tbuckley/cabot-search huggingface dataset:
An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations
Authors: Nicholas Pulliam, Fang Fang, Ali R. Ozes, Jessica Tang, Adeoluwa Adewuyi, Harold Keer, John Lyons, Stephen B. Baylin, Daniela Matei, Harikrishna Nakshatri, Feyruz V. Rassool, Kathy D. Miller, Kenneth P. Nephew
Journal: Clinical Cancer Research (2018)

Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status.Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed.Results: Combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP "trapping" by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models.Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers. Clin Cancer Res; 24(13); 3163-75. ©2018 AACR.
Growing Symbiotic Local Partnerships to Nurture Quality Pediatric Hospice Care in Rural Regions
Authors: Meaghann S. Weaver
Journal: JAMA Pediatrics (2018)

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The prognostic value of serum IL-6 and YKL-40 in colorectal cancer patients before liver resection.
Authors: Mathias Holsey Gramkow, Reetta Peltonen, Christian Dehlendorff, Pia J. Osterlund, Julia S. Johansen, Helena Isoniemi
Journal: Journal of Clinical Oncology (2017)

e15078 Background: IL-6 and YKL-40, markers of inflammation and cancer growth, are high in serum in patients with colorectal cancer (CRC) and associated with shorter overall survival (OS). We hypothesized that preoperative serum IL-6, YKL-40 and CEA are associated with disease free survival (DFS) and OS in patients with metastatic (mCRC) treated with liver resection. Methods: 457 patients (male/female: 267 (58%)/190 (42%), median age 65 [IQR: 58-71]) diagnosed with mCRC who underwent liver resection were included between March 1998 and February 2013. Preoperative serum samples were collected and stored at -80°C until analysis. Serum IL-6 (R&amp;D Systems, UK) and YKL-40 (Quidel, USA) were determined by ELISA. For DFS and OS we estimated crude and adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CIs) with Cox regression for each biomarker separately. The biomarkers were included as log 2 -transformed continuous variables and adjustment included mutual adjustment between the biomarkers in addition to adjusting for sex and age. Results: The median (IQR) preoperative biomarker levels were: IL-6 (3.5 pg/ml, 2.1-6.1), YKL-40 (75 ng/ml, 48-127) and CEA (5.2 kU/L, 2.6-18.8). Univariate analysis showed that high serum IL-6 and YKL-40 were associated with shorter DFS (IL-6: HR = 1.18, 1.06-1.31, p &lt; 0.01; YKL-40: HR = 1.19, 1.08-1.32, p &lt; 0.01). Serum CEA was not (p = 0.80). Multivariate analysis (all biomarkers) showed that high IL-6 was associated with shorter DFS (HR = 1.15, 1.02-1.29, p = 0.02), whereas YKL-40 (p = 0.08) and CEA (p = 0.51) were not. Univariate analysis showed that high preoperative serum IL-6 and YKL-40 were associated with shorter OS (IL-6: HR = 1.16, 1.03-1.29, p = 0.01; YKL-40: HR = 1.27, 1.14-1.42, p &lt; 0.01). Serum CEA was not associated with OS (p = 0.16). Multivariate analysis (all biomarkers) showed that high YKL-40 was associated with shorter OS (HR = 1.19, 1.05-1.34, p = 0.01), whereas IL-6 (p = 0.25) and CEA (p = 0.26) were not. Patients with elevated serum levels of all 3 biomarkers had the shortest OS (HR = 2.12; 1.29-3.50, p &lt; 0.01). Conclusions: Serum IL-6 and YKL-40 determined before liver resection may be valuable prognostic biomarkers in patients with metastatic CRC.
Biological foundations and beneficial effects of trance
Authors: Michael J. Hove, Johannes Stelzer
Journal: Behavioral and Brain Sciences (2018)

