tbuckley/cabot-search huggingface dataset:
Clinical Impact of Different Classes of Infiltrating T Cytotoxic and Helper Cells (Th1, Th2, Treg, Th17) in Patients with Colorectal Cancer
Authors: Marie Tosolini, Amos Kirilovsky, Bernhard Mlecnik, Tessa Fredriksen, Stéphanie Mauger, Gabriela Bindea, Anne Berger, Patrick Bruneval, Wolf-Herman Fridman, Franck Pagès, Jérôme Galon
Journal: Cancer Research (2011)

The tumor microenvironment includes a complex network of immune T-cell subpopulations. In this study, we systematically analyzed the balance between cytotoxic T cells and different subsets of helper T cells in human colorectal cancers and we correlated their impact on disease-free survival. A panel of immune related genes were analyzed in 125 frozen colorectal tumor specimens. Infiltrating cytotoxic T cells, Treg, Th1, and Th17 cells were also quantified in the center and the invasive margin of the tumors. By hierarchical clustering of a correlation matrix we identified functional clusters of genes associated with Th17 (RORC, IL17A), Th2 (IL4, IL5, IL13), Th1 (Tbet, IRF1, IL12Rb2, STAT4), and cytotoxicity (GNLY, GZMB, PRF1). Patients with high expression of the Th17 cluster had a poor prognosis, whereas patients with high expression of the Th1 cluster had prolonged disease-free survival. In contrast, none of the Th2 clusters were predictive of prognosis. Combined analysis of cytotoxic/Th1 and Th17 clusters improved the ability to discriminate relapse. In situ analysis of the density of IL17+ cells and CD8+ cells in tumor tissues confirmed the results. Our findings argue that functional Th1 and Th17 clusters yield opposite effects on patient survival in colorectal cancer, and they provide complementary information that may improve prognosis.
Clinical Tumor Sequencing: An Incidental Casualty of the American College of Medical Genetics and Genomics Recommendations for Reporting of Incidental Findings
Authors: D. Williams Parsons, Angshumoy Roy, Sharon E. Plon, Sameek Roychowdhury, Arul M. Chinnaiyan
Journal: Journal of Clinical Oncology (2014)

In 2013, the American College of Medical Genetics and Genomics (ACMG) issued recommendations for reporting incidental findings, defined as results of potential medical utility that are not related to the indication for ordering the sequencing test, in a panel of 56 disease-associated genes when performing clinical exome and genome sequencing.1 Given the increasing use of clinical sequencing for characterization of both germline and tumor genomes in diverse clinical settings, these recommendations reflect careful consideration of the complex issues related to these tests. Unsurprisingly, they have provoked vigorous discussion and debate regarding issues of patient autonomy and the ethics of returning results for pediatric patients.2–6 Although there has been comparatively little discussion of the impact of these recommendations on testing of tumor specimens,7 the scope of these recommendations does extend beyond germline genetic testing into the realm of tumor-focused testing with the statement that “incidental variants should be reported for the normal sample of a tumor-normal sequenced dyad.”
DEEP BRAIN STIMULATION
Authors: Joel S. Perlmutter, Jonathan W. Mink
Journal: Annual Review of Neuroscience (2006)

Deep brain stimulation (DBS) has provided remarkable benefits for people with a variety of neurologic conditions. Stimulation of the ventral intermediate nucleus of the thalamus can dramatically relieve tremor associated with essential tremor or Parkinson disease (PD). Similarly, stimulation of the subthalamic nucleus or the internal segment of the globus pallidus can substantially reduce bradykinesia, rigidity, tremor, and gait difficulties in people with PD. Multiple groups are attempting to extend this mode of treatment to other conditions. Yet, the precise mechanism of action of DBS remains uncertain. Such studies have importance that extends beyond clinical therapeutics. Investigations of the mechanisms of action of DBS have the potential to clarify fundamental issues such as the functional anatomy of selected brain circuits and the relationship between activity in those circuits and behavior. Although we review relevant clinical issues, we emphasize the importance of current and future investigations on these topics.
Endogenous Galectin-3 Determines the Routing of CD95 Apoptotic Signaling Pathways
Authors: Tomoharu Fukumori, Yukinori Takenaka, Natsuo Oka, Tadashi Yoshii, Victor Hogan, Hidenori Inohara, Hiro-omi Kanayama, Hyeong-Reh Choi Kim, Avraham Raz
Journal: Cancer Research (2004)

