tbuckley/cabot-search huggingface dataset:
Clinical assessment incorporating a personal genome
Authors: Euan A Ashley, Atul J Butte, Matthew T Wheeler, Rong Chen, Teri E Klein, Frederick E Dewey, Joel T Dudley, Kelly E Ormond, Aleksandra Pavlovic, Alexander A Morgan, Dmitry Pushkarev, Norma F Neff, Louanne Hudgins, Li Gong, Laura M Hodges, Dorit S Berlin, Caroline F Thorn, Katrin Sangkuhl, Joan M Hebert, Mark Woon, Hersh Sagreiya, Ryan Whaley, Joshua W Knowles, Michael F Chou, Joseph V Thakuria, Abraham M Rosenbaum, Alexander Wait Zaranek, George M Church, Henry T Greely, Stephen R Quake, Russ B Altman
Journal: The Lancet (2010)
Effects of MYCN Antisense Oligonucleotide Administration on Tumorigenesis in a Murine Model of Neuroblastoma
Authors: C. A. Burkhart, A. J. Cheng, J. Madafiglio, M. Kavallaris, M. Mili, G. M. Marshall, W. A. Weiss, L. M. Khachigian, M. D. Norris, M. Haber
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: Human MYCN (hMYCN) oncogene amplification is a powerful predictor of treatment failure in childhood neuroblastoma, and dysregulation of hMYCN protein expression appears to be critically involved in the pathogenesis of this disease. We used hMYCN antisense (AS) oligonucleotides to investigate, both in vitro and in vivo, the therapeutic potential of inhibiting hMYCN expression. Methods: We transiently transfected human neuroblastoma IMR-32 cells, which have an amplified hMYCN gene, with fluorescently labeled hMYCN AS or scrambled (SCR) control oligonucleotides and used fluorescence-activated cell sorting to enrich for cell populations containing different levels of the oligonucleotides. We used fluorescence immunocytochemistry or reverse transcription polymerase chain reaction to assay gene expression levels and trypan blue exclusion to assay growth inhibition in the cell populations. We examined the effects of continuous treatment for 6 weeks with AS or SCR oligonucleotides via subcutaneously implanted microosmotic pumps on tumor growth in a transgenic mouse model of hMYCN-induced neuroblastoma (n = 20 mice per group). All statistical tests were two-sided. Results: IMR-32 cells treated with AS oligonucleotides had approximately half as much hMYCN protein and cell proliferation as either SCR oligonucleotide–transfected or mock-transfected controls; the differences were statistically significant. Transgenic mice treated with AS oligonucleotides had lower tumor incidence and statistically significantly lower tumor mass than SCR-treated or untreated control mice. Compared with control treatments, AS oligonucleotide treatment in vitro and in vivo was associated with decreased expression of hMYCN and putative hMYCN target genes but not with that of closely related genes. Several AS oligonucleotide–treated mice developed tumors contralateral to the site of oligonucleotide administration, whereas SCR oligonucleotide–treated or untreated mice displayed bilateral tumor growth. Conclusions: Decreased expression of hMYCN protein is achievable with the use of AS oligonucleotide treatment, even in the presence of hMYCN oncogene amplification. Antisense strategies targeting the hMYCN oncogene in vivo decrease mouse neuroblastoma tumorigenesis. Investigation of their clinical effect in children with neuroblastoma is warranted.
The Membrane Mucin Muc4 Inhibits Apoptosis Induced by Multiple Insults via ErbB2-Dependent and ErbB2-Independent Mechanisms
Authors: Heather C. Workman, Colleen Sweeney, Kermit L. Carraway
Journal: Cancer Research (2009)

