tbuckley/cabot-search huggingface dataset:
B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response
Authors: K. P Ng, G. Cambridge, M. J Leandro, J. C W Edwards, M. Ehrenstein, D. A Isenberg
Journal: Annals of the Rheumatic Diseases (2007)

<b>Objectives:</b> To describe the long-term clinical outcome and safety profile of B cell depletion therapy (BCDT) in patients with systemic lupus erythematosus (SLE). It was also determined whether baseline parameters can predict the likelihood of disease flare. <b>Methods:</b> 32 patients with refractory SLE were treated with BCDT using a combination protocol (rituximab and cyclo-phosphamide). Patients were assessed with the British Isles Lupus Assessment Group (BILAG) activity index, and baseline serology was measured. Flare was defined as a new BILAG 'A' or two new subsequent 'B's in any organ system. <b>Results:</b> Of the 32 patients, 12 have remained well after one cycle of BCDT (median follow-up 39 months). BCDT was followed by a decrease of median global BILAG scores from 13 to 5 at 6 months (p = 0.006). Baseline anti-extractable nuclear antigen (ENA) was the only identified independent predictor of flare post-BCDT (p = 0.034, odds ratio = 8, 95% CI 1.2 to 55) from multivariable analysis. Patients with low baseline serum C3 had a shorter time to flare post-BCDT (p = 0.008). Four serious adverse events were observed. <b>Conclusion:</b> Autoantibody profiling may help identify patients who will have a more sustained response. Although the long-term safety profile of BCDT is favourable, ongoing vigilance is recommended.
Developmental and communicative interrelations of Ly123 and Ly1 cell sets.
Authors: F W Shen, J S McDougal, J Bard, S P Cort
Journal: The Journal of Experimental Medicine (1980)

To distinguish and define the differentiative and communicative relations of Ly123 and Ly1 cells in generating specific helper-effector (HE) (Ly1:HE) and specific suppression-inducing (SI) (Ly1:SI) cells, these two functional sets were generated from various combinations of congenic genetically marked sets of cortisone-resistant nylon-purified thymocytes (CRNPT) by culture on antigen-primed macrophages (M phi) (the (T-M phi culture system). It was thus shown that Ly1:HE and Ly1:SI cells are produced by differentiation from antecedent Ly123 cells. Ly1:HE and Ly1:SI are separate Ly1 populations; generationof Ly1:HE cells requires the presence of Ly1 cells, whereas the generation of Ly1:SI cells does not. Although the Ly23 CRNPT set, which is included when Ly123 cells are positively selected with Lty-2 antiserum is ruled out as a precursor source of Ly1:SI cells, the possibility of a communicative role for Ly23 cells in generating Ly1:SI cells remains to be investigated. The role of the Ly1 set required for the generation of Ly1:HE cells from CRNPT is communicative, not differential; and it is not a precursor source of Ly1:HE or Ly1:SI cells in the CRNPT population. It remains to be seen whether the use of additional phenotypic markers will distinguish subsets of Ly123 and Ly1 cells engaged in these several functions.
Incidence and Prognostic Influence of <i>DNMT3A</i> Mutations in Acute Myeloid Leukemia
Authors: Felicitas Thol, Frederik Damm, Andrea Lüdeking, Claudia Winschel, Katharina Wagner, Michael Morgan, Haiyang Yun, Gudrun Göhring, Brigitte Schlegelberger, Dieter Hoelzer, Michael Lübbert, Lothar Kanz, Walter Fiedler, Hartmut Kirchner, Gerhard Heil, Jürgen Krauter, Arnold Ganser, Michael Heuser
Journal: Journal of Clinical Oncology (2011)

To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia.A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1).DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients.DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
Viral Gene Transfer Rescues Arrhythmogenic Phenotype and Ultrastructural Abnormalities in Adult Calsequestrin-Null Mice With Inherited Arrhythmias
Authors: Marco Denegri, José Everardo Avelino-Cruz, Simona Boncompagni, Stefano Andrea De Simone, Alberto Auricchio, Laura Villani, Pompeo Volpe, Feliciano Protasi, Carlo Napolitano, Silvia Giuliana Priori
Journal: Circulation Research (2012)

Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum.We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2.We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias.We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application.
IMMUNE STATUS OF MICE TOLERANT OF LIVING CELLS
Authors: G. A. Voisin, R. G. Kinsky, H. T. Duc
Journal: The Journal of Experimental Medicine (1972)

