tbuckley/cabot-search huggingface dataset:
Grape seed proanthocyanidins inhibit UV radiation-induced oxidative stress and activation of MAPK and NF-κB signaling in human epidermal keratinocytes
Authors: Sudheer K. Mantena, Santosh K. Katiyar
Journal: Cancer Research (2006)

2271  Solar ultraviolet (UV) radiation-induced oxidative stress has been implicated in various skin diseases including melanoma and nonmelanoma skin cancers. Since the use of protective clothing and sunscreens is inadequate to protect the skin from UV radiation, the use of dietary botanical supplements has received considerable interest to protect the skin from adverse biological effects of UV radiation. Earlier, we have shown that dietary grape seed proanthocyanidins (GSPs) prevent UV radiation-induced skin carcinogenesis in terms of tumor incidence, tumor multiplicity and malignant transformation of papillomas to carcinomas in mice. To define the anti-photocarcinogenic mechanism of GSPs, here we report the photoprotective effect of GSPs on UV-induced oxidative stress, and activation of mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways using normal human epidermal keratinocytes (NHEK). Treatment of NHEK with GSPs (10-50 μg/mL) inhibited UVB (10-60 mJ/cm2)-induced hydrogen peroxide (H2O2), lipid peroxidation, protein oxidation and DNA damage in the form of 8-OHdG in NHEK. GSPs have the ability to scavenge hydroxyl radicals and superoxide anions in cell-free system. GSPs also prevented UVB-induced depletion of antioxidant defense components, such as, glutathione peroxidase, catalase, superoxide dismutase and endogenous antioxidant glutathione. As UV-induced oxidative stress mediates activation of MAPK and NF-κB signaling which are involved in various skin disorders, we determined the effect of GSPs on these pathways. Treatment of NHEK with GSPs inhibited UVB-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 proteins of MAPK family at different time points studied. Since UV-induced H2O2 plays a major role in activation of MAPK proteins, NHEK were treated with H2O2 with or without GSPs and other known antioxidants viz., (-)-epigallocatechin-3-gallate, silymarin, ascorbic acid and N-acetylcysteine to determine their effect on H2O2-induced activation of MAPK proteins. It was observed that H2O2-induced phosphorylation of ERK1/2, JNK, and p38 was decreased by these antioxidants. Under identical conditions, GSPs also inhibited UVB-induced activation of NF-κB/p65 which was mediated through inhibition of degradation and activation of IκBα and IKKα, respectively. Taken together, it is suggested that GSPs could be useful in attenuation of UV radiation-induced oxidative stress, and oxidative stress-mediated skin diseases in human skin, however more studies are required to validate these findings in in vivo system.
RARE-60. PREGNANCIES AFTER CHILDHOOD CRANIOPHARYNGIOMA – RESULTS OF KRANIOPHARYNGEOM 2000/2007
Authors: Panjarat Sowithayasakul, Svenja Boekhoff, Brigitte Bison, Hermann L Müller
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Data on female fertility, pregnancy, and outcome of offspring after childhood-onset craniopharyngioma (CP) are rare. STUDY DESIGN Observational study on pregnancy rate and offspring outcome in female CP patients recruited in KRANIOPHARYNGEOM 2000/2007. RESULTS A total of 451 CP patients (223 female) have been recruited, and 269 (133 female) were postpubertal at study. Six of 133 female CP patients (4.5%) with median age of 14.9 years at CP diagnosis had 9 pregnancies, giving birth to 10 newborns. Three patients achieved complete surgical resections. No patient underwent postoperative irradiation. Five natural pregnancies occurred in 3 CP patients without pituitary deficiencies. Four pregnancies in 3 CP patients with hypopituitarism were achieved under assisted reproductive techniques (ART) (median 4.5 cycles, range: 3–6 cycles). Median maternal age at pregnancy was 30 years (range: 22–41 years). Six babies (60%) were delivered by caesarean section. Median gestational age at delivery was 38 weeks (range: 34–43 weeks); median birth weight was 2,920 g (range: 2,270– 3,520 g), the rate of preterm delivery was 33%. Enlargements of CP cysts occurred in 2 women during pregnancy. Other complications during pregnancy, delivery, and postnatal period were not observed. CONCLUSIONS Pregnancies after CP are rare and were only achieved after ART in patients with hypopituitarism. Close monitoring by an experienced reproductive physician is necessary. Due to a potentially increased risk for cystic enlargement, clinical, ophthalmological, and MRI monitoring are recommended in patients at risk. Perinatal complications, birth defects, and morbidity of mothers and offspring were not observed.
Metapangenomics of the oral microbiome provides insights into habitat adaptation and cultivar diversity
Authors: Daniel R. Utter, Gary G. Borisy, A. Murat Eren, Colleen M. Cavanaugh, Jessica L. Mark Welch
Journal: Genome biology (2020)

