tbuckley/cabot-search huggingface dataset:
Disease-regulated local IL-10 gene therapy diminishes synovitis and cartilage proteoglycan depletion in experimental arthritis
Authors: Eline A Vermeij, Mathijs G A Broeren, Miranda B Bennink, Onno J Arntz, Inger Gjertsson, Peter L E M van Lent, Wim B van den Berg, Marije I Koenders, Fons A J van de Loo
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Rheumatoid arthritis is a chronic destructive autoimmune disease, but the course is unpredictable in individual patients. An attractive treatment would provide a disease-regulated therapy that offers personalised drug delivery. Therefore, we expressed the anti-inflammatory interleukin-10 (IL-10) gene under the control of inflammation-dependent promoters in a mouse model of arthritis. <h3>Methods</h3> Proximal promoters of <i>S100a8, Cxcl1, Mmp13, Saa3, IL-1b</i> and <i>Tsg6</i> were selected by whole-genome expression analysis of inflamed synovial tissues from arthritic mice. Mice were injected intraarticularly in knee joints with lentiviral vectors expressing a luciferase reporter or the therapeutic protein IL-10 under control of the Saa3 or Mmp13 promoter. After 4 days, arthritis was induced by intraarticular injection of streptococcal cell walls (SCW). At different time points after arthritis induction, in vivo bioluminescent imaging was performed and knee joints were dissected for histological and RNA analysis. <h3>Results</h3> The disease-regulated promoter-luciferase reporter constructs showed different activation profiles during the course of the disease. The <i>Saa3</i> and <i>Mmp13</i> promoters were significantly induced at day 1 or day 4 after arthritis induction respectively and selected for further research. Overexpression of IL-10 using these two disease-inducible promoters resulted in less synovitis and markedly diminished cartilage proteoglycan depletion and in upregulation of IL-1Ra and SOCS3 gene expression. <h3>Conclusions</h3> Our study shows that promoters of genes that are expressed locally during arthritis can be candidates for disease-regulated overexpression of biologics into arthritic joints, as shown for IL-10 in SCW arthritis. The disease-inducible approach might be promising for future tailor-made local gene therapy in arthritis.
c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma
Authors: Rafael B. Blasco, Sarah Francoz, David Santamaría, Marta Cañamero, Pierre Dubus, Jean Charron, Manuela Baccarini, Mariano Barbacid
Journal: Cancer Cell (2011)
Rituximab Plus Short-Duration Chemotherapy As First-Line Treatment for Follicular Non-Hodgkin’s Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network
Authors: John D. Hainsworth, Sharlene Litchy, Lisa H. Morrissey, Michael B. Andrews, Manuel Grimaldi, Matthew McCarty, F. Anthony Greco
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate the feasibility and efficacy of rituximab with short-duration chemotherapy in the first-line treatment of patients with follicular non-Hodgkin’s lymphoma (NHL). Patients and Methods Patients with previously untreated stage II-IV follicular NHL, grade 1 or 2, were eligible for this multicenter phase II trial. All patients received four weekly doses of rituximab (375 mg/m 2 intravenous), followed by three courses of combination chemotherapy (either cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], or cyclophosphamide, vincristine, and prednisone [CVP]) plus rituximab. Patients were evaluated for response after completing treatment, and were then followed up at 3-month intervals. Results Between January 2000 and July 2001, 86 patients were treated. Eight-two patients (95%) completed treatment; no patient was withdrawn due to toxicity. The overall response rate was 93%, with 55% complete responses. After a median follow-up of 42 months, the 3- and 4-year actuarial progression-free survivals were 71% and 62%, respectively. Five patients (6%) died from lymphoma; the overall actuarial survival at 3 years was 95%. Grade 3/4 leukopenia occurred in 53% of patients, but only six patients (7%) had neutropenia or fever. Grade 3/4 nonhematologic toxicities were uncommon. Conclusion Rituximab plus short-course chemotherapy is well tolerated as first-line treatment for patients with follicular NHL. The overall and complete response rates are similar to those reported with chemotherapy/rituximab combinations of longer duration. The actuarial progression-free survival of 62% at 4 years is encouraging, but further follow-up is necessary. Rituximab plus short-course chemotherapy may prove to be as effective as longer-duration chemotherapy and currently provides an attractive option for first-line treatment of elderly patients and others who tolerate chemotherapy poorly.
Potential Role for Kv3.1b Channels as Oxygen Sensors
Authors: O. N. Osipenko, R. J. Tate, A. M. Gurney
Journal: Circulation Research (2000)

