tbuckley/cabot-search huggingface dataset:
Abstract 1306: Density-based mutation clustering in 3D space
Authors: Amila Weerasinghe, Sohini Sengupta, Adam D. Scott, Maththew H. Bailey, Michael C. Wendl, Ken Chen, Gordon Mills, Li Ding
Journal: Cancer Research (2018)

Abstract Cancer driver mutation and gene discovery has been a major challenge in cancer research. Several computational tools focus on clustering mutations on 3D protein structures to identify cancer drivers, including HotSpot3D, CLUMPS, HotMAPS, 3DHotSpots.org and e-Driver. While other tools provide a single snapshot of mutation clusters on the 3D structure, HotSpot3D utilizes a unique density-based clustering module capable of providing a full dynamical profile of clusters with varying densities. The density module (DM) is capable of detecting subtle variation in the density of mutations in 3D structures with little computation time and complexity. DM gives users the ability to detect the bridging effect, where more dense subclusters form a less dense supercluster due to a small number of mutations in between the subclusters connecting them. In addition to clustering based on physical density of mutations, DM is capable of clustering by additional biologic properties, including mutation recurrence and pathogenicity. Moreover, the underlying OPTICS algorithm utilized in the DM is inherently a “fuzzy” clustering algorithm, allowing slight variation of clusters based on the start point of the clustering algorithm from one run to another. Therefore, the DM provides a cluster membership probability measure for each mutation, giving the user the ability to choose the preferred stringency. Additionally, DM allows users to visualize the density clusters using Pymol. Since the whole dynamical set of clusters is produced by a single run, the visualization is performed so that one can reveal other clusters with higher densities by zooming in and out. Using a curated set of experimentally validated oncogenic mutations, we evaluated the performance of DM in detecting functionally activating mutations; our tool performed well in identifying driver mutations at high density thresholds. Moreover, the DM was able to identify mutations clustering at high density in BRAF, PIK3CA and KEAP1, which were not detected by other 3D clustering tools and sequence-based tools (SIFT, PolyPhen2, CHASM, etc.). The DM was also better at detecting clusters along the interface of protein-protein complexes (e.g., BRAF-KEAP1) compared to other 3D tools. In summary, HotSpot3D-DM allows for dynamical clustering, improved visualization, and identifies novel driver mutations missed by previous tools. Citation Format: Amila Weerasinghe, Sohini Sengupta, Adam D. Scott, Maththew H. Bailey, Michael C. Wendl, Ken Chen, Gordon Mills, Li Ding. Density-based mutation clustering in 3D space [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 1306.
Abstract 5616: Rituximab chemotherapy induces a partial recovery from T-cell exhaustion in follicular lymphoma patients
Authors: Benoit Milcent, Pauline Brice, Catherine Thieblemont, Jean-Luc Teillaud, Sophie Siberil
Journal: Cancer Research (2018)

Abstract For many years, the clinical responses observed in cancer patients treated with antitumor antibodies have been viewed only as a consequence of the recruitment and activation of innate immune cells. Several preclinical studies have indicated that anti-tumor antibodies can also induce a potent anti-tumor adaptive T-cell response capable of protecting animals from tumor challenge. Our studies have shown that CD4+ Th1 cells play a central role in the response to anti-CD20 tumor therapy by opposing Treg expansion and that CD20-specific memory T cells are responsible for anti-tumor protection observed in surviving animals subjected to tumor rechallenge. Whether an adaptive T-cell response is elicited in patients with Follicular Lymphoma (FL) receiving anti-CD20-based treatment is not known. In the present work, we analyzed peripheral T cells before and during anti-CD20-chemotherapy treatment of FL patients (R-CHOP) with high tumor burden. We first examined in ELISPOT assays the IFN-γ production by PBMC from 20 patients against human CD20-derived peptides previously selected by combining in silico and in vivo screening using transgenic human HLA-DR mice. Both FL patients before treatment and patients undergoing R-CHOP treatment exhibited peripheral T-cell responses to the selected CD20-derived peptides. However, these responses were markedly lower than those observed in healthy donors. Similar results were also obtained when T cell responses against viruses commonly infecting large numbers of individuals (CMV, EBV, influenza) were assessed, suggesting that high tumor burden FL patients exhibit an immune exhaustion of T cells. Multiparametric flow cytometry analyses suggested that their poor ability to respond to viral and CD20-derived peptides is related to the presence of an immunocompromised and exhausted blood T-cell peripheral compartment with higher percentages of TIGIT- and PD-1-expressing T cells, of peripheral Treg, and terminally differentiated CD8+ TEMRA. R-CHOP therapy induced a shift of CD4+ and CD8+ T cells toward a central memory phenotype (TCM), an additional shift of CD8+ T cells to a naive phenotype, and a decrease in the number of PD-1+ and TIGIT+ T cells, making these cells evolving toward a lesser degree of exhaustion. However, it did not restore a level of specific responses similar to those observed in healthy donors. These results support the use of anti-PD-1 and anti-TIGIT antibodies in combination with anti-CD20 in FL patients with high-tumor burden. Citation Format: Benoit Milcent, Pauline Brice, Catherine Thieblemont, Jean-Luc Teillaud, Sophie Siberil. Rituximab chemotherapy induces a partial recovery from T-cell exhaustion in follicular lymphoma patients [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 5616.
Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study
Authors: Chun-Yan Lan, Yin Wang, Ying Xiong, Jun-Dong Li, Jing-Xian Shen, Yan-Fang Li, Min Zheng, Yan-Na Zhang, Yan-Ling Feng, Qing Liu, Hui-Qiang Huang, Xin Huang
Journal: The Lancet Oncology (2018)
Abstract 1730: A translational platform using primary human immune cells in vitro, syngeneic and humanized models in vivo to support and advance immuno-oncology drug discovery
Authors: Martin O'Rourke, Shilina Roman, Gary Salmon, Ian Waddell, Julia Schueler, Edgar Wood
Journal: Cancer Research (2018)

