tbuckley/cabot-search huggingface dataset:
NPM1 Mutant Mediated PML Delocalization and Stabilization Enhances Autophagy and Cell Survival in Leukemic Cells
Authors: Qin Zou, Shi Tan, Zailin Yang, Qian Zhan, Hongjun Jin, Jingrong Xian, Shuaishuai Zhang, Liyuan Yang, Lu Wang, Ling Zhang
Journal: Theranostics (2017)

Accumulating evidence has defined nucleophosmin 1 (NPM1) mutation as a driver genetic event in acute myeloid leukemia (AML), whereas the pathogenesis of NPM1-mutated AML remains to be fully elucidated.In this study, we showed that mutant NPM1 elevated autophagic activity and autophagic activation contributed to leukemic cell survival in vitro.Meanwhile, we also found high expression of promyelocytic leukemia gene (PML) and its cytoplasmic dislocation in primary NPM1-mutated AML blasts and NPM1-mA positive OCI-AML3 cells.Mechanically, mutant NPM1 interacted with PML and mediated it delocalization as well as stabilization.Notably, NPM1-mA knockdown impaired autophagic activity, while induced expression of PML reversed this effect.Finally, we confirmed that PML modulated autophagic activity via AKT signal.These findings suggest that aberrant PML expression and autophagy are beneficial to the leukemic transformation driven by NPM1 mutations.This indicates an attractive therapeutic avenue for PML targeting and/or autophagy inhibition in the treatment of NPM1-mutated AML.
Analysis of factors related to adjuvant chemotherapy decision in early breast cancer patients with intermediate recurrence score.
Authors: Feilin Qu, Jiayi Wu, Xiaosong Chen, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen
Journal: Journal of Clinical Oncology (2017)

e12032 Background: The 21-gene Recurrence Score (RS) assay has been routinely used to guide systemic chemotherapy in patients (pts) with estrogen receptor positive, node-negative early breast cancer (EBC). However, there has been less clarity in recommendation of adjuvant chemotherapy (ACT) in pts with intermediate RS (IRS). According to the definitions of IRS in retrospective NSABP B14, B20 trials and prospective validation of TAILORx trial, we adopted the broaden cut-offs of 11-30 in our study. We sought to analyze the factors related to ACT decision in this subset of pts. Additionally, the role of Adjuvant!Online (AOL) was evaluated in ACT decision. Methods: A cohort of 564 pts with RS of 11-30 was retrospectively analyzed from January 2014 to October 2016 in Ruijin Hospital Shanghai Jiaotong University School of Medicine. The Oncotype DX RS, a RT-PCR 21-gene assay, was performed on RNA extracted from formalin-fixed paraffin-embedded tissue. The AOL was used to determine pts’ clinical risk. Predictive factors of chemotherapy usage in different clinical risk catogories were also assessed. Results: 267 (47.3%) pts received chemotherapy. Age, tumor grade, pathologic type, pT, pN, molecular subtype and RS were significantly correlated with ACT decision ( p &lt;0.05). These factors were all independent predictors of ACT usage ( p&lt;0.05) in mutivariable model. AOL was successfully measured in 504 (89.4%) pts, of whom 279 (49.5%) were at low clinical risk and 225 (39.9%) had high clinical risk. The distribution of RS correlated significantly with AOL clinical risk catogories. The predictive factors of ACT administration in high and low clinical risk subgroups were highly consistent with the overall population, except pT in high clinical risk pts. Discordances between clinical risk and ACT decision were found in 158 pts (28.0%), probably due to different age, molecular subtype and RS. Conclusions: Age, tumor grade, pathologic type, pT, pN, molecular subtype and RS were independent predictors of ACT administration in EBC pts with IRS. AOL should not be used alone to aid chemotherapy decision in this subset of pts.
A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer.
Authors: Joseph A. Sparano, David W. Cescon, Mafalda Oliveira, Daniel G. Stover, Elizabeth Tan-Chiu, Brandon Edward Kremer, Olena Barbash, Yuehui Wu, Lijoy Mathew, Elizabeth Ann Cunningham, Christopher L. Carpenter, Marc S. Ballas, Arindam Dhar
Journal: Journal of Clinical Oncology (2017)

