tbuckley/cabot-search huggingface dataset:
Distinct clinical phenotypes of airways disease defined by cluster analysis
Authors: M. Weatherall, J. Travers, P. M. Shirtcliffe, S. E. Marsh, M. V. Williams, M. R. Nowitz, S. Aldington, R. Beasley
Journal: European Respiratory Journal (2009)

Airways disease is currently classified using diagnostic labels such as asthma, chronic bronchitis and emphysema. The current definitions of these classifications may not reflect the phenotypes of airways disease in the community, which may have differing disease processes, clinical features or responses to treatment. The aim of the present study was to use cluster analysis to explore clinical phenotypes in a community population with airways disease. A random population sample of 25-75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and chest computed tomography. Cluster analysis was performed on the subgroup with current respiratory symptoms or obstructive spirometric results. Subjects with a complete dataset (n = 175) were included in the cluster analysis. Five clusters were identified with the following characteristics: cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema; cluster 2: features of emphysema alone; cluster 3: atopic asthma with eosinophilic airways inflammation; cluster 4: mild airflow obstruction without other dominant phenotypic features; and cluster 5: chronic bronchitis in nonsmokers. Five distinct clinical phenotypes of airflow obstruction were identified. If confirmed in other populations, these findings may form the basis of a modified taxonomy for the disorders of airways obstruction.
The Pathogenesis of Canalicular Laceration
Authors: Allan E. Wulc, Joe F. Arterberry
Journal: Ophthalmology (1991)

Canalicular lacerations are seen commonly in ophthalmic practice, but the pathogenesis of canalicular lacerations has not been explored. The authors retrospectively reviewed 25 cases of canalicular laceration seen at their institutions. Only 4 patients (16%) had injuries attributable to direct trauma; the remaining 21 patients (84%) had diffuse trauma or trauma to the eyelid remote from the canaliculus. The authors postulate that, in many of their cases, canalicular "lacerations" resulted from indirect trauma, where the eyelid was ruptured when it was stretched acutely to the point of avulsion. Two experimental models were derived to test this hypothesis. The results suggest that the canalicular portion of the eyelid is a particularly vulnerable location, and that injuries morphologically similar to canalicular "lacerations" occur predictably if the eyelid is traumatized indirectly or diffusely to the point of rupture.
Chloride Transport in the Kidney: Lessons from Human Disease and Knockout Mice
Authors: Thomas J. Jentsch
Journal: Journal of the American Society of Nephrology (2005)

Knockout mouse models and human inherited diseases have provided important new insights into the physiologic role of chloride transport by CLC Cl(-) channels and KCC K-Cl co-transporters. ClC-K/barrtin Cl(-) channels are important for renal salt reabsorption and possibly for acid secretion by intercalated cells. The endosomal ClC-5 protein is crucial for proximal tubular endocytosis. Its disruption in mice and patients with Dent's disease leads to hypercalciuria and kidney stones through a pathologic cascade that may be entirely explained by an impairment of endocytosis. KCC4 is important for recycling Cl(-) for the basolateral anion exchanger in intercalated cells, as is evident from the renal tubular acidosis resulting from its knockout. Finally, both KCC3 and KCC4 are crucial for proximal tubular cell volume regulation.
Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy
Authors: O. Gasch, M. Camoez, M.A. Dominguez, B. Padilla, V. Pintado, B. Almirante, J. Molina, F. Lopez-Medrano, E. Ruiz, J.A. Martinez, E. Bereciartua, F. Rodriguez-Lopez, C. Fernandez-Mazarrasa, M.A. Goenaga, N. Benito, J. Rodriguez-Baño, E. Espejo, M. Pujol
Journal: Clinical Microbiology and Infection (2012)
Utility of prognostic genomic tests in breast cancer practice: The IMPAKT 2012 Working Group Consensus Statement
Authors: H.A. Azim, S. Michiels, F. Zagouri, S. Delaloge, M. Filipits, M. Namer, P. Neven, W.F. Symmans, A. Thompson, F. André, S. Loi, C. Swanton
Journal: Annals of Oncology (2013)
A Phase I Trial of AT9283 (a Selective Inhibitor of Aurora Kinases) in Children and Adolescents with Solid Tumors: A Cancer Research UK Study
Authors: Lucas Moreno, Lynley V. Marshall, Andrew D.J. Pearson, Bruce Morland, Martin Elliott, Quentin Campbell-Hewson, Guy Makin, Sarah E.R. Halford, Gary Acton, Philip Ross, Shamim Kazmi-Stokes, Victoria Lock, Ana Rodriguez, John F. Lyons, Alan V. Boddy, Melanie J. Griffin, Murray Yule, Darren Hargrave
Journal: Clinical Cancer Research (2014)

