tbuckley/cabot-search huggingface dataset:
CD1-mediated γ/δ T Cell Maturation of Dendritic Cells
Authors: David S. Leslie, Michael S. Vincent, Franca M. Spada, Hiranmoy Das, Masahiko Sugita, Craig T. Morita, Michael B. Brenner
Journal: The Journal of Experimental Medicine (2002)

Immature myeloid dendritic cells (DCs) express only low levels of major histocompatibility complex (MHC) class II but express high levels of CD1 a, b, and c antigen-presenting molecules at the cell surface. As Vδ1+ γ/δ T cells are the main tissue subset of γ/δ T cells and they are known to recognize CD1c in the absence of specific foreign antigen recognition, we examined the possible interaction of these T cells with immature DCs. We show that CD1-restricted γ/δ T cells can mediate the maturation of DCs. DC maturation required cell–cell contact and could be blocked by antibodies against CD1c. The maturation process was partially mediated by tumor necrosis factor α. Importantly, immature DCs matured in the presence of lipopolysaccharide and CD1-restricted γ/δ T cells produced bioactive interleukin-12p70. In addition, these DCs were able to efficiently present peptide antigens to naive CD4+ T cells. CD1-restricted γ/δ T cell recognition of immature DCs provides the human immune system with the capacity to rapidly generate a pool of mature DCs early during microbial invasion. This may be an important source of critical host signals for T helper type 1 polarization of antigen-specific naive T cells and the subsequent adaptive immune response.
Autonomic Nervous System and Benign Essential Hypertension in Man
Authors: JEAN-LOUIS CUCHE, OTTO KUCHEL, ANDRÉ BARBEAU, YVES LANGLOIS, ROGER BOUCHER, JACQUES GENEST
Journal: Circulation Research (1974)

The effect of upright posture as a physiological stimulus of the adrenergic nervous system was studied in 56 subjects with benign essential hypertension. The subjects received a controlled-sodium diet. Blood pressure, heart rate, catecholamines, plasma renin activity, and urinary creatinine, sodium, and potassium excretion were measured in the recumbent and upright positions. We found an alteration in the blood pressure response in subjects with benign essential hypertension; the postural increase in the mean blood pressure in normotensive subjects (3.18 ± 1.35 mm Hg) progressively disappeared and was replaced by a postural decrease in subjects with more severe stable hypertension (-6.71 ± 2.42 mm Hg). The hypertensive subjects also lacked the usual increase in urinary excretion of norepinephrine. A significant increase in plasma renin activity associated with a significant decrease in plasma norepinephrine occurred in subjects with labile hypertension with postural tachycardia. Finally, we found a highly significant correlation between the excretion of sodium and potassium in the recumbent position and the retention of both ions in the upright position.
Design of a pH-Sensitive Polymeric Carrier for Drug Release and Its Application in Cancer Therapy
Authors: Haruhiko Kamada, Yasuo Tsutsumi, Yasuo Yoshioka, Yoko Yamamoto, Hiroshi Kodaira, Shin-ichi Tsunoda, Takayuki Okamoto, Yohei Mukai, Hiroko Shibata, Shinsaku Nakagawa, Tadanori Mayumi
Journal: Clinical Cancer Research (2004)

Abstract Purpose: In this study, to optimize the polymeric drug delivery system for cancer chemotherapy, we developed a new pH-sensitive polymeric carrier, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) [PVD], that could gradually release native form of drugs with full activity, from the conjugates in response to changes in pH. We examined the usefulness of PVD as a polymeric drug carrier. Experimental Design: PVD was radically synthesized with vinylpyrrolidone and 2,3-dimethylmaleic anhydride, which is known to be a pH-reversible amino-protecting reagent. Conjugates between PVD and other drugs, such as Adriamycin (ADR), were prepared under the slightly basic conditions (pH 8.5). The drug-release pattern and the antitumor activity of PVD were examined. Results: At pH 8.5, the release of the drugs from the conjugate was not observed. In contrast, PVD could release fully active drugs in the native form in response to the change in pH near neutrality, and gradually released drugs at neutral pH (7.0) and slightly acidic pH (6.0). The drug-release pattern in serum was almost similar to that observed during these physiological conditions. The PVD-conjugated ADR showed superior antitumor activity against sarcoma-180 solid tumor in mice, and it had less toxic side effects than free ADR. This enhancement in the antitumor therapeutic window may be due to not only the improvement of plasma half-lives and tumor accumulation of ADR, but also its controlled and sustained release from the conjugates in vivo. Conclusions: These results indicate that PVD is an effective polymeric carrier for optimizing cancer therapy.
<b> <i>In Vivo</i> </b> Targeting of Underglycosylated MUC-1 Tumor Antigen Using a Multimodal Imaging Probe
Authors: Anna Moore, Zdravka Medarova, Andreas Potthast, Guangping Dai
Journal: Cancer Research (2004)

