tbuckley/cabot-search huggingface dataset:
Reversal of nephrotic syndrome due to reactive amyloidosis (AA‐type) after excision of localized Castleman's disease
Authors: Vittorio Perfetti, Vittorio Bellotti, Anna Maggi, Eloisa Arbustini, Fabrizio De Benedetti, Marco Paulli, Maria Gabriella Marinone, Giampaolo Merlini
Journal: American Journal of Hematology (1994)

Abstract The patient (TAL), a chronic asymptomatic HBV carrier with HBsAg‐anti‐HBsAg circulating immune complexes, was admitted to our hospital because of a nephrotic syndrome due to renal amyloidosis. There was no family history of hereditary amyloidosis. Recurrent arthralgias, asthenia, and weight loss were the prominent clinical features. Laboratory test results showing that severe chronic inflammatory activity had been present for 6 years. Interleukin‐6 (IL‐6) serum concentration was 10 times normal and C‐reactive protein was 1.9 mg/ml. A complex immunological picture was also present (immune complex formation, exuberant B‐cell reactivity, and decrease in the number of CD4 T cells). A localized form of Castleman's disease (CD) (plasma‐cell type) was diagnosed by surgical excision of a giant axillary lymph node. AA amyloid was present in the blood vessels. Within 60 days after excision of the mass, the systemic symptoms subsided, laboratory signs of inflammatory activity disappeared and IL‐6 serum concentration returned to normal, thus establishing a causal relationship between the localized Castleman's disease, elevated IL‐6 concentration and the chronic inflammation responsible for AA amyloidosis. At 10 months of follow‐up, the nephrotic syndrome has reversed, kidney function has slowly ameliorated, and the patient has gained 12 kg. Abdominal fat aspirates drawn to search for amyloid, positive before surgery, were subsequently negative. The latter finding, and the remission of the nephrotic syndrome, provided strong evidence for regression of the amyloid deposits. However, the HBsAg‐anti‐HBsAg immune complexes and depression of T‐helper cell activity persist. This immunological derangement is therefore not a consequence of CD. Chronic stimulation of the immune system due to the patient's inability to eliminate HBV, in the contest of perturbed immunity, may have favored the genesis of the lymphadenopathy. © 1994 Wiley‐Liss, Inc.
Combination radioimmunotherapy with adoptive NK transfer targets cancer stem cells in canine models of bone and soft tissue sarcoma
Authors: Robert Canter, Steven K Grossenbacher, Jiwon Sarah Park, Jaime Modiano, Erik Ames, Stephanie Mac, Arta M Monjazeb, Michael Kent, William Culp, Mingyi Chen, William Murphy
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts We have previously shown that NK cells preferentially target cancer stem cells (CSCs) in diverse human solid malignancies and that radiotherapy (RT) enhances NK targeting of CSCs in an NKG2D-dependent manner. We hypothesized that dog PBMC-derived NK cells could be similarly
Inhibition of Progression and Stabilization of Plaques by Postnatal Interferon-γ Function Blocking in ApoE-Knockout Mice
Authors: Mitsuhisa Koga, Hisashi Kai, Hideo Yasukawa, Tomoka Yamamoto, Yumiko Kawai, Seiya Kato, Ken Kusaba, Mamiko Kai, Kensuke Egashira, Yasufumi Kataoka, Tsutomu Imaizumi
Journal: Circulation Research (2007)

A role of interferon-γ is suggested in early development of atherosclerosis. However, the role of interferon-γ in progression and destabilization of advanced atherosclerotic plaques remains unknown. Thus, the aim of this study was to determine whether postnatal inhibition of interferon-γ signaling could inhibit progression of atherosclerotic plaques and stabilize the lipid- and macrophage-rich advanced plaques. Atherosclerotic plaques were induced in ApoE-knockout (KO) mice by feeding high-fat diet from 8 weeks old (w). Interferon-γ function was postnatally inhibited by repeated gene transfers of a soluble mutant of interferon-γ receptors (sIFNγR), an interferon-γ inhibitory protein, into the thigh muscle every 2 weeks. When sIFNγR treatment was started at 12 w (atherosclerotic stage), sIFNγR not only prevented plaque progression but also stabilized advanced plaques at 16 w: sIFNγR decreased accumulations of the lipid and macrophages and increased fibrotic area with more smooth muscle cells. Moreover, sIFNγR downregulated expressions of proinflammatory cytokines, chemokines, adhesion molecules, and matrix metalloproteinases but upregulated procollagen type I. sIFNγR did not affect serum cholesterol levels. In conclusion, postnatal blocking of interferon-γ function by sIFNγR treatment would be a new strategy to inhibit plaque progression and to stabilize advanced plaques through the antiinflammatory effects.
Functional Evidence for an Inward Rectifier Potassium Current in Rat Renal Afferent Arterioles
Authors: Lisa Chilton, Rodger Loutzenhiser
Journal: Circulation Research (2001)