Abstract Background The increasing availability of microbial genomes and environmental shotgun metagenomes provides unprecedented access to the genomic differences within related bacteria. The human oral microbiome with its diverse habitats and abundant, relatively well-characterized microbial inhabitants presents an opportunity to investigate bacterial population structures at an ecosystem scale. Results Here, we employ a metapangenomic approach that combines public genomes with Human Microbiome Project (HMP) metagenomes to study the diversity of microbial residents of three oral habitats: tongue dorsum, buccal mucosa, and supragingival plaque. For two exemplar taxa, Haemophilus parainfluenzae and the genus Rothia , metapangenomes reveal distinct genomic groups based on shared genome content. H. parainfluenzae genomes separate into three distinct subgroups with differential abundance between oral habitats. Functional enrichment analyses identify an operon encoding oxaloacetate decarboxylase as diagnostic for the tongue-abundant subgroup. For the genus Rothia , grouping by shared genome content recapitulates species-level taxonomy and habitat preferences. However, while most R. mucilaginosa are restricted to the tongue as expected, two genomes represent a cryptic population of R. mucilaginosa in many buccal mucosa samples. For both H. parainfluenzae and the genus Rothia , we identify not only limitations in the ability of cultivated organisms to represent populations in their native environment, but also specifically which cultivar gene sequences are absent or ubiquitous. Conclusions Our findings provide insights into population structure and biogeography in the mouth and form specific hypotheses about habitat adaptation. These results illustrate the power of combining metagenomes and pangenomes to investigate the ecology and evolution of bacteria across analytical scales.
Lymphoma Severity and Type Are Associated With Aortic FDG Uptake by 18F-FDG PET/CT Imaging
Authors: Charalambos V. Vlachopoulos, Iosif P. Koutagiar, Alexandros T. Georgakopoulos, Anastasia G. Pouli, Anastasia Κ. Sioni, Stavroula Ε. Giannouli, Spiros D. Chondropoulos, Ioanna Ε. Stergiou, Eirini G. Solomou, Dimitrios G. Terentes-Printzios, Ioannis G. Karakitsios, Pavlos P. Kafouris, Anastasios Gaitanis, Nikoletta K. Pianou, Aikaterini Petrocheilou, Constantina I. Aggeli, Euaggelia Stroumpouli, Theodoros P. Marinakis, Michael Voulgarelis, Dimitrios M. Tousoulis, Constantinos D. Anagnostopoulos
Journal: JACC CardioOncology (2020)

There is evidence that metabolic disease burden in lymphoma influences patient outcome. However, the impact of disease severity on the cardiovascular system is unknown.The aim of this study was to examine whether lymphoma is associated with arterial inflammation by investigating the relationship between disease metabolic burden and arterial fluorodeoxyglucose (FDG) uptake.Sixty-two chemotherapy-naïve patients with active Hodgkin's or non-Hodgkin's lymphoma were matched (2:1) to individual control groups of lymphoma patients previously treated and free of active disease. All groups underwent 18F-FDG position emission tomography-computed tomography imaging. Disease severity was quantified by metabolic tumor volume (MTV) and total lesion glycolysis corresponding to standardized uptake values (SUVs) ≥41% or ≥2.5 of the maximum SUV within lymphoma regions, and aortic FDG uptake was quantified through the target-to-background ratio (TBR). Inflammatory and disease severity biomarkers were also measured.MTV and total lesion glycolysis measurements were significantly correlated with inflammatory and disease biomarkers. Aortic TBR was higher in patients with active non-Hodgkin's lymphoma compared with control subjects (median difference 0.51; 95% confidence interval [CI]: 0.28 to 0.78; p < 0.001). Similarly, patients with active Hodgkin's lymphoma had higher values of aortic TBR compared with control subjects (median difference 0.31; 95% CI: 0.15 to 0.49; p < 0.001). In addition, aortic TBR was modestly increased in patients with stage III to IV disease compared with those with stage I to II disease (median aortic TBR: 2.23 [interquartile range: 2.01 to 2.54] vs. 2.06 [interquartile range: 1.83 to 2.27; p = 0.050). In multivariable analysis, aortic FDG uptake and MTV≥2.5 values were independently associated (β = 0.425; 95% CI: 0.189 to 0.662; p = 0.001; R2 = 0.208), as were aortic FDG uptake and MTV≥41% (β = 0.407; 95% CI: 0.167 to 0.649, p = 0.001; R2 = 0.191).Aortic wall FDG uptake is related with disease severity indicative of a possible vascular effect of lymphoma. This work highlights a new potential role of molecular imaging in cardio-oncology for evaluating disease severity and its consequences on the vasculature.
Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease
Authors: Joakim Nordanstig, Stefan James, Manne Andersson, Mattias Andersson, Peter Danielsson, Peter Gillgren, Martin Delle, Jan Engström, Torbjörn Fransson, Maher Hamoud, Anna Hilbertson, Patrik Johansson, Lars Karlsson, Björn Kragsterman, Hans Lindgren, Karin Ludwigs, Stefan Mellander, Niklas Nyman, Henrik Renlund, Birgitta Sigvant, Per Skoog, Joachim Starck, Gustaf Tegler, Asko Toivola, Maria Truedson, Carl-Magnus Wahlgren, Jonas Wallinder, Andreas Öjersjö, Mårten Falkenberg
Journal: New England Journal of Medicine (2020)

