tbuckley/cabot-search huggingface dataset:
Aberrant intestinal stem cell lineage dynamics in Peutz–Jeghers syndrome and familial adenomatous polyposis consistent with protracted clonal evolution in the crypt
Authors: Danielle Langeveld, Marnix Jansen, D V de Boer, Mariska van Sprundel, Lodewijk A A Brosens, Folkert H Morsink, Francis M Giardiello, G Johan A Offerhaus, Wendy W J de Leng
Journal: Gut (2011)

<h3>Objective</h3> Genetic predisposition to cancer in Peutz–Jeghers syndrome (PJS) and the role of germline serine–threonine kinase (<i>LKB1</i>) mutations are poorly understood. The authors studied the effect of germline <i>LKB1</i> mutations on intestinal stem cell dynamics in unaffected flat PJS mucosa. Recent research has documented that the intestinal crypt houses multiple equipotent stem cell lineages. Lineages continuously compete through random drifts, while somatically inherited methylation patterns record clonal diversity. <h3>Design</h3> To study the effect of germline <i>LKB1</i> mutations on clonal expansion, the authors performed quantitative analyses of <i>c</i>ardiac-<i>s</i>pecific homeobo<i>x</i> methylation pattern diversity in crypts isolated from unaffected colonic mucosa obtained from archival PJS patient material. The authors compared methylation density and methylation pattern diversity in patients with PJS to those in patients with familial adenomatous polyposis and age-matched controls. <h3>Results</h3> The percentage of total methylation is comparable between groups, but the number of unique methylation patterns is significantly increased for patients with familial adenomatous polyposis and patients with PJS compared to control subjects. <h3>Conclusions</h3> Monoallelic <i>LKB1</i> loss is not silent and provokes a protracted clonal evolution in the crypt. The increased methylation pattern diversity observed in unaffected PJS mucosa predicts that premalignant lesions will arise at an accelerated pace compared to the general population.
Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque
Authors: Ruth Seggewiss, Stefania Pittaluga, Rima L. Adler, F. Javier Guenaga, Cole Ferguson, Ingo H. Pilz, Byoung Ryu, Brian P. Sorrentino, W. Scott Young, Robert E. Donahue, Christof von Kalle, Arthur W. Nienhuis, Cynthia E. Dunbar
Journal: Blood (2006)
Quality of Life in Patients Receiving High-Dose Interferon Alfa-2b After Resected High-Risk Melanoma
Authors: Peter Mohr, Axel Hauschild, Uwe Trefzer, Michael Weichenthal
Journal: Journal of Clinical Oncology (2009)

TO THE EDITOR: We noticed with interest a recent report in Journal of Clinical Oncology on a modified high-dose treatment schedule involving interferon alfa-2b (IFN-2b) for high-risk melanoma. In the standard high-dose IFNregimen registered for adjuvant treatment in high-risk malignant melanoma, 20 10 U/m of IFNis administered intravenously five times per week for 1 month, followed by 48 weeks of 3 10 U/m of IFNsubcutaneously per week. The modified high-dose IFN-2b trial reported by Pectasides et al compared 1 month of high-dose IFN-2b intravenously with 1 month of high-dose IFN-2b intravenously followed by 48 weeks of maintenance therapy with 15 10 U/m of IFN-2b subcutaneously three times per week in the adjuvant treatment of patients with high-risk melanoma. Pectasides et al conclude that no additional benefit of maintenance therapy was detected in overall or relapse-free survival, although the limited sample size allowed for a nearly 10% difference in relapse rates at 3 years. Therefore, the results of additional studies are awaited to clarify the relevance of short-term treatment with highdose IFN-2b in malignant melanoma. A crucial aspect not addressed by the study relates to the quality of life (QoL) of patients during long-term treatment with high-dose IFN-2b. Pectasides et al report on toxicity rates in the 1-year schedule, with a significant difference in neuropsychiatric adverse effects in favor of the 1-month schedule, but there are only single instances of severe toxicity. There is no indication of how patients’ health-related QoL was affected in either treatment arm. In particular, chronic fatigue syndrome could have had a major impact in a significant number of patients, as evidenced by other studies, but this is not reported by Pectasides et al. The MM-ADJ-5 trial by the German Dermatologic Cooperative Oncology Group compared 1 month of high-dose IFN-2b intravenously, repeated three times in 1 year (a pulsed regimen), with standard high-dose IFNin high-risk melanoma patients. An interim analysis of QoL data evaluating the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 questionnaire modified for IFN adverse effects was presented at the 2007 ASCO Annual Meeting, indicating that depression seems to have an unexpectedly low impact on high-dose IFN-2b tolerability, which is in accordance with a recently published observation. In contrast, chronic fatigue syndrome was the most important factor impairing QoL in patients treated with high-dose IFN-2b, and this corresponds to a statistically significant difference in early termination rates in the study by the German Dermatologic Cooperative Oncology Group. Therefore, any comparison between conventional and short-term high-dose IFN-2b treatment should take into account impairment of patients’ QoL, particularly the occurrence of chronic fatigue syndrome.
Should we look for osteoporosis in patients with rheumatoid arthritis?
Authors: W F LEMS, B A C DIJKMANS
Journal: Annals of the Rheumatic Diseases (1998)

