tbuckley/cabot-search huggingface dataset:
Recording from human gut tissue: a major step towards more efficient drug development?
Authors: M. Schemann
Journal: Gut (2011)

Translational research is a rewarding challenge and of major relevance for the field of gastroenterology, in particular neurogastroenterology, in our endeavour to improve treatment of patients suffering from functional, inflammatory or structural gut disorders. Although in vivo and in vitro animal models have provided insights into potential mechanisms of gut disorders and identified putative drugs targets, these often failed to translate into successful treatments in humans. There are many reasons for this failure such as limited bioavailability, low efficacy of drugs or safety issues. While these obstacles are intrinsic to every drug development programme it is species specific action of endogenous mediators or expression of signalling cascades that restrict translation of data from animal models to human conditions. This, however, is an issue that can be tackled by developing new techniques or adapting existing methods from animal studies to investigate receptor expression, pharmacology of signalling molecules and intracellular pathways involved in drug actions on behaviour of human gut tissue.

Measurements of gastrointestinal functions, in particular motility and transit, are routinely performed in healthy volunteers and patients.1 2 While such studies provide important information on the nature of motor disorders or the efficacy of a drug to alter gastrointestinal transit they are not suitable to characterise the modes of action of drugs or to identify novel targets to treat a particular pathology. This requires experiments in isolated gut tissue which derives from bowel resections or biopsies obtained during endoscopy.

Recordings from human isolated gut tissues have provided information on the effects of drugs on secretion,3 motility4 or enteric nerve activity,5 to mention only a few examples. Beyond revealing novel insights these types of studies also reveal human tissue specific action of mediators. One striking example is the ability of 5-HT3 receptor antagonists to modulate peristaltic reflex …
Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis.
Authors: L A Fitzpatrick, A Severson, W D Edwards, R T Ingram
Journal: Journal of Clinical Investigation (1994)

Coronary atherosclerosis is frequently associated with calcification of arterial plaque. To understand the mechanisms responsible for the formation of atherosclerotic calcification, we examined human coronary arteries for the presence and extent of mineral. In sections stained specifically for mineral, staining was diffuse and present in all atherosclerotic plaques. Hydroxyapatite was not detected in normal coronary artery sections. Distribution of hydroxyapatite coincided with a similar distribution of calcium detected by a radiodense pattern using contact microradiography of the same sections before cytochemical staining. By energy-dispersive x-ray microanalysis, the chemical composition of calcified sites was identical to hydroxyapatite (Ca10[PO4]6[OH]2), the major inorganic component of bone. Osteopontin is a phosphorylated glycoprotein with known involvement in the formation and calcification of bone and is regulated by local cytokines. Human coronary artery segments (14 normal and 34 atherosclerotic) obtained at autopsy were evaluated immunohistochemically using polyclonal antibodies generated against human osteopontin. Immunohistochemistry for osteopontin indicated intense, highly specific staining in the outer margins of all diseased segments at each calcification front; staining was evident throughout the entire plaque. Conversely, arterial segments free of atheroma and calcification and sections treated with nonimmune serum had no evidence of positive staining. Osteopontin, a protein involved in mineralization is specifically associated with calcific coronary atheroma and may play an important role in the onset and progression of this disease in human coronary arteries. The deposition of noncollagenous proteins such as osteopontin may regulate the presence or absence of calcification and ultimately alter vessel compliance.
The efficacy of aerosol treatment with non-ionic surfactant vesicles containing amphotericin B in rodent models of leishmaniasis and pulmonary aspergillosis infection
Authors: M. Alsaadi, J.L. Italia, A.B. Mullen, M.N.V. Ravi Kumar, A.A. Candlish, R.A.M. Williams, C.D. Shaw, F. Al Gawhari, G.H. Coombs, M. Wiese, A.H. Thomson, M. Puig-Sellart, J. Wallace, A. Sharp, L. Wheeler, P. Warn, K.C. Carter
Journal: Journal of Controlled Release (2012)
15-Epi-lipoxin A<sub>4</sub>Inhibits Myeloperoxidase Signaling and Enhances Resolution of Acute Lung Injury
Authors: Driss El Kebir, Levente József, Wanling Pan, Lili Wang, Nicos A. Petasis, Charles N. Serhan, János G. Filep
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Apoptosis is essential for removal of neutrophils from inflamed tissues and efficient resolution of inflammation. Myeloperoxidase (MPO), abundantly expressed in neutrophils, not only generates cytotoxic oxidants but also signals through the beta(2) integrin Mac-1 to rescue neutrophils from constitutive apoptosis, thereby prolonging inflammation.Because aspirin-triggered 15-epi-lipoxin A(4) (15-epi-LXA(4)) modulates Mac-1 expression, we investigated the impact of 15-epi-LXA(4) on MPO suppression of neutrophil apoptosis and MPO-mediated neutrophil-dependent acute lung injury.Human neutrophils were cultured with MPO with or without 15-epi-LXA(4) to investigate development of apoptosis. Acute lung injury was produced by intratracheal injection of carrageenan plus MPO or intraperitoneal injection of live Escherichia coli in mice, and the animals were treated with 15-epi-LXA(4) at the peak of inflammation.15-Epi-LXA(4) through down-regulation of Mac-1 expression promoted apoptosis of human neutrophils by attenuating MPO-induced activation of extracellular signal-regulated kinase and Akt-mediated phosphorylation of Bad and by reducing expression of the antiapoptotic protein Mcl-1, thereby aggravating mitochondrial dysfunction. The proapoptotic effect of 15-epi-LXA(4) was dominant over MPO-mediated effects even when it was added at 4 hours post MPO. In mice, treatment with 15-epi-LXA(4) accelerated the resolution of established carrageenan plus MPO-evoked as well as E. coli-induced neutrophil-dependent pulmonary inflammation through redirecting neutrophils to caspase-mediated cell death and facilitating their removal by macrophages.These results demonstrate that aspirin-triggered 15-epi-LXA(4) enhances resolution of inflammation by overriding the powerful antiapoptosis signal from MPO, thereby demonstrating a hitherto unrecognized mechanism by which aspirin promotes resolution of inflammation.
Overexpression of the KIT/SCF in Uveal Melanoma Does Not Translate into Clinical Efficacy of Imatinib Mesylate
Authors: Uta B. Hofmann, Claudia S. Kauczok-Vetter, Roland Houben, Jürgen C. Becker
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Recently, gene amplification and overexpression of KIT as well as activating mutations in the KIT gene have been described to occur in certain subsets of melanoma. These findings suggest KIT as a potential target for therapy with imatinib mesylate in these melanomas. To date, data on the KIT status in uveal melanoma (UM) is limited. Experimental Design: We analyzed the expression of the KIT protein (CD117, c-kit) and its ligand, stem cell factor (SCF), in primary and metastatic UM. Results: By immunohistochemistry, SCF-positive tumor cells (&amp;gt;90%) were detectable in 43% of primary UM and in 58% of UM metastases. Strong expression of KIT (&amp;gt;90%) in tumor cells was present in 55% of primary UM and in 76% of UM metastases. This overexpression of both KIT and SCF suggests the clinical application of imatinib mesylate in metastatic UM. This notion was tested in a clinical study using Simon's two-stage design. Patients received imatinib (600 mg p.o. daily) until progress or unacceptable toxicities. The trial did not enter stage II as no objective response was observed in the first group. This observation prompted further molecular analysis, which revealed no mutations in the genomic sequence of KIT in exons 11, 13, 17, and 18. Moreover, the mitogen-activated protein kinase pathway was not activated in any of the tumors as measured by ERK phosphorylation. Conclusions: These results show the lack of clinical effectiveness of imatinib in UM, which was originally anticipated based on the high levels of KIT and SCF expression.
Weight gain within the normal weight range predicts ultrasonographically detected fatty liver in healthy Korean men
Authors: Y Chang, S Ryu, E Sung, H-Y Woo, S-I Cho, S-H Yoo, H-Y Ahn, N-K Choi
Journal: Gut (2009)

We performed a prospective study to determine whether weight gain predicts future ultrasonographically detected fatty liver (USFL) in a lean adult population.Among 15,347 Korean male workers, aged 30-59 years, who participated in a health check-up programme in 2002, a USFL-free cohort of 4246 non-diabetic men was followed until September 2007. Alcohol consumption was assessed by a questionnaire. Weight change for each subject was calculated as the difference between baseline and subsequent measurements. Biochemical tests for liver and metabolic function were done. The primary outcome was ultrasound-diagnosed fatty liver. A standard Cox proportional hazards model and time-dependent Cox model were performed.During 16,829.7 person-years of follow-up, 622 participants developed USFL. After adjusting for age, the period from visit 1 to visit 2, BMI, HDL-C, triglyceride, uric acid, alanine aminotransferase, and HOMA-IR, the risk for USFL increased with increasing quartiles of weight change (p for trend <0.001). This association remained significant when weight change and covariates, except age and the period from visit 1 to visit 2, were modelled as time-dependent variables. Subjects in the fourth quartile (weight gain > or =2.3 kg) were at significantly elevated risk for USFL (adjusted hazard ratio (aHR), 1.26; 95% CI, 1.01 to 1.58). These associations did not change, even in normal weight men with a baseline BMI between 18.5 and 22.9 kg/m(2) (n = 2186).Weight gain per se appears to increase the risk for developing USFL. Thus, avoiding weight gain, even among lean adult individuals, can be helpful in preventing this disease.
Molecular Pathways: IDH2 Mutations—Co-opting Cellular Metabolism for Malignant Transformation
Authors: Eytan M. Stein
Journal: Clinical Cancer Research (2015)

Abstract Mutations in mitochondrial IDH2, one of the three isoforms of IDH, were discovered in patients with gliomas in 2009 and subsequently described in acute myelogenous leukemia (AML), angioimmunoblastic T-cell lymphoma, chondrosarcoma, and intrahepatic chloangiocarcinoma. The effects of mutations in IDH2 on cellular metabolism, the epigenetic state of mutated cells, and cellular differentiation have been elucidated in vitro and in vivo. Mutations in IDH2 lead to an enzymatic gain of function that catalyzes the conversion of alpha-ketoglutarate to beta-hydroxyglutarate (2-HG). Supranormal levels of 2-HG lead to hypermethylation of epigenetic targets and a subsequent block in cellular differentiation. AG-221, a small-molecule inhibitor of mutant IDH2, is being explored in a phase I clinical trial for the treatment of AML, other myeloid malignancies, solid tumors, and gliomas. Clin Cancer Res; 22(1); 16–19. ©2015 AACR.
Functional Screens Take On the Cancer Genome
Authors: R. S. Tuma
Journal: JNCI Journal of the National Cancer Institute (2012)

BRAF inhibitors are effective, by and large, only in melanoma.(One trial showed that just 5% of colorectal cancer patients with BRAF-mutant tumors responded to the BRAF inhibitor vemurafenib, compared with 80% or higher response rates in melanoma patients.)In other words, just knowing that a tumor carries a BRAF mutation is not the same as understanding how the mutation drives tumor growthor how it evades the therapeutic blockade.To understand what allows BRAFmutant colorectal cancer cells to resist BRAF inhibitors, Bernards ' team performed a loss-of-function screen in which they used short-hairpin RNAs (shRNAs) to turn off each kinase gene in BRAFmutant colon cancer cells.The team found that shRNAs against the epidermal growth factor receptor (EGFR) fl ipped resistant cells into sensitive ones, blocking growth in the presence of drug but having no effect without it.The team later found that the BRAF-mutant cells activate the EGFR pathway in response to vemurafenib and use the signaling pathway to resist the drug."That to me was very surprising, because we have learned that if you have a BRAF or KRAS mutation in colon cancer, you will not respond to EGFR inhibition by cetuximab," Bernards said."Those patients are actually selected for no cetuximab treatment.But this experiment suggested that if you give these patients a BRAF inhibitor and coinhibit EGFR, you would suddenly see cell death.And that indeed appears to be the case."
A MicroRNA Circuitry Links Macrophage Polarization to Metabolic Homeostasis
Authors: Zhuo-Xian Meng, Guo-Xiao Wang, Jiandie D. Lin
Journal: Circulation (2012)

an important role in tissue repair and remodeling and innate immune response.Tissue macrophages are highly heterogeneous and can undergo 2 distinct programs of functional specification termed classical (M1) and alternative (M2) activation. 1,2In response to signals elicited by bacterial infections, such as lipopolysaccharide (LPS) and interferon-␥, macrophages adopt a proinflammatory phenotype and contribute to defense against invading pathogens through phagocytosis, bactericidal activity, and the secretion of proinflammatory cytokines and chemokines.In contrast, interleukin-4 (IL-4) and IL-13 promote alternative activation of macrophages that favors tissue remodeling and repair, parasite elimination, and tumor progression.At the molecular level, M1 and M2 macrophages express unique cell surface markers and secrete distinct sets of effector molecules.Classically activated macrophages secrete proinflammatory cytokines, such as tumor necrosis factor ␣, IL-1␤, and IL-6, and produce reactive oxygen species and nitric oxide, whereas alternatively activated macrophages preferentially synthesize anti-inflammatory cytokines such as IL-10 and have subdued proinflammatory cytokine gene expression.A balance between classical and alternative macrophage activation serves to maintain tissue homeostasis and host defense.
Genetic studies in NZB mice. I. Spontaneous autoantibody production.
Authors: E S Raveché, A D Steinberg, L W Klassen, J H Tjio
Journal: The Journal of Experimental Medicine (1978)

The appearance of naturally occurring thymocytotoxic autoantibodies (NTA) and spontaneously produced antibodies to single-stranded DNA (ssDNA) was studied in NZB, and DBA/2 mice and their F1 and backcross progeny. NTA production was markedly decreased in males; however, castrated males produced quantities of NTA similar to those of females. Because the amount of NTA was influenced by sex hormones, it was necessary to gonadectomize all progeny to determine the mode of inheritance. Such studies suggested that NTA production was determined by a single locus with a gene dosage (codominant) mode of expression. The spontaneous production of antibodies to ssDNA appeared to be inherited as a single dominant genetic trait. The quantity of anti-ssDNA was also found to be under additional regulation; either a gene dosage effect or more likely a regulatory gene. The genes controlling the presence and quantity of ssDNA antibodies were not linked to the gene controlling the appearance of NTA.
The influence of early environmental exposures on immune development and subsequent risk of allergic disease
Authors: S. L. Prescott
Journal: Allergy (2011)

Environmental exposures in pregnancy and the early postnatal period affect early immune development. Early immune function and future allergy susceptibility appear to result from a combination of maternal phenotype, infant genotype, and environmental exposures in utero that affect early gene expression. Furthermore, epigenetic changes in gene expression in one generation can also be inherited across subsequent generations, potentially amplifying heritable allergy risk.
Echocardiographic assessment of left-to-right shunt volume in children with ventricular septal defect.
Authors: A B Lewis, M Takahashi
Journal: Circulation (1976)

Echocardiograms were performed in 20 infants and children with isolated ventricular septal defects (VSD) undergoing cardiac catheterization. The magnitude of the left-to-right shunt was expressed as the pulmonary-to-systemic flow ratio (Qp/Os) and was compared to a ratio of the echographic left atrial (LA) diameter to the aortic root (Ao) diameter (LA/Ao). The Qp/Qs was also compared to LA/m2. Thirty-three normal children served as controls. The LA/m2 and Ao/m2 were significantly larger in normal infants under one year of age than in children above one year. The LA/Ao, however, was not influenced by age or size. A strong linear relationship was found between Qp/Qs and the LA/Ao (r = 0.96). The LA/Ao measurement appears to be helpful in the noninvasive assessment of the left-to-right shunt in patients with VSD.
Need to prioritise: end-of-life decision-making in India
Authors: A. Singh
Journal: European Respiratory Journal (2007)

To the Editors: 

I read with interest the recent article “End-of-life decision-making in respiratory intermediate care units: a European survey” by Nava et al. 1, wherein the authors have beautifully covered the epidemiology, practice, behaviours and attitudes towards end-of-life decision-making in respiratory units in Europe. However, there are certain points regarding end-of-life decision-making in developing countries like India that merit attention.

First, Indian data on withdrawal of or withholding intensive care in terminally ill patients is sparse. Only two studies 2, …
Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: a micro CT study
Authors: Stephanie Finzel, Juergen Rech, Sarah Schmidt, Klaus Engelke, Matthias Englbrecht, Georg Schett
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Introduction</h3> Interleukin-6 receptor (IL-6R) blockade improves the signs and symptoms of rheumatoid arthritis (RA) and retards bone damage. Whether IL-6R blockade allows repair of existing bone erosions is so far unclear. <h3>Methods</h3> This study examined bone erosions in the metacarpophalangeal joints of 20 patients receiving treatment with the IL-6R blocker tocilizumab using micro CT (µCT). The maximal width and depth of individual bone erosions was measured at baseline and after 1 year of treatment. <h3>Results</h3> 133 bone erosions were identified at baseline with a mean (±SD) size of 2.23±1.26 mm and depth of 2.16±1.50 mm. Distribution analysis showed predominant involvement of the second compared with the third and fourth metacarpophalangeal joints, the metacarpal heads compared with the phalangeal bases and the radial quadrants compared with all other surfaces. Repair of bone erosions during tocilizumab treatment was confined to those lesions showing sclerosis at baseline and/or at follow-up and those with a width larger than 1.6 mm. The mean decrease in width of sclerosed erosions was thus 0.14±0.05 mm (p=0.0086) and 0.20±0.08 mm (p=0.019) for sclerosing lesions after 1 year of treatment. <h3>Conclusions</h3> Blockade of IL-6R by tocilizumab can induce limited repair in a subset of erosions, particularly in large lesions with sclerosis. Repair of erosions during tocilizumab treatment reflects the favourable impact of IL-6R blockade on local bone remodelling in patients with RA.
WU-CRISPR: characteristics of functional guide RNAs for the CRISPR/Cas9 system
Authors: Nathan Wong, Weijun Liu, Xiaowei Wang
Journal: Genome biology (2015)

