tbuckley/cabot-search huggingface dataset:
The effects of static charge in spacer devices on glucocorticosteroid aerosol deposition in asthmatic patients
Authors: CJ Kenyon, L Thorsson, L Borgstrom, SP Newman
Journal: European Respiratory Journal (1998)

Electrostatic charge in plastic spacer devices has been shown in vitro to reduce delivery of asthma medications intended for inhalation, but the effect of static charge on in vivo drug deposition is unknown. A six-way randomized crossover study was conducted in 10 mild asthmatic patients. Two plastic spacers (Nebuhaler and Volumatic) and one metal spacer (Nebuchamber) were tested. The spacers were used either "primed" or "unprimed". Priming was performed by firing 20 doses of placebo aerosol into a new spacer, hence coating the inner surface with surfactant and minimizing static charge. Unprimed spacers were new and were not treated. Pressurized aerosol canisters delivering budesonide (200 microg Pulmicort) were radiolabelled with the radionuclide 99mTc and lung deposition was measured by gamma scintigraphy. The radiolabel was shown to be a valid marker for the drug substance prior to the clinical phase of the study. Priming significantly increased mean whole lung deposition following inhalation from plastic spacers (Nebuhaler primed 37.7% and unprimed 26.7%, p=0.01; Volumatic primed 32.0% and unprimed 22.1%, p=0.02). Priming had no effect on the mean whole lung deposition following inhalation from the Nebuchamber (primed 33.5% and unprimed 32.9%). Lung deposition in vivo from plastic spacer devices will vary according to the electrostatic charge on the spacer walls. Priming reduces retention of drug on plastic spacer devices and increases lung deposition. Metal spacers are not susceptible to static charge, which should result in more predictable lung deposition.
Central Role of CD45RA− Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance
Authors: Faouzi Braza, Emilie Dugast, Ivo Panov, Chloé Paul, Katrin Vogt, Annaick Pallier, Mélanie Chesneau, Daniel Baron, Pierrick Guerif, Hong Lei, David-Axel Laplaud, Hans-Dieter Volk, Nicolas Degauque, Magali Giral, Jean-Paul Soulillou, Birgit Sawitzki, Sophie Brouard
Journal: Journal of the American Society of Nephrology (2015)

The role of Foxp3 + regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4 + T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4 + T cells with demethylated Foxp3 and a specific expansion of CD4 + CD45RA − Foxp3 hi memory Tregs exclusively in tolerant patients. The memory Tregs of tolerant recipients exhibited increased Foxp3 TSDR demethylation, expressed higher levels of CD39 and glucocorticoid-induced TNF-related receptor, and harbored greater suppressive properties than memory Tregs from patients with stable graft function. Taken together, our data demonstrate that operationally tolerant patients mobilize an array of potentially suppressive cells, including not only regulatory B cells but also Tregs. Our results also indicate that tolerant patients have potent CD4 + CD45RA − Foxp3 hi memory Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance.
Efficient management of rheumatoid arthritis significantly reduces long-term functional disability
Authors: E Tanaka, A Mannalithara, E Inoue, M Hara, T Tomatsu, N Kamatani, G Singh, H Yamanaka
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> The aim of this study was to examine the effect of efficient management of rheumatoid arthritis (RA) in relation to disability levels in a large cohort of patients with RA over a period of 3 years. <h3>Methods:</h3> We studied 2775 patients with RA who had continuous enrolment for at least 3 years from 7511 patients with RA enrolled in an observational cohort study (Institute of Rheumatology, Rheumatoid Arthritis (IORRA)) from October 2000 to April 2005. The 28-joint Disease Activity Scores (DAS28) were calculated at 6 month intervals for all the patients and a value &lt;2.6 was considered as a tight control. We have set up a new variable for each patient, “Avg-Dscore”, based on the transition of each patient’s DAS28 value, taking the threshold level of 2.6 into consideration. The “Avg-DAS28” is the average of DAS28 values over all the phases. Functional disability status was assessed by J-HAQ, the validated Japanese version of the Health Assessment Questionnaire (HAQ). The relationship of “Avg-Dscore” and “Avg-DAS28” with the functional disability level was determined using Spearman correlation coefficients and multiple linear regression models. <h3>Results:</h3> The baseline features of these 2775 patients were: female 83.7%, mean age 56.8 years, mean RA duration 9.5 years, mean initial DAS28 4.0, mean initial J-HAQ score 0.79, and mean final J-HAQ score 0.86. There was a statistically significant correlation between “Avg-DAS28” and final J-HAQ score (r = 0.57, p&lt;0.001), indicating that tighter disease control has significant association with lower disability levels. A similar relationship was observed between “Avg-Dscore” and final J-HAQ score (r = 0.47, p&lt;0.001). Multiple linear regression analysis, after adjusting for all the covariates, revealed that “Avg-Dscore” and “Avg-DAS28” were the most significant factors contributing to final J-HAQ score, and confirmed the strong relationship between disease activity and functional disability. <h3>Conclusions:</h3> In patients with RA efficient disease management, by maintaining the DAS28 values at a level under 2.6, has significant association with improving functional capability. The threshold DAS28 level of 2.6 may be useful in developing targeted treatment guidelines for patients with RA.
Cisplatin (CDDP) plus vinorelbine (VRB) as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC): Molecular correlates
Authors: R. de las Peñas, M. Provencio, C. Camps, M. Cobo, B. Massuti, U. Jimenez, A. Artal, F. Cardenal, M. Taron, R. Rosell
Journal: Journal of Clinical Oncology (2007)

