tbuckley/cabot-search huggingface dataset:
Improved PET Imaging of uPAR Expression Using new <sup>64</sup>Cu-labeled Cross-Bridged Peptide Ligands: Comparative <i>in vitro</i> and <i>in vivo</i> Studies
Authors: Morten Persson, Masood Hosseini, Jacob Madsen, Thomas J. D. Jørgensen, Knud J Jensen, Andreas Kjaer, Michael Ploug
Journal: Theranostics (2013)

The correlation between uPAR expression, cancer cell invasion and metastases is now well-established and has prompted the development of a number of uPAR PET imaging agents, which could potentially identify cancer patients with invasive and metastatic lesions.In the present study, we synthesized and characterized two new cross-bridged 64 Cu-labeled peptide conjugates for PET imaging of uPAR and performed a head-to-head comparison with the corresponding and more conventionally used DOTA conjugate.Based on in-source laser-induced reduction of chelated Cu(II) to Cu(I), we now demonstrate the following ranking with respect to the chemical inertness of their complexed Cu ions: DOTA-AE105 << CB-TE2A-AE105 < CB-TE2A-PA-AE105, which is correlated to their corresponding demetallation rate.No penalty in the uPAR receptor binding affinity of the targeting peptide was encountered by conjugation to either of the macrobicyclic chelators (IC50 ~ 5-10 nM) and high yields and radiochemical purities (>95%) were achieved in all cases by incubation at 95°C.In vivo, they display identical tumor uptake after 1h, but differ significantly after 22 hrs, where the DOTA-AE105 uptake remains surprisingly high.Importantly, the more stable of the new uPAR PET tracers, 64 Cu-CB-TE2A-PA-AE105, exhibits a significantly reduced liver uptake compared to 64 Cu-DOTA-AE105 as well as 64 Cu-CB-TE2A-AE105, (p<0.0001),emphasizing that our new in vitro stability measurements by mass spectrometry predicts in vivo stability in mice.Specificity of the best performing ligand, 64 Cu-CB-TE2A-PA-AE105 was finally confirmed in vivo using a non-binding 64 Cu-labeled peptide as control ( 64 Cu-CB-TE2A-PA-AE105 mut ).This control PET-tracer revealed significantly reduced tumor uptake (p<0.0001),but identical hepatic uptake compared to its active counterpart ( 64 Cu-CB-TE2A-PA-AE105) after 1h.In conclusion, our new approach using in-source laser-induced reduction of Cu(II)-chelated PET-ligands provides useful information, which are predictive for the tracer stability in vivo in mice.Furthermore, the increased stability of our new macrobicyclic 64 Cu-CB-TE2A-PA-AE105 PET ligand is paralleled by an excellent imaging contrast during non-invasive PET scanning of uPAR expression in preclinical mouse cancer models.The translational promises displayed by this PET-tracer for future clinical cancer patient management remains, however, to be investigated.
Remarks on Aneurysm of the Coronary Arteries of the Heart: With Notes of Two Cases
Authors: T. W. Griffith
Journal: BMJ (1901)

