tbuckley/cabot-search huggingface dataset:
Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study
Authors: Linda Wittkop, Huldrych F Günthard, Frank de Wolf, David Dunn, Alessandro Cozzi-Lepri, Andrea de Luca, Claudia Kücherer, Niels Obel, Viktor von Wyl, Bernard Masquelier, Christoph Stephan, Carlo Torti, Andrea Antinori, Federico García, Ali Judd, Kholoud Porter, Rodolphe Thiébaut, Hannah Castro, Ard I van Sighem, Céline Colin, Jesper Kjaer, Jens D Lundgren, Roger Paredes, Anton Pozniak, Bonaventura Clotet, Andrew Phillips, Deenan Pillay, Geneviève Chêne
Journal: The Lancet Infectious Diseases (2011)
A statistical approach for detecting genomic aberrations in heterogeneous tumor samples from single nucleotide polymorphism genotyping data
Authors: Christopher Yau, Dmitri Mouradov, Robert N Jorissen, Stefano Colella, Ghazala Mirza, Graham Steers, Adrian Harris, Jiannis Ragoussis, Oliver Sieber, Christopher C Holmes
Journal: Genome biology (2010)

Abstract We describe a statistical method for the characterization of genomic aberrations in single nucleotide polymorphism microarray data acquired from cancer genomes. Our approach allows us to model the joint effect of polyploidy, normal DNA contamination and intra-tumour heterogeneity within a single unified Bayesian framework. We demonstrate the efficacy of our method on numerous datasets including laboratory generated mixtures of normal-cancer cell lines and real primary tumours.
EBUS-TBNA in a tertiary care center: Real life experience and quality assessment
Authors: Philippe Nguyen, Michel Gagnon, Thomas Vandemoortele
Journal: European Respiratory Journal (2012)

INTRODUCTION  Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become the standard minimally invasive modality for sampling mediastinal lymph nodes. In this study, we evaluate our performance with the technique and propose a methodology that can be used in other center.  METHOD  We included all EBUS-TBNA procedures performed in 2011 in our service. We proceeded to a thorough analysis of each case from a pragmatic perspective to evaluate the regional node sampling yield and our ability to conclude the investigation by achieving diagnosis and staging, avoiding unnecessary surgery and allowing direction for management.  RESULTS  EBUS-TBNA was performed in 53 consecutive patients. The indication was suspicion of malignant disease in 46 patients (87%) and benign in 7 patients (13%). In total, 117 nodes were sampled. The overall sensitivity ranged from 76 to 91% and the negative predictive value ranged from 78 to 92%. The median size of nodes was 15 mm. If malignant cells were discovered, histological precision was obtained in 68%. EBUS-TBNA was clinically sufficient in 43 of the 53 patients (diagnostic yield = 81%) and prevented 18 out of 27 patients (67%) from undergoing surgery. No major complications were reported.  CONCLUSION  The attained sensitivity and negative predicitive value are similar to what has been published. Thorough analysis of patient cases is key in improving performance with this technique, and we encourage all centers to analyze their practice periodically in order to maintain quality standards. Finally, in our establishment, EBUS-TBNA offers clinicians an additional step to simplify healthcare and probably reduce the economic burden of such investigations.
Messenger RNA Expression Levels of CXCR4 Correlate with Metastatic Behavior and Outcome in Patients with Osteosarcoma
Authors: Caroline Laverdiere, Bang H. Hoang, Rui Yang, Rebecca Sowers, Jing Qin, Paul A. Meyers, Andrew G. Huvos, John H. Healey, Richard Gorlick
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine if osteosarcoma cells express chemokine receptors and if their presence or absence relates to clinical features. Experimental Design: Using fluorescent quantitative real-time PCR, the pattern of 17 chemokine receptors in 3 osteosarcoma cell lines and 68 osteosarcoma patient samples was analyzed. Results: The expression of the chemokine receptors was generally low among the cell lines. In the high-grade osteosarcoma patient samples (n = 47), CXCR4 was the most commonly expressed (63%) and its expression level was inversely correlated to overall survival (P &amp;lt; 0.0001), event-free survival (P &amp;lt; 0.001), and metastasis-free survival (MFS; P = 0.002). There was also a correlation between the expression level of CXCR4 and the presence of metastasis at diagnosis (P = 0.002). CCR7 was expressed in 43% of the samples and its expression level was inversely correlated with overall survival (P = 0.03) and MFS (P = 0.007). CCR10 mRNA expression level was inversely correlated with MFS (P = 0.009). There was no association between the expression of CXCR4, CCR7, and CCR10. Of the 26 samples studied for stromal cell–derived factor-1 expression, 77% expressed it, but there was no correlation with the clinical variables or CXCR4 expression. Multivariate analysis revealed that mRNA expression level of CXCR4 was the only significant variable for overall survival (P = 0.0006), event-free survival (P = 0.004), and MFS (P = 0.025). Conclusions: These data suggest that CXCR4 could be useful as a prognostic factor and as a predictor of potential metastatic development in osteosarcoma. If further studies confirm that it is relevant to metastases in this disease, it could represent a new therapeutic target.
Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics
Authors: Mona D. Lee, Yuhong She, Michael J. Soskis, Christopher P. Borella, Jeffrey R. Gardner, Paula A. Hayes, Benzon M. Dy, Mark L. Heaney, Mark R. Philips, William G. Bornmann, Francis M. Sirotnak, David A. Scheinberg
Journal: Journal of Clinical Investigation (2004)

Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.
1213 EFFICACY AND SAFETY OF MERICITABINE (MCB) IN COMBINATION WITH PEG-IFNa-2A/RBV IN G1/4 TREATMENT NAIVE HCV PATIENTS: FINAL ANALYSIS FROM THE PROPEL STUDY
Authors: H. Wedemeyer, D. Jensen, R. Herring, P. Ferenci, M.M. Ma, S. Zeuzem, M. Rodriguez-Torres, N. Bzowej, P. Pockros, J. Vierling, D. Ipe, I. Najera, J. Thommes
Journal: Journal of Hepatology (2012)
Changes in neural network homeostasis trigger neuropsychiatric symptoms
Authors: Aline Winkelmann, Nicola Maggio, Joanna Eller, Gürsel Caliskan, Marcus Semtner, Ute Häussler, René Jüttner, Tamar Dugladze, Birthe Smolinsky, Sarah Kowalczyk, Ewa Chronowska, Günter Schwarz, Fritz G. Rathjen, Gideon Rechavi, Carola A. Haas, Akos Kulik, Tengis Gloveli, Uwe Heinemann, Jochen C. Meier
Journal: Journal of Clinical Investigation (2014)

The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type–specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type–specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease–causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.
Minireview: Epigenetic Alterations in Human Prostate Cancers
Authors: William G. Nelson, Angelo M. De Marzo, Srinivasan Yegnasubramanian
Journal: Endocrine Reviews (2009)

Human prostate cancer cells carry a myriad of genome defects, including both genetic and epigenetic alterations. These changes, which can be maintained through mitosis, generate malignant phenotypes capable of selective growth, survival, invasion, and metastasis. During prostatic carcinogenesis, epigenetic changes arise earlier than genetic defects, linking the appearance of epigenetic alterations in some way to disease etiology. The most common genetic defect thus far described, leading to fusion transcripts between the androgen-regulated gene TMPRSS2 and genes from the ETS family of transcription factors, likely endows prostate cancer cells with the ability to co-opt androgen signaling, the major prostate differentiation pathway, to support the malignant phenotype. Whether epigenetic changes promote the appearance of TMPRSS2-ETS family fusion transcripts or collaborate with fusion transcript expression in the pathogenesis of prostate cancer has not been established. However, a growing list of epigenetic alterations has provided new opportunities for clinical tests that might aid in prostate cancer screening, detection, diagnosis, staging, and risk stratification. The epigenetic changes appear to be more attractive than genetic changes as prostate cancer biomarkers because epigenetic alterations are present in a greater fraction of prostate cancer cases than any of the known genetic defects. In addition, an emerging generation of assay strategies for detection of specific DNA sequences carrying 5-meC, the major epigenetic genome mark, has pushed somatic epigenetic alterations to the forefront of molecular biomarker assay development for cancer. Finally, a growing portfolio of epigenetic drugs, capable of reversing the phenotypic consequences of somatic epigenetic defects, has entered clinical trials for prostate cancer in the search for a new rational therapy for the disease.
Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family.
Authors: Judy A Cam, Guojun Bu
Journal: Molecular Neurodegeneration (2006)

Amyloid-β peptide (Aβ) accumulation in the brain is an early, toxic event in the pathogenesis of Alzheimer's disease (AD). Aβ is produced by proteolytic processing of a transmembrane protein, β-amyloid precursor protein (APP), by β- and γ-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Aβ. Recent studies have shown that members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apolipoprotein E (apoE) receptor 2, interact with APP and regulate its endocytic trafficking. Another common feature of these receptors is their ability to bind apoE, which exists in three isoforms in humans and the presence of the ε4 allele represents a genetic risk factor for AD. In this review, we summarize the current understanding of the function of these apoE receptors with a focus on their role in APP trafficking and processing. Knowledge of the interactions between these distinct low-density lipoprotein receptor family members and APP may ultimately influence future therapies for AD.
LL-03 * STEREOTACTIC RADIOSURGERY FOR SALVAGE TREATMENT OF RECURRENT CNS LYMPHOMA
Authors: R. Kumar, N. Laack, B. Pollock, M. Link, B. O'Neill, I. Parney
Journal: Neuro-Oncology (2014)

