tbuckley/cabot-search huggingface dataset:
Inhibition of Carboplatin-Induced DNA Interstrand Cross-link Repair by Gemcitabine in Patients Receiving these Drugs for Platinum-Resistant Ovarian Cancer
Authors: Jonathan A. Ledermann, Hani Gabra, Gordon C. Jayson, Victoria J. Spanswick, Gordon J.S. Rustin, Mark Jitlal, Lindsay E. James, John A. Hartley
Journal: Clinical Cancer Research (2010)

Abstract Background: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair. Patients and Methods: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m2 with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation. Results: The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA cross-links following administration of gemcitabine. Conclusion: An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule. Clin Cancer Res; 16(19); 4899–905. ©2010 AACR.
The beta-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice
Authors: Junpei Soeda, Angelina Mouralidarane, Shuvra Ray, Marco Novelli, Steven Thomas, Tania Roskams, Anna Mae Diehl, Jude A. Oben
Journal: Hepatology (2014)

Acetaminophen (APAP)-induced acute liver injury (AILI) is a major health problem. Accumulating evidence suggests that the sympathetic nervous system (SNS) regulates neuronal and hematopoietic progenitors. SNS signaling affects hepatic progenitor/oval cells (HPCs) and β-adrenoceptor agonism will expand HPCs to reduce AILI. Dopamine β-hydroxylase-deficient mice (Dbh −/− ), lacking catecholamine SNS neurotransmitters, isolated HPCs, and immature ductular 603B cells were initially used to investigate SNS involvement in HPC physiology. Subsequently, control mice were treated with APAP (350 mg/kg) followed by the β-adrenoceptor agonist, isoproterenol (ISO), or the β-adrenoceptor antagonist, propranolol. Mechanistic studies examined effects of non-SNS HPC expansion on AILI, involvement of the canonical Wnt/β-catenin pathway (CWP) in the action of ISO on HPC expansion and comparison of ISO with the current standard of care, N -acetylcysteine (NAC). Dbh −/− mice lacking catecholamines had low HPC numbers, reconstituted by ISO. In vitro , ISO-induced proliferation of 603B cells was CWP dependent. In control mice, AILI raised HPC numbers, further increased by ISO, with attenuation of liver injury. Delayed administration of NAC did not, but delayed ISO did, reverse AILI. Propranolol worsened AILI. AILI activated the CWP, and ISO enhanced Wnt-ligand production. HPCs were the major source of Wnt ligands. Recombinant Wnt3a and ISO-603B-conditioned media, but not ISO alone, protected isolated hepatocytes from death, reversed by DKK1—a Wnt antagonist. Additionally, tumor-associated weak inducer of apoptosis expanded HPCs and protected against AILI. Furthermore, allotransplantation of HPCs from APAP+ISO-treated mice to other APAP-injured mice improved AILI, an effect antagonized by DKK1. Conclusion : SNS catecholamines expand HPCs, which are both targets and sources of Wnt ligands. Hepatoprotection by ISO is mediated by para- and autocrine effects of Wnt signaling. ISO represents novel pharmacotherapy for AILI. (Hepatology 2014;60:1023–1034)
Physical Performance Limitations in the Childhood Cancer Survivor Study Cohort
Authors: Kirsten K. Ness, Melissa M. Hudson, Jill P. Ginsberg, Rajaram Nagarajan, Sue C. Kaste, Neyssa Marina, John Whitton, Leslie L. Robison, James G. Gurney
Journal: Journal of Clinical Oncology (2009)

Physical performance limitations are one of the potential long-term consequences following diagnosis and treatment for childhood cancer. The purpose of this review is to describe the risk factors for and the participation restrictions that result from physical performance limitations among childhood cancer survivors who participated in the Childhood Cancer Survivor Study (CCSS). Articles previously published from the CCSS cohort related to physical performance limitations were reviewed and the results summarized. Our review showed that physical performance limitations are prevalent among childhood cancer survivors and may increase as they age. Host-based risk factors for physical disability include an original diagnosis of bone tumor, brain tumor, or Hodgkin's disease; female sex; and an income less than $20,000 per year. Treatment-based risk factors include radiation and treatment with a combination of alkylating agents and anthracyclines. Musculoskeletal, neurologic, cardiac, pulmonary, sensory, and endocrine organ system dysfunction also increase the risk of developing a physical performance limitation. In summary, monitoring of physical performance limitations in an aging cohort of childhood cancer survivors is important and will help determine the impact of physical performance limitations on morbidity, mortality, and caregiver burden. In addition, in developing restorative and preventive interventions for childhood cancer survivors, we must take into account the special needs of survivors with physical disability to optimize their health and enhance participation in daily living activities.
Analysis of HLA-DR glycoproteins by DNA-mediated gene transfer. Definition of DR2 beta gene products and antigen presentation to T cell clones from leprosy patients.
Authors: D Wilkinson, R R de Vries, J A Madrigal, C B Lock, J P Morgenstern, J Trowsdale, D M Altmann
Journal: The Journal of Experimental Medicine (1988)