Abstract Singh proposes a cultural evolutionary theory of shamanic practices, including trance. We argue that cultural factors are deeply intertwined with biological aspects in shaping shamanic practices, and the underlying biology is critical. We discuss the neural underpinnings of rhythm-induced trance, how they can facilitate insight, and how altered states can promote healing.
Highly cytotoxic EGFR/CD16A TandAbs to recruit NK-cells to kill EGFR-expressing tumor cells.
Authors: Martin Treder, Kristina Ellwanger, Uwe Reusch, Ivica Fucek, Michael Weichel, Thorsten Gantke, Stefan Knackmuss, Oscar Kashala, Jens-Peter Marschner, Xing Zhao, Narendiran Rajasekaran, Holbrook Edwin Kohrt
Journal: Journal of Clinical Oncology (2016)

e14007 Background: The epidermal growth factor receptor (EGFR) is an important and established target for the treatment of several solid tumors, including colorectal, head and neck and lung cancer. Treatment with tyrosine kinase inhibitors and monoclonal antibodies targeting EGFR is dependent on mutation status of the receptor which may cause resistance to the treatments. An EGFR targeting therapy which is effective independent of the mutation status would offer a differentiated treatment approach. Methods: Natural killer cells (NK-cells) play a central role in the innate immune system and have the capacity to destroy neoplastic cells. To specifically utilize the cytotoxic potential of NK-cells for the elimination of EGFR-expressing cancer cells, we developed tetravalent bispecific EGFR/CD16A NK-cell TandAbs with two binding sites for EGFR and two binding sites for CD16A. CD16A is an isoform of CD16 which is specifically expressed by NK-cells and macrophages but not by neutrophils. Results: We identified high affinity antibodies recognizing epitopes in the extracellular domain 21 of EGFR, a domain that is not targeted by other therapeutic antibodies. We engineered a set of EGFR/CD16A TandAbs and analyzed their characteristics. TandAbs containing domain 21 showed single digit picomolar or subpicomolar EC50 values and were more potent than a control TandAb harbouring the antibody sequence from cetuximab. In addition, the EGFR/CD16A TandAbs showed excellent biophysical properties and a lead candidate has been progressed to IND-enabling studies, including in vivo pharmacology. Conclusions: Our data suggest that EGFR/CD16A TandAbs are novel, highly potent drug candidates suitable for the treatment of EGFR-expressing malignancies with the potential to overcome resistance to other EGFR targeting agents.
Comprehensive genomic profiling of ctDNA in patients with colon cancer and its fidelity to the genomics of the tumor biopsy.
Authors: Jeffrey P. Gregg, Gerald Li, Dean Pavlick, Jon Chung, Matthew Cooke, Jie He, Alexa Betzig Schrock, Doron Lipson, Brady Forcier, Travis A Clark, Michelle Nahas, Siraj Mahamed Ali, Phil Stephens, Vincent A. Miller
Journal: Journal of Clinical Oncology (2018)

569 Background: The liquid biopsy offers the ability to non-invasively analyze the genome of a tumor through circulating tumor (ct) DNA to identify targetable and prognostic genomic alterations. Few studies have rigorously analyzed ctDNA results and determined the fidelity with which they recapitulate the genomics of the tumor. The clinical utility study (CUS) for FoundationACT (Foundation Medicine, Cambridge, MA; NCT02620527) is a large multi-center prospective clinical study to validate this ctDNA assay for multiple solid tumor types. In this subset of the CUS study, paired specimens from 98 patients with colon cancer were analyzed with comprehensive genomic profiling of the tumor (FoundationOne) and a blood sample (FoundationACT). Methods: Maximum somatic allele fraction (MSAF) was used to estimate the fraction of ctDNA in the sample. The set of genes and targeted regions common to both FoundationOne and FoundationACT were compared for each subject. Results: 60% were male; 73 had stage IV, 17 had stage III, and 8 had stage II disease. 16% of cases had an MSAF value of 0, indicating that no ctDNA were in these samples. For the cases with MSAF &gt; 0, 153 insertion/deletions (indels)/substitutions were identified in the tumor, and 73% of these identical alterations were also identified in the ctDNA samples. As robust analytical performance for FoundationACT has been demonstrated at MSAF &gt; 0.5% for indel/subs, further analysis was conducted using this threshold. 83% of the alterations identified with FoundationOne were identified with FoundationACT. Further, 90% of NRAS/KRAS and 75% BRAF alterations (NCCN guideline genes) were concordant between the two assays. Lastly, there were 11 patients with tumor biopsy and blood draw taken within 30 days of each other, and in these there was 100% concordant. Association of the genomics results with other clinical variables will be presented for the available subset of patients. Conclusions: In cases where tumor profiling is not possible, these results provide compelling evidence that comprehensive molecular profiling of ctDNA in colon cancer can be used to identify most clinically relevant alterations and has fidelity to the genomics of the tumor. Clinical trial information: NCT02620527.
Autoinflammation behind the curtain
Authors: A.A. Navarini, L.E. French
Journal: British Journal of Dermatology (2018)

