tbuckley/cabot-search huggingface dataset:
IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII
Authors: Davide Matino, Marco Gargaro, Elena Santagostino, Matteo N.D. Di Minno, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Maria E. Mancuso, Giovanni Di Minno, Antonio Coppola, Vincenzo N. Talesa, Claudia Volpi, Carmine Vacca, Ciriana Orabona, Rossana Iannitti, Maria G. Mazzucconi, Cristina Santoro, Antonella Tosti, Sara Chiappalupi, Guglielmo Sorci, Giuseppe Tagariello, Donata Belvini, Paolo Radossi, Raffaele Landolfi, Dietmar Fuchs, Louis Boon, Matteo Pirro, Emanuela Marchesini, Ursula Grohmann, Paolo Puccetti, Alfonso Iorio, Francesca Fallarino
Journal: Journal of Clinical Investigation (2015)

The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.
Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors
Authors: M. Moore, H.W. Hirte, L. Siu, A. Oza, S.J. Hotte, O. Petrenciuc, F. Cihon, C. Lathia, B. Schwartz
Journal: Annals of Oncology (2005)
Comparative genome sequence analysis underscores mycoparasitism as the ancestral life style of Trichoderma
Authors: Christian P Kubicek, Alfredo Herrera-Estrella, Verena Seidl-Seiboth, Diego A Martinez, Irina S Druzhinina, Michael Thon, Susanne Zeilinger, Sergio Casas-Flores, Benjamin A Horwitz, Prasun K Mukherjee, Mala Mukherjee, László Kredics, Luis D Alcaraz, Andrea Aerts, Zsuzsanna Antal, Lea Atanasova, Mayte G Cervantes-Badillo, Jean Challacombe, Olga Chertkov, Kevin McCluskey, Fanny Coulpier, Nandan Deshpande, Hans von Döhren, Daniel J Ebbole, Edgardo U Esquivel-Naranjo, Erzsébet Fekete, Michel Flipphi, Fabian Glaser, Elida Y Gómez-Rodríguez, Sabine Gruber, Cliff Han, Bernard Henrissat, Rosa Hermosa, Miguel Hernández-Oñate, Levente Karaffa, Idit Kosti, Stéphane Le Crom, Erika Lindquist, Susan Lucas, Mette Lübeck, Peter S Lübeck, Antoine Margeot, Benjamin Metz, Monica Misra, Helena Nevalainen, Markus Omann, Nicolle Packer, Giancarlo Perrone, Edith E Uresti-Rivera, Asaf Salamov, Monika Schmoll, Bernhard Seiboth, Harris Shapiro, Serenella Sukno, Juan Antonio Tamayo-Ramos, Doris Tisch, Aric Wiest, Heather H Wilkinson, Michael Zhang, Pedro M Coutinho, Charles M Kenerley, Enrique Monte, Scott E Baker, Igor V Grigoriev
Journal: Genome biology (2011)

Abstract Background Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus, has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Hypocrea / Trichoderma . Results Here we report an analysis of the genome sequences of the two biocontrol species Trichoderma atroviride (teleomorph Hypocrea atroviridis ) and Trichoderma virens (formerly Gliocladium virens , teleomorph Hypocrea virens ), and a comparison with Trichoderma reesei (teleomorph Hypocrea jecorina ). These three Trichoderma species display a remarkable conservation of gene order (78 to 96%), and a lack of active mobile elements probably due to repeat-induced point mutation. Several gene families are expanded in the two mycoparasitic species relative to T. reesei or other ascomycetes, and are overrepresented in non-syntenic genome regions. A phylogenetic analysis shows that T. reesei and T. virens are derived relative to T. atroviride . The mycoparasitism-specific genes thus arose in a common Trichoderma ancestor but were subsequently lost in T. reesei . Conclusions The data offer a better understanding of mycoparasitism, and thus enforce the development of improved biocontrol strains for efficient and environmentally friendly protection of plants.
Telephone-based re-education on the day before colonoscopy improves the quality of bowel preparation and the polyp detection rate: a prospective, colonoscopist-blinded, randomised, controlled study
Authors: Xiaodong Liu, Hui Luo, Lin Zhang, Felix W Leung, Zhiguo Liu, Xiangping Wang, Rui Huang, Na Hui, Kaichun Wu, Daiming Fan, Yanglin Pan, Xuegang Guo
Journal: Gut (2013)