Abstract Purpose: A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity. Experimental Design: AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5, and 23 mg/m2/d). Pharmacokinetic and PD assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies. Results: Thirty-three patients were evaluable for toxicity. There were six dose-limiting toxicities and the MTD was 18.5 mg/m2/d. Most common drug-related toxicities were hematologic (neutropenia, anemia, and thrombocytopenia in 36.4%, 18.2%, and 21.2% of patients), which were grade ≥3 in 30.3%, 6.1%, and 3% of patients. Nonhematologic toxicities included fatigue, infections, febrile neutropenia and ALT elevation. One patient with central nervous system–primitive neuroectodermal tumor (CNS-PNET) achieved a partial response after 16 cycles and 3 cases were stable for four or more cycles. Plasma concentrations were comparable with those in adults at the same dose level, clearance was similar although half-life was shorter (4.9 ± 1.5 hours, compared with 8.4 ± 3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17 of 18 patients treated at ≥11.5 mg/m2/d. Conclusion: AT9283 was well tolerated in children and adolescents with solid tumors with manageable hematologic toxicity. Target inhibition was demonstrated. Disease stabilization was documented in intracranial and extracranial pediatric solid tumors and a phase II dose determined. Clin Cancer Res; 21(2); 267–73. ©2014 AACR.
Hypoxia Stimulates Carcinoma Invasion by Stabilizing Microtubules and Promoting the Rab11 Trafficking of the α6β4 Integrin
Authors: Sang-Oh Yoon, Sejeong Shin, Arthur M. Mercurio
Journal: Cancer Research (2005)

Abstract Hypoxia plays a key role in tumor cell survival, invasion, and metastasis. Here we show that hypoxia increases tumor cell invasion by the modulation of Rab11, an important molecule for vesicular trafficking, especially membrane protein recycling and translocation of proteins from trans-Golgi network to plasma membrane. Dominant-negative Rab11 dramatically decreased hypoxia-induced invasion of MDA-MB-231 breast carcinoma cells without affecting cell apoptosis. Hypoxia-induced Rab11 trafficking is regulated by microtubule stability, as evidenced by the findings that hypoxia increases Glu tubulin and that colchicine blocks Rab11 trafficking and invasion. Inhibition of GSK-3β activity by hypoxia seems to be central to microtubule stabilization and invasion. In fact, expression of a dominant-negative GSK-3β was sufficient to stimulate invasion in normoxia. One target of Rab11-mediated trafficking that contributes to invasion is the integrin α6β4. Hypoxia induced a significant increase in α6β4 surface expression but it had no effect on the surface expression of α3β1. This increase is dependent on Rab11 and stable microtubules. In summary, we identify vesicle trafficking as a novel target of hypoxic stimulation that is important for tumor invasion.
Development and external validation of a nomogram for overall survival after curative resection in serosa-negative, locally advanced gastric cancer
Authors: S. Hirabayashi, S. Kosugi, Y. Isobe, A. Nashimoto, I. Oda, K. Hayashi, I. Miyashiro, S. Tsujitani, Y. Kodera, Y. Seto, H. Furukawa, H. Ono, S. Tanabe, M. Kaminishi, S. Nunobe, T. Fukagawa, R. Matsuo, T. Nagai, H. Katai, T. Wakai, K. Akazawa
Journal: Annals of Oncology (2014)
Lung deposition patterns of directly labelled salbutamol in normal subjects and in patients with reversible airflow obstruction.
Authors: R Melchor, M F Biddiscombe, V H Mak, M D Short, S G Spiro
Journal: Thorax (1993)

