tbuckley/cabot-search huggingface dataset:
β1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections
Authors: Heike Grassmé, Brian Henry, Regan Ziobro, Katrin Anne Becker, Joachim Riethmüller, Aaron Gardner, Aaron P. Seitz, Joerg Steinmann, Stephan Lang, Christopher Ward, Edward H. Schuchman, Charles C. Caldwell, Markus Kamler, Michael J. Edwards, Malcolm Brodlie, Erich Gulbins
Journal: Cell Host & Microbe (2017)

Chronic pulmonary colonization with bacterial pathogens, particularly Pseudomonas aeruginosa, is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). We observed that β1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. β1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap β1-integrins on the luminal pole of bronchial epithelial cells. β1-integrins downregulate acid ceramidase expression, resulting in further accumulation of ceramide and consequent reduction of surface sphingosine, a lipid that kills bacteria. Interrupting this vicious cycle by triggering surface β1-integrin internalization via anti-β1-integrin antibodies or the RGD peptide ligand—or by genetic or pharmacological correction of ceramide levels—normalizes β1-integrin distribution and sphingosine levels in CF epithelial cells and prevents P. aeruginosa infection in CF mice. These findings suggest a therapeutic avenue to ameliorate CF-associated bacterial infections.
Abstract 255: A Fibroblast Population Shares A Developmental Origin With Cardiovascular Lineages
Authors: Sara Ranjbarvaziri, Shah Ali, Mahmood Talkhabi, Peng Zhao, Young-Jae Nam, Reza Ardehali
Journal: Circulation Research (2014)

Rationale: The traditional definition of “cardiovascular” lineages describes the eponymous cell types - cardiomyoctes, endothelial cells, and smooth muscle cells - that arise from a common mesodermal progenitor cell during heart development. Fibroblasts are an abundant mesenchymal population in the mammalian heart which may have multiple, discrete developmental origins. Mesp1 represents the earliest marker of cardiovascular progenitors, contributing to the majority of cardiac lineages. To date no link between Mesp1 and fibroblast generation has been reported. Objective: We hypothesized progenitor cells expressing Mesp1 can also give rise to cardiac fibroblasts during heart development. Methods and Results: We generated Mesp1cre/+;R26RmTmG reporter mice where Cre-mediated recombination results in GFP activation in all Mesp1 expressing cells and their progeny. To explore their developmental potential, we isolated GFP+ cells from E7.5 Mesp1cre/+;R26RmTmG mouse. In vitro culture and transplantation studies into SCID mouse kidney capsule as wells as chick embryos showed fibroblastic adoption. Results showed that at E9.5 Mesp1+ and Mesp1- progenitors contributed to the proepicardium organ and later at E11.5 they formed epicardium. Analysis of adult hearts demonstrated that the majority of cardiac fibroblasts are derived from Mesp1 expressing cells. Immunohistochemical analysis of heart sections demonstrated expression of fibroblast markers (including DDR2, PDGFRα and Col1) in cells derived from both Mesp1+ and Mesp1- progenitors. Additionally, we investigated whether the two distinct fibroblast populations have different potency towards reprogramming to cardiomyocytes. Results showed no significant difference between Mesp1 and non-Mesp1 isolated fibroblasts to convert to cardiomyocyte fate. Conclusions: Our data demonstrates that cardiovascular progenitors expressing Mesp1 contribute to the proepicardium. These cells, as cardiovascular progenitors, also give rise to the highest portion of cardiac fibroblasts in the mouse heart.
Direct peroral cholangioscopy for diagnosis of bile duct lesions using an I-SCAN ultraslim endoscope: a pilot study
Authors: Yun Lee, Jong Moon, Hyun Choi, Tae Lee, Moon Choi, Sang-Woo Cha, Young Cho, Sang-Heum Park
Journal: Endoscopy (2017)