Abstract Studies of CD95 (APO-1/Fas), a member of the death receptor family, have revealed that it is involved in two primary CD95 apoptotic signaling pathways, one regulated by the large amount of active caspase-8 (type I) formed at the death-inducing signaling complex and the other by the apoptogenic activity of mitochondria (type II). To date, it is still unclear which pathway will be activated in response to an apoptotic insult. Here, we demonstrate that the antiapoptotic molecule galectin-3, which contains the four amino acid-anti-death-motif (NWGR) conserved in the BH1 domain of the Bcl-2 member proteins, is expressed only in type I cells. Transfection of galectin-3 cDNA into galectin-3 null cells (type II) resulted converting them to type I apoptotic phenotype. In addition, we show that galectin-3 is complexed with CD95 in vivo identifying galectin-3 as a novel CD95-binding partner that determines which of the CD95 apoptotic signaling pathways the cell will select.
A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer
Authors: H.J. Burstein, A.M. Storniolo, S. Franco, J. Forster, S. Stein, S. Rubin, V.M. Salazar, K.L. Blackwell
Journal: Annals of Oncology (2008)
Characterization of [3H](+/-)carazolol binding to beta-adrenergic receptors. Application to study of beta-adrenergic receptor subtypes in canine ventricular myocardium and lung.
Authors: A S Manalan, H R Besch, A M Watanabe
Journal: Circulation Research (1981)

[3H](+/-)Carazolol, a newly available beta-adrenergic receptor antagonist, can be used to characterize beta-adrenergic receptor subtypes present in membrane vesicles derived from canine ventricular myocardium and canine lung. [3H](+/-)Carazolol binding is saturable, of high affinity, and is displaceable by beta-adrenergic agents in accordance with their known pharmacological potencies. The interaction of carazolol with beta-adrenergic receptors is stereospecific; the (-) stereoisomer demonstrates greater potency than the (+) stereoisomer. Kinetic analysis of [3H](+/-)carazolol interaction with beta-adrenergic receptors suggests that presence of two phases of interaction, consistent with initial rapidly reversible "low" affinity association of ligand with receptor, followed by isomerization to form a high affinity, slowly reversible complex. Through use of a [3H](+/-)carazolol binding assay based on the high affinity complex, pharmacological specificities of beta-adrenergic receptor populations of canine myocardium and lung were quantified. Analysis using computer-assisted techniques suggests a beta 1/beta 2 receptor ratio of approximately 85%/15% for canine myocardium and 5%/95% for canine lung. In the absence of added guanine nucleotides, comparison of potencies of beta-adrenergic agonists in the two membrane systems suggests significant beta 2 selectivity of l-isoproterenol and l-epinephrine, and non-selectivity of norepinephrine. In the presence of saturating levels of guanine nucleotides, comparison of agonist potencies confirms the non-selectivity of l-isoproterenol and l-epinephrine, and beta 1 selectivity of norepinephrine. These results demonstrate that the state of guanine nucleotide regulation of receptors should be defined when examining agonist selectivities for beta-adrenergic receptor subtypes in vitro.
Psychological interventions to improve glycaemic control in patients with type 1 diabetes: systematic review and meta-analysis of randomised controlled trials
Authors: Kirsty Winkley, Sabine Landau, Ivan Eisler, Khalida Ismail
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To determine whether psychological interventions have any effect on glycaemic control in people with type 1 diabetes. <b>Design</b> Systematic review and meta-analysis of psychological therapies to assess their effectiveness in improving glycaemic control in type 1 diabetes. <b>Data sources</b> Medline, PsycINFO, Embase, and Cochrane central register of controlled trials searched to September 2004. <b>Review methods</b> All included studies were randomised controlled trials in children (including adolescents) or adults with type 1 diabetes that evaluated the effect of a psychological therapy (counselling, cognitive behaviour therapy, family systems therapy, and psychodynamic therapy) on control of diabetes. Data were extracted on sample size, age, duration of diabetes, type of psychological therapy, its mode of delivery, and type of intervention in control group. <b>Main outcome measures</b> Glycaemic control measured by percentage of glycated haemoglobin and psychological distress. Pooled standardised effect sizes were calculated. <b>Results</b> 29 trials were eligible for the systematic review and 21 trials for the meta-analysis. In the 10 studies of children and adolescents included in the meta-analysis, the mean percentage of glycated haemoglobin was significantly reduced in those who had received a psychological intervention compared with those in the control group (pooled standardised mean difference −0.35 (95% confidence interval −0.66 to −0.04), equivalent to a 0.48% (0.05% to 0.91%) absolute reduction in glycated haemoglobin. In the 11 studies in adults the pooled standardised mean difference was −0.17 (−0.45 to 0.10), equivalent to 0.22% (−0.13% to 0.56%) absolute reduction in glycated haemoglobin. Psychological distress was significantly lower in the intervention groups in children and adolescents (pooled standardised effect size −0.46, −0.83 to −0.10) but not in adults (−0.25, −0.51 to 0.01). <b>Conclusion</b> Psychological treatments can slightly improve glycaemic control in children and adolescents with diabetes but have no effect in adults.
Identification of human CCR8 as a CCL18 receptor
Authors: Sabina A. Islam, Morris F. Ling, John Leung, Wayne G. Shreffler, Andrew D. Luster
Journal: The Journal of Experimental Medicine (2013)