Recently, rheumatologists have become more interested in osteoporosis.1 2 Obviously, this increased interest is a consequence of progress in diagnostic facilities3 and in therapeutic options of osteoporosis.1 

Dual energy x ray absorptiometry (DXA) is now the most commonly used method for measuring bone mineral density (BMD). This technology, (DXA), is crucial for the diagnosis, as osteoporosis is currently defined as a T score of ⩽ −2.5 SD, according to the WHO criteria.4 DXA has become a less expensive diagnostic procedure than five years ago and DXA machines are now widely accessible. Moreover, successful prevention of further bone loss in patients with primary osteoporosis can be offered now with the introduction of new and more potent anti-osteoporotic drugs. In postmenopausal women, a decrease in the number of vertebral5 and hip fractures6 has been found with the use of alendronate. Studies on the effect on bone of other promising drugs, such as new bisphosphonates and tissue specific oestrogens, are underway.1 

During the past decade, several authors have formulated guidelines on the prevention of bone loss in patients treated with corticosteroids.7-10 In addition, the ACR has recently developed recommendations for the prevention and treatment of osteoporosis in corticosteroid treated patients.11 In contrast, no consensus or guidelines exist for the prevention and treatment of osteoporosis in patients with rheumatoid arthritis (RA), although osteoporosis frequently occurs in patients with RA.2 Osteoporosis in RA patients is often related to the use of corticosteroids, but rheumatologists are increasingly aware that bone loss in RA patients may also occur in RA patients without (previous) use of corticosteroids.12-18 

The negative effects of RA on bone are illustrated by three types of study, focusing on: (a) markers of bone metabolism; (b) bone mineral density; (c) fracture incidence.

There is …
The role of genetic factors in occupational asthma: Table 1
Authors: C.E. Mapp
Journal: European Respiratory Journal (2003)

This article explores the influence of genetic factors on the development of sensitisation and occupational asthma (OA). First, several types of studies aimed at examining the role of genes, as well as the role of gene-environment interactions in asthma, including the available data for OA specifically, were reviewed. Genetic approaches include linkage and allele-sharing analysis and segregation analysis. Secondly, deoxyribonucleic acid banking for epidemiological studies was focused upon, highlighting the factors to be considered in choosing the appropriate specimens for genotyping. OA, like asthma, is a multifactorial condition and, to date, no ideal genetic study has been described to examine complex gene-environment interactions. Most studies in OA have examined human leukocyte antigen-associated polymorphisms with some nonreproducible results. The search for genes in occupational asthma is still in progress, and much of the information obtained has been based on small sample sizes, using different strategies for the recruitment of subjects. The best methodological approach still needs to be determined and the results of genetic identification need to be confirmed in different samples.
Cortisone Hypertension in Potassium-Deficient Rats with a Renal Ligature
Authors: RAY H. ROSENMAN, S. CHARLES FREED, SHIRLEY ST. GEORGE
Journal: Circulation Research (1956)

The pressor effects of cortisone were explored in potassium-deficient and control diet rats. It was found that marked hypertension was induced by cortisone only when there was the combined background of a renal-ligature, potassium depletion, and adrenalectomy.
L1 repeat is a basic unit of heterochromatin satellites in cetaceans
Authors: V. V. Kapitonov, G. P. Holmquist, J. Jurka
Journal: Molecular Biology and Evolution (1998)

