tbuckley/cabot-search huggingface dataset:
Efficacy of the Irreversible ErbB Family Blocker Afatinib in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)–Pretreated Non–Small-Cell Lung Cancer Patients with Brain Metastases or Leptomeningeal Disease
Authors: Petra Hoffknecht, Amanda Tufman, Thomas Wehler, Theo Pelzer, Rainer Wiewrodt, Martin Schütz, Monika Serke, Jan Stöhlmacher-Williams, Angela Märten, Rudolf Maria Huber, Nicolas J. Dickgreber
Journal: Journal of Thoracic Oncology (2014)

<h3>Introduction</h3> Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (<i>EGFR</i>)-mutated non–small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program. <h3>Methods</h3> Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, <i>EGFR</i> mutational status, and adverse events including tumor progression were documented. <h3>Results</h3> From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented <i>EGFR</i> mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21–395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol. <h3>Conclusion</h3> Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with <i>EGFR</i>-mutated or EGFR–TKI-sensitive NSCLC and CNS metastasis.
In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer
Authors: Franck Pagès, Amos Kirilovsky, Bernhard Mlecnik, Martin Asslaber, Marie Tosolini, Gabriela Bindea, Christine Lagorce, Philippe Wind, Florence Marliot, Patrick Bruneval, Kurt Zatloukal, Zlatko Trajanoski, Anne Berger, Wolf-Herman Fridman, Jérôme Galon
Journal: Journal of Clinical Oncology (2009)

Many patients who present with early-stage colorectal cancer (International Union Against Cancer TNM stages I and II) are nevertheless at high risk of relapse. We hypothesized that intratumoral immune reaction could influence their prognosis.The intratumoral immune reaction was investigated in 29 tumors by large-scale real-time polymerase chain reaction. Cytotoxic (CD8) and memory (CD45RO) T cells were quantified by immunohistochemical analyses of tissue microarrays from the center (CT) and the invasive margin (IM) of the 602 tumors from two independent cohorts. The results were correlated with tumor recurrence and patient survival.Patients with a strong infiltration of CD45RO(+) cells in the tumor exhibited an increased expression of T-helper 1 and cytotoxicity-related genes. Densities of CD45RO(+) and CD8(+) cells in tumor regions (CT/IM) classified the patients into four distinct prognostic groups based on the presence of high density of each marker in each tumor region. The four groups were associated with dramatic differences in disease-free, disease-specific, and overall survival (all P < .0001). Five years after diagnosis, only 4.8% (95% CI, 0.6% to 8.8%) of patients with high densities of CD8(+) plus CD45RO(+) cells had tumor recurrence, and 86.2% (CI, 79.4% to 93.6%) survived. In contrast, the tumor recurred in 75% (95% CI, 17% to 92.5%) of patients with low densities of these cells, and only 27.5% (95% CI, 10.5% to 72%) survived (all P < .0001). Multivariate analyses showed that the immune criteria had independent effects on the rates of complete remission and survival.The combined analysis of CD8(+) plus CD45RO(+) cells in specific tumor regions could provide a useful criterion for the prediction of tumor recurrence and survival in patients with early-stage colorectal cancer.
Diminished Survival in Patients With Inner Versus Outer Quadrant Breast Cancers
Authors: David K. Gaffney, Alexander Tsodikov, Charles L. Wiggins
Journal: Journal of Clinical Oncology (2003)

