tbuckley/cabot-search huggingface dataset:
Presenilin-dependent intramembrane cleavage of ephrin-B1
Authors: Taisuke Tomita, Sayaka Tanaka, Yuichi Morohashi, Takeshi Iwatsubo
Journal: Molecular Neurodegeneration (2006)

Presenilin-dependent gamma-secretase cleavage of several transmembrane proteins, including amyloid-beta precursor protein and Notch, mediates the intramembrane proteolysis to liberate their intracellular domains that are involved in cellular signaling. Considering gamma-secretase inhibitors as therapeutics for Alzheimer's disease, understanding the physiologically and biologically important substrate for gamma-secretase activity in brains is emerging issue. To elucidate the molecular mechanism and physiological role of gamma-secretase, we screened candidate molecules for gamma-secretase substrates.We show that ephrin-B1, that participates in cell-cell repulsive and attractive signaling together with its Eph receptor, constitutively undergoes ectodomain shedding and that the residual membrane-tethered fragment is sequentially cleaved by gamma-secretase to release the intracellular domain. Furthermore, overexpression of membrane-tethered ephrin-B1 caused protrusion of numerous cellular processes consisted of F-actin, that required the preservation of the most C-terminal region of ephrin-B1. In contrast, soluble intracellular domain translocated into the nucleus and had no effect on cell morphology.Our findings suggest that ephrin-B is a genuine substrate for gamma-secretase and regulates the cytoskeletal dynamics through intramembrane proteolysis.
Preclinical Evaluation of Illudins as Anticancer Agents: Basis for Selective Cytotoxicity
Authors: M. J. Kelner, T. C. McMorris, R. Taetle
Journal: JNCI Journal of the National Cancer Institute (1990)

Illudins are potent natural products derived from Omphalotus illudens and related fungi. The chemical structure of illudins differs from that of other conventional chemotherapeutic agents. While illudins are toxic to most tumor cells after prolonged exposure (greater than or equal to 48 hr), with shorter exposure times (less than or equal to 2 hr), they show selective toxicity for human myelocytic leukemia and epidermoid, lung, ovarian, and breast carcinoma cells of various species of origin. The apparent histologic specificity of illudin S toxicity is based on an energy-dependent transport mechanism present in sensitive cells, but absent in cells relatively resistant to illudin S. For human myeloid leukemia HL60 cells, the Michaelis constant was 4.2 microM and the maximum velocity was 12.2 pmol/minute per 10 million cells or 730 pmol/hour per 10 million cells. The energy-dependent transport mechanism was detected in other mammalian tumor cells.
Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study
Authors: Pablo M Lavados, Claudio Sacks, Liliana Prina, Arturo Escobar, Claudia Tossi, Fernando Araya, Walter Feuerhake, Marcelo Gálvez, Rodrigo Salinas, Gonzalo Álvarez
Journal: The Lancet Neurology (2007)
Smac Modulates Chemosensitivity in Head and Neck Cancer Cells through the Mitochondrial Apoptotic Pathway
Authors: Quanhong Sun, Xingnan Zheng, Lin Zhang, Jian Yu
Journal: Clinical Cancer Research (2011)

Overexpression of inhibitors of apoptosis proteins (IAP) contributes to therapeutic resistance. Second mitochondria-derived activator of caspase (Smac) promotes caspase activation by binding to IAPs upon release from the mitochondria. IAP antagonists, also called SMAC mimetics, are promising anticancer agents modeled after this mechanism. We investigated the role and mechanisms of Smac- and Smac mimetic-mediated chemosensitization in head and neck squamous cell carcinoma (HNSCC) cells.The effects of SMAC knockdown, SMAC overexpression, and a small molecule Smac mimetic on the chemosensitivities of HNSCC cells were determined. The mechanisms of Smac- and Smac mimetic-mediated chemosensitization were investigated by analyzing growth suppression, the mitochondrial apoptotic pathway, caspase activation, and IAP proteins. The therapeutic responses of HNSCC cells with different levels of Smac were compared in xenograft models.We found that Smac mediates apoptosis induced by several classes of therapeutic agents through the mitochondrial pathway. SMAC knockdown led to impaired caspase activation, mitochondrial membrane depolarization, and release of cytochrome c. A small molecule Smac mimetic, at nanomolar concentrations, significantly sensitized HNSCC cells to gemcitabine-induced apoptosis and restored gemcitabine sensitivity in SMAC knockdown cells, through caspase activation, X-linked IAP dissociation, and mitochondria-associated events, but not the TNF-α pathway. Furthermore, Smac levels modulated the therapeutic response of HNSCC cells to gemcitabine in xenograft models.Our results establish a critical role of Smac in mediating therapeutic responses of HNSCC cells and provide a strong rationale for combining Smac mimetics with other anticancer agents to treat HNSCC.
Pancreatic duct obstruction in rabbits causes digestive zymogen and lysosomal enzyme colocalization.
Authors: A Saluja, M Saluja, A Villa, U Leli, P Rutledge, J Meldolesi, M Steer
Journal: Journal of Clinical Investigation (1989)

