tbuckley/cabot-search huggingface dataset:
Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis
Authors: Satoshi Yamashita, Yukio Ando
Journal: Translational Neurodegeneration (2015)

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is characterized by neuronal loss and degeneration of the upper motor neurons (UMNs) and lower motor neurons (LMNs), and is usually fatal due to respiratory failure within 3-5 years of onset. Although approximately 5-10 % of patients with ALS have an inherited form of the disease, the distinction between hereditary and apparently sporadic ALS (SALS) seems to be artificial. Thus, genetic factors play a role in all types of ALS, to a greater or lesser extent. During the decade of upheaval, the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS, and the relationship between the genetic subtypes and clinical phenotype. In this review, we will focus on the possible genotype-phenotype correlation in hereditary ALS. Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis, but may also provide new approaches for preventing and treating the disease.
Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells
Authors: Jian-Zhong Qin, Jeffrey Ziffra, Lawrence Stennett, Barbara Bodner, Brian K. Bonish, Vijaya Chaturvedi, Frank Bennett, Pamela M. Pollock, Jeffrey M. Trent, Mary J.C. Hendrix, Paola Rizzo, Lucio Miele, Brian J. Nickoloff
Journal: Cancer Research (2005)

Abstract Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration–approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.
Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling
Authors: Robert Caesar, Valentina Tremaroli, Petia Kovatcheva-Datchary, Patrice D. Cani, Fredrik Bäckhed
Journal: Cell Metabolism (2015)

Highlights•The gut microbiota contributes to phenotypic differences in mice fed lard or fish oil•Mice lacking MyD88 or TRIF are protected against WAT inflammation•Microbial-derived factors induce CCL2 in adipocytes through TLR4, MyD88, and TRIF•Microbial-induced CCL2 enhances macrophage accumulation in WATSummaryDietary lipids may influence the abundance of circulating inflammatory microbial factors. Hence, inflammation in white adipose tissue (WAT) induced by dietary lipids may be partly dependent on their interaction with the gut microbiota. Here, we show that mice fed lard for 11 weeks have increased Toll-like receptor (TLR) activation and WAT inflammation and reduced insulin sensitivity compared with mice fed fish oil and that phenotypic differences between the dietary groups can be partly attributed to differences in microbiota composition. Trif−/− and Myd88−/− mice are protected against lard-induced WAT inflammation and impaired insulin sensitivity. Experiments in germ-free mice show that an interaction between gut microbiota and saturated lipids promotes WAT inflammation independent of adiposity. Finally, we demonstrate that the chemokine CCL2 contributes to microbiota-induced WAT inflammation in lard-fed mice. These results indicate that gut microbiota exacerbates metabolic inflammation through TLR signaling upon challenge with a diet rich in saturated lipids.Graphical abstract
Transcriptional Profiles in Peripheral Blood Mononuclear Cells Prognostic of Clinical Outcomes in Patients with Advanced Renal Cell Carcinoma
Authors: Michael E. Burczynski, Natalie C. Twine, Gary Dukart, Bonnie Marshall, Manuel Hidalgo, Walter M. Stadler, Theodore Logan, Janice Dutcher, Gary Hudes, William L. Trepicchio, Andrew Strahs, Fred Immermann, Donna K. Slonim, Andrew J. Dorner
Journal: Clinical Cancer Research (2005)

