tbuckley/cabot-search huggingface dataset:
Morphological Processes of Foot Process Effacement in Puromycin Aminonucleoside Nephrosis Revealed by FIB/SEM Tomography
Authors: Koichiro Ichimura, Takayuki Miyaki, Yuto Kawasaki, Mui Kinoshita, Soichiro Kakuta, Tatsuo Sakai
Journal: Journal of the American Society of Nephrology (2018)

Foot process effacement is one of the pathologic indicators of podocyte injury. However, the morphologic changes associated with it remain unclear.To clarify the developmental process, we analyzed puromycin nephrotic podocytes reconstructed from serial focused-ion beam/scanning electron microscopy (FIB/SEM) images.Intact podocytes consisted of four subcellular compartments: cell body, primary process, ridge-like prominence (RLP), and foot process. The RLP, a longitudinal protrusion from the basal surface of the cell body and primary process, served as an adhesive apparatus for the cell body and primary process to attach to the glomerular basement membrane. Foot processes protruded from both sides of the RLP. In puromycin nephrotic podocytes, foot process effacement occurred in two ways: by type-1 retraction, where the foot processes retracted while maintaining their rounded tips; or type-2 retraction, where they narrowed across their entire lengths, tapering toward the tips. Puromycin nephrotic podocytes also exhibited several alterations associated with foot process effacement, such as deformation of the cell body, retraction of RLPs, and cytoplasmic fragmentation. Finally, podocytes were reorganized into a broad, flattened shape.The three-dimensional reconstruction of podocytes by serial FIB/SEM images revealed the morphologic changes involved in foot process effacement in greater detail than previously described.
Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies
Authors: Ken Lee Chin, Richard Ofori-Asenso, Ingrid Hopper, Thomas G von Lueder, Christopher M Reid, Sophia Zoungas, Bing H Wang, Danny Liew
Journal: Cardiovascular Research (2018)

There is growing evidence from Phase III randomized clinical trials of the cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes mellitus. It is hypothesized that these benefits are mediated by mechanisms other than glucose control. To address this, we performed a systematic review of data from preclinical studies examining the direct cardioprotective effects of SGLT2 inhibitors. Medline, EMBASE, CINAHL, and International Pharmaceutical Abstracts databases were searched for preclinical studies that examined the potential cardioprotective effects of SGLT2 inhibitors. Submission documents to the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceutical and Medical Devices Agency for the registration of SGLT2 inhibitors were also reviewed. A total of 36 reports were included in the final analysis. The potential direct cardiovascular benefits of SGLT2 inhibitors include: augmentation of signal transducer and activator of transcription 3; inhibition of sodium hydrogen exchange; reduction of atherosclerosis; modulation of natriuretic peptides; vasodilation; modulation of sympathetic tone; and reduction of inflammation, oxidative stress, endoplasmic reticulum stress, and cardiac glucose uptake via down-regulation of SGLT1 expression. There are a number of mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits beyond glycaemic control.
Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells
Authors: Jiao Wang, Kyle B. Lupo, Andrea M. Chambers, Sandro Matosevic
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> The anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo. <h3>Methods</h3> NK cells were engineered non-virally with NKG2D.CAR-presenting vectors based on the piggyBac transposon system with DAP10 and CD3ζ co-signaling domains. The anti-tumor immunity of NKG2D.CAR.NK cells in combination with CD73 targeting was evaluated against multiple solid tumor targets in vitro and humanized mouse xenografts in immunodeficient tumor-bearing mice in vivo. Intratumoral migration was evaluated via immunohistochemical staining, while degranulation capacity and IFN-γ production of NK cells were measured in response to solid tumor targets. <h3>Results</h3> Our results showed that CD73 blockade can mediate effective purinergic reprogramming and enhance anti-tumor cytotoxicity both in vitro and in vivo by enhancing the killing ability of CAR-engineered NK cells against CD73<sup>+</sup> solid tumor targets via mechanisms that might imply alleviation from adenosinergic immunometabolic suppression. CD73 blockade improved the intratumoral homing of CD56<sup>+</sup> CAR-NK cells in vivo. These engineered NK cells showed synergistic therapeutic efficacy in combination with CD73 targeting against CD73<sup>+</sup> human lung cancer xenograft models. Interestingly, CD73 blockade could inhibit tumor growth in vivo independently of adaptive immune cells, innate immunity or NK cell-mediated ADCC. <h3>Conclusions</h3> Immunotherapies targeting the adenosinergic signaling cascade, which act by neutralizing CD73 ectoenzymatic activity, had thus far not been evaluated in humanized tumor models, nor had the implication of innate immunity been investigated. Taken together, our pre-clinical efficacy data demonstrate, for the first time, the potential of targeting CD73 to modulate purinergic signaling and enhance adoptive NK cell immunotherapy via mechanisms that could implicate autocrine tumor control as well as by mediating adenosinergic signaling.
Reply to Pontus Eriksson and Gottfrid Sjödahl's Letter to the Editor re: Tuan Zea Tan, Mathieu Rouanne, Kien Thiam Tan, Ruby Yun-Ju Huang, Jean-Paul Thiery. Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta-cohort Analysis of 2411 Tumors. Eur Urol 2019;75:423–32
Authors: Tuan Zea Tan, Mathieu Rouanne, Ruby Yun-Ju Huang, Jean-Paul Thiery
Journal: European Urology (2018)
Statins are overprescribed for primary prevention, study suggests
Authors: Ingrid Torjesen
Journal: BMJ (2018)