Abstract —An inward rectifier potassium current, Kir, has been identified in cerebral and coronary resistance vessels, where it is considered to be an important determinant of resting membrane potential (RMP) and to play a role in blood flow regulation. We investigated the functional role of Kir in the renal afferent arteriole using the in vitro–perfused hydronephrotic rat kidney. Increasing external KCl from 5 to 15 mmol/L induced afferent arteriolar vasodilation. This response was inhibited by 10 to 100 μmol/L Ba 2+ , concentrations selective for blockade of Kir, and by chloroethylclonidine (100 μmol/L) but was not blocked by glibenclamide (10 μmol/L) or ouabain (3 mmol/L). Reducing external KCl from 5 to 1.5 mmol/L to enhance rectification of Kir caused vasoconstriction at low renal arterial pressure (40 mm Hg) and vasodilation during myogenic vasoconstriction (120 mm Hg), suggesting that this current dominates RMP at low perfusion pressures. When administered to kidneys perfused at 40 mm Hg renal arterial pressure, 30 μmol/L Ba 2+ elicited afferent arteriolar depolarization, reducing RMP from −47±2 to −34±2 mV (n=10, P &lt;0.0001), and vasoconstriction, reducing diameters from 14.5±1 to 10.9±0.8 μm (n=10, P =0.0016). Although Ba 2+ reduced resting diameter, blockade of Kir did not prevent myogenic signaling in this vessel. Our findings thus demonstrate the presence of Kir in rat renal afferent arterioles and suggest that this current is an important determinant of RMP in situ.
The impact of Cysteine-Rich Intestinal Protein 1 (CRIP1) in human breast cancer
Authors: Natalie Ludyga, Sonja Englert, Kerstin Pflieger, Sandra Rauser, Herbert Braselmann, Axel Walch, Gert Auer, Heinz Höfler, Michaela Aubele
Journal: Molecular Cancer (2013)

Abstract Background CRIP1 (cysteine-rich intestinal protein 1) has been found in several tumor types, its prognostic impact and its role in cellular processes, particularly in breast cancer, are still unclear. Methods To elucidate the prognostic impact of CRIP1, we analyzed tissues from 113 primary invasive ductal breast carcinomas using immunohistochemistry. For the functional characterization of CRIP1, its endogenous expression was transiently downregulated in T47D and BT474 breast cancer cells and the effects analyzed by immunoblotting, WST-1 proliferation assay and invasion assay. Results We found a significant correlation between CRIP1 and HER2 (human epidermal growth factor receptor 2) expression levels ( p = 0.016) in tumor tissues. In Kaplan Meier analyses, CRIP1 expression was significantly associated with the distant metastases-free survival of patients, revealing a better prognosis for high CRIP1 expression ( p = 0.039). Moreover, in multivariate survival analyses, the expression of CRIP1 was an independent negative prognostic factor, along with the positive prognosticators nodal status and tumor size ( p = 0.029). CRIP1 knockdown in the T47D and BT474 breast cancer cell lines led to the increased phosphorylation of MAPK and Akt, to the reduced phosphorylation of cdc2, and to a significantly elevated cell proliferation in vitro ( p &lt; 0.001). These results indicate that reduced CRIP1 levels may increase cell proliferation and activate cell growth. In addition, CRIP1 knockdown increased cell invasion in vitro . Conclusions Because the lack of CRIP1 expression in breast cancer tissue is significantly associated with a worse prognosis for patients and low endogenous CRIP1 levels in vitro increased the malignant potential of breast cancer cells, we hypothesize that CRIP1 may act as a tumor suppressor in proliferation and invasion processes. Therefore, CRIP1 may be an independent prognostic marker with significant predictive power for use in breast cancer therapy.
Design and Characterization of a Multifunctional pH‐Triggered Peptide C8 for Selective Anticancer Activity
Authors: Sheng Lu, W. F. Drew Bennett, Yong Ding, Lei Zhang, Helen Y. Fan, Danyang Zhao, Tao Zheng, Ping‐Kai Ouyang, Jason Li, Yan Wu, Wen Xu, Dafeng Chu, Yongfang Yuan, Heiko Heerklotz, Mikko Karttunen, P. Chen
Journal: Advanced Healthcare Materials (2015)

