tbuckley/cabot-search huggingface dataset:
Interferon γ (IFN-γ) Is Necessary for the Genesis of Acetylcholine Receptor–induced Clinical Experimental Autoimmune Myasthenia gravis in Mice
Authors: Balaji Balasa, Caishu Deng, Jae Lee, Linda M. Bradley, Dyana K. Dalton, Premkumar Christadoss, Nora Sarvetnick
Journal: The Journal of Experimental Medicine (1997)

Experimental autoimmune myasthenia gravis (EAMG) is an animal model of human myasthenia gravis (MG). In mice, EAMG is induced by immunization with Torpedo californica acetylcholine receptor (AChR) in complete Freund's adjuvant (CFA). However, the role of cytokines in the pathogenesis of EAMG is not clear. Because EAMG is an antibody-mediated disease, it is of the prevailing notion that Th2 but not Th1 cytokines play a role in the pathogenesis of this disease. To test the hypothesis that the Th1 cytokine, interferon (IFN)-γ, plays a role in the development of EAMG, we immunized IFN-γ knockout (IFN-gko) (−/−) mice and wild-type (WT) (+/+) mice of H-2b haplotype with AChR in CFA. We observed that AChR-primed lymph node cells from IFN-gko mice proliferated normally to AChR and to its dominant pathogenic α146–162 sequence when compared with these cells from the WT mice. However, the IFN-gko mice had no signs of muscle weakness and remained resistant to clinical EAMG at a time when the WT mice exhibited severe muscle weakness and some died. The resistance of IFN-gko mice was associated with greatly reduced levels of circulating anti-AChR antibody levels compared with those in the WT mice. Comparatively, immune sera from IFN-gko mice showed a dramatic reduction in mouse AChR-specific IgG1 and IgG2a antibodies. However, keyhole limpet hemocyanin (KLH)–priming of IFN-gko mice readily elicited both T cell and antibody responses, suggesting that IFN-γ regulates the humoral immune response distinctly to self (AChR) versus foreign (KLH) antigens. We conclude that IFN-γ is required for the generation of a pathogenic anti-AChR humoral immune response and for conferring susceptibility of mice to clinical EAMG.
Involvement of PPAR nuclear receptors in tissue injury and wound repair
Authors: L. Michalik
Journal: Journal of Clinical Investigation (2006)

Tissue damage resulting from chemical, mechanical, and biological injury, or from interrupted blood flow and reperfusion, is often life threatening. The subsequent tissue response involves an intricate series of events including inflammation, oxidative stress, immune cell recruitment, and cell survival, proliferation, migration, and differentiation. In addition, fibrotic repair characterized by myofibroblast transdifferentiation and the deposition of ECM proteins is activated. Failure to initiate, maintain, or stop this repair program has dramatic consequences, such as cell death and associated tissue necrosis or carcinogenesis. In this sense, inflammation and oxidative stress, which are beneficial defense processes, can become harmful if they do not resolve in time. This repair program is largely based on rapid and specific changes in gene expression controlled by transcription factors that sense injury. PPARs are such factors and are activated by lipid mediators produced after wounding. Here we highlight advances in our understanding of PPAR action during tissue repair and discuss the potential for these nuclear receptors as therapeutic targets for tissue injury.
Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib
Authors: Paul G. Richardson, Hannah Briemberg, Sundar Jagannath, Patrick Y. Wen, Bart Barlogie, James Berenson, Seema Singhal, David S. Siegel, David Irwin, Michael Schuster, Gordan Srkalovic, Raymond Alexanian, S. Vincent Rajkumar, Steven Limentani, Melissa Alsina, Robert Z. Orlowski, Kevin Najarian, Dixie Esseltine, Kenneth C. Anderson, Anthony A. Amato
Journal: Journal of Clinical Oncology (2006)

To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma.Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13).Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%.Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.
Reimbursement for Cancer Treatment: Coverage of Off-Label Drug Indications
Journal: Journal of Clinical Oncology (2006)

