tbuckley/cabot-search huggingface dataset:
Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B
Authors: Amit C. Nathwani, Edward G.D. Tuddenham, Savita Rangarajan, Cecilia Rosales, Jenny McIntosh, David C. Linch, Pratima Chowdary, Anne Riddell, Arnulfo Jaquilmac Pie, Chris Harrington, James O'Beirne, Keith Smith, John Pasi, Bertil Glader, Pradip Rustagi, Catherine Y.C. Ng, Mark A. Kay, Junfang Zhou, Yunyu Spence, Christopher L. Morton, James Allay, John Coleman, Susan Sleep, John M. Cunningham, Deokumar Srivastava, Etiena Basner-Tschakarjan, Federico Mingozzi, Katherine A. High, John T. Gray, Ulrike M. Reiss, Arthur W. Nienhuis, Andrew M. Davidoff
Journal: New England Journal of Medicine (2011)

Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder.We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months.AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values.Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.).
β-Catenin Causes Renal Dysplasia via Upregulation of Tgfβ2 and Dkk1
Authors: Darren Bridgewater, Valeria Di Giovanni, Jason E. Cain, Brian Cox, Madis Jakobson, Kirsi Sainio, Norman D. Rosenblum
Journal: Journal of the American Society of Nephrology (2011)

Renal dysplasia, defined by defective ureteric branching morphogenesis and nephrogenesis, is the major cause of renal failure in infants and children. Here, we define a pathogenic role for a β-catenin-activated genetic pathway in murine renal dysplasia. Stabilization of β-catenin in the ureteric cell lineage before the onset of kidney development increased β-catenin levels and caused renal aplasia or severe hypodysplasia. Analysis of gene expression in the dysplastic tissue identified downregulation of genes required for ureteric branching and upregulation of Tgfβ2 and Dkk1. Treatment of wild-type kidney explants with TGFβ2 or DKK1 generated morphogenetic phenotypes strikingly similar to those observed in mutant kidney tissue. Stabilization of β-catenin after the onset of kidney development also caused dysplasia and upregulation of Tgfβ2 and Dkk1 in the epithelium. Together, these results demonstrate that elevation of β-catenin levels during kidney development causes dysplasia.
A new tool to help patients with obstructive sleep apnea syndrome (OSAS) make informed therapeutic choices
Authors: Nathalie Pelletier-Fleury, Amiram Gafni, Nicolas Krucien, Bernard Fleury
Journal: European Respiratory Journal (2011)

There remains concern that patients may not be fully informed regarding their mechanical treatment options for OSAS: continuous positive airway pressure (CPAP) or oral appliance (OA).

Objective: To develop a tool to help clinicians inform patients about treatment options, and to assess its validity, reliability and acceptability.

Methods: We developed a decision board (DB), to present information regarding the potential benefits and side effects of the 2 treatment options, using the best available evidence. To test validity, we evaluated in 34 healthy volunteers the extent to which the respondents' preferences for a treatment changed predictably when the rate of effectiveness and side-effects were modified. Reliability was tested by re-administering the DB 2 weeks after (kappa test). The DB acceptability was evaluated in 68 consecutive patients newly diagnosed with OSAS, AHI=39 (22).

Results: In healthy volunteers, 58.8% chose OA, 41.2% chose CPAP. In the former group, 85% switched preference when the rate of effectiveness was reduced from 6/10 to 3/10, and 90% when the occurrence of occlusal contacts modification increased from 4/10 to 8/10. In the CPAP group, 57% switched when effectiveness was reduced from 10/10 to 5/10, and 42% when non compliance due to adverse effects increased from 3/10 to 6/10. Reliability was excellent (k=0.94). Concerning acceptability, 90% of the patients were satisfied with the information provided in the DB and 88% indicated that it helped them make a decision. The average score of true/false test of comprehension was 7.9 of 10 (range, 4 to 10).

Conclusion: The DB is a valid, reliable and acceptable tool to assess OSAS patients' preferences.
Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL
Authors: Naoko Kanemitsu, Yasushi Isobe, Azuchi Masuda, Shuji Momose, Morihiro Higashi, Jun-ichi Tamaru, Koichi Sugimoto, Norio Komatsu
Journal: Clinical Cancer Research (2012)

