tbuckley/cabot-search huggingface dataset:
Building a Better Death, One Conversation at a Time
Authors: Rebecca Voelker
Journal: JAMA (2019)

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Intravital microscopy reveals a novel mechanism of nanoparticles excretion in kidney
Authors: Victor Naumenko, Aleksey Nikitin, Ksenia Kapitanova, Pavel Melnikov, Stepan Vodopyanov, Anastasiia Garanina, Marat Valikhov, Artem Ilyasov, Daniil Vishnevskiy, Aleksey Markov, Sergei Golyshev, Dmitry Zhukov, Irina Alieva, Maxim Abakumov, Vladimir Chekhonin, Alexander Majouga
Journal: Journal of Controlled Release (2019)
Predicting Mechanisms of Ibrutinib-Resistance in Chronic Lymphocytic Leukemia (CLL) Using Computational-Based Modeling for Personalized Therapy with Clinical Validation
Authors: Leylah M. Drusbosky, Aneel Paulus, Anne Quillet Mary, Loic Ysebaert, Ansu Kumar, Neeraj Kumar Singh, Yashaswini Ullal, Priyanka Bhargav, Humera Azam, Taher Abbasi, Shireen Vali, Asher A. Chanan-Khan, Christopher R. Cogle
Journal: Blood (2017)
Abstract 11107: Efficacy and Safety of Intensive Statin Therapy for Hypercholesterolemic Patients With Bioprosthetic Aortic Valve Replacement for Aortic Valve Stenosis
Authors: Yoshihisa Morimoto, Takaki Sugimoto, Hiroki Arase
Journal: Circulation (2014)

Objectives: Intensive rather than standard statin therapy has been proven to be superior in improving cardiovascular outcome, whereas the effects of intensive statin therapy on inflammation and lip...
Quantitative analysis of topical treatments in atopic dermatitis: unexpectedly low use of emollients and strong correlation of topical corticosteroid use both with depression and concurrent asthma
Authors: J.Y. Choi, R. Dawe, S. Ibbotson, C. Fleming, A. Doney, J. Foerster
Journal: British Journal of Dermatology (2019)

Despite decades of use, the actual amounts of topical corticosteroids (TCS) and emollients used in moderate-to-severe atopic dermatitis (AD) under real-world conditions are unknown. Thus, it remains unclear whether inadequate use is widespread.To quantify the use of TCS and emollients in moderate-to-severe AD.Double-blinded drug prescribing was recorded prospectively at the point of drug dispensing within a catchment area of approximately 450 000 people over a 31-year period in a population-based cohort marked by failure of disease control in primary care (n = 844). For each patient, prescribing was recorded over a 12-month period in order to minimize fluctuations.This approach resulted in a near-complete dataset, which was essentially free of reporting bias and recording bias. Atopic comorbidities matched expected frequencies. Median use of TCS was statistically significantly higher in juvenile patients (age < 16 years) compared with adult patients (49·2 vs. 38·1 g per month), in male vs. female patients (46·8 vs. 29·7 g per month) and in patients receiving concurrent asthma treatment (40·4 vs. 26·7 g per month). TCS use was strongly associated with antidepressant treatment. Emollient use was unexpectedly low with a median of 9·6 g per day (range 1·4-30·1). Results were replicated in an independent validation cohort.Deficient use of emollients may be a factor contributing to AD severity. Our analysis showed that the use of TCS does not exceed current guidelines. Accurate quantification of topical treatments provides a widely accessible strategy to measure the real-world impact of novel AD treatments. What's already known about this topic? Both emollient and topical corticosteroid (TCS) use have been a mainstay of atopic dermatitis (AD) treatment for over 60 years. The actual quantities used by patients under real-world conditions are unknown. What does this study add? The real-world use of emollients is fourfold lower than the amount recommended in current guidelines. Underuse of emollients may be a significant factor in disease exacerbation. The use of TCS is significantly higher in male patients and is higher in patients with AD who also have asthma. The use of TCS is strongly associated with concurrent antidepressant treatment.
Abstract P118: Differences in Tobacco Use of sexual minorities of Diverse Racial and Ethnic Backgrounds
Authors: Aida L Giachello, Thanh-Huyen T Vu, Joy L Hart, Robyn Landry, Kandi L Walker, Allison Groom, Anshula Kesh, Thomas J Payne, Rose M Robertson
Journal: Circulation (2018)