Given their accessibility, surrogate tissues, such as peripheral blood mononuclear cells (PBMC), may provide potential predictive biomarkers in clinical pharmacogenomic studies. In leukemias and lymphomas, the prognostic value of peripheral blast expression profiles is clear; however, it is unclear whether circulating mononuclear cells of patients with solid tumors might yield profiles with similar prognostic associations.In this study, we evaluated the association of expression profiles in PBMCs with clinical outcomes in patients with advanced renal cell cancer. Transcriptional patterns in PBMCs of 45 renal cell cancer patients were compared with clinical outcome data at the conclusion of a phase II study of the mTOR kinase inhibitor CCI-779 to determine whether pretreatment transcriptional patterns in PBMCs were correlated with eventual patient outcomes.Unsupervised hierarchical clustering of the PBMC profiles using all expressed genes identified clusters of patients with significant differences in survival. Cox proportional hazards modeling showed that the expression levels of many PBMC transcripts were predictors for the patient outcomes of time to progression and overall survival (time to death). Supervised class prediction approaches identified multivariate expression patterns in PBMCs capable of assigning favorable outcomes of time to death and time to progression in a test set of renal cancer patients, with overall performance accuracies of 72% and 85%, respectively.The present study provides the first example of gene expression profiling in peripheral blood, a clinically accessible surrogate tissue, for identifying patterns of gene expression associated with higher likelihoods of positive outcome in patients with a solid tumor.
Inhibition of Inflammation and Bone Erosion by RNA Interference–Mediated Silencing of Heterogeneous Nuclear RNP A2/B1 in Two Experimental Models of Rheumatoid Arthritis
Authors: Sonja Herman, Anita Fischer, Jessy Presumey, Markus Hoffmann, Marije I. Koenders, Virginie Escriou, Florence Apparailly, Guenter Steiner
Journal: Arthritis & Rheumatology (2015)

Objective The nuclear protein heterogeneous nuclear RNP A2/B1 (hnRNP A2/B1) is involved in posttranscriptional regulation of gene expression. It is constitutively expressed in lymphoid organs and highly up‐regulated in the synovial tissue of patients with rheumatoid arthritis (RA), who may also generate autoantibodies to this protein. This study was undertaken to investigate the potential involvement of hnRNP A2/B1 in the pathogenesis of autoimmune arthritis, by silencing hnRNP A2/B1 expression in 2 animal models of RA. Methods Collagen‐induced arthritis (CIA) and the K/BxN serum–transfer model were used as animal models of RA. Efficient silencing of hnRNP A2/B1 was achieved using a liposome‐based carrier system for delivery of small interfering RNAs. Expression of hnRNP A2/B1 was analyzed by flow cytometry, reverse transcription–quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. The number of osteoclasts was determined by tartrate‐resistant acid phosphatase staining. Cytokine levels and anticollagen antibody levels were measured by enzyme‐linked immunosorbent assay. Results Efficient silencing of hnRNP A2/B1 was achieved in all lymphoid organs. In both experimental models, the incidence and severity of arthritis were largely reduced and bone erosion was not detectable as compared to the control groups. Down‐modulation of hnRNP A2/B1 significantly interfered with the production of proinflammatory cytokines from monocyte/macrophages, but not from T cells. Consistent with these findings, production of T cell cytokines was not impaired when cells were restimulated in vitro with type II collagen. Furthermore, levels of anticollagen antibodies were not affected by hnRNP A2/B1 silencing. Conclusion Our findings suggest that hnRNP A2/B1 has an important role in regulation of the innate immune system, especially at the level of monocyte/macrophage activation. Therefore, down‐modulation of hnRNP A2/B1 seems to affect primarily the effector phase of autoimmune arthritis.
Prevention of tumor metastasis formation by anti-variant CD44.
Authors: S Seiter, R Arch, S Reber, D Komitowski, M Hofmann, H Ponta, P Herrlich, S Matzku, M Zöller
Journal: The Journal of Experimental Medicine (1993)

A splice variant of CD44 (CD44v) originally discovered on metastases of a rat pancreatic adenocarcinoma (BSp73ASML) has been shown by transfection to confer metastatic behavior to nonmetastatic tumor cells (Günthert U., M. Hofmann, W. Rudy, S. Reber, M. Zöller, I. Haussmann, S. Matzku, A. Wenzel, H. Ponta, and P. Herrlich. 1991. Cell. 65:13). A monoclonal antibody (mAb), 1.1ASML, to the metastasis-specific domain of the CD44v molecule retards growth of lymph node and lung metastases of the metastatic tumor line BSp73ASML, and can efficiently prevent formation of metastases by the transfected line. The antibody is only effective when given before lymph node colonization. Anti-CD44v does not downregulate the expression of CD44v, and prevention of metastatic growth by anti-CD44v is not due to activation of any kind of immune defense. We suggest that the mAb interferes with proliferation of metastasizing tumor cells in the draining lymph node, most probably by blocking a ligand interaction. The interference with metastatic spread will greatly facilitate the exploration of the function of CD44v and, in particular, may also open new strategies for the therapy of human metastases.
Ferroportin disease due to the A77D mutation in Australia
Authors: V N Subramaniam
Journal: Gut (2005)

