tbuckley/cabot-search huggingface dataset:
Divergence of the Mitochondrial Genome Structure in the Apicomplexan Parasites, Babesia and Theileria
Authors: K. Hikosaka, Y. i. Watanabe, N. Tsuji, K. Kita, H. Kishine, N. Arisue, N. M. Q. Palacpac, S. i. Kawazu, H. Sawai, T. Horii, I. Igarashi, K. Tanabe
Journal: Molecular Biology and Evolution (2009)

Mitochondrial (mt) genomes from diverse phylogenetic groups vary considerably in size, structure, and organization. The genus Plasmodium, causative agent of malaria, of the phylum Apicomplexa, has the smallest mt genome in the form of a circular and/or tandemly repeated linear element of 6 kb, encoding only three protein genes (cox1, cox3, and cob). The closely related genera Babesia and Theileria also have small mt genomes (6.6 kb) that are monomeric linear with an organization distinct from Plasmodium. To elucidate the structural divergence and evolution of mt genomes between Babesia/Theileria and Plasmodium, we determined five new sequences from Babesia bigemina, B. caballi, B. gibsoni, Theileria orientalis, and T. equi. Together with previously reported sequences of B. bovis, T. annulata, and T. parva, all eight Babesia and Theileria mt genomes are linear molecules with terminal inverted repeats (TIRs) on both ends containing three protein-coding genes (cox1, cox3, and cob) and six large subunit (LSU) ribosomal RNA (rRNA) gene fragments. The organization and transcriptional direction of protein-coding genes and the rRNA gene fragments were completely conserved in the four Babesia species. In contrast, notable variation occurred in the four Theileria species. Although the genome structures of T. annulata and T. parva were nearly identical to those of Babesia, an inversion in the 3-kb central region was found in T. orientalis. Moreover, the T. equi mt genome is the largest (8.2 kb) and most divergent with unusually long TIR sequences, in which cox3 and two LSU rRNA gene fragments are located. The T. equi mt genome showed little synteny to the other species. These results suggest that the Theileria mt genome is highly diverse with lineage-specific evolution in two Theileria species: genome inversion in T. orientalis and gene-embedded long TIR in T. equi.
Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection
Authors: Roy T. Steigbigel, David A. Cooper, Princy N. Kumar, Joseph E. Eron, Mauro Schechter, Martin Markowitz, Mona R. Loutfy, Jeffrey L. Lennox, Jose M. Gatell, Jurgen K. Rockstroh, Christine Katlama, Patrick Yeni, Adriano Lazzarin, Bonaventura Clotet, Jing Zhao, Joshua Chen, Desmond M. Ryan, Rand R. Rhodes, John A. Killar, Lucinda R. Gilde, Kim M. Strohmaier, Anne R. Meibohm, Michael D. Miller, Daria J. Hazuda, Michael L. Nessly, Mark J. DiNubile, Robin D. Isaacs, Bach-Yen Nguyen, Hedy Teppler
Journal: New England Journal of Medicine (2008)

Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs.We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio.In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups.In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)
Impact of a Multi-Disciplinary Patient Education Session on Accrual to a Difficult Clinical Trial: The Toronto Experience With the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial
Authors: Kris Wallace, Neil Fleshner, Michael Jewett, Joan Basiuk, Juanita Crook
Journal: Journal of Clinical Oncology (2006)

