tbuckley/cabot-search huggingface dataset:
Reply to E.S. Wang et al
Authors: Patricia M. LoRusso, Scott A. Boerner, Jeffrey L. Evelhoch, Jeffrey L. Evelhoch
Journal: Journal of Clinical Oncology (2012)

3][4] In ATTRACT-1 and other combination trials, [5][6][7] ASA404 at this dose significantly increased the incidence of grade 4 neutropenia and other toxicities when added to carboplatin and paclitaxel.In early preclinical studies, 8 the therapeutic synergy of ASA404 combined with carboplatin and paclitaxel occurred without any major dependence on sequencing or scheduling or significant changes in plasma or tumor-drug concentrations.In fact, optimal preclinical activity was achieved by administering chemotherapy at any time within a few hours either before or after the use of ASA404. 8Therefore, it is highly unlikely that the clear lack of efficacy of ASA404 in this large, well-conducted phase III study could have been attributed simply to a suboptimal dose, sequence, or schedule of drug delivery.Wang et al 1 also suggest that the optimal way of giving a vascular disrupting agent (VDA) is before chemotherapy rather than the other way around, as was done in the ATTRACT-1 trial.Their suggestion appears to be reasonable on theoretical grounds but, to our knowledge, is unsupported by any conclusive data that showed improved antitumor activity with this approach.For example, in early preclinical work on ASA404 combined with carboplatin and paclitaxel, 8 no advantage was apparent with the particular sequence suggested by Wang et al 1 over that used in the ATTRACT-1 trial.Our view is that the disappointing efficacy results of the ATTRACT-1 trial would not have been dramatically altered by subtle changes in the sequencing or scheduling of the study treatments.However, as we previously acknowledged in the Discussion of the ATTRACT-1 article, 5 the success of additional VDA drug development relies on a better understanding of the molecular determinants of tumor sensitivity to vascular disruption and the identification of a putative biomarker that will enrich the patient pool to those likely to benefit from VDA therapy.
SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development
Authors: Stefanie Weber, Jaclyn C. Taylor, Paul Winyard, Kari F. Baker, Jessica Sullivan-Brown, Raphael Schild, Tanja Knu[Combining Diaeresis]ppel, Aleksandra M. Zurowska, Alberto Caldas-Alfonso, Mieczyslaw Litwin, Sevinc Emre, Gian Marco Ghiggeri, Aysin Bakkaloglu, Otto Mehls, Corinne Antignac, Escape Network, Franz Schaefer, Rebecca D. Burdine
Journal: Journal of the American Society of Nephrology (2008)

Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.
Generation of the combined prothrombin activation peptide (F1-2) during the clotting of blood and plasma.
Authors: D L Aronson, L Stevan, A P Ball, B R Franza, J S Finlayson
Journal: Journal of Clinical Investigation (1977)

We have investigated the pathway of prothrombin activation in blood and plasma. By means of a rapid purification procedure involving chromatography on DEAE-cellulose and hydroxyapatite, we demonstrated that the major prothrombin fragment in serum is that representing the amino-terminal half of prothrombin (i.e. F1-2). The F1-2 isolated was characterized by its size, amino acid and antigenic compositions, amino-terminal residue, and the peptides (designated F1 and F2, respectively) it yielded upon hydrolysis by thrombin. Measurements by the isotope dilution technique showed that F1-2 could account for the fate of at least 90% of the prothrombin originally present in plasma. By contrast, the serum concentration of the fragment representing the amino-terminal third of prothrombin (viz. F1) was less than 10% that of F1-2. These results demonstrated that the major route of prothrombin conversion in blood or plasma involves the removal of the combined activation fragment (F1-2) as a single peptide.
Sargramostim for Active Crohn's Disease
Authors: Joshua R. Korzenik, Brian K. Dieckgraefe, John F. Valentine, Diana F. Hausman, Mark J. Gilbert
Journal: New England Journal of Medicine (2005)

