tbuckley/cabot-search huggingface dataset:
Mitochondrial Haplogroups
Authors: Marianne Benn, Marianne Schwartz, Børge G. Nordestgaard, Anne Tybjærg-Hansen
Journal: Circulation (2008)

Rare mutations in the mitochondrial genome may cause disease. Mitochondrial haplogroups defined by common polymorphisms have been associated with risk of disease and longevity. We tested the hypothesis that common haplogroups predict risk of ischemic cardiovascular disease, morbidity from other causes, mortality, and longevity in a general population of European descent.We followed 9254 individuals from the Danish general population, in the Copenhagen City Heart Study, prospectively for risk of ischemic cardiovascular disease, morbidity from other causes, and mortality during 25 and 11 years, respectively. Haplogroup frequencies were as follows: H (45.9%), U (15.9%), T (9.9%), J (9.1), K (6.2%), V (4.5%), W/I (3.8%), and Z (3.5%). Hazard ratios for hospitalization due to all cardiovascular disorders (haplogroup U: 1.0 [95% confidence interval{CI}, 0.9 to 1.1]; T: 0.9 [95% CI, 0.8 to 1.0]; J: 1.0 [95% CI, 0.9 to 1.1]; K: 1.0 [95% CI, 0.9 to 1.2]; V: 1.0 [95% CI, 0.9 to 1.2]; W/I: 0.8 [95% CI, 0.7 to 1.0]; Z: 1.0 [95% CI, 0.8 to 1.2]), ischemic heart disease (U: 0.9 [95% CI, 0.8 to 1.1]; T: 0.9 [95% CI, 0.7 to 1.0]; J: 1.1 [95% CI, 0.9 to 1.2]; K: 1.1 [95% CI, 0.9 to 1.3]; V: 1.1 [95% CI, 0.9 to 1.4]; W/I: 1.1 [95% CI, 0.8 to 1.4]; Z: 1.1 [95% CI, 0.8 to 1.4]), and ischemic cerebrovascular disease (U: 1.1 [95% CI, 0.9 to 1.4]; T: 0.9 [95% CI, 0.7 to 1.2]; J: 1.1 [95% CI, 0.9 to 1.4]; K: 1.0 [95% CI, 0.8 to 1.4]; V: 1.1 [95% CI, 0.8 to 1.5]; W/I: 0.8 [95% CI, 0.5 to 1.3]; Z: 0.9 [95% CI, 0.6 to 1.4]) did not differ from 1.0 for any haplogroup versus the most common haplogroup H. Results were similar for hospitalization due to infectious and parasitic diseases, respiratory infections, respiratory disorders, malignant neoplasms, digestive disorders, musculoskeletal disorders, neuropsychiatric disorders, and miscarriages. Likewise, hazard ratios for death from all causes were not different from 1.0 for any haplogroup versus haplogroup H (U: 1.0 [95% CI, 0.8 to 1.1]; T: 0.9 [95% CI, 0.8 to 1.1]; J: 0.9 [95% CI, 0.8 to 1.1]; K: 1.0 [95% CI, 0.8 to 1.2]; V: 1.1 [95% CI, 0.9 to 1.3]; W/I: 0.8 [95% CI, 0.7 to 1.1]; Z: 0.9 [95% CI, 0.7 to 1.2]). Finally, after stratification by major causes of death, hazard ratios remained insignificant.Our results do not support an association of mitochondrial haplogroups with risk of ischemic cardiovascular disease, morbidity from other causes, mortality, or longevity in a large general population of European descent.
Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes
Authors: Pablo E. Pergola, Philip Raskin, Robert D. Toto, Colin J. Meyer, J. Warren Huff, Eric B. Grossman, Melissa Krauth, Stacey Ruiz, Paul Audhya, Heidi Christ-Schmidt, Janet Wittes, David G. Warnock
Journal: New England Journal of Medicine (2011)

Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined.
Targeted Drug Delivery to Intestinal Macrophages by Bioactive Nanovesicles Released from Grapefruit
Authors: Baomei Wang, Xiaoying Zhuang, Zhong-Bin Deng, Hong Jiang, Jingyao Mu, Qilong Wang, Xiaoyu Xiang, Haixun Guo, Lifeng Zhang, Gerald Dryden, Jun Yan, Donald Miller, Huang-Ge Zhang
Journal: Molecular Therapy (2013)

The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit-derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1β and TNF-α in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease. The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit-derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1β and TNF-α in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease.
Microarray-based Detection of Multidrug Resistance in Human Tumor Cells by Expression Profiling of ATP-binding Cassette Transporter Genes
Authors: Jean-Pierre Gillet, Thomas Efferth, Daniel Steinbach, Jacques Hamels, Françoise de Longueville, Vincent Bertholet, José Remacle
Journal: Cancer Research (2004)