Random assignment to clinical trials involving different treatment modalities can be difficult. We describe our experience with the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT; ACOSOG Z0070 NCIC PR10), a randomized trial for early-stage prostate cancer comparing radical prostatectomy (RP), and brachytherapy (BT). A multidisciplinary educational session was developed to improve patient understanding of treatment options and to facilitate accrual.Prostate cancer referrals were screened and men who met favorable risk criteria (T1c/T2a, prostate-specific antigen [PSA] < 10 ng/mL, Gleason < or = 6) were invited to a structured education session before a specialty consultation. Men and their partners viewed the SPIRIT informed-consent video and heard from a cancer patient who described his participation in a randomized trial. Then, a urologist and radiation oncologist together compared and contrasted RP and BT to establish the rationale for the trial.In May 2002, SPIRIT opened for accrual and was endorsed by the University Health Network urologists and radiation oncologists. The first 27 eligible patients were approached about SPIRIT, consulted both specialties, and viewed an educational video. No patients consented. The multidisciplinary education session was then introduced. Forty-seven education sessions with 263 patients resulted in 34 consents. Of 203 patients who were suitable for the study but declined random assignment, 62 chose surgery, 94 chose brachytherapy, three patients chose external radiotherapy, and 11 chose no treatment. Consent rates for eligible and suitable patients were one in six.Men who understand their treatment options and trial rationale as presented jointly by representative specialists from competing treatment modalities may be better equipped to make an informed decision and are more likely to consent to random assignment.
Asbestos bodies in bronchoalveolar lavage in relation to asbestos bodies and asbestos fibres in lung parenchyma
Authors: A Karjalainen, R Piipari, T Mantyla, M Monkkonen, M Nurminen, P Tukiainen, E Vanhala, S Anttila
Journal: European Respiratory Journal (1996)

In Finland, unlike other countries, anthophyllite asbestos has been widely used due to its domestic production in 1918-1975. In this particular context, the aim of the present study was to analyse the relationship between asbestos bodies (ABs) in bronchoalveolar lavage (BAL) fluid and the concentration of ABs and the different amphibole asbestos fibres in lung tissue. Sixty five BAL lung tissue sample pairs from patients with pulmonary disease were analysed. The concentration of ABs in BAL fluid and lung tissue was determined with optical microscopy, and the concentration, type and dimensions of asbestos fibres in lung tissue with scanning electron microscopy. There was a significant correlation between the concentrations of ABs in BAL fluid and in lung tissue (r = 0.72; p < 0.001), between the concentrations of ABs and amphibole asbestos fibres in lung tissue (r = 0.73; p < 0.001), and between the concentration of ABs in BAL fluid and the concentration of amphibole asbestos fibres in lung tissue (r = 0.64; p < 0.001). In patients who had been exposed mainly to commercial anthophyllite, significantly higher concentrations of ABs were observed per total pulmonary amphibole fibre burden, as compared to patients whose main exposure was to crocidolite/amosite. The anthophyllite fibres in lung tissue were longer than the crocidolite/amosite fibres. The relationship between asbestos body counts in lung tissue and in bronchoalveolar lavage fluid was similar to previous international observations. When using the asbestos body count to predict the underlying total pulmonary amphibole asbestos burden in Finnish patients, however, it should be borne in mind that the relationship between the two parameters seems to be different with anthophyllite as compared to crocidolite/amosite fibres.
Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment
Authors: Hani N. Sabbah, Victor G. Sharov, Ramesh C. Gupta, Sudhish Mishra, Sharad Rastogi, Albertas I. Undrovinas, Pervaiz A. Chaudhry, Anastassia Todor, Takayuki Mishima, Elaine J. Tanhehco, George Suzuki
Journal: Circulation Research (2003)