The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.
Folic Acid Supplementation and the Association between Maternal Airborne Particulate Matter Exposure and Preterm Delivery: A National Birth Cohort Study in China
Authors: Qin Li, Yuan-Yuan Wang, Yuming Guo, Hong Zhou, Xiaobin Wang, Qiao-Mei Wang, Hai-Ping Shen, Yi-Ping Zhang, Dong-Hai Yan, Shanshan Li, Gongbo Chen, Lizi Lin, Yuan He, Ying Yang, Zuo-Qi Peng, Hai-Jun Wang, Xu Ma
Journal: Environmental Health Perspectives (2020)

Background: Potential modification of the association between maternal particulate matter (PM) exposure and preterm delivery (PTD) by folic acid (FA) supplementation has not been studied. Objective: We examined whether FA supplementation could reduce the risk of PTD associated with maternal exposure to PM in ambient air during pregnancy. Method: In a cohort study covering 30 of the 31 provinces of mainland China in 2014, 1,229,556 primiparas of Han ethnicity were followed until labor. We collected information on their FA supplementation and pregnancy outcomes and estimated each participant's exposure to PM with diameters of ≤10μm (PM10), 2.5μm (PM2.5), and 1μm (PM1) using satellite remote-sensing based models. Cox proportional hazard regression models were used to examine interactions between FA supplementation and PM exposures, after controlling for individual characteristics. Results: Participants who initiated FA ≥3 months prior to pregnancy (38.1%) had a 23% [hazard ratio (HR)=0.77 (95% CI: 0.76, 0.78)] lower risk of PTD than women who did not use preconception FA. Participants with PM concentrations in the highest quartile had a higher risk of PTD [HR=1.29 (95% CI: 1.26, 1.32) for PM1, 1.52 (95% CI: 1.46, 1.58) for PM2.5, and 1.22 (95% CI: 1.17, 1.27) for PM10] than those with exposures in the lowest PM quartiles. Estimated associations with a 10-μg/m3 increase in PM1 and PM2.5 were significantly lower among women who initiated FA ≥3 months prior to pregnancy [HR=1.09 (95% CI: 1.08, 1.10) for both exposures] than among women who did not use preconception FA [HR=1.12 (95% CI: 1.11, 1.13) for both exposures; pinteraction<0.001]. The corresponding association was also significantly lower for a 10-μg/m3 increase in PM10 [HR=1.03 (95% CI: 1.02, 1.03) for FA ≥3 months before pregnancy vs. 1.04 (95% CI: 1.03, 1.04) for no preconception FA; pinteraction<0.001]. Conclusion: Our findings require confirmation in other populations, but they suggest that initiating FA supplementation ≥3 months prior to pregnancy may lessen the risk of PTD associated with PM exposure during pregnancy among primiparas of Han ethnicity. https://doi.org/10.1289/EHP6386
Like Wings of a Bird: Functional Divergence and Complementarity between HLA-A and HLA-B Molecules
Authors: Da Di, Jose Manuel Nunes, Wei Jiang, Alicia Sanchez-Mazas
Journal: Molecular Biology and Evolution (2020)