7692 Background: The combination of cisplatin plus vinorelbine is a reference regimen as first-line therapy in advanced NSCLC. The correlation between predictive genetic markers and clinical endpoints may improve the prediction of treatment success and thereby the tailoring of chemotherapy. In this trial, predictive genetic markers of response to CDDP/VRB were examined in genomic DNA and cDNA derived from tumors and circulating tumors. Methods: 238 chemonaive p with stage IIIB (pleural effusion or supraclavicular lymph nodes)- IV or recurrent NSCLC were accrued at 35 sites between April 2004 and January 2006. Treatment consisted of CDDP 75 mg/m 2 IV day 1 plus VRB 25 mg/m 2 IV or 60–80 mg/m 2 oral, days 1, 8 every 21 days. DNA samples were collected from primary tumors for the assessment of microtubule associated protein 4 (MAP4) and from serum for the checkpoint forkhead-associated and ring finger (CHFR) methylation. Results: Data on 198 p is available. Median age 62 years (38–80); males: 83.8%; smokers: 77.8%; PS 0–1: 95.3%; adenocarcinoma, 48.9% / squamous, 32.8%; stage IIIB: 16.7%, IV: 83.3%. Median cycles: 4 (1–12). Hematological toxicities (%p): grade 3/4 neutropenia, 9.6%/7.6%; grade 3/4 thrombocytopenia, 0.5%/0.5%; grade 3 anemia, 2%. Febrile neutropenia appeared in 14 cycles / 10 p (1.8%/5,1%). Non-hematological toxicities (%p): pulmonary grade 3/4, 3.0%/2.5%; nausea/vomiting grade 3/4, 7.6%/0.5%; asthenia grade 3, 13.2%; pain grade 3, 6.6%; infection grade 3, 4.1%; neurotoxicity grade 3, 0.5%. Efficacy in evaluable population: CR, 2.3%; PR, 30.8%; ORR, 33.1% (95% CI, 26.1% to 40.2%); SD, 39.7%. With a median follow up of 6.7 months, median survival for the whole population was 9 months (m), progression free survival 5.07 m, event free survival 4.8 m, 1-year survival 39.9%. Conclusions: The tolerability, efficacy and survival results of this trial confirm that CDDP/VRB is effective as first-line therapy, presenting a favorable toxicity profile in p with advanced NSCLC. Complete data on genetic markers will be presented. No significant financial relationships to disclose.
Validation of the M. D. Anderson Symptom Inventory multiple myeloma module
Authors: Desiree Jones, Elisabeth G Vichaya, Xin Shelley Wang, Loretta A Williams, Nina D Shah, Sheeba K Thomas, Valen E Johnson, Richard E Champlin, Charles S Cleeland, Tito R Mendoza
Journal: Journal of Hematology & Oncology (2013)