Passive mechanical containment of failing left ventricle (LV) with the Acorn Cardiac Support Device (CSD) was shown to prevent progressive LV dilation in dogs with heart failure (HF) and increase ejection fraction. To examine possible mechanisms for improved LV function with the CSD, we examined the effect of CSD therapy on the expression of cardiac stretch response proteins, myocyte hypertrophy, sarcoplasmic reticulum Ca 2+ -ATPase activity and uptake, and mRNA gene expression for myosin heavy chain (MHC) isoforms. HF was produced in 12 dogs by intracoronary microembolization. Six dogs were implanted with the CSD and 6 served as concurrent controls. LV tissue from 6 normal dogs was used for comparison. Compared with normal dogs, untreated HF dogs showed reduced cardiomyocyte contraction and relaxation, upregulation of stretch response proteins (p21ras, c-fos, and p38 α/β mitogen-activated protein kinase), increased myocyte hypertrophy, reduced SERCA2a activity with unchanged affinity for calcium, reduced proportion of mRNA gene expression for α-MHC, and increased proportion of β-MHC. Therapy with the CSD was associated with improved cardiomyocyte contraction and relaxation, downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, increased affinity of the pump for calcium, and restoration of α- and β-MHC isoforms ratio. The results suggest that preventing LV dilation and stretch with the CSD promotes downregulation of stretch response proteins, attenuates myocyte hypertrophy and improves SR calcium cycling. These data offer possible mechanisms for improvement of LV function after CSD therapy.
Cytokine profiling at disease onset: support for classification of young antinuclear antibody-positive patients as a separate category of juvenile idiopathic arthritis
Authors: Theo van den Broek, Esther Hoppenreijs, Jenny Meerding, Rianne Scholman, Henny G Otten, Joost F Swart, Alberto Martini, Berent Prakken, Wilco de Jager
Journal: Annals of the Rheumatic Diseases (2014)

The current classification for juvenile idiopathic arthritis (JIA) separates the disease entity JIA into seven disease categories based on clinical and laboratory features1 It is postulated that the combination of early onset of disease and antinuclear antibody (ANA) positivity better classifies a homogeneous subset of patients than the current International League of Associations for Rheumatology (ILAR) categories, displaying asymmetric arthritis, female predominance and an increased risk of developing iridocyclitis.2–5 The classification by the number of joints involved might not be an adequate criterion for identifying homogeneous disease entities. We sought out to determine if this homogenous group of young ANA-positive patients could be distinguished from other JIA patients based on their soluble inflammatory profile. These profiles could aid in the differentiation of patient groups by identifying similar underlying inflammatory processes.

This study prospectively followed 40 patients with JIA at onset of disease at their first visit to the paediatric rheumatology clinic for oligoarthritis (n=24) and rheumatoid factor-negative polyarthritis (n=16). Ethics approval was given by the regional review boards. Informed consent was obtained from all patients. The occurrence of iridocylitis was determined by reviewing total clinical history; the time of follow-up did not differ between the groups analysed (table 1). Apart from nonsteroidal anti-inflammatory drugs (NSAID) therapy, …
Down-regulation of the Nucleotide Excision Repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells
Authors: Maria Antonietta Sabatino, Mirko Marabese, Monica Ganzinelli, Elisa Caiola, Cristina Geroni, Massimo Broggini
Journal: Molecular Cancer (2010)

Drug resistance is one of the major obstacles limiting the activity of anticancer agents. Activation of DNA repair mechanism often accounts for increase resistance to cancer chemotherapy.We present evidence that nemorubicin, a doxorubicin derivative currently in clinical evaluation, acts through a mechanism of action different from classical anthracyclines, requiring an intact nucleotide excision repair (NER) system to exert its activity. Cells made resistant to nemorubicin show increased sensitivity to UV damage. We have analysed the mechanism of resistance and discovered a previously unknown mechanism resulting from methylation-dependent silencing of the XPG gene. Restoration of NER activity through XPG gene transfer or treatment with demethylating agents restored sensitivity to nemorubicin. Furthermore, we found that a significant proportion of ovarian tumors present methylation of the XPG promoter.Methylation of a NER gene, as described here, is a completely new mechanism of drug resistance and this is the first evidence that XPG gene expression can be influenced by an epigenetic mechanism. The reported methylation of XPG gene could be an important determinant of the response to platinum based therapy. In addition, the mechanism of resistance reported opens up the possibility of reverting the resistant phenotype using combinations with demethylating agents, molecules already employed in the clinical setting.
Phase 1 Trial of Flavopiridol Combined with Cisplatin or Carboplatin in Patients with Advanced Malignancies with the Assessment of Pharmacokinetic and Pharmacodynamic End Points
Authors: Keith C. Bible, Janet L. Lensing, Sacha A. Nelson, Yean K. Lee, Joel M. Reid, Matthew M. Ames, Crescent R. Isham, Jill Piens, Stacie L. Rubin, Joseph Rubin, Scott H. Kaufmann, Pamela J. Atherton, Jeffrey A. Sloan, Michelle K. Daiss, Alex A. Adjei, Charles Erlichman
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC). Experimental Design: Therapy was given every 3 weeks. Stage I: cisplatin was fixed at 30 mg/m2 with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin. Results: Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (&amp;gt;3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m2 cisplatin and 100 mg/m2/24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1. Conclusions: Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.
Use of Indicator Dilution Techniques in Measuring Combined Aortic and Mitral Insufficiency
Authors: Dennis A. Bloomfield, Edward J. Battersby, Bruce C. Sinclair-Smith
Journal: Circulation Research (1966)

