tbuckley/cabot-search huggingface dataset:
Bcl-xL Gene Transfer Inhibits Bax Translocation and Prolongs Cardiac Cold Preservation Time in Rats
Authors: Jianhua Huang, Kiminori Nakamura, Yoshinori Ito, Takeshi Uzuka, Masayuki Morikawa, Sachie Hirai, Kei Tomihara, Toshihiro Tanaka, Yukari Masuta, Keiji Ishii, Kazunori Kato, Hirofumi Hamada
Journal: Circulation (2005)

Apoptosis is an important cause of early graft loss after heart transplantation. Bcl-xL was reported to protect the heart against normothermic ischemia and reperfusion injury. In this study, we determined whether overexpression of Bcl-xL could inhibit tissue injury resulting from prolonged cold preservation followed by warm reperfusion of heart transplants.Lewis rat hearts were transduced with an adenovirus vector harboring Bcl-xL cDNA (AxCAhBclxL) 4 days before collection of tissue. After preservation in University of Wisconsin solution at 4 degrees C for 24 hours, the heart was either perfused with a Langendorff device ex vivo or used for heterotopic heart transplantation in vivo. Bcl-xL gene transfer significantly reduced the infarct size (23.0+/-2.6% versus 47.7+/-7.0% in saline control and 48.6+/-6.1% in vector control, P<0.01) after 2-hour reperfusion at 37 degrees C with the Langendorff device and significantly decreased creatine kinase release (0.82+/-0.27 IU, versus 1.57+/-0.33 and 1.50+/-0.37 IU in saline and vector controls, respectively; P<0.05). In heart transplantation, overexpression of Bcl-xL inhibited Bax translocation from the cytosol to the mitochondria, resulting in decreased cytochrome c release from the mitochondria; it also significantly decreased cardiac cell apoptosis and improved graft survival rate after long cold preservation, followed by warm reperfusion.Bcl-xL gene transfer inhibited the translocation of Bax and prolonged the cold preservation time of cardiac transplants. This may be a potential therapeutic method in clinical practice.
Serial Estimates of Serum Permeability Activity and Clinical Correlates in Patients with Native Kidney Focal Segmental Glomerulosclerosis
Authors: Daniel Cattran, Tuhina Neogi, Ram Sharma, Ellen T. McCarthy, Virginia J. Savin
Journal: Journal of the American Society of Nephrology (2003)

A serum or plasma factor in certain patients with focal segmental glomerulosclerosis (FSGS) has been found to increase glomerular albumin permeability (P(alb)) and causes proteinuria in experimental animals. High P(alb) is associated with recurrence of FSGS after transplantation, but serial studies of P(alb) activity in patients with native kidney FSGS have not been performed, and the relationship between P(alb) and remission of proteinuria is not known. This study was designed to determine P(alb) activity before, during, and after 24 wk of treatment with cyclosporine or placebo given as part of a randomized controlled trial in steroid-resistant FSGS patients with nephrotic range proteinuria. Pretreatment P(alb) averaged 0.36 +/- 0.22 and was not significantly different between treatment groups and was not altered during or after the test medication. There was no association between P(alb) activity and remission or relapse in proteinuria. The average P(alb) activity in native kidney FSGS was lower than in previously reported patients with posttransplant recurrence of the disease, and its level did not vary during the course of the study. The antiproteinuric effect of cyclosporine appeared independent of changes in P(alb). This finding is consistent with a direct effect of cyclosporine on glomerular barrier function and/or that within this group of patients the variations in proteinuria are not reflected in changes in Palb because of its limits in terms of reproducibility and responsiveness.
Clinical outcomes of patients with low left ventricular ejection fraction undergoing intracoronary stenting
Authors: J.F. Saucedo, J.J. Popma, R. Mehran, T. Bucher, A.S. Abizaid, M. Mastoor, G. Mintz, K.M. Kent, A. Pichard, L.F. Satler, H.S. Wu, M.B. Leon
Journal: Journal of the American College of Cardiology (1998)
Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels
Authors: D M Forton
Journal: Gut (2004)