BACKGROUND: Primary and secondary central nervous system lymphoma (PCNSL, SCNSL) are typically treated with chemotherapy and external beam radiation therapy (EBRT). There is no standard salvage therapy for either. The role of stereotactic radiosurgery (SRS) as salvage therapy in PCNSL and SCNSL is poorly defined. METHODS: A retrospective analysis was performed of all patients having SRS, typically using the Gamma Knife (GK), for recurrent intracranial PCNSL and SCNSL at Mayo Clinic Rochester between 2004 and 2011. RESULTS: Fourteen patients underwent SRS. All had their SRS via the GK. The median patient age was 71 years. Seven patients (50%) had PCNSL and seven patients had SCNSL. All had received prior chemotherapy and 10 patients (71%) had undergone prior EBRT with a median dose of 40 Gy in 25 fractions. The median tumor volume was 6.7 cm3 (range, 0.5-37.7); the median margin dose was 15.5 Gy (range, 10-18). Eleven patients (79%) had tumor regression (n = 11) shown on MRI after SRS. The median overall survival after SRS was 288 days, 472 days for PCNSL and 288 days for SCNSL. Significant factors contributing to survival greater 9 months following SRS, were increased marginal dose (Odds ratio = 7.8, p = 0.006, 95% CI (1.74-188.79), increase in maximal dose (Odds ratio = 1.54, p = 0.008, 95% CI (1.09-2.77), and increase in pre-treatment Karnofsky score (Odds ratio = 4.69, p = 0.001, 95% CI (1.45-75.5). No patient had a major radiation-related complication. CONCLUSION: SRS for patients with recurrent CNS lymphoma is well-tolerated and has a high rate of radiographic response. Survival after SRS varied based on multiple factors including marginal and maximal radiation dose and pretreatment Karnofsky score. Control of microscopic disease using established therapies remains vitally important and is not addressed with SRS. SRS represents a viable therapy for local control of recurrent CNS lymphoma for properly selected patients.
Temporarily Dependent Patient in General Practice
Authors: K. B. Thomas
Journal: BMJ (1974)

Of 3,848 consultations with patients at 330 general practice surgeries during one year, no diagnosis was made in 1,656, The latter received no effective treatment other than contact with their doctor, and were asked to return if they did not feel better. But 1,191 did not return, Subsequent inquiry showed that 976 (82%) said they had been made better, and a further 131 (11%) said that, though they were no better, they had not sought further treatment. The “successfully untreated” patients were shown not to differ significantly from those patients in whom a definite diagnosis had been made, with regard to neuroticism, extraversion, intelligence, age, sex, marital status, social class, length of stay in the practice, number of consultations, and absence from work. These patients have been called “temporarily dependent” patients and their possible influence on diagnosis is discussed.
Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression
Authors: Katarina Rask, Yihong Zhu, Wanzhong Wang, Lars Hedin, Karin Sundfeldt
Journal: Molecular Cancer (2006)

The involvement of the cyclooxygenases (COX), in particular COX-2, is well documented for many tumours, e.g. colon, breast and prostate cancer, by both experimental and clinical studies. There are epidemiological data from subjects using NSAIDs, and experimental evidence supporting the hypothesis of prostaglandins (PGs) as regulators of tumourigenesis in the ovary. One of the end products of PG-synthesis, PGE2, regulates several key-processes, which are characteristic for tumour growth, e.g. angiogenesis, proliferation and apoptosisis. The present study investigated the pathway for PGE2-synthesis and signalling in ovarian tumourigenesis by analysing specimen from normal ovaries (n = 18), benign (B) (n = 8), borderline type (BL) (n = 6) and malignant tumours (AC) (n = 22). The expression and cell-specific localization of COX-1, COX-2, microsomal prostaglandin E synthase-1 (mPGES-1) and two of the receptors for PGE2, EP1 and EP2, were examined by immunoblotting (IB) and immunohistochemistry (IHC).The results are in line with earlier studies demonstrating an increase of COX-2 in AC compared to the normal ovary, B and BL tumours. Increased expressions were also observed for COX-1, mPGES-1 and EP-1 which all were significantly (p < 0.05) augmented in less differentiated AC (grades: moderately-, poorly- and undifferentiated). The increase of COX-2 was also correlated to stage (FIGO classification) with significant elevations in stages II and III. EP1 was increased in stage III while no significant alterations were demonstrated for COX-1, mPGES-1 or EP2 for stage. IHC revealed staining of the tumour cells, but also increase of COX-1, COX-2, mPGES-1 and EP1-2 in the stromal compartment of AC (grades: moderately-, poorly- and undifferentiated). This observation suggests interactions between tumour cells and stromal cells (fibroblasts, immune cells), e.g. paracrine signalling mediated by growth factors, cytokines and possibly PGs.The increases of COX-1, COX-2, mPGES-1 and EP1-2 in epithelial ovarian cancer, supports the hypothesis that PGE2-synthesis and signalling are of importance for malignant transformation and progression. The observed augmentations of COX-1, COX-2 and mPGES-1 have implications for future therapeutic strategies.
Human and canine pulmonary Mycobacterium bovis infection in the same household: re-emergence of an old zoonotic threat?
Authors: D Shrikrishna, R de la Rua-Domenech, N H Smith, A Colloff, I Coutts
Journal: Thorax (2008)

