tbuckley/cabot-search huggingface dataset:
A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity
Authors: Anna Schroeder, Jeroen Vanderlinden, Katlijn Vints, Luís F. Ribeiro, Kristel M. Vennekens, Natalia V. Gounko, Keimpe D. Wierda, Joris de Wit
Journal: Neuron (2018)

Pyramidal neurons express rich repertoires of leucine-rich repeat (LRR)-containing adhesion molecules with similar synaptogenic activity in culture. The in vivo relevance of this molecular diversity is unclear. We show that hippocampal CA1 pyramidal neurons express multiple synaptogenic LRR proteins that differentially distribute to the major excitatory inputs on their apical dendrites. At Schaffer collateral (SC) inputs, FLRT2, LRRTM1, and Slitrk1 are postsynaptically localized and differentially regulate synaptic structure and function. FLRT2 controls spine density, whereas LRRTM1 and Slitrk1 exert opposing effects on synaptic vesicle distribution at the active zone. All LRR proteins differentially affect synaptic transmission, and their combinatorial loss results in a cumulative phenotype. At temporoammonic (TA) inputs, LRRTM1 is absent; FLRT2 similarly controls functional synapse number, whereas Slitrk1 function diverges to regulate postsynaptic AMPA receptor density. Thus, LRR proteins differentially control synaptic architecture and function and act in input-specific combinations and a context-dependent manner to specify synaptic properties.
Abstract 4841: Prostate cancer cell death triggered by a small molecule interacting with the hTERT G-quadruplex
Authors: Jin H. Song, Libia A. Luevano, Hyunjin Kang, Vijay Gokhale, Laurence H. Hurley, Andrew S. Kraft
Journal: Cancer Research (2018)

Abstract Human telomerase reverse transcriptase (hTERT), a catalytic subunit of telomerase, is widely overexpressed in human cancers including prostate cancer. Along with its regulation of the telomere, hTERT was also shown to regulate various signal transduction mechanisms involving DNA damage response, cell cycle checkpoint, and apoptosis. The majority of human solid tumors display telomerase activity, which was found to be well correlated with hTERT expression, and hTERT inhibition led to reduced telomerase activity and telomere length. However, approaches that directly inhibit the action of telomerase have not produced a therapeutically useful response because of long lag times for subsequent cell division to produce telomere shortening. Alternatively, recent studies demonstrated that this delay problem can be solved through downregulation of hTERT transcription. It was shown that telomeric DNA is capable of folding into four-stranded guanine quadruplex (G4) structures, which then lock the hTERT promoter activity that leads to robust telomere shortening. Our new approach has focused on the discovery of small molecules that could stabilize G-quadruplexes by interacting with the telomeric G-rich overhang stem loop, producing a lead candidate compound that enhances the kinetic folding rate of the G4 silencer element. Our in vitro studies demonstrate that this singular mechanism of action permitted reduced telomerase production and telomere shortening. Significantly, hTERT downregulation with the identified molecule caused prostate cancer cell death, which was characterized by activation of the caspase cascade and increased Annexin V- positive cells. In contrast, this compound did not harm normal prostate epithelial cells. Similarly, mouse prostate cancer cells that do not contain a G-quadruplex were not killed, demonstrating that the unique mechanism of action is mediated through the hTERT promoter G-quadruplex element. Our in vivo study demonstrated that administration of this significantly delayed tumor growth on xenografted mice. The rapid onset of cell death by G4 stands in contrast to the delayed action of classic telomerase inhibition. Therefore, our current study provides important data to support developing inhibitors of hTERT as a cancer drug target. Citation Format: Jin H. Song, Libia A. Luevano, Hyunjin Kang, Vijay Gokhale, Laurence H. Hurley, Andrew S. Kraft. Prostate cancer cell death triggered by a small molecule interacting with the hTERT G-quadruplex [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 4841.
Abstract 1367: BRCA1 and BARD1 protein interactions that are required for DNA repair function
Authors: Aleksandra Adamovich, Margaret Wingo, Tapahsama Banerjee, Miranda Gardner, Michael Freitas, Jeffrey Parvin
Journal: Cancer Research (2018)

