tbuckley/cabot-search huggingface dataset:
AML1-like Transcription Factor Induces Serine Elastase Activity in Ovine Pulmonary Artery Smooth Muscle Cells
Authors: Dennis A. Wigle, Karen E. Thompson, Shmuel Yablonsky, Syed H. E. Zaidi, Claire Coulber, Peter L. Jones, Marlene Rabinovitch
Journal: Circulation Research (1998)

Abstract —In previous studies, we showed that induction of pulmonary artery (PA) smooth muscle cell (SMC) elastase activity by serum-treated elastin (STE) requires DNA transcription. We therefore used differential mRNA display to identify transcripts expressed coincident with elastase induction. Twenty-four individual transcripts were differentially expressed from a screen of ≈2000 mRNA sequences. An mRNA with sequence homology to the human transcription factor AML1 was identified and subsequently cloned from ovine PA SMCs. Since AML1 binds to a consensus sequence in the promoter of neutrophil elastase, we pursued the possibility that AML1 is a candidate transcription factor for SMC elastase. We documented by immunohistochemistry that serum stimulation induces increased expression of AML1 in the nucleus of PA SMCs. We also showed that STE induction of elastase activity is associated with early expression of AML1 mRNA and protein and that AML1 consensus sequence DNA binding activity is increased in nuclear extracts of STE-treated cells. In addition, AML1 antisense oligonucleotides reduced serum induction of elastase activity. Our study thus provides the first functional evidence of AML1 transcriptional activity related to elastase genes and offers novel insights into the broader biological significance of AML1 in nonmyeloid cells .
Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy
Authors: Vasant Jayasankar, Y. Joseph Woo, Lawrence T. Bish, Timothy J. Pirolli, Mark F. Berry, Jeffrey Burdick, Ramesh C. Bhalla, Ram V. Sharma, Timothy J. Gardner, H. Lee Sweeney
Journal: Circulation (2004)

Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients. This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy.Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 (n=8) or null virus as control vector (n=8), and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70+/-10 versus control 56+/-12 mmHg, P<0.05; maximum dP/dt 2697+/-842 versus 1622+/-527 mmHg/sec, P<0.01; minimum dP/dt -2900+/-917 versus -1195+/-593, P<0.001). Ventricular geometry was significantly preserved in the TIMP-1 group (LV diameter 13.0+/-0.7 versus control 14.4+/-0.4 mm, P<0.001; border-zone wall thickness 1.59+/-0.11 versus control 1.28+/-0.19 mm, P<0.05), and this was associated with a reduction in myocardial fibrosis (2.36+/-0.87 versus control 3.89+/-1.79 microg hydroxyproline/mg tissue, P<0.05). MMP activity was reduced in the TIMP-1 animals (1.5+/-0.9 versus control 43.1+/-14.9 ng of MMP-1 activity, P<0.05).TIMP-1 gene transfer inhibits MMP activity and preserves cardiac function and geometry in ischemic cardiomyopathy. The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals. TIMP-1 overexpression is a promising therapeutic target for continued investigation.
Heteroclitic CD33 Peptide With Enhanced Anti-Acute Myeloid Leukemic Immunogenicity
Authors: Jooeun Bae, Jeffrey A. Martinson, Hans G. Klingemann
Journal: Clinical Cancer Research (2004)

Abstract The goal of these studies was to engineer a synthetic CD33 peptide with enhanced immunogenicity for the induction of acute myeloid leukemia (AML)-specific CTLs. Eight modified CD33 peptides YLISGDSPV,YIGSGDSPV,YIIIGDSPV,YIILGDSPV,YIISGISPV,YIISGDLPV,YIISGDSWV andYIISGDSPL were designed for increased HLA-A2.1 or T cell receptor affinity and compared with the native CD3365–73 peptide, AIISGDSPV, for enhanced immunogenicity. The YLISGDSPV peptide was found to be the most immunogenic epitope producing highly cytolytic CTLs against AML target cells. The CTLs generated withYLISGDSPV peptide showed CD33 peptide-specificity through targeting of both native (AIISGDSPV) and modified (YLISGDSPV) peptide presenting EBV-BLCL. The CTL cultures displayed a distinct phenotype consisting of a high percentage of activated memory (CD69+/CD45RO+)-CD8+and a low percentage of naïve (CD45RA+/CCR7+)-CD8+cells. In addition, T-cell clones specific to theYLISGDSPV peptide were isolated and characterized to target AML cells. The clones exhibited both HLA-A2.1-restricted and AML cell-specific cytotoxicity that was mediated through a granule-dependent pathway. More importantly, the CTL clones did not lyse or inhibit the proliferation of normal CD34+ progenitor cells. In conclusion, we report on the identification of a highly immunogenic heterocliticYLISGDSPV CD33 epitope that is a promising candidate for immunotherapy targeting AML.
Transcriptome analysis reveals new insight into appressorium formation and function in the rice blast fungus Magnaporthe oryzae
Authors: Yeonyee Oh, Nicole Donofrio, Huaqin Pan, Sean Coughlan, Douglas E Brown, Shaowu Meng, Thomas Mitchell, Ralph A Dean
Journal: Genome biology (2008)