Most drug delivery systems have been developed for efficient delivery to tumor sites via targeting and on‐demand strategies, but the carriers rarely execute synergistic therapeutic actions. In this work, C8, a cationic, pH‐triggered anticancer peptide, is developed by incorporating histidine‐mediated pH‐sensitivity, amphipathic helix, and amino acid pairing self‐assembly design. We designed C8 to function as a pH‐responsive nanostructure whose cytotoxicity can be switched on and off by its self‐assembly: Noncytotoxic β‐sheet fibers at high pH with neutral histidines, and positively charged monomers with membrane lytic activity at low pH. The selective activity of C8, tested for three different cancer cell lines and two noncancerous cell lines, is shown. Based on liposome leakage assays and multiscale computer simulations, its physical mechanisms of pore‐forming action and selectivity are proposed, which originate from differences in the lipid composition of the cellular membrane and changes in hydrogen bonding. C8 is then investigated for its potential as a drug carrier. C8 forms a nanocomplex with ellipticine, a nonselective model anticancer drug. It selectively targets cancer cells in a pH‐responsive manner, demonstrating enhanced efficacy and selectivity. This study provides a novel powerful strategy for the design and development of multifunctional self‐assembling peptides for therapeutic and drug delivery applications.
Association of Circulating Tumor Cells with Serum Tumor-Related Methylated DNA in Peripheral Blood of Melanoma Patients
Authors: Kazuo Koyanagi, Takuji Mori, Steven J. O'Day, Steve R. Martinez, He-Jing Wang, Dave S.B. Hoon
Journal: Cancer Research (2006)

Abstract Although previous studies have separately shown the utility of circulating tumor cells (CTC) or cell-free tumor-related DNA in blood of cancer patients, there has been no investigation of their association and/or the prognostic value of combining these assessments. To date, the true source of tumor-related DNA in serum remains unknown. We hypothesized that CTC is a possible origin of serum tumor-related methylated DNA and their combination can predict disease outcome. To test this hypothesis, we obtained matched pairs of peripheral blood lymphocytes and serum specimens simultaneously from 50 American Joint Committee on Cancer stage IV melanoma patients before administration of biochemotherapy. Peripheral blood leukocytes were analyzed for three mRNA markers of CTC: MART-1, GalNAc-T, and MAGE-A3. Sera were analyzed for two methylated DNA markers: RASSF1A and RAR-β2. CTC were detected in 13 of 15 (86%) patients with serum tumor-related methylated DNA and only in 13 of 35 (37%) patients without methylated DNA (P = 0.001). The number of CTC markers detected significantly correlated with methylated DNA (P = 0.008). CTC and methylated DNA were significantly correlated with biochemotherapy-treated patients' outcome. Patients with both CTC and methylated DNA showed significantly poorer response to biochemotherapy (P = 0.02) and worse time to progression and overall survival (P = 0.009 and 0.02, respectively). The correlation between CTC and serum tumor-related methylated DNA and the significant effect of this correlation on disease outcome indicate that a composite molecular assessment in blood may be a useful determinant of disease status and efficacy of systemic therapy for melanoma. (Cancer Res 2006; 66(12): 6111-7)
Transcription Factor NFATc2 Controls the Emergence of Colon Cancer Associated with IL-6–Dependent Colitis
Authors: Katharina Gerlach, Carolin Daniel, Hans A. Lehr, Alexei Nikolaev, Thomas Gerlach, Raja Atreya, Stefan Rose-John, Markus F. Neurath, Benno Weigmann
Journal: Cancer Research (2012)

