tbuckley/cabot-search huggingface dataset:
Inability of Transforming Growth Factor-β to Cause SnoN Degradation Leads to Resistance to Transforming Growth Factor-β–Induced Growth Arrest in Esophageal Cancer Cells
Authors: Jeffery S. Edmiston, W. Andrew Yeudall, Theodore D. Chung, Deborah A. Lebman
Journal: Cancer Research (2005)

Abstract It is well established that loss of a growth inhibitory response to transforming growth factor-β (TGF-β) is a common feature of epithelial cancers including esophageal cancer. However, the molecular basis for the abrogation of this key homeostatic mechanism is poorly understood. In esophageal cancer cell lines that are resistant to TGF-β–induced growth inhibition, TGF-β also fails to decrease transcription of c-myc despite the presence of functional signaling components. Consequently, to gain a better understanding of the mechanisms leading to resistance to TGF-β–induced growth arrest, the basis for the inability to decrease c-myc transcription was investigated. Regardless of sensitivity to TGF-β–induced growth arrest, TGF-β enhanced the ability of Smad3-protein complexes to bind c-myc regulatory elements. However, in a growth inhibition–resistant esophageal cancer cell line, the Smad3-protein complexes contained the SnoN oncoprotein. Furthermore, in esophageal cancer cell lines that are resistant to TGF-β–induced growth arrest, TGF-β does not cause degradation of SnoN. Analyses of the effect of modulating SnoN expression in both growth inhibition–sensitive and growth inhibition–resistant cell lines showed that degradation of SnoN is a prerequisite for both TGF-β–induced repression of c-myc transcription and growth arrest. The data indicate that SnoN-Smad3 complexes do not cause repression of c-myc transcription but rather prevent functionality of active repressor complexes. Thus, these studies reveal a novel mechanism for resistance to TGF-β–induced growth inhibition in esophageal cancer, namely the failure to degrade SnoN. In addition, they show that SnoN can block TGF-β repression of gene transcription.
<i>Butyricicoccus pullicaecorum</i>in inflammatory bowel disease
Authors: Venessa Eeckhaut, Kathleen Machiels, Clémentine Perrier, Carlos Romero, Sofie Maes, Bram Flahou, Marjan Steppe, Freddy Haesebrouck, Benedikt Sas, Richard Ducatelle, Severine Vermeire, Filip Van Immerseel
Journal: Gut (2012)

Many species within the phylum Firmicutes are thought to exert anti-inflammatory effects. We quantified bacteria belonging to the genus Butyricicoccus in stools of patients with ulcerative colitis (UC) and Crohn's disease (CD). We evaluated the effect of Butyricicoccus pullicaecorum in a rat colitis model and analysed the ability to prevent cytokine-induced increases in epithelial permeability.A genus-specific quantitative PCR was used for quantification of Butyricicoccus in stools from patients with UC or CD and healthy subjects. The effect of B pullicaecorum on trinitrobenzenesulfonic (TNBS)-induced colitis was assessed and the effect of B pullicaecorum culture supernatant on epithelial barrier function was investigated in vitro.The average number of Butyricicoccus in stools from patients with UC and CD in active (UC: 8.61 log10/g stool; CD: 6.58 log10/g stool) and remission phase (UC: 8.69 log10/g stool; CD: 8.38 log10/g stool) was significantly lower compared with healthy subjects (9.32 log10/g stool) and correlated with disease activity in CD. Oral administration of B pullicaecorum resulted in a significant protective effect based on macroscopic and histological criteria and decreased intestinal myeloperoxidase (MPO), tumour necrosis factor α (TNFα) and interleukin (IL)-12 levels. Supernatant of B pullicaecorum prevented the loss of transepithelial resistance (TER) and the increase in IL-8 secretion induced by TNFα and interferon γ (IFN gamma) in a Caco-2 cell model.Patients with inflammatory bowel disease have lower numbers of Butyricicoccus bacteria in their stools. Administration of B pullicaecorum attenuates TNBS-induced colitis in rats and supernatant of B pullicaecorum cultures strengthens the epithelial barrier function by increasing the TER.
Growth Regulation of Estrogen Receptor-Negative Breast Cancer Cells Transfected With Complementary DNAs for Estrogen Receptor
Authors: S.-Y. Jiang, V. C. Jordan
Journal: JNCI Journal of the National Cancer Institute (1992)

