tbuckley/cabot-search huggingface dataset:
A Phase I and Pharmacological Study of the Platinum Polymer AP5280 Given as an Intravenous Infusion Once Every 3 Weeks in Patients with Solid Tumors
Authors: Jeany M. Rademaker-Lakhai, Catherine Terret, Stephen B. Howell, Christiane M. Baud, Richard F. de Boer, Dick Pluim, Jos H. Beijnen, Jan H. M. Schellens, Jean-Pierre Droz
Journal: Clinical Cancer Research (2004)

Abstract Purpose: This Phase I study was designed to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of AP5280 in patients with solid tumors. Furthermore, the platinum (Pt) pharmacokinetics after AP5280 administration and preliminary antitumor activity were evaluated. AP5280 is a Pt agent linked to the water-soluble, biocompatible copolymer N-(2-hydroxypropyl)methacrylamide, which potentially increases Pt accumulation in tumors via the enhanced permeability and retention effect. In this way, it is anticipated that a higher activity of therapeutic Pt can be reached. The pharmaceutical product contains approximately 8.5% of Pt by weight and has a molecular weight of approximately 25,000. Experimental Design: Adult patients with solid tumors received AP5280 as a 1-h i.v. infusion every 21 days. Pharmacokinetics of total and unbound Pt were determined during the first treatment course and before the start of each new cycle using noncompartmental pharmacokinetic analysis. Pt-DNA adduct concentrations in WBCs and, if available, in tumor tissue were quantified using a sensitive 32P postlabeling assay. Results: Twenty-nine patients were treated at eight dose levels (90–4500 mg Pt/m2). The dose-limiting toxicity was Common Toxicity Criteria grade 3 vomiting and was experienced at 4500 mg Pt/m2 in two of six patients. The maximum tolerated dose on this schedule was therefore 4500 mg Pt/m2, and the recommended dose for a Phase II study is 3300 mg Pt/m2. Renal toxicity and myelosuppression, toxicities typically observed with cisplatin and carboplatin, were minimal for AP5280. The area under the curve of total Pt increased with increasing AP5280 dose. Plasma clearance of total Pt was 644 ± 266 ml/h, and the terminal half-life was 116 ± 46.2 h. After AP5280 administration, Pt-guanine-guanine DNA adduct concentrations in WBCs ranged from 70 to 1848 amol/μg DNA, concentrations that were substantially lower than concentrations measured after administration of therapeutic doses of cisplatin. Conclusions: AP5280 can be administered safely as a 1-h i.v. infusion at a dose of 3300 mg Pt/m2 once every 3 weeks and produces prolonged plasma exposure compared with any of the free Pt-containing drugs. However, it remains to be determined whether AP5280 can actually increase Pt delivery to the DNA of tumor cells in man as has been shown in experimental models.
Hepatic encephalopathy: A central neuroinflammatory disorder?
Authors: Roger F. Butterworth
Journal: Hepatology (2011)

Encephalopathy and brain edema are serious central nervous system complications of liver failure. Recent studies using molecular probes and antibodies to cell-specific marker proteins have demonstrated the activation of microglial cells in the brain during liver failure and confirmed a central neuroinflammatory response. In animal models of ischemic or toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of encephalopathy and brain edema. Moreover, the prevention of these complications with mild hypothermia or N -acetylcysteine (two treatments known to manifest both peripheral and central cytoprotective properties) averts central neuroinflammation due to liver failure. Recent studies using anti-inflammatory agents such as ibuprofen and indomethacin have shown promise for the treatment of mild encephalopathy in patients with cirrhosis, whereas treatment with minocycline, a potent inhibitor of microglial activation, attenuates the encephalopathy grade and prevents brain edema in experimental acute liver failure. The precise nature of the signaling mechanisms between the failing liver and central neuroinflammation has yet to be fully elucidated; mechanisms involving blood-brain cytokine transfer and receptor-mediated cytokine signal transduction as well as a role for liver-related toxic metabolites such as ammonia have been proposed. The prevention of central proinflammatory processes will undoubtedly herald a new chapter in the development of agents for the prevention and treatment of the central nervous system complications of liver failure. (HEPATOLOGY 2011;)
Treatment of 16 patients with bullous pemphigoid with oral tetracycline and niacinamide and topical clobetasol
Authors: Barbara Hornschuh, Henning Hamm, Sabine Wever, Takashi Hashimoto, Ulf Schröder, Eva-B. Bröcker, Detlef Zillikens
Journal: Journal of the American Academy of Dermatology (1997)
Neural Correlates of Episodic Encoding and Recognition of Words in Unmedicated Patients During an Acute Episode of Schizophrenia: A Functional MRI Study
Authors: Alex Hofer, Elisabeth M. Weiss, Stefan M. Golaszewski, Christian M. Siedentopf, Claudia Brinkhoff, Christian Kremser, Stephan Felber, W. Wolfgang Fleischhacker
Journal: American Journal of Psychiatry (2003)

