tbuckley/cabot-search huggingface dataset:
Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity
Authors: I M de Kleer
Journal: Annals of the Rheumatic Diseases (2004)

To evaluate the safety and efficacy of autologous stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA).Retrospective analysis of follow up data on 34 children with JIA who were treated with ASCT in nine different European transplant centres. Rheumatological evaluation employed a modified set of core criteria. Immunological reconstitution and infectious complications were monitored at three month intervals after transplantation.Clinical follow up ranged from 12 to 60 months. Eighteen of the 34 patients (53%) with a follow up of 12 to 60 months achieved complete drug-free remission. Seven of these patients had previously failed treatment with anti-TNF. Six of the 34 patients (18%) showed a partial response (ranging from 30% to 70% improvement) and seven (21%) were resistant to ASCT. Infectious complications were common. There were three cases of transplant related mortality (9%) and two of disease related mortality (6%).ASCT in severely ill patients with JIA induces a drug-free remission of the disease and a profound increase in general wellbeing in a substantial proportion of patients, but the procedure carries a significant mortality risk. The following adjustments are proposed for future protocols: (1) elimination of total body irradiation from the conditioning regimen; (2) prophylactic administration of antiviral drugs and intravenous immunoglobulins until there is a normal CD4+ T cell count.
Inflammation on the move
Authors: Niels Borregaard
Journal: The Journal of Experimental Medicine (2015)

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Insight from Niels Borregaard



Inflammation is a major cause of morbidity, as illustrated by debilitating conditions such as rheumatoid arthritis and inflammatory bowel diseases. IL-1β and TNF are key mediators of inflammation, and agents that neutralize their effects have
A First-Generation Multiplex Biomarker Analysis of Urine for the Early Detection of Prostate Cancer
Authors: Bharathi Laxman, David S. Morris, Jianjun Yu, Javed Siddiqui, Jie Cao, Rohit Mehra, Robert J. Lonigro, Alex Tsodikov, John T. Wei, Scott A. Tomlins, Arul M. Chinnaiyan
Journal: Cancer Research (2008)

Abstract Although prostate-specific antigen (PSA) serum level is currently the standard of care for prostate cancer screening in the United States, it lacks ideal specificity and additional biomarkers are needed to supplement or potentially replace serum PSA testing. Emerging evidence suggests that monitoring the noncoding RNA transcript PCA3 in urine may be useful in detecting prostate cancer in patients with elevated PSA levels. Here, we show that a multiplex panel of urine transcripts outperforms PCA3 transcript alone for the detection of prostate cancer. We measured the expression of seven putative prostate cancer biomarkers, including PCA3, in sedimented urine using quantitative PCR on a cohort of 234 patients presenting for biopsy or radical prostatectomy. By univariate analysis, we found that increased GOLPH2, SPINK1, and PCA3 transcript expression and TMPRSS2:ERG fusion status were significant predictors of prostate cancer. Multivariate regression analysis showed that a multiplexed model, including these biomarkers, outperformed serum PSA or PCA3 alone in detecting prostate cancer. The area under the receiver-operating characteristic curve was 0.758 for the multiplexed model versus 0.662 for PCA3 alone (P = 0.003). The sensitivity and specificity for the multiplexed model were 65.9% and 76.0%, respectively, and the positive and negative predictive values were 79.8% and 60.8%, respectively. Taken together, these results provide the framework for the development of highly optimized, multiplex urine biomarker tests for more accurate detection of prostate cancer. [Cancer Res 2008;68(3):645–9]
Pathobiology of Pulmonary Hypertension
Authors: Marlene Rabinovitch
Journal: Annual Review of Pathology Mechanisms of Disease (2007)

A variety of conditions can lead to the development of pulmonary arterial hypertension (PAH). Current treatments can improve symptoms and reduce the severity of the hemodynamic abnormality, but most patients remain quite limited, and deterioration in their condition necessitates a lung transplant. This review discusses current experimental and clinical studies that investigate the pathobiology of PAH. An emerging theme is the consideration of ways in which one might reverse the advanced occlusive structural changes in the pulmonary circulation causing PAH. The current debate concerning the role of regeneration through stem cells is presented. This review also highlights investigations in a number of laboratories relating the pathobiology of PAH to mutations causing loss of function of bone morphogenetic protein receptor II in patients with familial PAH, as well as sporadic cases.
Relationship of Parent and Child Informants to Prevalence of Mania Symptoms in Children With a Prepubertal and Early Adolescent Bipolar Disorder Phenotype
Authors: Rebecca Tillman, Barbara Geller, James L. Craney, Kristine Bolhofner, Marlene Williams, Betsy Zimerman
Journal: American Journal of Psychiatry (2004)