We have used DNA-mediated gene transfer to express HLA class II molecules in mouse L cells for serological, biochemical, and functional analysis. cDNA clones encoding the DR2 beta a and DR2 beta b products of the DR2Dw2 haplotype were subcloned into a mouse Moloney leukemia virus-based expression vector (pJ4) and transfected separately into mouse L cells together with a HLA-DR alpha/pJ4 construct. These transfectants have allowed differential analysis of the two DR2 beta products in a manner normally prohibited by the concomitant expression seen in B cells. Two-dimensional SDS-PAGE analysis of the transfectants defines the more acidic beta chain as the product of the DR2 beta a sequence, and the more basic chain as the product of the DR2 beta b sequence. The LDR2a transfectants present antigen efficiently to M.leprae-specific T cell clones and are capable of presenting synthetic peptide, 65-kD recombinant mycobacterial antigen and M.leprae. Of the DR2Dw2-restricted T cell clones we have tested, all use the DR2 beta a chain as their restriction element. Inhibition studies with mAbs demonstrate the dependence of presentation by the transfectant on class II and CD4, while mAbs against LFA-1, which substantially inhibit presentation by B-lymphoblastoid cell lines, do not inhibit transfectant presentation.
The prokaryotic antecedents of the ubiquitin-signaling system and the early evolution of ubiquitin-like beta-grasp domains.
Authors: Lakshminarayan M Iyer, A Maxwell Burroughs, L Aravind
Journal: Genome biology (2006)

Ubiquitin (Ub)-mediated signaling is one of the hallmarks of all eukaryotes. Prokaryotic homologs of Ub (ThiS and MoaD) and E1 ligases have been studied in relation to sulfur incorporation reactions in thiamine and molybdenum/tungsten cofactor biosynthesis. However, there is no evidence for entire protein modification systems with Ub-like proteins and deconjugation by deubiquitinating enzymes in prokaryotes. Hence, the evolutionary assembly of the eukaryotic Ub-signaling apparatus remains unclear.We systematically analyzed prokaryotic Ub-related beta-grasp fold proteins using sensitive sequence profile searches and structural analysis. Consequently, we identified novel Ub-related proteins beyond the characterized ThiS, MoaD, TGS, and YukD domains. To understand their functional associations, we sought and recovered several conserved gene neighborhoods and domain architectures. These included novel associations involving diverse sulfur metabolism proteins, siderophore biosynthesis and the gene encoding the transfer mRNA binding protein SmpB, as well as domain fusions between Ub-like domains and PIN-domain related RNAses. Most strikingly, we found conserved gene neighborhoods in phylogenetically diverse bacteria combining genes for JAB domains (the primary de-ubiquitinating isopeptidases of the proteasomal complex), along with E1-like adenylating enzymes and different Ub-related proteins. Further sequence analysis of other conserved genes in these neighborhoods revealed several Ub-conjugating enzyme/E2-ligase related proteins. Genes for an Ub-like protein and a JAB domain peptidase were also found in the tail assembly gene cluster of certain caudate bacteriophages.These observations imply that members of the Ub family had already formed strong functional associations with E1-like proteins, UBC/E2-related proteins, and JAB peptidases in the bacteria. Several of these Ub-like proteins and the associated protein families are likely to function together in signaling systems just as in eukaryotes.
The −174G/C Interleukin-6 Polymorphism Influences Postoperative Interleukin-6 Levels and Postoperative Atrial Fibrillation. Is Atrial Fibrillation an Inflammatory Complication?
Authors: Mario Gaudino, Felicita Andreotti, Roberto Zamparelli, Augusto Di Castelnuovo, Giuseppe Nasso, Francesco Burzotta, Licia Iacoviello, Maria Benedetta Donati, Rocco Schiavello, Attilio Maseri, Gianfederico Possati
Journal: Circulation (2003)