Abstract Breast and ovarian cancers are prevalent among women, and hereditary breast and ovarian cancers (HBOCs) have been associated with germline mutations in genes such as BRCA1 and BARD1. BRCA1 and BARD1 form an obligate heterodimer, and the BRCA1/BARD1 complex is required for tumor suppression functions. Our lab has tested hundreds of BARD1 and BRCA1 variants and identified many that are deficient in homologous recombination, which we have shown to accurately predict cancer predisposition in the clinic. Several of these functionally defective BRCA1 mutants map to a pocket of amino acids on the surface of the protein that does not have any known binding partners. Repair-deficient mutations are also present on the surface of the BARD1 protein in domains that are not known to be associated with DNA repair. We hypothesize that the DNA repair deficiencies mediated by these BRCA1 and BARD1 mutants are due to differences in protein binding when compared to wild-type protein. We have found that BRCA1 mutants in this protein pocket do not phosphorylate and do not localize to the nucleus following DNA damage, both of which are characteristic of the DNA damage response. However, BARD1 repair-deficient mutants still bind phosphorylated BRCA1, indicating that their deficiencies are not due to loss of BRCA1 function. To investigate protein interaction differences we are creating fusion proteins of wild-type and mutant BRCA1 with BioID2, which will biotinylate proteins that bind to BRCA1. We will then be able to identify, via avidin purification and mass spectrometry, protein interactions that are present in the wild-type but absent in the mutant BRCA1. Novel proteins that we identify will be tested for DNA repair and tumor suppressor function. This information will allow us to better understand both BARD1 and BRCA1 function and the mechanism of homologous recombination. Citation Format: Aleksandra Adamovich, Margaret Wingo, Tapahsama Banerjee, Miranda Gardner, Michael Freitas, Jeffrey Parvin. BRCA1 and BARD1 protein interactions that are required for DNA repair function [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 1367.
Abstract LB-250: Oncogenic activation of mitochondrial phosphocreatine energy shuttle creates a druggable metabolic liability in cancer cells
Authors: Taro Hitosugi, Kiran Kurmi
Journal: Cancer Research (2018)

Abstract Many important metabolic processes such as energy homeostasis, regulation of reactive oxygen species (ROS) levels, production of signaling metabolites, and synthesis of precursors for macromolecules occur in mitochondria of cancer cells. However, targeting mitochondrial metabolism in cancer has been challenging due to toxicity in normal cells, which also depend on mitochondrial metabolism. Therefore, identification of tumor specific mitochondrial metabolic alterations would be crucial to develop drugs that can selectively target cancer cells while sparing normal tissue. Here, by using targeted metabolite profiling and mitochondria-specific phospho-proteomics approach, we identified Mitochondrial Creatine Kinase (MtCK) 1 as a metabolic target in HER2+ breast cancer cells. We show that the oncogenic HER2-ABL axis stabilizes MtCK1 through tyrosine 153 (Y153) phosphorylation to activate the PCr energy shuttle pathway that transfers ATP from mitochondria to cytosol. Inhibition of the PCr energy shuttle pathway either by genetically depleting MtCK1 or by pharmacologically with a creatine analogue cyclocreatine, decreases proliferation of trastuzumab-sensitive and -resistant HER2+ cancer cells and reduces tumor growth in vivo without obvious toxicity. These findings suggest that, once ATP is produced in the mitochondria, it is equally important for breast cancer cells to transfer this energy from mitochondria to the cytosol for maintenance of various biochemical processes and tumor growth. In summary, our study reveals MtCK1 stabilization by Y153 phosphorylation as a key molecular mechanism underlying the intersection between oncogenic HER2 signaling and mitochondrial energy metabolism, which creates a druggable metabolic vulnerability in cancer. Since cyclocreatine has been used as a dietary sport supplement, cyclocreatine might be able to inhibit trastuzumab-resistant tumors with much less toxicity in patients as compared to conventional anticancer drugs. Citation Format: Taro Hitosugi, Kiran Kurmi. Oncogenic activation of mitochondrial phosphocreatine energy shuttle creates a druggable metabolic liability in 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 LB-250.
Abstract 2007: A novel CRISPR/Cas9 reporter system to monitor TNBC cancer stem cells in real time
Authors: Nathan A. Truchan, Johanna Buschhaus, Michael Brooks, Andre Halabu, Hongwei Guo, Hebao Yuan, Kathryn Luker, Max Wicha, Duxin Sun, Joseph P. Burnett
Journal: Cancer Research (2018)