A controversy regarding pediatric bipolar disorder is whether to use child in addition to parent informants. To investigate this issue, the authors conducted a study comparing separate child and parent interview data for child bipolar disorder.Responses on the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia from 93 child and 93 parent informants were compared by using kappa statistics. Research nurses, blind to subject information, separately interviewed parents about their children and children about themselves. Different nurses were used for the parent and child in each family to avoid bias from the same research nurse interviewing a child after interviewing that child's parent. Mania was defined by DSM-IV criteria, with at least one of the two cardinal symptoms of mania (elated mood and/or grandiosity), to avoid diagnosing mania by symptoms that overlapped with those for attention deficit hyperactivity disorder (ADHD).Parent-child concordance was poor to fair for all cardinal and noncardinal mania symptoms. Kappas were not significantly different by age within the 7-14-year-old age range.Symptoms endorsed by just the child included substantial proportions of bipolar symptoms that have been shown to best differentiate mania from ADHD (i.e., elation, grandiosity, flight of ideas, racing thoughts, decreased need for sleep). These findings support the need for child informants in research on prepubertal and early adolescent bipolar disorder in children ages 7-14. Differences in mania symptom profiles between investigative groups may be, in part, due to whether child informants were assessed.
Maximum peak and sustained inspiratory and expiratory pressures in healthy children
Authors: Ingrid Guerra Azevedo, Tania Fernandes Campos, Laöse Chaves de Oliveira, Diana Amélia Freitas, Thalita Macêdo, Raquel Emanuele Mendes, Gabriela Suéllen Chaves, Karla Morganna Mendonça
Journal: European Respiratory Journal (2013)

Aim: to evaluate peak maximal respiratory pressures in children and compare them with the calculated values for plateau pressure. Methods: 144 healthy children (81 girls, BMI: 16,24 ± 1,57 Kg/m2, age: 8,7 ± 1,2 years; 63 boys, BMI: 16,61 ± 1,42 Kg/m2, age: 9 ± 1,2 years) were evaluated. After the consent of the responsible, the children underwent an anthropometric evaluation and performed maximal respiratory pressures through a digital manometer. The manometer was coupled to a disposable biological filter. The child chose which respiratory pressure would be performed first. Maximal inspiratory pressure was performed from total pulmonary capacity and maximal expiratory pressure, from residual volume. Data were analyzed through SPSS 17.0. A significant level of p  Conclusion: The utilization of peak values in the clinical practice may compromise the real measurement of respiratory muscle strength in children.
Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling
Authors: Klaus Godl, Oliver J. Gruss, Jan Eickhoff, Josef Wissing, Stephanie Blencke, Martina Weber, Heidrun Degen, Dirk Brehmer, László Őrfi, Zoltán Horváth, György Kéri, Stefan Müller, Matt Cotten, Axel Ullrich, Henrik Daub
Journal: Cancer Research (2005)

Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1-mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.
Next Generation of Preclinical Liver Cancer Models
Authors: Achim Weber, Tracy O'Connor, Mathias Heikenwalder
Journal: Clinical Cancer Research (2015)

Abstract Because of its heterogeneity, lack of prognostic markers, tumor-escape mechanisms, and frequent relapse upon surgical intervention, treatment of hepatocellular carcinoma (HCC) remains challenging. In this issue of Clinical Cancer Research, Groß and colleagues characterize a rodent model that might help identify novel drugs for combinatorial sorafenib-based therapies for HCC. Clin Cancer Res; 21(19); 4254–6. ©2015 AACR. See related article by Groß et al., p. 4440
Clinical Heterogeneity in Patients With <i>FOXP3</i> Mutations Presenting With Permanent Neonatal Diabetes
Authors: Oscar Rubio-Cabezas, Jayne A.L. Minton, Richard Caswell, Julian P. Shield, Dorothee Deiss, Zdenek Sumnik, Amely Cayssials, Mathias Herr, Anja Loew, Vaughan Lewis, Sian Ellard, Andrew T. Hattersley
Journal: Diabetes Care (2008)

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM).The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes.We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P = 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n = 2) or nephrotic syndrome (n = 1) and survival to 12-15 years.FOXP3 mutations result in approximately 4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.
Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study
Authors: Koon K Teo, Stephanie Ounpuu, Steven Hawken, MR Pandey, Vicent Valentin, David Hunt, Rafael Diaz, Wafa Rashed, Rosario Freeman, Lixin Jiang, Xiaofei Zhang, Salim Yusuf
Journal: The Lancet (2006)
Deducing the Origin of Soluble Adenylyl Cyclase, a Gene Lost in Multiple Lineages
Authors: Jeroen Roelofs, Peter J. M. Van Haastert
Journal: Molecular Biology and Evolution (2002)