Abstract One of the most difficult challenges of oncology is to improve methods for early tumor detection, which is crucial for the success of cancer therapy and greatly improves the survival rate. Underglycosylated mucin-1 antigen (uMUC-1) is one of the early hallmarks of tumorigenesis and is overexpressed and underglycosylated on almost all human epithelial cell adenocarcinomas as well as in nonepithelial cancer cell lines, as well as in hematological malignancies such as multiple myeloma, and some B-cell non-Hodgkin lymphomas. In this study, we designed, synthesized, and tested a novel multimodal imaging probe specifically recognizing in vivo uMUC-1 antigen in an animal model of human cancer. Furthermore, in vivo magnetic resonance- and near-infrared-imaging experiments on tumor-bearing animals showed specific accumulation of the probe in uMUC-1-positive tumors and virtually no signal in control tumors. We expect that this probe has a potential to greatly aid in screening prospective patients for early cancer detection and in monitoring the efficacy of drug therapy.
Testing for Rewards: A Pilot Study to Improve Type 1 Diabetes Management in Adolescents
Authors: Nancy M. Petry, Eda Cengiz, Julie A. Wagner, Kate Weyman, Eileen Tichy, William V. Tamborlane
Journal: Diabetes Care (2015)

To evaluate the effectiveness of monetary reinforcement to increase the frequency of self-monitoring blood glucose (SMBG).Ten adolescents with poorly controlled diabetes enrolled in a 12-week program in which they earned monetary reinforcers based on SMBG frequency ($0.10 per test, with bonuses for ≥4 tests per day, and $251.40 maximum).SMBG increased from 1.8 ± 1.0 to 4.9 ± 1.0 tests per day (P < 0.001) with 90% completing four or more tests per day. Mean A1C fell from 9.3 ± 0.9% to 8.4 ± 1.5% (P = 0.05). Adolescents and parents reported high satisfaction with procedures.Reinforcing adolescents for SMBG may increase testing and improve A1C.
Combination Immunotherapy of B-Cell Non-Hodgkin’s Lymphoma with Rituximab and Interleukin-2
Authors: Charles F. Eisenbeis, Andrew Grainger, Beth Fischer, Robert A. Baiocchi, Lester Carrodeguas, Sameek Roychowdhury, Lei Chen, Amy L. Banks, Thomas Davis, Donn Young, Nicole Kelbick, Julie Stephens, John C. Byrd, Michael R. Grever, Michael A. Caligiuri, Pierluigi Porcu
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immunodeficient (SCID) mice engrafted with peripheral blood leukocytes (PBLs) from Epstein Barr virus-seropositive donors develop human B-cell non-Hodgkin’s lymphomas [B-NHLs (hu-PBL-SCID mouse model)]. We used this hu-PBL-SCID mouse model to study the synergism between interleukin (IL)-2 and rituximab. We also conducted a phase I trial of IL-2 and rituximab in relapsed B-NHL to study whether expansion of natural killer (NK) cells and enhanced cellular cytotoxicity could be safely accomplished in vivo. Experimental Design: Hu-PBL-SCID mice were treated with various schedules of rituximab and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m2 weekly × 4) followed by daily low-dose IL-2 (1 MIU/m2/day × 4 weeks) with pulses of intermediate-dose IL-2 (3–15 MIU/m2). Toxicity, NK cell numbers, and cellular cytotoxicity were measured. Results: In the hu-PBL-SCID mouse, the combination of rituximab and IL-2 showed greater activity against B-NHL than either agent alone. Treatment was most effective when IL-2 was given before rituximab. Twelve patients with heavily pretreated B-NHL entered the phase I trial. Toxicity was manageable, and responses were observed. NK cell expansion and enhanced cellular cytotoxicity against a B-cell lymphoma target were observed but did not correlate with response. Conclusions: The combination of IL-2 and rituximab is synergistic against B-NHL in the hu-PBL-SCID model. In the phase I trial, a sequential combination of rituximab and IL-2 was well tolerated and achieved biological end points. Responses were observed.
Schistosoma mansoni infection in eosinophil lineage–ablated mice
Authors: Jonathan M. Swartz, Kimberly D. Dyer, Allen W. Cheever, Thirumalai Ramalingam, Lesley Pesnicak, Joseph B. Domachowske, James J. Lee, Nancy A. Lee, Paul S. Foster, Thomas A. Wynn, Helene F. Rosenberg
Journal: Blood (2006)
Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin
Authors: Sarit Assouline, Biljana Culjkovic, Eftihia Cocolakis, Caroline Rousseau, Nathalie Beslu, Abdellatif Amri, Stephen Caplan, Brian Leber, Denis-Claude Roy, Wilson H. Miller, Katherine L. B. Borden
Journal: Blood (2009)
FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling
Authors: Rudolf Zechner, Robert Zimmermann, Thomas O. Eichmann, Sepp D. Kohlwein, Guenter Haemmerle, Achim Lass, Frank Madeo
Journal: Cell Metabolism (2012)

Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. New findings that lipolytic products and intermediates participate in cellular signaling processes and that "lipolytic signaling" is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.
<i>CDK4</i> Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma
Authors: Mary E. Olanich, Wenyue Sun, Stephen M. Hewitt, Zied Abdullaev, Svetlana D. Pack, Frederic G. Barr
Journal: Clinical Cancer Research (2015)

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3- or PAX7-FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13-q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS.We examined the biologic consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts.Knockdown of CDK4 abrogated proliferation and transformation of 12q13-14-amplified and nonamplified fusion-positive RMS cells via G1-phase cell-cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell-cycle distribution, proliferation, or transformation were not observed in RMS cells overexpressing CDK4. Treatment with LEE011 phenocopied CDK4 knockdown, decreasing viability, RB phosphorylation, and E2F-responsive gene expression and inducing G1-phase cell-cycle arrest. Although all fusion-positive cell lines showed sensitivity to CDK4/6 inhibition, there was diminished sensitivity associated with CDK4 amplification and overexpression. This variable responsiveness to LEE011 was recapitulated in xenograft models of CDK4-amplified and nonamplified fusion-positive RMS.Our data demonstrate that CDK4 is necessary but overexpression is not sufficient for RB-E2F-mediated G1-phase cell-cycle progression, proliferation, and transformation in fusion-positive RMS. Our studies indicate that LEE011 is active in the setting of fusion-positive RMS and suggest that low CDK4-expressing fusion-positive tumors may be particularly susceptible to CDK4/6 inhibition.
The balance of expression of PTPN22 splice forms is significantly different in rheumatoid arthritis patients compared with controls
Authors: Marcus Ronninger, Yongjing Guo, Klementy Shchetynsky, Andrew Hill, Mohsen Khademi, Tomas Olsson, Padmalatha S Reddy, Maria Seddighzadeh, James D Clark, Lih-Ling Lin, Margot O'Toole, Leonid Padyukov
Journal: Genome Medicine (2012)

The R620W variant in protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with rheumatoid arthritis (RA). The PTPN22 gene has alternatively spliced transcripts and at least two of the splice forms have been confirmed to encode different PTPN22 (LYP) proteins, but detailed information regarding expression of these is lacking, especially with regard to autoimmune diseases.We have investigated the mRNA expression of known PTPN22 splice forms with TaqMan real-time PCR in relation to ZNF592 as an endogenous reference in peripheral blood cells from three independent cohorts with RA patients (n = 139) and controls (n = 111) of Caucasian origin. Polymorphisms in the PTPN22 locus (25 SNPs) and phenotypic data (gender, disease activity, ACPA and RF status) were used for analysis. Additionally, we addressed possible effects of methotrexate treatment on PTPN22 expression.We found consistent differences in the expression of the PTPN22 splice forms in unstimulated peripheral blood mononuclear cells between RA patients and normal controls. This difference was more pronounced when comparing the ratio of splice forms and was not affected by methotrexate treatment.Our data show that RA patients and healthy controls have a shift in balance of expression of splice forms derived from the PTPN22 gene. This balance seems not to be caused by treatment and may be of importance during immune response due to great structural differences in the encoded PTPN22 proteins.
Kidney Tumor Biomarkers Revealed by Simultaneous Multiple Matrix Metabolomics Analysis
Authors: Sheila Ganti, Sandra L. Taylor, Omran Abu Aboud, Joy Yang, Christopher Evans, Michael V. Osier, Danny C. Alexander, Kyoungmi Kim, Robert H. Weiss
Journal: Cancer Research (2012)