Abstract Background and study aims I-SCAN is a computed virtual chromoendoscopy (CVC) system designed to enhance surface and vascular patterns. In this study, we evaluated the usefulness of direct peroral cholangioscopy (POC) using I-SCAN compared with a conventional white-light image (WLI) to diagnose bile duct lesions. Patients and methods Patients with mucosal lesions in the bile duct detected during direct POC were enrolled prospectively. The quality of endoscopic visualization and the visual diagnosis were assessed using I-SCAN and WLI modes, respectively, during direct POC. Results A total of 20 patients (9 malignant and 11 benign lesions) underwent I-SCAN to evaluate lesions in the bile duct using direct POC. The quality of endoscopic visualization using direct POC with I-SCAN was significantly higher than that of WLI for surface structure (P = 0.04), surface microvascular architecture (P = 0.01), and margins (P = 0.02). Overall diagnostic accuracy of the visual diagnosis was not different between I-SCAN and WLI (90.0 % vs. 75.0 %; P = 0.20). Conclusion Direct POC using CVC by I-SCAN seems to be helpful for evaluating mucosal lesions of the bile duct, without the interference from bile. Clinical trial registration: UMIN000021009
MEDU-51. INSIGHTS INTO THE MECHANISM OF PID1, A NOVEL GROWTH SUPPRESSOR IN MEDULLOBLASTOMA
Authors: Sean Robinson, Anup Singh Pathania, Xiuhai Ren, Min Mahdi, Gregory M Shackleford, Anat Erdreich-Epstein
Journal: Neuro-Oncology (2017)

PID1 (Phosphotyrosine Interaction Domain containing 1) mRNA level is highly correlated with survival in medulloblastomas and gliomas (Erdreich-Epstein et al, Clin Cancer Res 2014). Cell culture data show that PID1 gain-of-function decreases medulloblastoma cell proliferation and increases their apoptosis, suggesting a causal role for PID1 in medulloblastoma growth. In vivo data showing that PID1 gain-of-function prolongs survival of mice with medulloblastoma and loss-of-function hastens their demise further indicates a causal role for PID1 as a growth-suppressor in medulloblastoma growth. We will present new data that sheds light on molecular mechanisms of PID1 function.
Monitoring the Vascular Response and Resistance to Sunitinib in Renal Cell Carcinoma <i>In Vivo</i> with Susceptibility Contrast MRI
Authors: Simon P. Robinson, Jessica K.R. Boult, Naveen S. Vasudev, Andrew R. Reynolds
Journal: Cancer Research (2017)

Abstract Antiangiogenic therapy is efficacious in metastatic renal cell carcinoma (mRCC). However, the ability of antiangiogenic drugs to delay tumor progression and extend survival is limited, due to either innate or acquired drug resistance. Furthermore, there are currently no validated biomarkers that predict which mRCC patients will benefit from antiangiogenic therapy. Here, we exploit susceptibility contrast MRI (SC-MRI) using intravascular ultrasmall superparamagnetic iron oxide particles to quantify and evaluate tumor fractional blood volume (fBV) as a noninvasive imaging biomarker of response to the antiangiogenic drug sunitinib. We also interrogate the vascular phenotype of RCC xenografts exhibiting acquired resistance to sunitinib. SC-MRI of 786-0 xenografts prior to and 2 weeks after daily treatment with 40 mg/kg sunitinib revealed a 71% (P &amp;lt; 0.01) reduction in fBV in the absence of any change in tumor volume. This response was associated with significantly lower microvessel density (P &amp;lt; 0.01) and lower uptake of the perfusion marker Hoechst 33342 (P &amp;lt; 0.05). The average pretreatment tumor fBV was negatively correlated (R2 = 0.92, P &amp;lt; 0.0001) with sunitinib-induced changes in tumor fBV across the cohort. SC-MRI also revealed suppressed fBV in tumors that acquired resistance to sunitinib. In conclusion, SC-MRI enabled monitoring of the antiangiogenic response of 786-0 RCC xenografts to sunitinib, which revealed that pretreatment tumor fBV was found to be a predictive biomarker of subsequent reduction in tumor blood volume in response to sunitinib, and acquired resistance to sunitinib was not associated with a parallel increase in tumor blood volume. Cancer Res; 77(15); 4127–34. ©2017 AACR.
Tobacco control: reducing cancer incidence and saving lives. American Society of Clinical Oncology.
Journal: Journal of Clinical Oncology (1996)