Abstract —Hypoxia inhibits voltage-gated K channels in pulmonary artery smooth muscle (PASM). This is thought to contribute to hypoxic pulmonary vasoconstriction by promoting membrane depolarization, Ca 2+ influx, and contraction. Several of the K-channel subtypes identified in pulmonary artery have been implicated in the response to hypoxia, but contradictory evidence clouds the identity of the oxygen-sensing channels. Using patch-clamp techniques, this study investigated the effect of hypoxia on recombinant Kv1 channels previously identified in pulmonary artery (Kv1.1, Kv1.2, and Kv1.5) and Kv3.1b, which has similar kinetic and pharmacological properties to native oxygen-sensitive currents. Hypoxia failed to inhibit any Kv1 channel, but it inhibited Kv3.1b channels expressed in L929 cells, as shown by a reduction of whole-cell current and single-channel activity, without affecting unitary conductance. Inhibition was retained in excised membrane patches, suggesting a membrane-delimited mechanism. Using reverse transcription–polymerase chain reaction and immunocytochemistry, Kv3.1b expression was demonstrated in PASM cells. Moreover, hypoxia inhibited a K + current in rabbit PASM cells in the presence of charybdotoxin and capsaicin, which preserve Kv3.1b while blocking most other Kv channels, but not in the presence of millimolar tetraethylammonium ions, which abolish Kv3.1b current. Kv3.1b channels may therefore contribute to oxygen sensing in pulmonary artery.
Erythromelalgia in thrombocythemia of various myeloproliferative disorders
Authors: Jan J. Michiels, Fiebo J. W. ten Kate
Journal: American Journal of Hematology (1992)

Abstract Erythromelalgia is caused by platelet‐mediated acral inflammation and arteriolar thrombosis in thrombocythemia in its primary form or associated with polycythemia vera. The prompt and lasting relief of burning pain by low‐dose aspirin is a prerequisite for the diagnosis of thrombocythemic erythromelalgia. Here we extend observations on the occurrence of erythtromelalgia in thrombocythemia associated with primary myelofibrosis, Philadelphia‐chromosome positive micromegakaryocytic myelofibrosis, and myelodysplastic syndrome type II. It is concluded that erythromelalgia may occur in thrombocythemia of all variants of chronic myeloproliferative disease as well as myelodysplastic syndrome if platelet counts are sufficiently high.
Effects of Immediate Blood Pressure Reduction on Death and Major Disability in Patients With Acute Ischemic Stroke
Authors: Jiang He, Yonghong Zhang, Tan Xu, Qi Zhao, Dali Wang, Chung-Shiuan Chen, Weijun Tong, Changjie Liu, Tian Xu, Zhong Ju, Yanbo Peng, Hao Peng, Qunwei Li, Deqin Geng, Jintao Zhang, Dong Li, Fengshan Zhang, Libing Guo, Yingxian Sun, Xuemei Wang, Yong Cui, Yongqiu Li, Dihui Ma, Guang Yang, Yanjun Gao, Xiaodong Yuan, Lydia A. Bazzano, Jing Chen
Journal: JAMA (2014)