Different mechanisms of drug resistance, including ATP-binding cassette (ABC) transporters, are responsible for treatment failure of tumors. We developed a low-density DNA microarray which contains 38 genes of the ABC transporter gene family. This tool has been validated with three different multidrug-resistant sublines (CEM/ADR5000, HL60/AR, and MCF7/CH1000) known to overexpress either the ABCB1 (MDR1), ABCC1 (MRP1), or ABCG2 (MXR and BCRP) genes. When compared with their drug-sensitive parental lines, we observed not only the overexpression of these genes in the multidrug-resistant cell lines but also of other ABC transporter genes pointing to their possible role in multidrug resistance. These results were corroborated by quantitative real-time reverse transcription-PCR. As the microarray allows the determination of the expression profile of many ABC transporters in a single hybridization experiment, it may be useful as a diagnostic tool to detect drug resistance in clinical samples.
Regrets or no regrets? No regrets! The fate of rejected manuscripts
Authors: T Opthof
Journal: Cardiovascular Research (2000)

In general, Editors are facing larger numbers of submitted manuscripts than they can publish. Thus they search for instruments to make a reasonable selection. One criterion may be a preference for certain topics within a broader field. Even then an imbalance may remain between submissions and available pages. Weighing of the relative quality of the submitted work is a prerequisite in order to make fair decisions. The most important instrument in this process is the advice of one or more peer reviewers [1]. Specialized research on the limitations of the peer review system is just starting to emerge [2–4]. From investigations on the editorial process of Radiology [5] and the Journal of Clinical Investigation [6], it has appeared that reviewers set markedly different standards in their appreciation of manuscripts even if based on a large group of reviewers that each handled many manuscripts. Also the concordance between reviewers on the same manuscripts is limited [6]. When fictitious manuscripts are sent to many more reviewers than what is usual for a standard journal, marked differences in reviewer's opinions become overt [7]. In the social sciences, papers published already have an almost 90% chance of being rejected when they are resubmitted to other journals [8]. The latter two types of studies raise ethical issues with respect to reviewers unaware of the fact that they are guinea pigs in an experiment [9].

The fate of rejected manuscripts, however, is terra incognita. We have explored this area by combining the data in the database of Cardiovascular Research with data in Ovid (Ovid Search …
International, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C
Authors: Stefan Zeuzem, Jean-Michel Pawlotsky, Esther Lukasiewicz, Michael von Wagner, Ioannis Goulis, Yoav Lurie, Elia Gianfranco, Jan-Maarten Vrolijk, Juan I. Esteban, Christophe Hezode, Martin Lagging, Francesco Negro, Alexandre Soulier, Elke Verheij-Hart, Bettina Hansen, Ronen Tal, Carlo Ferrari, Solko W. Schalm, Avidan U. Neumann, None for the DITTO-HCV Study Group
Journal: Journal of Hepatology (2005)
Novobiocin and Related Coumarins and Depletion of Heat Shock Protein 90-Dependent Signaling Proteins
Authors: Monica G. Marcu, Theodore W. Schulte, Leonard Neckers
Journal: JNCI Journal of the National Cancer Institute (2000)