To evaluate the role of breast tumor location on survival in patients with breast cancer.We evaluated tumor location within the breast on breast cancer-specific survival (BCSS) and overall survival (OS) in patients with invasive breast cancer using the Surveillance, Epidemiology, and End-Results (SEER) registries in the United States. Effects on survival were evaluated according to age, stage, tumor site, tumor size, grade, axillary lymph node status, extent of surgery, and radiotherapy (RT). A multivariate model was used with complete data on 45,880 patients. The median follow-up was 59 months.Patients with outer tumor location demonstrated superior BCSS on Kaplan-Meier analysis for both local stage (node-negative, P <.001) and regional stage disease (node-positive, P =.0002). For BCSS, the hazard ratio (HR) for inner quadrant location compared with outer quadrant was 1.31 (95% confidence interval [CI], 1.19 to 1.37; P <.001); and for OS, the HR was 1.12 (95% CI, 1.05 to 1.17; P <.001). When ER and PR status were included in the model, the HR for inner quadrant location compared with outer quadrant was 1.27 for BCSS (95% CI, 1.16 to 1.40; P <.001) and 1.11 for OS (95% CI, 1.03 to 1.19; P =.004). Patients treated by lumpectomy that received RT had a superior OS compared with patients that did not receive RT in both local (HR, 0.52; 95% CI, 0.48 to 0.61; P <.001) and regional (HR, 0.63; 95% CI, 0.56 to 0.72; P <.001) stage disease. Mastectomy patients with local stage disease that received RT had a diminished OS (HR, 1.24; 95% CI, 1.02 to 1.50; P =.033).On multivariate analysis, incorporating data on age, stage, tumor site, tumor size, grade, ER and PR status, axillary lymph node status, extent of surgery, and RT, this SEER registry-based study demonstrates that medial tumor location adversely impacts BCSS and OS.
EGFR Antagonists in Cancer Treatment
Authors: Fortunato Ciardiello, Giampaolo Tortora
Journal: New England Journal of Medicine (2008)

Functional activation of growth factors and receptors of the epidermal growth factor receptor (EGFR) family occurs in most epithelial-cell cancers, rendering EGFR a target for cancer treatment. This article discusses the mechanisms of action of EGFR inhibitors, their anticancer activity, and clinical issues concerning their use in the treatment of patients with cancer.
An interleukin 13 receptor α 2–specific peptide homes to human Glioblastoma multiforme xenografts
Authors: Hetal Pandya, Denise M. Gibo, Shivank Garg, Steven Kridel, Waldemar Debinski
Journal: Neuro-Oncology (2011)

Interleukin 13 receptor α 2 (IL-13Rα2) is a glioblastoma multiforme (GBM)–associated plasma membrane receptor, a brain tumor of dismal prognosis. Here, we isolated peptide ligands for IL-13Rα2 with use of a cyclic disulphide-constrained heptapeptide phages display library and 2 in vitro biopanning schemes with GBM cells that do (G26-H2 and SnB19-pcDNA cells) or do not (G26-V2 and SnB19-asIL-13Rα2 cells) over-express IL-13Rα2. We identified 3 peptide phages that bind to IL-13Rα2 in cellular and protein assays. One of the 3 peptide phages, termed Pep-1, bound to IL-13Rα2 with the highest specificity, surprisingly, also in a reducing environment. Pep-1 was thus synthesized and further analyzed in both linear and disulphide-constrained forms. The linear peptide bound to IL-13Rα2 more avidly than did the disulphide-constrained form and was efficiently internalized by IL-13Rα2–expressing GBM cells. The native ligand, IL-13, did not compete for the Pep-1 binding to the receptor and vice versa in any of the assays, indicating that the peptide might be binding to a site on the receptor different from the native ligand. Furthermore, we demonstrated by noninvasive near infrared fluorescence imaging in nude mice that Pep-1 binds and homes to both subcutaneous and orthotopic human GBM xenografts expressing IL-13Rα2 when injected by an intravenous route. Thus, we identified a linear heptapeptide specific for the IL-13Rα2 that is capable of crossing the blood-brain tumor barrier and homing to tumors. Pep-1 can be further developed for various applications in cancer and/or inflammatory diseases.
Management of Adult Idiopathic Thrombocytopenic Purpura
Authors: Douglas B. Cines, Robert McMillan
Journal: Annual Review of Medicine (2005)

Idiopathic thrombocytopenic purpura (ITP) is a common hematologic disorder manifested by immune-mediated thrombocytopenia. The diagnosis remains one of exclusion, after other thrombocytopenic disorders are ruled out based on history, physical examination, and laboratory evaluation. The goal of treatment is to raise the platelet count into a hemostatically safe range. The disorder is usually chronic, although there is considerable variation in the clinical course and most patients eventually attain safe platelet counts off treatment. However, a subset of patients has severe disease refractory to all treatment modalities, which is associated with considerable morbidity and mortality. This article focuses on the management of primary ITP in adults. We discuss criteria for treatment, the roles of splenectomy and other treatment options along with their side effects, and the management of ITP during pregnancy.
Circulating inhibitor bound elastase in patients with ankylosing spondylitis and rheumatoid arthritis and the influence of sulphasalazine treatment.
Authors: N Feltelius, R Hallgren
Journal: Annals of the Rheumatic Diseases (1988)