The symptom burden associated with multiple myeloma (MM) is often severe. Presently, no instrument comprehensively assesses disease-related and treatment-related symptoms in patients with MM. We sought to validate a module of the M. D. Anderson Symptom Inventory (MDASI) developed specifically for patients with MM (MDASI-MM). The MDASI-MM was developed with clinician input, cognitive debriefing, and literature review, and administered to 132 patients undergoing induction chemotherapy or stem cell transplantation. We demonstrated the MDASI-MM's reliability (Cronbach α values); criterion validity (item and subscale correlations between the MDASI-MM and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EORTC MM module (QLQ-MY20)), and construct validity (differences between groups by performance status). Ratings from transplant patients were examined to demonstrate the MDASI-MM's sensitivity in detecting the acute worsening of symptoms post-transplantation. The MDASI-MM demonstrated excellent correlations with subscales of the 2 EORTC instruments, strong ability to distinguish clinically different patient groups, high sensitivity in detecting change in patients' performance status, and high reliability. Cognitive debriefing confirmed that the MDASI-MM encompasses the breadth of symptoms relevant to patients with MM. The MDASI-MM is a valid, reliable, comprehensive-yet-concise tool that is recommended as a uniform symptom assessment instrument for patients with MM.
Phase II Clinical Trial of Amatuximab, a Chimeric Antimesothelin Antibody with Pemetrexed and Cisplatin in Advanced Unresectable Pleural Mesothelioma
Authors: Raffit Hassan, Hedy L. Kindler, Thierry Jahan, Lyudmila Bazhenova, Martin Reck, Anish Thomas, Ira Pastan, Jeff Parno, Daniel J. O'Shannessy, Penny Fatato, Julia D. Maltzman, Bruce A. Wallin
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its synergy with chemotherapy in preclinical studies, we evaluated the antitumor activity of amatuximab plus pemetrexed and cisplatin in patients with unresectable MPM. Experimental Design: In a single-arm phase II study, amatuximab (5 mg/kg) was administered on days 1 and 8 with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of 21-day cycles for up to six cycles. Patients with response or stable disease received amatuximab maintenance until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), response rate, and safety. Results: Eighty-nine patients were enrolled at 26 centers. Median of five cycles (range, 1–6) of combination treatment was administered, and 56 (63%) patients received amatuximab maintenance. Combination therapy resulted in no overlapping toxicities. Eleven patients (12.4%) had amatuximab-related hypersensitivity reactions. Responses included partial responses in 33 (40%) and stable disease in 42 (51%). Six-month PFS rate was 51% [95% confidence interval (CI), 39.1–62.3)], median PFS was 6.1 months (95% CI, 5.8–6.4), and median OS was 14.8 months (95% CI, 12.4–18.5) with 29 patients alive at data cut-off. Conclusions: Amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Although PFS was not significantly different from historical controls, the median OS was 14.8 months with a third of patients alive and 5 continuing to receive amatuximab at the time of analysis. Clin Cancer Res; 20(23); 5927–36. ©2014 AACR.
Intracellular Triggering of Fas Aggregation and Recruitment of Apoptotic Molecules into Fas-enriched Rafts in Selective Tumor Cell Apoptosis
Authors: Consuelo Gajate, Esther del Canto-Jañez, A. Ulises Acuña, Francisco Amat-Guerri, Emilio Geijo, Antonio M. Santos-Beneit, Robert J. Veldman, Faustino Mollinedo
Journal: The Journal of Experimental Medicine (2004)

We have discovered a new and specific cell-killing mechanism mediated by the selective uptake of the antitumor drug 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3, Edelfosine) into lipid rafts of tumor cells, followed by its coaggregation with Fas death receptor (also known as APO-1 or CD95) and recruitment of apoptotic molecules into Fas-enriched rafts. Drug sensitivity was dependent on drug uptake and Fas expression, regardless of the presence of other major death receptors, such as tumor necrosis factor (TNF) receptor 1 or TNF-related apoptosis-inducing ligand R2/DR5 in the target cell. Drug microinjection experiments in Fas-deficient and Fas-transfected cells unable to incorporate exogenous ET-18-OCH3 demonstrated that Fas was intracellularly activated. Partial deletion of the Fas intracellular domain prevented apoptosis. Unlike normal lymphocytes, leukemic T cells incorporated ET-18-OCH3 into rafts coaggregating with Fas and underwent apoptosis. Fas-associated death domain protein, procaspase-8, procaspase-10, c-Jun amino-terminal kinase, and Bid were recruited into rafts, linking Fas and mitochondrial signaling routes. Clustering of rafts was necessary but not sufficient for ET-18-OCH3–mediated cell death, with Fas being required as the apoptosis trigger. ET-18-OCH3–mediated apoptosis did not require sphingomyelinase activation. Normal cells, including human and rat hepatocytes, did not incorporate ET-18-OCH3 and were spared. This mechanism represents the first selective activation of Fas in tumor cells. Our data set a framework for the development of more targeted therapies leading to intracellular Fas activation and recruitment of downstream signaling molecules into Fas-enriched rafts.
Subclass distribution of mucosal IgG-producing cells in gastritis.
Authors: K Valnes, P Brandtzaeg
Journal: Gut (1989)