Heat shock protein 90 (Hsp90) interacts with and stabilizes several oncogenic protein kinases (e.g., p185(erbB2), p60(v-src), and Raf-1) and is required for the stability and dominant-negative function of mutated p53 protein. Two unrelated antibiotics, geldanamycin and radicicol, bind specifically to an atypical nucleotide-binding pocket of Hsp90, a site that shares homology with the adenosine triphosphate (ATP)-binding domain of bacterial DNA gyrase B. This interaction leads to destabilization of proteins that interact with Hsp90. Since the nucleotide-binding site of gyrase B is targeted by coumarin antibiotics (e.g., novobiocin), we investigated whether these drugs can also interact with Hsp90 and affect its activity.We used immobilized novobiocin, geldanamycin, or radicicol to isolate either endogenous Hsp90 from cell lysates or Hsp90 deletion fragments translated in vitro. Effects of the coumarin antibiotics novobiocin, chlorobiocin, and coumermycin A1 on several proteins interacting with Hsp90 were assessed in vitro and in vivo.Hsp90 binding to immobilized novobiocin was competed by soluble coumarins and ATP but not by geldanamycin or radicicol. A carboxy-terminal Hsp90 fragment bound immobilized novobiocin but not immobilized geldanamycin, while a geldanamycin-binding amino-terminal fragment did not bind novobiocin. All three coumarins markedly reduced cellular levels of p185(erbB2), p60(v-src), Raf-1, and mutated p53. Furthermore, novobiocin reduced Raf-1 levels in the spleens of mice treated with the drug.These coumarin antibiotics, particularly novobiocin, represent a first-generation alternative to other Hsp90-targeting drugs that are not as well tolerated. Novobiocin's unique interaction with Hsp90 identifies an additional site on this protein amenable to pharmacologic interference with small molecules.
Eotaxin Expression after Segmental Allergen Challenge in Subjects with Atopic Asthma
Authors: CRAIG M. LILLY, HIDETOSHI NAKAMURA, OLGA I. BELOSTOTSKY, KATHLEEN J. HALEY, EDUARDO A. GARCIA-ZEPEDA, ANDREW D. LUSTER, ELLIOT ISRAEL
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Expression of pulmonary eotaxin protein and mRNA was determined in six subjects with atopic asthma and five nonatopic normal subjects. Levels of eotaxin expression and eosinophil mobilization were compared before and after segmental allergen challenge in subjects with atopic asthma. In the absence of allergen challenge, we found significantly higher levels of eotaxin in the bronchoalveolar lavage (BAL) fluid of subjects with asthma than in that of normal subjects (25 ± 3 versus 15 ± 2 pg/ml, p < 0.05). BAL eotaxin levels increased after segmental allergen challenge in all six subjects with atopic asthma tested, with a mean increase from 22 ± 4 to 53 ± 10 pg/ml (p = 0.013). Segmental allergen challenge was associated with a significant increase in the percentage of BAL macrophages and eosinophils that were immunopositive for eotaxin. Eotaxin mRNA was detectable by northern analysis in BAL cells exclusively from allergen-challenged segments. Allergen- induced increases in eotaxin levels were strongly associated with increases in BAL eosinophil recovery (r2 = 0.88, p = 0.0036). Segmental allergen challenge also increased eotaxin expression in airway epithelial and endothelial cells obtained by endobronchial biopsy. These findings demonstrate, for the first time, that the airways of subjects with allergic asthma respond to allergen by increasing eotaxin expression. The tissue loci of eotaxin expression, the levels of eotaxin recovered in BAL fluid, and the association of eotaxin levels with eosinophil mobilization suggest either that eotaxin plays a mechanistic role in allergen-induced airway eosinophilia or that it serves as a biomarker for the causal mechanisms.
The European initiative for quality management in lung cancer care
Authors: T. G. Blum, A. Rich, D. Baldwin, P. Beckett, D. De Ruysscher, C. Faivre-Finn, M. Gaga, F. Gamarra, B. Grigoriu, N. C. G. Hansen, R. Hubbard, R. M. Huber, E. Jakobsen, D. Jovanovic, A. Konsoulova, J. Kollmeier, G. Massard, J. McPhelim, A.-P. Meert, R. Milroy, M. Paesmans, M. Peake, P.-M. Putora, A. Scherpereel, N. Schonfeld, H. Sitter, K. Skaug, S. Spiro, T.-E. Strand, S. Taright, M. Thomas, P. E. van Schil, J. F. Vansteenkiste, R. Wiewrodt, J.-P. Sculier
Journal: European Respiratory Journal (2014)

Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.
Cisplatin Sensitivity Mediated by WEE1 and CHK1 Is Mediated by miR-155 and the miR-15 Family
Authors: Lynn M. Pouliot, Yu-Chi Chen, Jennifer Bai, Rajarshi Guha, Scott E. Martin, Michael M. Gottesman, Matthew D. Hall
Journal: Cancer Research (2012)

Abstract Resistance to platinum-based therapies arises by multiple mechanisms, including by alterations to cell-cycle kinases that mediate G2–M phase arrest. In this study, we conducted parallel high-throughput screens for microRNAs (miRNA) that could restore sensitivity to cisplatin-resistant cells, and we screened for kinases targeted by miRNAs that mediated cisplatin resistance. Overexpression of the cell-cycle kinases WEE1 and CHK1 occurred commonly in cisplatin-resistant cells. miRNAs in the miR-15/16/195/424/497 family were found to sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHK1. Loss-of-function and gain-of-function studies showed that miR-15 family members controlled the expression of WEE1 and CHK1. Supporting these results, we found that in the presence of cisplatin altering expression of miR-16 or related genes altered cell cycle distribution. Our findings reveal critical regulation of miRNAs and their cell-cycle–associated kinase targets in mediating resistance to cisplatin. Cancer Res; 72(22); 5945–55. ©2012 AACR.
Novel interfering bifunctional molecules against the CCR5 coreceptor are efficient inhibitors of HIV-1 infection
Authors: José Luis Abad, Manuel A González, Gustavo del Real, Emilia Mira, Santos Mañes, Fernando Serrano, Antonio Bernad
Journal: Molecular Therapy (2003)