The CC chemokine ligand 18 (CCL18) is one of the most highly expressed chemokines in human chronic inflammatory diseases. An appreciation of the role of CCL18 in these diseases has been hampered by the lack of an identified chemokine receptor. We report that the human chemokine receptor CCR8 is a CCL18 receptor. CCL18 induced chemotaxis and calcium flux of human CCR8-transfected cells. CCL18 bound with high affinity to CCR8 and induced its internalization. Human CCL1, the known endogenous CCR8 ligand, and CCL18 competed for binding to CCR8-transfected cells. Further, CCL1 and CCL18 induced heterologous cross-desensitization of CCR8-transfected cells and human Th2 cells. CCL18 induced chemotaxis and calcium flux of human activated highly polarized Th2 cells through CCR8. Wild-type but not Ccr8-deficient activated mouse Th2 cells migrated in response to CCL18. CCL18 and CCR8 were coexpressed in esophageal biopsy tissue from individuals with active eosinophilic esophagitis (EoE) and were present at markedly higher levels compared with esophageal tissue isolated from EoE patients whose disease was in remission or in normal controls. Identifying CCR8 as a chemokine receptor for CCL18 will help clarify the biological role of this highly expressed chemokine in human disease.
The effects of one year of nocturnal cuirass-assisted ventilation in chest wall disease
Authors: W Kinnear, S Hockley, J Harvey, J Shneerson
Journal: European Respiratory Journal (1988)

The effects of one year of nocturnal cuirass-assisted ventilation using individually designed cuirass respirators have been investigated in twenty-five patients with chest wall disease. After one year, 22 (88%) of the patients were alive. Daytime arterial blood gases had improved. Functional residual capacity (FRC) had increased but there was no significant change in other lung volumes. Maximum inspiratory pressure (MIP) improved in the subjects with a scoliosis but not in those with a thoracoplasty or neuromuscular disease. Maximum expiratory pressure (MEP) was unchanged. Maximum voluntary ventilation (MVV), the ventilatory response to carbon dioxide and six minute walking distance had all increased. There was no improvement in respiratory symptoms, but a decrease in depression scores and in the time taken to complete a trail test. The mean (SD) number of days spent in hospital over the year was 21.5 (15.1) per patient, with patients consulting their general practitioners less frequently than in the year prior to commencing nocturnal cuirass-assisted ventilation. The cost of commencing a patient on domiciliary nocturnal cuirass-assisted ventilation is estimated as 2470 pounds, and of maintaining them at home for one year as 3302 pounds.
Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model.
Authors: P S Foster, S P Hogan, A J Ramsay, K I Matthaei, I G Young
Journal: The Journal of Experimental Medicine (1996)

