bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of the HPV16E7 Oncoprotein by Thymic Epithelium is Accompanied by Disrupted T Cell Maturation and a Failure of the Thymus to Involute with Age
Authors: Malcolm K. M. , Gill J. , Leggatt G. R. , Boyd R. , Lambert P. , Frazer I. H. 
Published: December 2003

Transgenic mice expressing the E7 protein of HPV16 from the keratin 14 promoter demonstrate increasing thymic hypertrophy with age. This hypertrophy is associated with increased absolute numbers of all thymocyte types, and with increased cortical and medullary cellularity. In the thymic medulla, increased compartmentalization of the major thymic stromal cell types and expansion of thymic epithelial cell population is observed. Neither an increased rate of immature thymocyte division nor a decreased rate of immature thymocyte death was able to account for the observed hypertrophy.Thymocytes with reduced levels of expression of CD4 and/or CD8 were more abundant in transgenic (tg) mice and became increasingly more so with age. These thymic SP and DP populations with reduced levels of CD4 and/or CD8 markers had a lower rate of apoptosis in the tg than in the non‐tg mice. The rate of export of mature thymocytes to peripheral lymphoid organs was less in tg animals relative to the pool of available mature cells, particularly for the increasingly abundant CD4lo population. We therefore suggest that mature thymocytes that would normally die in the thymus gradually accumulated in E7 transgenic animals, perhaps as a consequence of exposure to a hypertrophied E7‐expressing thymic epithelium or to factors secreted by this expanded thymic stromal cell population. The K14E7 transgenic mouse thus provides a unique model to study effects of the thymic epithelial cell compartment on thymus development and involution.
Characterization of a Lipoyl Domain‐Independent B‐Cell Autoepitope on the Human Branched‐Chain Acyltransferase in Primary Biliary Cirrhosis and Overlap Syndrome with Autoimmune Hepatitis
Authors: Csepregi Antal , Obermayer-Straub Petra , Kneip Susanne , Kayser Anne , Loges Stephanie , Schmidt Eleonore , Nemesánszky Elemér , Szalay Ferenc , Manns Michael P. , Strassburg Christian P. 
Published: December 2003

Background and aims: Antimitochondrial antibodies (AMA) which recognize pyruvate acetyltransferase (PDC‐E2) represent a highly diagnostic feature of primary biliary cirrhosis (PBC). The analysis of immunofluorescence (IF)‐AMA‐positive sera in PBC patients indicates a conformational epitope located within the lipoyl binding domain of bovine branched‐chain acyltransferase (BCKADC‐E2) alone or in combination with AMA directed against PDC‐E2 the significance of which is presently unclear. In the present study, immunoreactivities and disease associations of AMA against BCKADC‐E2 were analyzed. B‐cell autoepitopes on BCKADC‐E2 were mapped by immunoprecipitation assay.Methods: Sera of 96 IF‐AMA‐positive patients with serological evidence of anti‐BCKADC‐E2 alone (n=26), anti‐PDC‐E2 alone (n=15), and both anti‐BCKADC‐E2 and anti‐PDC‐E2 (n=55) were analyzed by Western blot and ELISA in addition to an analysis of B cell autoepitopes on BCKADC‐E2 by immunoprecipitation using in vitro translated, unmodified human proteins. Ninety‐four patients without IF‐AMA [blood donors (n=30), rheumatoid arthritis (n=40), autoimmune hepatitis (AIH) (n=10) and primary sclerosing cholangitis (PSC) (n=14] served as controls.Results: Eighty of 81 (99%) sera positive for BCKADC‐E2 recognized the full length, mature protein, while only 2/10 AIH sera and none of the other controls showed reactivity. Of the 68 PBC sera 58 (85%) recognized the N‐terminus consisting of aa 1‐144 representing the lipoyl domain. Surprisingly, C‐terminal sequences (aa 143‐421) were recognized by 46 out of 68 sera (68%). Three PBC sera reacted with the C‐terminus only. Only 1/7 serum from patients with an “overlap syndrome of PBC and AIH” was reactive with C‐terminal sequences.Conclusions: Our analysis of BCKADC‐E2‐positive PBC sera identified a novel B cell epitope on the C‐terminal part of the human protein. Our data indicate that a distinct subset of AMA recognize sequence(s) on BCKADC‐E2 which located outside of the lipoyl binding domain. The absence of immunoreactivity against C‐terminal sequences may serve as a marker differentiating patients with PBC and overlap syndrome of PBC with AIH.
Intensity Modulated Radiation Therapy for Retroperitoneal Sarcoma:A Case for Dose Escalation and Organ at Risk Toxicity Reduction
Authors: Koshy Mary , Landry Jerome C. , Lawson Joshua D. , Staley Charles A. , Esiashvili Natia , Howell Rebecca , Ghavidel Shahram , Davis Lawrence W. 
Published: December 2003