Abstract The aberrant expression of membrane mucins such as Muc1 and Muc4 by tumor cells has been shown to engage signaling pathways that promote cellular properties associated with tumor progression. Our previous studies have shown that Muc4 interacts with and potentiates signaling by the ErbB2 (HER2) receptor tyrosine kinase through an epidermal growth factor–like domain in its extracellular region. Here, we show that expression of Muc4 in human A375 melanoma cells and MCF7 breast cancer cells confers resistance to apoptosis induced by a variety of stimuli, including chemotherapeutic agents, the absence of serum factors, and the loss of cellular adhesion. Mapping experiments revealed that the O-glycosylation and cytosolic domains of Muc4 are dispensable for its antiapoptotic activity, and are also dispensable for the potentiation of signaling by ErbB2. Knockdown of endogenous Muc4 in JIMT-1 breast cancer cells sensitizes cells to apoptotic stimuli, and this can be rescued by Muc4 forms lacking the O-glycosylation or cytosolic domains. Surprisingly, however, the molecular mechanisms underlying Muc4 antiapoptotic activity vary among cell lines. Although Muc4 in JIMT-1 cells engages ErbB2 to promote cell survival, its antiapoptotic mechanism in MCF7 and A375 cells seems to be independent of ErbB2. However, Muc4 expression in all cell lines culminates in the phosphorylation and inactivation of the proapoptotic protein Bad and the elevation of the prosurvival protein Bcl-xL. Our observations suggest that tumor cells can exploit the versatile antiapoptotic activities of Muc4 to acquire resistance to therapeutic agents, and augment cell survival after the loss of adhesion and microenvironment-derived survival factors. [Cancer Res 2009;69(7):2845–52]
Alternative Ribonucleic Acid Processing in Endocrine Systems
Authors: Hua Lou, Robert F. Gagel
Journal: Endocrine Reviews (2001)

Alternative RNA processing is a mechanism for creation of protein diversity through selective inclusion or exclusion of RNA sequence during posttranscriptional processing. More than one-third of human pre-mRNAs undergo alternative RNA processing modification, making this a ubiquitous biological process. The protein isoforms produced have distinct and sometimes opposite functions, underscoring the importance of this process. This review focuses on important endocrine genes regulated by alternative RNA processing. We discuss how diverse events such as spermatogenesis or GH action are regulated by this process. We focus on several endocrine (calcitonin/calcitonin gene-related peptide) and nonendocrine (Drosophila doublesex and P-element and mouse c-src) examples to highlight recent progress in the elucidation of molecular mechanisms regulating this process. Finally, we outline methods (model systems and techniques) used by investigators in this field to study processing of individual pre-mRNAS:
Bleuler's Concept of Schizophrenia: A Confusing Heritage
Authors: HELM STIERLIN
Journal: American Journal of Psychiatry (1967)

In his work on schizophrenia, Eugen Bleuler attempted to reconcile contemporary psychiatric and psychoanalytic ideas. He found intrapsychic complexes, as described by Freud, at the root of the schizophrenic symptomatology and searched for a theory by which this symptomatology could be related to organic causes. Semon's theory of psychic engrams and their associative links seemed to fit this purpose. In creatively integrating viewpoints from Kraepelin, Freud, and Semon, Bleuler enriched and—to a degree—revolutionized the concept of schizophrenia. Still, Bleuler's reconciling efforts did not fulfill the promise they held. Today we deal with a confusing heritage.
Pseudomonas aeruginosa NfsB and nitro-CBI-DEI – a promising enzyme/prodrug combination for gene directed enzyme prodrug therapy
Authors: Laura K Green, Sophie P Syddall, Kendall M Carlin, Glenn D Bell, Christopher P Guise, Alexandra M Mowday, Michael P Hay, Jeffrey B Smaill, Adam V Patterson, David F Ackerley
Journal: Molecular Cancer (2013)

Abstract Background The nitro-chloromethylbenzindoline prodrug nitro-CBI-DEI appears a promising candidate for the anti-cancer strategy gene-directed enzyme prodrug therapy, based on its ability to be converted to a highly cytotoxic cell-permeable derivative by the nitroreductase NfsB from Escherichia coli . However, relative to some other nitroaromatic prodrugs, nitro-CBI-DEI is a poor substrate for E. coli NfsB. To address this limitation we evaluated other nitroreductase candidates from E. coli and Pseudomonas aeruginosa . Findings Initial screens of candidate genes in the E. coli reporter strain SOS-R2 identified two additional nitroreductases, E. coli NfsA and P. aeruginosa NfsB, as being more effective activators of nitro-CBI-DEI than E. coli NfsB. In monolayer cytotoxicity assays, human colon carcinoma (HCT-116) cells transfected with P. aeruginosa NfsB were &gt;4.5-fold more sensitive to nitro-CBI-DEI than cells expressing either E. coli enzyme, and 23.5-fold more sensitive than untransfected HCT-116. In three dimensional mixed cell cultures, not only were the P. aeruginosa NfsB expressing cells 540-fold more sensitive to nitro-CBI-DEI than pure cultures of untransfected HCT-116, the activated drug that they generated also displayed an unprecedented local bystander effect. Conclusion We posit that the discrepancy in the fold-sensitivity to nitro-CBI-DEI between the two and three dimensional cytotoxicity assays stems from loss of activated drug into the media in the monolayer cultures. This emphasises the importance of evaluating high-bystander GDEPT prodrugs in three dimensional models. The high cytotoxicity and bystander effect exhibited by the NfsB_Pa/nitro-CBI-DEI combination suggest that further preclinical development of this GDEPT pairing is warranted.
Implantable defibrillator event rates in patients with idiopathic dilated cardiomyopathy, nonsustained ventricular tachycardia on Holter and a left ventricular ejection fraction below 30%
Authors: Wolfram Grimm, J.ürgen Hoffmann, Hans-Helge Müller, Bernhard Maisch
Journal: Journal of the American College of Cardiology (2002)
The Effects of Running Mileage and Duration on Plasma Lipoprotein Levels
Authors: Paul T. Williams
Journal: JAMA (1982)

