tbuckley/cabot-search huggingface dataset:
An acetylcholine receptor alpha subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis.
Authors: A M Salmon, C Bruand, A Cardona, J P Changeux, S Berrih-Aknin
Journal: Journal of Clinical Investigation (1998)

Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor (AChR). Although the autoantigen is present in the thymus, it is not tolerated in MG patients. In addition, the nature of the cell bearing the autoantigen is controversial. To approach these questions, we used two lineages of transgenic mice in which the beta-galactosidase (beta-gal) gene is under the control of a 842-bp (Tg1) or a 3300-bp promoter fragment (Tg2) of the chick muscle alpha subunit AChR gene. In addition to expression in muscle cells, thymic expression was observed in both mouse lines (mainly in myoid cells in Tg1 and myoid cells and epithelial cells in Tg2). After challenge with beta-gal, Tg1 mice produced Th2-dependent anti-beta-gal antibodies, while Tg2 mice were almost unresponsive. By contrast, in a proliferation assay both Tg lines were unresponsive to beta-gal. Cells from Tg1 mice produce Th2-dependent cytokine whereas cells from Tg2 mice were nonproducing in response to beta-gal. These data indicate that the level of expression in Tg1 mice could be sufficient to induce tolerance of Th1 cells but not of Th2 cells, while both populations are tolerated in Tg2 mice. These findings are compatible with the hypothesis that AChR expression is not sufficiently abundant in MG thymus to induce a full tolerance.
Invariant NKT cells limit activation of autoreactive CD1d-positive B cells
Authors: Fredrik Wermeling, Sara M. Lind, Emilie Domange Jordö, Susanna L. Cardell, Mikael C.I. Karlsson
Journal: The Journal of Experimental Medicine (2010)

Faulty activation of autoreactive B cells is a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE). An important feature restricting activation of autoreactive B cells is efficient removal of apoptotic material. Mounting evidence also connects a primary defect in invariant natural killer T (iNKT) cells to autoimmune disease development. However, exactly how this unconventional T cell subset is involved remains to be defined. Here, we identify a suppressive role for iNKT cells in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells, resembling the situation in SLE patients. Absence or reduction of iNKT cells as well as absence of CD1d-expression on B cells, needed for direct iNKT–B cell interaction, leads to increased autoreactive B cell activation and symptoms of disease. The suppression mediated by the iNKT cells is observed before B cell entry into germinal centers and can be rescued by transferring iNKT cells to deficient mice. This links iNKT cells to handling of dying cells and identifies a novel peripheral tolerance checkpoint relevant for autoimmune disease. Thus, these observations connect two clinical observations in SLE patients previously considered to be unrelated and define a new target for immunotherapy.
Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer
Authors: Nancy U. Lin, Véronique Diéras, Devchand Paul, Dominique Lossignol, Christos Christodoulou, Hans-Joachim Stemmler, Henri Roché, Minetta C. Liu, Richard Greil, Eva Ciruelos, Sibylle Loibl, Stefania Gori, Andrew Wardley, Denise Yardley, Adam Brufsky, Joanne L. Blum, Stephen D. Rubin, Bernie Dharan, Klaudia Steplewski, Denise Zembryki, Cristina Oliva, Debasish Roychowdhury, Paolo Paoletti, Eric P. Winer
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
Epidemiology of injury in elite and subelite female gymnasts: a comparison of retrospective and prospective findings.
Authors: G S Kolt, R J Kirkby
Journal: British Journal of Sports Medicine (1999)

An 18 month prospective injury survey was conducted on 64 Australian elite and subelite female gymnasts. The aims were to determine the rate of injury, anatomical location, and types of injury incurred by female competitive gymnasts, and to compare the findings with data collected retrospectively from the same sample of gymnasts.The gymnasts recorded (weekly) in an injury record booklet the number of hours trained and information on any injuries suffered over that week.The sample reported 349 injuries, a rate of 5.45 per person (6.29 for the elite and 4.95 for subelite gymnasts) over the 18 month survey. Injuries to the ankle and foot (31.2%) were the most commonly reported, followed by the lower back (14.9%). The most prevalent type of injury were sprains (29.7%), followed by strains (23.2%), and growth plate injuries (12.3%). The elite gymnasts reported that, for each injury, they missed fewer training sessions (p = 0.01), but modified more sessions (p = 0.0001) than their subelite counterparts. Further, the elite gymnasts spent 21.0% of the year training at less than full capacity because of injury. Although a significantly higher number of injuries were recorded in the prospective study (p = 0.0004), no differences were found between the distribution of injury by anatomical location or type between the two methods of data collection.The findings have important implications in terms of training procedures and periodic screening of gymnasts.
Two-ply brain barrier
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