<h3>Background</h3> Despite advances in bowel preparation methods, the quality of bowel preparation in some patients undergoing colonoscopy remains unsatisfactory. The effect of telephone re-education (TRE) on the day before colonoscopy on the quality of bowel preparation and other outcome measures had not been studied. <h3>Methods</h3> A prospective colonoscopist-blinded study was conducted. All patients received regular instructions during a visit to discuss colonoscopy. Those scheduled for colonoscopy were randomly assigned to receive TRE on the day before colonoscopy (TRE group) for bowel preparation or no TRE (control group). The primary outcome was the rate of adequate bowel preparation. The secondary outcomes included polyp detection rate (PDR), non-compliance with instructions, and willingness to repeat bowel preparation. <h3>Results</h3> A total of 605 patients were randomised, 305 to the TRE group and 300 to the control group. In an intention-to-treat analysis of the primary outcome, adequate preparation was found in 81.6% vs 70.3% of TRE and control patients, respectively (p=0.001). PDR was 38.0% vs 24.7% in the TRE and control group, respectively (p&lt;0.001). Among patients with successful colonoscopy, the Ottawa scores were 3.0±2.3 in the TRE group and 4.9±3.2 in the control group (p&lt;0.001). Fewer patients who showed non-compliance with instructions were found in the TRE group (9.4% vs 32.6%, p&lt;0.001). No significant differences were observed between the two groups with regard to willingness to have a repeat bowel preparation (p=0.409). <h3>Conclusions</h3> TRE about the details of bowel preparation on the day before colonoscopy significantly improved the quality of bowel preparation and PDR.
Emerging concept: ‘central benefit model’ of exercise in falls prevention
Authors: Teresa Liu-Ambrose, Lindsay S Nagamatsu, Chun Liang Hsu, Niousha Bolandzadeh
Journal: British Journal of Sports Medicine (2012)

Falls are a common geriatric syndrome and are the third leading cause of chonic disability worldwide. Falls are not random events and occur, at least in part, due to impaired physiological function, such as impaired balance, and cognitive impairment. The clinical syndrome of falls is important for Sports and Exercise Medicine Clinicians as there is Level 1 evidence that targeted exercise prescription is an effective intervention strategy. The widely accepted dogma is that improved physical function, balance and muscle strength, underlies the effectiveness of the exercise in reducing falls. However, findings from randomised controlled trials suggest that exercise reduce falls via mechanisms other than improved physiological function. The authors propose that improved cognitive function - specifically, executive functions - and associated functional plasticity may be an important yet underappreciated mechanism by which the exercise reduces falls in older adults.
Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial
Authors: Saedis Saevarsdottir, Hamed Rezaei, Pierre Geborek, Ingemar Petersson, Sofia Ernestam, Kristina Albertsson, Kristina Forslind, Ronald F van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. <h3>Methods</h3> In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 &lt;3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. <h3>Results</h3> 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26). Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45). These results remained after further adjustment for treatment strategy. Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12–63% risk gradient from patients carrying none compared with all predictors. Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off. In a secondary exploratory analysis using cut-off &gt;1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses. The other parameters also remained significant using this lower cut-off. <h3>Conclusions</h3> In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA. <h3>Trial registration number</h3> NCT00764725.
Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma
Authors: S. Vincent Rajkumar, Paul G. Richardson, Martha Q. Lacy, Angela Dispenzieri, Philip R. Greipp, Thomas E. Witzig, Robert Schlossman, Carolyn F. Sidor, Kenneth C. Anderson, Morie A. Gertz
Journal: Clinical Cancer Research (2007)

Abstract Purpose: 2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties. We report on the first phase II trial of 2ME2 in multiple myeloma. Experimental Design: 2ME2 was administered orally at a dose of 1,000 mg daily. Sixty patients (31 men and 29 women) were treated. After 39 patients were accrued, the dose was increased to 800 mg twice daily for the remaining patients. Results: Thirty-one patients had relapsed or refractory multiple myeloma, and 29 had plateau phase multiple myeloma. Median age was 60 years (range, 27-84 years). Therapy was well tolerated. Common adverse events included anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flushes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most adverse events were mild (grade 1-2); 12% experienced grade 3-4 adverse events. Median time to progression was 3.8 months, with 5.6 months for plateau phase disease and 2.3 months for relapsed multiple myeloma. Estimated progression-free survival rates for all patients at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. Three patients, all with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months, respectively. Minor response was noted in 2 patients. Conclusions: Although no partial responses have been seen thus far, the minor responses and prolonged stable disease seen with 2ME2 therapy are promising. Plasma levels indicate that the dose of 2ME2 was inadequate. A new formulation with better bioavailability will be tested soon in multiple myeloma.
Self-Preservation: An Argument for Therapeutic Cloning, and a Strategy for Fostering Respect for Moral Integrity
Authors: Mary B. Mahowald
Journal: The American Journal of Bioethics (2004)