The American Society of Clinical Oncology (ASCO) supports the elimination of tobacco products. Toward that goal, ASCO urges the adoption of national policy that strengthens regulation of the sale, promotion, and distribution of such products. To reduce cancer mortality, our regulatory policies must recognize that the nicotine within tobacco is an addictive substance, the use of which leads to 30% of all cancer deaths and a total of 419,000 deaths each year.Tobacco-related advertising and promotion should be banned. At a minimum, national policies should: ban billboards; limit advertising to black and white text only; prohibit the sale or giveaway of products that contain tobacco brand names or logos; prohibit brand name sponsorship of sporting or entertainment events; and require stronger and more prominent warning labels on all tobacco products.Despite existing state laws prohibiting sale of tobacco products to minors, children are able to buy such products easily. National regulation of the sale and distribution of tobacco products is necessary to eliminate children's access to tobacco. Where sales are permitted, they should be limited to face-to-face purchases by individuals 18 and older. Vending machines and other means of distributing tobacco without a face-to-face purchase should be outlawed.To the extent tobacco sales are allowed to continue, the federal government should mandate that the tobacco industry contribute substantial funds for a national public education campaign to prevent young people from smoking and other tobacco use.ASCO has long advocated a substantial increase (in the range of $2) in the federal excise tax on cigarettes and other tobacco products- a measure known to decrease consumption, particularly among children. Revenue from a tax on tobacco products should be used to support retraining for tobacco farmers, biomedical research, health care delivery, and antitobacco education.United State trade policies should discourage the export of tobacco products and manufacturing to foreign markets. At a minimum, United States tobacco companies selling or manufacturing tobacco products in foreign markets that have not developed comparable health warning labels should be required to retain United States warning labels.Physicians, nurses, and other health care professionals-especially those in primary care disciplines-have the opportunity and responsibility to assist patients' efforts to quit tobacco use and to ensure that nonsmokers continue to avoid the addiction. Oncology specialists should discuss the causal relationship between tobacco use and cancer as well as a variety of other chronic diseases and assist, as required, the patient and family members to end tobacco dependency. In addition, health care professionals must advocate that public and private insurers be required to provide health care coverage for medically necessary interventions, such as counseling and nicotine transdermal systems.
Respiratory depression secondary to morphine use in a patient with COPD and refractory breathlessness
Authors: John Politis, Brian Le, Natasha Smallwood
Journal: European Respiratory Journal (2017)

Chronic obstructive pulmonary disease (COPD) is characterised by airflow obstruction and progressive respiratory failure. Patients develop increasing breathlessness, which can persist despite optimal medical management (refractory chronic breathlessness) [1]. Various studies suggests that low-dose morphine may safely reduce refractory breathlessness in patients with advanced respiratory disease [2–6]; however, the recent population cohort study by Vozoris et al. [7] in the European Respiratory Journal suggests opioids may be associated with increased adverse respiratory outcomes, including death in older COPD patients. We report a case of respiratory depression secondary to opioid use for refractory breathlessness. Respiratory depression secondary to morphine use in COPD patients with refractory breathlessness <http://ow.ly/8NVw30aLZXv> The authors would like to thank the patients and staff of the Respiratory Dept at the Royal Melbourne Hospital, Parkville, Australia.
Moving in the Wrong Direction — Health Care under the AHCA
Authors: Matthew Fiedler, Henry J. Aaron, Loren Adler, Paul B. Ginsburg
Journal: New England Journal of Medicine (2017)

Interview with Dr. Matthew Fiedler on the American Health Care Act and its likely effects on insurance coverage. (07:42)Download The American Health Care Act would change the U.S. health care system in several major ways, dramatically and immediately reducing insurance coverage. In many states, the seriously ill would be at particular risk of losing coverage.
Abstract 18411: NADPH oxidase Nox2 is Involved in Non-inflammatory Myeloid Cell Expansion in Bone Marrow after Hindlimb Ischemia: Mechanism for Reparative Angiogenesis
Authors: Norifumi Urao, Ronald D McKinney, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation (2010)

Neovascularization is an important repair process that depends on angiogenesis and inflammation associated with pro- and non-inflammatory monocytes/macrophages. We previously showed that NADPH oxid...
Previous concussion history influences neurological assessments following an acute bout of purposeful heading in women’s collegiate soccer
Authors: Thomas W Kaminski, Briana Kimmelmann, Jaclyn B Caccese, Joseph J Glutting
Journal: British Journal of Sports Medicine (2017)