Lipid loop instigates arthritisArthritic joints are chock-full of activated immune cells.These cells produce chemotactic proteins that lure other cells into the joint, setting up a vicious cycle of inflammation.But what instigates this cycle in the first place?A study by Kim et al. (page 829) puts much of the blame on neutrophils.Neutrophils-granular cells that are among the immune system's earliest responders during infection and injury-are required for the development of joint inflammation during autoantibody-induced arthritis in mice.But the signals that trigger this joint invasion had not been identified.Kim and colleagues now identify a chemotactic lipid called leukotriene B 4 (LTB 4 ) as the instigating signal.In the absence of the receptor for LTB 4 (called BLT1), neutrophils failed to invade the joints, and mice did not develop arthritis.This effect was reversed when wild-type neutrophils were transferred into the deficient mice.Consistent with these data, a study by Chen et al. (page 837) shows that LTB 4 is essential for disease induction in the same model.Once in the joint, the neutrophils triggered the production of chemokines that attracted other cells-including more neutrophils-to the area.BLT1 expression was mandatory only for the initial vanguard of neutrophils that infiltrated the joint; it was dispensable for those that followed-presumably because other neutrophil-attracting chemokines were produced.According to Chen et al., neutrophils were also the primary producers of LTB 4 .But what entices the first neutrophils to enter the joint and, once there, what signals cause them to produce LTB 4 are still unknown.
Using Neuroplasticity-Based Auditory Training to Improve Verbal Memory in Schizophrenia
Authors: Melissa Fisher, Christine Holland, Michael M. Merzenich, Sophia Vinogradov
Journal: American Journal of Psychiatry (2009)

Objective: Impaired verbal memory in schizophrenia is a key rate-limiting factor for functional outcome, does not respond to currently available medications, and shows only modest improvement after conventional behavioral remediation. The authors investigated an innovative approach to the remediation of verbal memory in schizophrenia, based on principles derived from the basic neuroscience of learning-induced neuroplasticity. The authors report interim findings in this ongoing study. Method: Fifty-five clinically stable schizophrenia subjects were randomly assigned to either 50 hours of computerized auditory training or a control condition using computer games. Those receiving auditory training engaged in daily computerized exercises that placed implicit, increasing demands on auditory perception through progressively more difficult auditory-verbal working memory and verbal learning tasks. Results: Relative to the control group, subjects who received active training showed significant gains in global cognition, verbal working memory, and verbal learning and memory. They also showed reliable and significant improvement in auditory psychophysical performance; this improvement was significantly correlated with gains in verbal working memory and global cognition. Conclusions: Intensive training in early auditory processes and auditory-verbal learning results in substantial gains in verbal cognitive processes relevant to psychosocial functioning in schizophrenia. These gains may be due to a training method that addresses the early perceptual impairments in the illness, that exploits intact mechanisms of repetitive practice in schizophrenia, and that uses an intensive, adaptive training approach.
The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up.
Authors: J A Baltus, J W Boersma, A P Hartman, J P Vandenbroucke
Journal: Annals of the Rheumatic Diseases (1983)

In a retrospective follow-up we compared the incidence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide with that in another group of patients with rheumatoid arthritis and also with the incidence of malignancies in the general population. Among 81 patients treated with cyclophosphamide in the past decade 15 malignancies occurred. This was 4.1 times the expected number obtained from a closely matched control group of patients with rheumatoid arthritis not treated with cytotoxic drugs (95% confidence interval 1.5 to 19.0), and 3.7 times the expected number calculated from general population rates (95% confidence interval 2.1 to 5.9). The increase in haematological and lymphoreticular malignancies was specially notable. The data also indicate that the development of malignancies after the start of cyclophosphamide therapy necessitates a certain induction time and that it is to some extent dose-dependent.
Familiality of Obsessive-Compulsive Disorder in Nonclinical and Clinical Subjects
Authors: Hans Joergen Grabe, Stephan Ruhrmann, Susan Ettelt, Friederike Buhtz, Andrea Hochrein, Svenja Schulze-Rauschenbach, Klaus Meyer, Susanne Kraft, Claudia Reck, Ralf Pukrop, Harald J Freyberger, Joachim Klosterkötter, Peter Falkai, Ulrich John, Wolfgang Maier, Michael Wagner
Journal: American Journal of Psychiatry (2006)