The issues of human cloning and stem cell retrieval are inseparable in circumstances in which the rationale of self-preservation may be invoked as a negative right. I apply this rationale to a hypothetical case in which cloning is necessary to preserve the bodily integrity or life of an individual. Self-preservation as moral integrity is examined in a narrower context, i.e., as applicable to those for whom deliberate termination of embryonic life is morally-problematic. This issue is addressed through comparison with two paradigms commonly used in support of clinical practice: the distinction between letting die and killing, and the permissibility of vital organ retrieval after death. Although these paradigms are questionable in their own right, they offer a rationale by which scientists and clinicians may respect the negative right to moral integrity of those with whom they disagree.
Pneumocystis carinii pneumonia in a HIV-seronegative patient with untreated rheumatoid arthritis and CD4+ T-lymphocytopenia
Authors: A Prekates, T Kyprianou, O Paniara, C Roussos
Journal: European Respiratory Journal (1997)

Pneumocystis carinii pneumonia (PCP) usually occurs in immunocompromised patients, and it is a life-threatening infection. We report the case of a human immunodeficiency virus (HIV)-seronegative patient with untreated rheumatoid arthritis (RA), who developed fatal PCP related to uncommon CD4+ T-lymphocytopenia. Although extremely rare and of uncertain aetiology, suppression of cellular immunity and subsequent opportunistic infections should be suspected in such patients.
Bone Sialoprotein Mediates the Tumor Cell–Targeted Prometastatic Activity of Transforming Growth Factor β in a Mouse Model of Breast Cancer
Authors: Jeong-Seok Nam, Adam M. Suchar, Mi-Jin Kang, Christina H. Stuelten, Binwu Tang, Aleksandra M. Michalowska, Larry W. Fisher, Neal S. Fedarko, Alka Jain, Jan Pinkas, Scott Lonning, Lalage M. Wakefield
Journal: Cancer Research (2006)

Abstract Transforming growth factor βs (TGF-β) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-β antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-β antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-β was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-β to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor cell–targeted prometastatic activity of TGF-β in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-β antibodies. (Cancer Res 2006; 66(12): 6327-35)
Cytokines and β-Cell Biology: from Concept to Clinical Translation
Authors: Marc Y. Donath, Joachim Størling, Lukas A. Berchtold, Nils Billestrup, Thomas Mandrup-Poulsen
Journal: Endocrine Reviews (2007)

The tale of cytokines and the β-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene- and protein expression patterns, molecular and biochemical effector mechanisms to in vivo studies in spontaneously diabetic and transgenic animal models. Only very recently have steps been taken to translate the accumulating compelling preclinical data into clinical trials. The aim of this chapter is to present an overview of early and recent key observations from our own groups as well as other laboratories that serve to illuminate the road from concept to clinical translation.
Spontaneous phasic activity of isolated human coronary arteries
Authors: G. ROSS, E STINSON, J SCHROEDER, R GINSBURG
Journal: Cardiovascular Research (1980)

The functional behaviour and pharmacological responses of ring segments of large coronary arteries removed from five patients undergoing cardiac transplantation were studied in vitro. All segments showed spontaneous rhythmic contractions which were markedly dependent on external calcium and were rapidly abolished in calcium-free solutions and by verapamil. The contractions were inhibited by cooling and by anoxia. Phasic activity was enhanced by increasing the external potassium concentration over the range 5 to 20 mmol·litre−1 but was abolished by 120 mmol·litre−1 potassium. Noradrenaline and ergonovine enhanced or induced phasic activity. The behaviour of human coronary arteries resembles that of the portal-mesenteric veins of many species and our results suggest that the activation mechanisms of these two tissues may be similar.
Forcible Dilatation of the Cervix in "Accouchement Force," more especially by means of the Bossi and Frommer Dilators
Authors: J. M. M. Kerr
Journal: BMJ (1904)

