tbuckley/cabot-search huggingface dataset:
Molecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal Cortex
Authors: Gülşen Sürmeli, Daniel Cosmin Marcu, Christina McClure, Derek L.F. Garden, Hugh Pastoll, Matthew F. Nolan
Journal: Neuron (2015)

Deep layers of the medial entorhinal cortex are considered to relay signals from the hippocampus to other brain structures, but pathways for routing of signals to and from the deep layers are not well established. Delineating these pathways is important for a circuit level understanding of spatial cognition and memory. We find that neurons in layers 5a and 5b have distinct molecular identities, defined by the transcription factors Etv1 and Ctip2, and divergent targets, with extensive intratelencephalic projections originating in layer 5a, but not 5b. This segregation of outputs is mirrored by the organization of glutamatergic input from stellate cells in layer 2 and from the hippocampus, with both preferentially targeting layer 5b over 5a. Our results suggest a molecular and anatomical organization of input-output computations in deep layers of the MEC, reveal precise translaminar microcircuitry, and identify molecularly defined pathways for spatial signals to influence computation in deep layers.
Timing of routine infant vaccinations and risk of food allergy and eczema at one year of age
Authors: N. Kiraly, J. J. Koplin, N. W. Crawford, S. Bannister, K. L. Flanagan, P. G. Holt, L. C. Gurrin, A. J. Lowe, M. L. K. Tang, M. Wake, A.-L. Ponsonby, S. C. Dharmage, K. J. Allen
Journal: Allergy (2015)

Epidemiological evidence suggests that routine vaccinations can have nontargeted effects on susceptibility to infections and allergic disease. Such effects may depend on age at vaccination, and a delay in pertussis vaccination has been linked to reduced risk of allergic disease. We aimed to test the hypothesis that delay in vaccines containing diphtheria-tetanus-acellular pertussis (DTaP) is associated with reduced risk of food allergy and other allergic diseases.HealthNuts is a population-based cohort in Melbourne, Australia. Twelve-month-old infants were skin prick-tested to common food allergens, and sensitized infants were offered oral food challenges to determine food allergy status. In this data linkage study, vaccination data for children in the HealthNuts cohort were obtained from the Australian Childhood Immunisation Register. Associations were examined between age at the first dose of DTaP and allergic disease.Of 4433 children, 109 (2.5%) received the first dose of DTaP one month late (delayed DTaP). Overall, delayed DTaP was not associated with primary outcomes of food allergy (adjusted odds ratio (aOR) 0.77; 95% CI: 0.36-1.62, P = 0.49) or atopic sensitization (aOR: 0.66; 95% CI: 0.35-1.24, P = 0.19). Amongst secondary outcomes, delayed DTaP was associated with reduced eczema (aOR: 0.57; 95% CI: 0.34-0.97, P = 0.04) and reduced use of eczema medication (aOR: 0.45; 95% CI: 0.24-0.83, P = 0.01).There was no overall association between delayed DTaP and food allergy; however, children with delayed DTaP had less eczema and less use of eczema medication. Timing of routine infant immunizations may affect susceptibility to allergic disease.
Abstract P4-07-10: MiRNAs are important regulators of Pax-5 expression and function during breast cancer progression
Authors: Jason M Harquail, Gilles A Robichaud
Journal: Cancer Research (2015)