Objective Do differences in neurological assessments exists in a cohort of intercollegiate soccer players with varied concussion histories after an acute bout of soccer heading? Design Pre-posttest. Setting Soccer turf field and clinic. Participants 67 female collegiate soccer athletes (age=19.1 ± 0.9 yr.; mass=60.5 ± 5.0 kg; height=165.3 ± 5.9 cm). Based on their concussion history subjects were assigned to either the control/simulated heading [G1-17], control/heading [G2-22] 1–2 previous concussion/heading [G3-19], and 3 or more concussion/heading [G4-9] groups. Interventions Concussion symptoms (SX), BESS errors, ImPACT NP test scores were derived prior to and immediately after a bout of heading (15 total headers/15 minutes @ 12 m/s). Subjects returned to the clinic for post-testing immediately after heading. Outcome measures SX, BESS and NP scores pre and post ROT and LIN heading. Main results G3 (3.9±4.4) and G4 (5.1±6.0) demonstrated higher SX pre-heading compared to G1 (1.9±2.4) and G2 (3.2±3.7). Excluding G1, all groups showed elevated SX post-heading. There was a significant (p=.05) time by group interaction for SX whereby SX in G4 (7.8±7.1; 95% CI=4.9 – 10.7) were significantly (p=0.03) higher post-heading than G1 (2.0±2.5; 95% CI=−0.02 – 4.2). Conclusions Subjects in G4 had elevated SX at baseline, and those SX appear to be greatly exaggerated immediately following an acute bout of heading. Clinicians should carefully monitor soccer players who have experienced multiple concussions and be cognizant that they may develop concussion-like symptoms, especially after acute bouts of heading. Limitations in soccer heading should also be considered for this group of soccer athletes. Competing interests None.
Inhibitory Plasticity: Balance, Control, and Codependence
Authors: Guillaume Hennequin, Everton J. Agnes, Tim P. Vogels
Journal: Annual Review of Neuroscience (2017)

Inhibitory neurons, although relatively few in number, exert powerful control over brain circuits. They stabilize network activity in the face of strong feedback excitation and actively engage in computations. Recent studies reveal the importance of a precise balance of excitation and inhibition in neural circuits, which often requires exquisite fine-tuning of inhibitory connections. We review inhibitory synaptic plasticity and its roles in shaping both feedforward and feedback control. We discuss the necessity of complex, codependent plasticity mechanisms to build nontrivial, functioning networks, and we end by summarizing experimental evidence of such interactions.
Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy
Authors: Laetitia Fend, Takahiro Yamazaki, Christelle Remy, Catherine Fahrner, Murielle Gantzer, Virginie Nourtier, Xavier Préville, Eric Quéméneur, Oliver Kepp, Julien Adam, Aurélien Marabelle, Jonathan M. Pitt, Guido Kroemer, Laurence Zitvogel
Journal: Cancer Research (2017)

Abstract Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK−RR−-Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar−/− tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146–57. ©2017 AACR.
MEDU-46. IDENTIFICATION AND CHARACTERIZATION OF TUMOR-INITIATING CELLS IN RECURRENT MEDULLOBLASTOMA
Authors: Xuelian He, Liguo Zhang
Journal: Neuro-Oncology (2017)

