tbuckley/cabot-search huggingface dataset:
Gallstone prevention in prairie dogs: Comparison of chow vs. semisynthetic diets
Authors: Bertram I. Cohen, Erwin H. Mosbach, Charles K. McSherry, Richard J. Stenger, Syoji Kuroki, Beverly Rzigalinski
Journal: Hepatology (1986)

The effects of a standard rodent chow were compared with those of a semisynthetic diet of known composition (with and without added cholesterol) in the prairie dog model of cholesterol cholelithiasis. Gallstone incidence was 40% higher in animals fed a semisynthetic diet plus cholesterol compared to chow plus cholesterol. The semisynthetic diet plus cholesterol caused significant increases in tissue cholesterol levels (serum, liver and bile) and lithogenic index, but significant decreases in the activity of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and cholesterol 7α-hydroxylase compared to chow plus cholesterol. Histologic study of liver sections revealed that the semisynthetic diet plus cholesterol resulted in moderate to marked portal tract changes characterized by bile duct proliferation, inflammatory infiltration and fibrosis, whereas the cholesterol-supplemented chow diet caused only slight bile duct proliferation with minimal inflammation and fibrosis in the portal areas. Dietary hyodeoxycholic acid prevented cholesterol gallstones and biliary cholesterol crystals when added to either chow plus cholesterol or semisynthetic plus cholesterol diets. The hyodeoxycholic acid supplements also prevented the development of severe histopathologic alterations along the portal tracts. Biliary cholesterol levels were elevated in prairie dogs fed cholesterol plus hyodeoxycholic acid; these animals had liquid crystals in the bile, and hyodeoxycholic acid and its 6β-isomer became the major biliary bile acids. A semisynthetic diet plus cholesterol is superior to a high cholesterol chow diet for gallstone formation and prevention studies, but in prolonged feeding experiments, the potential hepatotoxicity of this diet in the prairie dog must be appreciated.
Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions
Authors: Yu-Yu Lin, Yung-Ho Hsu, Hsin-Yi Huang, Yih-Jyh Shann, Chi-Ying F. Huang, Shu-Chen Wei, Chi-Ling Chen, Tzuu-Shuh Jou
Journal: Journal of Clinical Investigation (2012)

Dysregulation of canonical Wnt signaling is thought to play a role in colon carcinogenesis. β-Catenin, a key mediator of the pathway, is stabilized upon Wnt activation and accumulates in the nucleus, where it can interact with the transcription factor T cell factor (TCF) to transactivate gene expression. Normal colonic epithelia express a truncated TCF-1 form, called dnTCF-1, that lacks the critical β-catenin-binding domain and behaves as a transcriptional suppressor. How the cell maintains a balance between the two forms of TCF-1 is unclear. Here, we show that ERM-binding phosphoprotein 50 (EBP50) modulates the interaction between β-catenin and TCF-1. We observed EBP50 localization to the nucleus of human colorectal carcinoma cell lines at low cell culture densities and human primary colorectal tumors that manifested a poor clinical outcome. In contrast, EBP50 was primarily membranous in confluent cell lines. Aberrantly located EBP50 stabilized conventional β-catenin/TCF-1 complexes and connected β-catenin to dnTCF-1 to form a ternary molecular complex that enhanced Wnt/β-catenin signaling events, including the transcription of downstream oncogenes such as c-Myc and cyclin D1. Genome-wide analysis of the EBP50 occupancy pattern revealed consensus binding motifs bearing similarity to Wnt-responsive element. Conventional chromatin immunoprecipitation assays confirmed that EBP50 bound to genomic regions highly enriched with TCF/LEF binding motifs. Knockdown of EBP50 in human colorectal carcinoma cell lines compromised cell cycle progression, anchorage-independent growth, and tumorigenesis in nude mice. We therefore suggest that nuclear EBP50 facilitates colon tumorigenesis by modulating the interaction between β-catenin and TCF-1.
Inhibition of Adrenergic Activity at a Locus Peripheral to the Brain and Spinal Cord
Authors: LLOYD BECK, DONALD W. DUCHARME, GERARD L. GEBBER, JEROME A. LEVIN, ALBERT A. POLLARD
Journal: Circulation Research (1966)