CCR5 is the major coreceptor for the HIV-1 strains responsible for primary infection. Individuals homozygous for a 32-bp deletion in the CCR5 coding region are resistant to HIV-1 infection. Strategies to delete CCR5 functionally could thus be of substantial benefit in preventing HIV-1 infection or delaying disease. We evaluated new molecules for their ability to inhibit cell membrane CCR5 expression and to prevent HIV-1 infection. These inhibitors include several truncated forms of CCR5 that may act as negative transdominants, as well as bifunctional molecules resulting from the combination of a previously described anti-CCR5 ribozyme or a truncated CCR5 variant with an intracellular chemokine (RANTES-KDEL). These constructs efficiently blocked membrane CCR5 expression when cotransfected into HEK 293 cells. When expressed by retroviral transduction, some of these molecules significantly inhibited CCR5-dependent chemotaxis in the MCF-7 cell line and reduced CCR5 expression and HIV-1 infection in human T cells. Analysis of inhibitors with different efficiencies showed a strong linear correlation between CCR5 expression inhibition and prevention of HIV-1 infection. This study indicates the potential clinical application of several new CCR5 inhibitory molecules for HIV-1 gene therapy.
Progesterone Receptor in Estrogen Receptor–Positive Breast Cancer: The Association Between HER-2 and Lymph Node Involvement Is Age Related
Authors: Patrick Neven, Nathalie Pochet, Maria Drijkoningen, Frederic Amant, Frank De Smet, Robert Paridaens, Marie-Rose Christiaens, Ignace Vergote
Journal: Journal of Clinical Oncology (2006)
T cell receptors for responses to Mls determinants and allo-H-2 determinants appear to be encoded on different chromosomes.
Authors: S R Webb, J H Li, I MacNeil, P Marrack, J Sprent, D B Wilson
Journal: The Journal of Experimental Medicine (1985)

Previous studies have shown that T cell clones specific for strong Mlsa,d determinants concomitantly display apparently random reactivity to allo-H-2 determinants. One explanation for this finding is that T cell recognition of Mlsa,d and allo-H-2 determinants is controlled by separate sets of receptors. If these receptors were chromosomally unlinked, karyotypically unstable T cell hybrids with dual reactivity for Mlsa,d and particular allo-H-2 determinants would be expected, occasionally, to lose reactivity for one set of determinants, but not the other. The results presented here provide direct support for this prediction.
Depression and HIV Risk Behaviors Among Patients in a Sexually Transmitted Disease Clinic
Authors: Heidi E. Hutton, Constantine G. Lyketsos, Jonathan M. Zenilman, Richard E. Thompson, Emily J. Erbelding
Journal: American Journal of Psychiatry (2004)

The authors' goal was to investigate the relationship between depression and HIV risk behaviors or sexually transmitted disease (STD) diagnosis at an urban STD clinic.Using audio computer-assisted self-interview, 671 STD clinic patients answered questions about HIV risk behaviors and depression in a large-scale, cross-sectional study. A subset of the patients (N=201) was evaluated for current major depressive disorder by interviewers using the nonpatient edition of the Structured Clinical Interview for DSM-IV.Depressed patients were more likely to have sex for money or drugs, to have had sex with an intravenous drug user, to have sex when "high" on alcohol or drugs, to have a greater number of lifetime sex partners, and to abuse alcohol or drugs than were nondepressed patients. Associations of HIV risk behaviors with depression persisted after adjustment for substance abuse.Depression in STD clinic patients is associated with HIV risk behaviors but not STD diagnosis. Identifying depression and developing strategies to intervene effectively may reduce HIV risk behaviors and improve health outcomes.
Theranostic mRNA-loaded Microbubbles in the Lymphatics of Dogs: Implications for Drug Delivery
Authors: Heleen Dewitte, Katrien Vanderperren, Hendrik Haers, Emmelie Stock, Luc Duchateau, Myriam Hesta, Jimmy H. Saunders, Stefaan C. De Smedt, Ine Lentacker
Journal: Theranostics (2014)

Microbubbles have shown potential as intralymphatic ultrasound contrast agents while nanoparticle-loaded microbubbles are increasingly investigated for ultrasound-triggered drug and gene delivery. To explore whether mRNA-nanoparticle loaded microbubbles could serve as theranostics for detection of and mRNA transfer to the lymph nodes, we investigate the behavior of unloaded and mRNA-loaded microbubbles using contrast-enhanced ultrasound imaging after subcutaneous injection in dogs. Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained. Furthermore, additional observations were made regarding the dynamics of microbubble lymph node uptake. Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading. Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles.
THE PATHS OF RHEUMATIC INFECTION AND THEIR PROTECTION IN CHILDREN
Authors: J. R. Mackenzie
Journal: BMJ (1912)

TRftEUMATIC INFECTION.t UNE I, 1912.autoinoculation test we possess the means of diagnosing tuberculosis in its earlier stages, of the further fact that this test is so extraordinarily reliable, that on its verdict alone treatment may be confidently applied or as con- fidently omitted, and, lastly, of its utilitv in directing the course of our treatment and of deciding the moment when cure is complete, REFERENCES.