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  1. Article ; Online: Pressure induced tissue resection in the larynx: A preliminary canine study.

    Benninger, Michael S / Diep, Anh N / Kaplan, Seth

    The Laryngoscope

    2019  Volume 129, Issue 11, Page(s) 2557–2562

    Abstract: Objectives: The application of laser (light amplification by stimulated emission of radiation) energy in the larynx relies on thermal injury. The impact of this injury on adjacent tissue can be undesirable. Attempts have been made to limit the extent ... ...

    Abstract Objectives: The application of laser (light amplification by stimulated emission of radiation) energy in the larynx relies on thermal injury. The impact of this injury on adjacent tissue can be undesirable. Attempts have been made to limit the extent and range of injury to adjacent tissue. The O-Pel Surgical System (Precise Light Surgical, Inc., Campbell, CA), a new technology, utilizes kinetic energy through Pressure Induced Tissue Resection (PITR) (Precise Light Surgical, Inc.) to cut tissue, theoretically eliminating injury to adjacent tissue. The purpose of this study was to evaluate the PSL in canine vocal folds.
    Methods: Four dogs underwent PITR incisions (4 mJ pulses at 200 Hz) on their vocal folds, through mucosa into the muscle. The animals were sacrificed at days 0, 3, 7, and 21 days postsurgery. The larynges were harvested and histology was performed with hematoxylin and eosin, Masson trichrome, and Verhoeff-van Gieson.
    Results: At day 0, focal denudation of the epithelium and coagulation necrosis in the lamina propria and adjacent connective tissue are noted. On days 3 and 7, an inflammatory infiltrate of neutrophils is seen within the lamina propria and surrounding connective tissue with minimal edema and early deposition of collagen. At day 21, the mucosa is completely regenerated with the area of previous PITR into the muscle replaced with thick bundles of collagen.
    Conclusion: The unique PITR characteristics offer a potentially unique cutting technology for laryngeal microsurgery. The current canine study suggests appropriate and rapid healing. With refinements of the tip size of the probe and adjustment of energy, PITR will likely be an appropriate alternate to traditional lasers in laryngeal surgery.
    Level of evidence: NA. Laryngoscope, 129:2557-2562, 2019.
    MeSH term(s) Animals ; Disease Models, Animal ; Dogs ; Laryngeal Mucosa/surgery ; Laryngectomy/methods ; Microsurgery/methods ; Pressure ; Vocal Cords/surgery ; Wound Healing
    Language English
    Publishing date 2019-02-04
    Publishing country United States
    Document type Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80180-x
    ISSN 1531-4995 ; 0023-852X
    ISSN (online) 1531-4995
    ISSN 0023-852X
    DOI 10.1002/lary.27822
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  2. Article ; Online: Pathology in practice. Widespread, metastatic liposarcoma and moderate, acute, diffuse centrilobular hepatic necrosis.

    Diep, Anh N / Fleis, Rebekah I

    Journal of the American Veterinary Medical Association

    2012  Volume 240, Issue 4, Page(s) 391–393

    MeSH term(s) Animals ; Cat Diseases/pathology ; Cats ; Fatal Outcome ; Female ; Liposarcoma/pathology ; Liposarcoma/veterinary ; Liver Neoplasms/pathology ; Liver Neoplasms/veterinary ; Neoplasm Metastasis ; Rabies Vaccines/adverse effects ; Vaccination/adverse effects ; Vaccination/veterinary
    Chemical Substances Rabies Vaccines
    Language English
    Publishing date 2012-02-15
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 390811-2
    ISSN 1943-569X ; 0003-1488
    ISSN (online) 1943-569X
    ISSN 0003-1488
    DOI 10.2460/javma.240.4.391
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    Zs.A 423: Show issues Location:
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  3. Article ; Online: Chinese Box turtle (Cuora flavomarginata) with lymphoid leukemia characterized by immunohistochemical and cytochemical phenotyping.

    Bezjian, Marisa / Diep, Anh N / de Matos, Ricardo / Schaefer, Deanna

    Veterinary clinical pathology

    2013  Volume 42, Issue 3, Page(s) 368–376

    Abstract: Lymphoid leukemia of T-cell origin was diagnosed in a male Chinese Box turtle, Cuora flavomarginata, of approximately 25 years of age. The turtle presented with a history of anorexia, open-mouth breathing, and lethargy for one week. The CBC findings ... ...