TPS1114 Background: Advanced or metastatic ER+BC (estrogen receptor positive breast cancer) is an incurable illness that will prove fatal for most afflicted women. Current standards of care include endocrine, targeted, and chemotherapy. Preclinical data suggest that reducing expression of the estrogen receptor (ER) as well as other ER-responsive genes may provide therapeutic benefit for women for whom endocrine therapy alone has proven inadequate. The bromodomain (BRD) and extra-terminal (BET) family of proteins (BRD2, BRD3, BRD4 and BRDT) bind to acetyl-histone residues and epigenetically control transcription of genes driving cell survival and proliferation. In preclinical models, BET proteins reduce ER expression and down regulate ER-dependent gene expression and may be a novel therapeutic target in multiple tumors e.g. ER+BC. GSK525762 is a pan-BET inhibitor showing strong synergistic activity with fulvestrant in killing ER+BC cells in vitro and in xenograft models. The combination of BET agents with endocrine therapy may provide therapeutic benefit and restore sensitivity to ER targeting agents like fulvestrant. Methods: The study is a Phase I/II dose-escalation, expansion (Phase I) and randomized control (Phase II) study with oral administration of GSK525762 in combination with fulvestrant in advanced or metastatic ER+BC subjects, whose disease has progressed on prior treatment with ≥ 1 line of endocrine therapy. Phase I of the study is designed as parallel single arms to determine the recommended Phase 2 dose based on safety, tolerability, PK, and efficacy profiles in two distinct populations of ER+ BC: 1. Subjects with disease that progressed on anti-estrogen and/or ≥ 1 AIs, OR. 2. Subjects with disease that progressed on CDK4/6 inhibitor plus letrozole. Phase I will employ a Bayesian predictive adaptive design. Phase II of the study is a randomized, double-blind, placebo-controlled study, the composition of which will be selected at the end of Phase I. Patients must have received &lt; 3 lines of anti-cancer therapy (≤1 line of chemo), measurable disease, and PS 0-1. Funding: GSK. Clinical trial information: NCT02964507.
Genome-wide characterization of mammalian promoters with distal enhancer functions
Authors: Lan T M Dao, Ariel O Galindo-Albarrán, Jaime A Castro-Mondragon, Charlotte Andrieu-Soler, Alejandra Medina-Rivera, Charbel Souaid, Guillaume Charbonnier, Aurélien Griffon, Laurent Vanhille, Tharshana Stephen, Jaafar Alomairi, David Martin, Magali Torres, Nicolas Fernandez, Eric Soler, Jacques van Helden, Denis Puthier, Salvatore Spicuglia
Journal: Nature Genetics (2017)
Immune microenvironment in brain metastases of breast cancer.
Authors: Rin Ogiya, Naoki Niikura, Nobue Kumaki, Hiroyuki Yasojima, Tsutomu Iwasa, Chizuko Kanbayashi, Risa Oshitanai, Michiko Tsuneizumi, Ken-ichi Watanabe, Akira Matsui, Tomomi Fujisawa, Shigehira Saji, Yutaka Tokuda, Norikazu Masuda, Hiroji Iwata
Journal: Journal of Clinical Oncology (2017)