Eighty-one healthy, sedentary men aged 30 to 55 years were randomly assigned to supervised running (n=48) or to sedentary control groups (n=33) and followed up in a one-year trial. Measurements of plasma lipoproteins, fitness, and percent body fat were made at three-month intervals. Results and conclusions from this study are (1) that cross-sectional studies of lipoprotein concentrations in exercisers may be biased by a self-selection effect, since study participants with initially higher high-density lipoprotein cholesterol (HDL-C) and lower triglyceride concentrations were more easily persuaded to run more miles; (2) that plasma concentrations of HDL-C and low-density lipoprotein cholesterol (LDL-C) generally did not begin to change until a threshold exercise level (ten miles run per week) was maintained for at least nine months; and (3) that fitness increased and percent body fat decreased sooner and at lower exercise levels than required for HDL-C and LDL-C concentration changes. (<i>JAMA</i>1982;247:2674-2679)
The dissociated steroid receptor ligand from plant origin called compound A (CpdA) inhibits the production of steroid-resistant chemokines induced by TNFα/IFNγ in airway smooth muscle (ASM) cells in both asthma and healthy subjects
Authors: Latifa Chachi, Adelina Gavrila, Omar Tliba, Christopher Brightling, Yassine Amrani
Journal: European Respiratory Journal (2012)

Corticosteroids (GC) act by two molecular mechanisms known as transactivation or transrepression. Transrepression mediates the vast majority of the anti-inflammatory actions of corticosteroids, whereas transactivation has been associated with the unwanted side effects of corticosteroids. One unanswered question is whether compounds that can dissociate the transactivation from the beneficial transrepression function of GC could be used to treat severe patients who are refractory to steroid therapy. The purpose of the present study was to study the effect of CpdA, a dissociated steroid receptor ligand, on the production of steroid-resistant chemokines induced by TNFα/IFNγ in ASM cells. We found that TNFα/IFNγ combination stimulates the expression of CXCl10, CCl5 and CX3Cl1 in both asthmatic and healthy airway smooth muscle cells, with a greater production of CXCl10 and CCl5 by asthmatic cells (n=3 subjects). Pretreating cells with fluticasone (100 nM, 2 hr) did not affect cytokine-induced expression of CXCl10 while CX3Cl1 levels were significantly increased by 2.3 fold in the presence of fluticasone. Interestingly, CpdA (5 μM) suppressed cytokine-induced expression of CXCl10 by 50% while CCl5 and CX3Cl1 responses were completely inhibited in both asthmatic and healthy cells. These data show that CpdA can inhibit the expression of steroid-resistant inflammatory genes in airway smooth muscle cells. This study suggests that dissociated steroid receptor ligands could offer a novel therapeutic alternative to treat steroid resistance in severe asthmatics.
Ataxic Neurological Syndrome
Authors: D. S. McLaren
Journal: BMJ (1963)