Sargramostim, granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Preliminary studies suggest sargramostim may have activity in Crohn's disease. To evaluate this novel therapeutic approach, we conducted a randomized, placebo-controlled trial.Using a 2:1 ratio, we randomly assigned 124 patients with moderate-to-severe active Crohn's disease to receive 6 mug of sargramostim per kilogram per day or placebo subcutaneously for 56 days. Antibiotics and aminosalicylates were allowed; immunosuppressants and glucocorticoids were prohibited. The primary end point was a clinical response, defined by a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in disease severity and the health-related quality of life and adverse events.There was no significant difference in the rate of the primary end point of a clinical response defined by a decrease of at least 70 points in the CDAI score on day 57 between the sargramostim and placebo groups (54 percent vs. 44 percent, P=0.28). However, significantly more patients in the sargramostim group than in the placebo group reached the secondary end points of a clinical response defined by a decrease from baseline of at least 100 points in the CDAI score on day 57 (48 percent vs. 26 percent, P=0.01) and of remission, defined by a CDAI score of 150 points or less on day 57 (40 percent vs. 19 percent, P=0.01). The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment. The sargramostim group also had significant improvements in the quality of life. Mild-to-moderate injection-site reactions and bone pain were more common in the sargramostim group, and three patients in this group had serious adverse events possibly or probably related to treatment.This study was negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease.
Urinary Tract Infection and Reflux
Authors: A. Barry Belman
Journal: JAMA (1981)

The article by Berger et al in this issue ofTHE JOURNAL(p 56) points out the possible end results of a specific combination of urologic events in children. In 24 of the 25 patients described, urinary tract infection was noted on presentation. It is likely that infection played a role in the 25th patient as well. In the boys, obstruction was present in most; in the girls, however, primary vesicoureteral reflux was the only anatomic abnormality found in all except one. The fact that these patients present almost exclusively with urinary tract infection should alert us to the importance of that finding in young children. Studies have reiterated the importance of evaluating children with culture-documented (&gt;105 colonies per milliliter) urinary tract infection and confirm the high incidence of anatomic abnormalities that exist in that group.<sup>1</sup>Vesicoureteral reflux is not only the most common but also the most significant
Association of inflammatory bowel disease risk loci with sarcoidosis, and its acute and chronic subphenotypes
Authors: A. Fischer, M. Nothnagel, A. Franke, G. Jacobs, H.R. Saadati, K.I. Gaede, P. Rosenstiel, M. Schürmann, J. Müller-Quernheim, S. Schreiber, S. Hofmann
Journal: European Respiratory Journal (2010)

Sarcoidosis is a complex granulomatous inflammatory disorder that shares several clinical and pathogenic features with inflammatory bowel disease (IBD). Postulating a common genetic basis of inflammatory diseases, we tested 106 single-nucleotide polymorphisms (SNPs) that are known or have been suggested to be associated with IBD for a potential association with sarcoidosis and its acute and chronic subphenotypes. We genotyped 1,996 German sarcoidosis patients, comprising 648 acutely and 1,161 chronically affected individuals, 2,622 control subjects, and 342 German trios with affected offspring using SNPlex™ technology. The nonsynonymous SNP rs11209026 (Arg381Gln) in the interleukin (IL)-23 receptor ( IL23R ) gene was associated with chronic sarcoidosis (OR 0.63; p = 5.58×10 −5 ), which was supported by the result of a transmission disequilibrium test analysis in the independent family sample (OR 0.50; p = 0.031). Marker rs12035082 located at chromosome 1q24.3 was found to be associated with the acute subphenotype (OR 1.36; p = 6.80×10 −7 ) and rs916977 ( HERC2 locus; OR 1.30; p = 4.49×10 −5 ) was associated with sarcoidosis. Our results highlight the potential importance of the IL-23 signalling pathway for the development of chronic sarcoidosis. The finding links sarcoidosis pathogenesis to other inflammatory conditions and may contribute to new hypotheses on disease mechanisms.
Different proliferative and survival capacity of CLL-cells in a newly established in vitro model for pseudofollicles
Authors: M Plander, S Seegers, P Ugocsai, S Diermeier-Daucher, J Iványi, G Schmitz, F Hofstädter, S Schwarz, E Orsó, R Knüchel, G Brockhoff
Journal: Leukemia (2009)
Ischemic Preconditioning Reduces Apoptosis By Upregulating Anti-Death Gene Bcl-2
Authors: N. Maulik, R. M. Engelman, J. A. Rousou, J. E. Flack, D. Deaton, D. K. Das
Journal: Circulation (1999)