1081 Background: In patients with brain metastasis (BM) of melanoma or lung cancer, significant activity of immune checkpoint inhibitors has been reported. However, details of the immune microenvironment in BM has not been unveiled. In this study, we used immunohistochemistry (IHC) to compare primary breast tumors and BM tumor samples with respect to tumor infiltrating lymphocytes (TILs) and tumor characteristics related to the immune system. Methods: We retrospectively identified 107 patients with breast cancer, diagnosed with BM, who had undergone surgery between 2001 and 2012 at 8 institutions. We collected 191 samples which included both BM samples alone and pair-matched samples (primary and BM). Hematoxylin and eosin (H&amp;E) stained slides were evaluated for stromal TILs in 10% increments (0–1%, &gt; 1– &lt; 10%, 10%–100%). IHC was performed using the following primary antibodies: CD4, CD8, Foxp3, PD-L1, PD-L2 and HLA class I. The cells positive for each antibody signal were counted automatically using ImageJ (NIH). The expression of PD-L1, PD-L2, and HLA on the tumor cells was scored as 0 (negative), 1 (weak or focal), or 2 (strong). Results: The median category of TILs of BM tumors was &gt; 1– &lt; 10% (range: 1–30%). Forty-six pair-matched samples were analyzed and the percentage of TILs in the primary breast tumor was significantly higher than that in BM samples (paired t-test, P &lt; 0.01). The number of CD4/CD8/Foxp3 positive cells in primary breast tumor was also significantly higher than in BM samples (paired t-test, P &lt; 0.05 for all categories). The negative/positive conversion occurred with the expression of HLA/PD-L2 on tumor cells (paired t-test, P = 0.03/0.06, respectively). No significant difference was observed in the overall survival (OS) of patients, from initial BM, based on high or low TILs (log-rank test, P = 0.131). However, triple negative breast cancer patients with low TILs had significantly shorter OS compared with patients with high TILs (log-rank test, P = 0.04). Conclusions: We demonstrated that TILs in BM tumors was significantly lower as compared to primary breast tumors. The expression of immune related molecules on tumor cells was converted in BM tumors.
Fractional Flow Reserve and Cardiac Events in Coronary Artery Disease
Authors: Jung-Min Ahn, Duk-Woo Park, Eun-Seok Shin, Bon-Kwon Koo, Chang-Wook Nam, Joon-Hyung Doh, Jun Hong Kim, In-Ho Chae, Jung-Han Yoon, Sung-Ho Her, Ki-Bae Seung, Woo-Young Chung, Sang-Yong Yoo, Jin Bae Lee, Si Wan Choi, Kyungil Park, Taek Jong Hong, Sang Yeub Lee, Minkyu Han, Pil Hyung Lee, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Circulation (2017)

We evaluated the prognosis of deferred and revascularized coronary stenoses after fractional flow reserve (FFR) measurement to assess its revascularization threshold in clinical practice.The IRIS-FFR registry (Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve) prospectively enrolled 5846 patients with ≥1coronary lesion with FFR measurement. Revascularization was deferred in 6468 lesions and performed in 2165 lesions after FFR assessment. The primary end point was major adverse cardiac events (cardiac death, myocardial infarction, and repeat revascularization) at a median follow-up of 1.9 years and analyzed on a per-lesion basis. A marginal Cox model accounted for correlated data in patients with multiple lesions, and a model to predict per-lesion outcomes was adjusted for confounding factors.For deferred lesions, the risk of major adverse cardiac events demonstrated a significant, inverse relationship with FFR (adjusted hazard ratio, 1.06; 95% confidence interval, 1.05-1.08; P<0.001). However, this relationship was not observed in revascularized lesions (adjusted hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P=0.70). For lesions with FFR ≥0.76, the risk of major adverse cardiac events was not significantly different between deferred and revascularized lesions. Conversely, in lesions with FFR ≤0.75, the risk of major adverse cardiac events was significantly lower in revascularized lesions than in deferred lesions (for FFR 0.71-0.75, adjusted hazard ratio, 0.47; 95% confidence interval, 0.24-0.89; P=0.021; for FFR ≤0.70, adjusted hazard ratio 0.47; 95% confidence interval, 0.26-0.84; P=0.012).This large, prospective registry showed that the FFR value was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR (≤0.75) was associated with better outcomes than the deferral, whereas for a stenosis with a high FFR (≥0.76), medical treatment would be a reasonable and safe treatment strategy.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01366404.
Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study
Authors: R. Bissonnette, T. Luger, D. Thaçi, D. Toth, I. Messina, R. You, A. Guana, T. Fox, C. Papavassilis, I. Gilloteau, U. Mrowietz
Journal: British Journal of Dermatology (2017)