Extranodal NK/T-cell lymphoma, nasal type (ENKL) is closely associated with Epstein-Barr virus (EBV). To elucidate its pathogenetic role, we examined the expression profiles of EBV-encoded proteins, especially focusing on latent membrane protein 1 (LMP1).Immunohistochemistry was carried out using clinical samples from ENKL cases, which were diagnosed between 1996 and 2010 at our institution. We statistically assessed the correlation between LMP1 positivity and the clinicopathologic data and further examined phosphorylation status of NF-κB RelA and Akt in ENKL cell lines.Most of the 30 examined cases showed pleomorphic morphology, natural killer cell immunophenotype, and a localized disease. Immunohistochemistry detected EBERs, but not EBNA2, in all cases. LMP1 and LMP2A were positive in 22 (73.3%) and 12 cases (40.0%), respectively. LMP1-positive cases tended to show a localized disease (P = 0.060, the Fisher exact test). Nuclear localization of phosphorylated RelA and detection of phosphorylated Akt were predominantly observed in LMP1-positive cases (P = 0.002 and P < 0.001, respectively, the Fisher exact test). RNA silencing experiments of LMP1 in Hank1 cells suggested a positive correlation between LMP1 expression and phosphorylation of RelA and Akt. With a median follow-up period of 26.7 months (range, 0.2-142.3 months), the 2.5-year overall survival rates for LMP1-positive and -negative cases were estimated at 78.3% and 12.5%, respectively (P = 0.001, log-rank test).LMP1 expression shows correlations with phosphorylation of RelA and Akt and possibly has a favorable impact on clinical outcome in ENKL.
The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration.
Authors: V H Perry, M C Brown, S Gordon
Journal: The Journal of Experimental Medicine (1987)

Using mAbs and immunocytochemistry we have examined the response of macrophages (M phi) after crush injury to the sciatic or optic nerve in the mouse and rat. We have established that large numbers of M phi enter peripheral nerves containing degenerating axons; the M phi are localized to the portion containing damaged axons, and they phagocytose myelin. The period of recruitment of the M phi in the peripheral nerve is before and during the period of maximal proliferation of the Schwann cells. In contrast, the degenerating optic nerve attracts few M phi, and the removal of myelin is much slower. These results show the clearly different responses of M phi to damage in the central and peripheral nervous systems, and suggest that M phi may be an important component of subsequent repair as well as myelin degradation.
Connective Tissue Growth Factor Activates Pluripotency Genes and Mesenchymal–Epithelial Transition in Head and Neck Cancer Cells
Authors: Cheng-Chi Chang, Wen-Hao Hsu, Chen-Chien Wang, Chun-Hung Chou, Mark Yen-Ping Kuo, Been-Ren Lin, Szu-Ta Chen, Shyh-Kuan Tai, Min-Liang Kuo, Muh-Hwa Yang
Journal: Cancer Research (2013)

The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through αvβ3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC.
Bronchodilator treatment for partially reversible chronic obstructive airways disease.
Authors: M K Tandon, S G Kailis
Journal: Thorax (1991)

The effect of six weeks9 treatment with inhaled terbutaline (1 mg four times a day), optimised doses of theophylline (twice a day), the combination of theophylline and terbutaline, and placebo was studied in a randomised, double blind, crossover trial. Thirty patients with partially reversible chronic airflow obstruction and a mean forced expiratory volume in one second (FEV1) of 1.2 litres that improved by 25% were included in the study. Patients who developed non-infective exacerbations of airflow obstruction that required additional bronchodilator treatment were classed as "treatment failures." Such treatment failure occurred in 23 patients with placebo, in 22 patients with theophylline, in 12 patients with terbutaline, and in two patients taking the two drugs. Mean daily peak flow readings were highest with the combination of the two drugs, followed by terbutaline and then theophylline, and lowest with placebo. Thus a combination of terbutaline and theophylline was superior to either drug alone; inhaled terbutaline was superior to theophylline alone. Theophylline alone does not appear to have much place in the management of patients with partially reversible obstructive airways disease.
Comparison of resistance measured by the interrupter technique and by passive mechanics in sedated infants
Authors: R.J. Chavasse, Y. Bastian-Lee, P. Seddon
Journal: European Respiratory Journal (2001)

