tbuckley/cabot-search huggingface dataset:
Epidermal Growth Factor Receptor as a Genetic Therapy Target for Carcinoma Cell Radiosensitization
Authors: G. Lammering, T. H. Hewit, W. T. Hawkins, J. N. Contessa, D. B. Reardon, P.-S. Lin, K. Valerie, P. Dent, R. B. Mikkelsen, R. K. Schmidt-Ullrich
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Exposure of human cancer cells to ionizing radiation activates the epidermal growth factor receptor (EGFR), which, in turn, mediates a cytoprotective response that reduces the cells' sensitivity to ionizing radiation. Overexpression of a dominant-negative EGFR mutant, EGFR-CD533, disrupts the cytoprotective response by preventing radiation-induced activation of the receptor and its downstream effectors. To investigate whether gene therapy with EGFR-CD533 has the potential to increase tumor cell radiosensitivity, we introduced an adenoviral vector containing EGFR-CD533 into xenograft tumors in nude mice and evaluated the tumor response to ionizing radiation. Methods: Xenograft tumors established from the human mammary carcinoma cell line MDA-MB-231 were transduced via infusion with the adenoviral vector Ad-EGFR-CD533 or a control vector containing the β-galactosidase gene, Ad-LacZ. The transduced tumors were then exposed to radiation in the therapeutic dose range, and radiation-induced EGFR activation was assessed by examining the tyrosine phosphorylation of immunoprecipitated EGFR. Radiosensitization was determined in vitro by colony-formation assays. All statistical tests were two-sided. Results: The transduction efficiency of MDA-MB-231 tumors by Ad-LacZ was 44%. Expression of EGFR-CD533 in tumors reduced radiation-induced EGFR activation by 2.94-fold (95% confidence interval [CI] = 2.23 to 4.14). The radiosensitivity of Ad-EGFR-CD533-transduced tumors was statistically significantly higher (46%; P<.001) than that of Ad-LacZ-transduced tumors, yielding a dose-enhancement ratio of 1.85 (95% CI = 1.54 to 2.51). Conclusions: Transduction of MDA-MB-231 xenograft tumors with Ad-EGFR-CD533 conferred a dominant-negative EGFR phenotype and induced tumor radiosensitization. Therefore, disruption of EGFR function through overexpression of EGFR-CD533 may hold promise as a gene therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation.
Local relapse in primary breast cancer patients with unexcised positive surgical margins after lumpectomy, radiotherapy and chemoendocrine therapy
Authors: L. Assersohn, T.J. Powles, S. Ashley, A.G. Nash, A.J. Neal, N. Sacks, J. Chang, U. Querci della Rovere, N. Naziri
Journal: Annals of Oncology (1999)
Genome-Scale MicroRNA and Small Interfering RNA Screens Identify Small RNA Modulators of TRAIL-Induced Apoptosis Pathway
Authors: Dmitriy Ovcharenko, Kevin Kelnar, Charles Johnson, Nan Leng, David Brown
Journal: Cancer Research (2007)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors 4/5 and selectively induces caspase-dependent apoptosis. The RNA interference screening approach has led to the discovery and characterization of several TRAIL pathway components in human cells. Here, libraries of synthetic small interfering RNA (siRNA) and microRNAs (miRNA) were used to probe the TRAIL pathway. In addition to known genes, siRNAs targeting CDK4, PTGS1, ALG2, CLCN3, IRAK4, and MAP3K8 altered TRAIL-induced caspase-3 activation responses. Introduction of the miRNAs let-7c, mir-10a, mir-144, mir-150, mir-155, and mir-193 also affected the activation of the caspase cascade. Putative targets of these endogenous miRNAs included genes encoding death receptors, caspases, and other apoptosis-related genes. Among the novel genes revealed in the screen, CDK4 was selected for further characterization. CDK4 was the only member of the cyclin-dependent kinase gene family that bore a unique function in apoptotic signal transduction.
Hypogammaglobulinemia associated with accelerated catabolism of IgG secondary to its interaction with an IgG-reactive monoclonal IgM
Authors: Thomas A. Waldmann, John S. Johnson, Norman Talal
Journal: Journal of Clinical Investigation (1971)

