tbuckley/cabot-search huggingface dataset:
Nilotinib as co-adjuvant treatment with doxorubicin in sarcomas: Phase I trial results—A Spanish Group for Research on Sarcoma (GEIS) study.
Authors: Javier Martin Broto, Andrés Redondo, Javier Martinez-Trufero, Claudia María Valverde, Maria Angeles Vaz, Medina Javier, Antonia Obrador, Irene Felipe, Beatriz Castelo, Paula Hidalgo, Isabel Pajares, Jose Duran, Raul Amurrio, Regina Alemany
Journal: Journal of Clinical Oncology (2014)

10573 Background: Our group has recently published several relevant aspects of MDR proteins as potential targets in sarcomas: MRP1 expression was significantly correlated with poor prognosis in sarcoma patients, nilotinib was a strong inhibitor of MRP1/Pgp efflux activities and, finally, nilotinib plus doxorubicin (DX) showed to be synergistic regarding apoptosis in several sarcoma cell lines. Experiments in mice revealed that nilotinib plus DX did not increase either liver or cardiac toxicity. Supported by the previous information, a phase I/II trial was designed in order to explore the feasibility of nilotinib as co-adjuvant of DX by inhibiting MRP1/Pgp efflux activity. Methods: Nilotinib 400mg/12h was administered fixed from day 1 to 6 and DX on day 5th of each cycle. Three dose-escalation levels for DX at 60 mg/m2; 65 mg/m2 and 75 mg/m2were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma (LPS) and leiomyosarcoma (LMS) and metastatic high grade chondrosarcoma (CHO). Pharmacodynamic effects of nilotinib on the expression of MRP1 and Pgp RNA were measured by RT-PCR comparing day 1 and 5. Results: In the phase I trial, 13 patients were enrolled:7 CHO, 4 LPS and 2 LMS. In 46 administered cycles the most relevant non-hematological toxicities per patient were: alopecia (100%), asthenia (62%), nausea (54%), increased GGT (46%), increased ALP (38%), constipation (31%) and mucositis (23%). All of these were grade 1-2. Concerning non-hematological toxicity, there was 23% G1-2 neutropenia, 54% G3-4 neutropenia, and 61% G1-2 anemia. GCSF was recommended from day 11-17 after observing delayed neutrophil recovery on day 21. In general toxicity was easily manageable. Considering efficacy there were 2 PR (2 LPS), 8 SD (5 CHO, 2 LPS, 1 LMS), 3 PD (2 CHO and 1 LMS). Pgp and MRP1 RNA expression levels decreased by 58.47-fold and 1.47-fold respectively on day 5 of cycle. Conclusions: Combination of MRP1-Pgp inhibitor, nilotinib, as co-adjuvant with DX is feasible and it appears does not add substantial toxicity compared to DX alone. Pharmacodynamic study supports this concept. GEIS Group is currently conducting the phase II trial. Clinical trial information: 2011-002368-26.
What is the effect of aerobic exercise intensity on cardiorespiratory fitness in those undergoing cardiac rehabilitation? A systematic review with meta-analysis
Authors: Braden L Mitchell, Merilyn J Lock, Kade Davison, Gaynor Parfitt, John P Buckley, Roger G Eston
Journal: British Journal of Sports Medicine (2018)

