tbuckley/cabot-search huggingface dataset:
Phase I Clinical and Pharmacokinetic Study of Plitidepsin as a 1-Hour Weekly Intravenous Infusion in Patients with Advanced Solid Tumors
Authors: Miguel A. Izquierdo, Angela Bowman, Margarita García, Duncan Jodrell, Marisa Martinez, Beatriz Pardo, Javier Gómez, José A. López-Martin, José Jimeno, José R. Germá, John F. Smyth
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Plitidepsin, given as a 1-hour weekly i.v. infusion for 3 consecutive weeks during a 4-week treatment cycle, was investigated in patients with solid tumors to determine the maximum tolerated dose and the recommended dose (RD) using this administration schedule. Experimental Design: Consecutive cohorts of patients with metastatic solid tumors or non–Hodgkin's lymphomas were to be treated at escalating doses of plitidepsin in a conventional phase I study including pharmacokinetic analyses of plitidepsin in plasma, whole blood, and blood cell pellets. Results: Forty-nine patients with solid tumors were enrolled, and 48 were treated with plitidepsin (doses from 0.133 to 3.6 mg/m2/week). Dose-limiting toxicities (defining 3.6 mg/m2/week as the maximum tolerated dose) included myalgia, increased creatine phosphokinase levels, and sustained grade 3/4 increases of hepatic enzyme levels. The RD was established at 3.2 mg/m2/week. The most common toxicities were fatigue, vomiting/nausea, anorexia, injection site reaction, and pain, mostly of mild or moderate severity. Muscular toxicity manifested by mild-moderate myalgia, weakness, and/or creatine phosphokinase elevations occurred in ∼25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only ∼10% of patients. Plitidepsin lacked significant hematologic toxicity. No complete or partial tumor responses were observed; however, five patients had disease stabilization (including one patient with medullary thyroid carcinoma with an unconfirmed partial response and one patient with renal carcinoma with major tumor shrinkage in lung metastases). Pharmacokinetic results for the RD indicated a long plasma half-life give value (16.8 ± 7.7 hour) and a high volume of distribution value (525.2 ± 219.3 L). Conclusions: The recommended dose for plitidepsin given as a weekly 1-hour schedule was 3.2 mg/m2/week. Muscular and liver toxicity were dose limiting at 3.6 mg/m2/week. Additional evaluation of this dose dense schedule is warranted.
Iliac crest trabecular bone mass and structure in patients with non-steroid treated rheumatoid arthritis.
Authors: R W Mellish, M M O'Sullivan, N J Garrahan, J E Compston
Journal: Annals of the Rheumatic Diseases (1987)

Iliac crest trabecular bone volume and structure have been studied in bone biopsy specimens from 48 patients with classical or definite rheumatoid arthritis, none of whom had received steroids. Results were compared with those obtained from healthy controls matched for age and sex. The mean trabecular bone volume in female patients aged 34-50 years was significantly lower than in controls (p less than 0.01); in male patients aged 34-50 years values were also lower than those in controls (mean (SD) 17.8 (3.2) v 22.4 (5.6)% total medullary volume), though this difference was not statistically significant. Values in older patients were similar to those of controls. The mean trabecular plate thickness was significantly lower in female patients in all three age groups when compared with the controls (p less than 0.005, 0.05, and 0.005). Similar but non-significant changes were seen in male patients. The mean trabecular plate density, an index of trabecular number, and the mean trabecular plate separation showed no age related change in either male or female patients, in contrast with the female control group, in whom the mean trabecular plate density decreased and separation increased with age. These results suggest that non-steroid treated rheumatoid arthritis is associated with premature bone loss, the structural basis of which is trabecular thinning.
Cardiac-generated prostanoids mediate cardiac myocyte apoptosis after myocardial ischaemia
Authors: Hong Qiu, Jun-Yan Liu, Dongguang Wei, Ning Li, Ebenezer N. Yamoah, Bruce D. Hammock, Nipavan Chiamvimonvat
Journal: Cardiovascular Research (2012)