CORONARY ARTERIES.L EEB. 2, 19 1.painful and the seat of nunibness and "pins and needles;" a celtain amount of paresis anid anuostliesia existed, signis suggesting neuritis,' which might be attributed to the long-continued use of morphline lhypo- dermically.Constipation, alw;ivs troublesome, was now almost in- superable.There was continual vomiitiig of bile-coloured fluid.At no tine was ascites or (edema of the feet observed.The patient died on August i6th.Permission to performi a lost-mio)rtem examination was refused.The absence of ascites is niot unionmnon ill cancer of the liver.Accordinig to Frericlis2 it was present only in about half the number of his cases-i8 out of 31.He quotes 6o cases recorded by othler autlhors, in 30 of which ascites was present, in I9 it was absenit, anld in i i cases no mention was made of this symptomii.Jaunidice also is often absent, its presence, like that of ascites, depending upon the situation of the new growtlhs in tlle liver."W When only a few branches of the hepatic ducts are destroyed, or wlhen the compression is incomplete," the icterus is slight,*3 as in this case.Mur- chison asserts I that if tie ducts are not compressed, almost the whole of the secretinlg surface of the liver may be destroyed without jaunidice.The disappearance of pain during the course of the illness is usual.5Cancer of the liver is secondary four times out of five,6 and in many cases the primiiary seat of the disease is not dis- covered during life, but in this case the unconfirmed surmnise was that the lhepatic canicer was secondary to the tumours, probably intestilnal, in the left lumbar region.The general characters of the lhepatic enilargemenit also were niot those of primary cancer, of the liverj, conisequently this case was looked upon as one of seconidary carcinoma of the liver.Murchison8 says that primiiary canicer of the liver is " exceed- ingly rare" before the age of 35 or 40, but that secondary cancer may occur " at aniy age."9Budd'°likewise says that secondary cancer iiiay occur "4 at any age," but that it is " rare " under 30.Freri0is" observed only two cases of ";cancer" under 30, ancd these secondary to (i) eyeball anid(2) testis.Leiclhtensterii, quoted by Langenbuch,'2 gives a table compiledl fromii several authiors dealing witli this point, from which it is seeni tllat 7.8 per cent.occur between 20 and 30, 12.9 per cenit.betweell 3o and 40, 53 per cent.between 4o and 6o, I9.3 per cent.b)etween 6o and 70, 6.9 per cent.over 70.
Histochemistry and Electron Microscopy of Iron-Containing Granules, Lysosomes, and Lipofuscin in Mouse Mammary Glands<xref ref-type="fn" rid="FN2">2</xref>
Authors: Hideo Miyawaki
Journal: JNCI Journal of the National Cancer Institute (1965)

The mammary epithelium of virgin CBA mice contained ferritin-like granules and had acid phosphatase activity. The ferritin and acid phosphatase activity were in bodies considered to be lysosomes. In mammary tissue of mice over 20 weeks of age, the number of lysosomes increased quite rapidly and remained relatively high. Heavy deposits of iron-rich pigment, which characterized the fully involuted mammary epithelium of multiparous mice, were represented by heterogeneous groups of enlarged dense bodies composed of aggregates of ferritin-like grains, granular and membranous areas, and large round or oval bodies. They were iron-, acid phosphatase-, and periodic acid-Schiff-positive, acid fast, and contained insoluble lipides. They were defined as lipofuscin from both histochemical and ultrastructural characteristics. Mammary lipofuscin in parous mice was deposited, irrespective of the age of the animals and of the number of pregnancies. Structural association with lysosomes and the demonstration of acid phosphatase in certain portions led to the conclusion that lipofuscin accumulated in relation to lysosomes. The possible role of lysosomal iron as a catalyst for lipofuscin formation is discussed.
Phase I study of Gliadel™ wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas
Authors: Sridharan Gururangan, Ilkcan Cokgor, Jeremy N. Rich, Shari Edwards, Mary Lou Affronti, Jennifer A. Quinn, James E. Herndon, James M. Provenzale, Roger E. McLendon, Sandra Tourt-Uhlig, John H. Sampson, Valerie Stafford-Fox, Sara Zaknoen, Maureen Early, Alan H. Friedman, Henry S. Friedman
Journal: Neuro-Oncology (2001)

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.
The Glomerular Transcriptome and a Predicted Protein–Protein Interaction Network
Authors: Liqun He, Ying Sun, Minoru Takemoto, Jenny Norlin, Karl Tryggvason, Tore Samuelsson, Christer Betsholtz
Journal: Journal of the American Society of Nephrology (2007)