Ferroportin disease or type 4 haemochromatosis is an autosomal dominant iron overload disorder caused by mutations in the iron exporter ferroportin.1,2 Numerous mutations in ferroportin ( SLC40A1 ) have been identified (see review by Pietrangelo3). The A77D mutation of ferroportin has thus far only been reported in Italy.2 We report the first A77D mutation of ferroportin which resulted in hepatic iron overload in an Australian family. The study was approved by and performed in accordance with the ethical standards of the Queensland Institute of Medical Research Human Research Ethics Committee and the Helsinki Declaration of 1975, as revised in 1983. Informed and written consent was obtained from the patient and family members.

The subject, a 45 year old Caucasian male, presented with complaints of lethargy and malaise. He had no risk factors for viral hepatitis, consumed minimal alcohol (20 g/week), and was married with two …
P181 Better asthma control with montelukast than salmeterol in Arg-16 homozygous children with asthma
Authors: K. Basu, H. P. Donald, B. J. Lipworth, R. Tavendale, D. F. Macgregor, S. A. Ogston, C. N. A. Palmer, S. Mukhopadhyay
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> Diminished efficacy of salmeterol for improving asthma control is increased in children with asthma homozygous for arginine-16 (Arg16) allele of the <i>ADRB2</i>. Concerns have been raised regarding the efficacy and safety of long-term salmeterol use in patients with asthma. We investigated whether there is a genotype-specific difference in long-term asthma control with montelukast compared to salmeterol in individuals homozygous for Arg16 of <i>ADRB2</i>. <h3>Methods</h3> In this pragmatic randomised controlled trial, 62 children (5–18 years) with asthma, carrying Arg/Arg16 genotype and exacerbation of asthma at least once within the previous year, were randomly assigned to receive Flixotide<sup>®</sup> (fluticasone propionate) via accuhaler (Diskus) dry powder inhaler device plus oral montelukast (Group I); or Seretide<sup>®</sup> (salmeterol plus equivalent dose of fluticasone) via accuhaler dry powder inhaler device plus placebo for montelukast (Group II). No effort was made to blind the prescribed inhaler. The primary end point was school absence, prospectively measured as individual events over the period of 1 year. <h3>Results</h3> No significant difference was observed in school absences (p=0.097) between the treatment groups. The use of reliever medication was significantly decreased in Group I compared to Group II (p=0.004). Total exacerbations were reduced in Group 1 compared to Group 2 (p=0.049). Self-reported symptoms were significantly improved in Group I compared to Group II (morning cough p=0.018; morning wheeze p=0.001; morning dyspnoea p=0.008; night wheeze: p=0.004; night dyspnoea: p=0.001). A significant improvement in quality of life as per the Juniper paediatric asthma quality of life questionnaire was observed in Group I compared to Group II (activity limitation score (p=0.004), symptom score (p=0.009), emotional function score (p=0.002)). <h3>Conclusion</h3> In individuals homozygous for Arg16 of the <i>ADRB2</i> locus, montelukast is an effective step up medication compared with salmeterol. Montelukast, as an asthma controller added on to inhaled steroid, improved asthma symptoms and quality of life, while reducing the use of reliever medication, in comparison to salmeterol. A larger randomised controlled trial is required, comparing asthma control with salmeterol versus montelukast in the genotypic sub-groups in <i>ADRB2</i>, and to explore the cost-effectiveness of genotype-specific controller therapies in children with asthma.
A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced Cancer
Authors: Lee S. Rosen, Herbert I. Hurwitz, Michael K. Wong, Jonathan Goldman, David S. Mendelson, William D. Figg, Shawn Spencer, Bonne J. Adams, Delia Alvarez, Ben K. Seon, Charles P. Theuer, Bryan R. Leigh, Michael S. Gordon
Journal: Clinical Cancer Research (2012)

TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors.
Characteristics of serum IgA and liver IgA deposits in alcoholic liver disease
Authors: Albert Van De Wiel, Dominique L. Delacroix, Jan Van Hattum, Henk-Jan Schuurman, Louis Kater
Journal: Hepatology (1987)

Patients with alcoholic liver disease frequently reveal an increase in IgA serum concentration and IgA deposits in a continuous pattern along hepatic sinusoids. We investigated whether the hepatic IgA deposits are a passive reflection of changes in concentration or composition of IgA in the circulation, or represent a distinct effect of alcohol on the liver. Forty-one patients with alcoholic liver disease (daily alcohol intake at least 50 gm for more than five consecutive years) were compared with 41 patients with nonalcoholic liver disease. Patients in both groups were matched for serum IgA and histopathological changes in the liver biopsy. IgA deposits in the liver were found in 78% of the alcoholic patients and in 12% of the nonalcoholic patients. The presence of deposits was not related to histopathological changes in the liver or to the serum IgA concentration. In serum IgA subclass distribution, alcoholic patients differed from nonalcoholic patients by a slight but significant shift to IgA2; in contrast, the hepatic IgA deposits in alcoholic patients were almost of the IgA1 subclass. Serum secretory component (which is an equivalent of serum secretory IgA) was elevated in both alcoholic and nonalcoholic patients; patients with a liver biopsy revealing hepatitis showed the highest level. In contrast, the hepatic deposits did not contain secretory component. We conclude that the continuous deposits of IgA along liver sinusoids are not a passive reflection of changes in concentration or composition of circulating IgA, but may represent a distinct effect of alcohol on the liver related to the role of this organ in IgA metabolism.
Essential complicity of perforin-granzyme and FAS-L mechanisms to achieve tumor rejection following treatment with anti-CD137 mAb
Authors: Aizea Morales-Kastresana, Elena Catalán, Sandra Hervás-Stubbs, Asis Palazón, Arantza Azpilikueta, Elixabet Bolaños, Alberto Anel, Julián Pardo, Ignacio Melero
Journal: Journal for ImmunoTherapy of Cancer (2013)

Treatment with agonist anti-CD137 (4-1BB) immunostimulatory monoclonal antibodies elicits complete tumor regressions in a number of transplanted hematological and solid malignancies in mice. Rejection is mainly dependent on cytotoxic T lymphocytes (CTL) and IFNγ, although a role for NK cells and dendritic cells has been observed in some tumor models. Rejection of EG7-derived thymomas has been shown to be CTL-dependent but not NK-dependent.In this therapeutic setting, we show that both the perforin-granzyme and FasL effector systems are readily expressed by CD8(+) T lymphocytes infiltrating the EG7 lymphomas which are undergoing rejection. Using knock-out mice, we demonstrate that both effector cytolytic systems are involved in the execution of complete immune rejections against EG7 established tumors. In accordance, EG7 tumor cells were susceptible in vitro to both killing mechanisms acting in a synergistic fashion.CD137-elicited rejection of EG7-derived tumors involves the interplay of at least two final effector cytolytic mechanisms that act in cooperation.
A community survey of asthmatic characteristics.
Authors: M L Burr, A S St Leger, C Bevan, T G Merrett
Journal: Thorax (1975)