Background— It has been suggested that inflammation can have a role in the development of atrial arrhythmias after cardiac surgery and that a genetic predisposition to develop postoperative complications exists. This study was conceived to verify if a potential genetic modulator of the systemic inflammatory reaction to cardiopulmonary bypass (the −174 G/C polymorphism of the promoter of the Interleukin-6 gene) has a role in the pathogenesis of postoperative atrial fibrillation (AF). Patients and Results— In 110 primary isolated coronary artery bypass patients the −174G/C Interleukin-6 promoter gene variant was determined. Interleukin-6, fibrinogen and C-reactive protein plasma levels were determined preoperatively, 24, 48, and 72 hours after surgery and at discharge. Heart rate and rhythm were continuously monitored for the first 36 to 48 hours; daily 12-lead electrocardiograms were performed thereafter until discharge. GG, CT, and CC genotypes were found in 62, 38, and 10 patients, respectively. Multivariate analysis (which included genotype, age, sex, and classical risk factors for AF) identified the GG genotype as the only independent predictor of postoperative AF. The latter occurred in 33.9% of GG versus 10.4% of non-GG patients (hazard ratio 3.25, 95%CI 1.23 to 8.62). AF patients had higher blood levels of Interleukin-6 and fibrinogen after surgery ( P &lt;0.001 for difference between the area under the curve). Conclusion— The −174G/C Interleukin-6 promoter gene variant appears to modulate the inflammatory response to surgery and to influence the development of postoperative AF. These data suggest an inflammatory component of postoperative atrial arrhythmias and a genetic predisposition to this complication.
Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis
Authors: J Zochling
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To assess available management strategies in ankylosing spondylitis (AS) using a systematic approach, as a part of the development of evidence based recommendations for the management of AS. <b>Methods:</b> A systematic search of Medline, Embase, CINAHL, PEDro, and the Cochrane Library was performed to identify relevant interventions for the management of AS. Evidence for each intervention was categorised by study type, and outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, rate ratio, number needed to treat, and incremental cost effectiveness ratio were calculated for each intervention where possible. Results from randomised controlled trials were pooled where appropriate. <b>Results:</b> Both pharmacological and non-pharmacological interventions considered to be of interest to clinicians involved in the management of AS were identified. Good evidence (level Ib) exists supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs for symptomatic treatment. Non-pharmacological treatments are also supported for maintaining function in AS. The use of conventional antirheumatoid arthritis drugs is not well supported by high level research evidence. Tumour necrosis factor inhibitors (infliximab and etanercept) have level Ib evidence supporting large treatment effects for spinal pain and function in AS over at least 6 months. Level IV evidence supports surgical interventions in specific patients. <b>Conclusion:</b> This extensive literature review forms the evidence base considered in the development of the new ASAS/EULAR recommendations for the management of AS.
<i>BJSM</i>reviews: A to Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance—Part 18
Authors: P Newsholme, M Krause, E A Newsholme, S J Stear, L M Burke, L M Castell
Journal: British Journal of Sports Medicine (2011)

Part 18 extends the general amino acids overview in Part 2, by reviewing specifically glutamine and glutamate, and the tripeptide antioxidant, glutathione.

Glutamine supplementation has been well studied in both clinical and exercise situations, particularly in terms of its effects on immune function. Sports drinks containing glutamine as a free amino acid or part of a dipeptide are widely available but the low levels recommended are unlikely to help improve immune or muscle function.

The first product of glutamine metabolism, catalysed by the enzyme glutaminase, is the excitatory neurotransmitter glutamate. The latter has sometimes been used for supplementation. This may seem rather surprising, since its appearance in plasma at a high concentration correlates neurotoxicity and sometimes with clinical problems.

Glutathione, for which glutamine is a precursor via glutamate, is a powerful antioxidant and, in its reduced form, is a good marker of antioxidant capacity, while an increase in its oxidised form is a good marker of oxidative stress.