To increase our understanding of the molecular composition of the kidney glomerulus, we performed a meta-analysis of available glomerular transcriptional profiles made from mouse and man using five different methodologies. We generated a combined catalogue of glomerulus-enriched genes that emerged from these different sources and then used this to construct a predicted protein-protein interaction network in the glomerulus (GlomNet). The combined glomerulus-enriched gene catalogue provides the most comprehensive picture of the molecular composition of the glomerulus currently available, and GlomNet contributes an integrative systems biology approach to the understanding of glomerular signaling networks that operate during development, function, and disease.
Some new evidence on human joint lubrication.
Authors: A Unsworth, D Dowson, V Wright
Journal: Annals of the Rheumatic Diseases (1975)

Theoretical consideration has been given to the use of pendulum machines which are used to examine the frictional properties of human joints by incorporating them as fulcra. As a result, a new type of pendulum machine has been built which incorporates the facility to apply sudden loads to the joint on starting the swinging motion, and also the ability to measure directly the frictional torque experienced by the joint. The results obtained from natural hip joints indicate the presence of squeeze film lubrication under conditions of sudden loading of a joint. In addition, a self-generated fluid film process was observed at low loads while at higher loads boundary lubrication appeared to be important. These results have been used to describe the lubrication regimens occurring in a normal activity such as walking. A single experiment carried out on a hip from a patient suffering from severe rheumatoid arthritis has also been reported and the frictional resistance was seen to be increased fifteenfold compared to a normal hip.
Naturally acquired antibody responses to recombinant Pfs230 and Pfs48/45 transmission blocking vaccine candidates
Authors: Sophie Jones, Lynn Grignard, Issa Nebie, Jaffu Chilongola, Daniel Dodoo, Robert Sauerwein, Michael Theisen, Will Roeffen, Shrawan Kumar Singh, Rajesh Kumar Singh, Sanjay Singh, Eric Kyei-Baafour, Kevin Tetteh, Chris Drakeley, Teun Bousema
Journal: Journal of Infection (2015)
Identification of an Immunogenic CTL Epitope of HIFPH3 for Immunotherapy of Renal Cell Carcinoma
Authors: Eiji Sato, Toshihiko Torigoe, Yoshihiko Hirohashi, Hiroshi Kitamura, Toshiaki Tanaka, Ichiya Honma, Hiroko Asanuma, Kenji Harada, Hideo Takasu, Naoya Masumori, Naoki Ito, Tadashi Hasegawa, Taiji Tsukamoto, Noriyuki Sato
Journal: Clinical Cancer Research (2008)

Abstract Purpose: CD8+ CTLs have an essential role in immune response against tumor. Although tumor-associated antigens have been identified in renal cell carcinoma (RCC), few of these are commonly shared and investigated as therapeutic targets in the clinical medicine. In this report, we show that HIFPH3, a member of prolyl hydroxylases that function as oxygen sensor, is a novel tumor antigen and HIFPH3-specific CTLs are induced from peripheral blood lymphocytes of RCC patients. Experimental Design: Expression of HIFPH3 was examined by reverse transcription-PCR and immunostaining with anti-HIFPH3 antibody. To identify HLA-A24-restricted T-cell epitopes of HIFPH3, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. Peptide-specific CTLs were induced by stimulating peripheral blood lymphocytes of HLA-A24-positive RCC patients with these peptides in vitro. HLA-A24-restricted cytotoxicity of the CTLs against HIFPH3+ RCC lines was assessed by chromium release assay. Results: HIFPH3 was overexpressed in many RCC cell lines and primary RCC tissues, whereas it was not detectable in normal adult tissues by reverse transcription-PCR. Of the eight peptides that contained HLA-A24-binding motif, HIFPH3-8 peptide (amino acid sequence, RYAMTVWYF) could induce the peptide-specific CTLs from 3 of 6 patients with HIFPH3-positive RCC. Furthermore, HIFPH3-8 peptide-specific CTLs showed cytotoxicity against HIFPH3+ RCC cell lines in a HLA-A24-restricted manner. Conclusions: HIFPH3 may be a target antigen in immunotherapy for RCC and HIFPH3-8 peptide could be used as a peptide vaccine for HLA-A*2402+/HIFPH3+ RCC patients.
Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs.
Authors: I F McMurtry, A B Davidson, J T Reeves, R F Grover
Journal: Circulation Research (1976)

