tbuckley/cabot-search huggingface dataset:
Preclinical modeling of myelodysplastic syndromes
Authors: K Rouault-Pierre, S A Mian, M Goulard, A Abarrategi, A Di Tulio, A E Smith, A Mohamedali, S Best, A-M Nloga, A G Kulasekararaj, L Ades, C Chomienne, P Fenaux, C Dosquet, G J Mufti, D Bonnet
Journal: Leukemia (2017)

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematological clonal disorders. Here, we have tested the bone marrow (BM) cells from 38 MDS patients covering all risk groups in two immunodeficient mouse models: NSG and NSG-S. Our data show comparable level of engraftment in both models. The level of engraftment was patient specific with no correlation to any specific MDS risk group. Furthermore, the co-injection of mesenchymal stromal cells (MSCs) did not improve the level of engraftment. Finally, we have developed an in vitro two-dimensional co-culture system as an alternative tool to in vivo. Using our in vitro system, we have been able to co-culture CD34+ cells from MDS patient BM on auto- and/or allogeneic MSCs over 4 weeks with a fold expansion of up to 600 times. More importantly, these expanded cells conserved their MDS clonal architecture as well as genomic integrity.
Abstract 12089: The Association Between Post-Operative Pulmonary Hypertension and Survival After Mitral Valve Surgery
Authors: Todd L Kiefer, Zainab Samad, Gina-Marie Pomann, Victor Poon, Wassim Shatila, Yuliya Lokhnygina, Eric J Velazquez, Andrew Wang
Journal: Circulation (2016)

Introduction: Pulmonary hypertension (PH) is a common complication of mitral valve disease, but the prognostic significance of PH after mitral valve surgery (MVS) is unclear. Hypothesis: Post-operative PH after mitral valve repair or replacement is associated with worse survival. Methods: Retrospective study at a single, tertiary medical center (1995-2015) using echo database. Patients with moderate-severe or severe regurgitation and/or stenosis who had 1) preoperative transthoracic echocardiogram (TTE) within 6 months of MVS; 2) post-operative TTE at least 30 days after MVS; 3) right ventricular systolic pressure (RVSP) measurement on both TTEs. The primary endpoint of the study was survival after post-op TTE. Non-parametric Kaplan-Meier method was used to estimate distribution of time to death related to severity of pre-op and post-op RVSP. Cox proportional hazards modeling was used to evaluate the relationship between post-op RVSP and survival with adjustment for co-variates including pre-op RVSP. Results: 259 patients met inclusion criteria. Median time to post-operative TTE from MVS was 244 (IQR 86, 421) days. The mean RVSP was 47.2 (16) mm Hg. Following MVS, a statistically significant decrease in the post-operative compared with pre-operative RVSP was observed for the overall cohort (mean RVSP 39.1 [14.0] mm Hg), specifically in patients with baseline RVSP ≥35 mm Hg, but 53 (20.5%) patients had post-op RVSP &gt;50 mm Hg. PH after MVS was significantly associated with lower survival in follow-up in the unadjusted log-rank test for trend (Figure). Post-op RVSP, but not pre-op RVSP, was significantly associated with mortality in the Cox proportional hazards model with adjustment for age, race, comorbidities, mitral stenosis, and if performed, mitral replacement size (RVSP &gt;50mm Hg vs. RVSP ≥35 mm Hg: HR 2.214, 95% CI 1.316, 3.724, p=0.0027). Conclusion: Post-operative PH is significantly associated with lower survival after mitral valve surgery.
Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2
Authors: Sven Jäckel, Klytaimnistra Kiouptsi, Maren Lillich, Tim Hendrikx, Avinash Khandagale, Bettina Kollar, Nives Hörmann, Cora Reiss, Saravanan Subramaniam, Eivor Wilms, Katharina Ebner, Marie-Luise von Brühl, Philipp Rausch, John F. Baines, Sandra Haberichter, Bernhard Lämmle, Christoph J. Binder, Kerstin Jurk, Zaverio M. Ruggeri, Steffen Massberg, Ulrich Walter, Wolfram Ruf, Christoph Reinhardt
Journal: Blood (2017)
Quantifying the Benefits of Genome-Driven Oncology
Authors: Alison M. Schram, David M. Hyman
Journal: Cancer Discovery (2017)