Abstract Background Rice blast disease is caused by the filamentous Ascomycetous fungus Magnaporthe oryzae and results in significant annual rice yield losses worldwide. Infection by this and many other fungal plant pathogens requires the development of a specialized infection cell called an appressorium. The molecular processes regulating appressorium formation are incompletely understood. Results We analyzed genome-wide gene expression changes during spore germination and appressorium formation on a hydrophobic surface compared to induction by cAMP. During spore germination, 2,154 (approximately 21%) genes showed differential expression, with the majority being up-regulated. During appressorium formation, 357 genes were differentially expressed in response to both stimuli. These genes, which we refer to as appressorium consensus genes, were functionally grouped into Gene Ontology categories. Overall, we found a significant decrease in expression of genes involved in protein synthesis. Conversely, expression of genes associated with protein and amino acid degradation, lipid metabolism, secondary metabolism and cellular transportation exhibited a dramatic increase. We functionally characterized several differentially regulated genes, including a subtilisin protease ( SPM1 ) and a NAD specific glutamate dehydrogenase ( Mgd1 ), by targeted gene disruption. These studies revealed hitherto unknown findings that protein degradation and amino acid metabolism are essential for appressorium formation and subsequent infection. Conclusion We present the first comprehensive genome-wide transcript profile study and functional analysis of infection structure formation by a fungal plant pathogen. Our data provide novel insight into the underlying molecular mechanisms that will directly benefit efforts to identify fungal pathogenicity factors and aid the development of new disease management strategies.
Growth Rates Made Easy
Authors: B. G. Hall, H. Acar, A. Nandipati, M. Barlow
Journal: Molecular Biology and Evolution (2013)

In the 1960s–1980s, determination of bacterial growth rates was an important tool in microbial genetics, biochemistry, molecular biology, and microbial physiology. The exciting technical developments of the 1990s and the 2000s eclipsed that tool; as a result, many investigators today lack experience with growth rate measurements. Recently, investigators in a number of areas have started to use measurements of bacterial growth rates for a variety of purposes. Those measurements have been greatly facilitated by the availability of microwell plate readers that permit the simultaneous measurements on up to 384 different cultures. Only the exponential (logarithmic) portions of the resulting growth curves are useful for determining growth rates, and manual determination of that portion and calculation of growth rates can be tedious for high-throughput purposes. Here, we introduce the program GrowthRates that uses plate reader output files to automatically determine the exponential portion of the curve and to automatically calculate the growth rate, the maximum culture density, and the duration of the growth lag phase. GrowthRates is freely available for Macintosh, Windows, and Linux. We discuss the effects of culture volume, the classical bacterial growth curve, and the differences between determinations in rich media and minimal (mineral salts) media. This protocol covers calibration of the plate reader, growth of culture inocula for both rich and minimal media, and experimental setup. As a guide to reliability, we report typical day-to-day variation in growth rates and variation within experiments with respect to position of wells within the plates.
Disturbed alveolar fibrin turnover during pneumonia is restricted to the site of infection
Authors: G. Choi, M.J. Schultz, J.W.O. van Till, P. Bresser, J.S. van der Zee, M.A. Boermeester, M. Levi, T. van der Poll
Journal: European Respiratory Journal (2004)