Abstract Recent studies have enabled the identification of important factors regulating cancer progression, one of these being the Pax-5 gene. Pax-5, an essential developmental factor of B cells, is aberrantly expressed in various B cell cancer lesions and solid tumors such as breast carcinoma. Although Pax-5 downstream activity is relatively well characterized, the regulation of aberrant Pax-5 expression in a cancer specific context is poorly understood. To investigate the regulation of Pax-5 expression, we turned our attention to micro-RNAs (miRNAs). MiRNAs are highly conserved, small non-coding RNA molecules that regulate key biological processes. Extensive studies also show their deregulation in multiple cancer lesions. In this study, we aim to elucidate a causal link between differentially expressed miRNAs in cancer cells and their putative targeting of Pax-5-dependent cancer processes. With the help of biobank data and bioinformatics analyses, we observe that miRNAs 484 and 210 are aberrantly expressed in breast cancer cells and cross-reference with their predicted capacity to target the Pax-5 mRNA 3’ untranslated region (3’UTR). Using anti- or pre-miRNAs transfected into Pax-5 expressing breast cancer cell lines (MCF-7 and MB231), we demonstrate that miRNAs 484 and 210 are capable of regulating Pax-5 expression. In addition, miRNA-regulated Pax-5 expression resulted in a concomitant alteration in Pax-5-mediated phenotype and cancer processes. This is the first study demonstrating the regulation of Pax-5 expression and function by non-coding RNAs in cancer cells. We believe that the aberrant expression of Pax-5 in cancer cells is in part due to deregulated miRNA expression profiles. This study will bring insight in regards to cancer regulating processes associated with miRNA and Pax-5 deregulations and help us better understand aberrant Pax-5 expression levels within cancerous states. This study can therefore provide the eventual possibility of earlier, more efficient diagnostics as well as more targeted treatments for cancer patients. Citation Format: Jason M Harquail, Gilles A Robichaud. MiRNAs are important regulators of Pax-5 expression and function during breast cancer progression [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-07-10.
Estrogen Metabolite 16α-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II–Associated Pulmonary Arterial Hypertension Through MicroRNA-29–Mediated Modulation of Cellular Metabolism
Authors: Xinping Chen, Megha Talati, Joshua P. Fessel, Anna R. Hemnes, Santhi Gladson, Jaketa French, Sheila Shay, Aaron Trammell, John A. Phillips, Rizwan Hamid, Joy D. Cogan, Elliott P. Dawson, Kristie E. Womble, Lora K. Hedges, Elizabeth G. Martinez, Lisa A. Wheeler, James E. Loyd, Susan J. Majka, James West, Eric D. Austin
Journal: Circulation (2015)

Pulmonary arterial hypertension (PAH) is a proliferative disease of the pulmonary vasculature that preferentially affects women. Estrogens such as the metabolite 16α-hydroxyestrone (16αOHE) may contribute to PAH pathogenesis, and alterations in cellular energy metabolism associate with PAH. We hypothesized that 16αOHE promotes heritable PAH (HPAH) via microRNA-29 (miR-29) family upregulation and that antagonism of miR-29 would attenuate pulmonary hypertension in transgenic mouse models of Bmpr2 mutation.MicroRNA array profiling of human lung tissue found elevation of microRNAs associated with energy metabolism, including the miR-29 family, among HPAH patients. miR-29 expression was 2-fold higher in Bmpr2 mutant mice lungs at baseline compared with controls and 4 to 8-fold higher in Bmpr2 mice exposed to 16αOHE 1.25 μg/h for 4 weeks. Blot analyses of Bmpr2 mouse lung protein showed significant reductions in peroxisome proliferator-activated receptor-γ and CD36 in those mice exposed to 16αOHE and protein derived from HPAH lungs compared with controls. Bmpr2 mice treated with anti-miR-29 (20-mg/kg injections for 6 weeks) had improvements in hemodynamic profile, histology, and markers of dysregulated energy metabolism compared with controls. Pulmonary artery smooth muscle cells derived from Bmpr2 murine lungs demonstrated mitochondrial abnormalities, which improved with anti-miR-29 transfection in vitro; endothelial-like cells derived from HPAH patient induced pluripotent stem cell lines were similar and improved with anti-miR-29 treatment.16αOHE promotes the development of HPAH via upregulation of miR-29, which alters molecular and functional indexes of energy metabolism. Antagonism of miR-29 improves in vivo and in vitro features of HPAH and reveals a possible novel therapeutic target.
Self-adjuvanted hyaluronate – antigenic peptide conjugate for transdermal treatment of muscular dystrophy
Authors: Won Ho Kong, Dong Kyung Sung, Hyemin Kim, Jeong-A Yang, Nicholas Ieronimakis, Ki Su Kim, Jeehun Lee, Deok-Ho Kim, Seok Hyun Yun, Sei Kwang Hahn
Journal: Biomaterials (2015)
The effects of interleukin-1β in modulating osteoclast-conditioned medium’s influence on gelatinases in chondrocytes through mitogen-activated protein kinases
Authors: Jing Xie, Na Fu, Lin-Yi Cai, Tao Gong, Guo Li, Qiang Peng, Xiao-Xiao Cai
Journal: International Journal of Oral Science (2015)