Hypogammaglobulinemia due to a new pathophysiological mechanism was studied in a patient with Sjögren's syndrome, a monoclonal IgM and a mixed (IgM-IgG) cryoglobulinemia. The IgM (IgMdk) component of the cryogel possessed light chains of lambda-type with highly restricted electrophoretic mobility analagous to those of a Waldenström's macroglobulin. IgMdk reacted specifically with native IgG, with IgG subclasses 1, 2, and 4, and with the Fc piece of IgG to form a cryogel. Serum concentrations of IgG 1, 2, and 4 were 10% of normal, whereas the IgG3 level was slightly increased and the IgM level was markedly increased. Viscosity and analytical ultracentrifugation studies with the purified mixed cryogel (IgM-LgG) indicated soluble complex formation over a temperature range (36-38 degrees C) attainable in vivo. Immunoglobulin turnover studies revealed a markedly elevated rate of IgM synthesis with a normal survival of IgM, IgA, and IgE. IgG3, which failed to form complexes with IgMdk at body temperature, had a normal synthetic rate and survival. In contrast, the other IgG subclasses showed reduced synthesis and shortened survival. These studies are the first indicating a short survival of some IgG subclasses with a normal survival of another. The hypogammaglobulinemia appears to be due in part to a new mechanism of accelerated protein catabolism: The rapid elimination of IgG due to its interaction with an IgG-reactive monoclonal IgM.
Neurolinguistics must be computational
Authors: Michael A. Arbib, David Caplan
Journal: Behavioral and Brain Sciences (1979)

Abstract We provide a threefold taxonomy of models in neurolinguistics: faculty models, which embrace the work of classical connectionists and holists and of such modern workers as Geschwind; process models, which are exemplified by the work of Luria, and which fractionate psycholinguistic tasks and ascribe the components to particular brain regions; and representational models, which use specific linguistic representations to build a psycholinguistic analysis of aphasic performance. We argue that further progress requires that neurolinguistics become more computational, using techniques from Artificial Intelligence to model the cooperative computation underlying language processing at a level of detail consonant with linguistic representations. Finally, we note that current neurolinguistics makes virtually no contact with the synapse-cell-circuit level of analysis characteristic of twentieth-century neuroscience. We suggest that the cooperative computation models we envisage provide the necessary intermediary between current neurolinguistic analysis and the utilization of the fruits of modern neuroanatomy, neurochemistry, and neurophysiology.
RNA interference is not involved in natural antisense mediated regulation of gene expression in mammals.
Authors: Mohammad Faghihi, Claes Wahlestedt
Journal: Genome biology (2006)

Antisense transcription, yielding both coding and non-coding RNA, is a widespread phenomenon in mammals. The mechanism by which natural antisense transcripts (NAT) may regulate gene expression are largely unknown. The aim of the present study was to explore the mechanism of reciprocal sense-antisense (S-AS) regulation by studying the effects of a coding and non-coding NAT on corresponding gene expression, and to investigate the possible involvement of endogenous RNA interference (RNAi) in S-AS interactions.We have examined the mechanism of S-AS RNA base pairing, using thymidylate synthase and hypoxia inducible factor-1alpha as primary examples of endogenous genes with coding and non-coding NAT partners, respectively. Here we provide direct evidence against S-AS RNA duplex formation in the cytoplasm of human cells and subsequent activation of RNAi.Collectively, our data demonstrate that NAT regulation of gene expression occurs through a pathway independent of Dicer associated RNAi. Moreover, we introduce an experimental strategy with utility for the functional examination of other S-AS pair interactions.
P88 Is Hydrogen Cyanide a Marker of Burkholderia Cepacia Complex Infection?
Authors: FJ Gilchrist, H Simms, A Alcock, AM Jones, D Smith, P Spanel, AK Webb, W Lenney
Journal: Thorax (2012)