Abstract Increasing evidence suggests that breast cancers arise from so-called cancer stem cells (CSC), which, consistent with their normal adult counterpart, are uniquely capable of long term self-renewal and differentiation into all bulk cancer cell types that exhibit unique epigenetic states within a tumor. While FACS has been instrumental to isolating these cells and quantifying efficacy of CSC targeted drugs in vitro and in vivo, having to remove cells from their native environment is an inherent limitation, thereby only providing a snapshot of information with each experiment. In order to directly visualize CSC dynamics in real time the CRISPR/Cas9 system was used to precisely knockin mCherry directly downstream of the final exon of ALDH1A3 in SUM149 triple-negative breast cancer cells. With regard to CSC properties, ALDH1A3 high cells were shown to be dramatically correlated with the ALDEFLUOR assay and functionally, increased ammosphere and tumor formation in vitro and in vivo. Strikingly, a single ALDH1A3 high cell was capable of reconstituting the entire heterogeneity of the parental cell line. With the ability to directly visualize CSCs we sought to utilize live cell imaging to observe population changes in response to varying therapeutics. As evident by mCherry fluorescence intensity we confirm previous findings that suggest conventional chemotherapeutics such as docetaxel enrich for CSCs while the natural product sulforpahane reduces the population. Taken together, we believe our mCherry reporter cells could be adapted to rapidly screen for novel inhibitors of CSCs in triple-negative breast cancers. Citation Format: Nathan A. Truchan, Johanna Buschhaus, Michael Brooks, Andre Halabu, Hongwei Guo, Hebao Yuan, Kathryn Luker, Max Wicha, Duxin Sun, Joseph P. Burnett. A novel CRISPR/Cas9 reporter system to monitor TNBC cancer stem cells in real time [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 2007.
Screening for Osteoporosis to Prevent Fractures
Authors: Jill Jin
Journal: JAMA (2018)

Meera Viswanathan, PhD; Shivani Reddy, MD, MSc; Nancy Berkman, PhD; Katie Cullen, MEd; Jennifer Cook Middleton, PhD; Wanda K. Nicholson, MD, MPH, MBA; Leila C. Kahwati, MD, MPH
Abstract 14250: Differential Left Atrial Posterior Wall Remodeling With Proximity to the Thoracic Descending Aorta
Authors: Tarek Zghaib, Sohail Zahid, Esra G Ipek, Jonathan Chrispin, Bharath A Venkatesh, Dong Huang, Muhammad A Balouch, Satish Misra, Joseph E Marine, David D Spragg, Ronald D Berger, Stefan L Zimmerman, Natalia Trayanova, Hugh Calkins, Joao A Lima, Saman Nazarian
Journal: Circulation (2016)

Background:  Atrial fibrillation (AF) is associated with structural left atrial (LA) remodeling. The extent of late gadolinium enhancement (LGE) on cardiac MRI is associated with AF recurrence following ablation. In our experience, we have noticed LA posterior wall enhancement adjacent to the aorta that seems unrelated to extent of atrial disease.   Hypothesis:  Due to its pulsatile nature, the aorta is implicated in fibrotic remodeling of proximate LA. We examined here the association between aortic proximity and distensibility with the extent of adjacent LA LGE.   Methods:  One hundred and nine patients presenting for an index AF ablation underwent pre-procedural MRI. The descending thoracic aorta and LA myocardium were manually segmented (Figure). The extent of LGE was quantified using the normalized image intensity ratio as percent mass of LA wall. The average distance between the aorta and the atrial wall was quantified using a custom-written software and aortic distensibility (Δarea/area max ) was measured from cine-MR.   Results:  Overall 15.2±10.8% of the LA exhibited LGE. The extent of LGE was higher in the posterior LA (26.0±13.4% vs 8.0±6.3% in the anterior LA). Mean aortic distensibility was 11.4±5.3% and mean aorta-to-LA wall distance was 31.1±5.1mm. Aortic distensibility was directly associated with posterior LA LGE (p=0.009) after adjusting for age, CHA 2 DS 2 -VASc score, AF type, total atrial LGE burden and LA volume in multivariable linear regression. The average distance between the LA myocardium and aorta was inversely related to posterior myocardial LGE extent (p   Conclusion:  The extent of posterior LA LGE is higher in AF patients with greater aortic distensibility and shorter distance between the descending aorta and LA. Our findings support a potential direct remodeling effect from aortic distension upon the posterior LA.   Figure
Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands’ Susceptibility Gene Mutation Status
Authors: Samuel O Antwi, Sarah E Fagan, Kari G Chaffee, William R Bamlet, Chunling Hu, Eric C Polley, Steven N Hart, Hermela Shimelis, Jenna Lilyquist, Rohan D Gnanaolivu, Robert R McWilliams, Ann L Oberg, Fergus J Couch, Gloria M Petersen
Journal: JNCI Journal of the National Cancer Institute (2017)