<b>Background and aim:</b> Fatigue is the commonest symptom in primary biliary cirrhosis (PBC), affecting individuals at all stages of disease. The pathogenesis of fatigue in PBC is unknown although rat models suggest a central nervous system (CNS) cause. We examined the hypothesis that a CNS abnormality related to cholestasis, rather than cirrhosis per se, underlies this symptom. <b>Patients and methods:</b> Fourteen patients with precirrhotic PBC (stage I–II disease), four patients with stage III–IV PBC, and 11 healthy women were studied using cerebral magnetisation contrast imaging and proton magnetic resonance spectroscopy (MRS). <b>Results:</b> The globus pallidus magnetisation transfer ratio (MTR), a quantifiable tissue characteristic that may be abnormal in the presence of normal magnetic resonance imaging, was significantly reduced in precirrhotic PBC patients compared with healthy controls. These measurements correlated with blood manganese levels and were more abnormal in the more fatigued subjects. There were no differences in MRS measurements between the three study groups, suggesting that the abnormal MTR was not related to hepatic encephalopathy. <b>Conclusion:</b> This study suggests that impairments in liver function in PBC may adversely affect the brain long before the development of cirrhosis and hepatic encephalopathy, possibly as a result of altered manganese homeostasis within the CNS.
Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives
Authors: Harald Hampel, Richard Frank, Karl Broich, Stefan J. Teipel, Russell G. Katz, John Hardy, Karl Herholz, Arun L. W. Bokde, Frank Jessen, Yvonne C. Hoessler, Wendy R. Sanhai, Henrik Zetterberg, Janet Woodcock, Kaj Blennow
Journal: Nature Reviews Drug Discovery (2010)
Compartment Syndrome Caused by Computed Tomography Contrast Infiltration Seen on a Tc-99m Methylene Diphosphonate Bone Scan
Authors: Perry S. Gerard, Paul Z. Gerczuk, Raghu Idupuganti, Madhavi Patnana, Matthew D. Geller
Journal: Clinical Nuclear Medicine (2008)

A 72-year-old man was hospitalized for transurethral resection of bladder cancer. Two days after the procedure, the patient continued to have gross hematuria and a computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast was performed to check the integrity of the resection site. Later that day, the patient underwent technetium-99m methylene diphosphonate (MDP) bone scintigraphy to investigate the possibility of bone metastasis. The bone scan showed no signs of metastasis but did reveal increased uptake of the left hand and forearm on the opposite side of the injection site.
Involvement of Nuclear Factor-κB and Apoptosis Signal-Regulating Kinase 1 in G-Protein–Coupled Receptor Agonist–Induced Cardiomyocyte Hypertrophy
Authors: Shinichi Hirotani, Kinya Otsu, Kazuhiko Nishida, Yoshiharu Higuchi, Takashi Morita, Hiroyuki Nakayama, Osamu Yamaguchi, Toshiaki Mano, Yasushi Matsumura, Hikaru Ueno, Michihiko Tada, Masatsugu Hori
Journal: Circulation (2002)

Background — Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-κB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1), in G-protein–coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes. Methods and Results — Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-κB activation. Antioxidants such as N -acetyl cysteine, N -mercaptopropionyl glycine, and vitamin E attenuated the NF-κB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant of IκBα led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist–induced NF-κB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF-κB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-κB activation. Conclusions — These data indicate that GPCR agonist–induced cardiac hypertrophy is mediated through NF-κB activation via the generation of ROS. ASK1 is involved in GPCR agonist–induced NF-κB activation and resulting hypertrophy.
Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites.
Authors: L Schofield, F Hackett
Journal: The Journal of Experimental Medicine (1993)

