tbuckley/cabot-search huggingface dataset:
Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human bone
Authors: E. F Shead, C. S Haworth, A. M Condliffe, D. J McKeon, M. A Scott, J. E Compston
Journal: Thorax (2007)

Mutations within the CFTR gene are central to the pathophysiology of cystic fibrosis. CFTR encodes a chloride channel that is located primarily on epithelial cell membranes and is responsible for the regulation of transmembrane chloride and other ion transport. Recent studies indicate a potential association between mutation of the CFTR gene and osteoporosis in patients with CF. Dif et al 1 reported an abnormal skeletal phenotype in CFTR-null mice with striking osteopenia, reduced cortical width and thinning of the trabeculae, while in a study of adults with CF, the ΔF508 mutation was shown to be an independent risk factor for low bone mineral density.2 An association between CFTR mutations and bone disease might be mediated either indirectly by effects of the mutations on other systems (for example, the endocrine system), or it could be due to abnormally …
Hormone-elicited enzyme release by the small intestinal wall
Authors: H. Gotze, J. W. Adelson, H. B. Hadorn, R. Portmann, V. Troesch
Journal: Gut (1972)

Three enzymes of intestinal origin-enterokinase, alkaline phosphatase, and sucrase-were released into the perfused small intestinal lumen of the rat upon intravenous injection of the gastrointestinal hormone cholecystokinin-pancreozymin (CCK-PZ). The presence of bile in the perfusion fluid greatly augmented this release. The results suggest that a combined mechanism of enzyme liberation due to direct hormonal stimulation of the gut wall and further solubilization of released intestinal enzymes by bile may be responsible for the appearance of these enzymes in the gut lumen.
Treatment of periodontal disease in older adults
Authors: J L Wennström
Journal: Periodontology 2000 (1998)

The literature does not indicate that older adults differ from younger individuals in their response to periodontal treatment. However, in older adults, it is more common to find compromised general conditions that may negatively affect the patient's ability to maintain an adequate standard of self-performed plaque control. Although this can be compensated for partly by a carefully designed program for supportive therapy, the prevention and/or elimination of clinical signs of periodontal inflammation may not always be a reachable goal of periodontal therapy in older adults, particularly in those who are frail and functionally dependent. For many patients, a more realistic goal may be the control of disease progression in order to preserve a functional and comfortable dentition throughout life and hence, the decision making process regarding therapeutic levels for the individual patient must include factors such as the amount of remaining periodontal support, the risk for disease progression, demands for oral health and life expectancy.
Spectrum of Congenital Cardiac Anomalies Produced in Chick Embryos by Mechanical Interference with Cardiogenesis
Authors: Ira H. Gessner
Journal: Circulation Research (1966)

Stage 19 to 20 white leghorn chick embryos were subjected to an operative manipulation in which a wire device was passed under the outflow tract of the cardiac tube, and allowed to remain in place from 24 to 60 hours. The embryos were then permitted to develop until hatching. Twenty-eight embryos, including eight sham operated controls, all of whom were normal, survived to at least the 18th embryonic day, and are included in this report. A spectrum of cardiac anomalies was produced as follows: group 1, widening of the left ventricular outflow tract unassociated with other defects; group 2, widening of the left ventricular outflow tract with a subaortic ventricular septal defect, 0.8 mm or less in its greatest dimension; group 3, a large ventricular septal defect, 1.5 mm or more in its greatest dimension, with varying degrees of abnormal position of the aorta, including "overriding" of the aorta, but with maintenance of continuity between the aortic and mitral valve annuli; group 4, the double outlet syndrome, in which both great vessels arise from the anatomic right ventricle with complete muscular separation between the aortic and mitral valves. In the time period studied, the double outlet syndrome represents the extreme of the continuum. However, it is possible that other forms of this spectrum exist, some perhaps incompatible with embryonic life, and that these may be produced by changing the experimental technique.
Inhibition of Histone Demethylase JMJD1A Improves Anti-Angiogenic Therapy and Reduces Tumor-Associated Macrophages
Authors: Tsuyoshi Osawa, Rika Tsuchida, Masashi Muramatsu, Teppei Shimamura, Feng Wang, Jun-ichi Suehiro, Yasuharu Kanki, Youichiro Wada, Yasuhito Yuasa, Hiroyuki Aburatani, Satoru Miyano, Takashi Minami, Tatsuhiko Kodama, Masabumi Shibuya
Journal: Cancer Research (2013)