Memory impairment has been well documented in schizophrenia. In a previous study, the authors investigated patterns of brain activity during episodic encoding and recognition of words in remitted, stable schizophrenia outpatients being treated with novel antipsychotics. The same procedure was used in this study to investigate unmedicated patients during an acute episode of schizophrenia.Functional magnetic resonance imaging was used to study regional brain activation in 10 unmedicated patients experiencing an acute episode of schizophrenia and 10 healthy comparison subjects during performance of a modified version of the words subtest of Warrington's Recognition Memory Test.Despite intact recognition performance, patients with schizophrenia showed reduced activation of anterior prefrontal, posterior cingulate, and retrosplenial areas relative to comparison subjects during word encoding. During word recognition, reduced activation was found in the patients' dorsolateral prefrontal and limbic/paralimbic regions. On the other hand, higher metabolism in bilateral anterior prefrontal cortices was observed.The results suggest that different neural pathways are engaged during episodic encoding and recognition of words in patients experiencing an acute episode of schizophrenia relative to healthy comparison subjects. Furthermore, acute psychosis may prevent practice effects, reflected in a failure to engage brain regions associated with successful episodic memory retrieval in healthy subjects.
Variability of polymerase chain reaction detection of the bcl-2-IgH translocation in an international multicentre study
Authors: P.W.M. Johnson, K. Swinbank, S. MacLennan, D. Colomer, B. Debuire, T. Diss, J. Gabert, R.K. Gupta, A. Haynes, M. Kneba, M.S. Lee, E. Macintyre, E. Mensink, M. Moos, G.J. Morgan, A. Neri, A. Johnson, G. Reato, G. Salles, M.B. van’t Veer, J.L. Zehnder, E. Zucca, P.J. Selby, F.E. Cotter
Journal: Annals of Oncology (1999)
HIV-1 Rev–binding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice
Authors: Shariq S. Khwaja, Hudan Liu, Caili Tong, Fang Jin, Warren S. Pear, Jan van Deursen, Richard J. Bram
Journal: Journal of Clinical Investigation (2010)

Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Rev-binding protein (Hrb), a component of the clathrin-mediated endocytosis machinery, as a critical mediator of Notch-induced T-ALL development in mice. Hrb was found to be a direct transcriptional target of Notch1, and Hrb loss reduced the incidence or delayed the onset of T-ALL in mouse models in which activated Notch1 signaling either contributes to or drives leukemogenesis. Consistent with this observation, Hrb supported survival and proliferation of hematopoietic and T cell precursor cells in vitro. We demonstrated that Hrb accelerated the uptake of transferrin, which was required for upregulation of the T cell protooncogene p21. Indeed, iron-deficient mice developed Notch1-induced T-ALL substantially more slowly than control mice, further supporting a critical role for iron uptake during leukemogenesis. Taken together, these results reveal that Hrb is a critical Notch target gene that mediates lymphoblast transformation and disease progression via its ability to satisfy the enhanced demands of transformed lymphoblasts for iron. Further, our data suggest that Hrb may be targeted to improve current treatment or design novel therapies for human T-ALL patients.
SPOTTED FEVER
Authors: Henry Pinkerton, G. M. Hass
Journal: The Journal of Experimental Medicine (1932)