The 10 year risk levels at which guidelines recommend initiating statins for primary prevention of cardiovascular disease (CVD) are too low, a modelling study published in the Annals of Internal Medicine suggests.1

The study found that statins provided net benefits in primary prevention only at a substantially higher 10 year risk of cardiovascular disease than the 7.5%-10.0% cut-offs recommended by guidelines.

The findings support the National Institute for Health and Care Excellence’s (NICE) decision in 2014, when it revised its recommendations, not to follow recommendations by the American College of …
Case 37-2018: A 23-Year-Old Woman with Vision Loss
Authors: Sashank Prasad, Lucy H. Young, Marc Bouffard, Rajiv Gupta
Journal: New England Journal of Medicine (2018)

A 23-year-old woman presented with vertigo and vision loss affecting the right eye. Hearing loss and tinnitus of the right ear developed. Fluorescein angiography revealed delayed filling of two arteriolar branches in the right eye. A diagnosis was made.
Inhibition of angiogenesis and xenograft tumor growth by AMG 273 a novel multi-kinase inhibitor
Authors: Angela Coxon, Charles Starnes, James Bready, Juan Estrada, Stephen Kaufman, Robert Radinsky, Richard Kendall, Paul Hughes, Anthony Polverino
Journal: Cancer Research (2007)

2134  Background: Vascular endothelial growth factor (VEGF) is critical for tumor blood vessel formation and inhibition of VEGF receptors is a proven therapeutic strategy with promise for a wide range of human malignancies. AMG 273 is an orally bioavailable inhibitor of VEGF receptors, as well as PDGF receptors and c-Kit. We have examined the effect of AMG 273 on endothelial cell proliferation in vitro and on vascular permeability, angiogenesis, and tumor growth in animal models.  Materials and Methods: The effect of AMG 273 on human umbilical vein endothelial cell (HUVEC) proliferation was determined using a CyQuant assay. HUVECs were pretreated with AMG 273 for 2 hrs, followed by incubation for 72 hr in media containing either VEGF or bFGF. Proliferation of normal human dermal fibroblasts (NHDF) in response to platelet-derived growth factor (PDGF) was used to determine the potency of AMG 273 against PDGFR. VEGF signaling in vivo was assessed by examining levels of phosphorylated Flk-1 in the lungs of mice after a single dose of AMG 273 (10, 30 or 100 mg/kg). A VEGF-dependent vascular permeability assay was performed in the mouse skin. VEGF expressing cells were implanted subcutaneously into nude mice and 24 hr later mice received a single dose of AMG 273 (10, 30 or 100 mg/kg). Extravasated Evan’s Blue dye was measured 6 hr later. A rat corneal angiogenesis assay was also performed using VEGF as the neovascular stimulus. After treatment with AMG 273 (1, 3, 5 or 10 mg/kg) for 7 days, new blood vessel formation was quantified. Finally, the activity of AMG 273 (up to doses of 100mg/kg) was determined in A431 (human epidermoid carcinoma) and HT-29 (human colon carcinoma) tumor xenograft models in nude mice.  Results: AMG 273 inhibited VEGF-induced HUVEC proliferation with an IC50 of 0.012 µM, whereas it had little effect against bFGF-induced proliferation (IC50 > 3 µM). AMG 273 inhibited PDGF-stimulated NHDF proliferation with an IC50 of 0.103 µM. Treatment with AMG 273 completely inhibited both VEGF-induced vascular permeability and Flk-1 phosphorylation in mouse lungs. In addition, once daily administration of AMG 273 for 7 days significantly inhibited VEGF-induced angiogenesis in the rat corneal model with an ED50 of 2.3 mg/kg (p   Conclusions: AMG 273 is a novel, orally available inhibitor of VEGF, PDGF and c-Kit receptor tyrosine kinases that effectively blocks endothelial cell proliferation and angiogenesis and demonstrates significant anti-tumor activity in animal models.
Abstract P245: High Consumption of Caffeinated Tea is Associated With Increased Risk of Coronary Artery Disease but Caffeinated Coffee Consumption is Not
Authors: Sarah G Wolfrum, Xuan-Mai T Nguyen, Rachel E Ward, Yuk-Lam Ho, Rebecca J Song, David R Gagnon, Kelly Cho, J. Michael Gaziano, Luc Djousse
Journal: Circulation (2018)