The role of a transmembrane calcium influx in hypoxic pulmonary vasoconstriction was studied in isolated, blood-perfused, rat lungs. We reasoned that, if the influx of extracellular calcium mediated the hypoxic mechanism, pressor responses to alveolar hypoxia (2.5% O2) would be susceptible to inhibition by the calcium antagonists verapamil (2 X 10(-5) to 2 X 10(-1) mM) and SKF 525A (2.6 to 260 mM). Susceptibility of hypoxic pressor responses to inhibition by these calcium antagonists was contrasted to that of pressor responses elicited by the humoral vasoconstrictors angiotensin II(1 or 0.5 mug) and prostaglandin F2alpha (10 myg). Since neither saralasin (0.5 muM), a competitive antagonist of angiotensin II, nor meclofenamate (6.8 muM), an inhibitor of prostaglandin synthesis, depressed hypoxic pressor responses, it was concluded that these humoral transmitters were not directly involved in the hypoxic mechanism, and therefore served as independent reference agonists. The order of susceptibility of pulmonary pressor responses to inhibition by verapamil was hypoxia greater than angiotensin II greater than prostaglandin F2alpha. SKF 525A also reduced pressor responses to hypoxia more readily than those to angiotensin II. The greater inhibition of hypoxic pulmonary vasoconstriction by both calcium antagonists suggested that the hypoxic mechanism was critically dependent on the transmembrane influx of extracellular calcium. Mediation of the hypoxic response by this type of excitation-contraction coupling is consistent with the idea that hypoxia has a direct depolarizing effect on the vascular smooth muscle. It also provides a unifying explanation for inhibition of the hypoxic mechanism by various agents that have depressant or stabilizing actions on membranes in addition to other pharmacological effects.
Validity and predictive ability of the juvenile arthritis disease activity score based on CRP versus ESR in a Nordic population-based setting
Authors: E B Nordal, M Zak, K Aalto, L Berntson, A Fasth, T Herlin, P Lahdenne, S Nielsen, S Peltoniemi, B Straume, M Rygg
Journal: Annals of the Rheumatic Diseases (2012)

To compare the juvenile arthritis disease activity score (JADAS) based on C reactive protein (CRP) (JADAS-CRP) with JADAS based on erythrocyte sedimentation rate (ESR) (JADAS-ESR) and to validate JADAS in a population-based setting.The CRP and ESR values and the corresponding JADAS scores (JADAS10/27/71) were compared in a longitudinal cohort study of 389 children newly diagnosed with juvenile idiopathic arthritis (JIA) in the Nordic JIA study. The construct validity and the discriminative and predictive ability of JADAS were assessed during a median disease course of 8 years by comparing JADAS with other measures of disease activity and outcome.At the first study visit the correlation between JADAS27-CRP and JADAS27-ESR was r=0.99 whereas the correlation between CRP and ESR was r=0.57. Children with higher JADAS scores had an increased risk of concomitant pain, physical disability and use of disease-modifying antirheumatic drugs (DMARDs). A higher JADAS score at the first study visit also significantly predicted physical disability, damage and no remission off medication at the final study visit, and also use of DMARDs during the disease course. Sensitivity to change, demonstrated as change in JADAS score compared with the American College of Rheumatology paediatric measures of improvement criteria, mostly showed excellent classification ability.The JADAS-CRP and JADAS-ESR correlate closely, show similar test characteristics and are feasible and valid tools for assessing disease activity in JIA.
Procainamide‐induced thrombocytopenia
Authors: Robert Rosenstein, Rodney E. Kosfeld, Leonard Leight, Yong K. Liu
Journal: American Journal of Hematology (1984)