Airways resistance measured by the interrupter technique ( R int ) requires little patient cooperation and has been successfully used in young children, but little studied in infants. The authors aimed to evaluate the measurement of R int in infants, using a commercially available device (the MicroRint), by comparing it with an established technique to measure respiratory resistance: the single breath occlusion technique (SBT); and a measure of airflow obstruction during forced expiration. Infants &lt;18 months old with a history of wheeze, sedated with triclofos for pulmonary function testing, had measurements taken and compared to R int (using the MicroRint), respiratory system resistance ( R rs ) by SBT, and to maximal flow at functional residual capacity ( V ′ maxFRC ). Paired data from 25 of 37 infants studied was obtained. There was a significant difference between R int (mean 2.94±0.68) and R rs (4.02±0.87), but the two measures were strongly correlated (r=0.7). R int was negatively correlated with V ′ maxFRC (r=−0.63). Smaller infants failed to trigger the MicroRint. Interrupter resistance values in infants are significantly lower than values of respiratory system resistance obtained by passive mechanics. However, there is a strong correlation between the two measurements, as well as between resistance measured using the interrupter technique and maximal flow at functional residual capacity, which indicates that resistance measured using the interrupter technique may be a useful marker of airway obstruction in infants. There remain a number of theoretical and technical problems which require further exploration.
Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model
Authors: A. Tun-Kyi, J.-Z. Qin, P.A. Oberholzer, A.A. Navarini, J.C. Hassel, R. Dummer, U. Döbbeling
Journal: Annals of Oncology (2008)
Hormonal responses to a 160-km race across frozen Alaska
Authors: W J Kraemer, M S Fragala, G Watson, J S Volek, M R Rubin, D N French, C M Maresh, J L Vingren, D L Hatfield, B A Spiering, J Yu-Ho, S L Hughes, H S Case, K J Stuempfle, D R Lehmann, S Bailey, D S Evans
Journal: British Journal of Sports Medicine (2007)

Severe physical and environmental stress seems to have a suppressive effect on the hypothalamic-pituitary-gonadal (HPG) axis in men. Examining hormonal responses to an extreme 160-km competition across frozen Alaska provides a unique opportunity to study this intense stress.To examine hormonal responses to an ultra-endurance race.Blood samples were obtained from 16 men before and after racing and analyzed for testosterone, interleukin-6 (IL-6), growth hormone (GH) and cortisol. Six subjects (mean (SD) age 42 (7) years; body mass 78.9 (7.1) kg; height 1.78 (0.05) m raced by bicycle (cyclists) and 10 subjects (age 35 (9) years; body mass 77.9 (10.6) kg; height, 1.82 (0.05) m) raced by foot (runners). Mean (SD) finish times were 21.83 (6.27) and 33.98 (6.12) h, respectively.In cyclists there were significant (p< or =0.05) mean (SD) pre-race to post-race increases in cortisol (254.83 (135.26) to 535.99 (232.22) nmol/l), GH (0.12 (0.23) to 3.21 (3.33) microg/ml) and IL-6 (2.36 (0.42) to 10.15 (3.28) pg/ml), and a significant decrease in testosterone (13.81 (3.19) to 5.59 (3.74) nmol/l). Similarly, in runners there were significant pre-race to post-race increases in cortisol (142.09 (50.74) to 452.21 (163.40) ng/ml), GH (0.12 (0.23) to 3.21 (3.33) microg/ml) and IL-6 (2.42 (0.68) to 12.25 (1.78) pg/ml), and a significant decrease in testosterone (12.32 (4.47) to 6.96 (3.19) nmol/l). There were no significant differences in the hormonal levels between cyclists and runners (p>0.05).These data suggest a suppression of the hypopituitary-gonadal axis potentially mediated by amplification of adrenal stress responses to such an ultra-endurance race in environmentally stressful conditions.
Impaired utilization of serum folate in pernicious anemia
Authors: Peter F. Nixon, Joseph R. Bertino
Journal: Journal of Clinical Investigation (1972)

The possible role of cobalamins in the utilization of serum methyltetrahydrofolate has been investigated by means of radiolabeled methyltetrahydrofolate in subjects suffering from pernicious anemia. After intravenous administration, methyltetrahydrofolate-(3)H (SA 11,500 Ci/mole; dose 0.05 mug/kg) was cleared from the serum to tissues of B(12)-deficient subjects half as fast as after the same subjects had received vitamin B(12) therapy. B(12) deficiency was also associated with an increased rate of renal excretion of methyltetrahydrofolate or its derivatives, and a decreased rate of renal metabolism of methyltetrahydrofolate to other urinary folate derivatives.Intravenously administered methyl-(14)C-tetrahydrofolate-(3)H at a higher dose (5 mug/kg) caused a severalfold elevation of the total serum folate concentration and, in B(12)-deficient subjects, it did not disappear from the serum significantly more slowly although its urinary excretion was significantly increased. These results indicate that there is some cobalamin requirement for the utilization of serum methyltetrahydrofolate and verify one prediction of the "methyltetrahydrofolate trap" explanation for the megaloblastosis of B(12) deficiency.
Characterization of taxonomically restricted genes in a phylum-restricted cell type
Authors: Sabine Milde, Georg Hemmrich, Friederike Anton-Erxleben, Konstantin Khalturin, Jörg Wittlieb, Thomas CG Bosch
Journal: Genome biology (2009)