The objective of the present study is to elucidate the pathogenic role of eicosanoids in myocardial infarction (MI). The accumulation of eicosanoid metabolites in ischaemic myocardium has been demonstrated in animal models and patients with MI, and it occurs in parallel with the development of irreversible cardiac damage. However, the key question that remains unanswered is whether cardiac-generated eicosanoids are the cause or the consequence of cardiac cell damage in MI.We used a clinically relevant animal model of MI and metabolic profiling to monitor the eicosanoid profile in ischaemic myocardium. We demonstrate that ischaemia induces the generation of prostanoids mainly through the cyclooxygenase (COX)-1 pathway in the myocardium. Cardiac-generated prostanoids, particularly prostaglandin D(2) (PGD(2)), can directly induce apoptosis in cardiac myocytes. This effect involves the up-regulation of the pro-apoptotic gene, Fas ligand (FasL), in a D-type prostanoid receptor-independent manner. The treatment of the MI mice with low-dose aspirin effectively inhibits the ischaemia-induced prostanoid generation and FasL expression in the myocardium, leading to the reduction in cardiac apoptosis following cardiac ischaemia.Cardiac ischaemia results in COX-1-mediated generation of prostanoids, which by inducing cardiac myocyte apoptosis, contribute to the cardiac cell loss following MI. The benefits of low-dose aspirin treatment in MI may be attributable, in part, to the inhibition of cardiac prostanoid generation and attenuation of apoptosis. Further understanding of the mechanisms underlying prostanoid-induced cardiac apoptosis may be of significant value in designing new therapeutic strategies to prevent aberrant cell loss following MI and subsequent progression to heart failure.
Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines
Authors: Philip S. Lecane, Mazen W. Karaman, Mint Sirisawad, Louie Naumovski, Richard A. Miller, Joseph G. Hacia, Darren Magda
Journal: Cancer Research (2005)

Abstract There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element–binding transcription factor-1 (MTF-1)–regulated and hypoxia-inducible transcription factor-1 (HIF-1)–regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1– and HIF-1–regulated transcripts as well as additional transcripts regulated by NF-E2–related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies. (Cancer Res 2005; 65(24): 11676-88)
Inhibition of TNF during maturation of dendritic cells results in the development of semi-mature cells: a potential mechanism for the beneficial effects of TNF blockade in rheumatoid arthritis
Authors: A W T van Lieshout, P Barrera, R L Smeets, G J Pesman, P L C M van Riel, W B van den Berg, T R D J Radstake
Journal: Annals of the Rheumatic Diseases (2004)

Dendritic cells orchestrate pivotal immunological processes mediated by the production of cytokines and chemokines.To assess whether neutralisation of tumour necrosis factor alpha (TNF alpha) during maturation of dendritic cells affects their phenotype and behaviour, which might explain the beneficial effects of TNF alpha neutralisation in rheumatoid arthritis.Immature and fully matured dendritic cells were cultured from blood monocytes from patients with rheumatoid arthritis and healthy controls following standardised protocols. TNF alpha was neutralised by addition of the p55 soluble TNF alpha receptor, PEGsTNFRI. The effect of TNF alpha neutralisation on the phenotype (CD14, CD16, CD32, CD64, CD80, CD83, CD86, and MHC) of dendritic cells was investigated by flow cytometry. Expression of chemokines (CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8) and production of IL1 beta and IL6 during dendritic cell differentiation and maturation were examined.Neutralisation of TNF alpha during the differentiation and maturation of dendritic cells did not result in an altered dendritic cell phenotype in the rheumatoid patients or the healthy controls. In contrast, the expression of CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8 by dendritic cells was significantly reduced when TNF alpha activity was inhibited during lipopolysaccharide triggered dendritic cell maturation. The production of IL1 beta and IL6 by mature dendritic cells was inhibited by PEGsTNFRI.Inhibition of TNF alpha activity during dendritic cell maturation leads to the development of semi-mature cells. These data suggest a novel pathway by which the neutralisation of TNF alpha might exert its therapeutic effects.
Capacity and consent
Authors: B. J. Rushforth
Journal: Journal of the Royal Society of Medicine (2003)