CBA mice were rendered highly tolerant to A/Jax cells by neonatal intravenous injections of (CBA x A)F(1) spleen cells. The high degree of tolerance was ascertained by the absence of circulating antibodies detected in the sera by the usual tests and by the perfect state of A skin grafts during all the experiments. Tolerant sera (sera from tolerant animals) were studied at three periods of tolerance: before skin test grafting, from 2 to 11 wk after grafting, and at time of sacrifice at almost 6 months of age. The tolerant sera were shown to have specific facilitation-enhancing properties promoting the take and growth of A/Jax sarcoma (SaI and /Sa 15091a grafted on normal CBA mice. These properties were present throughout the duration of the experiments, showing that they were not the result of a beginning interruption of tolerance. The tolerant sera, although lacking the usual serological properties (hemagglutination, hemolysis, cytotoxicity, passive cutaneous anaphylaxis) had, however, specific synergistic hemagglutinating properties (increasing the hemagglutinating titer of a reference immune serum). Antibodies giving direct specific hemagglutination could be extracted from spleens of 20% of highly tolerant mice. The tolerant sera were also found to contain more IgG1 and more IgA than normal sera while they contained normal quantities of the complement-fixing immunoglobulins IgG2 and IgM. Fractionation of tolerant sera on DEAE chromatography column confirmed the data concerning immunoglobulin classes and demonstrated direct specific serological activities undetected in unfractionated sera: a weak hemolysis in the most cationic fractions and a weak hemagglutination in the middle fractions. Synergistic hemagglutination, detected in unfractionated serum, was localized in fast anionic fractions containing high IgA concentration, along with facilitation-enhancing activity, thus confirming a link suggested previously between these three properties. The relation between immunological tolerance and facilitating antibodies was discussed in the light of the fact that antibodies, possibly of a particular class continuously present at low dose in the sera of highly tolerant animals, are able to transfer (at least partly) this state of tolerance provided a sensitive test system is utilized.
Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production.
Authors: A Tominaga, S Takaki, N Koyama, S Katoh, R Matsumoto, M Migita, Y Hitoshi, Y Hosoya, S Yamauchi, Y Kanai
Journal: The Journal of Experimental Medicine (1991)

Interleukin 5 (IL-5) has been suggested to be involved in the growth and differentiation of B cells and eosinophils. Especially, Ly-1+ B cells, which have been considered to produce autoantibodies, are selectively developed by this lymphokine in long-term bone marrow culture. To envisage the possible engagement of IL-5 in the development of these cells in vivo, transgenic mice carrying the mouse IL-5 gene ligated with a metallothionein promoter were generated. Transgenic mice carrying the IL-5 gene exhibited elevated levels of IL-5 in the serum and an increase in the levels of serum IgM and IgA. A massive eosinophilia in peripheral blood, bone marrow, and spleen, and an infiltration of muscle and liver with eosinophils, were observed. When cadmium-containing saline was injected intraperitoneally into transgenic mice, IL-5 production was augmented about five times within 24 h, and a distinctive Ly-1+ B cell population became apparent in the spleen after 5 d. IL-5 receptors were detected on those cells by monoclonal antibodies against IL-5 receptors. Another interesting finding in these transgenic mice was an increase in polyreactive anti-DNA antibodies of IgM class. It is suggested, therefore, that aberrant expression of the IL-5 gene may induce accumulation of Ly-1+ B cells and eosinophils. Furthermore, this IL-5 transgenic mouse can be a model mouse for eosinophilia, and we can determine the role of IL-5 in the differentiation of Ly-1+ B cells and eosinophils by using this mouse.
Household chemicals, persistent wheezing and lung function: effect modification by atopy?
Authors: J. Henderson, A. Sherriff, A. Farrow, J. G. Ayres
Journal: European Respiratory Journal (2007)

The aims of the present study were to assess the effects of maternal use of domestic chemicals during pregnancy on wheezing and lung function in children aged ≤8.5 yrs and to explore the potential modifying effect of atopy. In the Avon Longitudinal Study of Parents and Children, a cohort study, a maternal composite household chemical exposure (CHCE) score was derived. Wheezing phenotypes from birth to age 7 yrs were assigned on the basis of reported wheeze. Lung function (forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC), forced midexpiratory flow between 25 and 75% of FVC (FEF 25–75% )) was measured at age 8.5 yrs; and atopy by skin-prick tests at age 7.5 yrs. Multinomial logistic and linear regression models assessed the relationship between wheezing outcomes, lung function and CHCE score, and interactions with atopy. Increased CHCE score was associated with early- (&lt;18 months) and intermediate- (18–30 months) persistent and late-onset (&gt;30 months) wheezing in nonatopic children (adjusted odds ratio per z-score of CHCE (95% confidence interval) 1.41 (1.13–1.76), 1.43 (1.02–2.13) and 1.69 (1.19–2.41), respectively). Increasing CHCE score was associated with decrements in FEV 1 and FEF 25–75% . Higher domestic chemical exposure during pregnancy was associated with persistent wheeze and lung function abnormalities in nonatopic children. This may result from pre-natal developmental effects or post-natal irritant effects on the developing airway, but is unlikely to be mediated through increased hygiene in the home.
Femoroacetabular impingement: what is its link with osteoarthritis?
Authors: Rintje Agricola, Harrie Weinans
Journal: British Journal of Sports Medicine (2015)