The family of eukaryotic adenylyl cyclases consists of a very large group of 12 transmembrane adenylyl cyclases and a very small group of soluble adenylyl cyclase (sAC). Orthologs of human sAC are present in rat Dictyostelium and bacteria but absent from the completely sequenced genomes of Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, and Saccharomyces cereviciae. sAC consists of two cyclase domains and a long ∼1,000 amino acid C-terminal (sCKH) region. This sCKH region and one cyclase domain have been found in only four bacterial genes; the sCKH region was also detected in bacterial Lux-transcription factors and in complex bacterial and fungal kinases. The phylogenies of the kinase and cyclase domains are identical to the phylogeny of the corresponding sCKH domain, suggesting that the sCKH region fused with the other domains early during evolution in bacteria. The amino acid sequences of sAC proteins yield divergence times from the human lineage for rat and Dictyostelium that are close to the reported divergence times of many other proteins in these species. The combined results suggest that the sCKH region was fused with one cyclase domain in bacteria, and a second cyclase domain was added in bacteria or early eukaryotes. The sAC was retained in a few bacteria and throughout the entire evolution of the human lineage but lost independently from many bacteria and from the lineages of plants, yeast, worms, and flies. We conclude that within the family of adenylyl cyclases, soluble AC was poorly fixed during evolution, whereas membrane-bound AC has expanded to form the subgroups of prevailing adenylyl and guanylyl cyclases.
EFFECT OF THYROIDECTOMY AND OF THYMECTOMY IN EXPERIMENTAL SYPHILIS OF THE RABBIT
Authors: Louise Pearce, Chester M. Van Allen
Journal: The Journal of Experimental Medicine (1926)

Experiments are described in which the thyroid or thymus gland of rabbits was removed prior to inoculation of the animals with Tr. pallidum. The effect of these procedures is described from the standpoint of the manifestations of the disease. After complete thyroidectomy, the disease was considerably more severe than in the controls and very markedly so in certain instances. Partial tyroidectomy, on the other hand, resulted in a milder disease than that of the controls. The effect of complete thymectomy was less pronounced than that of either complete or partial thyroidectomy, but, in general, the syphilis resembled that in partially thyroidectomized animals. These effects are discussed in relation to the host's reaction and resistance to experimental syphilis and the conclusion was reached that the integrity and balance of the glands of internal secretion play an important rôle in the mechanism of defense against this infection.
The Molecular and Cellular Origins of Hodgkin's Disease
Authors: Louis M. Staudt
Journal: The Journal of Experimental Medicine (2000)

Hodgkin's disease is divulging its secrets at last. Despite the fact that Hodgkin's disease was the first lymphoma to be recognized as a distinct clinical entity ([1][1]), it has proved to be one of the most difficult lymphomas to approach molecularly. The clonal, malignant Hodgkin/Reed-Sternberg (H
Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG 9402
Authors: Gregory Cairncross, Meihua Wang, Edward Shaw, Robert Jenkins, David Brachman, Jan Buckner, Karen Fink, Luis Souhami, Normand Laperriere, Walter Curran, Minesh Mehta
Journal: Journal of Clinical Oncology (2012)

Purpose Anaplastic oligodendrogliomas, pure (AO) and mixed (anaplastic oligoastrocytoma [AOA]), are chemosensitive, especially if codeleted for 1p/19q, but whether patients live longer after chemoradiotherapy is unknown. Patients and Methods Eligible patients with AO/AOA were randomly assigned to procarbazine, lomustine, and vincristine (PCV) plus radiotherapy (RT) versus RT alone. The primary end point was overall survival (OS). Results Two hundred ninety-one eligible patients were randomly assigned: 148 to PCV plus RT and 143 to RT. For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT v 4.7 years for RT; hazard ratio [HR] = 0.79; 95% CI, 0.60 to 1.04; P = .1). Patients with codeleted tumors lived longer than those with noncodeleted tumors (PCV plus RT: 14.7 v 2.6 years, HR = 0.36, 95% CI, 0.23 to 0.57, P &lt; .001; RT: 7.3 v 2.7 years, HR = 0.40, 95% CI, 0.27 to 0.60, P &lt; .001), and the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT (14.7 v 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = .03). For those with noncodeleted tumors, there was no difference in median survival by treatment arm (2.6 v 2.7 years; HR = 0.85; 95% CI, 0.58 to 1.23; P = .39). In Cox models that included codeletion status, the adjusted OS for all patients was prolonged by PCV plus RT (HR = 0.67; 95% CI, 0.50 to 0.91; P = .01). Conclusion For the subset of patients with 1p/19q codeleted AO/AOA, PCV plus RT may be an especially effective treatment, although this observation was derived from an unplanned analysis.
S67 Phenotypic differences between obese patients with eucapnic and hypercapnic sleep-disordered breathing (SDB)
Authors: K. K. Lee, E. Suh, J. Peisch, A. McGlone, A. Mistry, P. Murphy, A. J. Williams, A. C. Davidson, N. Hart
Journal: Thorax (2010)