In patients with combined aortic and mitral valvular insufficiency, the combined regurgitant fraction across both valves has been shown to equal the product of the regurgitant fractions at each valve. This relationship was validated in nine patients, and in eight other patients was used to predict the degree of regurgitation at one valve when the regurgitant fraction at the other valve and the combined regurgitant fraction were known. Confirmation of the predicted degrees of insufficiency were afforded by cineangiocardiography and surgical inspection. Information of considerable usefulness predicting the least possible degrees of valvular insufficiency could be obtained from the measurement of the combined regurgitant fraction alone.
Spreaders and Sponges Define Metastasis in Lung Cancer: A Markov Chain Monte Carlo Mathematical Model
Authors: Paul K. Newton, Jeremy Mason, Kelly Bethel, Lyudmila Bazhenova, Jorge Nieva, Larry Norton, Peter Kuhn
Journal: Cancer Research (2013)

Abstract The classic view of metastatic cancer progression is that it is a unidirectional process initiated at the primary tumor site, progressing to variably distant metastatic sites in a fairly predictable, although not perfectly understood, fashion. A Markov chain Monte Carlo mathematical approach can determine a pathway diagram that classifies metastatic tumors as “spreaders” or “sponges” and orders the timescales of progression from site to site. In light of recent experimental evidence highlighting the potential significance of self-seeding of primary tumors, we use a Markov chain Monte Carlo (MCMC) approach, based on large autopsy data sets, to quantify the stochastic, systemic, and often multidirectional aspects of cancer progression. We quantify three types of multidirectional mechanisms of progression: (i) self-seeding of the primary tumor, (ii) reseeding of the primary tumor from a metastatic site (primary reseeding), and (iii) reseeding of metastatic tumors (metastasis reseeding). The model shows that the combined characteristics of the primary and the first metastatic site to which it spreads largely determine the future pathways and timescales of systemic disease. Cancer Res; 73(9); 2760–9. ©2013 AACR.
Mucosal prolapse in the pathogenesis of Peutz-Jeghers polyposis
Authors: M Jansen
Journal: Gut (2005)

Germline mutations in <i>LKB1</i> cause the rare cancer prone disorder Peutz-Jeghers syndrome (PJS). Gastrointestinal hamartomatous polyps constitute the major phenotypic trait in PJS. Hamartomatous polyps arising in PJS patients are generally considered to lack premalignant potential although rare neoplastic changes in these polyps and an increased gastrointestinal cancer risk in PJS are well documented. These conflicting observations are resolved in the current hypothesis by providing a unifying explanation for these contrasting features of PJS polyposis. We postulate that a genetic predisposition to epithelial prolapse underlies the formation of the polyps associated with PJS. Conventional sporadic adenomas arising in PJS patients will similarly show mucosal prolapse and carry the associated histological features.
Triple inhaler therapy for COPD
Authors: Brian Lipworth
Journal: Thorax (2015)