<h3>Introduction</h3> Pseudomonas aeruginosa (PA) was thought to be the only organism found in the cystic fibrosis (CF) lung that produced hydrogen cyanide (HCN). A recent study used a cyanide selective electrode to demonstrate HCN production by <i>Burkholderia cepacia complex</i> (BCC) when cultured under biofilm conditions. We replicated this <i>in-vitro</i> experiment using selected ion flow tube mass spectroscopy (SIFT-MS) as a more sensitive method of detecting HCN We also investigated HCN as an <i>in-vivo</i> marker of BCC infection. <h3>Methods</h3> Twelve adults with CF were recruited as they had chronic BCC infection and were free from PA infection for &gt;12months. They provided mouth and nose exhalation breaths for HCN analysis and a sputum sample. The sputum sample was cultured and the isolated BCC recultured under planktonic (free floating) and biofilm (non-motile communities attached to glass beads) conditions. The HCN concentration in the headspace of the both culture types was measured after 24, 48, 72 and 96 hours of incubation. Sterile, control cultures were also analysed. Biofilm formation was assessed visually and with spectrophotometry after crystal violet staining. The mouth and nose exhaled breath from 10 patients with CF that were free from PA and BCC infection for &gt;12 months was also analysed. <h3>Results</h3> Biofilm formation was confirmed visually and using spectrophotometry: mean(SD) absorbance of crystal violet was 3.43(0.31) absorbance units (AU) in the biofilm cultures compared to 0.005(0.003)AU in the planktonic and control cultures (p&lt;0.001). At each of the 4 time points, the headspace HCN concentration was &lt;10ppbv (equivalent to background levels) for all biofilm, planktonic and control cultures. The mean(SD) breath HCN concentrations were no higher in the subjects with chronic BCC infection than in subjects without BCC infection for mouth exhaled breath (11.0(12.7) v 12.0(12.9) ppbv p=0.87) and nose exhaled breath (0.6(1.1) v 2.1(3.8) p=0.23). <h3>Conclusions</h3> Using SIFT-MS we did not identify elevated HCN concentrations in the headspace of BCC cultured under biofilm or planktonic conditions or in the breath of patients with chronic BCC infection. Therefore, HCN does not appear to be an <i>in-vitro</i> or <i>in-vivo</i> marker of BCC infection.
Specialist nurse intervention to reduce unscheduled asthma care in a deprived multiethnic area: the east London randomised controlled trial for high risk asthma (ELECTRA)
Authors: C. Griffiths
Journal: BMJ (2004)

<b>Objective</b> To determine whether asthma specialist nurses, using a liaison model of care, reduce unscheduled care in a deprived multiethnic area. <b>Design</b> Cluster randomised controlled trial. <b>Setting</b> 44 general practices in two boroughs in east London. <b>Participants</b> 324 people aged 4-60 years admitted to or attending hospital or the general practitioner out of hours service with acute asthma; 164 (50%) were South Asian patients, 108 (34%) were white patients, and 52 (16%) were from other, largely African and Afro-Caribbean, ethnicities. <b>Intervention</b> Patient review in a nurse led clinic and liaison with general practitioners and practice nurses comprising educational outreach, promotion of guidelines for high risk asthma, and ongoing clinical support. Control practices received a visit promoting standard asthma guidelines; control patients were checked for inhaler technique. <b>Main outcome measures</b> Percentage of participants receiving unscheduled care for acute asthma over one year and time to first unscheduled attendance. <b>Results</b> Primary outcome data were available for 319 of 324 (98%) participants. Intervention delayed time to first attendance with acute asthma (hazard ratio 0.73, 95% confidence interval 0.54 to 1.00; median 194 days for intervention and 126 days for control) and reduced the percentage of participants attending with acute asthma (58% (101/174) <i>v</i> 68% (99/145); odds ratio 0.62, 0.38 to 1.01). In analyses of prespecified subgroups the difference in effect on ethnic groups was not significant, but results were consistent with greater benefit for white patients than for South Asian patients or those from other ethnic groups. <b>Conclusion</b> Asthma specialist nurses using a liaison model of care reduced unscheduled care for asthma in a deprived multiethnic health district. Ethnic groups may not benefit equally from specialist nurse intervention.
Measurement of cold challenge responses in primary Raynaud's phenomenon and Raynaud's phenomenon associated with systemic sclerosis.
Authors: D O'Reilly, L Taylor, K el-Hadidy, M I Jayson
Journal: Annals of the Rheumatic Diseases (1992)