Objective: Studies of the familiality of obsessive-compulsive disorder (OCD) have yielded inconsistent results. This study compared the familial aggregation of OCD in first-degree relatives of community subjects with never-treated OCD, outpatients with OCD, and comparison subjects. Method: Fifteen persons from the community with untreated OCD were matched on age and interview type (direct or through family informants) with 90 OCD patients from four treatment facilities and 70 comparison subjects. Direct or indirect interviews using the German-language version of the Schedule for Affective Disorders and Schizophrenia—Lifetime Version for Anxiety Disorders (DSM-IV) were obtained from 58, 285, and 247 first-degree relatives, respectively, of the three groups. The rate of OCD in case versus comparison relatives was assessed with chi-square tests, and odds ratios were calculated for risk estimation. Cox proportional hazards analysis was used to estimate the age-related risk of relatives of being affected by OCD. Results: Cox proportional hazards analyses revealed a 6.2-fold higher risk (hazard ratio) for relatives of all OCD cases for definite OCD and a 2.2–fold higher risk for subclinical OCD compared with relatives of comparison subjects. For relatives of community subjects with OCD, the risk for definite OCD (10.3% versus 5.6%) was 1.6, and the risk for subclinical OCD (15.4% versus 4.1%) was 3.4 compared with relatives of OCD patients from treatment sites. Conclusions: These results from the first controlled European family study of OCD confirm earlier U.S. data on the familiality of OCD in patients recruited from treatment facilities. The finding of a comparable familial aggregation of definite OCD and a higher familial aggregation of subclinical OCD in relatives of never-treated persons with OCD from the community strongly supports the impact of familial-genetic factors in OCD.
Hematologic Changes in a Patient With Hodgkin's Disease in Relapse
Authors: A. David Ginsburg
Journal: JAMA (1977)

A patient with Hodgkin's disease also had anemia, hypochromia, and thrombocytosis, which were clues to an otherwise silent relapse. These features were corrected following chemotherapy. Repeated lymphangiography is shown to be of value in diagnosis. (<i>JAMA</i>238:1272-1273, 1977)
Multiple Paleopolyploidizations during the Evolution of the Compositae Reveal Parallel Patterns of Duplicate Gene Retention after Millions of Years
Authors: M. S. Barker, N. C. Kane, M. Matvienko, A. Kozik, R. W. Michelmore, S. J. Knapp, L. H. Rieseberg
Journal: Molecular Biology and Evolution (2008)

Of the approximately 250,000 species of flowering plants, nearly one in ten are members of the Compositae (Asteraceae), a diverse family found in almost every habitat on all continents except Antarctica. With an origin in the mid Eocene, the Compositae is also a relatively young family with remarkable diversifications during the last 40 My. Previous cytologic and systematic investigations suggested that paleopolyploidy may have occurred in at least one Compositae lineage, but a recent analysis of genomic data was equivocal. We tested for evidence of paleopolyploidy in the evolutionary history of the family using recently available expressed sequence tag (EST) data from the Compositae Genome Project. Combined with data available on GenBank, we analyzed nearly 1 million ESTs from 18 species representing seven genera and four tribes. Our analyses revealed at least three ancient whole-genome duplications in the Compositae—a paleopolyploidization shared by all analyzed taxa and placed near the origin of the family just prior to the rapid radiation of its tribes and independent genome duplications near the base of the tribes Mutisieae and Heliantheae. These results are consistent with previous research implicating paleopolyploidy in the evolution and diversification of the Heliantheae. Further, we observed parallel retention of duplicate genes from the basal Compositae genome duplication across all tribes, despite divergence times of 33–38 My among these lineages. This pattern of retention was also repeated for the paleologs from the Heliantheae duplication. Intriguingly, the categories of genes retained in duplicate were substantially different from those in Arabidopsis. In particular, we found that genes annotated to structural components or cellular organization Gene Ontology categories were significantly enriched among paleologs, whereas genes associated with transcription and other regulatory functions were significantly underrepresented. Our results suggest that paleopolyploidy can yield strikingly consistent signatures of gene retention in plant genomes despite extensive lineage radiations and recurrent genome duplications but that these patterns vary substantially among higher taxonomic categories.
Ephrin-B3 Ligand Promotes Glioma Invasion through Activation of Rac1
Authors: Mitsutoshi Nakada, Kelsey L. Drake, Satoko Nakada, Jared A. Niska, Michael E. Berens
Journal: Cancer Research (2006)