Osteoarthritis is recognised to be an interactive pathological process involving the cartilage, subchondral bone and synovium. The signals from the synovium play an important role in cartilage metabolism, but little is known regarding the influence of the signalling from bone. Additionally, the collagenases and stromelysin-1 are involved in cartilage catabolism through mitogen-activated protein kinase (MAPK) signalling, but the role of the gelatinases has not been elucidated. Here, we studied the influence of osteoclastic signals on chondrocytes by characterising the expression of interleukin-1β (IL-1β)-induced gelatinases through MAPK signalling. We found that osteoclast-conditioned media attenuated the gelatinase activity in chondrocytes. However, IL-1β induced increased levels of gelatinase activity in the conditioned media group relative to the mono-cultured chondrocyte group. More specifically, IL-1β restored high levels of gelatinase activity in c-Jun N-terminal kinase inhibitor-pretreated chondrocytes in the conditioned media group and led to lower levels of gelatinase activity in extracellular signal-regulated kinase or p38 inhibitor-pretreated chondrocytes. Gene expression generally correlated with protein expression. Taken together, these results show for the first time that signals from osteoclasts can influence gelatinase activity in chondrocytes. Furthermore, these data show that IL-1β restores gelatinase activity through MAPK inhibitors; this information can help to increase the understanding of the gelatinase modulation in articular cartilage. Signaling molecules released by bone-resorbing cells (osteoclasts) can regulate the activity of the gelatinase enzyme in cartilage. Xiao-Xiao Cai and co-workers at Sichuan University in China explored the hypothesis that cartilage metabolism might be controlled by signals from bone cells. They found that the protein interleukin-1β (IL-1β) in the fluid around osteoclasts increased the activity of gelatinase in mouse cartilage cells in tissue culture. Changes in gelatinase activity have previously been implicated in diseases that involve disruption of cartilage metabolism, including osteoarthritis. The researchers also found that IL-1βs effect on gelatinase activity was mediated through pathways involving regulatory proteins known as mitogen-activated protein kinases. These insights will help in understanding the role of gelatinase in the maintenance of cartilage in both health and disease.
Abstract 13789: A New, Comprehensive, Hospital-Level Time-to-Treatment Metric for Primary Percutaneous Coronary Intervention: A Report From the AHA Mission: Lifeline Program
Authors: Matthew Roe, William French, Anne Hellkamp, Laine Thomas, Eric Bates, Steven Manoukian, Michael Kontos, Robert Suter, Timothy Henry, Harold Dauerman
Journal: Circulation (2014)

