tbuckley/cabot-search huggingface dataset:
Abstract 116: IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma
Authors: Longhao Sun, Liang Liu, Weijun Tian, Zhixiang Zhang, Ya'an Kang, Huamin Wang, Jason B. Fleming, Boris C. Pasche, Wei Zhang
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most lethal and aggressive malignancy. Tumor-associated macrophages (TAMs) mainly represent the M2-like phenotype, with potent immunosuppressive activity, and play a pro-tumor role in nearly all aspects of PDAC biology. Elevated infiltration of M2 TAMs is associated with poor prognosis in PDAC. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogene that induces PDAC progression and is involved in the regulation of immune responses. Our recent study demonstrated that IGFBP2 potentiates signal transducer and activator of transcription 3 (STAT3) transactivation activities in glioma. Considering the essential role of IGFBP2 in governing tumor progression and immune evasion of PDAC, we hypothesized that IGFBP2 promotes tumor progression by inducing alternatively activated macrophages in PDAC. In this study, immunohistochemical (IHC) staining for human PDAC clinical samples was used to reveal the relationship among IGFBP2 expression, M2 TAM accumulation and patient survival. The function of IGFBP2 in inducing alternative polarization of macrophages and promoting tumor progression in PDAC through the STAT3 pathway were evaluated using in vitro and in vivo assays. Ingenuity pathway and gene set enrichment analyses were used to identify the correlation of IGFBP2 gene expression with all other genes in the genome and enriched pathways associated with IGFBP2 gene expression. Our results provide evidence that IGFBP2 expression is associated with M2 macrophage accumulation in the tumor microenvironment and with poor prognosis in PDAC. IGFBP2 augments the production and secretion of IL-10 through activation of STAT3 in PDAC cells, thus reprogramming the TAMs polarization toward an M2 phenotype and promoting tumor progression. These findings established IGFBP2 as an immune-suppressor in the PDAC microenvironment and suggested a strategy for targeting IGFBP2 to improve PDAC immunotherapy. Citation Format: Longhao Sun, Liang Liu, Weijun Tian, Zhixiang Zhang, Ya'an Kang, Huamin Wang, Jason B. Fleming, Boris C. Pasche, Wei Zhang. IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 116.
Spatial clustering and livestock exposure as risk factor for community-acquired Clostridium difficile infection
Authors: S.M. van Dorp, M.P.M. Hensgens, O.M. Dekkers, A. Demeulemeester, A. Buiting, P. Bloembergen, S.C. de Greeff, E.J. Kuijper
Journal: Clinical Microbiology and Infection (2018)
C-terminal HERG Mutations
Authors: MyriamBerthet, IsabelleDenjoy, ClaireDonger, LaurenceDemay, HichamHammoude, DidierKlug, EricSchulze-Bahr, PascaleRichard, HaraldFunke, KettySchwartz, PhilippeCoumel, BernardHainque, PascaleGuicheney
Journal: Circulation (1999)

Background—The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG. In this study, we investigated the 3′ part of HERG for mutations. Methods and Results—New specific primers allowed the amplification of the 3′ part of HERG, the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG, 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1. The 2 more severely affected sisters bore both mutations. Conclusions—The discovery of mutations in the C-terminal part of HERG emphasizes that...
Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity
Authors: MichaelSchupp, JürgenJanke, RonaldClasen, ThomasUnger, UlrichKintscher
Journal: Circulation (2004)

Background— Angiotensin type 1 receptor (AT1R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator–activated receptor-γ (PPARγ) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARγ function by ARBs. Methods and Results— The ARBs irbesartan and telmisartan (10 μmol/L) potently enhanced PPARγ-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3±0.1-fold induction; telmisartan: 3.1±0.3-fold induction; both P<0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 μmol/L: 3.6±0.3-fol...
Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association
Authors: Maria Carmo Pereira Nunes, Andrea Beaton, Harry Acquatella, Caryn Bern, Ann F. Bolger, Luis E. Echeverría, Walderez O. Dutra, Joaquim Gascon, Carlos A. Morillo, Jamary Oliveira-Filho, Antonio Luiz Pinho Ribeiro, Jose Antonio Marin-Neto
Journal: Circulation (2018)