The pancreatic duct of anesthetized rabbits was cannulated and, in some animals, flow of pancreatic exocrine secretions was blocked by raising the cannula to a vertical position. Blockage for 3-7 h caused a rapid and significant rise in serum amylase activity and an increase in amylase activity within the pancreas. The concentration of lysosomal enzymes in the pancreas was not altered but they became redistributed among subcellular fractions and, as a result, an increased amount was recovered in the 1,000-g, 15-min pellet, which was enriched in zymogen granules. Immunofluorescence studies indicated that lysosomal enzymes become localized within organelles which, in size and distribution, resemble zymogen granules. They also contain digestive enzyme zymogens. Blockage of pancreatic secretions also caused lysosomal enzyme-containing organelles to become more fragile and subject to in vitro rupture. These changes noted after short-term pancreatic duct obstruction are remarkably similar to those previously noted to occur during the early stages of diet and secretagogue-induced experimental pancreatitis, observations that have suggested that colocalization of digestive enzyme zymogens and lysosomal hydrolases might result in intracellular digestive enzyme activation and be an important early event in the evolution of those forms of experimental acute pancreatitis.
Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis.
Authors: D E Vaughan, S A Lazos, K Tong
Journal: Journal of Clinical Investigation (1995)

Plasminogen activator-inhibitor C-1 (PAI-1) plays a critical role in the regulation of fibrinolysis, serving as the primary inhibitor of tissue-type plasminogen activator. Elevated levels of PAI-1 are a risk factor for recurrent myocardial infarction, and locally increased PAI-1 expression has been described in atherosclerotic human arteries. Recent studies have shown that the administration of angiotensin converting enzyme inhibitors reduces the risk of recurrent myocardial infarction in selected patients. Since angiotensin II (Ang II) has been reported to induce PAI-1 production in cultured astrocytes, we have hypothesized that one mechanism that may contribute to the beneficial effect of angiotensin converting enzyme inhibitors is an effect on fibrinolytic balance. In the present study, we examined the interaction of Ang II with cultured bovine aortic endothelial cells (BAECs) and the effects of this peptide on the production of PAI-1. 125I-Ang II was found to bind to BAECs in a saturable and specific manner, with an apparent Kd of 1.4 nM and Bmax of 74 fmol per mg of protein. Exposure of BAECs to Ang II induced dose-dependent increases in PAI-1 antigen in the media and in PAI-1 mRNA levels. Induction of PAI-1 mRNA expression by Ang II was not inhibited by pretreating BAECs with either Dup 753 or [Sar1, Ile8]-Ang II, agents that are known to compete effectively for binding to the two major angiotensin receptor subtypes. These data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.
New targets for the treatment of follicular lymphoma
Authors: Nishant Tageja, Subhash Padheye, Prasad Dandawate, Ayad Al-Katib, Ramzi M Mohammad
Journal: Journal of Hematology & Oncology (2009)