Approximately half of the uses of anticancer chemotherapy drugs are for indications other than those referenced in the United States Food and Drug Administration approved label. Some managed care organizations and private health insurance plans have declined to reimburse the cost of drugs used off-label to treat cancer on the ground that these uses are "experimental" or "investigational." Cancer patients and their providers have experienced similar problems in the Medicare and Medicaid program. To a large extent, these issues have been addressed through legislation enacted in 1993 that requires coverage of medically appropriate cancer therapies including off-label uses recognized by established drug compendia and peer-reviewed literature. Congress has fashioned a system that has worked well, as reflected in improvements in cancer morbidity and mortality. Now, however, after more than a decade of success, the system requires attention. This statement of policy from the American Society of Clinical Oncology encourages the Secretary of the United States Department of Health and Human Services to address these unmet needs in order to ensure that patients with cancer have access to clinically appropriate treatment, as reflected in timely compendia listings and reports of studies in the medical literature.
Redirection of T cells with a first fully humanized bispecific CD33–CD3 antibody efficiently eliminates AML blasts without harming hematopoietic stem cells
Authors: C Arndt, M von Bonin, M Cartellieri, A Feldmann, S Koristka, I Michalk, S Stamova, M Bornhäuser, M Schmitz, G Ehninger, M Bachmann
Journal: Leukemia (2013)
Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain.
Authors: P Dowling, G Shang, S Raval, J Menonna, S Cook, W Husar
Journal: The Journal of Experimental Medicine (1996)

Immunohistochemical methods were used to search for Fas receptor/Fas ligand system involvement in multiple sclerosis (MS) white matter brain lesions. We found large numbers of Fas ligand (Fas-L)-bearing cells present in two acute lesions and 12 of 16 chronic MS lesions, and very few positive cells in non-inflammatory controls. Four of six brains from non-MS neuropathologic conditions associated with inflammation and white matter disease were, however, also positive for Fas-L. Double staining with cell-specific markers revealed that the pattern of ligand-positive cells in chronic MS lesions was complex and composed of several different cell types which were primarily resident glial cells with a small overlay of macrophages. Fas/APO 1 (CD95) receptor expression in MS tissue was also evaluated and marked upregulation of the receptor was found. In addition, Fas receptor was induced, but to a lesser extent, in numerous control brains. The observations that TUNEL-positive dying cells were present in MS lesions and showed excellent co-localization with Fas-L, indicate that the Fas death system may contribute to plaque pathogenesis and could lead to the development of a new category of therapeutic agents for MS.
The Outgrowth of Micrometastases Is Enabled by the Formation of Filopodium-like Protrusions
Authors: Tsukasa Shibue, Mary W. Brooks, M. Fatih Inan, Ferenc Reinhardt, Robert A. Weinberg
Journal: Cancer Discovery (2012)

Disseminated cancer cells that have extravasated into the tissue parenchyma must interact productively with its extracellular matrix components to survive, proliferate, and form macroscopic metastases. The biochemical and cell biologic mechanisms enabling this interaction remain poorly understood. We find that the formation of elongated integrin β(1)-containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these cells via activation of focal adhesion kinase. These plaques originate in and appear only after the formation of filopodium-like protrusions (FLP) that harbor integrin β(1) along their shafts. The cytoskeleton-regulating proteins Rif and mDia2 contribute critically to the formation of these protrusions and thereby enable the proliferation of extravasated cancer cells. Hence, the formation of FLPs represents a critical rate-limiting step for the subsequent development of macroscopic metastases.Although the mechanisms of metastatic dissemination have begun to be uncovered, those involved in the establishment of extravasated cancer cells in foreign tissue microenvironments remained largely obscure. We have studied the behavior of recently extravasated cancer cells in the lungs and identified a series of cell biologic processes involving the formation of filopodium-like protrusions and the subsequent development of elongated, mature adhesion plaques, which contribute critically to the rapid proliferation of the micrometastatic cells and thus are prerequisites to the eventual lung colonization by these cells.
Angiopoietin-like Protein 2 Is an Important Facilitator of Inflammatory Carcinogenesis and Metastasis
Authors: Jun Aoi, Motoyoshi Endo, Tsuyoshi Kadomatsu, Keishi Miyata, Masahiro Nakano, Haruki Horiguchi, Aki Ogata, Haruki Odagiri, Masato Yano, Kimi Araki, Masatoshi Jinnin, Takaaki Ito, Satoshi Hirakawa, Hironobu Ihn, Yuichi Oike
Journal: Cancer Research (2011)