Chagas disease, resulting from the protozoan Trypanosoma cruzi, is an important cause of heart failure, stroke, arrhythmia, and sudden death. Traditionally regarded as a tropical disease found only in Central America and South America, Chagas disease now affects at least 300 000 residents of the United States and is growing in prevalence in other traditionally nonendemic areas. Healthcare providers and health systems outside of Latin America need to be equipped to recognize, diagnose, and treat Chagas disease and to prevent further disease transmission.The American Heart Association and the Inter-American Society of Cardiology commissioned this statement to increase global awareness among providers who may encounter patients with Chagas disease outside of traditionally endemic environments. In this document, we summarize the most updated information on diagnosis, screening, and treatment of T cruzi infection, focusing primarily on its cardiovascular aspects. This document also provides quick reference tables, highlighting salient considerations for a patient with suspected or confirmed Chagas disease.This statement provides a broad summary of current knowledge and practice in the diagnosis and management of Chagas cardiomyopathy. It is our intent that this document will serve to increase the recognition of Chagas cardiomyopathy in low-prevalence areas and to improve care for patients with Chagas heart disease around the world.
Abstract 3002: Genome engineering approaches to generate models of chromosome arm-level cancer aneuploidy
Authors: Alison Marie Taylor, Xiaoyang Zhang, Juliann Shih, Gavin Ha, Galen F. Gao, Ashton C. Berger, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson
Journal: Cancer Research (2018)

Abstract Aneuploidy, whole chromosome or chromosome arm copy number imbalance, is a near-universal characteristic of human cancers. Although yeast and mammalian models of whole chromosome aneuploidies have been extensively investigated, chromosome arm-level aneuploidies have rarely been modeled. Cancer subtypes are often characterized by tumor-specific patterns of these arm-level copy number alterations; for example, squamous cell carcinomas (SCCs) from different tissues of origin (including lung, esophagus, and bladder) have a pattern of chromosome 3p loss and chromosome 3q gain. Our analysis of 495 lung SCCs found chromosome 3p deletion to be the most frequent genomic alteration, occurring in almost 80% of the tumors and covering the entire length of the chromosome arm. Over two-thirds of chromosome 3p genes showed significantly decreased expression in these samples. Without models of chromosome arm-level alterations, the phenotypic effects of specific aneuploidies in cancer, such as 3p deletion, remain unknown. However, recent advances in genome engineering and targeting of endonucleases allow new approaches to generate chromosomal alterations. Here, we used the CRISPR-Cas9 system to delete one copy of chromosome 3p in vitro. We successfully isolated almost 90 clones of immortalized lung epithelial cells with deletion of the 3p arm, with 8 validated by whole-genome sequencing. Consistent with patient data, expression of 3p genes was also decreased upon deletion. Phenotypic characterization revealed that cells with chromosome 3p deletion initially proliferated more slowly than their siblings. These chromosome 3p-deleted cells had increased G1 arrest, but did not undergo increased apoptosis or cell death. Interestingly, after several passages in culture, the proliferation defect was rescued in chromosome 3p-deleted cells; genome sequencing and karyotype analyses suggested that this was the result of chromosome 3 duplication. With our cellular model of chromosome arm-level aneuploidy, we uncovered a possible selection mechanism that allows aneuploidy tolerance in vitro. We used genome engineering to model chromosome arm-level deletions, providing a robust model that will address a gap in our understanding of aneuploidy in cancer. Citation Format: Alison Marie Taylor, Xiaoyang Zhang, Juliann Shih, Gavin Ha, Galen F. Gao, Ashton C. Berger, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson. Genome engineering approaches to generate models of chromosome arm-level cancer aneuploidy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3002.
Urinary incontinence after stroke
Journal: BMJ (1986)

Background and Purpose— Urinary incontinence (UI) is a common and distressing problem after stroke. Although there is evidence of new, effective UI poststroke rehabilitation intervention, it is unknown whether occupational therapists (OTs)’ and physical therapists (PTs)’ actual practices reflect best practices. We sought to determine the extent to which OTs and PTs identify, assess, and treat UI after stroke and to identify personal and organizational predictors of UI problem identification, best-practice assessment, and intervention. Methods— Six hundred sixty-three OTs (93% participation rate) and 656 PTs (87% participation rate) working in stroke rehabilitation in Canada were randomly selected and interviewed with a telephone-administered questionnaire. Each responded to a series of open-ended questions related to a generated case (vignette) of a typical client with stroke who was experiencing UI. Results— Only 39% of OTs and 41% of PTs identified UI after stroke as a problem. Fewer than 20% of OTs and...
Abstract 268: Combined inhibition of cyclooxygenase with docosahexaenoic acid augments apoptosis in KRAS mutant non-small cell lung cancer cells
Authors: Felix Amissah, Kylee J. Jones, Rosemary A. Poku
Journal: Cancer Research (2018)