Linked Articles:Wallach and Vignon‐Pennamen. Br J Dermatol 2018; 178:595–602. Satoh et al. Br J Dermatol 2018; 178:603–613. Pink et al. Br J Dermatol 2018; 178:619–631. Bachelez. Br J Dermatol 2018; 178:614–618.
Grounding responsibility in something (more) solid
Authors: William Hirstein, Katrina Sifferd
Journal: Behavioral and Brain Sciences (2018)

Abstract The cases that Doris chronicles of confabulation are similar to perceptual illusions in that, while they show the interstices of our perceptual or cognitive system, they fail to establish that our everyday perception or cognition is not for the most part correct. Doris's account in general lacks the resources to make synchronic assessments of responsibility, partially because it fails to make use of knowledge now available to us about what is happening in the brains of agents.
Outdoor air pollution, exhaled 8-isoprostane and current asthma in adults: the EGEA study
Authors: Anaïs Havet, Farid Zerimech, Margaux Sanchez, Valérie Siroux, Nicole Le Moual, Bert Brunekreef, Morgane Stempfelet, Nino Künzli, Bénédicte Jacquemin, Régis Matran, Rachel Nadif
Journal: European Respiratory Journal (2018)

Associations between outdoor air pollution and asthma in adults are still scarce, and the underlying biological mechanisms are poorly understood. Our aim was to study the associations between 1) long-term exposure to outdoor air pollution and current asthma, 2) exhaled 8-isoprostane (8-iso; a biomarker related to oxidative stress) and current asthma, and 3) outdoor air pollution and exhaled 8-iso. Cross-sectional analyses were conducted in 608 adults (39% with current asthma) from the first follow-up of the French case–control and family study on asthma (EGEA; the Epidemiological study of the Genetic and Environmental factors of Asthma). Data on nitrogen dioxide, nitrogen oxides, particulate matter with a diameter ≤10 and ≤2.5 µm (PM 10 and PM 2.5 ), road traffic, and ozone (O 3 ) were from ESCAPE (European Study of Cohorts for Air Pollution Effects) and IFEN (French Institute for the Environment) assessments. Models took account of city and familial dependence. The risk of current asthma increased with traffic intensity (adjusted (a)OR 1.09 (95% CI 1.00–1.18) per 5000 vehicles per day), with O 3 exposure (aOR 2.04 (95% CI 1.27–3.29) per 10 µg·m −3 ) and with exhaled 8-iso concentration (aOR 1.50 (95% CI 1.06–2.12) per 1 pg·mL −1 ). Among participants without asthma, exhaled 8-iso concentration increased with PM 2.5 exposure (adjusted (a)β 0.23 (95% CI 0.005–0.46) per 5 µg·m −3 ), and decreased with O 3 and O 3-summer exposures (aβ −0.20 (95% CI −0.39– −0.01) and aβ −0.52 (95% CI −0.77– −0.26) per 10 µg·m −3 , respectively). Our results add new insights into a potential role of oxidative stress in the associations between outdoor air pollution and asthma in adults.
The Extracorporeal Life Support Organization Maastricht Treaty for Nomenclature in Extracorporeal Life Support. A Position Paper of the Extracorporeal Life Support Organization
Authors: Steven A. Conrad, L. Mikael Broman, Fabio S. Taccone, Roberto Lorusso, Maximilian V. Malfertheiner, Federico Pappalardo, Matteo Di Nardo, Mirko Belliato, Lorenzo Grazioli, Ryan P. Barbaro, D. Michael McMullan, Vincent Pellegrino, Daniel Brodie, Melania M. Bembea, Eddy Fan, Malaika Mendonca, Rodrigo Diaz, Robert H. Bartlett
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Extracorporeal life support (ECLS) was developed more than 50 years ago, initially with venoarterial and subsequently with venovenous configurations. As the technique of ECLS significantly improved and newer skills developed, complexity in terminology and advances in cannula design led to some misunderstanding of and inconsistency in definitions, both in clinical practice and in scientific research. This document is a consensus of multispecialty international representatives of the Extracorporeal Life Support Organization, including the North America, Latin America, EuroELSO, South West Asia and Africa, and Asia-Pacific chapters, imparting a global perspective on ECLS. The goal is to provide a consistent and unambiguous nomenclature for ECLS and to overcome the inconsistent use of abbreviations for ECLS cannulation. Secondary benefits are ease of multicenter collaboration in research, improved registry data quality, and clear communication among practitioners and researchers in the field.
Abstract 19224: Fibrinogen And Neopterin Predict Future Myocardial Infarction Events In Patients With Stable Coronary Heart Disease
Authors: Øistein R Mjelva, Gard F Svingen, Eva K Pedersen, Reinhard Seifert, Per M Ueland, Jan E Nordrehaug, Dennis W Nilsen, Ottar Nygård
Journal: Circulation (2015)