Abstract Summary: The excitement surrounding genomically selected cancer therapy has led many to question whether this treatment paradigm is living up to its initial promise. The MOSCATO study suggests that a genome-driven strategy for cancer therapy improves outcomes in a significant minority of patients who undergo molecular screening. Cancer Discov; 7(6); 552–4. ©2017 AACR. See related article by Massard et al., p. 586.
Lysosome swelling precedes lysosomal membrane permeabilization in breast cancer cells
Authors: Nesrin Hasan, Tiffany Greenwood, Kristine Glunde
Journal: Cancer Research (2008)

LB-51    Introduction:  Recent studies demonstrated that lysosomal membrane permeabilization (LMP) resulted in the release of lysosomal enzymes into the cytosol, which induced mitochondrial cytochrome c release and apoptosis (1). In this study, we have investigated the role of LMP in breast cancer aggressiveness to test its future potential for breast cancer treatment. LMP was induced with the V-ATPase inhibitor Bafilomycin A1 (Baf A1) and/or the fluoroquinolone ciprofloxacin (CPX) (2, 3). We observed changes in cellular and lysosome morphology in the human breast cancer cell lines MCF-12A, MCF-7 and MD-MBA-231.   Methods:  We used non-malignant MCF-12A, weakly aggressive MCF-7, and highly aggressive MD-MBA-231 cells. Live cells were treated with 0.1 μM Baf A1 or 500-750 μg/ml CPX or a combination of 0.1 μM Baf A1 and 500 μg/ml CPX. Lysosomes were fluorescently labeled with Alexa-Fluor-488 bound to 10 kDa dextran. Dynamic changes in cell morphology were observed by phase contrast microscopy, and dynamic changes in lysosomes by fluorescence microscopy. These studies were corroborated by analogous confocal fluorescence microscopy detecting lysosomal CD63 immunofluorescence staining.   Results:  Dynamic phase contrast microscopy showed that both Baf A1 and CPX led to changes in cell morphology as characterized by cell shrinkage, blebbing, and loss of characteristic cell shape. Both LMP-inducing agents caused cell death in a time-dependent manner. Upon treatment, we either observed increased numbers of lysosomes, or enlarged lysosomes, or both. At later time points, we observed disappearance of dextran-labeling from lysosomes in treated cells, which was a sign of LMP.   Discussion:  We have shown for the first time that an enlargement of lysosomal vesicles and/or an increase in lysosome number preceded LMP. Recent studies demonstrated that in breast carcinoma cells, Baf A1 inhibited proton transport causing an alkalization in the lysosomal compartments (4). Such a change in the lysosomal pH could indirectly result in water influx into lysosomes and increase their volumes. This process was time-dependent as it resulted in increased numbers of large lysosomes over time, and eventually led to LMP, that resulted in cell death, probably by apoptosis. We will further investigate the mechanism of lysosome swelling preceding LMP in breast cancer cells, and its role in cell death pathways.   References :  (1) Kroemer, G. and M. Jaattela (2005), Nat Rev Cancer 5, 886-97.  (2) Boya, P., et al. (2003), J Exp Med 197, 1323-34.  (3) Nakashima, S., et al. (2003), J Biochem 134, 359-64.  (4) Martinez-Zaguilan, R., et al. (1993), Am J Physiol 265, C1015-29.
An ERBB1-3 Neutralizing Antibody Mixture With High Activity Against Drug-Resistant HER2+ Breast Cancers With ERBB Ligand Overexpression
Authors: Luis J Schwarz, Katherine E Hutchinson, Brent N Rexer, Mónica Valeria Estrada, Paula I Gonzalez Ericsson, Melinda E Sanders, Teresa C Dugger, Luigi Formisano, Angel Guerrero-Zotano, Monica Red-Brewer, Christian D Young, Johan Lantto, Mikkel W Pedersen, Michael Kragh, Ivan D Horak, Carlos L Arteaga
Journal: JNCI Journal of the National Cancer Institute (2017)