In this study, we have identified a dominant glycolipid toxin of Plasmodium falciparum. It is a glycosylphosphatidylinositol (GPI). The parasite GPI moiety, free or associated with protein, induces tumor necrosis factor and interleukin 1 production by macrophages and regulates glucose metabolism in adipocytes. Deacylation with specific phospholipases abolishes cytokine induction, as do inhibitors of protein kinase C. When administered to mice in vivo the parasite GPI induces cytokine release, a transient pyrexia, and hypoglycemia. When administered with sensitizing agents it can elicit a profound and lethal cachexia. Thus, the GPI of Plasmodium is a potent glycolipid toxin that may be responsible for a novel pathogenic process, exerting pleiotropic effects on a variety of host cells by substituting for the endogenous GPI-based second messenger/signal transduction pathways. Antibody to the GPI inhibits these toxic activities, suggesting a rational basis for the development of an antiglycolipid vaccine against malaria.
Inhibition of Superoxide Generation upon T-Cell Receptor Engagement Rescues Mart-127-35–Reactive T Cells from Activation-Induced Cell Death
Authors: Håkan Norell, Telma Martins da Palma, Aaron Lesher, Navtej Kaur, Meenal Mehrotra, Osama S. Naga, Natalie Spivey, Seye Olafimihan, Nitya G. Chakraborty, Christina Voelkel-Johnson, Michael I. Nishimura, Bijay Mukherji, Shikhar Mehrotra
Journal: Cancer Research (2009)

Abstract Cytotoxic T lymphocytes (CTL) may undergo massive expansion upon appropriate antigenic stimulation. Homeostasis is maintained by a subsequent “contraction” of these cells. Activation-induced cell death (AICD) and programmed cell death prevent the untoward side effects, arising from excessive numbers and prolonged persistence of activated CTL, that occur upon uncontrolled and/or continued expansion. However, effector cell persistence has been identified as a hallmark of successful T-cell–mediated adoptive immunotherapy. Thus, prevention of AICD may be critical to achieve more successful clinical results. We have previously shown that treatment with the c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 protects human melanoma epitope Mart-127-35–reactive CTL from apoptotic death upon their reencounter with cognate antigen. However, inhibition of JNK also interferes with the functional ability of the CTL to secrete IFN-γ. Here, we show that reactive oxygen species (ROS) inhibitors, such as the superoxide dismutase mimetic Mn (III) tetrakis (5, 10, 15, 20-benzoic acid) porphyrin (MnTBAP), efficiently protected Mart-127-35–reactive primary CTL from AICD without impairing their functional capability. MnTBAP prevented the increase in intracellular ROS, mitochondrial membrane collapse, and DNA fragmentation observed in control-treated cells upon cognate antigen encounter. Furthermore, the mechanism of AICD prevention in primary CTL included blockade of JNK activation. Finally, tumor-reactive in vitro expanded tumor infiltrating lymphocytes, which are used clinically in cancer immunotherapy, also benefit from MnTBAP-mediated antioxidant treatment. Thus, modulation of the redox pathway might improve CTL persistence and lead to better clinical results for T cell–based immunotherapies. [Cancer Res 2009;69(15):6282–9]
FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study
Authors: S. Iwamoto, T. Takahashi, H. Tamagawa, M. Nakamura, Y. Munemoto, T. Kato, T. Hata, T. Denda, Y. Morita, M. Inukai, K. Kunieda, N. Nagata, K. Kurachi, K. Ina, M. Ooshiro, T. Shimoyama, H. Baba, K. Oba, J. Sakamoto, H. Mishima
Journal: Annals of Oncology (2015)