Abstract NFAT transcription factors control T-cell activation and function. Specifically, the transcription factor NFATc2 affects the regulation of cell differentiation and growth and plays a critical role in the development of colonic inflammation. Here, we used an experimental model of colitis-associated colorectal carcinoma to investigate the contribution of NFATc2 to the promotion of colonic tumors. Compared with wild-type animals that readily presented with multiple colon tumors, NFATc2-deficient mice were protected from tumor development. This observed decrease in colonic tumor progression was associated with reduced endoscopic inflammation, increased apoptosis of lamina propria T lymphocytes, and significantly reduced levels of the critical proinflammatory cytokines interleukin (IL)-21 and IL-6. Administration of hyper IL-6 abrogated protection from tumor progression in NFATc2-knockout mice and restored tumor incidence to control levels. Taken together, our findings highlight a pivotal role for NFATc2 in the establishment of inflammation-associated colorectal tumors mediated by control of IL-6 expression. Cancer Res; 72(17); 4340–50. ©2012 AACR.
Preventive use of the co-administration of immunostimulatory DNA sequences (ISS-ODN) with olive pollen proteins in a mouse model of allergic asthma
Authors: L. Conejero, Y. Higaki, M.J. Fernandez-Bohorquez, I. Varela-Nieto, M.L. Baeza, J.M. Zubeldia
Journal: Journal of Allergy and Clinical Immunology (2005)
Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways
Authors: Malcolm Campbell, William E. Allen, Carol Sawyer, Bart Vanhaesebroeck, Elisabeth R. Trimble
Journal: Circulation Research (2004)

Atheroma formation involves the movement of vascular smooth muscle cells (VSMC) into the subendothelial space. The aim of this study was to determine the involvement of PI3K and MAPK pathways and the importance of cross-talk between these pathways, in glucose-potentiated VSMC chemotaxis to serum factors. VSMC chemotaxis occurred in a serum gradient in 25 mmol/L glucose (but not in 5 mmol/L glucose) in association with increased phosphorylation (activation) of Akt and ERK1/2 in PI3K and MAPK pathways, respectively. Inhibitors of these pathways blocked chemotaxis, as did an mTOR inhibitor. VSMC expressed all class IA PI3K isoforms, but microinjection experiments demonstrated that only the p110β isoform was involved in chemotaxis. ERK1/2 phosphorylation was reduced not only by MAPK pathway inhibitors but also by PI3K and mTOR inhibitors; when PI3K was inhibited, ERK phosphorylation could be induced by microinjected activated Akt, indicating important cross-talk between the PI3K and ERK1/2 pathways. Glucose-potentiated phosphorylation of molecules in the p38 and JNK MAPK pathways inhibited these pathways but did not affect chemotaxis. The statin, mevinolin, blocked chemotaxis through its effects on the MAPK pathway. Mevinolin-inhibited chemotaxis was restored by farnesylpyrophosphate but not by geranylgeranylpyrophosphate; in the absence of mevinolin, inhibition of farnesyltransferase reduced ERK phosphorylation and blocked chemotaxis, indicating a role for the Ras family of GTPases (MAPK pathway) under these conditions. In conclusion, glucose sensitizes VSMC to serum, inducing chemotaxis via pathways involving p110β-PI3K, Akt, mTOR, and ERK1/2 MAPK. Cross-talk between the PI3K and MAPK pathways is necessary for VSMC chemotaxis under these conditions.
Lack of renal effects of fish oil administration in patients with advanced cirrhosis and impaired glomerular filtration
Authors: S Badalamenti, F Salerno, J M Salmeron, E Lorenzano, A Rimola, P Ginès, W Jimenez, G Graziani, V Arroyo, J Rodes, C Ponticelli
Journal: Hepatology (1997)