Spotted fever infection has been studied in tissue cultures grown at 32°C. The behavior of spotted fever Rickettsiaeis compared and contrasted with that of typhus Rickettsiae under similar conditions. The spotted fever organisms multiply extensively in the nuclei of cells where they form spherical clusters of various sizes. These structures are compared and contrasted with intranuclear inclusion bodies.
Potential role of Cryptococcus neoformans in the pathogenesis of asthma
Authors: S A Nachman
Journal: Thorax (2006)

▴ Goldman DL, Davis J, Bommarito F, et al . Enhanced allergic inflammation and airway responsiveness in rats with chronic Cryptococcus neoformans infection: potential role for fungal pulmonary infection in the pathogenesis of asthma. J Infect Dis2006;193:1178–86[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] The potential of pulmonary Cryptococcus neoformans infection in immunocompetent subjects to modify allergic inflammation … [1]: {openurl}?query=rft.jtitle%253DJ%2BInfect%2BDis%26rft_id%253Dinfo%253Adoi%252F10.1086%252F501363%26rft_id%253Dinfo%253Apmid%252F16544260%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1086/501363&link_type=DOI [3]: /lookup/external-ref?access_num=16544260&link_type=MED&atom=%2Fthoraxjnl%2F61%2F8%2F705.atom [4]: /lookup/external-ref?access_num=000236102200017&link_type=ISI
Rapid induction of complete molecular remission by sequential therapy with LDAC and sorafenib in FLT3-ITD-positive patients unfit for intensive treatment: two cases and review of the literature
Authors: Denise Wolleschak, Enrico Schalk, Christian Krogel, Tina M Schnoeder, Helga Luehr, Kathleen Jentsch-Ullrich, Thomas Fischer, Florian H Heidel
Journal: Journal of Hematology & Oncology (2013)

Abstract Treatment of acute myeloid leukemia remains a therapeutic challenge. Even in younger patients with a low rate of co-morbidities less than 50% of patients can be cured. For older patients or patients with significant co-morbidities, the situation appears even worse. In patients not eligible for intensive treatment approaches - e.g. due to underlying medical conditions - therapeutic approaches remain almost exclusively palliative. However, even with less intense treatment approaches, temporary remission can be achieved and this contributes to prolonged survival and improved quality of life of the respective patient. Targeted therapies have been widely used as palliative treatment in- and outside clinical trials as single agents. Combination with low-dose cytarabine (LDAC) potentially improves remission rates and can be safely administered in an outpatient setting. Previous studies showed that additive hematologic toxicity of combinatory therapeutic approaches may arise from simultaneous treatment (e.g. chemotherapy plus targeted therapies). However, sequential therapies have already proven their feasibility in clinical trials. Here, we report two cases of rapid induction of complete molecular remission by sequential therapy with LDAC and sorafenib in patients unfit for intensive chemotherapy without significant long-term toxicity.
IL-18 Induces PD-1–Dependent Immunosuppression in Cancer
Authors: Magali Terme, Evelyn Ullrich, Laetitia Aymeric, Kathrin Meinhardt, Mélanie Desbois, Nicolas Delahaye, Sophie Viaud, Bernard Ryffel, Hideo Yagita, Gilles Kaplanski, Armelle Prévost-Blondel, Masashi Kato, Joachim L. Schultze, Eric Tartour, Guido Kroemer, Nathalie Chaput, Laurence Zitvogel
Journal: Cancer Research (2011)

Abstract Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1–dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18–binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18. Cancer Res; 71(16); 5393–9. ©2011 AACR.
Interleukin 8 Receptor Deficiency Confers Susceptibility to Acute Experimental Pyelonephritis and May Have a Human Counterpart
Authors: Björn Frendéus, Gabriela Godaly, Long Hang, Diana Karpman, Ann-Charlotte Lundstedt, Catharina Svanborg
Journal: The Journal of Experimental Medicine (2000)