Background : The growth of estrogen receptor (ER)-positive breast cancer cells is hormonally regulated, but the majority of breast cancers are ER negative and unresponsive to hormonal therapy. Purpose and Methods : To test whether hormonal control over replication can be re-established in ER-negative cells, we transfected ER-negative MDA-MB-231 (clone 10A) cells with sense and antisense constitutive ER expression vectors containing the gene for either wild-type or mutant ER linked to the gene for neomycin resistance aminoglycoside phosphotransferase (neo). A Northern blot analysis was done on total RNA from eight of the 10 transfectant clones produced to detect messenger RNA coding for ER and neo, and a Western blot analysis was done on protein extracted from the cells of one mutant and two wild-type ER sense transfectant clones to determine the molecular weight of the ER in transfectants. Levels of ER in transfectants were measured both by enzyme immunoassay and by ligand-binding methods. To ascertain whether the ER in wild-type and mutant sense transfectants was functional, we tested the effects of 17β-estradiol (E 2 ) and/or an antiestrogen, ICI 164, 384, on 1) ER-activated gene regulation (by transient transfection of these cells a second time with a reporter plasmid containing an estrogen response element linked to the chloramphenicol acetyl transferase [CAT] gene), 2) induction of progesterone receptor, 3) DNA replication, and 4) cell cycle kinetics. Results : Messenger RNA coding for ER and for neo was detectable in both sense and antisense transfectant clones. Sense transfectants (both mutant and wild-type) expressed ER protein with a molecular weight similar to that found in ER-positive control cells. By the ligand-binding method high levels of ER were detected in both wild-type and mutant transfectants, although by the enzyme immunoassay method lower levels were detected in mutant transfectants. ER from both wild-type and mutant sense transfectants appeared functional, since E 2 stimulated the expression of reporter-linked CAT and of progesterone receptor in these transfectants. E 2 inhibited DNA replication in wild-type sense transfectants at a concentration of 10 −10 M and mutant sense transfectants at a concentration of 10 −8 M, and ICI 164, 384 blocked this effect. Conclusion : ER-negative breast cancer cells stably transfected with either a mutant or wild-type ER gene regain hormonal responsiveness; however, E 2 inhibits rather than stimulates cell growth. Implication : Reactivation of quiescent ER may provide a novel therapeutic approach for controlling ER-negative breast cancers. [J Natl Cancer Inst 84:580–591, 1992]
Continuous Amplitude-Integrated Electroencephalographic Monitoring Is a Useful Prognostic Tool for Hypothermia-Treated Cardiac Arrest Patients
Authors: Sang Hoon Oh, Kyu Nam Park, Young-Min Shon, Young-Min Kim, Han Joon Kim, Chun Song Youn, Soo Hyun Kim, Seung Pill Choi, Seok Chan Kim
Journal: Circulation (2015)

Background— Modern treatments have improved the survival rate following cardiac arrest, but prognostication remains a challenge. We examined the prognostic value of continuous electroencephalography according to time by performing amplitude-integrated electroencephalography on patients with cardiac arrest receiving therapeutic hypothermia. Methods and Results— We prospectively studied 130 comatose patients treated with hypothermia from September 2010 to April 2013. We evaluated the time to normal trace (TTNT) as a neurological outcome predictor and determined the prognostic value of burst suppression and status epilepticus, with a particular focus on their time of occurrence. Fifty-five patients exhibited a cerebral performance category score of 1 to 2. The area under the curve for TTNT was 0.97 (95% confidence interval, 0.92–0.99), and the sensitivity and specificity of TTNT&lt;24 hours after resuscitation as a threshold for predicting good neurological outcome were 94.6% (95% confidence interval, 84.9%–98.9%) and 90.7% (95% confidence interval, 81.7%–96.2%), respectively. The threshold displaying 100% specificity for predicting poor neurological outcome was TTNT&gt;36 hours. Burst suppression and status epilepticus predicted poor neurological outcome (positive predictive value of 98.3% and 96.4%, respectively). The combination of these factors predicted a negative outcome at a median of 6.2 hours after resuscitation (sensitivity and specificity of 92.0% and 96.4%, respectively). Conclusions— A TTNT&lt;24 hours was associated with good neurological outcome. The lack of normal trace development within 36 hours, status epilepticus, and burst suppression were predictors of poor outcome. The combination of these negative predictors may improve their prognostic performance at an earlier stage.
Arterial desaturation in HIV positive patients undergoing sputum induction.
Authors: R F Miller, J Buckland, S J Semple
Journal: Thorax (1991)