2DILATATION of the cervix as a step in the operation of accouchement force may be carried out with the hands, rubber bags, or metal dilators.I shall bricfly refer to each of these methods, and then devote the main part of this contribution to a consideration of the use of metal dilators in obtaining forced dilatation.Manual Dilatation.-The obvious advantages of manual dilatation are that the operator requires no instruments, all the stretching being done with the fingers, and that he can tell what he is doing.The disadvantages are that the operation takes time, is sometimes impossible if the cervix is un- dilated and rigid, and is often very fatiguing.Before manual dilatation proper can be commenced one must be able to get at least two fingers through the canal.Sometimes the preliminary dilatation may be (arried out with one finger pushed further and further in, but often even that is impossible, and recourse must be had to the graduated dilators of Hegar or Cameron.Having got the two fingers through the os, the rest of the operation may be carried out by forcing more and more of the hand through, or by employing the fingers of the two hands (Bonnaire's method).Could one always dilate the cervix quickly enough by this method it would without doubt be the best, for there is less chanee of tearing it, especially if one moves the dilating fingers about, stretching sometimes antero-posteriorly and sometimes laterally, and one can tell better what is happening.Besides, there is another advantage, but one which I do not remeinber having seen mentioned, and that is that with finger manipulations the cervix oftea becomes softer.Let me with extreme brevity give a few illustrative cases: CASE i.-Mrs.L., 6-para, six months pregnant, was admitted to the Maternity Hospital for eclampsia, August, I900.The os admitted a finger with difficulty, and was extremely rigid.Manual dilatation.version and extraction.Duration of oneration an hour and a-half.CASE I --A 2-para; seen in consultation with Dr. McMillan, June, I962.Accouchement forc6 on account of dyspnoea.Manual dilatation and extraction with forceps.Duration of operation fifty minutes.CASE III.-A 2-para, six months pregnant, seen with Dr. Loudon, ofHamilton, September, I902.Eclampsia.Os admitted finger.Dilata- tion with bags and fingers, followed by version.Os very rigid, so sixty minutes at least elapsed before the child was extracted.CASE iv.-A primipara, about seven and a-half months pregnant, seen in consultation with Dr. Parker, Gartloch.Acute mania, Dilatation with fingers, followed by version and extraction.Duration of operation forty-five minutes.
Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma
Authors: Ashraf Badros, Angelika M. Burger, Sunita Philip, Ruben Niesvizky, Sarah S. Kolla, Olga Goloubeva, Carolynn Harris, James Zwiebel, John J. Wright, Igor Espinoza-Delgado, Maria R. Baer, Julianne L. Holleran, Merrill J. Egorin, Steven Grant
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Vorinostat, a histone deacetylase inhibitor, enhances cell death by the proteasome inhibitor bortezomib in vitro. We sought to test the combination clinically. Experimental Design: A phase I trial evaluated sequential dose escalation of bortezomib at 1 to 1.3 mg/m2 i.v. on days 1, 4, 8, and 11 and vorinostat at 100 to 500 mg orally daily for 8 days of each 21-day cycle in relapsed/refractory multiple myeloma patients. Vorinostat pharmacokinetics and dynamics were assessed. Results: Twenty-three patients were treated. Patients had received a median of 7 prior regimens (range, 3-13), including autologous transplantation in 20, thalidomide in all 23, lenalidomide in 17, and bortezomib in 19, 9 of whom were bortezomib-refractory. Two patients receiving 500 mg vorinostat had prolonged QT interval and fatigue as dose-limiting toxicities. The most common grade &amp;gt;3 toxicities were myelo-suppression (n = 13), fatigue (n = 11), and diarrhea (n = 5). There were no drug-related deaths. Overall response rate was 42%, including three partial responses among nine bortezomib refractory patients. Vorinostat pharmacokinetics were nonlinear. Serum Cmax reached a plateau above 400 mg. Pharmacodynamic changes in CD-138+ bone marrow cells before and on day 11 showed no correlation between protein levels of NF-κB, IκB, acetylated tubulin, and p21CIP1 and clinical response. Conclusions: The maximum tolerated dose of vorinostat in our study was 400 mg daily for 8 days every 21 days, with bortezomib administered at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. The promising antimyeloma activity of the regimen in refractory patients merits further evaluation. (Clin Cancer Res 2009;15(16):5250–7)