Dr Jackson and Dr Warner highlight worrying deficiencies in clinicians' judgments on capacity and consent to treatment (December 2002 JRSM1). Unfortunately, their summary may further confuse matters by stating that, ‘15% of all respondents wrongly believed that a competent adult could lawfully be treated against his or her will’. In fact, competent adults can be lawfully treated against their will, in certain clearly defined circumstances. The key omission here is the phrase, ‘under common law’ (which was included in the question posed to doctors). This was no doubt an oversight, but it draws attention to a related concern—namely, that doctors (and medical students) often seem to conflate judgments about capacity and the common law with judgments about mental disorder and the Mental Health Act, when discussing whether patients can be treated without their consent. In fact such judgments should be clearly distinct. Someone with a mental disorder who is detained under the Act may still meet the capacity criteria (and thereby be judged competent) to consent to, or refuse, certain medical treatments2. Contrariwise, an individual without a mental disorder may fail to meet the capacity threshold, and be deemed incompetent.

Jackson and Warner also found that medical students were very poor at identifying the criteria for capacity, with only 15% doing so correctly. That students are misinformed about issues of medical ethics and law is not surprising. In a recent teaching session, a senior doctor insisted to our group that in England an adult (such as a spouse) could consent to medical treatment on behalf of another adult. Until the teachers are correctly informed about these important issues, what hope for their students?
Learning and Memory in the Vestibulo-Ocular Reflex
Authors: S Lac, J L Raymond, T J Sejnowski, S G Lisberger
Journal: Annual Review of Neuroscience (1995)

Studies of the neural basis of learning and memory in intact animals must, by their nature, start from the top by choosing a behavior that can be modified through learning, revealing how iaeuronal activity gives rise to that behavior, and then investigating, in the awake, behaving animal, changes in neural signaling that are associated with learning. Such studies also must recognize that the learning and memory expressed in the behavior of an animal will reflect both the properties of the neural network that mediates the behavior and the nature of the underlying changes in the operation of cells or synapses. In the past 10 years, there has been an explosion of information about learning and memory in the vestibulo-ocular reflex (VOR) of the awake, behaving monkey. At the same time, there have been unprecedented advances in understanding mechanisms of cellular plasticity such as long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum. A prerequisite for understanding learning and memory is to elevate specific mechanisms of cellular plasticity into cellular mechanisms of learning by establishing their function in the context of a neural system that mediates learning and memory in a particular behavior. Our review synthesizes the
The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog−driven medulloblastoma
Authors: Xuelian He, Liguo Zhang, Ying Chen, Marc Remke, David Shih, Fanghui Lu, Haibo Wang, Yaqi Deng, Yang Yu, Yong Xia, Xiaochong Wu, Vijay Ramaswamy, Tom Hu, Fan Wang, Wenhao Zhou, Dennis K Burns, Se Hoon Kim, Marcel Kool, Stefan M Pfister, Lee S Weinstein, Scott L Pomeroy, Richard J Gilbertson, Joshua B Rubin, Yiping Hou, Robert Wechsler-Reya, Michael D Taylor, Q Richard Lu
Journal: Nature Medicine (2014)
Pharmacokinetics of Once Daily Intraperitoneal Cefazolin in Continuous Ambulatory Peritoneal Dialysis Patients
Authors: CHAI LUAN LOW, KAMANI GOPALAKRISHNA, WAI CHOONG LYE
Journal: Journal of the American Society of Nephrology (2000)