Background: Although studies have found that cigarette smoking is more prevalent among persons who identify as lesbian, gay, bisexual, transgender, or queer (LGBTQ) compared to persons who identify as heterosexual, limited research has examined tobacco use among LGBTQ individuals of different racial and ethnic backgrounds. Methods: During summer 2016, the AHA-Tobacco Regulation and Addiction Center (A-TRAC) Project 3 conducted 27 focus groups and 196 surveys in Chicago, New York City and San Diego with smokers and non-smokers. Study inclusion criteria were self-identifying as LGBTQ and White Non-Hispanic (WNH), African American (AA), or Hispanic/Latino (H/L). Our study aim is to examine potential differences in tobacco use by race/ethnicity and factors that may be associated with such differences. Chi-square tests were used for group comparisons using SAS version 9.4. Atlas ti.v 7.5 software was used for qualitative analyses. Results: Study participants were: 23% WNH, 16% AA, and 57% H/L; 60% identified as gay/lesbian, 20% as bisexual, and 20% as members of other groups. Socioeconomic status (SES) of the participants varied by smoking status. More smokers than nonsmokers lived in households with incomes under $20,000/year (50% of smokers vs. 39% of nonsmokers (p.001)) or were unemployed (34% vs. 19% (p.003)). Many participants suggested that easy access to tobacco products (e.g., cigarettes are “cheaper,” “you find single cigarettes sold everywhere") contributed to smoking initiation. Continued tobacco use was often mentioned as a way to deal with stress, such as the stress related to “coming out.” For racial minorities (AAs and H/Ls) compared to NHWs, sources of social stress included discrimination based on race, class, and sexual orientation as well as pressures to respond to community and cultural norms and expectations, such as gender roles (e.g., machismo). AAs and H/Ls also reported more heavy marketing of tobacco in their communities and indicated less knowledge about the risks associated with tobacco use. Racial minorities also expressed preferences for different tobacco products (e.g., cigarettes with menthol) than NHWs. Conclusion: Differences in knowledge, attitudes and perceptions related to tobacco use were found among LGBTQ individuals of diverse racial/ethnic backgrounds. These findings have implications for culturally tailoring health communication campaigns and educational programs for LGBTQs, as well as for low SES groups. The findings also suggest the need for additional tobacco regulatory efforts in populations most vulnerable to tobacco marketing.
Abstract 1049: Targeting YAP/TAZ pathway inhibits Ewing sarcoma metastasis
Authors: Lisa Bierbaumer, Anna M. Katschnig, Branka Radic-Sarikas, Jeffrey R. Petro, Karin Mühlbacher, Dave N. Aryee, Anna R. Pötsch, Sandra Högler, Lukas Kenner, Aykut Uren, Heinrich Kovar
Journal: Cancer Research (2019)