### P Newsholme and M Krause

Glutathione (γ-glutamyl-cysteinyl-glycine; GSH) is the predominant low molecular weight thiol (0.5–10 mmol/l) in mammalian cells. Most GSH (85–90%) is cytosolic, with the remainder located in organelles (including mitochondria, nuclear matrix and peroxisomes).1 This tripeptide is a key antioxidant within cells, critical to regulating the reactive oxygen species (ROS) concentration.2 Reduced glutathione (GSH) may be used to remove damaging ROS such as H2O2 and convert it to harmless H2O, generating oxidised glutathione (GSSG) via glutathione peroxidase (figure 1). Disulphide formation and gluathionylation are reversible forms of protein covalent modification dependent on glutathione and can provide mechanisms for regulation of metabolic, signalling and transcriptional processes,3 including skeletal muscle adaptation to exercise and training.4 The cellular redox state is crucial for molecular signalling, and glutathione is a key regulator/sensor for redox status; thus strategies aiming at …
IMMUNOCHEMICAL STUDIES ON THE ANTIGENIC DETERMINANTS REQUIRED TO ELICIT DELAYED AND IMMEDIATE HYPERSENSITIVITY REACTIONS
Authors: Stuart F. Schlossman, Shlomo Ben-Efraim, Arieh Yaron, Herbert A. Sober
Journal: The Journal of Experimental Medicine (1966)

Hartley and strain 2 guinea pigs were sensitized to chemically defined α-DNP(Lys)n-BuAm, α-DNP(Lys)n-, and (Lys)n-BuAm peptides and skin tested with individual members of these homologous series, related peptides and hapten-substituted proteins. The immediate skin response (Arthus) could be elicited with hapten-substituted tetra-, penta-, or hexamers, whereas both immediate and delayed skin responses could be provoked by the octamer or nonamer. The hapten is an integral part of the determinant for both immediate and delayed skin reactivity, since poly-L-lysine was unable to elicit either delayed or immediate reactions in sensitized animals. Arthus type cross-reactions occurred only when the sensitizing and test antigen shared a common haptenic determinant. In contrast to this, in this system, delayed type cross-reactions occurred only when the test antigen and the sensitizing antigen contained both a large oligo-L-lysine carrier as well as the same haptenic determinant. These observations imply that the mediation of the delayed response requires a larger determinant than is necessary to elicit the immediate response. The role of high affinity antibody as the mediator of the delayed response is discussed in terms of the size of the antigenic determinants required to elicit this response. It was found that the ability to elicit the delayed response paralleled the immunogenic capacity of these peptides, whereas the immediate response could be elicited by nonimmunogenic peptides. This finding suggests that the delayed response may require the continued biosynthesis of antibody and may be analogous to a local in vivo secondary response.
The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co-glycolic acid) microparticles
Authors: Davidson D. Ateh, Veronica H. Leinster, Sally R. Lambert, Afsha Shah, Ayub Khan, Hazel J. Walklin, Jennifer V. Johnstone, Nader I. Ibrahim, Mustafa M. Kadam, Zain Malik, Míriam Gironès, Gert J. Veldhuis, Gary Warnes, Silvia Marino, Iain A. McNeish, Joanne E. Martin
Journal: Biomaterials (2011)
Non-Specific Abdominal Pain-an Expensive Mystery
Authors: S K Raheja, P J McDonald, I Taylor
Journal: Journal of the Royal Society of Medicine (1990)

Non-specific abdominal pain (NSAP) is a common cause of urgent admission to surgical wards. We studied 80 such patients prospectively. NSAP was commonest in female patients under 30. The pain was localized in the right lower quadrant in 32 patients (40%) and in 56 (70%) the pain was aggravated by movement. Viral studies failed to show any abnormality except in one patient with raised acute and convalescent titres but three patients had raised antistreptolysin 0 titres. The psychological results demonstrated that the NSAP group had the same levels of anxiety and depression as the control group and also had no evidence of increased preceding life events.
Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart
Authors: Ralph R. Alcendor, Shumin Gao, Peiyong Zhai, Daniela Zablocki, Eric Holle, Xianzhong Yu, Bin Tian, Thomas Wagner, Stephen F. Vatner, Junichi Sadoshima
Journal: Circulation Research (2007)

Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4- to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.
Phase II Study of Denileukin Diftitox for Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
Authors: Nam H. Dang, Fredrick B. Hagemeister, Barbara Pro, Peter McLaughlin, Jorge E. Romaguera, Dan Jones, Barry Samuels, Felipe Samaniego, Anas Younes, Michael Wang, Andre Goy, Maria A. Rodriguez, Pamela L. Walker, Yolanda Arredondo, Ann T. Tong, Luis Fayad
Journal: Journal of Clinical Oncology (2004)

Purpose Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. Patients and Methods Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 μg/kg once daily for 5 days every 3 weeks, up to eight cycles. Results Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25− histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. Conclusion Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25− B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.