The treatment of renal failure in cirrhotic patients with ascites remains unsatisfactory. Recent studies have shown that the dietary supplementation with fish oil improves the renal function of normal subjects, as well as that of patients with renal failure of different etiologies. We have investigated the renal effects of a daily supplementation for 1 month of 12 g fish oil (27% C20:5 n-3 eicosapentanoic acid [EPA], and 23% C22:6 n-3 docosahexanoic acid [DHA]) in a prospective study of cirrhotic patients with ascites, nine with normal renal function (group 1) and eight with renal failure (glomerular filtration rate [GFR] < 60 mL/min, group 2). Compliance with the dietary regimen was confirmed by fatty acid chromatography that showed increased plasma concentration of EPA (from 1.5 +/- 0.7% to 3.7 +/- 0.8%, P = .024, in group 1; and from 0.53 +/- 0.3% to 2.9 +/- 0.8%, P = .03, in group 2) and of DHA (from 2.1 +/- 0.4% to 3.4 +/- 0.3%, P = .008, in group 1; and from 1.45 +/- 0.5% to 3.8 +/- 0.4%, P = .05, in group 2). At the end of the study, in patients from group 1, the glomerular filtration rate increased by 19% (from 94 +/- 8 to 113 +/- 13 mL/min, P = .039), and the urine flow increased by 39% (from 0.85 +/- 0.14 to 1.12 +/- 0.2 mL/min, P = .039), while no changes occurred in the renal function of patients from group 2. No changes were observed in the urinary excretion of prostaglandin (PG) E2 or of 6-keto prostaglandin-1-alpha (6-K-PGF1-alpha) nor in plasma renin activity (PRA) or the plasma concentration of aldosterone (PA) or antidiuretic hormone (ADH) in both groups. As far as undesirable effects of fish oils were considered, the mean arterial pressure (MAP) decreased in both groups (group 1: from 88.6 +/- 2 to 85.3 +/- 2 mm Hg, P = .015; group 2: from 88.2 +/- 3 to 82.8 +/- 3 mm Hg, P = .05), and bleeding time displayed a significant increase when patients were considered collectively (from 744 +/- 89 to 872 +/- 106 seconds, P = .0068). In conclusion, the administration of fish oil for 1 month was unable to improve renal function in cirrhotic patients with ascites and renal failure. The occurrence of undesirable effects, such as the reduction of arterial pressure and the prolongation of bleeding time, argues against the use of fish oils in these patients.
Vascular Endothelial Growth Factor C Stimulates Progression of Human Gastric Cancer via Both Autocrine and Paracrine Mechanisms
Authors: Michiyo Kodama, Yasuhiko Kitadai, Miwako Tanaka, Toshio Kuwai, Shinji Tanaka, Naohide Oue, Wataru Yasui, Kazuaki Chayama
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Vascular endothelial growth factor (VEGF)-C induces lymphangiogenesis by activating the VEGF receptor (VEGFR)-3, which is expressed by lymphatic endothelial cells. VEGFR-3 has also been detected on several malignant cells, but the significance of VEGFR-3 expression on malignant cells remains unclear. In this study, we examined the expression and function of VEGFR-3 in gastric carcinoma cells. Experimental Design: We examined the expression of VEGFR-3 by four human gastric carcinoma cell lines and in 36 surgical specimens of gastric carcinoma. We also used cDNA microarrays to examine the effect of VEGF-C on gene expression in VEGFR-3-expressing KKLS cells. To stimulate VEGF-C/VEGFR-3 signaling in an autocrine manner, the VEGF-C expression vector was transfected into KKLS cells, and stable transfectants were established. These cells were then transplanted into the gastric walls of nude mice. Results: Two of the four gastric carcinoma cell lines expressed VEGFR-3 mRNA. In 17 of 36 gastric carcinoma specimens, VEGFR-3-specific immunoreactivity was detected on tumor cells. In vitro treatment of KKLS cells with VEGF-C stimulated cell proliferation and increased expression of mRNAs encoding cyclin D1, placental growth factor, and autocrine motility factor. Following inoculation of VEGF-C-transfected and control cells into the gastric walls of nude mice, tumor growth of the VEGF-C-transfected cells was greatly accelerated in comparison with that of control cells. Greater angiogenesis and lymphangiogenesis were also detected in VEGF-C-transfected tumors than in control tumors. Conclusions: Gastric carcinoma cells express VEGF-C and VEGFR-3. VEGF-C may play a role in the progressive growth of human gastric carcinoma through both autocrine and paracrine mechanisms.
What shall we do with the damaged proteins in lung disease? Ask the proteasome!
Authors: Silke Meiners, Oliver Eickelberg
Journal: European Respiratory Journal (2012)

The proteasome constitutes the main protein waste disposal and recycling system of the cell. Together with endoplasmic reticulum stress and the autophagosome pathway, it takes centre stage in cellular protein quality control. In lung research, the proteasome is, first of all, a promising therapeutic target to intervene in the malignant growth of lung cancer cells. Therapeutic targeting of the proteasome has also been extended to pulmonary fibrosis and asthma using animal models. Moreover, the proteasome is involved in lung pathogenesis. In cystic fibrosis, rapid proteasomal degradation of mutant cystic fibrosis transmembrane conductance regulator contributes to loss of function of lung epithelial cells. In chronic obstructive pulmonary disease (COPD), pulmonary proteasome expression and activity are downregulated and inversely correlate with lung function. In addition, as the proteasome degrades signalling mediators that have been oxidatively modified in COPD, it contributes to further compromise cellular function. The consequences of proteasomal dysfunction are loss of protein quality control, accumulation of misfolded proteins and exacerbation of cellular stress, which are also hallmarks of protein quality diseases and premature ageing. This suggests that proteasome dysfunction can be regarded as a new pathomechanism for chronic lung diseases, awaiting further therapeutic exploration in the future.