Using computed thermography continuous temperature recordings were made before and after cold challenge of the fingers of control subjects and patients with primary Raynaud9s phenomenon and Raynaud9s phenomenon associated with systemic sclerosis. Basal skin temperature measurements (Tpre) were significantly lower in patients with primary Raynaud9s phenomenon and Raynaud9s phenomenon associated with systemic sclerosis than in the controls. Temperatures immediately after cold challenge (T0) were significantly lower in patients with primary Raynaud9s phenomenon and Raynaud9s phenomenon associated with systemic sclerosis than in controls. The lag phase before the start of temperature recovery (Tlag) was significantly greater in patients with primary Raynaud9s phenomenon and Raynaud9s phenomenon associated with systemic sclerosis than in control subjects. The maximum recovery index (R%) was significantly less in patients with primary Raynaud9s phenomenon and Raynaud9s phenomenon associated with systemic sclerosis than in controls. The maximum rate of change of temperature during the rapid phase of rewarming (Gmax) was significantly greater in controls than in patients with primary Raynaud9s phenomenon and Raynaud9s phenomenon associated with systemic sclerosis. Discriminant analysis showed that the dynamic parameters of rewarming (Tlag, Gmax, and R%) showed greater variation between the patients with primary Raynaud9s phenomenon and those with Raynaud9s phenomenon associated with systemic sclerosis than did Tpre or T0. This method of analysis of cold challenge will be used in studies of the effects of treatment of Raynaud9s phenomenon.
Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis
Authors: Nicole Reich, Michal Tomcik, Pawel Zerr, Veronika Lang, Clara Dees, Jérome Avouac, Katrin Palumbo, Angelika Horn, Alfiya Akhmetshina, Christian Beyer, Weilin Xie, Brydon L Bennett, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2012)

Objectives The hallmark of systemic sclerosis (SSc) is the accumulation of extracellular matrix proteins by pathologically activated fibroblasts. This study analysed the antifibrotic effects of the selective c-Jun N-terminal kinase (JNK) inhibitor, CC-930, which recently entered first clinical trials as a novel antifibrotic approach. Methods Phosphorylated c-Jun was detected by western blot and immunohistochemistry. The model of bleomycin-induced dermal fibrosis and the tight skin 1 (TSK1) mouse model were used to investigate the effects of CC-930 on the prevention of experimental fibrosis. The potential of CC-930 to induce regression of fibrosis was assessed in a modified model of established fibrosis. Results Transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) activate JNK and stimulate the phosphorylation of its downstream target c-Jun. Incubation with CC-930 prevented the phosphorylation of c-Jun and reduced the stimulatory levels of these cytokines on the release of collagen. Inhibition of JNK prevented dermal thickening, myofibroblast differentiation and the accumulation of collagen in a dose-dependent manner in mice challenged with bleomycin and in TSK1 mice. In addition to the prevention of fibrosis, treatment with pharmacologically relevant doses of CC-930 also induced regression of established experimental fibrosis. Conclusions These data identify JNK as a downstream mediator of the pro-fibrotic effects of of TGFβ and PDGF in SSc fibroblasts. Selective inhibition of JNK by CC-930 exerted potent antifibrotic effects in vitro and in different models in vivo. JNK might thus be a novel molecular target for the treatment of fibrosis in SSc.
PROTEIN TARGETS OF XENOBIOTIC REACTIVE INTERMEDIATES
Authors: Neil R. Pumford and, N. Christine Halmes
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract Many xenobiotics are metabolically activated to electrophilic intermediates that form covalent adducts with proteins; the mechanism of toxicity is either intrinsic or idiosyncratic in nature. Many intrinsic toxins covalently modify cellular proteins and somehow initiate a sequence of events that leads to toxicity. Major protein adducts of several intrinsic toxins have been identified and demonstrate significant decreases in enzymatic activity. The reactivity of intermediates and subcellular localization of major targets may be important in the toxicity. Idiosyncratic toxicities are mediated through either a metabolic or immune-mediated mechanism. Xenobiotics that cause hypersensitivity/autoimmunity appear to have a limited number of protein targets, which are localized within the subcellular fraction where the electrophile is produced, are highly substituted, and are accessible to the immune system. Metabolic idiosyncratic toxins appear to have limited targets and are localized within a specific subcellular fraction. Identification of protein targets has given us insights into mechanisms of xenobiotic toxicity.
Attempted Suicide With Methyprylon
Authors: Norman Burnstein
Journal: JAMA (1965)

METHYPRYLON is a nonbarbiturate central nervous system depressant frequently prescribed for nighttime sedation. It is relatively safe but there have been reports of acute methyprylon intoxication 1 including one fatal poisoning. 2 The following case history describes a suicidal attempt with this drug in which the alleged intake was 26.4 to 30 gm —the largest single dose ingestion to date.  Report of a Case  The patient is a 36-year-old married nurse and mother of three children with a five-year history of bizarre fever and possible breast pathology. She was admitted to the emergency room at about 8 PM on Sept 25, 1964, soon after an alleged suicidal ingestion of presumably one hundred 300-mg capsules of methyprylon (Noludar) and one hundred 50-mg capsules of dimenhydrinate (Dramamine). On arrival, she was comatose with a blood pressure of 80/40 mm Hg and a slow pulse rate. There was no cyanosis or pulmonary edema,
Two Rare Cases of Internal Strangulation
Authors: F. D. Hindmarsh
Journal: BMJ (1949)