Abstract. This study determined the pharmacokinetic characteristics of once daily intraperitoneal (IP) cefazolin in continuous ambulatory peritoneal dialysis (CAPD) patients. Each of the 10 volunteer CAPD patients without active peritonitis received a single IP dose of 1 g of cefazolin sodium for a 6-h dwell. All patients underwent a fixed CAPD regimen comprising a first 6-h dwell followed by two 3-h dwells and a final 12-h overnight dwell. Blood and dialysate samples were collected at 0, 0.5, 1, 2, 3, 6 (end of first dwell), and 24 h after the administration of IP cefazolin. Any urine produced was collected over the 24-h study period. A validated HPLC method was used to analyze cefazolin in plasma, dialysate, and urine. The bioavailability was found to be 77.9 ± 3.1%, volume of distribution 0.20 ± 0.05 L/kg, and plasma half-life 39.9 ± 25.4 h. Mean total, renal, and peritoneal clearances were 4.5 ± 2.3, 1.4 ± 1.1, and 3.5 ± 1.8 ml/min, respectively. Mean plasma and dialysate concentrations at 24 h were 42.8 ± 14.3 and 31.8 ± 11.7 mcg/ml, respectively, well above the minimum inhibitory concentrations (MIC) of susceptible organisms. A once daily IP cefazolin dose of 500 mg/L gave desirable pharmacokinetic attributes for use as a suitable alternative to vancomycin for empiric treatment of CAPD-associated peritonitis.
Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate
Authors: Nicole M. Okeley, Jamie B. Miyamoto, Xinqun Zhang, Russell J. Sanderson, Dennis R. Benjamin, Eric L. Sievers, Peter D. Senter, Stephen C. Alley
Journal: Clinical Cancer Research (2010)

SGN-35 is an antibody-drug conjugate (ADC) containing the potent antimitotic drug, monomethylauristatin E (MMAE), linked to the anti-CD30 monoclonal antibody, cAC10. As previously shown, SGN-35 treatment regresses and cures established Hodgkin lymphoma and anaplastic large cell lymphoma xenografts. Recently, the ADC has been shown to possess pronounced activity in clinical trials. Here, we investigate the molecular basis for the activities of SGN-35 by determining the extent of targeted intracellular drug release and retention, and bystander activities.SGN-35 was prepared with (14)C-labeled MMAE. Intracellular ADC activation on CD30(+) and negative cell lines was determined using a combination of radiometric and liquid chromatograhpy/mass spectrometry-based assays. The bystander activity of SGN-35 was determined using mixed tumor cell cultures consisting of CD30(+) and CD30(-) lines.SGN-35 treatment of CD30(+) cells leads to efficient intracellular release of chemically unmodified MMAE, with intracellular concentrations of MMAE in the range of 500 nmol/L. This was due to specific ADC binding, uptake, MMAE retention, and receptor recycling or resynthesis. MMAE accounts for the total detectable released drug from CD30(+) cells, and has a half-life of retention of 15 to 20 h. Cytotoxicity studies with mixtures of CD30(+) and CD30(-) cell lines indicated that diffusible released MMAE from CD30(+) cells was able to kill cocultivated CD30(-) cells.MMAE is efficiently released from SGN-35 within CD30(+) cancer cells and, due to its membrane permeability, is able to exert cytotoxic activity on bystander cells. This provides mechanistic insight into the pronounced preclinical and clinical antitumor activities observed with SGN-35.
Sialylation Determines the Nephritogenicity of IgG3 Cryoglobulins
Authors: Masako Otani, Aki Kuroki, Shuichi Kikuchi, Masao Kihara, Junichiro Nakata, Kiyoaki Ito, Jun-ichi Furukawa, Yasuro Shinohara, Shozo Izui
Journal: Journal of the American Society of Nephrology (2012)

Monoclonal 6-19 IgG3 anti-IgG2a rheumatoid factor derived from lupus-prone MRL-Fas(lpr) mice can induce GN and cryoglobulinemia, but the features that confer nephritogenic potential are not completely understood. Asparagine-linked oligosaccharide chains of 6-19 IgG3 mAb are poorly galactosylated and hardly sialylated, possibly contributing to the pathogenic potential of 6-19 IgG3 rheumatoid factors. Here, we used the 6-19 model of cryoglobulin-associated GN to define the relative contributions of galactosylation and sialylation, in relation to cryoglobulin activity, to the nephritogenic potential of IgG3 antibodies. We generated one highly sialylated and two distinct more galactosylated 6-19 IgG3 rheumatoid factor variants. Although the mere extent of galactosylation had no effect on either the cryogenic and nephritogenic activities of 6-19 IgG3 rheumatoid factor, terminal sialylation attenuated the nephritogenic potential of 6-19 IgG3 by limiting its cryoglobulin activity. These data suggest a protective role of IgG sialylation against the development of cryoglobulin-mediated GN, highlighting the anti-inflammatory activity of sialylated IgG antibodies.
Molecular Pharmacology of Botulinum Toxin and Tetanus Toxin
Authors: L L Simpson
Journal: The Annual Review of Pharmacology and Toxicology (1986)