Abstract The term epithelial to mesenchymal transition (EMT) and its reverse (MET) describe the dynamic and reversible metamorphosis of cells from a highly organized to a loose migratory phenotype through cytoskeletal reorganization causing cellular plasticity. EMT/MET are inherent to normal embryonal development and wound healing, but cancer cells hijack the underlying mechanisms to enable oscillations between proliferation, invasion and migration that cause metastasis, the major killer of cancer patients. Recently, fluctuations of the oncoprotein EWS-FLI1 were identified to drive EMT/MET in Ewing sarcoma. We previously demonstrated that, in presence of EWS-FLI1, transcriptional co-activators MRTFB and TAZ are largely blocked from associating with TEAD and its target genes keeping tumor cells in a poorly migratory, highly proliferative state. In contrast, under EWS-FLI-low conditions, MRTFB and TAZ associate with YAP/TEAD complexes on chromatin resulting in cytoskeletal target gene activation and phenotypic transition to a highly migratory and low proliferative state. We therefore hypothesized that pharmacologic inhibition of YAP/TAZ/TEAD protein interaction should prevent Ewing sarcoma cells from EMT and consequently interfere with their metastatic potential. Verteporfin is a small molecule safely used in the treatment of age-related macular degeneration. Independent of its photosensitizing activity exploited in ophthalmology, it is a YAP/TAZ pathway -blocking compound. In vitro treatment of EWS-FLI1-low Ewing sarcoma cells with verteporfin resulted in decreased YAP/TAZ/TEAD complex formation in the nanomolar range, reversal of the de-repression of a EWS-FLI1 controlled EMT transcriptional signature, and inhibition of tumor cell migration in a Boyden chamber assay. Upon orthotopic implantation of TC71 Ewing sarcoma cells into the tibial crest of SCID beige mice, intra-peritoneal treatment of mice with 25mg verteporfin/kg/day before and after amputation of the affected limb led to a drastic decrease of lung metastases without affecting primary tumor growth and without obvious general toxicity. Therefore, YAP/TAZ pathway blockade holds promise as a potential metastasis-preventive strategy in the treatment of Ewing sarcoma patients with primary localized disease. Citation Format: Lisa Bierbaumer, Anna M. Katschnig, Branka Radic-Sarikas, Jeffrey R. Petro, Karin Mühlbacher, Dave N. Aryee, Anna R. Pötsch, Sandra Högler, Lukas Kenner, Aykut Uren, Heinrich Kovar. Targeting YAP/TAZ pathway inhibits Ewing sarcoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1049.
Abstract 20550: Rictor/mTORC2 is a Critical Mediator of Cardiac Hypertrophy and Survival in Response to Pressure Overload
Authors: Sebastiano Sciarretta, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation (2010)

Mammalian target of rapamycin (mTOR) is a protein kinase which exerts its cellular functions by assembling into the multiprotein complexes 1 (mTORC1) and 2 (mTORC2) with the specific adaptor protei...
D2d — No Defense against Diabetes
Authors: Deborah J. Wexler
Journal: New England Journal of Medicine (2019)

The benefits of vitamin D on myriad health outcomes have been much debated.1,2 Although vitamin D sufficiency is crucial for skeletal health (Table 1), the relation between vitamin D and other health outcomes is less clear.3 One potential vitamin D–related disease of interest has been diabetes mellitus (both type 1 and type 2). Observational studies, preclinical data, and some smaller physiological studies have shown that low vitamin D levels were associated with impaired pancreatic beta-cell function as well as insulin resistance, leading to the hypothesis that vitamin D supplementation would reduce the risk of progression to type 2 diabetes.4 Consequently, . . .
Abstract LB-302: Whole genome sequencing reveals a significant role of ZNFs-PHLPP2-AKT axis in familial breast cancer of chaoshan area
Authors: Can-Bin Fang, Qian-Qian Ye, Jing Liu, Guo-Jun Zhang
Journal: Cancer Research (2019)