Reperfusion of ischemic myocardium causes cardiomyocyte apoptosis in concert with downregulation of Bcl-2 gene. Ischemic preconditioning (PC) mediated by cyclic episodes of short-term ischemia and reperfusion reduces apoptotic cell death. PC also triggers a signaling pathway by potentiating tyrosine kinase phosphorylation leading to the activation of p38 MAP kinase and MAPKAP kinase 2. The nuclear transcription factor, NFkappaB, plays a crucial role in this signaling process. Because NFkappaB is a target of oxygen free radicals and Bcl-2 is an antioxidant gene, we hypothesized that reactive oxygen species might play a role in the signaling process.Isolated rat hearts were perfused in the absence or presence of either dimethyl thiourea (DMTU), a hydroxyl radical scavenger, or SN50 peptide, a NFkappaB blocker. Hearts were then subjected to PC by 4 repeated episodes of 5-minute ischemia, each followed by 10 minutes reperfusion. All hearts were then made globally ischemic at normothermia for 30 minutes followed by 2 hours of normothermic reperfusion. Creatine kinase release and malonaldehyde formation were determined in the coronary effluent collected during reperfusion. At the end of each experiment, hearts were processed for infarct size determination and analyses of apoptosis, DNA fragmentation, NFkappaB, and Bcl-2. Myocardial infarction was reduced by PC. DMTU and SN50 abolished this cardioprotective effect of PC. PC resulted upregulation of Bcl-2 gene which was partially prevented by DMTU and SN50. Both ischemia/reperfusion and PC caused nuclear translocation and activation of NFkappaB, which was blocked by both DMTU and SN50. PC reduced cardiomyocyte apoptosis which was partially inhibited by DMTU and SN50. A substantial number of apoptotic cardiomyocytes were identified in the hearts subjected to 30 minutes ischemia and 2-hour reperfusion. PC significantly inhibited the extent of cardiomyocyte apoptosis and DMTU and SN50 reversed it only minimally.The results demonstrate that reactive oxygen species play a crucial role in signal transduction mediated by PC. This signaling process appears to involve NFkappaB. NFkappaB becomes translocated and activated by both ischemia/reperfusion, which induces apoptosis and PC which reduces apoptosis. However, the amount of NFkappaB binding activity is significantly higher in the PC hearts compared with ischemic reperfused hearts. The upregulation of the antioxidant gene, Bcl-2, is inversely correlated with the reduction of cardiomyocyte apoptosis associated with PC.
Enhancement of natural killer function through activation of the T11 E rosette receptor.
Authors: R E Schmidt, J M Michon, J Woronicz, S F Schlossman, E L Reinherz, J Ritz
Journal: Journal of Clinical Investigation (1987)