Abstract An 81‐year‐old female developed marked thrombocytopenia associated with numerous megakaryocytes in the bone marrow, but without anemia or leukopenia, after taking procainamide (3 g/day) for a period of 2 months. Despite continuation of this medication, treatment with prednisone led to rapid rise in platelet count, and withdrawal of steroid was followed by prompt recurrence of thrombocytopenia. The platelet counts returned to normal after discontinuation of procainamide, and read‐ministration of this drug was followed by reappearance of thrombocytopenia. These observations indicate that exposure to procainamide can cause isolated thrombocytopenia, probably due to immune‐mediated destruction of platelets, and that treatment with prednisone may be promptly beneficial in patients with procainamide‐induced severe thrombocytopenia and bleeding.
Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding.
Authors: Q J Sattentau, J P Moore
Journal: The Journal of Experimental Medicine (1991)

The human immunodeficiency virus (HIV) binds to the surface of T lymphocytes and other cells of the immune system via a high affinity interaction between CD4 and the HIV outer envelope glycoprotein, gp120. By analogy with certain other enveloped viruses, receptor binding by HIV may be followed by exposure of the hydrophobic NH2 terminus of its transmembrane glycoprotein, gp41, and fusion of the virus and cell membranes. A similar sequence of events is thought to take place between HIV-infected and uninfected CD4+ cells, resulting in their fusion to form syncytia. In this study, we have used a soluble, recombinant form of CD4 (sCD4) to model events taking place after receptor binding by the HIV envelope glycoproteins. We demonstrate that the complexing of sCD4 with gp120 induces conformational changes within envelope glycoprotein oligomers. This was measured on HIV-1-infected cells by the increased binding of antibodies to the gp120/V3 loops, and on the surface of virions by increased cleavage of this loop by an exogenous proteinase. At 37 degrees C, these conformational changes are coordinate with the dissociation of gp120/sCD4 complexes from gp41, and the increased exposure of gp41 epitopes. At 4 degrees C, gp120 dissociation from the cell surface does not occur, but increased exposure of both gp120/V3 and gp41 epitopes is detected. We propose that these events occurring after CD4 binding are integral components of the membrane fusion reaction between HIV or HIV-infected cells and CD4+ cells.
Effects of Long-Term Intravenous Ibandronate Therapy on Skeletal-Related Events, Survival, and Bone Resorption Markers in Patients With Advanced Multiple Myeloma
Authors: Hans D. Menssen, Adriana Sakalová, Aurélie Fontana, Zuzana Herrmann, Christian Boewer, Thierry Facon, Michail R. Lichinitser, C.R.J. Singer, Liana Euller-Ziegler, Marc Wetterwald, Denis Fiere, Mikulás Hrubisko, Eckhard Thiel, Pierre D. Delmas
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Bisphosphonates have been found to reduce the incidence of skeletal-related events (SREs) in patients with multiple myeloma. This is the first double-blind, randomized, placebo-controlled study to assess the efficacy of ibandronate, a third-generation amino-bisphosphonate, in preventing SREs in advanced-stage multiple myeloma patients. PATIENTS AND METHODS: Patients with multiple myeloma stage II or III were randomly assigned to receive either ibandronate 2 mg or placebo as a monthly intravenous (IV) bolus injection for 12 to 24 months in addition to conventional chemotherapy. SREs such as peripheral pathologic or vertebral fractures, hypercalcemia, severe bone pain, and bone radiotherapy or surgery were analyzed. Bone-turnover markers were also studied. Finally, post hoc analyses of bone morbidity and survival were performed. RESULTS: Ninety-nine patients per treatment group were assessable for efficacy analysis. The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups. In overall evaluation, no differences were found between the treatment groups regarding bone pain, analgesic drug use, quality of life, and median survival (33.1 v 28.2 months, respectively). Explorative post hoc analyses revealed that ibandronate patients with strongly suppressed bone-turnover markers (≥ 30% and ≥ 50% mean reduction of serum osteocalcin and urinary C-terminal telopeptides) developed significantly less bone morbidity. Ibandronate was tolerated well during as many as 25 therapy cycles. CONCLUSION: Monthly injections of ibandronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients.