tbuckley/cabot-search huggingface dataset:
Impaired interaction between the slide helix and the C-terminus of Kir2.1: A novel mechanism of Andersen syndrome
Authors: N DECHER, V RENIGUNTA, M ZUZARTE, M SOOM, S HEINEMANN, K TIMOTHY, M KEATING, J DAUT, M SANGUINETTI, I SPLAWSKI
Journal: Cardiovascular Research (2007)

Andersen syndrome (AS) is a rare genetic disease caused by mutations of the potassium channel Kir2.1 (KCNJ2). We identified two unrelated patients with mutations in the slide helix of Kir2.1 leading to AS. The functional consequences of these two mutations, Y68D and D78Y, were studied and compared with previously reported slide helix mutations.Channel function and surface expression were studied by voltage clamp recordings and a chemiluminescence assay in Xenopus laevis oocytes and by patch clamp recordings and fluorescence microscopy in HEK293 cells. In addition, a phosphatidylinositol bisphosphate (PIP(2)) binding assay and a yeast-two-hybrid assay were used to characterize the molecular mechanisms by which slide helix mutations cause AS.Neither mutant channel produced any current, but both had dominant negative effects on Kir2.2, Kir2.3, and Kir2.4 channels. We show that Y68D, D78Y, and previously reported AS mutations are clustered on the hydrophilic, cytosolic side of the slide helix and traffic normally to the plasma membrane. The in vitro lipid binding assay indicated that Y68D or D78Y N-terminal peptides bind PIP(2) similar to wild-type peptides. Yeast-two-hybrid assays showed that AS-associated mutations disturb the interaction between the slide helix and the C-terminal domain of the channel protein.Our experiments indicate a new disease-causing mechanism independent of trafficking and PIP(2) binding defects. Our findings suggest that the hydrophilic side of the slide helix interacts with a specific domain of the C-terminus facing the membrane. This interaction, which may be required for normal gating both in homomeric and heteromeric Kir2 channels, is disturbed by several mutations causing AS.
Integrative Radiogenomic Profiling of Squamous Cell Lung Cancer
Authors: Mohamed E. Abazeed, Drew J. Adams, Kristen E. Hurov, Pablo Tamayo, Chad J. Creighton, Dmitriy Sonkin, Andrew O. Giacomelli, Charles Du, Daniel F. Fries, Kwok-Kin Wong, Jill P. Mesirov, Jay S. Loeffler, Stuart L. Schreiber, Peter S. Hammerman, Matthew Meyerson
Journal: Cancer Research (2013)

Abstract Radiotherapy is one of the mainstays of anticancer treatment, but the relationship between the radiosensitivity of cancer cells and their genomic characteristics is still not well defined. Here, we report the development of a high-throughput platform for measuring radiation survival in vitro and its validation in comparison with conventional clonogenic radiation survival analysis. We combined results from this high-throughput assay with genomic parameters in cell lines from squamous cell lung carcinoma, which is standardly treated by radiotherapy, to identify parameters that predict radiation sensitivity. We showed that activation of NFE2L2, a frequent event in lung squamous cancers, confers radiation resistance. An expression-based, in silico screen nominated inhibitors of phosphoinositide 3-kinase (PI3K) as NFE2L2 antagonists. We showed that the selective PI3K inhibitor, NVP-BKM120, both decreased NRF2 protein levels and sensitized NFE2L2 or KEAP1-mutant cells to radiation. We then combined results from this high-throughput assay with single-sample gene set enrichment analysis of gene expression data. The resulting analysis identified pathways implicated in cell survival, genotoxic stress, detoxification, and innate and adaptive immunity as key correlates of radiation sensitivity. The integrative and high-throughput methods shown here for large-scale profiling of radiation survival and genomic features of solid-tumor–derived cell lines should facilitate tumor radiogenomics and the discovery of genotype-selective radiation sensitizers and protective agents. Cancer Res; 73(20); 6289–98. ©2013 AACR.
β1 Integrin: Critical Path to Antiangiogenic Therapy Resistance and Beyond
Authors: Arman Jahangiri, Manish K. Aghi, W. Shawn Carbonell
Journal: Cancer Research (2013)

Abstract Angiogenesis is an important tissue-level program supporting the growth of highly aggressive cancers and early-stage metastases. However, rapid emergence of resistance to antiangiogenic therapies, such as bevacizumab, greatly limits the clinical utility of these promising approaches. The mechanisms of resistance to antiangiogenic therapy remain incompletely understood. The tumor microenvironment has been demonstrated to be a source of broad therapeutic resistance in multiple cancers. Much of the interaction between the cells comprising a tumor and their microenvironment is driven by integrins. Notably, signaling downstream of integrins in tumor cells promotes fundamental programs vital to aggressive cancer biology, including proliferation, growth, invasion, and survival signaling. These functions then can contribute to malignant phenotypes, including metastasis, therapy resistance, epithelial-to-mesenchymal transition, and angiogenesis. Accordingly, we found β1 integrin to be functionally upregulated in tumor specimens from patients after bevacizumab failure and in xenograft models of bevacizumab resistance. Inhibition of β1 in tumor cells with stable gene knockdown or treatment with OS2966, a neutralizing β1 integrin monoclonal antibody, attenuated aggressive tumor phenotypes in vitro and blocked growth of bevacizumab-resistant tumor xenografts in vivo. Thus, β1 integrins promote resistance to antiangiogenic therapy through potentiation of multiple malignant programs facilitated by interactions with the tumor microenvironment. The elucidation of this mechanism creates an outstanding opportunity for improving patient outcomes in cancer. Cancer Res; 74(1); 3–7. ©2013 AACR.
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer
Authors: A. Tutt, M. Robson, J. E. Garber, S. Domchek, M. W. Audeh, J. N. Weitzel, M. Friedlander, J. Carmichael
Journal: Journal of Clinical Oncology (2009)

CRA501 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text]
Characteristics of ?-aspartate transport and expression of EAAC-1 in sarcolemmal vesicles and isolated cells from rat heart
Authors: Nicola King, Helen Williams, John D McGivan, M.-Saadeh Suleiman
Journal: Cardiovascular Research (2001)

L-Aspartate is an important intermediary metabolite in the heart and has also been implicated in myocardial protection, but little is known about its transport across the cardiac sarcolemma. In this study we have tested the hypothesis that the high affinity sodium-dependent aspartate transporter, EAAC-1 is expressed in heart and have also characterised aspartate transport into the myocardium.Characteristics of L-[14C]aspartate uptake into rat heart were investigated using sarcolemmal vesicles and isolated myocytes. The expression of EAAC-1 in the two preparations was also investigated by western blotting.The K(m) and V(max) of L-aspartate uptake was 9.78+/-0.7 microM and 1.17+/-0.27 pmol/mg/s in vesicles compared to 6.53+/-1.24 microM and 13.65+/-1.0 pmol/microl/s in cells. In vesicles, L-aspartate uptake was dependent on external sodium and internal potassium, and was rheogenic. In cells, L-aspartate uptake was also dependent on external sodium. Addition of unlabelled L- and D-aspartate and L-glutamate significantly inhibited L-[14C]aspartate uptake in both preparations but D-glutamate had no effect. An antibody to the aspartate transporter, EAAC-1 recognised a protein of appropriate size in both vesicles and cells.L-aspartate uptake in heart is mediated by a high affinity sodium-dependent transporter. This is accompanied by the expression in heart of EAAC-1. The physiological significance of this transporter with respect to aspartate utilisation in the heart is discussed.
Language and brain injury
Authors: G. Williams
Journal: Journal of the Royal Society of Medicine (2004)

In the patient described by Dr Coughlan and her colleagues (May 2004 JRSM1) the French accent that developed after a stroke turned out to be a disturbance of native speech patterns. I was reminded, however, of a case of head injury in which several languages were lost and serially regained. On a visit to London the patient, a Belgian who lived in Greece and was fluent in many languages, looked the wrong way and was knocked over by a passing car. For three days her whereabouts were unknown, and the Belgian Embassy eventually traced her to the National Hospital, Queen Square. It emerged that, on admission to the hospital, she had spoken a language that no-one recognized. This was Flemish. As she improved, she reacquired English and later Greek. She made a full recovery from the head injury, and the languages returned in the order she had learnt them.
Haemopoietic mechanisms in nasal polyposis and asthma
Authors: J. A Denburg
Journal: Thorax (2000)

Recent studies of the involvement of the bone marrow in human atopic asthmatic responses to inhaled allergen confirm what we have found in a canine model of Ascaris suum induced bronchial hyperresponsiveness: CD34/45+ haemopoietic progenitors, increased in numbers in the blood and marrow of atopic individuals, can be specifically upregulated following airway allergen challenge eliciting bronchial hyperresponsiveness and the late phase response. These progenitors are also found in nasal polyps1 and in asthmatic bronchial mucosa.2An interleukin (IL)-5 responsive subset of progenitors, marking the Eo-B lineage specifically, is upregulated in the marrow within 24 hours of allergen challenge in dual responder asthmatics; using triple colour flow cytometry it can be shown that this subpopulation of progenitors in the marrow is one that bears high affinity receptors for IL-5 (IL-5Rα), existing as a subpopulation of early progenitors bearing CD34/45.3 4 Thus, a readily mobilisable …
Strain Differences in Neointimal Hyperplasia in the Rat
Authors: Shahin Assadnia, John P. Rapp, Andrea L. Nestor, Timothy Pringle, Greg J. Cerilli, William T. Gunning, Thomas H. Webb, Mark Kligman, David C. Allison
Journal: Circulation Research (1999)

Abstract —We performed an initial screen of 11 rat strains by use of a standard balloon injury to the left iliac artery to observe whether genetically determined differences existed in the development of neointimal hyperplasia. Neointimal hyperplasia was assayed 8 weeks after the vascular injury on coded microscopic sections. Statistically significant differences in the percentages of the vascular wall cross-sectional areas composed of intima (percentage intima) secondary to neointimal hyperplasia were noted among the different rat strains ( P &lt;0.02), with the Brown-Norway (BN), Dark Agouti, and Milan normotensive strain rats having the highest and the spontaneously hypertensive rats (SHR) having the lowest percentages of intima. In a separate experiment, F 1 hybrids of SHR×BN strains and parental BN and SHR underwent the vascular injury, and the parental strains again showed a statistically significant difference from one another in the mean percentage of intima ( P &lt;0.0001). The F 1 hybrids showed an average percentage of intima intermediate between those of the parental strains. The average lumen size of the injured BN vessels were significantly smaller than that of the noninjured control vessels ( P =0.044), but this significance disappeared when the circular areas of these vessels were calculated without taking neointimal growth into consideration ( P =0.649). These results provide the groundwork for a genetic linkage analysis to identify the genes that influence the development of neointimal hyperplasia after vascular injury.
Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer—results of a first-in-man dose-escalation study with a fixed-dose extension phase
Authors: N. Isambert, J.-P. Delord, J.-C. Soria, A. Hollebecque, C. Gomez-Roca, D. Purcea, E. Rouits, R. Belli, P. Fumoleau
Journal: Annals of Oncology (2015)
Integrins and T Cell–Mediated Immunity
Authors: Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, Yoji Shimizu
Journal: Annual Review of Immunology (2004)

Integrin receptors mediate adhesive events that are critical for a specific and effective immune response to foreign pathogens. Integrin-dependent interactions of lymphocytes and antigen-presenting cells (APCs) to endothelium regulate the efficiency and specificity of trafficking into secondary lymphoid organs and peripheral tissue. Within these sites, integrins facilitate cell movement via interactions with the extracellular matrix, and promote and stabilize antigen-specific interactions between T lymphocytes and APCs that are critical for initiating T cell–activation events. In this review, we discuss the role of integrins in T cell–mediated immunity, with a focus on how these receptors participate in lymphocyte recirculation and T cell activation, how antigen stimulation regulates integrin activity, and how integrins define functionally unique subsets of T cells and APCs.
Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure
Authors: Alfonso Quintás-Cardama, Hagop Kantarjian, Susan O'Brien, Gautham Borthakur, John Bruzzi, Reginald Munden, Jorge Cortes
Journal: Journal of Clinical Oncology (2007)