Severe infection is associated with profound alterations in the systemic haemostatic balance, with activation of coagulation and suppressed fibrinolysis. Within the alveolar compartment, similar disturbances have been described during pulmonary inflammation. The current authors investigated whether local haemostasis was influenced during ventilator-associated pneumonia (VAP). In five patients with unilateral VAP, bronchoalveolar lavage fluid (BALF) was obtained from both the infected site (as identified on chest radiograph) and the contralateral noninfected lung (with no clinical or radiographic abnormalities). Markers for coagulation and fibrinolysis were compared between infected and noninfected lungs. A total of 10 healthy volunteers and 10 mechanically ventilated patients without pneumonia served as controls. Strong activation of coagulation (high levels of thrombin-antithrombin complexes, soluble tissue factor and factor VIIa) was detected in BALF from infected lungs, compared with that from noninfected lungs and controls. Furthermore, in infected lungs, fibrinolysis was depressed, with high levels of plasminogen activator inhibitor type 1. In conclusion, ventilator-associated pneumonia is characterised by a hypercoagulant state at the site of infection.
Interaction of Duffy Antigen Receptor for Chemokines and KAI1: A Critical Step in Metastasis Suppression
Authors: Megumi Iiizumi, Sucharita Bandyopadhyay, Kounosuke Watabe
Journal: Cancer Research (2007)

Abstract Tumor metastases suppressor protein KAI1/CD82 is capable of blocking the tumor metastases without affecting the primary tumor formation, and its expression is significantly down-regulated in many types of human cancers. However, the exact molecular mechanism of the suppressor function of KAI1 remains elusive. Evidence from our laboratory supports a model in which tumor cells dislodge from the primary tumor and intravasate into the blood or lymphatic vessels followed by attachment to the endothelial cell surface whereby KAI1 interacts with the Duffy antigen receptor for chemokines (DARC) protein. This interaction transmits a senescent signal to cancer cells expressing KAI1, whereas cells that lost KAI1 expression can proliferate, potentially giving rise to metastases. Our model of the mechanism of action of KAI1 shows that metastasis suppressor activity can be dependent on interaction with host tissue and explains how KAI1 suppresses metastasis without affecting primary tumor formation. Taken together, in vitro and in vivo studies identify the KAI1-DARC interaction as a potential target for cancer therapy. [Cancer Res 2007;67(4):1411–4]
A Central Hospital Board for London
Authors: H. N. Hardy
Journal: BMJ (1897)

Secondary immunoglobulin isotypes are produced by class switch recombination (CSR), which requires AID-dependent DNA deamination of intronic switch (S) regions within the immunoglobulin heavy chain gene. Non-canonical repair of deaminated DNA by mismatch repair (MMR) or base excision repair (BER) creates staggered DNA breaks that promote recombination between S regions. ATM-dependent phosphorylation of AID at serine-38 (pS38-AID) promotes its interaction with APE1, a BER protein, suggesting that ATM regulates CSR through BER. However, pS38-AID may also play a role in MMR during CSR, although the mechanism remains unknown. To examine whether ATM participates in MMR-mediated CSR, ATM<sup>−/−</sup> mice were bred to mice deficient for the MMR gene MSH2. Surprisingly, the predicted Mendelian frequencies of ATM<sup>−/−</sup> MSH2<sup>−/−</sup> adult mice were not obtained. To bypass the observed lethality, ATM was conditionally deleted on an MSH2<sup>−/−</sup> background using a floxed ATM allele [ATM<sup>F</sup>] and B cell-specific Cre recombinase expression. These ATM<sup>d/d</sup>MSH2<sup>−/−</sup> mice and B cells display a hypomorphic CSR phenotype comparable to ATM<sup>−/−</sup> B cells, which suggests that ATM may function genetically upstream of MSH2 and implicates a role for ATM in both MMR and BER.
S‐Nitrosated Polypropylene Sulfide Nanoparticles for Thiol‐Dependent Transnitrosation and Toxicity Against Adult Female Filarial Worms
Authors: Alex Schudel, Timothy Kassis, J. Brandon Dixon, Susan N. Thomas
Journal: Advanced Healthcare Materials (2015)

A synthetic polymer nanoparticle formulation utilizing the physiological nitrosothiol chemistry for nitric oxide delivery is shown. Toxicity of S-nitroso nanoparticles against adult female Brugia malayi worms, which are responsible for lymphatic filariasis, is dependent on nitric oxide release through transnitrosation as S-nitrosocysteine, a potent endogenous nitric oxide donor.
Combining Incretin-Based Therapies With Insulin
Authors: Jiten Vora
Journal: Diabetes Care (2013)

