tbuckley/cabot-search huggingface dataset:
Engineered Antibodies of IgG1/IgG3 Mixed Isotype with Enhanced Cytotoxic Activities
Authors: Akito Natsume, Mika In, Hiroyuki Takamura, Tomoaki Nakagawa, Yukiko Shimizu, Kazuko Kitajima, Masako Wakitani, So Ohta, Mitsuo Satoh, Kenya Shitara, Rinpei Niwa
Journal: Cancer Research (2008)

Enhancement of multiple effector functions of an antibody may be a promising approach for antibody therapy. We have previously reported that fucose removal from Fc-linked oligosaccharides greatly enhances antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies. Here, we report a unique approach to enhance complement-dependent cytotoxicity (CDC), another important effector function of antitumor antibodies, by using engineered constant region of human IgG1/IgG3 chimeric isotypes. We systematically shuffled constant domains of IgG1 and IgG3 to generate a comprehensive set of mixed chimeric isotypes of anti-CD20 antibodies. Among these, the variant 1133, consisting of the CH1 and the hinge each from IgG1 and the Fc from IgG3, was unexpectedly found to exhibit markedly enhanced CDC that exceeded wild-type levels. However, it lacked protein A-binding capacity, an important feature for the industrial production. To eliminate this deficiency, a portion in COOH-terminal CH3 domain of 1133 was substituted with IgG1, resulting in full recovery of protein A binding without compromising the enhanced CDC and ADCC activities. The CDC-enhancing effect using a chimeric isotype was also shown in CD52 antigen/antibody system. The ADCC activity of the variants was also maximized by the absence of fucose from its carbohydrate structure, a phenomenon that has previously been observed for wild-type antibodies. Enhanced cytotoxicity of a variant was confirmed in a cynomolgus monkey model. These findings suggest that the variant antibodies with IgG1/IgG3 chimeric constant regions and nonfucosylated oligosaccharides that possess dual-enhanced cytotoxic functions may be an improvement for the next generation of therapeutic antitumor antibodies.
Atelectasis and survival after bronchoscopic lung volume reduction for COPD
Authors: N.S. Hopkinson, S.V. Kemp, T.P. Toma, D.M. Hansell, D.M. Geddes, P.L. Shah, M.I. Polkey
Journal: European Respiratory Journal (2010)

Bronchoscopic therapies to reduce lung volumes in chronic obstructive pulmonary disease are intended to avoid the risks associated with lung volume reduction surgery (LVRS) or to be used in patient groups in whom LVRS is not appropriate. Bronchoscopic lung volume reduction (BLVR) using endobronchial valves to target unilateral lobar occlusion can improve lung function and exercise capacity in patients with emphysema. The benefit is most pronounced in, though not confined to, patients where lobar atelectasis has occurred. Few data exist on their long-term outcome. 19 patients (16 males; mean± sd forced expiratory volume in 1 s 28.4±11.9% predicted) underwent BLVR between July 2002 and February 2004. Radiological atelectasis was observed in five patients. Survival data was available for all patients up to February 2010. None of the patients in whom atelectasis occurred died during follow-up, whereas eight out of 14 in the nonatelectasis group died (Chi-squared p = 0.026). There was no significant difference between the groups at baseline in lung function, quality of life, exacerbation rate, exercise capacity (shuttle walk test or cycle ergometry) or computed tomography appearances, although body mass index was significantly higher in the atelectasis group (21.6±2.9 versus 28.4±2.9 kg·m −2 ; p&lt;0.001). The data in the present study suggest that atelectasis following BLVR is associated with a survival benefit that is not explained by baseline differences.
Mindfulness-Based Stress Reduction for Posttraumatic Stress Disorder Among Veterans
Authors: Melissa A. Polusny, Christopher R. Erbes, Paul Thuras, Amy Moran, Greg J. Lamberty, Rose C. Collins, John L. Rodman, Kelvin O. Lim
Journal: JAMA (2015)