Chronic inflammation plays important roles at different stages of cancer development, including carcinogenesis, tumor invasion, and metastasis, but molecular mechanisms linking inflammation to cancer development have not been fully clarified. Here, we report that expression of angiopoietin-like protein 2 (Angptl2), recently identified as a chronic inflammation mediator, is highly correlated with the frequency of carcinogenesis in a chemically induced skin squamous cell carcinoma (SCC) mouse model. Furthermore, Angptl2 expression in SCC is highly correlated with the frequency of tumor cell metastasis to distant secondary organs and lymph nodes. When SCC was induced in transgenic mice expressing Angptl2 in skin epithelial cells, epithelial-to-mesenchymal transitions in SCC as well as tumor angiogenesis and lymphangiogenesis were significantly increased, resulting in increased tumor cell metastasis and shortened survival compared with wild-type mice. Conversely, in a chemically induced SCC mouse model, carcinogenesis and metastasis were markedly attenuated in Angptl2 knockout mice, resulting in extended survival compared with wild-type mice. Overall, we propose that Angptl2 contributes to increased carcinogenesis and metastasis and represents a novel target to antagonize these pathologies.
Pre-Enucleation Chemotherapy for Eyes Severely Affected by Retinoblastoma Masks Risk of Tumor Extension and Increases Death From Metastasis
Authors: Junyang Zhao, Helen Dimaras, Christine Massey, Xiaolin Xu, Dongsheng Huang, Bin Li, Helen S.L. Chan, Brenda L. Gallie
Journal: Journal of Clinical Oncology (2011)

Purpose Initial response of intraocular retinoblastoma to chemotherapy has encouraged primary chemotherapy instead of primary enucleation for eyes with clinical features suggesting high risk of extraocular extension or metastasis. Upfront enucleation of such high-risk eyes allows pathologic evaluation of extraocular extension, key to management with appropriate surveillance and adjuvant therapy. Does chemotherapy before enucleation mask histologic features of extraocular extension, potentially endangering the child's life by subsequent undertreatment? Methods We performed retrospective analysis of 100 eyes with advanced retinoblastoma enucleated with, or without, primary chemotherapy, in Beijing Tongren Hospital, retrospectively, from October 31, 2008. The extent of retinoblastoma invasion into optic nerve, uvea, and anterior chamber on histopathology was staged by pTNM classification. The treatment groups were compared for pathologic stage (Cochran-Armitage trend test) and disease-specific mortality (competing risks methods). Results Children who received chemotherapy before enucleation had lower pTNM stage than primarily enucleated children (P = .01). Five patients who received pre-enucleation chemotherapy died as a result of extension into brain or metastasis. No patients who had primary enucleation died. For children with group E eyes, disease-specific survival (DSS) was lower with pre-enucleation chemotherapy (n = 45) than with primary enucleation (n = 37; P = .01). Enucleation longer than 3 months after diagnosis was also associated with lower DSS (P &lt; .001). Conclusion Chemotherapy before enucleation of group E eyes with advanced retinoblastoma downstaged pathologic evidence of extraocular extension, and increased the risk of metastatic death from reduced surveillance and inappropriate management of high-risk disease, if enucleation was performed longer than 3 months after diagnosis.
QTc Prolongation by Grapefruit Juice and Its Potential Pharmacological Basis
Authors: Edgar Zitron, Eberhard Scholz, Robert W. Owen, Sonja Lück, Claudia Kiesecker, Dierk Thomas, Sven Kathöfer, Feraydoon Niroomand, Johann Kiehn, Volker A.W. Kreye, Hugo A. Katus, Wolfgang Schoels, Christoph A. Karle
Journal: Circulation (2005)