Purpose: Radiation therapy for retroperitoneal sarcoma remains challenging because of proximity to surrounding organs at
risk (OAR). We report the use of intensity modulated radiation therapy (IMRT) in the treatment of retroperitoneal sarcomas
to minimize dose to OAR while concurrently optimizing tumor dose coverage.Patients and methods: From January 2000 to October 2002, 10 patients (average age 56 years) with retroperitoneal sarcoma
and one with inguinal sarcoma were treated with radiation at Emory University. Prescription dose to the planning treatment
volume (PTV) was commonly 50.4 at 1.8 Gy/fraction. CT simulation was used in each patient, three patients were treated
with 3D‐conformal treatment (3D‐CRT), and the remaining eight received multi‐leaf collimator‐based (MLC) IMRT.
IMRT treatment fields ranged from eight to 11 and average volume treated was 3498 cc. Optimal 3D‐CRT plans were
generated and compared with IMRT with respect to tumor coverage and OAR dose toxicity. Dose volume histograms were
compared for both the 3D‐CRT and IMRT plans.Results: Mean dose to small bowel decreased from 36 Gy with 3D‐CRT to 27 Gy using IMRT, and tumor coverage (V95)
increased from 95.3% with 3D‐CRT to 98.6% using IMRT. Maximum and minimum doses delivered to the PTV were
significantly increased by 6 and 22%, respectively (P = 0.011, P = 0.055). Volume of small bowel receiving > 30Gy was
significantly decreased from 63.5 to 43.1% with IMRT compared with conventional treatment (P = 0.043). Seven patients
developed grade 2 nausea, three developed grade 2 diarrhea, one had grade 2 skin toxicity, and one patient developed grade
3 liver toxicity (RTOG toxicity scale). No other delayed toxicities related to radiation were observed. At a median follow‐up
of 58 weeks, there were no local recurrences and only one patient developed disease progression with distant metastasis in
the liver.Conclusions: IMRT for retroperitoneal sarcoma allowed enhanced tumor coverage and better sparing of dose to
critical normal structures such as small bowel, liver, and kidney.
Escalation of dose has a positive impact on local control for retroperitoneal sarcoma;
IMRT may be an effective method to achieve this goal. We are evaluating preoperative dose escalation to 59.4 Gy.
Premonitory Pain Preceding Swelling: A Distinctive ClinicalPresentation of Synovial Sarcoma which may Prompt Early Detection
Authors: De Silva M. V. Chandu , Barrett Ann , Reid Robin 
Published: December 2003

Purpose: The aim of this paper is to document the unusual presentation of long‐standing pain at the tumour site before
development of a swelling in patients with synovial sarcoma.Patients/methods and results: The clinical presentation of 53 patients with synovial sarcoma was compared with 56 randomly
selected patients with other sarcomas of the trunk and extremities. The two groups were similar with regard to age
(P = 0.980), sex (P = 0.784) duration of symptoms
(P = 0.697), size (P = 0.931) and site of tumour (P = 0.288). Sixteen
(30.2%) patients with synovial sarcoma had pain before development of a swelling compared to two (3.6%) patients with
other sarcomas (P < 0.001, odds ratio = 11.68, 95% confidence interval 2.53, 53.83). The mean duration of such pain was
37 months (median 24, range 6–120 months). The nature of the pain was variable. Eight patients had sharply localised
tenderness. Calcification seen in the X‐rays of four patients was initially misdiagnosed as benign lesions. A swelling was
ultimately detected by MRI, CT, ultrasound or at physical examination. The mean duration from first presentation with pain
till diagnosis of synovial sarcoma was 20 months. In three patients, at explorative surgery there was friable, vascular or
necrotic tissue in the absence of a well‐defined tumour mass.Discussion: The occurrence of long‐standing pain at the tumour site prior to development of a swelling is significantly more
common with synovial sarcomas than with other sarcomas. Awareness of this unusual presentation and appropriate
investigation may enable detection of synovial sarcoma at a prognostically favourable early stage.
Pathway Illuminated: Visualizing Protein Kinase C Signaling
Authors: Violin Jonathan D. , Newton Alexandra C. 
Published: December 2003