BACKGROUND--Earlier studies of aerosol deposition in the lungs have relied on indirect labelling of Teflon spheres of a similar size distribution to the drug in question and have assumed similar aerodynamic properties. Using a modification of a new technique for directly labelling salbutamol, the deposition of salbutamol within the lungs of normal subjects and patients with asthma has been studied with the use of a metered dose inhaler (MDI) alone, an MDI with a spacer device, and a dry powder inhaler (DPI). METHOD--Salbutamol was directly labelled with technetium-99m and placed in an MDI or DPI. Ten normal subjects and 19 patients with asthma inhaled 200 micrograms of salbutamol by means of the MDI alone, the MDI with a spacer device attached, and by DPI on separate days. Deposition was assessed by a dual headed gamma camera after inhalation of the drug. RESULTS--The total mean (SD) percentage deposition of the drug in the normal subjects was 21.6% (8.9%) with the MDI alone, 20.9% (7.8%) with the MDI with spacer, and 12.4% (3.5%) with the DPI. For the patients, the mean percentage deposition was 18.2% (7.8%) with the MDI alone, 19.0% (8.9%) with the MDI and spacer, and 11.4% (5.0%) with the DPI. Bronchodilatation achieved by the patients was similar with all three techniques. Mean peripheral lung deposition was significantly greater with a spacer device than when the MDI was used alone in both normal subjects (49.4% (6.1%) v 44.1% (9.9%)) and patients (38.6% (11.1%) v 30.4% (9.4%)). CONCLUSIONS--The deposition of directly labelled salbutamol from an MDI is greater than previously estimated by indirect labelling techniques. The deposition of labelled salbutamol from a DPI, however, is little different from that measured by indirect techniques.
Critical Role of the Epithelial Ca2+ Channel TRPV5 in Active Ca2+ Reabsorption as Revealed by TRPV5/Calbindin-D28K Knockout Mice
Authors: Dimitra Gkika, Yu-Juei Hsu, Annemiete W. van der Kemp, Sylvia Christakos, René J. Bindels, Joost G. Hoenderop
Journal: Journal of the American Society of Nephrology (2006)

The epithelial Ca(2+) channel TRPV5 facilitates apical Ca(2+) entry during active Ca(2+) reabsorption in the distal convoluted tubule. In this process, cytosolic Ca(2+) remains at low nontoxic concentrations because the Ca(2+) influx is buffered rapidly by calbindin-D(28K). Subsequently, Ca(2+) that is bound to calbindin-D(28K) is shuttled toward the basolateral Ca(2+) extrusion systems. For addressing the in vivo role of TRPV5 and calbindin-D(28K) in the maintenance of the Ca(2+) balance, single- and double-knockout mice of TRPV5 and calbindin-D(28K) (TRPV5(-/-), calbindin-D(28K)(-/-), and TRPV5(-/-)/calbindin-D(28K)(-/-)) were characterized. These mice strains were fed two Ca(2+) diets (0.02 and 2% wt/wt) to investigate the influence of dietary Ca(2+) content on the Ca(2+) balance. Urine analysis indicated that TRPV5(-/-)/calbindin-D(28K)(-/-) mice exhibit on both diets hypercalciuria compared with wild-type mice. Ca(2+) excretion in TRPV5(-/-)/calbindin-D(28K)(-/-) mice was not significantly different from TRPV5(-/-) mice, whereas calbindin-D(28K)(-/-) mice did not show hypercalciuria. The similarity between TRPV5(-/-)/calbindin-D(28K)(-/-) and TRPV5(-/-) mice was supported further by an equivalent increase in renal calbindin-D(9K) expression and in intestinal Ca(2+) hyperabsorption as a result of upregulation of calbindin-D(9K) and TRPV6 expression in the duodenum. Elevated serum parathyroid hormone and 1,25-dihydroxyvitamin D(3) levels accompanied the enhanced expression of the Ca(2+) transporters. Intestinal Ca(2+) absorption and expression of calbindin-D(9K) and TRPV6, as well as serum parameters of the calbindin-D(28K)(-/-) mice, did not differ from those of wild-type mice. These results underline the gatekeeper function of TRPV5 being the rate-limiting step in active Ca(2+) reabsorption, unlike calbindin-D(28K), which possibly is compensated by calbindin-D(9K).
Increased levels of proinflammatory cytokines and nitric oxide metabolites in neuropsychiatric lupus erythematosus
Authors: E Svenungsson
Journal: Annals of the Rheumatic Diseases (2001)