Plasticity of the ERBB receptor network has been suggested to cause acquired resistance to anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we studied whether a novel approach using an ERBB1-3-neutralizing antibody mixture can block these compensatory mechanisms of resistance.HER2+ cell lines and xenografts (n ≥ 6 mice per group) were treated with the ERBB1-3 antibody mixture Pan-HER, trastuzumab/lapatinib (TL), trastuzumab/pertuzumab (TP), or T-DM1. Downregulation of ERBB receptors was assessed by immunoblot analysis and immunohistochemistry. Paired pre- and post-T-DM1 tumor biopsies from patients (n = 11) with HER2-amplified breast cancer were evaluated for HER2 and P-HER3 expression by immunohistochemistry and/or fluorescence in situ hybridization. ERBB ligands were measured by quantitative reverse transcription polymerase chain reaction. Drug-resistant cells were generated by chronic treatment with T-DM1. All statistical tests were two-sided.Treatment with Pan-HER inhibited growth and promoted degradation of ERBB1-3 receptors in a panel of HER2+ breast cancer cells. Compared with TL, TP, and T-DM1, Pan-HER induced a similar antitumor effect against established BT474 and HCC1954 tumors, but was superior to TL against MDA-361 xenografts (TL mean = 2026 mm 3 , SD = 924 mm 3 , vs Pan-HER mean = 565 mm 3 , SD = 499 mm 3 , P = .04). Pan-HER-treated BT474 xenografts did not recur after treatment discontinuation, whereas tumors treated with TL, TP, and T-DM1 did. Post-TP and post-T-DM1 recurrent tumors expressed higher levels of neuregulin-1 (NRG1), HER3 and P-HER3 (all P < .05). Higher levels of P-HER3 protein and NRG1 mRNA were also observed in HER2+ breast cancers progressing after T-DM1 and trastuzumab (NRG1 transcript fold change ± SD; pretreatment = 2, SD = 1.9, vs post-treatment = 11.4, SD = 10.3, P = .04). The HER3-neutralizing antibody LJM716 resensitized the drug-resistant cells to T-DM1, suggesting a causal association between the NRG1-HER3 axis and drug resistance. Finally, Pan-HER treatment inhibited growth of HR6 trastuzumab- and T-DM1-resistant xenografts.These data suggest that upregulation of a NRG1-HER3 axis can mediate escape from anti-HER2 therapies. Further, multitargeted antibody mixtures, such as Pan-HER, can simultaneously remove and/or block targeted ERBB receptor and ligands, thus representing an effective approach against drug-sensitive and -resistant HER2+ cancers.
Abstract 248: Baseline Cognitive Impairment a Predictor of Mortality in Cardiovascular Disease
Authors: Antonio D Lassaletta, Frank W Sellke, Ronald A Cohen
Journal: Circulation Research (2012)

Objective: Few longitudinal studies have examined outcomes of patients with cardiovascular disease (CVD) in relation to earlier, baseline cognitive function, or examined the relationship between specific cognitive domains and mortality. This study attempted to clarify the relationship between cognitive function and long-term outcomes, particularly mortality, in patients with cardiovascular disease. Methods: One hundred seventy seven participants between 55 and 85 years of age with an established history CVD were recruited from healthcare institutions. A comprehensive neurophysiological test battery was administered to all patients at baseline assessing 4 cognitive domains: language, visual-spatial, memory, and attention-executive function. Composite scores were calculated by averaging z-scores of all component measures. At 6-year the follow-up, of the 136 patients who were still enrolled, the 116 who were still alive were contacted by phone for assessment of level of independent living, and subjective assessment of cognitive function, and quality of life.Results were corrected for age. Results: At follow-up, participants who were deceased had significantly lower baseline attention-executive function (M=-0.51, SD=0.78 vs. M=0.06, SD=0.54 in survivors, p &lt; 0.01). Poorer memory performance at baseline was associated with a greater degree of cognitive dysfunction at follow-up (p = 0.085). No significant relationships were found between baseline cognitive performance and independent living status or quality of life. Conclusion: Impaired executive function was predictive of poorer outcomes, specifically, 6-year mortality. This finding reinforces the frontal nature of vascular cognitive impairments, especially in regard to the long term sequelae of cognitive dysfunction in patients with CVD. The higher mortality observed in patients with baseline executive domain impairment may be due to behaviors such as impaired self-care, treatment adherence and rehab participation or functional impairments that exacerbate health problems, resulting in death. Patients with cardiovascular disease and executive function impairment should be identified and measures taken to address these potential problems.
Prospective molecular analysis of small cell lung cancer (SCLC) using next generation sequencing (NGS).
Authors: Maria Catherine Pietanza, Helen H. Won, Natasha Rekhtman, Lu Wang, William D. Travis, Lee M. Krug, Anna M. Varghese, Paul K. Paik, Gregory J. Riely, Maureen Frances Zakowski, Marc Ladanyi, Michael F. Berger, Mark G. Kris, Charles M. Rudin
Journal: Journal of Clinical Oncology (2015)