Natural killer (NK) cells, which represent a small fraction of normal peripheral blood mononuclear cells, were purified by immunofluorescent cell sorting of NKH1+ cells. cytotoxicity of NKH1+ cells could be enhanced through activation by monoclonal antibodies (anti-T11(2) and anti-T11(3)) specific for epitopes of the sheep erythrocyte receptor or by recombinant interleukin-2 (rIL-2). After 18 h, incubation with both anti-T11(2/3) and rIL-2 resulted in similar levels of enhanced cytotoxicity against NK-resistant as well as NK-sensitive targets. Before and after induction, cytotoxicity was found predominantly within the NKH1+ population. These results suggest that several distinct mechanisms may be capable of enhancing NK activity and that the cells responsible for lymphokine-activated killing are likely to be the same population capable of spontaneous or natural killing before activation in vitro.
Moxifloxacin-containing Regimen Greatly Reduces Time to Culture Conversion in Murine Tuberculosis
Authors: Eric L. Nuermberger, Tetsuyuki Yoshimatsu, Sandeep Tyagi, Richard J. O'Brien, Andrew N. Vernon, Richard E. Chaisson, William R. Bishai, Jacques H. Grosset
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Tuberculosis continues to be a major cause of morbidity and mortality in the world. The expansion of tuberculosis control programs has been limited by the lengthy and cumbersome nature of current chemotherapeutic regimens. A new drug that improves the sterilizing activity of current regimens would reduce the duration of therapy without sacrificing efficacy, thereby enhancing treatment completion rates and preserving precious public health resources. The new 8-methoxyfluoroquinolone moxifloxacin has potent activity against both actively multiplying and nonactively multiplying tubercle bacilli. Using a murine model that is representative of chemotherapy for human tuberculosis, we show that the combination of moxifloxacin, rifampin, and pyrazinamide reduced the time needed to eradicate Mycobacterium tuberculosis from the lungs of infected mice by up to 2 months when compared with the standard regimen of isoniazid, rifampin, and pyrazinamide. The findings suggest that this regimen has the potential to substantially shorten the duration of therapy needed to cure human tuberculosis.
TICAGRELOR VERSUS PRASUGREL IN ACUTE CORONARY SYNDROME PATIENTS WITH HIGH ON CLOPIDOGREL TREATMENT PLATELET REACTIVITY POST PCI: A PHARMACODYNAMIC STUDY
Authors: Dimitrios Alexopoulos, Ioanna Xanthopoulou, Eleni Mavronasiou, Anastasia Galati, George Kassimis, Konstantinos C. Theodoropoulos, George Makris, Anastasia Damelou, Grigorios Tsigkas, Periklis Davlouros, George Hahalis
Journal: Journal of the American College of Cardiology (2012)
Predictive value of fetal serum β2-microglobulin for neonatal renal function
Authors: S.M. Berry, R.S. Smith, M.P. Dombrowski, K.S. Puder, D.B. Cotton, M.P. Johnson, K. Kithier, B. Lecolier, G. Bercau, L. Bidat
Journal: The Lancet (1995)
Naive and memory T cells show distinct pathways of lymphocyte recirculation.
Authors: C R Mackay, W L Marston, L Dudler
Journal: The Journal of Experimental Medicine (1990)

In this report, we have addressed two questions concerning immunological memory: the way in which naive and memory T cells recirculate through the body, and the intrinsic rate of division within the naive and memory populations. We identified naive and memory T cells in sheep by their cell surface phenotype and their ability to respond to recall antigen. Memory T cells were CD2hi, CD58hi, CD44hi, CD11ahi, and CD45R-, as pertains in man. T cells that crossed from blood to the tissues of the hind leg and accumulated in the popliteal afferent lymph were all of memory phenotype. Conversely, T cells in efferent lymph, 90% of which entered the lymph node (LN) via high endothelial venules (HEV), were mostly of the naive phenotype (CD2lo, CD58lo, CD44lo, CD11alo, and CD45R+). The marked enrichment of these two phenotypes in different recirculatory compartments indicated that memory T cells selectively traffic from blood to peripheral tissues to LN (via afferent lymph), whereas naive T cells selectively traffic from blood to LN (via HEV). We argue that the differential use of these two recirculation pathways probably optimizes lymphocyte interactions with antigen. The nonrandom distribution of T cell subsets in various recirculatory compartments may be related to the relative proportion of memory cells in each subset. In particular, gamma/delta T cells in blood were almost exclusively of memory phenotype, and accumulated preferentially in afferent, but not in efferent, lymph. Finally, using the bromo-deoxyuridine labeling technique, we found that at least a sizeable proportion of memory T cells, whether in blood or afferent lymph, were a dividing population of cells, whereas naive T cells were a nondividing population. This result supports an alternative model of lymphocyte memory that assumes that maintenance of memory requires persistent antigenic stimulation.
VEGF as a Marker for Outcome Among Advanced Breast Cancer Patients Receiving anti-VEGF Therapy with Bevacizumab and Vinorelbine Chemotherapy
Authors: Harold J. Burstein, Yu-Hui Chen, Leroy M. Parker, Jennifer Savoie, Jerry Younger, Irene Kuter, Paula D. Ryan, Judy E. Garber, Helen Chen, Susana M. Campos, Lawrence N. Shulman, Lyndsay N. Harris, Rebecca Gelman, Eric P. Winer
Journal: Clinical Cancer Research (2008)