The CRISPR/Cas9 system has been rapidly adopted for genome editing. However, one major issue with this system is the lack of robust bioinformatics tools for design of single guide RNA (sgRNA), which determines the efficacy and specificity of genome editing. To address this pressing need, we analyze CRISPR RNA-seq data and identify many novel features that are characteristic of highly potent sgRNAs. These features are used to develop a bioinformatics tool for genome-wide design of sgRNAs with improved efficiency. These sgRNAs as well as the design tool are freely accessible via a web server, WU-CRISPR ( http://crispr.wustl.edu ).
Distinct Biological Roles for the Akt Family in Mammary Tumor Progression
Authors: Rachelle L. Dillon, William J. Muller
Journal: Cancer Research (2010)

The phosphatidylinositol 3' kinase/Akt pathway is frequently dysregulated in cancer, which can have unfavorable consequences in terms of cell proliferation, survival, metabolism, and migration. Increasing evidence suggests that Akt1, Akt2, and Akt3 play unique roles in breast cancer initiation and progression. We have recently shown that in contrast to Akt1, which accelerates mammary tumor induction in transgenic mice, Akt2 promotes metastasis of tumor cells without affecting the latency of tumor development. Despite the distinct phenotypic outputs resulting from Akt1 or Akt2 activation, very little is known about the mode by which such unique functions originate from these highly related kinases. Here we discuss potential mechanisms contributing to the differing functional specificity of Akt1 and Akt2 with respect to migration, invasion, and metastasis.
Finger-in-glove sign in bronchial atresia
Authors: Y. Nussbaumer-Ochsner, M. Kohler
Journal: Thorax (2010)

Finger-in-glove sign in bronchial atresiaA 31-year-old, HIV-positive man presented with a history of chronic dry cough.Chest x-ray showed a rounded, branching opacity in the left upper lung (finger-in-glove sign,figure 1A).CT showed mucoid impaction, segmental hyperlucency and decreased vascularity of the left upper lobe (figure 1B).3D reconstruction of the bronchial tree revealed an atretic apicoposterior segmental bronchus of the left upper lobe confirming the diagnosis of congenital bronchial atresia (figure 1C).Congenital bronchial atresia is a rare, mostly incidental radiographic finding, and consists of atresia of a lobar, segmental or subsegmental bronchus at or near its origin 1 2 .The apicoposterior segmental bronchus of the left upper lobe is most commonly affected.Distal to the bronchial atresia secretions accumulate, leading to mucoid impaction surrounded by segmental hyperlucency caused by a combination of trapped air and oligaemia.The differential diagnosis of the finger-in-glove sign includes mucus impaction due to cystic fibrosis, allergic bronchopulmonary aspergillosis, broncholithiasis, foreign body aspiration and malignancies.
Towards Universal Voluntary HIV Testing and Counselling: A Systematic Review and Meta-Analysis of Community-Based Approaches
Authors: Amitabh B. Suthar, Nathan Ford, Pamela J. Bachanas, Vincent J. Wong, Jay S. Rajan, Alex K. Saltzman, Olawale Ajose, Ade O. Fakoya, Reuben M. Granich, Eyerusalem K. Negussie, Rachel C. Baggaley
Journal: PLoS Medicine (2013)

In a systematic review and meta-analysis, Amitabh Suthar and colleagues describe the evidence base for different HIV testing and counseling services provided outside of health facilities. Please see later in the article for the Editors' Summary