<h3>Background</h3> Obesity-related SDB requiring domiciliary non-invasive ventilation (NIV) can present as (1) eucapnic obstructive sleep apnoea (OSA) (2) hypercapnic OSA (P<sub>a</sub>CO<sub>2</sub> &gt;6 kPa) (3) hypercapnic OSA with obesity hypoventilation syndrome (OHS) and (4) lone OHS. We have adopted the term obesity-related respiratory failure (ORRF) to group these differing conditions. The aim of this study was to determine the clinical features prevalent in each of these conditions in order to guide respiratory management. <h3>Method</h3> Data from patients initiated on domiciliary NIV at a tertiary referral unit, between August 2005 and December 2009, were obtained from a purpose-designed discharge summary database. Patients were categorised into four groups, as described above. Comparative analyses were performed between (1) eucapnic OSA and the hypercapnic groups (2) hypercapnic OSA and a group combining the OSA with OHS and the lone OHS groups (OSA &amp; OHS and lone OHS) and (3) eucapnic and hypercapnic OSA. Logistic regression analysis was performed to determine factors associated with hypercapnia. <h3>Results</h3> 163 patients were included in the analyses. Group mean (SD) age 54.3±14.2 years, weight 134.4±33.1 kg, body mass index (BMI) 48.4±2.5 kg/m<sup>2</sup> and Epworth sleepiness (ESS) score 14.8±5.8. Results are shown in Abstract S67 Table 1. The hypercapnic groups demonstrated a higher prevalence of diabetes. In addition, hypercapnic patients were overall, compared with eucapnic patients, more hypoxic with greater lung restriction, despite a non-significant increase in BMI in the hypercapnic OSA group. Compared with the hypercapnic OSA group, the combined OSA and OHS and lone OHS group had a higher BMI, ESS and greater hypercapnia. However, logistic regression analysis failed to demonstrate any factors that predicted hypercapnia. <h3>Conclusion</h3> Demographic, anthropometric, spirometric and clinical features allow the different ORRF conditions to be distinguished. BMI, daytime symptoms and degree of chronic respiratory failure distinguished between hypercapnic OSA from obesity-related hypoventilation. Although we hypothesise that ORRF is a disease spectrum, from eucapnic OSA progressing to hypercapnic OSA to OSA with OHS, we were unable to identify factors that predicted hypercapnia. From these data, we propose that more detailed physiological assessment, including neural respiratory drive and pulmonary mechanics, is required.
Clinically Relevant Pneumonitis After Sequential Paclitaxel-Based Chemotherapy and Radiotherapy in Breast Cancer Patients
Authors: T.-K. Yu, G. J. Whitman, H. D. Thames, A. U. Buzdar, E. A. Strom, G. H. Perkins, N. R. Schechter, M. D. McNeese, S.-W. Kau, E. S. Thomas, G. N. Hortobagyi, T. A. Buchholz
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Taxane-based chemotherapy has been associated with an increased risk of radiation pneumonitis in patients with breast cancer. To obtain additional information about this association, we investigated the association between paclitaxel chemotherapy and radiation pneumonitis in patients participating in a phase III randomized study. Methods: Five hundred and twenty-four breast cancer patients were prospectively and randomly assigned to receive either four cycles of paclitaxel followed by four cycles of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) or eight cycles of FAC. One hundred and eighty-nine of these patients (100 in the paclitaxel–FAC group and 89 in the FAC group) subsequently underwent radiation therapy in our institution and had medical records available to review for pulmonary symptoms. In addition, a radiologist who was unaware of the type of treatment scored chest x-ray changes after radiation treatment. Crude rates of radiation pneumonitis were compared with chi-square or Fisher's exact test, and actuarial rates were assessed with Kaplan–Meier and log-rank tests. All statistical tests were two-sided. Results: No difference in the rate of clinically relevant radiation pneumonitis was observed between the two groups (5.0% in the paclitaxel–FAC group versus 4.5% in the FAC group; difference = 0.5%, 95% CI = –6.6% to 5.5%; P = 1.00). Oral steroids for pneumonitis were taken by two patients in the paclitaxel–FAC group but by none in the FAC group, and no patient was hospitalized for or died of radiation pneumonitis. The paclitaxel–FAC group (39.3%) had a higher rate of radiographic changes after irradiation than the FAC group (23.7%; difference = 15.6%, 95% CI = –0.11% to 28.8%; P = .034). Conclusion: Patients with breast cancer treated with sequential paclitaxel, FAC, and radiation therapy appeared to have a very low rate of clinically relevant radiation pneumonitis that was no different from that of patients treated with FAC alone.