Background: Fibrinogen is synthesized by hepatocytes. It is a precursor of fibrin and forms bridges between platelets during thrombus formation, but it is also a marker of ongoing inflammation. Neopterin is released by monocyte/ macrophage activation associated with atherosclerosis. Whether these markers interact or act independently among patients with suspected stable coronary heart disease has previously not been given much attention. Methods: We included 3526 patients undergoing elective coronary angiography at two university hospitals in Norway during 2000-2004, with a median follow-up of 7.3 years. Cox regression analysis was used to obtain hazard ratios (HR) and 95% confidence intervals (CI) for incident AMI of fibrinogen and neopterin levels in a crude model and a model adjusted for age, gender, diabetes, current smoking, hypertension and serum apoA1 and apoB. Potential effect modifications were investigated according to strata of fibrinogen or neopterin below or above the median, as well as across subgroups of age, gender, smoking status, diabetes, serum apoA1 and apoB. A p-value &lt;0.05 was considered significant. Results: During follow-up, 580 patients experienced an AMI. In the unadjusted model, both fibrinogen and neopterin predicted future AMI [HR = 1.32; 95% CI 1.22-1.43; p&lt;0.001 and HR = 1.31; 95% CI 1.23-1.40; p&lt;0.001, respectively]. The estimates were only slightly attenuated in the multivariate model, and still associated with incident AMI when both biomarkers were added simultaneously [HR = 1.15; 95% CI 1.05-1.25; p&lt;0.001 and HR = 1.20; 95% CI 1.12-1.28; p&lt;0.001, respectively]. Baseline fibrinogen and neopterin levels were modestly correlated (Spearman’s rho = 0.18, p-value &lt;0.001). There were no statistically significant interaction across subgroups (p for interaction fibrinogen and high/ low neopterin = 0.26, neopterin and high/low fibrinogen = 0.46, respectively). Conclusion: Patients with increased levels of fibrinogen or neopterin are at increased risk of future AMI. Neopterin levels did not significantly interact with the prognostic utility of fibrinogen. This suggests that circulating fibrinogen and neopterin may reflect different pathophysiological mechanisms.
Risk of Incident Heart Failure in Patients With Diabetes and Asymptomatic Left Ventricular Systolic Dysfunction
Authors: Rasmus Rørth, Pardeep S. Jhund, Ulrik M. Mogensen, Søren L. Kristensen, Mark C. Petrie, Lars Køber, John J.V. McMurray
Journal: Diabetes Care (2018)