Abstract Cyclooxygenase (COX) inhibitors are widely used in the treatment of various inflammatory disorders. Their antiproliferative effects have also been widely reported. This health benefit of COX inhibitors is limited by some potential adverse effects, including gastrointestinal irritation. Docosahexaenoic (DHA), commonly derived from fish oils, is also known to possess anticancer effects. We examined whether COX inhibitors (aspirin and diclofenac) combined with DHA would synergize their antiproliferative activity. This would allow for a decrease in the amounts of each compound used for chemoprevention, which may likely decrease the risk of adverse effects. While treatment with DHA resulted in concentration-dependent cell death in K-Ras mutant (A549 and NCI-H1573) lung cancer cells (EC50 of 5.5 µM and 9.5 µM), combination with diclofenac resulted in relatively more significant reduction in cell viability (EC50 of 3.7 µM and 3.2 µM) and cell proliferation (p&amp;lt;0.0001). In addition, the combination treatment was more effective in inhibiting clonogenic cell growth and inducing apoptosis with a significant increase in proapoptotic proteins (p&amp;lt;0.001). Furthermore, the combination treatment yielded more marked inhibition of K-Ras expression as well as altered localization in the cell membrane. These data point to the promising chemopreventive potential of combining low doses of COX inhibitors with DHA with a possible decrease in their adverse effects. Citation Format: Felix Amissah, Kylee J. Jones, Rosemary A. Poku. Combined inhibition of cyclooxygenase with docosahexaenoic acid augments apoptosis in KRAS mutant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 268.
The Size of the Heart during the Course of Essential Hypertension
Authors: Morriskleinfeld, Julesredish
Journal: Circulation (1952)

Changes in cardiac size, as measured by teleroentgenogram, in the course of essential hypertension were studied in 45 patients. Although the majority showed progressive cardiac enlargement from the discovery of hypertension, a goodly number revealed a stationary cardiac size for 10 or more years. Congestive heart failure was found to occur with normal heart measurements. Weight loss did not affect a reduction in cardiac size. Normal cardiac measurements for a decade or more were not unusual. Marked cardiac enlargement was present in several patients for 10 years with little functional limitation. Prognosis on the basis of cardiac size alone was unwarranted.
Discoveries on the Genetics of ADHD in the 21st Century: New Findings and Their Implications
Authors: Anita Thapar
Journal: American Journal of Psychiatry (2018)

The 21st century has witnessed the discovery of multiple rare and common gene variants associated with attention deficit hyperactivity disorder (ADHD), and these discoveries have already provided a starting point for the investigation of the biology of the disorder and novel treatments. The purpose of this selective review is to examine genetic findings from the past 5 years and consider their implications for the conceptualization of ADHD and future clinical practice. Recent discoveries reveal the strong genetic overlaps between ADHD and autism spectrum disorder (ASD) as well as intellectual disability. Thus, the removal of the previous diagnostic exclusion criteria for ADHD in the presence of ASD is a welcome change in DSM-5. However, ADHD also shows substantial genetic correlations with a much broader group of neuropsychiatric disorders as well as with nonpsychiatric conditions (e.g., lung cancer). Investigating potential explanations for these links is an important next step. ADHD, while usefully conceptualized as a disorder in clinical practice, can be viewed as a trait. Recent genome-wide association study findings, consistent with twin studies, highlight that ADHD lies at the extreme end of a continuously distributed dimension, akin to hypertension along the continuum of blood pressure. Although ADHD levels typically decline with age, twin and molecular genetic studies suggest that a persistent trajectory is associated with higher genetic loading. Routine testing for rare mutations in ADHD is not yet recommended, although guidelines in many countries recommend testing individuals with mild intellectual disability or ASD, so practice could change. Common gene variants for ADHD are only weakly predictive and therefore have limited clinical value at present, as does pharmacogenomics. [AJP at 175: Remembering Our Past As We Envision Our Future November 1938: Electroencephalographic Analyses of Behavior Problem Children The electroencephalogram was the first biological technique to be applied to childhood behavioral disorders. Jasper, Solomon, and Bradley reported that "the electroencephalogram has succeeded in revealing a definite abnormality of brain function in over one half of a group of childhood behavior disorders which had been previously considered as largely psychogenic." (Am J Psychiatry 1938; 95:641-658 )].
Control of Plasma Nitric Oxide Bioactivity by Perfluorocarbons
Authors: OlgaRafikova, ElenaSokolova, RuslanRafikov, EvgenyNudler
Journal: Circulation (2004)