Abstract Charles River Laboratories (CRL) has established a powerful translational immuno-oncology platform with the capability of progressing biologics or small-molecule modulators of immune response from in vitro to in vivo assays using human and mouse variants of current checkpoint inhibitors and small molecules. Utilizing a blood donor panel, our in vitro platform includes primary human immune cell assays that profile T-cell activation, T cell mediated-cancer cell kill, expansion of T-cell populations, mixed lymphocyte reactions (MLR), T-cell invasion, and antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The platform is currently being expanded to determine the effect of activated immune cell populations on tumor cell spheroid cultures. It has been validated with standard-of-care chemotherapeutics, including anti-CTLA4, anti-PD1 and a selection of small-molecule inhibitors of targets known to modulate immune responses including IDO inhibitors. Ex vivo analysis of activated mouse splenocyte response to checkpoint inhibitors, measured as cytokine release, and modulation of immune cell populations, as determined by flow cytometry, supports the translation of important compounds from the bench to preclinical models. Syngeneic mouse tumor models have frequently been used to profile immune responses in tumors; CRL has optimized and profiled existing checkpoint inhibitors to support immuno-oncology drug discovery using mouse and rat antibody variants of anti-CTLA4 and anti-PD1. To confirm the translational development of our platform in human tissue, CRL has developed and optimized humanized mouse models using subcutaneous implanted patient-derived xenografts (PDX) with human engraftment via CD34+ haematopoeitic stem cells in NOG mice, which were treated with anti-CTLA4 and anti-PD1. Infiltration of human immune cells and PDL-1 expression was detected by flow cytometry (FC) and immunohistochemistry (IHC) in hematopoietic organs and tumor tissue, supporting the initial in vitro response in primary immune cells. Here we present a screening platform, validated with standard-of-care chemotherapeutics, which will support translation of compounds from in vitro primary immune cell assays to modulation of mouse immune cell population in spleen and tumors, resulting in efficacy and tumor immune cell activation in humanized mouse models. Citation Format: Martin O'Rourke, Shilina Roman, Gary Salmon, Ian Waddell, Julia Schueler, Edgar Wood. A translational platform using primary human immune cells in vitro, syngeneic and humanized models in vivo to support and advance immuno-oncology drug discovery [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 1730.
Targeted Disruption of TGF-β–Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury
Authors: KazukiKobayashi, KoutaroYokote, MasakiFujimoto, KimihiroYamashita, AkemiSakamoto, MasakiKitahara, HarukiyoKawamura, YoshiroMaezawa, SunaoAsaumi, TakeshiTokuhisa, SeijiroMori, YasushiSaito
Journal: Circulation Research (2005)

The role of transforming growth factor (TGF)-β and its signal in atherogenesis is not fully understood. Here, we examined mice lacking Smad3, a major downstream mediator of TGF-β, to clarify the precise role of Smad3-dependent signaling in vascular response to injury. Femoral arteries were injured in wild-type and Smad3-null (null) male mice on C57Bl/6 background. Histopathological evaluation of the arteries 1 to 3 weeks after the injury revealed significant enhancement of neointimal hyperplasia in null compared with wild-type mice. Transplantation of null bone marrow to wild-type mice did not enhance neointimal thickening, suggesting that vascular cells in situ play a major role in the response. Null intima contained more proliferating smooth muscle cells (SMC) with less amount of collagen compared with wild-type intima. TGF-β caused significant inhibition of cellular proliferation in wild-type aortic SMC, whereas the growth of null SMC was only weakly inhibited by TGF-β in vitro, indicating a crucial ro...
Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue
Authors: Seung-PyoLee, Seock-WonYoun, Hyun-JaiCho, LianLi, Tae-YounKim, Hyung-SeonYook, Jae-WoongChung, JinHur, Chang-HwanYoon, Kyung-WooPark, Byung-HeeOh, Young-BaePark, Hyo-SooKim
Journal: Circulation (2006)