The plasma concentration of granulocyte elastase in complex with alpha 1 proteinase inhibitor was determined in 42 patients with ankylosing spondylitis (AS) and 33 patients with rheumatoid arthritis (RA). Significantly raised levels of plasma elastase were found in patients with RA, whereas patients with AS had normal values. No correlation was seen between the elastase values and erythrocyte sedimentation rate (ESR), serum haptoglobin, immunoglobulins, or polymorphonuclear cell (PMN) count in either of the patient groups. A correlation was found between the Ritchie index and plasma elastase in patients with RA. After three months9 treatment with sulphasalazine a clinical improvement was seen and this paralleled a reduction of the acute phase reaction in both patient groups. A reduction of the circulating elastase values was seen in the patients with RA, whereas no change was seen in patients with AS.
The Temperature of Phthisis
Authors: C. T. Williams
Journal: BMJ (1875)

being a body in a state of very unstable equilibrium, and very prone to oxydation.The odour of terebene is far from being d'isagreeable; in mass it is somewhat terebinthinous, though quite distinct from that of turpentine, and is generally said to smell like oil of thyme or oil of cinnamon; but, when diffused tbrough the air, in which condition it probably soon passes into incipient oxydation, it has an aroma quite peculiar, and not at all unlike that of fresh pine-wood, of the odour of which wood it is not at all improbable that terebene is the cause.At any rate, terebene possesses the same powers in a very active degree; and that it evolves ozone or else peroxide of hydrogen, may be shiown by its producing the characteristic effect on tincture of gtaiacum and blood-solution.It is not inappropriate, in connection with this fact, to note that attention has lately been drawn by several writers, especially by Dr.
Determinants of Atherosclerosis Susceptibility in the C3H and C57BL/6 Mouse Model
Authors: Weibin Shi, Nicholas J. Wang, Diana M. Shih, Victor Z. Sun, Xuping Wang, Aldons J. Lusis
Journal: Circulation Research (2000)

Lipids, monocytes, and arterial wall cells are primary components involved in atherogenesis. Using the inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H), which have been extensively studied as models of the genetic control of diet-induced atherosclerosis, we examined which of these components determine genetic susceptibility. To test whether dietary responsiveness is involved, a congenic strain of C3H carrying an apoE-null allele (apoE(-/-)) was constructed. Although C3H.apoE(-/-) mice had higher plasma cholesterol levels, they developed much smaller lesions than their B6.apoE(-/-) counterpart on either chow or Western diets. Reciprocal bone marrow transplantation between the strains, with congenics carrying the same H-2 haplotype, was performed to examine the role of monocytes. The atherosclerosis susceptibility was not altered in the recipient mice, indicating that variations in monocyte function were not involved. Endothelial cells isolated from the aorta of B6 mice exhibited a dramatic induction of monocyte chemotactic protein-1, macrophage colony-stimulating factor, vascular cell adhesion molecule-1, and heme oxygenase-1 in response to minimally modified LDL, whereas endothelial cells from C3H mice showed little or no induction. In a set of recombinant inbred strains derived from the B6 and C3H parental strains, endothelial responses to minimally modified LDL cosegregated with aortic lesion size. These data provide strong evidence that endothelial cells, but not monocytes or plasma lipid levels, account for the difference in susceptibility to atherosclerosis between the 2 mouse strains.
Tetraethylammonium transport by OK cells.
Authors: T D McKinney, M B Scheller, M Hosford, J A McAteer
Journal: Journal of the American Society of Nephrology (1990)