    Abstract Lymphoid leukemia of T-cell origin was diagnosed in a male Chinese Box turtle, Cuora flavomarginata, of approximately 25 years of age. The turtle presented with a history of anorexia, open-mouth breathing, and lethargy for one week. The CBC findings included a mildly increased PCV, and severe leukocytosis due to high numbers of atypical cells interpreted to be blasts. The blasts were medium-sized cells with round to pleomorphic nuclei, slightly clumped chromatin, indistinct nucleoli, and scant moderate-to-dark blue cytoplasm with occasional red-to-purple cytoplasmic granulation. Cytochemical and immunohistochemical staining indicated that the neoplastic cells were positive for CD3 and α-naphthyl butyrate esterase (ANBE), leading to the diagnosis of T-cell lymphoid leukemia. Histology of tissues collected at necropsy showed multifocal infiltrations of neoplastic round cells in the liver, spleen, kidneys, testicles, pancreas, thyroid, duodenum, bone marrow, epicardium, and myocardium. Transmission electron microscopy failed to identify viral particles within the neoplastic cells. This article describes the hematologic, histologic, and ultrastructural abnormalities associated with lymphoid leukemia in this turtle, and advanced diagnostic methods used for phenotyping the T-cell origin.
    MeSH term(s) Animals ; Blood Cell Count/veterinary ; Bone Marrow/pathology ; Duodenum/pathology ; Histocytochemistry/veterinary ; Immunohistochemistry/veterinary ; Kidney/pathology ; Leukemia, Lymphoid/pathology ; Leukemia, Lymphoid/veterinary ; Liver/pathology ; Male ; Microscopy, Electron, Transmission/veterinary ; Myocardium/pathology ; Pancreas/pathology ; Pericardium/pathology ; Spleen/pathology ; T-Lymphocytes/pathology ; Testis/pathology ; Thyroid Gland/pathology ; Turtles
    Language English
    Publishing date 2013-09
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 2114702-4
    ISSN 1939-165X ; 0275-6382
    ISSN (online) 1939-165X
    ISSN 0275-6382
    DOI 10.1111/vcp.12061
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  4. Article ; Online: The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling.

    Moon, Eui Jung / Mello, Stephano S / Li, Caiyun G / Chi, Jen-Tsan / Thakkar, Kaushik / Kirkland, Jacob G / Lagory, Edward L / Lee, Ik Jae / Diep, Anh N / Miao, Yu / Rafat, Marjan / Vilalta, Marta / Castellini, Laura / Krieg, Adam J / Graves, Edward E / Attardi, Laura D / Giaccia, Amato J

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 4308

    Abstract: Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this ... ...

    Abstract Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.
    MeSH term(s) Animals ; Basic-Leucine Zipper Transcription Factors/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Cell Hypoxia ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Interleukin-11/metabolism ; MafF Transcription Factor/genetics ; MafF Transcription Factor/metabolism ; Mice ; Neoplasm Invasiveness/pathology ; Neoplasm Metastasis/pathology ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Prognosis ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Transcription, Genetic
    Chemical Substances BACH1 protein, human ; Basic-Leucine Zipper Transcription Factors ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; IL11 protein, human ; Interleukin-11 ; MAFF protein, human ; MafF Transcription Factor ; Nuclear Proteins ; STAT3 Transcription Factor ; STAT3 protein, human
    Language English
    Publishing date 2021-07-14
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-24631-6
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  5. Article ; Online: Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer.

    Miao, Yu Rebecca / Thakkar, Kaushik N / Qian, Jin / Kariolis, Mihalis S / Huang, Wei / Nandagopal, Saravanan / Yang, Teddy Tat Chi / Diep, Anh N / Cherf, Gerald Maxwell / Xu, Yu / Moon, Eui Jung / Xiao, Yiren / Alemany, Haizea / Li, Tiane / Yu, Wenhua / Wei, Bo / Rankin, Erinn B / Giaccia, Amato J

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2021  Volume 27, Issue 15, Page(s) 4435–4448

    Abstract: Purpose: Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and ... ...