Abstract Metabolomics is increasingly being used in cancer biology for biomarker discovery and identification of potential novel therapeutic targets. However, a systematic metabolomics study of multiple biofluids to determine their interrelationships and to describe their use as tumor proxies is lacking. Using a mouse xenograft model of kidney cancer, characterized by subcapsular implantation of Caki-1 clear cell human kidney cancer cells, we examined tissue, serum, and urine all obtained simultaneously at baseline (urine) and at, or close to, animal sacrifice (urine, tissue, and plasma). Uniform metabolomics analysis of all three “matrices” was accomplished using gas chromatography– and liquid chromatography–mass spectrometry. Of all the metabolites identified (267 in tissue, 246 in serum, and 267 in urine), 89 were detected in all 3 matrices, and the majority was altered in the same direction. Heat maps of individual metabolites showed that alterations in serum were more closely related to tissue than was urine. Two metabolites, cinnamoylglycine and nicotinamide, were concordantly and significantly (when corrected for multiple testing) altered in tissue and serum, and cysteine–glutathione disulfide showed the highest change (232.4-fold in tissue) of any metabolite. On the basis of these and other considerations, three pathways were chosen for biologic validation of the metabolomic data, resulting in potential therapeutic target identification. These data show that serum metabolomics analysis is a more accurate proxy for tissue changes than urine and that tryptophan degradation (yielding anti-inflammatory metabolites) is highly represented in renal cell carcinoma, and support the concept that PPAR-α antagonism may be a potential therapeutic approach for this disease. Cancer Res; 72(14); 3471–9. ©2012 AACR.
Image-Guided Interventions: Technology Review and Clinical Applications
Authors: Kevin Cleary, Terry M. Peters
Journal: Annual Review of Biomedical Engineering (2010)

Image-guided interventions are medical procedures that use computer-based systems to provide virtual image overlays to help the physician precisely visualize and target the surgical site. This field has been greatly expanded by the advances in medical imaging and computing power over the past 20 years. This review begins with a historical overview and then describes the component technologies of tracking, registration, visualization, and software. Clinical applications in neurosurgery, orthopedics, and the cardiac and thoracoabdominal areas are discussed, together with a description of an evolving technology named Natural Orifice Transluminal Endoscopic Surgery (NOTES). As the trend toward minimally invasive procedures continues, image-guided interventions will play an important role in enabling new procedures, while improving the accuracy and success of existing approaches. Despite this promise, the role of image-guided systems must be validated by clinical trials facilitated by partnerships between scientists and physicians if this field is to reach its full potential.
Costs of ankylosing spondylitis in three European countries: the patient's perspective
Authors: A Boonen
Journal: Annals of the Rheumatic Diseases (2003)