To investigate systemic and intrathecal production of proinflammatory cytokines in relation to cerebrospinal fluid (CSF) nitric oxide (NO) release in patients with neuropsychiatric lupus erythematosus (NPLE).Thirty patients with NPLE rated as mild, moderate, or severe were studied and CSF was obtained from 21 of these. Cytokine mRNA expressing cells were detected by in situ hybridisation. Soluble cytokines were assessed by enzyme linked immunosorbent assay (ELISA). Nitrite and nitrate were determined by capillary electrophoresis.Patients with NPLE had high numbers of lymphocytes expressing mRNA for tumour necrosis factor alpha (TNFalpha), interferon gamma, and interleukin 10 in blood. The number of peripheral blood TNFalpha mRNA positive cells correlated strongly with the level of NO metabolites in the CSF (r(2)=0.69). Both the number of peripheral blood mononuclear cells expressing mRNA for TNFalpha as well as the CSF level of NO metabolites correlated with NPLE disease severity.These data suggest that increased peripheral production of proinflammatory cytokines such as TNFalpha may contribute both to an increased production of NO in the central nervous system and to generation of clinical NPLE. The data also support the possibility that measurements of NO metabolites in CSF may be of value in the diagnosis of neurological symptoms related to SLE.
Persistent agmination of lymphomatoid papulosis: A new case with immunohistopathologically confirmed mycosis fungoides component
Authors: Judit Csomor, Nóra Erős, Ágota Szepesi, Balázs Csernus, Jozsef Szakonyi, Orsolya Kontár, András Matolcsy, Sarolta Kárpáti, Márta Marschalkó
Journal: Journal of the American Academy of Dermatology (2011)
Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study
Authors: P S Burge
Journal: Thorax (2003)

<h3>Abstract</h3> The extinct Steller's sea cow (<i>Hydrodamalis gigas</i>; †1768) was a whale-sized marine mammal that manifested profound morphological adjustments to exploit the harsh coastal climate of the North Pacific. Yet despite first-hand accounts of their biology, little is known regarding underlying physiological specializations to this extreme environment. Here, the adult-expressed hemoglobin (Hb) of this species is shown to harbor a fixed amino acid replacement at an otherwise invariant position (β/δ82Lys→Asn) that is predicted to profoundly alter multiple aspects of Hb function. To unravel the functional and evolutionary consequences of this substitution, we recombinantly synthesized Hb proteins of Steller's sea cow, a <i>H. gigas</i> β/δ82Asn→Lys Hb mutant, the dugong (<i>Dugong dugon</i>), the last common dugongid ancestor, and the Florida manatee (<i>Trichechus manatus</i>). Our detailed functional analyses demonstrate that the Hb–O<sub>2</sub> affinity of Steller's sea cow evolved to become less affected by temperature compared to other sea cows. This phenotype presumably safeguarded O<sub>2</sub> delivery to cool peripheral tissues and largely arises from a reduced intrinsic temperature sensitivity of the <i>H. gigas</i> protein owing to the β/δ82Lys→Asn substitution. We further confirm that this same exchange also underlies the secondary evolution of a reduced blood–O<sub>2</sub> affinity phenotype that is moreover unresponsive to the intraerythrocytic allosteric effector 2,3-diphosphoglycerate. This radical modification, which augments O<sub>2</sub> offloading by the protein, and presumably impacted maternal/fetal O<sub>2</sub> exchange, is the first documented example of this phenotype among mammals. Notably, this replacement also increases protein solubility and is consistent with increased Hb concentrations within both the adult and pre-natal circulations that may have contributed to the elevated metabolic (thermoregulatory) requirements and fetal growth rates associated with their cold adaptation.
Effect of Acute Antidepressant Administration on Negative Affective Bias in Depressed Patients
Authors: Catherine J. Harmer, Ursula O’Sullivan, Elisa Favaron, Rachel Massey-Chase, Rachael Ayres, Andrea Reinecke, Guy M. Goodwin, Philip J. Cowen
Journal: American Journal of Psychiatry (2009)