That morphological abnormalities of the hip could be a cause rather than a result of osteoarthritis (OA) was observed many years before the actual mechanism of femoroacetabular impingement (FAI) was described. Morphological abnormalities, currently termed as cam and pincer, were often present in people with hip OA. Ganz et al 1 first described how these morphological abnormalities may cause intra-articular hip damage by a motion-dependent process called FAI.

Although FAI is a motion-dependent process, valid techniques to quantify the dynamic nature of FAI are still elusive. For epidemiological purposes, a cam-type femoral head or acetabular overcoverage on X-ray is often used to study its relationship with OA. In several cohort studies, there is conflicting evidence regarding the association between pincer deformity and OA. Importantly, the higher quality prospective cohort studies fail to demonstrate an association between the two.2 ,3 It is unknown whether this is due to the relatively high prevalence of pincer deformities in the general population that remain asymptomatic, or because the heterogeneous definition of a pincer deformity makes quantification …
<i>In vitro</i> and <i>In vivo</i> Radiation Sensitization of Human Tumor Cells by a Novel Checkpoint Kinase Inhibitor, AZD7762
Authors: James B. Mitchell, Rajani Choudhuri, Kristin Fabre, Anastasia L. Sowers, Deborah Citrin, Sonya D. Zabludoff, John A. Cook
Journal: Clinical Cancer Research (2010)

Inhibition of checkpoint kinase 1 has been shown to enhance the cytotoxicity of DNA-damaging targeted chemotherapy through cell cycle checkpoint abrogation and impaired DNA damage repair. A novel checkpoint kinase 1/2 inhibitor, AZD7762, was evaluated for potential enhancement of radiosensitivity for human tumor cells in vitro and in vivo xenografts.Survival of both p53 wild-type and mutant human cell lines was evaluated by clonogenic assay. Dose modification factors (DMF) were determined from survival curves (ratio of radiation doses for control versus drug treated at 10% survival). Flow cytometry, Western blot, and radiation-induced tumor regrowth delay assays were conducted.AZD7762 treatment enhanced the radiosensitivity of p53-mutated tumor cell lines (DMFs ranging from 1.6-1.7) to a greater extent than for p53 wild-type tumor lines (DMFs ranging from 1.1-1.2). AZD7762 treatment alone exhibited little cytotoxicity to any of the cell lines and did not enhance the radiosensitivity of normal human fibroblasts (1522). AZD7762 treatment abrogated radiation-induced G(2) delay, inhibited radiation damage repair (assessed by gamma-H2AX), and suppressed radiation-induced cyclin B expression. HT29 xenografts exposed to five daily radiation fractions and to two daily AZD7762 doses exhibited significant radiation enhancement compared with radiation alone.AZD7762 effectively enhanced the radiosensitivity of mutated p53 tumor cell lines and HT29 xenografts and was without untoward toxicity when administered alone or in combination with radiation. The results of this study support combining AZD7762 with radiation in clinical trials.
Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: experience from a large international series
Authors: W Fischbach, M E Goebeler, A Ruskone-Fourmestraux, T Wundisch, A Neubauer, M Raderer, A Savio
Journal: Gut (2007)

<h3>Background:</h3> Eradication of <i>Helicobacter pylori</i> is the established initial treatment of stage I MALT (mucosa associated lymphoid tissue) lymphoma. Patients with minimal persisting lymphoma infiltrates after successful eradication of <i>H</i><i>pylori</i> are considered treatment failures and referred for radiation, chemotherapy, immunotherapy, or surgery. <h3>Aim:</h3> To report a watch and wait strategy in such patients. <h3>Methods:</h3> 108 patients were selected from a larger series of patients treated at various European institutions. Their mean age was 51.6 years (25 to 82), and they were all diagnosed as having gastric marginal zone B cell lymphoma of MALT type stage I. After successful <i>H</i><i>pylori</i> eradication and normalisation of the endoscopic findings, lymphoma infiltrates were still present histologically at 12 months (minimal histological residuals). No oncological treatment was given but the patients had regular follow up with endoscopies and multiple biopsies. <h3>Findings:</h3> Based on a follow up of 42.2 months (2–144), 102 patients (94%) had a favourable disease course. Of these, 35 (32%) went into complete remission. In 67 (62%) the minimal histological residuals remained stable and no changes became evident. Local lymphoma progression was seen in four patients (5%), and one patient developed a high grade lymphoma. <h3>Conclusions:</h3> Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of <i>H</i><i>pylori</i> had a favourable disease course without oncological treatment. A watch and wait strategy with regular endoscopies and biopsies appears to be safe and may become the approach of choice in this situation. Longer follow up is needed to establish this definitively.
Reduced Evoked Gamma Oscillations in the Frontal Cortex in Schizophrenia Patients: A TMS/EEG Study
Authors: Fabio Ferrarelli, Marcello Massimini, Michael J. Peterson, Brady A. Riedner, Mariana Lazar, Michael J. Murphy, Reto Huber, Mario Rosanova, Andrew L. Alexander, Ned Kalin, Giulio Tononi
Journal: American Journal of Psychiatry (2008)