Background— Recruitment and adhesion of endothelial progenitor cells (EPCs) to hypoxic endothelial cells (ECs) is essential for vasculogenesis in ischemic tissue; little is known, however, about the key signals or intracellular signaling pathways involved in orchestrating the expression of adhesion molecules by ECs in response to hypoxia and how this is related to the recruitment of EPCs to the ischemic tissue. Here, we report that endogenous integrin-linked kinase (ILK) is a novel molecule that responds to hypoxia in ECs that regulates the expression of stromal cell–derived factor-1 (SDF-1) and intercellular adhesion molecule-1 (ICAM-1) through nuclear factor-κB and hypoxia-inducible factor-1α and induces recruitment of EPCs to ischemic areas. Methods and Results— Under hypoxia, both the endogenous amount and kinase activity of ILK were time-dependently upregulated in ECs, which was associated with increased ICAM-1 and SDF-1. This upregulation of ILK was mediated by stabilization of ILK by heat shock pro...
Assessment of Aortic Line of Elasticity Using Polynomial Regression Analysis
Authors: ChristodoulosStefanadis, JohnDernellis, EleftheriosTsiamis, LeonidasDiamantopoulos, AndreasMichaelides, PavlosToutouzas
Journal: Circulation (2000)

Background—The aim of this study was to assess the sigmoid line of elasticity in the human aorta. Methods and Results—The pressure-diameter relation was measured in the descending aorta in 120 subjects. In an additional group of 6 subjects, transient vena caval occlusion produced 5 sets of pressure-diameter data. We found that the best fit curve of the pooled pressure-diameter data was a third-order polynomial. A polynomial equation was used to calculate the sigmoid line of elasticity in the entire population and after the administration of diltiazem (15 patients) or enalaprilat (10 patients). The sigmoid line of elasticity was significantly different with respect to age (P<0.001), history of hypertension (P<0.004), and hypercholesterolemia (P<0.02). The difference between the transition point and the peak systolic pressure was increased in normal subjects compared with patients (P<0.0001). The sigmoid line shifted leftward and upward with diltiazem, but it remained unchanged with enalaprilat. During an a...
ChromTime: modeling spatio-temporal dynamics of chromatin marks
Authors: Petko Fiziev, Jason Ernst
Journal: Genome biology (2018)

To model spatial changes of chromatin mark peaks over time we develop and apply ChromTime, a computational method that predicts peaks to be either expanding, contracting, or holding steady between time points. Predicted expanding and contracting peaks can mark regulatory regions associated with transcription factor binding and gene expression changes. Spatial dynamics of peaks provide information about gene expression changes beyond localized signal density changes. ChromTime detects asymmetric expansions and contractions, which for some marks associate with the direction of transcription. ChromTime facilitates the analysis of time course chromatin data in a range of biological systems.
Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids
Authors: Yanhang Gao, Zhou Zhou, Tianyi Ren, Seung-Jin Kim, Yong He, Wonhyo Seo, Adrien Guillot, Yanhua Ding, Ruihong Wu, Shuang Shao, Xiaomei Wang, Hong Zhang, Wei Wang, Dechun Feng, Mingjiang Xu, Elaine Han, Wei Zhong, Zhanxiang Zhou, Pal Pacher, Junqi Niu, Bin Gao
Journal: Gut (2018)

Objective Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. Design Wild-type (WT) and Aldh2 knockout ( Aldh2 -/- ) mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for binge drinking and plasma cortisol and corticosterone measurement. Results Ethanol feeding exacerbated ConA-induced hepatitis in WT mice but surprisingly attenuated it in Aldh2 -/- mice despite higher acetaldehyde levels in Aldh2 -/- mice. Elevation of serum cytokines and their downstream signals in the liver post-ConA injection was attenuated in ethanol-fed Aldh2 -/- mice compared to WT mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated interferon-γ production in phytohaemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to WT mice, ethanol-fed Aldh2 -/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2 -/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. Conclusions ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post-alcohol consumption, thereby inhibiting T-cell activation and hepatitis.
FGF2 Signaling Is Required for the Development of Neuronal Circuits Regulating Blood Pressure
Authors: RosannaDono, JörgFaulhaber, AntonellaGalli, AiméeZuniga, TilmannVolk, GemmaTexido, RolfZeller, HeimoEhmke
Journal: Circulation Research (2002)