Abstract The last two decades have witnessed striking advances in our understanding of the biological factors underlying the development of Follicular lymphoma (FL). Development of newer treatment approaches have improved the outlook for many individuals with these disorders; however, with these advances come new questions. Given the long-term survival of patients with FL, drugs with favourable side-effect profile and minimal long-term risks are desired. FL is incurable with current treatment modalities. It often runs an indolent course with multiple relapses and progressively shorter intervals of remission. The identification of new targets and development of novel targeted therapies is imperative to exploit the biology of FL while inherently preventing relapse and prolonging survival. This review summarizes the growing body of knowledge regarding novel therapeutic targets, enabling the concept of individualized targeted therapy for the treatment of FL.
P03.09 * PHARMACOLOGICAL MODULATION OF BLOOD-BRAIN BARRIER: FUTURE STRATEGY FOR TREATMENT OF BRAIN TUMORS
Authors: I. Sardi, S. Cardellicchio, A. L. Iorio, M. da Ros, G. la Marca, L. Giunti, M. Massimino, L. Genitori
Journal: Neuro-Oncology (2014)

A prerequisite for the efficacy of chemotherapy is that it reaches the tumor mass at a therapeutic concentration. In brain tumors this phenomenon is hampered by the presence of the blood brain barrier (BBB) which limits the spread of chemotherapeutic agents within the brain. It is lately emerged as this Multi Drug Resistance (MDR) phenomenon is explained through the cooperation of P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), two “gatekeeper" transporters that work in tandem on the BBB and are also present on the plasma membrane of certain brain tumors. Recently, we have attempted to improve the therapeutic efficacy of pharmacological treatment in malignant brain tumors by safe and temporary BBB permeabilization. We have demonstrated that morphine and, to a lower level, ondansetron and dexamethasone allow an accumulation of doxorubicin within the rat brain by LC-MS/MS mass spectrometry. All these drugs are substrates of P-gp and BCRP efflux pumps. The aim of the current proposal is to expand our preliminary observation, to understand the mechanism of action of BBB “permeabilization” induced by morphine or other drugs, and to exploit this method for the “treatment” of brain tumour in an animal model. i) Quantifying the level drugs that do not usually cross the BBB (mitoxantrone or melphalan) after morphine pre-treatment in a preclinical model. Verifying the cytotoxic effect of morphine plus doxorubicin (and other chemotherapeutic agents) treatment by using MTT and TUNEL analysis in glioblastoma cell lines ii) Quantifying the level of drugs that do not usually cross the BBB after morphine pre-treatment in an artificial BBB through a monolayer of MDCKII cells over-expressing the human P-gp or BCRP. iii) Investigating the regulatory role of certain microRNA in MDR mechanism by RT-PCR and western blot analysis of P-gp, BCRP, miR-21, miR-27a and miR-451. Our data suggest that blocking efflux transporters by pretreatment with morphine, ondansetron or desamethasone is able to allow doxorubicin penetration inside the brain. This is not associated with acute cardiac or renal toxicity. These preliminary results will enable us to novel therapeutic approaches to refractory or recurrent brain tumors in which molecules usually stopped by the BBB may have a therapeutic impact.
Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents
Authors: Christopher Vearing, Fook-Thean Lee, Sabine Wimmer-Kleikamp, Violeta Spirkoska, Catherine To, Con Stylianou, Mark Spanevello, Martin Brechbiel, Andrew W. Boyd, Andrew M. Scott, Martin Lackmann
Journal: Cancer Research (2005)

Abstract The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands form a unique cell-cell contact–mediated system for controlling cell localization and organization. Their high expression in a wide variety of human tumors indicates a role in tumor progression, and relatively low Eph and ephrin levels in normal tissues make these proteins potential targets for anticancer therapies. The monoclonal antibody IIIA4, previously used to isolate EphA3, binds with subnanomolar affinity to a conformation-specific epitope within the ephrin-binding domain that is closely adjacent to the “low-affinity” ephrin-A5 heterotetramerization site. We show that similar to ephrin-A5, preclustered IIIA4 effectively triggers EphA3 activation, contraction of the cytoskeleton, and cell rounding. BIAcore analysis, immunoblot, and confocal microscopy of wild-type and mutant EphA3 with compromised ephrin-A5 or IIIA4-binding capacities indicate that IIIA4 binding triggers an EphA3 conformation which is permissive for the assembly of EphA3/ephrin-A5-type signaling clusters. Furthermore, unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling. Radiometal conjugates of ephrin-A5 and IIIA4 retain their affinity, and in mouse xenografts localize to, and are internalized rapidly into EphA3-positive, human tumors. These findings show the biological importance of EphA3/ephrin-A5 interactions and that ephrin-A5 and IIIA4 have great potential as tumor targeting reagents.
Abstract 4894: Effect of lysosome destabilization on response to ceramide in prostate cancer cells over-expressing acid ceramidase
Authors: Lorianne S. Turner, Stephen Dungee, Frank Pezzimenti, Margot Weatherford
Journal: Cancer Research (2012)