Objective Assess the role of exercise intensity on changes in cardiorespiratory fitness (CRF) in patients with cardiac conditions attending exercise-based cardiac rehabilitation. Design Systematic review with meta-analysis. Data sources MEDLINE, Embase, CINAHL, SPORTDiscus, PsycINFO and Web of Science. Eligibility criteria for selection Studies assessing change in CRF (reported as peak oxygen uptake; V̇O 2peak ) in patients post myocardial infarction and revascularisation, following exercise-based cardiac rehabilitation. Studies establishing V̇O 2peak via symptom-limited exercise test with ventilatory gas analysis and reported intensity of exercise during rehabilitation were included. Studies with mean ejection fraction &lt;40% were excluded. Results 128 studies including 13 220 patients were included. Interventions were classified as moderate, moderate-to-vigorous or vigorous intensity based on published recommendations. Moderate and moderate-to-vigorous-intensity interventions were associated with a moderate increase in relative V̇O 2peak (standardised mean difference±95% CI=0.94±0.30 and 0.93±0.17, respectively), and vigorous-intensity exercise with a large increase (1.10±0.25). Moderate and vigorous-intensity interventions were associated with moderate improvements in absolute V̇O 2peak (0.63±0.34 and 0.93±0.20, respectively), whereas moderate-to-vigorous-intensity interventions elicited a large effect (1.27±0.75). Large heterogeneity among studies was observed for all analyses. Subgroup analyses yielded statistically significant, but inconsistent, improvements in CRF. Conclusion Engagement in exercise-based cardiac rehabilitation was associated with significant improvements in both absolute and relative V̇O 2peak . Although exercise of vigorous intensity produced the greatest pooled effect for change in relative V̇O 2peak , differences in pooled effects between intensities could not be considered clinically meaningful. Registration Prospero CRD42016035638.
Abstract LB-358: Abnormal O-glycosylation promotes prostate cancer stemness and mediates metastatic niche
Authors: Chin-Hsien Tsai, Sheue-Fen Tzeng
Journal: Cancer Research (2018)

Abstract Oncofetal Galβ1-3GalNAc O-glycan, T antigen, is increased in about 60% carcinomas of breast, colon, stomach, and prostate. Notably, coexpression of T antigen with CD44 or CD133, markers of cancer stem cells, has been identified in lung, breast, and liver cancers. Using spontaneous metastasis model of 22Rv1 cells, we derived high metastatic 22Rv1-M4 cells and found altered O-glycosylation in the 22Rv1-M4 cells and also 22Rv1-M4-derived host microenvironment compared to parental cells. Our study indicated that high expressions of T antigen synthase C1GALT1 are associated with metastatic PCa and poor survival, probably contributed by the interaction of galectin-4 and glycan. Galectin-4 engaged with MYC-dependent C1GALT1 mediated O-glycan and resulted in RTK phosphorylation; activation of RTKs enhanced not only androgen-independent growth but also metastatic colonization which mediated by ERK-AP1-mediated SOX9 expression. Downregulation of SOX9 significantly inhibited the tumorsphere formation and in vivo metastasis. Moreover, coexpression of SOX9 and MYC in immortalized prostate epithelial cells RWPE1 generates the heterogeneous population presenting both epithelial type and cancer-like cells in mouse renal capsule. On the other hand, analyses of lung tissues from mice bearing tumor of 22Rv1-M4 cells relative to that bearing tumor of 22Rv1 parental cells exhibit the upregulated O-glycosylation enzymes, which associated with increased plant Jacalin lectin staining, CD45+ cells infiltration, and endothelial permeability indicated by dextran leakage. Tail-vein injection of 22Rv1-M4 cells exhibits aggressive systemic metastasis in a mouse conditioned by subcutaneous 22Rv1-M4 tumor compared to that in a mouse conditioned by subcutaneous 22Rv1 tumor These data suggest high metastatic prostate cancer cells adapt the lung microenvironment for seeding and colonization of cancer cells. Citation Format: Chin-Hsien Tsai, Sheue-Fen Tzeng. Abnormal O-glycosylation promotes prostate cancer stemness and mediates metastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-358.
Multiple Pacemaker Sites in Spontaneously Active Vascular Muscle
Authors: Kenthermsmeyer
Journal: Circulation Research (1973)

Multiple-electrode extracellular recording was used to determine the degree to which membrane electrical activity spreads through the rat anterior mesenteric-hepatic portal vein. Glass-pore electrodes filled with physiological salt solution were placed against the isolated intact vein or longitudinal strips of vein at 1-mm intervals to record spontaneous spiking. No pressure electrode effect was found in the rat portal vein. Patterns and amplitudes of spiking indicated that spike activity was conducted for only a few millimeters. Multiple pacemaker sites and decremental conduction were found in both normal physiological solution and solution in which calcium concentration was halved or doubled and potassium concentration was doubled or tripled. An average of three or four pacemaker sites was found in all solutions. Approximate equipotential contours were constructed from a grid map of average spike amplitudes, and they showed the multiple regions of high-amplitude spiking, the nonuniform spatial decay of ...
Association of response to neoadjuvant chemotherapy (NAC) in premenopausal patients with hormone receptor-positive early breast cancer with chemotherapy-induced ovarian function suppression by NAC.
Authors: Yutaka Yamamoto, Risa Yamaguchi, Yoshitaka Fujiki, Mutsuko Ibusuki, Keiichi Murakami, Hirotaka Iwase
Journal: Journal of Clinical Oncology (2012)