Airways inflammation is thought to play a central role in the pathogenesis of asthma. However, the precise role that individual inflammatory cells and mediators play in the development of airways hyperreactivity and the morphological changes of the lung during allergic pulmonary inflammation is unknown. In this investigation we have used a mouse model of allergic pulmonary inflammation and interleukin (IL) 5-deficient mice to establish the essential role of this cytokine and eosinophils in the initiation of aeroallergen-induced lung damage and the development of airways hyperreactivity. Sensitization and aerosol challenge of mice with ovalbumin results in airways eosinophilia and extensive lung damage analogous to that seen in asthma. Aeroallergen-challenged mice also display airways hyperreactivity to beta-methacholine. In IL-5-deficient mice, the eosinophilia, lung damage, and airways hyperreactivity normally resulting from aeroallergen challenge were abolished. Reconstitution of IL-5 production with recombinant vaccinia viruses engineered to express this factor completely restored aeroallergen-induced eosinophilia and airways dysfunction. These results indicate that IL-5 and eosinophils are central mediators in the pathogenesis of allergic lung disease.
Effects of vasopressin antagonist on vasopressin binding, adenylate cyclase activation, and water flux.
Authors: J K Kim, M A Dillingham, S N Summer, S Ishikawa, R J Anderson, R W Schrier
Journal: Journal of Clinical Investigation (1985)

We studied the effect of an arginine vasopressin (AVP) analogue, (1-[beta-mercapto-beta, beta-cyclopentamethylenepropionic acid],2-O-ethyltyrosine, 4-valine)AVP(d[CH2]5Tyr[Et]VAVP), on the stimulation of adenylate cyclase by various hormones in the isolated nephron segments and 3H-AVP binding to renal papillary membranes from the rat. The net water flux across the renal cortical collecting tubules of the rabbit was also examined. We found that d(CH2)5Tyr(Et)VAVP significantly inhibited adenylate cyclase activation by AVP in cortical, medullary, and papillary collecting tubules and in the medullary thick ascending limb. In contrast, the AVP analogue did not alter the stimulation of adenylate cyclase by parathyroid hormone in the cortical thick ascending limb, by glucagon in the medullary thick ascending limb, and by calcitonin in cortical collecting tubules. In addition, d(CH2)5Tyr(Et)VAVP blocked [3H]AVP binding to renal papillary membranes. The enhanced net water transport induced by AVP in isolated, perfused rabbit cortical collecting tubules also was completely blocked by this AVP analogue. These results indicate that d(CH2)5Tyr(Et)VAVP specifically antagonizes the cellular action of AVP on the medullary thick ascending limb and on the cortical, medullary, and papillary collecting tubules. Evidence is also presented for competitive antagonism as the cellular mechanism of action.
Acute atrial arrhythmogenicity and altered Ca2+ homeostasis in murine RyR2-P2328S hearts
Authors: Yanmin Zhang, James A. Fraser, Kamalan Jeevaratnam, Xiaojin Hao, Sandeep S. Hothi, Andrew A. Grace, Ming Lei, Christopher L.-H. Huang
Journal: Cardiovascular Research (2010)

AimsThe experiments explored for atrial arrhythmogenesis and its possible physiological background in recently developed hetero-(RyR2+/S) and homozygotic (RyR2S/S) RyR2-P2328S murine models for catecholaminergic polymorphic ventricular tachycardia (VT) for the first time. They complement previous clinical and experimental reports describing increased ventricular arrhythmic tendencies associated with physical activity, stress, or catecholamine infusion, potentially leading to VT and ventricular fibrillation.
Prevalence of Prostate Cancer among Men with a Prostate-Specific Antigen Level ≤4.0 ng per Milliliter
Authors: Ian M. Thompson, Donna K. Pauler, Phyllis J. Goodman, Catherine M. Tangen, M. Scott Lucia, Howard L. Parnes, Lori M. Minasian, Leslie G. Ford, Scott M. Lippman, E. David Crawford, John J. Crowley, Charles A. Coltman
Journal: New England Journal of Medicine (2004)

The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less.Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years.Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter.Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less--levels generally thought to be in the normal range.
Infectious Causes of Esophagitis
Authors: J S Goff
Journal: Annual Review of Medicine (1988)

In recent years there has been an increasing awareness of infections in the esophagus and their potential to cause considerable morbidity and mortality in both normal subjects and immunocompromised patients. It is important to be cognizant of the pathogens involved, because their treatment is quite different from noninfectious esophagitis, and because inadequate treatment can lead to local complications in the esophagus or to dissemination of the infectious agent, especially in the immunocompromised host. Also, the esophagus is a site where opportunistic infections may present as one of the manifestations of the acquired immune deficiency syndrome (AIDS).
Heightened response of eosinophilic asthmatic patients to the <scp>CRTH</scp>2 antagonist <scp>OC</scp>000459
Authors: R. Pettipher, M. G. Hunter, C. M. Perkins, L. P. Collins, T. Lewis, M. Baillet, J. Steiner, J. Bell, M. A. Payton
Journal: Allergy (2014)