A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy.Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety.Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups.Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment.UMIN000002557.
Double Antiplatelet Therapy After Drug-Eluting Stent Implantation
Authors: Ignacio Ferreira-González, Josep R. Marsal, Aida Ribera, Gaietà Permanyer-Miralda, Bruno García-Del Blanco, Gerard Martí, Purificación Cascant, Mónica Masotti-Centol, Xavier Carrillo, Josepa Mauri, Nuria Batalla, Eduard Larrousse, Eva Martín, Antonio Serra, José Ramón Rumoroso, Rafael Ruiz-Salmerón, Jose M. de la Torre, Angel Cequier, Jose A. Gómez-Hospital, Fernando Alfonso, Victoria Martín-Yuste, Manel Sabatè, David García-Dorado
Journal: Journal of the American College of Cardiology (2012)
Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines.
Authors: J L Browning, K Miatkowski, I Sizing, D Griffiths, M Zafari, C D Benjamin, W Meier, F Mackay
Journal: The Journal of Experimental Medicine (1996)

Surface lymphotoxin (LT) is a heteromeric complex of LT-alpha and LT-beta chains that binds to the LT-beta receptor (LT-beta-R), a member of the tumor necrosis factor (TNF) family of receptors. The biological function of this receptor-ligand system is poorly characterized. Since signaling through other members of this receptor family can induce cell death, e.g., the TNF and Fas receptors, it is important to determine if similar signaling events can be communicated via the LT-beta-R. A soluble form of the surface complex was produced by coexpression of LT-alpha and a converted form of LT-beta wherein the normally type II LT-beta membrane protein was changed to a type I secreted form. Recombinant LT-alpha 1/beta 2 was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB-468, and HT-3 when added with the synergizing agent interferon (IFN) gamma. When immobilized on a plastic surface, anti-LT-beta-R monoclonal antibodies (mAbs) induced the death of these cells, demonstrating direct signaling via the LT-beta-R. Anti-LT-beta-R mAbs were also identified that inhibited ligand-induced cell death, whereas others were found to potentiate the activity of the ligand when added in solution. The human WiDr adenocarcinoma line forms solid tumors in immunocompromised mice, and treatment with an anti-LT-beta-R antibody combined with human IFN-gamma arrested tumor growth. The delineation of a biological signaling event mediated by the LT-beta-R opens a window for further studies on its immunological role, and furthermore, activation of the LT-beta-R may have an application in tumor therapy.
Neuropsychological Differences Between Late-Onset and Recurrent Geriatric Major Depression
Authors: Michael A. Rapp, Karen Dahlman, Mary Sano, Hillel T. Grossman, Vahram Haroutunian, Jack M. Gorman
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Executive dysfunction, possibly related to vascular pathology, has been well documented in patients with a first episode of major depressive disorder in later life (late-onset geriatric major depression). However, it is unclear whether the neuropsychological presentation differs in patients with a lifetime history of major depressive disorder (recurrent geriatric major depressive disorder). The purpose of this study was to explore differences in neuropsychological function, symptoms, and cardiovascular comorbidity between patients with late-onset and recurrent geriatric major depression. METHOD: The study used a two-by-two factorial design in which one factor was current major depressive disorder (present versus absent) and the second factor was lifetime history of depression (present versus absent). Neuropsychological measures of executive functioning and episodic memory, as well as psychopathological symptoms and comorbid medical illness, were examined in a total of 116 older adults. RESULTS: Patients with late-onset major depressive disorder showed specific deficits in attention and executive function, whereas patients with recurrent major depressive disorder exhibited deficits in episodic memory. The rates of anhedonia and comorbid cardiovascular illness were higher in patients with late-onset geriatric major depressive disorder. CONCLUSIONS: In contrast to recurrent geriatric major depressive disorder, late-onset major depressive disorder is characterized by specific deficits in tasks of attention and executive function, consistent with increased anhedonia and cardiovascular comorbidity. These findings, if confirmed, suggest that recurrent and late-onset geriatric major depressive disorder may represent distinct phenomenological entities. Such phenomenological differences as a function of lifetime history of major depression can guide research in the neurophysiology, prevention, and treatment of geriatric major depressive disorder.
Precision cut lung slices: A novel method for examining mechanisms underlying respiratory diseases
Authors: Carla Bauer, Javad Golgi, Kristen Lambert, Donavan Cheng, Mario Giron, John Allard, Holly Hilton, Hans Bitter, Martin Stampfli, Christopher Stevenson
Journal: European Respiratory Journal (2013)