Human leukocyte antigen (HLA) genes are among the most polymorphic of our genome, as a likely consequence of balancing selection related to their central role in adaptive immunity. HLA-A and HLA-B genes were recently suggested to evolve through a model of joint divergent asymmetric selection conferring all human populations, including those with severe loss of diversity, an equivalent immune potential. However, the mechanisms by which these two genes might undergo joint evolution while displaying very distinct allelic profiles in populations are still unknown. To address this issue, we carried out extensive data analyses (among which factorial correspondence analysis and linear modeling) on 2,909 common and rare HLA-A, HLA-B, and HLA-C alleles and 200,000 simulated pathogenic peptides by taking into account sequence variation, predicted peptide-binding affinity and HLA allele frequencies in 123 populations worldwide. Our results show that HLA-A and HLA-B (but not HLA-C) molecules maintain considerable functional divergence in almost all populations, which likely plays an instrumental role in their immune defense. We also provide robust evidence of functional complementarity between HLA-A and HLA-B molecules, which display asymmetric relationships in terms of amino acid diversity at both inter- and intraprotein levels and in terms of promiscuous or fastidious peptide-binding specificities. Like two wings of a flying bird, the functional complementarity of HLA-A and HLA-B is a perfect example, in our genome, of duplicated genes sharing their capacity of assuming common vital functions while being submitted to complex and sometimes distinct environmental pressures.
RADT-39. 68Ga- DOTATATE CT/PET FOR GAMMA KNIFE RADIOSURGERY PLANNING AND TARGET DELINEATION IN PATIENTS WITH MENINGIOMA
Authors: Daniel Ma, Zaker Rana, Sirisha Viswanatha, Louis Potters, Jenghwa Chang, Michael Schulder, Anuj Goenka
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Stereotactic radiosurgery (SRS) planning for patients with meningiomas can be confounded by difficulty in identifying the tumor boundary, especially in those who have had prior surgery. Recent data have suggested the benefit of 68Ga-DOTATATE CT/PET scans in delineation of meningioma compared to MRI alone. We propose that incorporating 68Ga-DOTATATE PET scans in addition to MRI in SRS planning will provide better target identification and tumor coverage compared to MRI alone. METHODS We reviewed patients with meningioma who had MRI and 68Ga-DOTATATE PET imaging over 12 months. Images were imported into Velocity treatment planning software and separated into two different sessions, one in which only the MRI was accessible, and a second which had the PET scan fused to the MRI. Three different users were asked to contour the residual meningioma as gross tumor volume (GTV) first with MRI alone, and then with the PET/MRI fusion. The volume of each GTV pre-and post-PET fusion was compared and a Dice index was generated. RESULTS Four patients with 6 GTV targets were identified. PET fusion identified new lesions close to the initial GTV targets in 2 patients. The first was a discontinuous dural lesion in the post-op bed. The second was a nodular dural lesion along the left high parietal convexity adjacent to a prior craniectomy and mesh duraplasty site. In the third patient, PET scan identified a greater extent of disease in the skull base. Across all observers, GTV volumes were significantly increased when PET fusion was used. The average volume (cc) increase was 111.6%±66.2%. The average Dice index was 0.58±0.17. CONCLUSION 68Ga-DOTATATE PET scan fused with MRI improved the visualization of meningiomas in patients undergoing SRS. A larger experience is needed to confirm this trend. We have begun to use DOTATATE-PET imaging regularly when imaging patients with meningiomas for SRS.
EXTH-72. CONTINUOUS INFUSION STUDIES REVEAL THE POTENCY OF ELACRIDAR TO ACT AS A PHARMACO-ENHANCER FOR TREATMENT OF INTRACRANIAL DISEASES BY INHIBITING ABCB1 AND ABCG2 AT THE BLOOD-BRAIN BARRIER
Authors: Olaf van Tellingen, Mark C de Gooijer, Stefanie Zuidema, Amber Meurs, Ceren H Çitirikkaya, Nikkie Venekamp, Jos H Beijnen
Journal: Neuro-Oncology (2020)