Neutrophils migrate to infected mucosal sites that they protect against invading pathogens. Their interaction with the epithelial barrier is controlled by CXC chemokines and by their receptors. This study examined the change in susceptibility to urinary tract infection (UTI) after deletion of the murine interleukin 8 receptor homologue (mIL-8Rh). Experimental UTIs in control mice stimulated an epithelial chemokine response and increased chemokine receptor expression. Neutrophils migrated through the tissues to the epithelial barrier that they crossed into the lumen, and the mice developed pyuria. In mIL-8Rh knockout (KO) mice, the chemokine response was intact, but the epithelial cells failed to express IL-8R, and neutrophils accumulated in the tissues. The KO mice were unable to clear bacteria from kidneys and bladders and developed bacteremia and symptoms of systemic disease, but control mice were fully resistant to infection. The experimental UTI model demonstrated that IL-8R–dependent mechanisms control the urinary tract defense, and that neutrophils are essential host effector cells. Patients prone to acute pyelonephritis also showed low CXC chemokine receptor 1 expression compared with age-matched controls, suggesting that chemokine receptor expression may also influence the susceptibility to UTIs in humans. The results provide a first molecular clue to disease susceptibility of patients prone to acute pyelonephritis.
Interaction of BCG-Activated Macrophages With Neoplastic and Nonneoplastic Cell Lines in Vitro: Quantitation of the Cytotoxic Reaction by Release of Tritiated Thymidine From Prelabeled Target Cells
Authors: Monte S. Meltzer, Robert W. Tucker, Katherine K. Sanford, Edward J. Leonard
Journal: JNCI Journal of the National Cancer Institute (1975)

Peritoneal cells from mice infected ip with Mycobacterium bovis, strain BCG, were cytotoxic to syngeneic tumor cells in vitro. Cytotoxicity was estimated by measurement of release of tritiated-thymidine (3-H-TDR) from prelabeled target cells. The cell responsible for tumor cytotoxicity was the macrophage. Macrophages from uninfected mice or from oil-, starch-, or thioglycollate-induced peritoneal exudates had little effect on labeled tumor monolayers. Tumoricidal macrophages were present at 3-7 days and persisted through 6 weeks after a single BCG injection. Two neoplastic/nonneoplastic cell-line pairs, all four of the cell lines derived from a cloned syngeneic embryo cell line, were used as target cells for BCG-activated macrophages. Both tumor cell lines released significantly more 3-H-TDR than did the two nonneoplastic lines. In a mixed neoplastic/nonneoplastic target cell population, BCG-activated macrophages selectively destroyed the neoplastic cells; nonneoplastic cells were not affected as "innocent bystanders".
Endothelin Receptor Blockers in Cardiovascular Disease
Authors: Stuart Rich, Vallerie V. McLaughlin
Journal: Circulation (2003)

The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. The selective ET A receptor antagonist sitaxsentan also improves hemodynamics and exercise capacity in patients with pulmonary arterial hypertension. Results with ET receptor antagonists in congestive heart failure have been disappointing. Although some studies have suggested benefit, larger studies have been neutral. The use of ET receptor antagonists for other conditions has not been fully explored. Future studies with the use of ET receptor antagonists as part of a multidrug regimen are also needed.
Electronic Health Record Vendor Adherence to Usability Certification Requirements and Testing Standards
Authors: Raj M. Ratwani, Natalie C. Benda, A. Zachary Hettinger, Rollin J. Fairbanks
Journal: JAMA (2015)

This study uses data reported by electronic health record (EHR) vendors to the US Department of Health and Human Services’ Office of the National Coordinator for Health Information Technology to determine whether usability certification requirements and testing standards were met.
Bactericidal activity of a superoxide anion-generating system. A model for the polymorphonuclear leukocyte.
Authors: H Rosen, S J Klebanoff
Journal: The Journal of Experimental Medicine (1979)