OBJECTIVE Although diabetes is well known to be common in prevalent heart failure (HF) and portends a poor prognosis, the role of diabetes in the development of incident HF is less well understood. We studied the role of diabetes in the transition from asymptomatic left ventricular systolic dysfunction (ALVSD) to overt HF in the prevention arm of the Studies of Left Ventricular Dysfunction (SOLVD-P). RESEARCH DESIGN AND METHODS We examined the development of symptomatic HF, HF hospitalization, and cardiovascular death according to diabetes status at baseline in patients in SOLVD-P. These outcomes were analyzed by using cumulative incidence curves and Cox regression models adjusted for age, sex, and other prognostic factors, including randomized treatment, HF severity, and comorbidity. RESULTS Of the 4,223 eligible participants, 647 (15%) had diabetes at baseline. Patients with diabetes were older and had a higher average weight, systolic blood pressure, and heart rate. During the median follow-up of 36 months, 861 of the 3,576 patients without diabetes (24%) developed HF compared with 214 of the 647 patients with diabetes (33%). In unadjusted analyses, patients with diabetes had a higher risk of development of HF (hazard ratio 1.53 [95% CI 1.32–1.78]; P &amp;lt; 0.001), HF hospitalization (2.04 [1.65–2.52]; P &amp;lt; 0.0001), and the composite outcome of development of HF or cardiovascular death (1.48 [1.30–1.69]; P &amp;lt; 0.001). The effect of enalapril on outcomes was not modified by diabetes status. CONCLUSIONS In patients with ALVSD, diabetes is associated with an increased risk of developing HF. Development of HF is associated with an increased risk of death irrespective of diabetes status.
Advances on the BRAF Front in Colorectal Cancer
Authors: Filip Janku
Journal: Cancer Discovery (2018)

Abstract Summary: Colorectal cancer with BRAFV600E mutation can be effectively treated with combination approaches involving inhibition of BRAF, MEK, and EGFR proteins. However, activation of the MAPK pathway, often due to emergence of previously undetected molecular alterations, ultimately leads to adaptive therapeutic resistance. Novel combination strategies combining inhibition of BRAF, ERK, and EGFR can be used to prevent MAPK pathway–driven resistance and warrant further investigation. Cancer Discov; 8(4); 389–91. ©2018 AACR. See related article by Corcoran et al., p. 428. See related article by Hazar-Rethinam et al., p. 417.
Hormone replacement therapy and its effect on HER2 neu status in primary breast cancer.
Authors: Tina Ashley Khair, Priyanka Mittar, Susan K. Boolbol, Kwadwo Boachie-Adjei, Paula Klein
Journal: Journal of Clinical Oncology (2012)

e11057 Background: Controversy has developed over the use of hormone replacement therapy (HRT) and its association with the future risk of breast cancer. The biology of breast cancer diagnosed after the use of HRT is different than in non HRT users. One such pathologic feature that may be affected by the use of HRT is HER2 neu. While there is existing data illustrating the relationship between HRT and breast cancer, there is little data examining the relationship between HRT and HER2 neu. The purpose of this study is to investigate that relationship and determine whether or not the use of HRT has any effect on the HER2 neu status of primary breast cancers. Methods: A retrospective review of a prospective database identified 2,928 patients with primary breast cancer with a history of prior/current HRT use. Tumor specimens were evaluated for HER2 neu expression at the time of surgery using either IHC or FISH. Pearson’s χ² test along with evaluation of odds ratios were used to determine whether or not there was an association of HER2 neu expression with HRT use. Results: Table 1A illustrates the lack of a correlation between increasing HER2 expression and HRT. There was no significant change in odds of HRT use as HER2 expression increased. After confirming HER2 neu status using FISH, the odds of HER2 positivity among HRT users was OR= 1.05 times the odds of HER2 neu positivity among non-HRT users [C.I. 0.85, 1.29; p = 0.63] (Table 1B). Conclusions: Contrary to our expectation of an inverse relationship between HRT use and HER2 negative phenotype, we found no clear association between the two. Limitations of this study include the inability to discriminate from our data set between current and prior users, and between estrogen alone and combination estrogen/progesterone supplementation. Additionally, the definition of HER2 positivity by membranous staining has changed over the last decade, which may be contributory. We plan on determining the relationship between HER2 status and ER status as it relates to HRT use in future studies. [Table: see text] [Table: see text]