Bovine tuberculosis (bTB), caused by <i>Mycobacterium bovis</i>, remains a serious animal health problem in the UK, despite longstanding statutory surveillance and control measures. Endemic infection in the Eurasian badger population is thought to complicate bTB eradication efforts. Sporadic cases of <i>M bovis</i> infection have also been reported in domestic animals other than cattle. Human <i>M bovis</i> infection is extremely rare in the native UK population in the absence of unpasteurised milk consumption or residence abroad. Here, pulmonary TB infection in a UK born female and her pet dog is described, caused by an identical strain of <i>M bovis</i>. Latent TB infection was also identified in a household contact. The potential routes of infection and implications of this case are discussed.
Comparison of human lung surface protein profiles from the central and peripheral airways sampled using two regional lavage techniques
Authors: SF Smith, A Guz, AJ Winning, NT Cooke, GH Burton, TD Tetley
Journal: European Respiratory Journal (1988)

This study describes two new techniques of lung lavage which selectively remove material from the central airways, or from the lung below the seventh generation. Bronchograms confirmed that discrete regions of the lung were washed by central lavage (CL; maximum airway diameter approximately 6.5 mm) and peripheral lavage (PL; maximum airway diameter approximately 1.3 mm), and that both could be clearly distinguished from conventional bronchoalveolar lavage (BAL). These techniques were used to establish whether or not large-airway proteins made a major contribution to the protein profile of BAL. Twenty consecutive patients undergoing routine fibreoptic bronchoscopy were investigated. More bronchial mucus proteinase inhibitor per unit albumin and per unit total measured antiproteinase was present in CL than PL or BAL. In contrast alpha 1-proteinase inhibitor per unit albumin and as a percentage of total measured antiproteinase was lower in CL than in other lavage types. There were no differences in elastase activity, irrespective of the way in which the data were expressed. As no differences were found between BAL and PL for any of the variables measured, it was concluded that in the subjects studied the contribution of CL proteins to BAL was minimal.
Characterization of PKD Protein-Positive Exosome-Like Vesicles
Authors: Marie C. Hogan, Luca Manganelli, John R. Woollard, Anatoliy I. Masyuk, Tatyana V. Masyuk, Rachaneekorn Tammachote, Bing Q. Huang, Alexey A. Leontovich, Thomas G. Beito, Benjamin J. Madden, M. Cristine Charlesworth, Vicente E. Torres, Nicholas F. LaRusso, Peter C. Harris, Christopher J. Ward
Journal: Journal of the American Society of Nephrology (2009)

Proteins associated with autosomal dominant and autosomal recessive polycystic kidney disease (polycystin-1, polycystin-2, and fibrocystin) localize to various subcellular compartments, but their functional site is thought to be on primary cilia. PC1+ vesicles surround cilia in Pkhd1del2/del2 mice, which led us to analyze these structures in detail. We subfractionated urinary exosome-like vesicles (ELVs) and isolated a subpopulation abundant in polycystin-1, fibrocystin (in their cleaved forms), and polycystin-2. This removed Tamm-Horsfall protein, the major contaminant, and subfractionated ELVs into at least three different populations, demarcated by the presence of aquaporin-2, polycystin-1, and podocin. Proteomic analysis of PKD ELVs identified 552 proteins (232 not yet in urinary proteomic databases), many of which have been implicated in signaling, including the molecule Smoothened. We also detected two other protein products of genes involved in cystic disease: Cystin, the product of the mouse cpk locus, and ADP-ribosylation factor-like 6, the product of the human Bardet-Biedl syndrome gene (BBS3). Our proteomic analysis confirmed that cleavage of polycystin-1 and fibrocystin occurs in vivo, in manners consistent with cleavage at the GPS site in polycystin-1 and the proprotein convertase site in fibrocystin. In vitro, these PKD ELVs preferentially interacted with primary cilia of kidney and biliary epithelial cells in a rapid and highly specific manner. These data suggest that PKD proteins are shed in membrane particles in the urine, and these particles interact with primary cilia.