Abstract Eph receptor tyrosine kinases are involved in nervous system development. Eph ligands, termed ephrins, are transmembrane proteins that bind to Eph receptors, the mutual activation of which causes repulsive effects in reciprocally contacting cells. Previously, we showed that overexpression of EphB2 in glioma cells increases cell invasion. Here, expression profiles of ephrin-B family members were determined in four glioma cell lines and in invading glioblastoma cells collected by laser capture microdissection. Ephrin-B3 mRNA was up-regulated in migrating cells of four of four glioma cell lines (1.3- to 1.7-fold) and in invading tumor cells of eight of eight biopsy specimens (1.2- to 10.0-fold). Forced expression of ephrin-B3 in low expressor cell lines (U87, T98G) stimulated cell migration and invasion in vitro and ex vivo, concomitant with tyrosine phosphorylation of ephrin-B3. In high expressor cell lines (U251, SNB19), ephrin-B3 colocalized with Rac1 to lamellipodia of motile wild-type cells. Cells transfected with ephrin-B3 small interfering RNA (siRNA) showed significant morphologic change and decreased invasion in vitro and ex vivo. Depletion of endogenous ephrin-B3 expression abrogated the increase of migration and invasion induced by EphB2/Fc, indicating increased invasion is dependent on ephrin-B3 activation. Furthermore, using a Rac1-GTP pull-down assay, we showed that ephrin-B3 is associated with Rac1 activation. Reduction of Rac1 by siRNA negated the increased invasion by addition of EphB2/Fc. In human glioma specimens, ephrin-B3 expression and phosphorylation correlated with increasing tumor grade. Immunohistochemistry revealed robust staining for phosphorylated ephrin-B and ephrin-B3 in invading glioblastoma cells. These data show that ephrin-B3 expression and signaling through Rac1 are critically important to glioma invasion. (Cancer Res 2006; 66(17): 8492-500)
Antigen- and receptor-driven regulatory mechanisms. III. Induction of delayed type hypersensitivity to azobenzenearsonate with anti-cross-reactive idiotypic antibodies.
Authors: M S Sy, A R Brown, B Benacerraf, M I Greene
Journal: The Journal of Experimental Medicine (1980)

Delayed-type hypersensitivity (DTH) to p-azobenzenearsonate (ABA) can be induced in A/J mice with intravenous injection of minute amounts of anti-cross-reactive idiotypic (CRI) antibodies, providing that the animals have been pretreated 2 d earlier with low doses of cyclophosphamide (50 mg/kg). However intravenous injection of the F(ab')2 fragments of the anti-CRI antibodies or subcutaneous administration with anti-CRI antibodies induces comparable immunity in both cyclophosphamide-pretreated and normal nontreated animals. Furthermore adoptive transfer experiments indicate that lymph node cells taken from animals sensitized with anti-CRI 4 d earlier can adoptively transfer immunity to naive recipients. Transfer of immunity is mediated by a population of thymus-dependent (T) cells, which express idiotypic structures on their surface. Treatment of effector cells with either anti-theta serum or anti-idiotypic antibodies plus complement completely abrogated their ability to transfer immunity. In addition idiotype-bearing suppressor T cells induced with ABA-coupled spleen cells inhibit the development of ABA-specific DTH induced with anti-CRI antibodies. Genetic analysis revealed that the ability of anti-CRI antibodies to induce ABA-specific DTH was linked to Igh-1 heavy-chain allotype. Anti-idiotypic antibodies to the major CRI associated with anti-ABA antibodies in A/J mice failed to induce significant immunity in BALB/c mice (H-2d, Igh-1a). Nevertheless, they were able to induce significant immunity in C.AL20 mice (H-2d, Igh-1d) which possess a heavy-chain allotype similar to that of A/J mice.
MELLARIL IN THE TREATMENT OF CHRONICALLY DISTURBED PATIENTS : WITH SPECIAL REFERENCE TO REDUCED EXTRAPYRAMIDAL COMPLICATIONS
Authors: A. KHAKEE, G. F. HESS
Journal: American Journal of Psychiatry (1960)

Moderate to marked improvement in psychomotor behavior was obtained with Mellaril in 17 of the 22 cases in this series. In addition, there was complete elimination of extrapyramidal activity in 15 of 18 patients who had manifested Parkinsonian symptoms with the drugs previously employed. Our observations indicate that Mellaril is equally effective, or more so, than other phenothiazines in the treatment of various psychiatric disorders, but has a distinctly lessened tendency to induce extrapyramidal stimulation. In our experience, this is a significant contribution to the more effective management of larger numbers of disturbed patients.