tbuckley/cabot-search huggingface dataset:
Mitochondrial Biogenesis in Kidney Disease
Authors: Joel M. Weinberg
Journal: Journal of the American Society of Nephrology (2011)

The transcriptional regulation of mitochondrial biogenesis by normal metabolic adaptation or injury has been clarified over the past decade. Mitochondrial biogenesis and its attendant processes enhance metabolic pathways such as fatty acid oxidation and increase antioxidant defense mechanisms that ameliorate injury from aging, tissue hypoxia, and glucose or fatty acid overload, all of which contribute to the pathogenesis of acute and chronic kidney disease. There has been considerable interest in peroxisome proliferator-activated receptors (PPAR) in the kidney, which affect multiple processes in addition to mitochondrial biogenesis. As yet there is relatively little information focused specifically on mitochondrial biogenesis and its regulation by PPARγ coactivators and their modulators such as SIRT1. The available data indicate that these pathways will be fruitful areas for study in the modification of renal disease.
Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer
Authors: Giorgio Vittorio Scagliotti, Purvish Parikh, Joachim von Pawel, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Piotr Serwatowski, Ulrich Gatzemeier, Raghunadharao Digumarti, Mauro Zukin, Jin S. Lee, Anders Mellemgaard, Keunchil Park, Shehkar Patil, Janusz Rolski, Tuncay Goksel, Filippo de Marinis, Lorinda Simms, Katherine P. Sugarman, David Gandara
Journal: Journal of Clinical Oncology (2008)

Purpose Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. Patients and Methods This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] &lt; 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m 2 on day 1 and gemcitabine 1,250 mg/m 2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 on day 1 (n = 862) every 3 weeks for up to six cycles. Results Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P &lt; .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. Conclusion In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.
SURVIVAL AND CAUSES OF DEATH IN THALASSAEMIA MAJOR
Authors: MariaGrazia Zurlo, Piero De Stefano, Caterina Borgna-Pignatti, Annunziata Di Palma, Caterina Melevendi, Antonio Piga, Felicia Di Gregorio, MariaGabriella Burattini, Severina Terzoli
Journal: The Lancet (1989)
Porous tissue grafts sandwiched with multilayered mesenchymal stromal cell sheets induce tissue regeneration for cardiac repair
Authors: Chun-Hung Chen, Hao-Ji Wei, Wei-Wen Lin, Iwen Chiu, Shiaw-Min Hwang, Chung-Chi Wang, Wen-Yu Lee, Yen Chang, Hsing-Wen Sung
Journal: Cardiovascular Research (2008)

AimsTo provide the basis for uniform cardiac tissue regeneration, a spatially uniform distribution of adhered cells within a scaffold is a prerequisite. To achieve this goal, a bioengineered tissue graft consisting of a porous tissue scaffold sandwiched with multilayered sheets of mesenchymal stromal cells was developed.
Increased heinz body formation and impaired erythrocyte pentose phosphate shunt function during pregnancy
Authors: Neil A. Lachant, Arlan J. Gottlieb, Santo M. Difino, Stephen A. Landaw, Kouichi R. Tanaka
Journal: American Journal of Hematology (1985)

Abstract The erythrocytes of 90 pregnant women were evaluated for the presence of in vivo or in vitro oxidant damage. The reduced glutathione (P &lt; 0.005) and the membrane reduced sulfhydryl (P &lt; 0.001) concentrations were decreased in fresh erythrocytes. Following incubation with acetylphenylhydrazine, Heinz body formation was significantly increased (P &lt; 0.001). Both the increase in Heinz body formation and the reduction in membrane reduced sulfhydryl content correlated strongly with duration of pregnancy. Glucose consumption was significantly decreased before, but not after, new methylene blue stimulation. Pentose phosphate shunt activity was impaired both before (P &lt; 0.05) and after (P &lt; 0.001) stimulation. No changes were observed in pentose phosphate recycling. The only alteration observed in the activity of the enzymes of the pentose shunt was an elevation of 6‐phosphogluconate dehydrogenase activity. Although the clinical significance of these findings remains to be determined, medications with an oxidant potential should be used judiciously during gestation.
Correlation of suppressor cell development in parental and F1 hybrid mouse strains with the growth of a parental tumor in vivo.
Authors: R B Levy, S D Waksal, G M Shearer
Journal: The Journal of Experimental Medicine (1976)