    Abstract Purpose: Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and other malignancies exhibiting suboptimal response to ICB but not in cancers that are ICB sensitive. Therefore, we hypothesize that PD-L2 can facilitate immune escape from ICB through incomplete blockade of the PD-1 signaling pathway.
    Experimental design: We engineered a soluble form of the PD-1 receptor (sPD-1) capable of binding and neutralizing both PD-L2 and PD-L1 with ×200 and ×10,000 folds improvement in binding affinity over wild-type PD-1 leading to superior inhibition of ligand-mediated PD-1 activities.
    Results: Both
    Conclusions: The data presented in this study provide justification for using a dual targeting, high-affinity sPD-1 receptor as an alternative to PD-1 or PD-L1 therapeutic antibodies for achieving superior therapeutic efficacy in cancers expressing both PD-L2 and PD-L1.
    MeSH term(s) Animals ; Drug Resistance, Neoplasm ; Female ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Mice ; Ovarian Neoplasms/drug therapy ; Programmed Cell Death 1 Ligand 2 Protein/antagonists & inhibitors
    Chemical Substances Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Ligand 2 Protein
    Language English
    Publishing date 2021-05-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-20-0482
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    Zs.A 4223: Show issues Location:
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  6. Article ; Online: Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination-deficient cancer models.

    Mehibel, Manal / Xu, Yu / Li, Caiyun G / Moon, Eui Jung / Thakkar, Kaushik N / Diep, Anh N / Kim, Ryan K / Bloomstein, Joshua D / Xiao, Yiren / Bacal, Julien / Saldivar, Joshua C / Le, Quynh-Thu / Cimprich, Karlene A / Rankin, Erinn B / Giaccia, Amato J

    The Journal of clinical investigation

    2021  Volume 131, Issue 11

    Abstract: Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination-proficient (HR-proficient) ... ...

    Abstract Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination-proficient (HR-proficient) cells through suppression of HR. While this synergistic killing occurs under severe hypoxia (<0.5% oxygen), our study shows that moderate hypoxia (2% oxygen) instead promotes PARPi resistance in both HR-proficient and -deficient cancer cells. Mechanistically, we identify reduced ROS-induced DNA damage as the cause for the observed resistance. To determine the contribution of hypoxia to PARPi resistance in tumors, we used the hypoxic cytotoxin tirapazamine to selectively kill hypoxic tumor cells. We found that the selective elimination of hypoxic tumor cells led to a substantial antitumor response when used with PARPi compared with that in tumors treated with PARPi alone, without enhancing normal tissue toxicity. Since human breast cancers with BRAC1/2 mutations have an increased hypoxia signature and hypoxia reduces the efficacy of PARPi, then eliminating hypoxic tumor cells should enhance the efficacy of PARPi therapy.
    MeSH term(s) Animals ; Cell Hypoxia/drug effects ; Cell Hypoxia/genetics ; Cell Line, Tumor ; DNA Damage ; Female ; Homologous Recombination ; Humans ; Mice ; Mice, Nude ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors ; Reactive Oxygen Species
    Language English
    Publishing date 2021-05-31
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI146256
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  7. Article ; Online: Transient hyperlipidemia in a litter of kittens.

    Blackstock, Kelly J / Schoeffler, Gretchen / Wakshlag, Joseph J / Diep, Anh N / Bauer, John E

    Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)

    2012  Volume 22, Issue 6, Page(s) 703–709

    Abstract: Objective: To describe an entire litter of kittens with severe hyperlipidemia and subsequent successful, low-cost treatment that included high protein enteral support and parasite control. Previous case studies of similarly affected kittens have focused ...