A high intake of dietary flavonoids, which are abundant in fruits, vegetables, tea, and wine, is known to reduce cardiovascular mortality. The effects of flavonoids on cardiac electrophysiology, which theoretically may have both antiarrhythmic and proarrhythmic consequences, have not been studied systematically to date.We screened a broad spectrum of flavonoids for their inhibitory activity on HERG channels by using heterologous expression in Xenopus oocytes. At a concentration of 1 mmol/L, 10 compounds caused a significant inhibition of HERG currents, whereas 11 other flavonoids had no effect. The IC50 value for HERG block by naringenin, the most potent inhibitor, was 102.3 micromol/L in Xenopus oocytes and 36.5 micromol/L in HEK cells. To demonstrate the physiological relevance of these findings, we studied the effects of pink grapefruit juice, which contains large amounts of naringenin glycosides (>1000 micromol/L), in human volunteers. In 10 persons, we observed a peak QTc prolongation of 12.5+/-4.2 ms 5 hours after oral ingestion of 1 L of grapefruit juice. This effect was significant (P=0.02).We found a significant QTc prolongation by grapefruit juice in healthy volunteers, probably caused by block of HERG channels by flavonoids. These findings reveal new perspectives on the potential for dietary modification of cardiac electrophysiology.
Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules
Authors: Mei-Chin Chen, Fwu-Long Mi, Zi-Xian Liao, Chun-Wen Hsiao, Kiran Sonaje, Min-Fan Chung, Li-Wen Hsu, Hsing-Wen Sung
Journal: Advanced Drug Delivery Reviews (2012)
Bilateral Dislocation of the Superior Tibio-fibular Joint
Authors: P. M. Higgins
Journal: BMJ (1962)

Bilateral Dislocation of the Superior Tibio-fibular Joint Dislocation of the superior tibio-fibular joint is a con- dition not described in the standard textbooks, but cases are occasionally reported in the literature (Lyle, 1925; Harrison and Hindenach, 1959).The dislocation may be anterior, posterior, or upwards, the first variety being the most common, and the last occurring only in connexion with injuries of the ankle-joint.Damage to the lateral popliteal nerve may occur, usually giving rise to no more than transitory paraesthesiae (Delaney et al., 1956;Stratford, 1959).The injury occurs most commonly as the result of a fall with the-foot inverted and the knee semi-flexed; several cases have been reported in parachutists (Vitt, 1948).The patient com- plains of pain locally and in the calf, with inability to bear full weight.On examination the fibular head is > , ^. . . . . . . . . . . . . ., I~~"Lateral and antero-posterior views showmg the dislocation.
Surface‐Micromachined Microfiltration Membranes for Efficient Isolation and Functional Immunophenotyping of Subpopulations of Immune Cells
Authors: Weiqiang Chen, Nien‐Tsu Huang, Boram Oh, Raymond H. W. Lam, Rong Fan, Timothy T. Cornell, Thomas P. Shanley, Katsuo Kurabayashi, Jianping Fu
Journal: Advanced Healthcare Materials (2013)