This report confirms that adrenergic discharge can be neurogenically inhibited at a site outside of the central nervous system. Centers controlling peripheral inhibition are located in both the spinal cord and the brain. The inhibition is of the competitive-equilibrium type and can be surmounted by increasing the frequency of lumbar sympathetic stimulation. Inhibition of adrenergic discharge at an extraspinal locus occurs in the dog and in two species of monkey. Confirming evidence for central inhibition of vasomotor activity was also obtained in the cat and dog. Reflex dilatation can still be obtained after brain transections which abolish all neurogenic tone, confirming that reflex dilatation is in part active, and further showing that the centers that control active reflex dilatation and neurogenic tone can be differentiated by selected lesioning. The pathways in the spinal cord that mediate active reflex dilatation, adrenergic discharge, and inhibition of adrenergic discharge were explored. Sensitization (loss of accommodation) of pressoreceptors in the carotid sinus of the dog vvas noted within two hours of maintained hypotension. Reaccommodation of pressoreceptors occurred rapidly when the blood pressure was returned to normal. Marked sensitization of the vasomotor center to inhibitory input occurred in the same time period. Deaccommodation to inhibitory input also took place rapidly.
Endobronchial secretion of interleukin-13 following local allergen challenge in atopic asthma: relationship to interleukin-4 and eosinophil counts
Authors: C Kroegel, P Julius, H Matthys, None Virchow JC, W Luttmann
Journal: European Respiratory Journal (1996)

We investigated the secretion of interleukin (IL)-13 into the airways in 10 mild allergic asthmatics by employing local allergen challenge, and compared the data both to IL-4 levels and eosinophil numbers obtained by bronchoalveolar lavage (BAL). Appropriate allergen or saline were endoscopically instilled into different airway segments, which were lavaged 10 min and 18 h after allergen or sham challenge. IL-4 and IL-13 were measured in unconcentrated BAL fluid using a double sandwich enzymes-linked immunosorbent assay (ELISA). Endobronchial allergen challenge induced a highly significant increase in the numbers of eosinophils after 18 h in the allergen exposed segment. Ten minutes following allergen exposure, low levels of IL-4 and IL-13 could be detected, whilst concentrations of both cytokines were significantly raised 18 h following local allergen exposure. In contrast to IL-4, the concentration of IL-13 strongly correlated with the eosinophil numbers found 18 h post-allergen challenge. The results suggest that interleukin-13 is actively secreted during the late asthmatic response in mild asthmatic subjects. In view of its action on eosinophils and other cell types, we conclude that interleukin-13, in addition to interleukin-4, may play an important role in the pathogenesis of eosinophil-related inflammation, such as bronchial asthma.
Immunoliposome Targeting to Mesangial Cells
Authors: Gérald Tuffin, Ernst Waelti, Jo[Combining Diaeresis]rg Huwyler, Caroline Hammer, Hans-Peter Marti
Journal: Journal of the American Society of Nephrology (2005)

<h3>Abstract</h3> The central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer’s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for &gt;90% of the brain, is the first site of pathological tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses dysfunction in early AD prior to cognitive impairment. In the TgF344-AD rat model, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6-9 month old wild type and TgF344-AD rats, we discovered that loss of LC-NA axons co-insides with heightened β-AR function at medial perforant path-dentate granule cell synapses (MPP-DCG) that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory. <h3>Significance Statement</h3> The locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer’s disease pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.
The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition
Authors: Nicole Cloonan, Mellissa K Brown, Anita L Steptoe, Shivangi Wani, Wei Ling Chan, Alistair RR Forrest, Gabriel Kolle, Brian Gabrielli, Sean M Grimmond
Journal: Genome biology (2008)