Transcranial magnetic stimulation (TMS) combined with high-density electroencephalography (EEG) can be used to directly examine the properties of thalamocortical circuits in the brain without engaging an individual in cognitive or motor tasks. The authors investigated EEG responses in schizophrenia patients and healthy comparison subjects following the application of TMS to the premotor cortex.Sixteen schizophrenia patients and 14 healthy comparison subjects were recruited to participate in the study. Participants underwent three to five TMS/high-density EEG sessions at various TMS doses. The following three aspects of TMS-evoked responses were analyzed: amplitude, synchronization, and source localization.Relative to healthy comparison subjects, schizophrenia patients had a marked decrease in evoked gamma oscillations that occurred within the first 100 msec after TMS, particularly in a cluster of electrodes located in a fronto-central region. These oscillations were significantly reduced in amplitude (calculated using global-mean field power and event-related spectral perturbation analysis) and synchronization (measured using intertrial coherence). Furthermore, source modeling analysis revealed that the TMS-evoked brain activation underlying these gamma oscillations in patients with schizophrenia did not propagate (as it did in healthy comparison subjects) and was mostly confined to the stimulated brain region.Schizophrenia patients showed a decrease in EEG-evoked responses in the gamma band when TMS was applied to directly stimulate the frontal cortex while these responses were recorded. Since EEG responses to direct cortical stimulation are not affected by an individual's motivation, attention, or cognitive capacity and are not relayed through peripheral afferent pathways, these findings suggest that there might be an intrinsic dysfunction in frontal thalamocortical circuits in individuals with schizophrenia.
Integrin 3 Leu33Pro Homozygosity and Risk of Cancer
Authors: S. E. Bojesen, A. Tybjaerg-Hansen, B. G. Nordestgaard
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: Increased tumor cell expression of integrins containing the β3 subunit is associated with increased progression to invasive tumors, whereas inhibition of β3 integrin expression and/or function may reduce tumor growth and metastasis. The Leu33Pro polymorphism of the β3 subunit modulates the function of αIIbβ3 integrin. We examined whether this polymorphism influences cancer risk. Methods: Using participants (n = 9242) from the Copenhagen City Heart Study with 24 years of follow-up and endpoints from the Danish Cancer Registry, we assessed the risk of all cancers and of 27 cancer types in individuals who carry the Leu33Pro polymorphism (heterozygotes and homozygotes) relative to those without the polymorphism (non-carriers). Relative risks (RRs) of cancer and 95% confidence intervals (CIs) were calculated by Cox proportional hazards regression analysis. Differences in cumulative cancer incidence (per 10 000 person-years) were tested using log-rank statistics. Statistical tests were two-sided. Results: Among the participants, 70.0% were non-carriers, 27.3% were heterozygotes, and 2.7% were homozygotes. We detected 1296 participants with a first cancer. Cumulative incidences in non-carriers, heterozygotes, and homozygotes were 81, 83, and 112, respectively (homozygotes versus non-carriers, P = .02). The age-adjusted RR of all cancers in homozygotes relative to non-carriers was 1.4 (95% CI = 1.1 to 1.9). Incidences in non-carriers, heterozygotes, and homozygotes were 3, 4, and 16 for ovarian cancer; 19, 24, and 36 for breast cancer; and 2, 3, and 7 for melanoma (homozygotes versus non-carriers; P = .002, P = .06, and P = .03, respectively). The age-adjusted RR in homozygotes relative to non-carriers was 4.7 (95% CI = 1.6 to 14) for ovarian cancer, 1.9 (95% CI = 1.0 to 3.7) for breast cancer, and 3.5 (95% CI = 1.1 to 12) for melanoma. Adjustment for other cancer risk factors did not alter these results. Heterozygotes did not differ from non-carriers with respect to cancer risk. Conclusion: Individuals homozygous for the Leu33Pro polymorphism of the β3 integrin subunit have an increased cancer risk.