Medulloblastoma represents the most common childhood brain tumor. Despite aggressive multimodal therapy, a significant proportion of surviving patients suffer from severe treatment-related side effects, including tumor relapse. Thus, there is an urgent need for novel therapeutic modalities that can improve patient survival while minimizing tumor recurrence. Our recent study identified GNAS as a novel tumor-suppressor gene in Sonic hedgehog-driven medulloblastomas (Ref.1). Low expression or mutation of GNAS was tightly correlated with poor prognosis of Sonic hedgehog-group tumors and their resistance to the treatment of Sonic hedgehog signaling inhibitors alone. Ablation of the single GNAS gene in anatomically-distinct progenitors in the ventricular zone of the cerebellum and dorsal brainstem is sufficient to induce medulloblastoma formation, recapitulating their human counterparts. Gsα activation suppresses Sonic hedgehog signaling by regulating both the cAMP-dependent PKA pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor growth in GNAS mutants. Strikingly, we find that in the drug-resistant tumor lesion and recurrent tumors after radiation therapy, there is an increase of Olig2 expression and Olig2+ progenitor cells. High levels of Olig2 are correlated with poor prognosis of medulloblastomas in human patients. We show that elimination of the mitotic Olig2-expressing cells blocks tumor progression in Olig2-TK transgenic mice. In addition, cell type-specific deletion of Olig2 halts tumor progression. Moreover, we find that Olig2 activates gene regulatory networks inferred for tumor cell stemness and regulates chromatin accessibility of oncogenic factors by altering epigenome landscapes. Furthermore, our single cell analyses reveal that Olig2-expressing progenitors are the distinct tumor-initiating cells during the onset of primary and recurrent medulloblastoma, highlighting potential therapeutic avenues for treating recurrent medulloblastomas by targeting Olig2-expressing progenitors. Ref.1: He, X. et al., “The G protein-alpha subunit Ga is a tumor suppressor in Sonic hedgehog-driven medulloblastoma”. Nat Med 20: 1035–1042.
“Cost and cost-effectiveness of multidrug-resistant tuberculosis treatment in Estonia and Russia”. Katherine Floyd, Raymond Hutubessy, Kai Kliiman, Rosella Centis, Nina Khurieva, Wieslaw Jakubowiak, Manfred Danilovits, Genadi Peremitin, Salmaan Keshavjee and Giovanni Battista Migliori.<i>Eur Respir J</i>2012; 40: 133–142.
Authors: Katherine Floyd, Raymond Hutubessy, Kai Kliiman, Rosella Centis, Nina Khurieva, Wieslaw Jakubowiak, Manfred Danilovits, Genadi Peremitin, Salmaan Keshavjee, Giovanni Battista, Robert Wilson, Antonio Anzueto, Marc Miravitlles, Pierre Arvis, Jeff Alder, Daniel Haverstock, Mila Trajanovic, Jordi Roig, Yves Sibille, Eamonn Shanahan, Fernando De Benedetto, Nadeem Rizvi
Journal: European Respiratory Journal (2012)
Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction
Authors: Julio A. Chirinos, Francisco Londono‐Hoyos, Payman Zamani, Melissa Beraun, Philip Haines, Izzah Vasim, Swapna Varakantam, Timothy S. Phan, Thomas P. Cappola, Kenneth B. Margulies, Raymond R. Townsend, Patrick Segers
Journal: European Journal of Heart Failure (2017)
Biomimetic Model of Tumor Microenvironment on Microfluidic Platform
Authors: Minhwan Chung, Jungho Ahn, Kyungmin Son, Sudong Kim, Noo Li Jeon
Journal: Advanced Healthcare Materials (2017)

The “Tumor microenvironment” (TME) is a complex, interacting system of the tumor and its surrounding environment. The TME has drawn more attention recently in attempts to overcome current drug resistance and the recurrence of cancer by understanding the cancer and its microenvironment systematically, beyond past reductionist approaches. However, a lack of experimental tools to dissect the intricate interactions has hampered in‐depth research into the TME. Here, a biomimetic TME model using a microfluidic platform is presented, which enables the interaction between TME constituents to be studied in a comprehensive manner. Paracrine interactions of cocultured tumor cell lines (SK‐OV‐3, MKN‐74, and SW620) with primary fibroblasts show marked morphological changes in the tumor cells, depending on the type of tumor cells, and, importantly, the composition of the extracellular matrix. Furthermore, this model allows direct observation of angiogenesis induced by the tumor–stroma interaction. Finally, reconstituting simultaneous angiogenesis and lymphangiogenesis induced by the tumor‐stromal interaction with TME mimicking extrinsic factors is enabled. It is believed that the in vitro biomimetic model and the experimental concepts described will help to shed light on the complex biology of the TME.
Conclusions of a seven-year translational research initiative: Defining and validating a molecular signature of high-risk multiple myeloma
Authors: John Shaughnessy, Fenghuang Zhan, Bart Barington, John Crowley, Bart Barlogie
Journal: Clinical Cancer Research (2007)

PR-2  Introduction: Survival of patients diagnosed with multiple myeloma (MM) can vary considerably. While most disease is initially responsive to intervention, a small subset is primary refractory and acquisition of drug resistance represents a difficult barrier to long-term disease control. Aim: We used genome-wide mRNA expression profiling to identify molecular signatures to improve risk stratification. Methods:  We performed expression analyses, using Affymetrix U133Plus2.0 microarrays, on mRNA from CD138-enriched bone marrow plasma cells from 532 consecutive newly diagnosed patients treated with tandem stem ell transplants on two separate protocols at our center. We segregated gene expression levels into quartiles and performed log rank tests to identify genes whose expression extremes were linked to disease related death. Results: We identified 70 genes, 30% mapping to chromosome 1 (P