AbstractProtein kinase C has been at the center of cell signaling since the discovery 25 years ago that it transduces signals that promote phospholipid hydrolysis. In recent years, the use of genetically encoded fluorescent reporters has enabled studies of the regulation of protein kinase C signaling in living cells. Advances in imaging techniques have unveiled unprecedented detail of the signal processing mechanics of protein kinase C, from the second messengers calcium and diacylglycerol that regulate protein kinase C activity, to the locations and kinetics of different protein kinase C isozymes, to the spatial and temporal dynamics of substrate phosphorylation by this key enzyme. This review discusses how fluorescence imaging studies have illuminated the fidelity with which protein kinase C transduces rapidly changing extracellular information into intracellular phosphorylation signals. IUBMB Life, 55: 653‐660, 2003
Competitive, Reversible, Physiological? Inhibition of Mitochondrial Cytochrome Oxidase by Nitric Oxide
Authors: Cooper Chris 
Published: December 2003

AbstractIn the mid 1990s a number of research groups recognized that mitochondrial oxygen consumption could be reversibly inhibited by nitric oxide at the level of the enzyme cytochrome c oxidase. The inhibition was apparently competitive with respect to the oxygen concentration. This review critically assesses the present state of knowledge as regards the hypothesis that nitric oxide is a competitive, reversible, physiological inhibitor of cytochrome oxidase. IUBMB Life, 55: 591‐597, 2003
The Contribution of Salvador Moncada to Our Understanding of the Biology of Nitric Oxide
Authors: Clementi Emilio 
Published: December 2003

AbstractThe observation, by Furchgott and Zawadzki, that a factor of short average life, released by endothelial cells accounted for vasodilation was the beginning of one of the most fascinating adventures in the recent history of science. The discovery that this released factor was nitric oxide had tremendous implications for our understanding not only of the homeostasis of the vascular tissue, but also of a variety of other biological processes ranging from synaptic plasticity to regulation of immune responses. This review article will lead the reader through the landmark events in this adventure, highlighting the fundamental role played by Salvador Moncada and his team. IUBMB Life, 55: 563‐565, 2003
Peroxynitrous Acid ‐ Where is the Hydroxyl Radical?
Authors: Kissner Reinhard , Nauser Thomas , Kurz Christophe , Koppenol Willem 
Published: December 2003

AbstractPeroxynitrite is an inorganic toxin of physiological interest, formed from the diffusion‐controlled reaction of superoxide and nitrogen monoxide with a rate constant of (1.6 ± 0.3) × 1010 M ‐ 1 s ‐ 1. On the basis of three experiments we conclude that homolysis of the O‐O bond in peroxynitrous acid is unlikely: (1) the yield of nitrite from the decomposition of peroxynitrite shows a dependence on the peroxynitrite concentration and is lower than expected for homolysis; (2) the yield of [15N]nitrate from the reaction of [15N]nitrite with peroxynitrous acid predicted by homolysis does not correspond to that found experimentally, and (3) the reaction of peroxynitrous acid with monohydroascorbate does not yield ascorbyl radicals. Activation volumes determined from high‐pressure kinetic studies are inconclusive. IUBMB Life, 55: 567‐572, 2003
Truncated Hemoglobins and Nitric Oxide Action
Authors: Milani Mario , Pesce Alessandra , Ouellet Hugues , Guertin Michel , Bolognesi Martino 
Published: December 2003

AbstractTruncated hemoglobins (trHbs) build a separate subfamily within the hemoglobin superfamily; they are scarcely related by sequence similarity to (non‐)vertebrate hemoglobins, displaying amino acid sequences in the 115 ‐ 130 residue range. The trHb tertiary structure is based on a 2‐on‐2 α‐helical sandwich, which hosts a unique hydrophobic cavity/tunnel system, traversing the protein matrix, from the molecular surface to the heme distal site. Such a protein matrix system may provide a path for diffusion of ligands to the heme. In Mycobacterium tuberculosis trHbN the heme‐bound oxygen molecule is part of an extended hydrogen bond network including the heme distal residues TyrB10 and GlnE11. In vitro experiments have shown that M. tuberculosis trHbN supports efficiently nitric oxide dioxygenation, yielding nitrate. Such a reaction would provide a defense barrier against the nitrosative stress raised by host macrophages during lung infection. It is proposed that the whole protein architecture, the heme distal site hydrogen bonded network, and the unique protein matrix tunnel, are optimally designed to support the pseudo‐catalytic role of trHbN in converting the reactive NO species into the harmless NO3‐. IUBMB Life, 55: 623‐627, 2003
The Anti‐Parasitic Effects of Nitric Oxide
Authors: Ascenzi Paolo , Bocedi Alessio , Gradoni Luigi 
Published: December 2003