Parental AKR/J, and AKB6F1 and AKD2F1 hybrid mice were injected subcutaneously with a spontaneously arising AKR/J tumor. The highly responsive AKB6F1 strain never exhibited any depression of immune functioning during the course of tumor growth and regression. The (AKR/J) intermediately responsive strain, while able to generate a successful anti-tumor response, did display a transient reduction of immunological capability, but only during the period tumor growth and not during tumor regression. Cells able to suppress antibody, but not cell-mediated responses, were found. The unresponsive AKD2F1 strain was characterized by both a marked depression of immune responsiveness, as well as the generation of suppressor cells to both antibody, and later, cell-mediated responses. Depression of immune responsiveness, and the generation of suppressor cells, appeared to correlate with the strength or weakness of the anti-tumor response in these strains of mice.
Tumor-Specific Efficacy of Transforming Growth Factor-βRI Inhibition in Eker Rats
Authors: Nicholas J. Laping, Jeffrey I. Everitt, Kendall S. Frazier, Mark Burgert, Melisa J. Portis, Caprice Cadacio, Leslie I. Gold, Cheryl L. Walker
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Transforming growth factor β (TGF-β), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-β signaling could be efficacious for lesions in which TGF-β promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions. Experimental Design: We examined the effect of a TGF-β inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency. Results: Blockade of TGF-β signaling with the ALK5/type I TGF-βR kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals. Conclusion: Although pharmacologic inhibition of TGF-β signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.
Isolation and Properties of Phagocytic Vesicles II. ALVEOLAR MACROPHAGES
Authors: Thomas P. Stossel, Robert J. Mason, Thomas D. Pollard, Martha Vaughan
Journal: Journal of Clinical Investigation (1972)

Phagocytic vesicles were obtained by density gradient centrifugation of homogenized rabbit alveolar macrophages that had ingested emulsified paraffin oil contained Oil Red O. The phagocyte vesicles floated and thereby were separated from the soluble fraction and from other cell components which sedimented. The purity of the isolated vesicles was documented by electron microscopy, chemical and enzyme analysis. The vesicles contained 87% of the cell-associated Oil Red O, and were essentially free of DNA, RNA, succinic dehydrogenase, and glucose-6-phosphatase. Acid phosphatase, beta-glucuronidase, and catalase were transferred from the sedimenting fraction to the phagocytic vesicle fraction during phagocytosis, whereas enzyme activities of the soluble fraction remained unchanged. Half of the catalase of resting macrophages was in the pellet fraction and, compared with acid phosphatase, greater amounts of digitonin were required to release full activity. Such differential latency has been described for enzymes of peroxisomes vs. those of lysosomes. Compared with polymorphonuclear leukocyte vesicles studied previously, phagocytic vesicles of macrophages had more electron-dense material and lower Oil Red O:protein, phospholipid:protein, and enzyme:protein ratios. It is thus probable that secondary lysosomes become part of the macrophage vesicle. When paraffin oil particles, the stimulus for phagocytic vesicle formation, were washed away from the macrophages, acquisition of hydrolases by preformed vesicles ceased, i.e. transfer of these enzymes into phagocytic vesicles occurred only during or shortly after the formation of new vesicles. As noted previously by others, the content of acid hydrolases of stimulated alveolar macrophages was doubled in comparison to normal cells. The difference between stimulated and normal macrophages was even more marked when isolated phagocytic vesicles were analyzed. Vesicles from stimulated macrophages had 3-5 times more enzyme activity (per milligram of vesicle protein or per amount of paraffin oil ingested) than did vesicles from normal cells.
Protein p67. A calcium-binding protein localized at the sarcolemma of secretory atrial myocytes.
Authors: H Iida, H Nishitani, Y Shibata
Journal: Circulation Research (1992)