Background: Regional ST-elevation myocardial infarction (STEMI) networks have been established to improve timely access to primary percutaneous coronary intervention (PCI) in the United States, but the assessment of hospital-level performance in this setting is challenging due to the stratification of reperfusion timing metrics by initial mode of patient presentation. Methods: We developed a new hospital-level time-to-treatment metric for primary PCI at 588 PCI-capable hospitals (&gt;40 patients/yr) participating in the AHA Mission: Lifeline® program from 2007[[Unable to Display Character: &amp;#8211;]]2013. Patients were categorized as Group 1: Self or ambulance transport with no pre-hospital electrocardiogram (ECG), Group 2: Ambulance transport with ST-elevation on a pre-hospital ECG, and Group 3: Inter-hospital transfer with ST-elevation on an ECG at the referring hospital. Timing metrics for these populations were 1: Door-to-device time, 2: First medical contact-to-device time, 3: First door-to-device time, respectively. Patient times were converted to minutes ahead or behind of their group-specific mean, and overall hospital performance was measured by taking the mean time for all STEMI patients at a given site (using the new “centered time-to-device” metric with negative values behind the mean representing longer time intervals). Results: A total of 120,208 STEMI patients were evaluated across 588 hospitals with a median number of 85 (25 th , 75 th percentiles: 61, 128) patients/hospital/year. The median hospital-level proportion of patients in Groups 1, 2, and 3 were 46%, 33%, and 20%, respectively. Significant differences in time-to-treatment and “centered time-to-device” were seen from lowest to highest hospital tertiles (Table). Conclusions: A new, comprehensive hospital-level assessment of time-to-treatment for primary PCI that accounts for all STEMI patients treated at a given hospital, regardless of mode of presentation, reliably distinguished top-performing hospitals.
Cyclosporine before PCI in Patients with Acute Myocardial Infarction
Authors: Thien-Tri Cung, Olivier Morel, Guillaume Cayla, Gilles Rioufol, David Garcia-Dorado, Denis Angoulvant, Eric Bonnefoy-Cudraz, Patrice Guérin, Meier Elbaz, Nicolas Delarche, Pierre Coste, Gérald Vanzetto, Marc Metge, Jean-François Aupetit, Bernard Jouve, Pascal Motreff, Christophe Tron, Jean-Noel Labeque, Philippe Gabriel Steg, Yves Cottin, Grégoire Range, Jérome Clerc, Marc J. Claeys, Patrick Coussement, Fabrice Prunier, Frédéric Moulin, Olivier Roth, Loic Belle, Philippe Dubois, Paul Barragan, Martine Gilard, Christophe Piot, Patrice Colin, Fabien de Poli, Marie-Claude Morice, Omar Ider, Jean-Luc Dubois-Randé, Thierry Unterseeh, Hervé Le Breton, Thierry Béard, Didier Blanchard, Gilles Grollier, Vincent Malquarti, Patrick Staat, Arnaud Sudre, Eskil Elmer, Magnus J. Hansson, Cyrille Bergerot, Inesse Boussaha, Claire Jossan, Geneviève Derumeaux, Nathan Mewton, Michel Ovize
Journal: New England Journal of Medicine (2015)

Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling.In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume.A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups.In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).
Factors Affecting the Risk of Brain Metastases After Definitive Chemoradiation for Locally Advanced Non–Small-Cell Lung Carcinoma
Authors: Theodore J. Robnett, Mitchell Machtay, James P. Stevenson, Kenneth M. Algazy, Stephen M. Hahn
Journal: Journal of Clinical Oncology (2001)