<h3>Importance</h3> Mindfulness-based interventions may be acceptable to veterans who have poor adherence to existing evidence-based treatments for posttraumatic stress disorder (PTSD). <h3>Objective</h3> To compare mindfulness-based stress reduction with present-centered group therapy for treatment of PTSD. <h3>Design, Setting, and Participants</h3> Randomized clinical trial of 116 veterans with PTSD recruited at the Minneapolis Veterans Affairs Medical Center from March 2012 to December 2013. Outcomes were assessed before, during, and after treatment and at 2-month follow-up. Data collection was completed on April 22, 2014. <h3>Interventions</h3> Participants were randomly assigned to receive mindfulness-based stress reduction therapy (n = 58), consisting of 9 sessions (8 weekly 2.5-hour group sessions and a daylong retreat) focused on teaching patients to attend to the present moment in a nonjudgmental, accepting manner; or present-centered group therapy (n = 58), an active-control condition consisting of 9 weekly 1.5-hour group sessions focused on current life problems. <h3>Main Outcomes and Measures</h3> The primary outcome, change in PTSD symptom severity over time, was assessed using the PTSD Checklist (range, 17-85; higher scores indicate greater severity; reduction of 10 or more considered a minimal clinically important difference) at baseline and weeks 3, 6, 9, and 17. Secondary outcomes included PTSD diagnosis and symptom severity assessed by independent evaluators using the Clinician-Administered PTSD Scale along with improvements in depressive symptoms, quality of life, and mindfulness. <h3>Results</h3> Participants in the mindfulness-based stress reduction group demonstrated greater improvement in self-reported PTSD symptom severity during treatment (change in mean PTSD Checklist scores from 63.6 to 55.7 vs 58.8 to 55.8 with present-centered group therapy; between-group difference, 4.95; 95% CI, 1.92-7.99;<i>P</i>=.002) and at 2-month follow-up (change in mean scores from 63.6 to 54.4 vs 58.8 to 56.0, respectively; difference, 6.44; 95% CI, 3.34-9.53,<i>P</i> &lt; .001). Although participants in the mindfulness-based stress reduction group were more likely to show clinically significant improvement in self-reported PTSD symptom severity (48.9% vs 28.1% with present-centered group therapy; difference, 20.9%; 95% CI, 2.2%-39.5%;<i>P</i> = .03) at 2-month follow-up, they were no more likely to have loss of PTSD diagnosis (53.3% vs 47.3%, respectively; difference, 6.0%; 95% CI, −14.1% to 26.2%;<i>P</i> = .55). <h3>Conclusions and Relevance</h3> Among veterans with PTSD, mindfulness-based stress reduction therapy, compared with present-centered group therapy, resulted in a greater decrease in PTSD symptom severity. However, the magnitude of the average improvement suggests a modest effect. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01548742
Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin
Authors: Peter V. E. van den Berghe, Janneke M. Stapelbroek, Elmar Krieger, Prim de Bie, Stan F. J. van de Graaf, Reinoud E. A. de Groot, Ellen van Beurden, Ellen Spijker, Roderick H. J. Houwen, Ruud Berger, Leo W. J. Klomp
Journal: Hepatology (2009)

Wilson disease (WD) is an autosomal recessive copper overload disorder of the liver and basal ganglia. WD is caused by mutations in the gene encoding ATP7B, a protein localized to the trans-Golgi network that primarily facilitates hepatic copper excretion. Current treatment comprises reduction of circulating copper by zinc supplementation or copper chelation. Despite treatment, a significant number of patients have neurological deterioration. The aim of this study was to investigate the possibility that defects arising from some WD mutations are ameliorated by drug treatment aimed at improvement of protein folding and restoration of protein function. This necessitated systematic characterization of the molecular consequences of distinct ATP7B missense mutations associated with WD. With the exception of p.S1363F, all mutations tested (p.G85V, p.R778L, p.H1069Q, p.C1104F, p.V1262F, p.G1343V, and p.S1363F) resulted in reduced ATP7B protein expression, whereas messenger RNA abundance was unaffected. Retention of mutant ATP7B in the endoplasmic reticulum, increased protein expression, and normalization of localization after culturing cells at 30°C, and homology modeling suggested that these proteins were misfolded. Four distinct mutations exhibited residual copper export capacity, whereas other mutations resulted in complete disruption of copper export by ATP7B. Treatment with pharmacological chaperones 4-phenylbutyrate (4-PBA) and curcumin, a clinically approved compound, partially restored protein expression of most ATP7B mutants. Conclusion: These findings might enable novel treatment strategies in WD by directly enhancing the protein expression of mutant ATP7B with residual copper export activity. (HEPATOLOGY 2009;50:1783–1795.)
BCR-ABL down-regulates the DNA repair protein DNA-PKcs
Authors: Eric Deutsch, Aymeric Dugray, Bassam AbdulKarim, Elisabetta Marangoni, Laurence Maggiorella, Sabine Vaganay, Radia M'Kacher, Setha Douc Rasy, François Eschwege, William Vainchenker, Ali G. Turhan, Jean Bourhis
Journal: Blood (2001)
Does Depression Precede or Follow Executive Dysfunction? Outcomes in Older Primary Care Patients
Authors: Xingjia Cui, Jeffrey M. Lyness, Xin Tu, Deborah A. King, Eric D. Caine
Journal: American Journal of Psychiatry (2007)