Bovine heart 67-kd protein (p67) was coisolated with calpactin I complex by cycles of Ca(2+)-dependent precipitation followed by solubilization with EGTA-containing buffer. Using affinity-purified anti-p67 antibody and anti-p36 (36-kd subunit of calpactin I) antibody, we examined the localization of the two proteins in secretory atrial myocytes and other endocrine tissues of adult rats. Immunofluorescence microscopy showed that p67 was expressed both in the atrial myocytes in situ and in cultured atrial myocytes in which we failed to detect p36 and that p67 appeared to be closely associated with the cell surface. We also found that p67 was colocalized with p36 in the thyroid follicle epithelium and zona reticularis of the adrenal gland. On the other hand, neither p67 nor p36 was detectable in pancreas islet cells. Immunoelectron microscopy revealed that p67 was localized at the sarcolemma in the atrial myocytes in situ. The p67, which was shown to be a globular molecule with a diameter of 18-25 nm by a low-angle rotary shadowing method, bound radioactive Ca2+ on a nitrocellulose membrane. The results suggest that Ca(2+)-binding proteins expressed in endocrine cells seem to vary from tissue to tissue and that p67 may function in Ca(2+)-mediated events at the plasma membrane of secretory atrial myocytes and some types of endocrine cells expressing this protein.
Coordination of glioblastoma cell motility by PKCι
Authors: R Mitchell Baldwin, Gordon M Barrett, Doris AE Parolin, Jana K Gillies, Judith A Paget, Sylvie J Lavictoire, Douglas A Gray, Ian AJ Lorimer
Journal: Molecular Cancer (2010)

Abstract Background Glioblastoma is one of the deadliest forms of cancer, in part because of its highly invasive nature. The tumor suppressor PTEN is frequently mutated in glioblastoma and is known to contribute to the invasive phenotype. However the downstream events that promote invasion are not fully understood. PTEN loss leads to activation of the atypical protein kinase C, PKCι. We have previously shown that PKCι is required for glioblastoma cell invasion, primarily by enhancing cell motility. Here we have used time-lapse videomicroscopy to more precisely define the role of PKCι in glioblastoma. Results Glioblastoma cells in which PKCι was either depleted by shRNA or inhibited pharmacologically were unable to coordinate the formation of a single leading edge lamellipod. Instead, some cells generated multiple small, short-lived protrusions while others generated a diffuse leading edge that formed around the entire circumference of the cell. Confocal microscopy showed that this behavior was associated with altered behavior of the cytoskeletal protein Lgl, which is known to be inactivated by PKCι phosphorylation. Lgl in control cells localized to the lamellipod leading edge and did not associate with its binding partner non-muscle myosin II, consistent with it being in an inactive state. In PKCι-depleted cells, Lgl was concentrated at multiple sites at the periphery of the cell and remained in association with non-muscle myosin II. Videomicroscopy also identified a novel role for PKCι in the cell cycle. Cells in which PKCι was either depleted by shRNA or inhibited pharmacologically entered mitosis normally, but showed marked delays in completing mitosis. Conclusions PKCι promotes glioblastoma motility by coordinating the formation of a single leading edge lamellipod and has a role in remodeling the cytoskeleton at the lamellipod leading edge, promoting the dissociation of Lgl from non-muscle myosin II. In addition PKCι is required for the transition of glioblastoma cells through mitosis. PKCι therefore has a role in both glioblastoma invasion and proliferation, two key aspects in the malignant nature of this disease.
Epicutaneous immune modulation with Bet v 1 plus R848 suppresses allergic asthma in a murine model
Authors: S. Siebeneicher, S. Reuter, M. Krause, A. Wangorsch, J. Maxeiner, S. Wolfheimer, S. Schülke, S. Naito, A. Heinz, C. Taube, S. Vieths, S. Scheurer, M. Toda
Journal: Allergy (2013)