JOUM4ALIn the case of children undergoing preliminary skingrafting for burns or scalds, intubation is rarely necessary.At the Fleming Memorial Hospital for Children, Newcastle upon Tyne, such cases are given "nepenthe" intramuscularly or orally two or three hours before operation, and a blood transfusion is set up; apart from the nepenthe, no further sedation is given unless the child is exceptionally apprehensive.During the operation a light anaesthetic with nitrous oxide and oxygen plus a minimal amount of halothane given intermittently is all that is required.Post-operative recovery is extremely rapid, so that the problems of aftercare and feeding are made much easier from the nursing point of view.-Iam, etc., Newcastle upon Tyne 3. PHILIP AYREmToxicity of Methaqualone SIR,-A statement to the effect that serious toxic effects have not been reported for methaqualone appeared in your "To-day's Drugs" section (January 12, p. 107).It should be noted, however, that a record of toxicity from this drug appears in the July, 1962, issue of the Registry on Blood Dyscrasias of the American Medical Association Council on Drugs.The Registry lists one case of aplastic anaemia with pancytopenia due to methaqualone.In addition there are listed two cases of thrombocytopenia due to
VEGF levels in pulmonary fibrosis
Authors: A G Richter
Journal: Thorax (2005)

We read with interest the paper by Simler et al investigating angiogenic cytokines in patients with idiopathic interstitial pneumonia.1 We were surprised by their reported high levels of vascular endothelial growth factor (VEGF) in the plasma in the normal control group. Several other groups—including the manufacturers of the ELISA (R&D Systems)—have previously quoted normal plasma VEGF levels in the range 36–76 pg/ml.2,3 Indeed, one of the authors of the paper previously quoted normal VEGF levels as 76 pg/ml using a matched pair ELISA.4 It is clear therefore that the levels of 648 pg/ml quoted for normal controls are nearly 10 times higher than …
Role of probiotics in correcting abnormalities of colonic flora induced by stress
Authors: H. Eutamene, L. Bueno
Journal: Gut (2007)

Irritable bowel syndrome (IBS) is a common condition that can have a significant impact on a person9s quality of life.<sup>1</sup> The cause of IBS is unknown but several mechanisms have been proposed including visceral hypersensitivity, central sensitisation, abnormal gut motility and altered gut microbiota.<sup>2,3</sup> IBS is challenging to manage and many patients report insufficient symptomatic relief from treatment.<sup>2</sup> Approximately 60% of patients identify food as a trigger for their symptoms,<sup>2</sup> and there has been interest in exclusion diets for managing IBS.<sup>4</sup> Dietary adaptation is a common self-management strategy for patients with IBS, with many self-diagnosing intolerance to specific foods. This&nbsp;may lead&nbsp;to patients adopting over-restrictive or inappropriate diets.<sup>5</sup> In recent years, a diet low in poorly absorbed short-chain carbohydrates, known collectively as FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols), has been advocated for the treatment of IBS.<sup>2</sup> Here, we discuss the background to the FODMAP diet and review the evidence supporting its use for people&nbsp;with IBS.
Signal transduction in mesangial cells.
Authors: P Menè, G A Cinotti, F Pugliese
Journal: Journal of the American Society of Nephrology (1992)

Phenotype, growth, and functional characteristics of glomerular mesangial "myofibroblasts" are under the control of multiple hormones, vasoactive agents, autacoids, and cytokines. Several parallel signal transduction pathways couple receptor occupancy with functional changes, including phospholipases C, A2, and D breakdown of membrane phospholipids, and adenylate/guanylate cyclase activation. Changes of cytosolic ion concentrations, cyclic nucleotide accumulation, and eicosanoid biosynthesis are currently interpreted as intracellular signals for protein kinase activation. Phosphorylation of multiple substrates by serine/threonine kinases C, A, and G or by tyrosine kinases directly coupled to receptors, is a final step in cell activation. Cross-talk between signal transduction pathways, along with the release of eicosanoids and cytokines acting as intercellular mediators, provides the potential for interactive regulation of glomerular cell functions.
Multiple BCL6 translocation partners in individual cases of gastric lymphoma
Authors: Yun-Wen Chen, Anthony C. T. Liang, Wing Y. Au, Kent-Man Chu, Kai-Yau Wong, Xiaotong Hu, Liwei Lu, Johnny C. O. Tang, Kwok-Wah Chan, Swan-Lip Beh, Yok-Lam Kwong, Raymond H. S. Liang, Gopesh Srivastava
Journal: Blood (2003)
Rac3-Mediated Transformation Requires Multiple Effector Pathways
Authors: Patricia J. Keller, Christyn M. Gable, Michele R. Wing, Adrienne D. Cox
Journal: Cancer Research (2005)