Secukinumab has demonstrated significant efficacy with a good safety profile through 1 year in plaque psoriasis. Given the chronic nature of this disease, long‐term follow‐up is needed to evaluate psoriasis therapies fully. To determine the long‐term (3‐year) efficacy and safety of secukinumab in moderate‐to‐severe psoriasis. Patients completing 52 weeks of secukinumab treatment in the SCULPTURE core study entered an extension in which they continued the same double‐blind regimens. Dosing regimens included a fixed‐interval schedule (FI; every 4 weeks) and retreatment as needed (RAN), in which patients were withdrawn from secukinumab and received placebo until the start of relapse, at which time secukinumab every 4 weeks was reinitiated. The study was registered with number NCT01640951. In total 168 patients receiving secukinumab 300 mg FI and 172 receiving secukinumab 300 mg RAN entered the extension. Secukinumab 300 mg FI sustained high efficacy: at the end of year 3, the proportion of responders achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) was 63·8%, and of PASI 100 responders it was 42·6%. The mean absolute PASI remained low (2–4) from week 52 to week 152 with 300 mg FI, with approximately two‐thirds of patients reporting no impact of skin disease on their lives (Dermatology Life Quality Index of 0 or 1). Improvements in overall and subscale scores on all quality‐of‐life instruments were well sustained. As in the core study, FI dosing was consistently more efficacious than RAN. No new safety signals were identified to year 3. Secukinumab 300 mg FI sustained high responses and improved quality of life with no new safety concerns through 3 years.
The underlying mechanism contributing to P-gp over-expression and drug resistance in the MCF-7 breast cancer cells induced by adriamycin.
Authors: Guangji Wang, Jiye Aa, Chun Ge
Journal: Journal of Clinical Oncology (2017)

e12028 Background: Continuous exposure of breast cancer cells to adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and reduced glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over-expressed P-gp induced by ADR. Methods: Based on MCF-7 breast cancer cells and the adriamycin-resistant MCF-7 subline (MCF-7R), we investigated the P-gp expression on mRNA, protein and function level by qPCR, western blotting, flow cytometry and laser scanning confocal and so on, under SLC7A11 down-regulation/over-expression, cystine depletion/supplement, increased ROS generation and combined factors. Results: The present study showed that ADR inhibited cystine influx (source material of GSH) and SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that a down-regulation/silence of SLC7A11, or cystine deprivation, or an enhanced exposure of ROS agents directly and significantly increased P-gp expression; yet, a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and an increased ROS dramatically promoted the P-gp expression in MCF-7 cells. On the contrary, an over-expression of SLC7A11, or sufficiently supplementary cystine, or scavenger of ROS significantly depressed P-gp expression and activity. Moreover, the down-regulation of SLC7A11 and cystine deprivation induced an elevation of ROS and P-gp that could be reversed by N-acetylcysteine. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the upregulated expression and function of P-gp. Conclusions: This study provided the direct evidences suggesting that ROS triggered over-expression of P-gp and demonstrated that the combination of either an inhibition of SLC7A11 or cystine influx and elevated ROS was the underlying mechanism contributing to P-gp over-expression induced by ADR. It was indicated that the SLC7A11 might be a potential target modulating ADR resistance.
Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA
Authors: Wael Jdey, Sylvain Thierry, Tatiana Popova, Marc-Henri Stern, Marie Dutreix
Journal: Cancer Research (2017)