Introduction: Prior studies have suggested a link between diet and Coronary Artery Disease (CAD), but there have been mixed findings on the risks and benefits of coffee and tea consumption. We assessed whether there is an association and dose response between coffee and tea intake on CAD incidence among Veterans. Methods: Million Veteran Program (MVP) is a national, representative longitudinal study of Veterans for genomic and non-genomic research that combines data from self-reported surveys, electronic health records, and biospecimens. Using food frequency data collected from 2011-2017 and CAD outcomes obtained from electronic health records, we used cox proportional hazard ratios (HR) to evaluate the association of coffee or tea intake with CAD incidence among Veterans with complete data. Follow-up began at the completion of the food frequency survey. Tea and coffee were evaluated separately, with intake categorized as never or less than one cup/month, 1-3 cups/month, one cup/week, 2-4 cups/week, 5-6 cups/week, one cup/day, 2-3 cups/day, 4-5 cups/day, or 6+ cups/day. For tea, the last two categories were combined to obtain stable estimates. Multivariate models were adjusted for known CAD risk factors (age, smoking status, physical activity, and education) and other caffeine use (e.g. tea for coffee). We plan to use restricted cubic splines to assess dose-response relationships. Results: Among 139,549 participants (90.3% male, mean age 64 ± 12 years), 74.2% consumed 1+ cups of coffee a month and 53.7% consumed 1+ cups of tea a month. During a median follow up of 3.2 years, we observed 4,715 new cases of CAD. Compared to those who drank less than one cup of coffee/month, adjusted HRs (95% CI) for CAD were 1.06 (0.92-1.22) for 1-3 cups/month, 1.09 (0.91-1.29) for one cup/week, 0.96 (0.84-1.10) for 2-4 cups/week, 0.92 (0.81-1.04) for 5-6 cups/week, 0.93 (0.85-1.01) for one cup/day, 0.99 (0.91-1.07) for 2-3 cups/day, 1.05 (0.93-1.19) for 4-5 cups/day, and 1.08 (0.92-1.28) for 6+ cups/day (p-linear trend=0.24). Compared to those who drank less than one cup of caffeinated tea/month, adjusted HRs (95% CI) for CAD were 1.08 (0.99-1.17) for 1-3 cups/month, 1.11 (0.99-1.23) for one cup/week, 1.01 (0.91-1.12) for 2-4 cups/week, 1.03 (0.89-1.17) for 5-6 cups/week, 1.04 (0.93-1.17) for one cup/day, 1.12 (0.98-1.28) for 2-3 cups/day, and 1.27 (1.04-1.58) for 4+ cups/day (p-linear trend=0.14). Conclusion: While coffee intake was not associated with incidence of CAD, there was an elevated risk of CAD restricted to Veterans consuming 4+ cups of caffeinated tea per day.
Targeting indoleamine-2,3-dioxygenase in cancer: Scientific rationale and clinical evidence
Authors: Biagio Ricciuti, Giulia Costanza Leonardi, Paolo Puccetti, Francesca Fallarino, Vanessa Bianconi, Amirhossein Sahebkar, Sara Baglivo, Rita Chiari, Matteo Pirro
Journal: Pharmacology & Therapeutics (2018)
Abstract 18858: Assessment of Coronary Artery Aneurysms Caused by Kawasaki Disease Using Transluminal Attenuation Gradient Analysis of Coronary CT Angiograms
Authors: Noelia Grande Gutierrez, Olga Shirinsky, Nina V Gagarina, Galina A Lyskina, Ryuji Fukazawa, Shunichi Ogawa, Jane C Burns, Alison L Marsden, Andrew M Kahn
Journal: Circulation (2015)