We investigated the risk factors and management of pleural effusion associated with dasatinib therapy for chronic myelogenous leukemia (CML) after failure of imatinib.We analyzed 138 patients with CML treated with dasatinib from November 2003 to January 2006 in one phase I (n = 50) and four phase II (n = 88) studies for the development of pleural effusion.Pleural effusion occurred in 48 patients (35%; grade 3/4 in 23 [17%]), including 29% of those treated in chronic phase (CP), 50% in accelerated phase (AP), and 33% in blast phase (BP). By multivariate analysis, history of cardiac disease, hypertension, and use of a twice-daily schedule (v once daily) were identified as factors associated with development of pleural effusions. Effusions were exudative in 78% of the assessable cases. In some patients, effusions were associated with reversible increments of right ventricular systolic pressure. Management included transient dasatinib interruption in 83%, diuretics in 71%, pulse steroids in 27%, and thoracentesis in 19% of patients.Pleural effusions occur during dasatinib therapy, particularly among patients in AP or BP. A twice-daily schedule may result in a higher incidence of pleural effusion. Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit.
Fundic accommodation assessed by SPECT scanning: comparison with the gastric barostat
Authors: B D J van den Elzen
Journal: Gut (2003)

<b>Background:</b> Recently, single photon emission computed tomography (SPECT) scanning was described as a non-invasive technique to assess fundic accommodation. However, in contrast with the barostat, no intragastric distending force is applied during SPECT scanning. We hypothesised that in the absence of a barostat balloon, SPECT scanning largely detects the volume effect of the ingested meal and is a rather insensitive tool to detect fundic relaxation. <b>Methods:</b> After an overnight fast, healthy volunteers underwent a barostat study and SPECT scanning on two separate days to assess: (1) meal induced fundic accommodation (Nutridrink, 200 ml, 300 kcal); and (2) gastric relaxation to 1 mg intravenous glucagon. <b>Results:</b> Fasting fundic volumes (145 (8) <i>v</i> 280 (32) ml; p=0.001) and average postprandial volume (329 (10) <i>v</i> 571 (53) ml; p=0.001) were significantly lower measured with SPECT compared with the barostat study. Meal induced fundic relaxation (183 (10) <i>v</i> 289 (46) ml; p=0.050) and the postprandial/fasting volume ratio (2.32 (0.10) <i>v</i> 2.27 (0.29); p=0.892) did not differ significantly between SPECT scanning and the barostat. However, no correlation could be determined between accommodation volumes measured by both techniques. In contrast with meal induced relaxation, the glucagon induced increase in fundic volume (19 (5) <i>v</i> 406 (56) ml; p=0.007) and post/pre glucagon ratio (1.16 (0.03) <i>v</i> 3.02 (0.54); p=0.046) were significantly lower when measured by SPECT scanning compared with the barostat. <b>Conclusion:</b> SPECT scanning detects changes in postprandial volume but is less suitable than the gastric barostat in detecting changes in gastric tone. Our study therefore questions its role as a tool to detect impaired accommodation and warrants further validation of this technique.
Medical complications of lung transplantation
Authors: R.M. Kotloff, V.N. Ahya
Journal: European Respiratory Journal (2004)

Surgical advances, in conjunction with more effective immunosuppressive strategies, have propelled the field of lung transplantation forward and have made intermediate-term survival an achievable goal. Nonetheless, the post-transplant course is often marked by complications that threaten both the quality and duration of the recipient's life. Many of the medical complications that arise are the direct consequence of the need to administer potent immunosuppressive agents, with their attendant risks of infection, malignancy and drug toxicity. This article will review the major medical complications, excluding allograft rejection, which may be encountered in the lung transplant recipient. Familiarity with, and vigilance for, these problems should facilitate earlier recognition, more expeditious intervention and more favourable outcomes.
Histone deacetylase degradation andMEF2 activation promote the formation of slow-twitch myofibers
Authors: Matthew J. Potthoff, Hai Wu, Michael A. Arnold, John M. Shelton, Johannes Backs, John McAnally, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson
Journal: Journal of Clinical Investigation (2007)