    Abstract Objective: To describe an entire litter of kittens with severe hyperlipidemia and subsequent successful, low-cost treatment that included high protein enteral support and parasite control. Previous case studies of similarly affected kittens have focused on a genetic etiology and on advanced interventions. The role of negative energy balance and additional factors influencing hyperlipidemia, as well as treatment and prognosis are discussed.
    Case summary: Three of 6 kittens died or were euthanized due to severe clinical signs attributable to multiorgan failure associated with subacute hyperlipidemia. The remaining 3 kittens, although subclinical, were found to have similar biochemical abnormalities, including severe anemia and hypertriglyceridemia. Flea treatment and weaning with assisted enteral support prevented the worsening of clinical signs and returned biochemical parameters to within reference intervals.
    Unique information provided: Transient hyperlipidemia in kittens has been previously reported and successfully treated with administration of oxygen, blood transfusion, and diet change; these treatment recommendations may not always be financially feasible, resulting in euthanasia of affected kittens. In contrast, this report describes a successful, low-cost, outpatient approach of flea control, weaning, and introduction of a high protein enteral diet. It also highlights the importance of screening and treating seemingly unaffected littermates, provides new, previously unreported biochemical and histopathology findings, and proposes that negative energy balance is a significant factor in the development of transient hyperlipidemia in kittens.
    MeSH term(s) Animal Feed/analysis ; Animals ; Cat Diseases/genetics ; Cat Diseases/pathology ; Cats ; Diet/veterinary ; Dietary Supplements ; Ectoparasitic Infestations/drug therapy ; Ectoparasitic Infestations/veterinary ; Enteral Nutrition ; Fatal Outcome ; Genetic Predisposition to Disease ; Hyperlipidemias/etiology ; Hyperlipidemias/genetics ; Hyperlipidemias/mortality ; Hyperlipidemias/prevention & control ; Hyperlipidemias/veterinary ; Insecticides/therapeutic use ; Neonicotinoids ; Pyridines/therapeutic use ; Siphonaptera ; Weaning
    Chemical Substances Insecticides ; Neonicotinoids ; Pyridines ; nitenpyram (3A837VZ81Y)
    Language English
    Publishing date 2012-12
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 2077212-9
    ISSN 1476-4431 ; 1479-3261
    ISSN (online) 1476-4431
    ISSN 1479-3261
    DOI 10.1111/j.1476-4431.2012.00797.x
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  8. Article ; Online: S100A10 Is a Critical Mediator of GAS6/AXL-Induced Angiogenesis in Renal Cell Carcinoma.

    Xiao, Yiren / Zhao, Hongjuan / Tian, Lei / Nolley, Rosalie / Diep, Anh N / Ernst, Anne / Fuh, Katherine C / Miao, Yu Rebecca / von Eyben, Rie / Leppert, John T / Brooks, James D / Peehl, Donna M / Giaccia, Amato J / Rankin, Erinn B

    Cancer research

    2019  Volume 79, Issue 22, Page(s) 5758–5768

    Abstract: Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression ... ...

    Abstract Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival. Here, we establish a role for GAS6/AXL signaling in promoting the angiogenic potential of ccRCC cells through the regulation of the plasminogen receptor S100A10. Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule. GAS6/AXL signaling activated the expression of S100A10 through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis. Importantly, treatment with the small molecule AXL inhibitor cabozantinib or an ultra-high affinity soluble AXL Fc fusion decoy receptor (sAXL) reduced the growth of a pazopanib-resistant ccRCC patient-derived xenograft. Moreover, the combination of sAXL synergized with pazopanib and axitinib to reduce ccRCC patient-derived xenograft growth and vessel density. These findings highlight a role for AXL/S100A10 signaling in mediating the angiogenic potential of ccRCC cells and support the combination of AXL inhibitors with antiangiogenic agents for advanced ccRCC. SIGNIFICANCE: These findings show that angiogenesis in renal cell carcinoma (RCC) is regulated through AXL/S100A10 signaling and support the combination of AXL inhibitors with antiangiogenic agents for the treatment of RCC.
    MeSH term(s) Animals ; Annexin A2/metabolism ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Line ; Cell Line, Tumor ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Kidney/metabolism ; Kidney/pathology ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Mice ; Mice, Knockout ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/metabolism ; S100 Proteins/metabolism ; Signal Transduction/physiology
    Chemical Substances Annexin A2 ; Intercellular Signaling Peptides and Proteins ; Proto-Oncogene Proteins ; S100 Proteins ; S100 calcium binding protein A10 ; growth arrest-specific protein 6 ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1)
    Language English
    Publishing date 2019-10-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-19-1366
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    Uh III Zs.135/5: Show issues Location:
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  9. Article ; Online: The m

    Xiao, Yiren / Thakkar, Kaushik N / Zhao, Hongjuan / Broughton, James / Li, Yang / Seoane, Jose A / Diep, Anh N / Metzner, Thomas J / von Eyben, Rie / Dill, David L / Brooks, James D / Curtis, Christina / Leppert, John T / Ye, Jiangbin / Peehl, Donna M / Giaccia, Amato J / Sinha, Subarna / Rankin, Erinn B

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 117, Issue 35, Page(s) 21441–21449

    Abstract: Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, ... ...