Although the benefit of reducing blood pressure for primary and secondary prevention of stroke has been established, the effect of antihypertensive treatment in patients with acute ischemic stroke is uncertain.To evaluate whether immediate blood pressure reduction in patients with acute ischemic stroke would reduce death and major disability at 14 days or hospital discharge.The China Antihypertensive Trial in Acute Ischemic Stroke, a single-blind, blinded end-points randomized clinical trial, conducted among 4071 patients with nonthrombolysed ischemic stroke within 48 hours of onset and elevated systolic blood pressure. Patients were recruited from 26 hospitals across China between August 2009 and May 2013.Patients (n = 2038) were randomly assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10% to 25% within the first 24 hours after randomization, achieving blood pressure less than 140/90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discontinue all antihypertensive medications (control) during hospitalization (n = 2033).Primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 14 days or hospital discharge.Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg (-12.7%) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg (-7.2%) in the control group within 24 hours after randomization (difference, -5.5% [95% CI, -4.9 to -6.1%]; absolute difference, -9.1 mm Hg [95% CI, -10.2 to -8.1]; P < .001). Mean systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after randomization (difference, -9.3 mm Hg [95% CI, -10.1 to -8.4]; P < .001). The primary outcome did not differ between treatment groups (683 events [antihypertensive treatment] vs 681 events [control]; odds ratio, 1.00 [95% CI, 0.88 to 1.14]; P = .98) at 14 days or hospital discharge. The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups (500 events [antihypertensive treatment] vs 502 events [control]; odds ratio, 0.99 [95% CI, 0.86 to 1.15]; P = .93).Among patients with acute ischemic stroke, blood pressure reduction with antihypertensive medications, compared with the absence of hypertensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge.clinicaltrials.gov Identifier: NCT01840072.
T CELL ANTIGEN RECEPTOR SIGNAL TRANSDUCTION PATHWAYS
Authors: Doreen Cantrell
Journal: Annual Review of Immunology (1996)

▪ Abstract The T cell antigen receptor (TCR) regulates the activation and growth of T lymphocytes. The initial membrane proximal event triggered by the TCR is activation of protein tyrosine kinases with the resultant phosphorylation of cellular proteins. This biochemical response couples the TCR to a divergent array of signal transduction molecules including enzymes that regulate lipid metabolism, GTP binding proteins, serine/threonine kinases, and adapter molecules. The ultimate aim of studies of intracellular signaling mechanisms is to understand the functional consequences of a particular biochemical event for receptor function. The control of cytokine gene expression is one of the mechanisms that allows the TCR to control immune responses. Accordingly, one object of the present review is to discuss the role of the different TCR signal transduction pathways in linking the TCR to nuclear targets: the transcription factors that control the expression of cytokine genes.
Epstein–Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis
Authors: Cristina Croia, Barbara Serafini, Michele Bombardieri, Stephen Kelly, Frances Humby, Martina Severa, Fabiana Rizzo, Eliana Marina Coccia, Paola Migliorini, Francesca Aloisi, Costantino Pitzalis
Journal: Annals of the Rheumatic Diseases (2012)