Abstract The blood-brain barrier (BBB) is a formidable hurdle to successful pharmacotherapy of intracranial diseases. ABCB1 and ABCG2 are efflux transporters that play an important role in the BBB, keeping substances out of the brain. Elacridar and tariquidar are third-generation ABCB1-inhibitors developed for treatment of multidrug-resistant tumors. Later, they were shown to also inhibit ABCG2. We aim to improve pharmacotherapy of brain cancer by concomitant use of potentially effective drugs with elacridar. This study was undertaken to determine the relationship between the plasma concentration of the inhibitor and the brain-to-plasma (B/P) ratio of (model) substrate drugs in order to assess which type of drug may best qualify taking into account clinically achievable plasma levels of the inhibitor. We used Abcg2;Abcb1a/b double knockout (DKO), Abcb1a/b KO, Abcg2 KO and wild-type mice receiving a cocktail of 9 drugs at a fixed low dose plus a range of doses of inhibitor by 3-h intraperitoneal infusion to achieve steady-state conditions. DKO mice are the reference for complete inhibition, while single KO mice allow interrogation of the other transporter when using dual substrate drugs. Complete inhibition of Abcb1 by elacridar requires plasma levels of about 1000 nM. Inhibition of Abcg2 is more difficult. For erlotinib and palbociclib about 1000 nM of elacridar is sufficient, but other more profound substrate drugs (e.g. vemurafenib and afatinib) do not reach the B/P ratios achieved in DKO mice, even at 4000 nM. The improvement in B/P ratio that can be reached differs per substrate. Compounds like palbociclib benefit markedly from elacridar with B/P ratios rising from 0.25 to 7, whereas others (e.g. erlotinib and dasatinib) increase from about 0.10 to only 0.40. Thus, elacridar is an efficient pharmaco-enhancer of ABCB1 substrates and weaker ABCG2 substrates, but is not able to improve brain delivery of drugs that are profound ABCG2 substrates.
EXTH-75. IN VITRO AND IN VIVO EFFICACY OF COMBINATORIAL INHIBITION OF LSD1 AND HDACS IN PATIENT DERIVED GLIOBLASTOMA STEM CELL MODELS
Authors: Achintyan Gangadharan, Leslie Grasse, Alexsandra Espejo, Ravesanker Ezhilarasan, Tiara Collier, Verlene Henry, Joy Gumin, Erik Sulman, Frederick Lang, Joya Chandra
Journal: Neuro-Oncology (2020)

Abstract Inhibitors of histone deacetylases (HDACi) have been tested in glioblastoma (GBM), however, single agent clinical efficacy has not been proven, prompting study of combinatorial approaches. A rational HDACi combination strategy is with inhibition of LSD1, lysine specific demethylase 1, a histone demethylase known to exist in complex with HDAC1/2. We previously showed in vivo efficacy of combining a brain permeant LSD1 inhibitor, tranylcypromine (TCP) together with vorinostat. More selective inhibitors of LSD1 have been developed and were tested in the current study together with the HDACi, vorinostat or panobinostat in a panel of patient derived glioblastoma stem cell (GSC) lines that have been characterized as radio-resistant or radiosensitive. To test in vitro sensitivity, dose response experiments were conducted in nine GSC cell lines using three LSD1 inhibitors or two HDACi as single agents or in combination. Two non-tumor lines were also tested to assess selective cytotoxicity for brain tumor lines. Cell viability and clonogenicity assays were performed. Several radio-resistant GSC lines showed sensitivity to single agent LSD1 inhibitors, whereas some radio-sensitive GSCs did not, indicating distinct molecular mechanisms of response. Intracranial orthotopic xenograft models were used to test in vivo efficacy using the radioresistant GSC20 line. Interestingly, LSD1 inhibition alone promoted tumor burden reduction and better survival rates than combination treatment. RNA-Seq guided biomarkers of sensitivity to the LSD1/HDAC inhibitor combination were assessed in vitro and in vivo. Both in vivo and in vitro data show that GSC20 treated with GSK LSD1 inhibitor had higher levels of HKDC1 gene with in vivo data also showing elevated levels of FTH1. In vivo mouse data for vorinostat and combination treatment groups showed that only the FTH1 gene level was elevated, providing a potential explanation for low in vivo efficacy. Collectively, our data suggests that LSD1 inhibition represents a viable strategy in GBM.
Hemoglobin Concentration in Acute Decompensated Heart Failure: A Marker of Volume Status?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Akshay S. Desai
Journal: Journal of the American College of Cardiology (2013)
Abstract 12011: Impact of Enterectomy on Coronary Microcirculation in Patients With Inflammatory Bowel Disease
Authors: Kentaro Kakuta, Kaoru Dohi, Takayuki Yamamoto, Naoki Fujimoto, Takahiro Shimoyama, Satoru Umegae, Yasuhiro Saito, Masaaki Ito
Journal: Circulation (2019)

Introduction: Inflammatory bowel disease (IBD) is a complex multisystem disease characterized by chronic inflammation, which can lead to coronary microvascular dysfunction (CMD). Hypothesis: We hyp...