7518 Background: Recent studies using NGS on resected SCLC have provided insights into the landscape of genetic alterations in this disease. We report our experience with prospective genomic profiling of SCLC patients using the biopsy specimens available in clinical practice and a targeted, hybrid capture-based, NGS assay, MSK-IMPACT. Methods: Utilizing an IRB approved protocol, we are evaluating SCLC tumors of patients in active treatment. FFPE surgical resections, core biopsies, and fine needle aspirates (FNA) are being evaluated by NGS to identify single nucleotide variants, indels, and copy number alterations in a common set of 222 cancer-associated genes shared by pre-clinical and clinical versions of MSK-IMPACT. Clinical data are collected (smoking status; stage [extensive (ES), limited (LS)]; treatment response). Results: Currently, 50 patient samples have undergone evaluation, 58% from core biopsies or FNA. The 50 SCLC patients include 4 never smokers, 58% with ES-SCLC, and 30% resistant to first line therapy. Alterations have been noted in 202 of 222 targeted genes. The median number of non-synonymous somatic mutations is 7. Of 526 total non-synonymous mutations, 5% are hotspot COSMIC mutations, 25% are loss-of-function, and 47% are G-to-T transversions, reflective of tobacco induced carcinogenesis. We observe frequent inactivation of RB1 (96%) and TP53 (92%). Other common genomic events include alterations in SOX2 (26%), EPHA5 (22%), CDKN2C (20%), MYCL1 (20%), and PIK3CA (18%). Tumors from the 4 never smokers (0 pk yrs) displayed a median of 3 mutations, of which none were G-to-T transversions, while those from moderate ( < 20 pk yrs) and heavy (20+ pk yrs) smokers contained 4.5 and 8 mutations, respectively (P< 0.05). ES-SCLC patients had a lower median number of mutations (5/tumor) than LS-SCLC patients (9/tumor). Diverse amplifications, deletions, and mutations are noted in sensitive tumors, while homozygous deletions are more common in refractory tumors. Conclusions: Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens using a targeted NGS assay. Prospective analyses allow us to fully characterize the molecular diversity of SCLC in the clinical setting.
Abstract 337: cAbl Tyrosine Kinase Increases Catalase Activity in the Catalase-Dysregulated Newborn Rabbit Heart
Authors: E Bernadette Cabigas, Jie Liu, Archana Boopathy, Pao Lin Che, Brian Crawford, Gitanjali Baroi, Mary B Wagner, Michael E Davis
Journal: Circulation Research (2013)