Arterial oxygen saturation (SaO2) was monitored continuously during and immediately after sputum induction in 41 HIV positive patients with respiratory symptoms and in 20 symptomless medical and nursing staff, who acted as control subjects. Arterial oxygen desaturation (defined as SaO2 less than or equal to 92%) occurred during sputum induction and persisted for up to 20 minutes after the end of the procedure in 11 of the 20 patients with Pneumocystis carinii pneumonia and in nine of the 21 patients with other respiratory diagnoses. None of the control subjects showed oxygen desaturation. Neither the severity of chest radiographic abnormalities, the alveolar-arterial oxygen gradient (both measured before sputum induction), nor baseline SaO2 prospectively identified the patients who developed oxygen desaturation. Two patients, one with pneumocystis pneumonia, developed dyspnoea and had a fall in arterial oxygen saturation to 84% within 10 minutes of starting sputum induction. The procedure was abandoned in both patients and in two further patients, who developed severe nausea and reaching but no oxygen desaturation. Sputum induction in HIV positive patients with respiratory symptoms may induce a fall in SaO2 that persists after this procedure. This may be important if other procedures are performed soon after sputum induction.
Peptide Vaccination Breaks Tolerance to HER-2/<i>neu</i>by Generating Vaccine-Specific FasL+ CD4+ T Cells: First Evidence for Intratumor Apoptotic Regulatory T Cells
Authors: Angelos D. Gritzapis, Ioannis F. Voutsas, Eftychia Lekka, Michael Papamichail, Constantin N. Baxevanis
Journal: Cancer Research (2010)

BALB/c mice transgenic (Tg) for the transforming rat neu oncogene (BALB-neuT) are genetically predestined to develop mammary carcinogenesis in a process similar to that in humans. We crossed HLA-A2.1/HLA-DR1 (A2.1/DR1) Tg mice with BALB-neuT mice to generate A2.1/DR1 x BALB-neuT triple Tg (A2.1/DR1 x neuT(+)) mice, which represent an improvement over BALB-neuT mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. A vaccine formulation strategy, consisting of synthetic peptides from the rat HER-2/neu oncogene combined with granulocyte macrophage colony-stimulating factor, was highly effective in preventing the growth of established transplantable tumors in male A2.1/DR1 x neuT(+) mice. Vaccination with HER-2(435-443) (p435) CTL peptide alone induced weak antitumor responses, which were characterized by increased numbers of regulatory T cells (Treg) and low numbers of vaccine-specific CD8(+) CTL and helper T cells (Th). The administration of p435 plus HER-2(776-790) (p776; helper peptide) reversed this situation, inducing functionally active, peptide-specific CTL and Th. There was a striking change in the intratumoral balance of Tregs (decrease) and vaccine-specific Th (increase) that directly correlated with tumor rejection. Intratumoral administration of anti-FasL antibody promoted tumor growth. The decrease in Tregs (Fas(+)) was due to apoptosis induced by cell contact with Fas ligand(+) (L)(+) Th. Mice vaccinated with p435 plus p776 exhibited long-lasting antitumor immunity. Our vaccine regimen also significantly delayed the outgrowth of mammary carcinomas in female A2.1/DR1 x neuT(+) animals. We provide a mechanism to overcome tolerance against HER-2/neu, which proposes a combined vaccination with two (Th and CTL) HER-2 peptides against HER-2/neu-expressing tumors.
A Drosophila protein-interaction map centered on cell-cycle regulators
Authors: Clement A Stanyon, Guozhen Liu, Bernardo A Mangiola, Nishi Patel, Loic Giot, Bing Kuang, Huamei Zhang, Jinhui Zhong, Russell L Finley
Journal: Genome biology (2004)