A survey was undertaken among adults aged 20-44 years in a South Wales town. Persons with a history of wheezing with breathlessness and in the absence of a cold were identified by postal questionnaires and seen at a clinic, together with a sample of subjects without these symptoms. The response rates for the first and second stages of the survey were 99.6% and 91.0% respectively, and 574 subjects were ultimately seen. Asthmatic patients (those receiving treatment within the previous year) had some airways obstruction at rest, which increased after exercise. They also had strong allergic tendencies, as shown by personal and family history, skin tests, and serum IgE levels. The ex-asthmatics (those not receiving treatment within the previous year) showed these tendencies to a lesser extent. A larger group gave a history of wheezing but stated that they had never had asthma; in their response to exercise and allergic traits they resembled the control group rather than the asthmatics, and appeared to have the features of chronic bronchitis. Asthma and chronic bronchitis would therefore seem to be distinct entities within the population studied.
Multiple-Treatments Meta-analysis of Chemotherapy and Targeted Therapies in Advanced Breast Cancer
Authors: Davide Mauri, Nikolaos P. Polyzos, Georgia Salanti, Nicholas Pavlidis, John P. A. Ioannidis
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundMany systemic nonhormonal regimens have been evaluated across several hundreds of randomized trials in advanced breast cancer. We aimed to quantify the relative merits of these regimens in prolonging survival.
Denosumab Dose Selection for Patients with Bone Metastases from Solid Tumors
Authors: Sameer Doshi, Liviawati Sutjandra, Jenny Zheng, Winnie Sohn, Mark Peterson, Graham Jang, Andrew T. Chow, Juan Jose Pérez-Ruixo
Journal: Clinical Cancer Research (2012)

To quantitatively characterize the longitudinal dose exposure-response [urinary N-telopeptide normalized to urinary creatinine (uNTx/Cr) suppression] relationship for denosumab in patients with bone metastases from solid tumors.Data from 373 patients who received denosumab as single or multiple subcutaneous doses ranging from 30 to 180 mg (or 0.01 to 3 mg/kg) administered every 4 or 12 weeks for up to 3 years were used in this analysis. An inhibitory sigmoid I(Max) model was used to characterize the time course of uNTx/Cr as a function of serum denosumab concentrations and the M3 method was used to analyze the 52% of uNTx/Cr values below the limit of quantification in the context of a mixed-effects model. Age, weight, sex, race, and cancer type were evaluated as potential covariates for model parameters. Model-based simulations were undertaken to explore and predict the role of denosumab dose and dosing intervals on uNTx/Cr suppression.The typical value (between-subject variability; %) for uNTx/Cr at baseline was 49.2 nmol/L/mmol/L (76.8%), denosumab maximal uNTx/Cr suppression (efficacy) was 93.7% (127%), and the denosumab concentration providing half-maximal uNTx/Cr suppression (potency) was 31.8 ng/mL (287%). No effect of covariates on denosumab efficacy and potency was identified. Simulations indicated that a s.c. denosumab dose of 120 mg administered every 4 weeks provides more than 90% suppression of uNTx/Cr in the maximum proportion of patients relative to other every 4- and 12-week doses evaluated.Over the wide range of dosing regimens examined, a s.c. denosumab dose of 120 mg administered every 4 weeks is the optimal dosing regimen to suppress uNTx/Cr in patients with bone metastases from solid tumors. Clin Cancer Res; 18(9); 2648-57. ©2012 AACR.
Aberrant Time to Most Recent Common Ancestor as a Signature of Natural Selection
Authors: Haley Hunter-Zinck, Andrew G. Clark
Journal: Molecular Biology and Evolution (2015)

Natural selection inference methods often target one mode of selection of a particular age and strength. However, detecting multiple modes simultaneously, or with atypical representations, would be advantageous for understanding a population’s evolutionary history. We have developed an anomaly detection algorithm using distributions of pairwise time to most recent common ancestor (TMRCA) to simultaneously detect multiple modes of natural selection in whole-genome sequences. As natural selection distorts local genealogies in distinct ways, the method uses pairwise TMRCA distributions, which approximate genealogies at a nonrecombining locus, to detect distortions without targeting a specific mode of selection. We evaluate the performance of our method, TSel, for both positive and balancing selection over different time-scales and selection strengths and compare TSel’s performance with that of other methods. We then apply TSel to the Complete Genomics diversity panel, a set of human whole-genome sequences, and recover loci previously inferred to be under positive or balancing selection.