Introduction: Pediatric patients undergoing corrective cardiothoracic surgery numbered in the tens of thousands annually and therefore it is necessary that pre- and post-operative strategies be employed to limit ischemia-reperfusion (IR) injury. We have found differences in the way the newborn (versus the adult) heart responds to IR injury. In the adult, catalase activity increases appropriately with increasing levels of hydrogen peroxide (H2O2), conferring cardioprotection. This effect however does not occur in the newborn. Materials and Methods: Hypoxia studies were carried out using primary cardiomyocytes from adult (&gt;8 weeks) and newborn rats. Ischemia-reperfusion (IR) studies were performed using newborn (4-5 days) rabbits. Isolated rat cardiomyocytes were exposed to 1 hour of hypoxia (95%N2,5%CO2). Immunoprecipitation and western blot analysis were done for phosphorylated and total catalase and c-Abl. In addition, catalase activity was determined spectrophotometrically by measuring the decomposition of H2O2. Newborn rabbit hearts were perfused using Langendorff method with ischemia and reperfusion periods lasting 30 and 60 minutes, respectively. DPH (200µM), a cAbl activator was injected directly into the newborn right ventricle (RV) two minutes before the reperfusion period. Results: Following hypoxia, the ratio of phosphorylated to total catalase and c-Abl in isolated newborn rat myocytes did not increase and were significantly lower (1.92- and 6.21-fold, respectively; p&lt;0.05) than their adult counterparts. Interestingly, when DPH was administered one hour prior to hypoxia, not only was catalase activity significantly increased 6.28-fold (p&lt;0.01) but phosphorylation levels were also altered. Finally, direct injection of DPH into the RV of Langendorff-perfused newborn rabbit hearts caused a significant improvement in percent recovery of developed pressure (from 49.53±5.42% to 125.5±15.5%) after IR, a key indicator of cardiac function. Catalase activity in these same hearts increased 2.92-fold. Conclusion: In the newborn, decreased phosphorylation of catalase by c-Abl potentially mediates IR-induced dysfunction. Activation of c-Abl may be a strategy to prevent ischemic injury associated with surgical procedures.
Activated plasmacytoid dendritic cells regulate type 2 innate lymphoid cell–mediated airway hyperreactivity
Authors: Hadi Maazi, Homayon Banie, German R. Aleman Muench, Nisheel Patel, Bowen Wang, Ishwarya Sankaranarayanan, Vipul Bhargava, Takahiro Sato, Gavin Lewis, Matteo Cesaroni, James Karras, Anuk Das, Pejman Soroosh, Omid Akbari
Journal: Journal of Allergy and Clinical Immunology (2017)
Phase II trial of dacomitinib, a pan–human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification
Authors: Juan Manuel Sepúlveda-Sánchez, María Ángeles Vaz, Carmen Balañá, Miguel Gil-Gil, Gaspar Reynés, Óscar Gallego, María Martínez-García, Elena Vicente, María Quindós, Raquel Luque, Ana Ramos, Yolanda Ruano, Pedro Pérez-Segura, Manuel Benavides, Pilar Sánchez-Gómez, Aurelio Hernández-Laín
Journal: Neuro-Oncology (2017)

We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion.Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6).Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs.Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.
Enhanced anti-tumor immunity by coadministration of tumor-associated antigen and immunomodulatory protein Fve
Authors: Ying Ding, See-Voon Seow, Chiung-Hui Huang, Lee-Mei Liew, Yaw-Chyn Lim, I-Chun Kuo, Kaw-Yan Chua
Journal: Clinical Cancer Research (2007)

B7  Abstract  The main aim of this study is to evaluate the potential application of an immunomodulatory protein, Fve, as an adjuvant for tumor immunotherapy. Using HPV-16 E7 oncoprotein as a model antigen, we have demonstrated that mice co-immunized with E7 and Fve showed enhanced E7-specific antibodies as compared to mice immunized with E7 alone. Furthermore, intracellular cytokine staining revealed that there was an increased expansion of E7-specific IFN-γ-producing CD4+ and CD8+ T cells in the co-immunized mice. Tumor protection assays showed that 60% of mice co-immunized with E7 plus Fve remained tumor free up to 167 days after the TC-1 tumor cells challenge whereas only 20% of the E7-immunized mice remained tumor free. Tumor therapeutic assays showed that E7 plus Fve treatment significantly retarded tumor growth and prolonged survival of tumor bearing mice as compared to those treated by E7 alone. In the metastatic settings, similar enhanced prophylactic and therapeutic anti-tumor effects were observed in the co-immunized mice. Antibody depletion assays illustrated that the CD4+, CD8+ T cells and IFN-γ play critical roles in conferring the anti-tumor effects. Adoptive transfer of purified T cells to the tumor-bearing mice further indicated that T cells play a pivotal role in the therapeutic anti-tumor effects and such effects are correlated to the magnitude of the E7-specific T cell responses. In summary, this study demonstrates that Fve protein has potent adjuvant properties, in driving enhanced antigen-specific humoral and cellular type 1 immune responses, which confer effective anti-tumor effects, representing an attractive vaccination strategy for cancer immunotherapy.
Comparative Effectiveness of Clinical-Community Childhood Obesity Interventions
Authors: Elsie M. Taveras, Richard Marshall, Mona Sharifi, Earlene Avalon, Lauren Fiechtner, Christine Horan, Monica W. Gerber, E. John Orav, Sarah N. Price, Thomas Sequist, Daniel Slater
Journal: JAMA Pediatrics (2017)

Novel approaches to care delivery that leverage clinical and community resources could improve body mass index (BMI) and family-centered outcomes.