Abstract Background: Anti-vascular endothelial growth factor therapy (VEGF) is an important new treatment modality in oncology. We sought to determine the efficacy and safety of the humanized monoclonal anti-VEGF antibody, bevacizumab, and vinorelbine as treatment for refractory breast cancer and to explore the role of plasma VEGF as a predictor of treatment outcome. Experimental Design: Eligible patients had received one or two prior chemotherapy regimens for metastatic breast cancer or recurred within 12 months of adjuvant therapy and had measurable disease and adequate end-organ function. Patients received bevacizumab 10 mg/kg every 2 weeks, and vinorelbine each week, until tumor progression or prohibitive toxicity. Plasma VEGF was measured at baseline. Results: Among 56 women treated on protocol, bevacizumab and vinorelbine yielded a 34% response rate (95% confidence interval, 22-48%) and median time to progression of 5.5 months. Activity was observed regardless of tumor hormone receptor status or type or extent of prior chemotherapy. Side effects included uncomplicated neutropenia, hypertension, nasal congestion/epistaxis, and neuropathy, consistent with well-described side effects of the respective agents. Three patients had impaired wound healing following surgical procedures. There were only rare instances of thrombosis or clinically significant proteinuria. Lower levels of baseline VEGF were associated with longer time to progression. Conclusions: Bevacizumab and vinorelbine are well tolerated and effective as treatment for refractory breast cancer. Plasma VEGF warrants further evaluation as a prognostic marker for treatment outcome in advanced breast cancer patients receiving anti-VEGF therapy.
Adult Outcomes of Child- and Adolescent-Onset Schizophrenia: Diagnostic Stability and Predictive Validity
Authors: Chris Hollis
Journal: American Journal of Psychiatry (2000)

The goal of the study was to establish the predictive validity of a diagnosis of schizophrenia in childhood and early adolescence by examining diagnostic continuity into adult life and comparing social and symptomatic outcomes of child- and adolescent-onset schizophrenia with those of nonschizophrenic psychoses.A total of 110 consecutive patients with first-episode child- or adolescent-onset psychosis (mean age at onset=14.2 years) presenting to the Maudsley Hospital in London between 1973 and 1991 were followed up an average of 11.5 years after first contact. Ninety-three (84.5%) of 110 patients were successfully followed-up, 51 with a first-episode diagnosis of DSM-III-R schizophrenia and 42 with nonschizophrenic psychoses. Consensus best-estimate DSM-III-R diagnoses were made at follow-up, and course and outcome were assessed blind to first-episode diagnosis.Diagnostic stability was high for child- and adolescent-onset DSM-III-R schizophrenia (positive predictive value=80%) and affective psychoses (positive predictive value=83%) but much lower for schizoaffective and atypical psychoses. Compared with other psychoses, child- or adolescent-onset schizophrenia was associated with significantly worse symptomatic and social outcomes, which were characterized by a chronic illness course and severe impairments in social relationships and independent living.The diagnosis of DSM-III-R schizophrenia in childhood and adolescence has good predictive validity. The high level of diagnostic stability suggests etiological continuity with adult schizophrenia, with onset in childhood and adolescence associated with a particularly malignant course and outcome.
Regulation by complementary idiotypes. Ig protects the clone producing it.
Authors: D A Rowley, P Griffith, I Lorbach
Journal: The Journal of Experimental Medicine (1981)

A/He mice actively producing complementary or anti-idiotypic antibody directed against a combining site structure for phosphorylcholine (PC) have profound and long-lasting suppression of their response to PC. B cells from unresponsive mice are unresponsive in vitro, and attempts to demonstrate suppressor cells in unresponsive mice were unsuccessful. Although the process ultimately responsible for suppression has not been defined, suppression can be initiated by anti-idiotypic antibody alone and prevented by complementary Ig; i.e., by anti-PC antibody. Furthermore, a suppressed anti-PC response can be rescued by sublethal irradiation and anti-PC antibody given passively. The recovery of the suppressed response is slow and presumably results from maturation from "stem" cells, which are protected from tolerization by the passively given antibody. Thus, by extrapolation, one of the functions of secreted Ig may be to protect the clone that produces it.