The authors sought to test the potentially reciprocal relationships between depression and executive dysfunction in older patients over time.In this prospective 2-year cohort study, the authors enrolled 709 patients age 65 years and older who presented for primary care on selected days and gave informed consent. Of these, 431 and 284 patients completed follow-up interviews at 1 year and 2 years, respectively. The main outcome measures included depression diagnosis, and measures assessing selected components of executive functions: the initiation-perseveration subscale of the Mattis Dementia Rating Scale, Trail Making tests A and B, and D Trails (Trails B time minus Trails A time).No cognitive measure was significantly independently associated with depression diagnosis concurrently or in 1-year lagged outcomes. A diagnosis of depression was independently associated with concurrent poorer Trails B time and with both Trails B and D Trails times in 1-year lagged models. In path analyses testing 2-year competing dynamic models, no baseline executive function measure predicted the score on the Hamilton Depression Rating Scale (HAM-D), but HAM-D score independently predicted poorer Trails B and D Trails times. Overall medical burden also independently predicted both depressive and cognitive outcomes, but cerebrovascular risk factors only predicted Trails B time.Older persons with depression are at risk of subsequent decline in at least some aspects of executive functioning. The study's findings leave open the possibility that either neurobiological or psychosocial factors play prominent roles in the mechanisms underlying the course of geriatric depression.
Transbronchial needle aspirates: how many passes per target site?
Authors: A. H. Diacon, M. M. Schuurmans, J. Theron, K. Brundyn, M. Louw, C. A. Wright, C. T. Bolliger
Journal: European Respiratory Journal (2006)

Transbronchial needle aspiration is a bronchoscopic sampling method for a variety of bronchial and pulmonary lesions. The present study investigated whether and how serial needle passes contribute to the yield of transbronchial needle aspiration at specific target sites. A total of 1,562 needle passes, performed at 374 target sites in 245 patients with neoplastic disease (82%), non-neoplastic disease (15%) or undiagnosed lesions (3%), were prospectively recorded and rated for anatomical location, size, bronchoscopic appearance and underlying disease. Positive aspirates were obtained in 75% of patients and at 68% of target sites. A diagnosis was established with the first, second, third and fourth needle pass at 64, 87, 95 and 98% of targets, respectively. The absolute yield varied strongly with target site features, but the stepwise increment to the maximum yield provided by serial passes was similar across target sites. In conclusion, three transbronchial needle passes per site are appropriate when only a tissue diagnosis is sought and when alternative sites or sampling modalities are available. At least four or five passes should be carried out at lymph node stations critical for the staging of lung cancer.
Activation of Notch Signaling in a Xenograft Model of Brain Metastasis
Authors: Do-Hyun Nam, Hye-Min Jeon, Shiyeon Kim, Mi Hyun Kim, Young-Ju Lee, Min Su Lee, Hyunggee Kim, Kyeung Min Joo, Dong-Sup Lee, Janet E. Price, Sa Ik Bang, Woong-Yang Park
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The potential of metastasis can be predicted from clinical features like tumor size, histologic grade, and gene expression patterns. We examined the whole-genome transcriptomic profile of a xenograft model of breast cancer to understand the characteristics of brain metastasis. Experimental Design: Variants of the MDA-MB-435 cell were established from experimental brain metastases. The LvBr2 variant was isolated from lesions in a mouse injected in the left ventricle of the heart, and these cells were used for two cycles of injection into the internal carotid artery and selection of brain lesions, resulting in the Br4 variant. To characterize the different metastatic variants, we examined the gene expression profile of MDA-MB-435, LvBr2, and Br4 cells using microarrays. Results: We could identify 2,016 differentially expressed genes in Br4 by using the F test. Various metastasis-related genes and a number of genes related to angiogenesis, migration, tumorigenesis, and cell cycle were differentially expressed by the Br4 cells. Notably, the Notch signaling pathway was activated in Br4, with increased Jag2 mRNA, activated Notch intracellular domain, and Notch intracellular domain/CLS promoter-luciferase activity. Br4 cells were more migratory and invasive than MDA-MB-435 cells in collagen and Matrigel Transwell assays, and the migration and invasion of Br4 cells were significantly inhibited by inactivation of Notch signaling using DAPT, a γ-secretase inhibitor, and RNA interference–mediated knockdown of Jagged 2 and Notch1. Conclusions: Taken together, these results suggest that we have isolated variants of a human cancer cell line with enhanced brain metastatic properties, and the activation of Notch signaling might play a crucial role in brain metastasis.
Two-dimensional echocardiographic evaluation of aneurysms of the descending thoracic aorta.
Authors: S Iliceto, G Antonelli, G Biasco, P Rizzon
Journal: Circulation (1982)