Abstract Introduction Up to 15% cases of breast cancer are familial. However, the two most prevalent susceptibility genes, BRCA1 and BRCA2, only account for 25% of the familial cases. To this regard, we aimed to identify recurrent variants associated with familial breast cancer in Chaoshan Area of China by whole genome sequencing. Materials &amp; Methods In the present study, Whole Genome Sequencing was performed in 8 familial breast cancer families with 13 familial breast cancer cases and 25 healthy relatives from Chaoshan Area. All the variants were filtered and prioritized by co-segregation analysis and bioinformatic tools. Results A total of 714 variants in 609 genes were selected as rare, probably damaging pathogenic mutations after co-segregation and functional prediction analysis in each family. In all the 609 genes, the zinc finger protein family was overlapped in all the 8 families, among which the c.120-130del of ZNF77 was overlapped in 3 families, c.279_791de of ZNF544 and c.T895A of ZNF479 in 2 families respectively, which emphasized the great significance of ZNF family in the mutational spectrum of Chaoshan Area. After that, the KEGG Pathway analysis in KOBAS 3.0 implied the significance of PI3K-Akt pathway in all the mutated 609 genes. At the same time, the PPI analysis by Cytoscape 3.6.1 indicated that all ZNF genes were interacted with one specific gene, PHLPP2, which inhibits the PI3K-Akt pathway similar to PTEN. Furthermore, two website-based bioinformatic tools cBioportal and Oncomine have predicted the positive correlations between ZNF77 and PHLPP2. All the analysis above was demonstrated the great significance of ZNFs-PHLPP2-AKT axis in the mutational spectrum of familial breast cancer of Chaoshan Area, in China. Conclusions Zinc finger protein family, especially ZNF77, are frequently mutated in the familial breast cancer of Chaoshan Area, which results in the down regulation of PHLPP2 and subsequently reverse the inhibition of PI3K-Akt pathway, and finally lead to tumorigenesis. Citation Format: Can-Bin Fang, Qian-Qian Ye, Jing Liu, Guo-Jun Zhang. Whole genome sequencing reveals a significant role of ZNFs-PHLPP2-AKT axis in familial breast cancer of chaoshan area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-302.
Abstract 434: Cardiomyopathy-associated Point Mutation in the ADP-ATP Carrier Reveals Translation-dependent Regulation of Cytochrome <i>c o</i> xidase Activity in Yeast
Authors: Oluwaseun B Ogunbona, Matthew G Baile, Steven M Claypool
Journal: Circulation Research (2017)

The interaction between the ADP/ATP carrier and the respiratory supercomplexes is evolutionarily-conserved, is dependent on cardiolipin, and is functionally significant as yeast lacking Aac2p have reduced activity of respiratory complex IV ( cytochrome c oxidase or COX). We have leveraged a transport-dead pathogenic AAC2 point mutant discovered in a patient with hypertrophic cardiomyopathy and mild myopathy to determine whether the reduction in complex IV activity in the absence of Aac2p reflects the absence of the interaction between Aac2p and components of the electron transport chain and/or the absence of nucleotide transport (i.e. Aac2p function). Importantly, the pathogenic A137D allele of AAC2 is expressed normally and still interacts with components of the yeast respiratory supercomplex but is unable to support growth on respiratory media due to its inability to transport ADP/ATP. Amazingly, in the absence of Aac2p function, the expression levels of complex IV subunits that are encoded by the mitochondrial genome (and which form the catalytic core of the complex IV holoenzyme) are specifically reduced, even though assembly and interaction with the respiratory supercomplexes are preserved in the mutant Aac2p. This reduction in the levels of complex IV subunits is not caused by a reduction in either the mitochondrial genome copy number or the steady state level of mitochondrial DNA transcripts. Instead, there is a noticeable alteration in the pattern of the mitochondrial translation in the absence of Aac2p activity. Our results suggest that Aac2p function is important for normal translation of the mitochondrial encoded complex IV subunits and that Aac2p activity plays a significant role in regulating oxidative phosphorylation.
Abstract 16503: Adequacy of Hypertension Control Among Patients With Atrial Fibrillation at High Cardiovascular Risk: Insights From a Canadian Prospective Registry
Authors: Milan Gupta, Andrew Ha, Mahesh Kajil, Michelle Tsigoulis, Jafna Cox, Paul Dorian, John Mancini, David Gladstone, Evan Lockwood, Ashfaq Shuaib, Hridyesh Sikri, Narendra Singh, Christopher Labos
Journal: Circulation (2017)

Background: Hypertension (HTN) and atrial fibrillation (AF) commonly co-exist, and optimizing blood pressure (BP) control will reduce morbidity and mortality for this patient population. After publ...
Abstract 500: Predicting patient response to immuno-oncology agents in vitro using 3D cultures
Authors: Kathryn M. Appleton, Qi Guo, Ashley Elrod, Alina Lotstein, Lillia Holmes, Teresa M. DesRochers
Journal: Cancer Research (2019)