Abstract Background The CRTH 2 antagonist OC 000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. A study was conducted to determine the effect of lower once daily doses of OC 000459 and to define the phenotype of subjects most responsive to treatment. Methods Adult subjects (percentage of predicted forced expiratory volume in 1 s ( FEV 1 ) 60–85%) were randomized to OC 000459 at three dose levels (25 mg once daily, 200 mg once daily or 100 mg twice daily) or placebo for 12 weeks ( n = 117–125 per group, full analysis set). The primary endpoint was the change from baseline in prebronchodilator FEV 1 , and secondary endpoints included Asthma Control Questionnaire ( ACQ ) and Standardised Asthma Quality of Life Questionnaire [ AQLQ (S)], and incidence of exacerbations and respiratory tract infections. Results OC 459 caused a significant improvement in FEV 1 compared with placebo at a dose of 25 mg once daily ( P = 0.028). A similar increase was observed in the other dose groups, and the mean change in FEV 1 in the pooled dose groups at endpoint was 95 ml greater than placebo ( P = 0.024). In a post hoc analysis of atopic eosinophilic subjects with uncontrolled asthma, a mean increase in FEV 1 of 220 ml was observed compared with placebo ( P = 0.005). The mean increase in FEV 1 was more marked in younger subjects in this group: for subjects aged ≤40 years, there was a mean increase of 355 ml compared with placebo ( P = 0.007). Improvements in ACQ and AQLQ (S) were observed in both the full analysis set and the atopic eosinophilic subgroup. There was a lower incidence of exacerbations and respiratory infections in subjects treated with OC 000459. There were no drug‐related serious adverse events. Conclusions OC 000459 is a safe and effective oral anti‐inflammatory agent, which achieved clinically meaningful improvements in lung function and asthma control in allergic asthmatics with an eosinophil‐dominant form of the disease. A dose of 25 mg given once daily was as effective as the higher doses studied.
Cutaneous presentation of steroid responsive blastoid natural killer cell lymphoma
Authors: C.P.R. Bower, G.R. Standen, J. Pawade, C.J. Knechtli, C.T.C. Kennedy
Journal: British Journal of Dermatology (2000)

Journal Article Cutaneous presentation of steroid responsive blastoid natural killer cell lymphoma Get access C.P.R. Bower, C.P.R. Bower Departments of Dermatology, Dr C.P.R.Bower. E‐mail: gif.bower@virgin.net Search for other works by this author on: Oxford Academic Google Scholar G.R. Standen, G.R. Standen Haematology and Search for other works by this author on: Oxford Academic Google Scholar J. Pawade, J. Pawade Histopathology, Bristol Royal Infirmary, Bristol BS2 8HW, U.K. Search for other works by this author on: Oxford Academic Google Scholar C.J. Knechtli, C.J. Knechtli Haematology and Search for other works by this author on: Oxford Academic Google Scholar C.T.C. Kennedy C.T.C. Kennedy Departments of Dermatology, Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 5, 1 May 2000, Pages 1017–1020, https://doi.org/10.1046/j.1365-2133.2000.03489.x Published: 01 May 2000
The mouse vitronectin receptor is a T cell activation antigen.
Authors: K Moulder, K Roberts, E M Shevach, J E Coligan
Journal: The Journal of Experimental Medicine (1991)

In this report, we demonstrate that the T cell activation antigen, recognized by monoclonal antibody H9.2B8, is the murine homologue of the vitronectin receptor (VNR) and, thereby, we provide initial evidence that VNR is expressed on lymphoid cells. VNR is expressed on a variety of T cell lines, tumors, and Con A-activated splenocytes, but not resting T cells, and is capable of binding to the extracellular matrix proteins fibronectin, fibrinogen, and vitronectin, via the tripeptide sequence RGD. There was no evidence of novel beta chains pairing with the VNR alpha chain, as has been demonstrated in some human cells. In view of recent studies demonstrating that this molecule functions as an accessory molecule in T cell activation, the VNR may play an important role in mouse T cell functions.