Rheumatoid arthritis (RA) is associated with an increased Epstein-Barr virus (EBV) blood DNA load, a robust immune response to EBV and cross-reactive circulating antibodies to viral and self-antigens. However, the role of EBV in RA pathogenesis remains elusive. Here, we investigated the relationship between synovial EBV infection, ectopic lymphoid structures (ELS) and immunity to citrullinated self and EBV proteins.Latent and lytic EBV infection was investigated in 43 RA synovial tissues characterised for presence/absence of ELS and in 11 control osteoarthritis synovia using RT-PCR, in situ hybridisation and immunohistochemistry. Synovial production of anti-citrullinated protein (ACPA) and anti-citrullinated EBV peptide (VCP1/VCP2) antibodies was investigated in situ and in vivo in the severe combined immunodeficiency (SCID)/RA chimeric model.EBV dysregulation was observed exclusively in ELS+ RA but not osteoarthritis (OA) synovia, as revealed by presence of EBV latent (LMP2A, EBV-encoded small RNA (EBER)) transcripts, EBER+ cells and immunoreactivity for EBV latent (LMP1, LMP2A) and lytic (BFRF1) antigens in ELS-associated B cells and plasma cells, respectively. Importantly, a large proportion of ACPA-producing plasma cells surrounding synovial germinal centres were infected with EBV. Furthermore, ELS-containing RA synovia transplanted into SCID mice supported production of ACPA and anti-VCP1/VCP2 antibodies. Analysis of CD4+ and CD8+ T-cell localisation and granzyme B expression suggests that EBV persistence in ELS-containing synovia may be favoured by exclusion of CD8+ T cells from B-cell follicles and impaired CD8-mediated cytotoxicity.We demonstrated active EBV infection within ELS in the RA synovium in association with local differentiation of ACPA-reactive B cells.
Dicer-Mediated Upregulation of BCRP Confers Tamoxifen Resistance in Human Breast Cancer Cells
Authors: Jennifer Selever, Guowei Gu, Michael T. Lewis, Amanda Beyer, Matthew H. Herynk, Kyle R. Covington, Anna Tsimelzon, Gabriela Dontu, Patrick Provost, Attilio Di Pietro, Ahcène Boumendjel, Kathy Albain, Lucio Miele, Heidi Weiss, Ines Barone, Sebastiano Ando, Suzanne A. W. Fuqua
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Tamoxifen (Tam) is the most prescribed hormonal agent for treatment of estrogen receptor α (ERα)-positive breast cancer patients. Using microarray analysis, we observed that metastatic breast tumors resistant to Tam therapy had elevated levels of Dicer. Experimental Design: We overexpressed Dicer in ERα-positive MCF-7 human breast cancer cells and observed a concomitant increase in expression of the breast cancer resistance protein (BCRP). We thus hypothesized that Tam resistance associated with Dicer overexpression in ERα-positive breast cancer cells may involve BCRP. We analyzed BCRP function in Dicer-overexpressing cells using growth in soft agar and mammosphere formation and evaluated intracellular Tam efflux. Results: In the presence of Tam, Dicer-overexpressing cells formed resistant colonies in soft agar, and treatment with BCRP inhibitors restored Tam sensitivity. Tumor xenograft studies confirmed that Dicer-overexpressing cells were resistant to Tam in vivo. Tumors and distant metastases could be initiated with as few as five mammosphere cells from both vector and Dicer-overexpressing cells, indicating that the mammosphere assay selected for cells with enhanced tumor-initiating and metastatic capacity. Dicer-overexpressing cells with elevated levels of BCRP effluxed Tam more efficiently than control cells, and BCRP inhibitors were able to inhibit efflux. Conclusion: Dicer-overexpressing breast cancer cells enriched for cells with enhanced BCRP function. We hypothesize that it is this population which may be involved in the emergence of Tam-resistant growth. BCRP may be a novel clinical target to restore Tam sensitivity. Clin Cancer Res; 17(20); 6510–21. ©2011 AACR.
A COMPARATIVE STUDY OF THINKING IN SCHIZOPHRENIC CHILDREN AND IN CHILDREN OF PRESCHOOL AGE
Authors: J. LOUISE DESPERT
Journal: American Journal of Psychiatry (1940)

An analogy is frequently drawn between schizophrenic and child thinking. In order to check the validity of such analogy, verbal productions from protocols of fifteen normal children of pre- school age (two to five years) and three schizophrenic children (with ages varying between seven years, ten months and fourteen years, seven months) are presented and compared. These productions were obtained under very similar conditions, i. e., favoring the spontaneous expression of phantasy, allowance being made for differences in ages, clinical needs and situational contingencies. The systematic investigation of the phantasies of young normal children with regard to the evaluation of reality shows that responses fall within three categories: denial of character of reality, which is the most common type of response; evasion; and finally, reiteration with apparent belief. The latter category, containing the smallest number, includes those responses in which a strong emotional component is evident, chiefly fears, but also wishes. It is not possible to demonstrate in normal children true delusions and hallucinations or disorders characteristic of schizophrenic thinking. Experiences which come closest to these belong to the third category, i. e., reiteration with apparent belief, but are not appreciably different from similar experiences initiated in the adult by some strong emotional stimulus. It is recognized, however, that the child shows a greater emotional lability and greater susceptibility to somatic changes than the adult. In one instance where a confusion between reality and phantasy seemed apparent, the child showed emotional immaturity and a lack of social adaptation which point to a relation between the coincidence of such experience and a tendency toward faulty integration and adjustment in the future. Follow-up studies of the children's later adjustment should throw light on this point. From the present records it appears evident that experiences which most closely resemble those found in the schizophrenic are dependent upon emotional factors and not upon characteristics inherent in child thinking.
Treatment of central sleep apnea in patients with heart failure: A retrospective observational study
Authors: Grietje de Vries, Petra Meijer, Trinette Blijham, Huib Kerstjens, Peter Wijkstra
Journal: European Respiratory Journal (2012)