Fibroblast growth factor 2 (FGF2) signaling is involved in angiogenesis, vascular contractility, and cardiac hypertrophy. Mice lacking a functional FGF2 gene (FGF2−/−) are hypotensive, but the primary physiological role of FGF2 in cardiovascular homeostasis remained unknown. Using a chicken FGF2 (cFGF2) transgene under control of the Wnt-1 promotor, we selectively re-expressed FGF2 in the developing nervous system of FGF2−/− (transgenic FGF2 mutant) embryos. Expression of the cFGF2 transgene in the developing nervous system, including its autonomic region, was limited to the period between embryonic day 9.5 and 14.5. Significantly, no FGF2 re-expression was detected in developing heart and blood vessels. Pharmacological analysis revealed a normalization of the blood pressure response to isoproterenol-induced vasodilation in adult transgenic FGF2 mutant mice. In addition, the hypotensive phenotype was rescued in 1 line (of 2) transgenic FGF2 mutant adult mice having expressed higher levels of cFGF2 protein...
Abstract 16803: Relationships Between Invasive and Non-invasive Measures of Cardiac Function During Exercise in Heart Failure With Preserved or Reduced Ejection Fraction
Authors: Erik H Van Iterson, Eric M Snyder, Barry A Borlaug, Thomas P Olson
Journal: Circulation (2015)

Introduction: Assessment of cardiac function during exercise is critical in the clinical evaluation of patients with heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction. Direct invasive measurement of cardiac power (CP) and stroke work (SW) are robust measures of cardiac function. Non-invasive gas exchange based surrogates may provide practical means of assessing cardiac function in clinical and research settings; however, the relationship between invasive and non-invasive measurement of CP or SW during exercise is unclear in HFpEF and HFrEF. We aimed to assess relationships between invasive and non-invasive measures of CP and SW during exercise in HFpEF and HFrEF. Methods: HFpEF (n=47) and HFrEF (n=29) (age 71±10 vs 55±10 yrs; EF% 62±8 vs 21±6%; BSA 2.1±0.3 vs 2.1±0.2 m 2 ; weight 99±22 vs 87±15 kg; peak work 36±14 vs 37±13 watts (W), respectively; all p&lt;0.05, except peak work) underwent peak exercise testing during right heart catheterization. Invasive measurement of cardiac pressures, hemodynamics, and arterial pressures were recorded at rest, 20 W, and peak work. Continuous measurement of HR and VO 2 occurred from rest to peak work via 12-lead ECG and metabolic measurement system, respectively. Invasive measurements were calculated as, CP=(MAP–RAP) x Q x 2.22х10 -3 ; SW=(MAP–PCWP) x SV I x 0.133; and non-invasive as, CP=VO 2 x MAP; SW=VO 2 /HR x MAP. All indices adjusted for body surface area. Results: At rest, there were moderate relationships between invasive and non-invasive measures of CP and SW in HFpEF (r=0.56 and 0.48) and HFrEF (0.57 and 0.73), respectively (all p&lt;0.05). At 20 W, relationships between invasive and non-invasive measures of CP and SW strengthened in HFpEF (r=0.74 and 0.69) and HFrEF (0.74 and 0.72), respectively (all p&lt;0.05). The relationships noted between invasive and non-invasive measures of CP and SW at 20 W persisted at peak work in HFpEF (r=0.74 and 0.67) and HFrEF (0.78 and 0.69), respectively (all p&lt;0.05). Conclusion: These data suggest that non-invasive estimates of CP and SW correlate closely with invasive measures and may be reasonable surrogates for these indices during peak exercise testing in both HFpEF and HFrEF patients.
Reporting of Sex as a Variable in Research Published in Surgical Journals
Authors: Melina R. Kibbe
Journal: JAMA Surgery (2018)

Conducting sex-inclusive biomedical and clinical research is imperative to improving the health outcomes of women and men. 1 (Note that the word sex is being used rather than the term gender.Sex is the genotype that an individual is born with, and gender is the phenotype.For most research, it is the chromosomal sex of the human, animal, tissue, or cell that is important.)Recent studies have shown that most biomedical research in the field of surgery and associated topics is conducted on male animals and male cells, even when the diseases being studied are prevalent in females. 2 Human clinical research is challenged by a lack of sex-based reporting and sex-based analysis of study results. 3,4Given these findings, the National Institutes of Health has asked that sex be considered as a biologic variable in all National Institutes of Health-funded research. 5he surgical journals whose editors are members of the Surgery Journals Editors Group will require this information in their journals.As such, defined reporting of the sex used for human, animal, tissue, and cell research in all articles published in JAMA Surgery is required. 6This information can be collected by self-report, administrative data, or (less commonly) genetic evaluation.If only 1 sex is studied, authors must include a justification statement as to why a single-sex study was conducted.Sex-based analysis of data for all human, animal, tissue, and cell research is also required.
Accounting for the Harms of Lung Cancer Screening
Authors: Mark H. Ebell, Kenneth W. Lin
Journal: JAMA Internal Medicine (2018)

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