e11017 Background: The purpose of this study is to assess the additive endocrine effect by chemotherapy-induced ovarian function suppression (CIOS) for premenopausal women with early breast cancer in neoadjuvant chemotherapy (NAC). Methods: We retrospectively compared the clinical efficacy to NAC between premenopausal and postmenopausal patients with early breast cancer to evaluate the endocrine effect by CIOS. One-hundred twenty two patients received NAC with anthracycline-containing regimen and/or taxane in Kumamoto University Hospital between April 2004 and March 2011. Results: Objective response rate by NAC in premenopausal ER-positive/HER2-negative patients is greater than that in postmenopausal ER-/HER2+ patients (premenopausal 93% vs. postmenopausal 63%, p=0.0121). Reduction rate of primary tumor by NAC on imaging studies in premenopausal ER+/HER2- patients is greater than that in postmenopausal ER-/HER2+ patients (premenopausal 54% vs. postmenopausal 40%, p=0.006). However, no significant difference in response rate between in premenopausal patients with other subtypes and postmenopausal patients with those was found (ER+/HER2+; premenopausal 50% vs. postmenopausal 48%, ER-/HER2+; premenopausal 43% vs. postmenopausal 77%, Triple-negative; premenopausal 86% vs. postmenopausal 65%). All of premenopausal women were suppressed ovarian function within two months after initiation of NAC. Expression levels of progesterone receptor on primary tumor in premenopausal ER+ cancer were significantly decreased after NAC compared with that in postmenopausal ER+ cancer (premenopausal -40.3% vs. postmenopausal +3.6%, p&lt;0.001). Conclusions: These data suggests that CIOS by NAC contributes the additive effects through the endocrine fashion in premenopausal patients with ER+/HER2- breast cancer.
Abstract LB-383: Towards automation of germline variant curation in cancer genetics
Authors: Vignesh Ravichandran, Zarina Shameer, Kenneth Offit, Vijai Joseph
Journal: Cancer Research (2018)

Abstract Cancer care professionals are now increasingly asked to interpret multiplexed gene sequencing of patients at hereditary risk for cancer. Assessments for variant classification now require orthogonal data searches, requiring aggregation of multiple lines of evidence from diverse resources. The burden of evidence required for each variant to meet thresholds for pathogenicity or actionability now poses a growing challenge for those seeking to counsel patients and families following germline genetic testing. A computational tool that automates, provides uniformity and significantly accelerates this interpretive process is required. The automated tool described here, Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein and disease specific information from public sources. When compared against expert curation aggregated from three groups - (i) Prostate Cancer Study; (ii) Breast Cancer Study and (iii) ClinVar. PathoMAN achieves high concordance (83.1% pathogenic, 75.5% benign) and negligible discordance (0.04% pathogenic, 0.9% benign) when contrasted against expert curation. Loss of resolution (8.6% pathogenic, 23.64% benign) and gain of resolution (6.6% pathogenic, 1.6% benign) are observed. We highlight the advantages and weaknesses related to the use of programmable automation of variant classification. PathoMAN provides a substantial advance in rapid classification of genetic variants by generation of robust models using a knowledge-base of diverse genetic data. It is an easily accessible, web-based resource that allows rapid pathogenicity assessment of a large number of variants. We also propose a new nosology for the five ACMG classes to facilitate more accurate reporting to ClinVar. The proposed refinements will better structure ClinVar to allow automation in cancer susceptibility reporting. Such bioinformatics tools are an essential prerequisite to reduce the manual workload of domain level experts. Citation Format: Vignesh Ravichandran, Zarina Shameer, Kenneth Offit, Vijai Joseph. Towards automation of germline variant curation in cancer genetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-383.
Abstract 3370: Mad2l2 inhibits colorectal cancer growth by promoting ncoa3 ubiquitination and degradation
Authors: yixin li, ge qin, qian long, changlin zhang, dingbo shi, miao chen, wuguo deng
Journal: Cancer Research (2018)