To determine the ability of two-dimensional echocardiography (2-D echo) to detect aneurysms and dissections of the descending thoracic aorta (DTA), we studied 15 patients, five with proved DTA dissections (group A) and 10 with proved aneurysms without dissection (group B), using 2-D echo in three recording positions: precordial, suprasternal and a modified apical. The DTA was visualized in 14 of 15 patients (93%); in each patient in group A, an intimal flap was recognized (in two patients only by the apical approach and in one patient by all approaches). The DTA was visualized in nine of 10 patients in group B; in each patient, the internal dimension of the DTA was enlarged (25-43 mm/m2). In one group B patient, aortic dissection was erroneously suspected because spurious echoes were present in the lumen; in another patient, 2-D echo failed to demonstrate a thrombotic stratification in the enlarged lumen. We conclude that 2-D echo using all available approaches appears to be a reliable technique for evaluating dissections and aneurysms of the DTA.
Bronchial asthma: New approach to airways functional diagnostics
Authors: Vitaliy Mishlanov, Andrey Zuev
Journal: European Respiratory Journal (2012)

It's known that bioelectrical impedance value depends on electrical current path length and diameter. The aim of the study was to investigate electrical impedance of airways and lung by new technique of polyfrequent electrical impedance analysis using “BIA-lab” software. 39 asthmatics and 20 healthy people at the age of 19-45 years old were examined. There were 24 females in asthmatic group and 11 ones among healthy people. Of the asthmatic patients 10 had a severe asthma, 15 suffer from moderate and 9 ones were with mild form of disease. All patients were examined with physical methods and spirometry tests performed. The polyfrecuent electrical impedance technique demanded of 0.9% NaCl airsole inhalation for 1-2 minit to load the airways. The results revealed elevated electrical impedance module values on diapasons of frequencies: 20, 98, 1000, 5000, 10000 and 20000 Hz in asthmatic patients.

View this table:

Table 1. The estimation of |Z, OhM| in asthmatic patients by polyfrequent electrical impedance analysis





But we didn't registered angle φ changes. There was a significant correlation between FEV1 and electrical impedance module |Z| of airways (r=-0,57; p=0,032). Conclusion. Polyfrequent electrical impedance analysis, which caracterize the diameter of airways as the main electrical current condacter loaded by 0,9% NaCl airsole, get adiquit essessment of bronchial obstruction in any severety asthmatic patients.
Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy
Authors: Karl Josef Osterziel, Oliver Strohm, Jochen Schuler, Matthias Friedrich, Dankward Hänlein, Roland Willenbrock, Stefan D Anker, Philip A Poole-Wilson, Michael B Ranke, Rainer Dietz
Journal: The Lancet (1998)
Evolution of Caenorhabditis Mitochondrial Genome Pseudogenes and Caenorhabditis briggsae Natural Isolates
Authors: M. J. Raboin, A. F. Timko, D. K. Howe, M. A. Felix, D. R. Denver
Journal: Molecular Biology and Evolution (2009)

Although most metazoan mitochondrial genomes are highly streamlined and encode little noncoding DNA outside of the "AT" region, the accumulation of mitochondrial pseudogenes and other types of noncoding DNA has been observed in a growing number of animal groups. The nematode species Caenorhabditis briggsae harbors two mitochondrial DNA (mtDNA) pseudogenes, named Ψnad5-1 and Ψnad5-2, presumably derived from the nad5 protein-coding gene. Here, we provide an in-depth analysis of mtDNA pseudogene evolution in C. briggsae natural isolates and related Caenorhabditis species. Mapping the observed presence and absence of the pseudogenes onto phylogenies suggests that Ψnad5-1 originated in the ancestor to C. briggsae and its recently discovered outcrossing relative species Caenorhabditis sp. 5 and Caenorhabditis sp. 9. However, Ψnad5-1 was not detected in Caenorhabditis sp. 9 natural isolates, suggesting a lineage-specific loss of this pseudogene in this species. Our results corroborated the previous finding that Ψnad5-2 originated within C. briggsae. The observed pattern of mitochondrial pseudogene gain and loss in Caenorhabditis was inconsistent with predictions of the tandem duplication–random loss model of mitochondrial genome evolution and suggests that intralineage recombination–like mechanisms might play a major role in Caenorhabditis mtDNA evolution. Natural variation was analyzed at the pseudogenes and flanking mtDNA sequences in 141 geographically diverse C. briggsae natural isolates. Although phylogenetic analysis placed the majority of isolates into the three previously established major intraspecific clades of C. briggsae, two new and unexpected haplotypes fell outside of these conventional groupings. Ψnad5-2 copy number variation was observed among C. briggsae isolates collected from the same geographic site. Patterns of nucleotide diversity were analyzed in Ψnad5-1 and Ψnad5-2, and confidence intervals were found to overlap values from synonymous sites in protein-coding genes, consistent with neutral expectations. Our findings provide new insights into the mode and tempo of mitochondrial genome and pseudogene evolution both within and between Caenorhabditis nematode species.
Glucocorticoid resorption and influence on the hypothalamic-pituitary-adrenal axis after intra-articular treatment of the knee in resting and mobile patients
Authors: T Weitoft
Journal: Annals of the Rheumatic Diseases (2005)