Therapeutic strategies targeting DNA repair pathway defects have been widely explored, but often only benefit small numbers of patients. Here we characterized potential predictive biomarkers for treatment with AsiDNA, a novel first-in-class DNA repair inhibitor. We evaluated genetic instability and DNA repair defects by direct and indirect assays in 12 breast cancer cell lines to estimate the spontaneous occurrence of single-strand and double-strand breaks (DSB). For each cell line, we monitored constitutive PARP activation, spontaneous DNA damage by alkaline comet assay, basal micronuclei levels, the number of large-scale chromosomal rearrangements (LST), and the status of several DNA repair pathways by transcriptome and genome analysis. Sensitivity to AsiDNA was associated with a high spontaneous frequency of cells with micronuclei and LST and specific alterations in DNA repair pathways that essentially monitor DSB repair defects. A high basal level of micronuclei as a predictive biomarker for AsiDNA treatment was validated in 43 tumor cell lines from various tissues and 15 models of cell- and patient-derived xenografts. Micronuclei quantification was also possible in patient biopsies. Overall, this study identified genetic instability as a predictive biomarker for sensitivity to AsiDNA treatment. That micronuclei frequency can be measured in biopsies and does not reveal the same genetic instability as conventional genome assays opens new perspectives for refining the classification of tumors with genetic instability. Cancer Res; 77(16); 4207-16. ©2017 AACR.
The “susceptibility to exacerbation” phenotype in COPD and response to pulmonary rehabilitation
Authors: J.L. Canavan, K.A. Ingram, R.P. Fowler, P. Marns, K. Dobson, A.L. Clark, C.M. Nolan, M.I. Polkey, W.D.-C. Man
Journal: European Respiratory Journal (2011)

Introduction:  Exacerbations are a key feature of COPD and are known to impact lung function, daily physical activity level, quality of life, survival, and health resource usage. Pulmonary rehabilitation (PR) is an effective treatment for disability in COPD, with previous research identifying improved outcome for patients reporting no exacerbations (NE) when compared with patients suffering exacerbations (Riario-Sforza et al., 2005). A frequent susceptibility exacerbation phenotype (≥2 exacerbations in previous year) has been identified (Hurst et al., 2010) which may have implications for response to PR. We hypothesised that patients with frequent exacerbations (FE) would gain less benefit from an 8-week outpatient PR program.   Method:  In 93 COPD patients reporting NE (n=28), one exacerbation (OE) (n=28) or FE (n =37) in the previous year, the following assessments were made before (T0) and after (T1) PR: fat free mass (FFM), incremental shuttle walk (ISW), self-report Chronic Respiratory Disease Questionnaire (CRDQ-SR).Median (IQR) change in ISW, FFM, and CRDQ-SR total score from T0 to T1 was compared between groups using Kruskal-Wallis tests.   Results:  ISW distance and CRDQ-SR increased in NE (80 (13-148)m, 13.5 (1.5-23.8)) OE (50 (0-110)m, 19.0 (2.0-32.0)) and FE (60 (20-270)m, 21.0 (8.0-28.0)) groups.FFM increased in NE (0.36 (-1.32-1.26)kg) and OE (0.51 (-0.85-1.33)kg) but not FE (-0.07 (-1.38-2.29)kg).No significant differences were found between groups for any variables (ISW: p = 0.46, CRDQ total p = 0.35, FFM: p = 0.94).   Conclusion:  The “susceptibility to exacerbation” phenotype does not appear to affect improvements in exercise capacity, or health related quality of life gained during PR.
A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions
Authors: Qing Li, Min Cui, Fan Yang, Na Li, Baichun Jiang, Zhen Yu, Daolai Zhang, Yijing Wang, Xibin Zhu, Huili Hu, Pei-Shan Li, Shang-Lei Ning, Si Wang, Haibo Qi, Hechen Song, Dongfang He, Amy Lin, Jingjing Zhang, Feng Liu, Jiajun Zhao, Ling Gao, Fan Yi, Tian Xue, Jin-Peng Sun, Yaoqin Gong, Xiao Yu
Journal: Journal of Clinical Investigation (2017)

Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in δ cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies showed that the CRL4B-PRC2 complex, under the control of the δ cell-specific transcription factor hematopoietically expressed homeobox (HHEX), determines the levels of intracellular calcium and cAMP through histone posttranslational modifications, thereby altering expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin 3 (UCN3) stimulation, increased expression of cullin 4B (CUL4B) and the PRC2 subunit histone-lysine N-methyltransferase EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of δ cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.