Abstract Acid ceramidase (AC) over-expression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC over-expression is the ability to convert ceramide, which is often produced as a pro-apoptotic response to stress, to sphingosine, which can then be converted to the pro-survival molecule sphingosine-1-phosphate. In addition to the ability to metabolize ceramide produced in response to stress, prostate cancer cell lines over-expressing AC also have increased lysosomal density and increased levels of autophagy. Autophagy is a cellular mechanism for recycling proteins and organelles which can be used as a survival mechanism in response to stress. Therefore, in addition to the increased capacity to metabolize ceramide produced in response to insult, the increased basal level of autophagy results in cells that have a heightened resistance to cellular stress. Preliminary results suggest that prostate cancer cell lines over-expressing AC have increased expression of lysosomal-stabilizing proteins, which highlights lysosome stability as a potential therapeutic target for cancer therapy. We have evaluated the effect of chloroquine, an FDA-approved drug that localizes to lysosomes, on the response of these cells to ceramide treatment. Pre-treatment with chloroquine increased the sensitivity of the cells to ceramide treatment, possibly due to AC disruption. These studies suggest that chloroquine may increase the efficacy of treatments that induce ceramide. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4894. doi:1538-7445.AM2012-4894
Evaluation of Biox IIA ear oximeter.
Authors: P M Tweeddale, N J Douglas
Journal: Thorax (1985)

Arterial blood gas tensions, pH, and carboxyhaemoglobin were measured on 322 occasions in 165 patients and the actual oxygen saturation of the haemoglobin (Sao2) was compared with the ear oxygen saturation (SEO2) recorded during the arterial sampling with a Biox IIA ear oximeter. The overall agreement between SEO2 and Sao2 was good, with a mean difference in saturation (SEO2-Sao2) of + 1.5% (SD 3.0). The difference in saturation remained similar at all levels of arterial saturation observed and was unaffected by carboxyhaemoglobin concentration. On four occasions (1% of readings), however, SEO2 and Sao2 differed by more than 10% and such occasional errors might be misleading in clinical practice.
Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol Are Associated With Monocytosis and Atherosclerosis
Authors: Anjali Ganda, Martin Magnusson, Laurent Yvan-Charvet, Bo Hedblad, Gunnar Engström, Ding Ai, Thomas J. Wang, Robert E. Gerszten, Olle Melander, Alan R. Tall
Journal: Circulation (2013)

Background— The number of circulating blood monocytes impacts atherosclerotic lesion size, and in mouse models, elevated levels of high-density lipoprotein cholesterol suppress blood monocyte counts and atherosclerosis. We hypothesized that individuals with mild renal dysfunction at increased cardiovascular risk would have reduced high-density lipoprotein levels, high blood monocyte counts, and accelerated atherosclerosis. Methods and Results— To test whether mild renal dysfunction is associated with an increase in a leukocyte subpopulation rich in monocytes that has a known association with future coronary events, we divided individuals from the Malmö Diet and Cancer study (MDC) into baseline cystatin C quintiles (n=4757). Lower levels of renal function were accompanied by higher monocyte counts, and monocytes were independently associated with carotid bulb intima-media thickness cross-sectionally ( P =0.02). Cystatin C levels were positively and plasma high-density lipoprotein cholesterol levels negatively associated with monocyte counts at baseline, after adjustment for traditional risk factors. Several amino acid metabolites tied to low levels of high-density lipoprotein cholesterol and insulin resistance measured in a subset of individuals (n=752) by use of liquid chromatography–mass spectrometry were independently associated with a 22% to 34% increased risk of being in the top quartile of monocytes ( P &lt;0.05). Conclusions— A low high-density lipoprotein cholesterol, insulin resistance phenotype occurs in subjects with mild renal dysfunction and is associated with elevated monocytes and atherosclerosis. High blood monocyte counts may represent a previously unrecognized mechanism underlying the strong relationship between cystatin C and cardiovascular risk.
Intravenous Bisphosphonate Therapy and Inflammatory Conditions or Surgery of the Jaw: A Population-Based Analysis
Authors: G. S. Wilkinson, Y.-F. Kuo, J. L. Freeman, J. S. Goodwin
Journal: JNCI Journal of the National Cancer Institute (2007)