AbstractEndogenous and exogenous nitric oxide (NO) possesses anti‐parasitic effects on both Protozoa and Metazoa. However, NO production requires a tight control to limit cytotoxic damage to the host's own cells. The best known parasitic macromolecular targets for NO(‐donors) are cysteine proteases, which are relevant in several aspects of the parasite life cycle and parasite‐host relationships, and appear as promising targets for anti‐parasitic chemotherapy. IUBMB Life, 55: 573‐578, 2003
Nitric Oxide Signaling in Plant‐Pathogen Interactions
Authors: Romero‐Puertas María , Delledonne Massimo 
Published: December 2003

AbstractNitric oxide (NO), first characterized as an endothelium‐derived relaxation factor, is involved in diverse cellular processes including neuronal signaling, blood pressure homeostasis, and immune response. Recent studies have also revealed a role for NO as a signaling molecule in plants. As a developmental regulator, NO promotes germination, leaf extension and root growth, and delays leaf senescence and fruit maturation. Moreover, NO acts as a key signal in plant resistance to incompatible pathogens by triggering resistance‐associated hypersensitive cell death. In addition, NO activates the expression of several defense genes (e.g. pathogenesis‐related genes, phenylalanine ammonialyase, chalcone synthase) and could play a role in pathways leading to systemic acquired resistance. IUBMB Life, 55: 579‐583, 2003
Mitochondria as Targets of Apoptosis Regulation by Nitric Oxide
Authors: Vieira Helena , Kroemer Guido 
Published: December 2003

AbstractIn addition to their vital role as the cell's power stations, mitochondria exert an important function in apoptosis. In response to most if not all apoptosis inducers, mitochondrial membranes are permeabilized, leading to the release of potentially toxic proteins, mostly from the intermembrane space to the rest of the cells. Such pro‐apoptotic intermembrane proteins include the caspase‐independent death effector AIF, as well as cytochrome c, which can trigger the activation of caspases, once it has reached the cytosol. The mitochondrial permeabilization process can be induced by a variety of different xenobiotics, via a direct effect on mitochondrial membranes. Alternatively, mitochondrial permeabilization can be induced by endogenous second messengers, which are elicited in response to stress. The permeabilization process is controlled by the mitochondrial permeability transition pore complex (PTPC), by proteins of the Bcl‐2/Bax family, as well as by lipids and metabolites. Nitric oxide (NO) is one of the second messengers that can trigger apoptosis by inducing mitochondrial membrane permeabilization. This effect may involve a direct effect on the PTPC and/or indirect effects secondary to the NO‐mediated inhibition of oxidative phosphorylation. This has far‐reaching implications for the pathophysiology of NO. IUBMB Life, 55: 613‐616, 2003
Trichosanthin Induces Leakage and Membrane Fusion of Liposome
Authors: Xia Xiao‐feng , Zhang Fan , Shaw Pang‐Chui , Sui Sen‐Fang 
Published: December 2003

AbstractTrichosanthin (TCS) is a ribosome inactivating protein with multiple pharmacological properties. Here the interaction between TCS and a phospholipid bilayer is investigated to provide evidence for membrane translocation mechanism of TCS. The results show that TCS can destabilize liposomes made by phospholipids with negatively charged head group. The destabilization effect is pH‐dependent and happens only under acidic conditions. Membrane fusion is also seen to accompany the destabilizing process. The interaction between a phospholipid bilayer and C7, a mutant of TCS with 7 residues at its C‐terminus deleted, has been investigated. Deleting the C‐terminus almost completely abolishes the destabilizing effect of TCS on the phospholipid bilayer, which implicates the C‐terminus in the interaction between trichosanthin and the membrane. IUBMB Life, 55: 681‐687, 2003
Mechanistic Insights Revealed Through Characterization of a Novel Chromophore in Selenophosphate Synthetase from Escherichia coli
Authors: Wolfe Matt D. 
Published: December 2003