Background Combining allergen(s) with an adjuvant is a strategy to improve the efficacy and safety of allergen-specific immunotherapy. Here, we aimed at investigating the adjuvant effects of polyadenylic–polyuridylic acid (poly(A:U)), a TLR3 agonist, and R848 (resiquimod), a TLR7 agonist, in epicutaneous immunotherapy with Bet v 1, the major birch pollen allergen, to intervene in birch pollen allergy. Methods and Results BALB/c mice received epicutaneous immunization (EPI) with recombinant Bet v 1 (rBet v 1) alone, or plus poly(A:U), or R848 on their depilated back using patches. Among the groups, EPI with rBet v 1 and R848 induced detectable levels of IFN-γ-producing CD4+ T cells in lymph nodes and Bet v 1-specific IgG2a antibodies in the sera of mice. Before or after EPI, mice were sensitized with rBet v 1 plus aluminium hydroxide adjuvant and intranasally challenged with birch pollen extract. Prophylactic EPI with rBet v 1 plus R848 inhibited the production of biologically active Bet v 1-specific IgE antibodies in sensitization. Prophylactic and therapeutic EPI with rBet v 1 plus R848 suppressed lung inflammation upon challenges. Remarkably, only rBet v 1 plus R848 reduced the development of enhanced pause (PenH), a substituted parameter for airway hyper-reactivity, in challenged mice. In contrast to R848, poly(A:U) did not present adjuvant effect on the suppression of asthmatic features. Conclusion Epicutaneous immunization with rBet v 1 plus R848 induced predominant Bet v 1-specific Th1 responses and efficiently suppressed asthmatic features elicited by birch pollen. R848 could be a promising adjuvant in epicutaneous immunotherapy for birch pollen-induced allergic asthma.
The Runx1 Transcription Factor Inhibits the Differentiation of Naive CD4<b>+</b> T Cells into the Th2 Lineage by Repressing <i>GATA3</i> Expression
Authors: Okiru Komine, Keitaro Hayashi, Waka Natsume, Toshio Watanabe, Youichi Seki, Noriyasu Seki, Ryoji Yagi, Wataru Sukzuki, Hidekazu Tamauchi, Katsuto Hozumi, Sonoko Habu, Masato Kubo, Masanobu Satake
Journal: The Journal of Experimental Medicine (2003)

Differentiation of naive CD4+ T cells into helper T (Th) cells is controlled by a combination of several transcriptional factors. In this study, we examined the functional role of the Runx1 transcription factor in Th cell differentiation. Naive T cells from transgenic mice expressing a dominant interfering form of Runx1 exhibited enhanced interleukin 4 production and efficient Th2 differentiation. In contrast, transduction of Runx1 into wild-type T cells caused a complete attenuation of Th2 differentiation and was accompanied by the cessation of GATA3 expression. Furthermore, endogenous expression of Runx1 in naive T cells declined after T cell receptor stimulation, at the same time that expression of GATA3 increased. We conclude that Runx1 plays a novel role as a negative regulator of GATA3 expression, thereby inhibiting the Th2 cell differentiation.
Interaction between Cancer Cells and Stromal Fibroblasts Is Required for Activation of the uPAR-uPA-MMP-2 Cascade in Pancreatic Cancer Metastasis
Authors: Yu He, Xiang-de Liu, Zhi-yu Chen, Jin Zhu, Yan Xiong, Kun Li, Jia-hong Dong, Xiaowu Li
Journal: Clinical Cancer Research (2007)