Maps depicting binary interactions between proteins can be powerful starting points for understanding biological systems. A proven technology for generating such maps is high-throughput yeast two-hybrid screening. In the most extensive screen to date, a Gal4-based two-hybrid system was used recently to detect over 20,000 interactions among Drosophila proteins. Although these data are a valuable resource for insights into protein networks, they cover only a fraction of the expected number of interactions. To complement the Gal4-based interaction data, we used the same set of Drosophila open reading frames to construct arrays for a LexA-based two-hybrid system. We screened the arrays using a novel pooled mating approach, initially focusing on proteins related to cell-cycle regulators. We detected 1,814 reproducible interactions among 488 proteins. The map includes a large number of novel interactions with potential biological significance. Informative regions of the map could be highlighted by searching for paralogous interactions and by clustering proteins on the basis of their interaction profiles. Surprisingly, only 28 interactions were found in common between the LexA- and Gal4-based screens, even though they had similar rates of true positives. The substantial number of new interactions discovered here supports the conclusion that previous interaction mapping studies were far from complete and that many more interactions remain to be found. Our results indicate that different two-hybrid systems and screening approaches applied to the same proteome can generate more comprehensive datasets with more cross-validated interactions. The cell-cycle map provides a guide for further defining important regulatory networks in Drosophila and other organisms.
When dermatology meets gastroenterology: a case of odynophagia
Authors: Grigoriy E Gurvits
Journal: Gut (2012)

<h3>Objective</h3> Concurrent presence of endometrial hyperplasia or cancer in patients with granulosa cell tumors (GCTs) is common, with reported incidences of 25.6% to 65.5%. Consequently, bilateral salpingo-oophorectomy and hysterectomy is usually recommended in patients with a GCT, but this remains debatable. Our aim was to evaluate the need for hysterectomy in patients with GCTs by studying the incidence of pathologically confirmed endometrial abnormalities at the time of diagnosis of GCT and during follow-up. <h3>Materials/Methods</h3> All cases of GCT between 1991 and 2012 were evaluated for endometrial pathology using the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). <h3>Results</h3> A total of 1031 cases of GCT were identified at a mean ± SD age of 55 ± 17 years. The incidence of GCTs in the period 1991–2012 was 0.61 per 100,000 women per year. Concurrent endometrial cancer at the time of diagnosis of GCT was found in 58 patients (5.9%) and endometrial hyperplasia in 251 patients (25.5%), including complex hyperplasia in 89 patients (9.1%) and simple hyperplasia in 162 patients (16.5%). Long-term follow-up of 490 patients (47.5%) without a hysterectomy showed that endometrial abnormalities were found in 10 patients (2.0%) of which 2 had endometrial cancer. Interestingly, 8 (80%) of the 10 patients with endometrial abnormalities had recurrent GCT at the time of diagnosis of endometrial hyperplasia or cancer. <h3>Conclusions</h3> Our data suggest that after surgical removal of GCT, development of an endometrial abnormality, especially cancer, is very rare. Therefore, hysterectomy is not recommended in patients with a GCT without endometrial abnormalities at the time of diagnosis.
Immune Modulation in Cancer with Antibodies
Authors: David B. Page, Michael A. Postow, Margaret K. Callahan, James P. Allison, Jedd D. Wolchok
Journal: Annual Review of Medicine (2013)

Ipilimumab is the prototypical immunomodulatory antibody, approved by the FDA in 2011 for advanced melanoma on the basis of survival benefit. Since that time, we have made significant strides in optimizing this therapy: we have characterized the spectrum of immune-related adverse events and learned how to mitigate them with treatment algorithms, discovered potential biomarkers of activity, and identified the potential synergy between checkpoint modulation and other therapeutic modalities. Recent phase I trials have established the efficacy and safety of next-generation checkpoint agents, including PD-1 and PD-L1 inhibitors, across multiple tumor types. Much work lies ahead in developing these next-generation checkpoint agents, testing them in combination, and determining how to integrate them into the treatment paradigms of various tumor types.
Anti-liver kidney microsome antibody recognizes a cytochrome P450 from the IID subfamily.
Authors: M Gueguen, M Meunier-Rotival, O Bernard, F Alvarez
Journal: The Journal of Experimental Medicine (1988)