Abstract Immuno-oncology (I/O) based therapeutics, including cellular therapies and checkpoint inhibitors have surged in the last 2 years, but the technology to accurately test them in a pre-clinical setting is significantly lacking. While animal models have tried to provide accurate testing platforms, the ultimate goal of a matched patient tumor and immune system is not achievable in mice. To overcome this issue, we have developed two 3D tissue systems for in vitro testing that combine a patient’s tumor cells and autologous immune cells for accurate testing and prediction. We hypothesize that our 3D cell culture systems can recapitulate the patient’s tumor microenvironment to detect I/O response. Our spheroid-based system allows us to monitor how primary T-cells are affected by paired tumor cells and/or the PD-1 inhibitor pembrolizumab using flow cytometry. We have successfully detected pembrolizumab binding to T-cells in a dose dependent manner, clonal expansion of lymphocyte populations, as well as increased expression of activation markers on CD3+ cells following combination with tumor cells and exposure to pembrolizumab. This model also accurately detects CD3+CD8+ T-cell mediated tumor cell death and can be used to track changes in secreted cytokines and chemokines such as Granzyme B and IFN gamma. Our second model, a 3D microtumor platform, allows us to detect immune cell migration and infiltration and therapy related cell death. Our results show pembrolizumab can increase lymphocyte infiltration while simultaneously decreasing microtumor growth in matched patient samples whose tumor cells express PD-L1 and whose lymphocytes are CD8+. Cytokine secretion detected by multiplex technology from our microtumor model supports our observed enhanced T-cell activation in the presence of pembrolizumab. The data generated from our two complex 3D in vitro models can recapitulate in vivo biology in order to derive correlations to I/O drug response. These models can be utilized for preclinical testing of new I/O agents as well as for patient response predictions to I/O therapies. Citation Format: Kathryn M. Appleton, Qi Guo, Ashley Elrod, Alina Lotstein, Lillia Holmes, Teresa M. DesRochers. Predicting patient response to immuno-oncology agents in vitro using 3D cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 500.
Dominant-negative PD1-armored CART cells induce remission in refractory diffuse large B-cell lymphoma (DLBCL) patients.
Authors: Tong Chen, Yan Yuan, Liansheng Huang, Chengfei Pu, Tianling Ding, Xibin Xiao, Zhiyuan Cao, Ting Wu, Luying Ding, He Sun, Zhao Wu, Lei Xiao, Xiaohong Zhang
Journal: Journal of Clinical Oncology (2019)

e19028 Background: The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to relapse/refractory B cell malignancy. However, tumor microenvironment influences and affects CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated Programmed cell death protein 1 (PD1) during T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy. Methods: We generated CAR T cells including an anti-CD19 second generation (2G) CAR molecule and a dominant negative PD1 molecule (Figure A). Compared with conventional CART cells, these “armored” CART cells show the enhanced capability of tumor killing after multiple-round tumor challenging and more “memory-like” phenotypes (Figure B). These results suggest dominant negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment. Results: We report clinical trials of three refractory diffuse large B cell lymphomas (DLBCLs) patients that were successfully treated using the armored CAR T cells described above. All of these three patients failed to achieve response after multiple rounds of chemotherapy and radiotherapy. However, after infused with autologous CART cells at 5.23×10^6/kg and 1.97×10^6/kg, respectively, they showed significant tumor mass decrease and SUV max declines in PET/CT results and ongoing responses (e.g., from 34.48 to 3.89 at day 27, from 25.02 to 2.38 at day 31, respectively, see Figure C). Conclusions: These three clinical trials revealed the significant anti-bulky lymphoma response with respect to these armored CAR T cells and limited and tolerated cytokine release syndrome and central nervous system toxicity. Also, dominant negative PD1 molecules may augment CAR T cells persistence in patients after activation by lymphoma cells, thus enhancing the efficacy of CAR T cells in the treatment of hematomas. Finally, the techniques described herein are a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to recruit more patients for the clinical trials. Clinical trial information: ChiCTR1900021295.