Mechanisms exist in renal proximal tubules for the mediated transepithelial secretion or reabsorption of endogenous and exogenous organic cations. In the studies presented here, the uptake of the organic cation tetraethylammonium (TEA) into confluent monolayers of opossum kidney cells was evaluated to determine if these cells might serve as an in vitro model of this transport pathway. 3H-TEA entered opossum kidney cells in a time-dependent manner. Uptake at early time points was saturable with an apparent Km of 59.1 +/- 11.2 microM and a Vmax of 1,292 +/- 210 fmol/micrograms of DNA. TEA uptake was inhibited in a dose-dependent manner by several other organic cations including amiloride, cimetidine, verapamil, procainamide, quinidine and N1-methylnicotinamide. With 1 mM concentrations of these compounds, uptake was virtually eliminated. However, another organic cation, N'-methylnicotinamide caused only minimal inhibition. TEA uptake was significantly reduced by sodium azide, suggesting dependence on oxidative phosphorylation. An alkaline medium pH enhanced TEA uptake, but, at the same pH, uptake was similar in the presence or absence of bicarbonate. When cellular pH was altered by ammonium chloride addition or removal, TEA uptake was not affected. Thus, organic cation/proton exchange, as has been demonstrated previously in apical membrane vesicles prepared from proximal tubules, is evidently not responsible for TEA uptake. Similarly, uptake does not appear to result from organic cation/organic cation exchange. These results indicate that the plasma membrane of opossum kidney cells contains a transport system(s) for the mediated uptake of organic cations and that these cells may be a useful mode for further study of renal epithelial transport of these solutes.
Effect of saliva contamination on induced sputum cell counts, IL‐8 and eosinophil cationic protein levels
Authors: J.L. Simpson, N.L. Timmins, K. Fakes, P.I. Talbot, P.G. Gibson
Journal: European Respiratory Journal (2004)

Excessive salivary contamination of induced sputum samples prevents the satisfactory examination of lower airway inflammation. The effects of salivary contamination on different sputum fluid phase measures and the levels of salivary contamination preventing analysis are not defined. The present study sought to examine this by investigating the effect of increasing salivary contamination on induced sputum samples. Sputum and saliva samples from subjects with asthma and healthy controls were collected, and treated with dithiothreitol (DTT). Saliva was then added to aliquots of dispersed sputum in increasing proportions (0% to 100%). The effect of increasing saliva contamination was assessed on sputum total cell count, viability, differential cell count and fluid phase levels of interleukin (IL)-8, eosinophil cationic protein (ECP) and total protein. The addition of saliva to induced sputum reduced total cell counts and absolute cell counts but did not change the differential cell count. Levels of fluid phase ECP and IL-8 were significantly reduced with increased salivary contamination. There was a progressive reduction in ECP and IL-8, which reached significance at 70% and 80% saliva contamination, respectively. IL-8 levels corrected for total protein showed no change with increasing saliva concentrations. Induced sputum differential cell counts expressed as the proportion of nonsquamous cells are robust measures that are not influenced by salivary contamination. Studies reporting total and absolute cell counts and fluid phase mediator levels require control for squamous contamination.
ADAMTS13: a new link between thrombosis and inflammation
Authors: Anil K. Chauhan, Janka Kisucka, Alexander Brill, Meghan T. Walsh, Friedrich Scheiflinger, Denisa D. Wagner
Journal: The Journal of Experimental Medicine (2008)

von Willebrand factor (VWF) levels are elevated and a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 (ADAMTS13) activity is decreased in both acute and chronic inflammation. We hypothesized that by cleaving hyperactive ultralarge VWF (ULVWF) multimers, ADAMTS13 down-regulates both thrombosis and inflammation. Using intravital microscopy, we show that ADAMTS13 deficiency results in increased leukocyte rolling on unstimulated veins and increased leukocyte adhesion in inflamed veins. Both processes were dependent on the presence of VWF. Depletion of platelets in Adamts13(-/-) mice reduced leukocyte rolling, suggesting that platelet interaction with ULVWF contributes to this process. Increased levels of endothelial P-selectin and plasma VWF in Adamts13(-/-) compared with wild-type (WT) mice indicated an elevated release of Weibel-Palade bodies. ULVWF multimers released upon stimulation with histamine, a secretagogue of Weibel-Palade bodies, slowed down leukocyte rolling in Adamts13(-/-) but not in WT mice. Furthermore, in inflammatory models, ADAMTS13 deficiency resulted in enhanced extravasation of neutrophils, and this process was also dependent on VWF. Our findings reveal an important role for ADAMTS13 in preventing excessive spontaneous Weibel-Palade body secretion, and in the regulation of leukocyte adhesion and extravasation during inflammation.
Absent in Melanoma 2 is predominantly present in primary melanoma and primary squamous cell carcinoma, but largely absent in metastases of both tumors
Authors: Heleen D. de Koning, Ivonne M.J.J. van Vlijmen-Willems, Patrick L.J.M. Zeeuwen, Willeke A.M. Blokx, Joost Schalkwijk
Journal: Journal of the American Academy of Dermatology (2014)
THE PALLIATIVE ROLE OF HEPATIC ARTERIAL INFUSION AND ARTERIAL OCCLUSION IN COLORECTAL CARCINOMA METASTATIC TO THE LIVER
Authors: Y.Z. Patt, S. Wallace, E.J. Freireich, V.P. Chuang, E.M. Hersh, G.M. Mavligit
Journal: The Lancet (1981)
Bacteria-triggered CD4+ T Regulatory Cells Suppress <i>Helicobacter hepaticus</i>–induced Colitis
Authors: Marika C. Kullberg, Dragana Jankovic, Peter L. Gorelick, Patricia Caspar, John J. Letterio, Allen W. Cheever, Alan Sher
Journal: The Journal of Experimental Medicine (2002)