The acetaldehyde-xanthine oxidase system in the presence and absence of myeloperoxidase (MPO) and chloride has been employed as a model of the oxygen-dependent antimicrobial systems of the PMN. The unsupplemented xanthine oxidase system was bactericidal at relatively high acetaldehyde concentrations. The bactericidal activity was inhibited by superoxide dismutase (SOD), catalase, the hydroxyl radical (OH.) scavengers, mannitol and benzoate, the singlet oxygen (1O2) quenchers, azide, histidine, and 1,4-diazabicyclo[2,2,2]octane (DABCO) and by the purines, xanthine, hypoxanthine, and uric acid. The latter effect may account for the relatively weak bactericidal activity of the xanthine oxidase system when purines are employed as substrate. A white, carotenoid-negative mutant strain of Sarcina lutea was more susceptible to the acetaldehyde-xanthine oxidase system than was the yellow, carotenoid-positive parent strain. Carotenoid pigments are potent 1O2 quenchers. The xanthine oxidase system catalyzes the conversion of 2,5-diphenylfuran to cis-dibenzoylethylene, a reaction which can occur by a 1O2 mechanism. This conversion is inhibited by SOD, catalase, azide, histidine, DABCO, xanthine, hypoxanthine, and uric acid but is only slightly inhibited by mannitol and benzoate. The addition of MPO and chloride to the acetaldehyde-xanthine oxidase system greatly increases bactericidal activity; the minimal effective acetaldehyde concentration is decreased 100-fold and the rate and extent of bacterial killing is increased. The bactericidal activity of the MPO-supplemented system is inhibited by catalase, benzoate, azide, DABCO, and histidine but not by SOD or mannitol. Thus, the acetaldehyde-xanthine oxidase system which like phagocytosing PMNs generates superoxide (O.2-) and hydrogen peroxide, is bactericidal both in the presence and absence of MPO and chloride. The MPO-supplemented system is considerably more potent; however, when MPO is absent, bactericidal activity is observed which may be mediated by the interaction of H2O2 and O.2- to form OH. and 1O2.
Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity.
Authors: B H Lauterburg, M E Velez
Journal: Gut (1988)

Patients chronically abusing ethanol are more susceptible to the hepatotoxic effects of paracetamol. This could be due to an increased activation of the drug to a toxic metabolite or to a decreased capacity to detoxify the toxic metabolite by conjugation with glutathione (GSH). To test these hypotheses paracetamol 2 g was administered to five chronic alcoholics without clinical evidence of alcoholic liver disease and five control subjects. The urinary excretion of cysteine- plus N-acetyl-cysteine-paracetamol, the two major products of detoxification of the reactive metabolite of paracetamol, was not significantly higher in chronic alcoholics arguing against a substantially increased metabolic activation of paracetamol. Chronic alcoholics had significantly lower plasma concentrations of GSH than healthy volunteers, however (4.35 (1.89) microM v 8.48 (2.68) microM, p less than 0.05) before the administration of paracetamol, and plasma GSH reached lower concentrations in the alcoholics after paracetamol (2.40 (1.36) v 6.26 (2.96) microM). In a group of patients with alcoholic hepatitis intrahepatic GSH was significantly lower than in patients with chronic persistent hepatitis and patients with non-alcoholic cirrhosis, suggesting that low plasma GSH in alcoholics reflects low hepatic concentrations of GSH. The data indicate that low GSH may be a risk factor for paracetamol hepatotoxicity in alcoholics because a lower dose of paracetamol will be necessary to deplete GSH below the critical threshold concentration where hepatocellular necrosis starts to occur.
Cough and hypereosinophilia due to FIP1L1-PDGFRA fusion gene with tyrosine kinase activity
Authors: K. F. Chung, M. Hew, J. Score, A. V. Jones, A. Reiter, N. C. P. Cross, B. J. Bain
Journal: European Respiratory Journal (2005)

Eosinophil-associated conditions, such as asthma and eosinophilic bronchitis, have been associated with chronic persistent cough, usually responding to corticosteroid therapy. This case study reports a case of persistent cough associated with gastro-oesophageal reflux (GOR) and hypereosinophilia. Treatment of GOR with proton pump inhibitors and fundoplication did not control the cough. However, high dose prednisolone, but not inhaled corticosteroids, did. The presence of the FIP1L1-PDGFRA fusion gene in myeloid cells was confirmed by fluorescence in situ hybridisation analysis using CHIC2 deletion as a surrogate marker. The cough and other disease features were subsequently suppressed by the tyrosine kinase inhibitor, imatinib. This is the first case of persistent cough caused by hypereosinophilic syndrome characterised by FIP1L1-PDGFRA fusion gene and aberrant tyrosine kinase activity.