### What is the rationale for adding incretin-based therapies to insulin?

The combination of the incretin-based therapies, i.e., the dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists (GLP-1RAs), with basal insulin has, in theory, logical appeal. While basal insulin primarily improves fasting plasma glucose (FPG) control, the glucose-dependent effect of incretins will additionally benefit postprandial plasma glucose (PPG) control. This should enable improved control of A1C with the expectation of relatively stable blood glucose concentrations, and the combination of incretins with basal insulin might reduce insulin dose requirement and, consequently, weight gain. This also supports the concept that combining the incretin-based therapies with basal insulin should enable tight glycemic control with a low risk of hypoglycemia. Furthermore, a reciprocal benefit of this combination is that the basal insulin will theoretically supplement endogenous insulin production and “rest” the β-cell, enabling greater recovery of the endogenous insulin response when required. The basis of this theory is formed from research showing benefits with incretin therapies for β-cell function (1) and β-cell mass in experimental systems (2–4).

In addition to their antihyperglycemic properties, GLP-1RAs also reduce gastrointestinal motility, which, together with increased satiety, produces a weight-sparing effect (2). This quality could mitigate the weight gain associated with insulin therapy and might be further enhanced through any reductions in insulin dose.

### Evidence to date: how do the data from insulin plus incretin clinical studies meet with expectations?

#### Glycemic control.

Using basal insulin to reduce FPG is an effective way of improving glycemic control; however, the second component of glycemic control, PPG, requires additional consideration. This is one area where incretin-based therapies and basal insulin should have complementary actions.

##### Adding incretin-based therapies to insulin.

In an uncontrolled, retrospective investigation involving a cohort of 188 patients receiving insulin, the addition of exenatide produced an A1C reduction of –0.66% ( P < 0.001) from a baseline value of 8.05% after 6 months of combination therapy—an improvement that was maintained at 27 months (5). Moreover, the patients in this …
Appropriate interpretation of aerobic capacity: allometric scaling in adult and young soccer players
Authors: K Chamari, I Moussa-Chamari, L Boussaïdi, Y Hachana, F Kaouech, U Wisløff
Journal: British Journal of Sports Medicine (2005)

Objective: To compare aerobic capacity of young and adult elite soccer players using appropriate scaling procedures. Methods: Twenty four male adult (mean (SD) age 24 (2) years, weight 75.7 (7.2) kg, V o 2 max 66.6 (5.2) ml/lbm/min, where lbm is lean body mass in kg) and 21 youth (14 (0.4) years, 60.2 (7.3) kg, 66.5 (5.9) ml/lbm/min) elite soccer players took part in the study. Allometric equations were used to determine the relation between maximal and submaximal oxygen cost of running (running economy) and body mass. Results: Maximal and submaximal oxygen uptake increased in proportion to body mass raised to the power of 0.72 (0.04) and 0.60 (0.06) respectively. The V o 2 max of adult players was similar to that of the youth players when expressed in direct proportion to body mass—that is, ml/kg/min—but 5% higher (p&lt;0.05) when expressed using appropriate procedures for scaling. Conversely, compared with seniors, youth players had 13% higher (p&lt;0.001) energy cost of running—that is, poorer running economy—when expressed as ml/kg/min but not when expressed according to the scaling procedures. Conclusions: Compared with the youth soccer players, V o 2 max in the seniors was underestimated and running economy overestimated when expressed traditionally as ml/lbm/min. The study clearly shows the pitfalls in previous studies when aerobic capacity was evaluated in subjects with different body mass. It further shows that the use of scaling procedures can affect the evaluation of, and the resultant training programme to improve, aerobic capacity.
THE INVERSE CARE LAW
Authors: Julian Tudor Hart
Journal: The Lancet (1971)