Introduction: Patients with coronary artery aneurysms (CAA) resulting from Kawasaki Disease (KD) are at risk for thrombosis and myocardial infarction. Current guidelines recommend using CAA diameter &gt;8mm as the criterion for initiating systemic anticoagulation, but this is not based on outcome or simulation data. Transluminal Attenuation Gradient (TAG) has been proposed as a non-invasive method for evaluating the functional significance of coronary stenoses from CT Angiography (CTA). However TAG has not been previously used for the assessment of CAA. Hypothesis: We hypothesized that abnormal flow conditions in CAA caused by KD could be quantified using TAG. Methods: We studied 23 patients with a history of KD who had undergone clinically indicated CTA. We quantified TAG in the major coronary arteries by performing linear regression of the average lumen intensity as a function of vessel length. Aneurysm geometry was characterized using maximum aneurysm diameter, aneurysm shape index (ASI) and sphericity index. Results: A total of 41 arteries were analyzed, 22 of which had at least one aneurysmal region. TAG of aneurysmal arteries was significantly lower than in normal arteries (-22.4±10.5 vs. -9.3±10, p=0.0003). Differences were also significant in aneurysmal vs. normal LAD and RCA sub-groups (-26.7±9.7 vs. -16.5±9.0, p=0.02; -14.7±8.2 vs. -0.1±4.4, p=0.001). Aneurysm diameter, ASI, and sphericity index showed little to no correlation with TAG (r2=0.04, r2=0.18, r2=0.17). Conclusions: This study is the first application of TAG in CAA from KD, and demonstrates significantly different TAG values in aneurysmal compared to normal arteries. Lack of correlation between TAG and CAA geometry suggests that TAG may provide information on hemodynamic conditions not available from anatomy alone. The use of TAG in KD patients represents a possible extension to standard CTA that could aid in clinical decision-making and help to better evaluate the risk of thrombus formation.
Translation and evaluation of a lung cancer palliative care intervention for community practice.
Authors: Huong Q Nguyen, Loraine Martinez, Chrissie Mirasol, Meesha Land, Tami R. Borneman, Mayra Macias, Nora Ruel, Betty R. Ferrell
Journal: Journal of Clinical Oncology (2018)

77 Background: A notable gap in the evidence-base for outpatient palliative care (PC) for cancer is that most trials were conducted in specialized centers with limited translation and further evaluation in “real-world” settings. Health systems are desperate for guidance on effective, scalable models. The purpose of this study was to determine the effects of a nurse-led PC intervention (PCI) for patients with non-small cell lung cancer (NSCLC) and their family caregivers (FCGs) in a community-based setting. Methods: Two-group, prospective sequential, quasi-experimental design with phase 1 (usual care) followed by phase 2 (intervention) conducted at three Kaiser Permanente Southern California sites. Participants included patients with stage 2 - 4 NSCLC and their FCG. Standard measures of quality of life included FACT-L, FACIT- SP12, City of Hope Family QOL; other outcomes were distress, healthcare utilization, caregiver preparedness and perceived burden. Results: Patients in the intervention cohort had significant immediate improvements in three (physical, emotional, and functional well-being) of the five quality of life (QOL) domains at 1 month that were sustained through 3 months compared to usual care (p &lt; .01). Caregivers in the intervention cohort had improvements in physical (p = .04) and spiritual well-being (p = .03) and preparedness (p = .04) compared to usual care. There were no differences in distress or health care utilization between cohorts. Conclusions: Our findings suggest that a research-based PC intervention can be successfully adapted to community settings to achieve similar, if not better, QOL outcomes for patients and FCGs compared to usual care. Nonetheless, additional modifications to ensure consistent referrals to PC and streamlining routine assessments and patient/FCG education are needed to sustain and disseminate the PCI. Clinical trial information: NCT02243748.
A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma
Authors: Jezabel Rodriguez-Blanco, Bin Li, Jun Long, Chen Shen, Fan Yang, Darren Orton, Sara Collins, Noriyuki Kasahara, Nagi G. Ayad, Heather J. McCrea, Martine F. Roussel, William A. Weiss, Anthony J. Capobianco, David J. Robbins
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1α activator against TRP53-mutant, MYCN-amplified medulloblastoma. Experimental Design: The ability of this CK1α activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1α activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft. Results: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival. Conclusions: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitor–resistant medulloblastoma, including those harboring mutations in TRP53.
Residual Tumor Volume, Cell Volume Fraction, and Tumor Cell Kill During Fractionated Chemoradiation Therapy of Human Glioblastoma using Quantitative Sodium MR Imaging
Authors: Keith R. Thulborn, Aiming Lu, Ian C. Atkinson, Mohan Pauliah, Kathryn Beal, Timothy A. Chan, Antonio Omuro, Josh Yamada, Michelle S. Bradbury
Journal: Clinical Cancer Research (2018)

Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival.
Investigation of taxol-resistance using folate-targeted ternary therapeutic nanoparticle
Authors: Kwangjae Cho, Xu Wang, Gloria Kim, Ada Gjyrezi, Paraskevi Giannakakou, Shuming Nie, Zhuo Chen, Dong Shin
Journal: Cancer Research (2007)

2311  Development of novel drug delivery using nanotechnology has been an important strategy to increase the therapeutic efficacy and decrease the side effects of chemotherapeutics. Moreover, conjugation of a drug to a ligand specifically targeted to a cancer cell surface receptor may help not only reduce dose-limiting toxicities but also enable the drug to bypass drug resistance mechanisms, especially those mediated by P-glycoprotein(P-gp), as the drug would get internalized via receptor-mediated endocytosis. We have recently conjugated a novel ternary structure nanoparticle, Heparin-Folate-Taxol (HFT) which demonstrated higher antitumor efficacy than the free Taxol in vivo. In this study, we sought to investigate whether HFT could also minimize P-gp mediated Taxol resistance using a xenograft model of KB-8-5 and KB-V1 Taxol-resistant cells. HFT was composed of heparin as the carrier, folate as the targeting moiety to folate receptor (FR), and Taxol as the anticancer drug. Flow cytometry revealed high expression levels of FR in both parental (KB-3-1) and drug resistant derivatives (KB-8-5, and KB-V1), while higher P-gp levels were observed in the drug resistant cells (KB-8-5, KB-V1) compared with the parental cells, consistent with their Taxol-resistant phenotype. KB-8-5 and KB-V1 cells, which were known to be about 10 times and 1000 times more resistant to Taxol than their parental KB-3-1 cells respectively, were then injected subcutaneously into nude mice. The animals were treated with free Taxol, HT, HFT or Cremophor EL as a control. Each drug (80mg/kg Taxol equivalent) was administrated via tail vein once a week for 4 weeks (totally 4 injections). The in vivo study showed that only HFT significantly inhibited growth of KB-8-5 and KB-V1 xenograft tumors as compared with the control (KB-8-5:p=0.03/KB-V1:p=0.027). Although inhibitory effect of HFT on KB-8-5 tumor growth was not significantly better than that of free Taxol (p=0.33), we observed a trend that HFT was superior to free Taxol in KB-V1 tumors (p=0.06). Confocal microscopy analysis of freshly fixed KB-8-5 xenograft tumor sections revealed perturbations of the microtubule cytoskeleton in the HFT treated animals, such as microtubule bundling, aberrant mitotic spindles and cells with a lagging chromosome phenotype, consistent with the in vivo antitumor efficacy of HFT. No such effects were observed in the tumors treated with either free Taxol or HT. Furthermore, the weighted index of Ki-67 expression was lower in HFT treated-samples compared with the other three treatment groups, reflecting the in vivo antitumor efficacy of each treatment. These results indicate that a novel nanotherapeutic drug HFT can minimize or overcome the resistance of KB-8-5 and KB-V1 to Taxol and deserves further investigation in clinical trials. (This study is supported in part by NIH CCNE grant to DMS and SN).