Abstract Background MicroRNAs are modifiers of gene expression, acting to reduce translation through either translational repression or mRNA cleavage. Recently, it has been shown that some microRNAs can act to promote or suppress cell transformation, with miR-17-92 described as the first oncogenic microRNA. The association of miR-17-92 encoded microRNAs with a surprisingly broad range of cancers not only underlines the clinical significance of this locus, but also suggests that miR-17-92 may regulate fundamental biological processes, and for these reasons miR-17-92 has been considered as a therapeutic target. Results In this study, we show that miR-17-92 is a cell cycle regulated locus, and ectopic expression of a single microRNA (miR-17-5p) is sufficient to drive a proliferative signal in HEK293T cells. For the first time, we reveal the mechanism behind this response - miR-17-5p acts specifically at the G1/S-phase cell cycle boundary, by targeting more than 20 genes involved in the transition between these phases. While both pro- and anti-proliferative genes are targeted by miR-17-5p, pro-proliferative mRNAs are specifically up-regulated by secondary and/or tertiary effects in HEK293T cells. Conclusion The miR-17-5p microRNA is able to act as both an oncogene and a tumor suppressor in different cellular contexts; our model of competing positive and negative signals can explain both of these activities. The coordinated suppression of proliferation-inhibitors allows miR-17-5p to efficiently de-couple negative regulators of the MAPK (mitogen activated protein kinase) signaling cascade, promoting growth in HEK293T cells. Additionally, we have demonstrated the utility of a systems biology approach as a unique and rapid approach to uncover microRNA function.
Agranulocytosis from Carbimazole
Authors: A. B. Shaw
Journal: BMJ (1955)

MEDICALJOURNAL246~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~FDA JULY23,N Six weeks later, however, she was readmitted with a small hard swelling on the left cheek and oedema of both eyelids.She was again treated with oral phenylindanedione, 30 mg. daily for six days, followed by 20 mg.daily for six days, and chlortetracycline 250 mg.daily in divided doses, which was continued for three weeks.Progress to recovery was uneventful.Radiological evidence of sequestrum formation could not be demonstrated at any time.The patient was followed up for six months after her final discharge, during which time she remained well.COMMENT
Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies
Authors: Christopher W. Ryan, Nicholas J. Vogelzang, Everett E. Vokes, Hedy L. Kindler, Samir D. Undevia, Rod Humerickhouse, Amy K. André, Qiang Wang, Robert A. Carr, Mark J. Ratain
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ETA. Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies. Experimental Design: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28. Results: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant. Conclusions: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.
Lymphotoxin Is Required for Maintaining Physiological Levels of Serum IgE That Minimizes Th1-mediated Airway Inflammation
Authors: Hyung-Sik Kang, Sarah E. Blink, Robert K. Chin, Youjin Lee, Oliver Kim, Joel Weinstock, Thomas Waldschmidt, Daniel Conrad, Bohao Chen, Julian Solway, Anne I. Sperling, Yang-Xin Fu
Journal: The Journal of Experimental Medicine (2003)