Abstract Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation coupled with mass spectrometry analysis was used to detect, identify and verify the proteins that interacted with NCOA3 in CRC cells. The biological functions of the candidate proteins and the underlying molecular mechanism were investigated in CRC cell lines and a mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We discovered and identified mitotic arrest deficient 2-like protein 2 (MAD2L2, also known as MAD2B or REV7) as an interaction partner of NCOA3 by immunoprecipitation coupled with mass spectrometry analysis. Overexpression of MAD2L2 suppressed the cell proliferation, migration and clonogenecity in CRC cell lines and a mouse model by inducing the degradation of NCOA3. We also found that increased MAD2L2 expression in CRC cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. Moreover, we demonstrated that MAD2L2 predicted favorable prognosis in CRC patients. These results indicate that MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation. Our study have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation, and proposed that MAD2L2 serves as a potential tumor suppressor in CRC. Citation Format: yixin li, ge qin, qian long, changlin zhang, dingbo shi, miao chen, wuguo deng. Mad2l2 inhibits colorectal cancer growth by promoting ncoa3 ubiquitination and degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3370.
Abstract 1816: Mechanism of resistance to single treatment with MET inhibitor inEGFR-mutant lung cancer cell secondarily acquiringc-METamplification
Authors: Youngjoo Lee, Yu-Ra Choi
Journal: Cancer Research (2018)

Abstract Amplification in c-MET is the second most common mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in lung cancer harboring activated EGFR mutations. An acquired resistance mechanism to single treatment with MET kinase inhibitor remains unknown. In this study, we modeled acquired resistance to experimental type I MET kinase inhibitor PHA66572 in MET-amplified HCC827 lung cancer cell line, which was established under chronic exposure to gefitinib in our lab. We found that reactivation of the EGFR pathway emerges as a resistance mechanism in MET secondarily amplified EGFR-mutant lung cancer cells after prolonged exposure to PHA66572. Any gene alteration influencing sensitivity to the drugs was not observed. Long treatment with only MET inhibitor resulted in partial resensitization to EGFR-TKI in these resistant lung cancer cells. Thus, the combination of gefitinib and PHA66572 could completely suppress the cell growth. Our findings support an intimate relationship between the EGFR and MET signaling pathways in HCC827 lung cancer cell line. Citation Format: Youngjoo Lee, Yu-Ra Choi. Mechanism of resistance to single treatment with MET inhibitor in EGFR-mutant lung cancer cell secondarily acquiring c-MET amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1816.
Swedish Version of the Distress Thermometer: Validity Evidence in Patients With Colorectal Cancer
Authors: Elisabeth Kenne Sarenmalm, Salmir Nasic, Cecilia Håkanson, Joakim Öhlén, Eva Carlsson, Monica E. Pettersson, Richard Sawatzky
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: The objective of this study was to validate the NCCN Distress Thermometer (DT), including the accompanying Problem List (PL), in a Swedish population of patients diagnosed with colorectal cancer (CRC). Methods: A total of 488 patients diagnosed with CRC completed the DT/PL and EORTC core quality-of-life questionnaire (QLQ-C30) before surgery. Construct validity of the PL was analyzed using a confirmatory factor analysis. Internal consistency reliability (ICR) was tested using Cronbach's alpha coefficient. Correlations between the reported PL areas and QLQ-C30 function scales were used to explore convergent validity. Discriminant validity was examined by evaluating associations between the DT and QLQ-C30 measures of overall health-related quality of life (HRQoL). Results: Findings showed that the Swedish translation of the DT/PL is consistent with the original English version. The DT has good ICR, with the total number of reported problems significantly correlating with DT scores (r=0.67; P<.001). Analysis of convergent validity indicated that the PL areas significantly correlated with QLQ-C30 function scales, with emotional problems showing the highest correlation (r=0.76; P<.001), and item-level correlation analyses showed significant correlations between symptoms. There was also good discriminant validity between the DT and the QLQ-C30 in terms of HRQoL, including overall health status (r=-0.49; P<.001) and overall quality of life (r=-0.57; P<.001). Furthermore, there was good discriminant validity between the DT and QLQ-C30 regarding poor, moderate, and excellent HRQoL. Conclusions: These findings provide validity evidence regarding the DT, including the PL. Findings also show that the DT has good potential for screening distress-related practical, family, emotional, and physical problems during the cancer trajectory in Swedish-speaking patients. Additionally, the DT seems to be an effective screening tool to detect patients with poor, moderate, and excellent HRQoL.
Abstract 2462: Epstein-Barr virus-encoded microRNAs regulate the expression of BRCA1 in nasopharyngeal carcinoma
Authors: Ka-Hei Lam, Raymond Wai-Ming Lung, Pok-Man Hau, Kevin Yuk-Lap Yip, George Sai-Wah Tsao, Ken Hung-On Yu, Joanna Hung-Man Tong, Kwok-Wai Lo, Ka-Fai To
Journal: Cancer Research (2018)