AbstractThe incorporation of selenium into specific proteins and tRNAs requires selenophosphate (SePO3), whose formation is catalyzed by selenophosphate synthetase. In a Mg/ATP‐dependent reaction, selenophosphate synthetase catalyzes the phosphorylation of selenide to yield AMP, inorganic phosphate, and SePO3. In this report, a previously unrecognized chromophore covalently attached to selenophosphate synthetase is characterized. The UV/Vis spectrum of selenophosphate synthetase has a feature centered at 315 nm that is irreversibly destroyed by alkylation. Moreover, addition of Zn2 +, which is known to inhibit selenophosphate synthetase, reversibly quenches the 315 nm absorption. Since Zn2 + is known to bind to Cys17, these data strongly suggest that this residue participates in the 315 nm absorption. Upon incubation with both Mg2 + and ATP, the λmax of the chromophore shifts to 340 nm, and it is shown that the shift requires binding of nucleotide having a hydrolyzable γ‐phosphoryl group. These data indicate that either the chromophore is directly involved in phosphoryl transfer or indirectly reflects a phosphorylation‐dependent conformational change in selenophosphate synthetase. This work provides the first spectroscopic handle on catalytic steps associated with SePO3 synthesis, which will be used to study the molecular structure of the chromophore and its role in the catalytic mechanism of selenophosphate synthetase. IUBMB Life, 55: 689‐693, 2003
Effect of Lower Dosage of Oral Conjugated Equine Estrogen on Inflammatory Markers and Endothelial Function in Healthy Postmenopausal Women
Authors: Wakatsuki Akihiko , Ikenoue Nobuo , Shinohara Koichi , Watanabe Kazushi , Fukaya Takao 
Published: December 2003

Objective—Although oral estrogen replacement therapy (ERT) in postmenopausal women improves endothelial function, it also increases plasma C-reactive protein (CRP) and interleukin-6 (IL-6) concentration. The proinflammatory effect of oral ERT may explain the increased risk of coronary heart disease (CHD) associated with this treatment. Recent observational studies have demonstrated that a lower dose of oral estrogen reduces the risk for CHD. The purpose of the present study was to investigate the effects of low-dose oral estrogen on vascular inflammatory markers and endothelium-dependent vasodilation in postmenopausal women.Methods and Results—Postmenopausal women were randomized into 3 groups to receive no treatment (n=14) or oral conjugated equine estrogen (CEE) at a dosage of 0.625 mg (n=15) or 0.3125 mg (n=15) daily for 3 months. CEE at a dosage of 0.625 mg resulted in significant increases in plasma concentrations of CRP from 690.9±749.5 to 1541.9±1608.0 ng/mL, serum amyloid A from 6.12±4.15 to 8.25±4.40 μg/mL, and IL-6 from 1.45±0.73 to 2.35±1.16 pg/mL. In contrast, CEE at a dosage of 0.3125 mg had no effect on these inflammatory markers. Both dosages of estrogen significantly decreased E-selectin concentration, whereas the concentrations of intercellular and vascular cell adhesion molecules remained unchanged. In both CEE groups, flow-mediated vasodilation in the brachial artery was increased significantly, whereas nitroglycerine-induced vasodilation was unaltered.Conclusions—Oral CEE at a low dose of 0.3125 mg in postmenopausal women eliminated the adverse effects of high-dosage oral CEE on vascular inflammatory markers in addition to preserving the favorable effects of estrogen on cell adhesion molecules and endothelial function.
Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone
Authors: Strömberg Thomas , Dimberg Anna , Hammarberg Anna , Carlson Kristina , Österborg Anders , Nilsson Kenneth , Jernberg-Wiklund Helena 
Published: December 2003

AbstractCircumvention of chemoresistance in the B-cell neoplasm multiple myeloma (MM) might be achieved by targeting certain intracellular signaling pathways crucial for survival of the malignant clone. The use of the macrolide rapamycin, selectively inhibiting the phosphoprotein mammalian target of rapamycin (mTOR) downstream of, for example, insulin-like growth factor-I receptor (IGF-IR), possibly represents such a molecular mode of therapy. By using a panel of MM cell lines we showed that rapamycin induced G0/G1 arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of cyclins D2 and D3. Interestingly, in primary, mainly noncycling MM cells, rapamycin, at clinically achievable concentrations, induced apoptosis. More important, rapamycin sensitized both MM cell lines and primary MM cells to dexamethasone-induced apoptosis. This effect was associated with a decreased expression of cyclin D2 and survivin. The phosphorylation of the serine/threonine kinase p70S6K at Thr389 and Thr421/Ser424 was down-regulated by rapamycin and/or dexamethasone. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the antiapoptotic effects of exogenously added IGF-I and interleukin 6 (IL-6) as well as their stimulation of p70S6K phosphorylation. The induction of apoptosis by rapamycin and dexamethasone despite the presence of survival factors was also demonstrated in primary MM cells, thus suggesting this drug combination to be active also in vivo. (Blood. 2004;103:3138-3147)