Skeletal muscle is composed of heterogeneous myofibers with distinctive rates of contraction, metabolic properties, and susceptibility to fatigue. We show that class II histone deacetylase (HDAC) proteins, which function as transcriptional repressors of the myocyte enhancer factor 2 (MEF2) transcription factor, fail to accumulate in the soleus, a slow muscle, compared with fast muscles (e.g., white vastus lateralis). Accordingly, pharmacological blockade of proteasome function specifically increases expression of class II HDAC proteins in the soleus in vivo. Using gain- and loss-of-function approaches in mice, we discovered that class II HDAC proteins suppress the formation of slow twitch, oxidative myofibers through the repression of MEF2 activity. Conversely, expression of a hyperactive form of MEF2 in skeletal muscle of transgenic mice promotes the formation of slow fibers and enhances running endurance, enabling mice to run almost twice the distance of WT littermates. Thus, the selective degradation of class II HDACs in slow skeletal muscle provides a mechanism for enhancing physical performance and resistance to fatigue by augmenting the transcriptional activity of MEF2. These findings provide what we believe are new insights into the molecular basis of skeletal muscle function and have important implications for possible therapeutic interventions into muscular diseases.
Acute Generalized Exanthematous Pustulosis
Authors: Zhenying Zhang, Xiaoming Liu
Journal: New England Journal of Medicine (2015)

A 60-year-old woman with a history of Sjögren's syndrome, who had begun receiving hydroxychloroquine 25 days previously, presented with generalized erythematous plaques followed by a pruritic, pustular eruption. The patient was febrile, with a temperature of 38.5°C.
A randomized, double-blind, negatively controlled pilot study to determine whether the use of emollients or calcipotriol alters the sensitivity of the skin to ultraviolet radiation during phototherapy with narrowband ultraviolet B
Authors: A. Skellett, L. Swift, E. Tan, J. Garioch
Journal: British Journal of Dermatology (2010)

There is contradictory evidence suggesting that emollients increase, decrease or have no effect on minimal erythema dose (MED) or minimal phototoxic dose values prior to phototherapy. Few studies have looked at the in vivo use of emollients or calcipotriol prior to narrowband ultraviolet (UV) B (NB-UVB) treatment.To investigate whether emollients or calcipotriol alter MED readings of skin on the back of healthy subjects prior to NB-UVB irradiation.Topical agents were applied to the backs of 20 healthy volunteers for 30 min prior to MED testing. These agents were aqueous cream, 50:50 white soft paraffin and liquid paraffin, Diprobase(®) (Schering-Plough, Welwyn Garden City, U.K.), Epaderm(®) (Medlock, Oldham, U.K.) and calcipotriol ointment and cream. A control MED strip was used with no topical agent applied prior to testing. MED readings were recoded as integer steps between 1 and 9 (one is lowest MED dose for skin type; eight is highest; nine is no response, i.e. a higher MED).The median MED was between step 5 and 6 for all treatments and control. There was no significant difference at the 5% level between control and each topical agent. The study was powered to detect a median difference of approximately 0·4-0·6 steps.This has important implications at a practical level when advising patients not to apply creams prior to treatment with NB-UVB. Studies where agents are applied immediately prior to phototherapy have been more likely to show that emollients block transmission of UV radiation. If they are applied at least 30 min prior to treatment, they have no effect.
A Primitive Endogenous Lentivirus in a Colugo: Insights into the Early Evolution of Lentiviruses
Authors: Guan-Zhu Han, Michael Worobey
Journal: Molecular Biology and Evolution (2014)

Lentiviruses infect a wide range of mammal species. Much remains unknown about their deep history and host distribution. Here, we report the discovery of an endogenous lentivirus within the genome of the Sunda flying lemur (Galeopterus variegatus) (which we designate "Galeopterus variegatus endogenous lentivirus" [GvaELV]). We estimate the GvaELV genome invasion to have occurred more than 14 Ma, supporting an ancient origin of the lentivirus clade and an ancient lentiviral infection in colugo. Phylogenetic analyses show that GvaELV is a sister group of all previously known lentiviruses. The GvaELV genome appears to possess some primitive genomic features of a lentivirus, encoding not only a trans-activator of transcription (tat) gene but also two additional putative accessory genes that share no discernible similarity with other lentiviral accessory genes. The discovery of GvaELV provides novel insights into the prehistory and host distribution of lentivirus.