The randomised controlled trial (GLISTEN) by Frith et al 1 showed significant improvements in trough FEV1, health-related quality of life and rescue medication when long-acting muscarinic antagonists (LAMA: as either tiotropium or glycopyrronium) were added to inhaled corticosteroid/long-acting beta-agonist (ICS/LABA: as fluticasone/salmeterol) in 773 patients with moderate-to-severe COPD (FEV1 57.2%) over 12 weeks. The authors concluded that this was the first …
Effect of Age, Gender, and Diabetes on Excess Death in End-Stage Renal Failure
Authors: Emmanuel Villar, Laurent Remontet, Michel Labeeuw, René Ecochard
Journal: Journal of the American Society of Nephrology (2007)

Life expectancy is short in elderly individuals with end-stage renal failure (ESRF). This study aimed to compare mortality in patients with ESRF versus the general population (GP) to assess the evolution of excess mortality by age, gender, nephropathy, and dialysis modality after first dialysis. All incident adult dialysis patients from January 1,1999, to December 31, 2003, who lived in Rho[Combining Circumflex Accent]ne–Alpes Region (France) were included and followed up to death or December 31, 2005. Standardized mortality ratios (SMR) in comparison with GP were computed in the first to the fifth years after first dialysis. In the whole cohort (3025 incident patients), SMR decreased during these 5 yr from 7.4 to 5.2 (P = 0.002). In the 18- to 44-, 45- to 64-, 65- to 74-, 75- to 84-, and ≥85-yr-old groups, SMR decreased from 26.7 to 6.2 (P = 0.01), from 12.8 to 8.1 (P = 0.03), from 8.6 to 5.6 (P = 0.051), from 7.1 to 4.5 (P = 0.02), and from 3.5 to 1.2 (P = 0.14), respectively. Among age categories, differences were significant in the first 3 yr (P < 0.05). SMR were higher 1.5-fold in women than in men in the first 4 yr (P < 0.05). In patients with diabetic nephropathy (DN), SMR increased during the first 3 yr (P = 0.045) and were higher than in patients without DN in the second, third, and fourth years (P < 0.05). SMR were higher in the peritoneal dialysis than in the hemodialysis group in the fourth year (P < 0.01). Patients with ESRF have a high excess mortality compared with the GP. Older patients with ESRF experienced less excess mortality. ESRF cancels out women's survival advantage noted in the GP. SMR evolution in patients with DN was different from that in patients without DN.
Effects of Respiratory Rate, Plateau Pressure, and Positive End-Expiratory Pressure on Pa<sub>O2</sub> Oscillations after Saline Lavage
Authors: James E. Baumgardner, Klaus Markstaller, Birgit Pfeiffer, Marcus Doebrich, Cynthia M. Otto
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

One of the proposed mechanisms of ventilator-associated lung injury is cyclic recruitment of atelectasis. Collapse of dependent lung regions with every breath should lead to large oscillations in PaO2 as shunt varies throughout the respiratory cycle. We placed a fluorescence-quenching PO2 probe in the brachiocephalic artery of six anesthetized rabbits after saline lavage. Using pressure-controlled ventilation with oxygen, ventilator settings were varied in random order over three levels of positive end-expiratory pressure (PEEP), respiratory rate (RR), and plateau pressure minus PEEP (Δ). Dependence of the amplitude of PaO2 oscillations on PEEP, RR, and Δ was modeled by multiple linear regression. Before lavage, arterial PO2 oscillations varied from 3 to 22 mm Hg. After lavage, arterial PO2 oscillations varied from 5 to 439 mm Hg. Response surfaces showed markedly nonlinear dependence of amplitude on PEEP, RR, and Δ. The large PaO2 oscillations observed provide evidence for cyclic recruitment in this model of lung injury. The important effect of RR on the magnitude of PaO2 oscillations suggests that the static behavior of atelectasis cannot be accurately extrapolated to predict dynamic behavior at realistic breathing frequencies.