Studies have shown that intra-articular glucocorticoid injection treatment for knee synovitis has a better outcome in resting patients than in mobile patients. One reason for this observation might be that rest retards steroid resorption, causing an enhanced local treatment effect.To study drug resorption and the impact on hormone production in the hypothalamic-pituitary-adrenal axis after intra-articular glucocorticoid administration, with and without postinjection rest.Twenty patients with rheumatoid arthritis and knee synovitis were randomised to either 24 hour bed rest or normal activity after intra-articular glucocorticoid treatment with 20 mg triamcinolone hexacetonide (THA). Serum levels of THA, cortisol, and adrenocorticotropic hormone (ACTH) were followed during 2 weeks.Short term and reversible decreases in serum cortisol and ACTH levels (p<0.001) were seen, without any significant differences between resting and mobile patients. The THA levels increased similarly in both groups, with the median serum peak seen after 8 hours.Immobilisation does not appear to retard glucocorticoid resorption after intra-articular administration. Further studies are therefore needed to clarify the mechanism behind the beneficial effects of rest after intra-articular glucocorticoid treatment for knee synovitis.
Clinical and Immunologic Effects of Subcutaneously Administered Interleukin-12 and Interferon Alfa-2b: Phase I Trial of Patients With Metastatic Renal Cell Carcinoma or Malignant Melanoma
Authors: Gheath Alatrash, Thomas E. Hutson, Luis Molto, Amy Richmond, Cheryl Nemec, Tarek Mekhail, Paul Elson, Charles Tannenbaum, Thomas Olencki, James Finke, Ronald M. Bukowski
Journal: Journal of Clinical Oncology (2004)

Purpose Interleukin-12 (IL-12) and interferon alfa-2b (IFN-α-2b) are pleiotropic cytokines with activity in renal cell carcinoma (RCC) and malignant melanoma (MM) as single agents. Preclinical studies suggest concurrent administration may have synergistic antitumor effects. We conducted a phase I trial of concurrent subcutaneous (SC) administration of IL-12 and IFN-α-2b in patients with metastatic RCC or MM to determine toxicity, maximum-tolerated dose, preliminary efficacy, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs). Patients and Methods Cohorts of three to six patients were treated with escalating doses of IL-12 (dose I, 100 ng/kg; dose II, 300 ng/kg; dose III, 500 ng/kg; dose IV, 500 ng/kg SC) given twice weekly and IFN-α-2b (dose I, 1.0 MU/m 2 ; dose II, 1.0 MU/m 2 ; dose III, 1.0 MU/m 2 ; dose IV, 3.0 MU/m 2 SC) three times weekly in 4-week cycles. Effects on gene expression were assessed by reverse transcriptase polymerase chain reaction. Results Twenty-six patients (19 with RCC, seven with MM) were accrued at dose levels I (n = 3), II (n = 3), III (n = 13), and IV (n = 7). Dose-limiting toxicity included grades 3 and 4 hepatotoxicity and neutropenia/leukopenia. Patients received a median of three cycles of treatment. Two patients with RCC and one patient with MM had partial responses. Median survival was 13.8 months. Reverse transcriptase polymerase chain reaction on PBMCs revealed induction of IP-10, Mig, B7.1 (CD80), interleukin-5, and interferon gamma in selected patients. Conclusion Concurrent SC administration of IL-12 and IFN-α-2b is possible at the dose levels utilized. Recommended doses for phase II trials are 500 ng/kg IL-12 and 1.0 MU/m 2 IFN-α-2b. Consistent induction of IP-10 and Mig, as well as variable induction of B7.1, interleukin-5, and interferon gamma expression was noted in PBMCs.