IgG-mediated immune reactions are probably involved in the maintenance of gastritis and glandular atrophy; the mucosal IgG-subclass pattern may therefore influence the effect of local hypersensitivity mechanisms. In this study the proportions of IgG1-, IgG2-, IgG3-, and IgG4-producing immunocytes were determined by paired immunofluorescence staining in specimens from simple gastritis, gastritis after Billroth II (BII) resection, and gastritis associated with dermatitis herpetiformis (DH). The results were related to histopathological degree of inflammation and atrophy. Generally, IgG1 immunocytes predominated (48-60%) in all types of gastritis. With increasing severity of inflammation, the IgG2-cell proportion was significantly increased from 4-6% to 26-34% in simple and BII gastritis, whereas the ratio of IgG1 immunocytes was correspondingly decreased from 58-69% to 38-43%. In the same types of gastritis the proportion of IgG3 cells was increased in association with severe (35-38%) compared with mild (15-23%) atrophy, whereas the proportion of IgG1 cells was correspondingly decreased. In severe gastritis associated with DH, the proportion of IgG1 cells was relatively high (60%) and that of IgG2 cells relatively low (13%), and severe atrophy did not seem to influence significantly the subclass proportions.
Overlapping Gene Expression in Fetal Mouse Intestine Development and Human Colorectal Cancer
Authors: Michael Hu, Ramesh A. Shivdasani
Journal: Cancer Research (2005)

Pathways relevant to cancer are well known to overlap with fetal development, as reflected in reactivation of embryonic genes in tumors. However, molecular evidence for this notion has gathered in piecemeal fashion, and systematic approaches have rarely been applied to gauge the extent and global characteristics of the overlap in gene expression between developing tissues and cancer. The fraction of genes that is expressed aberrantly in a given cancer and also developmental in primary function is unknown, and the tissue specificity of recapitulated gene expression remains unexplored. We developed a statistical method to relate expression profiles from human colon cancer and diverse nonintestinal tumors to transcripts that decline in expression with epithelial differentiation in the fetal mouse gut. For genes that are overexpressed in colon cancer, we computed 8% to 19% likelihood that they were expressed transiently during epithelial morphogenesis in intestine development. Among genes dysregulated in other tumors, the corresponding likelihood fell between 1% and 6%. Similarly, low probabilities were obtained when we compared genes not overexpressed in colon cancer with transcriptional profiles in intestine organogenesis. Genes that increase after fetal gut epithelial differentiation were not differentially represented between cancerous and normal colon. Our findings systematically characterize the global extent and tissue specificity of developmental expression programs in colorectal cancer and illustrate the use of such an approach to identify candidate biomarkers and therapeutic targets.
High-dose carboplatin and recombinant granulocyte-macrophage colony-stimulating factor in advanced-stage recurrent ovarian cancer.
Authors: E Reed, J Janik, M A Bookman, M Rothenberg, J Smith, R C Young, R F Ozols, L VanderMolen, E Kohn, J L Jacob
Journal: Journal of Clinical Oncology (1993)