To assess a patient's out of pocket costs, income loss, time consumption, and quality of life (QoL) due to ankylosing spondylitis (AS) in three European countries and to assess variables predicting these outcomes.216 patients with AS from the Netherlands, France, and Belgium participated in a two year study. Health resource use, days absent from work, time lost, and quality of life (EuroQol) were assessed by bimonthly questionnaires. AS related healthcare and non-healthcare expenditure and income loss were calculated taking into account country-specific regulations. Predictors of costs, time consumption, and QoL were analysed by Cox's regression.209 patients provided data for cost analysis. Average annual healthcare and non-healthcare expenditure was euro;431 per patient and average annual income loss was euro;1371 per patient. Healthcare costs were highest for Belgian and lowest for French patients, while non-healthcare costs were highest for Dutch patients. A patient's total costs were associated with higher age and worse physical function. On average, patients with AS needed 75 minutes additional time a day because of AS. Worse physical function and higher disease activity predicted time consumption. After adjusting for baseline confounders, QoL was worse in Belgian and French than in Dutch patients. Peripheral arthritis, worse physical function, higher disease activity, and loss of income contributed to worse QoL.AS is time consuming and associated with substantial out of pocket costs. Belgian patients incur the highest healthcare payments. Poor physical function increases patient's costs and time consumption. Loss of income is associated with lower QoL.
Prognostic Role of <i>PIK3CA</i> Mutation in Colorectal Cancer: Cohort Study and Literature Review
Authors: Xiaoyun Liao, Teppei Morikawa, Paul Lochhead, Yu Imamura, Aya Kuchiba, Mai Yamauchi, Katsuhiko Nosho, Zhi Rong Qian, Reiko Nishihara, Jeffrey A. Meyerhardt, Charles S. Fuchs, Shuji Ogino
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Mutations in PIK3CA [the gene encoding the p110α catalytic subunit of phosphatidylinositide-3-kinase (PI3K)] play an important role in colorectal carcinogenesis. Experimental evidence suggests that PIK3CA exon 9 and exon 20 mutations trigger different biologic effects, and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects. Thus, we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer, and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior. Experimental Design: We sequenced PIK3CA by pyrosequencing in 1,170 rectal and colon cancers in two prospective cohort studies, and found 189 (16%) PIK3CA mutated tumors. Mortality HR according to PIK3CA status was computed using Cox proportional hazards model, adjusting for clinical and molecular features, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and BRAF and KRAS mutations. Results: Compared with PIK3CA wild-type cases, patients with concomitant PIK3CA mutations in exons 9 and 20 experienced significantly worse cancer-specific survival [log-rank P = 0.031; multivariate HR = 3.51; 95% confidence interval (CI): 1.28–9.62] and overall survival (log-rank P = 0.0008; multivariate HR = 2.68; 95% CI: 1.24–5.77). PIK3CA mutation in either exon 9 or 20 alone was not significantly associated with patient survival. No significant interaction of PIK3CA mutation with BRAF or KRAS mutation was observed in survival analysis. Conclusion: Coexistence of PIK3CA (the PI3K p110α subunit) exon 9 and 20 mutations, but not PIK3CA mutation in either exon 9 or 20 alone, is associated with poor prognosis of colorectal cancer patients. Clin Cancer Res; 18(8); 2257–68. ©2012 AACR.
Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus.
Authors: D E Kelley, J A Simoneau
Journal: Journal of Clinical Investigation (1994)

This study was undertaken to assess utilization of FFA by skeletal muscle in patients with non-insulin-dependent diabetes mellitus (NIDDM). 11 NIDDM and 9 nondiabetic subjects were studied using leg balance methods to measure the fractional extraction of [3H]oleate. Limb indirect calorimetry was used to estimate RQ. Percutaneous muscle biopsy samples of vastus lateralis were analyzed for muscle fiber type distribution, capillary density, and metabolic potential as reflected by measurements of the activity of seven muscle enzyme markers of glycolytic and aerobic-oxidative pathways. During postabsorptive conditions, fractional extraction of oleate across the leg was lower in NIDDM subjects (0.31 +/- 0.08 vs. 0.43 +/- 0.10, P < 0.01), and there was reduced oleate uptake across the leg (66 +/- 8 vs. 82 +/- 13 nmol/min, P < 0.01). Postabsorptive leg RQ was increased in NIDDM (0.85 +/- 0.03 vs. 0.77 +/- 0.02, P < 0.01), and rates of lipid oxidation by skeletal muscle were lower while glucose oxidation was increased (P < 0.05). In subjects with NIDDM, proportions of type I, IIa, and IIb fibers were 37 +/- 2, 37 +/- 6, and 26 +/- 5%, respectively, which did not differ from nondiabetics; and capillary density, glycolytic, and aerobic-oxidative potentials were similar. During 6 h after ingestion of a mixed meal, arterial FFA remained greater in NIDDM subjects. Therefore, despite persistent reduced fractional extraction of oleate across the leg in NIDDM (0.34 +/- 0.04 vs. 0.38 +/- 0.03, P < 0.05), rates of oleate uptake across the leg were greater in NIDDM (54 +/- 7 vs. 45 +/- 8 nmol/min, P < 0.01). In summary, during postabsorptive conditions there is reduced utilization of FFA by muscle, while during postprandial conditions there is impaired suppression of FFA uptake across the leg in NIDDM. During both fasting and postprandial conditions, NIDDM subjects have reduced rates of lipid oxidation by muscle.
Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study
Authors: Bengt Winblad, Lena Kilander, Sture Eriksson, Lennart Minthon, Stellan Båtsman, Anna-Lena Wetterholm, Catarina Jansson-Blixt, Anders Haglund
Journal: The Lancet (2006)