Children with autoimmune hepatitis have high serum titers of antibodies directed against a 50-kD protein of rat liver endoplasmic reticulum. Affinity-purified anti-50-kD antibodies were used to screen a rat liver cDNA library in lambda GT-11 expression vector. 12 immunopositive clones were obtained. Crossreactivities between fusion proteins of these clones and the 50-kD protein was demonstrated, and four clones were analyzed by restriction mapping, one of them by nucleotide sequencing. Complete identity was found between the restriction maps of two clones (LKMC1 and LKMC2) and that of the 5' end of the rat cytochrome P450 db2. Sequence of a 608-bp fragment of LKMC1 showed complete homology with the rat P450 db2 form. The restriction map of the other two clones (LKMC3 and LKMC4) was identical to that of rat P450 db1. These results suggest that the antigen recognized by LKMA is a P450 of the IID subfamily.
Clinical assessment of osteoarthritis of the knee.
Authors: J Cushnaghan, C Cooper, P Dieppe, J Kirwan, T McAlindon, F McCrae
Journal: Annals of the Rheumatic Diseases (1990)

The repeatability of physical signs used to assess osteoarthritis of the knee has not been systematically examined. The within and between observer variation of 10 commonly used physical signs to determine osteoarthritis of the knee has been assessed here. The results obtained show variation in the repeatability of these signs. For those examining the tibiofemoral joints the repeatability was greater than for those examining the patellofemoral joint. It would therefore seem vital to take note of the repeatability of physical signs in determining the number of subjects to be studied in epidemiological studies and therapeutic studies in osteoarthritis.
Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant.
Authors: J P Lebreton, F Joisel, J P Raoult, B Lannuzel, J P Rogez, G Humbert
Journal: Journal of Clinical Investigation (1979)

A nonspecific opsonin function has been ascribed to human alpha 2 HS glycoprotein. Its serum level has been shown to be decreased in trauma patients. Recent studies from this laboratory revealed a heterogeneity among the products obtained in the course of the preparation of the protein. To date, no definitive agreement existed with regard to a molecular homogeneous entity of alpha 2 HS glycoprotein (Ba-alpha 2 glycoproteins). The purpose of the current work was to study the variations in serum level of alpha 2 HS in patients suffering from an acute inflammatory process of bacterial etiology and to determine whether a decrease in alpha 2 HS was accompanied by the appearance of fragments of this protein in the serum. A method of preparing alpha 2 HS was thus developed, using an immune absorbent as a final purification step. In an intermediary step of the preparation, alpha 2 HS was found to bind zinc when metal chelate affinity chromatography was employed. Immunologically and physico-chemically pure alpha 2 HS was obtained. The protein consists of a unique polypeptide chain of about 50,000 daltons and has a unique amino-terminal residue, alanine. However, the protein maintained its molecular integrity with difficulty, and spontaneous fragments ranging from 30,000 to less than 10,000 daltons were produced in some of the preparations. No major modification in the molecular structure of the protein was noted in the sera of subjects suffering from an acute inflammatory process. Serum level of alpha 2 HS and alpha 1 antitrypsin (AT)was determined in 23 patients. When the acute-phase (AP-)reactant alpha 1 AT was increased (difference with normal mean greater than +2 or +3 SD), the sera showed a large decrease in alpha 2 HS (difference with normal mean less than -2 or -3 SD). The serum level of alpha 2 HS, albumin, alpha 2 macroglobulin, and of positive AP-reactants, orosomucoidinal study of seven patients. The results were submitted to a principal components analysis. Alpha 2 HS showed a negative correlation with the AP-reactants alpha 1 AT, orosomucoid, and haptoglobin (P less than 0.05) and a positive correlation with albumin (P less than 0.05); these findings indicate that alpha 2 HS is a negative AP-reactant. In addition, analysis of the principal components confirms thestrong analogy between alpha 2 HS and albumin and indicates that serum level behavior of the AP-reactants during the course of the disease closely depends on the protein studied.
Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Authors: Björn C. Knollmann
Journal: Circulation Research (2013)

This article reviews the strengths and limitations of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) as models of cardiac arrhythmias. Specifically, the article attempts to answer the following questions: Which clinical arrhythmias can be modeled by iPSC-CM? How well can iPSC-CM model adult ventricular myocytes? What are the strengths and limitations of published iPSC-CM arrhythmia models? What new mechanistic insight has been gained? What is the evidence that would support using iPSC-CM to personalize antiarrhythmic drug therapy? The review also discusses the pros and cons of using the iPSC-CM technology for modeling specific genetic arrhythmia disorders, such as long QT syndrome, Brugada Syndrome, or Catecholaminergic Polymorphic Ventricular Tachycardia.