The availability of good medical care tends to vary inversely with the need for it in the population served. This inverse care law operates more completely where medical care is most exposed to market forces, and less so where such exposure is reduced. The market distribution of medical care is a primitive and historically outdated social form, and any return to it would further exaggerate the maldistribution of medical resources.
A Prospective Study of the Prevalence of Primary Aldosteronism in 1,125 Hypertensive Patients
Authors: Gian Paolo Rossi, Giampaolo Bernini, Chiara Caliumi, Giovambattista Desideri, Bruno Fabris, Claudio Ferri, Chiara Ganzaroli, Gilberta Giacchetti, Claudio Letizia, Mauro Maccario, Francesca Mallamaci, Massimo Mannelli, Mee-Jung Mattarello, Angelica Moretti, Gaetana Palumbo, Gabriele Parenti, Enzo Porteri, Andrea Semplicini, Damiano Rizzoni, Ermanno Rossi, Marco Boscaro, Achille Cesare Pessina, Franco Mantero
Journal: Journal of the American College of Cardiology (2006)
Multicenter, Randomized, Cross-Over Clinical Trial of Venlafaxine Versus Gabapentin for the Management of Hot Flashes in Breast Cancer Survivors
Authors: Louise Bordeleau, Kathleen I. Pritchard, Charles L. Loprinzi, Marguerite Ennis, Olivera Jugovic, David Warr, Rashida Haq, Pamela J. Goodwin
Journal: Journal of Clinical Oncology (2010)

Purpose Nonhormonal pharmacologic interventions are recommended for the treatment of hot flashes in breast cancer survivors. Antidepressants and gabapentin have been shown to be both effective and well tolerated; however, it is not clear which is preferred. Patients and Methods This was a group-sequential, open-label, randomized, cross-over trial of 4 weeks of venlafaxine (37.5 mg daily for 7 days followed by 75 mg daily for 21 days) versus gabapentin (300 mg once per day for 3 days, then 300 mg twice per day for 3 days, then 300 mg three times per day for 22 days), with patient preference as the primary outcome. Postmenopausal women with at least 14 bothersome hot flashes per week for the prior month were eligible. A 2-week baseline period and a 2-week tapering/washout time was used before the first and second treatment periods, respectively. Diaries were used to measure hot flashes and potential toxicities throughout the study. Participants completed a preference questionnaire at the end of the study. A predefined Pocock stopping rule was applied. Patient preference and hot flash and toxicity outcomes were compared between treatments. Results Sixty-six patients were randomly assigned, 56 of whom provided a preference (eight dropped out and two had no preference); 18 (32%) preferred gabapentin and 38 (68%) preferred venlafaxine (P = .01). Both agents reduced hot flash scores to a similar extent (66% reduction). Venlafaxine was associated with increased nausea, appetite loss, constipation, and reduced negative mood changes compared with gabapentin, whereas gabapentin was associated with increased dizziness and appetite compared with venlafaxine (all P &lt; .05). Conclusion Breast cancer survivors prefer venlafaxine over gabapentin for treating hot flashes.
Exercise, sports and musculoskeletal medicine in UK medical school curricula: a survey
Authors: F Oluwajana
Journal: British Journal of Sports Medicine (2010)

Exercise and obesity (EO) and sports and exercise medicine (SEM) are becoming increasingly important topics in today's society, due to rising obesity and inactivity rates, the emphasis on physical activity in the community and the London 2012 Olympics. Musculoskeletal medicine is a well established subject in medical schools, whose adequacy has been regularly investigated. Despite the importance of these subjects and the benefits they offer to the public, little is known about their occurrence in medical school curricula. The study aimed to investigate the availability of EO, SEM and musculoskeletal medicine in UK medical schools, opinions regarding the importance and quality of the teaching and to compare SEM and EO with musculoskeletal medicine teaching. A survey consisting of 14 questions was designed, piloted and then distributed to the deans of undergraduate medical education at 33 UK medical schools, as an anonymous online survey. After the initial launch of the survey, reminder emails were sent to participants every 4 weeks for 4 months. The response rate was 76%. All medical schools have a direct focus on musculoskeletal medicine in their curriculum. 68% have a direct focus on EO and 40% on SEM. There are more optional study opportunities in musculoskeletal medicine. 92% of medical schools assess musculoskeletal knowledge, while only 60% and 28% do so for EO and SEM, respectively. Musculoskeletal medicine is perceived to be more important and have better quality teaching than EO and SEM. The most common barrier to improving education was space in the curriculum. EO and SEM teaching are relatively uncommon in UK medical schools compared to musculoskeletal teaching. Increasing the perceived importance of these subjects and providing curricular guidance to medical schools will help improvements to be implemented. The optional curriculum, particularly student selected components, is likely to be the most appropriate initial method of increasing and improving teaching in EO and SEM.