Increased risk of malignancies other than pancreatic cancer (PC) has been reported among first-degree relatives (FDRs) of PC patients; however, the roles of susceptibility gene mutations are unclear. We assessed risk for 15 cancers among FDRs of unselected PC probands.
The role of parenting experiences, rather than age of onset or presence of the skin condition, in the development of early maladaptive schemas in a community sample of patients with atopic dermatitis
Authors: E. Kalaki, A. Mizara
Journal: British Journal of Dermatology (2018)

The relevance of personality in atopic dermatitis (AD) has long been a focus of research. Patients with atopic dermatitis (AD) appear to show a distinct cluster of traits that may increase susceptibility to development or exacerbation via the stress pathway of AD. Mizara et al. found that people with AD presented with a maladaptive schematic (personality) profile that predicted anxiety-and-depression. This article is protected by copyright. All rights reserved.
Galectin-3 aggravates experimental polymicrobial sepsis by impairing neutrophil recruitment to the infectious focus
Authors: Raphael G. Ferreira, Lilian C. Rodrigues, Daniele C. Nascimento, Alexandre Kanashiro, Paulo H. Melo, Vanessa F. Borges, Aline Gozzi, Douglas da Silva Prado, Marcos C. Borges, Fernando S. Ramalho, Sean R. Stowell, Richard D. Cummings, Marcelo Dias-Baruffi, Fernando Q. Cunha, Jose C. Alves-Filho
Journal: Journal of Infection (2018)
Long-Term Shape, Curvature, and Depth Changes of the Lamina Cribrosa after Trabeculectomy
Authors: Aistė Kadziauskienė, Ernesta Jašinskienė, Rimvydas Ašoklis, Eugenijus Lesinskas, Tomas Rekašius, Jacqueline Chua, Ching-Yu Cheng, Jean Martial Mari, Michaël J.A. Girard, Leopold Schmetterer
Journal: Ophthalmology (2018)
Abstract 1769: Antibody blockade of IL1RAP signaling reduces metastasis in a breast cancer model
Authors: David Liberg, Per-Ola Önnervik, Matteo Riva, Liselotte Larsson, Göran Forsberg, Karin von Wachenfeldt
Journal: Cancer Research (2018)

Abstract Blockade of tumor inflammation has potential for cancer therapy, both as a primary mechanism to counter tumor growth but also in combination with other therapeutics. IL-1 signaling has been shown preclinically to be involved in tumor development and chemoresistance of pancreatic cancer, and blockade of IL-1 was recently shown to have a significant clinical impact on development of lung cancer. IL-1 receptor associated protein (IL1RAP) is a coreceptor for the IL-1 receptor (IL1R1) and is required for IL-1 signaling. IL1RAP is expressed in a number of tumor tissues, including lung and pancreatic cancer, both on tumor cells and on infiltrating immune cells. We have, using antibodies directed against IL1RAP, shown the ability to target and kill IL1RAP-expressing tumor cells by ADCC, to inhibit IL-1 signaling in those cells and to reduce growth of transplanted human tumors in vivo. To study effects of IL1RAP targeting on the tumor microenvironment and in an immune competent setting, an antibody towards mouse IL1RAP was generated. This antibody potently blocks mouse IL-1 (IC50 = 13 nM), binds to IL1RAP protein with high affinity (Kd = 4,2 nM), labels IL1RAP-expressing cells and can be administered to mice with good pharmacokinetics. In vivo imaging shows that the antibody is not generally distributed in tissues but localizes to tumor sites after injection. Treatment of mice with orthotopically implanted 4T1 breast cancer cells did not reduce primary tumor growth significantly but reduced both the number of (47% reduction, p=0.02) and size of lung metastases. Interestingly, 4T1 tumor cells express low levels of IL1RAP and are not responsive to IL1RAP blockade, but the effects instead relate to effects on the tumor microenvironment. We conclude that targeting of IL1RAP can, in addition to induce ADCC of tumor cells and block their response to IL-1, also inhibit metastasis by affecting the tumor microenvironment. Citation Format: David Liberg, Per-Ola Önnervik, Matteo Riva, Liselotte Larsson, Göran Forsberg, Karin von Wachenfeldt. Antibody blockade of IL1RAP signaling reduces metastasis in a breast cancer model [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 1769.
Abstract 1156: New spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for immune therapeutic approaches
Authors: Peter Jantscheff, Janette Beshay, Thomas Lemarchand, Cynthia Obodozie, Christoph Schaechtele, Holger Weber
Journal: Cancer Research (2018)