Bacterial infections and smoking have been linked to exacerbations of many respiratory diseases. To this end, responses to toll-like receptor (TLR) agonists and bacterial pathogens were studied in precision cut lung slices (PCLS) from room air and smoke-exposed mice.  Ex vivo  cultured PCLS were either left untreated or stimulated with toll-like receptor agonists, lipopolysaccharide (LPS), or Pam3CSK. An additional set of PCLS were challenged with either live or heat-killed  Haemophilus influenzae,  or  Streptococcus pneumoniae.  RNA was isolated and microarray analysis performed. Principal component analysis showed that live  S. pneumoniae  stimulation of PCLS led to a distinct response and a greater number of differentially expressed genes (DEGs) when compared to the responses elicited by the two TLR agonists or  H. influenzae . Unsupervised hierarchical clustering analysis was performed on 1846 DEGs identified 24 hours post-stimulation in room air exposed PCLS, and two distinct clusters were present, confirming the principal component analysis. Of the 1354 genes identified following live  S. pneumoniae  challenge of room air PCLS, several signaling cascades were identified following ingenuity pathways analysis (IPA); these included the IL-1 and IL-10 signaling cascades. In the context of cigarette smoke exposure, IPA analysis captured pathways involved in airway pathology in COPD. These data highlight the strength of this technique for evaluating pathways that may be linked to disease (or exacerbation) susceptibility. Finally, mechanisms that have been implicated in COPD pathogenesis are captured in this model, and therefore increase the validity of this method to test interventions.
Renal Hemodynamics, Electrolyte Excretion and Water Metabolism in Pregnant Sheep Before and After the Induction of Toxemia of Pregnancy
Authors: N. S. ASSALI, LOUIS HOLM, DONALD L. HUTCHINSON
Journal: Circulation Research (1958)

Renal hemodynamics, electrolyte excretion and plasma level of glucorticoids were studied in pregnant sheep before and after the experimental induction of toxemia. Marked renal ischemia occurred in the animals which developed toxemia. This abnormality occurred concomitantly with an increase in plasma corticoids. Despite the renal ischemia, arterial pressure remained the same. There are some similarities between the toxemia of the sheep and that of human pregnancy.
Comparison of 5-aminosalicylic acid and N-acetylaminosalicylic acid uptake by the isolated human colonic epithelial cell.
Authors: A Ireland, J D Priddle, D P Jewell
Journal: Gut (1992)

Isolated human colonic epithelial cell suspensions were incubated with either 0.1 mM 5-aminosalicylic acid (5-ASA) or 0.1 mM acetylaminosalicylic acid (Ac-ASA) for up to two hours. Intra- and extracellular 5-ASA and Ac-ASA were measured by high performance liquid chromatography. Mean 5-ASA uptake in one hour was 160.5 nmol/g dry weight, compared with an Ac-ASA uptake of only 5.75 nmol/g dry weight. No unchanged 5-ASA was detected inside the cell. Repeated washing had no effect on the intracellular Ac-ASA concentration. This discrepancy in drug uptake may explain why Ac-ASA seems to be ineffective when given to patients with ulcerative colitis.
Redistribution of myosin accompanying capping of surface Ig.
Authors: G F Schreiner, K Fujiwara, T D Pollard, E R Unanue
Journal: The Journal of Experimental Medicine (1977)

The capping of surface Ig on B cells occurs with a striking redistribution of cytoplasmic myosin. Our results suggest a close association between surface Ig and myosin which could be the basis for Ig redistribution and stimulated motility.