Abstract An accurate measurement of the immune status in patients with immune system disorders is critical in evaluating the stage of diseases and tailoring drug treatments. The functional cellular immunity test is a promising method to establish the diagnosis of immune dysfunctions. The conventional functional cellular immunity test involves measurements of the capacity of peripheral blood mononuclear cells to produce pro‐inflammatory cytokines when stimulated ex vivo. However, this “bulk” assay measures the overall reactivity of a population of lymphocytes and monocytes, making it difficult to pinpoint the phenotype or real identity of the reactive immune cells involved. In this research, we develop a large surface micromachined poly‐dimethylsiloxane (PDMS) microfiltration membrane (PMM) with high porosity, which is integrated in a microfluidic microfiltration platform. Using the PMM with functionalized microbeads conjugated with antibodies against specific cell surface proteins, we demonstrated rapid, efficient and high‐throughput on‐chip isolation, enrichment, and stimulation of subpopulations of immune cells from blood specimens. Furthermore, the PMM‐integrated microfiltration platform, coupled with a no‐wash homogeneous chemiluminescence assay (“AlphaLISA”), enables us to demonstrate rapid and sensitive on‐chip immunophenotyping assays for subpopulations of immune cells isolated directly from minute quantities of blood samples.
The support of human genetic evidence for approved drug indications
Authors: Matthew R Nelson, Hannah Tipney, Jeffery L Painter, Judong Shen, Paola Nicoletti, Yufeng Shen, Aris Floratos, Pak Chung Sham, Mulin Jun Li, Junwen Wang, Lon R Cardon, John C Whittaker, Philippe Sanseau
Journal: Nature Genetics (2015)
Guidelines of care for primary cutaneous melanoma
Authors: Arthur J. Sober, Tsu-Yi Chuang, Madeleine Duvic, Evan R. Farmer, James M. Grichnik, Allan C. Halpern, Vincent Ho, Victoria Holloway, Antoinette F. Hood, Timothy M. Johnson, Barbara J. Lowery
Journal: Journal of the American Academy of Dermatology (2001)
Nova regulates brain-specific splicing to shape the synapse
Authors: Jernej Ule, Aljaž Ule, Joanna Spencer, Alan Williams, Jing-Shan Hu, Melissa Cline, Hui Wang, Tyson Clark, Claire Fraser, Matteo Ruggiu, Barry R Zeeberg, David Kane, John N Weinstein, John Blume, Robert B Darnell
Journal: Nature Genetics (2005)
Mixed Lineage Leukemia Translocations and a Leukemia Stem Cell Program
Authors: Joerg Faber, Scott A. Armstrong
Journal: Cancer Research (2007)

Cancer stem cells (CSC) may provide the self-renewal capacity required to sustain a tumor. One possibility is that CSC arise from the stem cell counterparts in normal tissues. Alternatively, CSC may arise from more differentiated progenitor cells found in certain tissues. In support of this idea, we showed recently that mixed lineage leukemia fusion oncoproteins can convert committed hematopoietic progenitors into leukemias, which include leukemia stem cells expressing a self-renewal associated program in the context of a differentiated myeloid cell. The findings suggest a basis to understand the pathobiology of CSC and possible strategies to attack them to undermine the self-renewal capacity of a tumor.
Cryptic na+, k+-atpase activity in rat liver canalicular plasma membranes: Evidence for its basolateral origin
Authors: Marcus Sellinger, Carolyn Barrett, Phillipe Malle, Ellen R. Gordon, James L. Boyer
Journal: Hepatology (1990)

Controversy exists concerning the localization of the enzyme Na+, K+–ATPase to canalicular membranes in hepatocytes. Most studies find enzyme activity only at the basolateral plasma membrane domain of the hepatocyte. However, Na+, K+–ATPase activity has been detected recently in a canalicular membrane fraction prepared by Mg++ precipitation, suggesting that differences in membrane domain fluidity account for these discrepancies. To reinvestigate this question, we used free–flow electrophoresis to further purify canalicular liver plasma membranes originally separated by sucrose density centrifugation. With this technique, canalicular membranes devoid of Na+, K+–ATPase activity by routine assay were separated into six subfractions. More than 80% of the activities of canalicular marker enzymes was recovered in two subfractions closest to the anode, which were totally devoid of Na+, K+–ATPase activity. However, Na+, K+–ATPase activity could now be detected in the four other fractions that contained only small amounts of canalicular marker enzymes. The basolateral marker enzyme, glucagonstimulated adenyl cyclase, comigrated with this cryptic Na+, K+–ATPase activity. Furthermore, addition of 6 μmol/L [12–(2–methoxyethoxy)–ethyl–8–(cis–2–noctylcyclopropyl)–octanoate], a membrane–fluidizing agent, to the original canalicular membrane preparation and to all subfractions did not stimulate or unmask latent Na+, K+–ATPase activity. Finally, when canalicular membranes isolated by Mg++ precipitation were subjected to free–flow electrophoresis, they could not be separated from the more positively charged Na+, K+–ATPase–containing fractions, probably because of alterations in surface charge. Together these findings suggest that Na+, K+–ATPase is a basolateral enzyme, that represents a small contaminant when present in canalicular liver plasma membranes and that methodological differences may account for previous discrepancies.