We investigated whether carboplatin myelosuppression could be favorably modulated by the administration of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) in patients with advanced-stage ovarian cancer.Thirty-four patients with advanced-stage recurrent ovarian cancer were treated with high-dose carboplatin (800 mg/m2 per 35-day cycle) and rGM-CSF. rGM-CSF was administered as a daily subcutaneous injection starting 72 hours after the carboplatin dose and continuing until 7 days beyond the WBC nadir. rGM-CSF was administered in a phase I fashion. Seven patients were treated at an rGM-CSF dose of 3 micrograms/kg, 11 at 5 micrograms/kg, 10 at 10 micrograms/kg, and six at 20 micrograms/kg.rGM-CSF-related toxicities that were not dose-related included nonneutropenic fever, rib pain, acute hypersensitivity reaction, and pericarditis. At the rGM-CSF dose of 20 micrograms/kg, debilitating malaise was seen in four of six patients and this was the dose-limiting toxicity. Patient tolerance of the 3-micrograms/kg and 5-micrograms/kg doses was good, but tolerance was limited for the 10-micrograms/kg dose. Febrile neutropenia was seen in four of seven patients at 3 micrograms/kg, two of 11 at 5 micrograms/kg, two of 10 at 10 micrograms/kg, and one of six at 20 micrograms/kg. Cumulative carboplatin myelotoxicity was blunted only in respect to WBC count, and not for platelets or RBCs. Gastrointestinal bleeding was seen in seven patients. The administered dose-intensity of carboplatin averaged 134 mg/m2/wk for the cohort, or 670 mg/m2 per 35-day cycle. There were two clinical complete responses and eleven partial responses, for a response rate of 38%.rGM-CSF appears to be effective and tolerable at 5 micrograms/kg/d administered subcutaneously, if given with carboplatin doses up to approximately 600 mg/m2 over 35 days. The use of rGM-CSF with high-dose carboplatin is associated with a substantial response rate in poor-prognosis ovarian cancer patients.
The Combination of the Proteasome Inhibitor Bortezomib and the Bcl-2 Antisense Molecule Oblimersen Sensitizes Human B-Cell Lymphomas to Cyclophosphamide
Authors: Owen A. O'Connor, Emily A. Smith, Lorraine E. Toner, Julie Teruya-Feldstein, Stanley Frankel, Mark Rolfe, Xiaohui Wei, Shujun Liu, Guido Marcucci, Kenneth K. Chan, Asher Chanan-Khan
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide. Experimental Design: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored. Bcl-2 and oblimersen levels were determined in treated tumors, some of which were resected at the end of the in vivo experiment and evaluated pathologically. Results: The results suggest that the combination of bortezomib and oblimersen seem to interact in at least an additive fashion, and that the addition of cyclophosphamide to this drug combination can markedly improve tumor cell kill. In addition, it seems that these drug combinations may be schedule-dependent, with a requirement for oblimersen pretreatment. Animals treated with the triplet drug combination in a schedule-dependent manner experienced pathologic complete regression of disease, which was not observed in other treatment cohorts. The addition of bortezomib also seemed to increase the levels of intracellular oblimersen, which resulted in a marked reduction in Bcl-2. Histologic studies confirmed marked necrosis and caspase-3 activation only in the cohort receiving all three drugs. Conclusion: The use of Bcl-2-directed therapy and a proteasome inhibitor sensitizes human lymphoma cells to cytotoxic drugs like cyclophosphamide. This combination may offer new opportunities for integrating novel targeted therapies with conventional chemotherapy.
ASTHMA AND THE RADIUM MENOPAUSE
Authors: J. N. M. Ross
Journal: BMJ (1922)

ASTHMA AND THE RADIUM MIENOPAUSE.r Ta.flPRTqIlt ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.On admission, the vari-ous syeteiis were founiid normal, except as follows: T-hle right upper and lower extremities are smaller tlan the left, anid tljis lholds hoth as re-ards lenigth and circumiiference; the difference varies fromii onie 1/4 inich to 1L inch.It is more marked in the arm tlhani in the leg, anid most lmiarkhed in. the h ids; t.he left metacarpos measures L-inchiles round, the right onily 6 inches.No ilifference is seen ini abdomen, buttock, or back; the lelt knee-joinit is slightly swollen, buLit the x rays slhow no bony change.
Genome-wide patterns of genetic variation among elite maize inbred lines
Authors: Jinsheng Lai, Ruiqiang Li, Xun Xu, Weiwei Jin, Mingliang Xu, Hainan Zhao, Zhongkai Xiang, Weibin Song, Kai Ying, Mei Zhang, Yinping Jiao, Peixiang Ni, Jianguo Zhang, Dong Li, Xiaosen Guo, Kaixiong Ye, Min Jian, Bo Wang, Huisong Zheng, Huiqing Liang, Xiuqing Zhang, Shoucai Wang, Shaojiang Chen, Jiansheng Li, Yan Fu, Nathan M Springer, Huanming Yang, Jian Wang, Jingrui Dai, Patrick S Schnable, Jun Wang
Journal: Nature Genetics (2010)