Despite decades of research, the molecular mechanisms responsible for the evolution of morphological diversity remain poorly understood. While current models assume that species-specific morphologies are governed by differential use of conserved genetic regulatory circuits, it is debated whether non-conserved taxonomically restricted genes are also involved in making taxonomically relevant structures. The genomic resources available in Hydra, a member of the early branching animal phylum Cnidaria, provide a unique opportunity to study the molecular evolution of morphological novelties such as the nematocyte, a cell type characteristic of, and unique to, Cnidaria.We have identified nematocyte-specific genes by suppression subtractive hybridization and find that a considerable portion has no homologues to any sequences in animals outside Hydra. By analyzing the transcripts of these taxonomically restricted genes and mining of the Hydra magnipapillata genome, we find unexpected complexity in gene structure and transcript processing. Transgenic Hydra expressing the green fluorescent protein reporter under control of one of the taxonomically restricted gene promoters recapitulate faithfully the described expression pattern, indicating that promoters of taxonomically restricted genes contain all elements essential for spatial and temporal control mechanisms. Surprisingly, phylogenetic footprinting of this promoter did not reveal any conserved cis-regulatory elements.Our findings suggest that taxonomically restricted genes are involved in the evolution of morphological novelties such as the cnidarian nematocyte. The transcriptional regulatory network controlling taxonomically restricted gene expression may contain not yet characterized transcription factors or cis-regulatory elements.
Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca<sup>2+</sup>-dependent mitochondrial dysfunction and acute pancreatitis
Authors: Wei Huang, David M Booth, Matthew C Cane, Michael Chvanov, Muhammad A Javed, Victoria L Elliott, Jane A Armstrong, Hayley Dingsdale, Nicole Cash, Yan Li, William Greenhalf, Rajarshi Mukherjee, Bhupendra S Kaphalia, Mohammed Jaffar, Ole H Petersen, Alexei V Tepikin, Robert Sutton, David N Criddle
Journal: Gut (2013)

<h3>Objective</h3> Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable. <h3>Design</h3> Intracellular calcium ([Ca<sup>2+</sup>]<sub>C</sub>), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism. <h3>Results</h3> Inhibition of OME with 4-MP converted predominantly transient [Ca<sup>2+</sup>]<sub>C</sub> rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3-BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice. <h3>Conclusions</h3> A combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation.
Obstructive Sleep Apnea and Diabetic Nephropathy
Authors: Abd A. Tahrani, Asad Ali, Neil T. Raymond, Safia Begum, Kiran Dubb, Quratul-ain Altaf, Milan K. Piya, Anthony H. Barnett, Martin J. Stevens
Journal: Diabetes Care (2013)

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Obstructive sleep apnea (OSA) is common in type 2 diabetes and increases oxidative stress. Hence, OSA could promote the development and progression of DN.This was a cohort study in adults with type 2 diabetes. Patients with known OSA or ESRD were excluded. DN was defined as the presence of albuminuria or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. DN progression was based on eGFR measurements. OSA was defined as apnea hypopnea index (AHI) ≥5 events/h. Serum nitrotyrosine abundance (a marker of nitrosative stress) was measured by ELISA.A total of 224 patients were included. OSA and DN prevalence was 64.3 and 40.2, respectively. DN prevalence was higher in patients with OSA (OSA+) compared with those without OSA (OSA-) (49.3% vs. 23.8%, P < 0.001). After adjustment, OSA (odds ratio 2.64 [95% CI 1.13-6.16], P = 0.02) remained independently associated with DN. After an average follow-up of 2.5 (0.7) years, eGFR decline was greater in OSA+ compared with OSA- patients (median -6.8% [interquartile range -16.1 to 2.2] vs. -1.6% [-7.7 to 5.3%], P = 0.002). After adjusting, both baseline OSA (B = -3.8, P = 0.044) and AHI (B = -4.6, P = 0.02) remained independent predictors of study-end eGFR. Baseline serum nitrotyrosine abundance (B = -0.24, P = 0.015) was an independent predictor of study-end eGFR after adjustment.OSA is independently associated with DN in type 2 diabetes. eGFR declined faster in patients with OSA. Nitrosative stress may provide a pathogenetic link between OSA and DN. Interventional studies assessing the impact of OSA treatment on DN are needed.