    Abstract Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m
    MeSH term(s) Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism ; Amino Acid Transport System ASC/metabolism ; Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/metabolism ; Cell Line, Tumor ; Computer Simulation ; Humans ; Hypoxia-Inducible Factor 1/metabolism ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; Mice, Knockout ; Minor Histocompatibility Antigens/metabolism ; Synthetic Lethal Mutations ; Von Hippel-Lindau Tumor Suppressor Protein/genetics
    Chemical Substances Amino Acid Transport System ASC ; Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1 ; Minor Histocompatibility Antigens ; SLC1A5 protein, human ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO (EC 1.14.11.33) ; FTO protein, human (EC 1.14.11.33) ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27) ; VHL protein, human (EC 6.3.2.-)
    Language English
    Publishing date 2020-08-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2000516117
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    Zs.A 1148: Show issues Location:
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  10. Article ; Online: PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2.

    Taniguchi, Cullen M / Miao, Yu Rebecca / Diep, Anh N / Wu, Colleen / Rankin, Erinn B / Atwood, Todd F / Xing, Lei / Giaccia, Amato J

    Science translational medicine

    2014  Volume 6, Issue 236, Page(s) 236ra64

    Abstract: Radiation-induced gastrointestinal (GI) toxicity can be a major source of morbidity and mortality after radiation exposure. There is an unmet need for effective preventative or mitigative treatments against the potentially fatal diarrhea and water loss ... ...

    Abstract Radiation-induced gastrointestinal (GI) toxicity can be a major source of morbidity and mortality after radiation exposure. There is an unmet need for effective preventative or mitigative treatments against the potentially fatal diarrhea and water loss induced by radiation damage to the GI tract. We report that prolyl hydroxylase inhibition by genetic knockout or pharmacologic inhibition of all PHD (prolyl hydroxylase domain) isoforms by the small-molecule dimethyloxallyl glycine (DMOG) increases hypoxia-inducible factor (HIF) expression, improves epithelial integrity, reduces apoptosis, and increases intestinal angiogenesis, all of which are essential for radioprotection. HIF2, but not HIF1, is both necessary and sufficient to prevent radiation-induced GI toxicity and death. Increased vascular endothelial growth factor (VEGF) expression contributes to the protective effects of HIF2, because inhibition of VEGF function reversed the radioprotection and radiomitigation afforded by DMOG. Additionally, mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure. Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures.
    MeSH term(s) Amino Acids, Dicarboxylic/chemistry ; Animals ; Apoptosis ; Basic Helix-Loop-Helix Transcription Factors/chemistry ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Body Weight ; Cell Line, Tumor ; Chelating Agents/chemistry ; Gastrointestinal Tract/drug effects ; Gastrointestinal Tract/radiation effects ; Gene Expression Regulation ; Hematocrit ; Heterozygote ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Mice ; Mice, Knockout ; Prolyl-Hydroxylase Inhibitors/chemistry ; Protein Isoforms/chemistry ; Protein Isoforms/genetics ; Protein Structure, Tertiary ; Radiation Injuries/drug therapy ; Radiation Injuries/prevention & control ; Vascular Endothelial Growth Factor A/chemistry
    Chemical Substances Amino Acids, Dicarboxylic ; Basic Helix-Loop-Helix Transcription Factors ; Chelating Agents ; Hif1a protein, mouse ; Hypoxia-Inducible Factor 1, alpha Subunit ; Prolyl-Hydroxylase Inhibitors ; Protein Isoforms ; Vascular Endothelial Growth Factor A ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; oxalylglycine (VVW38EB8YS)
    Language English
    Publishing date 2014-05-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.3008523
    Database MEDical Literature Analysis and Retrieval System OnLINE

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