tbuckley/cabot-search huggingface dataset:
Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas
Authors: Jennifer K. Lue, Sathyen A. Prabhu, Yuxuan Liu, Yulissa Gonzalez, Akanksha Verma, Prabhjot S. Mundi, Nebiyu Abshiru, Jeannie M. Camarillo, Swasti Mehta, Emily I. Chen, Changhong Qiao, Renu Nandakumar, Serge Cremers, Neil L. Kelleher, Olivier Elemento, Jennifer E. Amengual
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Both gain-of-function enhancer of zeste homolog 2 (EZH2) mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC)–derived lymphomas. We hypothesized that direct inhibition of EZH2 and histone deacetyltransferase (HDAC) would be synergistic in GC-derived lymphomas. Experimental Design: Lymphoma cell lines (n = 21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor. Synergy was assessed by excess over bliss. Western blot, mass spectrometry, and coimmunoprecipitation were performed. A SU-DHL-10 xenograft model was utilized to validate in vitro findings. Pretreatment RNA-sequencing of cell lines was performed. MetaVIPER analysis was used to infer protein activity. Results: Exposure to GSK126 and romidepsin demonstrated potent synergy in lymphoma cell lines with EZH2 dysregulation. Combination of romidepsin with other EZH2 inhibitors also demonstrated synergy suggesting a class effect of EZH2 inhibition with romidepsin. Dual inhibition of EZH2 and HDAC led to modulation of acetylation and methylation of H3K27. The synergistic effects of the combination were due to disruption of the PRC2 complex secondary to acetylation of RbAP 46/48. A common basal gene signature was shared among synergistic lymphoma cell lines and was characterized by upregulation in chromatin remodeling genes and transcriptional regulators. This finding was supported by metaVIPER analysis which also revealed that HDAC 1/2 and DNA methyltransferase were associated with EZH2 activation. Conclusions: Inhibition of EZH2 and HDAC is synergistic and leads to the dissociation of PRC2 complex. Our findings support the clinical translation of the combination of EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas.
ERCC1 induction after oxaliplatin exposure may depend on KRAS mutational status in colorectal cancer patient: preliminary data from liquid biopsy.
Authors: Mariantonietta Di Salvatore, Carmela Paolillo, Armando Orlandi, Maria Grazia Rodriquenz, Ernesto Rossi, Michele Basso, Antonia Strippoli, Francesca Aroldi, Cinzia Bagalà, Ettore Domenico Capoluongo, Carmelo Pozzo, Alessandra Cassano, Carlo Barone
Journal: Journal of Clinical Oncology (2015)

11033 Background: Basing on preliminary observations of OPUS and PRIME studies, our group retrospectively suggested that KRAS mutational status could affect response to oxaliplatin. We further confirmed this evidence in vitro demonstrating that KRAS mutated cell lines were more sensitive to oxaliplatin due to their inability to induce ERCC1 after drug exposure. Using CTCs as a surrogate, dynamic tissue, in this study we sought to confirm in vivo the relationship between KRAS mutational status, ERCC1 inducibility and clinical outcome in oxaliplatin-treated colorectal cancer patients. Methods: We collected blood samples from colorectal cancer patients treated with oxaliplatin-based regimen at 0 and 48 hours during the first cycle of chemotherapy. The presence of CTC was detected by AdnaGene system followed by multiplex RT-PCR including ERCC1 transcript. In CTC-positive ERCC1-positive patients, ERCC1 mRNA expression was measured using a quantitative real time RT-PCR method, before and after drug exposure. We evaluated the relationship between ERCC1 induction and KRAS mutational status and we tried to correlate this association with clinical outcome Results: On a total of 38 patients enrolled, 19 were KRAS wild type and 19 KRAS mutated. CTCs were detected in 12 (31,5 %) patients. ERCC1 was expressed in 8/12 CTCs-positive patients, 5 KRAS wild type and 3 mutated. After Oxaliplatin exposure, among ERCC1-positive patients, only 3 showed a significant induction of ERCC1 expression; interestingly all of them were KRAS wild-type and experimented a rapid progression of disease. The median PFS of patients with ERCC1 induction was shorter than that observed in patients with stable or reduced ERCC1 (2,5 months vs 7,2 months). Notably none of the KRAS mutated ERCC1-positive CTCs was able to induce ERCC1 and median PFS was 11,6 months. Conclusions: Although based on a small sample size,this study could support the relationship between KRAS mutational status, ERCC1 inducibility, and clinical outcome, corroborating our hypothesis that KRAS mutational status could be a surrogate marker of efficacy of oxaliplatin therapy. Further studies are warranted to study this association.
Potential resistance mechanisms using next generation sequencing from Chinese EGFR T790M+ non-small cell lung cancer patients with primary resistance to osimertinib: A multicenter study
Authors: C. Xu, W. Wang, Y. Zhu, Z. Yu, H. Zhang, H. Wang, J. Zhang, W. Zhuang, T. Lv, Y. Song
Journal: Annals of Oncology (2019)