Antiangiogenic strategies can be effective for cancer therapy, but like all therapies resistance poses a major clinical challenge. Hypoxia and nutrient starvation select for aggressive qualities that may render tumors resistant to antiangiogenic attack. Here, we show that hypoxia and nutrient starvation cooperate to drive tumor aggressiveness through epigenetic regulation of the histone demethylase JMJD1A (JHDM2A; KDM3A). In cancer cells rendered resistant to long-term hypoxia and nutrient starvation, we documented a stimulation of AKT phosphorylation, cell morphologic changes, cell migration, invasion, and anchorage-independent growth in culture. These qualities associated in vivo with increased angiogenesis and infiltration of macrophages into tumor tissues. Through expression microarray analysis, we identified a cluster of functional drivers such as VEGFA, FGF18, and JMJD1A, the latter which was upregulated in vitro under conditions of hypoxia and nutrient starvation and in vivo before activation of the angiogenic switch or the prerefractory phase of antiangiogenic therapy. JMJD1A inhibition suppressed tumor growth by downregulating angiogenesis and macrophage infiltration, by suppressing expression of FGF2, HGF, and ANG2. Notably, JMJD1A inhibition enhanced the antitumor effects of the anti-VEGF compound bevacizumab and the VEGFR/KDR inhibitor sunitinib. Our results form the foundation of a strategy to attack hypoxia- and nutrient starvation-resistant cancer cells as an approach to leverage antiangiogenic treatments and limit resistance to them.
Anti–B Cell Antibody Therapies for Inflammatory Rheumatic Diseases
Authors: Mikkel Faurschou, David R.W. Jayne
Journal: Annual Review of Medicine (2013)

Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti–B cell antibody-based therapies for rheumatoid arthritis, systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, polymyositis/dermatomyositis, and primary Sjögren's syndrome. For some anti–B cell agents, clinical benefits have been convincingly demonstrated, while other B cell–targeted therapies failed to improve outcomes when added to standard-of-care treatment or were associated with increased rates of adverse events. Although the risk-benefit balance seems to be acceptable for currently licensed anti–B cell agents, additional studies are required to fully assess the safety of treatment regimens involving prolonged interference with B cell counts and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti–B cell antibodies.
Relationship between monocyte-derived macrophage phagocytosis and airway inflammation in stable COPD
Authors: Richa Singh, Kiran Chana, Kylie Such, Anant Patel, Alex Mackay, Davinder Garcha, Gavin Donaldson, Peter Barnes, Jadwiga Wedzicha, Louise Donnelly
Journal: European Respiratory Journal (2013)

Despite increased numbers o f alveolar macrophages (mΦ) in stable COPD patients, lower airway bacterial colonisation (LABC) is often seen. We investigated the relationship between LABC status, airway inflammation & monocyte-derived mΦ (MDMs) phagocytosis.  Whole blood & sputa were collected from stable COPD patients. MDMs were cultured & phagocytosis of fluorescently-labeled inert beads, or heat-killed  Haemophilus influenzae  (HI) &  Streptococcus pneumoniae  (SP) measured. Sputa were analysed by qPCR for HI, SP &  Moraxella catarrhalis  & airway cytokines by ELISA.  Clinical characteristics are shown in Table 1.  19/40 patients had evidence of LABC on qPCR & had significantly higher levels of IL-8 and IL-1β, but not MPO, than non-LABC patients. There was a trend towards increasing airway inflammation with increasing bacterial load. Phagocytosis of HI & SP, but not beads, significantly increased with increasing airway IL-8 & IL-1β (Figure 1).  There was no significant relationship between airway MPO and phagocytosis of any prey.  Higher levels of airway IL-8 and IL-1β are associated with increased phagocytic response by MDMs to HI & SP but not beads. Higher bacterial loads seen in LABC patients may increase airway inflammation & this may in turn influence phagocytic ability.
Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer
Authors: Roy S. Herbst, Vincent J. O'Neill, Louis Fehrenbacher, Chandra P. Belani, Philip D. Bonomi, Lowell Hart, Ostap Melnyk, David Ramies, Ming Lin, Alan Sandler
Journal: Journal of Clinical Oncology (2007)

Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, and erlotinib, a reversible, orally available epidermal growth factor receptor tyrosine kinase inhibitor, have demonstrated evidence of a survival benefit in the treatment of non-small-cell lung cancer (NSCLC). A single-arm phase I and II study of bevacizumab plus erlotinib demonstrated encouraging efficacy, with a favorable safety profile.A multicenter, randomized phase II trial evaluated the safety of combining bevacizumab with either chemotherapy (docetaxel or pemetrexed) or erlotinib and preliminarily assessed these combinations versus chemotherapy alone, as measured by progression-free survival (PFS). All patients had histologically confirmed nonsquamous NSCLC that had progressed during or after one platinum-based regimen.One hundred twenty patients were randomly assigned and treated. No unexpected adverse events were noted. Fewer patients (13%) in the bevacizumab-erlotinib arm discontinued treatment as a result of adverse events than in the chemotherapy alone (24%) or bevacizumab-chemotherapy (28%) arms. The incidence of grade 5 hemorrhage in patients receiving bevacizumab was 5.1%. Although not statistically significant, relative to chemotherapy alone, the risk of disease progression or death was 0.66 (95% CI, 0.38 to 1.16) among patients treated with bevacizumab-chemotherapy and 0.72 (95% CI, 0.42 to 1.23) among patients treated with bevacizumab-erlotinib. One-year survival rate was 57.4% for bevacizumab-erlotinib and 53.8% for bevacizumab-chemotherapy compared with 33.1% for chemotherapy alone.Results for PFS and overall survival favor combination of bevacizumab with either chemotherapy or erlotinib over chemotherapy alone in the second-line setting. No unexpected safety signals were noted. The rate of fatal pulmonary hemorrhage was consistent with previous bevacizumab trials. The toxicity profile of the bevacizumab-erlotinib combination is favorable compared with either chemotherapy-containing group.
A CD4+ T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease
Authors: William H H Reece, Margaret Pinder, Philip K Gothard, Paul Milligan, Kalifa Bojang, Tom Doherty, Magdalena Plebanski, Peter Akinwunmi, Simone Everaere, Katherine R Watkins, Gerald Voss, Nadia Tornieporth, Ali Alloueche, Brian M Greenwood, Kent E Kester, Keith P W J McAdam, Joe Cohen, Adrian V S Hill
Journal: Nature Medicine (2004)
Care and Outcomes of Patients Newly Hospitalized for Heart Failure in the Community Treated by Cardiologists Compared With Other Specialists
Authors: Philip Jong, Yanyan Gong, Peter P. Liu, Peter C. Austin, Douglas S. Lee, Jack V. Tu
Journal: Circulation (2003)

It is not known whether subspecialty care by cardiologists improves outcomes in heart failure patients from the community over care by other physicians.Using administrative data, we monitored 38 702 consecutive patients with first-time hospitalization for heart failure in Ontario, Canada, between April 1994 and March 1996 and examined differences in processes of care and clinical outcomes between patients attended by physicians of different disciplines. We found that patients attended by cardiologists had lower 1-year risk-adjusted mortality than those attended by general internists, family practitioners, and other physicians (28.5% versus 31.7%, 34.9%, and 35.9%, respectively; all pairwise comparisons, P<0.001). The 1-year risk-adjusted composite outcome of death and readmission for heart failure was also lower for the cardiologists compared with family practitioners and other physicians but not general internists (54.7% versus 58.1%, 58.3%, and 55.4%; P<0.001, P<0.001, and P=0.39, respectively). Multivariable hierarchical modeling demonstrated a significant physician-level effect for both outcomes in favor of the cardiologists, particularly against non-general internists. Cardiologist care was associated with higher adjusted rates of invasive interventions and postdischarge prescriptions of heart failure medications.In this population-based cohort, heart failure patients attended by cardiologists in hospital had lower risk of death as well as the composite risk of death or readmission than patients attended by noncardiologists. These data raise the need to identify specialty-driven differences in processes of care for heart failure patients, which may explain the observed disparity in clinical outcomes that presently favor cardiologist care.
Transdermal Estrogen Replacement Therapy Decreases Sympathetic Activity in Postmenopausal Women
Authors: Wanpen Vongpatanasin, Meryem Tuncel, Yasser Mansour, Debbie Arbique, Ronald G. Victor
Journal: Circulation (2001)