Abstract First findings in the late 1990s and the early 2000s, that blockade of immune checkpoint inhibitors (ICI) by antibodies could induce rejection of established tumors and induce immunity also to secondary exposure with these tumor cells, led again to a stronger focus of experimental studies on syngeneic tumor models in immunocompetent animals. The availability of such models, however, is mainly limited by the small number of genetically-modified (GEM) or long-term passaged cell line-derived tumor models. We here describe establishment and first characterization of a new type of animal tumor models, named Mouse-Derived-Isografts (MDI), from spontaneously appearing or carcinogen-induced syngeneic tumors in both sexes of various mouse strains (C3H/HeN, CBA/J, BALB/C, DBA/2N and C57BL/6N). The tumors were obtained from animals during long-term observation (≥ 1-2 years) of normally fed, otherwise untreated animals (spontaneous - sMDI) or during short-term observation (3-9 month) of once subcutaneously, intramuscularly, intraperitoneally or orally methylcholanthrene (MCA) or methyl-nitroso-urea (MNU) treated animals (carcinogen - cMDI). Criteria to perform a primary necropsy were critical weight loss, bad general conditions or externally observable tumor growth in monitored animals. At this first step, tissues were assessed only macroscopically, and conspicuous ones were transplanted (in PDX-like manner) as small pieces into sex-matched syngeneic animals. If possible tissue/tumor pieces were also frozen and stored in 10% DMSO freezing medium at -80°C. In a second step these re-transplanted, outgrowing tumors were amplified once again in syngeneic mice for freeze storing, and then the models were finally established by re-transplantation and testing outgrowth of the frozen stored tumor pieces in the syngeneic animals. The tumors appear phenotypically stable, as far as routine standard HE stained sections could show. General characteristics of these models are; they are primary spontaneous or carcinogen-induced tumors, of low passage number (&amp;lt;10), propagated as tissue pieces only in mice without tissue culturing, and thus with conserved original tumor characteristics as assessed microscopically and intra-tumoral immune cell populations analyzed by flow cytometry. Citation Format: Peter Jantscheff, Janette Beshay, Thomas Lemarchand, Cynthia Obodozie, Christoph Schaechtele, Holger Weber. New spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for immune therapeutic approaches [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 1156.
Abstract 2995: Undernutrition is an Important Prognostic Factor of Cardiac Death in Patients With Diastolic Heart Failure
Authors: Jun Takahashi, Nobuyuki Shiba, Kotaro Nochioka, Hiroaki Shimokawa
Journal: Circulation (2009)

Background:   Wasting in chronic heart failure (CHF) is known as cardiac cachexia, which occurs in some patients with reduced systolic function. However, it remains to be examined whether the nutritional status also is associated with poor outcome of patients with diastolic heart failure (DHF).    Methods:   In our cohort study with a total of 1278 patients with CHF, 263 consecutive patients with DHF (68±14 [SD] years, male 59%), defined by the Framingham criteria (history of CHF with LV ejection fraction (LVEF) ≥50%), were prospectively followed-up for 45±19 months. At the enrollment, their nutritional status was assessed by the CONUT score, a widely used nutritional status score representing the combined impact of serum albumin, total cholesterol level, and total lymphocyte count.    Results:   Mean LVEF obtained by echocardiography was 63±10% at the enrollment, and 85% of the patients showed mild to moderate CHF symptoms (NYHA functional class I or II). In the follow-up period, 34 cardiac deaths (sudden death in 13 and CHF death in 21) and 37 non-cardiac deaths were observed. The Kaplan-Meier analysis revealed that among the 263 patients with DHF, both cardiac and non-cardiac deaths occurred more frequently in patients with undernutrition (CONUT score≥2) than in those with normal nutrition (CONUT score=0 or 1) ( Figure ). Importantly, multivariate Cox regression analysis showed that undernutrition is an independent predictor for cardiac death (HR: 2.8, 95%CI: 1.2– 6.5) but not for non-cardiac death (HR: 1.3, 95%CI: 0.6 –2.8).    Conclusions:   These results suggest that undernutrition is an important prognostic factor for cardiac death in patients with DHF.