Background: Osimertinib (AZD9291) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated significant clinical benefits in patients with EGFR sensitizing mutations or T790M mutation. However, approximately 5% to 15% of patients with non-small-cell lung cancer (NSCLC) with EGFR T790M mutation has primary resistance to osimertinib treatment. The underlying mechanism is unknown. Methods: A total of 117 patients with stage IIIb-IV EGFR-T790M NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to osimertinib, including FFPE samples, serum samples and serous effusions. We used targeted NGS to detect genes status of patients. Results: Among 117 patients treated with osimertinib, 82.91% (97/117) developed acquired resistance, and 7.69% (9/117) had primary resistance. Using the specimens at the baseline, there were 3 (33.33%) patients with MET amplification, 1 (11.11%) patient with BCL2L11 loss (BIM deletion polymorphism), 1 (11.11%) patient with ERBB2 amplification, 1 (11.11%) patient with PTEN mutation, 1 (11.11%) patient with EZH2 mutation, and 2 (22.22%) patients with unknown status. Conclusions: The mechanisms of primary resistance to EGFR-T790M may be highly heterogeneous. BCL2L11 loss, MET amplification, ERBB2 amplification, PTEN mutations, EZH2 mutations might contribute to molecular mechanisms of primary resistance to osimertinib in EGFR-T790M NSCLC. Further investigations are warranted to overcome these primary resistances. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Reducing the cardiovascular disease burden for people of all ages in the Americas region: analysis of mortality data, 2000–15
Authors: Peter Lloyd-Sherlock, Shah Ebrahim, Ramon Martinez, Martin McKee, Pedro Ordunez
Journal: The Lancet Global Health (2019)

BackgroundIn accordance with the age parameters specified in Sustainable Development Goal target 3.4, current policy and monitoring of non-communicable disease (NCD) mortality trends focus on people aged 30–69 years. This approach excludes the majority of NCD deaths, which occur at older ages. We aimed to compare cardiovascular mortality for different age groups in the WHO Region of the Americas.MethodsWe extracted mortality data from the Pan American Health Organization regional mortality database for 36 countries for the period 2000 to 2015. We calculated age-standardised mortality rates (ASMRs) from cardiovascular diseases for different age groups for these countries. Joinpoint regression models were used to estimate mortality trends, providing estimates of the average annual percentage change for the period 2000–15.FindingsIndividuals aged 70 years or older accounted for the majority of cardiovascular disease deaths in all countries (range 52–82%). Considerable variation in cardiovascular deaths was observed between countries for all age categories. Between 2000 and 2015, in most countries, the largest reductions in ASMR were observed in the older age groups (aged ≥70 years). The total number of regional cardiovascular disease deaths that hypothetically could have been averted in 2015 for people aged 30–79 years was 440 777, of which 211 365 (48%) occurred among people aged 70–79 years.InterpretationData for the WHO Region of the Americas are sufficiently robust to permit comparative analysis of cardiovascular disease mortality trends for people aged 70 years and older over time and across countries. Although the reduction of cardiovascular disease mortality in individuals aged 30–69 years is a valid policy goal for the Americas region, this objective should be expanded to include people at older ages.FundingNone.
<i>Notes from the Field:</i> Six Cases of Acute Flaccid Myelitis in Children — Minnesota, 2018
Authors: Heidi Moline, Anupama Kalaskar, William F. Pomputius, Adriana Lopez, Janell Routh, Cynthia Kenyon, Jayne Griffith
Journal: MMWR Morbidity and Mortality Weekly Report (2019)
Relationship of the CYP19 RS1008805 polymorphism to prognosis of stage I–II and operable stage III breast cancer.
Authors: Xiying Shao, Yabing Zheng, Lei Shi, Yuan Huang, Yuheng Ding, Yong Guo, Xiaohong Xu, Xiaojia Wang
Journal: Journal of Clinical Oncology (2015)