Background —Menopause heralds a dramatic increase in incident hypertension, suggesting a protective effect of estrogen on blood pressure (BP). In female rats, estrogen has been shown to decrease sympathetic nerve discharge (SND) and BP. SND, however, has not been recorded during estrogen replacement therapy (ERT) in humans. Methods and Results —In 12 normotensive postmenopausal women, we conducted a randomized crossover placebo-controlled study to test whether chronic ERT caused a sustained decrease in SND and BP. Twenty-four-hour ambulatory BP, SND, and arterial baroreflex sensitivity were measured before and after 8 weeks of transdermal estradiol (200 μg/d), oral conjugated estrogens (0.625 mg/d), or placebo. To test the acute effects of estrogen on SND, additional studies were performed in the same women receiving intravenous conjugated estrogens or sublingual estradiol. After 8 weeks of transdermal ERT, the basal rate of SND decreased by 30% (from 40±4 to 27±4 bursts per minute, P =0.0001) and ambulatory diastolic BP fell by 5±2 mm Hg ( P =0.0003). In contrast, SND and BP were unaffected either by 8 weeks of oral ERT or by acute estrogen administration. Neither transdermal nor oral ERT had any effects on baroreflex sensitivity. Conclusions —In normotensive postmenopausal women, chronic transdermal ERT decreases SND without augmenting arterial baroreflexes and causes a small but statistically significant decrease in ambulatory BP. Sympathetic inhibition is evident only with chronic rather than acute estrogen administration, implying a genomic mechanism of action. Because the effects of transdermal ERT are larger than those of oral ERT, the route of administration may be an important consideration in optimizing the beneficial effects of ERT on BP and overall cardiovascular health.
Monitoring of Minimal Residual Disease in <i>NPM1</i>-Mutated Acute Myeloid Leukemia: A Study From the German-Austrian Acute Myeloid Leukemia Study Group
Authors: Jan Krönke, Richard F. Schlenk, Kai-Ole Jensen, Florian Tschürtz, Andrea Corbacioglu, Verena I. Gaidzik, Peter Paschka, Shiva Onken, Karina Eiwen, Marianne Habdank, Daniela Späth, Michael Lübbert, Mohammed Wattad, Thomas Kindler, Helmut R. Salih, Gerhard Held, David Nachbaur, Marie von Lilienfeld-Toal, Ulrich Germing, Detlef Haase, Hans-Günther Mergenthaler, Jürgen Krauter, Arnold Ganser, Gudrun Göhring, Brigitte Schlegelberger, Hartmut Döhner, Konstanze Döhner
Journal: Journal of Clinical Oncology (2011)

To evaluate the prognostic value of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1(mut)).RNA-based real-time quantitative polymerase chain reaction (RQ-PCR) specific for the detection of six different NPM1(mut) types was applied to 1,682 samples (bone marrow, n = 1,272; blood, n = 410) serially obtained from 245 intensively treated younger adult patients who were 16 to 60 years old.NPM1(mut) transcript levels as a continuous variable were significantly associated with prognosis after each treatment cycle. Achievement of RQ-PCR negativity after double induction therapy identified patients with a low cumulative incidence of relapse (CIR; 6.5% after 4 years) compared with RQ-PCR-positive patients (53.0%; P < .001); this translated into significant differences in overall survival (90% v 51%, respectively; P = .001). After completion of therapy, CIR was 15.7% in RQ-PCR-negative patients compared with 66.5% in RQ-PCR-positive patients (P < .001). Multivariable analyses after double induction and after completion of consolidation therapy revealed higher NPM1(mut) transcript levels as a significant factor for a higher risk of relapse and death. Serial post-treatment assessment of MRD allowed early detection of relapse in patients exceeding more than 200 NPM1(mut)/10(4) ABL copies.We defined clinically relevant time points for NPM1(mut) MRD assessment that allow for the identification of patients with AML who are at high risk of relapse. Monitoring of NPM1(mut) transcript levels should be incorporated in future clinical trials to guide therapeutic decisions.
Towards a comprehensive structural variation map of an individual human genome
Authors: Andy W Pang, Jeffrey R MacDonald, Dalila Pinto, John Wei, Muhammad A Rafiq, Donald F Conrad, Hansoo Park, Matthew E Hurles, Charles Lee, J Craig Venter, Ewen F Kirkness, Samuel Levy, Lars Feuk, Stephen W Scherer
Journal: Genome biology (2010)

