real-world" medical settings. Methods: We used AERSMine, an open-source data mining platform to identify drug toxicity signatures in the FDA’s Adverse Event Reporting System of 8.6 million patients. We identified patients (n = 732,198) who received either traditional and targeted cancer therapy &amp; identified therapy-specific toxicity patterns. Patients were classified based on exposures: anthracyclines (n = 83,179), platinum (117,993), antimetabolites (93,062), alkylators (81,507), antimicrotubule agents (97,726), HER2 inhibitors (40,040), VEGFis (79,144), VEGF-TKis (90,734), multi TKis (34,457), anaplastic lymphoma Kis (7,635), PI3K-AKT-mTOR inhibitors (33,864), Bruton TKis (9,247), MEKis (4,018), immunomodulatory agents (174,810), proteasome inhibitors (44,681), immune checkpoint inhibitors (20,287). Pharmacovigilance metrics [Relative Risks &amp; safety signals] were used to establish statistical correlation &amp; toxicity signatures were differentiated using the Kolmogorov–Smirnov test. Results: To validate the use of the AERSMine to detect AEs, we focused on cardiotoxicity. It identified classic drug associated AEs (e.g. ventricular dysfunction with anthracyclines, HER2is &amp; VEGFis; VEGFi hypertension &amp; vascular toxicity; multi TKIs vascular events). AERSMine also identified recently reported uncommon toxicities of myositis/myocarditis with immune checkpoint inhibitors. It indicated a higher frequency of myositis/myocarditis with combination immune checkpoint therapy, paralleling industry corporate safety databases. These toxicities were reported at higher frequencies in patients &gt; 65 yrs. Conclusions: AERSMine “big data” analyses provide a sensitive tool to detect potential new patterns of AEs simultaneously across multiple clinical trials &amp; in the real-world setting.
Abstract 11314: Inverse Relationship Between Body Mass Index and Coronary Artery Calcification in Older Patients with Clinically Significant Coronary Lesions
Authors: Jason C Kovacic, Paul Lee, Usman Baber, Rucha Karajgikar, Pedro Moreno, Roxana Mehran, George Dangas, Valentin Fuster, Samin K Sharma, Annapoorna S Kini
Journal: Circulation (2011)

Background: Extensive animal and clinical data indicate a ‘calcification paradox’, whereby reduced bone mineral density is associated with increased vascular calcification. In addition, it is well described that reduced bone mineral density is prevalent in leaner persons with small body size. Therefore, although a positive relationship exists between body mass index (BMI) and coronary artery calcification (CAC) in younger persons, we hypothesized that in older persons and/or those at risk for osteoporosis an inverse relationship between BMI and CAC may apply. Methods: We accessed our single-center registry for 07/1999 - 06/2009, identifying 20068 consecutive patients (age 65.9 ± 12.1; 34.3% females) that underwent percutaneous coronary intervention (PCI). Index lesion calcification (ILC; none, mild, moderate, severe) was analyzed with respect to BMI. Results: Lower BMI was observed among those with greater ILC. Comparing index lesions with no angiographic calcification to those with the most severe, mean ...
YD277 Suppresses Triple-Negative Breast Cancer Partially Through Activating the Endoplasmic Reticulum Stress Pathway
Authors: Zekun Chen, Qiuju Wu, Ye Ding, Wenhui Zhou, Rong Liu, Haiying Chen, Jia Zhou, Jing Feng, Ceshi Chen
Journal: Theranostics (2017)

Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor clinical outcomes. YD277 is a novel small molecule derived from ML264, a KLF5 inhibitor that elicits cytotoxic effects in colon cancer cell lines. Our previous studies suggest that Krüpple-like factor 5 (KLF5) is a promising therapeutic target for TNBC. In this study, we demonstrated that YD277 significantly induced G1 cell cycle arrest and apoptosis in MDA-MB-231 and MDA-MB-468 TNBC cells, independent of KLF5 inhibition. YD277 also reduced the protein expression levels of Cyclin D1, Bcl2 and Bclxl and promoted the expression of p21 and p27. Moreover, the pro-apoptotic activity of YD277 in TNBC was mediated by the transcription of IRE1α, a key molecule in the endoplasmic reticulum (ER) stress pathway. Finally, YD277 (15 mg/kg) significantly suppressed the growth of MDA-MB-231 tumor xenografts in nude mice. These findings indicate that YD277 is a promising chemotherapeutic candidate for TNBC.
Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-nitrosated human serum albumin dimer
Authors: Ryo Kinoshita, Yu Ishima, Victor T.G. Chuang, Hideaki Nakamura, Jun Fang, Hiroshi Watanabe, Taro Shimizu, Keiichiro Okuhira, Tatsuhiro Ishida, Hiroshi Maeda, Masaki Otagiri, Toru Maruyama
Journal: Biomaterials (2017)
Abstract P050: Novel Mechanism of Ser-496 ERK5 Phosphorylation and Association with p90RSK Is Critical for Regulating C Terminus of Hsc70-Interacting Protein (CHIP) Ubiquitin E3 Ligase Activity in Diabetes-Mediated Exacerbation of Cardiomyocyte Apoptosis and Left Ventricular Dysfunction After Myocardial Infarction
Authors: Nhat-Tu Le, Yuichiro Takei, Chang-Hoon Woo, Tetsuro Shishido, Yan Lu, Carolyn McClain, Chen Yan, Cam Patterson, Jay Yang, Jun-ichi Abe
Journal: Circulation Research (2011)

Rationale: Cardiac dysfunction is accelerated in DM patients after MI. Previously, we reported the critical role of ERK5 and CHIP association on CHIP Ub E3 ligase activity, which inhibits inducible cAMP early repressor (ICER)-mediated apoptosis and left ventricle (LV) dysfunction after MI in DM (DM + MI). Yet the regulatory mechanism of ERK5-CHIP has not been established. Objective: Since we found that p90RSK activation was increased in DM heart, we investigated whether p90RSK activation may inhibit ERK5-mediated CHIP activation, and subsequent ICER induction and apoptosis. Methods and Results: The inhibition of p90RSK activation prevented the reduction of ERK5-CHIP binding, CHIP activity, as well as ICER induction and cardiac apoptosis both in vitro after angiotensin II (ang II) stimulation and in vivo after DM + MI. p90RSK and CHIP share a same binding site with ERK5 C-terminal domain (aa571–807), and overexpression of both p90RSK and ERK5 (aa571–807) fragment, but not kinase dead mutant of p90RSK, inhibited ERK5-CHIP association, suggesting the critical role of p90RSK activation on ERK5-CHIP interaction, and competitive nature of p90RSK and CHIP against ERK5 association. Furthermore. LC-MS/MS analysis identified ERK5-S496 as being directly phosphorylated by p90RSK, and ERK5 S496A mutant significantly impaired ang II-mediated inhibition of CHIP Ub ligase activity, suggesting the critical role of Ser-496 phoaphorylation of ERK5 on CHIP activity. Therefore, p90RSK activation is critical for both p90RSK-ERK5 association as well as ERK5-Ser496 phosphorylation, and following disruption of ERK5-CHIP interaction and subsequent inhibition of CHIP Ub ligase activity. The reduction of CHIP Ub ligase activity and LV dysfunction were accelerated both in cardio-specific ERK5 knock out and wild type p90RSK transgenic mice (WT-p90RSK-Tg). Furthermore, double transgenic mice of WT-p90RSK and constitutively active form of MEK5α (specific ERK5 activator) inhibited single WT-p90RSK-Tg-medaited reduction of CHIP Ub ligase activity, LV dysfunction, and improved mortality after MI. Conclusions: These data strongly suggested that p90RSK activation accelerated cardiac dysfunction and apoptosis after DM + MI via inhibiting ERK5-CHIP module.