Abstract Nasopharyngeal carcinoma (NPC) is an aggressive epithelial malignancy and is endemic in southern China and Southeast Asia. It is well-known to be associated with Epstein-Barr virus (EBV) infection. The miRNAs derived from EBV BamH1-A rightward transcripts (miR-BARTs) are abundantly expressed in NPC and have been suggested that can contribute to cancer development by regulating several gene expression. In this study, we established comprehensive expression profile of miRNAs in an EBV positive NPC cell line and 5 xenografts by small RNA sequencing. By using the prediction algorithm of miRanda and RNAhybrid, in silico analysis identified that several abundantly expressed miRNAs from viral and cellular genomes could negatively regulate BRCA1 expression via the 3' untranslated region (3'UTR). Notably, the regulatory role of miR-BART17-5p, miR-BART19-3p, miR182-5p on endogenous BRCA1 expression was demonstrated by transient transfection assays in HeLa cells and the direct recognitions were verified by luciferase reporter assays, while the downregulation of BRCA1 in primary NPCs was substantiated in the immunohistochemical (IHC) staining in a cohort of 61 histologically normal nasopharyngeal (NP) and 37 primary NPC cases (p&amp;lt;0.001). Taken togethher, we showed that the highly expressed miRNAs could work co-operatively to modulate BRCA1 activity. It has been reported that BRCA1 deficient tumor cells are defective in repairing the DNA double-strand breaks (DSBs) via error-free homologous recombination (HR). The impaired DSB repair by EBV latent infection may induce genome instability during NPC tumorigenesis and also contribute to sensitizing the tumor cells to ionizing radiation and DNA-damaging agent treatments. Acknowledgement: Theme-based Research Scheme (T12-401/13-R) and GRF (14104415, 14138016), Research Grant Council, Hong Kong Citation Format: Ka-Hei Lam, Raymond Wai-Ming Lung, Pok-Man Hau, Kevin Yuk-Lap Yip, George Sai-Wah Tsao, Ken Hung-On Yu, Joanna Hung-Man Tong, Kwok-Wai Lo, Ka-Fai To. Epstein-Barr virus-encoded microRNAs regulate the expression of BRCA1 in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2462.
Assessment of Nonuniformity of Transmural Myocardial Velocities by Color-Coded Tissue Doppler Imaging
Authors: GenevièveDerumeaux, MichelOvize, JosephLoufoua, GérardPontier, XavierAndré-Fouet, AlainCribier
Journal: Circulation (2000)

Background—Transmural myocardial contractile performance is nonuniform across the different layers of the left ventricular wall. We evaluated the accuracy of color M-mode tissue Doppler imaging (TDI) to assess the transmural distribution of myocardial velocities and to quantify the severity of dysfunction induced by acute ischemia and reperfusion in the inner and outer myocardial layers. Methods and Results—Thirteen open-chest dogs underwent 15 minutes of left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. M-mode TDI was obtained from an epicardial short-axis view. Systolic velocities were calculated within endocardium and epicardium of the anterior and posterior walls. Regional myocardial blood flow was assessed by radioactive microspheres. Segment shortening was measured by sonomicrometry in endocardium and epicardium of both the anterior and posterior walls. At baseline, endocardial velocities were higher than epicardial velocities, resulting in an inner/outer myo...