Several genomes have now been sequenced, with millions of genetic variants annotated. While significant progress has been made in mapping single nucleotide polymorphisms (SNPs) and small (<10 bp) insertion/deletions (indels), the annotation of larger structural variants has been less comprehensive. It is still unclear to what extent a typical genome differs from the reference assembly, and the analysis of the genomes sequenced to date have shown varying results for copy number variation (CNV) and inversions. We have combined computational re-analysis of existing whole genome sequence data with novel microarray-based analysis, and detect 12,178 structural variants covering 40.6 Mb that were not reported in the initial sequencing of the first published personal genome. We estimate a total non-SNP variation content of 48.8 Mb in a single genome. Our results indicate that this genome differs from the consensus reference sequence by approximately 1.2% when considering indels/CNVs, 0.1% by SNPs and approximately 0.3% by inversions. The structural variants impact 4,867 genes, and >24% of structural variants would not be imputed by SNP-association. Our results indicate that a large number of structural variants have been unreported in the individual genomes published to date. This significant extent and complexity of structural variants, as well as the growing recognition of their medical relevance, necessitate they be actively studied in health-related analyses of personal genomes. The new catalogue of structural variants generated for this genome provides a crucial resource for future comparison studies.
Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors
Authors: Raul Alba, Angela C. Bradshaw, Lynda Coughlan, Laura Denby, Robert A. McDonald, Simon N. Waddington, Suzanne M. K. Buckley, Jenny A. Greig, Alan L. Parker, Ashley M. Miller, Hongjie Wang, Andre Lieber, Nico van Rooijen, John H. McVey, Stuart A. Nicklin, Andrew H. Baker
Journal: Blood (2010)
Norepinephrine Transporter–Deficient Mice Exhibit Excessive Tachycardia and Elevated Blood Pressure With Wakefulness and Activity
Authors: Nancy R. Keller, André Diedrich, Martin Appalsamy, Sunti Tuntrakool, Suzanna Lonce, Charlene Finney, Marc G. Caron, David Robertson
Journal: Circulation (2004)

Norepinephrine (NE) is a primary neurotransmitter of central autonomic regulation and sympathetic nerve conduction, and the norepinephrine transporter (NET) is crucial in limiting catecholaminergic signaling. NET is sensitive to antidepressants, cocaine, and amphetamine. NET blockade often is associated with cardiovascular side effects, and NET deficiency is linked to tachycardia in familial orthostatic intolerance.We telemetrically monitored NET-deficient (NET(-/-)) mice to determine the cardiovascular effects of reduced NE reuptake. Mean arterial pressure was elevated in resting NET(-/-) mice compared with NET(+/+) controls (103+/-0.6 versus 99+/-0.4 mm Hg; P<0.01), and corresponding pressures increased to 122+/-0.3 and 116+/-0.3 mm Hg (P<0.0001) with activity. Heart rate was also greater in resting NET(-/-) mice (565+/-5 versus 551+/-3 bpm; P<0.05), and genotypic differences were highly significant during the active phase (640+/-5 versus 607+/-3 bpm; P<0.0001). Conversely, the respiratory rate of resting NET(-/-) mice was dramatically reduced, whereas increases after the day/night shift surpassed those of controls. Plasma catecholamines in NET(-/-) and NET(+/+) mice were as follows: NE, 69+/-8 and 32+/-7; dihydroxyphenylglycol, 2+0.4 and 17+/-3; epinephrine, 15+/-3 and 4+/-0.6; and dopamine, 13+/-4 and 4+/-1 pmol/mL. Catechols in urine, brain, and heart also were determined.Resting mean arterial pressure and heart rate are maintained at nearly normal levels in NET-deficient mice, most likely as a result of increased central sympathoinhibition. However, sympathetic activation with wakefulness and activity apparently overwhelms central modulation, amplifying peripheral catecholaminergic signaling, particularly in the heart.