As therapy for locally advanced non-small-cell lung carcinoma (NSCLC) improves, brain metastases (BM) may become a greater problem. We analyzed our chemoradiation experience for patients at highest risk for the brain as the first failure site.Records for 150 consecutive patients with stage II/III NSCLC treated definitively with chemoradiation from June 1992 to June 1998 at the University of Pennsylvania were reviewed. Most patients (89%) received cisplatin, paclitaxel, or both. All had negative brain imaging before treatment. Posttreatment brain imaging was performed for suspicious symptoms. Incidence of BM was examined as a function of age, sex, histology, stage, performance status, weight loss, tumor location, surgery, radiation dose, initial radiation field, chemotherapy regimen, and chemotherapy timing.Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (P <.04) versus stage II/IIIA. Histology alone was not significant (P <.12), although patients with IIIB nonsquamous tumors had an exceptionally high 2-year BM rate of 42% (P <.01 v all others). Examining treatment-related parameters, crude and 2-year actuarial risk of BM were 27% and 39%, respectively, in patients receiving chemotherapy before radiotherapy and 15% and 20%, respectively, when radiotherapy was not delayed (P <.05). On multivariate analysis, timing of chemotherapy (P <.01) and stage IIIA versus IIIB (P <.01) remained significant.Patients with later stage, nonsquamous NSCLC, particularly those receiving induction chemotherapy, have sufficiently common BM rates to justify future trials including prophylactic cranial irradiation.
PD-1 is a marker of activation on tumor infiltrating NK cells in head and neck cancer
Authors: Fernando Concha-Benavente, Raghvendra M Srivastava, Benjamin Kansy, Robert L Ferris
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Co-inhibitory immune checkpoint receptors have become important targets for cancer immunotherapy. Programmed death 1 (PD-1) has been well-characterized on T cells in many cancer types, including head and neck cancer (HNC), for its ability to mediate activation and eventually T
Characteristics and Survival of Malignant Cardiac Tumors
Authors: Guilherme H. Oliveira, Sadeer G. Al-Kindi, Christopher Hoimes, Soon J. Park
Journal: Circulation (2015)

The aim of this study was to investigate the incidence, histopathology, demographics, and survival associated with primary malignant cardiac tumors (PMCTs).We queried the Surveillance, Epidemiology and End Results (SEER) 18 registry from the National Cancer Institute for all PMCTs diagnosed from 1973 to 2011. We describe PMCT histopathology and incidence, comparing characteristics and survival of these patients with those of patients with extracardiac malignancies of similar histopathology. From a total of 7 384 580 cases of cancer registered in SEER, we identified 551 PMCTs (0.008%). The incidence of PMCT diagnosis is 34 cases per 100 million persons and has increased over time (25.1 in 1973-1989, 30.2 in 1990-1999, and 46.6 in 2000-2011). Most patients are female (54.1%) and white (78.6%) with median age at diagnosis of 50 years. The most common PMCTs are sarcomas (n=357, 64.8%), followed by lymphomas (n=150, 27%) and mesotheliomas (n=44, 8%). Most patients are diagnosed with tissue sample (96.8%). Although use of chemotherapy is not documented in SEER, 19% of patients received radiation and 44% had surgery. After a median follow-up of 80 months, 413 patients had died. The 1-, 3-, and 5-year survival rates were 46%, 22%, and 17% and have improved over the eras, with 1-, 3-, and 5-year survival rates of 32%, 17%, and 14% for 1973 to 1989 and 50%, 24%, and 19% for 2000 to 2011 (P=0.009). Cardiac sarcomas and mesotheliomas are the most lethal PMCTs, with 1-, 3-, 5-year survival rates of 47%, 16%, and 11% and of 51%, 26%, and 23% compared with 59%, 41%, and 34% for lymphomas, respectively (log rank test P<0.001). Patients with cardiac lymphomas and sarcomas are younger and have worse survival than patients with extracardiac disease of similar histopathology (P<0.001).PMCTs are extremely rare and continue to be associated with poor prognosis. Over the past 5 decades, the incidence and survival of patients diagnosed with PMCT appear to have increased. Compared with those with extracardiac cancers of similar histopathology, patients with PMCTs are often younger and have worse survival.
EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model
Authors: Tao Wang, Michael P. Gantier, Dongxi Xiang, Andrew G Bean, Matthew Bruce, Shu-Feng Zhou, Mustafa Khasraw, Alister Ward, Li Wang, Ming Q. Wei, Hadi AlShamaileh, Lijue Chen, Xiaodong She, Jia Lin, Lingxue Kong, Sarah Shigdar, Wei Duan
Journal: Theranostics (2015)

Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology.Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells.Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours.Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours.This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.