Although elevated levels of IgE in asthmatic patients are strongly associated with lung infiltration by activated T helper (Th) 2 cells, the physiological role of immunoglobulin E (IgE) in the airway remains largely undefined. Lymphotoxin-deficient α (LTα−/−) mice exhibit increased airway inflammation, paradoxically accompanied by diminished levels of IgE and reduced airway hyperresponsiveness in response to both environmental and induced antigen challenge. The severe lung inflammation in LTα−/− mice is Th1 in nature and can be alleviated by IgE reconstitution. Conversely, depletion of IgE in wild-type mice recapitulates the lung pathologies of LTα−/− mice. Therefore, this work has revealed that lymphotoxin is essential for IgE production, and a physiological role of IgE in the airway may consist of maintaining the balance of Th1 and Th2 responses to prevent aberrant inflammation.
Combination of Viral Oncolysis and Tumor-Specific Immunity to Control Established Tumors
Authors: Chi-Mu Chuang, Archana Monie, Annie Wu, Sara I. Pai, Chien-Fu Hung
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Advanced-stage cancers are extremely difficult to treat and rarely result in a cure. The application of oncolytic viruses is a potential strategy for controlling advanced-stage cancer because intratumoral (i.t.) injection of an oncolytic virus, such as vaccinia virus, results in tumor cell lysis and subsequent release of tumor antigens into the microenvironment. Furthermore, the viruses can serve as a vehicle for delivering genes of interest to cancer cells. Experimental Design: In the current study, we hypothesize that in tumor-bearing mice primed with DNA encoding an immunogenic foreign antigen, ovalbumin (OVA) followed by a boost with i.t. administration of vaccinia virus encoding the same foreign antigen, OVA, can generate enhanced antitumor effects through the combination of viral oncolysis and tumor-specific immunity. Results: We observed that tumor-bearing mice primed with OVA DNA and boosted with vaccinia encoding OVA (Vac-OVA) generated significant therapeutic antitumor effects as well as induced significant levels of OVA-specific CD8+ T cells in two different tumor models. Furthermore, treatment with Vac-OVA not only kills the tumor and stromal cells directly but also renders the tumor cells and surrounding stromal cells susceptible to OVA-specific CD8+ T-cell killing, resulting in enhanced antitumor therapeutic effects. Conclusions: Thus, the current study may provide a novel therapeutic strategy for the control of advanced-stage cancers.
Hypoxic mesenchymal stem cells engraft and ameliorate limb ischaemia in allogeneic recipients
Authors: Wei-Hua Huang, Hen-Li Chen, Po-Hsun Huang, Tu-Lai Yew, Ming-Wei Lin, Shing-Jong Lin, Shih-Chieh Hung
Journal: Cardiovascular Research (2013)

AimsLocal injection of stem cells or endothelial progenitors directly into the ischaemic tissue remains an option for the management of arterial occlusion. Bone marrow-derived mesenchymal stem cells (MSCs) represent a promising alternative autologous cell source for ischaemic limb cell therapy. However, methods for applying MSCs in allogeneic transplantation remain to be developed. The purpose of this study was to evaluate the therapeutic potential of MSCs cultured under a different environment in ameliorating limb ischaemia in allogeneic recipients.
Immunopharmacologic Analysis of an Autologous, Hapten-Modified Human Melanoma Vaccine
Authors: David Berd, Takami Sato, Henry C. Maguire, John Kairys, Michael J. Mastrangelo
Journal: Journal of Clinical Oncology (2003)

We have previously reported a clinical trial of a human cancer vaccine consisting of autologous tumor cells modified with the hapten, dinitrophenyl (DNP), in patients with clinical stage III melanoma. Here we present a follow-up report expanded to 214 patients with 5-year follow-up.Two hundred fourteen patients with clinical stage III melanoma (117 patients with stage IIIC and 97 patients with stage IIIB) who were melanoma-free after standard lymphadenectomy were treated with multiple intradermal injections of autologous, DNP-modified vaccine mixed with bacille Calmette-Guérin. Four vaccine dosage schedules were tested sequentially, all of which included low-dose cyclophosphamide. Patients were tested for delayed-type hypersensitivity (DTH) to autologous melanoma cells, both DNP-modified and unmodified, and to control materials.The 5-year overall survival (OS) rate of the 214 patients was 44%. DTH responses to unmodified autologous melanoma were induced in 47% of patients. The OS of this DTH-positive group was double that of DTH-negative patients (59.3% v 29.3%; P <.001). In contrast, positive DTH responses to DNP-modified autologous melanoma cells and to purified protein derivative developed in almost all patients but did not affect OS. Surprisingly, the OS after relapse was also significantly longer in patients who developed positive DTH to unmodified tumor cells (25.2% v 12.3%; P <.001). Finally, the development of DTH was dependent on the schedule of administration of the vaccine, specifically, the timing of an induction dose administered at the beginning of the treatment program.This study underscores the importance of the immunopharmacology of the autologous, DNP-modified vaccine and may be relevant to other cancer vaccine technologies.
Eight-and-a-Half Syndrome
Authors: Jone Bocos-Portillo, Javier Ruiz Ojeda, Marian Gomez-Beldarrain, Raquel Vazquez-Picon, Juan Carlos Garcia-Monco
Journal: JAMA Neurology (2015)

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