Acute administration of an antidepressant increases positive affective processing in healthy volunteers, an effect that may be relevant to the therapeutic actions of these medications. The authors investigated whether this effect is apparent in depressed patients early in treatment, prior to changes in mood and symptoms.In a double-blind, placebo-controlled, between-groups randomized design, the authors examined the effect of a single 4-mg dose of the norepinephrine reuptake inhibitor reboxetine on emotional processing. Thirty-three depressed patients were recruited through primary care clinics and the community and matched to 31 healthy comparison subjects. Three hours after dosing, participants were given a battery of emotional processing tasks comprising facial expression recognition, emotional categorization, and memory. Ratings of mood, anxiety, and side effects were also obtained before and after treatment.Depressed patients who received placebo showed reduced recognition of positive facial expressions, decreased speed in responding to positive self-relevant personality adjectives, and reduced memory for this positive information compared to healthy volunteers receiving placebo. However, this effect was reversed in patients who received a single dose of reboxetine, despite the absence of changes in subjective ratings of mood or anxiety.Antidepressant drug administration modulates emotional processing in depressed patients very early in treatment, before changes occur in mood and symptoms. This effect may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. It also suggests a mechanism of action compatible with cognitive theories of depression.
P01.13 * EXPRESSION OF HUMAN ENDOGENOUS RETROVIRUS K (HERV-K) IN HUMAN ASTROCYTIC TUMORS
Authors: A. F. Kessler, M. Wiesner, J. Denner, U. Kammerer, M. Lohr, T. Linsenmann, G. H. Vince, R. Ernestus, C. Hagemann
Journal: Neuro-Oncology (2014)

OBJECTIVE: Human endogenous retroviruses (HERVs) are suspected to be involved in oncogenesis and tumor progression. Transcripts of HERV-K have been detected in a multitude of human cancers as e.g., teratocarcinoma, mamma carcinoma or melanoma. The HERV-K splice variants env, rec, 1.5 kb transcript and Np9 have been suggested to be tumorigenic. To date, no reports about HERV-K expression are available concerning glioblastoma multiforme (GBM), the most common malignant brain tumor in adults, rapidly progressing and with a limited prognosis of 14.6 months in median. Therefore, we elucidated whether HERV-K transcripts could be detected in these tumors and serve as new molecular targets for treatment. METHODS: Five human GBM cell lines (U87, U138, U251, U343 and GaMG), a panel of patients' tissue samples (13 astrocytoma WHO° II, 17 GBM WHO° IV and 3 normal brain biopsies) and primary cell cultures of passages 2 and 6 were analyzed for the expression of HERV-K full length mRNA and env, rec and 1.5 kb transcripts by semiquantitative RT-PCR. RESULTS: Full length mRNA was strongly expressed in the GBM cell line U87, but weakly expressed in the GBM cell lines U138, U251, U343 and GaMG. The splice products could not be detected, despite a weak expression of env mRNA in U87 cells. Very few samples of the tissue panel showed weak expression of env mRNA, but none of the rec or 1.5 kb transcripts. Primary cells expressed the 1.5 kb transcript weakly in early passages, but lost HERV-K expression with extended culture time. CONCLUSIONS: Although expression of different splice variants of HERV-K have been reported to play a role in several malignancies and they were found in variable amounts in GBM cell lines, the lack of their expression in human tumor-biopsies confirms that HERV-K splice products do not play a role in human malignant gliomas and therefore, are not suitable as targets for new therapy regimen.
Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.
Authors: T W Synold, M V Relling, J M Boyett, G K Rivera, J T Sandlund, H Mahmoud, W M Crist, C H Pui, W E Evans
Journal: Journal of Clinical Investigation (1994)

High-dose methotrexate (HDMTX) is a component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL), yet recent studies of receptor-mediated transport and saturable polyglutamylation have questioned its rationale. To investigate this in vivo, methotrexate and its active polyglutamated metabolites (MTX-PG) were measured in bone marrow blasts obtained from 101 children randomized to single-agent therapy with either HDMTX (1 g/m2 per 24 h i.v., n = 47) or low-dose MTX (LDMTX, 30 mg/m2 by mouth every 6 h x 6, n = 54), before remission induction therapy. Blast concentrations of total MTX-PGs (median 460 vs 1380 pmol/10(9) cells) and of long-chain MTX-glu4-6 were both significantly higher after HDMTX (P < 0.001). With either treatment, MTX-PGs were significantly higher in B-lineage blasts than in T-lineage blasts (LDMTX P = 0.001, HDMTX P = 0.03). In a multiple regression analysis of B-lineage ALL, blast MTX-PG was significantly related to MTX dose (or plasma MTX concentration), lymphoblast ploidy (hyperdiploid > nonhyperdiploid), and percentage S-phase. This is the first evidence that HDMTX achieves higher MTX-PG concentrations in ALL blasts in vivo, establishing a rationale for HDMTX in the treatment of childhood ALL, especially T-lineage or nonhyperdiploid B-lineage ALL, disease characteristics associated with a poor prognosis on conventional therapy.