FIG. 1.—Alignment of dolphin satellite monomer and L1 consensus sequence. The top sequence is the satellite monomer (GenBank sequence M36451; opposite orientation) and the bottom sequence is the L1MA9 consensus sequence (Smit et al. 1995) (positions 81–685; RepBase Update: http://www.girinst.org). Numbering refers to satellite sequence positions. Identical nucleotides are indicated by asterisks, transversions by dots, transitions by colons, and alignment gaps by hyphens. Mammalian heterochromatin, pericentric, telomeric, or intercalary, is usually composed of long arrays of tandemly repeated DNA sequences called satellites, which contribute up to 15%–30% of the entire genome. Rapid divergence of heterochromatin satellites, sometimes between closely related species, raises the fundamental question of whether satellite monomers rapidly evolve from the preexisting pool of satellites or some of them are recruited from nonsatellite DNA. Previous analyses of sequence periodicities indicate that alphoid satellites might have evolved from smaller heptanucleotide units (Zaitsev and Rogaev 1986), which suggests continuous evolution of satellites from the preexisting satellites. The alternative model is that individual satellite units can be recruited from a wide spectrum of nonsatellite DNA and propagated into satellites by unequal crossing over (Smith 1976). This model is rooted in the fact that no stringent functional requirements seem to be imposed on individual satellite units, and many DNA fragments, particularly abundant interspersed repeats, should occasionally be expanded into satellites. However, to date, no evidence of such events has been recorded. In this correspondence, we report that the so-called ‘‘common satellite’’ in cetaceans originated by amplification of a DNA fragment which includes the L1 interspersed repetitive element (Boeke 1997). The common cetacean satellites, constituting about 15% of all cetacean genomes, of both odontocetes (toothed whales) and mysticetes (whalebone whales) were first used to prove a monophyletic origin of the Cetacea at the DNA level (Arnason, Hoglund, and Widegren 1984). These satellites are predominantly located in most interstitial and terminal heterochromatin Cbands. The monomeric repeat is ;1,760 bp long in all cetaceans except dolphins, where its length is ;1,580 bp (Arnason, Gretarsdottir, and Widegren 1992; Gretarsdottir and Arnason 1992). There is no reported satellite DNA similar to the common cetacean satellite in other mammalian species. We have found that a 540-bp DNA fragment of the common cetacean satellite monomer is 63% similar to the 39-terminal portion of the mammalian L1 (LINE-1) retrotransposon (figs. 1 and 2). This is also the first sequence record of the L1 retroelement in the genome of marine mammals. In addition to the nucleotide similarity, we have found protein sequence similarity to the
Treatment of Idiopathic Pulmonary Fibrosis With Ambrisentan
Authors: Ganesh Raghu, Juergen Behr, Kevin K Brown, Jim J Egan, Steven M Kawut, Kevin R Flaherty, Fernando J Martinez, Steven D Nathan, Athol U Wells, Harold R Collard, Ulrich Costabel, Luca Richeldi, Joao de Andrade, Nasreen Khalil, Lake D Morrison, David J Lederer, Lixin Shao, Xiaoming Li, Patty S Pedersen, A Bruce Montgomery, Jason W Chien, Thomas G O'Riordan
Journal: Annals of Internal Medicine (2013)

Chinese translation This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. Objective: To determine whether ambrisentan, an ETA receptor–selective antagonist, reduces the rate of IPF progression. Design: Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300) Setting: Academic and private hospitals. Participants: Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. Intervention: Ambrisentan, 10 mg/d, or placebo. Measurements: Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. Results: The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. Limitation: The study was terminated early. Conclusion: Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. Primary Funding Source: Gilead Sciences.
Metabotropic Glutamate Receptor-Mediated LTD Involves Two Interacting Ca2+ Sensors, NCS-1 and PICK1
Authors: Jihoon Jo, Seok Heon, Myung Jong Kim, Gi Hoon Son, Yunkyung Park, Jeremy M. Henley, Jamie L. Weiss, Morgan Sheng, Graham L. Collingridge, Kwangwook Cho
Journal: Neuron (2008)
Surface proteins of Plasmodium falciparum merozoites binding to the erythrocyte receptor, glycophorin.
Authors: M E Perkins
Journal: The Journal of Experimental Medicine (1984)

Invasion of erythrocytes by the malarial parasite is a receptor-mediated process. P. falciparum merozoites recognize and bind to erythrocyte surface sialoglycoproteins, glycophorins A and B, and the glycophorins bind to saturable sites on the merozoite surface. The purpose of the present work was to identify a receptor or ligand molecule on the merozoite surface that mediates binding to the erythrocyte. A fraction containing the sialoglycoproteins was coupled to an acrylamide matrix and incubated with metabolically labeled merozoites. A merozoite protein of 155 kD that labeled prominently with [3H]glycine bound to glycophorin. A minor protein of 130 kD also bound. Both proteins are rich in proline and glycine, poor in methionine, and may be related. The proteins are also stable to heating to 100 degrees C for 10 min. Immunoelectron microscopy demonstrated that the 155 kD and 130 kD proteins are located on the merozoite surface coat. The antibodies significantly inhibited merozoite invasion into erythrocytes and also binding of the proteins to the glycophorin-matrix. The specific binding of the 155-kD and 130-kD proteins to the erythrocyte receptor and the demonstration that they are located on the merozoite surface suggest they could be receptor proteins that mediate binding of the merozoite to the erythrocyte surface.
Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation
Authors: Luis Sanchez-Urdazpal, Gregory J. Gores, Ellen M. Ward, Timothy P. Maus, Erwin G. Buckel, Jeffrey L. Steers, Russell H. Wiesner, Ruud A. F. Krom
Journal: Hepatology (1993)