It would appear that an individual subsisting on the unsupplemented diet, as provided at the Hope Bay base, passes gradually into the subscorbutic state over a period of about 12 weeks.This is about the time taken for a saturated individual to develop scorbutic manifestations when completely deprived of ascorbic acid.In the absence of more accurate methods for the determination of the ascorbic acid content of the diet at the base, this time-lag suggests that the vitamin is present in negligible quantities or entirely lacking in the food provided.The importance of all personnel taking a regular ration of ascorbic acid cannot be over-emphasized.At Hope Bay it was found that cuts and abrasions, particularly on the fingers, though more painful than in temperate climates did not take longer to heal.It seems reasonable that the delay in healing of such minor wounds observed by Pirie and his companions was due not to a diminished blood supply in low temperatures, as he thought, but to a deficiency of vitamin C.
Heading in football. Part 2: Biomechanics of ball heading and head response
Authors: N Shewchenko, C Withnall, M Keown, R Gittens, J Dvorak
Journal: British Journal of Sports Medicine (2005)

Controversy surrounding the long term effects of repeated impacts from heading has raised awareness among the public and the medical community. However, there is little information about the human response to the impacts and what measures can be taken to alter their effect. The objective of the current study was to gain a better understanding of heading biomechanics through the implementation of a numerical model and subsequent investigation of parameters related to heading technique and ball characteristics.A controlled laboratory study was carried out with seven active football players, aged 20-23 years who underwent medical screening and were instrumented with accelerometers mounted in bite plates and electromyographic electrodes on the major neck muscle groups. Balls were delivered at two speeds (6 m/s and 8 m/s) as the subjects demonstrated several specific heading manoeuvres. Photographic targets were tracked via high speed video to measure heading kinematics. One subject demonstrating reasonably averaged flexion-extension muscle activity phased with head acceleration data and upper torso kinematics was used to validate a biofidelic 50th percentile human numerical model with detailed representation of the head and neck.Heading kinematics and subject responses were used with a detailed numerical model to simulate impact biomechanics for a baseline heading scenario. Changes to heading techniques and ball characteristics which mitigated head impact response were identified.A numerical model combined with biomechanical measurement techniques is an important tool for parametric investigation of strategies to reduce head impact severity via changes in heading technique or the physical properties of the ball.
Heart Rate Variability and Sensorimotor Polyneuropathy in Type 1 Diabetes
Authors: Steven Orlov, Vera Bril, Andrej Orszag, Bruce A. Perkins
Journal: Diabetes Care (2012)

Reduced heart rate variability (HRV) is classically viewed as an early phenomenon in diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the characteristics of HRV across the spectrum of clinical DSP in type 1 diabetes.Eighty-nine diabetic subjects and 60 healthy volunteers underwent assessment of RR interval variation (RR(var)) during deep breathing and clinical and electrophysiological examination. We examined the distribution of age-standardized RR(var) across the spectrum of clinical DSP, identified variables associated with RR(var) in multivariate regression, and compared RR(var) with validated measures of neuropathy.Age-standardized RR(var) had a significant, step-wise, inverse relationship with ordinal categories of increasing DSP severity (β = -5.4, P < 0.0001) among subjects with diabetes. Case subjects with DSP had substantially lower age-standardized RR(var) compared with diabetic control subjects without DSP (β = -5.2, P < 0.01), although there was substantial overlap of RR(var) between diabetic case subjects and control subjects and the healthy volunteer cohort. In multivariate analysis, advanced age was independently associated with lower RR(var) in both healthy volunteers and diabetic subjects, whereas higher glycated hemoglobin A(1c) and systolic blood pressure were independently associated with lower RR(var) in diabetic subjects. RR(var) had a significant association with validated measures of large and small fiber neuropathy.HRV may be a biomarker for clinical DSP and is associated cross-sectionally with both early and late measures of neuropathy. The low HRV observed in some control subjects without DSP and in most case subjects with severe DSP may signify that HRV has different prognostic implications in these groups, requiring further longitudinal study.