Recent reports have identified an association between osteonecrosis of the jaw or facial bones and treatment with nitrogen-containing intravenous bisphosphonates. We investigated this association by use of data from the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare claims. We identified 16073 cancer patients who were diagnosed between January 1, 1986, and December 31, 2002, and were treated intravenously with the bisphosphonates pamidronate and/or zoledronic acid between January 1, 1995, and December 31, 2003. We matched 28698 bisphosphonate nonusers, at a 2:1 ratio, to 14349 bisphosphonate users on month and year of the first bisphosphonate administration received by users, cancer type, age, sex, risk factors for osteonecrosis (diabetes, alcoholism, cigarette smoking, obesity, hyperlipemia, pancreatitis, or chemotherapy with L -asparaginase), bone metastasis, and SEER program geographic region. Patients were followed until the study's end on December 31, 2003; loss of coverage from Medicare Parts A and B; or one of the following outcomes: a diagnosis of inflammatory conditions or osteomyelitis of the jaw, surgery on the facial bones, or death, whichever occurred first. Use of intravenous bisphosphonates was associated with an increased risk of jaw or facial bone surgery (hazard ratio [HR] = 3.15, 95% confidence interval [CI] = 1.86 to 5.32) and an increased risk of being diagnosed with inflammatory conditions or osteomyelitis of the jaw (HR = 11.48, 95% CI = 6.49 to 20.33), compared with nonuse. The absolute risk at 6 years for any jaw toxicity was 5.48 events per 100 patients using intravenous bisphosphonates and 0.30 events per 100 patients not using such drugs. The risk of each outcome increased as cumulative dose increased (e.g., for 4–8 infusions, HR for operations on the jaw and facial bones = 3.63, 95% CI = 0.77 to 17.08; for more than 21 infusions, HR = 9.18, 95% CI = 1.74 to 48.53). Users of intravenous bisphosphonates had an increased risk of inflammatory conditions, osteomyelitis, and surgical procedures of the jaw and facial bones. The increased risk may reflect an increased risk for osteonecrosis of the jaw.
Release of endogenous catecholamines in the ischemic myocardium of the rat. Part B: Effect of sympathetic nerve stimulation.
Authors: A M Dart, A Schömig, R Dietz, E Mayer, W Kübler
Journal: Circulation Research (1984)

The contribution of centrally originating sympathetic activity to the myocardial extracellular accumulation of noradrenaline during the early phase of ischemia has been assessed in a perfused (Langendorff) rat heart preparation isolated except for its sympathetic innervation. A 10-minute electrical stimulation (4 Hz, 5 V) of the left cervicothoracic ganglion during normal perfusion causes the overflow of 177.5 +/- 13.7 pmol noradrenaline/g heart, whereas such stimulation during ischemia liberates only 21.5 +/- 3.6 pmol/g (collected during reperfusion). When neuronal reuptake is blocked by desipramine, corresponding values are 321.5 +/- 22.5 pmol/g (normal flow) and 151.8 +/- 22.4 pmol/g (ischemia). After combined blockade of neuronal uptake, extraneuronal uptake, and alpha 2-receptors, nerve stimulation liberates 674 +/- 22 pmol/g during normal flow and 206 +/- 24.3 pmol/g during ischemia. These results suggest that, in vivo, centrally originating neural activity would not lead to substantial accumulation of noradrenaline within the extracellular space of the ischemic myocardium. This failure of accumulation is due to both a functioning neuronal uptake of noradrenaline and a failure of neurotransmission.
Examining punishment at different explanatory levels
Authors: Miguel dos Santos, Claus Wedekind
Journal: Behavioral and Brain Sciences (2012)

Abstract Experimental studies on punishment have sometimes been over-interpreted not only for the reasons Guala lists, but also because of a frequent conflation of proximate and ultimate explanatory levels that Guala's review perpetuates. Moreover, for future analyses we may need a clearer classification of different kinds of punishment.