The clinical significance and outcome of nonanastomotic strictures and dilatations involving only the biliary tree of the graft with a radiological appearance of biliary ischemia is unknown. Therefore we analyzed the grafts of 128 patients to evaluate the biochemical, radiological and histological features that prompted the diagnosis of ischemic-type biliary stricture and the clinical outcome of this complication. Ischemic-type biliary strictures were diagnosed in 25 patients (19%). Initial graft function was similar in all patients, whether or not this complication developed. Most ischemic-type biliary strictures occurred between 1 and 4 mo after orthotopic liver transplantation. However, the appearance of ischemic-type biliary stricture in the month after transplantation was predictive for a poor outcome in all six grafts with early onset of ischemic-type biliary strictures. Eighteen patients (72%) were treated with biliary stents and repeated dilatations. Long-term patency was achieved in 88% of these patients. Repeat transplantation was performed in six patients (24%); five survived. Finally, patients with ischemic-type biliary strictures spent more time in the hospital during the first year after orthotopic liver transplantation than did patients without the complication (62 ± 27 days vs. 37 ± 20 days; p ± 0.001). This was due to repeated hospitalizations and a higher incidence of retransplantation. One-year graft survival was lower in patients with ischemic-type biliary strictures than in patients without ischemic-type biliary strictures (69% vs. 88%; p = 0.006). However, 1-yr patient survival was similar in the two groups (91% vs. 89%). In conclusion, early appearance of ischemic-type biliary stricture features is associated with poor graft prognosis. The occurrence of ischemic-type biliary stricture after transplantation is associated with increased morbidity, extended hospitalization and a higher incidence of repeat transplantation. (Hepatology 1993;17:605-609.)
Exenatide-Induced Reduction in Energy Intake Is Associated With Increase in Hypothalamic Connectivity
Authors: Haiko Schlögl, Stefan Kabisch, Annette Horstmann, Gabriele Lohmann, Karsten Müller, Jöran Lepsien, Franziska Busse-Voigt, Jürgen Kratzsch, Burkhard Pleger, Arno Villringer, Michael Stumvoll
Journal: Diabetes Care (2013)

Glucagon-like peptide-1 receptor agonists such as exenatide are known to influence neural activity in the hypothalamus of animals and to reduce energy intake. In humans, however, significant weight loss has been observed in only a subgroup of patients. Why only some individuals respond with weight loss and others do not remains unclear. In this functional magnetic resonance imaging (fMRI) study, we investigated differences in hypothalamic connectivity between "responders" (reduction in energy intake after exenatide infusion) and "nonresponders."We performed a randomized, double-blinded, placebo-controlled, cross-over fMRI study with intravenous administration of exenatide in obese male volunteers. During brain scanning with continuous exenatide or placebo administration, participants rated food and nonfood images. After each scanning session, energy intake was measured using an ad libitum buffet. Functional hypothalamic connectivity was assessed by eigenvector centrality mapping, a measure of connectedness throughout the brain.Responders showed significantly higher connectedness of the hypothalamus, which was specific for the food pictures condition, in the exenatide condition compared with placebo. Nonresponders did not show any significant exenatide-induced changes in hypothalamic connectedness.Our results demonstrate a central hypothalamic effect of peripherally administered exenatide that occurred only in the group that showed an exenatide-dependent anorexigenic effect. These findings indicate that the hypothalamic response seems to be the crucial factor for the effect of exenatide on energy intake.
Enhanced Cardiac Function in Transgenic Mice Expressing a Ca <sup>2+</sup> -Stimulated Adenylyl Cyclase
Authors: Larissa Lipskaia, Nicole Defer, Giovanni Esposito, Iman Hajar, Marie-Claude Garel, Howard A. Rockman, Jacques Hanoune
Journal: Circulation Research (2000)

Abstract —The predominant functional adenylyl cyclases normally expressed in cardiac tissue and coupled to β-adrenergic receptors are inhibited by micromolar Ca 2+ concentration. To modify the overall balance of activities, we have generated transgenic mice expressing the Ca 2+ -stimulatable adenylyl cyclase type 8 (AC8) specifically in the heart. AC activity is increased by at least 7-fold in heart membranes from transgenic animals and is stimulated by Ca 2+ in the same range of concentration that inhibits the endogenous activity. Moreover, the in vivo basal protein kinase A activity was augmented 4-fold. Overexpression of AC8 in the heart has no detrimental consequences on global cardiac function. Basal heart rate and contractile function, measured by noninvasive echocardiography, were unchanged. In contrast, on release of parasympathetic tone, the intrinsic contractility is heightened and unresponsive to further β-adrenergic receptor stimulation. AC8 transgenic mice thus represent an original model to investigate the relative influence of Ca 2+ and cAMP on cardiac function within a phenotype of enhanced cardiac contractility and relaxation.