We have previously demonstrated that interleukin (IL)-10-deficient (IL-10 knockout [KO]) but not wild-type (WT) mice develop colitis after infection with Helicobacter hepaticus. Here, we show that infected recombination activating gene (RAG) KO mice develop intestinal inflammation after reconstitution with CD4(+) T cells from IL-10 KO animals and that the cotransfer of CD4(+) T cells from H. hepaticus-infected but not uninfected WT mice prevents this colitis. The disease-protective WT CD4(+) cells are contained within the CD45RB(low) fraction and unexpectedly were found in both the CD25(+) and the CD25(-) subpopulations of these cells, their frequency being higher in the latter. The mechanism by which CD25(+) and CD25(-) CD45RB(low) CD4(+) cells block colitis involves IL-10 and not transforming growth factor (TGF)-beta, as treatment with anti-IL-10R but not anti-TGF-beta monoclonal antibody abrogated their protective effect. In vitro, CD45RB(low) CD4(+) cells from infected WT mice were shown to produce IL-10 and suppress interferon-gamma production by IL-10 KO CD4(+) cells in an H. hepaticus antigen-specific manner. Together, our data support the concept that H. hepaticus infection results in the induction in WT mice of regulatory T cells that prevent bacteria-induced colitis. The induction of such cells in response to gut flora may be a mechanism protecting normal individuals against inflammatory bowel disease.
Chymase-Dependent Angiotensin II Formation in Human Vascular Tissue
Authors: Shinji Takai, Denan Jin, Masato Sakaguchi, Mizuo Miyazaki
Journal: Circulation (1999)

Some reports have suggested that, in vitro, human heart chymase in homogenates contributes little to angiotensin (Ang) II formation in the presence of natural protease inhibitors such as alpha-antitrypsin. We studied whether chymase bound to heparin, resembling an in vivo form, could contribute to Ang II formation in the presence of natural protease inhibitors.The Ang II formation was increased time-dependently after incubation in an extract (1 mg of protein/mL) of human vascular tissues containing Ang I. The concentration of Ang II in the extract after incubation for 30 minutes was 1.67+/-0.06 nmol/mL, and we regarded this quantity of Ang II as 100%. The Ang II formation was inhibited 10%, 95%, and 96% by 1 micromol/L lisinopril, 100 micromol/L chymostatin, and 0.1 g/L alpha-antitrypsin, respectively. The extract was applied to a heparin affinity column. After the column was washed with PBS, the eluted PBS contained a weak Ang II-forming activity, which was completely inhibited by lisinopril. The eluted PBS, to which >0.8 mol/L NaCl had been added, showed a strong Ang II-forming activity which was inhibited by chymostatin and alpha-antitrypsin. After the application of the extract, the column was washed with PBS and then an Ang I solution in PBS was applied to the column. The Ang II formation in the PBS eluted from the incubated column was increased time-dependently. The concentration of Ang II in the PBS (1 mL) eluted from the column after incubation for 30 minutes was 2.56+/-0.28 nmol/mL, and we regarded this quantity of Ang II as 100%. To study the effects of inhibitors, the extract (1 mg of protein/mL) was applied to a heparin affinity column (1 mL) which was preequilibrated with PBS (3 mL); 100 micromol/L chymostatin or 0.1 g/L alpha-antitrypsin in PBS (1 mL) was then applied to the column. After the column was washed with PBS (3 mL), Ang I solution (1 mg/mL) in PBS was applied to the column, and the column was incubated for 30 minutes. The Ang II formation in the PBS eluted from the column was suppressed up to 5% by application of chymostatin, although this was not affected by application of alpha-antitrypsin.These findings suggest that human chymase bound to heparin plays a functional role in Ang II formation in the presence of natural protease inhibitors such as alpha-antitrypsin.