Abstract Our initial characterization of Rac3, a close relative of the small GTPase Rac1, established its ability to promote membrane ruffling, transformation, and activation of c-jun transcriptional activity. The finding that Rac3 is transforming, and its similarity to Rac1, a protein that has a well-established connection to many processes important for cancer progression, prompted further investigation into Rac3 transformation. We used effector domain mutants (EDMs) to explore the relationship among Rac signaling, transformation, and effector usage. All Rac3 EDMs tested (N26D, F37L, Y40C, and N43D) retained the ability to promote membrane ruffling and focus formation. In contrast, only the N43D mutant promoted anchorage independence. This differs from Rac1, where both N26D and N43D mutants were impaired in both types of transformation. To learn more about the signaling pathways involved, we did luciferase reporter assays and glutathione S-transferase pull-down assays for effector binding. We found evidence for a functional link between activation of phospholipase Cβ2 by Rac3 and signaling to the serum response factor (SRF). Surprisingly, we also found that Rac3 binds poorly to the known Rac1 effectors mixed lineage kinases 2 and 3 (MLK2 and MLK3). Transcription of cyclin D1 was the only pathway that correlated with growth in soft agar. Our experiments show that activation of membrane ruffling and transcriptional activation of c-jun, SRF, or E2F are not sufficient to promote anchorage-independent growth mediated by Rac3. Instead, multiple effector pathways are required for Rac3 transformation, and these overlap partially but not completely with those used by Rac1.
X-Linked Alport Syndrome
Authors: Jean Philippe Jais, Bertrand Knebelmann, Iannis Giatras, Mario De Marchi, Gianfranco Rizzoni, Alessandra Renieri, Manfred Weber, Oliver Gross, Kai-Olaf Netzer, Frances Flinter, Yves Pirson, Karin Dahan, Jörgen Wieslander, Ulf Persson, Karl Tryggvason, Paula Martin, Jens Michael Hertz, Cornelis Schröder, Marek Sanak, Maria Fernanda Carvalho, Juan Saus, Corinne Antignac, Hubert Smeets, Marie Claire Gubler
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A “European Community Alport Syndrome Concerted Action” (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect. E-mail: [email protected]
The effect of male factors in repeated spontaneous abortion: lesson from in-vitro fertilization and intracytoplasmic sperm injection
Authors: S Hamamah
Journal: Human Reproduction Update (1997)

Between 6.5 and 21% of pregnancies result in spontaneous abortion. The incidence of repeated spontaneous abortion. The incidence of repeated spontaneous abortion (RSA) is, however, lower: 0.05-1.0% of pregnancies. These values vary, not only according to the populations studied and the means of diagnosing the miscarriages, but also to the age and the parity of the patient: 4% at 20 years of age versus 16% after 35 years. These differences are greater if biochemical pregnancies are taken into account. The aetiologies of RSA are multiple and at times even multifactorial. While certain aetiologies, such as chromosomal, anatomic, hormonal, immunological or unexplained anomalies, have been extensively explored, the sperm characteristics likely to influence the quality of the conceptus have rarely been examined. This review examines the male factor's contribution in RSA.
The driving circuit of HBx and androgen receptor in HBV-related hepatocarcinogenesis
Authors: Sheng-Han Wang, Shiou-Hwei Yeh, Pei-Jer Chen
Journal: Gut (2014)

Hepatocellular carcinoma (HCC) is a global health concern. The sixth most common neoplasm, HCC yields a poor prognosis and high mortality rate, causing approximately 500 000 deaths per year. Chronic viral hepatitis—especially HBV and HCV—are major aetiologies of HCC, accounting for approximately 80% of HCC cases, particularly in endemic areas. Another clinical feature of HCC is that it disproportionately occurs in men, and the ratio of male to female patients ranges from 2 to 7:1.1 In large cohort studies, this predominance is only partly explained by gendered differences in environmental influences and behaviours, for example, carcinogen exposure and alcohol consumption; this implies that host genetic factors are crucial determinants. One Taiwanese study revealed that higher serum androgen levels and more active androgen receptor (AR) alleles were associated with an increased risk of HCC among male carriers of HBV, but not men infected with HCV.2 The animal study supported the importance of androgen and AR signalling pathway in determining the male predominance in a chemically induced HCC mouse model.3 These studies have emphasised the carcinogenic effect exerted by the male sex hormone pathway in HBV-related HCC.

Among men, androgen is primarily produced in the testes and circulates in body serum, eventually being converted to potent dihydrotestosterone by 5α-reductase within target cells. The biological functions of androgen are elicited when it binds …