e22088 Background: Aromatase, encoded by the CYP19A1 gene, catalyzes the essential step of the conversion of androgens to estrogens. Given the critical role of CYP19A1 gene in estrogen synthesis, CYP19A1 gene rs1008805 polymorphism may affect the prognosis of breast cancer. Methods: CYP19A1 gene rs1008805 variants were genotyped on 406 Chinese Han women with stage I–II and operable stage III breast cancer. Associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS). Results: Totally, there were 200 (49.3%) patients with AA genotype, 169 (41.6%) with AG variant, and 37 (9.1%) carrying GG variant. AA genotype was significantly associated withearly stage (57.0% versus 51.5%, P = 0.047). No significant differences were found in DFS as well as 5-year DFS rate among the whole population with these three genotypes. However, postmenopausal women with GG variant had a poorer DFS, 5-years DFS rate when compared with those carrying AG or AA genotype (GG versus AG or AA: 13.7 months versus 56.3 months; 0% versus 52.1%; HR, 2.462; 95 % CI, 1.310-4.628; P = 0.004). And what’s more, being adjusted by patients features in multivariate analyses, GG genotype remained an independent prognostic factor for DFS (HR, 2.706; 95 % CI, 1.393-5.257; P = 0.003). Premenopausal women with the homozygous minor allele had a marginally improved DFS, 5-years DFS rate when compared with those carrying the common allele (GG versus AG or AA: 87.0 months versus 48.7 months; 60.3% versus 42.7 %; HR, 0.544; 95% CI, 0.295-1.003; P = 0.051). However, this difference was not confirmed by multivariate analyses. Conclusions: The present study indicates that GG genotype of rs1008805 SNP in the first exon of CYP19A1 gene was significantly related to lower DFS and 5-year DFS rate in postmenopausal women with early breast cancer. This founding is novel, if confirmed, CYP19A1 rs1008805 genotypes may turned to be a prognostic factor for early breast cancer.
FRI-161-Complication is a major risk factor for mortality of cirrhotic hepatitis B virus-related acuted-on-chronic liver failure patients: A multi-national study from Asian-pacific region
Authors: Tao Chen, Zhongyuan Yang, Jun Li, Tao Han, Jinhua Hu, Shaojie Xin, Ashok Choudhury, Mamun Al-Mahtab, Yuemin Nan, Soek-Siam Tan, Saeed Sadiq Hamid, Amna Subhan, Wasim Jafri, Guan Huei Lee, Hasmik Ghazinian, Yogesh Chawla, Man-Fung Yuen, Ji-Dong Jia, Zaigham Abbas, Harshad Devarbhavi, A. Kadir Dokmeci, Deepak Amarapurkar, Manoj Kumar, Laurentius A. Lesmana, George Lau, Osamu Yokosuka, Zhongping Duan, Wei Guo, Ke Ma, Zhongwei Zhang, Shiv Kumar Sarin, Qin Ning
Journal: Journal of Hepatology (2019)
Progress Toward Improved Cardiovascular Health in the United States
Authors: Katherine Pahigiannis, Angela M. Thompson-Paul, Whitney Barfield, Emmeline Ochiai, Fleetwood Loustalot, Susan Shero, Yuling Hong
Journal: Circulation (2019)

The Healthy People Initiative has served as the leading disease prevention and health promotion roadmap for the nation since its inception in 1979. Healthy People 2020 (HP2020), the initiative’s current iteration, sets a national prevention agenda with health goals and objectives by identifying nationwide health improvement priorities and providing measurable objectives and targets from 2010 to 2020. Central to the overall mission and vision of Healthy People is an emphasis on achieving health equity, eliminating health disparities, and improving health for all population groups. The Heart Disease and Stroke (HDS) Work Group of the HP2020 Initiative aims to leverage advances in biomedical science and prevention research to improve cardiovascular health across the nation. The initiative provides a platform to foster partnerships and empower professional societies and nongovernmental organizations, governments at the local, state, and national levels, and healthcare professionals to strengthen policies and improve practices related to cardiovascular health. Disparities in cardiovascular disease burden are well recognized across, for example, race/ethnicity, sex, age, and geographic region, and improvements in cardiovascular health for the entire population are only possible if such disparities are addressed through efforts that target individuals, communities, and clinical and public health systems. This article summarizes criteria for creating and tracking the 50 HDS HP2020 objectives in 3 areas (prevention, morbidity/mortality, and systems of care), reports on progress toward the 2020 targets for these objectives based on the most recent data available, and showcases examples of relevant programs led by participating agencies. Although most of the measurable objectives have reached the 2020 targets ahead of time (n=14) or are on track to meet the targets (n=7), others may not achieve the decade’s targets if the current trends continue, with 3 objectives moving away from the targets. This summary illustrates the utility of HP2020 in tracking measures of cardiovascular health that are of interest to federal agencies and policymakers, professional societies, and other nongovernmental organizations. With planning for Healthy People 2030 well underway, stakeholders such as healthcare professionals can embrace collaborative opportunities to leverage existing progress and emphasize areas for improvement to maximize the Healthy People initiative’s positive impact on population-level health.
Setting traps for NKG2A gives NK cell immunotherapy a fighting chance
Authors: Frank Cichocki, Jeffrey S. Miller
Journal: Journal of Clinical Investigation (2019)

The equilibrium of signaling through activating and inhibitory receptors dictates whether a given NK cell will execute cellular cytotoxicity. In this issue of the JCI, Kamiya et al. describe a novel approach to efficiently inhibiting surface expression of the inhibitory receptor CD94/NK group 2 member A (NKG2A) through retention of the protein in the endoplasmic reticulum. In adoptive transfer experiments into tumor-bearing immunodeficient mice, NKG2Anull NK cells were significantly more effective at eliminating HLA-E-expressing tumor cells than NKG2A+ NK cells. This study provides proof of concept for a new immunotherapeutic approach using NKG2Anull NK cells.
Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial
Authors: Katherine N. Cahill, Jing Cui, Parul Kothari, Katherine Murphy, Benjamin A. Raby, Joseph Singer, Elliot Israel, Joshua A. Boyce, Tanya M. Laidlaw
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease.Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease.Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet–leukocyte aggregates, and granulocyte transcripts were assessed.Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite (P < 0.05) and increased urinary leukotriene E4 (P < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D2 and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide (P < 0.05), plasma tryptase (P < 0.01), and blood eosinophil (P < 0.01) and basophil (P < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r = 0.514; P < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet–leukocyte aggregates, platelet activation markers, or plasma cytokines in either group.Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.
Increased expression of IL‐24 in chronic spontaneous urticaria
Authors: Laurence de Montjoye, Anne Herman, Emilie Hendrickx, Paméla Chéou, Christophe Blanchetot, Erik Hofman, Marie Baeck, Laure Dumoutier
Journal: Allergy (2019)

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The Interaction of Natural Selection and GC Skew May Drive the Fast Evolution of a Sand Rat Homeobox Gene
Authors: Yichen Dai, Peter W H Holland
Journal: Molecular Biology and Evolution (2019)

Several processes can lead to strong GC skew in localized genomic regions. In most cases, GC skew should not affect conserved amino acids because natural selection will purge deleterious alleles. However, in the gerbil subfamily of rodents, several conserved genes have undergone radical alteration in association with strong GC skew. An extreme example concerns the highly conserved homeobox gene Pdx1, which is uniquely divergent and GC rich in the sand rat Psammomys obesus and close relatives. Here, we investigate the antagonistic interplay between very rare amino acid changes driven by GC skew and the force of natural selection. Using ectopic protein expression in cell culture, pulse-chase labeling, in vitro mutagenesis, and drug treatment, we compare properties of mouse and sand rat Pdx1 proteins. We find that amino acid change driven by GC skew resulted in altered protein stability, with a significantly longer protein half-life for sand rat Pdx1. Using a reversible inhibitor of the 26S proteasome, MG132, we find that sand rat and mouse Pdx1 are both degraded through the ubiquitin proteasome pathway. However, in vitro mutagenesis reveals this pathway operates through different amino acid residues. We propose that GC skew caused loss of a key ubiquitination site, conserved through vertebrate evolution, and that sand rat Pdx1 evolved or fixed a new ubiquitination site to compensate. Our results give molecular insight into the power of natural selection in the face of maladaptive changes driven by strong GC skew.
Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma
Authors: Cesar Sommer, Bijan Boldajipour, Tracy C. Kuo, Trevor Bentley, Janette Sutton, Amy Chen, Tao Geng, Holly Dong, Roman Galetto, Julien Valton, Thomas Pertel, Alexandre Juillerat, Annabelle Gariboldi, Edward Pascua, Colleen Brown, Sherman M. Chin, Tao Sai, Yajin Ni, Philippe Duchateau, Julianne Smith, Arvind Rajpal, Thomas Van Blarcom, Javier Chaparro-Riggers, Barbra J. Sasu
Journal: Molecular Therapy (2019)

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.