Introduction  In patients with heart failure (HF) and central sleep apnea syndrome (CSAS) different therapeutic options, such as continuous positive airway pressure (CPAP), bi-level PAP (BiPAP) and adaptive servoventilation (ASV) are available. All are potentially effective in improving heart function and in reducing apnea-hypopnea index (AHI), while ASV is generally considered to be most effective.  Aim  To assess how HF-patients with CSAS (AHI ≥15) respond to the different treatments in terms of AHI.  Methods  CPAP was given first, and when ineffective or when patients still experienced SAS related complaints, followed by BiPAP and/or ASV. Efficacy was assessed by a sleep study under treatment. Treatment was considered effective when AHI reduced   Results  14 males (70 y) were assessed.  Conclusions  Although ASV seems to prove to be most effective in HF-patients with CSAS, CPAP and BiPAP together are still effective in 57% of the patients. Given the lower costs of CPAP and BiPAP, algorithms and guidelines are needed for initial treatment mode selection in patients with both HF and CSAS.
Estimating Quality of Life in Acute Venous Thrombosis
Authors: Kerstin Hogg, Miriam Kimpton, Marc Carrier, Douglas Coyle, Melissa Forgie, Philip Wells
Journal: JAMA Internal Medicine (2013)

<h3>Importance</h3>Future funding for new treatments in venous thromboembolism will be guided by cost-utility analyses. There is little available information on the utility of acute venous thromboembolism, limiting the validity of economic analyses.<h3>Objective</h3>To measure the quality of life in the health states relating to thromboembolism cost-utility analyses.<h3>Design</h3>A prospective cohort study.<h3>Setting</h3>A single-center, university-affiliated thrombosis clinic.<h3>Participants</h3>Two hundred sixteen thrombosis clinic patients with a history of lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE).<h3>Exposures</h3>Participants consented to take a standard gamble interview. Each participant rated the quality of life in acute DVT, acute PE, and bleeding complication health states.<h3>Main Outcomes and Measures</h3>The standard gamble measured quality of life (utility value) for acute DVT, acute PE, major intracranial bleeding event, minor intracranial bleeding event, and gastrointestinal bleeding event. <h3>Results</h3>Two hundred fifteen responses were included in the analysis. Twenty-six percent had experienced both PE and DVT; 54%, DVT alone; and 20%, PE alone. Forty-two percent had experienced more than 1 episode of thrombosis, and 23% had had cancer-associated thrombosis. We found the median utility for acute DVT was 0.81 (interquartile range [IQR], 0.55-0.94); acute PE, 0.75 (IQR, 0.45-0.91); major intracranial bleeding event, 0.15 (IQR, 0.00-0.65); minor intracranial bleeding event, 0.75 (IQR, 0.55-0.92); and gastrointestinal bleeding event, 0.65 (IQR, 0.15-0.86). The median length of symptoms for DVT or PE was 1 week (IQR, &lt;1-3 weeks).<h3>Conclusions and Relevance</h3>To our knowledge, this is the largest published study on utilities in which the participants had personal experience of venous thromboembolism. We present unique information for economic analyses but have also identified future challenges for research in this area. Our summary results differ from those previously published, and we found wide variation in individual responses.
Solid tumor size on high-resolution computed tomography and maximum standardized uptake on positron emission tomography for new clinical T descriptors with T1 lung adenocarcinoma
Authors: Y. Tsutani, Y. Miyata, H. Nakayama, S. Okumura, S. Adachi, M. Yoshimura, M. Okada
Journal: Annals of Oncology (2013)
Frequent Intron Loss in the White Gene: A Cautionary Tale for Phylogeneticists
Authors: Jaroslaw Krzywinski, Nora J. Besansky
Journal: Molecular Biology and Evolution (2002)

The BLASTP searches with the D. melanogaster white sequence used as a query identified 8 sequences within the C. elegans genome with E values ranging from e-75 to e-99. Four top-scoring sequences (AAA20989, AAB66050, AAC77504, and CAA86750 with similarity to D. melanogaster white ranging from 53% to 57%) were aligned with the white of four insect representatives (D. menagaster, Ceratitis capitata, Anopheles gambiae, Tribolium castaneum), a human white homologue and the D. melanogaster scarlet gene (like white, a member of ABC transporters). Parsimony analysis of these sequences resulted in clustering insect and human white along with C. elegans sequences AAA20989 and AAB66050 in a single clade, with human sequence diverging earliest. For further analyses sequence AAA20989, most similar to the dipteran white on the amino acid and gene structure (sharing three introns) levels, was selected.