Interaction between tumor cells and surrounding stromal fibroblast (SF) plays a critical role in tumor growth and invasion. The aim of the study is to determine the role of SF in regulating the invasive behaviors of pancreatic cancer by evaluating the mode of SF activating the urokinase plasminogen activator (uPA)-plasmin-matrix metalloproteinase (MMP)-2 cascade.The expression patterns of uPA, MMP-2, and uPA receptor (uPAR) in human metastatic pancreatic cancer were analyzed by immunohistochemistry and the roles of SF in activation of the uPA-plasmin-MMP-2 cascade were evaluated by coculturing pancreatic cancer cell lines with SF.uPA expression and fibroblastic uPAR expression were correlated with liver metastasis of human pancreatic cancer. MMP-2 rather than MMP-9 was activated in the metastatic pancreatic cancer. In the in vitro culture system, the coculture of peritumor fibroblasts with metastatic pancreatic cancer BxPc3 cells resulted in activation of MMP-2 and up-regulation of uPAR expression. In this coculture system, the uPA-plasminogen cascade was involved in MMP-2 activation. This activation required a direct interaction between SF and cancer cells. In the coculture system, intergrin alpha(6)beta(1) expression was increased in BxPc3 cells, and blocking the function of integrin alpha(6)beta(1) decreased the activation of uPA and MMP-2. This suggests that interaction between integrins of cancer cells and the uPARs of the SF might be involved in the activation of the uPAR-uPA-MMP-2 cascade.Our results suggest that SF plays a role in promoting pancreatic cancer metastasis via activation of the uPA-plasminogen-MMP-2 cascade.
Antigenicity and immunogenicity of allogeneic retinal transplants
Authors: Natalie G. Anosova, Ben Illigens, Florence Boisgérault, Eugenia V. Fedoseyeva, Michael J. Young, Gilles Benichou
Journal: Journal of Clinical Investigation (2001)

The transplantation of neuronal cells and tissues represents a promising approach for the treatment of incurable neurodegenerative diseases. Indeed, it has been reported recently that retinal transplantation can rescue photoreceptor cells and delay age-related changes in various retinal layers in rodents. However, retinal grafts deteriorate progressively after placement in recipients’ eyes. Here we investigated whether a host’s immune response elicited toward the graft contributes to its deterioration. Using an ELISA spot assay, we measured T cell responses to retinal tissues placed in the vitreous cavity of syngeneic and allogeneic mice. We found that allogeneic retinas induced potent alloimmune responses mediated by T cells secreting type 1 cytokines (IFN-γ and IL-2). No response was found in mice engrafted with syngeneic retinas. In addition, all syngeneic retinal grafts displayed no signs of tissue damage (at 55 days), while the majority of allogeneic retinas deteriorated as early as 12 days after placement. Next, we showed that anti-donor responses occurred within two phenotypically and functionally distinct T cell subsets: CD4+ T cells secreting IL-2 and CD8+ T cells producing IFN-γ. Importantly, CD4+ T cells were necessary and sufficient to cause graft deterioration, while CD8+ T cells did not contribute to this process.
Complement drives Th17 cell differentiation and triggers autoimmune arthritis
Authors: Motomu Hashimoto, Keiji Hirota, Hiroyuki Yoshitomi, Shinji Maeda, Shin Teradaira, Shuji Akizuki, Paz Prieto-Martin, Takashi Nomura, Noriko Sakaguchi, Jörg Köhl, Birgitta Heyman, Minoru Takahashi, Teizo Fujita, Tsuneyo Mimori, Shimon Sakaguchi
Journal: The Journal of Experimental Medicine (2010)

Activation of serum complement triggers Th17 cell–dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or β-glucan, both of which activate serum complement, evoked Th17 cell–mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or β-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)−/− mice but not in C5aR-deficient RAG−/− recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease.
The Effects of Estrogen on Serum Level and Hepatocyte Expression of PCSK9
Authors: Wen Guo, Jinxiang Fu, Xiaoli Chen, Beibei Gao, Zhenzhen Fu, Hongqi Fan, Qin Cui, Xiaohui Zhu, Yang Zhao, Tao Yang, Daping Fan, Hongwen Zhou
Journal: Metabolism (2015)