Botulinum toxin is a term that has been used to describe eight different substances designated types A, B, Cb C2, D, E, F, and G. For many years it was assumed that these eight substances acted at the neuromuscular junction to block acetylcholine release. It is now known that this assumption is not entirely correct. Seven Of the substances do act at cholinergic junctions (types A, B, C b D, E, F, and G), and they are properly referred to as botulinum neurotoxins. The eighth substance (type C2) is unique in its structure and pharmacological actions. It is called the botulinum binary toxin. Tetanus toxin is a term that has been used to describe a single substance that acts mainly in the central nervous system to block inhibitory transmission. There are many similarities between tetanus toxin and botulinum neurotoxin, including a common origin, a closely related structure, and perhaps the same subcellular mechanism of action. The similarities between tetanus toxin and the botulinum binary toxin are less clear. The purpose of the present review is to discuss the proposed mechanism( s) of action of the three groups of clostridial toxins. Recent findings suggest that research is moving quickly toward a full determination of the cellular and subcellular actions of these substances. This is an encouraging tum of events, because the clostridial toxins are generally regarded as the most poisonous substances known to mankind.
STAT5A-Mediated SOCS2 Expression Regulates Jak2 and STAT3 Activity Following c-Src Inhibition in Head and Neck Squamous Carcinoma
Authors: Banibrata Sen, Shaohua Peng, Denise M. Woods, Ignacio Wistuba, Diana Bell, Adel K. El-Naggar, Stephen Y. Lai, Faye M. Johnson
Journal: Clinical Cancer Research (2011)

The inhibition of c-Src results in a striking reduction in cancer cell invasion, but the effect on cell survival is modest. Defining mechanisms that limit apoptosis following c-Src inhibition could result in an ideal therapeutic approach that both inhibits invasion and leads to apoptosis. In this regard, we discovered a novel feedback loop that results in STAT3 reactivation following sustained c-Src inhibition. Here we define the mechanism underlying this feedback loop and examine the effect of inhibiting it in vivo.We measured levels and activity of pathway components using PCR, Western blotting, and kinase assays following their manipulation using both molecular and pharmacologic approaches. We used a heterotransplant animal model in which human oral squamous cancer is maintained exclusively in vivo.Following c-Src inhibition, STAT5 is durably inhibited. The inhibition of STAT5A, but not STAT5B, subsequently reduces the expression of suppressors of cytokine signaling 2 (SOCS2). SOCS2 inhibits Janus kinase 2 (Jak2) activity and Jak2-STAT3 binding. SOCS2 expression is necessary for STAT3 inhibition by c-Src inhibitors. Overexpression of SOCS2 is adequate to prevent STAT3 reactivation and to enhance the cytotoxic effects of c-Src inhibition. Likewise, the combination of Jak and c-Src inhibitors led to significantly more apoptosis than either agent alone in vivo.To our knowledge, ours is the first study that fully defines the mechanism underlying this feedback loop, in which sustained c-Src inhibition leads to diminished SOCS2 expression via sustained inhibition of STAT5A, allowing activation of Jak2 and STAT3, Jak2-STAT3 binding, and survival signals.
What Is the Role of β-Adrenergic Signaling in Heart Failure?
Authors: Martin J. Lohse, Stefan Engelhardt, Thomas Eschenhagen
Journal: Circulation Research (2003)

This review addresses open questions about the role of β-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three β-adrenergic receptor subtypes—β 1 , β 2 , and, at least in some species, β 3 . The β 1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The β 2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the β 1 subtype. In heart failure, the sympathetic system is activated, cardiac β-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, β-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the β-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.