Background— Perfluorocarbons (PFCs) are promising blood substitutes because of their chemical inertness and unparalleled ability to transport and upload O2 and CO2. Here, we report that PFC emulsions also efficiently absorb and transport nitric oxide (NO). Methods and Results— Accumulation of NO and O2 in PFC micelles results in rapid NO oxidation and generation of reactive NOx species. Such micellar catalysis of NO oxidation leads to formation of vasoactive S-nitrosothiols (RSNO) in vitro and in vivo as detected electrochemically. The efficiency of PFC-mediated S-nitrosation depends on the amount of PFC in aqueous solution. The optimal PFC concentration that produced the maximum level of RSNO was ≈1% (vol/vol). Larger PFC amounts were progressively less efficient in generating RSNO and functioned simply as NO sink. These results explain the characteristic hemodynamic effects of PFCs. Intravenous bolus application of PFC (0.14 g/kg, ≈1% vol/vol) to Wistar-Kyoto rats decreased mean arterial pressure signif...
Abstract 11924: Prevalence and Predictors of End-of-Life Discussions in Patients Hospitalized With Acute Decompensated Heart Failure
Authors: Kathleen A Young, Jacob J Strand, Margaret M Redfield, Shannon M Dunlay
Journal: Circulation (2016)

Introduction: Although national guidelines call on physicians to conduct regular conversations about end-of-life (EOL) care and planning with patients with heart failure (HF), research suggests that physicians often avoid these discussions. The aim of this study was to evaluate whether patients hospitalized with acute decompensated HF (ADHF) reported ever discussing their preferences for EOL care with their physicians. Methods: Between January 2014 and January 2016, Southeastern Minnesota residents hospitalized with ADHF at Mayo Clinic hospitals in Rochester, MN were prospectively recruited into an observational cohort study that included the administration of face-to-face questionnaires. Patients were asked questions regarding details of EOL discussions with their physicians, their preference for prognostic information, whether they had an advanced directive, attitudes about dying and hospice, and familiarity with palliative care and hospice. Results: Among 400 patients (mean age 77.7 years, 46% female, 48% preserved ejection fraction), only 68 (17.5%) reported previously discussing EOL wishes with their physician. Most patients (62.2%) indicated a preference to discuss their prognosis with their physician. Patients reporting prior EOL discussions were more often anemic (82.6% vs. 68.9%, p=0.022), hyponatremic (28.6% vs. 12.5%, p=0.002), and married (68.1% vs. 51.5%, p=0.012). They more often recognized the term ‘hospice’ (95.7% vs. 87.3%, p=0.045), had more favorable attitudes of dying and hospice (p=0.030), and more often had an advanced directive (83.6% vs. 67.7%, p=0.010). No other differences in demographics, comorbidity burden, HF characteristics, or in-hospital and 30-day outcomes were observed. Conclusions: Only 17.5% of patients hospitalized with ADHF reported previously discussing their preferences for EOL care with their physician. Patients reporting EOL discussions were more knowledgeable about EOL options and more likely to have completed advance care planning documents. Despite increasing recognition of the importance of these conversations, they are still occurring infrequently, and represent an important modifiable gap in the optimal longitudinal care of patients with HF.
Abstract 1865: The combined treatment of 150 kHz Tumor Treating Fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro
Authors: Karnit Gotlib, Einav Zeevi, Rosa S. Schneiderman, Tali Voloshin, Moshe Giladi, Adrian Kinzel, Eilon D. Kison, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) remains a major health problem worldwide as the third cause of cancer related mortality and the primary cause of death. Currently, sorafenib, an oral multikinase inhibitor that blocks various signaling pathways, is the only drug that has been approved for patients with advanced hepatocellular carcinoma, yet its survival benefit is still limited. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields are employed as a local treatment with the intent to target dividing cells by disrupting microtubules leading to mitotic catastrophe, abnormal chromosome segregation and the induction of different forms of cancer cell death. The aim of this work is to explore the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC. HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined at the end of treatment. The optimal TTFields frequency leading to the highest reduction in cell counts was found to be 150 kHz for both HepG2 and Huh-7D12 cells. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 53-64% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number of HepG2 and Huh-7D12 cells (2-way ANOVA, p&amp;lt;0.001 in both cell lines) as compared to each treatment alone. The results presented in this work demonstrate that TTFields can be an effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy. Based on the above, there is a strong rational to continue exploring the potential of the use of TTFields together with standard of care for the treatment of HCC in the clinical settings. Citation Format: Karnit Gotlib, Einav Zeevi, Rosa S. Schneiderman, Tali Voloshin, Moshe Giladi, Adrian Kinzel, Eilon D. Kison, Uri Weinberg, Yoram Palti. The combined treatment of 150 kHz Tumor Treating Fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1865.